Site- and enantioselective formation of allene-bearing tertiary or quaternary carbon stereogenic centers through NHC-Cu-catalyzed allylic substitution

Article abstract of DOI:10.1021/ja211269w

Catalytic enantioselective allylic substitutions that result in addition of an allenyl group (<2% propargyl addition) and formation of tertiary or quaternary C-C bonds are described. Commercially available allenylboronic acid pinacol ester is used. Reacti

Full text of DOI:10.1021/ja211269w

Communication
pubs.acs.org/JACS
Site- and Enantioselective Formation of Allene-Bearing Tertiary or
Quaternary Carbon Stereogenic Centers through NHC−Cu-Catalyzed
Allylic Substitution
Byunghyuck Jung and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
allenylboron 1 proceed with exclusive addition of an allenyl unit
ABSTRACT: Catalytic enantioselective allylic substitutions
that result in addition of an allenyl group (<2% propargyl addi-
tion) and formation of tertiary or quaternary C−C bonds are
described. Commercially available allenylboronic acid pinacol
ester is used. Reactions are promoted by a 5.0−10 mol %
loading of sulfonate-bearing chiral bidentate N-heterocyclic
carbene (NHC) complexes of copper, which exhibit the
unique ability to furnish chiral products arising from the SN2′
mode of addition. Allenyl-containing products are generated
in up to 95% yield, >98% SN2′ selectivity, and 99:1 enan-
tiomeric ratio (er). Site-selective NHC−Cu-catalyzed hydro-
boration of enantiomerically enriched allenes and conversion
to the corresponding β-vinyl ketones demonstrates the
method's utility.
(<2% propargyl addition). Transformations are performed with
10 mol % of sulfonate-bearing chiral bidentate NHC−Cu com-
plexes, which exhibit the unique ability to promote site-selective
addition of an allenyl group (77% to >98% SN2′); the desired
products are generated in 63−95% yield and 90.5:9.5−99:1
enantiomeric ratio (er).
The design of an efficient EAS with a boron-based reagent12
raises a number of questions that are distinct from those
pertaining to reactions with organometallics (e.g., a vinylmetal
or an allenylmetal). One issue relates to the significance of
Lewis acidic metal salts. For example, our studies indicate
that in Cu-catalyzed allylic substitutions of trisubstituted
allylic phosphates,7c the equatorial Lewis basic sulfonate oxygen
can be involved in a metal chelate with the phosphate unit
(I, Scheme 2);5 the reactivity might be accordingly enhanced,
llenes are of significant utility in chemical synthesis.1
AEfficient protocols for preparing enantiomerically enriched
allene-containing molecules can therefore be of substantial
value; such procedures, however, are uncommon.2 We have
developed methods for enantioselective allylic substitution
(EAS) reactions,3 through which alkylmetals (i.e., Zn ,4 Mg ,5
or Al alkyls6) or vinyl-,7 aryl-, heteroaryl-,8 and alkynylalumi-
nums9 can be utilized to generate tertiary or quaternary carbon
stereogenic centers.10 We recently set out to explore whether
the chiral NHC−Cu complexes11 used to promote the
aforementioned reactions with organometallic reagents4−8 can
catalyze additions with the commercially available and air-stable
allenylboronic acid pinacol ester 1 (Scheme 1). We judged that
Scheme 2. Reaction Modes with Organometallic Reagents
allowing reactions to be performed at lower temperatures
(e.g., −50 °C), leading to an improvement in enantioselectivity.
Although in I and II, the bound substrate is orientated such
that there is proper alignment of the Cu−R σ bond with the
LUMO of the allylic phosphate, Lewis acid activation in I
together with unfavorable steric interactions in II result in the
former delivering the major isomer. Lewis acidic metal activa-
tion and organization is absent with an organoboron.
a
Scheme 1.
The second problem is that the allenylcuprate13
(cf. complexes in Scheme 2) might not be efficiently generated
with a substantially less nucleophilic organoboron (vs an organo-
metallic). We surmised that the presence of a metal alkoxide, such
as NaOMe,14 should allow the NHC−Cu−allene to be formed by
transmetalation via the allenylboronate (eq 1).15
a
B(pin) = pinacolatoboron.
the boron-based reagent would likely offer a more practical
and functional group-tolerant alternative to a corresponding
organometallic entity. Herein, we demonstrate that reactions of
allylic phosphates bearing a di- or a trisubstituted alkene with
Received: December 1, 2011
Published: January 3, 2012
© 2012 American Chemical Society
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Communication
Scheme 3.
