Full Final Thesis - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/10339/10/10_chapter...

��

Development of

green process for

epoxidation Novel amino

benzocycloheptene

derivatives

Novel imino

benzocycloheptene

derivatives

Himachalenes

N

R

NR1R2

Br

O

Synthetic modifications of himachalenes ……. Chapter 2

125

Synthetic modifications of himachalenes isolated from Cedrus deodara for value

added products

2.1 Introduction

The essential oil of the Himalayan Cedar (Cedrus deodara) is an important raw material

for the synthesis of fragrances [Hossini et al. (2011)] and pharmaceutical compounds

[Tripathy et al. (1986); Das et al. (1993); Hazarika et al. (1995); Bhushan et al. (2006)].

The volatile oil is mainly composed of three sesquiterpenic bicyclic hydrocarbons: �-cis-,

�- and �-cis-himachalene; containing hexahydrobenzocycloheptene as basic skeleton

(Figure 1) [Joseph and Dev (1961); Pandey and Dev (1968)]. Three himachalenes differ

from each other only in the position of an ethylenic linkage in the seven-membered ring.

H

H

H

H

�-cis-Himachalene �-Himachalene �-cis-Himachalene

Figure 1

2.2 Reported methods for synthesis of himachalene derivatives

The reactivity of himachalenes has been studied extensively since their isolation by Dev

and co-workers. Himachalenes have been subjected to various modifications such as

cyclopropanation, oxidation, hydroxylation and epoxidation and total syntheses.

2.2.1 Synthetic modifications of himachalenes by aromatization, oxidation and

rearrangement reactions

In 1961, Joseph and Dev performed selenium dehydrogenation of �- and �-himachalenes

mixture at 305-310°C for 48 h to yield cadalene (30%), 2-methyl-6-(p-tolyl)heptane (39%)

and aryl (ar) himachalene (28%) (Scheme 1). Sulphur dehydrogenation (210-215°C/2 h)

produced same constiutents [2-methyl-6-(p-tolyl)heptane, 56%, ar-himachalene, 33% and

traces of cadalene] [Joseph and Dev (1961)].

On treatment with lithioethylenediamine, �- and �-himachalene mixture gave a mixture of

two hydrocarbons; identified as dihydro-ar-curcumene (68%) and ar-himachalene (32%)

(Scheme 1) [Joshi et al. (1964)]. �-Himachalene with chloranil in refluxing benzene

afforded three constituents in 90% yield consisting of himachala-2,5,7-triene, ar-

himachalene and an unidentified compound (Scheme 2) [Pandey and Dev (1968)].

Abouhamza et al. dehydrogenated �-, �- and �-himachalene mixture with Raney-

nickel/activated charcoal to afford ar-himachalene in good yield (83%) and high selectivity

(Scheme 3) [Abouhamza et al. (2001)].


126

+

+

Li

ethylene diamine,16 h

Dihydro-ar-curcumene ar-Himachalene

Cadalene ar-Himachalene2-Methyl-6-(p-tolyl)heptane

+ +Se or Sdehydrogenation

Scheme 1

chloranildry benzene,

reflux, 2 h, N2

1. 20% Pd/C,dry xylene, reflux, N2, 12 h

2. KMnO4, H2O:CH3COCH3

+

ar-HimachaleneHimachala-2,5,7-triene

Scheme 2

+ +Raney Ni

activated charcoal

Scheme 3

From ar-himachalene, chiral ketone-peroxides were synthesized which could be a useful

starting material for the preparation of aromatic musk odorants [Hossini et al. (2011)].

Friedel-Crafts acylation of ar-himachalene at 100°C led to a mixture of (3,5,5,9-

tetramethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)-ethanone (69%) and 1-(8-ethyl-

8-hydroperoxy-3,5,5-trimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-ethanone (21%)

(Scheme 4). �-Himachalene was subjected to oxidation with t-butylperbenzoate in

presence of cuprous bromide or with 90% H2O2 (aq.) in EtOAc under UV irradiations to

give oxidohimachalene in 2% and 13% yields respectively (Scheme 5) [Shankaranarayan

et al. (1977)].

�-Himachalene was epoxidized by 1 equiv peracid [Joshi et al. (1971); Lassaba et al.

(1997); Chekroun et al. (2000)] or peroxide [Shankaranarayan et al. (1977)] regio-and

stereoselectively with attack on C6-C7 double bond on its �-side giving �-himachalene

monoepoxide (Scheme 6). With an excess of peracid, the C2-C3 double bond was also

oxidized on both �- and �- sides. �-cis-Himachalene and �-cis-himachalene gave their


127

respective monoepxides with 1 equiv of peracid and diepoxides were formed with excess

of peracid [Lassaba et al. (1998)]. Mixture of �- and �-himachalenes on reaction with

stoichiometric amount of peracid gave two monoepoxides (I, II) in 1:9 ratio (Scheme 7)

[Haib et al. (2010)]. �-Himachalene monoepoxide produced isohimachalone in 25% yield

on exposure to BF3-Et2O [Shankaranarayan et al. (1977)]. O

+

O O OH

ar-Himachelene

AlCl3, 100°C

CH3COCl

(3,5,5,9-Tetramethyl-6,7,8,9-tetrahydro-5Hbenzocyclohepten-2-yl)-ethanone

1-(8-Ethyl-8-hydroperoxy-3,5,5-trimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-ethanone

Scheme 4

Oxidohimachalene

CuBr, t-butyl perbenzoate, 85-90°C, N2, 2.5 h

O

90% H2O2, EtOAc, irradiation, N2

or

Scheme 5

O

1 equiv peracid

Monoepoxide

ether/DCM, 0°C

30% H2O2, 0.5 NaOH, 0.1 M Na2HPO4

5 h, 50-55°C

Cu(NO3)2.3H2O, 30% H2O2, MeOH, 80°C, 12 h, N2

or

2 equiv peracid

O

O

O

O

+

Diepoxidesβ-Himachalene

2

3 67

O

H

BF3-Et2O

dry toluene, N2, 40 min

Isohimachalone

Scheme 6

+ m-CPBA

CH2Cl2/rtO

+

O

I IIβ-himachalene, 90%α-himachalene, 10%

Scheme 7

The Lewis acid (BF3.Et2O) promoted the rearrangement of � and �-epoxy-himachalenes,

respectively into enantiomerically pure ketones, a and c in good yields (71 and 62%) with

high selectivities (Scheme 8, 9). The core substructures of these two ketones a and c can be

found in some natural products like isoxochitlolone and xochitlolone an antibacterial agent

(against Escherichia coli and Staphylococcus aureus) and rosmaridiphenol, an active

antioxidant [Haib et al. (2010)].


128

0.1% BF3.Et2O

CH2Cl2, rt, 45 minO

OHH

O

a

+

bI

Scheme 8

0.1% BF3.Et2O

CH2Cl2, rt, 24 h H

OO

+

c dII

Scheme 9

2.2.2 Synthesis of organometallic complexes of himachalenes

The tricarbonylphenyl-chromium(0) residue is a well known motif in organometallic

chemistry and known as potentially important synthons. The reaction of ar-himachalene

with hexacarbonylchromium(0) yielded two stereoisomers of the corresponding

organometallic compound (Scheme 10).

Cr(CO)6

(CO)3Cr

15 14

Scheme 10

Na2PdCl4, CuCl2

NaOAc, AcOH

Pd complex

Cl2Pd

Scheme 11

The relative proportion was 60/40, respectively, for the syn and anti dispositions of the

Cr(CO)3 group with respect to the methyl group (C15) at the asymmetric carbon

[Abouhamza et al. (1999)]. A Pd complex was prepared regio- and stereospecifically (54%

yield) when an AcOH solution of Na2PdCl4 and CuCl2 were added to �-himachalene

(Scheme 11) [Firdoussi and Karim (2001)].

2.2.3 Synthesis of himachalene derivatives by cycloaddition of dihalocarbenes

Auhmani et al. reported a method for the preparation of chiral N-substituted pyrazole

which could be used as chiral auxiliaries for stetreoselective synthesis. Cyclopropanation

of �-himachalene with dichlorocarbene, generated in a phase-transfer-catalytic system and

followed by oxidative cleavage of the cyclohexene double bond yielded the

dichlorocyclopropane adduct. This adduct on allylic oxidation with N-bromosuccinimide


129

(NBS) afforded the enone (80%). The enone was easily transformed into enaminone (60%)

and iminol (32%) on treatment with sodium azide in trifluoroacetic acid. The reaction of

enaminone with regioselective attack of terminal amino group of unsymmetrical

hydrazines under drastic conditions produced the corresponding pyrazole [Auhmani et al.

(2002)]. The cycloprapane adduct was also used as a valuable precursor for the synthesis

of pyrethroid derivatives (Scheme 12) [Ziyat et al. (2004)].

