A chemoselective hydroxymethylation: New route for the synthesis of 6-aroyl-4-(4H-triazol-3-yl)thiomorpholin-3-ones

Article abstract of DOI:10.1016/j.tetlet.2011.12.100

Treatment of 2-(2-oxo-2-arylethylthio)-N-(4H-1,2,4-triazol-3-yl)acetamides with paraformaldehyde in the presence of a base has led to a tandem chemoselective hydroxymethylation followed by cyclization yielding a set of novel 6-aroyl-4-(4H-triazol-3-yl)thi

Full text of DOI:10.1016/j.tetlet.2011.12.100

Tetrahedron Letters 53 (2012) 1149–1152
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A chemoselective hydroxymethylation: new route for the synthesis
of 6-aroyl-4-(4H-triazol-3-yl)thiomorpholin-3-ones
⇑
Thulasiraman Krishnaraj, Shanmugam Muthusubramanian
Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of 2-(2-oxo-2-arylethylthio)-N-(4H-1,2,4-triazol-3-yl)acetamides with paraformaldehyde in
the presence of a base has led to a tandem chemoselective hydroxymethylation followed by cyclization
yielding a set of novel 6-aroyl-4-(4H-triazol-3-yl)thiomorpholin-3-ones. The thiomorpholine ring has
been found to have a boat like conformation in these compounds as evidenced by NOESY NMR spectrum.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 28 October 2011
Revised 21 December 2011
Accepted 23 December 2011
Available online 30 December 2011
Keywords:
Chemoselective hydroxymethylation
Paraformaldehyde
6-Aroyl-4-(4H-triazol-3-yl)thiomorpholin-
3-one
Boat conformation
Tandem cyclization
Thiomorpholin-3-one is a well-known heterocycle that has
been the subject of an intense research after its first preparation
in 19501 because of its unique pharmacological properties. This
nucleus is present in the 1,4-benzothiazine calcium antagonist
Semotiadil2 as well as in pyrimidothiazine derivatives3 designed
as an inhibitor of the glycinamide ribonucleotide transformylase
with potent cell growth inhibition. Recently, thiomorpholine and
its pyrrole derivatives have been found to exhibit antihyperten-
sive4 and antimycobacterial5 activities. Chiral thiomorpholines
have been used as a recyclable chiral catalyst for sulfur ylide med-
iated asymmetric epoxidation of aldehydes.6 Various methods like
Ugi reactions,7 microwave assisted Smiles rearrangement,8 and
copper catalyzed cascade methods9 are being employed for the
synthesis of thiomorpholines.
ring and another heterocycle are linked or fused. In one such at-
tempt, the reaction of 4H-3-amino-1,2,4-triazole (1) with thiogly-
colic acid (2) has yielded the mercaptan 3, which was allowed to
react with substituted phenacyl bromide to provide a host of com-
pounds, 2-(2-oxo-2-phenylethylthio)-N-(1H-pyrrol-2-yl)acetam-
ide 4a–4i (Scheme 1).15
These compounds are allowed to react with paraformaldehyde
in the presence of triethylamine. The expectation is that the
hydroxylmethylation can take place at the 4 position of the triazole
ring. If that happens, the lactam form of the side chain amide may
involve in dehydration under acidic condition to yield [1,2,4]triaz-
olo[1,3,5]oxadiazine (Scheme 2).
The compounds 4a–4i are all new and have been well character-
ized. The 1H NMR spectrum of 4b has three broad one hydrogen sing-
lets at 7.70, 11.64, and 13.40 ppm. The pair of doublets (J = 8.4 Hz)
for the aromatic hydrogens appears at 7.60 and 7.98 ppm. Two
hydrogen singlets are centered at 3.42 and 4.22 ppm. The triazole
ring carbons appear with very poor intensity at 148.5 and
149.2 ppm, while the methylene carbons appear at 34.6 and
38.4 ppm.
