A New Route to Guanidines from Bromoalkanes

Full text of DOI:10.1021/jo9704164

J . Org. Chem. 1997, 62, 4867-4869
4867
Our interest in this synthetic route relates to the
development of radiolabeled derivatives of (m-iodoben-
zyl)guanidine (MIBG), an agent used in the diagnosis and
treatment of neuroendocrine tumors.12,13 In this connec-
tion, we wanted to prepare 2-(guanidinomethyl)-6-ni-
trobenzoic acid, which could be synthesized from com-
mercially available 2-methyl-6-nitrobenzoic acid. Fol-
lowing benzylic bromination, the desired guanidine could
be prepared by a number of methods.10,14 However, these
routes involved several additional synthetic transforma-
tions, and encouraged by the alkylation of the monoso-
dium salt of N1,N2-bis(tert-butyloxycarbonyl)hydrazine,15,16
we investigated the conversion of a number of bromoal-
kanes to the corresponding protected guanidines by
treatment with the sodium salt of 2 (Na-2).
A New Rou te to Gu a n id in es fr om
Br om oa lk a n es
Ganesan Vaidyanathan* and Michael R. Zalutsky
Box 3808, Department of Radiology, Duke University
Medical Center, Durham, North Carolina 27710
Received March 6, 1997X
Traditionally, guanidines have been prepared by the
treatment of ammonia or an amine with cyanamide1 or
S-alkylisothiouronium salts.2 Subsequent studies mainly
have focused on the search for better guanylating agents
of amines. Applications of reagents such as aminoimi-
nomethanesulfonic acid,3 1H-pyrazole-1-carboxamidine
hydrochloride,4 and benzotriazole-1-carboxamidinium to-
sylate5 have been reported. In the last few years, a
number of carbamate-protected reagents such as N1, N2-
bis(tert-butyloxy/benzyloxycarbonyl)thiourea, N1,N2-bis-
(tert-butyloxy/benzyloxycarbonyl)-S-methylisothiourea, as
well as 1H-pyrazole-1-[N1,N2-bis(tert-butyloxy/benzyloxy-
carbonyl)]carboxamidine and its dimethyl substituted
derivative have been developed.6 Additionally, the use-
fulness of sulfonyl-protected 2-methyl-2-thiopseudourea
in the conversion of amines to guanidines has been
demonstrated,7 and conditions for utilizing carbamate
derivatives have been improved and applied to the
synthesis of various compounds.8 Excellent yields of
protected guanidines often have been obtained using
these reagents and purification by chromatography has
been facile due to the less polar nature of protected
guanidines. Guanidines can be easily generated from
these derivatives in excellent yields by simple treatment
with hydrochloric acid or trifluoroacetic acid.6a,8a
Resu lts a n d Discu ssion
The results obtained from the guanylation of bromoal-
kanes (eq 1) are summarized in Table 1. Although our
main interest was in the preparation of benzylguanidine
derivatives, the general applicability of the reaction was
investigated using some aliphatic and heterocyclic com-
pounds. The conditions were mild, and the reactions
often were clean.
While 1a was converted to 3a , 1b failed to react. In
contrast, the yield of guanidine derivatives from both
primary and secondary alcohols under Mitsunobu condi-
tions was more than 95%.10 Although a dual mechanistic
pathway has been proposed for Mitsunobu reaction,17 the
final step involves the SN2 substitution of a nucleophile
on the alkoxyphosphonium intermediate resulting in the
inversion of configuration at carbon in asymmetric alco-
hols. Such inversion has been observed in the conversion
of 2-butanol to the guanidine derivative.10 It is believed
that an SN2 mechanism most likely is involved in the
conversion of 1 to 3 (eq 1). Thus, it is not clear why
Whereas most methods for guanidine preparation
involve guanylation of ammonia or an amine, conversion
of nitriles9 and alcohols under Mitsunobu conditions10, 11
has been reported. In light of these reports, a protocol
for the direct conversion of a bromoalkane to a protected
guanidine using N1,N2-bis(tert-butyloxycarbonyl)guani-
dine (2) would be advantageous.
