Highly efficient asymmetric conjugate additions of aldehydes with vinyl sulfones using a sulfonamide organocatalyst

Article abstract of DOI:10.1055/S-0032-1317137

A sulfonamide organocatalyst promotes the asymmetric conjugate addition of branched aldehydes to vinyl sulfones to afford the corresponding adducts with all-carbon quaternary stereocenters in excellent yields with up to 95% ee. Georg Thieme Verlag Stuttga

Full text of DOI:10.1055/S-0032-1317137

LETTER
▌2385
letter
Highly Efficient Asymmetric Conjugate Additions of Aldehydes with Vinyl
Sulfones Using a Sulfonamide Organocatalyst
Sulfonamide-Catalyzed Conjugate Additions
Tsuyoshi Miura,* Hiroki Yuasa, Miho Murahashi, Mariko Ina, Kosuke Nakashima, Norihiro Tada, Akichika Itoh
Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
Fax +81(58)2308105; E-mail: miura@gifu-pu.ac.jp
Received: 29.06.2012; Accepted after revision: 26.07.2012
tion of all-carbon quaternary centers using organocata-
Abstract: A sulfonamide organocatalyst promotes the asymmetric
lysts. Herein, we would like to report highly efficient
conjugate addition of branched aldehydes to vinyl sulfones to afford
conjugate additions of branched aldehydes 10 to vinyl sul-
fone 9 using novel organocatalyst 6.
the corresponding adducts with all-carbon quaternary stereocenters
in excellent yields with up to 95% ee.
Key words: organocatalyst, conjugate addition, sulfonamide, vinyl
sulfone, quaternary stereocenter
Ph
R1HN
NHR2
R1HN
NHR2
1 R1 = SO2CF3, R2 = H
2 R1 = H, R2 = SO2CF3
3 R1 = H, R2 = SO2C8F17
4 R1 = H, R2 = SO2C6F5
5 R1 = H, R2 = SO2CF3
6 R1 = H, R2 = SO2C4F9
All-carbon quaternary stereocenters are ubiquitous motifs
in many natural products and bioactive compounds; how-
ever, relatively harsh conditions are needed for their con-
struction and the electrophile–nucleophile combinations
are limited due to their steric hindrance. Therefore, stereo-
selective formation of carbon–carbon bonds for the con-
struction of all-carbon quaternary stereocenters is one of
the most challenging research themes in organic synthe-
sis.1 Synthetic methods for compounds with quaternary
stereogenic centers using an organocatalyst have attracted
considerable attention, particularly in the field of green
chemistry.2 1,1-Bis(benzenesulfonyl)ethylene (9) is a
good Michael acceptor and reacts with various carbonyl
compounds as a nucleophile in the presence of organocat-
alysts to afford valuable addition products.3 In particular,
the conjugate additions of branched aldehydes with 9 en-
able the effective construction of chiral all-carbon quater-
nary centers. However, despite the importance of
effective synthetic methods, successful conjugate addi-
tions of branched aldehydes to vinyl sulfone 9 for the con-
struction of all-carbon quaternary stereogenic center have
rarely been reported.4 We investigated organocatalysts
that can effectively promote this reaction under mild con-
ditions.
Figure 1 Structures of organocatalysts 1–6
C4F9SO2F, Et3N
CH2Cl2, r.t., 46 h
BOCHN
NHSO2C4F9
BOCHN
NH2
79%
7
8
HCl, EtOAc
H2N
NHSO2C4F9
r.t., 2.5 h
90%
6
Scheme 1 Preparation of organocatalyst 6
We examined the β-aminosulfonamide organocatalysts 1–
5 that we reported for the direct aldol reactions,5 as shown
in Table 1. With the exception of 1, high enantioselectiv-
ities were obtained (entries 1–5). Trifluoromethane-
sulfonamide 5, derived from L-valine, was the most
suitable catalyst for the conjugate addition with vinyl sul-
fone 9, although 2 and 3, derived from L-phenylalanine,
were superior to 5 for the direct aldol reactions.5d Further-
more, to develop a more powerful organocatalyst, we at-
tempted to prepare novel organocatalyst 6, which
enhanced the acidity of the sulfonamide group by the in-
troduction of the perfluorobutyl group that has strong
electron-withdrawing characteristics (Scheme 1). Treat-
ment of 7, which is an intermediate in the preparation of
organocatalyst 5,5d with perfluorobutanesulfonyl fluoride
in the presence of triethylamine in dichloromethane af-
forded 8 in 79% yield. Next, the Boc group of 8 was re-
moved by treatment with hydrogen chloride in ethyl
acetate to give the desired sulfonamide 6 in high yield. Or-
ganocatalyst 6 was the most effective catalyst for conju-
On the other hand, we have recently reported that β-amino-
sulfonamide organocatalysts 1–5 (Figure 1), which are
easily prepared from L-phenylalanine or L-valine, inex-
pensive natural amino acids, are good organocatalysts for
the direct asymmetric aldol reaction in water.5 In addition,
we also have reported an asymmetric Michael reaction of
aldehydes with maleimides using a primary amine thio-
urea organocatalyst derived from L-phenylalanine.6 To
further demonstrate the effectiveness of organocatalysts
derived from L-phenylalanine or L-valine, we attempted
additional applications for the stereoselective construc-
SYNLETT 2012, 23, 2385–2388
Advanced online publication: 31.08.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317137; Art ID: ST-2012-U0554-L
© Georg Thieme Verlag Stuttgart · New York

