A readily available chiral Ag-based N-heterocyclic carbene complex for use in efficient and highly enantioselective Ru-catalyzed olefin metathesis and Cu-catalyzed allylic alkylation reactions

Article abstract of DOI:10.1021/ja050179j

A new chiral bidentate N-heterocyclic carbene (NHC) ligand has been designed and synthesized. The NHC ligand bears a chiral diamine backbone and an achiral biphenol group; upon metal complexation (derived from Ag(I), Ru(II), or Cu(II)), the diamine moiety

Full text of DOI:10.1021/ja050179j

Published on Web 04/13/2005
A Readily Available Chiral Ag-Based N-Heterocyclic Carbene
Complex for Use in Efficient and Highly Enantioselective
Ru-Catalyzed Olefin Metathesis and Cu-Catalyzed Allylic
Alkylation Reactions
Joshua J. Van Veldhuizen, John E. Campbell, Russell E. Giudici, and
Amir H. Hoveyda*
Contribution from the Department of Chemistry, Merkert Chemistry Center,
Boston College, Chestnut Hill, Massachusetts 02467
Received January 11, 2005; E-mail: amir.hoveyda@bc.edu
Abstract: A new chiral bidentate N-heterocyclic carbene (NHC) ligand has been designed and synthesized.
The NHC ligand bears a chiral diamine backbone and an achiral biphenol group; upon metal complexation
(derived from Ag(I), Ru(II), or Cu(II)), the diamine moiety induces >98% diastereoselectivity such that the
biaryl unit coordinates to the metal center to afford the desired complex as a single atropisomer. Because
the ligand does not require optically pure biaryl amino alcohols, its synthesis is significantly shorter and
simpler than the related first generation ligands bearing a chiral binaphthyl-based amino alcohol. The chiral
NHC ligand can be used in the preparation of highly effective Ru- and Cu-based complexes (prepared and
used in situ from the Ag(I) carbene) that promote enantioselective olefin metathesis and allylic alkylations
with scope that is improved from previously reported protocols. In many cases, transformations promoted
by the chiral NHC-based complexes proceed with higher enantioselectivity and reactivity than was observed
with previously reported complexes.
Scheme 1. First Generation Bidentate Ru- and Ag-NHC
Complexes
Introduction
The development of efficient and practical chiral ligands and
catalysts is one of the most critical research objectives in modern
organic synthesis.1 Investigations in these laboratories during
the past several years have been focused on the identification
of various classes of optically pure chiral ligands that promote
a range of enantioselective C-C bond forming reactions.2 One
area of investigation has resulted in the synthesis of chiral
bidentate N-heterocyclic carbene (NHC) ligands,3 which have
led to Ru-based chiral complexes 1,2c shown in Scheme 1. These
chiral metal carbenes are noteworthy partly due to their ability
to promote highly enantioselective ring-opening metathesis/
cross-metathesis (AROM/CM) reactions4 that cannot be effected
with chiral Mo-based complexes;2d olefin metathesis reactions
catalyzed by 1 can be performed under conditions that do not
require rigorous exclusion of air, in the absence of solvent or
without the need for purified solvents. We have also disclosed
the synthesis of air-stable dimeric Ag(I) complex 2 (Scheme
1),5 which, in the presence of various Cu salts, can be used to
initiate enantioselective allylic alkylations with alkylzinc re-
(3) For additional examples of chiral NHC ligands in metal-catalyzed asym-
metric catalysis, see: (a) Powell, M. T.; Hou, D.-R.; Perry, M. C.; Cui,
X.; Burgess, K. J. Am. Chem. Soc. 2001, 123, 8878-8879. (b) Ma, Y.;
Song, C.; Ma, C.; Sun, Z.; Chai, Q.; Andrus, M. B. Angew. Chem., Int.
Ed. 2003, 42, 5871-5874. (c) Bonnet, L. C.; Douthwaite, R. E.; Kariuki,
B. M.; Organometallics 2003, 22, 4187-4189. (d) Alexakis, A.; Winn, C.
L.; Guillen, F.; Pytkowicz, J.; Roland, S.; Mangeney, P. AdV. Synth. Catal.
