Phase-transfer-catalyzed alkylation of guanidines by alkyl halides under biphasic conditions: A convenient protocol for the synthesis of highly functionalized guanidines

Article abstract of DOI:10.1021/jo0265535

An operationally straightforward and efficient method for the alkylation of carbamate-protected guanidines with various alkyl halides and mesylates is described. This protocol proceeds via deprotonation of the acidic N-carbamate hydrogen of the guanidine under biphasic conditions using a catalytic amount of a tetrabutylammonium salt as a phase-transfer catalyst. In this manner, highly functionalized guanidines can be obtained. The reaction is tolerant of a wide range of functional groups on both the alkyl halide and guanidine component. In addition, the reaction is sufficiently mild such that simple aqueous workup and filtration through a short silica gel column yields the substituted guanidines in high purity. In conjunction with the EDCI-mediated guanylation of disubstituted thioureas with amines, phase-transfer catalyzed alkylation of guanidines via a one-pot, three-component synthesis of substituted guanidines was achieved.

Full text of DOI:10.1021/jo0265535

P h a se-Tr a n sfer -Ca ta lyzed Alk yla tion of Gu a n id in es by Alk yl
Ha lid es u n d er Bip h a sic Con d ition s: A Con ven ien t P r otocol for th e
Syn th esis of High ly F u n ction a lized Gu a n id in es
David A. Powell, Philip D. Ramsden, and Robert A. Batey*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street,
Toronto, Ontario M5S 3H6, Canada
rbatey@chem.utoronto.ca
Received October 10, 2002
An operationally straightforward and efficient method for the alkylation of carbamate-protected
guanidines with various alkyl halides and mesylates is described. This protocol proceeds via
deprotonation of the acidic N-carbamate hydrogen of the guanidine under biphasic conditions using
a catalytic amount of a tetrabutylammonium salt as a phase-transfer catalyst. In this manner,
highly functionalized guanidines can be obtained. The reaction is tolerant of a wide range of
functional groups on both the alkyl halide and guanidine component. In addition, the reaction is
sufficiently mild such that simple aqueous workup and filtration through a short silica gel column
yields the substituted guanidines in high purity. In conjunction with the EDCI-mediated guanylation
of disubstituted thioureas with amines, phase-transfer catalyzed alkylation of guanidines via a
one-pot, three-component synthesis of substituted guanidines was achieved.
A growing number of biologically and pharmaceutically
relevant compounds incorporate guanidine functionality.
Guanidine secondary metabolites, for example,1 occur in
a variety of species and display a correspondingly diverse
range of structures, substitution patterns, and biological
behavior.2 Moreover, guanidines are also present in
pharmaceuticals,3 such as the synthetically derived
influenza inhibitor zanamivir.4 Substituted guanidines,
whether of natural or unnatural origin, pose significant
challenges as synthetic targets. Multiple substitution
patterns are possible for guanidines, including alkyl and
aryl substituents, present at varying oxidation states.
Furthermore, the high basicity and polarity, and conse-
quent water solubility of many guanidines, also cause
considerable practical difficulties. These considerations
place stringent limitations on the synthetic planning for
complex guanidines, both strategically and tactically.
New methods for guanidine synthesis are required to
address their increasing importance as natural product
and pharmaceutical targets.
Gu a n yla tion a n d Gu a n id in yla tion Meth od s. In
this paper, we refer to the conversion of an amine to a
guanidine, where the amine nitrogen is incorporated into
the newly formed guanidine functional group, as a
guanylation,5 since this reaction formally involves the
attachment of a -C(dNH)NH2 group (or substituted
derivative), traditionally referred to as a guanyl group.6
Most guanylating methods involve the reaction of a
primary or secondary amine 1 with guanylating reagents
of general structure 2. Improvements to this process have
focused on the use of more electrophilic amidine species
and better leaving groups that can be displaced under
milder conditions (Scheme 1).7-12 Significant advances in
guanidine synthesis were achieved with the introduction
(5) There is little consensus in the literature over the use of the
terms guanylation and guanidinylation. For a thorough discussion of
guanidine terminology as used in the scientific community, see: J ones,
J . H. J . Peptide Sci. 2002, 8, 285-287.
(6) The term guanyl has officially been superseded by the term
carbamimidoyl, and this conversion should technically be referred to
as a carbamimidoylation; however, this is a rather laborious term and
is rarely used in the literature.
(7) For guanylations with reagent 2a , see: Hg promoted: (a) Yu,
Y.; Ostresh, J . M.; Houghten, R. A. J . Org. Chem. 2002, 67, 3138-
3141. (b) Zhang, J .; Shi, Y.; Stein, P.; Atwal, K.; Li, C. Tetrahedron
Lett. 2002, 43, 57-59. (c) Cunha, S.; Costa, M. B.; Napolitano, H. B.;
Lariucci, C.; Vencato, I. Tetrahedron 2001, 57, 1671-1675. (d) Levallet,
C.; Lerpiniere, J .; Ko, S. Y. Tetrahedron, 1997, 53, 5291-5304. (e)
J irgensons, A.; Kums, I.; Kauss, V.; Kalvins, I. Synth. Comm. 1997,
27, 315-322. (f) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 48, 7677-
7680. EDCI promoted: (g) Manimala, J . C.; Anslyn, E. V. Tetrahedron
Lett. 2002, 43, 565-567. (h) Linton, B. R.; Carr, A. J .; Orner, B. P.;
Hamilton, A. D. J . Org. Chem. 2000, 65, 1566-1568. (i) Poss, M. A.;
Iwanowicz, E.; Reid, J . A.; Lin, J .; Gu, Z. Tetrahedron Lett. 1992, 33,
5933-5936. Other promoters: (j) Guisado, O.; Mart´ınez, S.; Pastor, J .
Tetrahedron Lett. 2002, 43, 7105-7109.
* To whom correspondence should be addressed. Tel/Fax: (416) 978-
5059.
(1) (a) Guanidines: Historical, Biological, Biochemical and Clinical
Aspects of the Naturally Occurring Guanidino Compounds; Mori, A.;
Cohen, B. D.; Lowenthal, A. Eds.; Plenum Press: New York, 1985. (b)
Guanidines 2: Further Explorations of the Biological and Clinical
Significance of Guanidino Compounds; Mori, A., Cohen, B. D., Koide,
H., Eds.; Plenum Press: New York, 1987.
(2) Berlinck, R. G. S. Nat. Prod. Rep. 1999, 16, 339-365 and
references therein.
(3) Greenhill, J . L.; Lue, P. In Progress in Medicinal Chemistry; Ellis,
G. P., Luscombe, D. K., Eds.; Elsevier Science: New York, 1993; Vol.
30, Chapter 5.
(4) (a) von Itzstein, M.; Wu, W.-Y.; Kok, G. B.; Pegg, M. S.; Dyason,
J . C.; J in, B.; Phan, T. V.; Smythe, M. L.; White, H. F.; Oliver, S. W.;
Colman, P. M.; Varghese, J . N.; Ryan, D. M.; Woods, J . M.; Bethell, R.
C.; Hotham, V. J .; Cameron, J . M.; Penn, C. R. Nature 1993, 363, 418-
423. (b) Howes, P. D.; Smith, P. W. Tetrahedron Lett. 1996, 37, 6595-
6598. (c) Staschke, K. A.; Colacino, J . M.; Baxter, A. J .; Air, G. M.;
Bansal, A.; Hornback, W. J .; Munroe, J . E.; Laver, W. G. Virology 1995,
214, 642-646.
10.1021/jo0265535 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/15/2003
2300
J . Org. Chem. 2003, 68, 2300-2309

Synthesis of Highly Functionalized Guanidines
SCHEME 1
substituted guanidines is often required. Consequently,
methods wherein guanidines of general type 3 could, by
virtue of their fairly acidic N-H protons, be further
functionalized with a variety of electrophiles are of clear
value. Such methods would also expand the range of
substrates that could be converted into guanidine prod-
ucts, as currently amines serve as the most common
entry point into guanidine-containing compounds. This
type of reaction, in which an electrophile is reacted with
a nucleophilic guanidine 3, to give a more highly substi-
tuted guanidine 5, we refer to as a guanidinylation14
(Scheme 1), as here a guanidino moiety -NH(CdNH)-
NH2 is introduced onto the alkyl halide/alcohol.15 Thus,
we propose a clear distinction between the terms gua-
nylation and guanidinylation, which are often confusingly
16
used in an interchangeable manner.
In contrast to the significant number of guanylation
methods available for the synthesis of guanidines, to the
best of our knowledge, there are only two methods that
are commonly used for the further functionalization of
protected guanidines of general structure 3.17-20 The first
involves deprotonation of guanidine 3 (PG ) Boc) with
NaH followed by reaction with an alkyl halide to give
the functionalized guanidine 5 (Scheme 1).21 Although
the reaction works for certain alkyl halides including
methyl iodide and benzyl bromide, less reactive sub-
strates such as 2-iodopropane and n-butyl bromide give
lower yields of product (50% and 45%, respectively). In
of more activated carbamate-protected (typically Boc or
Cbz) guanylating reagents 2 that allow for the direct
synthesis of protected guanidines. Unlike free guanidines,
protected guanidines are less polar and basic and can be
easily purified by chromatography and utilized in sub-
sequent reactions. Though much progress has been made
in the range of primary or secondary amines which can
be guanylated to give 3 (Scheme 1), this transformation
remains fundamentally restricted to the synthesis (fol-
lowing deprotection) of mono- or N1,N1-disubstituted
guanidines 4.13 Entry into more highly and differentially
(13) There have been some reports on the synthesis and reaction of
guanylating reagents of general structure 7 (where X ) SCH3 or
pyrazole) with primary or secondary amines, although the yields for
this type of reaction are generally low and require forcing conditions;
see: (a) Pa´tek, M.; Smrcina, M.; Nakanishi, E.; Izawa, H. J . Comb.
Chem. 2000, 2, 370-377. (b) Kim, H.-O.; Mathew, F.; Ogbu, C. Synlett
1999, 193-194.
(8) For guanylations with reagent 2b, see: (a) Moroni, M.; Koksch,
B.; Osipov, S. N.; Crucianelli, M.; Frigerio, M.; Bravo, P.; Burger, K.
J . Org. Chem. 2001, 66, 130-133. (b) Guo, Z.-X.; Cammidge, A. N.;
Horwell, D. C. Synth. Comm. 2000, 30, 2933-2943. (c) Miel, H.; Rault,
S. Tetrahedron Lett. 1998, 39, 1565-1568. (d) Elliott, A. J .; Morris, P.
E., J r.; Petty, S. L.; Williams, C. H. J . Org. Chem. 1997, 62, 8071-
8075. (e) Chandrakumar, N. S. Synth. Comm. 1996, 26, 2613-2616.
