Reaction of thioacids with lsocyanates and lsothiocyanates: A convenient amide ligation process

Article abstract of DOI:10.1021/ol901370y

Thiocarboxylates, prepared conveniently by cleavage of 9-fluorenylmethyl or trimethoxybenzyl thioesters, react at room temperature with isocyanates and isothiocyanates to give amide bonds in good to excellent yield. A carboxylate salt is also shown to rea

Full text of DOI:10.1021/ol901370y

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3514-3517
Reaction of Thioacids with Isocyanates
and Isothiocyanates: A Convenient
Amide Ligation Process
David Crich* and Kaname Sasaki
Centre Scientifique de Gif, Institut de Chimie des Substances Naturelles, 1 AVenue de
la Terrasse, 91198 Gif-sur-YVette, France, and Department of Chemistry, Wayne State
UniVersity, 5101 Cass AVenue, Detroit, Michigan 48202
dcrich@icsn.cnrs-gif.fr
Received June 17, 2009
ABSTRACT
Thiocarboxylates, prepared conveniently by cleavage of 9-fluorenylmethyl or trimethoxybenzyl thioesters, react at room temperature with
isocyanates and isothiocyanates to give amide bonds in good to excellent yield. A carboxylate salt is also shown to react with an electron-
deficient isocyanate to give the corresponding amide in excellent yield at room temperature.
Given the widespread availability of amines and of carboxy-
lic acids, amide bond forming reactions are necessarily some
of the most widely applied transformations in parallel
synthesis and combinatorial chemistry. The needs for atom
ecomony, ever milder conditions, and greater selectivity
combine to drive the search for new and improved methods
for the formation of amide bonds.1 The condensation of
isocyanides with carboxylic acids has recently received much
interest in this regard,2 and this despite the relatively limited
range of commercially available isocyanides and the some-
what forcing reaction conditions. Our attention was caught
by a little known reaction3 involving condensations of the
much more widely available isocyanates and isothiocyanates
with monothiocarboxylates, which result in the formation
of amides with loss of a simple, volatile byproduct, carbon
oxysulfide or carbon disulfide, respectively. Although this
reaction was described in 1973 for use with very simple
substrates, it has seen very limited application subsequently,4
perhaps due to the relative paucity of commercially available
thioacids.5 We reasoned that the advent of convenient mild
methods for thioacid synthesis6 would combine with this
reaction to afford a convenient and mild method for amide
formation and report here that this is indeed the case. In
addition, we report promising preliminary results of a
(1) For recent advances see: (a) Bode, J. W Curr. Opin. Drug DiscoVery
DeV. 2006, 9, 765–775. (b) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron
2005, 61, 10827–10852. (c) Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60,
2447–2467.
(4) Beyond the original paper,3 which itself has only been cited 14 times
to date, we are only aware of four isolated examples of the reaction of
isothiocyanates with simple thioacids (three with thioacetic acid and one
with indolethioacetic acid) and of none between isocyanates themselves
and thioacids. The four examples of isothiocyanates and thioacids all make
use of heating to 60 or 80 °C to achieve the reactions described, and none
of the four papers makes reference to the original work of Kricheldorf and
Leppert.3 (a) Gonda, J.; Martinkova, M.; Walko, M.; Zavacka, E.;
Budesinsky, M.; Cisarova, I. Tetrahedron Lett. 2001, 42, 4401–4404. (b)
Gonda, J.; Zavacka, E.; Budesinsky, M.; Cisarova, I.; Podlaha, J. Tetra-
hedron Lett. 2000, 41, 525–529. (c) Gonda, J; Bednarikova, M. Tetrahedron
Lett. 1997, 38, 5569–5572. (d) Schoepfer, J.; Marquis, C.; Pasquier, C.;
Neier, R. J. Chem. Soc., Chem. Commun. 1994, 1001–1002.
(2) (a) Li, X.; Yuan, Y.; Kan, C.; Danishefsky, S. J. J. Am. Chem. Soc.
2008, 130, 13225–13227. (b) Li, X.; Yuan, Y.; Berkowitz, W. F.; Todaro,
L. J.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 13222–13224. (c)
Li, X.; Danishefsky, S. J. J. Am. Chem. Soc. 2008, 130, 5446–5448. (d)
Jones, G. O.; Li, X.; Hayden, A. E.; Houk, K. N.; Danishefsky, S. J. Org.
Lett. 2008, 10, 4093–4096. (e) Restrop, P.; Rebek, J. R. J. Am. Chem. Soc.
2008, 130, 11850–11851.
(3) Kricheldorf, H. R.; Leppert, E. Makromol. Chem. 1973, 167, 47–
68.
10.1021/ol901370y CCC: $40.75
Published on Web 07/07/2009
 2009 American Chemical Society