2386
T. Miura et al.
LETTER
Table 1 Selection of Organocatalysts
Table 2 Optimization of Reaction Conditions
TFA (0.1 equiv)
cat. (0.1 equiv)
CHO SO2Ph
SO2Ph
CHO
SO2Ph
+
Ph
SO2Ph
Ph
PhMe, r.t.
H2N
6 (0.1 equiv)
NHSO2C4F9
CHO
SO2Ph
SO2Ph
CHO SO2Ph
SO2Ph
9
10a
11a
+
Ph
(2 equiv)
Ph
9
10a
11a
Entry
Catalyst
Time (h)
Yield (%)a
ee (%)b
(2 equiv)
Entry Solvent
Temp
Additive
(equiv)
Time Yield ee
(h)
1
2
3
4
5
6
1
2
3
4
5
6
1
95
99
–2
80
86
79
88
91
(%)a (%)b
1.5
2
1
2
toluene
toluene
CH2Cl2
MeOH
Et2O
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
none
24
2
75 86
100 91
97 91
33 32
87 82
98 86
87 77
99 91
98 92
94 92
95 93
97 89
46 80
85 82
88
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
TFA (0.1)
PhCO2H (0.1)
2
97
3
2.5
2
95
4
24
5
2
100
5
a Isolated yield.
b Determined by HPLC analysis.
6
EtOAc
MeCN
2.5
7
4
gate additions with vinyl sulfone 9 resulting in the highest
enantioselectivity (91% ee) and excellent yield (Table 1,
entry 6).
8
CHCl3
2
9
DCE
2
Optimized conditions for enantioselective conjugate addi-
tions using 6 are shown in Table 2. Conjugate additions
were carried out with 1,1-bis(benzenesulfonyl)ethylene
(9) and 2-methylphenylethanal (10a) as test reactants in
the presence of a catalytic amount of 6 and trifluoroacetic
acid (TFA) at room temperature. Among the reaction sol-
vents examined, m-xylene was the most suitable (Table 2,
entries 2–12). When no TFA was added, a slight reduction
in enantioselectivity was observed and a longer reaction
time was necessary (Table 2, entry 1). Furthermore, we
examined the effects associated with the presence of other
protic acids; however, TFA was found to be the most suit-
able additive (Table 2, entries 13–15). Additions of 0.2 or
0.05 equivalents of TFA resulted in a slight reduction in
stereoselectivity (Table 2, entries 16 and 17). The highest
enantioselectivity (95% ee) was obtained when the reac-
tion was carried out at 0 °C (Table 2, entry 18). High
enantioselectivities were retained although prolongation
of the reaction time was needed when lowering the cata-
lyst loading to 0.05 and 0.01 equivalents (Table 2, entries
20 and 21). Therefore, considering the reaction time, the
optimal conditions were determined to be 0.1 equivalents
of 6 and 0.1 equivalents of TFA, in m-xylene at room tem-
perature (Table 2, entry 11).
10
11
12
13
14
p-xylene
m-xylene
o-xylene
m-xylene
m-xylene
2
2
2
5.5
4-O2NC6H4CO2H 24
(0.1)
15
16
17
18
19
20c
21d
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
r.t.
r.t.
r.t.
TfOH (0.1)
TFA (0.2)
TFA (0.05)
24
2
24 83
97 91
98 91
99 95
94 95
99 90
96 89
2
0 °C TFA (0.1)
21
72
3
–10 °C TFA (0.1)
r.t.
r.t.
TFA (0.05)
TFA (0.01)
20
a Isolated yield.
b Determined by HPLC analysis.
c Catalyst (0.05 equiv) was used.
d Catalyst (0.01 equiv) was used.
aldehydes 10h and 10i, possessing a naphthalene skele-
ton, and 9. Vinyl sulfone 9 reacted smoothly with both al-
dehydes 10h and 10i to afford the corresponding adducts
11h and 11i, respectively, in excellent yields with 92% ee
(Table 3, entries 8 and 9). The stereochemistry of the ad-
dition products 11 obtained using 6 was determined by
comparison with reported chiral-phase HPLC retention
times and optical rotation data.4
With the optimal conditions in hand, the scope and limita-
tion of the conjugate additions between branched alde-
hydes 10 and 9 were examined (Table 3).7 We selected
methyl and methoxy substituents as representative elec-
tron-donating groups and halogen substituents as elec-
tron-withdrawing groups on the benzene ring. The
reactions of branched aldehydes 10b–g with 9 proceeded
smoothly and resulted in the corresponding adducts in ex-
cellent yields with 83–92% ee (Table 3, entries 2–7).
Moreover, we examined the reactions between branched
We infer that the conjugate additions of aldehydes with
vinyl sulfone 9 using organocatalyst 6 proceed via a plau-
Synlett 2012, 23, 2385–2388
© Georg Thieme Verlag Stuttgart · New York