(f) Yuan, C.; Williams, R. M. Tetrahedron Lett. 1996, 37, 1945-1948.
Silver promoted: (g) Chen, B.-C.; Shiu, S.; Yang, D.-Y. J . Chin. Chem.
Soc. 1998, 45, 549-553. (h) Feldman, P. L. Tetrahedron Lett. 1991,
32, 875-878.
(9) For guanylations with reagent 2c, see: (a) Miller, A. E.; Bischoff,
J . J . Synthesis 1986, 777-779. For examples where R ) H, see: (b)
J ursic, B. S.; Neumann, D.; McPherson, A. Synthesis 2000, 1656-1658.
(c) Maryanoff, C. A.; Stanzione, R. C.; Plampin, J . N.; Mills, J . E. J .
Org. Chem. 1986, 51, 1882-1884.
(10) For guanylations with reagent 2d , see: (a) Goodman, M.; Zapf,
C.; Rew, Y. Biopolymers 2001, 60, 229-245. (b) Zapf, C. W.; Creighton.
C. J .; Tomioka, M.; Goodman, M. Org. Lett. 2001, 3, 1133-1136. (c)
Tamaki, M.; Han, G.; Hruby, V. J . J . Org. Chem. 2001, 66, 1038-
1042. (d) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J . Org.
Chem. 1998, 63, 3804-3805.
(11) For guanylations with reagent 2e, see: (a) Ghosh, A. K.; Hol,
W. G. J .; Fan, E. J . Org. Chem. 2001, 66, 2161-2164. (b) Drake, B.;
Patek, M.; Lebl, M. Synthesis 1994, 579-582. (c) Bernatowicz, M. S.;
Wu, Y.; Matsueda, G. R. Tetrahedron Lett. 1993, 34, 3389-3392.
(12) For guanylations with other reagents, see: (a) Wu, Y.-Q.;
Hamilton, S. K.; Wilkinson, D. E.; Hamilton, G. S. J . Org. Chem. 2002,
67, 7553-7556 (b) Musiol, H.-J .; Moroder, L. Org. Lett. 2001, 3, 3859-
3861. (c) Katritzky, A. R.; Rogovoy, B. V.; Chassaing, C.; Vvedensky,
V. J . Org. Chem. 2000, 65, 8080-8082. (d) Isobe, T.; Fukuda, K.;
Ishikawa, T. J . Org. Chem. 2000, 65, 7770-7773. (e) Isobe, T.; Fukuda,
K.; Yamaguchi, K.; Seki, H.; Tokunaga, T.; Ishikawa, T. J . Org. Chem.
2000, 65, 7779-7785. (f) Isobe, T.; Fukuda, K.; Tokunaga, T.; Seki,
H.; Yamaguchi, K.; Ishikawa, T. J . Org. Chem. 2000, 65, 7774-7778.
(g) Kent, D. R.; Cody, W. L.; Doherty, A. M. Tetrahedron Lett. 1996,
37, 8711-8714.
(14) The terms guanidinylation and guanylation have previously
been used interchangeably to describe the same conversion (an amine
to a guanidine), despite the strictly incorrect use of the word guanidi-
nylation for this reaction (guanidinylation of an amine would imply
the conversion -NH2 to -NH-NH(CdNH)NH2). The terminology
outlined in this paper avoids such confusions.
(15) Of course, this transformation can also formally be classified
as an alkylation of a guanidine (i.e., for the case where R3 ) alkyl,
Scheme 1). For intermolecular reactions, the usage of these descriptions
will depend on the degree of complexity associated with the guanidine
and the alkylating group. In the case where the alkylating group R3-X
is the more complex component, the reaction can be described as a
guanidinylation of R3-X.
(16) This terminology is different from that proposed by J ones, who
does not distinguish between the two reaction types and favors the
use of guanidinylation to describe the conversion of an amine to a
guanidine (see ref 5).
(17) Unprotected guanidines, which are considerably more nucleo-
philic than their carbamate-protected counterparts, can be further
functionalized under
a variety of conditions, including conjugate
addition, addition to aldehydes/ketones, and nucleophilic displacement.
For some representative examples, see refs 18-20.
(18) Conjugate additions: (a) Black, G. P.; Murphy, P. J .; Thornhill,
A. J .; Walshe, N. D. A.; Zanetti, C. Tetrahedron 1999, 55, 6547-6554
(b) Louwrier, S.; Tuynman, A.; Hiemstra, H. Tetrahedron 1996, 52,
2629-2646. (c) Snider, B. B.; Shi, Z. J . Org. Chem. 1993, 58, 3828-
3839.
(19) Addition of unprotected guanidines to aldehydes/ketones and
nucleophilic displacements: (a) Nishikawa, T.; Urabe, D.; Yoshida, K.;
Iwabuchi, T.; Asai, M.; Isobe, M. Org. Lett. 2002, 4, 2679-2682. (b)
Nagasawa, K.; Georgieva, A.; Koshino, H.; Nakata, T.; Kita, T.;
Hashimoto, Y. Org. Lett. 2002, 4, 177-180. (c) Franklin, A. S.; Gilbert,
S. K. L.; Mackin, G. H.; Overman, L. E.; Shaka, A. J . J . Org. Chem.
1999, 64, 1512-1519. (d) Snider, B. B.; Chen, J . Tetrahedron Lett.
1998, 39, 5697-5700. (e) Xie, C.; Runnegar, M. T. C.; Snider, B. B. J .
Am. Chem. Soc. 2000, 122, 5017-5024.
J . Org. Chem, Vol. 68, No. 6, 2003 2301

Powell et al.
TABLE 1. P h a se-Tr a n sfer Ca ta lyzed Alk yla tion of
Gu a n id in es 3 w ith Allyl Br om id e
addition, the strongly basic conditions employed are not
tolerated by base-sensitive functional groups such as
esters. The second method involves the reaction of
guanidine 3 with a primary or secondary alcohol under
Mitsunobu conditions.22 This method is more general and
works well for a wide variety of alcohols; however, it
requires expensive stoichiometric coupling reagents,
which often complicate the purification procedure.
Herein, we describe a relatively mild and efficient
protocol for the guanidinylation of various alkyl halides
in a biphasic medium containing an aqueous solution of
KOH, an organic solvent, and a catalytic amount of a
phase-transfer catalyst (PTC). This procedure is scaleable
to multigram quantities, yielding highly functionalized
and protected guanidines 5 that are readily purified.
Syn th esis. Guanidines 3 were prepared, using a
known procedure,8b,e in good to excellent yields by reac-
tion of amines 1 with N1,N2-bis-(Boc or Cbz)-S-methyl-
isothiourea 2b23 in the presence of a mercury(II) salt
promoter (Table 1). The protected guanidines were then
alkylated with allyl bromide (1.2 equiv) in the presence
of the phase-transfer catalyst Bu4NI (10 mol %) and KOH
(2.0 equiv) in a 1:1 mixture of H2O and CH2Cl2. After 4
h, simple aqueous workup and purification through a
short silica gel column, to remove the PTC, yielded the
corresponding substituted guanidines 5. Both the Boc-
and Cbz-protected pyrrolidine-derived guanidines were
readily allylated under the reaction conditions in excel-
lent yields (Table 1, entries 1 and 2). The N1,N2-bis-Boc-
guanidine (Table 1, entry 3) was regioselectively allylated
at one of the carbamate nitrogens. Alkylation of this
substrate under phase-transfer conditions provides an
alternative method for the synthesis of monosubstituted
guanidines from alkyl bromides under milder conditions
than previously reported.21 Furthermore, alkylation oc-
curs only once even in the presence of a large excess of
allyl bromide (5 equiv), with extended reaction times (24
h) or with heating (50 °C). Other N1,N2-bis-Boc-N3,N3-
disubstituted guanidines were similarly allylated in high
yield (Table 1, entries 4-11). The reaction is tolerant to
a wide range of functional groups on the guanidine
including esters, amines, ketones, alcohols, and alkenes.
Competitive hydrolysis of the ethyl ester in substrate 3e
was minimized by reducing the reaction time. (-)-
Ephedrine-derived guanidine 3k was allylated in 78%
yield to give protected guanidine 5k .24 Deprotection of
the Boc groups using 1 M aqueous HCl gave the optically
active trisubstituted guanidine 6k as an HCl salt in 64%
yield (Table 1, entry 11).
a
b
Isolated yield. Guanylation carried out in the absence of
HgCl2. c Reaction carried out for 2 h. Reaction conducted on a
d
31 mmol scale. e Yield with Bu4NBr as the PTC. f Yield with
The procedure is readily adapted to larger scales, as
exemplified by the allylation of the tetrahydroisoquino-
g
Bu4NCl as the PTC. Yield of the corresponding HCl salt after
deprotection of both Boc groups.
(20) Other reactions of unprotected guanidines: (a) Overman, L. E.;
Wolfe, J . P. J . Org. Chem. 2001, 66, 3167-3175. (b) Coffey, D. S.;
Overman, L. E. Stappenbeck, F. J . Am. Chem. Soc. 2000, 122, 4904-
4914. (c) Coffey, D. S.; McDonald, A. I.; Overman, L. E.; Rabinowitz,
M. H.; Renhowe, P. A. J . Am. Chem. Soc. 2000, 122, 4893-4903. (d)
McDonald, A. I.; Overman, L. E. J . Org. Chem. 1999, 64, 1520-1528.
(21) (a) Ko, S. Y.; Lerpiniere, J .; Christofi, A. M. Synlett 1995, 815-
816. (b) Vaidyanathan, G.; Zalutsky, M. R. J . Org. Chem. 1997, 62,
4867-4869.
line-derived guanidine 3g, which was conducted on a 12.0
g (31.2 mmol) scale (Table 1, entry 7). Aqueous workup
and purification of 5g through a short column of silica
gel gave the desired product in 79% yield. The Boc
protecting groups were then removed, using aqueous 1
M HCl, to yield the trisubstituted guanidine 6g as the
HCl salt in 90% yield.
Unfortunately, reaction of primary amine derived
guanidines 3, where R2 ) H, with alkyl halides under
the biphasic conditions proved to be problematic as these
classes of compounds contain two possible alkylation
sites. For example, reaction of N1,N2-bis-Boc-N3-phe-
(22) Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994, 35, 977-
980.
(23) Bergeron, R. J .; McManis, J . S. J . Org. Chem. 1987, 52, 1700-
1703.
