T~wuhedron Lam. Vol. 36, No 51, pp. 9269-9272, 199.5 Elsevier Saence Ltd

Prmtai tn Great Britain 0040-403Y/YS $9.50+0.00

0040-4039 (9.5 )02009-8

A General Synthesis of Mono- and Disubstituted

1,4,7-Triazacyclononanes

Zoltan Kovacs and A Dean Sherry*

Depanment of Chemistry. Unncrslty of Texas at Dallas,

P 0 Box 830688. Ekhardson. Texas 750X7-0688

Abstract I.J.7-Tnalac!clononalle reacts sclcct~vel~ vtth 2-(t-butoxycarbonyloxyimtno)- and

2-(benz~lox~carbon~lo~~tm~no)-2-phen~laceton~tr~le to gne I.&dlprotected dertvatives which

could be comerted to mono and dlsubstltuted trla/acyclononanes

Numerous derivatives of triazacyclononane contarntng more than one type of functionalized side-chain

have appeared in the recent literature ’ The synthetic routes to these derivatives usually involve either

reacting the amine in excess and isolating a monoprotected derivative, protecting via N-formylation,’ or

selective detosylation ’ Interest in the coordination chemistry of these compounds ranges from models of

protein active sites to centers for molecular recognition We have an interest in using these systems for

monitoring free Mg’- concentrations by “P NMR in brological tissues ’ Thus, it is important for our work to

not only introduce a variety of different coordinating srde-chain groups to fine tune the Mg2’ binding constant

but also to prepare such ligands in large quantities for ultimate use irr VIVO

Recently we reported a general. high yield synthesis of I .7-disubstituted 1,4,7,10-tetraaza-

cyclododecanes through the 1.7-biscarbamate dertvatrves ’ Regioselective diprotection was achieved by

reacting the tetramine with different chloroformates m acid solution (pH-2-3) Unfortunately, when the

selective protection of triazacyclononane was attempted under these conditions, a mixture of products were

obtained Several other reagents used for the prepat-ation of carbamates were tried We have found that the

free triamme reacts with exactly two equivalents of 7-(t-butoxvcarbonyloxyimino)-2-phenylacetonitrile (BOC-

ON)6 and 2-(benzyloxycarbonylo\cyimino)-2-phen~lacetonltrile (Z-ON)’ in chloroform under anhydrous

conditions to give high yields (>90%) of the diprotected dertvatives I and 3 (Scheme 1).

At present the reason for the high selectivity is unclear When the reaction was run with one equivalent

of the reagent a mixture of unreacted triamine. mono- and diprotected derivatives was isolated As the

)1f>O

9210

butoxycarbonyl and benzyloxycarbonyl groups can be removed independently and in any order,

monoprotection was achieved indirectly through the diprotected compounds (Scheme 1)

cH3 iA I, II

tBUO:CAN/JNkO*tBU

Scheme 1 Reagents and conditrons il N-(benzyloxycarbonyloxy)succinimide, CH$& ii, CF3C02H, CHCIs, iii, BOC-ON (1 equiv ), CHCh, iv, N-(tert-butoxycarbonyloxy)- succinimide, CH2C12; v, H2, Pd on C, EtOH, vi. Z-ON, (I equiv), CHCls.

The remarkable preference of BOC-ON and Z-ON for disubstitution was demonstrated by the reaction of the

monoprotected derivatives with these reagents Both reactions afforded compound 5 having two different

protecting groups in nearly quantitative yields (Scheme 1) The mono- and diprotected derivatives were

successfully applied in the synthesis of di- and monosubstituted triazacyclononanes (Table I) The reactivity

of the diprotected triamines toward alkylating agents is much lower than that of the free amine and only the

very reactive triflates TfDCH2C02tBu8 and TfOCH2PO(OEt)29 gave satisfactory results On the other hand,

the monoprotected compounds reacted readily with ordinary alkylating agents. Acid hydrolysis of the BOC

derivatives conveniently provided the free actds 1a.b and 4a,b while the benzyloxycarbonyl group could be

selectively removed by catalytic hydrogenation to afford the esters 2a,b and 3a,b which are useful

Intermediates in the synthesis of tilly substituted trraracyclononane derivatives with two different pendant

arms

.41l compounds were characterized by analytical and spectroscopic methods ‘”

Star

bng

Table

1

Synt

hese

s of

Mon

o-

and

Dtsu

bsttt

uted

I ,

4,7-

Trta

zacy

clono

nane

s

Reag

ents

and

con

ditto

ns

Prod

uct

Yteld

H

to/,\

-

5

I. Tt

DCH2

CO-J

Bu.

tPrz

NEt,

CHC’

li II.

HCL

HzO

, 50

°C

I. TtD

CH2P

O(OE

t)2,

iPr*N

Et,

CHCI

?.

25.5

0°C

II. H

C’L

H20,

90

“C

I. Br

CH2C

0,tB

u,

tPr2

NEt.

MeC

N.