2003, 345, 345-348. (e) Jensen, D. R.; Sigman, M. S. Org. Lett. 2003, 5,
63-65. (f) Gade, L. H.; Cesar, V.; Bellemin-Laponnaz, S. Angew. Chem.,
Int. Ed. 2004, 43, 1014-1017. (g) Bappert, E.; Helmchen, G. Synlett 2004,
1789-1793. (h) Arnold, P. L.; Rodden, M.; Davis, K. M.; Scarisbrick, A.
C.; Blake, A. J.; Wilson, C. Chem. Commun. 2004, 1612-1613. (i)
Tominaga, S.; Oi, Y.; Kato, T.; An, D. K.; Okamoto, S. Tetrahedron Lett.
2004, 45, 5585-5588. For brief overviews, see: (j) Enders, D.; Gielen, H.
J. Organomet. Chem. 2001, 617-618, 70-80. (k) Perry, M. C.; Burgess,
K. Tetrahedron: Asymmetry 2003, 14, 951-961.
(1) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
moto, H., Eds.; Springer: Berlin, Germany, 1999.
(2) For representative examples, see: (a) Cole, B. M.; Shimizu, K. D.; Krueger,
C. A.; Harrity, J. P.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1668-1671. (b) Krueger, C. A.; Kuntz, K. W.; Dzierba,
C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 1999, 121, 4284-4285. (c) Van Veldhuizen, J. J.; Garber,
S. B.; Kingsbury, J. S.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124,
4954-4955. (d) Schrock, R. R.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2003, 42, 4592-4633. (e) Josephsohn, N. S.; Snapper, M. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 2003, 125, 4018-4019. (f) Mampreian, D. M.;
Hoveyda, A. H. Org. Lett. 2004, 6, 2829-2832. (g) Hoveyda, A. H.; Hird,
A. W.; Kacprzynski, M. A. Chem. Commun. 2004, 1779-1785.
(4) (a) Reference 2c. (b) Van Veldhuizen, J. J.; Gillingham, D. G.; Garber, S.
B.; Kataoka, O.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 12502-
12508. (c) Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H.
J. Am. Chem. Soc. 2004, 126, 12288-12290.
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J. AM. CHEM. SOC. 2005, 127, 6877-6882
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A R T I C L E S
Van Veldhuizen et al.
agents with unprecedented levels of generality (in terms of both
substrate and alkylzincs) and enantioselectivity.6
pure binaphthyl-based amino alcohol, we decided to employ a
readily available optically pure chiral diamine backbone as the
source of chirality. Thus, we surmised that the asymmetric
diamine structure could allow us to employ an achiral biphenyl-
based amino alcohol: diastereoselectivity would be induced
once the transition metal is inserted within the structure of the
bidentate ligand.9,10
As a result of the promising developments mentioned above
in connection with Ru- and Cu-catalyzed transformations, and
because N-heterocyclic carbenes are effective in initiating a
range of organic transformations as ligands7 or catalysts,8 we
set out to design, synthesize, and develop a new generation of
the chiral bidentate NHCs that can be prepared more readily.
Specifically, a significant drawback regarding the general utility
of the first generation ligands (cf., Scheme 1) arises from the
level of efficiency and practicality with which the requisite
optically pure axially chiral amino alcohols are typically
prepared.4
Herein, we describe the synthesis, structure, and utility of a
significantly more easily accessible chiral bidentate NHC and
the utility of the corresponding Ag(I) complex in promoting
Ru-catalyzed asymmetric olefin metathesis and Cu-catalyzed
allylic alkylations. We also demonstrate that metal complexes
derived from the new bidentate NHC often provide higher
reactivity and enantioselectivity in comparison to the chiral
complexes depicted in Scheme 1.