* To whom correspondence should be addressed. Tel.: (919) 684-
7811. Fax: (919) 684-7122. E-mail: g405@acpub.duke.edu.
(1) Kampf, A. Chem. Ber. 1904, 37, 1681. (b) Davis, T. L. Org. Synth.
1927, 7, 46.
(2) (a) Braun, C. E. J . Am. Chem. Soc. 1993, 55, 1280. (b) Rasmus-
sen, C. R.; Villani, F. J ., J r.; Reynolds, B. E.; Plampin, J . N.; Hood, A.
R.; Hecker, L. R.; Nortey, S. O.; Hanslin, A.; Costanzo, M. J .; Howse,
R. M., J r.; Molinari, A. J . Synthesis 1988, 460.
(3) (a) Maryanoff, C. A.; Stanzione, R. C.; Plampin, J . N.; Mills, J .
E. J . Org. Chem. 1986, 51, 1882. (b) Arzeno, H. B.; Bingenheimer, W.;
Morgans, D. J ., J r. Synth. Commun. 1990, 20, 3433.
(4) (a) Bernatowicz, M. S.; Wu, Y.; Matsueda, G. R. J . Org. Chem.
1992, 57, 2497. (b) Bernatowicz, M. S.; Matsueda, G. R. Synth.
Commun. 1993, 23, 657.
2-bromobutane failed to yield any substitution product.
Being a secondary halide, 2-bromobutane should be
susceptible to undergoing elimination in the presence of
a base. To investigate this possibility, the reaction was
conducted using 1c. Again, no substitution product 3c
was obtained; however, a product identical in TLC
(hexane) and NMR to commercially available trans-â-
methylstyrene was isolated in almost quantitative yield.
This suggests that, under these reaction conditions,
secondary bromides undergo elimination rather than
substitution.
(5) Katritzky, A. R.; Parris, R. L.; Allin, S. M. Synth. Commun. 1995,
25, 1173.
(6) (a) Poss, M. A.; Iwanowicz, E.; Reid, J . A.; Lin, J .; Gu, Z.
Tetrahedron Lett. 1992, 33, 5933. (b) Bergeron, R. J .; McManis, J . S.
J . Org. Chem. 1987, 52, 1700. (c) Bernatowicz, M. S.; Wu, Y.; Matsueda,
G. Tetrahedron Lett. 1993, 34, 3389. (d) Drake, B.; Patek, M.; Lebl,
M. Synthesis 1994, 579. (e) Verdini, A. S.; Lucietto, P.; Fossati, G.;
Giordani, C. Tetrahedron Lett. 1992, 33, 6541. (f) Kowalski, J .; Lipton,
M. A. Tetrahedron Lett. 1996, 37, 5839.
(12) Wafelman, A. R.; Hoefnagel, C. A.; Maes, R. A. A.; Beijnen, J .
H. Eur. J . Nucl. Med. 1994, 21, 545.
(13) (a) Vaidyanathan, G.; Zalutsky, M. R. Bioconjugate Chem. 1992,
3, 499. (b) Vaidyanathan, G.; Affleck, D. J .; Zalutsky, M. R. J . Med.
Chem. 1994, 37, 3655. (c) Vaidyanathan, G.; Affleck, D. J .; Zalutsky,
M. R. Bioconjugate Chem. 1996, 7, 102.
(7) Kent, D. R.; Cody, W. L. and Doherty, A. M. Tetrahedron Lett.
1996, 37, 8711.
(8) (a) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7195. (b)
Ramadas, K.; Srinivasan, N. Tetrahedron Lett. 1995, 36, 2841. (c) Kim,
K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677. (d) Lal, B.; Gango-
padhyay, A. K. Tetrahedron Lett. 1996, 37, 2483.
(9) Garigipati, R. S. Tetrahedron Lett. 1990, 31, 1969.
(10) Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994, 35, 977.
