Enantioselective methoxyselenenylation of a,β-unsaturated aldehydes

Article abstract of DOI:10.1055/s-0028-1087936

In this communication we propose a convenient methodology to effect the asymmetric methoxyselenenylation of β-aryl α,β-unsaturated aldehydes using as electrophilic reagent an optically pure sulfur-containing selenenyl chloride. Mechanistic aspects of the

Full text of DOI:10.1055/s-0028-1087936

LETTER
743
Enantioselective Methoxyselenenylation of a,b-Unsaturated Aldehydes
Enantioselective
l
a
yselenenyl
u
ation of
a
,
b
-
d
iodes Santi,* Stefano Santoro, Cristina Tomassini, Fabio Pascolini, Lorenzo Testaferri, Marcello Tiecco
Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy
Fax +39(075)5855116; E-mail: santi@unipg.it
Received 10 December 2008
Abstract: In this communication we propose a convenient method-
SMe
Se)2
SO2Cl2
Et2O
ology to effect the asymmetric methoxyselenenylation of b-aryl
a,b-unsaturated aldehydes using as electrophilic reagent an optical-
ly pure sulfur-containing selenenyl chloride. Mechanistic aspects of
the reaction were investigated and simple manipulations to prepare
optically pure derivatives are reported.
SMe
Se
Cl
1
2
Scheme 1 Preparation of chiral electrophilic selenium reagent
Key words: selenium, asymmetric synthesis, aldehydes, electro-
philic addition
acetal intermediate, which undergoes electrophilic
selenomethoxylation via seleniranium ion intermediate.
This process, however, occurs with poor regio- and stereo-
selectivity and it is strongly conditioned by the nature of
the substrate.
Organoselenium compounds are very useful reagents in
organic synthesis and they have been extensively used in
a wide range of reactions, varying from cationic, radical
and anionic transformations, to rearrangements and elim-
inations.1
In order to find the best reaction conditions preliminary
experiments were carried out starting from cinnamalde-
hyde (3a) using the Ar*SeCl 2 as electrophilic seleneny-
lating reagent at different temperatures and evaluating
also the effect of MgSO4 as an additive. The results are
summarized in Table 1.
During the last decades the design of enantiomerically
pure diselenides and their use as electrophilic reagents
precursors have emerged as practical and powerful tools
for the stereoselective preparation of chiral molecules.1–3
We reported the synthesis of a new class of enantiopure
sulfur-containing diselenides and their synthetic applica-
tions to promote enantioselective selenium addition reac-
tions to unsaturated substrates.4 Electrophilic reagents
generated starting from diselenide 1 were successfully
employed to prepare enantiomerically enriched alcohols,5
ethers,5 azides,6 heterocycles7 as well as for the kinetic
resolution of allylic alcohols.8 All the investigated reac-
tions showed a very high facial selectivity, higher than
those obtained with the corresponding nitrogen- or oxy-
gen-containing reagents.3
All of the reactions led to the formation of four enantio-
merically pure diastereomers 4a–7a, one of which in
much higher yield (4a). Only this major isomer could be
purified from the reaction mixture by flash chromatogra-
Table 1 Preliminary Investigation Starting from 3a
OMe OMe
OMe OMe
OMe
OMe
SeAr*
SeAr*
O
We demonstrated also that the facial selectivity is strongly
correlated to the nonbonding interaction established be-
tween the electrophilic selenium and the sulfur atom in
compounds like 2.9 This compound is an air-stable solid
that can be easily prepared starting from diselenide 1 by
treatment with SO2Cl2 and crystallization from diethyl
ether (Scheme 1). It can be successfully used in a large se-
ries of asymmetric conversions.5–9
4a
2
6a
H
MeOH
OMe OMe
OMe OMe
3a
OMe
OMe
SeAr*
SeAr*
7a
5a
Entry Additive Temp Time Overall
Yield of 4a/5a/6a/7ab
(°C) (d) yield (%)a 4a (%)a
In this communication the first efficient asymmetric
methoxyselenenylation of a,b-unsaturated aldehydes is
reported. Paulmier and co-workers have already described
a methodology for the methoxyselenenylation of these
substrates using PhSeCl in MeOH at –30 °C.10 The au-
thors claim that this process proceeds through a dimethyl-
1
2
3
4
5
–
–
0
6
20
30
8
34:16:25:25
61:15:12:12
61:15:12:12
81:9:5:5
–30
6
20
–
–30 10
83
34
91
55
26
65
MgSO4
MgSO4
0
0
6
10
81:9:5:5
SYNLETT 2009, No. 5, pp 0743–0746
x
x.
x
x.