H

CHCl3, NaOH / PTC

H

ClCl

β-Himachalene

NBS

THF / H2O

Enone

H

ClCl

O

HN3

H

ClCl

Iminol

O

H2NH

ClCl

HO

HN

+Py-NH-NH2

H

ClCl

N

NAcOH, Reflux

Pyrazole derivative

CHCl3, tBuOK, BnNEt3

+Cl- (cat.)CH2Cl2

NaIO4, NaOH

RuCl3.3H2O (cat.)H2O, CCl4, ACN HOOC

ClCl

O

Pyrethroid derivative

or

Dichlorocyclopropane

Scheme 12

t-BuOK/CHCl3

O

ClCl

H

O

ClCl

H

NaOH/ CHBr3

H

O

H

PTC

CBrBr

HCBrBr

+

t-BuOK/ CHBr3

H

PTC

CBrBr

HCBrBr

+

O O

+

Scheme 13

�-Himachalene monoepoxide on condensation with dibromocarbene in the presence of

sodium hydroxide as base and N-benzyltriethylammonium chloride as catalyst, by phase

transfer process, led to the formation of two products formed by the opening of the

oxiranic ring of epoxide to give diol, followed by a dehydratation to give diene (Scheme

13) [Auhmani et al. (2000)]. The addition of dihalocarbene in the presence of a bulky base

(t-BuOK) produced two dihalopropane compounds; indicated that the opening of the

epoxide cannot be obtained when using a bulky base (t-BuOK) [Lassaba et al. (1997)].


130

Around 150 tonnes of cedarwood oil is produced in India per annum. The oil has been used

as an alternative for conventional pesticides against different insect-pests. It is an important

ingredient of various commercial products with perfumery and biological (Himax,

Pestoban) properties [Shinde et al. (1999); Mercer and Towers (1984); Hossini et al.

(2011)]. A number of analogues of abundantly available constituent of cedarwood oil

(himachalenes) have been synthesized having pharmaceutical importance. With

himachalenes as the lead molecules, we sought to synthesize a series of ar-himachalene,

amino and imino benzocycloheptene derivatives from isomeric mixture of himachalenes.

This would help in value addition of Himalayan Cedrus oil. The results and discussion is

followed by experimental section and references are included at the end of the chapter.

2.3 Results and discussion

2.3.1 Synthesis of aryl himachalene derivatives from himachalenes mixture

The fused rings system of himachalenes has been the subject of interest for last five

decades [Joseph and Dev (1961); Hossini et al. (2011)]. Himachalenes on reaction with

various aromatizing agents yielded mixture of products [Shankaranarayan et al. (1977)].

Chemical analysis of the pheromone gland extract of sandfly and flea beetles revealed ar-

himachalene, himachalene and their methyl derivatives (1-3) as sex pheromones (Figure 2)

[Watts et al. (2005); Zilkowski et al. (2006)]. Insecticidal principles, himachalol and �-

himachalene showed potency against pulse beetle and housefly [Singh and Agarwal

(1988)]. Hydroxylated derivatives of �-himachalene possess promising antifungal potential

against phytopathogen Botrytis cinerea [Daoubi et al. (2005)]. In the present study, we

have developed a simple and practical pathway for the synthesis of ar-himachalene

derivatives by oxidative aromatization.

1 2 3

Figure 2

We treated mixture of �- (21%), �- (55%) and �- (14%) himachalene (4-6) with various

oxidising agents such as SeO2, chloranil and DDQ in different solvents (1,4-dioxan,

benzene and toluene). Himachalenes (4-6) (1 equiv) and DDQ (2 equiv) in dry benzene

under nitrogen at reflux conditions gave best results; yielding a mixture of three products,

�-dehydro-ar-himachalene (7, 50%), bisdehydro-ar-himachalene (8, 21%) and �-

himachalene (9, 15%) (Scheme 14) and were easily separated by silica gel column


131

chromatography using heptane. The isolated products (7, 8 and 9) were characterized on

the basis of IR, NMR and mass spectrometry.

+ +

7 8 9

+ +a

α−Himachalene

(21%)β−Himachalene

(55%)

γ−Himachalene

(14%)

54 6

Scheme 14: Oxidation of himachalene mixture with DDQ; a) DDQ, dry benzene, reflux,

24 h, N2, 7 (50%), 8 (21%), 9 (15%)

7 81011

a bc

Scheme 15: (a) Pd/C, H2, 5 h, rt, EtOAc:MeOH (1:1), 80%; (b) Pd/C, H2, 6 h, rt,

EtOAc:MeOH (1:1), 75%; (c) Pd/C, H2, 6 h, rt, EtOAc:MeOH (1:1, v/v), 80%

Aryl himachalene (11) (yield 80%) was obtained by catalytic hydrogenation of �-dehydro-

ar-himachalene (7) with Pd/C in ethyl acetate and methanol (1:1, v/v). In earlier reports,

aryl himachalene was prepared from mixture of himachalenes or 3-methylacetophenone

[Pandey and Dev (1968); Abouhamza et al. (2001)]. Aryl himachalene (11) was also

obtained by dual reduction of bisdehydro-ar-himachalene (8) with Pd/C in ethyl acetate

and methanol via �-dehydro-ar-himachalene (10) (Scheme 15).

2.3.2 Synthesis of amino benzocycloheptene bromide derivatives from �-dehydro-ar-

himachalene

Benzocycloheptene derivatives are attractive biological targets in theoretical chemistry,

pharmaceutical sciences, and coordination chemistry [Shiraishi et al. (2000); Tandon et al.

(2004); Wyrwa et al. (2009)]. These have been synthesized by various methods, such as

the enlargement of six-membered rings [Scholikopf and Mittendorf (1989); Hattori and

Tanaka (2002)], cyclization [Lynch and Macdonald (2009)] and coupling reactions

[Takahashi et al. 2000)] or from benzocycloheptanone [Ozeki et al. (1993); Bohlmann et

al. (2006)]. Amino substituted benzocycloheptenes were reported to act as ORL-1 receptor

agonists for treatment of mental disorders (12) (Figure 3) [Nakano et al. (2010)], �3

adrenergic receptor agonists for urinary bladder muscle relaxation (13) [Imanishi et al.

(2008)], �-sympathomimetic, anorexigenic (14) [Tandon et al. (2004)], antidepressant (15)

[Nedelec et al. (1979)], analgesic, antiarrhythmic agents (16) [Baumgarth et al. (1996)],


132

for modulation of small-conductance calcium-activated potassium (SK) channels (17)

[Sorensen et al. (2008)], treatment of psoriasis (18) [Shih et al. (1995)], cardiovascular

(19) [Amsterdam (2002)], neurodegenerative diseases [Kato et al. (2007)], sarcoma,

carcinoma [Strobel and Wohlfart (2004)] and chronic pain [Zaratin et al. (2004); Chow et

al. (2009)].

Vinyl halides are also emerging as versatile substrates in a variety of chemical

transformations and their importance as valuable synthons is increasing accordingly. The

role of vinyl halides as precursors of vinyl anions [Franklin et al. (1988)] and as coupling

components in a wide range of transition metal-catalyzed coupling reactions [Duncton et

al. (1999)] has stimulated a great deal of interests in their synthesis. These are also present

in a wide variety of natural products, pharmaceuticals, and agrochemicals [Gribble

(1999)].

Owing to the relevance of amino benzocycloheptenes in a wide range of biological

activities, the abundantly available less explored himachalenes have attracted attention as

synthetic intermediates for synthesis of amino benzocycloheptenes. Therefore, the work

was focused on the synthesis of novel skeletons of amino benzocycloheptene derivatives

starting from �-dehydro-aryl-himachalene (7) using milder process.

N

N

HN

O

12

NH

O

19

MeO

OMe NOH

OMe

OMe

18

HONH2

14

OEtO2C

HN

HO Cl

13N

X

O

O

16X=N/CH

N

N

NHR1

R

17

N

R

H

15

Figure 3: Biologically active amino substituted benzocycloheptene derivatives

The optimization for bromination of �-dehydro-ar-himachalene (7) with Br2/DCM,

Br2/AcOH and NBS were attempted that led to the formation of mixture of products.


133

Finally bromination using KBr (4 equiv) and ceric ammonium nitrate (CAN) (3 equiv) in

DCM:water (1:1, v/v) for 5 h at room temperature was standardized to yield the dibromide

(20) as the major product (Scheme 16). The dibromide formed was unstable as observed

during purification and could not be detected in the LC-MS. Mechanistically, the alkene

reacted with bromide radical to form a dibromo intermediate (20) or the rearranged product

(21). This intermediate was further treated with 1.5 equiv of morpholine and 2 equiv of

K2CO3 in DMF at 90°C for 15 h to produce amino substituted benzocycloheptene bromide

derivative (22a) as major product. Final structure of 22a (Figure 4) was confirmed by

NMR and X-ray crystallographic studies (CCDC Number: 836369) of single colorless

crystals produced from DCM:n-hexane (1:1) mixture.

