Highly chemoselective Pummerer reactions of sulfinyldiacetic acid derivative

Article abstract of DOI:10.1016/S0040-4039(02)00051-5

Sulfinyldiacetic acid amide ester rac-1 was efficiently synthesized starting from thiodiacetic acid 4. Treatment of rac-1 with Ac₂O and TMSOTf in CH₂Cl₂ at -40°C gave chemoselectively amide site α-acetoxy sulfide rac-2 in a ratio (91:9) of rac-2 and rac-3 and in a 90% total yield. Similar treatment of 1 with Ac₂O and TMSOTf in DMF at room temperature furnished ester site α-acetoxy sulfide rac-3 in a highly chemoselective manner (rac-2:rac-3=3:97) and in a 92% total yield.

Full text of DOI:10.1016/S0040-4039(02)00051-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1519–1522
Highly chemoselective Pummerer reactions of sulfinyldiacetic
acid derivative
Yoshimitsu Nagao,* Satoshi Miyamoto, Kazuhiko Hayashi, Ado Mihira and Shigeki Sano
Faculty of Pharmaceutical Sciences, The University of Tokushima, Sho-machi, Tokushima 770-8505, Japan
Received 5 December 2001; accepted 28 December 2001
Abstract—Sulfinyldiacetic acid amide ester rac-1 was efficiently synthesized starting from thiodiacetic acid 4. Treatment of rac-1
with Ac2O and TMSOTf in CH2Cl2 at −40°C gave chemoselectively amide site a-acetoxy sulfide rac-2 in a ratio (91:9) of rac-2
and rac-3 and in a 90% total yield. Similar treatment of 1 with Ac2O and TMSOTf in DMF at room temperature furnished ester
site a-acetoxy sulfide rac-3 in a highly chemoselective manner (rac-2:rac-3=3:97) and in a 92% total yield. © 2002 Elsevier
Science Ltd. All rights reserved.
Pummerer reactions,1 providing various a-substituted
(1)
sulfides from the corresponding sulfoxides, have been
attractive in regard to their value in the synthesis of
natural products and biologically active compounds,2
However, there have been a few reports of the Pum-
and in regard to their reaction mechanisms.3 Thus,
merer-type reaction of the sulfoxide having similarly
numerous Pummerer-type reactions have been
acidic two a-methylene groups such as CH2CO2R and
reported.1–3 The Pummerer reaction of dicarboxylic
acid derivatives A bearing a sulfinyl group must be
interested in the viewpoint of the development of new
enzyme inhibitors; a-acetoxy sulfides B or C having
CH2CONHR ones.5 We herein describe highly
chemoselective Pummerer reactions of sulfinyldiacetic
acid amide ester rac-1 as a model for A giving amide
site a-acetoxy sulfide rac-2 or ester site a-acetoxy
sulfide rac-3 each having high selectivity, as shown in
Scheme 1 and Tables 1–3.
rationally designed
(vide infra).
D- or L-amino acid amide group(s)
The synthesis of rac-1 was efficiently performed by
exploiting the synthetic route represented in Scheme 2.
Thiodiacetic acid 4 was treated with Ac2O (2.0 mol
equiv.) under reflux for 3 h to give anhydride 5 [mp
92–95°C (AcOEt)] in an 87% yield. The compound 5
was allowed to react with aminodiphenylmethane (1.1
mol equiv.) in the presence of pyridine (0.1 mol equiv.)
in Et2O under reflux to give mono amide 6 [mp 115–
117°C (AcOEt)] in a quantitative yield. After esterifica-
In general, regio- and chemoselective Pummerer reac-
tions of the sulfoxides having two kinds of a-methylene
groups can be performed at the more acidic methylene
site with an electron-withdrawing group (EWG), as
illustrated in Eq. (1).4
Keywords: Pummerer reactions; sulfoxides; chemoselectivity; Lewis
acid; solvents and solvent effects.
