Cu-catalyzed chemoselective preparation of 2-(pinacolato)boron-substituted allylcopper complexes and their insitu site-, diastereo-, and enantioselective additions to aldehydes and ketones

Article abstract of DOI:10.1002/anie.201301018

Sustainable, efficient, selective: A three-component, single-vessel Cu-catalyzed method for chemo-, diastereo-, and enantioselective conversion of B₂(pin)₂, monosubstituted allenes, and aldehydes or ketones to 2-B(pin)-substituted homoallylic alkoxides is described. Subsequent functionalization delivers valuable products in up to >98:2 d.r. and 97:3 e.r. (see scheme). Copyright

Full text of DOI:10.1002/anie.201301018

Angewandte
Chemie
DOI: 10.1002/anie.201301018
Multicomponent Reactions
Cu-Catalyzed Chemoselective Preparation of 2-(Pinacolato)boron-
Substituted Allylcopper Complexes and their In Situ Site-, Diastereo-,
and Enantioselective Additions to Aldehydes and Ketones**
Fanke Meng, Hwanjong Jang, Byunghyuck Jung, and Amir H. Hoveyda*
Transformations that entail catalytic
generation of reactive entities for
in situ use in stereoselective synthesis
are in high demand;[1] such processes are
more efficient and operationally simpler
than when a priori preparation and
purification of stoichiometric quantities
of
sensitive
intermediates
are
required.[2] Successful design of multi-
component pathways hinges on high
chemoselectivity: A starting material
and a reagent must first be catalytically
transformed into a new species, which
then has to undergo reaction with
another substrate. If the catalyst struc-
ture is incorporated within the inter-
mediate molecule, reactivity and selec-
tivity can be further controlled. When
one or both partners carry several
potentially reactive sites, other issues
ꢀ
Scheme 1. Chemoselective Cu B addition to an allene, followed by site-, diastereo-, and
enantioselective addition of the resulting 2-(pinacolato)boron-substituted allylcopper species to
aldehydes and ketones can lead to a range of valuable organic molecules by a catalytic
multicomponent operation. B(pin)=(pinacolato)boron, L=ligand.
of selectivity must be addressed. Matters of efficiency and
site- and/or stereoselectivity need to be resolved at every
stage, and conditions must be found to ensure facile catalyst
turnover.
Herein, we present a sustainable, three-component,
single-vessel catalytic protocol for the chemo-, diastereo-
and enantioselective conversion of bis(pinacolato)diboron
[B2(pin)2], monosubstituted allenes, and aldehydes or ketones
into 2-B(pin)-substituted homoallylic alkoxides (Scheme 1).
Transformations commence by catalytic generation of 2-
B(pin)-allylcopper complexes through chemoselective reac-
each offering advantages in chemo- and/or stereoselectivity;
allenes are purchased or prepared by high-yielding process-
es.[4] High-value products are formed in no more than 18 h at
4–228C with > 98% g-selectivity and 88:12 to > 98:2 d.r. (in
68–92% yield after oxidation); enantioselectivity can be
achieved in up to 97:3 enantiomeric ratio (e.r.). To the best of
our knowledge, direct catalytic additions of 2-boryl-allyl units
to aldehydes are unknown; in cases where 2-boron-substi-
tuted allylboron species are prepared separately, alternative
modes of site selectivity are observed (more below). There
are also no catalytic methods for nucleophilic additions of 2-
boryl-allyl units to ketones.[3]
ꢀ
tions of Cu B species with allenes, followed by in situ
additions to carbonyl substrates.[3] When a,b-unsaturated
carbonyls are used, efficient 1,2-allylations remain favored
versus boryl or allyl conjugate additions. Catalysts are derived
from abundant Cu salts and commercially available precur-
sors of N-heterocyclic carbene (NHC) or phosphine ligands,
We have shown that 2-B(pin)-substituted allylcopper
ꢀ
complexes may be accessed by site-selective Cu B(pin)
addition to allenes (Scheme 1).[5a] As reactions were per-
formed in the presence of MeOH, in situ protonation of the
(pin)B-substituted allylcopper complex resulted in net proto-
ꢀ
boration and regeneration of a catalytically active Cu B(pin)
ꢀ
ꢀ
complex (via a Cu OMe intermediate). We wondered if Cu
B additions to allenes could proceed chemoselectively with an
aldehyde also present (Scheme 1), and whether, without
MeOH, the resulting B(pin)-substituted allylcopper complex
would react with the carbonyl substrate to generate B with
high g- and diastereoselectivity. Such a sequence could
proceed via A and involve the less congested Cu center of
II; reaction through I (Scheme 1), which might be in
equilibrium with II,[6] would afford isomeric products with
one stereogenic center.[7,8] Another question related to Cu
[*] F. Meng, H. Jang, Dr. B. Jung, Prof. A. H. Hoveyda
Department of Chemistry, Merkert Chemistry Center
Boston College
Chestnut Hill, MA 02467 (USA)
E-mail: amir.hoveyda@bc.edu
[**] Financial support was provided by the NSF (CHE-1111074) and the
NIH (GM-57212). We thank Dr. F. Haeffner and E. M. Vieira for
valuable discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301018.