Br

BrBr

N R1

72220

Br

Br

21

or

a

R2

b

Scheme 16: Synthetic protocol of benzocycloheptene substituted amino vinyl bromide

derivatives. Reagents & conditions: (a) CAN, KBr, DCM/H2O, rt, 5 h; (b) Amine, K2CO3,

DMF, 80-90ºC, 50-76%

Figure 4: Structure confirmation of amino

benzocycloheptene bromide derivative (22a) (Number

CCDC 836369), by X-ray crystallography

With the optimized reaction conditions, the scope of this

reaction was investigated for different aromatic and aliphatic amines. Secondary amines

such as morpholine, piperidine, piperazine, pyrrolidine and diethyl amine were tested

under same conditions to give 22a-22e with satisfactory yields (62-76%) (Table 1, entries

1-5). To broaden the scope of this method, primary amines like cyclohexyl amine, benzyl

amine, isobutyl amine, t-butyl amine, and phenylethyl amine were tested for the same

reaction with good yields to afford 22f-22j (61-72%) (Table 1, entries 6-10). Considering

the yields of the products (Table 1, entries 11, 12), it could be mentioned that electron

releasing groups has no significant effect in case of aromatic primary amines. In case of

diamines, the reaction of one amino group was observed and another amino group

remained unreacted (10c, Table 1, entries 3). Sterically hindered amines (Table 1, entries

14, 15) did not react even on increasing concentrations.


134

Table 1: Description for the synthesis of amino benzocycloheptene bromide derivatives

(22a-22m)

Entry Amine Product (22) Yielda (%)

2

1

HN64

Br

N

22b

HN 62

Br

N

22d

HN O 76

Br

N

O

22a

4

NH

HN Br

N

NH

22c

3

5

63

75NH

Br

N

22e

Time (h)/Temp (°C)

15/90

18/90

17/90

16/90

18/90

6 72

NH2

Br

NH

22f

H2N7

61

Br

NH

22g

18/90

16/90

aIsolated yield


135

Table 1 contd……..

Time (h)/Temp (°C)

8

9

10

H2N

H2N

67

63

Br

HN

Br

NH

22h

22j

63

H2NBr

NH

22i

H2N

54

Br

NH

H2N

Br

NH

22k

22l52

11

12

NH4OH

50

Br

NH2

22m

13

Entry Amine Product (22) Yielda (%)

18/90

20/90

18/90

16/90

16/80

16/80

14No reaction

-

15 No reaction-

NH

18/80

19/90N

aIsolated yield


136

2.3.3 Synthesis of imine analogues of aryl himachalene from �-dehydro-ar-

himachalene

The fused rings of benzocycloheptanone with a wide spectrum of biological activities such

as cytotoxic, anticancer, antimicrobial and antagonistic activity have been considered

important in drug discovery programs [Bohlmann et al. (2006)]. They act as intermediate

for synthesis of benzocycloheptene moiety which serve as important biological targets.

The benzocycloheptanone was mostly synthesized by cyclization of phenyl pentanoic acid

[Liu et al. (2008)]. Here, for the first time we conducted the synthesis of

benzocycloheptanone starting from �-dehydro-ar-himachalene (7). Oxidation of terminal

alkene (7) was attempted with different oxidizing agents such as KMnO4, Hg(OAc)2,

RuCl3/NaIO4, Pd(OAc)2/O2 that led to the formation of mixture of products. Finally

oxidation of exocyclic double bond of �-dehydro-ar-himachalene (7) with NaIO4 and

OsO4 in water:THF (1:1, v/v) for 20 h at room temperature was optimized to produce

corresponding benzocycloheptanone (23) in 73% yield (Scheme 17).

The nitrogen containing amino and imino benzocycloheptenes have been reported to show

diverse range of biological activities and the experimental procedure of their synthesis

from benzocycloheptanone involved either oxime formation [Tandon et al. (2004)],

reductive amination [Nakano et al. (2010)], through azide formation, �-bromination

[Nedelec et al. (1979)] or cyanoboration [Chow et al. (2009)]. Such conversion of

carbonyl moiety of benzocycloheptanone (23) into imino substituted benzocycloheptenes

(24) was tried with reported conditions in several solvents such as toluene, benzene, DMF,

THF but no successful result was obtained. Using dry silica gel (H) as Lewis acid and an

appropriate amine gave good conversion of imine derivatives of benzocycloheptene and no

work up was required before purification through column chromatography (Scheme 17).

a

O

b

N

R

7 23 24a-24e

Scheme 17: Synthesis of imine derivatives (24a-24e) of ar-himachalene from �-dehydro-

ar-himachalene (7); (a) OsO4, NaIO4, 20 h, rt, water:THF (1:1, v/v), 73%; (b) amine, silica

gel, 4-7 h, 65-79%

The mixture was directly transferred to column and purified with n-hexane:EtOAc eluent.

With the optimized reaction conditions in hand, the scope of this reaction was then

investigated with a range of different amines (Table 2). Under similar conditions, the


137

reactions of benzocyclohepten-5-one (23) with corresponding amines proceeded smoothly

to form 24a-24e in 65-79% yields (Table 2, entries 1-5).

Table 2: Synthesis of imine derivatives (24a-24e) of aryl himachalenes

Entry Amine Time (h)/ Temp (°C)Product (24) Yielda (%)

H2N

NH2

H2N

CH3NH2

N

O

NH2

1

2

3

4

5

5/60

6/60

7/50

4/25

4/80

N

N

N

N

N

NO

74

78

71

79

65

24a

24b

24c

24d

24e

aIsolated yield


138

2.3.4 Selective epoxidation of himachalenes by a metal- and peroxide-free method

The chemistry of epoxides has generated intensive scientific interest because they act as

potential intermediates and precursors for the preparation of antifreeze compositions,

humectants [Corma et al. (2007)], pharmaceutical preparations [Kauffman et al. (2006)],

cosmetic formulations [Seo et al. (2006)], as monomers for the preparation of polymers

[Lowe et al. (2009)] and many natural products [Back et al. (2000)]. Epoxidation of

alkenes is an attractive chemical transformation; the process might be enzymatic, metal

catalyzed or photochemical. The chemoselective epoxidation constitute an ongoing

challenge in synthetic organic chemistry.

The epoxidation have been successfully catalyzed by activation of peroxides by transition-

metal complexes of Pd [Muzart (2007)], Mo [Tangestaninejad et al. (2009)], Ti [Nijhuis et

al. (2005)], W [Poli et al. (2009)], Ru [Chatterjee (2008)], Mn [Bahramian et al. 2006), V

[Amano et al. (2004)], peroxide [Fujiwara et al. (2002)] and phase transfer catalyst (PTC)

[Shigeru et al. (2002)]. However, these transformations are often unpredictable as

disproportionation and free-radical types of processes can compete with or dominate the

metal-based epoxidation [Garcia-Bosch et al. (2009)]. Moreover, the negative impact of

these reagents on the environment has urged the development of alternative, greener

methodologies. Kropp et al. have observed that photoirradiation of substituted alkenes in

methanol resulted in cis and trans isomerization, formation of ethers, rearranged or

reduced products [Kropp (1969); Kropp and Tise (1981); Inoue et al. (1983); Kropp et al.

(1985)].

Himachalene epoxides have been synthesized from himachalenes mixture in the presence

of peroxide or peracid [Chekroun et al. (2000)]. Narula and Dev (1977) used oxygenating

agents like copper peroxide and Ag2CO3-celite to oxygenate �-himachalene to produce �-

himachalene monoepoxide in 16% and 19% yields respectively. Owing to the recent

interest and in continuation of the work in the area of natural product transformation a

simple metal and peroxide free green protocol was developed for selective epoxidation of

himachalenes at highly substituted olefinic position using UV radiations in the presence of

air (Scheme 18).

During the last few years, we have been working on isolation, purification and chemical

modification of himachalenes (�, � and �) present in Himalayan cedar. During the course

of study, we observed a gradual decrease in percentage of himachalenes with a

corresponding increase in himachalene epoxide quantity in C. deodara oil while keeping in

air. To support our observation, the mixture of �- (21%), �- (55%), and �-himachalene


139

(14%) (4-6) was kept in a closed vessel but no appreciable formation of himachalene

epoxide was observed under this condition. A series of reactions led to the confirmation

that the sunlight in open air was responsible for partial epoxidation. Under these conditions

the formation of epoxide was identified by GC-MS analysis. As the Himalayan region is

prone to high UV radiations, therefore, the mixture of himachalenes was exposed to UV

radiations and it was astonishing to find the sharp increase in the epoxide content. The

optimization studies were performed in different solvents and the most successful result

were observed in methanol and ethyl acetate (1:1 v/v) mixture under UV exposure for 10 h

(Figure 4).