Synthesis of Chiral NHC Ligand and the Derived Ag(I)
Complex. The above hypothesis was brought to fruition in the
manner illustrated in Scheme 2. Treatment of commercially
available optically pure diamine 311 with aryliodide 412 in the
presence of 5 mol % Pd(OAc)2 and rac-BINAP with NaOt-Bu
(toluene, 110 °C, 24 h) leads to the formation of secondary
arylamine 5.13 At this point, the reaction mixture is charged
with 2 equiv of mesityl bromide (for 12 h), leading to the
formation of the desired diamine 6 in 65% overall yield for the
two-step, one-vessel procedure. Conversion of the methyl ether
to the corresponding phenol, followed by treatment with HCl
and triethylorthoformate, results in the generation of optically
pure imidazolinium salt 7 in 45% overall yield. Subjection of 7
to Ag2O at reflux for 3 h in a 1:1 mixture of THF and C6H6
leads to facile generation of Ag(I) complex 8 in >98% isolated
yield as a single diastereomer (>98% de, as judged by 400 MHz
1H NMR analysis). Thus, the diamine chirality is readily
transferred to the biphenol moiety, such that metal complexation
proceeds with complete control of stereoselectivity. The dia-
stereomer that is formed exclusively is one where the chelating
phenol moiety points away from the proximal phenyl unit of
the chiral diamine backbone. The structural assignment for
complex 8 is supported by an X-ray crystal structure, illustrated
in Scheme 2 (details in the Supporting Information).
Results and Discussion
1. A Readily Available Chiral Imidazolinium Salt and Its
Derived Ag(I) Complex. Chiral Ligand Design Consider-
ations. To obviate the requirement for the use of an optically
(5) Larsen, A. O.; Leu, W.; Nieto Oberhuber, C.; Campbell, J. E.; Hoveyda,
A. H. J. Am. Chem. Soc. 2004, 126, 11130-11131.
(6) For representative reports regarding Cu-catalyzed allylic alkylations involv-
ing alkylmetal reagents, see: (a) Dubner, F.; Knochel, P. Angew. Chem.,
Int. Ed. 1999, 38, 379-381. (b) Borner, C.; Gimeno, J.; Gladiali, S.;
Goldsmith, P. J.; Ramazzotti, D.; Woodward, S. Chem. Commun. 2000,
2433-2444. (c) Meuzelaar, G. J.; Karlstrom, A. S. E.; van Klaveren, M.;
Persson, E. S. M.; del Villar, A.; van Koten, G.; Backvall, J.-E. Tetrahedron
2000, 56, 2895-2903. (d) Luchaco-Cullis, C. A.; Mizutani, H.; Murphy,
K. E.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2001, 40, 1456-1460. (e)
Malda, H.; van Zijl, A. W.; Arnold, L. A.; Feringa, B. L. Org. Lett. 2001,
3, 1169-1171. (f) Karlstrom, A. S. E.; Huerta, F. F.; Meuzelaar, G. J.;
Backvall, J.-E. Synlett 2001, 923-926. (g) Alexakis, A.; Malan, C.; Lea,
L.; Benhaim, C.; Fournioux, X. Synlett 2001, 927-930. (h) Alexakis, A.;
Croset, K. Org. Lett. 2002, 4, 4147-4149. (i) Ongeri, S.; Piarulli, U.; Roux,
M.; Monti, C.; Gennari, C. HelV. Chim. Acta 2002, 85, 3388-3399. (j)
Murphy, K. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4690-
4691. (k) Shi, W.-J.; Wang, L.-X.; Fu, Y.; Zhu, S.-F.; Zhou, Q.-L.
Tetrahedron: Asymmetry 2003, 14, 3867-3872. (l) Tissot-Croset, K.; Polet,
D.; Alexakis, A. Angew. Chem., Int. Ed. 2004, 43, 2426-2428. (m)
Kacprzynski, M. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 10676-
10681. (n) Murphy, K. E.; Hoveyda, A. H. Org. Lett. 2005, 7, in press.
(7) For representative recent examples involving NHC ligands in metal-
catalyzed reactions, see: (a) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.;
Lee, H. M.; Yang, C.; Nolan, S. P. J. Organomet. Chem. 2002, 653, 69-
82. (b) Desmarets, C.; Schneider, R.; Fort, Y. J. Org. Chem. 2002, 67,
3029-3036. (c) Poyatos, M.; Uriz, P.; Mata, J. A.; Claver, C.; Fernandez,
E.; Peris, E. Organometallics 2003, 22, 440-444. (d) Viciu, M. S.; Kelly,
R. A.; Stevens, E. D.; Naud, F.; Studer, M.; Nolan, S. P. Org. Lett. 2003,
5, 1479-1482. (e) Pytkowicz, J.; Roland, S.; Mangeney, P.; Meyer, G.;
Jutand, A. J. Organomet. Chem. 2003, 678, 166-179. (f) Gibson, S. E.;
Johnstone, C.; Loch, J. A.; Steed, J. W.; Stevenazzi, A. Organometallics
2003, 22, 5374-5377. (g) Park, K. H.; Kim, S. Y.; Son, S. U.; Chung, Y.