The third potential complication is whether C−C bond
formation can occur selectively at the C3 position (pro-
pargyl addition) or C1 position (allenyl addition; cf. cuprate in
eq 1).16 Such issues did not concern the previously reported
reactions with vinylmetals.7 In this connection, during recent
studies regarding allyl additions to imines,17 we established that
the corresponding NHC−Cu−allyls collapse readily to the
derived π-allyl complexes, resulting in a nonselective mode of
reaction at the two termini.
4a, bearing a 3,5-di-tert-butylphenyl group (Table 1, entry 4),
promoted the formation of 6a efficiently and with 83:17 er. As
implied by the proposed model, the S isomer is generated
predominantly with 4a (vs 74% R with 3b; entry 3). With the
larger triisopropylphenyl groups at C3 and C5 (4b), the
enantioselectivity improved to 95.5:4.5 er (entry 5), presum-
ably since III was further disfavored.
Additional studies led us to discover that high SN2′ selectivity
is a unique attribute of sulfonate-bearing NHC−Cu catalysts. In
strong contrast to EAS with sulfonate-containing imidazolinium
salts 2−4 (Table 2), reactions with monodentate salts 7 and 8
With 5a serving as the substrate, we first examined the ability
of the NHC−Cu complex derived from sulfonate 2 to promote
the desired addition. As the data in entry 1 of Table 1 illustrate,
a
Table 1. Evaluation of Chiral NHC Complexes
a
Table 2. Control of Site Selectivity
b
b
c
d
entry
imide salt
conv (%)
SN2′:SN2
er ; config.
1
2
3
4
5
2
67
82
>98:2
90:10
>98:2
98:2
34:66; R
45:55; R
26:74; R
83:17; S
b
e
b
c
d
entry
imide salt
conv(%); yield (%)
SN2′:SN2
er ; config.
3a
3b
4a
4b
f
1
2
3
4
7
8
79; 68
74; 68
71; 65
<2:>98
<2:>98
5:95
n.a.
83
f
n.a.
92
9
36:64; R
>98
96:4
95.5:4.5; S
f
a
b
10
76; 66
<2:>98
n.a.
f
Reactions were performed under N2. Determined by analysis of
400 MHz 1H NMR spectra of unpurified mixtures and based on
e
a−dSee footnotes a−d of Table 1. Yield of purified product. n.a. = not
c
consumption of the substrate. Determined by GLC analysis.
Configuration of the major enantiomer; see the SI for details.
applicable.
d
and the bidentate variants 9 and 10 delivered achiral 11
with exceptional but opposite sense of site selectivity (≥95%
SN2). Complexes derived from bidentate sulfonate complexes
(cf. Table 1) favor SN2′ addition likely because of the stronger
(vs allenyl−Cu) association of the more electron-rich cuprates
with the alkene of the substrate (more appreciable Cu→π*
back-bonding). Allenyl−Cu complexes derived from mono-
dentate 7 or 8 are probably more prone (vs cuprate) to displace
the phosphate directly (SN2),19 a process that could involve
chelation of the more Lewis acidic and less hindered Cu center
(vs a cuprate) with the Lewis basic phosphate.20 Moreover, the
alkoxy−Cu or phenoxy−Cu bonds in complexes derived from
9 and 10 can undergo cleavage,12c yielding a monodentate
NHC−Cu−allene.20 Such intramolecular transmetalation is less
likely through the poorly Lewis basic oxygen of a sulfonate
ligand.21 The ability to preserve their cuprate character appears
to be another special attribute of sulfonate-bearing NHC−Cu
complexes, translating into a unique preference for SN2′
selectivity.
the reaction proceeded with complete group- and site selectivity
(<2% propargyl18 and <2% SN2 addition); <2% conversion was
observed without the Cu salt. The enantioselectivity was low,
however (34:66 er); presumably, in the absence of a metal
chelate between the catalyst and substrate and without a third
alkene substituent, reaction via complexes otherwise repre-
sented as I and II (Scheme 2) become competitive. Among the
catalysts probed subsequently, the findings related to 3a and 3b
were particularly informative (Table 1, entries 2 and 3).
