Cross-coupling of homoallylic alcohols with styrene

Article abstract of DOI:10.1016/j.tetlet.2010.08.054

A cross-coupling reaction between a homoallylic alcohol and styrene is described to broaden the scope of the titanium alkoxide tether-mediated coupling reactions. Particularly noteworthy is exceptional 1,3-diastereoselectivity by o-vinylanisole in coupling with a Z-homoallylic alcohol.

Full text of DOI:10.1016/j.tetlet.2010.08.054

Tetrahedron Letters 51 (2010) 5571–5573
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Tetrahedron Letters
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Cross-coupling of homoallylic alcohols with styrene
⇑
Madhesan Balakrishnan, Jin Kun Cha
Department of Chemistry, Wayne State University, 5101 Cass Ave, Detroit, MI 48202, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2010
Revised 13 August 2010
Accepted 17 August 2010
Available online 21 August 2010
A cross-coupling reaction between a homoallylic alcohol and styrene is described to broaden the scope of
the titanium alkoxide tether-mediated coupling reactions. Particularly noteworthy is exceptional 1,3-dia-
stereoselectivity by o-vinylanisole in coupling with a Z-homoallylic alcohol.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Cross-coupling
Homoallylic alcohols
Styrene
Allylic strain
Despite impressive advances in transition metal-catalyzed C–C
bond-forming reactions, an intermolecular cross-coupling of two
unactivated alkenes stands as a challenging goal. Known examples
Our study began with the coupling reaction between E- and
Z-3-hexen-1-ol (E-1 and Z-1) and styrene (Table 1). When a mix-
ture of E-1 and styrene was treated with the Kulinkovich reagent
(generated under previously reported conditions for coupling reac-
tions of allylic alcohols),6,9 a 3:2 mixture of the coupling products 2
and 3 was isolated in 51% yield, along with unreacted starting alco-
hol (36%) (entry 1). Homo-dimerization products (not shown) of E-
1 and styrene were also isolated in 9% and 44% yields, respectively.
A slightly higher conversion was possible by employing an excess
of styrene (entry 2). However, an excess amount of the Kulinkovich
reagent was deleterious due to competing formation of the cyclo-
pentane adduct 4 (entry 5). The use of MeTi(O-i-Pr)3 was not
advantageous over that of ClTi(O-i-Pr)3 (entry 3). The product ratio
of 2 to 3 was dependent on reaction temperature and time, where
3 was believed to arise from b-hydride elimination of the pre-
sumed alkyltitanium intermediate (vide infra). When the reaction
mixture was allowed to stand at room temperature for a longer
period (15 h instead of 6 h), selective formation of 3 was observed
(entry 4). The corresponding coupling reactions with Z-1 were also
examined, in which the reaction mixture was allowed to warm to
room temperature to promote complete conversion to 3. As shown
in entries 6–9, the competing formation of the side product 4 was
more pronounced.
typically involve the coupling of alkynes with polarized
p-bonds
(e.g., carbonyl groups or alkenes bearing electron-withdrawing
groups).1 As part of mechanistic and synthetic studies of the Kulin-
kovich cyclopropanation, we became interested in utilizing the
Kulinkovich reagent in cross-coupling reactions, as well as
cyclopropanation of carboxylic acid derivatives. The Kulinkovich
reagent had been shown to be effective for regioselective homo-
coupling of terminal olefins,2,3 but selective cross-coupling proved
to be a particularly difficult task. A convenient solution was subse-
quently found in in situ generation of a titanium alkoxide tether,
which had first been developed for trans-dialkyl selective cyclo-
propanation of homoallylic alcohols.4,5 Our laboratory and the
Micalizio group reported cross-coupling of allylic alcohols with
vinylsilanes or styrene,6,7 followed by that with imines.8–10 We re-
port herein cross-coupling of homoallylic alcohols and styrene to
broaden the scope of the titanium alkoxide tether-mediated cou-
pling reactions (Eq 1).
