N-bromosuccinimide promoted one-pot synthesis of guanidine: Scope and mechanism

Article abstract of DOI:10.1021/ol202402y

A novel electrophilic one-pot guanidine synthesis has been developed using an olefin, a cyanimide, an amine, and N-bromosuccinimide. A number of guanidine derivatives were prepared with good to excellent yields. An rTRTVI precursor was also prepared based on this useful process.

Full text of DOI:10.1021/ol202402y

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5804–5807
N-Bromosuccinimide Promoted One-Pot
Synthesis of Guanidine: Scope and
Mechanism
Ling Zhou, Jie Chen, Jing Zhou, and Ying-Yeung Yeung*
3 Science Drive 3, Department of Chemistry, National University of Singapore,
Singapore 117543
chmyyy@nus.edu.sg
Received September 5, 2011
ABSTRACT
A novel electrophilic one-pot guanidine synthesis has been developed using an olefin, a cyanimide, an amine, and N-bromosuccinimide. A number
of guanidine derivatives were prepared with good to excellent yields. An rTRTVI precursor was also prepared based on this useful process.
Guanidine is an important class of nitrogen-containing
heterocyclic compounds, which is the fundamental unit of
many natural products, biologically active molecules, and
metal complexation ligands.1 Due to its strong basicity,
guanidine is also considered as an organic superbase that is
useful in both stoichiometric and catalytic deprotonation
processes.2 Guanidine is also an attractive scaffold that is
found in chiral auxiliaries3 and chiral Brønsted base organo-
catalysts.4
Compared to other heterocyclic compounds’ syntheses,5
the synthetic methodologies for guanidine are limited to
several representative approaches.1iÀk,3,4 Additionally, the
demand for more environmentally benign processes has
emerged in recent years due to the concern for sustainable
development.6 Herein we report a facile and efficient ap-
proach toward guanidine using a one-pot multicomponent
strategy.
(1) (a) Pearson, W. H.; Lian, B. W.; Bergmeier, S. C. In Comprehen-
sive Heterocyclic Chemistry II, Vol. 1A; Padwa, A., Ed.; Pergamon Press:
Oxford, UK, 1996; pp 1À60. (b) Rai, K. M. L.; Hassner, A. In Com-
prehensive Heterocyclic Chemistry II, Vol. 1A; Padwa, A., Ed.; Pergamon
Press: Oxford, U.K., 1996; pp 61À96. (c) Grimmett, M. R. In Compre-
hensive Heterocyclic Chemistry II, Vol. 3; Katritsky, A. R., Scriven,
E. F. V., Eds.; Pergamon: Oxford, 1996; pp 77À220. (d) Berlinck,
R. G. S.; Burtoloso, A. C. B.; Kossuga, M. H. Nat. Prod. Rep. 2008, 25,
919–954. (e) Berlinck, R. G. S.; Kossuga, M. H. Nat. Prod. Rep. 2005, 22,
516–550. (f) Nagasawa, K.; Hashimoto, Y. Chem. Rec. 2003, 3, 201–211.
(g) Bellina, F.; Cauteruccio, S.; Rossi, R. Tetrahedron 2007, 63, 4571–
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Koenig, B. Mini Rev. Org. Chem. 2006, 3, 315–331. (j) Sullivan, J. D.;
Giles, R. L.; Looper, R. E. Curr. Bioact. Compd. 2009, 5, 39–78.
(k) Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237–243.
(2) (a) Kumamoto, T. In Superbases for Organic Synthesis: Guani-
dines, Amidines, Phosphazenes and Related Organoctalysts; Ishikawa, I.,
Ed.; John Wiley & Sons Press: West Sussex, U.K., 2009; pp 295À313.
(b) Ishikawa, T.; Kumamoto, T. Synthesis 2006, 737–752.
Recently, we have reported a novel electrophilic Br
initiated cascade, which is applicable to the synthesis of
aminoalkoxylation and imidazolines.7 Indeed, we found
that the same protocol can be applied to the construction
of a guanidine skeleton.
Based on our previous study on the one-pot imidazoline
synthesis,7a we modified the system by replacing the nitrile
(4) Leow, D.; Tan, C.-H. Chem.;Asian J. 2009, 4, 488–507.
(5) (a) Kemp, J. E. In Comprehensive Organic Synthesis, Vol. 7; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; pp 469À513.
(b) Booker-Milburn, K. I.; Guly, D. J.; Cox, B.; Procopiou, P. A. Org,.
Lett. 2003, 5, 3313–3315. (c) Abe, T.; Takeda, H.; Miwa, Y.; Yamada,
K.; Yamada, R.; Ishikura, M. Helv. Chim. Acta 2010, 93, 233–241.
(6) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. L.; Linderman, R. J., Jr.; Lorenz, K.; Manley, J.; Pearlman,
B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411–420.
(7) (a) Zhou, L; Zhou, J.; Tan, C. K.; Chen, J.; Yeung,
Y.-Y. Org. Lett. 2011, 13, 2448–2451. (b) Zhou, L.; Tan, C. K.; Zhou,
J.; Yeung, Y.-Y. J. Am. Chem. Soc. 2010, 132, 10245–10247.
(3) (a) Isobe, T.; Fukuda, K.; Ishikawa, T. J. Org. Chem. 2000,
65, 7770–7773. (b) Isobe, T.; Fukuda, K.; Tokunaga, T.; Seki, H.;
Yamaguchi, K.; Ishikawa, T. J. Org. Chem. 2000, 65, 7774–7778.
(c) Isobe, T.; Fukuda, K.; Yamaguchi, K.; Seki, H.; Tokunaga, T.;
Ishikawa, T. J. Org. Chem. 2000, 65, 7779–7785. (d) Ishikawa, T.; Isobe,
T. Chem.;Eur. J. 2002, 8, 552–557.
r
10.1021/ol202402y
Published on Web 10/11/2011
2011 American Chemical Society

