Thioamides via thiatriazolines

Article abstract of DOI:10.1016/j.tetlet.2005.12.020

A method for thioamide formation from dithioacids and azides is described and a mechanistic framework is presented.

Full text of DOI:10.1016/j.tetlet.2005.12.020

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Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1163–1166
Thioamides via thiatriazolines
Robert V. Kolakowski, Ning Shangguan and Lawrence J. Williams*
Contribution from the Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey,
Piscataway, NJ 08854, USA
Received 4 November 2005; revised 2 December 2005; accepted 5 December 2005
Abstract—A method for thioamide formation from dithioacids and azides is described and a mechanistic framework is presented.
Ó 2005 Elsevier Ltd. All rights reserved.
Thioamides serve as isosteric replacements for amides
and as versatile synthetic precursors to thiazolines and
thiazoles.1 Most approaches to the construction of thio-
amides involve formation of the parent amide followed
by thionation.2 Recently, we showed that thioacids
and azides form amides in a base-promoted reaction:3,4
the azide and thioacid appear to couple directly to form
a thiatriazoline and then fragment to form amide, N2,
and S8 products (Eq. 1, X = O).5 Here we report a
new route to thioamides (X = S) from dithioacids and
azides and introduce data suggestive of the mechanistic
pathway.
Electron deficient azides couple with thioacids rapidly
and quantitatively.6 Consequently, we studied the reac-
tion between dithiobenzoic acid (1) and benzene sulfon-
azide (2). As shown in Scheme 1, the reaction outcome is
remarkably dependent on the nature of the base pro-
moter. We focus here on the effects of lutidine, piperi-
dine, and triethylamine. In the presence of lutidine
(path A), 1 converted 2 rapidly and completely to benz-
enesulfonamide (3), nitrogen, and sulfur. Dithiobenzoic
anhydride (4) also formed. Thus, while being the base of
choice for the thioacid/azide amidation, lutidine is in-
effective for the thioamide coupling. Piperidinium salts
of dithioacids are easy to handle and are stable at room
temperature. The piperidine salt of 1 also proved stable
in solution;7 however, subsequent addition of 2 led to
rapid formation of piperidine-derived thioamide (5), as
well as 3, nitrogen, and sulfur (path B). Table 1 summa-
rizes a series of experiments that more completely probe
this outcome. Piperidinium dithiobenzoate (1.3 equiv)
HX
X
S
X
B-
- N2S
+
N
N3 R'
R
R'
R
N
N
N
R
SH
H
R'
X = O,S
ð1Þ
path A
(PhCS)2S
S8
+
H2N SO2Ph
+
+
N2
+
lutidine
4
3
S
S
path B
piperidine
Ph
Ph
N
N3 SO2Ph
Ph
SH
S8
+
H2N SO2Ph
N2
+
1
2
5
3
S
path C
SO2Ph
S8
+
N2
+
triethyl amine
N
H
6
Scheme 1.
Keywords: Thioamides; Thioacids; Azides; Amidation; Thiatriazolines.
*
Corresponding author. E-mail: ljw@rutchem.rutgers.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.020

