1,3-Benzodithiole-1,1,3,3-tetraoxide (BDT) as a versatile methylation reagent in catalytic enantioselective Michael addition reaction with enals

Article abstract of DOI:10.1016/j.tetlet.2010.01.102

A protocol of an organocatalytic highly enantioselective conjugate addition of nucleophilic BDT to enals has been developed and the versatile Michael adducts serve as useful building blocks for a variety of organic transformations.

Full text of DOI:10.1016/j.tetlet.2010.01.102

Tetrahedron Letters 51 (2010) 1766–1769
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
1,3-Benzodithiole-1,1,3,3-tetraoxide (BDT) as a versatile methylation reagent
in catalytic enantioselective Michael addition reaction with enals
a
a,b,
Shilei Zhang a, Jian Li b, , Sihan Zhao , Wei Wang
*
*
a Department of Chemistry & Chemical Biology, University of New Mexico, Albuquerque, NM 87131, United States
b School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A protocol of an organocatalytic highly enantioselective conjugate addition of nucleophilic BDT to enals
has been developed and the versatile Michael adducts serve as useful building blocks for a variety of
organic transformations.
Received 5 January 2010
Revised 25 January 2010
Accepted 27 January 2010
Available online 1 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Methylation
Michael
Organocatalysis
Chiral methyl unit is one of the most important organic groups
widely distributed in natural products, drugs and various chiral
chemical products and intermediates. Asymmetric methods to
F
cat. I (20 mol %)
PhCO2H
PhO2S
R
SO2Ph
CHO
F
CHO
(20 mol%)
+
PhO2S
PhO2S
SO2Ph
R
toluene, 0 o
C
construct methyl moiety include
a- or b-alkylation of carbonyl
up to 83% yield
>99% ee
compounds with chiral auxiliaries,1 enantioselective protonation
cat.
O
S
Ph
at a
-position of carbonyl compounds,2 asymmetric hydrogenation
O
Ph
of double bond with H2/metal/ligand method,3 resolution of race-
mic alcohol with lipase4 and conjugate addition of methyl metal
to electron-deficient olefins.5 Recently, organocatalytic asymmet-
N
SO2Ph
H
OR
S
I: R = TMS
O
O
II: R = TES
BPSM (1)
BDT (2)
III: R = TBDMS
ric transfer hydrogenation of b-branched
a-, b-unsaturated alde-
hydes or nitroolefins with Hantzsch ester as ‘H’ source was
proved to be an efficient method for the synthesis of chiral b-alkyl
aldehydes or nitroalkanes.6 However, the examples of organocata-
lytic direct Michael addition of methyl group or its precursor to
Figure 1. Nucleophilic bissulfonylmethanes.
bis(phenylsulfonyl)methane is more valuable. It is believed that a
variety of electrophiles can be introduced. Therefore, the strategy
is particularly attractive in medicinal chemistry and drug discovery
with the ease of making analogues.
However, as demonstrated in our early studies, the reaction be-
tween bis(phenylsulfonyl)methane (BPSM) (1) and 4-nitrocinnam-
a
-, b-unsaturated aldehydes remain elusive.7
Recently, sulfones have received much attention in the synthetic
communities. The sulfonyl moiety in products can be conveniently
converted into various useful functionalities, and accordingly vinyl
sulfones8 and -substitutedsulfones9 havebeenwidelyusedaselec-
a
trophiles and nucleophiles in a variety of organic transformations.
Very recently, we, Moyano and Rios, Kim, Cordova and Shibata
groups independently reported the Michael addition of fluor-
aldehyde gave only
adduct.10a The same outcome was observed by Ruano and Alemán
group in similar studies.11 Only b-alkyl substituted
-, b-unsatu-
a trace amount (<5% yield) of Michael
a
obis(phenylsulfonyl)methane to
a-, b-unsaturated carbonyls with
rated aldehydes effectively participate in the organocatalytic Mi-
chael reaction. We surmise that this may result from the steric
hindrance and low reactivity of methylene moiety in bis(phenyl-
sulfonyl)methane. To generate a more reactive sulfonyl-derived
methylene species, we believe that a rigid cyclic structure such
as 1,3-benzodithiole-1,1,3,3-tetraoxide (BDT, 2) could be a useful
reagent for the direct conjugate addition process. To our knowl-
edge, although this reagent was reported more than 10 years ago,
high enantioselectivities for the preparation of monofluoromethyl
compounds (Fig. 1).10 In our continuing effort on expanding the via-
ble synthetic strategy, we envision that the use of the unsubstituted
* Corresponding authors. Tel./fax: +86 21 6425 2584 (J.L.); tel.: +1 505 277 0756;
fax: +1 505 277 2609 (W.W.).
E-mail addresses: jianli@ecust.edu.cn (J. Li), wwang@unm.edu (W. Wang).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.102

