Bidentate NHC-based chiral ligands for efficient Cu-catalyzed enantioselective allylic alkylations: Structure and activity of an air-stable chiral Cu complex

Article abstract of DOI:10.1021/ja046245j

Cu-catalyzed addition of alkylzinc reagents to a range of allylic phosphates is promoted efficiently and with high enantioselectivity to afford tertiary as well as quaternary carbon centers (up to 98% ee). Reactions proceed to completion with 0.5-5 mol % catalyst loading and are best promoted by commercially available CuCl2·₂H₂O. The X-ray structure of the chiral NHC-Ag(I) complex used in the study as well as that of a catalytically active NHC-Cu(II) complex are also reported; both complexes are air-stable and are formed in ≥95% isolated yield. The isolated Cu complex, which can be handled in air, is catalytically active. The present report provides the first precedent for efficient Cu-catalyzed allylic alkylations with chiral NHC ligands. Copyright

Full text of DOI:10.1021/ja046245j

Published on Web 08/17/2004
Bidentate NHC-Based Chiral Ligands for Efficient Cu-Catalyzed
Enantioselective Allylic Alkylations: Structure and Activity of an Air-Stable
Chiral Cu Complex
Andrew O. Larsen, Wenhao Leu, Christina Nieto Oberhuber, John E. Campbell, and
Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received June 24, 2004; E-mail: amir.hoveyda@bc.edu
N-Heterocyclic carbenes (NHCs) readily promote a variety of
organic transformations. Accordingly, development of chiral NHCs
Chart 1. Chiral Bidentate NHC Ligands
1
for use in enantioselective synthesis has emerged as a critical
objective. To date, however, there are only a few reports regarding
NHC-metal complexes that have been effectively used in asym-
2
metric catalysis. One instance is a disclosure from these laboratories
regarding asymmetric ring-opening/cross metathesis reactions that
are catalyzed by chiral Ru complexes shown below (up to 96%
3
ee). In light of the above findings, we initiated a program to prepare
additional members of this new class of chiral NHCs and examine
their ability to effect other useful enantioselective transformations.
Table 1. Initial Screening of Various Chiral NHC Ligands
entry
NHC ligand mol %a
T (°C); time (h)
conv (%)b
S
N
2′:S
N
2b
ee (%)c
1
2
3
4
5
6
7
8
1a; 10
1a; 1
1a; 1
1b; 10
1b; 1
2; 10
3; 10
4; 10
-15; 1
>98
>98
<2
87
<2
20
>98:2
>98:2
-
82
65
nd
80
-
21
64
52
-15; 1
-78; 1
Herein, we disclose the synthesis, structure, and catalytic activity
of an optically pure NHC-Ag(I) complex that can be used to effect
Cu-catalyzed enantioselective formation of tertiary and quaternary
carbon centers in up to 97% ee. Synthesis and structure of an
isolable, air-stable, and catalytically active chiral NHC-Cu(II)
complex are reported as well. Data are presented indicating that
the bidentate nature of the NHC ligand is required for effective
asymmetric C-C bond formation. The NHC-promoted alkylations
can be carried out under less stringent conditions than related former
methods;4 levels of regio- and enantioselectivity, as well as effi-
-15; 36
-78; 36
-15; 10
-15; 24
-15; 24
>98:2
-
>98:2
>98:2
>98:2
18
70
a
5
mol % (10 mol % ligand) and 0.5 mol % (1 mol % ligand)
CuOTf)2‚C6H6 were used. b Determined by H NMR analysis. See
Supporting Information for details.
1
c
(
6
and Cu salts. We obtained Ag(I) complex of 7 as an air-stable
tan-colored solid in 97% yield by treatment of 1a with Ag O (22
2
,5
4
ciency and substrate generality, are superior to previous methods.
We initiated our investigations by examining the ability of chiral
NHC ligands 1-4 (Chart 1) to promote Cu-catalyzed asymmetric
°C). As indicated by the X-ray crystal structure (Scheme 1), 7 exists
as a dimer. NOE experiments indicate that the Ag complex remains
largely as a dimer in solution; a representative nOe is shown in
Scheme 1. It should be noted that, as expected, such enhancements
are not observed with the monomeric Ru complexes shown above.
When complex 7 (5 mol %) is used to promote Cu-catalyzed
alkylations. Addition of Et
6
2
Zn to phosphate 5 (Table 1) to afford
served as the representative transformation. We selected (CuOTf)
6 6
H for comparison with related protocols involving amino acid-
2
‚
C
4f
based ligands.
alkylation of allylic phosphate 5 with Et
formed in 84% ee within 15 min (>98% S
2
Zn (entry 1, Table 2), 6 is
2′; <2% conv without
As shown in entry 1 of Table 1, alkylation of 5 in the presence
of 10 mol % 1a affords 6 in 82% ee. When 1 mol % 1a is used,
reaction proceeds to >98% conv in 1 h but affords the desired
product in 65% ee (entry 2); there is <2% conv at -78 °C (entry
N
Cu salt). Even 0.25 mol % 7 is sufficient for >98% conv; unlike
1a (entry 2, Table 1), enantioselectivity does not suffer with lower
catalyst loading (84% ee). With 0.5 mol % 7 at -78 °C (entry 2),
conditions that result in <2% conv with 1a (cf. entry 3, Table 1),
>98% conv is observed in 1 h to afford 6 in 89% ee. The data in
entries 3-5 (Table 2) illustrate that the Ag(I) complexes of 2 and
3 (Chart 1) are more effective than their parent ligands, but alkyl-
ations are significantly less effective and selective than with 7.
We have examined the utility of Ag(I) complex 7 in promoting
Cu-catalyzed asymmetric alkylations of a wide range of allylic
phosphates (Table 3). Noteworthy features of these findings are:
(i) Catalyst loading is significantly lower than required with amino
acid-based ligands (2 vs 10 mol %). (ii) Enantioselective additions
can be catalyzed with air-stable, moisture-insensitive, commercially
3
). As the data in entries 4 and 5 indicate, electron-deficient 1b is
less effective than NHC ligand 1a (36 h needed for 87% conv at
15 °C). The significantly lower activity of methyl ether 2 (entry
) indicates that formation of a covalent O-metal bond (vs dative
MeO f metal) is critical for effective catalysis. Results in entries
2 6 3
and 8 show that if the mesityl unit is replaced by a 2,6-(i-Pr) C H
-
6
7
or an adamantyl group, conversion and enantioselectivity suffer
significantly.
To enhance efficiency and selectivity, we prepared Ag(I) complex
of 1a, a decision that was based on disclosures pointing to facile
exchange between Ag-based complexes of heterocyclic carbenes
11130
9
J. AM. CHEM. SOC. 2004, 126, 11130-11131
10.1021/ja046245j CCC: $27.50 © 2004 American Chemical Society

