Synthesis of substituted 1,4-dienes by direct alkylation of allylic alcohols

Article abstract of DOI:10.1021/ja075678u

A regio- and stereoselective cross-coupling reaction between unactivated allylic alcohols and alkynes is described for the synthesis of 1,4-dienes. Copyright

Full text of DOI:10.1021/ja075678u

Published on Web 11/16/2007
Synthesis of Substituted 1,4-Dienes by Direct Alkylation of Allylic Alcohols
Filip Kolundzic and Glenn C. Micalizio*
Department of Chemistry, Yale UniVersity, New HaVen, Connecticut 06520-8107
Received July 30, 2007; E-mail: glenn.micalizio@yale.edu
Convergent C-C bond formation is a central theme in modern
synthetic organic chemistry. Among the many strategies to ac-
complish this type of bond construction, allylic alkylation represents
an emerging and powerful reaction class. Generally, the chemistry
of allyl electrophiles dominates this area, and major challenges
within the field reside in the control of regio- and stereoselection
in the bimolecular C-C bond forming event (i.e., 1 f 2-5; Figure
1).1 Here, we describe a metal-mediated alkylation of unactivated
allylic alcohols with internal alkynes2 that proceeds with net allylic
transposition and delivers stereodefined 1,4-dienes in a regioselec-
tive manner.3
Figure 1. Issues of selectivity in modern allylic alkylation.
Table 1
Treatment of substituted allylic alkoxides with preformed
titanium-π complexes, generated in situ from the corresponding
alkyne and Ti(Oi-Pr)4 or ClTi(Oi-Pr)3,4 results in efficient allylic
alkylation (Table 1). As depicted in entries 1 and 2, cross-coupling
of the cyclic allylic alcohol 6 or 9 with the symmetric alkyne 7
provides stereodefined 1,4-dienes 8 or 10 in 65 and 68% yields,
respectively. Entries 3-6 demonstrate that this convergent C-C
bond forming reaction occurs with allylic transposition, providing
the stereodefined 1,4-diene products 12, 14, 16, and 18 as single
isomers.
In addition to being regioselective, this cross-coupling reaction
proceeds with a high degree of stereochemical control. As depicted
in entry 7, coupling of a stereodefined allylic alcohol 19 (er ) 97:
3) with alkyne 7 provides the functionalized 1,4-diene 20 with
negligible erosion of stereochemistry (er ) 96:4). The absolute
stereochemistry of 20 was assigned on the basis of the stereose-
lection observed in the coupling of 21 with alkyne 7 (entry 8). This
process provides the trans-trisubstituted cyclohexene 22 in 50%
yield (dr g 20:1), demonstrating that C-C bond formation occurs
in a suprafacial manner across the allyl system.
Whereas simple primay allylic alcohols can be employed in
coupling reactions with internal alkynes (Table 2, entry 1), increased
efficiency is observed with more substituted coupling partners (entry
2). Tertiary acyclic allylic alcohols are also effective in this reaction,
and provide highly substituted 1,4-dienes when coupled with
internal alkynes. For example, coupling of 2-methyl-3-buten-2-ol
(27) with alkyne 7 furnishes the prenylated product 28 in 53% yield
(entry 3). Similarly, both (E)- and (Z)-2-methyl-3-penten-2-ol (29
and 31) can be coupled to an internal alkyne to furnish a 3-alkyl-
1,4-diene-containing product (30) (entries 4 and 5). As depicted in
entry 6, even tetrasubstituted olefins can be preparred with this cross
coupling reaction.
a Reaction conditions for cross coupling: alkyne (1.0 equiv), ClTi(Oi-
Pr)3, PhMe, C5H9MgCl, -78 to -35 °C, then recool to -78 °C, add Li-
alkoxide of allylic alcohol (1.0 equiv) (-78 to 0 °C). b ClTi(Oi-Pr)3 was
replaced with Ti(Oi-Pr)4 in this experiment. c Absolute stereochemistry not
determined.
stereodefined (Z)-trisubstituted olefin are produced with high
selectivity (entries 9 and 10).
Coupling of acyclic secondary allylic alcohols with internal
alkynes is also possible, yet these processes are more complex due
to the generation of an additional stereodefined double bond.
Whereas secondary allylic alcohols containing monosubstituted
olefins (34 and 36) can be coupled to internal alkynes in an efficient
manner, these processes proceed without stereoselection (E/Z ca.
1:1) (entries 7 and 8). In contrast, secondary allylic alcohols bearing
1,1-disubstituted olefins can be coupled with internal alkynes in a
highly stereoselective manner. In these cases, 1,4-dienes bearing a
As depicted in entry 11, this stereoselective cross-coupling
reaction can be employed with unsymmetrical alkynes. In this case,
cross-coupling of allylic alcohol 38 with the TMS-substituted alkyne
42 provides the stereodefined 1,4-diene 43 in 59% yield. In accord
with known preferences for titanium alkoxide-mediated function-
alization of silyl-substituted alkynes, C-C bond formation occurs
selectively at the site distal to the TMS-substituent of alkyne 42.5
As depicted in entries 12 and 13, allylic alcohols bearing (Z)-
disubstituted olefins provide 1,4-diene products with superior
