π-Face-selective hetero Diels-Alder reactions of 3,4-di-tert-butylthiophene 1-oxide. An excellent trapping reagent for thioaldehydes and thioketones

Article abstract of DOI:10.1016/S0040-4039(03)01268-1

Hetero Diels-Alder reactions of 3,4-di-tert-butylthiophene 1-oxide (1) with thioaldehydes and thioketones take place exclusively, except the reaction with thiobenzophenone, at the syn-π-face of 1 with respect to the S=O bond. The π-face selectivity was ex

Full text of DOI:10.1016/S0040-4039(03)01268-1

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5159–5162
p-Face-selective hetero Diels–Alder reactions of
3,4-di-tert-butylthiophene 1-oxide. An excellent trapping reagent
for thioaldehydes and thioketones
Jun Takayama, Seiko Fukuda, Yoshiaki Sugihara, Akihiko Ishii and Juzo Nakayama*
Department of Chemistry, Faculty of Science, Saitama University, Sakura-ku, Saitama, Saitama 338-8570, Japan
Received 6 May 2003; revised 20 May 2003; accepted 22 May 2003
Abstract—Hetero Diels–Alder reactions of 3,4-di-tert-butylthiophene 1-oxide (1) with thioaldehydes and thioketones take place
exclusively, except the reaction with thiobenzophenone, at the syn-p-face of 1 with respect to the SꢀO bond. The p-face selectivity
was explained in terms of the extent of conformational changes of 1 that are brought about in the process to the transition states.
© 2003 Elsevier Science Ltd. All rights reserved.
Recently, considerable interest has been paid to the
chemistry of thiophene 1-oxides from a number of
viewpoints such as syntheses, structures, reactivities,
applications to organic synthesis, and intermediates in
the metabolism of thiophenes.1 Thiophene 1-oxides,
which have the general structure shown in Figure 1,2
Scheme 1. p-Face-selective Diels–Alder reactions (syn to the
possess two p-faces for Diels–Alder reactions, i.e. syn-
SꢀO bond).
and anti-p-faces with respect to the SꢀO bond. Recent
studies uncovered that the Diels–Alder reactions of
thiophene 1-oxides take place exclusively or predomi-
Thiobenzaldehyde and thioacetaldehyde are unstable,
nantly at the syn-p-face to the SꢀO bond in an endo-
transient intermediates. They are generated, for exam-
mode
(Scheme
1).2d,3
Although
thiocarbonyl
ple, by thermolyses of thiosulfinates 2a and 2b, respec-
tively.5,6 Thus, 1 was heated with an equimolar amount
of 2a in refluxing toluene for 1.5 h with the intention of
examining the Diels–Alder reaction of 1 with thioben-
zaldehyde.7 The reaction produced the single Diels–
Alder adduct 3a8 in 79% yield, thus revealing that the
reaction took place exclusively at the syn-p-face to the
SꢀO bond in an endo-mode (Scheme 2).9 The endo-
mode stereochemistry of 3a was determined based on
the coupling constant value of 3.4 Hz between Ha and
Hb; a much smaller value (nearly zero) would be
expected for the exo-mode adduct.10 Furthermore, the
structure of 3a was established by X-ray crystallo-
graphic analysis (Fig. 2).11 Similarly, the reaction with
thioacetaldehyde, generated in the same manner, pro-
duced 3b8 in 87% yield. Even thioformaldehyde,6 the
simplest thioaldehyde, generated from 2c, could be
satisfactorily trapped to furnish 3c8 in a surprisingly
high yield. These results indicate that 1 serves as an
extremely excellent trapping agent for unstable, tran-
sient dienophiles such as thioaldehydes.12
compounds serve as a heterodienophile,4 their Diels–
Alder reactions with thiophene 1-oxides have not hith-
erto been reported. Here we report that
3,4-di-tert-butylthiophene 1-oxide (1)2c undergoes
efficient, syn-p-face-selective Diels–Alder reactions with
thiocarbonyl compounds.
Figure 1. General structure and two p-faces of thiophene
1-oxides.
