O-Aminothiophenol in reactions with carbonyl compounds and isocyanides: A word of caution

Article abstract of DOI:10.1055/s-0030-1258500

The reaction of o-aminothiophenol with carbonyl compounds and t-BuNC was revisited and shown to provide 1-[1,3-benzothiazol-3(2H)-yl]methanimines (not described hitherto) and not the earlier reported 4H-benzo[1,4]thiazine. To isolate the latter using this reaction a due amount of caution and structure scrutiny is warranted. The basis for assignment of the products to both structural classes is provided. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258500

LETTER
1935
o-Aminothiophenol in Reactions with Carbonyl Compounds and Isocyanides:
A Word of Caution
o
-Aminothiop
e
r
CR gey Tsirulnikov,a,b Dmitry Dmitriev,b Mikhail Krasavin*a,b
a
Science and Education Center ‘Innovative Research’, Yaroslavl State Pedagogical University, 150000 Yaroslavl, Russian Federation
Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, 141400 Moscow Region, Russian Federation
Fax +7(495)6269780; E-mail: myk@chemdiv.com
b
Received 26 April 2010
compound and an isocyanide-intercepting N-nucleophile
(Scheme 2).
Abstract: The reaction of o-aminothiophenol with carbonyl com-
pounds and t-BuNC was revisited and shown to provide 1-[1,3-ben-
zothiazol-3(2H)-yl]methanimines (not described hitherto) and not
the earlier reported 4H-benzo[1,4]thiazine. To isolate the latter us-
ing this reaction a due amount of caution and structure scrutiny is
warranted. The basis for assignment of the products to both struc-
tural classes is provided.
H
N
H
N
NH2
NH2
O
H
R2
R2 N+ C–
+
1
+
R
N
H
R1
Key words: isocyanide-based multicomponent reactions, bifunc-
tional reagents, isocyanide-intercepting nuceophiles, thiophenol,
amidines
acid catalyst
H
R2
N
H
N
N+
R1
H
N
R2
R1
N+
+
N
H
–C
Recently, we reported1 on a new variant of an isocyanide-
based multicomponent reaction (IMCR) of o-phenylene-
diamines with aldehydes and isocyanides leading to easily
oxidized dihydroquinoxalines and, ultimately, providing a
conceptually new route to quinoxalines (Scheme 1).
NH2
R1
N
H
NH2
R2
Scheme 2 Plausible mechanism for IMCR of 1,2-diamines
We also tested o-aminothiophenol under the reaction con-
ditions depicted in Scheme 1, aiming to verify if the re-
spective 3-aryl-4H-benzo[1,4]thiazine-2-amine 1 would
form. However, this attempt only resulted in a complex
mixture of products, one of which could be identified as 2,
that is, the products of Ugi reaction involving water5 as
isocyanide-intercepting nucleophile (Scheme 3).
N+
C–
H
N
NH2
NH2
NH
PhCHO
concd HCl (1equiv)
MeOH, r.t.
18 h, under Ar
N
H
DDQ (1 equiv)
benzene
r.t., 1–3 h
+
C–
N
NH2
SH
S
NH
PhCHO
X
N
N
NH
concd HCl (1equiv)
MeOH, r.t.
18 h, under Ar
N
H
1
53% for 2 steps
Scheme 1 IMCR of an o-phenylenediamine1
O
N
H
This methodology has been recently extended by Kysil et
al.2 to include cyclic ketone components as well as
[1,2,5]oxadiazole-3,4-diamine under reaction conditions
including TMSCl as the promoter. In addition, similar
reactions involving 1,2-diamines have also been pub-
lished.3,4 In all of these transformations, the diamines act
as bifunctional reagents providing both the amine compo-
nent to form the Schiff base adduct with the carbonyl
NH
+ by-products
SH
2 (<10%)
Scheme 3 Attempted IMCR of o-aminothiophenol
Our interest to the reaction of o-aminothiophenol has been
refueled by a publication6 reporting on a facile and high-
yielding preparation of compounds related to 1. Accord-
ing to this article, compound 1 was formed in 89% isolat-
ed yield (along with 11 other examples) upon mixing all
SYNLETT 2010, No. 13, pp 1935–1938
x
x
.x
x
.2
0
1
0
Advanced online publication: 16.07.2010
DOI: 10.1055/s-0030-1258500; Art ID: D10710ST
© Georg Thieme Verlag Stuttgart · New York

