Carbolithiation of substituted stilbenes and styrenes with dithianyllithiums

Article abstract of DOI:10.1016/j.tetlet.2007.12.085

Carbolithiation of a range of substituted stilbenes and styrenes with dithianyllithiums is described, leading to the rapid, efficient and stereocontrolled assembly of highly functionalized dithiane intermediates for acyl-equivalents synthesis.

Full text of DOI:10.1016/j.tetlet.2007.12.085

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1348–1351
Carbolithiation of substituted stilbenes and styrenes
with dithianyllithiums
Shouchu Tang a, Junjie Han a, Jinmei He a, Jiyue Zheng a, Yongping He a,
Xinfu Pan a, Xuegong She a,b,
*
a Department of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, PR China
b State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics,
Chinese Academy of Sciences, Lanzhou 730000, PR China
Received 29 October 2007; revised 14 December 2007; accepted 18 December 2007
Available online 23 December 2007
Abstract
Carbolithiation of a range of substituted stilbenes and styrenes with dithianyllithiums is described, leading to the rapid, efficient and
stereocontrolled assembly of highly functionalized dithiane intermediates for acyl-equivalents synthesis.
Ó 2007 Elsevier Ltd. All rights reserved.
The carbolithiation of unactivated alkenes has been
widely used as a powerful tool for creating a carbon–car-
bon bond and a new organolithium species in a single step.1
A range of commercial and homemade organolithium
reagents to styrene derivatives have been studied exten-
sively during the past 50 years and widely used in organic
synthesis; however, the organolithium reagents are usually
simple alkyl organolithium reagents such as n-BuLi or t-
BuLi, leading to the further synthetic transformations lim-
ited in synthesis (Scheme 1, Eq. 1). Dithianes have evolved
as invaluable tools in organic synthesis, serving primarily
as acyl anion equivalents for constructing carbon–carbon
bonds. In these early examples, two building blocks were
joined, one a substituted lithiated 1,3-dithiane, the other
an electrophile such as an iodide, epoxide, aldehyde, or
ketone.2 In contrast, the relatively unstudied carbolithia-
tion with dithianes poses a considerable challenge. Herein,
we wish to disclose the carbolithiation reaction of dithiane
Li
R2
R2Li
E
E
R
R2
(eq 1)
(eq 2)
R
R2 =alkyl
R
R=H, Ph
Ar
E
S S
R1
1)
O
E
R
S
S
R1
E
Ar
2) HgCl2
R1 Li
E= -H, -alkyl, -CH2OH, -CH2CH(OH)CH=CH2
Scheme 1.
E
R
*
Corresponding author. Fax: +86 0 931 8912582.
E-mail address: shexg@lzu.edu.cn (X. She).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.085

S. Tang et al. / Tetrahedron Letters 49 (2008) 1348–1351
1349
Table 1
Carbolithiation of substituted stilbene derivatives with lithiated 2-H-1,3-dithiane
S
S
S
S
Ph
S
1)
Ph
, Et2O/HPMA
R3
Li
-50 oC to rt
2) MeOH
Substrate
R3
Ph
+
S
R3
1
3
2
Entrya
1
1
Productsb
Ratio 2:3
—
Yield (%)
82
Ph
1a
2a
Ph
2
3
4
5
1b
1c
1d
1e
1f
2b, 3b
2c, 3c
2d, 3d
2e, 3e
2f, 3f
98:2
71
76
78
69
54c
MeO
OMe
Ph
85:15
90:10
96:4
OMe
Ph
MeO
Ph
Ph
6
5:95
Cl
a
Reaction conditions: (1) 1 mmol of substrate, 2.5 mmol of lithiated carbonanion, 1–3 mmol of HMPA, 20 mL of anhydrous Et2O, À50 °C to rt, 3 h; (2)
1 mL MeOH, 1 h.
b
The products were identified by 1H NMR, 13C NMR, HRMS and ratios determined by 1H NMR.
Recovered 20% starting material.
c
anions for the preparation of advanced fragments3
(Scheme 1, Eq. 2).
finding in which carbolithiation of ortho-substituted stilb-
enes with n-BuLi gave the major isomers having the butyl
group substituted at the carbon to the ortho functionalized
benzene ring.4e The reaction of the Cl-substituted stilbene
was slower and provided a mixture of 2f/3f in a ratio of
5:95 (Table 1, entry 6). The regioselective carbolithiation
was presumably due to the electron donating effect and
the ortho effect of unsymmetrical stilbenes.
Having established the protocol of a regioselective car-
bolithiation reaction with dithiane, our next aim was to
demonstrate the utility of lithiated compounds in cascade
reaction sequences, to provide a new entry to the compli-
cated substituted dithiane analogues, which could be intro-
duced invaluable tools in acyl-equivalents synthesis.
According to the work of Taylor,7 we demonstrated that
the reaction was applicable to 2-substituted oxystyrene
with a variety of dithianyllithiums and the reaction results
are summarized in Table 2. Because of the difficulty in
purifying the immediates of carbolithiation, the reaction
was performed directly from À50 °C to room temp-
erature before work-up. 2-Allyl-oxystyrene underwent
Recently, regioselective carbolithiation of unactivated
alkenes has been expanded by O’Shea.4 Our current goal
is to advance this methodology with lithiated dithiane
anions. Initially, (E)-stilbene 1a was first examined with
lithiated 2-H-1,3-dithiane. After many trials, we found that
the carbolithiation reaction proceeded smoothly from
À50 °C to room temperature in the presence of HMPA5
in anhydrous Et2O (82%, Table 1). With optimal reaction
condition in hand, several substituted stilbenes were pre-
pared6 and the reaction results are summarized in Table
1. The carbolithiation selectivity was determined by react-
ing the lithiated intermediates with methanol and the crude
reaction products were analyzed by NMR. The reactions of
the three methoxy substituted stilbenes and methyl substi-
tuted stilbene (Table 1, entries 2–5) gave the corresponding
protonation in good yields (69–78%) and high regioselec-
tivity (85:15–98:2). For example, the reaction of 1b with
lithiated 2-H-1,3-dithiane provided a mixture of 2b/3b in
98:2 ratio (Table 1, entry 2). We became aware of a similar

