NHC-Cu-catalyzed enantioselective hydroboration of acyclic and exocyclic 1,1-disubstituted aryl alkenes

Article abstract of DOI:10.1002/anie.201102398

Tough nut to crack: Chiral bidentate N-heterocyclic carbene copper complexes were designed that promote enantioselective hydroborations of one of the most difficult substrate classes: acyclic and exocyclic 1,1-disubstituted alkenes undergo reaction with >98% site selectivity, in up to >98% yield and e.r=96.5:3.5 (see scheme, B₂(pin)₂ = bis(pinacolato)diboron). Copyright

Full text of DOI:10.1002/anie.201102398

DOI: 10.1002/anie.201102398
Enantioselective Catalysis
NHC-Cu-Catalyzed Enantioselective Hydroboration of Acyclic and
Exocyclic 1,1-Disubstituted Aryl Alkenes**
Rosa Corberꢀn, Nicholas W. Mszar, and Amir H. Hoveyda*
We recently discovered that hydroboration of 1,2-disubsti-
tuted aryl olefins can be catalyzed by chiral Cu-based
bidentate N-heterocyclic carbene (NHC)[1] complexes.[2,3]
À
Reactions proceed to deliver homobenzylic C B bonds
exclusively,[4] which is in contrast to transformations with
alkylboranes or those catalyzed by the more costly Rh- or Ir-
À
based complexes, where formation of benzylic C B bonds is
preferred.[3] We later showed that the NHC Cu-catalyzed
À
transformations proceed efficiently with b-vinylboronates to
afford acyclic vicinal diboronates with complete site selectiv-
ity (< 2% geminal).[5] The above protocols are enantioselec-
tive, delivering boron-substituted stereogenic centers at
secondary carbon atoms in 86:14–99:1 enantiomeric ratio
À
Scheme 1. The outcome of catalytic enantioselective NHC Cu-cata-
lyzed hydroborations of 1,1-disubstituted aryl olefins, in contrast to
those involving 1,2-disubstituted olefins, depends on two stereochem-
(e.r.). Despite such advances, as well as seminal findings
reported by other research groups,[3] several shortcomings
persist. One long-standing problem relates to catalytic
À
istry-determining events: enantioselective Cu B addition and the
subsequent stereoselective Cu C protonation. G=aryl substituent.
enantioselective
hydroborations
of
1,1-disubstituted
À
alkenes.[6] The use of stoichiometric quantities of chiral
boranes in reactions of 1,1-disubstituted alkenes has been
outlined;[7] however, high enantioselectivity (e.r. > 90:10) is
only observed when there is a significant size difference
between the olefin substituents. Rh- and Ir-catalyzed pro-
cesses with catecholborane typically furnish low enantiose-
lectivity with 1,1-disubstituted alkenes and, in some cases,
control of site selectivity is problematic.[8] Recently, an Ir-
catalyzed process with pinacolatoborane was found to afford
complete site selectivity and e.r. ꢀ 90:10 in the case of two a-
methylstyrene derivatives (overall range of e.r. = 66:34–
formations of exocyclic alkenes, which, to the best of our
knowledge, have not been previously reported.
