A mild method for the synthesis of carbamate-protected guanidines using the burgess reagent

Article abstract of DOI:10.1021/ol5002208

A simple method for the synthesis of carbamate-protected guanidines from primary amines is described. A variety of thioureas derived from primary amines and isothiocyanates react with the Burgess reagent to give the corresponding guanidines via either a stepwise or one-pot procedure. By tuning the carbamoyl units of isothiocyanates and the Burgess reagent, differentially N,N′-diprotected guanidines can be obtained. Selective deprotection of the products affords N-monoprotected guanidines.

Full text of DOI:10.1021/ol5002208

Letter
pubs.acs.org/OrgLett
A Mild Method for the Synthesis of Carbamate-Protected Guanidines
Using the Burgess Reagent
Toshikatsu Maki,* Takayuki Tsuritani, and Tatsuro Yasukata
Chemical Development Center, CMC Development Laboratories, Shionogi & Co., Ltd., 3-1-1, Futaba-cho, Toyonaka-shi, Osaka
561-0825, Japan
S
* Supporting Information
ABSTRACT: A simple method for the synthesis of
carbamate-protected guanidines from primary amines is
described. A variety of thioureas derived from primary amines
and isothiocyanates react with the Burgess reagent to give the
corresponding guanidines via either a stepwise or one-pot
procedure. By tuning the carbamoyl units of isothiocyanates
and the Burgess reagent, differentially N,N′-diprotected
guanidines can be obtained. Selective deprotection of the
products affords N-monoprotected guanidines.
he guanidine moiety is found in a number of biologically
T
active compounds.1 Guanidines are also employed as base
catalysts, chiral auxiliaries, and ligands in organic synthesis.2
Consequently, a large number of synthetic methods have been
developed to install the guanidine unit.3
Figure 2. Burgess reagent 3a and related compounds 3b−3e.
While there are many methods for the synthesis of N,N′-
diprotected guanidines,4 only a few have been reported for the
preparation of differentially N,N′-diprotected guanidines, which
are valuable intermediates for the construction of more
complex derivatives.5,6 One example involves the reaction of
amines with Boc, Cbz-protected methylisothiourea (1, Figure
1).5 This method is mild and works well for a variety of amines
mines.11 On the basis of these findings, we hypothesized that it
would be possible to prepare carbamate-protected guanidines
through rearrangement of intermediate 4, which can be
generated in situ from thiourea and 3 (Scheme 1).
Scheme 1. Strategy to Guanidines from Thioureas Using the
Burgess Reagent 3
Figure 1. Examples of guanylating reagents.
Herein, we describe a method for the synthesis of
differentially N,N′-diprotected guanidines by desulfurative
condensation of carbamoyl thiourea with 3 under mild reaction
conditions. In this reaction, the Burgess reagent plays dual roles
as a carbamate source and a desulflurizing agent. To the best of
our knowledge, this is the first application of the Burgess
reagent as a desulfurizing agent.12
We first investigated the desulfurative condensation of N-
benzylthiourea derivatives 5a−5d with 3a (2 equiv) in THF at
ambient temperature (Table 1). As expected, thioureas 5b−5d
with electron-withdrawing protecting groups, such as Cbz, Ts,
and Bz, gave the desired guanidines 6ab−6ad, while N,N′-
but requires stoichiometric amounts of highly toxic HgCl2 and
generates insoluble mercuric sulfide, which often complicates
the purification procedure. Another example involves the
reaction of amines with Boc, Cbz-protected 1H-pyrazole-1-
carboxamidine (2, Figure 1).6 Although this reaction proceeds
cleanly, preparation of 2 requires multistep synthesis6b and 2 is
unstable and difficult to handle.6a Thus, there is a need for
more convenient methods to produce such guanidines.
On the other hand, the Burgess reagent7 (3, Figure 2) has
been used as a powerful dehydrating agent in chemical
synthesis for decades. It has also been employed as a
convenient source of nitrogen in synthetically useful trans-
formations such as the conversion of alcohols into carbamate
derivatives,7,8 1,2-diols or epoxides into sulfamidates,9,10
aminoalcohols into sulfamides,9 and sulfoxides into sulfili-
Received: January 21, 2014
Published: March 14, 2014
© 2014 American Chemical Society
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Letter
Table 1. Reactivity of 3a toward Diverse Thioureas 5a−5d
Table 3. Desulfurative Condensation of Various Carbamoyl
Thioureas 5 with the Burgess Reagent 3
entry
5 (R)
time (h)
6
yield (%)
1
2
3
4
5a (Ph)
5b (Cbz)
5c (Ts)
5d (Bz)
4
2
3
1
6aa
6ab
6ac
6ad
0
73
63
29
dibenzylthiourea 5a did not give the desired product.