* Corresponding author. Tel.: +81-88-633-7271; fax: +81-88-633-9503;
e-mail: ynagao@ph2.tokushima-u.ac.jp
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00051-5

1520
Y. Nagao et al. / Tetrahedron Letters 43 (2002) 1519–1522
Table 1. Investigation of Lewis acids in the Pummerer reaction of rac-1a
Entry
Lewis acid
Time
Yield (%)b
Ratioc
:
rac-2
rac-3
1
2
3
4
5
6
BF3·OEt2
TMSOTf
TBDMSOTf
Zn(OTf)2
TiCl4
1 h
97
90
63
18
76
76
80
16
:
:
:
:
–
–
24
24
20
84
5 min
5 min
48 h
16 h
3 h
d
–
d
BBr3
–
a All reactions with the use of Ac2O (5 mol equiv.) and Lewis acid (3 mol equiv.) were carried out in CH2Cl2 at room temperature.
b Total yield of rac-2 and rac-3.
c Determined by 1H NMR (200 MHz, CDCl3) analysis.
d Reduction product 7 was obtained in 63% (entry 5) or 12% (entry 6) yield.
tion of 6 with MeOH in the presence of a catalytic
amount of H2SO4 under reflux, the resultant methyl
ester 7 [mp 55–56°C (n-hexane–CHCl3)] (quantitative
yield) was submitted to oxidation with NaIO4 (1.5 mol
equiv.) in an aqueous MeOH solution at room temper-
ature to afford rac-1 [mp 112–113°C (n-hexane–
CHCl3)] in a 99% yield.
(entries 1–6 in Table 2). Surprisingly, the direction of
chemoselectivity in the aprotic dipolar solvents (‘elec-
tron-donating solvents’)8 involving an amide carbonyl
group or a cyano group is reverse to that in CH2Cl2,
ClCH2CH2Cl or Et2O.
Finally, an effect of the reaction temperature on the
Pummerer reactions of rac-1 was investigated by using
Ac2O (5 mol equiv.) and TMSOTf (3 mol equiv.) in
CH2Cl2 or DMF at the indicated temperatures for the
arbitrary reaction times, as shown in Table 3. In
CH2Cl2, a clear trend toward higher chemoselectivity
for production of rac-2 was observed to be dependent
on a lower reaction temperature (entries 1–5 in Table
3). In DMF, a remarkably high chemoselectivity for
yielding rac-3 was recognized even at room temperature
(entry 6).
Scheme 2. (a) Ac2O (2.0 mol equiv.) reflux,
3 h; (b)
Consequently, we have achieved the chemoselective
Pummerer reactions of rac-1 to obtain the amide site
a-acetoxy sulfide rac-29 in a ratio (91:9) of rac-2 and
rac-3 and in a 90% total yield but also the ester site
a-acetoxy sulfide rac-39 in a highly chemoselective man-
ner (rac-2:rac-3=3:97) and in a 92% total yield.
Ph2CHNH2 (1.1 mol equiv.), pyridine (0.1 mol equiv.), Et2O,
reflux, 45 min; (c) H2SO4 (cat.) MeOH, reflux, 1 h; (d) NaIO4
(1.5 mol equiv.), MeOH–H2O, rt, 5 h.
In order to determine a suitable Lewis acid, we first
examined the Pummerer reactions of rac-1 by using
Ac2O (5 mol equiv.) and several Lewis acids (3 mol
equiv.) in CH2Cl2 at room temperature. All experimen-
tal results are summarized in Table 1. The desired
chemoselective reactions proceeded to give rac-2 and
rac-3 in ratios of 76:24 (BF3·OEt2 and TMSOTf), 80:20
(TBDMSOTf) and 16:84 [Zn(OTf)2], respectively
(entries 1–4 in Table 1). In the cases using TiCl4 and
BBr3, a reduction product 7 was obtained in 63 and
12% yields (entries 5 and 6 in Table 1).6 Among the
results described above, the reaction conditions employ-
This complementary chemoselective Pummerer reaction
can be rationalized in terms of an affinity of TMSOTf
and certain other Lewis acids except for Zn(OTf)2 with
Table 2. Effect of the solvent on the Pummerer reaction
of rac-1 using TMSOTfa
Entry
Solvent
Yield (%)b
Ratioc
rac-2
:
rac-3
7
ing TMSOTf intrigued us for further investigation
toward the development of highly chemoselective Pum-
merer reactions.