(24) Characterization of compound 5k was problematic due to
rotamers, and it was therefore deprotected to give 6k which was fully
characterized.
2302 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of Highly Functionalized Guanidines
TABLE 2. P h a se-Tr a n sfer -Ca ta lyzed Alk yla tion of
N1,N2-Bis-Boc-N3-p yr r olid in e-1-ca r boxa m id in e 3a w ith
Va r iou s Electr op h iles
SCHEME 2
nylguanidine 3l with allyl bromide gave a separable
mixture of diallylated compounds 5l and 5j in a 7:3 ratio,
in addition to the guanidine starting material 3l (eq 1).
Treatment of N1,N2-bis-Boc-N3-benzylguanidine 3m with
5 equiv of allyl bromide also gave a mixture of diallylated
compounds in a similar ratio, although these compounds
could not be separated. These results are similar to
previous studies where reaction of primary amine-derived
guanidines 3 with allyl alcohols under Mitsunobu condi-
tions gave mixtures of diallylated compounds.25
However, it is possible to achieve selective monoally-
lation of primary amine-derived guanidines 3 (R2 ) H)
for those substrates where the nucleophilicity of the
nitrogen attached to R1 is very low. As described above,
N1,N2-bis-Boc-guanidine 3c could be monoallylated re-
gioselectively at the carbamate nitrogen (Table 1, entry
3). In addition, N1,N2-bis-Boc-N3-methoxyguanidine 3n
gave the corresponding monoallylated guanidine 5n in
69% yield, with the other regioisomeric N-methoxyally-
lated and bis-allylated guanidines being formed in less
than 5% yield (Scheme 2).
Having demonstrated functional group tolerance in the
guanidine component, the effect of variation of the
electrophilic component was required. Specifically, guani-
dinylation of a range of electrophiles using the bis-Boc-
protected model substrate 3a was examined (Table 2).
Saturated alkyl halides such as iodomethane (Table 2,
entry 1) and bromopropane (Table 2, entry 3) were
cleanly displaced by the guanidine nucleophile, although
in the latter case, the reaction needed to be heated to 50
°C for 12 h. Secondary alkyl bromides could also be
guanidinylated regioselectively to provide the isopropyl
a
Isolated yield. b 2.2 equiv of electrophile used. c Starting mate-
d
rial isolated. Reaction carried out in
a biphasic mixture of
toluene/water (1:1). e Benzyl mesylate must be prepared and used
immediately to avoid decomposition at rt, but may be stored for
extended periods (>3 months) at 0 °C.
and cyclohexenyl guanidines in moderate yield (Table 2,
entries 5 and 11). In contrast, secondary alkyl bromides
underwent elimination using the sodium hydride/DMF
methodology, rather than alkylation.21 For larger scale
syntheses, the use of alkyl chlorides over the more costly
alkyl bromides is highly desirable. It was gratifying to
observe that the biphasic alkylation of 3a with reactive
alkyl halides such as benzyl chloride ($2.27/mol) pro-
ceeded under similar conditions and yield (Table 2, entry
4) as with the more expensive benzyl bromide ($39.80/
mol)26 (Table 2, entries 6 and 7). However, the guanidi-
(25) Tomioka, M. Book of Abstracts. 219th National Meeting of the
American Chemical Society, San Francisco, CA, March 26-31, 2000;
American Chemical Society: Washington, DC, 2000; MEDI-230.
J . Org. Chem, Vol. 68, No. 6, 2003 2303

Powell et al.
SCHEME 3
nylation of unreactive alkyl chlorides, such as 1-chloro-
propane, was not successful (Table 2, entry 4). Since non-
chlorinated solvents, such as toluene, are often preferred
industrially, the use of toluene as a cosolvent in the
biphasic protocol was examined. Heating of guanidine
substrate 3a with benzyl chloride in a biphasic mixture
of toluene and water at 50 °C for 10 h in the presence of
the PTC and KOH gave the benzylated product 5r in 89%
yield (Table 2, entry 7). The scope of the guanidinylation
procedure was also extended to the use of mesylates
(Table 2, entry 8) which are readily accessible from the
corresponding alcohols. Clean alkylation of the guanidine
was observed with propargyl bromide (Table 2, entry 9)
and 4-bromo-2-methyl-2-butene (Table 2, entry 10). Reac-
tion at the secondary carbon of 3-bromocyclohexene
(Table 2, entry 11), as with 2-bromopropane, was slower
than displacement at a primary carbon, and conse-
quently, longer reaction times were required. This dif-
ference in reactivity at primary and secondary sites may
also be responsible for the regioselective alkylation of
cinnamyl bromide (Table 2, entry 12) which undergoes
guanidinylation at the SN2 site rather than the SN2′ site.
Other phase-transfer catalysts, such as Bu4NBr and
Bu4NCl, afforded products in yields similar to those
obtained with Bu4NI. Treatment of tetrahydroisoquino-
line-derived guanidine 3g with allyl bromide, using either
Bu4NCl or Bu4NBr as the PTC, afforded 5g in similar
yields compared to the Bu4NI catalyst (Table 1, entry 7).
Phase-transfer catalysis conditions have been used to
prepare alkyl iodides via a Finkelstein reaction,27 and we
investigated whether such a process was occurring under
our reaction protocol. Reaction of guanidine 3a and
1-chloropropane did not occur under refluxing biphasic
conditions, with either Bu4NCl or Bu4NI, even after 24
h (Table 2, entry 4). In contrast, treatment of 3a with
1-iodopropane under the same conditions, using Bu4NI
as the phase-transfer catalyst, gave 5p in 77% yield
(Table 2, entry 2). Since alkylation of 3a using Bu4NI
phase-transfer catalyst failed with 1-chloropropane, but
was successful using 1-iodopropane, an in situ Finkel-
stein reaction does not occur under the reaction condi-
tions.
for the guanidinylation of alcohols under Mitsunobu
conditions.28 This substrate can similarly be alkylated
with alkyl halides using the newly developed biphasic
reaction conditions. For example, N1,N2,N3-tri-Boc-guani-
dine 8 was dialkylated in the presence of 2.5 equivalents
of geranyl bromide to give the substituted guanidine 9
in 65% yield (eq 2).
The tri-Boc-guanidine 8 could also be treated with 1
equiv of 3-chloro-2-chloromethyl-1-propene in the pres-
ence of 1 equiv of KI to give the cyclic guanidine 10,
resulting from tandem-intermolecular and intramolecu-
lar alkylation (Scheme 3). Alkylation of tri-Boc-guanidine
8 with two separate electrophiles is possible using a two-
step procedure. Thus, reaction of 3 equiv of the tri-Boc-
guanidine 8 with 1 equiv of prenyl bromide gave the
alkylated guanidine 11. After purification to remove
excess tri-Boc-guanidine 8, reaction of 11 with 1 equiv
of benzyl mesylate gave the differentially dialkylated
guanidine 12 in 62% yield over the two-step procedure
(Scheme 3).
Th r ee-Com p on en t Cou p lin g. The PTC guanidiny-
lation method was successfully applied to a one-pot,
three-component synthesis of highly substituted guani-
dines. Reaction of the N1,N2-bis-Boc-thiourea 2a guany-
lating reagent7 with a secondary amine in the presence
of EDCI, a phase-transfer catalyst, and a base afforded
N1,N2-bis-Boc-N3,N3-disubstituted guanidine intermedi-
ate 3. Direct treatment of 3 in the same reaction vessel
with an alkylating reagent in the presence of a small
amount of water afforded the substituted guanidine 5
(Table 3). This protocol represents one of the few ex-
Recently, Goodman and co-workers have demonstrated
the use of N1,N2,N3-tri-Boc-guanidine 8 as a nucleophile
(26) Listed prices available from the Aldrich Chemical Co., 2002.
(27) Phase-Transfer Catalysis: Principles and Techniques; Starks,
C. M., Liotta, C., Eds.; Academic Press: New York, 1978; pp 112-125
(28) Feichtinger, K.; Sings, H. L.; Baker, T. J .; Matthews, K.;
Goodman, M. J . Org. Chem. 1998, 63, 8432-8439.
2304 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of Highly Functionalized Guanidines
TABLE 3. On e-P ot, Th r ee-Com p on en t Gu a n id in e
Syn th esis
atmosphere in flame dried or oven dried glassware. NMR
spectra were recorded at either 300 or 400 MHz (1H NMR)
and 75 or 100 MHz (13C NMR), referenced to an internal
standard (TMS) or residual solvent protons and signals are
reported in ppm (δ). Line broadening is apparent in some NMR
spectra and is due to rotamers around the carbamate nitrogen.
Flash chromatography was performed using silica gel (60 Å,
230-400 mesh) with reagent-grade solvents.
Gen er a l P r oced u r e for th e Syn th esis of Gu a n id in es
3.8b,c To a solution of amine 1 (3.00 mmol), N1,N2-bis(tert-
butoxycarbonyl)-S-methylisothiourea 2b (3.30 mmol, 960 mg),
and triethylamine (9.00 mmol, 1.25 mL) in dry DMF (10 mL)
was added HgCl2 (3.30 mmol, 891 mg). The suspension was
stirred at room temperature for 4 h and then concentrated in
vacuo. The crude reaction mixture was taken up in Et2O (40
mL), filtered through a pad of Celite on a sintered glass funnel,
washed with saturated aqueous NH4Cl (50 mL), H2O (50 mL),
and brine (50 mL), and dried over MgSO4. The mixture was
concentrated in vacuo and purified by flash chromatography
to yield the guanidine product 3.
Gen er a l P r oced u r e for th e Bip h a sic, P h a se-Tr a n sfer -
Ca ta lyzed Syn th esis of Gu a n id in es 5. A biphasic solution
of guanidine 3 (0.50 mmol), tetrabutylammonium iodide (0.05
mmol, 18 mg), and KOH (1.0 mmol, 56 mg) in a 1:1 mixture
of CH2Cl2/H2O (5 mL) was treated with the alkyl halide or
alkyl mesylate (0.60-1.0 mmol, depending on the electrophile,
see Table 2). The reaction was stirred at 25-50 °C (depending
on electrophile, see Table 2) for 2-4 h, and then the reaction
mixture was poured into H2O (25 mL) and extracted with CH2-
Cl2 (3 × 10 mL). The combined organic layers were washed
with brine, dried over MgSO4, filtered, and concentrated in
vacuo. The product 5 was purified by flash chromatography
through a short column of silica gel.