In considering the mechanism of catalytic 1,1-disubsti-
tuted alkene hydroborations (Scheme 1), we surmised that
transformations would likely be initiated by [(NHC)Cu{B-
(pin)}][11] i [formed from reaction of bis(pinacolato)diboron
À
(1) with an NHC-Cu-alkoxide]. Subsequent Cu B addition
would afford b-alkylborane ii, which contains a quaternary
À
Cu-substituted stereogenic center. Protonation of the Cu C
96:4).[9] Herein, we present an NHC Cu-catalyzed process
bond,[12] likely occurring with retention of configuration,[4] can
deliver the desired product and regenerate iii, which reacts
with 1 to form i. An uncommon feature of the catalytic
processes is that the eventual stereochemical outcome does
À
for the site- and enantioselective catalytic hydroboration of
1,1-disubstituted aryl olefins (Scheme 1);[10] a-alkyl-b-pina-
colatoboranes are formed with > 98% site selectivity, in up to
> 98% yield and e.r. = 96.5:3.5. Reactions involving a range
of acyclic 1,1-disubstituted aryl olefins, including those that
contain alkyl substituents other than the typically utilized
methyl unit, have been developed. Also included are trans-
À
not depend only on the enantioselectivity of the Cu B
addition: the stereochemistry of the intermolecular protona-
tion of the enantiomerically enriched alkylcopper species
with the alcohol additive (MeOH) is crucial as well.[13]
Furthermore, the copper-containing intermediates might be
utilized to access entities other than alkylboranes;[14] this is in
contrast to the more traditional approach to metal-catalyzed
[*] Dr. R. Corberꢀn, N. W. Mszar, Prof. A. H. Hoveyda
Department of Chemistry, Merkert Chemistry Center
Boston College
hydroboration,[3] where the C B bond is formed through an
À
Chestnut Hill, MA 02467 (USA)
Fax: (+1)617-552-1442
E-mail: amir.hoveyda@bc.edu
alkyl-metal–boron reductive elimination. Within this latter
context, application of the catalytic method towards the
synthesis of versatile 2-substituted allylboronates will be
described.
[**] Financial support was provided by the NSF (CHE-0715138). R.C. is a
Spanish Ministry of Science and Innovation postdoctoral fellow. We
thank Dr. Y. Lee and H. Jang for helpful discussions and Frontier
Scientific for generous gifts of bis(pinacolato)diboron. Mass
spectrometry facilities at Boston College are supported by the NSF
(CHE-0619576). NHC=N-heterocyclic carbene.
À
We began by examining the ability of NHC Cu com-
plexes obtained from enantiomerically pure imidazolinium
salts 2–8 (Table 1) to promote the enantioselective hydro-
boration of a-methylstyrene (9a; À158C, thf). The mono-
dentate variants derived from C1- or C2-symmetric 2 and 3,
the latter of which is effective for reactions with cyclic
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102398.
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Table 1: Initial evaluation of chiral NHC complexes.[a]
Entry
Imidazolinium Salt
Conv. [%][b]
e.r.[c]
1
2
3
4
5
6
7
8
2
3
4
5a
5b
6
7
8
>98
95
>98
98
47
67
59:41
56:44
65:35
75:25
93:7
74:26
82:18
85.5:14.5
Scheme 2. Variations in the substitution pattern of the nonchelating N-
À
aryl moiety of the NHC Cu complex can have an impact on the course
of a catalytic process.
>98
>98
permitting improved reactivity and/or selectivity. Accord-
ingly, we prepared and examined several C1-symmetric chiral
bidentate imidazolinium salts, such as 7 and 8 (Table 1). These
investigations led us to establish that positioning a tert-butyl
group at the meta position of the nonchelating N-Ar moiety of
the NHC (7; Table 1, entry 7) results in enhanced efficiency as
well as an increase in enantioselectivity (> 98% vs. 67%
conv., e.r. = 82:18 vs. 74:26 ). Further improvement in the
enantiomeric purity of the product is achieved through the
use of naphthyl-substituted salt 8 (> 98% conv., e.r. =
85.5:14.5; Table 1, entry 8). When the reaction is performed
[a] Reactions were performed under N2; >98% site selectivity in all
cases. [b] Determined through analysis of the 400 MHz 1H NMR spectra
of unpurified mixtures. [c] Determined by HPLC analysis; see the
Supporting Information for details. B2(pin)2 =bis(pinacolato)diboron.
À
at À508C (vs. À158C), and with an NHC Cu complex derived
from 8 as the catalyst, 10a is isolated in 95% yield and e.r. =
93.5:6.5 (Table 2, entry 1).
[a]
À
Table 2: NHC Cu-catalyzed hydroboration of a-methylstyrenes.
disubstituted aryl olefins,[4] led to minimal stereoselectivity
(Table 1, entries 1 and 2).