1350
S. Tang et al. / Tetrahedron Letters 49 (2008) 1348–1351
Table 2
Intramolecular alkylation processes of 2-substituted oxystyrene with dithianyllithiums
R4
O
OH R4
S S
R1
Et2O, HMPA,
+
S S
R1
-50 oC to rt, 2hrs.
6
Li
5
4
Entrya
1
4
Substrateb
R1
Et
Product
Yieldc (%)
80
4a
OH
S
S
S
OH
S
O
2
3
4a
4a
Ph
76
67
OH
S
S
S
S
i-Pr
OH
4
5
6
4a
4b
4c
H
—
75
73
OBn
S
S
S
S
Et
Et
OH
O
OH
OBn
S
S
7
4d
Et
Et
69
72
MeO
MeO
OH
OH
S
S
O
8
4e
Cl
Cl
a
Reaction conditions: 0.5 mmol of substrate, 1.2 mmol of lithiated carbonanions, 3 mmol of HMPA, 15 mL of anhydrous Et2O, À50 °C to rt, 2 h.
b
c
The substrates were prepared by Wittig reaction of the corresponding benzaldehydes.
Isolated yield.
carbolithiation-allyl transfer with a variety of 1,3-dithianyl-
lithiums in good yields of 67–80% (Table 2, entries 1–3).
We found that the steric hindrance of the dithianes did
not affect product outcome, whereas for lithiated 2-H-
1,3-dithiane, the expected product was obtained in a minor
amount, the intermediate organolithium may be unstable