K. Eur. J. Org. Chem. 2003, 4341-4345. (h) Mahandru, G. M.; Liu, G.;
Montgomery, J. J. Am. Chem. Soc. 2004, 126, 3698-3699. (i) Lebel, H.;
Janes, M. K.; Charette, A. B.; Nolan, S. P. J. Am. Chem. Soc. 2004, 126,
5046-5047. (j) Kaur, H.; Kauer Zinn, F.; Stevens, E. D.; Nolan, S. P.
Organometallics 2004, 23, 1157-1160. (k) Hanasaka, F.; Fujita, K.-i.;
Yamaguchi, R. Organometallics 2004, 23, 1490-1492. (l) Navarro, O.;
Kaur, H.; Mahjoor, P.; Nolan, S. P. J. Org. Chem. 2004, 69, 3173-3180.
(m) Palencia, H.; Garcia-Jiminez, F.; Takacs, J. M. Tetrahedron Lett. 2004,
45, 3849-3853.
2. Chiral Ru-Based Complexes Bearing Readily Available
Bidentate NHC Ligands as Efficient Catalysts for Enantio-
selective Olefin Metathesis. Synthesis of Chiral Ru-Chloride
and Iodide Complexes. As illustrated in Scheme 3, treatment
of chiral Ag(I) complex 8 with 1 equiv of achiral Ru complex
9 at 70 °C in THF leads to the formation of chiral Ru-chloride
10 in 42% isolated yield after silica gel chromatography. The
low isolated yield is due to partial decomposition of complex
(9) For application of a related strategy, see: Seiders, T. J.; Ward, D. W.;
Grubbs, R. H. Org. Lett. 2001, 3, 3225-3228.
(10) A chiral ligand may induce asymmetry in the coordination of a second
(and achiral in the absence of metal coordination) ligand, see: (a) Ringwald,
M.; Sturmer, R.; Brintzinger, H. H. J. Am. Chem. Soc. 1999, 121, 1524-
1527. (b) Mikami, K.; Korenaga, T.; Terada, M.; Ohkuma, T.; Pham, T.;
Noyori, R. Angew. Chem., Int. Ed. 1999, 38, 495-497. (c) Becker, J. J.;
White, P. S.; Gagne, M. R. J. Am. Chem. Soc. 2001, 123, 9478-9479. (d)
Mikami, K.; Aikawa, K. Org. Lett. 2001, 3, 243-245. (e) Mikami, K.;
Aikawa, K.; Yusa, Y.; Hatano, M. Org. Lett. 2002, 4, 91-94. (f) Mikami,
K.; Aikawa, K.; Yusa, Y. Org. Lett. 2002, 4, 95-97. (g) Mikami, K.;
Aikawa, K.; Org. Lett. 2002, 4, 99-101. (h) Aikawa, K.; Mikami, K.
Angew. Chem., Int. Ed. 2003, 42, 5458-5461. (i) Aikawa, K.; Mikami, K.
Angew. Chem., Int. Ed. 2003, 42, 5455-5458. (j) Pelz, K. A.; White, P.
S.; Gagne, M. R. Organometallics 2004, 23, 3210-3217.
(11) Diamine 3 can be prepared in the optically pure form (both antipodes) in
multigram quantities in ∼20% overall yield (five steps from benzaldehydes).
Procedures leading to the preparation of optically pure diamine 3 were
obtained from: (a) Kupfer, R.; Brinker, U. H. J. Org. Chem. 1996, 61,
4185-4186. (b) Williams, O. F.; Bailar, J. C. J. Am. Chem. Soc. 1959, 81,
4464-4469. (c) Corey, E. J.; Kuhnle, F. N. M. Tetrahedron Lett. 1997,
38, 8631-8634. (d) Pikul, S.; Corey, E. J. Org. Synth. 1993, 71, 22-29.
(12) Multigram quantities of aryl iodide 4 can be prepared in four steps, based
on modified published procedures, in 66% overall yield. See: (a) Collette,
J.; McGreer, D.; Crawford, R.; Chubb, F.; Sandin, R. B. J. Am. Chem.
