Synthetic routes to N-Pmc-N′,N″-disubstituted guanidines via EDCI-mediated guanylation of amines with N-Pmc-N′-substituted thioureas

Article abstract of DOI:10.1055/s-2007-983706

An overview of the facile and high-yielding EDCI-mediated reaction of amines with N-Pmc-N′-alkyl thioureas to afford guanidines is presented, in which the general scope and limitations of the reaction are probed. It was found that the N-sulfonyl-N′-substi

Full text of DOI:10.1055/s-2007-983706

1848
PAPER
Synthetic Routes to N-Pmc-N¢,N¢¢-Disubstituted Guanidines via EDCI-
Mediated Guanylation of Amines with N-Pmc-N¢-Substituted Thioureas
D
ual Synthetic
t
Route
e
s
to
N
-Pmc
v
-
N
¢
,
N
¢¢-Disub
e
stitute
d
G
u
n
a
nidines son Flemer, Jr., Jose S. Madalengoitia*
Cook Physical Sciences Building, Chemistry Department, University of Vermont, Burlington, VT 05405, USA
Fax +1(802)6568705; E-mail: jose.madalengoitia@uvm.edu
Received 2 November 2006; revised 15 February 2007
ide intermediate. However, as discovered by Atwal et al.
in 198918a and further developed by Hamilton and co-
workers in 1999,21 discrete substituted guanidine systems
were accessible through the gentle EDCI-mediated con-
Abstract: An overview of the facile and high-yielding EDCI-medi-
ated reaction of amines with N-Pmc-N¢-alkyl thioureas to afford
guanidines is presented, in which the general scope and limitations
of the reaction are probed. It was found that the N-sulfonyl-N¢-sub-
stituted thioureas cannot possess internal nucleophiles or disubstitu- densation of urethane-protected, substituted thioureas
tion, and that the incoming amine must possess adequate
with amines. It is noteworthy, however, that in this proto-
nucleophilicity in order for the reaction to be viable. However, it is
col the alkoxycarbonyl moiety was not readily deprotect-
noted that the guanidine products can be accessed through two pos-
ed by acidic conditions. Most recently, the research
sible synthetic approaches, and that a simple reversal of amine and
groups of Anslyn and Fan have utilized this approach to-
thiourea substituents allows the reaction to proceed successfully.
ward the solid-phase synthesis of guanidine oligo-
Key words: guanidine, guanylation, thiourea, EDCI, N-sulfonyl
mers,22,23 with the development of sulfonyl-based, acid-
labile guanidine protection protocol for these solid-phase
oligomeric systems allowing for concurrent deblocking
Guanidines represent an important class of compounds in
and cleavage at the end of the synthesis.
organic and bioorganic chemistry. The guanidine frame-
work has been used as an organic superbase,1 while oligo-
X
meric guanidines have seen frequent application as
R
R
NH2
NH2
R'
R''
+
+
effective germicides and pesticides.2 In enzymes, the
guanidine headgroup of arginine is responsible for a di-
verse array of processes including protein-enzyme ion-
pairing,3 NO synthesis,4 and insulin sensitivity.5 Further-
more, arginine-rich peptide sequences such as HIV-1
TAT and Penetratin are known for their cell membrane
translocating properties.6
N
H
N
R'
N
XS
XS
HN
R'' NH2
AgNO3
N
R
R''
R'
N
H
S
thiophile
R
NH2
R'
R''
+
Since alkyl-substituted guanidines are present in natural
products7 and arginine-containing peptide systems,8
methods for the synthesis of guanidines with multiple sub-
stitution patterns are desirable. A review of the literature
illustrates numerous examples of synthetic entries into
substituted guanidine systems. These transformations
generally involve a condensation reaction between an
amine and a guanylating agent (Scheme 1).9 Guanylation
of an amine involves either the direct displacement of a
leaving group from the central carbon atom of the guanyl
transfer agent by the amine,10–14 utilization of various
dithiocarboimidate derivatives with amine nucleo-
philes,15,16 or attack of the amine on what is generally ac-
cepted to be an in situ generated carbodiimide from a
thiourea.17–19 The latter methodology has become the
more accepted one, as it has been established that thio-
ureas bearing an electron-withdrawing group presumably
afford activated carbodiimides.20 Classically, heavy metal
thiophiles (i.e., Hg salts) have been necessary to effect
transformation of a thiourea into the putative carbodiim-
N
H
N
H
Scheme 1 Three general types of synthetic entry into substituted
guanidine systems
The present research explores the EDCI-mediated reac-
tion of N-Pmc-N¢-alkylthioureas (Pmc = 2,2,5,7,8-pen-
tamethylchroman-6-sulfonyl) with amines to afford N-
Pmc-protected guanidines that may then be cleanly and
conveniently deprotected with TFA. One of the compel-
ling attributes of this chemistry was the ability to access
the desired guanidines through two possible approaches
(Scheme 2). It quickly became evident during this inves-
tigation that, in many cases, while one approach failed to
furnish the desired guanidine, reversing the substitutions
on the thiourea and amine allowed facile access to the tar-
get guanidine. This dual approach illustrates very nicely
the flexible utility of this method.
For facile entry into this framework, we envisioned the
use of Pmc-isothiocyanate 1 as the key precursor
(Scheme 3). Reaction of isothiocyanate 1 with an array of
amine nucleophiles afforded N-Pmc-N¢-alkylthioureas 2
in excellent yields, comprising a wide range of N¢-substi-
SYNTHESIS 2007, No. 12, pp 1848–1860
x
x.
x
x
.
2
0
0
7
Advanced online publication: 08.06.2007
DOI: 10.1055/s-2007-983706; Art ID: M06706SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Dual Synthetic Routes to N-Pmc-N¢,N¢¢-Disubstituted Guanidines
1849
ylene)sulfonamide intermediate with phosgene.27 Al-
though the first method is more direct, we investigated the
second method instead due to the lower cost of
Bu4N+NCS–. Commercial PmcCl 5 was converted into
Pmc-sulfonamide 6 in quantitative yield by treatment with
NH3 in CH2Cl2. Reaction of Pmc-NH2 with CS2 and KOH
followed by phosgene (as described) afforded Pmc-
isothiocyanate 1 in 50% yield. Although this yield was
consistent with published yields,26 there was room for op-
timization of this transformation. We found that by using
benzene as a co-solvent to azeotropically remove water,
Pmc-isothiocyanate 1 could be obtained in 75% yield
(Scheme 4). In addition, it was found that triphosgene27
could be used instead of phosgene without compromising
the yield of Pmc-isothiocyanate 1. Reagent 1, once isolat-
ed, was stable for months at –20 °C with minimal degra-
dation observed. Prior to use, trituration of the compound
in hexanes followed by filtration of accumulated solid im-
purities yielded regenerated 1 following solvent removal.
S
Y
H2N
Pmc
X
N
H
N
H
X
HN
Pmc
Y
N
N
H
S
X
Pmc
Y
H2N
N
H
N
H
Scheme 2 Dual synthetic approach into each guanidine system is
made possible by reversing the substitution patterns on the thiourea
and amine partners
tution. Treatment of these electron-deficient thioureas
with EDCI·HCl (to generate a highly-activated carbodi-
imide intermediate) in the presence of a primary (or sec-
ondary) amine smoothly and cleanly afforded an array of
Pmc-protected guanidines 3. Finally, treatment of com-
pounds 3 with TFA promoted the Pmc-deprotection to
yield the substituted guanidine compounds 4 as their cor-
responding TFA salts.
With Pmc-isothiocyanate 1 in hand, we began the prepa-
ration of a number of N-Pmc-thioureas. As summarized in
Table 1, isothiocyanate 1 was allowed to react with a
number of different primary amines and anilines to yield
a variety of structurally diverse thioureas 2a–r in excel-
lent yields.
The synthesis of sulfonyl isothiocyanates has been ac-
complished through either reaction of sulfonyl chlorides
with NCS(–)24a,25 or through the reaction of a (dithiometh-
S
O
O
R
NH2
R
O
S
NCS
O
S
N
N
CH2Cl2, r.t., 30 min
H
H
O
O
2
1
R' NH
2, EDCI⋅HCl
CH2Cl2, r.t., 30 min
R'
R'
HN
O
HN
TFA, H2O
3 h
R
R
O
S
N
N
H2N
N
H
–
H
+
TFA
O
4
3
Scheme 3
O
S
NH3
O
S
O
Cl
O
NH2
CH2Cl2, 0 °C, 30 min
100%
O
O
5
6
1) CS2, KOH, benzene
∆, D.S. trap, 12 h
2) COCl2, toluene
0 °C, 6 h
O
75%
O
S
NCS
O
1
Scheme 4
Synthesis 2007, No. 12, 1848–1860 © Thieme Stuttgart · New York

1850
S. Flemer Jr., J. S. Madalengoitia
PAPER
Table 1 Substitution Patterns for N-Pmc-thioureas 2a
R1
R2
S
O
O
S
HN
R1
1.1 equiv
O
S
N
C
S
O
N
N
H
R2
O
O
CH2Cl2, r.t., 30 min
1
2a–r
Entry
R1
Yield (%)
Entry
R1
Yield (%)
83
H
N
N
O
2a
2b
2c
~100
99
2j
N
O
2k
2l
81
44
(CH2)2
94
2d
2e
42
2m
2n
81
81
O
OMe
Cl
78
88
Cl
NO2
90b
99
OH
2f
2g
2h
2o
2p
2q
82
58
87
N
NH2
CO2Bn
2i
~100
2r
ndc
a R2 = H in all cases except thiourea 2l, in which R1 and R2 comprise a pyrrolidine carbocycle.
b The yield for thiourea 2o includes traces of its dissociated components.
c Not determined.