We realized that the presence of a t-Bu at C5 of the NAr moiety
leads to a more favorable formation of (R)-6a, likely by dis-
favoring IV versus III (Scheme 3). Follow-up examination of
molecular models suggested that substitution at C3 and C5 of
the NAr can exert a significant effect on the association of the
alkene substrate with the NHC−Cu complex. We also noted
that a group at C3 blocks substrate coordination more effec-
tively (see III in Scheme 3) relative to the ability of a C5
substituent to impede the same in IV; we attributed this partly
to the lack of the methyls at C2 and C6 (cf. I and II, Scheme 2)
allowing the NAr to be oriented such that the group at C3
more effectively hinders substrate approach in III. Such con-
siderations led us to discover that the Cu complex derived from
A range of aryl-substituted allylic phosphates can be used to
generate allene-substituted tertiary C−C bonds in 64−92% yield,
77% to >98% SN2′ selectivity, and 95:5−99:1 er (Table 3).
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a
a
Table 3. Additions to Aryl Containing Substrates
Table 4. Additions to Trisubstituted Alkenes
b
temp (°C); conv (%);
b
c
b
d
c
b
d
entry
Ar
conv (%); yield (%)
SN2′:SN2
er
entry
G
time (h)
yield (%) SN2′:SN2
er
1
2
Ph, 5a
>98; 79
>98; 79
>98; 80
>98; 67
>98; 68
>98; 79
>98; 92
>98; 65
>98; 71
>98; 88
>98; 64
96:4
94:6
95.5:4.5
96:4
1
2
3
4
5
6
Ph, 15a
−30; 48
22; 24
89; 74
>98; 79
>98;83
82; 72
>98:2
91:9
93.5:6.5
98:2
o-FC6H4, 5b
o-BrC6H4, 15b
o-MeOC6H4, 15c
m-BrC6H4, 15d
p-ClC6H4, 15e
Cy, 15f
3
o-BrC6H4, 5c
o-CF3C6H4, 5d
o-MeC6H4, 5e
o-MeOC6H4, 5f
m-BrC6H4, 5g
m-CF3C6H4, 5h
m-MeC6H4, 5i
2-naphthyl, 5j
p-ClC6H4, 5k
p-O2NC6H4, 5l
88:12
77:23
>98:2
>98:2
97:3
96:4
22; 24
>98:2
>98:2
>98:2
>98:2
95.5:4.5
90.5:9.5
91:9
4
96:4
−30; 48
−30; 48
−30; 48
5
95:5
85; 77
6
96.5:3.5
98.5:1.5
98:2
>98; 72
94:6
7
a−dSee footnotes a−d of Table 3.
8
91:9
9
>98:2
98:2
97:3
vs −30 °C for Table 4, entries 1 and 4−6); otherwise <5%
conversion was observed after 24 h. Unlike the reactions of
disubstituted allylic phosphates, when 4b was employed to prepare
the Cu-based catalyst, low enantioselectivity was observed
(33:67 er; 94% SN2′).23 When imidazolinium salt 2 was used,
16a was formed in 93.5:6.5 er (Table 4, entry 1). It is plausible
that the alkene’s methyl substituent induces an unfavorable
steric interaction with the catalyst’s NAr unit in the complex
corresponding to IV (Scheme 3), rendering it a less favored
mode of reaction. Similar repulsive forces are present in II (G =
Me) but not in I (Scheme 2), which accounts for the observed
level and sense of enantioselectivity when the NHC−Cu
complex derived from 2 served as the catalyst [93.5% (R)-16a
vs 67% (S)-16a with 4b]. When the reactions were performed
at reduced temperatures to improve the enantioselectivity, the
reactivity suffered (e.g., 89% conv. to 16a in 48 h at −30 °C),
which might be partly due to the absence of the activating effect
of a Lewis acidic metal salt (see Scheme 2).