with a cyanimide partner. Thus, a mixture of N-bro-
mosuccinimide (NBS), p-toluenesulfonamide (TsNH2),
cyclohexene, and N,N-dimethylcyanimide was reacted
at 25 °C for 4 h and yielded guanidine 1a (R = Ts) in 72%
yield (Scheme 1). Replacing TsNH2 with p-nitrobenzene-
sulfonamide (NsNH2) allowed us to obtain the corre-
sponding guanidine 1a (R = Ns) in 85% yield.
Table 1. One-Pot Synthesis of Guanidines Using Various
Olefins
Scheme 1. One-Pot Guanidine Synthesis
With this positive result in hand, various olefinic sub-
strates were subjected to investigation. In general, good to
excellent yields of the desired products were obtained
(Table 1).8 The reactions were also highly regioselec-
tive, with only Markovnikov-type products were isolated
(Table 1, entries 2À5, 7À13). This reaction also worked
well not only with the electron-rich olefins (Table 1, entries
8À9, 13) but also with the relatively electron-deficient
olefins (Table 1, entries 10À12). The reaction also worked
well with N,N-diethylcyanimide (Table 1, entry 17).
Potentially due to the high basicity of guanidine, most of
the products were isolated as the corresponding cyclized
products (Table 1, entries 2À14). For those reactions
which yielded open-chain guanidines (e.g., Scheme 2, 1s),
the corresponding cyclized product (e.g., Scheme 2, 2s)
could easily be achieved by simply heating up the same pot
of reaction mixture at 80 °C for 2 h. The structures of 1p,
2c, 2f, 2k, and 2s were unambiguously confirmed by X-ray
studies.9
In an effort toward the development of efficient and
diversity-orientated approaches toward biologically im-
portant heterocycles in our laboratory,7 we attempted to
synthesize guanidine 6, a key intermediate for the syn-
thesis of rTRPVI inhibitor 7 which has been prepared by a
multistep sequence.10 Preliminary studies showed that 6
(8) General procedure: To a solution of N-bromosuccinimide (107
mg, 0.6 mmol) and sulfonamide (0.5 mmol) in dry N,N-dimethylcyani-
mide (1 mL) in the dark was added olefin (0.6 mmol). After stirring for
4 h at 25 °C, the reaction was quenched with saturated Na2S2O3 (5 mL)
and NaHCO3 (5 mL). The mixture was extracted with CH2Cl2 (3 Â
15 mL). The combined extracts were washed with brine (15 mL), dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography to yield the correspond-
ing product.
(9) The details appear in the Supporting Information.
(10) Gore, V. K.; Ma, V. V.; Tamir, R.; Gavva, N. R.; Treanor,
J. J. S.; Norman, M. H. Bioorg. Med. Chem. Lett. 2007, 17, 5825–5830.
(11) Promotors are typically required to activate the weakly electro-
philic Br in NBS: (a) Schmid, G. H.; Garrat, D. G. In The Chemistry of
Double Bonded Functional Groups; Patai, S., Ed.; Wiley: New York, 1977;
Suppl. A, Part 2, p 725. (b) DeLaMare, P. B. D.; Bolton, R. Electrophilic
Additions to Unsaturated Systems, 2nd ed.; Elsevier: New York, 1982;
pp 136À197. (c) Ruasse, M.-F. Adv. Phys. Org. Chem. 1993, 28, 207–291.
For recent examples of electrophilic Br initiated cascades, see:
(d) Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed. 2009, 48, 7899–
7903. (e) Snyder, S. A.; Treitler, D. S.; Brucks, A. P. J. Am. Chem. Soc.
2010, 132, 14303–14314. (f) Alcaide, B.; Almendros, P.; Luna, A.;
Torres, M. R. Adv. Synth. Catal. 2010, 352, 621–626.
a Reactions were carried out with olefin (0.6 mmol), NBS (0.6 mmol),
and RNH2 (0.5 mmol) in N,N-dimethylcyanimide (1 mL) at 25 °C for
4 h. The yields were isolated yields. b 1.0 mmol of olefin was used. c Excess
cis-2-butene (gas) was used. d Et2NCN was used instead of Me2NCN.
Org. Lett., Vol. 13, No. 21, 2011
5805