The reaction of most amines proceeded to completion The general methodology for the synthesis of guanidines
with Pmc-isothiocyanate within 15 minutes with the ex- 3 involved stirring the thiourea, the reacting amine, and
ception of 2-(4-methylpyrimidyl)amine and 2,6-dichloro- one equivalent Hünig’s base in CH2Cl2 while adding 2
aniline, which required 24 hours reaction time. equivalents of EDCI·HCl in one portion to the reaction
Disubstituted thiourea 2l, in addition to requiring extend- mixture (Scheme 3). TLC analysis of the resulting solu-
ed reaction time, was obtained in low yield and exhibited tion generally showed the reaction to be complete within
a tendency to decompose within a few hours of chromato- a few minutes. Analytical samples for compound charac-
graphic purification. Subsequently, guanylation reactions terization were typically purified chromatographically
requiring this thiourea were carried out immediately fol- over silica gel.
lowing its synthesis and purification. p-Nitrophenyl deriv-
ative 2o proved to be an exceptionally difficult compound
to work with, as it was always contaminated with p-nitroa-
Table 2 illustrates the detailed preparation of the series of
guanidines, demonstrating the utility of having dual syn-
thetic approaches toward each target molecule. Interest-
niline. This contaminant persisted regardless of how care-
ingly, for the majority of guanidines, one approach was
fully the compound was chromatographically purified. It
favored over the other. As expected, certain of the
is hypothesized that, once dissolved in solution, 2o is in
guanidines could be synthesized via either route (3g and
equilibrium with the Pmc-isothiocyanate 1 and p-nitro-
3h). However, the more interesting results arose when
aniline (Scheme 9, vide infra).
only one approach was successful.
Synthesis 2007, No. 12, 1848–1860 © Thieme Stuttgart · New York

PAPER
Dual Synthetic Routes to N-Pmc-N¢,N¢¢-Disubstituted Guanidines
1851
Table 2 Synthetic Routes to Substituted Guanidines 3a–h, Illustrating Dual Potential for Entry into Each System
R2
S
N
EDCI⋅HCl (2 equiv)
Pmc
R1
H2N R2
Pmc
R1
N
H
N
N
H
N
H
CH2Cl2, r.t., 30 min
(1.1 equiv)
H
2a–r
3a–h
Yield
(%)
Thiourea R1
Amine R2
Guanidine product
N
N
Pmc
2a
82
N
N
N
N
H
N
N
N
H
2b
2c
2d
0
74
0
3a
Pmc
N
O
O
N
N
H
H
O
3b
Cl
OH
2e
2f
67
0
Cl
Pmc
N
Cl
OH
N
H
N
H
Cl
Cl
Cl
OH
3c
Cl
Cl
Pmc
N
2g
91
N
N
H
H
N
2h
2i
0
N
3d
Pmc
H
98
N
N
Boc
H
N
N
N
Boc
H
H
H
2j
0
N
Boc
3e
Pmc
N
(CH2)2
2k
2l
100
0
N
N
H
(CH2)2
3f
MeO
Pmc
2m
2p
99
88
N
N
H
N
MeO
H
OMe
3g
Synthesis 2007, No. 12, 1848–1860 © Thieme Stuttgart · New York

1852
S. Flemer Jr., J. S. Madalengoitia
PAPER
Table 2 Synthetic Routes to Substituted Guanidines 3a–h, Illustrating Dual Potential for Entry into Each System (continued)
R2
S
N
EDCI⋅HCl (2 equiv)
Pmc
R1
H2N R2
Pmc
R1
N
H
N
N
H
N
H
CH2Cl2, r.t., 30 min
(1.1 equiv)
H
2a–r
3a–h
Yield
(%)
Thiourea R1
Amine R2
Guanidine product
MeO
Pmc
Pmc
N
N
2m
2q
91
70
HN
N
H
N
H
NH
OMe
MeO
MeO
3h
S
The synthesis of guanidine 3a was only viable through the
reaction of cyclopropylamine on 3-methylpyrimidyl-de-
rived transfer agent 2a, as the opposite approach afforded
an intractable mixture. The inability to form guanidines 3c
and 3d via the routes in which the substituents on the
transfer agents were 2-hydroxyethyl- and 2-methylpy-
ridyl, respectively, was a unique occurrence. Both thio-
ureas possess an internal nucleophile (the hydroxyl on 3c
and the pyridyl nitrogen on 3d), that cyclized intramolec-
ularly on the EDCI-generated carbodiimide, even in the
presence of a reacting amine. In both cases, reversing the
substitution patterns on the thiourea and the amine afford-
ed the desired guanidines in good yield. Products from the
intramolecular cyclization of thioureas 2f and 2h (7 and 8,
respectively) were easily isolated and characterized
(Scheme 5). The product 8 was found to quickly change
color in solution to deep blue. Interestingly, although
highly colored within a few minutes of being dissolved in
a solvent, its 1H NMR spectrum did not show the buildup
of significant amounts of any degradation product, or give
any indication of chemical change of the dissolved sam-
ple.
N
EDCI⋅HCl, DIPEA
Pmc
OH
Pmc
N
H
N
H
O
N
H
CH2Cl2
7
2f
S
EDCI⋅HCl, DIPEA
N
Pmc
N
H
N
H
Pmc
N
CH2Cl2
N
H
N
2h
8
Scheme 5 Self-condensation reactions of thioureas 2f and 2h
3e. It thus appears that tert-butyl carbazate is a sufficiently
good leaving group to be displaced by benzylamine.
While N-Pmc-N¢,N¢-disubstituted thioureas (e.g., reaction
of thiourea 2l with s-butylamine) failed to afford
guanidines under our reaction conditions, the target
guanidines can still be accessed. For example, N-Pmc-N¢-
s-butylthiourea cleanly reacts with pyrrolidine affording
guanidine 3f in quantitative yield. This particular limita-
tion was previously noted by Hamilton in his urethane-
protected guanidine study.21
Some interesting results were observed during attempts at
the synthesis of guanidine 3e. The reaction pathway in-
volving N-Pmc-N¢-benzylthiourea 2i and tert-butyl carba-
zate smoothly afforded the desired product in 98% yield.
However, the reaction of benzylamine with N-Pmc-N¢-
NHCO2t-Bu thiourea 2j gave the dibenzyl guanidine 9 in
24% yield (Scheme 6) instead of the expected guanidine
As shown in Scheme 7, the synthesis of cyclic guanidine
10 was achieved through a one-pot procedure. Under con-
ditions of high dilution, an excess of lysine benzyl ester
was treated sequentially with Pmc-isothiocyanate 1 fol-
S
EDCI⋅HCl, DIPEA, CH2Cl2
H2N
H
Pmc
N
O
N
N
HN
H
H
O
Pmc
N
N
2j
H
9
Scheme 6 Unexpected product from the reaction of thiourea 2j with benzylamine under EDCI-mediated guanylation conditions
Synthesis 2007, No. 12, 1848–1860 © Thieme Stuttgart · New York

PAPER
Dual Synthetic Routes to N-Pmc-N¢,N¢¢-Disubstituted Guanidines
1853
Pmc
NO2
N
S
H2N
NO2
S
H2N
CO2Bn
1) Pmc-NCS
2) EDCI⋅HCl, DIPEA
HN
NH
Pmc
N
N
H
H
CO2Bn
CH2Cl2 (high dilution)
65%
Pmc
N C
2o
NH2
1
10
Scheme 7 One-pot, sequential formation of cyclic guanidine 10, de-
rived from lysine benzyl ester
NH2
Pmc
N
NH2
S
lowed by EDCI·HCl to give 10 in 65% yield. The synthe-
sis of this compound is significant in that it can offer a
non-iterative, general approach toward the conversion of
alkyldiamines into cyclic guanidines.
Pmc
N
N
N
N
H
H
H
H
EDCI⋅HCl
12
2n
Scheme 9 Putative mechanism of 2o disproportionation in the
presence of isopropylamine and EDCI·HCl
Interestingly, the reaction of N-Pmc-N¢-p-nitrophenyl-
thiourea 2o with isopropylamine afforded none of the
expected guanidine, but rather a mixture of bis(p-nitro-
phenyl)guanidine 11 and diisopropyl guanidine 12 in 35%
and 22% yield, respectively (Scheme 8). The formation of
these bis-substituted compounds supports the hypothesis
that N-Pmc-N¢-p-nitrophenylthiourea 2o is in equilibrium
with Pmc-isothiocyanate 1 and nitroaniline (Scheme 9).
Isopropylamine attacks isothiocyanate 1 irreversibly, and
the thiourea intermediate 2n can subsequently react with
another equivalent of isopropylamine to yield diisopropy-
lguanidine 12. Disubstituted guanidine 11 is probably de-
rived from a similar disproportionation of released p-
nitroaniline with 2o.
agents to a solution of Pmc-isothiocyanate 1 in CH2Cl2.
Since these two compounds could only be formed through
one of their two possible synthetic pathways, synthesis of
3d involved the addition of one equivalent of n-butyl-
amine followed (shortly after) by the sequential addition
of two equivalents of EDCI·HCl and one equivalent of 2-
(aminomethyl)pyridine. Similarly, the synthesis of 3f in-
volved the addition of one equivalent of sec-butylamine
followed (shortly after) by two equivalents of EDCI·HCl
and one equivalent of pyrrolidine. Aqueous workup and
purification over silica gel yielded 3d and 3f in 55% and
87%, respectively.
Direct synthesis of bis(p-nitrophenyl) guanidine 11 was
achieved in a one-pot fashion by the addition of two
equivalents of p-nitroaniline to a solution of Pmc-isothio-
cyanate 1, followed by direct addition of EDCI·HCl and
Hünig’s base (Scheme 10). Chromatographic purification
of the reaction product proved tedious, as unreacted p-ni-
troaniline co-eluted with the desired guanidine. Purifica-
tion of 11 was achieved through the treatment of the crude
reaction mixture with tert-butyl nitrite in DMF28 in order
to selectively convert the free nitroaniline to nitrobenzene
via its diazonium salt (Scheme 11).