(11) Chen, L.; Trilles, R. V.; Tilley J . W. Tetrahedron Lett. 1995,
36, 8715.
(14) Vaidyanathan, G.; Zalutsky, M. R. Appl. Radiat. Isot. 1993, 44,
621.
(15) Di Grandi, M. J .; Tilley, J . W. Tetrahedron Lett. 1996, 37, 4327.
(16) We were not aware of a similar work (Ko, S. Y.; Lerpiniere, J .;
Christofi, A. M. Synlett 1995, 815) that was pointed out to us by one
of the reviewers.
(17) Varasi, M.; Walker, K. A. M; Maddox, M. L. J . Org. Chem. 1987,
52, 4235.
S0022-3263(97)00416-7 CCC: $14.00 © 1997 American Chemical Society

4868 J . Org. Chem., Vol. 62, No. 14, 1997
Notes
Ta ble 1. Con ver sion of Br om oa lk a n es 1 to th e
Cor r esp on d in g P r otected Gu a n id in es 3
of 1i (Na-1i). The reaction was conducted using both 1
and 2 equiv of base. In both cases, the starting material
was completely consumed within 1 h. When 1 equivalent
of base was used, more than 50% of 2 was recovered; a
substantial amount of a solid insoluble even in DMSO
was isolated. The remainder was a mixture of two
components-3i (minor) and an unidentified compound.
Performing the reaction with 2 equiv of base resulted in
3i as the major product. While no DMSO-insoluble
product was formed, the amount of the unidentified
compound was minimal; about 25% of 2 was recovered.
The byproducts may be oligomers of 1i. Proton abstrac-
tion by Na-2 from 1i is faster than the desired reaction,
which in turn is faster than the polymerization of Na-1i.
In conclusion, a new method for the efficient prepara-
tion of guanidines starting from bromoalkanes under
facile conditions has been developed. In the case of
secondary bromides, elimination rather than substitution
is the preferred mode of reaction. For arylalkyl sub-
strates, the electron-withdrawing/donating nature or
position of the ring substituent does not seem to have
any significant influence on the reaction.
Exp er im en ta l Section
Gen er a l Meth od s. Bromoalkanes 1a -g,i,n -q and other
starting materials were obtained from Aldrich and were used
as such. Silylation-grade DMF (Pierce, Rockford, IL) was used
without any further purification for all reactions. The com-
pound 1h was obtained by the benzylic bromination of p-tolyl
benzoate. Although chromatographically homogeneous, NMR
indicated the presence of a small amount (about 10%) of
dibromo derivative. The compound 1i was prepared from
R-bromo-p-toluic acid by the carbodiimide-mediated esterifi-
cation. The substrates 1k and 1m were prepared from
2-methyl-6-nitrobenzoic acid and 3-iodo-4-methylbenzoic acid,
respectively, by esterification followed by benzylic bromination.
A three-step synthesis (BuLi-mediated silylation, esterifica-
tion, and benzylic bromination) was used for the preparation
of 1l from 3-bromo-4-methylbenzoic acid. For the preparation
of 1r , 2-bromo-5-methylpyridine was brominated using NBS/
benzoyl peroxide. Most of the above intermediates were used
for the subsequent reaction without extensive purification.
Typ ica l Rea ction P r oced u r e for th e Con ver sion of 1
to 3. To a suspension of 24 mg (1 mmol) of sodium hydride in
5 mL of dry DMF was added 259 mg (1 mmole) of 2.10 The
suspension turned to a clear solution after 5 min of stirring
at room temperature. To this solution was added dropwise a
solution of 1 mmol of the 1 in 2 mL of DMF, and the reaction
mixture was stirred at room temperature until TLC indicated
the complete consumption of 1 (usually 1 h). The reaction
mixture was partitioned between water and ethyl acetate, and
the pure product was isolated by silica gel chromatography
(column or preparative plate) using ethyl acetate/hexane
mixtures.
a
Yields of pure products isolated by chromatography; reaction
b
scale varied from 0.2 to 5.0 mmol. No 3b was isolated; most of 2
was recovered. c See discussion. Yield based on the recovered
d
starting material (∼20%); a considerable amount unknown product
was also isolated. e Two equiv of NaH was used. f R ) -CH2-
g
CH2SiMe3. Overnight stirring was required for completion of
reaction.