Gen er a l P r oced u r e for th e Dep r otection of N1,N2-Bis-
(ter t-bu toxyca r bon yl)gu a n id in es 5. A solution of the guani-
dine 5 (0.25 mmol) in 1 M aqueous HCl (2 mL) was stirred at
room temperature for 4 h or until all of the starting material
was consumed, as monitored by TLC. The reaction was
concentrated in vacuo and purified by silica gel chromatogra-
phy to give the unprotected guanidine as an HCl salt.
Gen er a l P r oced u r e for th e On e-P ot, Th r ee-Com p o-
n en t Syn th esis of Gu a n id in es 5. A solution of N1,N2-bis-
(tert-butoxycarbonyl)thiourea 2a (0.910 mmol, 250 mg), EDCI
(1.20 mmol, 237 mg), tetrabutylammonium iodide (0.170 mmol,
61.0 mg), and finely ground KOH (2.50 mmol, 140 mg) in CH2-
Cl2 (5 mL) was treated with amine 1 (0.82 mmol). The reaction
was stirred vigorously for 4 h, at which point TLC indicated
the complete consumption of thiourea 2a . Water (5 mL) and
the alkyl halide (1.60 mmol) were added, and the biphasic
reaction mixture was stirred for 4-16 h. The mixture was
poured into saturated aqueous NH4Cl (50 mL) and extracted
with CH2Cl2 (3 × 10 mL). The combined organic layers were
washed with brine (3 × 10 mL), dried over MgSO4, concen-
trated in vacuo, and purified by flash chromatography to yield
the guanidine product 5.
N1,N2-Bis(ben zyloxyca r b on yl)p yr r olid in e-1-ca r b oxa -
m id in e (3b). Obtained as a clear oil in 80% yield: Rf ) 0.10
(80% hexanes/20% EtOAc); IR (neat) ν 3033, 2972, 2888, 1752,
1614, 1492, 1271, 1214, 1054 cm-1; 1H NMR (400 MHz, CDCl3)
δ 10.70 (1H, bs), 7.38-7.29 (10H, m), 5.13 (4H, s), 3.57 (4H,
bs), 2.02-1.85 (4H, m); 13C NMR (75 MHz, CDCl3) δ 154.0,
128.3, 128.0, 67.4, 49.1, 24.9 (4 carbons not observed); MS (EI)
m/e 274 (34), 166 (100), 139 (56), 91 (74); HRMS (EI) m/e (M+)
calcd (for C21H23N3O4) 381.1689, found 381.1678.
a
Isolated yield.
amples of a sequential multicomponent guanidine synthe-
sis,7b,h a process which we anticipate will be increasingly
demanded given the importance of the guanidine func-
tionality in biologically significant molecules.
Con clu sion . An efficient method for the alkylation of
N-dicarbamate-protected guanidines using a variety of
alkyl halides has been established. Under this procedure,
the acidic N-carbamate hydrogen is deprotonated using
biphasic conditions, with a catalytic amount of a tetrabu-
tylammonium salt, as the phase-transfer catalyst, and
then subsequently alkylated to yield highly functionalized
guanidines. This protocol provides an alternate method
for the alkylation of protected guanidines from those
currently utilized. In addition, the need for stoichiometric
amounts of costly or highly reactive coupling reagents is
circumvented. An attractive feature of this methodology
is that few byproducts are generated and at the end of
the reaction, simple aqueous workup followed by filtra-
tion through a short plug of silica gel (to remove the PTC)
gives high yields of the desired products. Furthermore,
less expensive benzyl chlorides serve as effective elec-
trophiles. Replacement of dichloromethane with toluene
as the organic solvent gives comparable results and is
ideal for larger-scale preparation of substituted guanidines.
A convenient protocol for sequential three-component
coupling, was achieved by combination of the guanidi-
nylation methodology with an initial guanylation reac-
tion. Finally, we propose a differentiation in the termi-
nology for two distinct classes of reactions, guanylations
and guanidinylations.
N1,N2-Bis(ter t-b u t oxyca r b on yl)-N3-m et h ylgu a n id in o-
N3-a cetic Acid Eth yl Ester (3e). Obtained as a white solid
in 87% yield: Rf ) 0.18 (80% hexanes/20% EtOAc); mp 72-
73 °C; IR (KBr) ν 3175, 2980, 1750, 1613, 1393, 1143, 1082
Exp er im en ta l Section
Gen er a l Meth od s. All reagents, unless otherwise stated,
were used as received from commercial suppliers. Toluene was
distilled from sodium metal/benzophenone ketyl under argon.
CH2Cl2 was distilled from CaH2 under argon. DMF was
distilled from 4 Å molecular sieves under reduced pressure.
Where appropriate, reactions were conducted under an inert
1
cm-1; H NMR (400 MHz, CDCl3) δ 10.15 (1H, bs), 4.22 (2H,
q, J ) 7.0 Hz), 4.16 (2H, bs), 3.11 (3H, s), 1.48 (18H, s), 1.29
(3H, t, J ) 7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 168.5, 162.1,
156.1, 61.1, 52.1, 38.3, 28.0, 14.0 (2 equivalent carbons not
J . Org. Chem, Vol. 68, No. 6, 2003 2305

Powell et al.
observed); MS (EI) m/e 230 (37), 212 (35), 203 (24), 186 (20),
156 (27), 116 (35), 112 (28), 59 (40), 57 (100); HRMS (EI) m/e
(M+) calcd (for C16H29N3O6) 359.2056, found 359.2040.
128.1, 127.4, 126.4, 82.2, 79.5, 62.5, 57.6, 36.1, 28.2, 28.0, 12.8;
MS (EI) m/e 244 (41), 235 (35), 217 (37), 189 (40), 188 (199),
170 (41), 144 (100), 118 (32), 100 (34), 59 (47), 58 (56), 57 (100);
HRMS (EI) m/e (MH+) calcd (for C21H34N3O5) 408.2498, found
N1,N2-Bis(ter t-bu toxycar bon yl)ph en ylpiper azin e-1-car -
boxa m id in e (3f). Obtained as a white foam in 86% yield: Rf
) 0.19 (80% hexanes/20% EtOAc); IR (neat) ν 2976, 1747, 1603,
1491, 1366, 1230, 1133, 1015 cm-1; 1H NMR (400 MHz, CDCl3)
δ 10.29 (1H, bs), 7.30 (2H, t, J ) 7.5 Hz), 6.94 (2H, d, J ) 8.5
Hz), 6.92 (1H, t, J ) 7.5 Hz), 3.78 (4H, bs), 3.28 (4H, t, J ) 5.0
Hz), 1.54 (18H, s); 13C NMR (100 MHz, CDCl3) δ 155.0, 150.7,
129.0, 120.2, 116.4, 48.9, 46.7, 28.0 (2 equivalent quaternary
carbons not observed); MS (EI) m/e 285 (13), 231 (14), 230 (15),
229 (13), 187 (16), 160 (40), 145 (41), 132 (100), 120 (32), 104
(44), 59 (37); HRMS (EI) m/e (M+) calcd (for C21H32N4O4)
404.2424, found 404.2439.
N1,N2-Bis(ter t-bu toxycar bon yl)-3,4-dih ydr o-1H-isoqu in -
olin e-2-ca r boxa m id in e (3g). Obtained as a clear oil in 86%
yield: Rf ) 0.28 (80% hexanes/20% EtOAc); IR (neat) ν 3104,
2978, 1747, 1614, 1415, 1366, 1299, 1146, 1047 cm-1; 1H NMR
(400 MHz, CDCl3) δ 10.23 (1H, bs), 7.19-7.09 (4H, m), 4.71
(2H, bs), 3.77 (2H, bs), 2.97 (2H, t, J ) 6.0 Hz), 1.51 (18H, s);
13C NMR (100 MHz, CDCl3) δ 155.1, 134.6, 132.7, 128.3, 126.7,
126.3, 126.2, 82.2, 79.4, 48.8, 45.0, 28.6, 28.2, 28.1 (2 quater-
nary carbons not observed); MS (EI) m/e 375 (6, M+), 319 (19),
263 (61), 246 (32), 219 (40), 174 (27), 132 (87), 131 (29), 59
(30), 57 (100); HRMS (EI) m/e (M+) calcd (for C20H29N3O4)
375.2158, found 375.2141.
N1,N2-Bis(ter t-bu toxyca r bon yl)-3,4-d ih yd r o-2H-qu in o-
lin e-1-ca r boxa m id in e (3h ). Obtained as a white powder in
89% yield: Rf ) 0.38 (80% hexanes/20% EtOAc); mp 159-161
°C; IR (KBr) ν 3211, 2951, 2246, 1750, 1634, 1574, 1602, 1493,
1391, 1303, 1243, 1162, 1131 cm-1; 1H NMR (300 MHz, CDCl3,
rotamers) δ 9.96 (1H, br s), 7.25-6.91 (4H, m), 3.89 (2H, t, J
) 6.5 Hz), 2.77 (2H, t, J ) 6.5 Hz), 2.03-1.91 (2H, m), 1.52
(9H, br s), 1.19 (9H, br s); 13C NMR (100 MHz, CDCl3,
rotamers) δ 154.5, 139.8, 132.6, 129.4, 128.6, 126.7, 126.2,
124.4, 120.8, 116.9, 114.1, 46.5, 41.9, 28.0 (br), 26.8, 23.8, 22.1;
MS (EI) m/e 375 (45, M+), 319 (28), 274 (13), 262 (10), 245
(53), 218 (50), 200 (62), 175 (66), 158 (29), 132 (100); HRMS
(EI) m/e (M+) calcd (for C20H29N3O4) 375.2158, found 375.2156.
N1,N2-Bis(ter t-bu toxyca r bon yl)-4-oxop ip er id in e-1-ca r -
boxa m id in e (3i). Obtained as a white solid in 78% yield: Rf
) 0.13 (70% hexanes/30% EtOAc); mp 123-124 °C; IR (KBr)
ν 3184, 2979, 2932, 1747, 1614, 1486, 1367, 1297, 1231, 1150,
1079, 1052 cm-1; 1H NMR (400 MHz, CDCl3) δ 10.26 (1H, bs),
3.82 (4H, s), 2.58-2.56 (4H, m), 1.48 (18H, s); 13C NMR (100
MHz, CDCl3) δ 207.0, 155.3, 45.5, 40.4, 28.0 (2 quaternary
carbons not observed); MS (EI) m/e 341 (7, M+), 285 (26), 229
(83), 212 (69), 129 (36), 98 (47), 84 (46), 57 (100); HRMS (EI)
m/e (M+) calcd (for C16H27N3O5) 341.1951, found 341.1956.
408.2492; [R]20 ) -13.8 (c 0.10, MeOH).