2
0
0
9
Advanced online publication: 24.02.2009
DOI: 10.1055/s-0028-1087936; Art ID: G36808ST
© Georg Thieme Verlag Stuttgart · New York
a Isolated yields.
b Determined by 1H NMR.

744
C. Santi et al.
LETTER
OMe
O
OMe OMe
OMe
AcOH
THF–H2O
H
SeAr*
SeAr*
8 (98%)
4a
MeLi
OMe OH
OMe OH
Bu3SnH
AIBN
C6H6, reflux
OMe OH
Me
Me
Me
SeAr*
SeAr*
(–)-9
CF3SO3H
(+)-10
(–)-(2R,4S)-11 (90%)
(70:30)
styrene
OH
Me
(R)-12 (90%)
Scheme 2 Assignment of the absolute configuration of 4a
phy on silica gel. Unfortunately the mixture of the minor Furthermore treatment of (–)-9 with a catalytic amount of
products 5a–7a could not be separated and the structures, CF3SO3H in the presence of styrene (2 equiv) afforded the
as well as the ratios, were assigned by the NMR analysis corresponding enantiomerically pure (R)-allylic alcohol
of the crude.
12.8
A ‘one-pot’ carbonyl protection as dimethylacetal and The relative configuration of derivatives similar to 4 can
methoxyselenenylation occurred.10 In a typical optimized be also assigned on the basis of the value of the 1H NMR
procedure, to one equivalent of aldehyde 3, one equivalent coupling constants of the vicinal protons. The anti deriv-
of Ar*SeCl 2, dissolved in a CH2Cl2–MeOH mixture was atives show larger J values (7–10 Hz) than the syn
added, and the reaction mixture was stirred in the condi- ones.13,14
tions shown in Table 1.
This assessment has been confirmed by evaluation of the
The reaction carried at 0 °C (entry 1) was slow and afford- coupling constants measured for 4a between ArSeCH and
ed the products 4a–7a in very poor yields and with low se- PhCH (J = 9.1 Hz), which is very similar to that measured
lectivity. Moreover several unidentified by products were by Paulmier10 in the analogous compound obtained with
formed. Using lower temperature (–30 °C, entries 2 and 3) PhSeCl (J = 8.7 Hz; Figure 1).
we observed an increase in yield as well as in diastereo-
selectivity. An unexpected improvement in yield and se-
lectivity was also observed at 0 °C in the presence of one
equivalent of MgSO4 (entries 4 and 5).
J2,3 = 9.1 Hz
Ar =
OMe OMe
H
SMe
In order to determine the absolute and relative configura-
tions of the addition products, the pure isomer 4a was hy-
drolyzed by treatment with acetic acid in THF–H2O
affording the corresponding aldehyde 8 that was treated
with MeLi to give 98 and 1011 in a 70:30 diastereoisomeric
ratio. After chromatographic purification (–)-9 was sub-
jected to radical deselenenylation that furnished the enan-
tiomerically pure b-methoxy alcohol 1112 (Scheme 2).
The comparison of the experimental optical rotation of 11
with the value reported in literature8 allowed us to assign
the R configuration to the benzylic carbon. Taking into
consideration that the methoxyselenenylation is a ste-
reospecific anti addition we could assign R configuration
to the selenium-binding carbon.
2
3
OMe
ArSe
H
J2,3 = 8.7 Hz
Ar =
Figure 1 The vicinal J coupling values confirm the relative confi-
guration
The experimental conditions reported in entry 4 were ap-
plied on acetals 13 and 14 (Figure 2) in order to evaluate
the effect of different protections at the carbonyl function.