Except in the case of 1h and 1i, TLC of reaction
mixtures with arylalkyl substrates indicated a single
species corresponding to that of 3 with little or no
byproduct. In the cases of 3k and 3l, where the reactions
were run on a small scale (0.2 mmol), lower yields may
be due to loss during workup.
In the case of 1h , side reactions in addition to the
expected substitution are possible. Substitution can
occur at the desired benzylic carbon and/or at the ester
carbonyl carbon. Although the NH2 of 3h is not very
acidic, it can be potentially alkylated with 1h . However,
the spectral (NMR, IR, and MS) data of the major
byproduct do not match those expected for the byproducts
from the above possibilities. Yet another possibility is a
product formed from the reaction of a small amount of
dibromo impurity present in 1h (see Experimental Sec-
tion) and 2 equiv of 2, but neither the spectral data nor
the mass amount are consistent with this explanation.
With 1i, the acid functionality could be deprotonated
with Na-2. With 1 equiv of base, not only does this not
yield (or at least decrease the amount of) the desired
product but could result in polymeric product(s) by the
self-condensation (intermolecular) of the conjugate base
N 1,N 2-Bis(t er t -b u t yloxyca r b on yl)-N 1-n -b u t ylgu a n i-
d in e (3a ): 1:3 ethyl acetate:hexane, Rf 0.55; oil; 1H NMR
(CDCl3) δ 0.94 (t, 3H, J ) 7.8 Hz), 1.24-1.40 (m, 2H), 1.5 (s,
9H), 1.52 (s, 9H), 1.46-1.62 (m, 2H), 3.9 (t, 2H, J ) 10.8 Hz),
9.30 (br s, 2H); HRMS (FAB+) calcd for C15H30N3O4 (MH+)
316.2236, found 316.2229. Anal. Calcd for C15H29N3O4: C,
57.12; H, 9.27; N, 13.32. Found: C, 57.16, H, 9.34; N, 13.26.
N 1-Be n zyl-N 1,N 2-b is(t er t -b u t yloxyca r b on yl)gu a n i-
d in e (3d ): 1:3 ethyl acetate:hexane, Rf 0.80); white crystals;
1
mp 84 °C; H NMR (CDCl3) δ 1.31 (s, 9H), 1.49 (s, 9H), 5.19
(s, 2H), 7.23-7.29 (m, 5H) 9.40 (br s, 2H); HRMS (FAB+) calcd
for C18H28N3O4 (MH+) 350.2080, found 350.2069. Anal. Calcd
for C18H27N3O4: C, 61.87; H, 7.79; N, 12.03. Found: C, 62.44;
H, 7.69; N, 11.63.
N 1,N 2-Bis(t er t -b u t yloxyca r b on yl)-N 1-(3-flu or ob e n -
zyl)gu a n id in e (3e): 1:4 ethyl acetate:hexane, Rf 0.39; white
1
crystals; mp 102 °C; H NMR (CDCl3) δ 1.34 (s, 9H), 1.49 (s,
9H), 5.17 (s, 2H), 6.85-7.10 (m, 3H), 7.20-7.30 (m, 1H), 9.30

Notes
J . Org. Chem., Vol. 62, No. 14, 1997 4869
(br s, 1H), 9.45 (br s, 1H); HRMS (FAB+) calcd for C18H27FN3O4
0.08 (s, 9H), 0.40 (s, 9H), 1.14 (t, 2H, J ) 11.2 Hz), 1.26 (s,
9H), 1.41 (s, 9H), 4.41 (t, 2H, J ) 11.2 Hz), 5.37 (s, 2H), 7.05
(d, 1H, J ) 8.9 Hz), 7.95 (d, 1H, J ) 8.9 Hz), 8.18 (s, 1H), 9.45
(br s, 2H); HRMS (FAB+) calcd for C27H48N3O6Si2 (MH+)
566.3082, found 566.3069. Anal. Calcd for C27H47N3O6Si2: C,
57.31; H, 8.37; N, 7.42. Found: C, 57.23; H, 8.33; N, 7.28.