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1164
R. V. Kolakowski et al. / Tetrahedron Letters 47 (2006) 1163–1166
Table 1.
S
S
CH3OH
0.5 h, rt
H2N SO2Ph
Ph
N
+
N3 SO2Ph
Ph
S H2N
Equiv
% Yield (equiv)
1.3
1.3
1.3
1.3
1.3
0.0
0
10
35
54
63
62
0.25
0.50
0.75
1.0
96 (0.24)
94 (0.47)
84 (0.63)
62 (0.62)
Table 2.
PhCS2H or iso-Butyl-CS2H
formed small quantities of 5 (10%) in methanol at room
temperature over the course of 30 min. In the presence
of 2, piperidinium dithiobenzoate effected the nearly
quantitative conversion of 2 to 3 and the formation of
significantly more 5 than expected under these condi-
tions. As the amount of sulfonazide was increased, the
amount of 5 and 3 isolated from the reaction mixture
increased as well, while the relative ratio of 5:3 remained
1:1. These experiments establish that the conversion of
piperidinium dithiobenzoate to 5 is stoichiometric in sul-
fonyl azide (2) and produces an equivalent amount of 3.
In contrast to the weakly basic lutidine and the highly
nucleophilic piperidine, triethylamine promoted the
smooth coupling of 1 with 2 to give N-benzenesulfonyl
thioamide (6) in excellent yield (path C).
2 eqv. N(CH2CH3)3
Thioamide
11
10
Azide
Dithioacid
Conditions
Yield (%)
83
a
2
10
—
O
a
10
—
85
N3
O
12
O2N
NO2
a
10
10
—
75
56
N3
13
N3–Bn
14
b
Having determined that triethylamine displays the
desired properties for the coupling, we moved to develop
a dithioacid/azide thioamidation method. We generated
the dithioacid from the corresponding Grignard reagent
and carbon disulfide.8 Exposure of the dithioacid to the
azide in the presence of triethylamine gave the desired
thioamide. Examples of thioamidation are shown in
Table 2.9 The most convenient method was to generate
the dithioacid under standard conditions, to carry out
an aqueous acid workup, which removes magnesium
salts, and then to treat the dithioacid with triethylamine
and then azide. By using a slight excess of dithioacid
(1.3 equiv crude), triethylamine (2 equiv), and azide
(1.0 equiv) in a suitable solvent at 0 °C for 1–4 h, the
desired thioamide could be obtained in good overall
yield.
—
a
2
12
11
11
11
11
10
—
93
67
75
36
86
a
—
a
13
14
—
b
—
c
2
—
a Conditions: CH3OH, 0 °C to rt, 4 h.
b Conditions: CHCl3, reflux, 36 h.
c Conditions: H2O/acetone 3:1, 0 °C to rt, 30 min.
equilibrium with the neutral species (I/II). Intermediate
I would be expected to exhibit active ester character.
The weaker base, lutidine, should favor the protonated
form to a much greater degree than piperidine or trieth-
ylamine. Nucleophilic attack of a second molecule of
dithioacid at the thiocarbonyl of I should result in frag-
mentation to 3, 4, nitrogen, and sulfur as shown (path
A).11 This pathway would be less relevant in the pres-
ence of stronger bases; however, the active ester could
undergo nucleophilic acyl substitution by the highly
nucleophilic piperidine (path B). Addition of piperidine
to I followed by collapse of the tetrahedral intermediate
would give the observed products.12 In this way, benz-
enesulfonazide appears to serve as a stoichiometric
activator of a dithioacid, and piperidine appears suffi-
ciently nucleophilic to intercept the linear intermediate
(I/II). As shown in path C, triethylamine enforces for-
mation of the anion (I!II) but does not otherwise inter-
fere and thus enables II to cyclize to thiatriazoline III.
The thiatriazoline then undergoes fragmentation, either
stepwise or in a concerted [3+2] mechanism,13 to give
the thioamide (6).
As with our thioacid/azide amidation, electron deficient
azides react rapidly and efficiently with dithioacids,
while electron rich azides require heating for prolonged
periods in order to achieve good conversions. Thiona-
tion of amides N-substituted with electron withdrawing
groups, such as with sulfonyl, often require heating at
150 °C with phosphorous pentasulfide or exposure to
LawessonÕs reagent in refluxing toluene for 24 h.10 The
method reported here is mild, chemoselective, compati-
ble with hydroxylic solvents, and complementary to
other thioamide syntheses.
The mechanistic framework in Scheme 2 readily ratio-
nalizes the reaction outcomes in Scheme 1. In the pres-
ence of base, the thiolate adds to the terminal nitrogen
of the azide forming a linear anionic intermediate in

