TFA-sensitive arylsulfonylthiourea-assisted synthesis of N,N′-substituted guanidines

Article abstract of DOI:10.1021/jo026807m

An efficient synthesis of N,N′-substituted guanidine derivatives was developed via an aromatic sulfonyl-activated thiourea intermediate. The use of certain aromatic sulfonamides, such as PbfNH₂, as the key reagent to incorporate a TFA-labile guanidine protection group greatly facilitates solid-phase synthesis of N,N′-substituted guanidine compounds.

Full text of DOI:10.1021/jo026807m

synthetic methods and guanidinylation reagents for
different classes of guanidine compounds.2-43
TF A-Sen sitive
Ar ylsu lfon ylth iou r ea -Assisted Syn th esis of
N,N′-Su bstitu ted Gu a n id in es
We are interested in the preparation of N,N′-substi-
tuted guanidines using common solid-phase supports that
can be conveniently cleaved with TFA treatment. Cur-
rently, preparation of this class of guanidine compounds
is possible through two major synthetic routes. One route
is based on di-Boc (or equivalent TFA-labile group)-
activated pyrazole- or triazolecarboxamidines8,19,20,23,44 or
triflyl guanidines,11,27,45 either in solution or on solid
support. In these cases, it usually requires reaction with
a primary alcohol under Mitsunobu conditions before the
guanidinylation step to produce the desired substitution.
However, this may limit the diversity of compounds
generated because Mitsunobu conditions work best with
primary alcohols. The other widely used route is based
on modification of a thiourea, of which the solid-phase
methods have been reviewed recently.2 Common ways of
improving reaction efficiency through this type of reaction
are the activation of thiourea with electron-withdrawing
groups such as alkoxycarbonyl, acyl, triazene, or N-
aryl.4,14,15,21,22,26,41 Subsequent guanidinylation is usually
done with the assistance of a carbodiimide,41 heavy metal
salts,7,40 or Mukaiyama reagent.46 The characteristic of
J izhen Li, Guangtao Zhang,† Zhongsheng Zhang, and
Erkang Fan*
Biomolecular Structure Center,
Departments of Biochemistry and Biological Structure, and
Department of Chemistry, Box 357742,
University of Washington, Seattle, Washington 98195
erkang@u.washington.edu
Received December 4, 2002
Abstr a ct: An efficient synthesis of N,N′-substituted guani-
dine derivatives was developed via an aromatic sulfonyl-
activated thiourea intermediate. The use of certain aromatic
sulfonamides, such as PbfNH2, as the key reagent to
incorporate a TFA-labile guanidine protection group greatly
facilitates solid-phase synthesis of N,N′-substituted guani-
dine compounds.
The guanidine group plays important roles in biological
systems and is therefore a component of many therapeu-
tic agents that aim to mimic or block the function of a
guanidine-containing biomolecule.1 The synthesis of guani-
dine derivatives has also attracted continued research
interests in recent years, resulting in many new efficient
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† Department of Chemistry.
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10.1021/jo026807m CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/22/2003
J . Org. Chem. 2003, 68, 1611-1614
1611