Aiming at the construction of additional heterocyclic system
with triazole, the reaction of 4 with paraformaldehyde has been car-
ried out in 1,4-dioxan at 95 °C. Triethyl amine has been used as the
catalyst and paraformaldehyde was used in equimolar ratio with
4. It took nearly 20 h to get the reaction completed and even then
the conversion was only to the extent of less than 50%.16 Neverthe-
less, a new product has been formed. The reaction product 5
(Scheme 2) has been isolated, purified through flash column, and
1,2,4-Triazole10 nucleus is an important structural motif pres-
ent in a large number of functionalized molecules with a wide vari-
ety of uses, including applications in medicinal chemistry and
materials science. Clubbed 1,2,4-triazoles are a new class of azole
known for their promising antimicrobial activities both in vitro
and in vivo.11,12 The triazolyl–thiazoles are potent antimicrobial
and antitubercular agents.13 The activity of 1,2,4-triazole could
be improved by the introduction of substituents in the triazole
ring.14
Realizing the biological importance of triazole and other hetero-
cycles, it is planned to generate several systems where the triazole
⇑
Corresponding author. Tel.: +91 452 2458246; fax: +91 452 2459845.
E-mail address: muthumanian2001@yahoo.com (S. Muthusubramanian).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.100

1150
T. Krishnaraj, S. Muthusubramanian / Tetrahedron Letters 53 (2012) 1149–1152
H
N
O
H2N
NH
175 C
N
N
COOH
SH
+
HS
3
N
N
H
15 min
N
N
EtOH,
2
ArCOCH2Br
1
RT,
5 h
O
S
O
NH
Y
X
N
N
H
4
Scheme 1. Synthesis of 4.
Y
X
O
S
O
HO
O
H
H
N
N
S
NH
X
S
NH
X
Y
N
N
N
N
N
N
O
O
N
Y
4
NH
O
5
HO
N
O
S
NH
X
N
N
a
: X = Y = H
O
b
: X = Cl; Y = H
c: X = CN; Y = H
Y
d
: X = CH3; Y = H
e: X = F; Y = H
f
: X = OCF3; Y = H
O
N
Y
g
: X = H, Y = Cl
h: X = H; Y = OCH3
N
S
X
i
: X = H; Y = NO2
N
N
O
Scheme 2. Reaction of 4 with paraformaldehyde yielding 5.
characterized for its structure. Compound 5b has a set of mutually
coupled doublets at 3.37 and 3.73 ppm with a large coupling con-
stant of 14.8 Hz in its 1H NMR spectrum. An AMX pattern at 4.56
(J = 14.8, 9.2 Hz), 4.87 (J = 9.2, 5.2 Hz), and 5.09 (J = 14.8, 5.2 Hz)
ppm proves the presence of a CH2–CH system. The aryl region has
a pair of doublets for the p-chlorophenyl ring apart from a one
hydrogen singlet. The presence of two CH2 carbons and a CH carbon
in the region below 100 ppm and a free carbonyl and an amide car-
bonyl, apart from the carbons due to the triazolyl ring and the p-
chlorophenyl ring, is note worthy in the 13C NMR spectrum. The
HMBC connectivities are shown in the Figure 1. Thus from the one
and two dimensional NMR data, the structure of compound 5 has
been unambiguously assigned as 5-aroyl-N-triazolylthiomorpho-
lin-3-one (Table 1). The expected [1,2,4]triazolo[1,3,5]oxadiazine
has not been formed at all.
Table 1
Yield and melting points of 6-aroyl-4-(4H-triazol-3-yl) thiomorpholin-3-one 5
Entry
Compound
Yield (%)
Mp (°C)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
40
43
48
40
42
38
44
42
40
190–191
171–172
235–236
Viscous liquid
Viscous liquid
Viscous liquid
Viscous liquid
Viscous liquid
Viscous liquid
It is clear that the initial hydroxymethylation has occurred at
the active methylene and not either at ring nitrogen or amide
H
Het
H
H
H
O
N
ArOC
S
H
N
O
N
H
S
Figure 2. Conformation of 5 and the NOESY connectivity.