D
N 1,N 2-Bis(t er t -b u t oxyca r b on yl)-N 3-m e t h oxygu a n i-
d in e (3n ). Obtained as a white foam in 61% yield: Rf ) 0.17
(80% hexanes/20% EtOAc); IR (neat) ν 3421, 3310, 2979, 1760,
1660, 1454, 1394, 1369, 1246, 1151, 1055, 893 cm-1; 1H NMR
(300 MHz, CDCl3) δ 9.11 (1H, bs), 7.76 (1H, bs), 3.86 (3H, s),
1.50 (9H, s), 1.49 (9H, s); 13C NMR (75 MHz, CDCl3) δ 151.6,
149.4, 141.0, 83.0, 81.1, 61.6, 27.9, 27.8; MS (EI) m/e 160 (12),
133 (58), 89 (29), 57 (100); HRMS (EI) m/e (M+) calcd (for
C12H23N3O5) 289.1638, found 289.1652.
N1-Allyl-N1,N2-bis(ter t-bu toxyca r bon yl)p yr r olid in e-1-
ca r boxa m id in e (5a ). Obtained as a clear oil in 89% yield:
Rf ) 0.22 (50% hexanes/50% Et2O); IR (neat) ν 2976, 1720,
1597, 1455, 1366, 1243, 1141 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.84 (1H, ddt, J ) 17.0, 10.0, 7.0 Hz), 5.21 (1H, dd, J ) 17.0,
1.0 Hz), 5.12 (1H, dd, J ) 10.0, 1.0 Hz), 4.23 (1H, bs), 3.63-
3.43 (5H, m), 1.87 (4H, bs), 1.46 (9H, s), 1.45 (9H, s); 13C NMR
(100 MHz, CDCl3) δ 159.2, 153.0, 152.2, 133.0, 118.9, 81.3,
78.8, 49.9, 48.0, 47.6, 28.2, 28.1, 25.2, 24.8; MS (EI) m/e 354
(MH+, 10), 353 (M+, 9), 253 (16), 224 (21), 197 (54), 152 (19),
97 (23), 72 (22), 70 (49), 57 (100); HRMS (EI) m/e (M+) calcd
(for C18H31N3O4) 353.2315, found 353.2306.
N1-Allyl-N1,N2-b is(b en zyloxyca r b on yl)p yr r olid in e-1-
ca r boxa m id in e (5b). Obtained as a clear oil in 87% yield:
Rf ) 0.55 (50% hexanes/50% EtOAc); IR (neat) ν 2975, 2880,
1725, 1590, 1456, 1392, 1235, 1150, 1026 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.40-7.26 (10H, m), 5.81 (1H, ddt, J ) 17.0,
10.0, 4.5 Hz), 5.19-5.04 (6H, m), 4.21 (1H, m), 3.72-3.38 (5H,
m), 1.80 (4H, bs); 13C NMR (75 MHz, CDCl3) δ 159.7, 153.6,
153.0, 136.6, 135.7, 131.9, 128.4, 128.3, 128.1, 128.0, 127.7,
127.7, 119.5, 67.6, 67.0, 50.2, 48.2, 47.7, 24.9, 24.5; MS (EI)
m/e 351 (17), 286 (17), 242 (12), 91 (100); HRMS (EI) m/e (M+)
calcd (for C24H27N3O4) 421.2002, found 421.2000.
N1-Allyl-N1,N2-bis(ter t-bu toxyca r bon yl)gu a n id in e (5c).
Obtained as a clear oil in 94% yield: Rf ) 0.52 (80% hexanes/
20% EtOAc); IR (neat) ν 3386, 2979, 1715, 1611, 1509, 1368,
1295, 1246, 1151 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.40 (1H,
bs), 9.28 (1H, bs), 5.84 (1H, ddt, J ) 16.5, 10.0, 5.0 Hz), 5.15-
5.09 (2H, m), 4.56 (2H, d, J ) 5.5 Hz), 1.49 (18H, s); 13C NMR
(75 MHz, CDCl3) δ 163.8, 160.5, 154.9, 134.0, 115.9, 83.7, 78.8,
46.7, 28.3, 27.9; MS (EI) m/e 300 (6, MH+), 244 (13), 187 (72),
170 (27), 143 (24), 128 (43), 98 (25); HRMS (EI) m/e (MH+)
calcd (for C14H26N3O4) 300.1923, found 300.1928. Anal. Calcd
for C14H25N3O4: C, 56.17; H, 8.42; N, 14.04. Found: C, 56.47;
H, 8.42; N, 14.01.
N1-Allyl-N1,N2-bis(ter t-bu toxycar bon yl)-N3-dieth ylgu an i-
d in e (5d ). Obtained as a light yellow oil in 90% yield: Rf )
0.39 (80% hexanes/20% EtOAc); IR (neat) ν 2977, 2934, 1720,
1594, 1457, 1366, 1251, 1164, 1083 cm-1; 1H NMR (400 MHz,
CDCl3) δ 5.83 (1H, ddt, J ) 17.0, 10.0, 7.0 Hz), 5.17 (1H, dd,
J ) 17.0, 1.0 Hz), 5.09 (1H, dd, J ) 10.0, 1.0 Hz), 4.19 (1H,
bs), 3.72 (1H, bs), 3.56 (1H, bs), 3.22 (3H, m), 1.43 (9H, s),
1.42 (9H, s), 1.09 (6H, t, J ) 7.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 159.5, 153.7, 152.5, 132.8, 118.9, 81.4, 78.6, 50.3, 41.7,
28.1, 28.0, 13.6, 11.5; MS (EI) m/e 355 (8, M+), 255 (19), 226
(25), 199 (49), 182 (20), 170 (24), 126 (22), 99 (22), 74 (22), 72
(55), 57 (100); HRMS (EI) m/e (M+), calcd (for C18H33N3O4)
355.2471, found 355.2478.
N1-Allyl-N2,N3-bis(ter t-bu toxycar bon yl)-N1-ph en ylgu an i-
d in e (3j). Obtained as a clear oil in 69% yield: Rf ) 0.27 (80%
hexanes/20% EtOAc); IR (neat) ν 3199, 2983, 1755, 1632, 1450,
1368, 1251, 1152, 1079, 1000 cm-1; 1H NMR (400 MHz, CDCl3)
δ 9.29 (1H, s), 7.32 (2H, t, J ) 7.5 Hz), 7.21 (2H, d, J ) 7.5
Hz), 7.17 (1H, t, J ) 7.5 Hz), 5.96 (1H, ddt, J ) 17.0, 10.5, 5.5
Hz), 5.18 (1H, dd, J ) 17.0, 1.0 Hz), 5.11 (1H, d, J ) 10.5 Hz),
4.53 (2H, d, J ) 5.5 Hz), 1.52 (9H, s), 1.20 (9H, s); 13C NMR
(100 MHz, CDCl3) δ 162.1, 153.7, 149.0, 132.9, 128.7, 126.2,
125.9, 117.6, 81.5, 79.4, 54.5, 28.1, 27.5; MS (EI) m/e 264 (22),
247 (32), 220 (67), 200 (29), 160 (35), 132 (36), 93 (27), 59 (47),
57 (100); HRMS (EI) m/e (M+) calcd (for C20H29N3O4) 375.2159,
found 375.2154.
N1,N2-Bis(ter t-bu toxyca r bon yl)-N3-[(1S,2R)-2-h yd r oxy-
1-m eth yl-2-p h en yleth yl]-N3-m eth ylgu a n id in e (3k ). Ob-
tained as white foam in 87% yield: Rf ) 0.10 (80% hexanes/
20% EtOAc); IR (neat) ν 3289, 2979, 1750, 1600, 1495, 1453,
1392, 1367, 1298, 1243, 1145 cm-1; 1H NMR (400 MHz, CDCl3)
δ 10.18 (1H, bs), 7.39 (2H, d, J ) 8.0 Hz), 7.33 (2H, t, J ) 8.0
Hz), 7.27 (1H, t, J ) 8.0 Hz), 4.90 (1H, s), 4.28-4.26 (1H, m),
2.59 (3H, s), 1.50 (9H, s), 1.47 (9H, s), 1.28 (3H, d, J ) 7.5
Hz);); 13C NMR (100 MHz, CDCl3) δ 161.6, 156.8, 150.1, 141.6,
N1-Allyl-N1,N2-bis(ter t-bu toxycar bon yl)-N3-m eth ylgu an i-
d in o-N3-a cetic Acid Eth yl Ester (5e). Obtained as a clear
oil in 78% yield: Rf ) 0.08 (80% hexanes/20% EtOAc); IR (neat)
ν 2979, 1720, 1603, 1456, 1368, 1252, 1146, 1074 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 5.92-5.88 (1H, m), 5.27-5.16 (2H,
m), 4.20 (2H, q, J ) 7.0 Hz), 4.14-3.77 (4H, m), 3.04 (3H, bs),
1.48 (18H, s), 1.28 (3H, t, J ) 7.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 168.3, 159.0, 154.5, 152.2, 132.5, 119.2, 81.8, 79.5,
61.2, 51.5, 50.6, 37.0, 28.2, 28.1, 14.1; MS (EI) m/e 199 (18),
2306 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of Highly Functionalized Guanidines
152 (34), 112 (17), 69 (100), 57 (48); HRMS (EI) m/e (M+) calcd
(for C19H33N3O6) 399.2369, found 399.2372.
(1H, ddt, J ) 17.0, 10.0, 5.5 Hz), 5.53-5.39 (1H, m), 5.24 (1H,
d, J ) 17.0 Hz), 5.15 (1H, d, J ) 10.0 Hz), 5.01-4.96 (2H, m),
4.37 (2H, d, J ) 5.5 Hz), 3.74 (2H,d, J ) 6.5 Hz), 1.49 (9H, s),
1.34 (9H, s); 13C NMR (100 MHz, CDCl3) δ 152.5, 147.1, 145.9,
133.8, 133.0, 128.8, 123.7, 121.1, 117.9, 117.2, 82.1, 81.5, 50.9,
28.2, 28.1; MS (EI) m/e 415 (6, M+), 259 (23), 214 (28), 174
(27), 159 (27), 57 (100); HRMS (EI) m/e (M+) calcd (for
N1-Allyl-N1,N2-bis(ter t-bu toxyca r bon yl)p h en ylp ip er a -
zin e-1-ca r boxa m id in e (5f). Obtained as a clear oil in 87%
yield: Rf ) 0.28 (50% hexanes/50% Et2O); IR (neat) ν 2977,
1715, 1600, 1446, 1367, 1140, 1088, 1017, 935, 858, 760 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.28 (2H, t, J ) 8.0 Hz), 6.93
(2H, d, J ) 8.0 Hz), 6.91 (1H, t, J ) 8.0 Hz), 5.87 (1H, ddt, J
) 17.0, 10.0, 4.5 Hz), 5.26 (2H, d, J ) 17.0 Hz), 5.19 (2H, d, J
) 10.0 Hz), 4.32-3.64 (6H, m), 3.28-3.09 (4H, m), 1.50 (9H,
s), 1.48 (9H, s); 13C NMR (100 MHz, CDCl3) δ 159.3, 153.6,
152.1, 150.6, 132.3, 129.1, 120.5, 119.6, 116.5, 81.7, 79.3, 50.1,
49.2, 45.5, 28.2, 28.0; MS (EI) m/e 445 (12, MH+), 315 (13),
271 (28), 243 (16), 213 (27), 200 (55), 169 (23), 161 (21), 156
(31), 145 (86), 132 (82), 112 (35), 105 (30), 104 (38), 83 (27), 57
(100); HRMS (EI) m/e (M+) calcd (for C24H36N4O4) 444.2737,
found 444.2747.