C O MMU N I C A T I O N S
Scheme 1. Synthesis and Structure of NHC‚Ag Complex 7
Scheme 2. Synthesis and X-ray Structure of NHC‚Cu(II) Complex
a
8
Table 2. Cu-Catalyzed Alkylations (5 f 6) with Chiral NHC‚Ag
a
Selected bond lengths (Å): Cu1-C1 ) 1.926(8), Cu1-O1 ) 1.986(6),
Complexes
Cu1-O2 ) 1.950(6), Cu2-C2 ) 1.964(8), Cu2-O1 ) 1.933(6), Cu2-O2 )
.975(6).
entry
NHC ligand mol %a
T (°C); time (h)
conv (%)b
S
N
2′:S
N
2b
ee (%)b
1
1
2
3
4
5
7; 5
7; 0.5
2‚Ag; 5
2‚Ag; 0.5
3‚Ag; 0.5
-15; 0.2
-15; 1
>98
>98
>98
29
>98:2
>98:2
>98:2
>98:2
>98:2
84
89
34
39
70
dimeric Cu complex 8 (X-ray, Scheme 2) was isolated as a dark
red solid in 95% yield. Importantly, 8 gives rise to enantioselective
alkylation: as shown in eq 1, treatment of the trisubstituted olefin
-15; 1
7
-78; 36
-15; 24
>98
2
in entry 4 of Table 3 with 0.5 mol % 8 and Et Zn affords the desired
product in 92% ee (48 h; 68% yield).
a,b
See corresponding footnotes for Table 1.
Table 3. Cu-Catalyzed Asymmetric Allylic Alkylationsa
In conclusion, the present study extends the utility of chiral NHC
ligands to highly enantioselective Cu-catalyzed allylic alkylations
with alkylzincs. Development of new chiral NHC ligands and
applications to other catalytic asymmetric methods, as well as
mechanistic studies (e.g., monomeric vs dimeric active catalytic
complex) are in progress.
Acknowledgment. NIH (GM-47480) and NSF (CHE-0213009)
supported this research. A.O.L. and C.N.O. are grateful to the NIH
and the Spanish government for postdoctoral (GM-66510) and
visiting fellowships.
Supporting Information Available: Experimental procedures,
spectral, analytical data for reaction products, and X-ray data. This
material is available free of charge via the Internet at http://pubs.acs.org.
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J. AM. CHEM. SOC.
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