Regio- and diastereoselective addition of allylic thioethers to aldehydes

Article abstract of DOI:10.1016/j.tetlet.2008.12.009

We have developed a regioselective allylation and a regio- and diastereoselective crotylation of aldehydes with pyridin-2-yl sulfides. In the process, we have also optimized the diastereoselectivity of the addition of crotyl phenyl sulfide to aldehydes.

Full text of DOI:10.1016/j.tetlet.2008.12.009

Tetrahedron Letters 50 (2009) 883–885
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Tetrahedron Letters
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Regio- and diastereoselective addition of allylic thioethers to aldehydes
*
Diego Gamba-Sanchez, Raphaël Oriez, Joëlle Prunet
Laboratoire de Synthèse Organique, CNRS UMR 7652, Ecole Polytechnique, DCSO, F-91128 Palaiseau, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a regioselective allylation and a regio- and diastereoselective crotylation of aldehydes
with pyridin-2-yl sulfides. In the process, we have also optimized the diastereoselectivity of the addition
of crotyl phenyl sulfide to aldehydes.
Received 3 October 2008
Revised 25 November 2008
Accepted 3 December 2008
Available online 7 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
In the course of our investigations of new methods for the
diastereoselective synthesis of 1,3-diols by intramolecular oxa
Michael addition,1 we needed to develop a rapid access to vinyl
pyridin-2-yl sulfides with a homoallylic alcohol function, such as
compounds 1 (Scheme 1). To our knowledge, there is no precedent
for the addition of anions of pyridinyl allyl sulfides to aldehydes. In
addition, the few examples of this allylation reaction with alkyl or
phenyl derivatives described by the Y. Yamamoto,2 H. Yamamoto,3
and Sato4 groups are illustrated in Scheme 2. Reaction of the lith-
ium anions of allyl thioethers with aldehydes slightly favors the
anion at the a-position through chelation by the nitrogen atom
of the pyridine ring.5
Unexpectedly, reaction in the presence of HMPA (3.3 equiv)
gave exclusively the
a-product in 60% yield. Possible disruption
of the chelate could be invoked to explain this result. Reaction of
2 under the optimized conditions with heptanal and isobutyralde-
hyde led to compounds 3b–c in similar yields and selectivities
(Scheme 3). The E/Z selectivity is variable, slightly favoring the
Z-isomer in most cases.
We next attempted the addition of crotyl pyridin-2-yl sulfide 6 to
hydrocinnamaldehyde under the conditions used by H. Yamamoto
c
addition product.2 Transmetallation with titanium isopropoxide
leads to the
-product exclusively.3 The latter result can be ex-
plained by invoking a Zimmerman–Traxler transition state, where
the metal counterion occupies the less hindered
-position.3b In
the case of the crotyl thioethers, the metal is positioned near the
sulfide group, and the
-product is the major regioisomer.3 The
a
(BuLi, THF, and Ti(Oi-Pr)4).3 Unfortunately, a 1:1 mixture of
a
and
the crotylation reaction with the corresponding phenyl sulfide 4
(Scheme 4). Under Yamamoto’s conditions, the -isomer was
c compounds was obtained. We thus decided to reinvestigate
c
c
c
obtained exclusively in 85% yield. The anti/syn ratio was 61:39,
which corresponds with Sato’s result with propanal (see Scheme
2). Changing the solvent to ether improved the selectivity to
80:20 in favor of the anti-diastereomer, but 4 equiv of titanium iso-
propoxide was required for complete conversion of the aldehyde.