1936
S. Tsirulnikov et al.
LETTER
Table 1 Compounds 4 and 5 Prepared via IMCR of o-Amino-
thiophenol
three components in ethanol and heating the solution at re-
flux for five hours in presence of p-toluenesulfonic acid
(Scheme 4). Although in our hands, the outcome of this
reaction was similar to the one presented in Scheme 3, we
decided to test it under TMSCl-promoted conditions.2
Entry Compd R1
R2
Yield of 4 Yield of 5
(%)
(%)
12
38
–
1
2
3
4
5
6
7
8
9
3–5a
3–5b
3–5c
3–5d
3–5e
3–5f
3–5g
3–5h
3–5i
3–5j
-(CH2)5-
66
-(CH2)4-
45
+
–C
N
SH
S
NH
-(CH2)2O(CH2)2-
54
PhCHO
PTSA, EtOH
reflux, 5 h
89%
-(CH2)2N(Ac)(CH2)2-
43
–
NH2
N
H
-(CH2)2CH(t-Bu)(CH2)2- 62
5
1
(+ 11 other examples)
4-MeOC6H4
4-i-PrC6H4
2-MeC6H4
3-NCC6H4
3,4-Me2C6H3
H
H
H
H
H
70
59
48
63
64
–
Scheme 4 Reported preparation of 3-aryl-4H-benzo[1,4]thiazine-2-
amine 16
–
–
Simple mixing of o-aminothiophenol an aromatic alde-
hyde and t-BuNC with TMSCl (1.0 equiv) in methanol
–
and heating the reaction mixture at reflux for 12 hours 10
again provided a complex mixture of products. This was
entirely in accordance with the earlier observations made
for 1,2-diamines2 that preformation of an aminal adduct
with the carbonyl compound is critical for a successful
IMCR. Therefore, in all our subsequent experiments we
used 2,3-dihydro-1,3-benzothiazoles 3 (as confirmed by
NMR experiments) prepared by reacting equimolar
amounts of o-aminothiophenol with aldehydes or ketones,
without further purification.
–
The products 4 and 5 are isomers that can be distinguished
by characteristic signals in their H NMR spectra corre-
sponding to the amidine C–H proton and the thiazine N–
H proton, respectively (Figure 1). Such structural assign-
ment was further confirmed by single-crystal X-ray
analysis8 obtained for 4f and 5a (Figure 2).
1
S
N
R1
S
N
R1
R2
R1
SH
R1
R2
R2
H
S
O
N
H
R2
i-PrOH
70 °C, 16 h
N
H
5
4
NH2
N
3
~ 6.0 ppm
~ 8.0 ppm
R1
S
N
Figure 1 Characteristic signals in the 1H NMR spectra of 4 and 5
t-BuNC
TMSCl
MeCN–CHCl3–MeOH
(10:2:3)
70 °C, 12 h
R2
+
S
N
R1
N
N
H
R2
4
5
Scheme 5 IMCR of o-aminothiophenol investigated in this work
Ten 2,3-dihydro-1,3-benzothiazoles 3a–j were prepared
and reacted with t-BuNC in the presence of TMSCl (1.0
equiv). Contrary to the expectations, in all cases the major
component of the product mixture (according to 1H NMR
analysis of the crude product) was 1-[1,3-benzothiazol-
3(2H)-yl]methanimine 4 and not the 4H-benzo[1,4]thiaz-
ine 5 (Scheme 5). In fact, in all reactions except those with
3a, 3b, and 3e, the latter product was detected in negligi-
ble amount that did not warrant isolation. Accordingly,
the products 4a–j and 5a,b,e were isolated in low to mod-
erate yields (Table 1) by column chromatography and
characterized.7
Figure 2 X-ray structures of 4f and 5a
The unexpected formation of 1-[1,3-benzothiazol-3(2H)-
yl]methanimines 4 was likely due to the ability of isocya-
Synlett 2010, No. 13, 1935–1938 © Thieme Stuttgart · New York

LETTER
o-Aminothiophenol in IMCR
Typical Procedure 1: Synthesis of 4
1937
nides to form amidines via a direct, Lewis acid catalyzed
reaction with amines (in this case, the secondary aniline
3). This is a less studied yet not unprecedented9 reactivity
of isocynides.