Entry
Substrate (aryl)
Conv. [%][b] Yield [%][c]
e.r.[d]
1
2
3
4
5
6
7
8
C6H5
9a
9b
9c
9d
9e
9 f
9g
9h
9i
96
84
95
62
93.5:6.5
92:8
96:4
87.5:12.5
89.5:10.5
80.5:19.5
91.5:8.5
93.5:6.5
82:18
Enantioselectivity improves when bidentate complexes
derived from 4 and 5a are utilized (Table 1, entries 3 and 4).
Alkylboronate 10a is formed in a significantly higher
enantiomeric ratio (93:7; Table 1, entry 5) when 5b serves
as the catalyst precursor; however, the reaction is less
efficient (47% vs. ꢀ 98% conversion with 4 and 5a). We
then turned to sulfonate-containing 6, where both N-aryl units
of the chiral imidazolinium salt are dissymmetric (vs. 4 and
5a,b); here, moderate efficiency and enantioselectivity are
observed (67% conversion, e.r. = 74:26).
2-naphthyl
1-naphthyl
mFC6H4
mBrC6H4
mCF3C6H4
mMeOC6H4
mMeC6H4
pCF3C6H4
pMeC6H4
2-benzofuryl
50
37
73
60
61
58
63
52
>98
98
>98
83
9
10
11
93
79
9j
9k
80
80
87:13
93.5:6.5
>98
89
[a] Reactions were performed under N2; >98% site selectivity in all
cases. [b] Conversion determined through analysis of the 400 MHz
1H NMR spectra of unpurified mixtures. [c] Yields of isolated purified
products (Æ5%). [d] Enantiomeric ratio (e.r.) determined by HPLC
analysis (Æ2%); see the Supporting Information for details.
The higher activity of the C1-symmetric complex derived
from 6, despite its larger ortho-phenyl unit (vs. iPr in 5b),
suggested that, as shown in I versus II (Scheme 2), the more
severe tilting of the dissymmetric N-Ar group might be
allowing better accommodation of the alkene. We argued that
the enhanced flexibility of the N-Ar group in II towards
adopting a more favorable conformation for substrate binding
might be because the orthogonal conformation of the ortho-
phenyl unit causes this substituent to engender less severe
steric repulsion with the NHC backbone. We thus surmised
that placement of substituents at the opposite side of the aryl
group could increase its slant (III, Scheme 2), thereby
Various a-methyl aryl olefins can be used in Cu-catalyzed
enantioselective hydroborations (Table 2); in all cases, > 98%
site selectivity is observed.[15] A similarly high e.r. value (92:8)
is obtained with 2-naphthyl-substituted 9b (Table 2, entry 2);
À
Cu B addition to the more sterically demanding olefin 9c
(Table 2, entry 3), on the other hand, does not proceed
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beyond 50% conversion (37% yield) but the reaction is
highly enantioselective (e.r. = 96:4). Although the electronic
attributes of the alkene do not seem to have an impact on
selectivity, reactions are less selective with substrates that
carry a trifluoromethyl-substituted aryl group (compare
Table 2, entries 6 and 7 as well as 9 and 10). The case of
benzofuryl-substituted 10k (Table 2, entry 11; 89% yield,
e.r. = 93.5:6.5) illustrates that heterocyclic substrates can be
used.[16]
provides an effective solution to this problem, as indicated by
the examples in Scheme 4; the Cu complex derived from 12 is
generally most effective.[20] Hetero- (17 and 18) and carbocy-
clic (19) alkenes are converted into alkylboronates in 72–75%
yield and in up to e.r. = 96:4.[21]
À
NHC Cu-catalyzed hydroborations of 1,1-disubstituted
aryl olefins that bear larger alkyl groups (vs. Me, Table 2)
proceed efficiently and with high enantioselectivity
(Scheme 3). Catalytic hydroborations of such substrates
Scheme 4. Hydroborations of heterocyclic and carbocyclic 1,1-disubsti-
tuted olefins are most effectively promoted by the Cu complex derived
from imidazolinium salt 12. [a] Reaction performed at À308C. See the
Supporting Information for details.