+ +a

O

α−Himachalene β−Himachalene γ−Himachalene β−Himachalene

monoepoxide4-626

Scheme 18: Epoxidation of himachalenes mixture by ultraviolet radiations; (a) h�, air, rt,

MeOH:EtOAc (1:1, v/v), 31%

Figure 4: Epoxidation of himachalenes mixture under different conditions

In this study, there was exclusive formation of only one product from the three isomers

even if the radiations were used for longer duration, whereas, in earlier reports,

stoichiometric amount of m-CPBA was used for selective epoxidation of himachalenes

[Eljamili et al. (2002)].

It was proposed that under UV radiations, the three isomers first get converted into the

most stable form i.e. �-himachalene (25) (Scheme 20). The double bond present at highly

substituted C6-C7 position was found to be more reactive than that present at C2-C3

position. The �-side of C6-C7 double bond was strongly protected by gem-dimethyl groups,


140

therefore, the attack of atmospheric oxygen in the presence of UV radiations occurred

stereoselectively on �-side and led to the formation of �-himachalene monoepoxide (26).

The chemical structure of (26) was confirmed on the basis of spectral analysis (1H, 13C

NMR and LC-MS).

26

hυ, air, rt,

MeOH:EtOAc (1:1)

+ +

O

25

4-6

6 7

23

Scheme 20

�-Himachalene monoepoxide (26) was isolated as a

colorless oil and showed a molecular ion peak at m/z

221.3582 [M+H]+ (calcd. 221.3584) in the HRESI-QTOF-

MS spectrum in positive mode which correspond to the

molecular formula C15H25O. Its 1H-NMR spectrum

exhibited one signal for olefinic proton at � 5.31 (1H, m,

H-9), indicating the presence of one double bond. The

decoupled 13C NMR spectrum displayed signals for fifteen carbons. Two signals at � 121.3

and 134.1 were assigned to olefinic carbons C-9 and C-10. The four methyl singlets at �

18.5, 23.7, 25.3 and 29.7 were assigned to C-3, C-10 and C-7 carbons respectively. The 2D

NMR spectral techniques (DEPT, HMBC and HMQC) permitted assignments for all 1H

and 13C signals for 26 (Figure 5). The MS/MS spectra in positive ion mode produced

fragments ions at m/z 203, 177, 163, 147, 121, 109, 95, 81 and 67. Thus on the basis of

above evidences and previous literature [Lassaba et al. (1997); Chekroun et al. (2000)], the

compound 26 was unambiguously characterized as �-himachalene monoepoxide.

The regioselectivity of the developed method was confirmed by performing the

monoepoxidation of naturally occurring sesquiterpenes. Caryophyllene (27) and �-

humulene (29) were converted into their respective epoxides (28 and 30) in 50 and 35%

yields (Table 3, entry 2-3) under similar conditions. In contrast to cyclic terpenes, acyclic

terpenes, citronellol (31) led to formation of allyl alcohol (32) (Table 3, entry 4). Based on

NMR analysis, hydroxyl group was found directly linked with the highly substituted

position. It was proposed that in the first step, the formation of epoxide takes place, which

O

1

2

34

5

6

7

8

910

11

12

13

14

1516

Figure 5: HMBC correlations of compound 26


141

further undergoes rearrangement to the allyl alcohol (Scheme 21). Similarly, linalool (33)

participated in the same reaction to produce allyl alcohol (34) (Table 3, entry 5).

Table 3: Epoxidation and allylic alcohol formation of naturally occurring terpenes under

UV radiations in air

Entry Reactant Conditions (UV, air, time, tempereature, solvent)

Product Yield (%)a,b

1

2

3

4

5

UV, air, 10 h, rt, MeOH:EtOAc















O

O

O

OHOH

HO

OH

HOHO

4-626

27 28

29 30

31 32

33 34

31a/32b

27B

3b

50a/52b

46b

22b

35a/47b

26b

20b

25a/26b

25b

11b

22a/36b

21b

13b

aIsolated yield; bGC yield

OH OHhυ, air, rt,

MeOH:EtOAc (1:1)

O

OHHO

H

rearrangement

Scheme 21


142

2.4 Experimental

2.4.1 Instrumentation and conditions

All reagents and solvents were purchased from commercial sources (Sigma-Aldrich,

Merck India Ltd). Column chromatography was carried out on silica gel (60-120 mesh).

Reactions were monitored by thin layer chromatography (TLC) plates coated with 0.2 mm

silica gel 60 F254 (Merck). TLC plates were visualized by the UV irradiation (254 and 365

nm) and iodine spray. 1H and 13C NMR spectra were recorded on a Bruker Avance-300

instrument using TMS as reference. Chemical shifts (�) were given in parts per million.

GC-MS analysis was conducted on a GC-MS (QP2010) Shimadzu gas chromatograph-

mass spectrometer. A carbowax phase, BP-20 capillary column (30 m × 0.25 mm i.d. with

film thickness 0.25 �m) was used with helium as a carrier gas at a flow rate of 1.1 ml/min

on split mode (1:50). The injector temperature was programmed from 40-220ºC @ at

4ºC/min rise with 4 min hold at 40ºC and 15 min hold at 220ºC and interface temperatures

were 250ºC. Ion source temperature was 200ºC. Sample (20 �L) was dissolved in 2 ml GC

grade dichloromethane and sample injection volume was 2 �L. IR spectra were obtained

on a Nicolet 5700 FTIR (Thermo, USA) spectrophotometer in the region 4000-400 cm-1

using KBr discs. Mass spectra were recorded on a Waters QTOF-MS with ESI using

Waters Mass lynx 4.1 software. Photoirradiation was done in laminar flow chamber UV

light (Klenzaids).

2.4.2 Synthesis of aryl himachalene derivatives from himachalenes mixture

2.4.2.1 General procedure for oxidative aromatization of himachalenes (4-6)

To a solution of himachalenes (4-6) (1 g, 4.902 mmol) in dry benzene (30 ml) was added

DDQ (1.1 g, 9.804 mmol) and the mixture was stirred at reflux for 24 h under N2. The

solvent was removed under reduced pressure. The reaction was then quenched by adding

5% sodium bicarbonate solution and extracted with ethyl acetate. Organic layer was finally

concentrated and chromatographed on silica gel (heptane 100%) to afford 7, 8 and 9 as

colorless oil.

2,9,9-Trimethyl-5-methylene-6,7,8,9-tetrahydro-5H-benzocycloheptene (7)

Colorless oil (yield 50%); IR (KBr, cm-1): 3051, 2976, 2955, 1573, 1266, 882; 1H NMR (CDCl3, 300 MHz): � 7.26 (1H, m); 7.14 (1H, m), 7.05 (m, 1H), 5.13 (1H, s),

5.05 (1H, s), 2.43 (3H, s), 1.99 (2H, m), 1.80 (2H, m), 1.42 (6H, s), 0.96-0.98 (2H, m); 13C

NMR (CDCl3, 75.4 MHz): � 154.4, 146.9, 141.3, 135.4, 130.5, 127.0, 113.7, 41.2, 39.3,


143

38.0, 30.9, 26.7, 21.9; GC–MS (70 eV): tR = 33.528 min, m/z 200 [M]+ for C15H20, 185,

170, 157, 143, 128, 115 105, 91, 77.

3,5,5,9-Tetramethyl-5H-benzocycloheptene (8)

Colorless oil (yield 21%); IR (KBr, cm-1): 2955, 2924, 2873, 1721, 1283, 774; 1H NMR (CDCl3, 300 MHz): � 7.59 (1H, d, J = 7.6 Hz), 7.26 (1H, s), 7.16 (1H, d, J = 7.5

Hz), 6.40-6.42 (1H, m), 6.00-6.05 (1H, m), 5.61 (1H, d, J = 10.2 Hz), 2.47 (6H, s), 1.41

(6H, s); 13C NMR (CDCl3, 75.4 MHz): � 144.9, 139.5, 138.4, 138.1, 134.0, 126.8, 125.6,

125.1, 124.2, 123.8, 37.9, 29.3, 25.5, 21.0; GC–MS (70 eV): tR = 35.704 min, m/z 200

[M]+ for C15H18, 198, 183, 168, 153, 141, 128, 115, 83.

3,5,5-Trimethyl-9-methylene-2,4a,5,6,7,8,9,9a-octahydro-1H-benzocycloheptene (9)

Colorless oil (yield 15%); IR (KBr, cm-1): 3056, 1606, 1643, 1362, 720, 945; 1H

NMR (CDCl3, 300 MHz): � 5.50 (1H, s), 4.79 (1H, s), 4.74 (1H, s), 2.83 (1H, m), 1.77-2.16

(7H, m), 1.69 (3H, s), 1.18-1.40 (4H, m), 1.02 (6H, s); 13C NMR (CDCl3, 75.4 MHz): �

157.9, 133.9, 123.8, 111.3, 47.9, 40.0, 36.7, 38.4, 36.6, 32.2, 28.3, 26.7, 25.2, 24.2; GC–

MS (70 eV): tR = 31.627 min, m/z 204 [M]+ for C15H24, 189, 175, 161, 147, 134, 119, 105,

93, 79, 69, 55.