In a non-polar solvent such as pentane, no reaction occurred. How-
ever, upon addition of 1 equiv of TMEDA, the reaction proceeded
smoothly and the anti/syn ratio increased to 88:12.6 In all cases,
the E-isomer was slightly favored, implying that the thio group is
preferentially equatorial in the Zimmerman–Traxler transition
state.
regioselectivity is excellent with the bulkier titanium. Regarding
the diastereoselectivity of this addition, H. Yamamoto and co-
workers gave no details.3 Sato et al. report a moderate selectivity
in favor of the anti-diastereomer, and a 1:1 mixture of E and Z
olefins.4
We first embarked on the study of the allylation reaction. Reac-
tion of pyridin-2-yl allyl sulfide 2 with hydrocinnamaldehyde in
the presence of butyllithium in THF furnished the desired
c-prod-
uct 3a in 55% yield, along with 8% of the isomeric -product, and
a
30% of recovered 2. In order to improve the conversion, we per-
formed the reaction in the presence of 1 equiv of TMEDA (Scheme
We extended the scope of the optimized reaction conditions to
a range of aldehydes (Scheme 5). The anti/syn selectivity varies
3). Compound 3a was isolated in 67% yield. The
isolated, but the 1H NMR of the unpurified product showed a
ratio of 89:11. The selectivity is substantially better than that
a-isomer was not
c/a
c/a
observed by Y. Yamamoto with the corresponding isopropyl sulfide
(Scheme 2). This is probably due to stabilization of the lithium
OH
Base
SPy
H,Me
SPy
R
RCHO
H,Me
Py = Pyridin-2-yl
1
* Corresponding author. Tel.: +33 1 69 33 59 79; fax: +33 1 69 33 59 72.
E-mail address: joelle.prunet@polytechnique.fr (J. Prunet).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.12.009

884
D. Gamba-Sanchez et al. / Tetrahedron Letters 50 (2009) 883–885
OH
OH
OH
OH
Y. Yamamoto
Y. Yamamoto
SiPr
SiPr
s-BuLi
Et2O
s-BuLi
Et2O
R
R
Ph
Ph
SiPr
SPh
SiPr
SPh
RCHO
PhCHO
g/a
= 92:8
g/a
= 1.3 to 2.6:1
SiPr
OH
SiPr
OH
H. Yamamoto
BuLi, THF
Ti(Oi-Pr)4
H. Yamamoto
BuLi, THF
Ti(Oi-Pr)4
SPh
R
R
or Sato
RCHO
SPh
anti/syn > 99:1
t-BuLi, THF
E/Z = 1:1
anti/syn = 66:34
HMPA, Cp2TiCl
RCHO
Scheme 2.
BuLi, THF
OH
TMEDA
SPy
N
R
H
H
S
RCHO
2
3a-c
SPy
Ti(Oi-Pr)3
Ti(Oi-Pr)3
g/a
3a R = PhCH2CH2 67%
= 89:11 Z/E = 1:2 to 2:1
O
O
N
S
R
R
3b
3c
Hex
i-Pr
64%
71%
1.4:1
2:1
Axial SPy
Equatorial SPy
Scheme 3.
Scheme 7.
BuLi, Solvent
OH
conversion of the starting sulfide 6, even in the presence of an
excess of aldehyde (66% yield based on recovered starting mate-
rial).6 Unexpectedly, the use of 4 equiv of titanium isopropoxide
lowered the yield of the reaction to 20%. Addition to cyclohexane
carbaldehyde led to similar results (83% yield based on recovered
starting material).
Ti(Oi-Pr)4
SPh
SPh
Ph
PhCH2CH2CHO
4
5a
THF
Et2O
85%
72%
anti/syn = 61:39 E/Z = 4:1
80:20
88:12
3:1
2:1
Pentane/TMEDA 71%
Contrary to the reactions with phenyl sulfide 4, the Z-isomer
was obtained almost exclusively with pyridinyl sulfide 6. Chelation
of the titanium by the nitrogen atom of the pyridine ring can be
invoked to explain this selectivity (Scheme 7). The transition state
in which the thio group is equatorial is disfavored by unfavorable
1,3-diaxial interactions involving the axial pyridinyl group.
In conclusion, we have developed a regioselective allylation and
a regio- and diastereoselective crotylation of aldehydes with pyrid-
inyl sulfide derivatives. In the process, we have optimized the con-
ditions reported by H. Yamamoto to render the addition of crotyl
phenyl sulfide to aldehydes diastereoselective.
Scheme 4.