An advantage of this guanylation methodology is its ame-
nability toward removal of the sulfonyl blocking group.
Table 3 illustrates the ease with which most of the Pmc-
guanidines 3 underwent deprotection, using TFA–H2O
(98:2) for six hours. After removal of excess TFA fol-
lowed by trituration of the crude deprotection product
with cold diethyl ether, the majority of the isolates were
pure enough for immediate spectrographic characteriza-
tion as their TFA salts. Occasionally, the crude isolate
proved somewhat more impure, and chromatographic pu-
rification over silica gel was necessary using the unusual
solvent system formic acid–MeOH–EtOAc (1:2:7) to af-
ford guanidines 4 as their corresponding formate salts.
We have explored the amenability of this two-step guany-
lation chemistry toward a general one-pot process. As
shown in Scheme 12, two of the Pmc-guanidine structures
3d and 3f were constructed via sequential addition of re-
Pmc
O2N
NO2
N
N
H
N
H
NO2
NH2
S
11
Pmc
N
N
H
H
EDCI⋅HCl, DIPEA
Pmc
CH2Cl2
N
20
N
H
N
H
12
Scheme 8 Guanylation product profile from the disproportionation of thiourea 2o with isopropylamine
Synthesis 2007, No. 12, 1848–1860 © Thieme Stuttgart · New York

1854
S. Flemer Jr., J. S. Madalengoitia
PAPER
Pmc
O2N
NO2
1) 2 equiv p-nitroaniline
2) EDCI⋅HCl, DIPEA
N
Pmc
N
C S
1
N
N
H
CH2Cl2
H
11
Scheme 10 Direct synthesis of guanidine 11
O2N
NH2
O2N
nitrobenzene
p-nitroaniline
tert-butyl nitrite
DMF, 65 °C
Pmc
Pmc
O2N
NO2
O2N
NO2
N
N
N
N
N
N
H
H
H
H
11
11
Scheme 11 Separation of residual p-nitroaniline from guanidine 11 via selective reduction of p-nitroaniline impurity using tert-butyl nitrite
Pmc
N C S
Table 3 TFA Deprotection of N-Pmc-Protected Guanidines
–TFA
+
NH
Pmc
N
sec-butyl
amine
n-butyl
amine
TFA–H2O (98:2)
r.t., 6 h
R1
R2
R1
R2
N
N
N
N
H
H
H
H
4a–i,k
3a–i,k
S
S
Pmc-protected
guanidine
Pmc-deprotected guanidine
Pmc
N
Pmc
N
N
N
H
H
H
H
4a: 96%
3a
3b
3d
3e
3f
R1 = 3-methylpyrimidyl
R2 = cyclopropyl
2-aminomethyl-
pyridine
(1.1 equiv)
EDCI⋅HCl
pyrrolidine
(1.1 equiv)
EDCI⋅HCl
(2.0 equiv)
4b: 86%
(2.0 equiv)
R1 = cyclohexyl
R2 = benzyloxy
4d: 84%
R1 = n-Bu
Pmc
Pmc
N
N
R2 = 2-methylpyridyl
N
N
N
H
N
4e: 83%
R1 = Bn
H
H
N
3f
3d
R2 = NH2-
Scheme 12 One-pot synthesis of representative N-Pmc-guanidines
3d and 3f
4f: ~100%
R1 = 1-methylpropyl
R2 = pyrrolidyl
In conclusion, we have investigated the scope and limita-
tions of the guanidine-forming reaction sequence between
N-sulfonyl-N¢-substituted thioureas and amines under
EDCI-mediated conditions. The general reaction is shown
to easily tolerate a diversity of substitution patterns on the
thiourea and amine fragments, affording products in gen-
erally high yield and purity. The four types of limitations
encountered in this study were as follows:
4g: ~100%
R1 = 2-methoxyphenyl
R2 = allyl
3g
3h
4h: 89%
R1 = 2-methoxyphenyl
R2 = bis(4-methylenephenyl)
4i: ~100%
3i (= 10)
1. The substituent on the N-Pmc-thiourea cannot possess
an internal nucleophilic center.
2. The N-Pmc-thiourea can only tolerate monosubstitution
R1,R2 = lysyl benzyl ester
4k: 71%
3k
R1 = R2 = p-nitrophenyl
patterns.
3. The amine component of the reaction must possess suf-
ficient nucleophilicity to attack the in situ derived carbo-
Synthesis 2007, No. 12, 1848–1860 © Thieme Stuttgart · New York

PAPER
Dual Synthetic Routes to N-Pmc-N¢,N¢¢-Disubstituted Guanidines
1855
IR (film): 1898 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.67 (t, J = 6.8 Hz, 2 H), 2.59 (s,
3 H), 2.57 (s, 3 H), 2.14 (s, 3 H), 1.85 (t, J = 6.8 Hz, 2 H), 1.34 (s, 6
diimide. Amines and anilines bearing an electron-
withdrawing substituent can be problematic in the forma-
tion of both the thiourea and the guanidine component.
H).
Finally, due to the ability of accessing these guanidine
systems through two possible synthetic routes (i.e., the
‘pairs approach’), all of the systems prohibited by these
limitations using one approach could be realized by
switching the substitution patterns on the thiourea and the
amine.
13C NMR (125 MHz, CDCl3): d = 156.3, 154.9, 137.31, 137.27,
129.4, 125.2, 118.8, 74.8, 32.5, 26.8, 21.4, 18.4, 17.4, 12.2.
MS (CI): m/z = 205, 267, 326 (M + H).
Anal. Calcd for C15H19NO3S2: C, 55.36; H, 5.88; N, 4.30. Found: C,
55.30; H, 6.01; N, 4.12.
N-Pmc-N¢-Substituted Thioureas 2a–r; General Procedure
To a 0 °C solution of Pmc-thiocyanate 1 (0.5 g, 1.5 mmol) in
CH2Cl2 (15 mL) was added dropwise the respective primary amine
(1.05 equiv) dissolved in CH2Cl2 (10 mL). After 30 min, the solvent
was removed in vacuo to yield crude product, which was purified
by flash chromatography on silica gel using 20% EtOAc–hexanes
as eluent, except for N¢-4-methyl-2-pyrimidyl-derived thiourea
which was purified by way of trituration with CH2Cl2–hexanes (1:1)
and filtration.
Unless otherwise specified, all reagents were purchased from com-
mercial sources and were used without further purification. CH2Cl2
was distilled from CaH2. All reactions were carried out under N2 at-
mosphere. Flash chromatography was carried out on Sorbent Tech-
nologies silica gel (230–400 mesh). Melting points were recorded
on a Thomas Hoover capillary melting point apparatus and are un-
corrected. IR spectra were obtained using a PerkinElmer 2000 FT-
IR spectrometer. 500 MHz and 125 MHz 1D NMR spectra were
collected using standard pulse sequences provided by Bruker. Low-
resolution mass spectrometric data were obtained using a Finnigan
EI-CI mass spectrometer. High-resolution mass spectra were ac-
quired from the Mass Spectrometry Resource of Washington Uni-
versity. Elemental analyses were performed by Atlantic Microlab,
Inc., Norcross, GA.
N-Pmc-N¢-2-(4-methylpyrimidyl)thiourea (2a)
Yield: 0.67 g (~100%); amorphous colorless solid; mp 160–162 °C
(dec.).
IR (KBr): 3415, 1153 cm–1.
1H NMR (500 MHz, CDCl3): d = 14.27 (br s, 1 H), 8.73 (br s, 1 H),
6.94 (d, J = 5.2 Hz, 1 H), 2.61–2.70 (m, 8 H), 2.57 (s, 3 H), 2.14 (s,
3 H), 1.84 (t, J = 6.7 Hz, 2 H), 1.34 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 177.4, 156.7, 155.7, 138.0, 137.5,
127.0, 124.6, 118.2, 115.7, 74.1, 32.6, 26.7, 23.9, 21.5, 17.9, 17.1,
12.3.
2,2,5,7,8-Pentamethylchroman-6-sulfonamide (6)
2,2,5,7,8-Pentamethylchroman-6-sulfonyl chloride (5; 5.0 g, 0.017
mL) was dissolved in CH2Cl2 (75 mL). The resulting solution was
brought to 0 °C in an ice bath, and gaseous ammonia was bubbled
through it for 20 min. At the end of this time, it was noted that a
white solid had precipitated out of the solution. This slurry was
poured into a 500 mL separatory funnel containing EtOAc (150
mL) and H2O (150 mL). After repeated shaking, the organic layer
was separated, dried (MgSO4) and concentrated to give the sulfon-
amide as a colorless solid (4.67 g, ~100%); mp 157–159 °C.
MS (CI): m/z = 204, 267, 435 (M + H).
Anal. Calcd for C20H26N4O3S2: C, 55.28; H, 6.03; N, 12.89. Found:
C, 55.29; H, 6.03; N, 12.71.
IR (film): 3287 cm–1 (NH).
N-Pmc-N¢-cyclopropylthiourea (2b)
Yield: 0.58 g (99%); colorless friable foam; mp 142–143 °C.
1H NMR (500 MHz, acetone-d6): d = 6.20 (br s, 2 H), 2.68 (t, J = 6.2
Hz, 2 H), 2.54 (s, 3 H), 2.52 (s, 3 H), 2.11 (s, 3 H), 1.84 (t, J = 6.5
Hz, 2 H), 1.31 (s, 6 H).
13C NMR (125 MHz, acetone-d6): d = 154.4, 135.9, 135.6, 134.3,
124.4, 119.0, 74.5, 33.2, 26.8, 21.8, 18.6, 17.5, 12.1.