Carbamoyl thiourea 5b prepared from benzylamine and Cbz-
isothiocyanate 713 gave the best results. The Cbz group was
also found to be a superior protecting group compared to the
Ts or Bz group.
Encouraged by these results, we next examined the reaction
of 5b with the Burgess-type reagents 3b−3e9,11 to incorporate
more easily removable protecting groups, such as Boc, Alloc,
Troc, and Cbz (Table 2). In all cases, the desired guanidines
6bb−6eb were obtained in good yields similar to the case of 3a.
Table 2. Reactivity of the Burgess-Type Reagents 3b−3e
toward 5b
entry
1
3 (R)
time (h)
6
yield (%)
3b (Boc)
3c (Alloc)
3d (Troc)
3e (Cbz)
1
2
5
3
6bb
6cb
6db
6eb
80
86
63
79
a
2
3
b
4
a
b
2.5 equiv of 3c were used. 3.0 equiv of 3e were used.
To explore the generality and scope of this reaction, various
substrates (5e−5s) were examined (Table 3). Thioureas
derived from aliphatic and aromatic amines reacted with 3 to
give the desired guanidines in good yields (6ae, 6af, 6ag, 6ch,
6ai). Functional groups such as ketone, ester, vinyl, alkynyl,
nitrile, and silyl groups were also tolerated (6aj, 6ak, 6al, 6am,
6an, 6ao). Fmoc or ethyl carbamate protected thiourea also
gave the product in 76% and 72% yields, respectively (6bp,
6aq). However, sterically demanding thiourea resulted in a low
yield (6ar), and secondary amine derived thiourea gave none of
the desired guanidines 6as, but did yield the methyl carbamate
protected thiourea 8.
a
b
c
2.5 equiv of 3c were used. 2.5 equiv of 3b were used. 4.0 equiv of
d
3a were used. 8 (Figure 3) was isolated in 61% yield.
Figure 3.
Next, we tried a one-pot synthesis of guanidine from the
corresponding amine, isothiocyanate, and 3 (Scheme 2).
Carbamoyl thiourea 5b, which was prepared from benzylamine
and 7 in situ, was directly treated with 3c to give the desired
guanidine 6cb in 80% yield.
Scheme 2. One-Pot Synthesis of 6cb from Benzylamine, 7,
and 3c
Finally, we demonstrated the selective deprotection of
differentially N,N′-diprotected guanidines (Table 4). Cbz,
Boc, and Fmoc protecting groups of guanidines 6ab, 6bb,
and 6bo were cleaved selectively under standard conditions
(hydrogenolysis, acidic, and basic conditions) to afford the
desired N-monoprotected guanidines14 9−12 in high yields.
Based on literature precedents,7−12 we propose the following
reaction mechanism (Scheme 3). The reaction of thiourea 5
with the Burgess reagent 3 affords intermediate 4. This
postulated intermediate 4 rearranges to 13, which is hydrolyzed
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Table 4. Selective Deprotection of Differentially N,N′-Diprotected Guanidines
entry
6 (R1,R2)
conditions
product (R3)
yield (%)
1
2
3
4
6ab (CO2Me, Cbz)
6bb (Boc, Cbz)
H2, Pd/C (5 mol %) MeOH/THF, rt, 1 h
TFA/CH2CI2 = 1/1, rt, 1 h
9 (CO2Me)
10 (Cbz)
95
92
99
91
6bo (Boc, Fmoc)
6bo (Boc, Fmoc)
TFA/CH2Cl2 = 1/1, rt, 1 h
11 (Fmoc)
12 (Boc)
piperidine/DMF = 1/10, rt, 5 min
(2) For recent reviews, see: (a) Ishikawa, T. Superbases for Organic
Synthesis; Ishikawa, T., Ed.; John Wiley & Sons Ltd: Chichester, 2009;
p 93. (b) Leow, D.; Tan, C.-H. Chem.Asian J. 2009, 4, 488.
(c) Ishikawa, T. Chem. Pharm. Bull. 2010, 58, 1555. (d) Selig, P.
Synthesis 2013, 703.
(3) For reviews of guanylating reagents, see: (a) Schneider, S. E.;
Bishop, P. A.; Salazar, M. A.; Bishop, O. A.; Anslyn, E. V. Tetrahedron
1998, 54, 15063. (b) Manimala, J. C.; Anslyn, E. V. Eur. J. Org. Chem.
2002, 67, 3909. (c) Katritzky, A. R.; Rogovoy, B. V. ARKIVOC 2005,
49.
to give guanidine 6 with the release of thiosulfuric acid under
the workup conditions.
Scheme 3. Proposed Mechanism for the Synthesis of
Guanidines from Thioureas Using the Burgess Reagent
(4) For selected examples, see: (a) Bernatowicz, M. S.; Wu, Y.;
Matsueda, G. R. Tetrahedron Lett. 1993, 34, 3389. (b) Kim, K. S.;
Qian, L. Tetrahedron Lett. 1993, 34, 7677. (c) Drake, B.; Patek, M.;
Lebl, M. Synthesis 1994, 579. (d) Chandrakumar, N. S. Synth.