2-(Tr im eth ylsilyl)eth yl 4-[[N1,N2-bis(ter t-bu tyloxyca r -
bon yl)gu a n id in o]m eth yl]-3-iod oben zoa te (3m ): 1:9 ethyl
acetate:hexane, Rf 0.24; white crystals; mp 55-56 °C; 1H NMR
(CDCl3) δ 0.08 (s, 9H), 1.14 (t, 2H, J ) 6.6 Hz), 1.25 (s, 9H),
1.47 (s, 9H), 4.41 (t, 2H, J ) 6.6 Hz), 5.22 (s, 2H), 7.05 (d, 1H,
J ) 8.5 Hz), 7.95 (d, 1H, J ) 8.5 Hz), 8.45 (s, 1H), 9.45 (br s,
2H); HRMS (FAB+) calcd for C24H39IN3O6Si (MH+) 620.1653,
found 620.1649. Anal. Calcd for C24H38IN3O6Si: C, 46.53; H,
6.18; N, 6.78. Found: C, 46.66; H, 6.25; N, 6.76.
(MH+) 368.1986, found 368.1993. Anal. Calcd for C18H26
-
FN3O4: C, 58.84; H, 7.13; N, 11.44. Found: C, 58.98; H, 7.23;
N, 11.42.
N1,N2-Bis(ter t-b u t yloxyca r b on yl)-N1-(3-iod ob en zyl)-
gu a n id in e (3f): 3:17 ethyl acetate:hexane, Rf 0.60; white
granular solid; mp 135 °C; 1H NMR (CDCl3) δ 1.36 (s, 9H),
1.50 (s, 9H), 5.11 (s, 2H), 6.98-7.08 (m, 1H), 7.20-7.24 (m,
1H), 7.50-7.70 (m, 2H), 9.23 (br s, 1H), 9.42 (br s, 1H); HRMS
(FAB+) calcd for C18H27IN3O4 (MH+) 476.1046, found 476.1055.
Anal. Calcd for C18H26IN3O4: C, 45.48; H, 5.51; N, 8.84.
Found: C, 45.27; H, 5.49; N, 8.56.
N1,N2-Bis(ter t-b u t yloxyca r b on yl)-N1-(3-n it r ob en zyl)-
gu a n id in e (3g): 1:4 ethyl acetate:hexane, Rf 0.25; pale yellow
solid; mp 119 °C; 1H NMR (CDCl3) δ 1.40 (s, 9H), 1.49 (s, 9H),
5.24 (s, 2H), 7.44-7.52 (m, 1H), 7.63-7.66 (m, 1H), 8.10-8.15
(m, 1H), 8.20-8.22 (m, 1H), 9.30 (br s, 2H); HRMS (FAB+)
calcd for C18H27IN4O6 (MH+) 395.1931, found 395.1936. Anal.
Calcd for C18H26N4O6: C, 54.80; H, 6.65; N, 14.21. Found: C,
54.70; H, 6.61; N, 14.27.
N 1,N 2-Bis(t er t -b u t yloxyca r b on yl)-N 1-(2-m e t h ylb e n -
zyl)gu a n id in e (3n ): 1:19 ethyl acetate:hexane, Rf 0.18; white
crystals; mp 123-124 °C; 1H NMR (CDCl3) δ 1.23 (s, 9H), 1.46
(s, 9H), 2.29 (s, 3H), 5.18 (s, 2H), 6.95-7.20 (m, 4H), 9.45 (br
s, 2H); HRMS (FAB+) calcd for C19H30N3O4 (MH+); 364.2236,
found 364.2226. Anal. Calcd for C19H29N3O4: C, 62.79; H,
8.04; N, 11.56. Found: C, 62.81; H, 8.02; N, 11.63.