SCHEME 1
this route is that N,N′-substitution can be introduced
with two amine starting materials, although di-Boc-
activated isothiourea still requires Mitsunobu conditions
to introduce desired substitution patterns.30 Despite the
extensive knowledge about solid-phase synthesis of
guanidines, current solid-phase methods for the prepara-
tion of N,N′-substituted guanidines starting from two
amines only demonstrate limited success.19,24,25,28,29 Here,
we report an extension of current methodologies by
exploration of thiourea activation using a single TFA-
sensitive aromatic sulfonyl group, along with a compari-
son to existing methods.
The major goal of our investigation is to achieve in
solid-phase synthesis concomitant cleavage of product
and removal of the activating arylsulfonyl group, without
any loss in overall synthetic efficiency. The question then
comes down to (i) if an arylsulfonyl group can sufficiently
activate thiourea for guanidine synthesis and (ii) if a
TFA-labile protection group can be generated after the
guanidinylating step. In addition, we would like to learn
if guanidinylation with arylsulfonylthiourea can be car-
ried out under mild experimental conditions for amines
with steric hindrance without the need of using toxic
heavy metal salts or excessive heating. We should point
out that the recently reported use of bismuth nitrate for
promoting guanidinylation7 should be much more envi-
ronmentally friendly as compared to the use of HgCl2 or
analogous salts; however, such a reaction protocol still
requires heating (>18 h) or prolonged time at room
temperature (up to 117 h) to achieve satisfactory yields.
Although sulfonylguanidines are known, especially in
the patented preparation of herbicides, most of the
syntheses were done by preformation of the guanidine
moiety followed by sulfonylation with sulfonyl chlorides.
A survey of literature reporting use of arylsulfonyl
activated thiourea for guanidine synthesis showed, to the
best of our knowledge, only three reports in solution
synthesis.47-49 Two of these reports used mercury salts
to promote the reaction,47,48 while the third report showed
only one example of arylsulfonylthiourea-based guanidi-
nylation using a carbodiimide.49 In all cases, the formed
arylsulfonyl guanidines were not adaptable to solid-phase
synthesis using TFA for cleavage/deprotection. We en-
visioned that if TFA-sensitive arylsulfonyl groups could
be introduced into the thiourea-based synthetic method,
then adaptation to resin-supported synthesis should be
straightforward. The use of the TFA-sensitive sulfonyl
group in guanidine synthesis through other types of
guanidinylating reagents has also been reported.36,39
Since many arylsulfonyl protection groups for the argi-
nine side chain are known in Fmoc chemistry, we
demonstrate our synthetic method based on one of the
best TFA-sensitive arginine protecting groups: 2,2,4,6,7-
pentamethyldihydrobenzofuran-5-sulfonyl (Pbf).50
studied in more detail,49 we first tested the Pbf-thiourea-
assisted guanidine formation reaction in solution in the
hope of obtaining basic knowledge about the guanidiny-
lating step with a variety of amine nucleophiles. As
shown in Scheme 1, a primary amine 1 was first turned
into the corresponding pentafluorophenyl thiocarbamate.
This allowed for the smooth synthesis of the arylsulfonyl-
activated thiourea 2, using PbfNHK (formed by treating
PbfNH2 with potassium tert-butoxide) as nucleophile.48
This preparation of arylsulfonyl modified thiourea has
some advantages over an alternative procedure through
the use of arylsulfonyl isothiocyanate48 in that both the
starting materials (thiocarbamate and PbfNH2) are fairly
stable and easy to handle, while the alternative synthesis
of arylsulfonyl-activated thioureas involves the prepara-
tion and handling of highly labile arylsulfonyl isothiocy-
anate, which can react with alcohol without activation
under neutral conditions.51 The resulting compound 2 is
an excellent guanidinylating reagent. Treatment of 2
with an amine in the presence of Mukaiyama reagent
produced the subsequent guanidine derivatives 3a -d in
very good yields at room temperature in 12-18 h, while
most of the product was formed within 1-2 h as judged
by TLC. The reaction works for either primary or second-
ary amine nucleophiles, including the sterically hindered
tert-butylamine, as well as diethylamine and diisopro-
pylamine, both of which are known to cause problems in
other guanidine syntheses performed in solution.11 In
addition, the high efficiency of Mukaiyama reagent in
promoting the guanidinylating reaction is also in contrast
to its role in sulfamoylthiourea based systems.49 The
transformation was similarly good with the use of EDC
in place of Mukaiyama reagent. The use of toxic heavy
metal salts or excessive heating proved to be unneces-
sary.
Since the original report of carbodiimide-promoted
arylsulfonylthiourea-assisted guanidine synthesis did not
provide enough information about the reactivity for
different amines and only sulfamoyl-based systems were
The success in solution transformation led us to
investigate a facile solid-phase route for guanidine
synthesis via Pbf-activated thiourea, so that free N,N′-
substituted guanidines could be obtained directly after
TFA cleavage. The adaptation of solution synthesis to
(47) Deprez, P.; Vevert, J .-P. Synth. Commun. 1996, 26, 4299-4310.
(48) Levallet, C.; Lerpiniere, J .; Ko, S. Y. Tetrahedron 1997, 53,
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2705-2716.
1612 J . Org. Chem., Vol. 68, No. 4, 2003