IR (film): 3333, 1138 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.40 (br s, 1 H), 7.79 (br s, 1 H),
2.90–2.93 (m, 1 H), 2.65 (t, J = 6.8 Hz, 2 H), 2.56 (s, 3 H), 2.55 (s,
3 H), 2.13 (s, 3 H), 1.84 (t, J = 6.8 Hz, 2 H), 1.33 (s, 6 H), 0.75–0.78
(m, 2 H), 0.30 (s, 2 H).
13C NMR (125 MHz, CDCl3): d = 179.9, 155.7, 136.9, 136.8, 127.3,
125.3, 118.9, 74.5, 32.4, 27.7, 26.6, 21.3, 18.2, 17.2, 12.1, 7.2.
MS (CI): m/z = 284 (M + H).
Anal. Calcd for C14H21NO3S: C, 59.34; H, 7.47; N, 4.94. Found: C,
59.40; H, 7.66; N, 5.00.
MS (CI): m/z = 204, 267, 383 (M + H).
2,2,5,7,8-Pentamethylchroman-6-sulfonyl Thiocyanate (1)
2,2,5,7,8-Pentamethylchroman-6-sulfonamide (6; 4.67 g, 0.017
mol) and KOH (2.00 g, 0.036 mol) were refluxed for 24 h in a 4:1
mixture of benzene–CS2 (100 mL) under Dean–Stark conditions. At
the end of this time, most of the residual solvent had been distilled
away and to the mixture was added additional benzene (75 mL) and
redistilled again until the solvent was reduced to about 0.75 of its
original volume. This was repeated one more time with additional
benzene (75 mL) in order to remove any residual CS2. The resulting
yellow slurry was cooled to 0 °C in an ice bath and phosgene (20%
in toluene; 15 mL, 2 equiv) was added dropwise over 30 min with
vigorous stirring. The mixture was allowed to reach r.t. overnight,
at which time N2 was bubbled through it for 20 min in order to re-
move the remaining phosgene. The solvent was removed in vacuo
and the residue was taken up and triturated in hexane (100 mL). Fil-
tration of the solids and concentration in vacuo afforded 1 as a light
yellow gum, which was used without further purification (4.15 g,
75%).
Anal. Calcd for C18H26N2O3S2: C, 56.51; H, 6.85; N, 7.32. Found:
C, 56.78; H, 6.92; N, 7.29.
N-Pmc-N¢-cyclohexylthiourea (2c)
Yield: 0.61 g (94%); colorless friable foam; mp 72–76 °C.
IR (film): 3335, 3335, 1123 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.06 (br s, 1 H), 7.67 (d, J = 7.3
Hz, 1 H), 3.97–4.07 (m, 1 H), 2.65 (t, J = 6.8 Hz, 2 H), 2.59 (s, 3 H),
2.57 (s, 3 H), 2.12 (s, 3 H), 1.83 (t, J = 6.8 Hz, 2 H), 1.76–1.79 (m,
2 H), 1.54–1.56 (m, 3 H), 1.29–1.32 (m, 8 H), 1.17–1.23 (m, 1 H),
1.05–1.12 (m, 2 H).
13C NMR (125 MHz, CDCl3): d = 176.6, 155.7, 136.9, 136.8, 127.4,
125.3, 118.9, 74.5, 54.0, 32.4, 31.4, 26.6, 25.3, 24.1, 21.3, 18.3,
17.3, 12.1.
MS (CI): m/z = 205, 425 (M + H).
Synthesis 2007, No. 12, 1848–1860 © Thieme Stuttgart · New York

1856
S. Flemer Jr., J. S. Madalengoitia
PAPER
Anal. Calcd for C21H32N2O3S2: C, 59.40; H, 7.60; N, 6.60. Found:
C, 59.50; H, 7.73; N, 6.46.
1H NMR (500 MHz, CDCl3): d = 9.01 (br s, 1 H), 8.52 (d, J = 3.7
Hz, 1 H), 7.59 (t, J = 7.3 Hz, 1 H), 7.19 (t, J = 6.1 Hz, 1 H), 7.02 (d,
J = 7.6 Hz, 1 H), 4.77 (d, J = 3.6 Hz, 2 H), 2.52–2.75 (m, 8 H), 2.08
(s, 3 H), 1.78 (t, J = 6.5 Hz, 2 H), 1.28 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 177.7, 155.5, 154.3, 148.7, 136.9,
136.6, 127.5, 125.0, 122.4, 121.3, 118.7, 74.3, 50.3, 32.4, 26.6,
21.2, 18.1, 17.2, 12.1.
N-Pmc-N¢-benzyloxythiourea (2d)
Yield: 0.29 g (42%); amorphous colorless solid; mp 128–129 °C.
IR (film): 3228, 1150 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.72 (br s, 1 H), 7.29–7.48 (m, 5
H), 4.88 (s, 2 H), 2.64 (t, J = 6.1 Hz, 2 H), 2.53 (s, 3 H), 2.52 (s, 3
H), 2.11 (s, 3 H), 1.81 (t, J = 6.4 Hz, 2 H), 1.31 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 155.9, 137.3, 133.8, 129.3, 129.0,
127.0, 124.9, 118.5, 78.9, 74.3, 32.6, 26.7, 21.5, 18.1, 17.2, 12.3.
MS (APCI): m/z = 434 (M + H).
Anal. Calcd for C21H27N3O3S2: C, 58.17; H, 6.28; N, 9.69. Found:
C, 58.45; H, 6.38; N, 9.50.
N-Pmc-N¢-benzylthiourea (2i)
Yield: 0.65 g (~100%); colorless friable foam; mp 60–66 °C.
IR (film): 3336, 1123 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.31 (br s, 1 H), 7.96 (br s, 1 H),
7.21–7.27 (m, 3 H), 6.94–6.96 (m, 2 H), 4.67 (d, J = 5.3 Hz, 2 H),
2.61 (t, J = 6.8 Hz, 2 H), 2.49 (s, 3 H), 2.48 (s, 3 H), 2.10 (s, 3 H),
1.84 (t, J = 6.8 Hz, 2 H), 1.35 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 178.2, 155.8, 136.9, 136.7, 135.9,
128.7, 127.8, 127.4, 125.5, 119.0, 74.6, 49.8, 32.5, 26.7, 21.3, 18.2,
17.2, 12.2.
MS (MALDI): m/z = 449 (M + H).
HRMS: m/z calcd for C22H29N2O4S2: 449.1570; found: 449.1565
(M + H).
N-Pmc-N¢-(2,6-dichlorophenyl)thiourea (2e)
Yield: 0.58 g (78%); colorless friable foam; mp 75–78 °C.
IR (film): 3291, 1521 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.02 (br s, 1 H), 8.98 (br s, 1 H),
7.28 (d, J = 8.0 Hz, 2 H), 7.17 (t, J = 7.9 Hz, 1 H), 2.55–2.76 (m, 8
H), 2.12 (s, 3 H), 1.82 (t, J = 6.3 Hz, 2 H), 1.32 (s, 6 H).
MS (CI): m/z = 205, 267, 433 (M + H).
13C NMR (125 MHz, CDCl3): d = 178.6, 155.8, 136.9, 134.6, 132.9,
129.6, 128.3, 127.6, 125.3, 118.9, 74.5, 32.4, 26.6, 21.2, 18.4, 17.4,
12.0.
Anal. Calcd for C22H28N2O3S2: C, 61.08; H, 6.52; N, 6.48. Found:
C, 61.38; H, 6.64; N, 6.37.
MS (MALDI): m/z = 488 (M + H).
N-Pmc-N¢-(tert-butoxycarbonyl)aminothiourea (2j)
Anal. Calcd for C21H24Cl2N2O3S2: C, 51.74; H, 4.96; N, 5.75.
Found: C, 51.69; H, 5.00; N, 5.66.
Yield: 0.57 g (83%); colorless friable foam; mp 84–87 °C.
IR (film): 3228, 1150 cm–1.
N-Pmc-N¢-(2-hydroxyethyl)thiourea (2f)
1H NMR (500 MHz, CDCl3): d = 9.06 (br s, 1 H), 7.15 (br s, 1 H),
2.65 (t, J = 6.3 Hz, 2 H), 2.58 (s, 3 H), 2.57 (s, 3 H), 2.12 (s, 3 H),
1.82 (t, J = 6.5 Hz, 2 H), 1.44 (s, 9 H), 1.32 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 155.9, 153.9, 137.4, 137.1, 127.1,
125.2, 118.8, 82.6, 74.5, 32.4, 28.0, 26.7, 21.3, 18.1, 17.3, 12.1.
Yield: 0.52 g (88%); colorless gum.
IR (film): 3331, 1547 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.98 (br s, 1 H), 8.16 (br s, 1 H),
3.64 (s, 4 H), 2.65 (t, J = 6.1 Hz, 2 H), 2.58 (s, 3 H), 2.56 (s, 3 H),
2.12 (s, 3 H), 1.82 (t, J = 6.5 Hz, 2 H), 1.32 (s, 6 H).
MS (MALDI): m/z = 400 (M – t-Bu).
13C NMR (125 MHz, CDCl3): d = 178.5, 155.6, 137.0, 136.9, 127.1,
125.0, 118.8, 74.4, 60.3, 60.1, 47.6, 32.2, 26.5, 21.2, 18.0, 17.1,
14.0, 12.0.
Anal. Calcd for C20H31N3O5S2: 52.49; H, 6.83; N, 9.18. Found: C,
52.72; H, 6.95; N, 9.15.
N-Pmc-N¢-(1-methylpropyl)thiourea (2k)
MS (MALDI): m/z = 388 (M + H).
Yield: 0.50 g (81%); light yellow transparent gum.
Anal. Calcd for C17H26N2O4S2: C, 52.82; H, 6.78; N, 7.25. Found:
C, 52.97; H, 6.95; N, 7.22.