Table 1. Preparation of Thioesters and Their Reaction with Isocyanates and Isothiocyanatesa
a The isocyanates used in this study were either commercial or prepared by reaction of the corresponding amine with phosgene in the presence of
aqueous sodium bicarbonate in excellent yield. The isothiocyanate 4 was similarly prepared in quantitative yield by reaction of the amine with thiophosgene
under phase transfer conditions.
comparable reaction between simple carboxylic acids and
electron-deficient isocyanates, with loss of carbon dioxide,
also leading to the formation of amide bonds.
The 9-fluorenylmethyl (Fm) thioesters are a readily
prepared class of self-stable thioesters whose treatment with
piperidine provides a convenient in situ means of entry into
Org. Lett., Vol. 11, No. 15, 2009
3515

Table 2. Three-Component Coupling Reactions of Amines with Succinic Thioanhydride and Isocyanates or Isothiocyanates
thiocarboxylates.6b Their complement, the equally readily
available 2,4,6-trimethoxybenzyl (Tmob) thioesters, release
thioacids on exposure to trifluoroacetic acid.6a Accordingly,
the Fm and Tmob thioesters were selected as the precursors
of choice for thioacids in this study, and several were
prepared as outlined in Table 1. The thiocarboxylates were
released with piperidine or trifluoroacetic acid and triethyl-
silane, according to the thioester employed, and then exposed
to either isocyanates or an isothiocyanate at room temper-
ature, leading to the results set out in Table 1.
isothiocyanates behave more or less analogously in this
chemistry; this observation led us to favor the more readily
available isocyanates in the subsequent studies. Examples 3
and 4 of Table 1 illustrate the coupling of 9-fluorenylmethyl
thioester derived thiocarboxylates with an R-isocyanato ester
and hint at the potential for the application of this chemistry
in the formation of neoglycopeptides.7 Entries 5-9 of Table
1 use the 2,4,6-trimethoxybenzylthioester technology, with
release of the thioacid by treatment with trifluoroacetic acid
and triethylsilane, thereby enabling the generation of the
thioacid in the presence of the 9-fluorenylmethoxy carbamate
protecting group favored in solid-phase peptide synthesis.
Entries 5 and 6 (Table 1) indicate that both aromatic and
aliphatic isocyanates function correctly in this chemistry.
Entry 7 of Table 1 is directed at the formation of a peptide
bond, while entries 8 and 9 are again directed at the
neoglycopeptide area. Only modest yields were obtained in
entries 8 and 9, and in the latter case the symmetrical urea
18 was isolated as the major byproduct in 45% yield.
Entry 1 of Table 1 establishes the viability of the method
and nicely illustrates the potential for application to a
hindered tertiary thioacid. The release of the thioacid from
the 9-fluorenylmethyl thioester by simple treatment with
piperidine in DMF at room temperature is an important
feature of this reaction and one that ensures compatibility
with the two acetonide groups of the substrate. A comparison
of entries 1 and 2 of Table 1 indicates that isocyanates and