10
11
12
99:1
93:7
96:4
>98; 69
85:15
97:3
a
b
Reactions were performed under N2. Determined by analysis of 400
MHz H NMR spectra of unpurified mixtures; conversion refers to
consumption of the substrate. Yields of isolated and purified allenyl
addition products. Determined by GLC analysis; see the SI for
1
c
d
details.
Substrates with an electron-withdrawing (entries 2−4, 7, 8, 11,
and 12) or an electron-donating (entries 5, 6, and 9) group as
well as those that carry a sterically demanding aryl unit (entries
5 and 10) undergo EAS to furnish the desired products site-
and enantioselectively. Analysis of the data in Table 3 indicates
that an electron-deficient substituent at the more influential
ortho or para position within a substrate can lead to diminution
of the site-selectivity (up to 23% SN2 product; entries 1 and 5 vs
entries 3, 4, 8, and 12).22
Two additional points merit a brief discussion: (1)
Preliminary studies indicate that lower catalyst loadings can
be used. For example, 6e (Table 3, entry 5) and 16c (Table 4,
entry 3) were obtained in 70 and 78% yield (>98 and 95%
conv.), 98% SN2′ selectivity, and 95:5 er (both cases) with 5.0
mol % 4b and 2, respectively.
Allylic phosphates that contain an alkyl group (including
a sterically demanding t-Bu) or a silyl group can be used in
highly site- and enantioselective allene additions; the examples
presented in Scheme 4 are illustrative. Similar to the reactions
a
Scheme 4.
(2) The availability of EAS products containing an allenyl-
substituted stereogenic center offers new opportunities to
synthesize a variety of useful enantiomerically enriched organic
molecules that cannot be easily accessed by an alternative
protocol; representative cases are shown in Scheme 5.
NHC−Cu-catalyzed hydroboration of allenyl alkene 6f, based
on the conditions developed recently for transformations of aryl
alkenes and terminal alkynes,24 resulted in the formation of 17
and 18 in 84% yield with 9:1 selectivity. Oxidation of the
mixture of 17 and 18 furnished enantiomerically enriched (96:4
er; Scheme 5) methyl ketone 19 in 86% yield (i.e., 70% overall
yield from 6f). Similarly, 21 was obtained in 78% overall yield
(through a 4:1 mixture of vinylboronates); the aldehyde
derived from ozonolysis of the terminal alkene in 21 was used
to synthesize α-cuparenone (22).25 The high chemoselectivity
in the catalytic hydroborations in Scheme 5 are noteworthy;
when 6f or 20 was treated with a common hydroborating agent,
such as 9-BBN, a range of products was generated from
reaction at the alkene and allene sites. Moreover, the two-step
procedure constitutes a method for the enantioselective
formation of β-vinyl carbonyls. The latter is a significant
feature of the present approach, since protocols that allow
a
Reactions were performed under the conditions in Table 2. The
relatively low yields of 13a and 13c were due to volatility.
shown in Table 3, none of the alternative propargyl addition
products were detected. Unlike the reactions of aryl-substituted
substrates, there was complete SN2′ selectivity in all instances.
The catalytic EAS can be performed with trisubstituted allylic
phosphates to generate all-carbon quaternary stereogenic
centers in up to 83% yield, >98% SN2′ selectivity, and 98:2 er
(Table 4).10 Reactions with substrates carrying an ortho
substituent must be performed at 22 °C (Table 4, entries 2−3,
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Veldhuizen, J. J.; Campbell, J. E.; Giudici, R. E.; Hoveyda, A. H. J. Am.
Chem. Soc. 2005, 127, 6877. (e) Kacprzynski, M. A.; May, T. L.;
Kazane, S. A.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 4554.
(5) Lee, Y.; Li, B.; Hoveyda, A. H. J. Am. Chem. Soc. 2009, 131,
11625.
Scheme 5. Catalytic Hydroboration of Allenes
(6) Gillingham, D. G.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2007,
46, 3860.
(7) (a) Lee, Y.; Akiyama, K.; Gillingham, D. G.; Brown, M. K.;
Hoveyda, A. H. J. Am. Chem. Soc. 2008, 130, 446. (b) Akiyama, K.;
Gao, F.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2010, 49, 419. (c) Gao,
F.; McGrath, K. P.; Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2010,
132, 14315.