IR (film): 3332, 1542 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.31 (br s, 1 H), 7.54 (d, J = 6.9
Hz, 1 H), 4.13–4.19 (m, 1 H), 2.65 (t, J = 6.3 Hz, 2 H), 2.60 (s, 3 H),
2.58 (s, 3 H), 2.12 (s, 3 H), 1.83 (t, J = 6.6 Hz, 2 H), 1.35–1.44 (m,
2 H), 1.32 (s, 6 H), 1.03 (d, J = 6.4 Hz, 3 H), 0.71 (t, J = 7.3 Hz, 3
H).
13C NMR (125 MHz, CDCl3): d = 177.1, 155.7, 136.8, 136.7, 127.4,
125.3, 118.9, 74.5, 53.0, 32.4, 28.7, 26.6, 21.3, 18.9, 18.2, 17.2,
12.0, 9.6.
N-Pmc-N¢-butylthiourea (2g)
Yield: 0.50 g (82%); colorless transparent gum.
IR (film): 3337, 1549 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.56 (br s, 1 H), 7.79 (s, 1 H),
3.45–3.50 (m, 1 H), 2.65 (t, J = 6.4 Hz, 2 H), 2.58 (s, 3 H), 2.57 (s,
3 H), 2.12 (s, 3 H), 1.83 (t, J = 6.6 Hz, 2 H), 1.36–1.44 (m, 2 H),
1.32 (s, 6 H), 1.11–1.20 (m, 2 H), 0.84 (t, J = 7.2 Hz, 3 H).
MS (CI): m/z = 399 (M + H).
13C NMR (125 MHz, CDCl3): d = 178.0, 155.6, 136.8, 136.6, 127.5,
125.2, 118.8, 74.4, 45.3, 32.3, 30.2, 26.6, 21.2, 19.5, 18.2, 17.2,
13.5, 12.0.
Anal. Calcd for C19H30N2O3S2: 57.25; H, 7.59; N, 7.03. Found: C,
57.42; H, 7.61; N, 6.98.
MS (CI): m/z = 399 (M + H).
N-Pmc-N¢¢,N¢¢-bis(a,b-methylene)thiourea (2l)
Anal. Calcd for C19H30N2O3S2: 57.25; H, 7.59; N, 7.03. Found: C,
57.09; H, 7.44; N, 7.02.
Yield: 0.26 g (44%); colorless amorphous solid; mp 126–128 °C.
IR (film): 3244, 1549 cm–1.
N-Pmc-N¢-(2-methylpyridyl)thiourea (2h)
1H NMR (500 MHz, CDCl3): d = 8.33 (br s, 1 H), 3.52–3.76 (m, 4
H), 2.67 (t, J = 6.0 Hz, 2 H), 2.63 (s, 6 H), 2.13 (s, 3 H), 1.85–2.09
(m, 4 H), 1.82 (t, J = 6.4 Hz, 2 H), 1.32 (s, 6 H).
Yield: 0.39 g (58%); colorless friable foam; mp 51–54 °C.
IR (film): 3276, 1532 cm–1.
Synthesis 2007, No. 12, 1848–1860 © Thieme Stuttgart · New York

PAPER
Dual Synthetic Routes to N-Pmc-N¢,N¢¢-Disubstituted Guanidines
1857
13C NMR (125 MHz, CDCl3): d = 155.4, 137.7, 137.1, 124.6, 123.0
(br), 118.2, 74.1, 52.2 (br), 49.3 (br), 32.7, 26.8, 26.4 (br), 24.5 (br),
21.6, 18.2, 17.3, 12.3.
MS (CI): m/z = 204, 267, 383 (M + H).
Anal. Calcd for C18H26N2O3S2: C, 56.51; H, 6.85; N, 7.32. Found:
C, 56.93; H, 6.95; N, 7.20.
MS (APCI): m/z = 397 (M + H).
Bis[N-(4,4¢-methylene)]-N¢-Pmc-thiourea (2q)
Anal. Calcd for C19H28N2O3S2: 57.54; H, 7.12; N, 7.06. Found: C,
57.31; H, 7.15; N, 6.98.
Yield: 1.30 g (87%); colorless friable foam; mp 120–123 °C.
IR (film): 3304, 2930 cm–1.
N-Pmc-N¢-(o-methoxyphenyl)thiourea (2m)
1H NMR (500 MHz, CDCl3): d = 9.42 (br s, 2 H), 8.18 (br s, 2 H),
7.22 (d, J = 7.9 Hz, 4 H), 7.10 (d, J = 7.9 Hz, 4 H), 3.90 (s, 2 H),
2.53–2.68 (m, 16 H), 2.12 (s, 6 H), 1.81 (t, J = 6.4 Hz, 4 H), 1.31 (s,
12 H).
13C NMR (125 MHz, CDCl3): d = 177.3, 155.9, 139.4, 136.9, 135.7,
129.3, 127.4, 125.5, 124.5, 119.0, 74.6, 40.9, 32.4, 26.6, 21.3, 18.2,
17.3, 12.1.
Yield: 0.56 g (81%); colorless friable foam; mp 76–78 °C.
IR (film): 3272, 1123 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.94 (br s, 1 H), 8.36 (d, J = 7.9
Hz, 1 H), 8.04 (br s, 1 H), 7.12–7.16 (m, 1 H), 6.84–6.93 (m, 2 H),
3.84 (s, 3 H), 2.56–2.76 (m, 8 H), 2.12 (s, 3 H), 1.82 (t, J = 6.8 Hz,
2 H), 1.31 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 175.4, 155.7, 150.4, 136.8, 136.7,
127.7, 127.0, 126.4, 125.2, 122.7, 120.1, 118.8, 110.6, 74.4, 55.8,
32.4, 26.6, 21.3, 18.1, 17.1, 12.1.
MS (APCI): m/z = 524 (M – PmcNCS).
Anal. Calcd for C43H52N4O6S4: C, 60.82; H, 6.17; N, 6.60. Found:
C, 60.80; H, 6.20; N, 6.61.
MS (CI): m/z = 205, 267, 449 (M + H).
N-Pmc-N¢,N¢¢-Substituted Guanidines 3 from Thioureas 2 and
Amines; General Two-Step Procedure
HRMS: m/z calcd for C22H28N2O4S2: 449.1569; found: 449.1577
(M + H).
To a 100 mL round-bottomed flask containing a stirred solution of
the representative thiourea transfer agent 2 (1.25 mmol) in CH2Cl2
(50 mL) was added EDCI·HCl (0.48 g, 2.50 mmol) in one portion.
Following dissolution of the EDCI·HCl (~15 s), the appropriate
amine (1.1 equiv) was added to the mixture and the solution was al-
lowed to stir for 30 min. At the end of this time, the solvent was re-
moved in vacuo. The crude product was then chromatographically
purified over silica gel (20–40% EtOAc–hexanes).
N-Pmc-N¢-isopropylthiourea (2n)
Yield: 0.48 g (81%); colorless amorphous solid; mp 122–124 °C.
IR (film): 3334, 1541 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.69 (br s, 1 H), 7.56 (d, J = 7.2
Hz, 1 H), 4.21–4.33 (m, 1 H), 2.65 (t, J = 6.2 Hz, 2 H), 2.59 (s, 3 H),
2.58 (s, 3 H), 2.12 (s, 3 H), 1.83 (t, J = 6.4 Hz, 2 H), 1.32 (s, 6 H),
1.05 (d, J = 6.3 Hz, 6 H).
N-Pmc-N¢,N¢¢-Substituted Guanidines 3 from Pmc-Isothio-
cyanate 1 and Sequential Addition of Amine and EDCI·HCl
Reagents; General One-Pot Procedure
13C NMR (125 MHz, CDCl3): d = 176.7, 155.5, 136.8, 136.7, 127.2,
125.0, 118.7, 74.3, 47.4, 32.2, 29.4, 26.4, 21.2, 21.1, 18.0, 17.0,
11.9.
To a 100 mL round-bottomed flask containing a stirred solution of
Pmc-isothiocyanate 1 (1.25 mmol) in CH2Cl2 (50 mL), was added
the first amine (1.0 equiv) and allowed to stir for 30 min. To this so-
lution was added EDCI·HCl (2 equiv) in one portion followed im-
mediately by the second amine (1.1 equiv) and the solution was
stirred for an additional 30 min. At the end of this time, the solvent
was removed in vacuo. The crude product was then chromatograph-
ically purified over silica gel (EtOAc–hexane).
MS (CI): m/z = 385 (M + H).
HRMS: m/z calcd for C18H28N2O3S2: 384.1542; found: 384.1537
(M + H).
N-Pmc-N¢-(p-nitrophenyl)thiourea (2o)
Yield: 0.64 g (90%); yellow solid; mp 144–146 °C.
IR (film): 3285, 1898 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.85 (br s, 1 H), 8.17 (d, J = 8.1
Hz, 2 H), 7.69 (d, J = 8.3 Hz, 2 H), 2.56–2.68 (m, 8 H), 2.11 (s, 3
H), 1.82 (t, J = 6.6 Hz, 2 H), 1.32 (s, 6 H).
N-Pmc-N¢-(4-methylpyrimid-2-yl)-N¢¢-cyclopropylguanidine
(3a)
Yield: 0.56 g (82%); colorless friable foam; mp 70–73 °C.
IR (film): 3261, 1442 cm–1.
13C NMR (125 MHz, CDCl3): d = 176.9, 156.2, 145.0, 143.2, 137.0,
136.9, 127.1, 125.7, 124.5, 123.0, 119.2, 74.8, 32.3, 26.6, 21.3,
18.3, 17.3, 12.2.
1H NMR (500 MHz, CDCl3): d = 10.31 (br s, 1 H), 9.79 (br s, 1 H),
8.29 (d, J = 4.8 Hz, 1 H), 6.82 (d, J = 4.8 Hz, 1 H), 6.83 (s, 1 H),
2.72 (s, 3 H), 2.69 (s, 3 H), 2.64 (t, J = 6.2 Hz, 2 H), 2.42 (s, 3 H),
2.12 (s, 3 H), 1.79 (t, J = 6.4 Hz, 2 H), 1.30 (s, 6 H), 0.79 (d, J = 6.2
Hz, 2 H), 0.58 (s, 2 H).