Scheme 2. One-Pot Synthesis of 2s
Scheme 4. Synthetic Studies toward 8 Using Acetamides
appears that the intermediate was formed by the Br ex-
change between RNH2 (R = Ts, Ns) and NBS accom-
panied with the formation of succinimide. We have also
conducted a 1H NMR study on a 1:1 mixture of NBS and
NsNH2 (orTsNH2) inCD3CN.9,15 A set of new signalswas
observed (7.04 ppm, singlet; 8.11 ppm, doublet; 8.41 ppm,
doublet) accompanied by another new signal at 2.60 ppm
which belongs to succinimide. Based on the calculation of
the integration ratio, ca. 20% of NBS was consumed and
ca. 20%ofNsNH2 (8.06, 8.35ppm) was transformed tothe
new species (8.11, 8.41 ppm). The above results and obser-
vations suggest that the Br exchange afforded an inter-
mediate which should be NsNHBr.
Scheme 3. Study towards the Synthesis of 7
Based on these observations, it appears that (1) an amine
nucleophilic partner, which contains acidic protons, is
critical for the reaction and (2) RNHBr (R = Ts, Ns)
may be an important intermediate.16 Although the me-
chanism remains unclear, a possible pathway is that the
in situ generated NsNHBr may act as a more reactive Br
source in the formation of bromonium intermediate 9
(Scheme 3, Mode A). Subsequent trapping of 9 with a
cyanimide (e.g., Me2NCN) or a cyclic ether (e.g., ethylene
oxide) can afford the cationic species 10a or 10b, respec-
tively.
could readily be furnished by simply mixing p-trifluoro-
methylstyrene (3), NsNH2, cyanimide 4, and NBS in
CH2Cl2 at 25 °C for 4 h (Scheme 3).
It is important to notice that the above-mentioned
reactions proceeded smoothly in the absence of any addi-
tional NBS activator.11 Moreover, the same phenomenon
was observed in our previous reports on the imidazoline
and the cyclic ether cascades;7 this led us to probe the sole
origin of the reactivity. We had suspected that the reaction
might proceed through an autocatalytic process; i.e. the
guanidine product might act as a Lewis base catalyst to
promote the halogenation reaction.12 However, this hypo-
thesis was ruled out by using tetramethylguanidine as the
catalyst, for which no improvement in reaction rate and
yield was observed.13 We have also investigated the im-
portance of the acidity of the amide nucleophile using p-
bromostyrene as the model substrate. Instead of NsNH2, it
was found that the use of trifluoroacetamide could afford
the corresponding guanidine 8 in 90% yield.14 However,
the reaction was sluggish when using trichloroacetamide
(Scheme 4).
Scheme 5. Proposed Mechanism of the Br Activation
Other than the above-mentioned studies, an important
mechanistic clue was unearthed by the discovery of an
intermediate (traced by TLC) that was detected consistently
in each of the reactions. After extensive experimentations, it
Finally, 10 can be captured by the amide to yield the de-
sired products. On the other hand, we also spectulate that
the halogen source (NBS or NsNHBr) may be activated by
(12) (a) Ahmad, S. M.; Braddock, D. C.; Cansell, G.; Hermitage,
S. A.; Redmond, J. M.; White, A. J. P. Tetrahedron Lett. 2007, 48, 5948–
5952. (b) Ahmad, S. M.; Braddock, D. C.; Cansell, G.; Hermitage, S. A.
Tetrahedron Lett. 2007, 48, 915–918.
(13) 10 mol% of tetramethylguanidine was added to the reaction
using cyclohexene or styrene, for which the rate and yield were identical
to those of the original reaction.
(14) The trifluoroacetyl group was not stable and was deprotected
during the workup process. The same free guanidine 8 could be furnished
by removing the Ns group of 2m.
(15) Attempts to prepare pure TsNHBr or NsNHBr were unsuccess-
ful. For related studies, see: (a) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.;
Yeung, Y.-Y. J. Am. Chem. Soc. 2010, 132, 15474–15476. (b) Catino,
A. J.; Nichols, J. M.; Forslund, R. E.; Doyle, M. P. Org. Lett. 2005, 7,
2787–2790.
(16) Cai, Y.; Liu, X.; Jiang, J.; Chen, W.; Lin, L.; Feng, X. J. Am.
Chem. Soc. 2011, 133, 5636–5639.
5806
Org. Lett., Vol. 13, No. 21, 2011