1,3-Dioxolane derivate 13 proved to be unstable and the
acetal converted completely to the related dimethylacetal
derivative. On the contrary the dimethylacetal 14 com-
pared to the unprotected 3a gave higher yields (overall
Synlett 2009, No. 5, 743–746 © Thieme Stuttgart · New York

LETTER
Enantioselective Methoxyselenenylation of a,b-Unsaturated Aldehydes
Table 2 Asymmetric Methoxyselenenylation of 3a–f
745
O
OMe
OMe
OMe OMe
OMe OMe
O
R
OMe
R
OMe
O
SeAr*
13
14
SeAr*
4
6
2
R
H
Figure 2 Acetals 13 and 14
MeOH–CH2Cl2
MgSO4, 0 °C
6 d
3
OMe OMe
OMe OMe
yield: 62%; yield of 4a: 49%) but lower diastereo- and
enantioselectivity (4a/5a/6a/7a = 47:13:20:20). This
clearly suggests that starting from the aldehyde the reac-
tion involves an intermediate different from 14 and that in
the ‘one-pot’ reaction the formation of the dimethylacetal
is not the first reaction step. We suppose that this interme-
diate is the hemiacetal 15 and that methoxyselenenylation
occurs on it rather than on the acetal. In this way the ste-
reocontrol of the process may be improved by a stronger
nonbonding interaction between seleniranium ion and the
hydroxy group in the allylic position (16; Scheme 3). We
recently demonstrated that this coordination plays an im-
portant role in governing the stereochemistry of electro-
philic addition reactions during the kinetic resolution of
allylic alcohols.8 Finally we performed the reaction in op-
timized conditions on some a,b-unsaturated aldehydes
(Table 2). Substrates 3b–d were prepared by Wittig reac-
tions, while compound 3e was prepared by refluxing
2-naphthaldehyde, vinyl acetate and Ba(OH)2 in THF.15
R
OMe
R
OMe
SeAr*
SeAr*
5
7
Entry
Substrate
Overall Yield of
yield (%)
Ratioa
4
11 (%)
26b
65b
39b
45b
–
4/5/6/7
81:9:5:5
81:9:5:5
72:8:10:10
73:13:7:7
–
1
2c
3
3a
R = Ph
R = Ph
34b
3a
3b
91b
R = 4-ClC6H4
82b
4
3c R = 4-MeC6H4
66b
5
3d R = 4-NO2C6H4
3e R = 2-naphthyl
3e R = 2-naphthyl
–
6
29b
18b
48b
–
72:8:10:10
72:8:10:10
35:35:15:15
7c
8
67b
3f
R = Me
64b
a Determined by 1H NMR.
b Isolated yields.
With the exception of the reaction performed on (E)-3-(4-
nitrophenyl)acrylaldehyde (3d) all processes showed
good yields and good diastereo- and enantioselectivities.
Moreover in each case the major isomer 4 could be recov-
ered by chromatography on silica gel as a single diastereo-
mer (de >99%).
c Reaction time was 10 d.
be due to a match/mismatch effect during the addition to
the couple of enantiomerically enriched isomers 17. The
results reported in entry 8 (Table 2) clearly indicate that in
order to obtain a good diastereoselectivity, an aryl substit-
Surprisingly no selectivity was observed in the formation
of the diastereoisomers 6 and 7. Presumably this data can
OMe
O
OMe
OH
MeOH
H
Ar*Se
OH
Se
*Ar
MeOH
3a
15
16
MeOH
OMe OMe
OH
OMe OMe
OMe
Ar*SeOMe
OMe
OMe
MeOH
MeOH
H2O
SeAr*
SeAr*
Ar*SeOMe
H2O
14
4a/5a
Ar*SeOMe
Ar*SeOMe
OMe OMe
Ar*SeOMe
OMe
Ar*SeOMe
OMe
OMe
SeAr*
17
6a/7a
Scheme 3 Proposed mechanism
Synlett 2009, No. 5, 743–746 © Thieme Stuttgart · New York

746
C. Santi et al.
LETTER
1.2, 7.5 Hz), 6.95 (dt, 1 H, J = 1.4, 7.5 Hz), 4.84 (d, 1 H, J =
2.9 Hz), 4.36 (d, 1 H, J = 9.1 Hz), 4.19 (q, 1 H, J = 6.9 Hz),
3.60 (dd, 1 H, J = 2.9, 9.1 Hz), 3.58 (s, 3 H), 3.56 (s, 3 H),
uent on the b-carbon of the a,b-unsaturated aldehydes is
required.
3.17 (s, 3 H), 1.87 (s, 3 H), 1.35 (d, 3 H, J = 6.9 Hz). 13
C
In addition we observed that on increasing the reaction
time the yields could be positively affected without a
change in the diastereoisomeric ratios.
NMR (100.62 MHz): d = 145.9, 139.5, 136.1, 132.6, 128.6
(2 × CHAr), 128.2, 128.1 (2 × CH), 127.7, 127.3, 126.3,
105.7, 84.8, 57.7, 57.02, 57.01, 56.4, 43.7, 21.4, 13.9. GC–
MS: m/z (%) = 442 (5), 440 (20) [M+], 438 (10), 436 (4), 231
(100), 215 (2), 183 (71), 121 (72), 91 (19), 75 (69).
