Catalytic enantioselective allyl-allyl cross-coupling with a borylated allylboronate

Article abstract of DOI:10.1021/ol400088g

Catalytic enantioselective allyl-allyl cross-coupling of a borylated allylboronate reagent gives versatile borylated chiral 1,5-hexadienes. These compounds may be manipulated in a number of useful ways to give functionalized chiral building blocks for asymmetric synthesis.

Full text of DOI:10.1021/ol400088g

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Catalytic Enantioselective AllylꢀAllyl
Cross-Coupling with a Borylated
Allylboronate
Hai Le, Robert E. Kyne, Laura A. Brozek, and James P. Morken*
Department of Chemistry, Boston College, Chestnut Hill, Massachusetts 02467,
United States
morken@bc.edu
Received January 11, 2013
ABSTRACT
Catalytic enantioselective allylꢀallyl cross-coupling of a borylated allylboronate reagent gives versatile borylated chiral 1,5-hexadienes. These
compounds may be manipulated in a number of useful ways to give functionalized chiral building blocks for asymmetric synthesis.
Recent advances in the palladium-catalyzed cross-
coupling of allyl electrophiles and allyl boronates have
provided an effective strategy for the enantio- and diaste-
A
central feature of this reaction is that, with appropriately
selected ligands, the transformation proceeds by way of a
stereoselective 3,30-reductive elimination that delivers the
branched 1,5-hexadiene as the predominant reaction
product.3,4 While enantioselective allylꢀallyl couplings
have been developed that facilitate the construction of
1,5-hexadienes bearing single tertiary or quaternary cen-
ters, or that possess adjacent tertiary stereocenters, con-
siderable limitations remain. A foremost barrier to the use
of allylꢀallyl coupling as a tool for molecular assembly lies
in the development of general strategies for differentiation
of the product alkenes. In isolated cases, selective function-
alization of the 1,5-diene can be accomplished by exploit-
ing steric bias inthe substrate; however, thisisnot a reliable
site-selective tactic. To more directly address this issue, we
considered that installation of a functional group handle
on one of the allyl coupling partners might provide a more
reoselective construction of chiral 1,5-hexadienes.1,2
(1) For enantioselective allylꢀallyl cross-coupling, see: (a) Zhang, P.;
Brozek, L. A.; Morken, J. P. J. Am. Chem. Soc. 2010, 132, 10686. (b)
Zhang, P.; Le, H.; Kyne, R. E.; Morken, J. P. J. Am. Chem. Soc. 2011,
133, 9716. (c) Brozek, L. A.; Ardolino, M. J.; Morken, J. P. J. Am. Chem.
Soc. 2011, 133, 16778.
(2) For linear selective allylꢀallyl couplings, see the following:
Allylstannanes: (a) Trost, B. M.; Keinan, E. Tetrahedron Lett. 1980,
21, 2595. (b) Godschalx, J.; Stille, J. K. Tetrahedron Lett. 1980, 21, 2599.
(c) Goliaszewski, A.; Schwartz, J. J. Am. Chem. Soc. 1984, 106, 5028. (d)
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J. Org. Chem. 1986, 51, 4006. (i) Cuerva, J. M.; Gomez-Bengoa, E.;
ꢀ
Mendez, M.; Echavarren, A. M. J. Org. Chem. 1997, 62, 7540. (j) van
(4) For operation of 3,30-reductive elimination in other processes,
see: (a) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu,
S. C.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A., III. J. Am. Chem. Soc.
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B. M. Angew. Chem., Int. Ed. 2009, 48, 6840. (e) Zhang, P.; Morken, J. P.
J. Am. Chem. Soc. 2009, 131, 12550. (f) Trost, B. M.; Zhang, Y. Chem.;
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Y.-D. J. Am. Chem. Soc. 2011, 133, 14180. (h) Ardolino, M. J.; Morken,
J. P. J. Am. Chem. Soc. 2012, 134, 8770. (i) Keith, J. A.; Behenna, D. C.;
Sherden, N.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Nielsen, R. J.;
Oxgaard, J.; Stoltz, B. M.; Goddard, W. A., III. J. Am. Chem. Soc. 2012,
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Heerden, F. R.; Huyser, J. J.; Williams, D. B. G.; Holzapfel, C. W.
Tetrahedron Lett. 1998, 39, 5281. (k) Nakamura, H.; Bao, M.;
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alcohols: (j) Sumida, Y.; Hayashi, S.; Hirano, K.; Yorimitsu, H.;
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E. F.; Schneider, U.; Kobayashi, S. Chem.;Eur. J. 2009, 15, 12247. (m)
ꢀ
Jimenez-Aquino, A.; Flegeau, E. F.; Schneider, U.; Kobayashi, S. Chem.