S. Zhang et al. / Tetrahedron Letters 51 (2010) 1766–1769
1767
it has rarely been used in the organic synthesis.12 Herein, we wish
to report our discovery of BDT as an efficient nucleophile in the di-
rect Michael addition to various substituted enals including aro-
matic systems with good to excellent enantioselectivities and in
moderate to high yields.13 Moreover, the viable Michael adducts
can be used for further synthetic elaborations to conveniently be
transformed to new functionalities.
phy. To demonstrate the advantage of our methodology, 1.0 mmol
scale of BDT was applied under the optimal reaction conditions as
described in Table 1, (entry 14). After 72 h, 4.0 mL of hexane was
added into the reaction mixture, stirred for another 20 min and
then filtered; the solid was washed with 10 mL of t-BuOMe/hexane
(1/1) to afford pure 4a as a white solid in 84% yield. Lowering the
catalyst loading to 5 mol % required a long reaction time as well
(60 h), even at higher temperature (40 °C) with slight drop in both
yield (91%) and ee (93%) (entry 15). It should be noted that the
enantiomeric excess found by us was enriched in this simple puri-
fication process. The ee of the crude product was determined to be
97%, while the purified product by filtration was reached to 99%.
With optimal reaction conditions in hand, we then explored the
We initially examined the Michael reaction of BDT (2) and cin-
namaldehyde 3a in the presence of diphenylprolinol silyl ether I
(20 mol %) in toluene at rt. To our delight, even when no base
was added, the reaction proceeded smoothly to provide the desired
product 4a in 78% yield and with 94% ee after 72 h (Table 1, entry
1), indicating that indeed the methylene moiety in BDT is much
more active. Further investigation of the reaction medium revealed
that the reaction was tolerated by various solvents. Good to high
enantioselectivities and moderate to excellent yields were ob-
tained in most of the solvents screened (entries 2–8). The best re-
sult was achieved when t-BuOMe was used (86% yield and 96% ee)
(entry 8). Survey of catalysts identified the bulky TBDMS catalyst
III as the best promoter by improving the ee value to excellent le-
vel without sacrificing the yield (entry 10 vs entry 8). Reducing the
loading of 3a from 1.5 equiv to 1.2 equiv gave similar results, but
longer reaction time was needed (entry 11). The effect of additives
on the reaction was also probed. Surprisingly, the basic additive
NaOAc hindered the reaction significantly, giving only 43% yield
even after 5 d (entry 12). In contrast, benzoic acid accelerated the
process dramatically to generate improved yield albeit with
slightly decreased enantioselectivity (96% yield and 97% ee) (entry
13). Finally, decreasing the catalyst loading from 20 mol % to
10 mol % and simultaneously reducing the volume of solvent from
0.8 mL to 0.4 mL gave the same results (Table 1, entry 14 vs entry
13). It is noteworthy that adduct 4a can easily precipitate from t-
BuOMe to give highly pure product without column chromatogra-
scope of Michael addition of BDT to a wide range of
a-, b-unsatu-
rated aldehydes. As shown in Table 2, a number of cinnamaldehy-
des bearing electron-donating and electron-withdrawing
substituents were successfully applied in the Michael reaction with