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complexes adding efficiently to less-reactive ketones and
ꢀ
whether d.r. values would be high. Oxidation of the C B bond
(after C!D) would render allylcopper complex II a metal
enolate equivalent, delivering products of value for stereose-
lective synthesis of biologically active polyketides.[9,10]
We began by evaluating different Cu-based catalysts
(Table 1). Treatment of aldehyde 1a and allene 3a with
5.0 mol% of CuCl and either 6 or 7 affords, after oxidative
Table 1: Screening of representative catalyst types.[a]
Scheme 2. Products from sequential 2-B(pin)-substituted allylcopper
formation/aldehyde addition/oxidation reactions catalyzed by rac-
binap/Cu complex. Reactions performed with 4.0 mol% of rac-binap,
4.0 mol% of CuCl, and 16 mol% of NaOtBu under otherwise the same
conditions as shown in Table 1, except 5.0 equivalents of allene used
for 8a and 8b and 2.0 equivalents of allene used for 8c. >98% conv.
in all cases. See the Supporting Information for details.
Entry
Substrate
Ligand
Conv. [%][b]
d.r.[b]
Yield [%][c]
1
2
3
4
5
6
1a
1a
1a
2a
2a
2a
6
7
47
58
>98
>98
>98
>98
92:8
94:6
95:5
91:9
93:7
94:6
36
41
80
76
83
85
rac-binap
6
7
rac-binap
[a] Reaction conditions: 1) substrate (1.1 equiv), ligand (5.0 mol%),
CuCl (5.0 mol%), NaOtBu (20 mol% for 1a or 1.5 equiv for 2a), B2(pin)2
(1.1 equiv), thf, 22 8C, 8.0 h (1a) or 18 h (2a) under N2 atm;
Methyl-substituted allenes are effective substrates (see 8a–c).
Aldehydes with aryl groups of diverse electronic and steric
attributes are suitable as well (see 4b–f, 8a, and 8b); those
with an electron-deficient substituent (see 8a and 8b) require
excess allene (5.0 equiv) as, otherwise, B(pin)-addition pre-
dominates. Reactions with alkyl-substituted aldehydes are
equally facile and selective (see 4g and 8c).
2) NaBO3·4H2O, thf/H2O (1:1), 22 8C, 1.0 h (for 1a and 2a) under N2
1
atm. [b] Determined by analysis of 400 MHz H NMR spectra of
unpurified mixtures (ꢂ2%). [c] Yields of isolated and purified products
(ꢂ5%; major isomer for entries 1–3 and both isomers for entries 4–6).
See the Supporting Information for details. binap=2,2’-bis(diphenyl-
phosphino)-1,1’-binaphthyl, TBS=tert-butyldimethylsilyl.