HO
ClTi(OiPr)3
c-C5H9MgCl
R1
R1
R2
HO
+
ð1Þ
Et2O
With regard to selective preparation of 2 versus 3, easy access to
the latter product is readily available by allowing b-hydride
elimination to proceed to completion at room temperature (Table 1,
entry 4). On the other hand, formation of 2 was less straightfor-
ward, as it would require careful control of reaction variables,
especially reaction temperatures. We sought a more convenient
route to 2. As a vacant coordination site is obligatory for b-hydride
elimination, we hypothesized that the presence of a substituent
capable of coordinating to the titanium metal, such as an o-alkoxy
R2
⇑
Corresponding author.
E-mail address: jcha@chem.wayne.edu (J.K. Cha).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.054

5572
M. Balakrishnan, J. K. Cha / Tetrahedron Letters 51 (2010) 5571–5573
Table 1
Common functional groups can be incorporated into
Cross-coupling between E- & Z-1 and styrene
homoallylic alcohol substrates. Two additional examples of alcohols
bearing an allylic moiety and a siloxy group are shown in (Eq 2).12
HO
HO
ClTi(OiPr)3
c-C5H9MgCl
HO
Ph
RTi(OiPr)3 (y equiv)
OMe
2: CH2CH2
3: CH=CH
c-C5H9MgCl (z equiv)
Et2O
7
9
HO
HO
+
+
Et2O
—78 ºC to rt
E-1
+
—78 to —10 ºC or rt
+
8
MeO
66% (81%)
Ph
(x equiv)
ð2Þ
OTBDPS
ClTi(OiPr)3
HO
4
TBDPSO
HO
OMe
c-C5H9MgCl
Entry
R
x
y
z
2 + 3
4
1
2
3
4
5
Cl
Cl
Me
Cl
Cl
1.1
1.4
1.4
1.4
1.4
1.0
1.0
1.0
1.0
2.0
3.0
3.0
2.0
3.0
5.0
51%
69%
61%
65%
36%
(69%)a
(78%)a
(77%)a
(74%)a
(3:2)b
(7:3)b
(1:3)b
(0:1)b,c
(1:0)b,d
Trace
Trace
trace
Trace
30%
Et2O
—78 ºC to rt
10
MeO
63% (73%)
RTi(OiPr)3 (y equiv)
c-C5H9MgCl (z equiv)
Et2O
Our next investigation focused on diastereoselectivity of the
HO
coupling reactions of substituted homoallylic alcohols. Coupling
of 3-(hydroxymethyl)cyclohexene13 with styrene and o-vinylani-
sole afforded 11 and 12, respectively, to corroborate syn addition
(Scheme 1). Coupling of secondary alcohol 13 with styrene pro-
ceeded to provide 14 with no 1,4-stereoselectivity,14 but that of
o-vinylanisole gave 15 in 4:1 selectivity. The unexpected stereodi-
recting effect of the o-methoxy substituent was conspicuous in the
coupling reactions of 16, where 18 was obtained as a single isomer
in marked improvement over 2:1 (anti:syn) selectivity for the for-
mation of 17.15,16
Z-1
+
—78 ºC to rt
+
3
4
Ph
(x equiv)
Entry
R
x
y
z
3
4
6
7
8
9
Cl
Cl
Me
Me
1.1
1.4
1.1
1.4
1.0
1.0
1.0
1.0
3.0
3.0
2.0
2.0
34% (40%)a
47% (60%)a
44% (54%)a
52% (62%)a
29% (35%)a
15% (19%)a
14% (19%)a
14% (17%)a
a
b
c
High 1,3-diastereoselectivity displayed by Z-homoallylic alco-
hol 16 is consistent with the involvement of conformer I, where
1,3-allylic strain is minimized, leading to stereoselective formation
of the intermediate II (Scheme 2). At present, the nature of the
directing effect by the o-methoxy substituent is unclear. Its
predisposition to form a five-membered titanium chelate appears
Yields based on reacted starting material.
Ratios of 2 to 3.