3,5,5,9-Tetramethyl-6,7-dihydro-5H-benzocycloheptene (10)

To a solution of compound 8 (46 mg, 0.232 mmol) in 2 ml of ethyl acetate and

methanol (1:1, v/v) was added 40 mg of 10% palladium on activated carbon. The mixture

was stirred for 6 h under hydrogen, the reaction mixture was filtered, and the filtrate was

evaporated. The crude product was purified by silica gel column chromatography (100%

heptane) to give compound 10 (35 mg, Yield 75%) as colorless oil; IR (KBr, cm-1): 3103,

2955, 2876, 1450, 1281, 872; 1H NMR (CDCl3, 300 MHz): � 7.19-7.29 (2H, m), 7.05-7.14

(1H, m), 5.94 (1H, m), 2.44 (3H, s), 2.40 (2H, m), 2.03 (3H, s), 1.84 (2H, m), 1.40 (6H, s), 13C NMR (CDCl3, 75.4 MHz): � 146.6, 138.1, 137.3, 135.8, 127.7, 126.7, 126.5, 48.0,

38.2, 31.4, 26.3, 24.2, 21.6; GC–MS (70 eV): tR = 34.085 min, m/z [M]+ 200 for C15H20,

185, 171, 157, 143, 128, 115, 105, 91, 77.

2,5,9,9-Tetramethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene (11)


144

To a solution of compound 7 (45 mg, 0.225 mmol) in 2.0 ml of ethyl acetate and

methanol (1:1, v/v) was added 40 mg of 10% palladium on activated carbon. The mixture

was stirred for 5 h under hydrogen, the reaction mixture was filtered, and the filtrate was

evaporated. The crude product was purified by silica gel column chromatography (100%

heptane) to afford compound 11 (36 mg, yield 80%) as colorless oil. The compound 10

(100 mg, 0.5 mmol) on reaction with 10% palladium on activated carbon (100 mg) gave 11

(81 mg, yield 80%) as described above in the form of colorless oil; IR (KBr, cm-1): 3043,

2876, 2853, 1566, 1292, 905; 1H NMR (CDCl3, 300 MHz): � 7.29 (1H, s), 7.22 (1H, d, J =

7.8 Hz), 7.08 (1H, d, J = 7.7 Hz), 3.34-3.39 (1H, m), 2.41 (3H, s), 1.85-1.92 (2H, m), 1.57-

1.63 (2H, m), 1.52 (3H, s), 1.45 (2H, m); 1.43 (6H, s); 13C NMR (CDCl3, 75.4 MHz): �

147.9, 141.4, 135.1, 128.4, 126.7, 125.6, 41.3, 39.7, 36.7, 34.7, 34.2, 24.3, 21.4, 21.2; GC–

MS (70 eV): tR = 34.401 min, m/z [M]+ 202, for C15H22, 187, 159, 145, 131, 119, 105, 91,

77, 57.

2.4.3 Synthesis of amino benzocycloheptene bromide derivatives from �-dehydro-

ar-himachalene

2.4.3.1 General procedure for the synthesis of compounds (22a-22m)

To a solution of compound 7 (101 mg, 0.505 mmol) in dichloromethane (1.5 ml) KBr (241

mg, 2.02 mmol) and a solution of CAN (831 mg, 1.515 mmol) in water (1.5 ml) were

added at room temperature and stirred for 5 h. After completion of the reaction, the

dichloromethane layer was separated and washed with brine and dried over anhyd.

Na2SO4. The solvent was removed to get a yellowish oily liquid (20 or 21). This yellowish

oil, morpholine (66 mg, 0.758 mmol), K2CO3 (139 mg, 1.01 mmol) and 3 ml dried DMF

were placed in a round bottom flask and stirred at 90°C for 15 h. The reaction was

monitored by TLC and the reaction mixture was extracted with ethyl acetate. The ethyl

acetate layer was washed with 5% aq. NaHCO3 and finally with water. The organic layer

was dried with anhyd. Na2SO4 and the solvent was removed in rotary evaporator.

Purification by silica gel column chromatography gave 22a (140 mg) as white crystals

(hexane:EtOAc, 97:3).


145

4-(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-

morpholine (22a)

Br

N

O

White solid (yield 76%) m.p. 120-122ºC; IR (KBr, cm-1): 3455, 2939, 2911,

2856, 2369, 1732, 1659, 1365, 834; 1H NMR (CDCl3, 300 MHz): � 7.89 (1H, d, J = 8.0

Hz), 7.24 (1H, s), 7.11 (1H, d, J = 8.0 Hz), 3.76 (4H, m), 3.43 (2H, s), 2.62 (4H, m), 2.52-

2.56 (2H, m), 2.41 (3H, s), 2.09-2.15 (2H, m), 1.38 (6H, s); 13C NMR (CDCl3, 75.4 MHz)

� 146.0, 137.4, 136.9, 134.6, 128.8, 126.8, 126.7, 126.6, 67.4, 63.8, 54.0, 47.4, 38.8, 37.6,

32.1, 21.7; MS-ESI: m/z [M]+ for C19H26BrNO, calculated 364.3198, observed 364.4533;

Crystal data: Orthorhombic crystal system, space group P212121 with a = 11.388(3) Å, b =

11.756(2) Å, c = 13.384 (3) Å, U = 1791.8(7) Å3, Dc = 1.351 mg/m-3, � = 2.296 mm-1,

MoK� = 0.71073, R1 = 0.0276, wR2 = 0.0578, Z = 4. Crystallographic data for the structure

has been deposited with the Cambridge Crystallographic Data Centre as supplementary

publication nos. CCDC 836369. Copies of the data can be obtained, free of charge, on

application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44 (0)1223

336033 or e-mail: [email protected]).

1-(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-piperidine

(22b)

Br

N

Prepared as described for compound 22a; starting from 7 (102 mg, 0.51

mmol), KBr (243 mg, 2.04 mmol), CAN (839 mg, 1.53 mmol), piperidine (65 mg, 0.765

mmol), K2CO3 (141 mg, 1.02 mmol) and after purification with silica gel column

chromatography (hexane: EtOAc, 97.5:2.5) gave 22b (118 mg, yield 64%) as light yellow

semisolid; IR (KBr, cm-1): 3459, 2964, 2932, 2844, 2360, 1740, 1665, 1340, 863; 1H NMR

(CDCl3, 300 MHz): � 7.91-7.96 (1H, m), 7.23-7.34 (1H, m), 7.10-7.12 (1H, m), 3.42 (2H,

br s), 2.55 (5H, m), 2.41-2.44 (4H, m), 2.18 (2H, m), 1.63 (4H, m), 1.48 (2H, m), 1.38 (6H,

s); 13C NMR (CDCl3, 75.4 MHz): � 145.9, 137.5, 136.7, 135.1, 129.1, 126.7, 126.6, 126.4,

64.0, 54.8, 47.1, 38.8, 38.1, 32.1, 26.2, 24.5, 21.7; MS-ESI: m/z [M]+ for C20H28BrN,

calculated 362.3470 , observed 362.7314.


146

1-(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-piperazine

(22c)

Br

N

NH


mmol), KBr (250 mg, 2.10 mmol), CAN (863 mg, 1.575 mmol), piperazine (68 mg, 0.788

mmol) and K2CO3 (145 mg, 1.05 mmol) and after purification with silica gel column

chromatography (hexane:EtOAc, 95:5) yielded 22c (120 mg, yield 63%) as white solid;

m.p. 147-150ºC; IR (KBr, cm-1): 3451, 2955, 2917, 2847, 2362, 1735, 1662, 1336, 857; 1H

NMR (CDCl3, 300 MHz): � 7.83 (1H, d, J = 7.9 Hz), 7.17 (1H, s), 7.04 (1H, d, J = 7.6 Hz),

3.37 (2H, s), 2.45-2.73 (10H, m), 2.35 (3H, s), 2.04-2.08 (2H, m), 1.31 (6H, s); 13C NMR

(CDCl3, 75.4 MHz): � 145.9, 137.1, 136.8, 134.9, 129.0, 126.7, 126.5, 63.4, 53.3, 51.8,

47.4, 38.8, 38.1, 32.0, 21.8; MS-ESI: m/z [M]+ for C19H27BrN2, calculated 363.3351,

observed 363.5243.