C
23H33N3O4) 415.2471, found 415.2469.
N1-Allyl-N1,N2-b is(ter t-b u t oxyca r b on yl)-N3-m et h oxy-
gu a n id in e (5n ). Obtained as a clear oil in 69% yield: Rf )
0.55 (80% hexanes/20% EtOAc); IR (neat) ν 3424, 2979, 1752,
1645, 1457, 1369, 1250, 1146, 1049 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.33 (1H, bs), 5.93 (1H, ddt, J ) 17.0, 10.0, 4.5 Hz),
5.22 (1H, dd, J ) 17.0, 1.0 Hz), 5.13 (1H, d, J ) 10.0 Hz), 4.06
(2H, d, J ) 6.0 Hz), 3.84 (3H, s), 1.47 (9H, s), 1.45 (9H, s); 13
C
NMR (100 MHz, CDCl3) δ 153.1, 148.9, 142.6, 133.5, 117.5,
81.4, 81.2, 61.8, 51.3, 28.0, 27.9; MS (EI) m/e 330 (13, MH+),
218 (24), 173 (36), 128 (32), 98 (27), 57 (100); HRMS (EI) m/e
(MH+) calcd (for C15H28N3O5) 330.2029, found 330.2031.
N1-Allyl-N1,N2-b is(ter t-b u t oxyca r b on yl)-3,4-d ih yd r o-
1H-isoqu in olin e-2-ca r boxa m id in e (5g). Obtained as a clear
oil in 96% yield: Rf ) 0.32 (50% hexanes/50% Et2O); IR (neat)
ν 2977, 1720, 1600, 1454, 1366, 1268, 1140 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.20-7.12 (4H, m), 5.91-5.86 (1H, m), 5.25
(1H, d, J ) 17.0 Hz), 5.16 (1H, d, J ) 10.0 Hz), 4.88-4.08
(4H, m), 3.80-3.52 (2H, m), 2.90-2.88 (2H, m), 1.51-1.43
(18H, m); 13C NMR (75 MHz, CDCl3) δ 159.2, 153.5, 152.1,
134.8, 133.6, 132.3, 128.2, 126.3, 119.5, 81.5, 79.1, 50.0, 47.6,
43.3, 29.1, 28.0 (2 quaternary carbons not observed); MS (EI)
m/e 415 (4, M+), 259 (22), 144 (22), 132 (58), 86 (31), 84 (40),
57 (100); HRMS (EI) m/e (M+) calcd (for C23H33N3O4) 415.2471,
found 415.2480.
N1,N2-Bis(ter t-bu toxyca r bon yl)p yr r olid in e-N1-m eth yl-
1-ca r boxa m id in e (5o). Obtained as a clear oil in 95% yield:
Rf ) 0.10 (70% hexanes/30% EtOAc); IR (neat) ν 2935, 1717,
1680, 1595, 1474, 1454, 1363, 1282, 1141 cm-1; 1H NMR (300
MHz, CDCl3) δ 3.50 (2H, bs), 3.41 (2H, bs), 2.96 (3H, s), 1.91
(4H, bs), 1.48 (9H, s), 1.47 (9H, s); 13C NMR (100 MHz, CDCl3)
δ 152.6, 81.3, 78.9, 48.0, 47.2, 28.3, 28.1, 25.3, 24.9 (2
quaternary carbons not observed); MS (EI) m/e 327 (11, M+),
271 (17), 215 (44), 198 (33), 170 (17); HRMS (EI) m/e (M+) calcd
(for C16H29N3O4) 327.2158, found 327.2149.
N1,N2-Bis(ter t-b u t oxyca r b on yl)-N1-(1-p r op yl)p yr r oli-
d in e-1-ca r boxa m id in e (5p ). Obtained as a light yellow oil
in 81% yield: Rf ) 0.15 (50% hexanes/50% Et2O); IR (neat) ν
2974, 1718, 1596, 1453, 1366, 1242, 1141 cm-1; 1H NMR (300
MHz, CDCl3) δ 3.55-3.42 (5H, m), 2.99 (1H, bs), 1.88 (4H, bs),
N1-Allyl-N1,N2-Bis(ter t-b u t oxyca r b on yl)-3,4-d ih yd r o-
2H-qu in olin e-1-ca r boxa m id in e (5h ). Obtained as a clear,
colorless oil in 96% yield: Rf ) 0.41 (80% hexanes/20% EtOAc);
IR (neat) ν 2971, 2922, 2253, 1718, 1620, 1577, 1496, 1454,
1391, 1366, 1243, 1145 cm-1
;
1H NMR (400 MHz, CDCl3) δ
1.57-1.50 (2H, m), 1.45 (18H, s), 0.85 (3H, t, J ) 7.5 Hz); 13
C
7.19-7.01 (4H, m), 5.84 (1H, ddt, J ) 17.0, 10.5, 6.5 Hz), 5.10-
5.06 (2H, m), 4.18-3.42 (4H, br m) 2.75 (2H, br t, J ) 6.0 Hz
), 1.99 (2H, bs), 1.43 (9H, s), 1.41 (9H, s); 13C NMR (100 MHz,
CDCl3) δ 138.6, 133.3, 128.6, 126.3, 124.6, 122.1, 118.0, 82.1,
79.7, 50.8, 46.9, 28.1, 26.7, 23.6 (4 quaternary carbons not
observed); MS (EI) m/e 416 (20, MH+), 415 (38, M+), 259 (26),
215 (20), 134 (22), 133 (100), 132 (35); HRMS (EI) m/e (M+)
calcd (for C23H33N3O4) 415.2471, found 415.2465.
N1-Allyl-N1,N2-bis(ter t-bu toxycar bon yl)-4-oxopiper idin e-
1-ca r boxa m id in e (5i). Obtained as a yellow oil in 91%
yield: Rf ) 0.10 (50% hexanes/50% EtOAc); IR (neat) ν 2977,
1719, 1597, 1453, 1367, 1284, 1248, 1146 cm-1; 1H NMR (400
MHz, CDCl3) δ 5.83 (1H, ddt, J ) 17.0, 10.0, 4.5 Hz), 5.20 (1H,
d, J ) 17.0 Hz), 5.13 (1H, d, J ) 10.0 Hz), 3.81-3.69 (4H, m),
2.49-2.43 (4H, m), 1.43 (9H, s), 1.41 (9H, s); 13C NMR (100
MHz, CDCl3) δ 206.2, 159.0, 153.2, 152.1, 132.2, 119.6, 82.0,
79.6, 50.3, 44.3, 40.2, 28.0, 27.9; MS (EI) m/e 381 (6, M+), 325
(17), 269 (37), 252 (50), 225 (72), 181 (20); HRMS (EI) m/e (M+)
calcd (for C19H31N3O5) 381.2264, found 381.2270.
N1,N3-Bisa llyl-N1,N2-bis(ter t-bu toxyca r bon yl)-N3-p h e-
n ylgu a n id in e (5j). Obtained as a clear oil in 91% yield: Rf
) 0.05 (90% hexanes/10% Et2O); IR (neat) ν 2978, 1719, 1617,
1584, 1496, 1367, 1252, 1223, 1150 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.30-7.17 (5H, m), 5.95 (1H, ddt, J ) 17.0, 10.5, 6.0
Hz), 5.52 (1H, ddt, J ) 17.0,10.0, 6.5 Hz), 5.13-5.07 (2H, m),
5.00-4.95 (2H, m), 4.35 (2H, bs), 3.67-3.60 (2H, m), 1.45 (9H,
s), 1.40 (9H, s); 13C NMR (100 MHz, CDCl3) δ 152.8, 152.4,
142.3, 133.4, 132.8, 128.9, 127.0, 126.6, 118.0, 117.4, 81.8, 79.7,
55.0, 51.0, 28.1; MS (EI) m/e 416 (5, MH+), 342 (1), 314 (12),
286 (37), 257 (61), 258 (63), 214 (42), 132 (40), 57 (100); HRMS
(EI) m/e (M+) calcd (for C23H33N3O4) 415.2471, found 415.2471.
NMR (75 MHz, CDCl3) δ 158.9, 153.2, 152.2, 81.0, 78.7, 49.3,
48.1, 47.5, 28.3, 28.1, 25.3, 24.9, 22.3, 11.4; MS (EI) m/e 355
(12, M+), 299 (10), 243 (15), 226 (19), 201 (22), 157 (19), 143
(31), 142 (50), 141 (46), 140 (40), 129 (36), 97 (27), 86 (43), 84
(84), 70 (95), 57 (100); HRMS (EI) m/e (M+) calcd (for
C
18H33N3O4) 355.2471, found 355.2474.
N1,N2-Bis(ter t-b u t oxyca r b on yl)-N1-(2-p r op yl)p yr r oli-
d in e-1-ca r boxa m id in e (5q). Obtained as a clear oil in 60%
yield: Rf ) 0.23 (50% hexanes/50% Et2O); IR (neat) ν 2974,
1712, 1588, 1455, 1264, 1146 cm-1; 1H NMR (400 MHz, CDCl3)
δ 4.00-3.96 (1H, m), 3.44 (4H, bs), 1.89 (4H, bs), 1.46 (9H, s),
1.44 (9H, s), 1.23 (6H, d, J ) 6.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 159.1, 152.1, 151.5, 80.6, 78.8, 49.3, 48.1, 48.0, 28.3,
28.2, 25.3, 25.0, 20.9; MS (EI) m/e 355 (M+, 19), 254 (20), 226
(27), 198 (44), 154 (42), 142 (32), 98 (38), 70 (75), 58 (59), 57
(100); HRMS (EI) m/e (M+) calcd (for C18H33N3O4) 355.2471,
found 355.2471.