A thoroughly degassed solution of o-aminothiophenol (3 mmol)
and the carbonyl compound (3 mmol) in i-PrOH (3 mL) was heated
at 70 °C for 16 h. The solvent was removed in vacuo, and the resi-
due was re-dissolved in anhyd MeCN (10 mL). A solution of
TMSCl (3 mmol) in CHCl3 (2 mL) was added followed by a solu-
tion of t-BuNC in MeOH (3 mL). The resulting mixture was heated
at 70 °C for 12 h, cooled to r.t., evaporated to dryness, and the resi-
due was dispersed in H2O (20 mL). The resulting suspension was
basified with aq NaOH and extracted with CHCl3 (3 × 30 mL). The
combined organic extracts were dried over anhyd Na2SO4, filtered,
and concentrated. The crude products was purified by column chro-
matography on basic alumina using 0% → 2.5% MeOH in CH2Cl2
as eluent.
Using 2,3-dihydro-1,3-benzothiazole 3b, for which the
formation of the respective 4H-benzo[1,4]thiazine 5b was
most pronounced, we screened a small set of Lewis and
Brønsted acids (in catalytic to equimolar quantities, in
compatible solvents) while monitoring the ratio of the
characteristic signals corresponding to the products 4b
and 5b in the 1H NMR spectrum of the crude reaction mix-
ture. As can be seen from Table 2, despite the initial
promise of improvement (entries 1 and 7) or even reversal
(entries 2 and 6) of the 4b/5b ratio from the 1H NMR data,
the isolated yields of 5b were still highest when TMSCl
was used as a promoter (and optimal in MeOH–CHCl3
solvent system), due to noticeable formation of unidenti-
fied polymeric byproducts in all other cases.
Typical Procedure 2: Synthesis of 5
To prepare these compounds, the same procedure was used but the
time prior to the addition of t-BuNC was extended to 40 min. A sim-
ilar chromatographic isolation procedure was used, however, these
products generally had higher Rf values than 4.
Acknowledgment
Table 2 Acid-Promoter Screening for the Reaction of 3b with
t-BuNC
This research was supported by the Federal Agency for Science and
Innovation
(Russian
Federation
Government
Contract
Entry Acid promoter
Ratio 4b/5b by Isolated
crude 1H NMR yield of 5b
(%)
02.740.11.0092). Dr. Alexander Manaev of Chemical Diversity
Research Institute is acknowledged for his help in obtaining X-ray
structures.
1
2
3
TsOH (1.0 equiv), MeCN
2:3
<10
References and Notes
Yb(OTf)3 (0.2 equiv), MeCN 1:3
12
(1) Krasavin, M.; Parchinsky, V. Synlett 2008, 645.
(2) Kysil, V.; Khvat, A.; Tsirulnikov, S.; Tkachenko, S.;
Williams, C.; Churakova, M.; Ivachtchenko, A. Eur. J. Org.
Chem. 2010, 1525.
(3) Shaabani, A.; Maleki, A.; Moghimi-Rad, J. J. Org. Chem.
2007, 72, 6309.
(4) Heravi, M. M.; Baghernejad, B.; Oskooie, H. A.
Tetrahedron Lett. 2009, 50, 767.
(5) Ugi, I.; Steinbrückner, C. Chem. Ber. 1961, 94, 734.
(6) Heravi, M. M.; Baghernejad, B.; Oskooie, H. A. Synlett
2009, 1123.
HCl (1.0 equiv), dioxane
(3 M)
9:1
not isolated
4
TMSCl (1.0 equiv), MeCN 3:1
29
41
5a
TMSCl (1.0 equiv), MeCN– 3:2
MeOH–CHCl3 (10:3:2)
6
7
Sc(OTf)3 (0.2 equiv), MeCN 1:3
15
TsOH (0.3 equiv), EtOH
1:1
<10
a Re-run of entry 2, Table 1.
(7) Characterization Data for Selected Compounds
Compound 5a: emerald green solid, mp 172 °C (decomp.).
