Stereoselective borylative ketone-diene coupling

Article abstract of DOI:10.1021/ol202138v

In the presence of catalytic Ni(cod)₂ and P(t-Bu)₃, ketones, dienes, and B₂(pin)₂ undergo a stereoselective multicomponent coupling reaction. Upon oxidation, the reaction furnishes 1,3-diols as the major reactio

Full text of DOI:10.1021/ol202138v

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5267–5269
Stereoselective Borylative Ketone-Diene
Coupling
Hee Yeon Cho, Zhiyong Yu, and James P. Morken*
Department of Chemisty, Merkert Chemistry Center, 2609 Beacon Street,
Boston College, Chestnut Hill, Massachusetts 02467, United States
morken@bc.edu
Received August 6, 2011
ABSTRACT
In the presence of catalytic Ni(cod)2 and P(t-Bu)3, ketones, dienes, and B2(pin)2 undergo a stereoselective multicomponent coupling reaction.
Upon oxidation, the reaction furnishes 1,3-diols as the major reaction product.
Tertiary alcohols are common motifs in natural pro-
ducts and in medicinally active agents. Indeed, roughly
20% of the top 50 pharmaceuticals bear tertiary alcohols
or their derivatives.1 While construction of these func-
tional groups is readily accomplished by nucleophilic
additions to ketones, such reactions can be challenging,
particularly when stereocontrol is a required element.2
(1) See http://cbc.arizona.edu/njardarson/group/top-pharmaceuti-
cals-poster.
(2) Reviews: (a) Hatano, M; Ishihara, K. Synthesis 2008, 1647.
(b) Shibasaki, M.; Kanai, M. Chem. Rev. 2008, 108, 2853. (c) Garcia,
C.; Martin, V. S. Curr. Org. Chem. 2006, 10, 1849.
Scheme 1. Borylative DieneÀCarbonyl Coupling
(3) (a) Cho, H. Y.; Morken, J. P. J. Am. Chem. Soc. 2008, 130, 16140.
(b) Cho, H. Y.; Morken, J. P. J. Am. Chem. Soc. 2010, 132, 7576.
(4) For related reductive or alkylative Ni-catalyzed diene carbonyl
couplings, see: (a) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am.
Chem. Soc. 1998, 120, 4033. (b) Takimoto, M.; Hiraga, Y.; Sato, Y.;
Mori, M. Tetrahedron Lett. 1998, 39, 4543. (c) Sato, Y.; Takanashi, T.;
Hoshiba, M.; Mori, M. Tetrahedron Lett. 1998, 39, 5579. (d) Sato, Y.;
Saito, N.; Mori, M. Tetrahedron 1998, 54, 1153. (e) Sato, Y.; Saito, N.;
Mori, M. J. Am. Chem. Soc. 2000, 122, 2371. (f) Kimura, M.; Shibata,
K.; Koudahashi, Y.; Tamaru, Y. Tetrahedron Lett. 2000, 41, 6789.
(g) Shibata, K.; Kimura, M.; Kojima, K.; Tanaka, S.; Tamaru, Y.
J. Organomet. Chem. 2001, 624, 348. (h) Sato, Y.; Sawaki, R.; Mori,
M. Organometallics 2001, 20, 5510. (i) Shibata, K.; Kimura, M.;
Shimizu, M.; Tamaru, Y. Org. Lett. 2001, 3, 2181. (j) Sato, Y.; Saito,
N.; Mori, M. J. Org. Chem. 2002, 67, 9310. (k) Sato, Y.; Sawaki, R.;
Saito, N.; Mori, M. J. Org. Chem. 2002, 67, 656. (l) Loh, T.-P.; Song,
H.-Y.; Zhou, Y. Org. Lett. 2002, 4, 2715. (m) Takimoto, M.; Kajima, Y.;
Sato, Y.; Mori, M. J. Org. Chem. 2005, 70, 8605. (n) Hirashita, T.;
Kambe, S.; Tsuji, H.; Araki, S. Chem. Commun. 2006, 2595.
(5) For reviews and selected recent examples of related nickel-
catalyzed couplings, see: (a) Montgomery, J. Angew. Chem., Int. Ed.
2004, 43, 3890. (b) Kimura, M.; Tamaru, Y. Top. Curr. Chem. 2007, 279,
173. (c) Moslin, R. M.; Miller-Moslin, K.; Jamison, T. F. Chem.
Commun. 2007, 4441. (d) Ho, C.-Y.; Jamison, T. F. Angew. Chem.,
Int. Ed. 2007, 46, 782. (e) Baxter, R. D.; Montgomery, J. J. Am. Chem.
Soc. 2008, 130, 9662. (f) Ng, S.-S.; Ho, C.-Y.; Schleicher, K. D.; Jamison,
T. F. Pure Appl. Chem. 2008, 80, 929. (g) Liu, P.; McCarren, P.; Cheong,
P. H.-Y.; Jamison, T. F.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 2050.
(h) Malik, H. A.; Sormunen, G. J.; Montgomery, J. J. Am. Chem. Soc.
2010, 132, 6304. (i) Baxter, R. D.; Montgomery, J. J. Am. Chem. Soc.
2011, 133, 5728.
Recent studies in our laboratory have focused on the
development of stereoselective borylative aldehydeÀdiene
coupling reactions (Scheme 1).3À6 These reactions occur
with exceptionally high levels of diastereoinduction when
aldehydes are employed as substrates and it was of interest
to ascertain whether these processes might also apply to
ketone electrophiles and to determine whether high levels
of stereocontrol could be maintained.7 In this report, we
show that borylative ketoneÀdiene coupling reactions can
be accomplished in high yields and with excellent levels of
diastereocontrol. Importantly, this reaction extends to aryl
(6) For aligned studies in dieneÀcarbonyl couplings, see: (a) Kim,
I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 6340.
(b) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008, 130,
14891. (c) Kim, I. S.; Han, S. B.; Krische, M. J. J. Am. Chem. Soc. 2009,
131, 2514. (d) Skucas, E.; Zbieg, J. R.; Krische, M. J. J. Am. Chem. Soc.
2009, 131, 5054. (e) Han, S. B.; Han, H.; Krische, M. J. J. Am. Chem. Soc.
2010, 132, 1760. (f) Han, S. B.; Gao, X.; Krische, M. J. J. Am. Chem. Soc.
2010, 132, 9153.
r
10.1021/ol202138v
2011 American Chemical Society
Published on Web 09/12/2011