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R. V. Kolakowski et al. / Tetrahedron Letters 47 (2006) 1163–1166
1165
S
S
path C
N
S
Nu
N
II
N
S
6
2
Ph
S
N
N
1
+
N
Ph
S
N
N
Ph
HN
SO2Ph
SO2Ph
SO2Ph
I
III
path A
Nu = PhCS2
path B
Nu = piperdine
-
3 + 4
5 + 3
Scheme 2.
other approaches using dithiocarboxylates or isothiacya-
nates see: Schaumann, E. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 6, pp 419–432; Schaumann, E.;
Moeller, M.; Adiwidjaja, G. Chem. Ber. 1988, 121, 689–
699; Papadopoulos, E. P. J. Org. Chem. 1975, 41, 962–965;
For an interesting side reaction that was noted to produce
a thioamide see: Paulsen, H.; Bielfeldt, T.; Peters, S.; Bock,
K. Liebigs Ann. Chem. 1994, 369.
Additional control experiments support this mechanistic
framework. Benzenesulfonamide (3) does not react
under these conditions with dithiobenzoic acid (1) or
dithiobenzoic anhydride (4), even in the presence of tri-
ethylamine, thus demonstrating that the dithioacid/
azide amidation does not proceed through an amine
intermediate. Examination of the reaction profile by
ESI-MS revealed the presence of a species that corre-
sponds to a 1:1 adduct of dithioacid:azide. ESI-MS/
MS of this species indicates loss of fragments corre-
sponding to phenyl (77), benzenesulfonyl (141), sulf-
hydryl (33), and nitrous sulfide (60), consistent with its
formulation as thiatriazoline III.4
3. Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams,
L. J. J. Am. Chem. Soc. 2003, 125, 7754–7755.
4. The thio acid/azide amidation does not involve in situ
reduction of azide to amine; see Ref. 3.
5. For a combined experimental and computational mecha-
nistic study of the thioacid/azide amidation, see: Koka-
kowski, R. V.; Shangguan, N.; Wang, Z.; Sauers, R. R.;
Williams, L. J., submitted for publication.
6. This amidation approaches the ideal ÔclickÕ reaction for
electron deficient azides, see: Kolb, H. C.; Finn, M. G.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–
2021; Lewis Warren, G.; Green Luke, G.; Grynszpan, F.;
Radic, Z.; Carlier Paul, R.; Taylor, P.; Finn, M. G.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 1053–
1057; Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2110–2113; Suh, B.-C.; Jeon, H.; Posner, G.
H.; Silverman, S. M. Tetrahedron Lett. 2004, 45, 4623–
4625.
7. See also: Tani, K.; Hanabusa, S.-i.; Kato, S.; Mutoh, S.-y.;
Suzuki, S.-i.; Ishida, M. J. Chem. Soc., Dalton Trans. 2001,
518–527; Kato, S.; Ono, Y.; Miyagawa, K.; Murai, T.;
Ishida, M. Tetrahedron Lett. 1986, 27, 4595–4598; Kato,
S.; Shibahashi, H.; Katada, T.; Takagi, T.; Noda, I.;
Mizuta, M.; Goto, M. Liebigs Ann. Chem. 1982, 7, 1229–
1408.
The thioacid/azide amidation may prove to be broadly
applicable for the synthesis of complex amides.14 The
reactivity principles deduced from the amidation pro-
vided the conceptual basis for this new route to thio-
amides. We have shown that dithioacids couple
efficiently with electron deficient azides to give thio-
amide products under very mild conditions. The dithio-
acid/azide thioamidation does not proceed through an
amine intermediate, but rather through a thiatriazoline.
The attributes of the thioacid/azide amidation, namely
the high degree of chemoselectivity, solvent compa-
tibility, high coupling efficiency of electron deficient
azides, and the non-toxic byproducts nitrogen and
sulfur, appear to be retained for thioamide synthesis
as well.
Acknowledgements
8. Houben, J. Ber 1906, 39, 3219; For general procedures,
see: Aycock, D. F.; Jurch, G. R., Jr. J. Org. Chem. 1979,
44, 569–572. The dithioacids were prepared according to
Aycock et al., and used without further purification.
CAUTION: Carbon disulfide vapors are malodorous and
cause liver and kidney damage upon inhalation. This
reagent is flammable, low boiling, and should be handled
in a well-ventilated hood. STENCH: Dithioacids should
be handled in a well-ventilated hood.
9. Procedure: To a 15 mL round bottom flask charged with
5 mL of MeOH cooled to 0 °C, was added dithiobenzoic
acid (202 mg, 1.3 mmol) and triethylamine (202 mg,
2.0 mmol). The resultant reddish/dark brown solution
was treated with 12 (125 mg, 1 mmol) in one portion.
Evolution of nitrogen was noted upon addition of azide
and precipitation of sulfur was noted during the course of
the reaction. The solution was allowed to warm to room
temperature, and after 4 h the solution was concentrated in
vacuo. Flash column chromatography (3:7 EtOAc/hex-
anes) provided 187 mg (85%) of the thioamide as viscous
yellow oil. IR (neat) mmax 3110, 1717, 1235; dH (400 MHz,
Financial support from Merck, Johnson and Johnson,
the Petroleum Research Fund administered by the
American Chemical Society, and Rutgers, The State
University of New Jersey, is gratefully acknowledged.
References and notes
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R. V. Kolakowski et al. / Tetrahedron Letters 47 (2006) 1163–1166
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