LETTER
Sulfonamide-Catalyzed Conjugate Additions
2387
sible transition state, as shown in Scheme 2, based on the
stereochemistry of addition products 11a–i. The primary
amino group of 6 condenses with aldehydes 10a to gener-
ate the E-enamine intermediates. Then, the acidic proton
of the sulfonamide group, which forms an intramolecular
coordination to nitrogen in the enamine transition state,
successfully interacts with the oxygen of the vinyl sulfone
to control the approach direction of the vinyl sulfone to
the enamine intermediates. This ultimately affords the
corresponding addition products with high stereoselectiv-
ity. We believe that the acidity of sulfonamide is enhanced
by the powerful electron-withdrawing effect of the per-
fluorobutyl chains to strongly coordinate to vinyl sulfone
and stabilize the rigid transition states during conjugate
additions. Moreover, the addition of TFA to the conjugate
additions might accelerate the formation of the enamine
intermediate, as well as reinforce the rigid transition state
of the conjugate additions.
Table 3 Conjugate Additions Using Organocatalyst 6
H2N
NHSO2C4F9
TFA
SO2Ph
SO2Ph
6 (0.1 equiv)
(0.1 equiv)
product
aldehyde
10
+
m-xylene, r.t.
9
11
(2 equiv)
Entry Product
Time Yield ee
(h)
(%)a
(%)b
CHO SO2Ph
SO2Ph
Ph
1
2
95
93
11a
CHO SO2Ph
SO2Ph
Br
11b
F
2
3
4
3
2
2
97
95
99
89
91
92
CHO SO2Ph
SO2Ph
H
Ph
CHO
H2N
H
N
10a
Ph
O2S
N
N
SO2
Ph
H
SO2C4F9
SO2C4F9
Ph
6
11c
Me
CHO SO2Ph
SO2Ph
Scheme 2 Proposed transition-state model of the reaction
In conclusion, the novel organocatalyst 6 can easily be
prepared from L-valine, an inexpensive and commercially
available amino acid. Organocatalyst 6, which is a simple
β-aminosulfonamide with only one stereogenic center, ef-
ficiently catalyzes conjugate additions of various
branched aldehydes to vinyl sulfone 9 with a short reac-
tion time at room temperature to afford the corresponding
addition products with high enantioselectivities. Organo-
catalyst 6 is an excellent catalyst and is more effective
than the reported organocatalysts4 for conjugate additions
of vinyl sulfone with branched aldehydes to give com-
pounds possessing all-carbon quaternary stereocenters.
The excellent performance is probably due to the carbon
skeleton of valine and the electron-withdrawing effect of
the perfluorobutyl group on 6. Further application of this
catalyst in the synthesis of bioactive compounds is cur-
rently being investigated in our laboratory.
11d
MeO
CHO SO2Ph
SO2Ph
5
6
7
8
4
10
4
99
98
99
99
92
83
91
92
11e
OMe
CHO SO2Ph
SO2Ph
11f
Br
CHO SO2Ph
SO2Ph
11g
11h
CHO SO2Ph
SO2Ph
3
Acknowledgment
This work was supported in part by Grants-in-Aid for Scientific Re-
search (C) (No. 22590007) from the Japan Society for the Promoti-
on of Science.
CHO SO2Ph
SO2Ph
9
4
97
92
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b Determined by HPLC analysis.
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2385–2388