BuLi
Pentane, TMEDA
4 equiv Ti(Oi-Pr)4
OH
SPh
SPh
R
RCHO
4
5a-e
5a
R = PhCH2CH2
c-Hex
71%
93%
75%
52%
anti/syn = 88:12 E/Z = 2:1
5b
5c
5d
5e
92:8
2:1
1:1
1:1
1:1
TrOCH2
BnOCH2
83:17
80:20
85:15
TBDPSOCH2 69%
Acknowledgments
Scheme 5.
Financial support was provided by the CNRS and the Ecole
Polytechnique. R.O. acknowledges the MENR for a fellowship.
D.G.S. thanks COLFUTURO for a fellowship.
BuLi, Et2O
1 equiv Ti(Oi-Pr)4
OH
SPy
E/Z = 4:1
References and notes
R
6
RCHO
7a-c
SPy
1. (a) Grimaud, L.; de Mesmay, R.; Prunet, J. Org. Lett. 2002, 4, 419; (b) Grimaud, L.;
Rotulo, D.; Ros-Perez, R.; Guitry-Azam, L.; Prunet, J. Tetrahedron Lett. 2002, 43,
7477; (c) Rotulo-Sims, D.; Grimaud, L.; Prunet, J. CR Chim. 2004, 941; (d) Rotulo-
Sims, D.; Prunet, J. Org. Lett. 2007, 9, 4147.
R = PhCH2CH2
41%
49%
anti/syn = 89:11 Z/E = 18:1
c-Hex
91:9 11:1
2. (a) Yamamoto, Y.; Yatagai, H.; Saito, Y.; Maruyama, K. J. Org. Chem. 1984, 49,
1096; (b) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
Scheme 6.
3. (a) Ikeda, Y.; Furuta, K.; Meguriya, N.; Ikeda, N.; Yamamoto, H. J. Am. Chem. Soc.
1982, 104, 7663; (b) Furuta, K.; Ikeda, Y.; Meguriya, N.; Ikeda, N.; Yamamoto, H.
Bull. Chem. Soc. Jpn. 1984, 57, 2781.
4. Sato, F.; Uchiyama, H.; Iida, K.; Kobayashi, Y.; Sato, M. Chem. Commun. 1983, 921.
5. (a) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147; (b) Katritzky, A. R.;
Piffl, M.; Lang, H.; Anders, E. Chem. Rev. 1999, 99, 665.
from good for
the hindered cyclohexanecarbaldehyde.
a-oxygenated aldehydes to excellent in the case of
Finally, we applied the latter conditions to the addition of crotyl
6. Formation of 5b: To a À78 °C solution of crotyl phenyl sulfide 4 (360 mg,
2.4 mmol) in pentane (8 mL) under nitrogen was added freshly distilled TMEDA
(0.362 mL, 2.4 mmol), then 1.5 M BuLi in hexane (1.6 mL, 2.4 mmol) was added
dropwise, and the mixture was warmed to 0 °C. After 1 h, the reaction mixture
was cooled to À78 °C, and freshly distilled Ti(iOPr)4 (2.8 mL, 9.6 mmol) was
pyridin-2-yl sulfide
6 to hydrocinnamaldehyde. In pentane/
TMEDA, no reaction occurred. Fortunately, in ether, the reaction
proceeded with total regioselectivity and a good level of diastere-
oselectivity (Scheme 6). The moderate yield is due to incomplete

D. Gamba-Sanchez et al. / Tetrahedron Letters 50 (2009) 883–885
885
added dropwise. The resulting mixture became clear red-orange, and was
stirred at 0 °C for 1.5 h. Next, the solution was cooled to À78 °C, and
cyclohexanecarbaldehyde was added dropwise (0.242 mL, 2.0 mmol). The
resulting mixture was stirred at 0 °C for 1.5 h then quenched with 2 N HCl
aqueous solution and stirred until the white solid was totally dissolved. The
aqueous phase was extracted with Et2O (Â3) and the combined organic extracts