Commun. 2011, 47, 9456.
(3) For examples of 3,30-reductive eliminations applied to allylꢀallyl
ꢀ
ꢀ
systems, see: Reference 1 and (a) Mendez, M.; Cuerva, J. M.; Gomez-
ꢀ
Bengoa, E.; Cardenas, D. J.; Echavarren, A. M. Chem.;Eur. J. 2002, 8,
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Alvarez, R.; Espinet, P. Organometallics 2010, 29, 4983.
r
10.1021/ol400088g
XXXX American Chemical Society

versatile product motif with well-differentiated alkenes.
Herein, we describe a highly enantioselective allylꢀallyl
cross-coupling reaction that utilizes bis(boryl) nucleophile
1 (Scheme 1), such that 3,30-reductive elimination (i.e.,
2f3) delivers a borylated 1,5-hexadiene framework 3.5
These products may be manipulated in a number of ways
and should enhance the utility of allylꢀallyl cross-coupling
in asymmetric synthesis.
To investigate the allylꢀallyl cross-coupling with 1,
cinnamyl chloride was chosen as a probe substrate. After
some tuning (Pd precursor and additives), it was found
that excellent reactivity and enantioselectivity could be
achieved using [(allyl)PdCl]2 and (R)-methoxyfurylbiphep8
as the catalyst system. With these conditions, borylated
1,5-hexadiene 4 was isolated in 77% yield and a 99:1
enantiomer ratio (Scheme 2). It merits mention that the
level of enantioselectivity observed between cinnamyl
chloride and 1 is substantially higher than that which is
observed between unsubstituted allylB(pin) and cinnamyl
electrophiles. The scope of the allylꢀallyl cross-coupling
was further examined as depicted in Scheme 2. These
studies revealed that both electron-rich and -poor aro-
matic substrates performed equally well under the reac-
tion conditions (Scheme 2, 5ꢀ10) and were converted to
the derived product with high enantiopurity and good
yields. Diene 8 is of particular note as this example
demonstrates that sulfur-containing heterocycles, preva-
lent structures in medicinally relevant targets, are not
necessarily detrimental to the reaction. The examples in
Scheme 2 also demonstrate that stereoisomeric mixtures
of allylic chlorides can be processed in the coupling and
provide high yields of single-isomer products. In addi-
tion, the scope of cross-couplings employing 1 was found
to extend to the enantioselective production of borylated
1,5-hexadiene 11, a compound bearing an all-carbon
quaternary center.
Scheme 1. Catalytic AllylꢀAllyl Cross-Coupling with
Bis(Boronate) 1
Implementation of the cross-coupling strategy described
above requires ready access to allylic boronate 1. While 1 is
available by diboration of allene using 3 mol % Pt(PPh3)4
at 80 °C as reported by Miyaura6 (Table 1, entry 1), we
sought a procedure that is more amenable to large scale
synthesis. Ideally, access to 1 would arise by a procedure
that uses low loadings of commercially available catalysts
and, given the low boiling point of allene (ꢀ34 °C), would
not require elevated temperatures. Our first experiments
examined lower catalyst loadings on a larger scale and
revealed that excellent yields could be obtained with the
0.3ꢀ0.6 mol % Pt catalyst (entries 2 and 3). Further
investigation found that Pd complexes are also effective
and, with as little as 0.25 mol % Pd2(dba)3 and 0.6 mol %
PCy3, the reaction could be run at room temperature and
still proceed efficiently.7 Most importantly, when run on
preparative scale these reactions provide excellent isolated
yields of 1, a shelf-stable compound that was readily
purified by distillation.
Examination of aliphatic substrates showed that while a
cyclohexyl-substituted allylic chloride reacted smoothly to
give 12 under the conditions described above, when other
aliphatic allylic chlorides were examined, elimination to
1,3-dienes was the predominant reaction pathway. Sup-
posing that generation of 1,3-dienes occurred by β-hydride
elimination from intermediate π-allyl complexes, other
catalysts were examined. Consistent with previous obser-
vations,1a,c the merged influence of (R,R)-QuinoxP*9 as a
ligand and THF/H2O as the solvent system minimized
β-hydrogen elimination and allowed for the preparation of
(5) For the use of 2-silylallylsilane reagents in synthesis, see: (a)
Fleming, I.; Taddei, M. Synthesis 1985, 9, 899. (b) Pernez, S.; Hamelin, J.
