A simple method for the conversion of carboxylic acids into thioacids with Lawesson's reagent

Article abstract of DOI:10.1016/j.tetlet.2009.09.080

A one-step protocol for the conversion of carboxylic acids to thioesters, using Lawesson's Reagent, has been developed.

Full text of DOI:10.1016/j.tetlet.2009.09.080

Tetrahedron Letters 50 (2009) 6684–6686
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple method for the conversion of carboxylic acids into thioacids with
Lawesson’s reagent
Yu Rao a, Xuechen Li a, Pavel Nagorny a, Joji Hayashida a, Samuel J. Danishefsky a,b,
*
a Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA
b Department of Chemistry, Columbia University, 3000 Broadway, New York, NY 10027, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-step protocol for the conversion of carboxylic acids to thioesters, using Lawesson’s Reagent, has
Received 1 September 2009
Revised 12 September 2009
Accepted 15 September 2009
Available online 19 September 2009
been developed.
Ó 2009 Elsevier Ltd. All rights reserved.
Thioacids represent a well-established and versatile class of or-
ganic compounds. Due to their nucleophilicity, thioacids have
found broad applications, for instance the synthesis of thiols and
thioesters1 as well as in reactions with azides and nitrosulfona-
mides.2,3 The recognition that thioacids are not only exploitable
nucleophiles, but also can function as overall acylating agents un-
der mild conditions, has enabled the development of a number of
new methods for the construction of simple amides, as well as
amide bonds in the context of peptide ligations.4
In the course of a current program directed toward the synthe-
sis of glycopeptides (and glycoproteins),5 we recently disclosed
several strategies which use thioacids as the coupling partners.6
The value of such methods depends on the accessibility of the thio-
acids. We have now directed our efforts to the development of a
new and practical protocol for the selective installation of thioacid
functionality.
Among the current methods for synthesizing thioacids, three
are most commonly used. One involves pre-formation of activated
carboxylic acids, which are converted to thioacids by reaction with
hydrosulfide (HS) anion.7 Another involves prior coupling of the
carboxylic acid with either HSFmoc, HSTrt, or HSTmob. Removal
of the protecting group releases the target thioacid.8 Finally, Boc
solid phase peptide synthesis (SPPS) with a thioester solid support
can be applied to the preparation of large peptide thioacids.9 The
major limitations of these approaches include the toxicity of H2S,
required recourse to activating agents, current commercial
unavailability of HSFmoc and HSTmob, and the inconvenience fac-
tors associated with a multistep protocol to accomplish a simple –
OH to –SH interconversion. We describe herein the development of
a new and efficient one-step synthesis of thioacids from the corre-
sponding carboxylic acids, using Lawesson’s reagent (LR).
Lawesson’s reagent is commercially available, inexpensive, and
widely used in organic synthesis, particularly for the transforma-
tion of a carbonyl functional group to its thiocarbonyl counter-
part.10 Remarkably, there had been no systematic study
investigating the preparation of thioacids by direct reaction be-
tween carboxylic acid and LR. As outlined in Scheme 1, we postu-
lated that, perhaps, a carboxylic acid (1) could react with LR in a
manner analogous to that observed in reaction with alcohols,
through a ‘Wittig-like’ mechanism, to provide the corresponding
thioacid (2).11
Accordingly, we initiated a model study with benzoic acid (3, Ta-
ble 1). In practice, no thioacid was observed when 3 was treated
with LR (0.55 equiv) at RT in DCM for 3 h (entry 1). Even when
the reaction was run overnight (entry 2), only trace amounts of
thiobenzoic acid 4 were observed. Since microwave (MW) treat-
ment is often employed for the rapid preparation of thiocarbonyl
compounds with LR,12 we wondered whether it might help to facil-
itate the desired transformation. Indeed, the conversion of 3?4 was
accomplished efficiently within 10 min under MW conditions at
100 °C, in 76% yield (entry 3). A preliminary screening of conditions
revealed that solvents, such as DCM, CHCl3, and CH3CN, promote
thioacid formation with high levels of efficiency (entries 3, 5, and 6).
S
S
S
O
S
P
Ar
S
O
P
P
Ar
R
OH
Ar
O
O
R
SH
1
2
(Ar = p-MeOC6H4-)
O
HS
Ar
S
P
S
R
SH
P
R
OH
O
R
S P
Ar
O
OH
Ar
S
* Corresponding author. Tel.: +1 212 639 5501; fax: +1 212 772 8691.
E-mail address: s-danishefsky@ski.mskcc.org (S.J. Danishefsky).
Scheme 1. Proposed mechanism for thioacid formation with LR.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.080