S. Tang et al. / Tetrahedron Letters 49 (2008) 1348–1351
1351
2. (a) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231; (b) Smith, A.
B., III; Pitram, S. M.; Gaunt, M. J.; Kozmin, S. A. J. Am.Chem. Soc.
2002, 124, 14516–14517; (c) Yus, M.; Najera, C.; Foubelo, F.
Tetrahedron 2003, 59, 6147; (d) Smith, A. B., III; Duffey, M. O.
Synlett 2004, 1363. and references cited therein.
(Table 2, entry 4). Related substrates 2-benzyloxystyrene
and 2-allyloxystyrene were examined under similar reaction
conditions, the steric factor (Table 2, entries 5 and 6) and
the electronic factor of substitution group whatever with
electron-donating (Table 2, entry 7) or withdrawing groups
(Table 2, entry 8) did not obviously affect the transfer
reaction. This process probably involves a tandem carbo-
lithiation addition of dithiane anions and intramolecular
alkylation sequences. Further exploration of dithiane
carbolithiation in conjunction with the anion relay chemis-
try (ARC) tactic8 is currently in progress.
In summary, we have established that application over
the more conventional stepwise addition reactions of dithi-
ane anions to a range of substituted stilbenes and styrenes
leading to the rapid, efficient and stereocontrolled assembly
of highly functionalized dithiane intermediates9 for acyl-
equivalents synthesis.
3. Xie, X.; Yue, G.; Tang, S.; Huo, X.; Liang, Q.; She, X.; Pan, X. Org.
Lett. 2005, 7, 4057.
4. For carbolithiation approaches to substituted fused ring systems, see:
(a) Coleman, C. M.; O’Shea, D. F. J. Am. Chem. Soc. 2003, 125, 4054;
(b) Kessler, A.; Coleman, C. M.; Charoenying, P.; O’Shea, D. F. J.
Org. Chem. 2004, 69, 7836; (c) Cottineau, B.; O’Shea, D. F.
Tetrahedron Lett. 2005, 46, 1935; (d) Hogan, A.-M. L.; O’Shea, D.
F. J. Am. Chem. Soc. 2006, 128, 10360; (e) Hogan, A.-M. L.; O’Shea,
D. F. Org. Lett. 2006, 8, 3769.
5. (a) Reich, H. J.; Borst, J. P.; Dykstra, R. R. Tetrahedron 1994, 50,
5869; (b) Sikorski, W. H.; Reich, H. J. J. Am. Chem. Soc. 2001,
123, 6527; (c) Reich, H. J.; Sikorski, W. H. J. Org. Chem. 1999, 64,
14.
6. Wang, J.; Fu, Y.; Hu, Y. Angew. Chem., Int. Ed. 2002, 41,
2757.
7. (a) Wei, X.; Johnson, P.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans.
1 2000, 1109; (b) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1996, 37,
4209.
Acknowledgements
8. Reaction of dithiane anions in anion relay chemistry, see: (a) Smith, A.
B.; Pitram, S. M.; Xian, M.; Kim, W. S.; Kim, D. S. J. Am. Chem. Soc.
2006, 128, 12368; (b) Smith, A. B., III; Xian, M. J. Am. Chem. Soc.
2006, 128, 66.
We are grateful for the generous financial support by
the Special Doctorial Program Funds of the Ministry of
Education of China (20040730008), NSFC (QT program,
No. 20572037), NCET-05-0879, the key grant project of
Chinese ministry of Education (No. 105169) and Gansu
Science Foundation (3ZS051-A25-004).
9. The spectral data of some products (Table 1, product 2b): 1H NMR
(300 MHz, CDCl3): d 7.25 (d, J = 5.7 Hz, 2H), 7.11–7.15 (dd, J = 8.7,
2.1 Hz, 3H), 7.06 (d, J = 5.7 Hz, 2H), 6.82 (dd, J = 8.4, 2.1 Hz, 2H),
4.28 (d, J = 5.4 Hz, 1H), 3.77 (s, 3H), 3.45 (dd, J = 10.2, 5.4 Hz, 1H),
3.16–3.20 (m, 1H), 2.93–2.98 (dd, J = 10.2, 6.6 Hz, 1H), 2.79–2.84 (m,
4H), 2.03–2.08 (m, 1H), 1.78–1.84 (m, 1H). 13C NMR (75 MHz,
CDCl3): d 158.5, 139.7, 132.0, 129.6, 129.1, 128.1, 125.9, 113.3, 55.0,
53.5, 51.8, 38.8, 30.9, 30.8, 25.8. Ms m/z 330, 239, 211, 135, 119, 84.
HRMS (ESI) calcd for C19H26OS2N (M+NH4)+: 348.1450. Found:
348.1451 (Table 2, product 6a). 1H NMR (300 MHz, CDCl3): d 7.17 (d,
J = 7.2 Hz, 1H), 7.07 (t, J = 7.5, 6.6 Hz, 1H), 6.91 (t, J = 7.2, 7.2 Hz,
1H), 6.82 (d, J = 7.8 Hz, 1H), 5.99 (s, 1H), 5.62–5.71 (m, 1H), 4.98 (t,
J = 12.1, 19.2 Hz, 2H), 3.22–3.26 (m, 1H), 2.75–2.78 (m, 2H), 2.66–
2.69 (m, 2H), 2.40–2.44 (m, 2H), 2.31 (d, J = 7.5 Hz, 2H), 1.81–1.88
(m, 2H), 1.70–1.78 (m, 2H), 0.84 (t, J = 7.5, 7.2 Hz, 3H). 13C NMR
(75 MHz, CDCl3): d 153.0, 136.7, 132.3, 127.8, 127.1, 121.2, 116.9,
116.7, 54.7, 42.9, 42.2, 34.5, 31.7, 26.0, 25.9, 25.0, 8.6. Ms m/z 308, 279,
233, 201, 161, 147, 107, 84. HRMS (ESI) calcd for C17H24OS2Na
(M+Na)+: 331.1161. Found: 331.1160.
References and notes
1. (a) Bartlett, P. D.; Friedman, S.; Stiles, M. J. Am. Chem. Soc. 1953, 75,
1771; (b) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K.; Ovaska, T.
V.; Rossi, K.; Thiel, Y.; Wiberg, K. B. J. Am. Chem. Soc. 1991, 113,
5720; (c) Wei, X.; Taylor, R. J. K. Chem. Commun. 1996, 187; (d)
Klein, S.; Marek, I.; Poisson, J. F.; Normant, J. F. J. Am. Chem. Soc.
1995, 117, 8853; (e) Norsikian, S.; Marek, I.; Normant, J. F.
Tetrahedron Lett. 1997, 38, 7523; (f) Norsikian, S.; Marek, I.; Klein,
S.; Poisson, J. F.; Normant, J. F. Chem. Eur. J. 1999, 5, 2055; (g) Song,
Q.; Chen, J.; Jin, X.; Xi, Z. J. Am. Chem. Soc. 2001, 123, 10419; (h)
Song, Q.; Li, Z.; Chen, J.; Wang, C.; Xi, Z. Org. Lett. 2002, 4,
4627.