1-(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)pyrrolidine

(22d)

Br

N


mmol), KBr (253 mg, 2.12 mmol), CAN (872 mg, 1.59 mmol), pyrrolidine (57 mg, 0.795


chromatography (hexane:EtOAc, 95:5) gave 22d (115 mg, yield 62%) as brown semisolid;

IR (KBr, cm-1): 3444, 2969, 2907, 2840, 2365, 1755, 1650, 1345, 863; 1H NMR (CDCl3,

300 MHz): � 7.68-7.76 (1H, m), 7.20-7.33 (1H, m), 7.08-7.11 (1H, m), 3.69 (2H, s), 2.67

(4H, m), 2.50-2.53 (2H, m), 2.39 (3H, s), 2.10-2.16 (2H, m), 1.78-1.82 (4H, m), 1.34 (6H,

s); 13C NMR (CDCl3, 75.4 MHz): � 146.2, 136.9, 136.9, 135.8, 128.7, 126.8, 126.3, 125.9,

60.2, 54.5, 47.7, 38.8, 38.1, 32.1, 23.8, 21.8; MS-ESI: m/z [M]+ for C19H26BrN, calculated

348.3204, observed 348.7452.


147

(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-diethyl-

amine (22e)

Br

N


mmol), KBr (241 mg, 2.02 mmol), CAN (831 mg, 1.515 mmol), diethylamine (55 mg,

0.758 mmol) and K2CO3 (139 mg, 1.01 mmol) and after purification with silica gel column

chromatography (hexane:EtOAc, 99:1) afforded 22e (132 mg, yield 75%) as brown

semisolid; IR (KBr, cm-1): 3461, 2962, 2917, 2871, 2360, 1671, 1383, 823; 1H NMR

(CDCl3, 300 MHz): � 7.88 (1H, d, J = 7.8 Hz), 7.18 (1H, s), 7.05 (1H, d, J = 7.8 Hz), 3.44

(2H, s), 2.55-2.62 (4H, m), 2.46-2.51 (2H, m), 2.36 (3H, s), 2.05-2.09 (2H, m), 1.34 (6H,

s), 1.02 (6H, t, J = 6.9 Hz); 13C NMR (CDCl3, 75.4 MHz): � 146.0, 137.4, 136.6, 136.1,

129.2, 126.5, 126.0, 59.2, 47.4, 46.7, 38.9, 38.1, 32.1, 21.8, 11.9; MS-ESI: m/z [M]+ for

C19H28BrN, calculated 350.3363, observed 350.4806.

(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-isobutyl-

amine (22f)

Br

NH


mmol), KBr (243 mg, 2.04 mmol), CAN (839 mg, 1.53 mmol), isobutylamine (56 mg,


chromatography (hexane:EtOAc, 97:3) to give 22f (128 mg, yield 72%) as brown

semisolid; IR (KBr, cm-1): 3463, 2960, 2915, 2883, 2320, 1746, 1660, 1385, 923, 830; 1H

NMR (CDCl3, 300 MHz): � 7.45 (1H, d, J = 7.8 Hz), 7.19 (1H, s), 7.06 (1H, d, J = 7.8 Hz),

3.64 (2H, s), 2.43-2.48 (4H, m), 2.35 (3H, s), 2.04-2.11 (2H, m), 1.70-1.81 (1H, m), 1.35

(6H, s), 0.89-0.92 (6H, m); 13C NMR (CDCl3, 75.4 MHz): � 146.6, 138.3, 136.9, 128.1,

126.9, 126.8, 123.8, 58.6, 55.6, 48.1, 38.3, 38.1, 32.2, 28.2, 21.8, 20.9; MS-ESI: m/z [M]+

for C19H28BrN, calculated 350.3363, observed 350.3078.


148

(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)t-butylamine

(22g)

Br

NH


mmol), KBr (243 mg, 2.04 mmol), CAN (839 mg, 1.53 mmol), t-butylamine (56 mg, 0.765


chromatography (hexane:EtOAc, 95:5) afforded 22g (108 mg, yield 61%) as yellowish

brown semisolid; IR (KBr, cm-1): 3460, 2970, 2875, 2315, 1665, 1390, 832; 1H NMR

(CDCl3, 300 MHz): � 7.65 (1H, d, J = 7.8 Hz), 7.22 (1H, s), 7.10. (1H, d, J = 7.7 Hz), 3.66

(3H, s), 2.52-2.54 (2H, m), 2.39 (3H, s), 2.12-2.15 (2H, m), 1.38 (6H, s), 1.21 (9H, s); 13C

NMR (CDCl3, 75.4 MHz): � 146.5, 138.3, 137.4, 136.8, 128.1, 126.9, 126.6, 123.9, 51.0,

49.0, 48.1, 38.3, 38.1, 32.2, 28.9, 21.7; MS-ESI: m/z [M]+ for C19H28BrN, calculated

350.3363, observed 350.4264.

Benzyl-(6-bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)amine

(22h)

Br

HN


mmol), KBr (238 mg, 2 mmol), CAN (822 mg, 1.5 mmol), benzylamine ((80 mg, 0.75

mmol) and K2CO3 (138 mg, 1 mmol) and after purification with silica gel column

chromatography (hexane:EtOAc, 92:8) gave 22h (130 mg, yield 67%) as light yellowish


NMR (CDCl3, 300 MHz): � 7.23-7.47 (7H, m), 7.07-7.09 (m, 1H), 3.90 (2H, s), 3.75 (2H,

s), 2.50-2.52 (2H, m), 2.39 (3H, s), 2.14-2.16 (2H, m), 1.39 (6H, s); 13C NMR (CDCl3, 75.4

MHz): � 146.8, 140.3, 138.0, 137.0, 136.7, 128.4, 128.2, 127.1, 126.9, 124.1, 54.8, 54.4,

48.1, 38.4, 38.1, 32.2, 21.7; MS-ESI m/z [M]+ for C22H26BrN, calculated 384.3525,

observed 384.5088.


149

(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-phenethyl-

amine (22i)

Br

NH


mmol), KBr (245 mg, 2.06 mmol), CAN (847 mg, 1.545 mmol), phenethylamine (94 mg,


chromatography (hexane:EtOAc, 95:5) gave 22i (130 mg, yield 63%) as light yellow

semisolid; IR (KBr, cm-1): 3455, 2915, 2873, 2349, 2333, 1645, 1460, 1380, 1160, 830; 1H-NMR (CDCl3, 300 MHz): � 7.33-7.36 (1H, m), 7.26-7.29 (2H, m), 7.20-7.22 (3H, m),

7.03 (1H, d, J = 7.8 Hz), 3.73 (2H, s), 2.92-2.95 (2H, m), 2.81-2.85 (2H, m), 2.43-2.48

(2H, m), 2.36 (3H, s), 2.07-2.12 (2H, m), 1.34 (6H, s); 13C NMR (CDCl3, 75.4 MHz): �

146.7, 140.2, 137.9, 136.9, 136.6, 128.9, 128.5, 128.0, 126.9, 126.2, 124.0, 55.3, 51.7,

48.0, 38.3, 38.1, 36.4, 32.2, 21.8; MS-ESI: m/z [M]+ for C23H28BrN, calculated 398.3372,

observed 398.3791.

(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)

cyclohexylamine (22j)

Br

NH


mmol), KBr (253 mg, 2.12 mmol), CAN (872 mg, 1.59 mmol), cyclohexylamine (79 mg,


chromatography (hexane:EtOAc, 95:5) afforded 22j (125 mg, yield 63%) as yellow


NMR (CDCl3, 300 MHz): � 7.55-7.57 (1H, m), 7.22-7.31 (1H, m), 7.11 (1H, m), 3.76 (2H,

m), 2.52-2.54 (3H, m), 2.40 (3H, s), 2.15-2.17 (2H, m), 1.95 (2H, m), 1.40 (6H, s), 1.34

(4H, m), 1.29 (4H, m); 13C NMR (CDCl3, 75.4 MHz): � 146.7, 137.9, 137.0, 136.7, 128.2,

127.0, 126.8, 124.4, 57.4, 52.5, 48.1, 38.4, 38.1, 33.1, 32.1, 29.8, 26.3, 25.1, 21.7; MS-ESI:

m/z [M]+ for C21H30BrN, calculated 376.3736, observed 376.5465.


150

(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)phenylamine

(22k)

Br

NH


mmol), KBr (245 mg, 2.062 mmol), CAN (847 mg, 1.545 mmol), aniline (72 mg, 0.773


chromatography (100% hexane) gave 22k (125 mg, yield 54%) as yellowish brown


NMR (CDCl3, 300 MHz): � 7.30-7.32 (1H, m), 7.22-7.24 (1H, m), 7.17-7.20 (1H, m), 7.05-

7.11 (2H, m), 6.75 (1H, m), 6.67-6.70 (2H, m), 4.28 (2H, s), 2.52 (2H, m), 2.37 (3H, s),

2.09-2.12 (2H, m), 1.33 (6H, s); 13C NMR (CDCl3, 75.4 MHz): � 147.1, 145.3, 137.4,

136.5, 135.6, 129.4, 128.0, 127.1, 124.9, 116.2, 113.8, 50.0, 48.0, 38.4, 38.1, 32.1, 21.6;

MS-ESI: m/z [M]+ for C21H24BrN, calculated 370.3260, observed 370.3029.