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10.1021/ja075678u CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2
Figure 2. Empirical model for this direct allylic alkylation reaction.
Overall, we have described a new stereoselective cross-coupling
reaction between allylic alcohols and alkynes for the synthesis of
1,4-dienes. While occurring with allylic transposition, high stereo-
selectivity in the generation of substituted olefins is observed in
coupling reactions with cyclic, as well as acyclic allylic alcohols.
In general, the stereochemical results from this cross-coupling are
consistent with an empirical model whereby C-C bond formation
occurs through a boatlike geometry of a transient mixed titanate
ester (i.e., A and B; Figure 2).6 Further study of the mechanism
and scope of this and related coupling reactions is underway.
Acknowledgment. We gratefully acknowledge financial support
of this work by the American Cancer Society (Grant RSG-06-117-
01), the American Chemical Society (Grant PRF-45334-G1), the
Arnold and Mabel Beckman Foundation, Boehringer Ingelheim,
Eli Lilly & Co., and the National Institutes of Health-NIGMS
(Grant GM80266). The authors also thank Dr. Gorka Peris for the
determination of er in entry 7 of Table 1.
Supporting Information Available: Experimental procedures and
tabulated spectroscopic data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) For a review of nucleophilic addition reactions to allylic electrophiles,
see: (a) Magid, R. M. Tetrahedron, 1980, 36, 1901-1930. For a review
cross-coupling reactions via π-allyl intermediates, see: (b) Kazmaier, U.;
Pohlman, M. In Metal Catalyzed Cross-Coupling Reactions; De Meijere,
A., Ed.; Wiley-VCH: Weinheim, Germany, 2004; pp 531-583. For a
recent review of asymmetric allylic substitution catalyzed by copper
complexes, see: (c) Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed.
2005, 44, 4435-4439. For recent examples, see: (d) Zheng, W.; Zheng,
B.; Zhang, Y.; Hou, X. J. Am. Chem. Soc. 2007, 129, 7718-7719. (e)
Weix, D. J.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7720-7721.
(2) For examples of metal-mediated coupling reactions of allylic alcohols with
alkynes, see: (a) Trost, B. M.; Kulawiec, R. J. J. Am. Chem. Soc. 1992,
114, 5579-5584. (b) Trost, B. M.; Martinez, J. A.; Kulawiec, R. J.;
Indolese, A. F. J. Am. Chem. Soc. 1993, 115, 10402-10403. (c) Trost,
B. M.; Indolese, A. F.; Mu¨ller, T. J. J.; Treptow, B. J. Am. Chem. Soc.
1995, 117, 615-623. (d) De´rien, S.; Jan, D.; Dixneuf, P. H. Tetrahedron
1996, 52, 5511-5524.
a Reaction conditions for cross coupling: alkyne (1.0 equiv), ClTi(Oi-
Pr)3, PhMe, C5H9-MgCl, -78 to -35 °C, then recool to -78 °C, add Li-
alkoxide of allylic alcohol (1.0 equiv) (-78 to 0 °C). b All 1,4 diene products
were isolated as a single olefin isomers. c No evidence was found for the
production of regioisomeric products. d In the formation of the titanium-
alkyne complex, the temperature was kept under -55 °C (see Supporting
Information for details). e rr g 20:1.
(3) For copper-mediated alkylation of allylic alcohols, see: (a) Tanigawa,
Y.; Ohta, H.; Sonoda, A;, Murahashi, S.-I. J. Am. Chem. Soc. 1978, 100,
4610-4612. (b) Yamamoto, Y.; Maruyama, K. J. Organomet. Chem. 1978,
156, C9-C11. (c) Goering, H. L.; Kantner, S. S. J. Org. Chem. 1981, 46,
2144-2148.
(4) Harada, K.; Urabe, H.; Sato, F. Tetrahedron Lett. 1995, 36, 3203-3206.
(5) Sato, F.; Urabe, H. In Titanium and Zirconium in Organic Synthesis;
Marek, I., Ed.; Wiley-VCH: Weinheim, Germany, 2002, pp 319-354.
(6) The empirical model presented for understanding selectivity in these cross-
coupling reactions invokes a formal metallo-[3,3]-rearrangement; we are
aware that a plausible mechanistic proposal for these reactions can be
based on directed formation of intermediate bicyclic metallacyclopentenes,
followed by syn elimination: (a) Ryan, J.; Micalizio, G. C. J. Am. Chem.
Soc. 2006, 128, 2764-2765. (b) Reichard, H. A.; Micalizio, G. C. Angew.
Chem., Int. Ed. 2007, 46, 1440-1443. (c) McLaughlin, M.; Takahashi,
M.; Micalizio, G. C. Angew. Chem., Int. Ed. 2007, 46, 3912-3914. (d)
Takahashi, M.; Micalizio, G. C. J. Am. Chem. Soc. 2007, 129, 7514-
7516. An analysis of these mechanistic hypotheses is the subject of
ongoing studies in our laboratory.
selectivity in comparison to the (E)-disubstituted olefin isomers.
Whereas cross-coupling of (E)-44 with alkyne 7 affords the 1,4-
diene 45 as a 1:1 mixture of olefin isomers (entry 12), the
corresponding cross-coupling of (Z)-46 with 42 provides 1,4-diene
47 as an 8:1 mixture favoring the formation of a product containing
an (E)-disubstituted olefin (entry 13).
Finally, this new C-C bond forming reaction is tolerant of
neighboring π-unsaturation in the allylic alcohol coupling partner.
As illustrated in entry 14, cross-coupling of allylic alcohol 48 with
alkyne 7 provides the stereodefined triene 49 in 59% yield.
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