Keywords: p-face selectivity; Diels–Alder reaction; thiophene 1-oxide;
thioaldehydes and thioketones.
* Corresponding author. E-mail: nakaj@post.saitama-u.ac.jp
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01268-1

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
5160
J. Takayama et al. / Tetrahedron Letters 44 (2003) 5159–5162
stereochemistry of the SꢀO group of 3e was also deter-
mined by the same analysis.
Interestingly, only the Diels–Alder reaction of 1 with
thiobenzophenone, which required heating in refluxing
toluene to take place, gave the two diastereomers 3f8
and 3f% 8 (Scheme 4). The structure of the minor
diastereomer 3f% , isolated in 15% yield, was established
by X-ray diffraction analysis (Fig. 3).11 Thus, the major
diastereomer, isolated in 76% yield, was assigned 3f,
revealing that the reaction took place predominantly at
the syn-p-face to the SꢀO bond, though not exclusively.
The diastereomer ratio is kinetically controlled; thermal
isomerization between 3f and 3f% either by retro-Diels–
Alder reaction or by inversion at the sulfinyl sulfur
atom did not occur for prolonged heating in boiling
toluene. This is the first instance that 100% syn-p-face
selectivity of the Diels–Alder reactions of 1 and the
related compounds was violated.3e
Scheme 2. p-Face-selective Diels–Alder reaction of 1 with
thioaldehydes.
The reaction of 1 with thiophosgene proceeded at room
temperature to give the single diastereomer 3g8 in 94%
yield (Scheme 5). The reaction of 1 with adaman-
tanethione, a sterically hindered thioketone, in refluxing
toluene produced the expected adduct 3h8 only in 25%
yield. The oxidation of adamantanethione by 1 took
place competitively to result in the formation of 3,4-di-
tert-butylthiophene and adamantanone (Scheme 6).
Figure 2. ORTEP drawing of 3a.
Thioacetone and thiocyclohexanone,6 generated by
thermolysis of 2d and 2e in refluxing toluene, reacted
with 1 to give the corresponding single Diels–Alder
adduct 3d8 and 3e8 in 92 and 99% yields, respectively
(Scheme 3). The syn-addition stereochemistry of these
Scheme 4. Diels–Alder reaction of 1 with thiobenzophenone;
violation of 100% p-face-selectivity.
1
compounds was determined by H NMR analysis. The
shielding and deshielding zones of the SꢀO group are
well documented.13 The two methyl groups of 3d show
a large difference in chemical shift values (l 1.38 and
1.79) due to the diamagnetic anisotropy of the SꢀO
group. Thus the singlet at l 1.79 is assigned to the
methyl group which is placed in the SꢀO side, that is, in
the deshielding zone of the SꢀO group, while the singlet
at l 1.38 is assigned to the endo-methyl group. The
Figure 3. ORTEP drawing of 3f% .
Scheme 3. p-Face-selective Diels–Alder reaction of 1 with
thioacetone and thiocyclohexanone.
Scheme 5. p-Face-selective Diels–Alder reaction of 1 with
thiophosgene.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
J. Takayama et al. / Tetrahedron Letters 44 (2003) 5159–5162
5161
Sawada, T.; Mataka, S.; Tashiro, M. Eur. J. Org. Chem.
1998, 1841; (e) Otani, T.; Takayama, J.; Sugihara, Y.;
Ishii, A.; Nakayama, J. J. Am. Chem. Soc., accepted for
publication.
4. Weinreb, S. M. In Comprehensive Organic Synthesis;
Paquette, L. A., Vol. Ed.; Pergamon Press: Oxford, UK,
1991; Vol. 5, Chapter 4.2.
5. Baldwin, J. E.; Lopez, R. C. G. J. Chem. Soc., Chem.
Commun. 1982, 1029.
6. Generation of thioformaldehyde, thioacetone, and thio-
cyclohexanone by this thermolysis method was not
reported.5
Scheme 6. Reaction of 1 with adamantanethione.
7. If RCH2S(O)SCH2R could be reproduced repeatedly and
quantitatively by the following reaction from RCH2SOH,
generated as the counterpart of RCHꢀS, the stoichiomet-
ric relationship of 1:RCH2S(O)SCH2R=1.0:0.5 would be
valid.