13C NMR (125 MHz, CDCl3): d = 168.4, 157.1, 156.7, 153.4, 152.0,
135.5, 134.8, 133.5, 123.6, 117.7, 115.2, 73.4, 32.6, 26.5, 23.7,
23.6, 21.2, 18.3, 17.2, 11.9, 6.6.
MS (APCI): m/z = 464 (M + H).
Anal. Calcd for C21H25N3O5S2: C, 54.41; H, 5.44; N, 9.06. Found:
C, 54.23; H, 5.46; N, 8.91.
N-Pmc-N¢-allylthiourea (2p)
Yield: 0.58 g (99%); colorless friable foam; mp 112–116 °C.
IR (film): 3341, 1146 cm–1.
MS (MALDI): m/z = 458 (M + H).
1H NMR (500 MHz, CDCl3): d = 8.59 (br s, 1 H), 7.90 (br s, 1 H),
5.65–5.72 (m, 1 H), 5.08 (d, J = 10.4 Hz, 1 H), 4.98 (d, J = 14.5 Hz,
1 H), 4.15 (dd, J = 4.3, 1.0 Hz, 2 H), 2.66 (t, J = 6.8 Hz, 2 H), 2.59
(s, 3 H), 2.58 (s, 3 H), 2.14 (s, 3 H), 1.85 (t, J = 6.8 Hz, 2 H), 1.34
(s, 6 H).
Anal. Calcd for C23H31N5O3S: C, 60.37; H, 6.83; N, 15.30. Found:
C, 60.30; H, 6.88; N, 15.24.
N-Pmc-N¢-cyclohexyl-N¢¢-benzyloxyguanidine (3b)
Yield: 0.57 g (74%); colorless friable foam; mp 63–66 °C.
IR (film): 3306, 1576 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.22 (br s, 1 H), 7.25–7.43 (m, 3
H), 7.12–7.22 (m, 2 H), 5.28 (d, J = 6.6 Hz, 1 H), 4.69 (s, 2 H),
13C NMR (125 MHz, CDCl3): d = 178.3, 155.7, 136.8, 136.7, 131.7,
127.3, 125.3, 118.9, 117.1, 74.5, 47.7, 32.4, 26.6, 21.2, 18.2, 17.2,
12.0.
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S. Flemer Jr., J. S. Madalengoitia
PAPER
3.53–3.65 (m, 1 H), 2.65 (t, J = 6.1 Hz, 2 H), 2.56 (s, 3 H), 2.55 (s,
3 H), 2.13 (s, 3 H), 1.83 (t, J = 6.3 Hz, 2 H), 1.63–1.77 (m, 2 H),
1.49–1.63 (m, 3 H), 1.19–1.43 (m, 9 H), 1.03–1.17 (m, 1 H), 0.82–
1.00 (m, 2 H).
1H NMR (500 MHz, CDCl3): d = 6.33 (d, J = 8.2 Hz, 1 H), 3.42 (br
s, 4 H), 3.30–3.38 (m, 1 H), 2.59–2.67 (m, 8 H), 2.10 (s, 3 H), 1.84
(br s, 4 H), 1.80 (t, J = 6.8 Hz, 2 H), 1.19–1.40 (m, 8 H), 0.90 (d,
J = 6.2 Hz, 2 H), 0.80 (t, J = 7.3 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 155.0, 153.5, 135.7, 135.0, 134.6,
133.2, 129.5, 129.1, 128.8, 124.0, 117.8, 79.0, 73.6, 49.1, 32.9,
32.7, 26.8, 25.3, 24.5, 21.5, 18.4, 17.3, 12.1.
13C NMR (125 MHz, CDCl3): d = 156.7, 153.1, 135.4, 134.6, 134.1,
123.6, 117.6, 73.3, 51.1, 49.0, 32.7, 30.1, 26.5, 25.1, 21.2, 20.2,
18.6, 17.4, 11.8, 10.1.
MS (MALDI): m/z = 514 (M + H).
MS (APCI): m/z = 436 (M + H).
Anal. Calcd for C28H39N3O4S: C, 65.47; H, 7.65; N, 8.18. Found: C,
65.27; H, 7.73; N, 8.08.
Anal. Calcd for C23H37N3O3S: C, 63.41; H, 8.56; N, 9.65. Found: C,
63.08; H, 8.59; N, 9.52.
N-Pmc-N¢-(2,6-dichlorophenyl)-N¢¢-(2-hydroxyethyl)guanidine
(3c)
N-Pmc-N¢-allyl-N¢¢-(o-methoxyphenyl)guanidine (3g)
Yield: 0.42 g (99%); colorless friable foam; mp 43–45 °C.
Yield: 0.52 g (67%); colorless friable foam; mp 84–86 °C.
IR (film): 3294, 1107 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.69 (br s, 1 H), 7.24–7.37 (m, 2
H), 3.63 (br s, 2 H), 3.41 (br s, 2 H), 2.61 (t, J = 6.0 Hz, 2 H), 2.55
(s, 3 H), 2.53 (s, 3 H), 2.10 (s, 3 H), 1.80 (t, J = 6.4 Hz, 2 H), 1.30
(s, 6 H).
IR (film): 3314, 1582, 1558 cm–1.
1H NMR (500 MHz, CD3OD): d = 7.14–7.21 (m, 1 H), 7.06–7.14
(m, 1 H), 7.00 (d, J = 6.4 Hz, 1 H), 6.83–6.91 (m, 1 H), 5.69–5.80
(m, 1 H), 4.95–5.10 (m, 2 H), 3.83 (s, 2 H), 3.74 (s, 3 H), 2.63 (br s,
2 H), 2.55 (s, 3 H), 2.53 (s, 3 H), 2.08 (s, 3 H), 1.81 (br s, 2 H), 1.29
(s, 6 H).
13C NMR (125 MHz, CDCl3): d = 153.6, 135.7, 135.0, 134.6, 133.2,
129.2, 128.8, 123.8, 117.8, 73.6, 61.9, 44.0, 32.8, 26.7, 21.3, 18.5,
17.4, 12.0.
13C NMR (125 MHz, CDCl3): d = 153.4, 153.1, 135.5, 134.9, 133.7,
133.6, 127.1, 125.1, 123.7, 120.9, 117.7, 116.7, 111.5, 73.4, 55.6,
43.8, 32.8, 26.6, 21.3, 18.4, 17.3, 11.9.
MS (MALDI): m/z = 514 (M + H).
MS (MALDI): m/z = 472 (M + H).
Anal. Calcd for C23H29Cl2N3O4S: C, 53.70; H, 5.68; N, 8.17. Found:
C, 53.81; H, 5.68; N, 8.09.
Anal. Calcd for C25H33N3O4S: C, 63.67; H, 7.05; N, 8.91. Found: C,
63.77; H, 6.99; N, 8.87.
N-Pmc-N¢-(2-methylpyridyl)-N¢¢-butylguanidine (3d)
Yield: 0.65 g (91%); colorless gummy semisolid.
Bis[N-(4,4¢-methylene)-N¢-Pmc-N¢¢-(2-methoxyphenyl)guani-
dine (3h)
Yield: 0.70 g (91%); colorless friable foam; mp 103–107 °C.
IR (film): 3287, 1549 cm–1.
IR (film): 3337, 1111 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.47 (d, J = 3.6 Hz, 1 H), 7.61 (br
s, 1 H), 7.18 (d, J = 6.9 Hz, 2 H), 7.10 (br s, 1 H), 4.45 (br s, 2 H),
3.19 (d, J = 5.0 Hz, 2 H), 2.50–2.69 (m, 8 H), 2.03 (s, 3 H), 1.79 (t,
J = 6.5 Hz, 2 H), 1.45–1.60 (m, 2 H), 1.21–1.40 (m, 8 H), 0.89 (t,
J = 7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 156.2, 155.1, 153.2, 148.5, 137.0,
135.4, 134.6, 134.0, 123.6, 122.5, 117.6, 73.4, 41.2, 32.8, 31.0,
26.6, 21.3, 19.8, 18.4, 17.3, 13.5, 11.9.
1H NMR (500 MHz, CDCl3): d = 8.52 (br s, 2 H), 7.84–7.98 (m, 2
H), 7.70 (br s, 2 H), 7.21 (s, 8 H), 7.04 (t, J = 6.6 Hz, 2 H), 6.88 (t,
J = 7.5 Hz, 2 H), 6.79 (d, J = 7.9 Hz, 2 H), 3.99 (s, 2 H), 3.65 (s, 6
H), 2.57–2.73 (m, 16 H), 2.13 (s, 6 H), 1.80 (t, J = 6.4 Hz, 2 H), 1.31
(s, 12 H).
13C NMR (125 MHz, CDCl3): d = 153.6, 150.6, 139.4, 135.6, 135.0,
134.1, 133.3, 129.9, 129.5, 126.0, 125.2, 123.9, 122.5, 120.8, 117.8,
110.5, 73.6, 55.6, 40.7, 32.7, 26.6, 21.3, 18.5, 17.4, 12.0.
MS (MALDI): m/z = 476 (M + H).
MS (MALDI): m/z = 1028 (M + H).
Anal. Calcd for C25H36N4O3S: C, 63.53; H, 7.68; N, 11.85. Found:
C, 63.32; H, 7.64; N, 11.66.
Anal. Calcd for C57H66N6O8S2: C, 66.64; H, 6.48; N, 8.18. Found:
C, 66.93; H, 6.70; N, 8.19.