H
H
N
N
nitrogen. This is a chemoselective reaction, because there are also
reports wherein the acidic NH of secondary amine can be hydrox-
ymethylated with ease.17 The hydrogen on the nitrogen of the tri-
azole ring in 4 probably involves in a tautomeric 1,3 shift and
H
Cl
H
O
Figure 1. Hydrogen bonding and HMBC connectivities in 5.

T. Krishnaraj, S. Muthusubramanian / Tetrahedron Letters 53 (2012) 1149–1152
1151
Y
X
Y
O
S
HO
X
X
Y
H
N
H
N
S
S
N
O
O
O
O
O
8
6
7
X
H
N
S
Y
O
O
9
a: X = Y = H
b
: X =Me; Y = H
c
: X = Cl; Y = H
d: X = H; Y = OMe
Scheme 3. Reaction of 6 with paraformaldehyde yielding 7/8/9.
hence hydroxymethylation would have not occurred there. The
conformation of the resultant compound is also interesting. A sin-
gle crystal could not be grown for this class of compounds, but still,
the NOESY spectrum of 5b has revealed some important spatial
connections.
not 7, but 8. The additional signals at 5.08 ppm and 10.10 ppm
for OH and NH and the observed coupling pattern for the methy-
lene and methine hydrogens, different from AMX, clearly sug-
gested that the compound is 8a. The observed mass is not that of
the molecular ion but that of the M-18. It is obvious that the cycli-
zation has not been realized here. The nucleophilicity of PhNH
seems to be less than that of Het-NH.
In the case of 6b, the reaction has yielded not only 8b (18%), but
also the dehydrated product 9b (21%). Two sharp singlets at 2.43
and 3.64 ppm and a pair of doublets (J = 2.0 Hz) in the olefinic re-
gion, at 5.93 and 6.01 ppm, confirm the structure of 9b. With 6c,
interestingly, 8c was not formed. 9c was obtained in 15% and sur-
prisingly a trace of 7c has been obtained in this case. 7c has three
pairs of doublet of doublets at 4.14 (J = 14.0 Hz, 4.8 Hz), 4.43
(J = 14.0 Hz, 8.8 Hz), and 4.75 (J = 8.8 Hz, 4.8 Hz). A pair of doublets
for the geminal hydrogens appears at 3.34 and 3.65 ppm with a
coupling constant of 14.8 Hz. However with 6d, only 8d (20%)
could be isolated with no trace of 7d or 9d.
It is noticed that the deshielded methylene hydrogen of C-2 at
3.73 ppm has a NOESY contour with the shielded methylene
hydrogen of C-5 at 4.56 ppm. If these two hydrogens are to be
in spatial proximity, a chair like structure is totally ruled out
for the thiomorpholinone ring. Probably a boat like arrangement
can be visualized (Fig. 2), wherein the hydrogens showing NOESY
connectivity may be the flag pole bowsprit type hydrogens. The
shielding of the C-2 hydrogen could be ascribed to its position
over the carbonyl and the deshielding of C-5 hydrogen may be
due to its near planar arrangement with the triazole ring. The
hydrogen bonding between NH and amide carbonyl can also be
expected (Fig. 1). The signal due to NH hydrogen is not visible
in the 1H NMR spectra of some cases, probably due to this intra-
molecular hydrogen bonding.
The reaction when tried with other aldehydes, either alkyl or
aryl aldehyde, has not gone in the expected direction. The reaction
with formalin instead of paraformaldehyde was also tried, but the
results were not encouraging. An acid catalyzed reaction avoiding
triethylamine has also been attempted in the hope of noticing
any other chemoselective reaction, but in vain. In all the above
cases, the reaction has either not completed or resulted in a mix-
ture of products, which could not be isolated.