Aryl ketones are converted into products bearing tertiary
hydroxy groups in ꢁ 79% yield, > 98% g-selectivity, and
ꢁ 91:9 d.r. with NHC/Cu or rac-binap/Cu complexes
(Scheme 3). Sterically congested ketones (see 5b–d), those
that contain electron-withdrawing (see 5b, 5e, and 5 f) or
-donating substituents (see 5c) react with high efficiency and
selectivity. The transformation with an ethyl ketone (see 5g)
is facile but slightly less diastereoselective, presumably owing
to the diminished size difference between the carbonyl
substituents (see A, Scheme 1). Heterocyclic substituents
are tolerated (e.g., 5h in ꢁ 93:7 d.r.)[17] and cyclic ketones are
effective substrates: 5i is isolated in 82–88% yield and up to
94:6 d.r. (Scheme 3). Efficient and selective formation of 9
(83–87% yield, > 98:2 d.r.) is notable: it offers an attractive
alternative to a propionate ketone aldol process, where, as
would be true in all cases, access to the trisubstituted enolate
in high selectivity would be difficult. Unlike reactions with
aldehydes, however, use of alkyl-substituted ketones leads to
a preponderance of side reactions; it is plausible that the
lower electrophilicity of aliphatic ketones renders enolization
by NaOtBu and the ensuing undesired reactions more
competitive. Products expected from additions to aliphatic
ketones could be synthesized by catalytic hydrogenation of
the corresponding tertiary allylic alcohols derived from
transformations with a,b-unsaturated carbonyls.
workup,[11] b-hydroxyketone 4a with complete g-selectivity
and 92:8 and 94:6 d.r. but in 36% and 41% yield, respectively
(Table 1, entries 1 and 2).[12] Control experiments show that
the moderate efficiency arises from competitive NHC/Cu-
ꢀ
catalyzed Cu B addition to the aldehyde (approximately
90% conversion in 8.0 h without the allene). With the less
Lewis basic rac-binap (Table 1, entry 3), chemoselectivity
ꢀ
improves in favor of Cu B addition to the allene, delivering
4a in 80% yield, > 98% g-selectivity and 95:5 d.r. (< 2%
B(pin) addition to 1a).[13] In contrast, NHC- and rac-binap-
based catalysts promote efficient allylation of ketone 2a
(Table 1, entries 4–6),[14] consistent with a sluggish 1,2-addi-
[15]
ꢀ
ꢀ
tion of NHC Cu B to the carbonyl group. Complete g-
selectivity is observed and diastereoselectivity is high in spite
of the diminished size difference between the ketone
substituents (versus those of an aldehyde); unfavorable
diaxial interactions in A are likely less severe owing to
relatively long incipient bonds.[16]
Various aryl-substituted aldehydes can be used (4b–f,
Scheme 2); efficiency, g-, and diastereoselectivities are high.
2
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formations is underlined by the finding that without allene 3a,
under otherwise identical reaction conditions, there is com-
plete consumption of 10a in only 4.0 h (versus > 98% conv.
for the synthesis of 11a and 11b in 8.0 h).[19]
High diastereoselectivities are observed with a,b-unsatu-
rated ketones in spite of the diminished size difference
between the carbonyl substituents (versus aryl ketones;
Table 2). With either 5.0 mol% of 7 or rac-binap, enones
Table 2: Sequential catalytic reactions with a,b-unsaturated ketones.[a]
Entry
Substrate
G
Ligand
d.r.[b]
Yield
[%][c]
1
2
3
4
5
6
12a
12a
12b
12b
12c
12c
Ph
Ph
n-pent
n-pent
7
>98:2
91:9
>98:2
91.5:8.5
90:10
87:13
64
68
53
77
86
81
rac-binap
7
rac-binap
7
rac-binap
[a] Reaction conditions: with 7: 1) substrate (1.5 equiv), 7 (5.0 mol%),
CuCl (5.0 mol%), NaOtBu (1.5 equiv), B2(pin)2 (1.5 equiv), thf, 22 8C,
18 h under N2 atm; 2) NaBO3·4H2O, thf/H2O (1:1), 22 8C, 1.0 h under N2
atm. With rac-binap: 1) substrate (1.2 equiv), rac-binap (5.0 mol%),
CuCl (5.0 mol%), NaOtBu (1.5 equiv), B2(pin)2 (1.2 equiv), thf, 22 8C,
18 h under N2 atm; 2) NaBO3·4H2O, thf/H2O (1:1), 22 8C, 1.0 under N2
1
atm. [b] Determined by analysis of 400 MHz H NMR spectra of
unpurified mixtures (ꢂ2%). [c] Yields of isolated and purified products
(ꢂ5%; both isomers). See the Supporting Information for details.