1
2
3
4
5
6
CH2Cl2
ClCH2CH2Cl
Et2O
AcOEt
MeCN
90
67
63
46
41
12d
76
76
67
32
2
:
:
:
:
:
:
24
24
33
68
98
94
Subsequently, an effect of the solvent on the Pummerer
reactions of rac-1 was examined by using Ac2O (5 mol
equiv.) and TMSOTf (3 mol equiv.) in the indicated
solvents (Table 2) at room temperature. All of the
reactions were carried out for 5 min to give rac-2 and
rac-3 with good to high chemoselectivities in ratios of
76:24 (CH2Cl2 and ClCH2CH2Cl), 67:33 (Et2O), 32:68
(AcOEt), 2:98 (MeCN) and 6:94 (DMF), respectively
DMF
6
a All reactions with the use of Ac2O (5 mol equiv.) and TMSOTf (3
mol equiv.) were carried out at room temperature for 5 min.
b Total yield of rac-2 and rac-3.
c Determined by 1H NMR (200 MHz, CDCl3) analysis.
d Rac-1 was obtained in 77% recovery.

Y. Nagao et al. / Tetrahedron Letters 43 (2002) 1519–1522
1521
Table 3. Effect of the reaction temperature on the Pummerer reaction of rac-1 using TMSOTfa
Entry
Solvent
Temp (°C)
Time
Yield (%)b
Ratioc
:
rac-2
rac-3
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
Reflux
Rt
0
−20
−40
Rt
2 min
5 min
5 min
24 h
24 h
3 h
60
90
95
94
90
92
41d
60
76
82
88
91
3
:
:
:
:
:
:
:
–
40
24
18
12
9
97
96
DMF
DMF
0
12 h
30 h
4
e
−40
–
a All reactions with the use of Ac2O (5 mol equiv.) and Lewis acid (3 mol equiv.) were carried out in CH2Cl2 or DMF.
b Total yield of rac-2 and rac-3.
c Determined by 1H NMR (200 MHz, CDCl3) analysis.
d Rac-1 was obtained in 33% recovery.
e No reaction.
esterase and protease inhibitors, as illustrated in Fig.
1.11
Acknowledgements
This work was in part supported by a Grant-in-Aid for
Scientific Research (B)(2)(No. 12470482) from Japan
Society for the Promotion of Science.
Scheme 3.
References
1. (a) Pummerer, R. Chem. Ber. 1909, 42, 2282; (b) Pum-
merer, R. Chem. Ber. 1910, 43, 1401; (c) Horner, L.;
Kaiser, P. Justus Liebigs Ann. Chem. 1959, 626, 19; (d)
Horner, L. Justus Liebigs Ann. Chem. 1960, 631, 198; (e)
Numata, T.; Oae, S. Yuki Gosei Kagaku Kyokaishi 1977,
35, 726; (f) Kita, Y.; Shibata, N. Synlett 1996, 289; (g)
Volonterio, A.; Zanda, M.; Bravo, P.; Fronza, G.; Cavic-
chio, G.; Crucianelli, M. J. Org. Chem. 1997, 62, 8031.
2. (a) Ishibashi, H.; Ikeda, M. Yuki Gosei Kagaku Kyokaishi
1989, 47, 330; (b) De Lucchi, O.; Miotti, U.; Modena, G.
Org. React. 1991, 40, 157; (c) Kita, Y.; Shibata, N.;
Kawano, N.; Tohjo, T.; Fujimori, C.; Ohishi, H. J. Am.
Chem. Soc. 1994, 116, 5116; (d) Padwa, A.; Gunn, D. E.,
Jr.; Osterhout, M. H. Synthesis 1997, 1353; (e) Jousse, C.;
Desmae¨le, D. Eur. J. Org. Chem. 1999, 909; (f) Bennasar,
M.-L.; Zulaica, E.; Ram´ırez, A.; Bosch, J. Tetrahedron
1999, 55, 3117.
3. (a) Russell, G. A.; Mikol, G. J. In Mechanisms of Molec-
ular Migrations; Thyagarajan, B. S., Ed.; Wiley-Inter-
science: New York, 1968; Vol. 1, p. 157; (b) Oae, S.;
Numata, T.; Yoshimura, T. In The Chemistry of the
Sulphonium Group, Part 2; Stirling, C. J. M.; Patai, S.,
Eds.; John Wiley & Sons: New York, 1981; p. 571.
4. (a) Oae, S.; Kitao, T.; Kawamura, S. Tetrahedron 1963,
19, 1783; (b) Johnson, C. R.; Sharp, J. C.; Phillips, W. G.
Tetrahedron Lett. 1967, 8, 5299; (c) Parham, W. E.;
Edwards, L. D. J. Org. Chem. 1968, 33, 4150; (d) Russell,
G. A.; Sabourin, E. T. J. Org. Chem. 1969, 34, 2336; (e)
Davenport, D. A; Moss, D. B.; Rhodes, J. E.; Walsh, J.