N-Pmc-N¢-benzyl-N¢¢-(tert-butoxycarbonyl)aminoguanidine
(3e)
Yield: 0.67 g (98%); colorless friable foam; mp 79–84 °C.
N-Pmc-[N¢-(a)-N¢¢-(e)-Lysine Benzyl Ester]guanidine (3i = 10);
Typical Procedure
Lysine benzyl ester di-trifluoroacetate (0.490 g, 1.06 mmol) was
suspended in CH2Cl2 (250 mL) under an inert atmosphere with rap-
id stirring. Hünig’s base (910 mL, 10 equiv) was then added drop-
wise over 5 min, initiating dissolution of the reactant. After most of
the starting material had dissolved, Pmc-isothiocyanate 1 (0.340 g,
1.0 equiv) dissolved in CH2Cl2 (5 mL) was added dropwise over 20
min. After TLC confirmation of the absence of 1 from the reaction
(20 min), EDCI·HCl (0.202 g, 1.0 equiv) was added to the mixture
in one portion. After 10 min, the solvent was removed in vacuo, and
the crude product was purified via silica gel chromatography using
80% EtOAc–hexanes as eluent to yield 3i (= 10) as a colorless fri-
able foam (0.36 g, 65%); mp 84–86 °C.
IR (film): 3320, 1718 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.69 (br s, 1 H), 7.16–7.24 (m, 5
H), 6.71 (br s, 1 H), 6.06 (br s, 1 H), 4.40 (d, J = 5.7 Hz, 2 H), 2.60
(t, J = 6.8 Hz, 2 H), 2.56 (s, 3 H), 2.53 (s, 3 H), 2.09 (s, 3 H), 1.80
(t, J = 6.8 Hz, 2 H), 1.41 (s, 9 H), 1.31 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 155.3, 154.9, 153.7, 135.8, 135.1,
133.2, 128.5, 127.6, 127.4, 123.9, 117.8, 82.6, 73.6, 44.8, 32.9,
28.0, 26.8, 21.4, 18.5, 17.4, 12.0.
MS (MALDI): m/z = 531 (M + H), 553 (M + Na), 569 (M + K).
Anal. Calcd for C27H38N4O5S: C, 61.11; H, 7.22; N, 10.56. Found:
C, 61.01; H, 7.28; N, 10.65.
IR (film): 3245, 1741 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.59 (br s, 1 H), 7.27–7.43 (m, 5
H), 5.16 (s, 2 H), 4.62–4.74 (m, 1 H), 3.50–3.62 (m, 1 H), 3.36–3.48
(m, 1 H), 2.50–2.68 (m, 8 H), 2.08 (s, 3 H), 1.96–2.06 (m, 1 H),
1.83–1.95 (m, 1 H), 1.77 (t, J = 6.2 Hz, 2 H), 1.50–1.71 (m, 4 H),
1.28 (d, J = 4.0 Hz, 2 H).
N-Pmc-N¢-(1-methylpropyl)-N¢¢-bis(a,b-methylene)guanidine
(3f)
Yield: 0.65 g (~100%); colorless viscous oil.
IR (film): 3319, 1576 cm–1.
Synthesis 2007, No. 12, 1848–1860 © Thieme Stuttgart · New York

PAPER
Dual Synthetic Routes to N-Pmc-N¢,N¢¢-Disubstituted Guanidines
1859
13C NMR (125 MHz, CDCl3): d = 170.7, 156.5, 153.2, 135.8, 135.2,
134.8, 133.3, 128.6, 128.4, 123.7, 117.7, 73.4, 67.6, 54.1, 40.8,
34.0, 32.8, 29.0, 26.6, 26.5, 21.3, 20.0, 18.4, 17.3, 11.9.
Deprotection of N-Pmc-N¢,N¢¢-Disubstituted Guanidines
4a,b,d–i,k; General Procedure
The N-Pmc-N¢,N¢¢-disubstituted guanidine 3 (0.50 mmol) was
stirred in 98:2 TFA–H2O for 6 h, followed by removal of the acidic
supernatant in vacuo. The deprotected guanidine was isolated via
trituration of the residue in Et2O to afford the crude reaction product
as a white powder. In most cases, the resulting deprotected guani-
dine was pure enough for spectroscopic characterization as its TFA
salt. Occasionally, small amounts of residual pentamethylchroman
within the crude product necessitated chromatographic purification
over silica gel (eluent: 1:2:7 formic acid–MeOH–EtOAc), and the
compound then characterized as its formate salt.
MS (MALDI): m/z = 528 (M + H).
Anal. Calcd for C28H37N3O5S: C, 63.73; H, 7.07; N, 7.96. Found: C,
63.78; H, 7.13; N, 7.85.
2-(Pmc)amino-3,4-dihydrooxazole (7)
Yield: 0.48 g (91%); colorless friable foam; mp 60–63 °C.
IR (film): 3390, 1635 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.70 (br s, 1 H), 4.47 (t, J = 8.1
Hz, 2 H), 3.78 (t, J = 8.2 Hz, 2 H), 2.63 (t, J = 6.4 Hz, 2 H), 2.56 (s,
3 H), 2.55 (s, 3 H), 2.11 (s, 3 H), 1.80 (t, J = 6.6 Hz, 2 H), 1.30 (s, 6
H).
13C NMR (125 MHz, CDCl3): d = 161.3, 154.0, 135.8, 135.4, 131.8,
124.0, 117.9, 73.6, 66.4, 42.5, 32.7, 26.6, 21.3, 18.3, 17.2, 11.9.
N-(4-Methylpyrimidyl)-N¢-cyclopropylguanidine (4a)
Yield: 0.15 g (96%); isolated as its TFA salt.
1H NMR (500 MHz, CD3OD): d = 8.30 (d, J = 4.9 Hz, 1 H), 6.95 (d,
J = 4.9 Hz, 1 H), 2.53–2.60 (m, 1 H), 2.32 (s, 3 H), 0.82 (d, J = 5.9
Hz, 2 H), 0.62 (s, 2 H).
MS (CI): m/z = 353 (M + H).
MS (MALDI): m/z = 192 (M + H).
Anal. Calcd for C17H24N2O4S: C, 57.93; H, 6.86; N, 7.95. Found: C,
57.75; H, 6.88; N, 7.90.
N-Cyclohexyl-N¢-benzyloxyguanidine (4b)
Yield: 0.13 g (86%); isolated as its formate salt.
3-(Pmc)amino-2,4-diazaindene (8)
Yield: 0.56 g (93%); light yellow friable foam; mp 70–73 °C.
IR (film): 3294, 1599 cm–1.
1H NMR (500 MHz, CD3OD): d = 8.50 (s, 1 H), 7.28–7.47 (m, 5 H),
4.84 (s, 2 H), 3.29–3.41 (m, 1 H), 1.85–1.93 (m, 1 H), 1.77–1.85 (m,
1 H), 1.66–1.76 (m, 2 H), 1.54–1.66 (m, 1 H), 1.10–1.49 (m, 6 H).
1H NMR (500 MHz, CDCl3): d = 7.69 (d, J = 7.2 Hz, 1 H), 6.97 (d,
J = 9.3 Hz, 1 H), 6.80 (s, 1 H), 6.54 (t, J = 6.4 Hz, 1 H), 6.26 (t,
J = 6.6 Hz, 1 H), 2.59–2.78 (m, 8 H), 2.11 (s, 3 H), 1.79 (t, J = 6.5
Hz, 2 H), 1.30 (s, 6 H).
MS (MALDI): m/z = 248 (M + H).
N-Butyl-N¢-(2-pyridyl)methylguanidine (4d)
Yield: 0.18 g (84%); isolated as its 2 × TFA salt.
13C NMR (125 MHz, CDCl3): d = 153.4, 139.9, 135.5, 134.8, 134.1,
123.9, 122.1, 121.1, 117.8, 117.5, 111.2, 100.2, 73.5, 32.8, 26.7,
21.4, 18.7, 17.6, 12.0.
1H NMR (500 MHz, DMSO-d6): d = 8.56 (s, 1 H), 7.84 (t, J = 7.0
Hz, 1 H), 7.66 (s, 1 H), 7.51 (s, 1 H), 7.30–7.40 (m, 2 H), 4.51 (s, 2
H), 3.09–3.22 (m, 2 H), 1.41–1.54 (m, 2 H), 1.23–1.37 (m, 2 H),
0.88 (t, J = 7.1 Hz, 3 H).
MS (CI): m/z = 135 (M – Pmc).
MS (MALDI): m/z = 207 (M + H).
N-Pmc-N¢,N¢¢-bis(p-nitrophenyl)guanidine (11)
Pmc-isothiocyanate 1 (0.230 g, 0.707 mmol) and p-nitroaniline
(0.244 g, 2.5 equiv) were dissolved in DMF (15 mL) under an inert
atmosphere and stirred for 30 min. EDCI·HCl (0.176 g, 1.3 equiv)
was then added in one portion, and the mixture was stirred for an ad-
ditional 12 h. After this time, the mixture was heated to 65 °C in an
oil bath, and tert-butyl nitrite (94 mL, 1.0 equiv), dissolved in DMF
(5 mL) was added dropwise via syringe over 5 min. After 5 min, gas
evolution was evident and the mixture turned orange. The mixture
was maintained at 65 °C until gas evolution had ceased. The con-
tents of the reaction vessel were then poured into EtOAc (100 mL),
and extracted with 2% aq HCl (3 × 50 mL). The organic portion was
then dried (MgSO4), and the solvent removed in vacuo to yield the
crude product. Silica gel column purification (40% EtOAc–hex-
anes) afforded the pure product (0.16 g, 23%) as a yellow friable
foam; mp 110–112 °C.
N-Benzyl-N¢-aminoguanidine (4e)
Yield: 0.12 g (83%); isolated as its formate salt.
1H NMR (500 MHz, CD3OD): d = 8.48 (br s, 1 H), 8.15 (br s, 1 H),
7.23–7.43 (m, 5 H), 4.47 (s, 2 H).