With allylic alcohols as substrates, 2-substituted allylbor-
À
onates are generated (Scheme 5). Thus, Cu B addition
proceeds efficiently with the corresponding allylic alcohols
(i.e., formation of ii, Scheme 1), but the Cu-alkoxide elimi-
À
Scheme 3. NHC Cu-catalyzed hydroborations of 1,1-disubstituted ole-
fins can be performed with substrates bearing sterically demanding
alkyl groups; such transformations, as well as certain heterocyclic
alkenes, require a structurally modified chiral catalyst (derived from
12) for optimal selectivity. [a] Reaction performed at 48C. See the
Supporting Information for details.
have scarcely been examined previously and the few reported
cases proceed with low selectivity (e.g., 13 in e.r. = 65.5:34.5
with a chiral phosphinooxazoline-derived Ir complex[9]).
Several points regarding this set of reactions merit mention:
1) The use of imidazolinium salt 12,[17] which contains an o-
methyl-substituted N-aryl moiety (vs. m-tBu and naphthyl in 7
and 8, respectively), results in optimal efficiency and selec-
tivity. Hydroborations with Cu complexes derived from 7 or 8
give rise to lower yield and/or selectivity,[18] thus leading us to
identify 12 as a superior option by examination of the effect of
the aforementioned structural modifications (cf. Scheme 2).
À
Scheme 5. NHC Cu-catalyzed synthesis of 2-substituted allylboronates
directly from readily accessible allylic alcohols. n.d.=not determined.
[a] Yield was not measured due to instability, but treatment with
benzaldehyde affords the corresponding allylic alcohol in 70% yield
(over the two steps); see the Supporting Information for details.
À
2) The higher efficiency of the NHC Cu complex derived
À
from 12 (vs. 7 or 8) is consistent with the augmented tilt of the
dissymmetric N-Ar moiety, which accommodates a larger
alkyl substituent (R in I–III, Scheme 2). Enantioselectivities
remain high (vs. a-methylstyrene (9a)), even though reactions
are performed at À158C (vs. À508C in Table 2); although the
presence of the sterically demanding isopropyl group reduces
the rate of the catalytic process, alkylboronate 15 is formed in
e.r. = 96.5:3.5.[19]
nation is substantially faster than the rate of Cu C proto-
nation. The Cu-catalyzed approach to 2-aryl-substituted
allylboronates offers an attractive alternative to the Pd-
catalyzed process performed with allylic acetates and 1.[22]
À
Reactions can be easily promoted by the NHC Cu
complex derived from commercially available achiral 21 and
air-stable Cu(OAc)2. The derived allylboronates are formed
cleanly; the moderate yields are due to the relative instability
of such entities. A related Cu-catalyzed process, shown in
Equation (1), involves the conversion of trifluoromethyl-
substituted 26 into difluoroallylboronate 27. The transforma-
Exocyclic 1,1-disubstituted alkenes are another class of
substrates not previously utilized in highly enantioselective
À
catalytic hydroborations. The NHC Cu-catalyzed method
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Communications
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À
The development of additional catalytic C B bond-
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reactivity and selectivity are in progress.
Received: April 6, 2011
Revised: May 20, 2011
Published online: June 17, 2011
[15] The use of 80 mol% NaOtBu resulted in a higher degree of
reproducibility. See also Ref. [10c].
[16] Substrates that bear an ortho-aryl substituent are inert to the
reaction conditions (e.g., Br- or Me-substituted). This is likely
because formation of the Cu-substituted quaternary carbon
atom at the benzylic site is prohibited on steric grounds.
Moreover, adoption of the conformation for proper hyper-
conjugation with the alkene, leading to the required increase in
the latterꢀs p-Lewis acidity, is inhibited due to allylic strain; see:
L. Dang, H. Zhao, Z. Lin, T. B. Marder, Organometallics 2007,
26, 2824 – 2832.
Keywords: boron · copper · enantioselective catalysis ·
enantioselective hydroboration · N-heterocyclic carbenes
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À
À
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Supporting Information for details.
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À
[18] For example, with NHC Cu complexes derived from 7 and 8,
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[20] For example, reaction of exocyclic alkene 16 with complex 8
under the conditions shown in Scheme 4 proceeds to 94%
conversion, affording 17 in 65% yield and e.r. = 90:10.
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