In conclusion we have reported the first methodology to
effect the asymmetric methoxyselenenylation of b-aryl
a,b-unsaturated aldehydes using easily prepared chiral
electrophilic selenenylating reagents. The proposed syn-
thetic approach leads to the formation of useful intermedi-
ates that can be manipulated in order to prepare other
enantiomerically enriched derivatives.
Compound 4b (C21H27O3ClSSe): oil. 1H NMR (400 MHz):
d = 7.35 (d, 1 H, J = 7.3 Hz), 7.15–7.20 (m, 2 H), 7.05–7.13
(m, 3 H), 6.95–7.00 (m, 2 H), 4.85 (d, 1 H, J = 2.6 Hz), 4.33
(d, 1 H, J = 9.4 Hz), 4.10 (q, 1 H, J = 6.9 Hz), 3.60 (s, 3 H),
3.59 (s, 3 H), 3.58 (dd, 1 H, J = 2.6, 9.4 Hz), 3.15 (s, 3 H),
1.90 (s, 3 H), 1.41 (d, 3 H, J = 6.9 Hz). 13C NMR (100.62
MHz): d = 145.2, 137.6, 135.6, 133.5, 132.0, 129.5 (2 × CH),
127.7 (2 × CH), 127.2, 126.9, 125.9, 105.2, 83.9, 57.4, 56.6,
56.4, 56.3, 43.2, 20.6, 13.2. GC–MS: m/z (%) = 476 (6), 474
(12) [M+], 472 (6), 470 (2), 231 (100), 215 (9), 183 (68), 155
(45), 135 (8), 91 (16), 75 (60). Compound 4c
Acknowledgment
Financial support from the MIUR, the National Projects PRIN2005
and FIRB2001, the Consorzio CINMPIS, Bari and the University of
Perugia is gratefully acknowledged.
(C22H30O3SSe): oil. 1H NMR (400 MHz): d = 7.38 (dd, 1 H,
J = 1.3, 7.8 Hz), 7.19 (dd, 1 H, J = 1.7, 7.8 Hz), 7.14 (ddd, 1
H, J = 1.3, 7.3, 7.8 Hz) 7.04–7.08 (m, 2 H), 6.94–6.98 (m, 3
H), 4.83 (d, 1 H, J = 2.9 Hz), 4.32 (d, 1 H, J = 9.2 Hz), 4.15
(q, 1 H, J = 6.9 Hz), 3.58 (s, 3 H), 3.57 (dd, 1 H, J = 2.9, 9.2
Hz), 3.56 (s, 3 H), 3.16 (s, 3 H), 2.28 (s, 3 H), 1.87 (s, 3 H),
1.34 (d, 3 H, J = 6.9 Hz). 13C NMR (100.62 MHz): d = 145.4,
137.3, 136.0, 135.8, 132.3, 128.4 (2 × CH), 128.0 (2 × CH),
127.1, 126.8, 125.8, 105.3, 84.2, 57.4, 56.9, 56.5, 56.1, 43.3,
21.1, 20.9, 13.4. GC–MS: m/z (%) = 454 (21) [M+], 452 (10),
231 (72), 229 (37), 215 (11), 183 (49), 135 (100), 105(6), 91
(14), 75 (52). Compound 4e (C25H30O3SSe): oil. 1H NMR
(400 MHz): d = 7.70–7.75 (m, 2 H), 7.69 (s, 1 H), 7.53 (d, 1
H, J = 8.5 Hz), 7.45–7.50 (m, 2 H), 7.33 (d, 1 H, J = 7.8 Hz),
7.19 (d, 1 H, J = 8.6 Hz), 7.00 (dd, 1 H, J = 7.6, 8.0 Hz), 6.92
(d, 1 H, J = 7.5 Hz), 6.80 (t, 1 H, J = 7.5 Hz), 4.93 (d, 1 H,
J = 2.5 Hz), 4.52 (d, 1 H, J = 9.6 Hz), 3.83 (q, 1 H, J = 6.9
Hz), 3.71 (dd, 1 H, J = 2.5, 9.6 Hz), 3.63 (s, 3 H), 3.62 (s, 3
References and Notes
(1) (a) Krief, A.; Hevesi, L. Organoselenium Chemistry, Vol. 1;
Springer Verlag: Berlin, 1988. (b) Krief, A. In
Comprehensive Organometallic Chemistry; Trost, B. M.,
Ed.; Pergamon: Oxford, 1991, 85. (c) Organoselenium
Chemistry: Modern Developments in Organic Synthesis, In
Topics in Current Chemistry, Vol. 208; Wirth, T., Ed.;
Springer: Berlin, 2000. (d) Organoselenium Chemistry: A
Practical Approach; Back, T. G., Ed.; Oxford: New York,
2000. (e) Browne, D. M.; Niyomura, O.; Wirth, T. Org. Lett.