Tetrahedron Lett. 1989, 30, 3419. (c) Boukherroub, R.; Manuel, G.;
Weber, W. P. J. Organomet. Chem. 1993, 444, 37. (d) Overman, L. E.;
Renhowe, P. A. J. Org. Chem. 1994, 59, 4138. (e) Laclef, S.; Exner, C. J.;
Turks, M.; Videtta, V.; Vogel, P. J. Org. Chem. 2009, 74, 8882. For the
use of 2-stannylallylstannane reagents in synthesis, see: (a) Mitchell,
T. N.; Schneider, U.; Heesche-Wagner, K. Tetrahedron 1989, 45, 969. (b)
Mitchell, T. N.; Schneider, U.; Heesche-Wagner, K. J. Organomet.
Chem. 1991, 411, 107. (c) Curran, D. P.; Yoo, B. Tetrahedron Lett.
1992, 33, 6931. (d) Piers, E.; Kaller, A. M. Synlett 1996, 549. (e) Williams,
D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765. (f) Britton, R. A.;
Piers, E.; Patrick, B. O. J. Org. Chem. 2004, 69, 3068. (g) Bukovec, C.;
Wesquet, A. O.; Kazmaier, U. Eur. J. Org. Chem. 2011, 1047.
(6) Ishiyama, T.; Kitano, T.; Miyaura, N. Tetrahedron Lett. 1998, 39,
2357.
(7) For palladium catalyzed diboration of substituted allenes, see: (a)
Yang, F.-Y.; Cheng, C.-H. J. Am. Chem. Soc. 2001, 123, 761. (b) Pelz,
N. F.; Woodward, A. R.; Burks, H. E.; Sieber, J. D.; Morken, J. P. J. Am.
Chem. Soc. 2004, 126, 16328. (c) Burks, H. E.; Liu, S.; Morken, J. P.
J. Am. Chem. Soc. 2007, 129, 8766.
(8) Broger, E. A.; Foricher, J.; Heiser, B.; Schmid, R. U.S. Patent
5,274,125, 1993.
Table 1. Synthesis of 1 by Catalytic Diboration of 1,2-Propa-
dienea
temp
scale
yield
(%)b
entry
catalyst
3% Pt(PPh3)4
(°C)
(mmol)
1
2
80
80
80
rt
1
>98
88
0.3% Pt(PPh3)4
20
40
10
24
3
0.6% Pt(PPh3)4
>98
>98
>98
4c
5d
2.5% Pd2(dba)3; 6% PCy3
0.25% Pd2(dba)3; 0.6% PCy3
rt
a Excess allene was used, and reactions were carried out in a high
pressure vessel. b Value is for the isolated yield of purified material and is
an average of two experiments. c Reaction was run in a round-bottom
flask, under a positive N2 atmosphere. d 1.5 equiv of allene was
employed.
(9) Imamoto, T.; Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005,
127, 11934.
B
Org. Lett., Vol. XX, No. XX, XXXX

linear alkyl-substituted products in high enantioselectivity
and good yields (13ꢀ15).
Scheme 3. Enantioselective AllylꢀAllyl Coupling with 1, and Its
Utility in Cascade Reactionsa
Scheme 2. Asymmetric AllylꢀAllyl Cross-Coupling of
Allylboronate 1 and Allylic Chloridesa
a MFB
=
2,20-dimethoxy-6,60-bis(di-2-furylphosphino)biphenyl;
S-Phos = 2-Dicyclohexylphosphino-20,60-dimethoxybiphenyl.
In addition to the transformations in Scheme 3, a variety
of additional transformations using purified boronate 4
were examined to further probe the utility of the bory-
lated allylꢀallyl coupling products (Scheme 4). Copper
mediated halogenation of 2 was found to deliver vinyl
halides 18 and 19, in 85 and 80% yield, respectively.12
Alternatively, using conditions developed by Merlic, the
vinyl boronate 4 could be smoothly transformed to the
derived enol ether 20 in 71% yield.13 In addition to the
transformation of the boronate, it was found that the steric
differentiation of the two alkenes was sufficient to enable
chemoselective catalytic cross-metathesis with ethyl acry-
late; this furnishedR,β-unsaturatedester 21in 63% yield as
a single olefin isomer.14 This cross-metathesis is particu-
larly useful as it leaves the vinyl boronate in place for
subsequent transformation. Lastly, it was found that
OsO4-catalyzed dihydroxylation, in the presence of 2 equiv
of NMO, selectively transforms the borylated alkene,
leaving the nonborylated alkene untouched (4f22). In
this case, it appears that the Bpin group is sufficiently
electron-releasing that the vinyl boronate reacts faster than
the nonborylated olefin.15
a All yields are average of two experiments. Linear E-allylic chloride
substrates were used for 4ꢀ9. A mixture of linear and branched allylic
chloride substrates was used for 10ꢀ14. Linear Z-allylic chloride used
for 15. b Reaction was carried out at 60 °C, 24 h, and in 20/1 THF/H2O. c
This compound was isolated as a ca. 5:1 mixture along with the linear
diene isomer.