SCHEME 2
overall isolated yields of the final guanidine compounds
after TFA cleavage and HPLC purification.
Our solid-phase synthesis was also demonstrated with
an alternative amino acid starting material in place of
4. Starting with an aromatic Fmoc-protected amino acid
8, compounds 9a -c were efficiently synthesized following
either route in Scheme 2. We should note here that using
R-amino acids as starting materials for the preparation
of the corresponding guanidine derivatives will not lead
to isolation of desired products under our reaction condi-
tions since this class of compounds is known to go
through intramolecular cyclizations.2,41
The fate of the side product due to the removal of Pbf
protection by TFA treatment is also worth noting. TFA-
based removal of Pbf from a guanidine group is expected
to generate the corresponding aromatic ring moiety
without trapping. Since we use TIS ((i-Pr)3SiH) as a
scavenger, Pbf may also be trapped by TIS. In either case,
however, none of these byproducts has significant solu-
bility in aqueous solution while in contrast our desired
guanidine products as their TFA salts do. A simple
aqueous extraction and filtration removed most of these
contaminants before the final HPLC purification (see the
Supporting Information). Alternatively, washing the
crude cleavage product with ethyl ether also served to
remove most of the contaminants before HPLC purifica-
tion.
With the success of either solution- or solid-phase
guanidinylation using Pbf activated thiourea, it is worth
comparing in more detail our method to other known
procedures for preparing N,N′-substituted guanidines,
with regard to our goals stated earlier. The foremost
concern is the reaction efficiency of our approach. To this
end, our methodology proved to be comparable to many
other approaches. For example, in solution synthesis, the
yields of guanidinylation (Scheme 1) are similar to
solution phase guanidinylation using alkoxycarbonyl
thioureas.21 On solid-phase synthesis, our method pro-
duced slightly better isolated yields (Scheme 2) than
syntheses performed with N-ethoxycarbonyl thiourea
(63-83%).9 Certainly, our method does not leave a
guanidine protecting group after TFA cleavage, which is
advantageous when water soluble guanidinium com-
pounds are desired.
solid phase is shown in Scheme 2. A protected amino acid
molecule 4 was first attached to Rink Amide MBHA resin
through standard peptide chemistry. After removal of the
amine protection, the free amine was turned into the
desired guanidine function through two routes. The first
method is the direct guanidinylation with a Pbf-thiourea
such as 2 (reaction sequence 1 in Scheme 2). This route
produced the desired final N,N′-substituted guanidine in
high overall yield (82% for 7a from resin-supported amine
5). However, this method is sometimes less attractive due
to the requirement for pre-synthesis of Pbf-thioureas in
solution. Alternatively, we demonstrated that one can
form the Pbf-thiourea on solid support and subsequently
produce the desired guanidine compounds. As shown by
reaction sequence 2 in Scheme 2, the resin-supported
amine 5 was first turned into pentafluorophenyl thio-
carbamate. Reaction with PbfNHK, as in the solution
synthesis, produced the desired Pbf-thiourea 6 on solid-
support. Subsequent guanidinylation on solid support
was smoothly carried out with a variety of amine nu-
cleophiles in the presence of either EDC or the Mu-
kaiyama reagent. Again, sterically hindered aliphatic
amines or electron-deficient arylamines all gave very high
Compared to other synthetic methods using solid or
soluble support for N,N′-substituted guanidines starting
from two amines, our methodology also has its own
merits. For example, Kearney et al.29 and Chang et al.25
each described a methodology through activation of
thioureas by methylation to form isothioureas, while the
Burgess group reported direct conversion of thioureas to
carbodiimides through the use of Mukaiyama reagent.19
These methods have the advantage that there is no need
to handle protecting groups for the guanidine moiety
during synthesis or cleavage. However, even though our
method has to deal with the Pbf protecting group, its
removal is achieved concomitantly with product cleavage
and the side product was readily removed with simple
aqueous extraction and filtration. On the other hand, the
isothiourea method by Kearney et al. requires heating
in sealed pressure-tube for 12 h at 80 °C for guanidiny-
lation. In some instances, the final product purities were
less than 50%, which may be attributed to a variety of
J . Org. Chem, Vol. 68, No. 4, 2003 1613