2007, 9, 3169. (f) Browne, D. M.; Wirth, T. Curr. Org.
Chem. 2006, 10, 1893.
(2) Braga, A. L.; Ludtke, D. S.; Vargas, F.; Braga, R. C. Synlett
2006, 1453.
(3) Wirth, T. Angew. Chem. Int. Ed. 2000, 39, 3742.
(4) Tiecco, M.; Testaferri, L.; Bagnoli, L.; Marini, F.;
Temperini, A.; Tomassini, C.; Santi, C. Tetrahedron Lett.
2000, 41, 3241.
(5) Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini,
F.; Bagnoli, L.; Temperini, A. Chem. Eur. J. 2002, 8, 1118.
(6) Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Marini,
F.; Bagnoli, L.; Temperini, A. Angew. Chem. Int. Ed. 2003,
42, 3131.
(7) (a) Tiecco, M.; Testaferri, L.; Santi, C. Eur. J. Org. Chem.
1999, 797. (b) Tiecco, M.; Testaferri, L.; Santi, C.;
Tomassini, C.; Marini, F.; Bagnoli, L.; Temperini, A.
Tetrahedron: Asymmetry 2000, 11, 4645.
(8) Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Bonini,
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4751.
H), 3.25 (s, 3 H), 1.78 (s, 3 H), 0.88 (d, 3 H, J = 6.9 Hz). 13
C
NMR (100.62 MHz): d = 145.5, 136.9, 136.1, 133.6, 133.1,
132.7, 128.5, 128.4, 128.3, 127.9, 127.8, 127.4, 127.1,
126.3, 126.0, 125.7, 105.8, 85.2, 57.9, 57.0, 56.7, 43.6, 30.7,
20.3, 13.6. Compound 10 (C20H26O2SSe): oil; [a]D18.0 = 19.9
(c = 1.11, CHCl3). 1H NMR (400 MHz): d = 7.40 (d, 1 H,
J = 8.0 Hz), 7.10–7.30 (m, 7 H), 7.00–7.05 (m, 1 H), 4.35 (d,
1 H, J = 9.5 Hz), 4.25–4.30 (m, 1 H), 4.03 (q, 1 H, J = 7.0
Hz), 3.72 (dd, 1 H, J = 4.5, 9.5 Hz), 3.18 (s, 3 H), 3.07 (d, 1
H, J = 9.1 Hz), 1.89 (s, 3 H), 1.41 (d, 3 H, J = 7.0 Hz), 1.38
(d, 3 H, J = 6.3 Hz). 13C NMR (100.62 MHz): d = 144.5,
139.3, 134.8, 132.0, 128.6, 127.91 (2 × CH), 127.88 (2 ×
CH), 127.4, 127.2, 125.9, 86.2, 67.4, 63.6, 56.9, 43.1, 21.1,
20.1, 13.0. GC–MS: m/z (%) = 410 (7) [M+], 408 (3), 231
(82), 229 (40), 215 (13), 194 (31), 183 (100), 181 (57), 147
(13), 121 (36), 105 (28), 91 (45), 77 (21), 51 (4).
(9) Tiecco, M.; Testaferri, L.; Santi, C.; Tomassini, C.; Santoro,
S.; Marini, F.; Bagnoli, L.; Temperini, A.; Costantino, F.
Eur. J. Org. Chem. 2006, 4867.
(10) Huot, J. F.; Outurquin, F.; Paulmier, C. Chem. Lett. 1991, 20,
1599.
(12) Keck, G. E.; Wager, C. A. Org. Lett. 2000, 2, 2307.
(13) Ghosh, A. K.; Kim, J. H. Tetrahedron Lett. 2001, 42, 1227.
(14) Evans, D. A.; Nedson, J. V. In Topics in Stereochemistry,
Vol. 13; Eliel, N. L.; Wiken, S. H., Eds.; Wiley: New York,
1983, 1.
(11) Physical and spectral data for selected new compounds are
(15) Mahata, P. K.; Barun, O.; Ila, H.; Junjappa, H. Synlett 2000,
1345.
18.0
reported below: Compound 4a (C21H28O3SSe): oil; [a]D
–40.9 (c = 1.38, CHCl3). 1H NMR (400 MHz): d = 7.35 (dd,
1 H, J = 1.4, 7.7 Hz), 7.15–7.25 (m, 6 H), 7.10 (dd, 1 H, J =
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