(5) For other amide bond forming reactions employing thioacids, see:
(a) Blake, J. Int. Pept. Protein Res. 1981, 17, 273–274. (b) Yamashiro, D.;
Blake, J. F. Int. J. Pept. Protein Chem. 1981, 18, 383–392. (c) Blake, J.;
Yamashiro, D.; Ramasharma, K.; Li, C. H. Int. J. Pept. Protein Res. 1986,
28, 468–476. (d) Yamashiro, D.; Li, C. H. Int. J. Pept. Protein Res. 1988,
31, 322–334. (e) Mitin, Y. V.; Zapevalova, N. P. Int. J. Pept. Protein Chem.
1990, 35, 352–356. (f) Høeg-Jensen, T.; Olsen, C. E.; Holm, A. J. Org.
Chem. 1994, 59, 1257–1263. (g) Dawson, P. E.; Muir, T. W.; Clark-Lewis,
I.; Kent, S. B. H. Science 1994, 266, 776–779. (h) Tam, J. P.; Lu, Y.-A.;
Liu, C.-F.; Shao, J. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 12485–12489.
(i) Messeri, T.; Sternbach, D. D.; Tomkinson, N. C. O. Tetrahedron Lett.
1998, 39, 1673–1676. (j) Messeri, T.; Sternbach, D. D.; Tomkinson, N. C. O.
Tetrahedron Lett. 1998, 39, 1669–1672. (k) Crich, D.; Sharma, I. Angew.
Chem., Int. Ed. 2009, 48, 2355–2358. (l) Hakimelahi, G. H.; Just, G.
Tetrahedron Lett. 1980, 21, 2119–2122. (m) Rosen, T.; Lico, I. M.; Chu,
D. T. W. J. Org. Chem. 1988, 53, 1580–1582. (n) Rakotomanomana, N.;
Lacombe, J.-M.; Pavia, A. Carbohydr. Res. 1990, 197, 318–323. (o)
McKervey, M. A.; O’Sullivan, M. B.; Myers, P. L.; Green, R. H. J. Chem.
Soc., Chem. Commun. 1993, 94–96. (p) Dudkin, V. Y.; Crich, D.
Tetrahedron Lett. 2003, 44, 1787–1789. (q) Kolakowski, R. V.; Shangguan,
N.; Sauers, R. R.; Williams, L. J. J. Am. Chem. Soc. 2006, 128, 5695–
5702. (r) Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams, L. J.
J. Am. Chem. Soc. 2003, 125, 7754–7755. (s) Fazio, F.; Wong, C. H.
Tetrahedron Lett. 2003, 44, 9083–9085. (t) Barlett, K. N.; Kolakowski,
R. V.; Katukojvala, S.; Williams, L. J. Org. Lett. 2006, 8, 823–826. (u)
Merkx, R.; van Haren, M. J.; Rijkers, D. T. S.; Liskamp, R. M. J. J. Org.
Chem. 2007, 72, 4574–4577. (v) Zhu, X. M.; Pachamuthu, K.; Schmidt,
R. R. Org. Lett. 2004, 6, 1083–1085. (w) Merkx, R.; Brouwer, A. R.;
Rijkers, D. T. S.; Liskamp, R. M. J. Org. Lett. 2005, 7, 1125–1128.
To further extend the scope of this reaction, we have also
applied it to thioacids generated in situ through the nucleo-
philic ring-opening of succinic monothioanhydride (Table
2). Here too, generally good yields were obtained with the
exception of the use of the sugar-based isocyanate 2 and
isothiocyanate 4 (Table 2, entries 4 and 5). Entries 4 and 5
of Table 2 serve as a second comparison between the
isocyanates and the isothiocyanates and support the earlier
conclusion that the two have comparable reactivity in this
chemistry.
The general mechanism of the reaction of thiocarboxylates
with isocyanates and isothiocyanates likely involves attack
(6) (a) Vetter, S. Synth. Commun. 1998, 28, 3219–3223. (b) Crich, D.;
Sana, K.; Guo, S. Org. Lett. 2007, 9, 4423–4426. (c) Crich, D.; Bowers,
A. A. Org. Lett. 2007, 9, 5323–5325. (d) Crich, D.; Sasaki, K.; Rahaman,
Md.; Bowers, Y. J. Org. Chem. 2009, 74, 3886–3893.
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Org. Lett., Vol. 11, No. 15, 2009