Allowed to stand at rt for a longer (15 h) period.
Allowed to warm to ꢀ10 °C.
d
group, could prohibit b-hydride elimination. Toward this end,
o-vinylanisole and other styrene derivatives were examined
(Table 2). Indeed, coupling between E-1 and o-vinylanisole under
identical conditions afforded 5a cleanly, free from 6a (entry 1).
Similarly, selective formation of 5b was observed from 2,3-dime-
thoxystyrene (entry 2). Comparison with other examples (entries
3–7) provided additional evidence for chelation effects by an o-alk-
oxy substituent rather than electronic or steric effects.11
OH
OH
ClTi(OiPr)3 (1 equiv)
c-C5H9MgCl (3 equiv)
R
R
+
Et2O
—78 ºC to rt
R = H, OMe
11: R = H 46% (68% brsm)
12: R = OMe 49% (73% brsm)
ClTi(OiPr)3 (1 equiv)
c-C5H9MgCl (3 equiv)
OH
OH
Table 2
Ar
Cross-coupling of substituted styrenes
Ph
Ph
R
Et2O
—78 ºC to rt
13
ClTi(OiPr)3 (1 equiv)
14: R = H 43%, 1:1 dr
c-C5H9MgCl (3 equiv)
Et2O
HO
+
HO
HO
Ar
Ar
(69% brsm)13
E-1
+
5
+
15: R = OMe 36%, 4:1 dr
—78 ºC to rt
(59% brsm)
Ar
(1.4 equiv)
ClTi(OiPr)3 (1 equiv)
c-C5H9MgCl (3 equiv)
6
HO
Ph
HO
R
Entry
Ar
5a–h + 6a–h
16
Et2O
—78 ºC to rt
1
2
3
4
5
6
7
o-MeOC6H4
2,3-(MeO)2C6H3
3,4-(OCH2O)C6H3
p-MeOC6H4
p-ClC6H4
a
b
c
d
e
f
68% (82%)a (1:0)b
54% (69%)a (1:0)b
48% (65%)a (3:7)b
52% (84%)a (3:7)b
63% (78%)a (3:7)b
57% (78%)a (1:1)b
47% (65%)a (1:1)b
17: R = H 52%, 2:1 dr
+
(68% brsm)14
Ar
HO
p-FC6H4
18: R = OMe 57%, >97:3 dr
2-Naphthyl
g
(66% brsm)
a
Yields based on reacted starting material.
Ratios of 5 to 6.
b
Scheme 1.

M. Balakrishnan, J. K. Cha / Tetrahedron Letters 51 (2010) 5571–5573
5573
References and notes
Me
Ti
ClTi(OiPr)3
c-C5H9MgCl
Me
H
H
1. For reviews, see: (a) Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100,
2835–2886; (b) Montgomery, J. Angew. Chem., Int. Ed. 2004, 43, 3890–3908; (c)
Moslin, R. M.; Miller-Moslin, K.; Jamison, T. F. Chem. Commun. 2007, 4441–
4449; (d) Skucas, E.; Ngai, M.-Y.; Komanduri, V.; Krische, M. J. Acc. Chem. Res.
2007, 40, 1394–1401.
H
16
O
OiPr
I
2. Lee, J. C.; Sung, M. J.; Cha, J. K. Tetrahedron Lett. 2001, 42, 2059–2061.
3. Isakov, V. E.; Kulinkovich, O. G. Synlett 2003, 967–970.
OMe
4. (a) Quan, L. G.; Kim, S.-H.; Lee, J. C.; Cha, J. K. Angew. Chem., Int. Ed. 2002, 41,
2160–2162; (b) Babrov, D. N.; Kim, K.; Cha, J. K. Tetrahedron Lett. 2008, 49,
4089–4091; (c) Astashko, D.; Lee, H. G.; Babrov, D. N.; Cha, J. K. J. Org. Chem.
2009, 74, 5528–5532.
5. Savchenko, A. I.; Kulinkovich, O. G. Zh. Org. Khim. 1997, 33, pp 913–915; Russ. J.
Org. Chem. 1997, 33, pp 846–848.