1
8. 3a: mp 158–159°C (dec.); H NMR (200 MHz, CDCl3) l
0.80 (s, 9H), 1.41 (s, 9H), 4.31 (dd, 1H, J=3.4, 2.0 Hz),
4.86 (d, 1H, J=2.0 Hz), 5.29 (d, 1H, J=3.4 Hz), 7.15–
7.42 (m, 5H); 13C NMR (100.6 MHz, CDCl3) l 32.2,
32.3, 33.8, 35.5, 52.6, 73.6, 75.0, 128.0, 128.5, 129.2,
136.6, 139.3, 146.6; IR (KBr) 1084 (SꢀO) cm−1. Anal.
calcd for C19H26OS2: C, 68.21; H, 7.83. Found: C, 68.43;
1
Figure 4. Conformational changes required for transition
states.
H, 7.92. 3b: mp 112–114°C; H NMR (400 MHz, CDCl3)
l 1.28 (s, 9H), 1.34 (s, 9H), 1.37 (d, 3H, J=6.7 Hz),
4.14–4.20 (m, 2H), 4.67 (d, 1H, J=1.2 Hz); 1H NMR
(300 MHz, C6D6) l 0.91 (s, 9H), 0.99 (d, 3H, J=7.0 Hz),
1.03 (s, 9H), 3.69 (dd, 1H, J=3.3, 1.7 Hz), 4.23 (dq, 1H,
J=7.0, 3.3 Hz), 4.44 (d, 1H, J=1.7 Hz); 13C NMR (100.6
MHz, CDCl3) l 17.9, 32.2, 32.8, 33.6, 35.6, 43.4, 73.0,
73.1, 138.7, 147.0; IR (KBr) 1088 (SꢀO) cm−1. Anal. calcd
for C14H24OS2: C, 61.71; H, 8.88. Found: C, 61.85; H,
The observed syn-p-face selectivity would be explained
as follows, although other explanations were proposed
previously.14 The 1-oxide 1 has a bent structure at C2
and C4 with a tilt angle of 11° (Fig. 4). Thus, for the
syn-p-face addition, the transition state can be easily
reached with a small conformational change of 1,
whereas, for the anti-face addition, a large conforma-
tional change would be required; the inversions at C1
and C4 are required. Accordingly, the activation energy
would become much smaller for the syn-p-face addi-
tion, and hence it takes place exclusively in most cases.
1
8.99. 3c: mp 126–127°C; H NMR (400 MHz, CDCl3) l
1.28 (s, 9H), 1.32 (s, 9H), 2.80 (dd, 1H, J=10.6, 1.2 Hz),
3.53 (dd, 1H, J=10.6, 3.6 Hz), 4.30 (ddd, 1H, J=3.6, 1.7,
1.2 Hz), 4.81 (d, 1H, J=1.7 Hz); 13C NMR (100.6 MHz,
CDCl3) l 32.0, 32.5, 32.5, 34.7, 34.8, 68.6, 72.2, 140.2,
145.8; IR (KBr) 1086 (SꢀO) cm−1. Anal. calcd for
C13H22OS2: C, 60.41; H, 8.58. Found: C, 60.14; H, 8.67.
1
3d: mp 105–106°C; H NMR (400 MHz, CDCl3) l 1.27
References
(s, 9H), 1.32 (s, 9H), 1.37 (s, 3H), 1.79 (s, 3H), 3.84 (d,
1H, J=2.0 Hz), 4.76 (d, 1H, J=2.0 Hz); 13C NMR
(100.6 MHz, CDCl3) l 27.6, 31.7, 31.8, 32.7, 33.7, 35.5,
1. For reviews: (a) Nakayama, J.; Sugihara, Y. Sulfur
Reports 1996, 19, 349; (b) Nakayama, J. Sulfur Reports
2000, 22, 123.
57.6, 74.3, 77.9, 141.4, 144.5; IR (KBr) 1091 (SꢀO) cm−1
.