by the thiocarboxylate at the sp carbon to give an intermedi-
ate adduct 24 that undergoes rearrangement with loss of COS
or CS2 to give the final product 25 (Scheme 1).
intermediate adduct, thereby providing the time for the
desired rearrangement to take place.8
We have also attempted the reaction of simple carboxylate
esters with isocyanates, with a view to eliminating the
dependency on thiocarboxylates. In accord with the earlier
findings of Kricheldorf and Leppert, however, we find this
to be an unproductive avenue for most isocyanates (and
isothiocyanates) surveyed owing to the much reduced nu-
cleophilicity of the carboxylates. However, in the case of
suitably electron-deficient isocyanates, such reactions proceed
in a satisfactory manner over a period of several hours at
room temperature as illustrated in Scheme 2.
Scheme 1. Anticipated Reaction Mechanism
In view of this mechanism the somewhat poorer yields
obtained with the carbohydrate-based isocyanates 2 and 15
(Table 1, entries 8 and 9; Table 2, entry 4) and the related
isothiocyanate 4 (Table 2, entry 5) must be viewed in the
light of the intermediate adduct, particularly in view of the
good yield obtained with one of these isocyanates and a
different thioacid (Table 1, entry 1). We speculate the
reduced yields in these cases are due to the decomposition
of the intermediate adduct 24 to the product with loss of
COX being retarded by the multiplicity of electron-
withdrawing ꢀ-C-O (acetoxy groups and/or acetals), which
serves to reduce the nucleophilicity of the nitrogen atom in
the adduct. A slower decomposition enables competing
processes to intervene, such as the attack of a further
equivalent of thiocarboxylate at the thiocarboxyl center in
the adduct leading to the generation of a thioanhydride and
liberation of the amine (Scheme 1). The symmetric urea
byproducts (e.g., 18) are then formed by attack of the
liberated amine on the initial isocyanate. The good yield
obtained with the more hindered thioacid 1 (Table 1, entry
1) is the result of the steric hindrance about the thiocar-
boxylate that retards attack of external nucleophiles on the
Scheme 2
.
Reaction of a Carboxylate with an Electron-Deficient
Isocyanate
The reaction that we describe overall is closely related to
the reaction of thiocarboxylic acids with azides5l-w but is
potentially of broader scope for combinatorial and parallel
synthesis applications owing to the much wider commercial
availability of isocyanates. Although we have not investigated
the possibility, we anticipate that, as in the case of the azide
reaction, selenocarboxylates will also perform as suitable
nucleophiles in this chemistry.
Acknowledgment. We thank the NIH (GM62160) for
partial support of this work.
Supporting Information Available: Full experimental
details and copies of 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL901370Y
(7) (a) Nicotra, F.; Cipolla, L.; Peri, F.; La Ferta, B.; Redaelli, C. AdV.
Carbohydr. Chem. Biochem. 2007, 61, 353–398. (b) Roy, R. In Carbohy-
drate Chemistry; Boons, G.-J., Ed.; Blackie Academic and Professional:
London, 1998; pp 243-321. (c) Neoglycoconjugates: Preparation and
Applications; Lee, Y. C., Lee, R. T., Eds.; Academic Press: San Diego,
1994. (d) Haase, C.; Seitz, O. Top. Curr. Chem. 2007, 267, 1–36.
(8) In an attempt to accelerate the decomposition of the intermediate
and improve the yield of 2 and 9, a number of Lewis acids (nBu2BOTf,
BF3·OEt2, Sc(OTf)3, Sn(OTf)2, Yb(OTf)3, TiCl4, CuBr2, Fe(acac)3, Cu(acac)2,
Ti(OiPr)4, Zr(OiPr)4, and Sn(2-ethylhexanoate)2) were screened both with
and without the addition of Hunig’s base, unfortunately to no avail.
Org. Lett., Vol. 11, No. 15, 2009
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