Y. Rao et al. / Tetrahedron Letters 50 (2009) 6684–6686
6685
Table 1
O
O
O
a
a
BocHN
S
S
S
BocHN
(A)
(B)
O
SH
SH
O
OH
OH
MeO
OMe
P
P
S
13
OH
HO
SH
HO
Lawesson's Reagent (0.55 equiv)
O
3
4
BocHN
Conditions
BocHN
Entry
Conditions
Yield (%)
14
CONH2
1
2
3
4
5
6
DCM, rt, 3 h
DCM, rt, overnight
DCM, microwave, 100 °C, 10 min
THF, microwave, 100 °C, 10 min
CHCl3, microwave, 100 °C, 10 min
CH3CN, microwave, 100 °C, 10 min
NRa
Trace
76
46
73
CONH2
Scheme 2. Reagents and conditions: (a) DCM, LR, MW, 100 °C, 10 min.
77
a
NR = no reaction.
O
O
a, b
BocHN
BnS
O
BocHN
HO
(A)
(B)
OBn
OBn
Table 2
72%, two steps
Me
15
16
O
O
O
Me
Me
OH
Lawesson's Reagent
R
SH
R
OH
DCM, microwave, 100 °C, 10 min
O
O
Me
SH
c
FmocHN
FmocHN
N
78%
82%
N
H
O
O
O
H
Me
O
Me
O
FmocHN
SH
SH
17
18 68%, 4-5:1 dr
9
5
Scheme 3. Reagents and conditions: (a) DCM, MW, LR 100 °C; (b) BnBr, K2CO3, THF/
MeOH, rt; (72%, two steps); c) LR, DCM, rt, 24 h; (68%, 4–5:1 dr).
80%
83%
O
FmocHN
SH
through a ‘two-step’ procedure, in 72% overall yield. When dipep-
tide 17 was subjected to LR at rt overnight,13 the corresponding
thioacid 18 was obtained, with its internal amide bond intact.
However, significant epimerization (possibly resulting from
in situ oxazolone formation) was observed.
In summary, a practical new method for the synthesis of thioac-
ids with LR has been developed. This method has been found to be
generally useful for the preparation of a wide variety of thioacids.
The reaction demonstrates good chemoselectivity for a number of
functional groups, such as arenes, olefins, carbamates, esters, and
amides. It has been successfully demonstrated in the context of
the preparation of thioester 16. Although our preliminary results
indicate that epimerization may be a problem for the preparation
of peptidic thioacids such as 18, solutions to this issue are being
pursued. Application of these new capabilities will be described
in due course.
SH
Me
10
6
75%
80%
94%
O
O
FmocHN
Ph
SH
SH
Me Me
7
11
84%
MeO
SH
O
O
MeO
MeO
O
SH
8
12
OMe
OMe
Acknowledgments
Encouraged by these preliminary results, we next explored the
scope of the reaction (Table 2). We found that not only aliphatic
thioacids (8 and 12), but also cinnamic thioacid (7) and hindered
thioacids (5, 6, and 11) were produced under the conditions de-
scribed above, in serviceable yields. Furthermore, excellent che-
moselectivity was observed in the preparation of amino thioacids
(9, 10, and 11). Thus, when 0.55 equiv of LR was used, the Fmoc
protecting group was retained. However, reaction of substrates
13 and 14, possessing more reactive alcohol and primary amide
functionalities, respectively, did not yield the desired products
(Scheme 2). While the specific reasons for this failure are presently
unclear, conceivably, the primary alcohol and primary amides may
be competing with the carboxylic acid functionality during the
course of the reaction with LR. Alternatively, these functional
groups might interdict mechanistic intermediates.
Support was provided by the NIH (CA103823 to S.J.D.). P.N.
thanks the National Institutes of Health for a Ruth L. Kirschstein
postdoctoral fellowship (CA125934-02). We thank Professor W. F.
Berkowitz for helpful discussions. Special thanks to Ms. Rebecca
Wilson for editorial consultation. We acknowledge Ms. Dana Ryan
for assistance with the preparation of the Letter. We thank Dr.
George Sukenick, Ms. Hui Fang, and Ms. Sylvi Rusli of the Sloan-
Kettering Institute’s NMR core facility for mass spectral and NMR
spectroscopic analysis.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.09.080.
With this new method in hand, we sought to explore its poten-
tial applications to the preparation of synthetically valuable thioes-
ters and peptidic thioacids. As illustrated in Scheme 3, an aspartic
thioester (16) was efficiently prepared from aspartic acid (15)
References and notes
1. Mapp, A. K.; Dervan, P. B. Tetrahedron Lett. 2000, 41, 9451–9454.