were dried over Na2SO4, filtered, and were concentrated in vacuo. The crude
residue was purified by silica gel column chromatography (7:3 CH2Cl2/
petroleum ether) to afford phenyl vinyl sulfide 5b (514 mg, 93%) as a pale
yellow oil as a 2:1 mixture of E- and Z-isomers: 1H NMR (400 MHz, CDCl3) d
7.18–7.35 (m, 5H), 6.28 (d, J = 9.3 Hz, 0.31H), 6.22 (d, J = 15.1 Hz, 0.61H), 5.95
(dd, J = 15.1, 8.6 Hz, 0.61H), 5.84 (t, J = 9.5 Hz, 0.31H), 3.22 (t, J = 5.7 Hz, 0.31H),
3.15 (t, J = 5.7 Hz, 0.61H), 2.89–2.98 (m, 0.31H), 2.49–2.58 (m, 0.61H), 1.00–1.91
(m, 12H), 1.09 (d, J = 6.9 Hz, 1.8H), 1.08 (d, J = 6.8 Hz, 0.9H); 13C NMR (100 MHz,
CDCl3) d 137.5, 136.2, 136.1, 134.9, 129.0, 128.9, 128.8, 128.7, 126.3, 123.7,
122.9, 79.7, 79.2, 41.0, 40.7, 40.2, 36.7, 29.9, 29.8, 27.6, 27.5, 26.5, 26.4, 26.3,
(1 M, 2.6 mmol, 1.1 equiv) to the mixture. After stirring for 45 min, freshly
distilled Ti(iOPr)4 (770 L, 2.6 mmol, 1.1 equiv) was added dropwise, and the
mixture turned black. After 15 min, hydrocinnamaldehyde (340 L, 2.6 mmol,
1.1 equiv) was added dropwise and after 5 min, the mixture became red. After
1.5 h at À78 °C, 10 mL of 1 N aqueous HCl was added, followed by 10 mL of
ether.
Following decantation and separation, the aqueous mixture was extracted with
ether (3 Â 4 mL). The combined organic phases were washed with water (4 mL)
and brine (4 mL), dried over anhydrous MgSO4, filtered, and were concentrated
in vacuo. Purification by flash column chromatography on silica gel (20:80 to
l
l
30:70 ether/petroleum ether) gave 296 mg (41%) of
a mixture of three
diastereomers (8:1 anti/syn, 18:1 cis/trans) of pyridinyl sulfide 7a as
a
colorless oil and 150 mg (62% conversion) of recovered crotyl pyridin-2-yl
sulfide. Only the data for the major diastereomer of 7a are listed: 1H NMR
(400 MHz, CDCl3) d 8.51 (d of m, J = 5.2 Hz, 1H), 7.57–7.53 (m, 1H), 7.34–7.21 (m,
6H), 7.08–7.05 (m, 1H), 6.94 (d, J = 9.6 Hz, 1H), 5.94 (t, J = 9.6 Hz, 1H), 3.62–3.58
(m, 1H), 2.95–2.71 (m, 1H), 2.84–2.72 (m, 2H), 1.95–1.77 (m, 2H), 1.14 (d,
J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 157.4, 149.4, 142.0, 136.3, 134.8,
128.3, 128.2, 125.5, 122.2, 120.2, 120.0, 74.3, 40.6, 36.3, 31.9, 16.6; IR (thin film)
26.1, 26.0, 17.6, 17.4; IR (CH2Cl2)
m 3620, 2929, 2854, 1948, 1877, 1721, 1582,
1476, 1445, 1276, 1252 cmÀ1; HRMS (EI) m/z calcd for C17H24OS: 276.1548;
found: 276.1544.
Formation of 7a: To a solution of crotyl pyridin-2-yl sulfide (400 mg, 2.4 mmol)
in anhydrous Et2O (8 mL) at À78 °C under nitrogen was added freshly distilled
TMEDA (0.39 mL, 2.6 mmol, 1.1 equiv), followed by dropwise addition of BuLi
m 3941, 3685, 3605, 3061, 3049, 2985, 2932, 2870, 2683, 2359, 2332, 2305, 1745,
1604, 1578, 1494, 1447, 1422, 1389, 1345, 1292, 1258, 1124, 1085, 1039 cmÀ1
;
HRMS (EI) m/z calcd for C18H21NOS: 299.1344; found 299.1332.