alkyl ketones as well as to dialkyl ketones. Also of note,
this reaction occurs in a predictable fashion, yet with
regioselection that is distinct from related aldehydeÀdiene
coupling reactions.
depicted in Scheme 3, halogen substitution in the form of
chloro and fluoro groups is accommodated in the reaction
(compounds 3, 4, 5, 7) as is the presence of both electron-
donating (compounds 10, 11) and electron-withdrawing
substituents (compound 8). In all cases surveyed, >20:1
syn:anti diastereoselectivity was observed in the reaction
products.
To initiate studies in ketoneÀdiene coupling reactions,
acetophenone was treated with (E)-1,3-pentadiene under
conditions similar to those employed for aldehyde cou-
pling reactions (10 mol % Ni(cod)2, 15 mol % P(t-Bu)3, 2
equiv B2(pin)2) and the reaction mixture was treated to
oxidative workup. As depicted in Scheme 2 (eq 1), this
reaction occurred in good yield and >20:1 diastereoselec-
tivity. Surprisingly, the reaction of acetophenone followed
a different regiochemical course compared to the analo-
gous reaction with benzaldehyde. As depicted in Scheme 2
(eq 2), when benzaldehyde was subjected to similar reac-
tion conditions, 1,5-diol 2 was produced, not the 1,3-diol 1
that predominates with acetophenone. Not only is the
hydroxyl-positioning different between the two products,
but the diene is also incorporated into the product with
opposite connectivity in the case of the ketone relative to
the aldehyde electrophile.
Scheme 3. Borylative Coupling of Methyl Ketonesa
Scheme 2. Borylative Coupling of Acetophenone Compared to
Benzaldehyde
a (a) Stereoselectivity determined by 1H NMR analysis. Yields refer
to isolated yield of purified material; value is an average of two or more
experiments.
Whereas aromatic methyl ketones were found to react
with good yield and selectivity providing the 1,3 diol
regioselectively, reactions of aliphatic ketones delivered
the regioisomeric 1,5 diol. For example, 4-phenyl-2-buta-
none (entry 1, Table 1) underwent smooth coupling with
pentadiene but, in contrast to reactions of aromatic
ketones, was converted to the derived 1,5-diol in a manner
similar to that observed for reactions of benzaldehyde
(Scheme 2, eq 2). Suspecting that the steric encumbrance
surrounding the reacting carbonyl may determine the
regiochemical outcome, we examined constrained cyclic
ketones and found that these also deliver the 1,5-diol
product (entries 2À4, Table 1). It should be noted that
the product of entry 4 appears to arise by preferred
equatorial attachment of the diene to the carbonyl carbon
of the substrate. Lastly, isoprene was found to react in a
regioselective manner as well.
To learn whether the reactivity observed with acetophe-
none is unique to this substrate, a number of other ketone
electrophiles were employed in the coupling reaction. This
survey of the reaction revealed that many other ketones are
processed in a similar manner as acetophenone. Impor-
tantly, a variety of functional groups and substitution
patterns are tolerated in the ketone electrophile. As
(7) For dieneÀcarbonyl couplings that employ ketones, see: (a) Sato,
Y.; Takimoto, M.; Hayashi, K.; Katsuhara, T.; Takagi, K.; Mori, M.
J. Am. Chem. Soc. 1994, 116, 9771. (b) Sato, Y.; Takimoto, M.; Mori, M.
Tetrahedron Lett. 1996, 37, 887. (c) Kimura, M.; Fujimatsu, H.; Ezoe,
A.; Shibata, K.; Shimizu, M.; Matsumoto, S.; Tamaru, Y. Angew.
Chem., Int. Ed. 1999, 38, 397. (d) Kimura, M.; Matsuo, S.; Shibata,
K.; Tamaru, Y. Angew. Chem., Int. Ed. 1999, 38, 3386. (e) Sato, Y.;
Takimoto, M.; Mori, M. J. Am. Chem. Soc. 2000, 122, 1624. (f) Ezoe, A.;
Kimura, M.; Inoue, T.; Mori, M.; Tamaru, Y. Angew. Chem., Int. Ed.
2002, 41, 2784. (g) Kimura, M.; Kojima, K.; Tamaru, Y. Synthesis 2004,
3089. (h) Kimura, M.; Ezoe, A.; Mori, M.; Tamaru, Y. J. Am. Chem.
Soc. 2005, 127, 201. (i) Kimura, M.; Ezoe, A.; Mori, M.; Iwata, K.;
Tamaru, Y. J. Am. Chem. Soc. 2006, 128, 8559. (j) Saito, N.; Yamazaki,
T.; Sato, Y. Chem. Lett. 2009, 38, 594.
DieneÀcarbonyl coupling reactions have been exten-
sively studied by Tamaru and Mori, both of whom exe-
cuted these transformations under reducing conditions
with silane, organozinc reductants, and organoborane
reductants.4,7 Related alkylative reactions are known with
(8) Saito, N.; Yamazaki, T.; Sato, Y. Tetrahedron Lett. 2008, 49,
5073.
(9) Ogoshi, S.; Tonomori, K.; Oka, M.; Kurosawa, H. J. Am. Chem.
Soc. 2006, 128, 7077.
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Org. Lett., Vol. 13, No. 19, 2011