N1-Ben zyl-N1,N2-bis(ter t-bu toxyca r bon yl)p yr r olid in e-
1-ca r boxa m id in e (5r ). Obtained as a yellow oil in 95%
yield: Rf ) 0.30 (50% hexanes/50% Et2O); IR (neat) ν 2975,
1718, 1596, 1454, 1366, 1274, 1165, 1136 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.37-7.27 (5H, m), 4.97 (1H, bs), 4.09 (1H, bs),
3.44 (2H, bs), 3.21 (1H, bs), 2.76 (1H,bs), 1.80-1.75 (4H, m),
1.48 (9H, s), 1.46 (9H, s); 13C NMR (100 MHz, CDCl3) δ 159.2,
153.1, 152.3, 136.8, 129.2, 128.4, 127.7, 81.4, 78.8, 50.8, 47.9,
47.4, 28.3, 28.2, 25.0, 24.7; MS (EI) m/e 403 (M+, 25), 347 (23),
291 (26), 274 (32), 247 (43), 230 (28), 202 (43), 156 (28), 143
(21), 106 (97), 97 (34), 91 (64), 70 (91), 57 (100); HRMS (EI)
m/e (M+) calcd (for C22H33N3O4) 403.2471, found 403.2462.
N1,N2-Bis(ter t-bu toxyca r bon yl)-N1-(p r op a r gyl)p yr r oli-
d in e-1-ca r boxa m id in e (5s). Obtained as a yellow oil in 92%
yield: Rf ) 0.23 (50% hexanes/50% Et2O); IR (neat) ν 3252,
2975, 1722, 1592, 1455, 1367, 1243, 1141 cm-1; 1H NMR (400
MHz, CDCl3) δ 4.47 (1H, bs), 3.83-3.45 (5H, m), 2.21 (1H, t,
J ) 2.5 Hz), 1.88 (4H, bs), 1.44 (18H, s); 13C NMR (100 MHz,
CDCl3) δ 159.1, 152.5, 151.6, 81.9, 78.8, 77.3, 72.1, 48.0, 47.8,
36.1, 28.2, 28.1, 24.5, 24.3; MS (EI) m/e 278 (17), 251 (19), 239
N1,N2-Bisa llyl-N1,N2-bis(ter t-bu toxyca r bon yl)-N3-p h e-
n ylgu a n id in e (5l). Obtained as a clear oil in 69% yield (based
on allyl bromide): Rf ) 0.23 (90% hexanes/10% Et2O); IR (neat)
ν 3081, 2979, 1728, 1640, 1596, 1478, 1451, 1368, 1227, 1146,
1
982, 924 cm-1; H NMR (300 MHz, CDCl3) δ 7.25 (2H, t, J )
8.0 Hz), 7.02 (1H, t, J ) 7.5 Hz), 6.84 (2H, d, J ) 7.5 Hz), 6.01
J . Org. Chem, Vol. 68, No. 6, 2003 2307

Powell et al.
(17), 222 (63), 196 (28), 195 (82), 194 (30), 178 (37), 151 (94),
150 (47), 123 (21), 97 (23), 70 (39), 57 (100); HRMS (EI) m/e
(MH+) calcd (for C18H30N3O4) 352.2236, found 352.2243.
EtOAc); IR (neat) ν 2977, 2930, 1702, 1597, 1496, 1450, 1367,
1295, 1227, 1147, 1012 cm-1 1H NMR (400 MHz, CDCl3) δ
;
7.90 (2H, d, J ) 7.5 Hz), 7.59 (1H, t, J ) 7.5 Hz), 7.47 (2H, t,
J ) 7.5 Hz), 7.28 (2H, t, J ) 8.0 Hz), 6.94 (2H, d, J ) 8.0 Hz),
6.90 (1H, t, J ) 7.5 Hz), 5.29-5.07 (1H, m), 4.40-4.06 (3H,
m), 3.78-3.42 (4H, m), 3.18-3.13 (2H, m), 1.54 (9H, s), 1.48-
1.45 (9H, m); 13C NMR (100 MHz, CDCl3) δ 193.9, 159.1, 154.8,
152.0, 150.8, 134.9, 133.7, 129.2, 128.8, 127.8, 120.4, 116.5,
82.6, 79.3, 53.9, 48.8, 46.3, 28.2; MS (EI) m/e 522 (7, M+), 403
(24), 247 (28), 234 (27), 162 (67), 161 (58), 146 (66), 145 (100),
132 (33), 105 (25), 91 (43), 57 (45); HRMS (EI) m/e (M+) calcd
(for C29H38N4O5) 522.2842, found 522.2856.
N1,N2-Bis(ter t-bu toxycar bon yl)-N1-(2-m eth ylbu t-2-en yl)-
p yr r olid in e-1-ca r boxa m id in e (5t). Obtained as a yellow oil
in 99% yield: Rf ) 0.13 (80% hexanes/20% EtOAc); IR (neat)
ν 2975, 2879, 1720, 1594, 1455, 1366, 1242, 1137 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 5.17 (1H, t, J ) 7.0 Hz), 4.18 (1H,
bs), 3.68 (1H, bs), 3.52-3.38 (4H, m), 1.84 (4H, bs), 1.65 (3H,
s), 1.61 (3H, s), 1.44 (9H, s), 1.42 (9H, s); 13C NMR (100 MHz,
CDCl3) δ 159.1, 153.2, 152.2, 136.4, 119.0, 80.9, 78.6, 47.8, 47.5,
44.6, 28.2, 28.0, 25.6, 25.2, 24.8, 17.6; MS (EI) m/e 382 (MH+,
17), 381 (M+, 12), 281 (34), 225 (100), 184 (47), 180 (43), 166
(29), 97 (41), 84 (50), 72 (54), 70 (51), 57 (92); HRMS (EI) m/e
(M+) calcd (for C20H35N3O4) 381.2628, found 381.2611.
N1-Allyl-N2-3,4-d ih yd r o-1H-isoqu in olin e-2-ca r boxa m i-
d in e Hyd r och lor id e (6g). Obtained as a white powder in
90% yield as the HCl salt: Rf ) 0.30 (90% CH2Cl2/10% MeOH);
mp 163-164 °C; IR (KBr) ν 3295, 3133, 2922, 1648, 1606, 1454
N1,N2-Bis(ter t-bu toxyca r bon yl)-N1-(2-cycloh ex-2-en yl)-
p yr r olid in e-1-ca r boxa m id in e (5u ). Obtained as a yellow oil
in 78% yield: Rf ) 0.21 (50% hexanes/50% Et2O); IR (neat) ν
2975, 1716, 1589, 1455, 1366, 1330, 1270, 1141 cm-1; 1H NMR
(400 MHz, CDCl3, rotamers) δ 5.76-5.72 (2H, m), 4.36 (1H,
bs), 3.52-3.44 (4H, m), 1.98-1.78 (9H, m), 1.63-1.60 (1H, m),
1.47 (9H, s), 1.46 (9H, s); 13C NMR (100 MHz, CDCl3, rotamers)
δ 159.2, 152.0, 129.2, 80.9, 78.6, 54.4, 48.1, 28.3, 28.2, 27.1,
25.3, 24.9, 24.5, 21.6 (2 carbons not observed); MS (EI) m/e
393 (9, M+), 293 (18), 237 (58), 193 (25), 184 (24), 158 (23),
151 (21), 96 (46), 72 (42), 70 (37), 57 (100), 55 (26); HRMS
(EI) m/e (M+) calcd (for C21H35N3O4) 393.2628, found 393.2635.
N1,N2-Bis(ter t-bu toxyca r bon yl)-N1-(3-p h en yla llyl)p yr -
r olid in e-1-ca r boxa m id in e (5v). Obtained as a yellow oil in
95% yield: Rf ) 0.18 (50% hexanes/50% Et2O); IR (neat) ν
2976, 2878, 1715, 1593, 1454, 1367, 1271, 1138 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.36-7.22 (5H, m), 6.56 (1H, d, J ) 16.0
Hz), 6.25 (1H, dt, J ) 16.0, 7.5 Hz), 4.44 (1H, bs), 3.82 (1H,
bs), 3.54-3.44 (4H, m), 1.86 (4H, bs), 1.50 (9H, s), 1.49 (9H,
s); 13C NMR (100 MHz, CDCl3) δ 159.2, 153.0, 152.1, 136.4,
133.8, 128.5, 127.7, 126.4, 124.0, 81.3, 78.8, 49.2, 48.0, 47.7,
28.2, 28.1, 25.2, 24.8; MS (EI) m/e 273 (73), 228 (19), 132 (31),
117 (49), 115 (22), 97 (29), 91 (21), 72 (22), 70 (31), 57 (100);
HRMS (EI) m/e (M+) calcd (for C24H35N3O4) 429.2628, found
429.2632. Anal. Calcd for C24H35N3O4: C, 67.11; H, 8.21; N,
9.78. Found: C, 67.00; H, 8.18; N, 9.71.
N1,N2-Bis(ter t-bu toxyca r bon yl)-N1-(2-oxo-2-p h en yleth -
yl)p yr r olid in e-1-ca r boxa m id in e (5w ). Obtained as a clear,
viscous oil in 82% yield: Rf ) 0.22 (80% hexanes:20% EtOAc);
IR (neat) ν 3267, 3211, 2978, 1788, 1729, 1701, 1511, 1366,
1250, 1208, 1138 cm-1 ; 1H NMR (400 MHz, CDCl3, rotamers)
δ 7.92-7.83 (2H, m), 7.61-7.39 (3H, m), 5.34-5.28 (1H, m),
4.40-4.34 (1H, m), 3.61-3.46 (4H, m), 2.05-1.81 (4H, bs),
1.55-1.38 (18H, m); 13C NMR (100 MHz, CDCl3, rotamers) δ
193.6, 192.9, 159.6, 159.3, 154.2, 152.3, 151.2, 150.1, 149.3,
135.0, 133.5, 128.7, 127.7, 85.1, 82.0, 78.7, 54.4, 53.6, 49.6, 48.5,
48.3, 28.3, 28.0, 25.2, 24.9; MS (EI) m/e 431 (5, M+), 358 (5),
331 (8), 302 (8), 274 (13), 258 (23), 231 (32), 214 (19), 206 (21);
HRMS (EI) m/e (M+) calcd (for C23H33N3O5) 431.2420, found
431.2427.