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T. Miura et al.
LETTER
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(7) Typical Procedure for the Michael Additions Using 6
To a solution of 10a (30.8 mg, 0.100 mmol) and
organocatalyst 6 (3.8 mg, 0.010 mmol) in m-xylene (1.0 mL)
was added 2-phenylpropanal (26.8 μL, 0.200 mmol) and
TFA (0.7 μL, 0.010 mmol) at r.t. After stirring at r.t. for 2 h,
the reaction mixture was directly purified by flash column
chromatography on silica gel with a 3:1 mixture of hexane
and EtOAc to afford the pure 11a4 (42.0 mg, 95%) as a
colorless powder; [α]D18 –25.6 (c 1.00, CHCl3); 95% ee; the
ee was determined by HPLC with a Chiralpak AS-H column
(hexane–2-PrOH = 70:30), flow rate = 1.0 mL/min; λ = 220
nm; tR (major) = 21.7 min, tR (minor) = 25.9 min. 1H NMR
(400 MHz, CDCl3): δ = 1.46 (s, 3 H), 2.82 (dd, J = 5.8, 16.4
Hz, 1 H), 2.95 (dd, J = 3.4, 16.4 Hz, 1 H), 4.42 (dd, J = 3.4,
5.8 Hz, 1 H), 7.26–7.29 (m, 2 H), 7.36–7.73 (m, 11 H), 7.87
(d, J = 8.2 Hz, 2 H), 9.60 (s, 1 H). 13C NMR (125 MHz,
CDCl3): δ = 19.6, 30.9, 53.1, 80.2, 127.6, 128.1, 129.1,
129.3, 129.7, 129.8, 134.6, 137.3, 137.8, 138.3, 201.4.
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Synlett 2012, 23, 2385–2388
© Georg Thieme Verlag Stuttgart · New York