reasons including repeated treatment of the resin-bound
materials with MeI for activation.29 The isothiourea
method described by Chang et al. also requires heating
in DMSO, and the obtained yields vary widely (11-74%).
The carbodiimide method described by the Burgess group
is currently restricted to the starting amine being aniline
derivatives bearing electron-withdrawing groups.19 Com-
pared to these three methods, our synthetic route can
produce equivalent or better yields at room temperature
for 12-18 h and is applicable to starting alkylamines.
There are two other syntheses of N,N′-substituted
guanidines on solid-support, each using a carbonyl-based
thiourea activation strategy.24,28 The use of Wang resin
to form TFA-labile alkoxycarbonyl activated thiourea
allowed J osey at al to achieve efficient synthesis of
guanidines with N,N′ and other types of substitution
patterns.28 However, the authors only specifically de-
scribed product purity for phenyl and allyl based thio-
ureas, and left out yield information for other starting
alkyl thioureas. This makes it hard to compare with our
current method. The method described by Wilson et al.
used a novel carboxypolystyrene to produce acyl activated
thiourea for guanidinylation. However, this method
generally produced isolated yields in the 40% range,24
while our method produced yields in the 70-95% range.
Compared to other guanidinylating methods based on
TFA-sensitive arylsulfonyl groups (Mtr- and Pmc-based
isothioureas,36 and Mtr-based carbonimidodithioate,39
Mtr: 4-methoxy-2,3,6-trimethylbenzenesulfonyl; Pmc:
2,2,5,7,8-pentamethylchroman-6-sulfonyl), our methodol-
ogy can carry out guanidinylation at room temperature
while the other methods invariantly require heating to
displace the final MeS- group in the isothiourea moiety.
Although we chose to use Pbf-based reagents, we expect
that alternative use of either Mtr or Pmc should provide
equal efficiency in reaction because the Pbf group con-
tains a more electron-donating aromatic moiety than
either Pmc or Mtr.50 As for concomitant removal of these
arylsulfonyl groups during final TFA cleavage, the Pbf
or Pmc would probably perform equally in practical terms
(half-life in TFA as guanidine protection: Pbf, 8 min;50
Pmc, 13 min50), while the Mtr group should also be
adequate since its complete removal can be achieved in
one to 5 h,52,53 which is compatible to general solid-phase
cleavage protocols.
In summary, we have demonstrated the synthesis of
N,N′-substituted guanidine compounds through TFA-
sensitive arylsulfonyl activated thiourea that meets our
aforementioned goals. The high reaction yield, mild
reaction condition, and the flexibility of solution or solid-
phase synthesis should make it a valuable extension to
current synthetic methodologies. In addition, TFA-sensi-
tive arylsulfonyl moieties are excellent guanidine protec-
tion groups. It is well-known that a single arylsulfonyl
modification is sufficient to suppress side reactions on
an arginine side chain in peptide chemistry, in contrast
to carbonyl based protections.54 This suggests that our
novel guanidine synthesis method can be incorporated
into other multiple-step synthetic procedures and provide
a desirable protection for the guanidine moiety during
the entire process. We are currently investigating such
properties and will report our findings in due course.
Ack n ow led gm en t. We thank Dr. Wim Hol for
stimulating discussions. This work was supported in
part by the National Institutes of Health (GM94655,
AI44954, and AI34501).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization of compounds 2, 3, 7, and 9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O026807M
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1614 J . Org. Chem., Vol. 68, No. 4, 2003