Scheme 3. Products from sequential catalytic allylcopper formation/
ꢀ
aryl ketone addition/C B oxidation reactions catalyzed by either a
12a and 12b are converted into tertiary allylic alcohols in 53–
77% yield (Table 2, entries 1–4); the remainder of the
material is consumed by conjugate addition of adventitious
B(pin) (1H NMR analysis).[20] Dienones are appropriate
substrates (Table 2, entries 5 and 6); the increased efficiency
in the formation of 13c (81–86% yield) is likely because the
hindered cyclic moiety discourages conjugate addition. Dia-
stereoselectivities are higher with the NHC-based catalysts;
the larger size of the P-based ligand might destabilize the
chair-type transition state for the carbonyl addition (see
Scheme 1, A). Reactions shown in Scheme 3 do not exhibit
such a trend, as the more sizeable aryl units of the ketone
better enforce a chair-like transition structure.
7/Cu complex or rac-binap/Cu complex. >98% conv. in all cases. See
Table 1 for conditions and the Supporting Information for experimental
and analytical details.
Reactions with unsaturated carbonyls bear the extra
complication of possible competitive B(pin) or allyl conjugate
addition.[18] Nonetheless, we find that subjection of enals 10a
and 10b to the reaction conditions with 3a and 4.0 mol% of
rac-binap/Cu complex leads to complete allene consumption,
furnishing allylic alcohols 11a and 11b in ꢁ 73% yield and up
to 95:5 d.r. [Eq. (1)]. The challenge of such catalytic trans-
Several matters of efficiency and selectivity underscore
the distinguishing advantages of the present approach. Pd-
catalyzed diboron additions to allenes deliver 2-B(pin)-
substituted allylborons, which, unlike in the processes de-
scribed above, react with aldehydes to generate acetate aldol
products (after oxidation; Scheme 4a);[21] related transforma-
tions with ketones would require an additional catalyst (not
reported). Our attempts to utilize the same B(pin)-substituted
set of allylboron species as precursors to allylcopper inter-
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mediates, as summarized in
Scheme 4b, led to predomi-
nance of the same mode of
site selectivity as mentioned
above (see Scheme 4a); this is
largely because the requisite 2-
B(pin)-allylcopper
species
Scheme 5. The Cu-catalyzed protocol can be used to obtain valuable vinylbromides with high efficiency.
The reaction conditions for the formation of 14a and 14b are shown. Compound 15a is formed under the
same conditions from substrates 2a and 3a and 15b from 2a and the benzyl derivative of 3a.
cannot be generated effi-
ciently through such a path-
way.[22] A different type of Pd-
catalyzed diboron addition to
allenes furnishes achiral B-
(pin)-substituted allyboron isomers bearing a trisubstituted
vinylboron moiety[23] (Scheme 4c versus Scheme 4a). These
latter entities, similar to allylcopper II in Scheme 1, can react
with aldehydes to yield product isomers represented by B
(R2 = H, Scheme 1); however, enantioselective reactions with
aldehydes as well as any additions to ketones, would require
the use of a second catalyst. It is unlikely that allylcopper
species are converted into allylboron intermediates that then
undergo addition; otherwise, two equivalents of B2(pin)2
would be required for complete conversion (versus 1.1–
1.5 equiv used), additions to aldehydes would likely not be
subject to enantioselective catalysis (see below), and there
would be minimal reaction with ketones.
alcohols by direct allyl additions to ketones are unavaila-
ble.[25,26]
Phosphine/Cu complexes promote the catalytic process in
up to 97:3 enantiomeric ratio (e.r.);[27] reactions with aryl-,
alkenyl-, or alkyl-substituted carbonyls afford products that
are not readily accessible in high selectivity by catalytic
enantioselective aldol additions (Scheme 6).[28] With various
chiral NHC-based complexes, enantioselectivities do not
exceed 60:40 e.r.[4] The use of two commercially available
chiral bisphosphines (16 and 17) provide optimal enantio-
selectivities for additions to aldehydes and ketones;[29] the
precise origin of such variations is the subject of current
studies.
Vinyl halides (Scheme 5) are another set of useful isolable
derivatives that can be accessed.[11] By subjection of the initial
product mixtures to CuBr2 various vinyl bromides are
obtained including: 14a (89% yield and 92:8 d.r.) and 14b
(77% yield and 88:12 d.r), originating from the reaction of
phenyl-substituted allene 3b, 15a (83% yield and 94:6 d.r.),
from a process involving 3a, and 15b (86% yield and > 98:2
d.r.), generated through the use of the benzyl derivative of
3a.[24] As far as we are aware, methods for stereoselective
synthesis of this type of vinyl halide-containing tertiary
Scheme 4. Strategies involving initial preparation and use of 2-B(pin)-
substituted allylboron reagents lead to alternative product isomers or
demand the identification and use of a second catalyst, in contrast to the
present Cu-catalyzed approach.
Scheme 6. Cu-catalyzed g- and diastereoselective coupling of
allenes with carbonyls can be performed enantioselectively through
the use of chiral bisphosphine ligands. >98% conv. in all cases.
For exact reaction conditions, see Table 1 and Scheme 5.
4
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Chemie
[15] Treatment of ketone 2a to the reaction conditions in entry 5 of
Design of more effective chiral catalysts for reactions with
ketones as well as applications to natural product synthesis
are in progress.
Table 1 but in the absence of allene 3a results in < 2%
conversion after 18 h.
ꢀ
[16] Further Cu B additions to the vinylboron products do not occur,
see: Y. Lee, H. Jang, A. H. Hoveyda, J. Am. Chem. Soc. 2009,
131, 18234.
Received: February 4, 2013
Published online: && &&, &&&&
[17] Reactions with pyridyl aldehydes or ketones lead to < 2%
conversion.
[18] For Cu-catalyzed B(pin) conjugate additions to unsaturated
carbonyls, see: E. Hartmann, D. J. Vyas, M. Oestreich, Chem.
Commun. 2011, 47, 7917.
Keywords: aldol products · allylations · copper ·
.
enantioselective catalysis · vinylborons
[19] High chemoselectivity in favor of reaction initiating with
addition to the allene in spite of a slower rate of transformation
ꢀ
with an enal might be due to a substantially faster rate of Cu
allene coordination, see Ref. [5b] for further discussion.
[1] For a review on multicomponent catalytic reactions, see: B. B.
Tourꢀ, D. G. Hall, Chem. Rev. 2009, 109, 4439.
ꢀ
[20] As with aldehydes (Table 1), the initial Cu B(pin) additions are
more chemoselective with the P-based complex. As 1,2-addition
of B(pin) to ketones is slow, excess enone is used with 7 to
maximize efficiency.
[2] For a relevant discussion, see: J. F. Bower, I. S. Kim, R. L.
Patman, M. J. Krische, Angew. Chem. 2009, 121, 36; Angew.
Chem. Int. Ed. 2009, 48, 34. 2-Substituted allylmetal species
cannot be accessed by Ir- and Ru-catalyzed reductive couplings
with allenes, and there are no related processes involving
ketones.
[3] M. Yus, J. C. Gonzꢁlez-Gꢂmez, F. Foubelo, Chem. Rev. 2011,
111, 7774.
[4] See the Supporting Information for details.
[21] A. R. Woodward, H. E. Burks, L. M. Chan, J. P. Morken, Org.
Lett. 2005, 7, 5505.
[22] Because C B to C Cu transmetallation is inefficient, uncata-
lyzed allylboration of aldehydes and metal-alkoxide-catalyzed
addition of the same reagents to ketones predominate (NaOtBu
ꢀ
ꢀ
ꢀ
is needed for C Cu formation).
[23] a) F.-Y. Yang, C.-H. Cheng, J. Am. Chem. Soc. 2001, 123, 761; for
[5] a) B. Jung, A. H. Hoveyda, J. Am. Chem. Soc. 2012, 134, 1490;
b) F. Meng, B. Jang, F. Haeffner, A. H. Hoveyda, Org. Lett.,
DOI:10.1021/ol4004178; for a related study, see: c) W. Yuan, S.
Ma, Adv. Synth. Catal. 2012, 354, 1867.
ꢀ
reactions with (pin)B SiMe2Ph and diastereoselective addition
of 2-silyl-substituted allylborons to aldehydes, see: b) K.-J.
Chang, D. K. Rayabarapu, F.-Y. Yang, C.-H. Cheng, J. Am.
Chem. Soc. 2005, 127, 126; for related studies, see: c) M.
Suginome, H. Nakamura, T. Matsuda, Y. Ito, J. Am. Chem.
Soc. 1998, 120, 4248; d) J. R. Zbieg, J. Moran, M. J. Krische, J.
Am. Chem. Soc. 2011, 133, 10582.
[6] The allylcopper species are represented as h1 (vs. p-allyl)
complexes, based on computational studies and a report regard-
ing the electronically related allylzinc systems by Okuda. See: C.
Lichtenberg, J. Engel, T. P. Spaniol, U. Englert, G. Raabe, J.
Okuda, J. Am. Chem. Soc. 2012, 134, 9805.
[24] For references regarding synthesis of 2-halogen-substituted
products, see the Supporting Information.
[7] Catalytic coupling reactions of allenes and aldehydes, involving
in situ generated allylmetal complexes, have been reported;
none utilize Cu salts and allyl units are not 2-B(pin) substituted.
For Ir-catalyzed versions, see: a) E. Skucas, J. F. Bower, M. J.
Krische, J. Am. Chem. Soc. 2007, 129, 12678; for Ru-catalyzed
diastereoselective variants, see: b) J. R. Zbieg, E. L. McInturff,
J. C. Leung, M. J. Krische, J. Am. Chem. Soc. 2011, 133, 1141.
[8] For an overview of (largely Pd-catalyzed) three-component
coupling reactions with allenes, affording reagents that can be
used in allyl addition processes, see: M. Jeganmohan, C.-H.
Cheng, Chem. Commun. 2008, 3101.
[9] For three-component catalytic non-enantioselective access to
ketone aldol-type products, see: Y. Tanabe, N. Matsumoto, T.
Higashi, T. Misaki, T. Itoh, M. Yamamoto, K. Mitarai, Y. Nishii,
Tetrahedron 2002, 58, 8269.
[10] For a review on polyketide natural products, see: D. OꢃHagan,
The Polyketide Metabolites, Ellis Horwood, Chichester, UK,
1991.
[11] The vinylboron products are unstable to silica gel; such
instability might originate from boron chelation with the
neighboring alcohol.
[12] Similar results were obtained with aryl-substituted imidazolium
or alkyl-substituted imidazolinium salts; see the Supporting
Information.
[13] For direct Ti-catalyzed aldol addition involving ketones and aryl
aldehydes, see: R. Mahrwald, B. Schetter, Org. Lett. 2006, 8, 281.
[14] Excess NaOtBu is needed for reactions with ketones, presum-
[25] For catalytic diastereoselective allyl additions to ketones (not 2-
B(pin) substituted), see: a) H. Ren, G. Dunet, P. Mayer, P.
Knochel, J. Am. Chem. Soc. 2007, 129, 5376; b) Z. Peng, T. D.
Blꢄmke, P. Mayer, P. Knochel, Angew. Chem. 2010, 122, 8695;
Angew. Chem. Int. Ed. 2010, 49, 8516; c) T. Takeda, M.