Figure 1. Design of new enzyme inhibitors.
the amide carbonyl and cyano groups. In CH2Cl2,
TMSOTf, TBDMSOTf and BF3·OEt2 may be predomi-
nantly coordinated by the amide carbonyl group of
rac-1 causing a more acidic outcome of the methylene
protons of CH2CONHCHPh2 than that of the methyl-
ene protons of CH2CO2Me.10 In DMF and MeCN,
their amide carbonyl and cyano groups may exclusively
coordinate to TMSOTf, TBDMSOTf and BF3·OEt2,
and thus a higher acidic property of the methylene
protons of CH2CO2Me than that of the methylene
protons of CH2CONHCHPh2 in rac-1 must furnish the
high chemoselectivity to give rac-3.
The sutructures of rac-2 and rac-3 were explicitly deter-
mined by their alkaline hydrolyses, as shown in Scheme
3. Treatment of rac-2 or rac-3 with 1N NaOH in
MeOH gave each characteristic product, glyoxylic
amide 8 (77% yield) or mercaptoacetic amide 9 (69%
yield). These particular reactions seem to be useful for
a molecular design of new suicide substrates as the

1522
Y. Nagao et al. / Tetrahedron Letters 43 (2002) 1519–1522
A. J. Org. Chem. 1969, 34, 3353; (f) Jones, D. N.; Helmy,
(m, 11H). Anal. calcd for C20H21NO5S: C, 62.00; H, 5.46;
E.; Whitehouse, R. D. J. Chem. Soc., Perkin Trans. 1
1972, 1329; (g) Numata, T.; Oae, S. Tetrahedron Lett.
1977, 18, 1337.
N, 3.62. Found: C, 61.88; H, 5.51; N, 3.51. rac-3: color-
less crystals; mp 94–96°C; IR (KBr) 1746, 1640, 699 cm−1
;
1H NMR (200 MHz, CDCl3) l 1.88 (s, 3H), 3.45 (d,
J=16.1 Hz, 1H), 3.56 (d, J=16.1 Hz, 1H), 3.67 (s, 3H),
5.94 (s, 1H), 6.26 (d, J=8.1 Hz, 1H), 7.28–7.31 (m, 11H);
Anal. calcd for C20H21NO5S: C, 62.00; H, 5.46; N, 3.62.
Found: C, 61.93; H, 5.61; N, 3.56.
5. Ishibashi, H.; Okada, M.; Akiyama, A.; Nomura, K.;
Ikeda, M. J. Heterocyclic Chem. 1986, 23, 1163.
6. (a) Madesclaire, M. Tetrahedron 1988, 21, 6537; (b)
Shimizu, M.; Shibuya, K.; Hayakawa, R. Synlett 2000,
1437.
10. In the 1H NMR (300 MHz) spectrum analysis of a
mixture of DMF (0.1 mmol), MeCO2Me (0.1 mmol) and
TMSOTf (0.1 mmol) in CDCl3, downfield shifts of CH3
(Dl+0.32), CH3 (Dl+0.49) and CHO (Dl+0.53) signals of
DMF were recognized in comparison with those of a
mixture of DMF and MeCO2Me without TMSOTf.
However, significant downfield shifts of CH3O (Dl+0.00)
and CH3CO (Dl+0.00) signals of MeCO2Me were not
observed in the same manner as described above.
7. Procopius, P. A.; Baugh, S. P. D.; Flack, S. S.; Inglis, G.
G. A. J. Org. Chem. 1998, 63, 2342.
8. Gutmann, V. Electrochim. Acta 1976, 21, 661.
9. Pure compound rac-2 or rac-3 was obtained by recrystal-
lization of each crude solid in n-hexane–CHCl3. rac-2:
colorless needles; mp 111–112°C; IR (KBr) 1746, 1657,
700 cm−1 1H NMR (200 MHz, CDCl3) l 2.17 (s, 3H),
;
3.39 (d, J=13.4 Hz, 1H), 3.66 (d, J=13.4 Hz, 1H), 3.69
(s, 3H), 6.24 (d, J=6.3 Hz, 1H), 6.26 (s, 1H), 7.26–7.34
11. Otto, H.-H.; Schirmeister, T. Chem. Rev. 1997, 97, 133.