60°C

a.

H2,

Pd

onC’

, Et

OH

L Tt

WH2

PO(O

Et)2

, iP

rzNE

t, CH

C’h

IL H

Z, P

d on

C,

EtOH

X

Y =

CH2P

O(OE

th

I, Tt

DCH&

IO$B

u,

iPr2

NEt.

CHCh

X

= CH

2C02

tBu

a, H

2, P

d on

C,

EtOH

Y=

H

I, TR

I)CH2

PO(O

Et)2

, iP

rzNE

t, CH

Cl3,

25

-50°

C II,

Hz,

Pd

on C

, Et

OH

I, Bt

CH2C

02tB

u iP

rzNE

( M

eCN,

60

“C

is HC

l, H2

0,5O

”C

i, Tf

DCH2

PO(O

Et),,

iP

rzNE

t, CH

Ch

u, H

Cl,

H20,

90

“C

i, Tf

OCH

2CO

ztBy

Pa

NEt,

CHCI

3;

ti, H

z, P

d on

C, E

tOH

iii, T

A)CH

2PO(

OEt)2

, &N

E&

CHCl

s; i

v, H

CI,

H20,

9O”C

X CH

2C02

H Y=

H

X =

CyPO

(OH)

;?

Y=H

x Y

= CH

2C02

t.Bu

X =

CH2P

O(OE

t)2

Y=H

x =

Y =

CH2C

02H

X =

Y =

CH2P

O(OH

),

X =

CHzC

02H

Y =

CH,P

O(OH

)2

85

90

73

55

71

70

79

65

77

Entry

la lb 2a

2b

3a

3b

4a

4b

5a

9212

Acknowledgements: This work was supported in part from grants from the Robert A. Welch Foundation

(AT-584) and the NIH NCRR Biomedical Research Technology Program (P41-RRO2584).

References and Notes:

J. S Bradshaw, K. E. Krakowiak and R. M Iratt. .&a-crown ~~~acro~~cles (Chemrstr?; ofHeteroc~vcl~ Compounds, Vol.

511, John Wiley and Sons, Inc.. New York, 1993

G R Wersman. D 1 Vachon. V. B Johnson and D A Gronbeck. J Chem .Soc Chem. Commun. 1987, 886

I L Sessler, 1 W Sdben and V. Lynch, Inorg Chevt 1990. 29. 4143

R Ramasamy. 1 Lazw, E. Brucher, A. D. Sherry and C R Malloy, FEB.5 Lert 1991. 280, 121

Z Kovacs and A D Sherry, J Chem. Sm., Chem. Commun 1995. 185

M Itoh, D Hagtwara and T Kamrya, Tetrahedron Lett. 1975.1393

Z-ON was obtamed m 75 % yteld by reacting the sodium salt of 2-hydroxytmino-2-phenylacetonitrile with benzyl

chlorofomtate.

1 Jurayj and M. Cushman. Tetrahedron 1992. 48. X61) I

The reagent was prepared by the reactton of dtethyl (hydrouymethyl) phosphonate with triflic anhydride, (CFsS02)zO and

pyndine in 40 % weld ‘“C NMR (50 10 MH.?, CDCI,) 6 I18 55 (q, .I,, = 3 19 33 Hz), 66.38 (d, Jcp = 168 46 Hz), 63.91

(d. Jcp = 5.86 Hz), 16 23 (d, -‘cp = 5 86 Hz) 31P NMR (202 40 MHz.. rel to external H,PO,, CDCI,) 6: 12.87.

1 “C NMR (CDCL3) 6 155.92, I55 69 (CO). 7’) 60. 79 51 (tBu). 52 95. 52 43, 52.34, 51.64. 50.32, 49 74, 49.48,

48 22. 48.10. 47 66. 47 28 (ring carbons). 28 41 (tBu) 2 “C NMR (CDCI3) 6 156 12 (CO), 136.84, 128.34. 127.78

(aromattc carbons), 66 X3 (benzyl). 54 88, 53.86. 49 33. 49 21. 48 25, 47.26 (ring carbons). 3- t3C NMR (CD&) 6:

156 24 (CO). 136 72. 136.66. 12X 37. 128 16 (aromattc carbons) 66 95 (benzyl) 52.72, 52.37, 52.02, 51.00, 50.09, 49.77,

48 98. 4X.16. 4X 10, 47 64. 47 49 trmg carbons) 4 “C NMR (CDCI,) li. 155.48 (CO), 79.22 (tBu), 54 59. 54.33, 49.18,

48.19. 47 66. 47 2X (rmg carbons) 28.38 (tBu). 5 “C NMR (CDCI,) 6- 156.27, 155.6 (CO). 136.75, 12X.37. 127.90

(aromatic carbons). 79 57. 79.51 (&I). 66.95 (bewyl). 53 13-47 55 (rmg carbons). 28 38 (tBu).

(Received in USA 23 Augusf 1995; revised 16 October 1995; accepted I8 October 199.5)