Soc. 1956, 78, 3819-3820. (b) Fuson, R. C.; Albright, R. L. J. Am. Chem.
Soc. 1959, 81, 487-490.
(13) (a) Beletskaya, I. P.; Bessmertnykh, A. G.; Guillard, R. Tetrahedron Lett.
1997, 38, 2287-2290. (b) Canabal-Duvillard, I.; Mangeney, P. Tetrahedron
Lett. 1999, 40, 3877-3880. (c) Beletskaya, I. P.; Bessmertnykh, A. G.;
Guillard, R. Synlett 1999, 1459-1461. (d) Frost, C. G.; Mendonca, P.
Tetrahedron: Asymmetry 1999, 10, 1831-1834.
(8) For representative recent examples involving use of NHCs as chiral
catalysts, see: (a) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126,
8876-8877. (b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc.
2004, 126, 14370-14371. (c) Burstein, C.; Glorius, F. Angew. Chem., Int.
Ed. 2004, 43, 6205-6208. (d) Suzuki, Y.; Yamaguchi, K.; Muramatsu,
K.; Sato, M. Chem. Commun. 2004, 2770-2771. For related brief
overviews, see: (e) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem., Int.
Ed. 2004, 43, 5130-5135. (f) Enders, D.; Balensiefer, T. Acc. Chem. Res.
2004, 37, 534-541.
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Chiral Ag-Based N-Heterocyclic Carbene Complex
A R T I C L E S
Scheme 2. Synthesis of Chiral NHC Ligand 7 and the Derived Ag(I) Complex 8
Scheme 3. Synthesis of Chiral Ru-Based Complexes 10 and 11
Our previous studies show that chiral Ru-iodide 1c is more
stable than the corresponding chlorides 1a,b. Accordingly,
when4c the unpurified mixture derived from treatment of Ag(I)
complex 8 and Ru complex 9 is directly (without isolation of
sensitive 10) subjected to 10 equiv of NaI in THF at 70 °C for
1 h, chiral iodide complex 11 is isolated in 50% yield. Unlike
chloride 10, iodide complex 11 is stable to silica gel chroma-
tography in air.
Catalytic Activity of Ru-Based Chiral Complexes 10 and
11. As the data summarized in Table 1 illustrate, Ru carbene
10 is a generally effective chiral catalyst for olefin metathesis
(data for chiral complex 1b and 1c are provided for comparison).
Reactions promoted by complex 10 deliver similar (entry 3) or
higher (entries 1 and 4) enantioselectivity as compared to the
first generation Ru chloride 1b; reactions are typically complete
within a shorter period of time with 10. It is important to note
that the relatively sensitive (see above) chiral Ru complex 10
can be prepared and used in situ (without isolation) to pro-
mote efficient enantioselective olefin metathesis. Control ex-
periments generally indicate that the catalyst prepared and
used in situ14 affords reactivity and enantioselectivity similar
to that obtained with the isolated complex. As an example,
when isolated and purified Ru chloride 10 is employed in the
AROM/CM reaction in entry 1 of Table 1, anhydride 13 is
10 during chromatography; to minimize such loss, the purifica-
tion procedure was carried out under N2 atmosphere. It should
also be noted that lower stability of Ru-chloride 10 is in contrast
to the robustness of the first generation complexes 1a,b; the
exact reason for this difference in stability is unclear at the
present time.
(14) For other examples, where chiral olefin metathesis catalysts are prepared
and used in situ, see: (a) Aeilts, S. L.; Cefalo, D. R.; Bonitatebus, P. J.;
Houser, J. H.; Hoveyda, A. H.; Schrock, R. R. Angew. Chem., Int. Ed.
2001, 40, 1452-1456. (b) Dolman, S. J.; Sattely, E. S.; Hoveyda, A. H.;
Schrock, R. R. J. Am. Chem. Soc. 2002, 124, 6991-6997. (c) Teng, X.;
Cefalo, D. R.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002,
124, 10779-10784.
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A R T I C L E S
Van Veldhuizen et al.