Commun. 1996, 26, 2613. (e) Lal, B.; Gangopadhyay, A. K.
Tetrahedron Lett. 1996, 37, 2483. (f) Yong, Y. F.; Kowalski, J. A.;
Lipton, M. A. J. Org. Chem. 1997, 62, 1540. (g) Feichtinger, K.; Zapf,
C.; Singh, H. L.; Goodman, M. J. Org. Chem. 1998, 63, 8432.
(5) (a) Sawayama, Y.; Nishikawa, T. Synlett 2011, 651. (b) Sawayama,
Y.; Nishikawa, T. Angew. Chem., Int. Ed. 2011, 50, 7176.
(c) Birnkammer, T.; Spickenreither, A.; Brunskole, I.; Lopuch, M.;
Kagermeier, N.; Bernhardt, B.; Dove, S.; Seifert, R.; Elz, S.; Buschauer,
A. J. Med. Chem. 2012, 55, 1147.
(6) (a) Schroif-Gregoire, C.; Barale, K.; Zaparucha, A.; Al-Mourabit,
A. Tetrahedron Lett. 2007, 48, 2357. (b) Keller, M.; Pop, N.; Hutzler,
C.; Beck-Sickinger, A. G.; Bernhardt, G.; Buschauer, A. J. Med. Chem.
2008, 51, 8168. (c) Pluym, N.; Brennauer, A.; Keller, M.; Ziemek, R.;
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(d) Keller, M.; Erdmann, D.; Pop, N.; Pluym, N.; Teng, S.; Bernhardt,
G.; Buschauer, A. Bioorg. Med. Chem. 2011, 19, 2859.
In summary, we have developed a simple method for the
synthesis of differentially N,N′-diprotected guanidines from
carbamoyl thioureas by using the Burgess reagent. Further
studies of the mechanistic aspects and the application of this
approach to other types of desulfurative condensation are now
underway.
(7) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973,
38, 26.
ASSOCIATED CONTENT
■
S
(8) Wood, M. R.; Kim, J. Y.; Books, K. M. Tetrahedron Lett. 2002, 43,
3887.
* Supporting Information
Experimental procedures, full characterization of new com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
(9) (a) Nicolaou, K. C.; Huang, X.; Snyder, S. A.; Rao, P. B.; Bella,
M.; Reddy, M. V. Angew. Chem., Int. Ed. 2002, 41, 834. (b) Nicolaou,
K. C.; Longbottom, D. A.; Snyder, S. A.; Nalbanadian, A. Z.; Huang, X.
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(e) Metcalf, T. A.; Simionescu, R.; Hudlicky, T. J. Org. Chem. 2010,
75, 3447.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: toshikatsu.maki@shionogi.co.jp.
Notes
The authors declare no competing financial interest.
(10) (a) Rinner, U.; Adams, D. R.; dos Santos, M. L.; Abboud, K. A.;
Hudlicky, T. Synlett 2003, 1247. (b) Leisch, H.; Saxon, R.; Sullivan, B.;
Hudlicky, T. Synlett 2006, 445. (c) Sullivan, B.; Gilmet, J.; Leisch, H.;
Hudlicky, T. J. Nat. Prod. 2008, 71, 346. (d) Leisch, H.; Sullivan, B.;
Fonovic, B.; Dudding, T.; Hudlicky, T. Eur. J. Org. Chem. 2009, 2806.
(11) Raghavan, S.; Mustafa, S.; Rathore, K. Tetrahedron Lett. 2008,
49, 4256.
(12) Hudlicky and co-workers reacted thiols with the Burgess reagent
expecting desulfurization to alkenes, but instead disulfides were
produced in good yields: Banfield, S. C.; Omori, A. T.; Leisch, H.;
Hudlicky, T. J. Org. Chem. 2007, 72, 4989.
ACKNOWLEDGMENTS
■
We thank Ms. Naomi Umesako of the Shionogi Techno
Advance Research Co., Ltd., for performing high-resolution
mass spectroscopy analysis, and Mr. Naoya Iijima of the
Chemical Development Center, CMC Development Labora-
tories, Shionogi & Co., Ltd., for helpful discussions.
REFERENCES
■
(13) Linton, B. R.; Carr, A. J.; Orner, B. P.; Hamilton, A. D. J. Org.
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Prod. Rep. 2012, 29, 1382 and references therein.
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Letter
(14) (a) Padmanabhan, S.; Lavin, R. C.; Thakkar, P. M.; Durant, G. J.
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NOTE ADDED AFTER ASAP PUBLICATION
■
The header graphics in Tables 1 and 2 contained errors in the
version published ASAP March 14, 2014; the correct version
reposted March 18, 2014.
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