N1,N2-Bis(ter t-bu toxyca r bon yl)m or p h olin e-4-ca r boxa -
m id in e (5x). Obtained as a clear oil in 58% yield: Rf ) 0.38
(80% hexanes/20% EtOAc); IR (neat) ν 2976, 2926, 2858, 1720,
1598, 1455, 1367, 1285, 1253, 1146, 1025 cm-1; 1H NMR (400
MHz, CDCl3, rotamers) δ 5.82 (1H, ddt, J ) 17.0, 10.0, 4.5
Hz), 5.22 (1H, dd, J ) 17.0, 1.0 Hz), 5.16 (1H, dd, J ) 10.0,
0.5 Hz), 4.25-4.05 (1H, m), 3.70-3.48 (9H, m), 1.47 (9H, s),
1.46 (9H,s); 13C NMR (100 MHz, CDCl3, rotamers) δ 159.3,
153.7, 152.1, 132.2, 132.0, 119.7, 119.2, 81.8, 79.4, 66.3, 66.2,
50.2, 47.9, 46.0, 36.0, 28.2, 29.0; MS (EI) m/e 369 (5, M+), 313
(7), 269 (16), 257 (14), 240 (33), 213 (100), 196 (19), 169 (19),
113 (17), 86 (20), 57 (69); HRMS (EI) m/e (M+) calcd (for
C18H31N3O5) 369.2264, found 369.2269.
1
cm-1; H NMR (300 MHz, CD3OD) δ 7.23 (4H, m), 5.93 (1H,
ddt, J ) 17.0, 10.5, 5.0 Hz), 5.26 (2H, m), 4.86 (2H, s), 4.61
(2H, s), 3.97 (2H, m), 3.67 (2H, t, J ) 6.0 Hz), 3.00 (2H, t, J )
6.0 Hz); 13C NMR (100 MHz, CD3OD) δ 157.4, 136.0, 134.1,
133.0, 129.3, 128.7, 128.1, 127.5, 117.4, 48.6, 45.6, 45.4, 29.5;
MS (EI) m/e 216 (18, MH+), 215 (62, M+), 200 (18), 186 (8),
174 (11), 159 (7), 142 (5) 132 (100); HRMS (EI) m/e (M+, free
guanidine) calcd (for C13H17N3) 215.1422, found 215.1419.
N1-Allyl-N2-[(1S,2R)-2-h ydr oxy-1-m eth yl-2-ph en yleth yl]-
N2-m eth ylgu a n id in e Hyd r och lor id e (6k ). Obtained as a
yellow oil in 50% yield (two steps): IR (neat) ν 3332, 2401,
1
1708, 1590, 1455, 1423, 1045 cm-1; H NMR (300 MHz, CD3-
OD) δ 7.45-7.31 (5H, m), 5.80 (1H, ddt, J ) 17.0, 10.5, 5.0
Hz), 5.17 (1H, dd, J ) 10.5, 1.0 Hz), 5.09 (1H, d, J ) 17.0 Hz),
4.92 (4H, bs), 4.71 (1H, d, J ) 8.0 Hz), 4.18 (1H, dt, J ) 12.5,
6.5 Hz), 3.81-3.79 (2H, m), 2.61 (3H, s), 1.39 (3H, d, J ) 7.0
Hz); 13C NMR (75 MHz, CD3OD) δ 158.28, 141.95, 133.61,
129.32, 129.10, 127.67, 116.91, 76.87, 61.20, 45.41, 32.54,
15.16; MS (EI) m/e 229 (31), 175 (27), 146 (31), 132 (27), 118
(100), 117 (51), 91 (38), 58 (57), 57 (44); HRMS (EI) m/e (MH+,
free guanidine) calcd (for C14H22N3O) 248.1763, found 248.1768;
[R]20 ) -7.0 (c 0.08, MeOH).
D
N1,N2-Bis(3,7-d im et h yloct a -2,6-d ien yl)-N1,N2,N3-t r is-
(ter t-bu toxyca r bon yl)gu a n id in e (9). Obtained as a yellow
oil in 65% yield: Rf ) 0.54 (80% hexanes/20% EtOAc); IR (neat)
ν 2978, 2931, 1739, 1648, 1454, 1367, 1249, 1228, 1141 cm-1
;
1H NMR (300 MHz, CDCl3) δ 5.29 (2H, t, J ) 6.5 Hz), 5.07
(2H, t, J ) 6.5 Hz), 4.14 (4H, d, J ) 6.5 Hz), 2.05-1.98 (8H,
m), 1.67 (6H, s), 1.65 (6H, s), 1.59 (6H, s), 1.49 (9H, s), 1.46
(18H, s); 13C NMR (75 MHz, CDCl3) δ 157.9, 151.7, 149.0,
138.1, 131.2, 123.8, 119.5, 81.9, 80.7, 46.3, 39.7, 28.2, 26.7, 25.8,
17.8, 16.4; MS (EI) m/e 631 (5, M+), 562 (25), 350 (31), 306
(49), 214 (63), 57 (100); HRMS (EI) m/e (M+) calcd (for
C
36H61N3O6) 631.4560, found 631.4583.
N1,N2,N3-Tr is(ter t-bu toxylca r bon yl)-4,6-d ih yd r o-5-m e-
th ylen ep yr im id in e (10). To a biphasic solution of CH2Cl2/
H2O (1:1) (3 mL) were added 3-chloro-2-chloromethyl-1-
propene (45 µL, 0.39 mmol), KI (54 mg, 0.33 mmol), KOH (55
mg, 0.98 mmol), and Bu4NI (24 mg, 0.07 mmol). The mixture
was stirred vigorously at rt, and then a solution of the tri-
Boc-guanidine 8 (117 mg, 0.33 mmol) in CH2Cl2 (1 mL) was
added dropwise over a 1 h period. After 16 h, the mixture was
diluted with CH2Cl2 (10 mL) and H2O (10 mL). The layers were
separated, and the aqueous layer was extracted with CH2Cl2
(2 × 10 mL). The combined organic layers were dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography (80% hexanes/20% EtOAc
with 1% Et3N) gave the product as a white solid (89 mg,
67%): Rf ) 0.39 (70% hexanes/30% EtOAc); mp 109-110 °C;
IR (KBr) ν 2978, 2929, 1753, 1725, 1690, 1644, 1454, 1370,
1314, 1254, 1141 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.99 (2H,
s), 4.27 (4H, s), 1.49 (27H, s); 13C NMR (100 MHz, CDCl3) δ
158.1, 151.5, 148.0, 140.5, 108.6, 83.4, 79.8, 47.6, 28.2, 28.0;
MS (EI) m/e 412 (8, MH+), 360 (4), 312 (4), 260 (35), 204 (52),
148 (71), 130 (44), 104 (16), 57 (100); HRMS (EI) m/e (MH+)
calcd (for C20H34N3O6) 412.2448, found 412.2459.
N1,N2-Bis(ter t-bu toxyca r bon yl)-N1-(2-oxo-2-p h en yleth -
yl)p h en ylp ip er a zin e-1-ca r boxa m id in e (5y). Obtained as
an off-white foam in 64% yield: Rf ) 0.15 (80% hexanes/20%
2308 J . Org. Chem., Vol. 68, No. 6, 2003

Synthesis of Highly Functionalized Guanidines
N1-Ben zyl-N1,N2,N3-tr is(ter t-bu toxyca r bon yl)-N2-(3-m e-
th ylbu t-2-en e) (12). To a biphasic solution of CH2Cl2 (1.5 mL)
and H2O (1.5 mL) was added the tri-Boc-guanidine 8 (375 mg,
1.04 mmol) followed by KOH (58 mg, 1.04 mmol) and Bu4NI
(26 mg, 0.07 mmol). The mixture was stirred vigorously, and
then 4-bromo-2-methyl-2-butene (40 µL, 0.35 mmol) was
added. After 16 h, the mixture was diluted with CH2Cl2 (10
mL) and H2O (10 mL), and the layers were separated. The
aqueous layer was extracted with CH2Cl2 (2 × 20 mL), and
the combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The mixture was passed over a
small plug of silica gel (90% hexanes/10% EtOAc) to remove
the phase-transfer catalyst and excess tri-Boc-guanidine 8.
The tri-Boc-prenylguanidine 11 was stirred in a biphasic
mixture of CH2Cl2 (1.5 mL) and H2O (1.5 mL). To this mixture
were added KOH (53 mg, 0.95 mmol) and Bu4NI (23 mg, 0.06
mmol). Benzyl mesylate (88 mg, 0.47 mmol) was then added,
and the mixture was stirred vigorously at rt. After 16 h, the
mixture was diluted with CH2Cl2 (10 mL) and H2O (10 mL).
The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (2 × 10 mL). The combined organics
were dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification by flash chromatography (silica
gel, 90% hexanes/10% EtOAc with 1% Et3N) gave the product
(112 mg, 62% yield) as a clear oil: Rf ) 0.11 (90% hexanes/
10% EtOAc); IR (neat) ν 2978, 2936, 1736, 1722, 1644, 1454,
1387, 1370, 1250, 1222, 1138 cm-1; 1H NMR (400 MHz, CDCl3,
rotamers) δ 7.38-7.22 (5H, m), 5.23-5.18 (1H, m), 4.79 (2H,
s), 4.14 (0.5 H, d, J ) 6.5 Hz), 4.03 (1.5 H, d, J ) 6.5 Hz), 1.70
(0.7H, br s), 1.65 (2.3H, br s), 1.61 (1H, br s), 1.59 (2H, br s),
1.48 (9H, s), 1.47 (9H, s), 1.35 (9H, s); 13C NMR (100 MHz,
CD3CN, rotamers) δ 159.0, 153.1, 152.9, 150.5, 139.0, 136.9,
136.2, 129.3, 128,4, 128.1, 120.4, 83.8, 82.8, 81.7, 52.3, 47.0,
46.8, 28.5, 28.4, 28.2, 26.0, 18.2; MS (EI) m/e 518 (20, MH+),
517 (5, M+), 496 (9), 418 (12), 361 (12), 305 (28), 283 (10), 261
(35), 239 (15), 214 (20), 170 (16), 126 (16), 106 (20), 84 (49), 57
(100); HRMS (EI) m/e (M+) calcd (for C28H43N3O6) 517.3152,
found 517.3168.
Ack n ow led gm en t. The Natural Science and Engi-
neering Research Council (NSERC) of Canada, the
Ontario Research and Development Challenge Fund,
and AstraZeneca supported this work. D.A.P. thanks the
Ontario government for a graduate scholarship. P.D.R.
thanks the NSERC for a graduate scholarship. We
thank Dr. A. B. Young for mass spectrometric analysis.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O0265535
J . Org. Chem, Vol. 68, No. 6, 2003 2309