The formation of 8 clearly proves that the mechanism of the for-
mation of 5 from 4 involves the intermediate shown in Scheme 2,
involving initial hydroxymethylation at active methylene between
carbonyl and sulfur followed by cyclization. The presence of acid in
the medium could be the driving force for the dehydration of 8 to
form 9 in some cases, conjugation adding support.
Supplementary data
Having observed a selective hydroxymethylation with 4, it is
planned to generalize this reaction and accordingly, the reaction
was tried with simple 2-(2-oxo-2-phenylethylthio-N-phenylacet-
amide, 6a (Scheme 3), which has been prepared following the
method adopted for 4. Under identical reaction conditions, a prod-
uct with relatively poor yield (16%) was obtained. The EI mass
spectrum has a signal at m/e 297, which corresponds to the molec-
ular mass of the related thiomorpholine, 7a. The proton NMR sig-
nals in CDCl3 not only exhibited the expected signals for
thiomorpholine, but showed an additional one hydrogen singlet
at 8.30 ppm. As the compound was not sufficiently soluble in
CDCl3, the 13C NMR spectrum of the compound could not be re-
corded. When the proton and carbon-13 NMR spectra were re-
corded in DMSO-d6, it was realized that the compound formed is
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.100.
References and notes
1. Bestian, M. Liebigs Ann. Chem. 1950, 566, 210.
2. (a) Watanabe, Y.; Osanai, K.; Nishi, T.; Miyawaki, N.; Shji, D.; Honda, T.;
Shibano, T. Bioorg. Med. Chem. Lett. 1996, 6, 1923–1926; (b) Koidl, B.; Miyawaki,
N.; Tritthart, H. A. Eur. J. Pharm. 1997, 322, 243–247; (c) Takahashi, T.; Kanda,
T.; Imai, S.; Suzuki, T.; Kobayashi, I.; Murata, K. Eur. J. Pharm. 1996, 295, 229–
234.
3. Verney, M. D.; Palmer, C. L.; Romines, W. H., III; Boritzki, T.; Margosiak, S. A.;
Almassy, R.; Janson, C. A.; Barlett, C.; Howland, E. J.; Ferre, R. J. Med. Chem. 1997,
40, 2502–2524.
4. Ma, A.; Velazquez, L.; Martinez, V.; Abrego, V.; Balboa, M. A.; Torres, L. A.;
Camacho, B.; Diaz-Barriga, S.; Romero, A.; Lopez-Castanares, R.; Angeles, E. Eur.
J. Med. Chem. 2008, 43, 486–500.

1152
T. Krishnaraj, S. Muthusubramanian / Tetrahedron Letters 53 (2012) 1149–1152
5. Biava, M.; Porretta, G. C.; Poce, G.; Battilocchio, C.; Alfonso, S.; Logu, A. D.; Serra,
N.; Manetti, F.; Botta, M. Bioorg. Med. Chem. 2010, 18, 8076–8084.
6. Hansch, M.; Illa, O.; McGarrigle, E. M.; Aggarwal, V. K. Chem. Asian J. 2008, 3,
1657–1663.
7. Marcaccini, S.; Pepino, R.; Torroba, T.; Miguel, D.; Valverde, M. G. Tetrahedron
Lett. 2002, 43, 8591–8593.
15. General procedure as exemplified for 2-((2-oxo-2-phenylethyl)thio)-N-(4H-1,2,4-
triazol-3-yl)acetamide (4): The thiol 3 was treated with substituted phenacyl
bromides and potassium carbonate in equimolar amount taken in ethanol. The
mixture was left at room temperature for 5 h and the resultant was worked out
to give 4, which was purified by crystallization. The characterization data for
4a: 87% yield as a white solid; mp 220 °C; dH (400 MHz, DMSO-d6) 3.44 (s, 2H),
4.25 (s, 2H), 7.54 (t, J = 7.2 Hz, 2H), 7.66 (t, J = 7.2 Hz, 1H), 7.71 (s, 1H), 7.98 (d,
J = 7.2 Hz, 2H), 11.67 (bs, 1H), 13.4 (bs, 1H), dC (100 MHz, DMSO-d6) 34.5, 38.5,
128.5, 129.4, 133.9, 135.7, 148.5, 149.1, 168.4, 195.0; ESI-m/z calcd for
[C12H12N4O2S]+ 276.07, found 276.6.