6. Lysenko, I. L.; Kim, K.; Lee, H. G.; Cha, J. K. J. Am. Chem. Soc. 2008, 130, 15997–
16002.
7. Belardi, J. K.; Micalizio, G. C. J. Am. Chem. Soc. 2008, 130, 16870–16872.
8. (a) Takahashi, M.; McLaughlin, M.; Micalizio, G. C. Angew. Chem., Int. Ed. 2009,
48, 3648–3652; (b) Yang, D.; Micalizio, G. C. J. Am. Chem. Soc. 2009, 131, 17548–
17549.
Me Me
H
iPrO
H2O
Ti
O
OMe
18
9. Lysenko, I. L.; Lee, H. G.; Cha, J. K. Org. Lett. 2009, 11, 3132–3134.
10. For coupling between homoallylic alcohols and imines, see: Takahashi, M.;
Micalizio, G. C. J. Am. Chem. Soc 2007, 129, 7514–7516.
II
11. (a) The product ratios given in Tables were determined by analysis of 1H and
13C NMR spectra. (b) Experimental procedures and spectral data are available
in Supplementary Data.
vs a non-directed, stereorandom pathway
12. (a) The yields in parenthesis are based on reacted starting material. (b)
Comparable yields were also obtained for the corresponding coupling reactions
of styrene.
13. (a) Snider, B. B.; Rodini, D. J.; Kirk, T. C.; Cordova, R. J. Am. Chem. Soc. 1982, 104,
555–563; (b) Chini, M.; Crotti, P.; Flippin, L. A.; Gardelli, C.; Macchia, F. J. Org.
Chem. 1992, 57, 1713–1718; (c) Clausen, R. P.; Bols, M. J. Org. Chem. 2000, 65,
2797–2801.
14. The coupling product 14 was obtained along with a varying amount of the
corresponding dehydro compound (not shown for convenience). No attempt
was made to maximize the b-elimination product.
Me
1,3-syn
+
18 (1,3-anti
Me
H
H
via
H
)
OMet
Scheme 2.
to help disfavor a competing non-tethered (stereorandom) path-
way, thus promoting alkoxide-tethered carbometalation, I?II.17,18
In summary, we have delineated a titanium alkoxide-directed
cross-coupling reaction of homoallylic alcohols and styrenes. The
use of o-vinylanisole is effective for not only prevention of b-hy-
dride elimination but also stereocontrol; particularly noteworthy
is exceptional 1,3-diastereoselectivity by o-vinylanisole in cou-
pling with 16. Optimization and studies to elucidate the origin of
unique diastereocontrol by an o-alkoxy substituent of the styrene
substrate are in progress.
15. The coupling product 17 was obtained along with a varying amount of the
corresponding dihydro compound (not shown for convenience). The
stereochemical determination was made by hydrogenation of the former to
the latter and comparison of the spectral data with the known syn and anti
isomers: (a) Brand, G. J.; Studte, C.; Breit, B. Org. Lett. 2009, 11, 4668–4670; The
stereochemical assignment of 17 was further confirmed by its conversion (O3;
NaBH4) to 2,4-dimethyl-1,5-pentandiol: (b) Fujita, K.; Mori, K. Eur. J. Org. Chem.
2001, 493–502; (c) The stereochemistry of 18 was assigned by analogy to 17.
16. The coupling product of 16 with an alkyne was also assigned 1,3-anti
stereochemistry: Reichard, H. A.; Micalizio, G. C. Angew. Chem., Int. Ed 2007,
46, 1440–1443.
17. The five-membered titanium chelate could hinder an intermolecular cross-
coupling by occupying
carbometalation.
a
vacant coordination site necessary for
Acknowledgment
18. The titanium species are most likely to have an octahedral or trigonal
bipyramidal geometry, but the remaining coordination sites are not
indicated for convenience.
We thank NSF (CHE-0615604) for generous financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.08.054.