6686
Y. Rao et al. / Tetrahedron Letters 50 (2009) 6684–6686
2. Barlett, K. N.; Kolakowski, R. V.; Katukojvala, S.; Williams, L. J. Org. Lett. 2006, 8,
823–826.
3. Crich, D.; Sana, K.; Guo, S. Org. Lett. 2007, 9, 4423–4426.
7. Cronyn, M. W.; Jiu, J. J. Am. Chem. Soc. 1952, 74, 4726.
8. (a) Crich, D.; Bowers, A. A. Org. Lett. 2007, 9, 5323–5325; (b) Vetter, S. Synth.
Commun. 1998, 28, 3219–3223.
4. (a) Crich, D.; Sharma, I. Angew. Chem., Int. Ed. 2009, 48, 2355–2358; (b) Crich,
D.; Sasaki, K. Org. Lett. 2009, 11, 3514–3517; (c) Merkx, R.; van Haren, M. J.;
Rijkers, D. T. S.; Liskamp, R. M. J. J. Org. Chem. 2007, 72, 4574–4577; (d)
Kolakowski, R. V.; Shangguan, N.; Sauers, R. R.; Williams, L. J. J. Am. Chem. Soc.
2006, 128, 5695–5702; (e) Barlett, K. N.; Kolakowski, R. V.; Katukojvala, S.;
Williams, L. J. Org. Lett. 2006, 8, 823–826; (f) Tam, J. P.; Lu, Y.-A.; Liu, C.-F.; Shao,
J. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 12485–12489; (g) Dawson, P. E.; Muir, T.
W.; Clark-Lewis, I.; Kent, S. B. H. Science 1994, 266, 776–779; (h) Yamashiro, D.;
Li, C. H. Int. J. Pept. Protein Res. 1988, 31, 322–334; (i) Blake, J.; Yamashiro, D.;
Ramasharma, K.; Li, C. H. Int. J. Pept. Protein Res. 1986, 28, 468–476; (j) Blake, J.;
Li, C. H. Proc. Natl. Acad. Sci. U.S.A. 1981, 78, 4055–4058.
9. (a) Zhang, X.; Lu, X.; Liu, C. Tetrahedron Lett. 2008, 49, 6122–6125; (b) Gaertner,
H.; Villain, M.; Botti, P.; Canne, L. Tetrahedron Lett. 2004, 45, 2239–2241.
10. (a) Ozturk, T.; Ertas, E.; Mert, O. Chem. Rev. 2007, 107, 5210–5278; (b) Cava, M.
lP.; Levinson, M. I. Tetrahedron 1985, 41, 5061–5087; (c) Schmidt, A.; Merkel, L.;
Eisfeld, W. Eur. J. Org. Chem. 2005, 10, 2124–2130.
11. Nishio, T. Chem. Commun. 1989, 4, 205–206.
12. (a) Varma, R. S.; Kumar, D. Org. Lett. 1999, 1, 697–700; (b) Filippi, J.-J.;
Fernandez, X.; Lizzani-Cuvelier, L.; Loiseau, A.-M. Tetrahedron Lett. 2003, 44,
6647–6650.
13. When the reaction was carried out under the microwave conditions, extensive
decomposition of the starting material, 17, and
a low yield of 18 were
5. Nagorny, P.; Fasching, B.; Li, X.; Chen, G.; Aussedat, B.; Danishefsky, S. J. J. Am.
Chem. Soc. 2009, 131, 5792–5799.
observed. It is highly possible that the internal amide group may be competing
with the carboxylic acid functionality during the course of the reaction with LR
under the microwave conditions. However, the corresponding reaction was
found to proceed at room temperature, albeit at a slower rate. There is a
possibility that the superior reactivity of 17 at room temperature is facilitated
by the intermediacy of the oxazolone. Further studies, which will shed some
light into the origins of this effect, will be reported in a due course.
6. (a) Stockdill, J. L.; Wu, X.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 5152–
5155; (b) Wu, X.; Yuan, Y.; Li, X.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50,
4666–4669; (c) Yuan, Y.; Zhu, J.; Li, X.; Wu, X.; Danishefsky, S. J. Tetrahedron
Lett. 2009, 50, 2329–2333; (d) Rao, Y.; Li, X.; Danishefsky, S. J. J. Am. Chem. Soc.
2009, 131, 12924–12926.