π-allyl 20, which undergoes reductive elimination to fur-
nish the 1,3-diol. It is conceivable that with a substituted
π-allyl the πÀσÀπ isomerization is retarded relative to
reductive elimination and the geometry of the initial
σ-bond metathesis product dictates the regiochemical out-
come of the reaction.
Table 1. Borylative Coupling of Ketones and Dienesa
Scheme 4
a Stereoselectivity determined by 1H NMR analysis. Yields refer to
isolated yield of purified material; value is an average of two or more
experiments.
organoboronate reagents.7j,8 These processes are thought
to occur by conversion of the diene and aldehyde to
metallacyclic intermediates. The identity of this intermedi-
ate was secured by Ogoshi and Kurosawa who isolated
such structures from stoichiometric reactions of Ni(cod)2,
PCy3, a 1,3-diene, and benzaldehyde.9 Considering the
similar reaction conditions, it is considered likely that such
mechanisms also operate in the borylative carbonyl-diene
coupling reactions and these can be used to understand the
regiochemical course of the coupling processes with hin-
dered and nonhindered carbonyl substrates. As depicted in
Scheme 4, with nonhindered electrophiles, reaction with
pentadiene may occur to give nickellacycle 17. Subsequent
σ-bond metathesis with B2(pin)2 would then deliver π-allyl
18, a compound that may engage in πÀσÀπ isomerization
prior to reductive elimination to afford 19. With more
hindered carbonyls, it is tenable that steric effects retard
CÀC bond formation with the substituted terminus of the
diene and, instead, the less hindered end of the diene adds
to the carbonyl. Subsequent σ-bond metathesis delivers a
In conclusion, we have demonstrated that the borylative
carbonyl-diene coupling reaction can extend to ketone
substrates and that it occurs in a regio- and stereoselective
fashion. While the outcome of the reaction is distinct from
that which is observed with aldehyde substrates, it is
consistent with known features of this class of transforma-
tions. Further studies on the utility of these processes are in
progress.
Acknowledgment. AllyChem is acknowledged for a gen-
erous donation of B2(pin)2. Support by the NIGMS (GM-
59417) and the NSF (DBI-0619576, BC Mass. Spec. Center)
is gratefully acknowledged. H.Y.C. is grateful for a Rodin
Fellowship and an ACS Organic Division Fellowship.
Supporting Information Available. Complete experi-
mental procedures and characterization data (1H and 13C
NMR, IR, and mass spectrometry). This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
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