Anal. calcd for C15H26OS2: C, 62.88; H, 9.15. Found: C,
2. (a) Pouzet, P.; Erdelmeier, I.; Ginderow, D.; Mornon,
J.-P.; Dansette, P.; Mansuy, D. J. Chem. Soc., Chem.
Commun. 1995, 473; (b) Pouzet, P.; Erdelmeier, I.; Gin-
derow, D.; Mornon, J.-P.; Dansette, P.; Mansuy, D. J.
Heterocycl. Chem. 1997, 34, 1567; (c) Nakayama, J.; Yu,
T.; Sugihara, Y.; Ishii, A. Chem. Lett. 1997, 499; (d)
Furukawa, N.; Zhang, S.-Z.; Horn, E.; Takahashi, O.;
Sato, S. Heterocycles 1998, 47, 793.
3. (a) Naperstkow, A. M.; Macaulay, J. B.; Newlands, M.
J.; Fallis, A. G. Tetrahedron Lett. 1989, 30, 5077; (b)
Treiber, A.; Dansette, P. M.; Amri, H. E.; Girault, J.-P.;
Ginderow, D.; Mornon, J.-P.; Mansuy, D. J. Am. Chem.
Soc. 1997, 119, 1565; (c) Li, Y.-Q.; Thiemann, T.;
Sawada, T.; Mataka, S.; Tashiro, M. J. Org. Chem. 1997,
62, 7926; (d) Li, Y.-Q.; Thiemann, T.; Mimura, K.;
1
63.10; H, 9.32. 3e: mp 172–173°C; H NMR (400 MHz,
CDCl3) l 1.15–1.21 (m, 1H), 1.25 (s, 9H), 1.30 (s, 9H),
1.34–1.38 (m, 1H), 1.45–1.57 (m, 4H), 1.68–1.78 (m, 2H),
1.82–1.86 (m, 1H), 2.80–2.93 (m, 1H), 3.90 (d, 1H, J=2.1
Hz), 4.71 (d, 1H, J=2.1 Hz); 13C NMR (100.6 MHz,
CDCl3) l 25.0, 25.4, 26.5, 31.7, 32.7, 33.7, 35.6, 37.0,
40.1, 65.9, 72.9, 78.0, 140.2, 144.4; IR (KBr) 1090 (SꢀO)
cm−1. Anal. calcd for C25H30OS2: C, 66.20; H, 9.26.
Found: C, 66.26; H, 9.39. 3f: mp 242–243°C (dec.); 1H
NMR (400 MHz, CDCl3) l 0.71 (s, 9H), 1.35 (s, 9H),
4.91 (d, 1H, J=2.0 Hz), 5.11 (d, 1H, J=2.0 Hz), 7.12–
7.36 (m, 10H); 13C NMR (100.6 MHz, CDCl3) l 31.4,
31.6, 34.0, 35.7, 71.7, 75.3, 75.5, 126.5, 127.0, 127.7,
127.7, 127.9, 130.0, 140.6, 143.9, 144.3, 144.7; IR (KBr)

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
5162 J. Takayama et al. / Tetrahedron Letters 44 (2003) 5159–5162
1098 (SꢀO) cm−1. Anal. calcd for C25H30OS2: C, 73.12; H,
7.36. Found: C, 73.11; H, 7.42. 3f% : mp 234–235°C (dec.);
1H NMR (300 MHz, CDCl3) l 0.77 (s, 9H), 1.40 (s, 9H),
4.92 (d, 1H, J=2.2 Hz), 5.04 (d, 1H, J=2.2 Hz), 7.18–
7.34 (m, 10H); 13C NMR (100.6 MHz, CDCl3) l 31.2,
31.6, 33.6, 35.4, 62.8, 75.4, 79.3, 126.8, 127.1, 127.3,
127.9, 128.4, 130.3, 141.7, 143.3, 143.6, 147.6; IR (KBr)
1071 (SꢀO) cm−1. Anal. calcd for C25H30OS2: C, 73.12; H,
7.36. Found: C, 73.03; H, 7.40. 3g: mp 119–120°C (dec.);
1H NMR (300 MHz, CDCl3) l 1.33 (s, 9H), 1.37 (s, 9H),
4.89 (d, 1H, J=2.6 Hz), 5.10 (d, 1H, J=2.6 Hz); 13C
NMR (50 MHz, CDCl3) l 31.4, 32.8, 34.0, 36.0, 76.9,
83.8, 142.7, 146.0; IR (KBr) 1099 (SꢀO) cm−1. Anal. calcd
for C13H20OS2: C, 47.70; H, 6.16. Found: C, 47.79; H,
6.14. 3h: mp 178–179°C (dec.); 1H NMR (400 MHz,
CDCl3) l 1.30 (s, 9H), 1.31 (s, 9H), 1.46 (m, 1H),
1.71–1.91 (m, 8H), 2.00–2.20 (m, 4H), 2.82 (m, 1H), 4.46
(d, 1H, J=1.9 Hz), 4.57 (d, 1H, J=1.9 Hz); 13C NMR
(100.6 MHz, CDCl3) l 26.4, 26.5, 31.3, 32.0, 34.6, 34.9,
35.4, 35.8 (overlapping of two peaks), 37.5, 38.0, 38.3,
39.3, 72.3, 72.8, 73.2, 140.0, 146.6; IR (KBr) 1097 (SꢀO)
cm−1. Anal. calcd for C22H34OS2: C, 69.79, H, 9.05.
Found: C, 69.92; H, 9.24.
10. Marchand, A. P.; Rose, J. E. J. Am. Chem. Soc. 1968, 90,
3724.
11. X-Ray crystallographic data of 3a: C19H26OS2, 334.54 g
mol−1, triclinic, P-1, a=8.574(1) A, b=9.031(1) A, c=
,
,
,
12.258(1) A, h=100.363(2)°, i=94.250(2)°, k=
3
106.988(3)°, V=884.81(9) A , Dcalcd=1.256 g cm−1, Z=2,
,
v(Mo-Ka)=0.30 mm−1, no. of measured reflections 3367,
no. of independent reflections 3367, no. of reflections
with I>2|(I) 3028, R1=0.0483, wR2=0.1450, S=1.172,
T=153 K. X-Ray crystallographic data of 3f% :
C25H30OS2, 410.64
g , monoclinic, C2/c, a=
mol−1
,
,
23.493(2) A, b=9.052(1) A, c=21.970(1), i=105.635(2)°,
3
V=4492.2(4) A , Dcalcd=1.212 g cm−1, Z=8, v(Mo-
,
Ka)=0.249 mm−1, no. of reflections measured 5180, no.
of independent reflections 4889, no. of reflections with
I>2|(I) 3028, R1=0.0494, wR2=0.1085, S=0.849, T=
153 K.
12. Trapping experiments of transient intermediates such as
thioaldehydes have been usually carried out by using
excess dienes.
13. (a) Pritchard, J. G.; Lauterbur, P. C. J. Am. Chem. Soc.
1961, 83, 2105; (b) Buck, K. W.; Foster, A. B.; Pardoe,
W. D.; Qadir, M. H.; Webber, J. M. J. Chem. Soc.,
Chem. Commun. 1966, 759; (c) Foster, A. B.; Duxbury, J.
M.; Inch, T. D.; Webber, J. M. J. Chem. Soc., Chem.
Commun. 1967, 881; (d) Foster, A. B.; Inch, T. D.; Qadir,
M. H.; Webber, J. M. J. Chem. Soc., Chem. Commun.
1968, 1086.
14. We have explained the p-face selectivity in a different way
in our previous paper.3e The present explanation would
be more reasonable. It was also explained by nonequiva-
lent orbital extension rule2d or by Cieplak effect.3c
9. A typical procedure for the Diels–Alder reactions of 1
with thioaldehydes and thioketones. A solution of 66.2
mg (0.25 mmol) of 2a and 53.7 mg (0.25 mmol) of 1 in 3
mL of toluene was heated at reflux for 1.5 h under argon.
The reaction mixture was evaporated under reduced pres-
sure and the resulting residue was chromatographed on a
column of silica gel. Elution of the column with ether/
hexane (3:1) gave 66.5 mg (79%) of 3a.