While it was found that the borylated dienes in Scheme 2
could be isolated and purified by silica gel chromatogra-
phy, it was also of interest to examine their direct conver-
sion to other motifs. In one experiment, allylꢀallyl cross-
coupling was followed by treatment with NaOH and
H2O2; methyl ketone 16 was isolated in 78% yield
(Scheme 3, eq 1).10 Alternatively, the allylꢀallyl cross-
coupling could be followed by SuzukiꢀMiyaura cross-
coupling employing S-Phos as the ligand.11 In this experi-
ment, an additional palladium catalyst was not required
for the second step; the palladium employed for the
allylꢀallyl coupling suffices for the SuzukiꢀMiyaura reac-
tion and delivered styrene derivative 17 in 78% yield
(Scheme 3, eq 2).
A significant feature of cross-coupling reactions involv-
ing 1 is the enhanced level of enantioselectivity relative to
cross-coupling with allylB(pin). For example, as illustrated
in eq 3 (Scheme 5), when trifluoromethyl-substituted
cinnamyl carbonate 23 was subjected to allylꢀallyl cross-
coupling with allylB(pin), the cross-coupling product was
(12) Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2007,
129, 15434.
(13) (a) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. J. Am.
Chem. Soc. 2010, 132, 1202. (b) Winternheimer, D. J.; Merlic, C. A. Org.
Lett. 2010, 12, 2508.
(14) (a) Garber, S. B.; Kingsbury, J. K.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168. (b) Blackwell, H. E.; O’Leary, D. J.;
Chatterjee, A. K.; Washenfelder, R. A.; Bussman, D. A.; Grubbs, R. H.
J. Am. Chem. Soc. 2000, 122, 58. (c) Morrill, C.; Grubbs, R. H. J. Org.
Chem. 2003, 68, 6031. (d) Morrill, C.; Funk, T. W.; Grubbs, R. H.
Tetrahedron Lett. 2004, 45, 7733.
(10) For alternate approaches to compounds similar to 16, see: (a)
Shekhar, S.; Trantow, B.; Leitner, A.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 11770. (b) Weix, D. J.; Hartwig, J. F. J. Am. Chem. Soc. 2007,
129, 7720. (c) Jung, B.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134,
1490.
(11) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2004, 43, 1871. (b) Barder, T. E.; Walker,
S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
4685.
(15) For related osmium-catalyzed dihydroxylation of vinylsilane:
(a) Richer, J.-C.; Pokier, M. A.; Maroni, Y.; Manuel, G. Can. J. Chem.
1978, 56, 2049. (b) Hudrlik, P. F.; Hudrlik, A. M.; Kulkarni, A. K.
J. Am. Chem. Soc. 1985, 107, 4260.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Transformations of Vinylboronate 4
Scheme 5. Model for Enhanced Stereoselectivity in AllylꢀAllyl
Coupling Using 1
obtained in 74% ee; however, when the analogous cou-
pling was performed with 1, the enantioselection was
substantially higher (92% ee). We propose a stereochemi-
cal model depicted by A (Scheme 5) to rationalize the
significant enhancement of er. In this model, the allylꢀallyl
coupling occurs through a chairlike six-membered transi-
tion structure where the chair conformation is dictated by
the ligand chirality. In the transition structure leading to
the minor enantiomer, the pendant B(pin) group may
introduce an additional interaction with the pseudoequa-
torial furyl ring leading to an enhancement in selectivity
relative to the nonborylated nucleophile.
utility of these transformations in asymmetric synthesis
are underway.
Acknowledgment. Support by the NIGMS (GM-
64451) and the NSF (DBI-0619576, BC Mass. Spec.
Center) is gratefully acknowledged. We thank AllyChem
for a donation of B2(pin)2.
Supporting Information Available. Complete experi-
mental procedures and characterization data (1H and 13
C
NMR, IR, and mass spectrometry). This material is
available free of charge via the Internet at http://pubs.
acs.org.
In conclusion, we have described the catalytic enantio-
selective allylꢀallyl cross-coupling that provides ver-
satile vinyl boronate products. Further studies on the
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX