Metal-free catalytic enantioselective C-B bond formation: (Pinacolato)boron conjugate additions to ±,β-unsaturated ketones, esters, weinreb amides, and aldehydes promoted by chiral N-heterocyclic carbenes

Article abstract of DOI:10.1021/ja302929d

The first broadly applicable metal-free enantioselective method for boron conjugate addition (BCA) to ±,β-unsaturated carbonyls is presented. The C-B bond forming reactions are promoted in the presence of 2.5-7.5 mol % of a readily accessible C₁-symmetric chiral imidazolinium salt, which is converted, in situ, to the catalytically active diastereo- and enantiomerically pure N-heterocyclic carbene (NHC) by the common organic base 1,8-diazabicyclo[5.4.0]undec-7-ene (dbu). In addition to the commercially available bis(pinacolato)diboron [B₂(pin)₂], and in contrast to reactions with the less sterically demanding achiral NHCs, the presence of MeOH is required for high efficiency. Acyclic and cyclic ±,β-unsaturated ketones, as well as acyclic esters, Weinreb amides, and aldehydes, can serve as suitable substrates; the desired β-boryl carbonyls are isolated in up to 94% yield and >98:2 enantiomer ratio (er). Transformations are often carried out at ambient temperature. In certain cases, such as when the relatively less reactive unsaturated amides are used, elevated temperatures are required (50-66 °C); nonetheless, reactions remain highly enantioselective. The utility of the NHC-catalyzed method is demonstrated through comparison with the alternative Cu-catalyzed protocols; in cases involving a polyfunctional substrate, unique profiles in chemoselectivity are exhibited by the metal-free approach (e.g., conjugate addition vs reaction with an alkyne, allene, or aldehyde).

Full text of DOI:10.1021/ja302929d

Article
pubs.acs.org/JACS
Metal-Free Catalytic Enantioselective C−B Bond Formation:
(Pinacolato)boron Conjugate Additions to α,β-Unsaturated Ketones,
Esters, Weinreb Amides, and Aldehydes Promoted by Chiral N-
Heterocyclic Carbenes
Hao Wu, Suttipol Radomkit, Jeannette M. O’Brien, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: The first broadly applicable metal-free enantio-
selective method for boron conjugate addition (BCA) to α,β-
unsaturated carbonyls is presented. The C−B bond forming
reactions are promoted in the presence of 2.5−7.5 mol % of a
readily accessible C1-symmetric chiral imidazolinium salt,
which is converted, in situ, to the catalytically active diastereo-
and enantiomerically pure N-heterocyclic carbene (NHC) by
the common organic base 1,8-diazabicyclo[5.4.0]undec-7-ene
(dbu). In addition to the commercially available bis-
(pinacolato)diboron [B2(pin)2], and in contrast to reactions with the less sterically demanding achiral NHCs, the presence of
MeOH is required for high efficiency. Acyclic and cyclic α,β-unsaturated ketones, as well as acyclic esters, Weinreb amides, and
aldehydes, can serve as suitable substrates; the desired β-boryl carbonyls are isolated in up to 94% yield and >98:2 enantiomer
ratio (er). Transformations are often carried out at ambient temperature. In certain cases, such as when the relatively less reactive
unsaturated amides are used, elevated temperatures are required (50−66 °C); nonetheless, reactions remain highly
enantioselective. The utility of the NHC-catalyzed method is demonstrated through comparison with the alternative Cu-
catalyzed protocols; in cases involving a polyfunctional substrate, unique profiles in chemoselectivity are exhibited by the metal-
free approach (e.g., conjugate addition vs reaction with an alkyne, allene, or aldehyde).
hypothesis and the associated structural changes has more
recently been provided through X-ray crystallography.8
1. INTRODUCTION
We recently reported the discovery of the first metal-free
catalytic protocol for the formation of C−B bonds.1 We
demonstrated that N-heterocyclic carbenes (NHCs), a class of
organic molecules commonly used to catalyze C−C bond
formation,2 promote reactions between bis(pinacolato)diboron
[B2(pin)2; 1] and an assortment of cyclic and acyclic α,β-
unsaturated ketones and esters. Such processes deliver β-boryl
carbonyls, which are versatile intermediates in chemical
synthesis.3,4 The NHC-catalyzed (pinacolato)boron conjugate
addition (BCA) reactions were shown to be mechanistically
unique, allowing them to be complementary to the more
extensively examined Cu-catalyzed variants5 (e.g., distinct
chemoselectivity profiles, see below). A subsequent study
focused on the use of chiral phosphines to promote
enantioselective BCA.6 Additions to a limited number of
acyclic esters and ketones were performed at 70 °C, affording
products in 76:24−97.5:2.5 enantiomer ratio (er); reaction with
cyclohexenone was shown to proceed to 62% conversion (16 h,
70 °C), generating the cyclic β-boryl ketone in 68:32 er. In our
initial disclosure,1a we proposed that the metal-free reactions
are initiated by formation of an NHC·B2(pin)2 complex,
wherein the B−B bond is activated due to association of the
Lewis basic heterocycle;7 support for the aforementioned
Herein, we report the enantioselective version of the NHC-
catalyzed BCA process. From the outset, our goal was to
develop an efficient catalytic C−B bond-forming process that is
applicable to a wide substrate range. Accordingly, as illustrated
in Scheme 1, the method described can be performed with
acyclic α,β-unsaturated ketones, esters, Weinreb amides, or
aldehydes; in some cases, NHC-catalyzed variants have not
been previously reported (including with achiral catalysts; e.g.,
additions to amides and enals). We show that metal-free
catalytic BCA may be performed with cyclic enones of different
ring sizes. Conjugate additions proceed in the presence of 2.5−
7.5 mol % of a readily accessible C1-symmetric chiral
imidazolinium salt, a common organic base, and commercially
available B2(pin)2 (1), delivering a wide range of products in up
to 94% yield and >98:2 er. The NHC-catalyzed BCA reactions
furnish chemoselectivity profiles that are unavailable through
the use of alternative Cu-catalyzed variants and thus represent a
valuable addition to the arsenal of transformations that generate
organoborons in high enantiomeric purity.
Received: March 26, 2012
Published: May 4, 2012
© 2012 American Chemical Society
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Scheme 1. NHC-Catalyzed Enantioselective BCA to Unsaturated Carbonyls
2. RESULTS AND DISCUSSION
2.1. Identification of Optimal Conditions and Cata-
lysts. We began by probing the ability of the NHC derived
from chiral imidazolinium salt 3a to effect reactions of
unsaturated carbonyls with B2(pin)2 (1). The basis for such a
starting point was the finding that the latter heterocyclic
carbene is effective in promoting the corresponding enantio-
selective silyl conjugate additions with (dimethylphenylsilyl)-
boronic acid pinacol ester.9 Under conditions that result in
efficient transformations when achiral NHCs are utilized,1a as
illustrated in entry 1 of Table 1, there is hardly any product
Table 1. Study of Reaction Conditions with 3a as the Chiral
a
NHC Precursor
Figure 1. Catalytic cycle proposed for NHC-catalyzed BCA;
exchanging a B(pin) with smaller alkoxides could lead to a faster
rate of reaction.
mol % (47% conv, 92:8 er; entry 4). The positive influence of
the larger concentration of dbu could arise from a more
efficient generation of chiral NHC and/or it might be because
exchange of pinacol with MeOH is base-catalyzed (cf.
formation of i in Figure 1). Such issues are the subjects of
continuing investigations designed to clarify these and other
mechanistic intricacies of the metal-free process. It is
nonetheless worthy of note that, in contrast to the formerly
reported NHC-catalyzed silyl conjugate additions,9 water
cannot be utilized as the additive (vs MeOH), and only a
complex mixture of products is generated under such
conditions (data not shown).
b
c
entry
base; mol %
additive; equiv
conv (%)
er
1
2
3
4
NaOt-Bu; 7.5
NaOt-Bu; 7.5
dbu; 10
none
<5
24
31
47
na
MeOH; 20
MeOH; 20
MeOH; 20
86.5:13.5
90:10
dbu; 20
92:8
a
b
Reactions were performed under N2 atmosphere. Determined
through analysis of 400 MHz 1H NMR spectra of unpurified mixtures
c
( 5%). Determined by HPLC analysis ( 2%); see Supporting
Information for details. na = not applicable; dbu = 1,8-
diazabicyclo[5.4.0]undec-7-ene.
We thus took advantage of the facility with which chiral
imidazolinium salts can be structurally modified12 and began
search for a chiral NHC that can furnish higher conversion and
promote the C−B bond-forming reaction enantioselectively.
Because studies aimed at elucidating the identity of the active
chiral catalyst, required for outlining an appropriate stereo-
chemical model, remain in progress, we turned to the
systematic screening of C2- and C1-symmetric imidazolinium
salts. Representative findings, depicted in Table 2, demonstrate
that alteration of the structure of the chiral NHC has a notable
influence on the reaction outcome. Comparison of the activity
of 3b and 3c,d demonstrates that similar conversion and er
values can be obtained with C2- and C1-symmetric carbenes,
with the catalyst bearing two phenyl heterocyclic substituents
affording somewhat higher er values (3c vs 3d, entries 2 and 3,
Table 2). Overall, the NHC derived from C1-symmetric 3h,
bearing a sizable mesityl at its dissymmetric N−Ar moiety
furnishes the highest reactivity and enantioselectivity (Table 2,
entry 7; 81% conv, 95:5 er). Catalytic BCA with 3f (entry 5),
an imidazoliumum salt that carries a smaller phenyl unit at the
same site, is less discriminating (76:24 vs 95:5 er). Subsequent
optimization studies led us to establish that the presence of 60
generated in the presence of 3a and NaOt-Bu after 14 h at
ambient temperature. Inefficient BCA is not due to the inability
of the relatively more sterically congested chiral NHC (vs the
smaller achiral variants) to associate with 1;10 as with the
previously illustrated cases involving achiral heterocyclic
carbenes,1,8,9 spectroscopic studies point to rapid (within 15
min) generation of NHC·1 complexes. Ongoing studies aimed
at elucidating the exact nature of the catalytically active species
indicate that in reactions promoted by chiral NHCs, formation
of a less sterically demanding complex (i in Figure 1),
generated by the exchange of a pinacolato unit with a common
alcohol, can facilitate catalysis through the pathway originally
proposed in 2009.1a,11 Accordingly, we chose to probe the
effect of MeOH as an additive.
With 20 equiv of the alcohol present (entry 2, Table 1), there
is indeed 24% conversion to the desired β-boryl ketone 4a,
which is generated in 86.5:13.5 er. Use of the more robust and
user-friendly organic base 1,8-diazabicyclo[5.4.0]undec-7-ene
(dbu; vs NaOt-Bu) leads to similar reactivity and enantiose-
lectivity (31% conv, 90:10 er; entry 3). There is enhancement
in BCA efficiency when the amount of dbu is increased to 20
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a
Table 2. Initial Examination of Chiral NHC Catalysts
Table 3. NHC-Catalyzed Enantioselective BCA to Acyclic
Enones
a
imidazolinium
salt
conv
b
yield
c
d
entry
R1; R2
Me; Ph
(%)
(%)
er
92:8
96:4
1
2
3
2a
2a
2b
3a
3h
3h
87
82
92
90
Me; Ph
>98
95
Me; o-
MeC6H4
85.5:14.5
e
4
5
Me; p-
2c
2d
2e
3h
3h
90
60
80
43
94:6
f
MeOC6H4
a
a
imidazolinium salt
conv (%)
er
Me; p-
BrC6H4
92:8
g
1
2
3
4
5
6
7
3b
3c
3d
3e
3f
35
37
30
10
78
30
81
82:18
81:19
69:31
56:44
76:24
94:6
6
Me; 2-furyl
3h
3h
3h
3h
3h
3h
75
73
94
93
76
90
72
92:8
7
Me; n-pentyl 2f
>98
>98
81
94.5:5.5
94:6
8
Me; i-Pr
n-Bu; Ph
2g
2h
2i
9
91:9
h
10
11
i-Pr; Ph
94
90:10
93.5:6.5
3g
3h
i
Ph; Ph
2j
82
95:5
a
b
a
Reactions were performed under N2 atmosphere. Conversion
See Table 1. Mes = 2,4,6-(Me)3C6H2.
determined through analysis of 400 MHz 1H NMR spectra of
c
unpurified mixtures ( 5%). Yields of isolated purified products
( 2%). Enantiomeric ratio (er) determined by GLC or HPLC
analysis ( 2%); see Supporting Information for details. Reaction
performed at 50 °C. Reaction performed with 2.5 mol % 3h and 10
mol % dbu. In addition, ∼10% proto-deboration (saturated ketone)
product is formed (determined by analysis of 400 MHz H NMR
spectrum of the unpurified mixture). Reaction performed with 7.5
mol % 3h and 30 mol % dbu. Reaction time = 18 h.
d
e
equiv of MeOH results in optimal reactivity and selectivity
(>98% conv and 95:5 er); such a requirement points to the
possible significance of the requisite ligand exchange mentioned
above (pinacol with MeOH; cf. i, Figure 1).
f
g
1
h
An additional attribute of C1-symmetric catalysts merits
mention. Although it is possible that the C2-symmetric chiral
variants of certain highly hindered imidazolinium salts such as
3h could give rise to improved enantioselectivity, synthesis of
these sterically encumbered heterocycles is typically inefficient;
this shortcoming is largely due to minimal yields obtained for
the formation of the C−N bond required for installment of the
second hindered N−Ar moiety. The more readily accessible C1-
symmetric NHCs that contain a single sterically demanding
dissymmetric aryl unit are more easily synthesized and thus
offer an attractive option.
2.2. NHC-Catalyzed Enantioselective BCA. 2.2.1. Reac-
tions with Aryl- and Alkyl-Substituted Acyclic α,β-Unsatu-
rated Ketones. Under the optimal conditions, the NHC
derived from 3a, most suitable for catalytic silyl conjugate
additions, promotes BCA to enone 2a (cf. Table 1), affording
4a in 82% yield and 92:8 er (entry 1, Table 3). However, when
3h serves as the catalyst precursor (Table 3, entry 2), the
reaction is more facile (>98% conv and 92% yield vs 87% conv
and 82% yield), and the desired product is obtained with higher
enantiomeric purity (96:4 vs 92:8 er).13 As the additional data
in Table 3 illustrate, an array of acyclic α,β-unsaturated ketones
can be used as substrates. Enantioselective formation of 4b
(Table 3, entry 3), despite the presence of a sterically
demanding o-tolyl substituent, is worthy of note. Synthesis of
enantiomerically enriched 4b (entry 3), however, necessitates
that the BCA is performed at 50 °C; ∼15% conversion is
observed when the reaction is carried out at 22 °C. The
findings in Table 3 indicate that, in general, electron-rich
enones are superior substrates; indeed, as illustrated in entry 4
(Table 3), enantioselective addition to 2c can be performed
with 2.5 mol % 3h and 10 mol % dbu under otherwise identical
conditions with little or no loss of efficiency (90% conv, 80%
yield, 94:6 er).
i
Catalytic BCA with bromophenyl-substituted ketone 2d
(entry 5, Table 3) affords 4d in 43% yield (60% conv, 92:8 er).
As the findings in Scheme 2 indicate, the relative inefficiency
corresponds to a variety of halogen-substituted substrates.
Thus, reaction of p-fluoro-substituted 2k, under the conditions
employed for the transformations in Table 2, although
exceedingly enantioselective (98:2 er), results in only 27%
conversion after 14 h; NHC-catalyzed BCA of chloro-
substituted 2l is similarly inefficient.14 Our attempts to address
the above complications led to the finding that increasing the
amount of the organic base (dbu) from 20 mol % to 1 equiv
leads to substantial improvements in efficiency with similar or
higher enantioselectivity (Scheme 2). Such an advance was
made based on the assumption that a more efficient generation
of the NHC catalyst or the aforementioned methanol/pinacol
exchange (cf., i, Figure 1) might demand larger amounts of
base, thus allowing the enantioselective pathway to become
more competitive.15,16
The transformations in entries 7 and 8 show that alkyl-
substituted α,β-unsaturated ketones, including those that bear a
relatively hindered moiety (e.g., i-Pr in 2g), are suitable BCA
substrates. Enones with an n-alkyl, an isopropyl, or an aryl
substituent at the carbonyl carbon can be efficiently converted
to the β-boryl ketones through the NHC-catalyzed trans-
formation (Table 3, entries 9−11). Some of the more sterically
demanding electrophiles require 7.5 mol % 3h (Table 3, entry
10; 68% conv, 66% yield, 90:10 er with 5 mol %) or somewhat
longer reaction times (entry 11). It should be pointed out that
the positive influence of stoichiometric quantities of dbu is not
limited to the catalytic transformations depicted in Scheme 2.
As illustrated through improved yields obtained for BCA
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Scheme 2. Influence of Amine Base on BCA Efficiency
processes that give rise to the formation of furyl-substituted β-
boryl methyl ketone 4e and phenyl-substituted phenylketone
4j, the same strategy can be applied to other types of substrates
as well.
conditions. Accordingly, we set out to investigate their
respective NHC-catalyzed BCA processes.
We first examined the transformations involving the versatile
Weinreb amides, for which only one example of Cu-catalyzed
enantioselective BCA has thus far been reported.18 As the data
in Table 5 indicate, reactions with amides require relatively
Table 5. NHC-Catalyzed Enantioselective BCA to Acyclic
a
Unsaturated Amides
time (h);
conv
a
yield
a
2.2.2. Reactions with Aryl- and Alkyl-Substituted Acyclic
α,β-Unsaturated Esters. α,β-Unsaturated esters can be used in
NHC-catalyzed BCA (Table 4); the desired products are
generated in 62−87% yield and 94:6−98:2 er. In certain cases,
such as those involving an electron-deficient aryl substituent
(entry 2) and the sizable tert-butyl ester (entry 3), additions
require elevated temperatures (43% conv and 96.5:3.5 er and
57% conv and 98:2 er, respectively, at 22 °C). Despite the more
forcing conditions in entries 2 and 3 (Table 4), enantiose-
lectivities remain high (94:6−98:2 er).17
a
entry
R
temp (°C)
(%)
(%)
er
e
1
2
3
4
5
6
Ph
7a
7b
7c
7d
7e
7f
36; 50
10; 50
14; 50
24; 66
24; 66
24; 50
86
>98
77
96
78
67
61
70
74
92
73
60
86.5:13.5
94:6
e
p-BrC6H4
n-pentyl
95:5
(CH2)2OTBS
93:7
i-Bu
95:5
i-Pr
95:5
a
e
See Table 3. Reaction performed with 30 equiv of MeOH.
2.2.3. Reactions with Aryl- and Alkyl-Substituted Acyclic
α,β-Unsaturated Amides. α,β-Unsaturated amides and alde-
hydes are two substrate classes that have received relatively
scant attention in connection with catalytic enantioselective
BCA. There are no reported examples of reactions with the
aforementioned substrate types under any metal-free catalytic
higher catalyst loadings (7.5 mol %), elevated temperatures
(50−66 °C), and longer reaction times (up to 36 h);
nonetheless, aryl- and alkyl-substituted β-boryl amides are
obtained in 60−92% yield after purification and high
enantioselectivities are observed in most cases (86.5:13.5−
95:5 er). It is noteworthy that sterically demanding substrates
a
Table 4. NHC-Catalyzed Enantioselective BCA to Acyclic Unsaturated Esters
a
a
a
entry
R1; R2
Me; Ph
mol % 3 h
time (h); temp (°C)
conv (%)
yield (%)
er
1
2
3
4
5a
5b
5c
5d
5.0
7.5
5.0
5.0
14; 22
10; 50
14; 50
14; 22
>98
>98
88
87
62
80
80
98:2
94:6
98:2
95:5
b
Me; p-BrC6H4
t-Bu; Ph
Me; n-pentyl
83
a
b
See Table 3. Approximately 30% of the proto-deboration byproduct is generated (determined by analysis of 400 MHz 1H NMR spectrum of the
unpurified mixture).
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a
Table 6. NHC-Catalyzed Enantioselective BCA to Unsaturated Aldehydes
a
a
a
entry
R
imidazolinium salt; mol %
time (h); temp (°C)
conv (%)
yield (%)
er
1
2
3
4
5
n-propyl
n-propyl
(CH2)2Ph
i-Bu
9a
9a
9b
9c
9d
3a; 5.0
3h; 5.0
3h; 7.5
3h; 5.0
3h; 5.0
14; 22
14; 22
7.0; 50
14; 22
14; 22
>98
95
81
72
65
63
72
84:16
95:5
95:5
94:6
91:9
b
>98
95
i-Pr
>98
a
b
See Table 3. In addition, 18% of the derived β-methoxy aldehyde is obtained (determined by analysis of the 400 MHz 1H NMR spectrum of the
unpurified mixture).
Scheme 3. NHC-Catalyzed Enantioselective BCA to Cyclic Enones
7e and 7f (Table 5, entries 5 and 6) are converted to the
desired products in 60−73% yield and 95:5 er. In the case of
electron-deficient amide 7b (Table 5, entry 2), shorter reaction
times and reduced amounts of MeOH are preferred (30 vs 60
equiv), because the undesired proto-deboration14 (cf., 6b, entry
2, Table 4) as well as formation of the corresponding β-boryl
methyl ester is otherwise significantly more competitive19
(∼70% byproduct formation with 60 equiv of MeOH). Control
experiments indicate that it is the β-boryl Weinreb amide that is
subsequently converted to the ester (vs generation of the
unsaturated ester directly from the unsaturated amide followed
by BCA); the resident Lewis acidic β-boron likely activates the
amide group toward reaction with MeOH.20
presence of base had to be avoided if efficient generation of
β-boryl aldehydes were to be achieved.22 In another example,
an NHC−Cu-catalyzed BCA of cinnamaldehyde is shown to
afford the desired product in 70:30 er (86% conv; yield of
isolated product was not reported).23 Finally, a protocol for Cu-
catalyzed enantioselective BCA to enals was reported most
recently; transformations proceed through in situ-generated
chiral α,β-unsaturated iminiums formed from reaction with an
enantiomerically pure amine (20 mol %).24 Although high
efficiency and enantioselectivities can be achieved through the
latter method, and reactions can be carried out with aryl- as well
as alkyl-substituted enals, use of air- and moisture-sensitive
Cu(OTf)2 and 10 mol % of a Bro̷nsted acid (o-FC6H4CO2H)
2.2.4. Reactions with Alkyl-Substituted α,β-Unsaturated
Aldehydes. α,β-Unsaturated aldehydes are another set of
are required. Furthermore, the β-boryl aldehydes obtained were
not isolated but were directly functionalized (e.g., Wittig olefin
synthesis).
substrates that have been less extensively examined in the
context of Cu-catalyzed BCA. Part of the complication with
NHC−Cu-catalyzed BCA reactions involving aldehydes is that
the corresponding 1,2-addition to the carbonyl group can be
efficient.21 In one study, synthesis and isolation of an (achiral)
NHC−Cu−OMe complex proved necessary, because the
The NHC derived from imidazolinium salt 3h promotes
enantioselective BCA to alkyl-substituted enals, as indicated by
the examples shown in Table 6. As illustrated in entry 1, when
C2-symmetric 3a is used in the reaction, under otherwise
identical conditions, 10a is obtained in 81% yield (>98% conv)
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a
Scheme 4. Functional Group Tolerance: Differences between NHC- and Cu-Catalyzed Protocols
a
NHC-catalyzed conditions: Reactions a, b, and d: 5.0 mol % 3h, 20 mol % dbu, 1.1 equiv of B2(pin)2, thf, 60 equiv of MeOH, 22 °C, 14 h; reactions
c and e: 7.5 mol % 3h, 30 mol % dbu, 1.1 equiv of B2(pin)2, thf, 60 equiv of MeOH, 50 °C, 14 h. Cu-catalyzed conditions: Reactions a, b, and d: 5.0
mol % Josiphos, 5.0 mol % CuCl, 5.0 mol % NaOt-Bu, 1.1 equiv of B2(pin)2, thf, 1.0 equiv of MeOH, 22 °C, 14 h; reactions c and e: 7.5 mol %
Josiphos, 7.5 mol % CuCl, 7.5 mol % NaOt-Bu, 1.1 equiv of B2(pin)2, thf, 1.0 equiv of MeOH, 50 °C, 14 h. Conversion values relate to the percent
starting material consumed and were determined through analysis of the 400 MHz 1H NMR spectra of the unpurified mixtures ( 5%). Yield values
refer to isolated and purified β-boryl products ( 2%). See Supporting Information for details.
and 84:16 er; catalytic BCA with 3h delivers 10a in 72% yield
and the desired product is generated in significantly higher
enantioselectivity (95:5 vs 84:16 er; entry 2, Table 6). Thus,
reactions generally proceed to ≥95% conversion, are often
performed at 22 °C, and afford the desired β-boryl aldehydes in
63−72% yield after isolation and purification and in 91:9−95:5
er.
Attempts to carry out catalytic conjugate addition with aryl-
substituted variants resulted in the formation of a complex
product mixture. Alternative pathways that might render
transformations of aryl-substituted enals inefficient are addition
of the NHC to an enal, which can lead to substrate
homocoupling or generation of the derived saturated ester,25
reaction with a β-boryl aldehyde product, or methoxide
conjugate addition26 (a minor byproduct generated in the
reaction shown in entry 2 of Table 6).
2.2.5. Reactions with Cyclic α,β-Unsaturated Carbonyls.
The final class of substrates examined involved cyclic
enones.5c,d As already mentioned, only one case of a
phosphine-catalyzed BCA has been reported (cyclohexenone,
68:32 er).6 Preliminary studies indicated that NHCs derived
from 3a and 3h promote additions to cyclopentenone
efficiently (93% conv, 79% yield and >98% conv, 95% yield,
respectively) but with diminished enantioselectivity; for
example, β-boryl cyclopentanone 12 (Scheme 3) is obtained
in 67:33 and 78.5:21.5 er with 3a and 3h, respectively. The
relatively low stereoselectivity is consistent with the fact that
BCA to Z-2a delivers 4a in 55:45 er with 3h serving as the
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NHC precursor (vs 96:4 for the E isomer; see entry 2, Table
3).27 Catalyst screening led us to establish that use of
imidazolinium salt 3i (Scheme 3) promotes the BCA with
similar efficiency (90% conv, 80% yield) and with improved
enantioselectivity (92:8 er). Several additional examples,
involving enones of different ring sizes are provided in Scheme
3.28 Enantioselectivities are lower than those obtained with
acyclic enones; future studies, supported by a better
appreciation of the mechanistic nuances of the catalytic cycle,
will be aimed at identification of catalysts that furnish higher er.
Nevertheless, efficient formation of 13, involving the reaction of
sterically congested cyclopentenone, is particularly noteworthy,
because a previous report involving the use of chiral Cu−
phosphine catalysts indicates <2% conversion with a similarly
substituted cyclohexenone.5c Additions to lactones are
hampered by adventitious cleavage of the heterocyclic ring
(MeOH/dbu) and formation of various byproducts. Nonethe-
less, as the example regarding the conversion of 5e to 16
indicates (Scheme 3), such cyclic β-boryl esters can be readily
accessed by means of BCA of the acyclic unsaturated ester,
followed by an efficient cyclization.
2.3. Comparison with Cu-Catalyzed Variants. Com-
plementarity in Chemical Synthesis. An impetus for
performing the present studies was to develop a catalytic
protocol that offers distinct advantages to the more established
Cu-catalyzed versions.1a,5 Such an expectation has been based
on the principle that, because metal-free BCA reactions proceed
through an entirely different pathway compared to the
processes promoted by organocopper complexes, they can
deliver complementarities that would otherwise remain
unavailable. Certain distinctions, above all in connection with
reactions of enals, have been already mentioned. Additional
revealing examples, underscoring some of the specific attributes
of the NHC-catalyzed processes are illustrated in Scheme 4.
The chiral catalyst used as representative of Cu-based
approaches was introduced in previous studies (with S,R-
Josiphos as the chiral ligand).5a,b,f
Whereas NHC-catalyzed BCA to alkyne-substituted enone
17 proceeds with complete chemoselectivity to afford 18 in
80% yield and 94:6 er (Scheme 4a), under Cu-catalyzed
conditions, 10% of β-vinylboron product (19),29 derived from
Cu−B addition addition/protonation of the alkyne, is observed
as well. A more notable dissimilarity manifests itself in the
context of reactions with alkyne-substituted enal 20 (Scheme
4b). In contrast to the NHC-catalyzed reaction, which affords
β-boryl aldehyde 21 in 71% yield, when Josiphos−Cu complex
is employed, the desired product is isolated in 50% yield; the
diminished efficiency is likely the result of competitive 1,2-
addition.1a The greater degree of chemoselectivity that is
feasible through NHC-catalyzed BCA is further illustrated by
the reaction of unsaturated ketone 2a in the presence of 1 equiv
of benzaldehyde (Scheme 4c). Although the efficiency of the
NHC-catalyzed process is somewhat diminished, probably as a
result of reversible NHC addition to the aldehyde30 resulting in
partial sequestration of the catalytically active heterocycle, the
negative impact on the Cu-catalyzed reaction is significantly
more severe (32% conv and 16% yield vs 65% conv and 56%
yield under NHC-catalyzed conditions).31,32 As further
illustrated in Scheme 4d, the presence of phenol (1.0 equiv)
leads to a more significant rate reduction in the BCA promoted
by the Cu-based catalyst (70% conv and 55% yield vs 98% conv
and 88% yield with the NHC-catalyzed process); due to
reduced Lewis basicity of the oxygen atom (vs an alkoxide), the
intermediate Cu−OPh is likely more reluctant to undergo
reaction with B2(pin)2 to regenerate the active Cu−B(pin)
complex. Finally, whereas Cu-catalyzed processes involving an
allene33 appear to be significantly more favored (Scheme 4e),
leading to complete consumption of the available B2(pin)2 and
the formation of byproducts, the NHC-catalyzed BCA proceeds
readily to afford the desired 4a in 74% yield (vs <5% yield).34 It
should however be mentioned that, in certain aspects, the state-
of-the-art in Cu-catalyzed BCA is superior. The latter class of
metal-catalyzed reactions typically require lower loading and
shorter reaction times, and the corresponding additions to
cyclic enones are generally more enantioselective.5 Nonethe-
less, the examples provided in Scheme 4 clearly indicate that
the availability of the NHC-catalyzed enantioselective BCA can
serve as a set of transformations that provide a useful
complement to the highly effective metal-catalyzed variants.
3. CONCLUSIONS
The present account puts forth the first general metal-free
protocol that can be used for enantioselective synthesis of a
variety of β-boryl carbonyls. These studies emphasize the
substantially higher activity of NHCs as BCA catalysts (vs
phosphines6), as indicated in the initial disclosure.1a
A
significantly wider range of substrates participate in the C−B
bond forming reactions, including those that contain sterically
demanding substituents (e.g., 2g in Table 3, 7f in Table 5, 9d in
Table 6, 13 in Scheme 3). Conjugate additions are more facile
(e.g., elevated temperatures are not needed for acyclic
enones35) and generally proceed with superior enantioselectiv-
ity with a chiral NHC serving as the catalyst than when
phospines are utilized.6
The metal-free catalytic method possesses attributes that are
complementary to the Cu-catalyzed alternatives:5 in a
polyfunctional molecule, highly chemoselective boron addition
is more likely under the Cu-free conditions. In certain cases,
such as reactions with alkyl-substituted enals (cf., Table 6) or
sterically hindered cyclic enones (cf., Scheme 3), the NHC-
catalyzed protocol offers a milder, more efficient and/or
selective alternative to the Cu-catalyzed approach.
A critical finding disclosed in this report relates to the central
role of methanol, as otherwise there is minimal transformation
when sterically hindered chiral NHC are used (vs the originally
disclosed achiral variants1a). Studies to shed light on various
aspects of the enantioselective metal-free process will be
assisted by such findings, as well as by the variations in the
levels and profiles in reactivity and selectivity observed during
the screening of a wide range of chiral NHCs. Thus, a
mechanistic scenario must provide a rationale as to why the
aforementioned conditions are required for achieving efficient
and highly enantioselective BCA reactions; it must also account
for the dependence of the levels of reactivity and
enantioselectivity on specific steric and electronic attributes of
the chiral NHC catalysts.
Details of ongoing mechanistic investigations regarding
NHC-catalyzed BCA will be reported in due course. The
design and development of other NHC-catalyzed processes and
applications to total synthesis of complex molecules are
additional goals of future investigations.
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catalytic cycle and the reasons for its higher reactivity will be the
subject of a detailed upcoming disclosure.
ASSOCIATED CONTENT
■
S
* Supporting Information
(12) For a study that highlights the significance of easily modifiable
C1-symmetric chiral N-heterocyclic carbenes in enantioselective
synthesis, see: (a) Lee, K.-s.; Hoveyda, A. H. J. Org. Chem. 2009,
75, 4455−4462. For application of such entities in other catalytic
enantioselective processes, see: (b) Reference 5e. (c) Reference 9.
(13) Although C2-symmetric imidazolinium salt 3a typically gives rise
to less efficient and enantioselective (pinacolato)boron conjugate
addition than that of the C1-symmetric 3h, it can be prepared by a
shorter synthesis route (three vs five steps in 25−40% yield). See
Supporting Information for details.
Experimental procedures and spectral data for substrates and
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
amir.hoveyda@bc.edu
Notes
(14) Proto-deboration of the β-boryl ketone products can occur
when the substrates carry an aryl group with a relatively strong
electron-withdrawing substituent. As an example, formation of p-
bromophenyl-substituted 4d is accompanied with ∼10% of the
saturated β-aryl ketone (Table 3, entry 5). Indeed, resubjection of
pure β-boryl ketone 4d to the reaction conditions (22 °C, 14 h) leads
to >98% conversion to the saturated ketone. It is plausible that
protonation of the C−B bond occurs via the borate derived from
addition of MeOH, followed by intramolecular protonation of the C−
B bond. Thus, the more electrophilic boron atoms of a (pinacolato)
boron unit adjacent to an electron-withdrawing aryl substituent, where
polarization inherent in the protonation process might be better
stabilized, are expected to be more prone toward participating in this
undesired reaction pathway. In support of the significance of an
electron-withdrawing unit to the degree of proto-deboration, BCA
leading to the formation of p-fluoroaryl 4k is typically accompanied by
<2% of the saturated ketone (stronger hyperconjugative electron
donation by F vs Br). Finally, it is also possible that a small amount
(corresponding to the catalyst loading) of proto-deboration is caused
by the tetrafluoroboron counterion of the imidazolinium salt. See:
(a) Nave, S.; Sonawane, R. P.; Elford, T. G.; Aggarwal, V. K. J. Am.