BDT. The corresponding aldehyde products 4a–k were successfully
isolated with very high enantioselectivities (93–98% ee) and in
good to excellent yields (63–98%) (entries 1–11). In some cases,
toluene instead of t-BuOMe is the better solvent for the reaction
(entries 5–11). Furthermore, heteroaromatic and alkyl enals could
also effectively engage in the conjugate addition process with high
efficiency (entries 12–14). Although no single solvent was suitable
for the alkyl enals, the use of a mixture of toluene and THF was
optimal (entries 13–14). The absolute configuration of the Michael
adducts was determined to be S by single-crystal X-ray analysis of
corresponding alcohol 5 derived from 4c (Fig. 2).14
Finally, to demonstrate the synthetic utility of the Michael ad-
ducts 4, a series of organic transformations were performed.
Reduction of the aldehyde 4a gave an alcohol 6. Then direct reduc-
tive removal of the phenylsulfonyl group of compound 6 using a
modified protocol activated Mg (0) in the presence of Bu4N+BrÀ
Table 2
Table 1
Scope of Michael addition of BDT (2) to
a
-, b-unsaturated aldehydes (3)a
Optimization of the reaction conditionsa
cat. (10 mol%)
O2
S
O2
S
O2
S
cat. (20 mol%)
additive
O2
S
PhCO2H
CHO
CHO
CHO
(10 mol%)
solvent, rt
+
+
R
(20 mol%)
CHO
S
S
R
S
S
Ph
solvent, rt
2
O2
3
O2
O2
O2
4
Ph
4a
3a
BDT 2
Entry
R
Cat.
Solvent
t (h)
Yieldb
(%)
eec (%)
Entry
Cat.
Solvent
Additive
t (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11d
12d
13d
14e
15f
I
I
I
I
I
I
I
I
II
III
III
III
III
III
III
Toluene
CH2Cl2
EtOH
EtOAc
Et2O
None
None
None
None
None
None
None
None
None
None
None
NaOAc
PhCO2H
PhCO2H
PhCO2H
72
43
36
60
36
83
83
40
78
79
98
77
81
63
58
86
83
83
86
43
96
95
91
94
86
83
90
95
93
91
96
97
99
99
—
1
2
3
4
5
Ph, 4a
III
III
III
III
III
III
I
III
III
III
I
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene/THF
(1/1, v/v)
Toluene/THF
(1/1, v/v)
72
120
72
72
96
43
68
34
120
115
72
72
35
95
70
68
90
87
85
71
98
72
76
63
76
95
97
94
96
94
98
98
93
96
95
98
94
84
88
4-FC6H4, 4b
4-ClC6H4, 4c
4-BrC6H4, 4d
4-CNC6H4, 4e
4-NO2C6H4, 4f
4-MeC6H4, 4g
4-MeOC6H4, 4h
3-FC6H4, 4i
3-NO2C6H4, 4j
2-FC6H4, 4k
2-Furanyl, 4l
Me, 4m
THF
DME
6
7d
8e
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
9d
10
11d
12d,e
13d,e,f
40
72
120
120
72
72
60
I
III
97
97
93
14d,e,f
Et, 4n
III
135
73
92
a
Unless stated otherwise, the reaction was carried out with 3a (0.15 mmol), 2
(0.10 mmol), catalyst (0.02 mmol) and additive (0.02 mmol) in 0.8 mL of solvent at
rt for specified time. The mixture was then directly purified by silica gel
a
Unless stated otherwise, the reaction was carried out with 3 (0.18 mmol), 2
a
(0.15 mmol), catalyst (0.015 mmol) and PhCO2H (0.015 mmol) in 0.6 mL of solvent
at rt for a specified time. The mixture was then directly purified by silica gel
chromatography.
chromatography.
b
Isolated yield.
c
b
Determined by HPLC analysis (Chiralpak IB) by converting to corresponding
Isolated yield.
c
alcohol.
ee was determined by HPLC analysis (Chiralpak IA, IB or IC) of corresponding
d
0.12 mmol of 3a used.
Reaction conditions: 3a (0.12 mmol), 2 (0.10 mmol), catalyst III (0.01 mmol)
and PhCO2H (0.01 mmol) in 0.4 mL of t-BuOMe at rt.
alcohol of 4.
e
d
20 mol % catalyst used.
No PhCO2H used.
Two equivalents of aldehyde used.
e
f
f
5 mol % III used at 40 °C.