1H NMR (500 MHz, DMSO-d6): d = 6.95–7.07 (m, 3 H),
6.71 (td, J = 7.6, 1.3 Hz, 1 H), 5.78 (s, 1 H), 1.63–1.78 (m, 2
Extending the time of TMSCl activation of 3 prior to t-
BuNC addition to 40 minutes did not change the ratio of
4/5 for entries 2–4 and 6–10 (Table 1). However, it slight-
ly improved for entry 1 (from 4:1 to 7:3) and entry 5 (from
9:1 to 4:1) and the corresponding 4H-benzo[1,4]thiazines
5a and 5e were isolated in 26% and 14% yield, respective-
ly.
H), 1.42–1.56 (m, 7 H), 1.33 (s, 9 H), 1.12–1.27 (m, 1 H). 13
C
NMR (125 MHz, DMSO-d6): d = 156.2, 140.9, 126.2, 125.0,
118.9, 118.8, 117.2, 57.3, 55.3, 33.0, 28.6, 25.4, 21.0. LC-
MS: m/z = 289 [M + H]. Anal. Calcd for C17H24N2S: C,
70.79; H, 8.39; N, 9.71. Found: C, 70.72; H, 8.48; N, 9.83.
Compound 5b: brown solid, mp 169–172 °C(br). 1H NMR
(500 MHz, DMSO-d6): d = 7.05 (d, J = 7.6 Hz, 1 H), 6.97 (t,
J = 7.6 Hz, 1 H), 6.87 (d, J = 7.6 Hz, 1 H), 6.70 (t, J = 7.6
Hz, 1 H), 6.05 (s, 1 H), 2.01–2.14 (m, 2 H), 1.43–1.73 (m, 6
H), 1.33 (s, 9 H). 13C NMR (125 MHz, DMSO-d6): d =
156.0, 142.7, 126.3, 125.3, 118.8, 116.8, 67.7, 55.0, 36.4,
28.7, 23.6. LC-MS: m/z = 275 [M + H]. Anal. Calcd for
C16H22N2S: C, 70.03; H, 8.08; N, 10.21. Found: C, 69.89; H,
8.01; N, 10.13.
Compound 5e: brown solid, mp 186 °C (decomp.). Single
diastereomer! 1H NMR (500 MHz, DMSO-d6): d = 6.98 (d,
J = 7.6 Hz, 1 H), 6.93 (t, J = 7.6 Hz, 1 H), 6.82 (d, J = 7.6
Hz, 1 H), 6.67 (t, J = 7.6 Hz, 1 H), 5.77 (s, 1 H), 2.07 (d,
J = 12.6 Hz, 2 H), 1.54 (m, 4 H), 1.35 (s, 9 H), 1.15–1.25 (m,
2 H), 1.00 (m, 1 H), 0.82 (s, 9 H). 13C NMR (125 MHz,
In conclusion, we have revisited the reaction of o-ami-
nothiophenol with carbonyl compounds and t-BuNC and
established that, under Lewis and Brønsted acid catalysis
(especially, TMSCl), the major product is the previously
unreported 1-[1,3-benzothiazol-3(2H)-yl]methanimine 4
and not the earlier reported 4H-benzo[1,4]thiazine 5. To
isolate the latter using this reaction, a due amount of cau-
tion and structure scrutiny is warranted.
Synlett 2010, No. 13, 1935–1938 © Thieme Stuttgart · New York

1938
S. Tsirulnikov et al.
LETTER
DMSO-d6): d = 152.6, 141.5, 126.0, 124.6, 118.3, 117.6,
116.5, 56.5, 55.5, 46.9, 35.5, 32.1, 28.7, 27.3, 23.1. LC-MS:
m/z = 345 [M + H]. Anal. Calcd for C21H32N2S: C, 73.20; H,
9.36; N, 8.13. Found: C, 73.29; H, 9.49; N, 8.23.
NMR (125 MHz, DMSO-d6): d = 143.0, 141.7, 124.8, 121.6,
121.2, 113.8, 82.7, 54.6, 45.4, 37.5, 32.0, 30.6, 27.4, 24.8.
LC-MS: m/z = 345 [M + H]. Anal. Calcd for C21H32N2S: C,
73.20; H, 9.36; N, 8.13. Found: C, 73.17; H, 9.34; N, 8.02.