Chem. Soc. 2010, 132, 17096−17098. (b) Lennox, A. J. J.; Lloyd-Jones,
G. C. J. Am. Chem. Soc. 2012, DOI: 10/1021/ja300236k.
(15) Use of excess dbu, while substantially improving the yield of
isolated β-boryl ketones, in some cases increases the amount of proto-
deboration product as well (e.g., 4% vs 28% and 10 vs 21%
protodeboration for 4l and 4d with 20 mol % and 100 mol % dbu,
respectively). The latter observation is congruent with the
aforementioned proposal regarding the role of MeOH in causing the
protonation of the C−B bond, because borate formation is expected to
be more facile under more basic conditions.
(16) Performing the reactions shown in Scheme 2 with 20 mol % dbu
but at 50 °C (vs 22 °C) also leads to a more rapid rate of substrate
consumption. The product mixture, however, contains larger amounts
of the proto-deboration product. For example, under such conditions,
4d is obtained in 40% yield and 89:11 er along with ∼60% of the
saturated ketone.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to the memory of Professor Robert J.
Silbey. Financial support was provided by the NIH (GM-
57212) and the NSF (CHE-1111074). We thank Dr. K.-s. Lee
and Dr. F. Haeffner for helpful discussions, and Frontier
Scientific for gifts of bis(pinacolato)diboron.
REFERENCES
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reactions of α,β-unsaturated esters, somewhat lower conversion levels
are observed. For instance, in the reaction to generate 6b, there is 87%
conversion to the desired product along with 27% of the saturated
carboxylic ester (vs >98% conv and a similar degree of proto-
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(18) (a) Hirsch-Weil, D.; Abboud, K. A.; Hong, S. Chem. Commun.
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(19) As with the unsaturated esters, when 100 mol % dbu is used, the
desired β-boryl amides are formed with less efficiency (larger degree of
ester formation and similar amounts of proto-deboration).
(9) O’Brien, J. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2011, 133,
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(20) For examples of chelation between a carbonyl group and a β-
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(10) For example, treatment of imidazolinium salt 3h (see Table 2)
with B2(pin)2 at 22 °C leads to the clean formation of a new complex
(11B NMR: δ 33.57 ppm and δ 12.20 ppm vs δ 30.10 ppm for 1 in thf-
d8 at 22 °C). See Supporting Information for details.
(11) Details of the pathways that lead to the proposed NHC·diboron
complex i and the role of such an intermediate in the context of a
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(27) In addition, control experiments, with chiral NHC excluded,
indicate that BCA of the relatively more strained cyclic enones is
promoted more readily by dbu (e.g., ∼25% conv with cyclopentenone
under the conditions used to synthesize 12 in Scheme 3). In contrast,
there is ≤10% conversion under the same conditions with the acyclic
substrates.
(28) The absolute sense of enantioselectivity in NHC-catalyzed silyl
conjugate additions (ref 9) is opposite to those illustrated in Scheme 3.
The basis for this reversal of selectivity will be addressed in the
upcoming account regarding the mechanism of these classes of
transformations.
(29) For catalytic hydroborations of alkynes, which involve Cu−B
additions, see: (a) Takahashi, K.; Ishiyama, T.; Miayura, N. J.
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(31) With 5.0 mol % catalyst loading (1.1 equiv of B2(pin)2, 60 equiv
MeOH, 22 °C, 14 h), the NHC-catalyzed reaction affords the desired
β-boryl ketone product in 48% yield (54% conv) and 95:5 er. The
Josiphos−Cu-catalyzed BCA, under the same conditions, proceeds to
22% conversion to afford 4a in 15% yield and 85:15 er.
(32) Treatment of benzaldehyde to the BCA conditions (with 5.0
mol % 3h without an α,β-unsaturated carbonyl in otherwise identical
conditions as described for the reaction in Table 3) leads to <5%
conversion.
(33) For Cu-catalyzed hydroborations of allenes, see: Jung, B.;
Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 1490−1493.
(34) With 5.0 mol % catalyst loading (1.1 equiv of B2(pin)2, 60 equiv
of MeOH, 22 °C, 14 h), the NHC-catalyzed reaction affords the
desired β-boryl ketone product in 44% yield (52% conv) and in 95:5
er. The Josiphos−Cu-catalyzed BCA, under the same conditions,
proceeds to >98% conversion to afford 4a in 15% yield and 85:15 er.
(35) In one case involving a sterically demanding o-tolyl-substituted
substrate (enone 2b in entry 3, Table 3), NHC-catalyzed BCA is
performed at 50 °C for optimal results. However, with 100 mol % dbu
(vs 20 mol % used in the reaction in Table 3), this transformation can
be performed at ambient temperature to afford 4b in 93% yield (>98%
conv) and 88:12 er.
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