(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-p-tolyl-

amine (22l)

Br

NH


mmol), KBr (238 mg, 2.00 mmol), CAN (822 mg, 1.5 mmol), p-toluidine (80 mg, 0.75


chromatography (100% hexane) afforded 22l (100 mg, yield 52%) as light yellow


NMR (CDCl3, 300 MHz): � 7.30-7.33 (1H, d, J = 7.8 Hz), 7.22 (1H, s), 6.95-7.05 (3H, m),

6.57 (2H, d, J = 8.3 Hz), 4.21 (2H, s), 2.50 (2H, t, J = 6.5 Hz, 7.2 Hz), 2.36 (3H, s), 2.24

(3H, s), 2.12 (2H, t, J = 6.5 Hz, 7.2 Hz), 1.33 (6H, s); 13C NMR (CDCl3, 75.4 MHz): �

147.1, 146.1, 137.3, 136.9, 135.8, 129.8, 128.0, 127.0, 124.6, 113.5, 50.2, 48.0, 38.4, 38.1,

32.2, 21.8, 20.6; MS-ESI: m/z [M]+ for C22H26BrN, calculated 384.3525, observed

384.4817.


151

C-(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-yl)-methylamine

(22m)

Br

NH2


mmol), KBr (241 mg, 2.02 mmol), CAN (831 mg, 1.515 mmol), ammonia (13 mg, 0.758


chromatography (hexane:EtOAc, 98:2) gave 22m (74 mg, yield 50%) as light brown


NMR (CDCl3, 300 MHz): � 7.46-7.48 (1H, m), 7.15-7.17 (1H, s), 7.02-7.05 (1H, m), 3.71

(2H, s), 2.43-2.47 (2H, m), 2.35 (3H, s), 2.05-2.10 (2H, m), 1.32 (6H, s); 13C NMR

(CDCl3, 75.4 MHz): � 146.6, 136.9, 136.8, 135.8, 128.3, 127.8, 126.8, 126.7, 60.5, 48.0,

39.3, 38.0, 32.2, 21.7; MS-ESI: m/z [M]+ for C15H20BrN, calculated 294.2300, observed

294.2259.

2.4.4 Synthesis of imine analogues of aryl himachalenes from aryl himachalene

2,9,9-Trimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-one (23)

O

The compound 7 (95 mg, 0.475 mmol) and osmium tetroxide (1 mol%) in THF

(0.5 ml) were added over a period of 30 min to a solution of sodium periodate (550.9 mg,

2.575 mmol) in water (0.5 ml). The mixture was stirred for further 20 h at room

temperature. Extraction with ethyl acetate and diethyl ether followed by filtration through

basic alumina followed by evaporation, gave a yellow semisolid which on purification by

silica gel column chromatography (hexane:EtOAc, 97:3) yielded 23 (70 mg, yield 73%) as

light yellow semisolid. IR (KBr, cm-1): 2967, 2925, 2850, 1730, 800, 1H NMR (CDCl3, 300

MHz): � 7.60-7.67 (1H, m), 7.52-7.56 (1H, m), 7.38-7.41 (1H, m), 3.06 (2H, m), 2.69 (3H,

s), 2.45-2.52 (2H, m), 2.18-2.24 (2H, m), 1.66 (6H, s); 13C NMR (CDCl3, 75.4 MHz): �

208.5, 147.0, 140.7, 138.0, 128.5, 126.7, 126.3, 42.5, 40.1, 38.5, 31.6, 23.3, 21.4; HRMS-

ESI: m/z [M+H]+ for C14H18O, calculated 203.3001, observed 203.3000.


152

Cyclohexyl-(2,9,9-trimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-ylidene)-amine

(24a)

N

A mixture of 23 (56 mg, 0.277 mmol) and benzylamine (32.6 mg, 0.305

mmol) was uniformly adsorbed on the surface of activated silica gel (0.5 g) by dropwise

addition under stirring, and the mixture was then stirred at 60°C for 6 h to allow complete

formation of the corresponding imine. The reaction was monitored by TLC and the

mixture was extracted with ethyl acetate. The organic layer finally concentrated and

chromatographed on silica gel (hexane:EtOAc, 90:10) to afford 24a (60 mg, yield 74%) as

light brown semisolid. IR (KBr, cm-1): 3009, 2838, 2828, 1669, 1629, 1369, 843; 1H NMR

(CDCl3, 300 MHz): � 6.86-7.50 (8H, m), 4.37-4.63 (1H, m), 2.38 (3H, s), 1.77-1.84 (2H,

m), 1.45 (2H, m), 1.30 (6H, s), 1.24 (2H, m); 13C NMR (CDCl3, 75.4 MHz): � 176.8,

146.5, 141.0, 138.3, 135.8, 128.8, 128.2, 127.4, 127.2, 126.9, 126.7, 57.9, 41.8, 38.9, 32.2,

30.2, 25.4, 22.0; HRMS-ESI: m/z [M+H]+ for C21H25N, calculated 292.4378, observed

292.4380.

Cyclohexyl-(2,9,9-trimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-ylidene)-amine

(24b)

N


mmol) and cyclohexyl amine (27 mg, 0.272 mmol) and after purification with silica gel

column chromatography (hexane:EtOAc, 90:10) to afford 24b (55 mg, 78%) as light

brown semisolid. IR (KBr, cm-1): 3177, 2992, 2813, 1708, 1633, 1197, 920; 1H NMR

(CDCl3, 300 MHz): � 7.15 (1H, m), 7.01 (1H, m), 6.83 (1H, m), 2.57 (1H, m), 2.38 (3H, s),

2.05-2.07 (2H, m), 1.70-1.76 (4H, m), 1.58-1.65 (7H, m), 1.40-1.42 (3H, m), 1.28 (6H, s); 13C NMR (CDCl3, 75.4 MHz): � 174.0, 140.0, 138.1, 136.0, 129.2, 127.4, 126.6, 51.0,

41.4, 38.9, 32.3, 32.1, 31.4, 30.1, 25.3, 23.0, 21.9; HRMS-ESI: m/z [M+H]+ for C20H29N,

calculated 284.4589, observed 284.4588.

Isobutyl-(2,9,9-trimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-ylidene)-amine (24c)


153

N

Prepared as described for compound 24a; starting from 23 (99 mg, 0.491 mmol)

and isobutyl amine (39.5 mg, 0.539 mmol) and after purification with silica gel column

chromatography (hexane:EtOAc, 90:10) to afford 24c (90 mg, yield 71%) as light brown

semisolid; IR (KBr, cm-1): 3044, 2872, 2990, 1523, 1657, 1284, 791; 1H NMR (CDCl3,

300 MHz): � 7.03 (2H, m), 6.85 (1H, m), 2.38 (3H, s), 2.12 (1H, m), 1.92 (1H, m), 1.70

(4H, m), 1.41 (2H, m), 1.27 (12H, s); 13C NMR (CDCl3, 75.4 MHz): � 174.0, 145.8, 138.0,

136.1, 129.1, 127.3, 126.6, 61.8, 41.0, 38.9, 32.0, 31.7, 31.2, 30.3, 25.0, 21.8; HRMS-ESI:

m/z [M+H]+ for C21H25N, calculated 258.4216, observed 258.4210.

Methyl-(2,9,9-trimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-ylidene)-amine (24d)

N

Prepared as described for compound 24a; starting from 23 (100 mg, 0.495 mmol),

methyl amine (17 mg, 0.545 mmol) and after purification with silica gel column

chromatography (hexane:EtOAc 95:05) to afford 24d (85 mg, yield 79%) as light brown

semisolid; IR (KBr, cm-1): 3020, 2845, 2880, 1683, 1697, 1254, 870; 1H NMR (CDCl3, 300

MHz): � 7.06-7.20 (3H, m), 2.36 (3H, s), 2.12 (3H, s), 1.96 (2H, m), 1.72 (4H, m), 1.34

(6H, s); 13C NMR (CDCl3, 75.4 MHz): � 174.3, 147.8, 136.7, 130.4, 128.8, 126.9, 126.6,

41.0, 38.4, 37.8, 31.6, 30.1, 26.5, 21.9; HRMS-ESI: m/z [M+H]+ for C15H22N, calculated

216.3419, observed 216.3414.

(2-Morpholin-4-yl-ethyl)-(2,9,9-trimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-

ylidene)-amine (24e)

N

NO


mmol), methyl amine (75.2 mg, 0.578 mmol) and after purification with silica gel column

chromatography (hexane:EtOAc, 50:50) to afford 24e (108 mg, yield 65%) as light brown

semisolid. IR (KBr, cm-1): 2817, 2791, 1650, 1629, 1486, 1397, 1107. 1H NMR (CDCl3,

300 MHz): � 6.90-7.27 (3H, m), 3.57 (6H, m), 2.65 (2H, m), 2.31 (4H, m), 2.23 (3H, s),

1.50-1.98 (6H, m), 1.20 (6H, s); 13C NMR (CDCl3, 75.4 MHz): � 170.6, 147.1, 140.5,

136.8, 129.7, 127.3, 126.0, 66.7, 61.2, 53.5, 48.7, 40.8, 38.5, 36.2, 31.0, 25.9, 21.1;

HRMS-ESI: m/z [M+H]+ for C20H31N2O, calculated 315.4729, observed 315.4709.


154

2.4.3 Selective epoxidation of himachalenes by a metal- and peroxide-free method

Procedure for epoxidation of himachalenes (4-6)

The himachalenes mixture (4-6) (250 mg, 1.225 mmol) was taken in a 5 ml solvent

(MeOH:EtOAc 1:1, v/v) and stirred properly. The mixture was taken in a glass petridish

and the whole mixture was exposed under UV radiations (254 nm) in open air condition

for 10 h. The mixture was dried under reduced pressure and purified by column

chromatography on silica gel (hexane:EtOAc, 95:5) afforded 26 as a gummy colourless

liquid (83 mg, yield 31%).

3,7,7,10-Tetramethyl-2-oxa-tricyclo[6.4.0.01,3]dodec-9-ene (26)

O

UV �max (EtOH, nm) (�): 218; IR (KBr, cm-1): 2924, 1637, 1380, 1072, 863; 1H

NMR (CDCl3, 300 MHz): � 5.31 (1H, m), 2.07-2.12 (1H, m), 1.91-1.96 (3H, m), 1.71-1.82

(1H, m), 1.66 (3H, s), 1.46-1.58 (4H, m), 1.34-1.40 (1H, m), 1.27 (3H, s), 1.16-1.21 (1H,

m), 0.92 (3H, s), 0.79 (3H, s); 13C NMR (CDCl3, 75.4 MHz): � 134.1, 121.3, 64.9 , 48.9,

44.0, 36.3, 36.1, 29.7, 27.4, 25.3 , 24.7, 23.7, 20.6, 18.5; HRMS-ESI: m/z [M+H]+ for

C15H25O, calculated 221.3584, observed 221.3582.

4,12,12-Trimethyl-9-methylene-5-oxa-tricyclo[8.2.0.04,6] dodecane (28)

O

Prepared as described for compound 26; starting from 27 (260 mg, 1.275 mmol)

and after purification with silica gel column chromatography (hexane:EtOAc, 95:5)

afforded 28 as a gummy colorless liquid (140 mg, yield 50%); UV �max (EtOH, nm) �):

230; IR (KBr, cm-1): 2958, 1631, 1263, 1121, 864; 1H NMR (CDCl3, 300 MHz): � 4.97

(1H, s), 4.85 (1H, s), 2.21-2.33 (4H, m), 2.03-2.14 (2H, m), 1.72-1.79 (1H, m), 1.57-1.68

(2H, m), 1.25 (6H m), 1.19 (3H, s), 1.00 (3H, s), 0.97 (3H, s); 13C NMR (CDCl3, 75.4

MHz): � 151.9, 112.5, 63.9, 60.0, 50.9, 48.9, 39.9, 39.3, 34.1, 30.3, 30.0, 29.9, 27.3, 21.7,

17.1. HRMS-ESI: m/z [M+H]+ for C15H25O, calculated 221.3584, observed 221.3583.

1,5,5,8-Tetramethyl-12-oxa-bicyclo[9.1.0]dodeca-3,7-diene (30)

O

Prepared as described for compound 26; starting from 29 (200 mg, 0.980

mmol) and after purification with silica gel column chromatography (hexane:EtOAc, 93:7)

afforded 30 as a gummy colourless liquid (75 mg, yield 35%); UV �max (EtOH, nm) (�):

218; IR (KBr, cm-1): 2923, 1637, 1383, 1067, 801; 1H NMR (CDCl3, 300 MHz): � 4.99-


155

5.54 (3H, m), 2.53-2.66 (1H, m), 2.14-2.21 (6H, m), 2.05 (3H, s), 1.64-1.68 (2H, m), 1.61

(3H, s), 1.28-1.31 (3H, d), 1.08 (3H, s); 13C NMR (CDCl3, 75.4 MHz): � 143.2, 132.0,

125.8, 122.1, 62.1, 60.5, 42.7, 40.3, 36.6, 29.8, 25.3, 21.2, 17.3, 15.2, 14.3; HRMS-ESI:

m/z [M+H]+ for C15H25O, calculated 221.3584, observed 221.3581.

3,7-Dimethyl-oct-5-ene-1,7-diol (32)

OHHO Prepared as described for compound 26; starting from 31 (700 mg, 4.487

mmol) and after purification with silica gel column chromatography (hexane:EtOAc,

60:40) 32 as a gummy colourless liquid (190 mg, yield 25%). UV �max (EtOH, nm) (�):

230; IR (KBr, cm-1): 3414, 2925, 1637, 1378, 1061; 1H NMR (CDCl3, 300 MHz): � 5.67

(1H, m), 5.61 (1H, m), 3.70 (2H, m), 2.05-2.17 (2H, m), 1.50-1.61 (3H, m), 1.33 (6H, s),

0.90 (3H, s); 13C NMR (CDCl3, 75.4 MHz): � 136.6, 129.5, 82.2, 60.8, 40.8, 39.9, 32.7,

24.8, 23.4, 19.7; HRMS-ESI: m/z [M+H]+ for C10H21O2, calculated 173.2725, observed

173.2725.

2,6-Dimethyl-octa-3,7-diene-2,6-diol (34)

OH

HO

Prepared as described for compound 26; starting from 32 (200 mg, 1.298

mmol) and after purification with silica gel column chromatography (hexane:EtOAc,

60:40) afforded 34 as a gummy colourless liquid (48 mg, yield 22%); UV �max (EtOH, nm)

(�): 214; IR (KBr, cm-1): 3413, 2973, 1638, 1375, 1110, 923 cm-1; 1H NMR (CDCl3, 300

MHz): � 5.86-5.96 (1H, m), 5.63-5.67 (1H, m), 5.22 (1H, m), 5.17 (1H, m), 5.04-5.07 (1H,

m), 2.04-2.27 (2H, m), 1.30 (6H, s), 1.27 (3H, s); 13C NMR (CDCl3, 75.4 MHz): � 144.8,

142.6/138.2, 121.8/126.3, 112.1, 77.1/81.9, 72.9/70.9, 45.1, 29.9, 27.5, 24.8; HRMS-ESI:

m/z [M+H]+ for C10H19O2, calculated 171.2567, observed 171.2567.

2.5 Conclusion

Around 150 tonnes of cedarwood oil is commercially produced in Himalayan region.

Himachalenes are the major constituents present in this oil. Various products from

himachalenes have been synthesized as value added molecules. In this study, we first time

used the himachalenes as building blocks for synthesis of various derivatives of amino,

imino benzocycloheptenes and aromatized himachalenes. Different methods for value

addition of himachalenes were developed to prepare novel bioactive molecules. The

oxidative aromatization of himachalenes was performed with DDQ for the synthesis of

easily separable ar-himachalene derivatives. From ar-himachalene derivatives, the novel

amino benzocycloheptene bromides were synthesized via two steps consecutive reactions

in good yields. Himachalenes mixture also led to the formation of novel imino


156

benzocycleheptene derivatives. These molecules could find potential use in perfumery,

flavour industries and act as synthons for important pharmaceutical applications.

Furthermore, a milder, regio-, steroselective, metal- and peroxide-free green process for

epoxidation of himachalenes was developed utilizing atmospheric oxygen from air under

UV radiations. This method offered a potentially useful and green complement to the

existing methods of epoxidation and could be a useful approach in modern organic

synthesis for selective epoxidation of highly substituted alkenes.

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Spectral data of some compounds

1H NMR spectrum (in CDCl3) of �-dehydro-ar-himachalene (7)

220 200 180 160 140 120 100 80 60 40 20 ppm 13C NMR spectrum (in CDCl3) of �-dehydro-ar-himachalene (7)


164

1H NMR spectrum (in CDCl3) of �-himachalene (9)

13C NMR spectrum (in CDCl3) of �-himachalene (9)


165

1H NMR spectrum (in CDCl3) of 4-(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-ylmethyl)-morpholine (22a)

13C NMR spectrum (in CDCl3) of 4-(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-

benzocyclohepten-5-ylmethyl)-morpholine (22a)

Mass spectrum of 4-(6-Bromo-2,9,9-trimethyl-8,9-dihydro-7H-benzocyclohepten-5-

ylmethyl)-morpholine (22a)

Br

N

O


166

1H NMR spectrum (in CDCl3) of cyclohexyl-(2,9,9-trimethyl-6,7,8,9-tetrahydro-benzocyclohepten-5-ylidene)-amine (24a)

13C NMR spectrum (in CDCl3) of cyclohexyl-(2,9,9-trimethyl-6,7,8,9-tetrahydro-

benzocyclohepten-5-ylidene)-amine (24a)

N

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