MS (MALDI): m/z = 165 (M + H).
N-(1-Methylpropyl)-N¢-bis(a,b-methylene)guanidine (4f)
Yield: 0.14 g (~100%); isolated as its TFA salt.
1H NMR (500 MHz, CD3OD): d = 3.38–3.50 (m, 1 H), 3.26–3.38
(m, 4 H), 1.85–2.00 (m, 4 H), 1.41–1.60 (m, 2 H), 1.12 (d, J = 6.3
Hz, 3 H), 0.84 (t, J = 7.3 Hz, 3 H).
MS (MALDI): m/z = 170 (M + H).
N-(o-Methoxyphenyl)-N¢-allylguanidine (4g)
Yield: 0.16 g (~100%); isolated as its TFA salt.
1H NMR (500 MHz, CD3OD): d = 7.27 (t, J = 6.7 Hz, 1 H), 7.13 (t,
J = 6.7 Hz, 1 H), 7.02 (d, J = 7.5 Hz, 1 H), 6.91 (t, J = 7.6 Hz, 1 H),
5.73–5.82 (m, 1 H), 5.22 (d, J = 17.2 Hz, 1 H), 5.12 (d, J = 10.4 Hz,
1 H), 4.78 (s, 3 H), 3.77–3.85 (m, 2 H).
IR (film): 3284, 1622 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.46 (br s, 2 H), 8.08 (d, J = 8.8
Hz, 4 H), 7.41 (d, J = 9.0 Hz, 4 H), 2.62 (t, J = 6.7 Hz, 2 H), 2.54 (s,
3 H), 2.52 (s, 3 H), 2.10 (s, 3 H), 1.82 (d, J = 6.7 Hz, 2 H), 1.32 (s,
6 H).
13C NMR (125 MHz, CDCl3): d = 154.6, 149.1, 144.5, 142.3, 135.7,
135.4, 131.3, 125.0, 124.6, 122.4, 118.4, 74.1, 63.6, 32.6, 26.7,
21.3, 18.6, 17.5, 12.0.
MS (MALDI): m/z = 206 (M + H).
Bis[N-(4,4¢-methylene)-N¢-(2-methoxyphenyl)]guanidine (4h)
Yield: 0.32 g (89%); isolated as its formate salt.
HRMS: m/z calcd for C27H29N5O7S + Li: 574.1788; found:
1H NMR (500 MHz, CD3OD): d = 7.28 (t, J = 7.2 Hz, 2 H), 7.12–
7.25 (m, 10 H), 7.04 (d, J = 8.2 Hz, 2 H), 6.93 (t, J = 7.5 Hz, 2 H),
3.93 (s, 2 H), 3.82 (s, 6 H).
574.1972 (M + Li).
MS (MALDI): m/z = 575 (M + H).
Synthesis 2007, No. 12, 1848–1860 © Thieme Stuttgart · New York

1860
S. Flemer Jr., J. S. Madalengoitia
PAPER
N-(a)-N¢-(e)-(Lysine Benzyl Ester)guanidine (4i)
Yield: 0.15 g (~100%); isolated as its formate salt.
(8) (a) Wang, Y. X.; Pang, C. C. Y. J. Pharmacol. Exp. Ther.
1993, 265, 263. (b) Zahariev, S.; Guarnaccia, C.; Zanuttin,
F.; Pintar, A.; Esposito, G.; Maravic, G.; Krust, B.;
Hovanessian, A. G.; Pongor, S. J. Pep. Sci. 2005, 11, 17.
(9) Powell, D. A.; Ramsden, P. D.; Batey, R. A. J. Org. Chem.
2003, 68, 2300.
(10) Feichtinger, K.; Sings, H. L.; Baker, T. J.; Matthews, K.;
Goodman, M. J. Org. Chem. 1998, 63, 8432.
(11) Wu, Y.; Matsueda, G. R.; Bernatowicz, M. Synth. Commun.
1993, 23, 3055.
(12) (a) Maryanoff, C. A.; Stanzione, R. C.; Plampin, J. N.; Mills,
J. E. J. Org. Chem. 1986, 51, 1882. (b) Ramadas, K.;
Janarthanan, N.; Pritha, R. Synlett 1997, 1053.
(c) Srinivasan, N.; Ramadas, K. Tetrahedron Lett. 2001, 42,
343.
(13) Musiol, H. J.; Moroder, L. Org. Lett. 2001, 3, 3859.
(14) Xue, C. B.; Degrado, W. F. Tetrahedron Lett. 1995, 36, 55.
(15) Webb, T. R.; Eigenbrot, C. J. Org. Chem. 1991, 56, 3009.
(16) Gompper, R.; Hagele, W. Chem. Ber. 1966, 99, 2885.
(17) (a) Deprez, P.; Vevert, J. P. Synth. Commun. 1996, 26, 4299.
(b) Levallet, C.; Lerpiniere, J.; Ko, S. Y. Tetrahedron 1997,
53, 5291.
1H NMR (500 MHz, DMSO-d6): d = 10.15 (br s, 1 H), 8.44 (br s, 1
H), 8.12 (br s, 1 H), 7.58 (br s, 1 H), 7.30–7.45 (m, 5 H), 5.22 (q,
J = 9.6 Hz, 2 H), 5.01–5.12 (m, 1 H), 3.67–3.84 (m, 1 H), 3.01–3.13
(m, 1 H), 2.01–2.14 (m, 1 H), 1.61–1.85 (m, 4 H), 1.46–1.61 (m, 1
H).
MS (MALDI): m/z = 262 (M + H).
N,N¢-Bis(p-nitrophenyl)guanidine (4k)
Yield: 0.15 g (71%); isolated as its formate salt.
1H NMR (500 MHz, CD3OD): d = 8.18 (d, J = 8.4 Hz, 4 H), 7.45 (d,
J = 8.4 Hz, 4 H).
MS (CI): m/z = 302 (M + H).
Acknowledgment
Funding for this work was provided by CHE-0412831 from the
NSF.
(18) (a) Atwal, K. S.; Ahmed, S. Z.; O’Reilly, B. C. Tetrahedron
Lett. 1989, 30, 7313. (b) Wilson, L. J.; Klopfenstein, S. R.;
Li, M. Tetrahedron Lett. 1999, 40, 3999.
(19) Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem.
1997, 62, 1540.
References
(1) Ishikawa, T.; Kumamoto, T. Synthesis 2006, 737.
(2) Antonik, L. M.; Lopyrev, V. A.; Korchevin, N. A.; Tomin,
V. P. Russ. J. Appl. Chem. 2002, 75, 257.
(3) Schmidtchen, F. P.; Berger, M. Chem. Rev. 1997, 97, 1609.
(4) (a) Gobert, A. P.; Daulouede, S.; Lepoivre, M.; Boucher, J.
L.; Bouteille, B.; Buguet, A.; Cespuglio, R.; Veyret, B.;
Vincendeau, P. Infect. Immun. 2000, 68, 4653.
(20) Li, J.; Zhang, G.; Zhang, Z.; Fan, E. J. Org. Chem. 2003, 68,
1611.
(21) Linton, B. R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D. J.
Org. Chem. 2000, 65, 1566.
(22) Schneider, S. E.; Bishop, P. A.; Salazar, M. A.; Bishop, O.
A.; Anslyn, E. V. Tetrahedron 1998, 54, 15063.
(23) (a) Zhang, J. L.; Zhang, Z.; Fan, E. J. Org. Chem. 2003, 68,
1611. (b) Zhang, Z.; Carter, T.; Fan, E. Tetrahedron Lett.
2003, 44, 3063.
(24) (a) Zhang, Z.; Pickens, J. C.; Hol, W. G. J.; Fan, E. Org. Lett.
2004, 6, 1377. (b) Zhang, Z.; Fan, E. J. Org. Chem. 2005,
70, 8801.
(25) Briganti, F.; Pierattelli, R.; Scozzafava, A.; Supuran, C. T.
Eur. J. Med. Chem. 1996, 31, 1001.
(26) (a) Dickore, K.; Kuhle, E. Angew. Chem., Int. Ed. Engl.
1965, 4, 430. (b) Borsus, J. M.; L’Abbe, G.; Smets, G.
Tetrahedron 1975, 31, 1537.
(27) (a) Eckert, H.; Forster, B. Angew. Chem., Int. Ed. Engl.
1987, 26, 894. (b) Coghlan, M. J.; Caley, B. A. Tetrahedron
Lett. 1989, 30, 2033.
(b) Loscalzo, J. J. Clin. Invest. 2001, 108, 663.
(5) Piatti, P. M.; Monti, L. D.; Valsecchi, G.; Magni, F.; Setola,
E.; Marchesi, F.; Galli-Kienle, M.; Pozza, G.; Alberti, K. G.
Diabetes Care 2001, 24, 875.
(6) (a) Futaki, S. Biopolymers (Peptide Science) 2005, 84, 241.
(b) Fuchs, S. M.; Raines, R. T. Protein Sci. 2005, 14, 1538.
(c) Goun, E. A.; Shinde, R.; Dehnert, K. W.; Adams-Bond,
A.; Wender, P. A.; Contag, C. H.; Franc, B. L. Bioconjugate
Chem. 2006, 17, 787.
(7) (a) Chiswell, R. K.; Shaw, G. R.; Eaglesham, G.; Smith, M.
J.; Norris, R. L.; Seawright, A. A.; Moore, M. M. Environ.
Toxicol. 1999, 14, 155. (b) Black, G. P.; Murphy, P. J.;
Thornhill, A. J.; Walshe, N. D. A.; Zanetti, C. Tetrahedron
1999, 55, 6547.
(28) Doyle, M. P.; Dellaria, J. F. Jr.; Siegfried, B.; Bishop, S. W.
J. Org. Chem. 1977, 42, 3494.
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