N1-[4-(Ben zoyloxy)ben zyl]-N1,N2-bis(ter t-bu tyloxyca r -
bon yl)gu a n id in e (3h ): 1:4 ethyl acetate:hexane, Rf 0.39;
white crystals; mp 146 °C; 1H NMR (CDCl3) δ 1.37 (s, 9H),
1.50 (s, 9H), 5.20 (s, 2H), 7.15 (d, 2H, J ) 8.4 Hz), 7.26-7.38
(m, 2H), 7.48-7.56 (m, 2H), 7.60-7.69 (m, 1H), 8.20 (d, 2H, J
) 8.4 Hz), 9.35 (br s, 1H), 9.45 (br s, 1H); HRMS (FAB+) calcd
for C25H32N3O6 (MH+) 470.2291, found 470.2307. Anal. Calcd
for C25H31N3O6: C, 63.94; H, 6.66; N, 8.95. Found: C, 63.85;
H, 6.63; N, 8.89.
N 1,N 2-Bis(t er t -b u t yloxyca r b on yl)-N 1-(3-m e t h ylb e n -
zyl)gu a n id in e (3o): 1:9 ethyl acetate:hexane, Rf 0.27; white
crystals; mp 104-105 °C; 1H NMR (CDCl3) δ 1.31 (s, 9H), 1.49
(s, 9H), 2.32 (s, 3H), 5.14 (s, 2H), 7.04-7.20 (m, 4H), 9.40 (br
s, 2H); HRMS (FAB+) calcd for C19H30N3O4 (MH+) 364.2236,
found 364.2241. Anal. Calcd for C19H29N3O4: C, 62.79; H,
8.04; N, 11.56. Found: C, 63.40; H, 7.98; N, 11.13.
4-[[N1,N2-bis(ter t-b u t yloxyca r b on yl)gu a n id in o]m et h -
yl]ben zoic a cid (3i): 1:50:50 acetic acid:ethyl acetate:hexane,
Rf 0.41; white crystals (ethyl acetate/hexane); mp 165-67 °C
dec; 1H NMR (CDCl3) δ 1.30 (s, 9H), 1.48 (s, 9H), 5.24 (s, 2H),
7.28 (d, 2H, J ) 8.8 Hz), 8.01 (d, 2H, J ) 8.8 Hz), 9.38 (br s,
2H); HRMS (FAB+) calcd for C19H28N3O6 (MH+) 394.1977,
found 394.1981. Anal. Calcd for C19H27N3O6: C, 58.00; H,
6.92; N, 10.68. Found: C, 57.91; H, 6.99; N, 10.68.
2-(Tr im eth ylsilyl)eth yl 4-[[N1,N2-bis(ter t-bu tyloxyca r -
bon yl)gu a n id in o]m eth yl]ben zoa te (3j): 3:17 ethyl acetate:
N 1,N 2-Bis(t er t -b u t yloxyca r b on yl)-N 1-(4-m e t h ylb e n -
zyl)gu a n id in e (3p ): 1:9 ethyl acetate:hexane, Rf 0.2; white
crystals; mp 138-139 °C; 1H NMR (CDCl3) δ 1.33 (s, 9H), 1.48
(s, 9H), 2.32 (s, 3H), 5.13 (s, 2H), 7.19 (m, 4H), 9.40 (br s, 2H).