1768
S. Zhang et al. / Tetrahedron Letters 51 (2010) 1766–1769
good yield and with enriched enantioselectivity. These features
render the process particularly attractive for a large-scale synthe-
sis. Furthermore, the viable phenylsulfonyl group in Michael
adducts can be easily converted into a variety of new functional-
ities. Further investigations of this versatile reagent in new organic
transformations are currently underway in our laboratory and will
be reported in due course.
Acknowledgements
Financial support for this work provided by the NSF (CHE-
0704015, W.W.) and the China 111 Project (Grant B07023, J.L.
and W.W.) is gratefully acknowledged. Thanks are expressed to
Dr. Elieen N. Duesler for performing X-ray analysis. The Bruker
X8 X-ray diffractometer was purchased via an NSF CRIF:MU award
to the University of New Mexico, CHE-0443580.
Figure 2. X-ray crystallographic structure 5.
or ClÀ (TBAB or TBAC) in MeOH provided 3-methyl phenylpropanol
in a good yield (Eq. 1). It is noteworthy that without TBAB or TBAC,
a low yield for the cleavage of phenylsulfonyl group was obtained.
Treatment of compound 6 with selectfluor and t-BuOK in DMF was
followed by reductive removal of the phenylsulfonyl group to af-
ford monofluoromethylated product 8 (Eq. 2). Moreover, a methyl
group can be introduced readily to lead to 3-ethyl compound 11
(Eq. 3). Finally, the treatment of the sulfone 6 with oxidant oxazir-
idine 11 in the presence of t-BuOK followed by lactonization affor-
ded synthetically valuable chiral lactone 12 (Eq. 4).15 Significantly,
no racemization was observed in all cases.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.102.
References and notes
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O2
O2
CHO
S
NaBH4, MeOH
100%
CH2OH
S
(1)
S
Ph
S
Ph
O2
O2
6, 97% ee
4a, 97% ee
2. Ishihara, K.; Nakashima, D.; Hiraiwa, Y.; Yamamoto, H. J. Am. Chem. Soc. 2003,
125, 24.
Mg, TBAB, MeOH
70%
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Chem. Soc. 2000, 122, 11513; (b) Kllstrm, K.; Hedberg, C.; Brandt, P.; Bayer, A.;
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P.-A. R.; Patureau, F. W.; Reek, J. N. H. Angew. Chem., Int. Ed. 2009, 48, 2162.
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OH
7, 97% ee
O2
S
F
1) t-BuOK, selectflour
DMF, 90%
OH
(2)
OH
S
2) Mg, TBAC
MeOH, 78%
O2
Ph
8, 97% ee
6, 97% ee
O2
S
O2
S
TBSCl, imidazole
DMF
OTBS
(3)
S
S
6. (a) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
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A.; Ozores, L.; List, B. J. Am. Chem. Soc. 2007, 128, 8976.
92%
OH
O2
Ph
O2
Ph
9
6, >99% ee
7. Nájera, C.; Yus, M. Tetrahedron 1999, 55, 10547.
MeI, NaH
DMF
99%
8. (a) Mossé, S.; Alexakis, A. Org. Lett. 2005, 7, 4361; (b)Li, H.;Song, J.; Liu, X.; Deng, L.
J. Am. Chem. Soc. 2005, 127, 8948; (c) Zhu, Q.; Lu, Y. Org. Lett. 2008, 10, 4803; (d)
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Angew. Chem., Int. Ed. 2009, 48, 5694; (c) Ni, C.; Zhang, L.; Hu, J. J. Org. Chem.
2008, 73, 5699.
O2
S
1) HCl, MeOH
100%
Me
OTBS
OH
2) Mg, TBAC
MeOH, 79%
S
O2
Ph
10
11, >99% ee
10. (a) Zhang, S.; Zhang, Y.-N.; Ji, Y.-F.; Li, H.; Wang, W. Chem. Commun. 2009,
4886; (b) Alba, A.-N.; Companyó, X.; Moyano, A.; Rios, R. Chem. Eur. J. 2009, 15,
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Sun, J.; Córdova, A. Chem. Eur. J. 2009, 15, 10013; (e) Furukawa, T.; Shibata, N.;
Mizuta, S.; Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47, 8051.
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A.-N.; Companyó, X.; Moyano, A.; Rios, R. Chem. Eur. J. 2009, 15, 11095.
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Tetrahedron: Asymmetry 1996, 7, 1089; (b) Kündig, E. P.; Cunningham, A. F., Jr.
Tetrahedron 1988, 44, 6855; (c) Oppolzer, W.; Swenson, R. E.; Gaudin, J.-M.
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Chem. Soc. 1993, 115, 5294.
O2
S
Ph
1) 13, t-BuOK
O
N
Ts
THF, 0 ºC
O
(4)
S
2) HCl, MeOH
Ph
O
OH
O2
Ph
13
0 ºC
12, 99% ee
6, >99% ee
57%
In conclusion, we have developed a new nucleophilic reagent
BDT for the direct organoctalytic asymmetric Michael addition to
a wide range of a-, b-unsaturated aldehydes with good to excellent
ee’s and in good to excellent yields. The process features the simple
filtration without column chromatography to afford products in
13. During the preparation of this manuscript, a similar approach is reported by
Palomo and co-workers: Landa, A.; Puente, Á.; Santos, J. I.; Vera, S.; Oiarbide,
M.; Palomo, C. Chem. Eur. J. 2009, 15, 11954.

S. Zhang et al. / Tetrahedron Letters 51 (2010) 1766–1769
1769
14. CCDC 749599 contains the Supplementary data for this Letter. These data can
be obtained free of charge via www.ccdc.cam.ac.uk.
possible reaction pathway for the transformation is: oxidation of the
bissulfonyl moiety to carboxylic acid by oxaziridine 13 is followed by
O2
S
1) 13, t-BuOK
15.
A
OH
THF, 0 ºC
HO2C
a
S
O
lactonization to give lactone 12. The chemistry is developed based on the
works by Davis, F. A.; Jenkins, R., Jr.; Yocklovich, S. G. Tetrahedron Lett. 1978, 19,
5171. Further study of the reaction and application is under investigation
OH
O2
Ph
N
Ts
Ph
6, >99% ee
Ph
2) HCl, MeOH
0 ºC
13
Ph
O
O
12, 99% ee
.