(8) (a) Gao, F.; Lee, Y.; Mandai, K.; Hoveyda, A. H. Angew. Chem.,
Int. Ed. 2010, 49, 8370. (b) Reference 4e. For related studies, see:
(c) Selim, K. B.; Yamada, K.-i.; Tomioka, K. Chem. Commun. 2008,
5140. (d) Selim, K. B.; Matsumoto, Y.; Yamada, K.-i.; Tomioka, K.
Angew. Chem., Int. Ed. 2009, 48, 8733. (e) Polet, D.; Rathgeb, X.;
Falciola, C. A.; Langlois, J.-B.; Hajjaji, S. E.; Alexakis, A. Chem.Eur. J.
2009, 15, 1205.
(9) Dabrowski, J. A.; Gao, F.; Hoveyda, A. H. J. Am. Chem. Soc. 2011,
133, 4778.
(10) Das, J. P.; Marek, I. Chem. Commun. 2011, 47, 4593.
(11) Brown, M. K.; May, T. L.; Baxter, C. A.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2007, 46, 1097.
(12) For Cu-catalyzed allylic substitutions with arylboronates, see:
(a) Ohmiya, H.; Yokokawa, N.; Sawamura, M. Org. Lett. 2010, 12,
2438. (b) Whittaker, A. M.; Rucker, R. P.; Lalic, G. Org. Lett. 2010, 12,
3216. For an enantioselective version with the more reactive
arylboronic acid neopentyl glycol esters, see: (c) Shintani, R.; Takatsu,
K.; Takeda, M.; Hayashi, T. Angew. Chem., Int. Ed. 2011, 50, 8656.
access to such entities by enantioselective conjugate addition of
an unsubstituted vinyl unit to an enone or of an aryl or alkyl
group to the corresponding dienone are scarce, particularly in
cases where quaternary carbons are involved (e.g., 20).26
Catalytic EAS processes with enol-based reagents also remain
undisclosed.
ASSOCIATED CONTENT
* Supporting Information
■
S
́
(13) For a study of allenylcuprates, see: Vrancken, E.; Gerard, H.;
Linder, D.; Ouizem, S.; Alouane, N.; Roubineau, E.; Bentayeb, K.;
Marrot, J.; Mangeney, P. J. Am. Chem. Soc. 2011, 133, 10790.
(14) Ohishi, T.; Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed. 2008,
47, 5792.
Experimental procedures and spectral and analytical data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) It is equally feasible that the allenyl-NHC−cuprate is generated
through σ-bond metathesis involving a methoxycuprate derived from
reaction of the bidentate Cu complex and NaOMe.
(16) For example, see: Fandrick, D. R.; Saha, J.; Fandrick, K. R.; Sanyal,
S.; Ogikubo, J.; Lee, H.; Roschangar, F.; Song, J. J.; Senanayake, C. H.
Org. Lett. 2011, 13, 5616.
(17) Vieira, E. M.; Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc.
2011, 133, 3332.
(18) The absence of the propargyl addition can be attributed to a
Cu(III) intermediate and reductive elimination.
(19) Yoshikai, N.; Nakamura, E. Chem. Rev. 2011, DOI: 10.1021/
cr200241f.
AUTHOR INFORMATION
Corresponding Author
amir.hoveyda@bc.edu
■
ACKNOWLEDGMENTS
■
We thank Professor E. Nakamura for an advanced copy of a
review article (ref 19), J. L. Carr, J. A. Dabrowski and F. Gao for
helpful discussions, and Frontier Scientific for generous gifts of
1. Financial support was provided by the NIH (GM-47480)
and the NSF (CHE-1111074).
(20) See the Supporting Information (SI) for more details.
(21) In support of the proposal that a metal phenoxide (but not a
metal sulfonate) is sufficiently Lewis basic to promote allene transfer
from boron to Cu (cf. eq 1), we found that NaOPh (instead of
NaOMe) can be used as the base in the EAS process, affording 11.
When NaO2SOPh was used, <2% conversion was observed.
(22) For an analysis regarding the site selectivity patterns as a
function of the electronic attributes of the substrate, see the SI.
(23) See the SI for the efficiency and selectivity observed for reaction
of 15a with different NHC−Cu catalysts.
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