Compound 4f: beige solid, mp 201 °C (decomp.). 1H NMR
(500 MHz, DMSO-d6): d = 8.07 (s, 1 H), 7.42 (d, J = 7.8 Hz,
1 H), 7.23 (d, J = 8.6 Hz, 2 H), 7.20 (d, J = 7.8 Hz, 1 H), 7.07
(t, J = 7.8 Hz, 1 H), 6.93 (s, 1 H), 6.90 (t, J = 7.8 Hz, 1 H),
Compound 4b: brown oil. 1H NMR (500 MHz, DMSO-d6):
d = 7.98 (s, 1 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.10 (d, J = 7.8
Hz, 1 H), 6.98 (t, J = 7.8 Hz, 1 H), 6.82 (t, J = 7.8 Hz, 1 H),
2.76–2.92 (m, 2 H), 1.76–2.02 (m, 4 H), 1.58–1.74 (m, 2 H),
1.20 (s, 9 H). 13C NMR (125 MHz, DMSO-d6): d = 141.8,
141.4, 125.2, 125.0, 121.7, 121.4, 111.4, 85.2, 54.6, 30.6,
23.6. LC-MS: m/z = 275 [M + H]. Anal. Calcd for
6.83 (d, J = 8.6 Hz, 2 H), 3.70 (s, 3 H), 1.12 (s, 9 H). 13
C
NMR (125 MHz, DMSO-d6): d = 158.8, 143.6, 140.4, 134.6,
127.4, 127.0, 125.6, 122.8, 122.4, 113.6, 111.2, 65.8, 55.2,
54.1, 30.6. LC-MS: m/z = 327 [M + H]. Anal. Calcd for
C19H22N2OS: C, 69.90; H, 6.79; N, 8.58. Found: C, 70.03; H,
6.87; N, 8.65.
C16H22N2S: C, 70.03; H, 8.08; N, 10.21. Found: C, 70.12; H,
8.13; N, 10.30.
Compound 4c: dark yellow solid, mp 182–184 °C. 1H NMR
(500 MHz, DMSO-d6): d = 8.01 (s, 1 H), 7.59 (d, J = 7.8 Hz,
1 H), 7.15 (dd, J = 7.8, 1.3 Hz, 1 H), 6.99 (td, J = 7.8, 1.3 Hz,
1 H), 6.84 (td, J = 7.8, 1.3 Hz, 1 H), 3.95 (dd, J = 12.6, 4.6
Hz, 2 H), 3.45 (t, J = 12.6 Hz, 2 H), 3.05 (td, J = 12.6, 4.6
Hz, 2 H), 1.88 (d, J = 12.6 Hz, 2 H), 1.20 (s, 9 H). 13C NMR
(125 MHz, DMSO-d6): d = 142.4, 141.7, 125.2, 124.4,
121.8, 121.6, 112.7, 80.2, 65.3, 54.7, 37.5, 30.5. LC-MS:
m/z = 291 [M + H]. Anal. Calcd for C16H22N2OS: C, 66.17;
H, 7.64; N, 9.65. Found: C, 66.22; H, 7.70; N, 9.71.
Compound 4e: pale yellow solid, mp 181–183 °C. Single
diastereomer! 1H NMR (500 MHz, DMSO-d6): d = 7.98 (s,
1 H), 7.88 (d, J = 7.8 Hz, 1 H), 7.11 (dd, J = 7.8, 1.3 Hz, 1
H), 6.96 (td, J = 7.8, 1.3 Hz, 1 H), 6.81 (td, J = 7.8, 1.3 Hz,
1 H), 2.52–2.60 (m, 2 H), 2.03 (d, J = 12.6 Hz, 2 H), 1.81 (d,
(8) Crystallographic data (excluding structure factors) for the
structures 4f and 5a have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
numbers CCDC 774773 and CCDC 774774. Copies of the
data can be obtained free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: +44
(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].
(9) (a) Saegusa, T.; Ito, Y.; Kobayashi, S.; Hirota, K.; Yoshioka,
H. Tetrahedron Lett. 1966, 7, 6121. (b) Smith, R.;
Livinghouse, T. Synth. Commun. 1984, 14, 639.
(c) Hashida, Y.; Imai, A.; Sekiguchi, S. J. Heterocycl. Chem.
1989, 26, 9901. (d) Simon, J. R. Synthesis 2001, 2011.
(e) Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003,
125, 2880.
J = 12.6 Hz, 2 H), 1.17–1.30 (m, 11 H), 0.87 (s, 9 H). 13
C
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