16. General procedure as exemplified for 6-benzoyl-4-(4H-1,2,4-triazol-3-
yl)thiomorpholin-3-one (5): Compound 4 was treated with paraformaldehyde
in equimolar ratio along with a catalytic amount of triethylamine taken in
dioxane. The mixture was heated to 95 °C and maintained at that temperature
for 20 h. The product obtained was purified through silica column using a
mixture of chloroform and methanol (9:1) as eluent. The characterization data
for 5a: 40% yield as a white solid; mp 190–191 °C; dH (400 MHz, CDCl3) 3.38 (d,
J = 15.0 Hz, 1H), 3.76 (d, J = 15.0 Hz, 1H), 4.56 (dd, J = 14.6 Hz, 9.0 Hz, 1H), 4.87
(dd, J = 9.0 Hz, 5.0 Hz, 1H), 5.09 (dd, J = 14.6 Hz, 5.0 Hz, 1H), 7.52 (t, J = 7.2 Hz,
2H), 7.65 (t, J = 7.2 Hz, 1H), 7.78 (s, 1H), 7.90 (d, J = 7.2 Hz, 2H); dC (100 MHz,
CDCl3) 30.6, 46.1, 128.5, 129.0, 134.2, 134.5, 148.7, 168.3, 193.7; ESI-m/z calcd
for [C13H12N4O2S+H]+ 289.07, found 289.0.
8. Zuo, H.; Li, Z. B.; Ren, F. K.; Falck, J. R.; Lijuan, M.; Ahn, C.; Shin, D. S. Tetrahedron
2008, 64, 9669–9674.
9. Chen, D.; Wang, Z. H.; Bao, W. J. Org. Chem. 2010, 75, 5768–5771.
10. (a) Al-Masoudi, A.; Al-Soud, Y. A.; Al-Salihi, N. J.; Al-Masoudi, N. A. Chem.
Heterocycl. Compd. 2006, 42, 1377–1403; (b) Huntsman, E.; Balsells, J. Eur. J.
Org. Chem. 2005, 3761–3765; (c) Al-Masoudi, I. A.; Al-Soud, Y. A.; Al-Salihi, N.
J.; Al-Masoudi, N. A. Chem. Heterocycl. Compd. 2006, 42, 1377–1403.
11. Shiradkar, M. R.; Murahari, K. K.; Gangadasu, H. R.; Suresh, T.; Kalyan, C. A.;
Panchal, D.; Kaur, R.; Burange, P.; Ghogare, J. Bioorg. Med. Chem. 2007, 42,
3997–4008.
12. Joshi, S. D.; Vagdevi, H. M.; Vaidya, V. P.; Gadaginamath, G. S. Eur. J. Med. Chem.
2008, 43, 1989–1996.
13. Mallikarjun, B. P.; Suresh Kumar, G. V.; Sastry, B. Eur. J. Med. Chem. 2009, 44,
4739–4746.
14. (a) Bayrak, H.; Demirbas, H.; Karaoglu, S. A.; Demirbas, N. Eur. J. Med. Chem.
2009, 44, 1057–1066; (b) Ashol, M.; Holla, B. M.; Poojary, B. Eur. J. Med. Chem.
2009, 44, 1057–1066; (c) Karthikeyan, M. S.; Prasad, D. J.; Poojary, B.; Bhat, K.
S.; Holla, B. M.; Kumari, N. S. Bioorg. Med. Chem. 2006, 14, 7482–7489.
17. Manikannan, R.; Muthusubramanian, S. J. Heterocycl. Chem. 2011, 48, 671–677.