the mildly acidic NsNH2, potentially through the coordi-
nation of the carbonyl (or sulfonyl) oxygen (Scheme 5,
Mode B). The failure in obtaining a good yield when NCS
or NIS was employed suggests that the NsNH2/NBS acti-
vation mode (either A or B) is highly specific.17
NsNH2 (or TsNH2). Research toward the exploration
of reactions that are analogous to this methodology as
well as the synthesis of bioactive guanidine derivatives is
underway.
In summary, we have developed a general and efficient
one-pot guanidine synthesis using an olefin, NBS, an
amide, and a cyanimide. A wide range of guanidine deri-
vatives can be synthesized using this methodology. The
reaction can proceed smoothly in the absence of an addi-
tional NBS activator, in which the sole origin of the reac-
tivity can be ascribed to the unique chemical pair, NBS and
Acknowledgment. We thank the financial support
from the National University of Singapore (Grant No.
143-000-428-112). We also thank Prof. Scott E. Denmark
(University of Illinois) for his valuable advice on this
project.
Supporting Information Available. Experimental pro-
cedures and additional information. This material is
available free of charge via the Internet at http://
pubs.acs.org.
(17) The results were unsatisfactory when using NCS or NIS as the
halogen source. The same phenomenon was also observed in our
previous studies. For details, see ref 7.
Org. Lett., Vol. 13, No. 21, 2011
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