HRMS (FAB+) calcd for C19H30N3O4 (MH+) 364.2236, found
364.2226. Anal. Calcd for C19H29N3O4: C, 62.79; H, 8.04; N,
11.56. Found: C, 62.63; H, 7.97; N, 11.43.
N1,N2-Bis(ter t-b u t yloxyca r b on yl)-N1-(3-m et h oxyb en -
zyl)gu a n id in e (3q): 1:9 ethyl acetate:hexane, Rf 0.08; white
1
crystals; mp 79-80 °C; H NMR (CDCl3) δ 1.35 (s, 9H), 1.48
1
hexane, Rf 0.32; oil; H NMR (CDCl3) δ 0.08 (s, 9H), 1.13 (t,
(s, 9H), 3.79 (s, 3H), 5.15 (s, 2H), 6.81 (m, 3H), 7.23 (t, 1H, J
) 8.0), 9.42 (br s, 2H); HRMS (FAB+) calcd for C19H30N3O5
(MH+) 380.2185, found 380.2184. Anal. Calcd for
C19H29N3O4: C, 60.14; H, 7.70; N, 11.07. Found: C, 60.08; H,
7.69; N, 11.10.
2H, J ) 8.8 Hz), 1.29 (s, 9H), 1.48 (s, 9H), 4.43 (t, 2H, J ) 8.8
Hz), 5.23 (s, 2H), 7.27 (d, 2H, J ) 8.1 Hz), 7.97 (d, 2H, J ) 8.1
Hz), 9.35 (br s, 1H), 9.45 (br s, 1H); HRMS (FAB+) calcd for
C24H40N3O6Si (MH+) 494.2686, found 494.2689. Anal. Calcd
for C24H39N3O6Si: C, 58.39; H, 7.96; N, 8.51. Found: C, 58.37;
H, 7.95; N, 8.32.
5-[[N1,N2-Bis(ter t-bu tyloxycar bon yl)gu an idin o]m eth yl]-
2-br om op yr id in e (3r ): 1:3 ethyl acetate:hexane, Rf 0.29; pale
yellow powder; mp 147 °C; 1H NMR (CDCl3) δ 1.44 (s, 9H),
1.49 (s, 9H), 5.11 (s, 2H), 7.45 (d, 1H, J ) 10.0 Hz), 7.64 (d,
1H, J ) 10.0 Hz), 8.36 (s, 1H), 9.20 (br s, 1H), 9.44 (br s, 1H);
HRMS (FAB+) calcd for C17H26BrN4O4 (MH+) 429.1137, found
429.1138. Anal. Calcd for C17H25BrN4O4: C, 47.56; H, 6.02;
N, 13.05. Found: C, 47.83; H, 6.07; N, 13.13.
2-(Tr im eth ylsilyl)eth yl 2-[[N1,N2-bis(ter t-bu tyloxyca r -
bon yl)gu a n id in o]m eth yl]-6-n itr oben zoa te (3k ): 2:3 ethyl
1
acetate:hexane, Rf 0.56; pale yellow crystals; mp 123 °C; H
NMR (CDCl3) δ 0.08 (s, 9H), 1.11 (t, 2H, J ) 11.0 Hz), 1.28 (s,
9H), 1.46 (s, 9H), 4.43 (t, 2H, J ) 11.0 Hz), 5.32 (s, 2H), 7.42
(d, 1H, J ) 11.8 Hz), 7.50-7.58 (m, 1H), 8.00 (d, 1H, J ) 11.8
Hz), 9.35 (br s, 1H), 9.52 (br s, 1H); HRMS (FAB+) calcd for
C24H39N4O8Si (MH+) 539.2537, found 539.2538. Anal. Calcd
for C24H38N4O8Si: C, 53.51; H, 7.11; N, 10.41. Found: C,
53.47; H, 7.15; N, 10.35.
Ackn owledgm en t. This work is supported by grants
(CA 60066 and CA 42324) from the National Institutes
of Health. The authors thank Donna J . Affleck and
J ean Li for their excellent technical assistance.
2-(Tr im eth ylsilyl)eth yl 4-[[N1,N2-bis(ter t-bu tyloxyca r -
b on yl)gu a n id in o]m e t h yl]-3-(t r im e t h ylsilyl)b e n zoa t e
(3l): 1:9 ethyl acetate:hexane, Rf 0.34; oil; 1H NMR (CDCl3) δ
J O9704164