Yamamoto, S. Yoshida, A. Tsubouchi, Angew. Chem. 2012,
124, 7375; Angew. Chem. Int. Ed. 2012, 51, 7263; for reactions of
ketones and stoichiometric amounts of allylboronic acids (not 2-
B substituted), isolated from allylic alcohols by a Pd-catalyzed
process, see: d) M. Raducan, R. Alam, K. J. Szabꢂ, Angew.
Chem. 2012, 124, 13227; Angew. Chem. Int. Ed. 2012, 51, 13050.
See the Supporting Information for additional references.
[26] For use of enantiomerically pure reagents for additions of
substituted allyl units to carbonyls (no 2-B(pin) group), see the
Supporting Information.
[27] For catalytic enantioselective allyl additions to ketones (not 2-
B(pin)-substituted), see: a) R. Wada, K. Oisaki, M. Kanai, M.
Shibasaki, J. Am. Chem. Soc. 2004, 126, 8910; b) M. Wadamoto,
H. Yamamoto, J. Am. Chem. Soc. 2005, 127, 14556; c) S. Lou,
P. N. Moquist, S. E. Schaus, J. Am. Chem. Soc. 2006, 128, 12660;
d) X. Jiang, Y. Cao, Y. Wang, L. Liu, F. Shen, R. Wang, J. Am.
Chem. Soc. 2010, 132, 15328.
[28] Direct enantioselective catalytic aldol additions with aldehydes
have been reported (none with ketones). Reactions with cyclic
ketones (enol precursors) are more common and the large
majority of acyclic cases involve transformations with strongly
electron-deficient aryl aldehydes and generate products that
bear a methyl or an alkoxy unit adjacent to the carbonyl (higher
reactivity of the enol); low to moderate regioselectivity is
typically observed (propionate versus acetate aldol). For exam-
ple, see: a) S. Luo, H. Xu, J. Li, L. Zhang, J.-P. Cheng, J. Am.
Chem. Soc. 2007, 129, 3074; b) S. Aratake, T. Itoh, T. Okano, N.
ꢀ
ꢀ
ably because L Cu B(pin) regeneration by reaction of the more
ꢀ
sterically congested Cu alkoxide B with B2(pin)2 is slower via s-
bond metathesis and must proceed by alkoxide-assisted ligand
exchange (versus 16 mol% base needed with an aldehyde), see:
F. Gao, J. L. Carr, A. H. Hoveyda, Angew. Chem. 2012, 124,
6717; Angew. Chem. Int. Ed. 2012, 51, 6613.
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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.
Angewandte
Communications
Nagae, T. Sumiya, M. Shoji, Y. Hayashi, Chem. Eur. J. 2007, 13,
10246. Reactions with aliphatic aldehydes are scarce (none with
enals); one reported example requires > 140 h; see: c) G. Ma, A.
Bartoszewicz, I. Ibrahem, A. Cꢂrdova, Adv. Synth. Catal. 2011,
353, 3114.
[29] For example, 4a is generated in 95:5 d.r. and 90:10 e.r. (87%
yield) when 17 is used, whereas 5a is formed in 92:8 d.r. and
76:24 e.r. (82% yield) with 16.
6
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
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Angewandte
Chemie
Communications
Multicomponent Reactions
F. Meng, H. Jang, B. Jung,
A. H. Hoveyda*
&&&& — &&&&
Cu-Catalyzed Chemoselective
Preparation of 2-(Pinacolato)boron-
Substituted Allylcopper Complexes and
their In Situ Site-, Diastereo-, and
Enantioselective Additions to Aldehydes
and Ketones
Sustainable, efficient, selective: A three-
component, single-vessel Cu-catalyzed
method for chemo-, diastereo-, and
enantioselective conversion of B2(pin)2,
monosubstituted allenes, and aldehydes
or ketones to 2-B(pin)-substituted
homoallylic alkoxides is described. Sub-
sequent functionalization delivers valua-
ble products in up to >98:2 d.r. and 97:3
e.r. (see scheme).
Angew. Chem. Int. Ed. 2013, 52, 1 – 7
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!