Table 1. Catalytic Enantioselective Ring-Opening Metathesis/Cross-Metathesis (AROM/CM) with Various Ru-Based Chiral Complexesa
a Reactions carried out with 5 mol % Ru catalyst in THF (except entry 3 performed in the absence of solvent) in the presence of 5 equiv of styrene at
1
22 °C. See the Supporting Information for detailed conditions. b Conversions determined by analysis of 400 MHz H NMR spectra of unpurified product
mixtures. c Isolated yield after silica gel chromatography. d Enantioselectivities determined by chiral HPLC (see the Supporting Information for details).
e Reaction performed through slow addition of substrate to a solution of the catalyst and styrene in THF.
Table 2. Cu-Catalyzed Asymmetric Allylic Alkylations with
isolated in identical optical purity and yield as when the catalyst
is prepared and used in situ (84% ee and 59% isolated yield;
>98% conv in 0.1 h).
Ag(I)-Complex 8; Enantioselective Synthesis of Tertiary Carbonsa
Data shown in Table 1 illustrate that the more robust chiral
Ru complex 11 can serve as a highly effective catalyst for
enantioselective olefin metathesis. Several important points
regarding asymmetric olefin metatheses initiated by Ru iodide
11 are worthy of note: (a) Similar yields and enantioselectivities
are observed when chiral complex 11 is prepared in situ or used
after isolation and purification. Interestingly, in two cases, the
catalyst prepared in situ delivers a higher level of enantio-
selectivity (entries 2 and 4). (b) Biphenyl-based Ru complex
11 exhibits higher levels of reactivity (vs 1c), as is clearly
demonstrated by the data shown in entry 3 of Table 1.
3. Chiral Cu-Based Complexes Bearing Readily Available
Bidentate NHC Ligands as Efficient Catalysts for Enantio-
selective Allylic Alkylations. Cu-Catalyzed Asymmetric
Alkylations of Disubstituted Olefins. Enantioselective Syn-
thesis of Tertiary Carbon Stereogenic Centers. As the data
summarized in Table 2 illustrate, 0.5-1 mol % chiral Ag(I)
complex 8 can be used to promote efficient and enantioselective
alkylations of allylic phosphates bearing a disubstituted olefin
with aryl (entries 1-6, Table 2) as well as alkyl substituents
(entries 7-12, Table 2). Reactions are readily effected in the
presence of air-stable CuCl2‚2H2O,15 and achiral products from
the SN2 mode of addition are not observed (<2% by 400 MHz
1H NMR analysis).
mol % 8;
conv (%);b
time (h)
yield (%);c
ee (%)d
entry
R1
alkylzinc
mol % Cu salt
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
Me2Zn
Et2Zn
n-Bu2Zn
i-Pr2Zn
Me2Zn
Et2Zn
Me2Zn
Et2Zn
Me2Zn
Et2Zn
1
>98; 24
>98; 2
68; 90
80; 90
94; 89
80; 86
92; 91
78; 90
75; 88
72; 88
60; 95
80; 95
52; 96
68; 97
0.5
0.5
0.5
1
0.5
1
0.5
1
0.5
1
>98; 20
>98; 2
C6H5
o-NO2C6H4
o-NO2C6H4
C7H15
C7H15
Cy
>98; 24
>98; 2
>98; 24
>98; 15
>98; 24
>98; 15
>98; 24
>98; 24
10
11
12
Cy
Cy
Cy
n-Bu2Zn
i-Pr2Zn
1
a See the Supporting Information for further details; >98% regio-
isomeric excess (re; SN2′:SN2) in all cases. b Determined by GLC analy-
sis; details in the Supporting Information. c Isolated yield of purified
products. d Determined by chiral GLC analysis; details in the Supporting
Information.
generation Ag(I) complex 2, the desired products can be
obtained in significantly higher optical purity. For example, the
products from transformations shown in entries 1 and 2 of Table
2 were obtained in 71% and 86% ee when 2 was used (vs 90%
ee in both cases with complex 8).5 (b) A key attribute of the
present method is that Cu-catalyzed asymmetric alkylations with
larger alkylzincs such as n-Bu2Zn (entries 3 and 11) and even
(i-Pr)2Zn (entries 4 and 12) are catalyzed in the presence of
0.5-1 mol % of Ag(I) complex 8.
Several additional points regarding the data in Table 2 merit
specific mention: (a) Not only is the new chiral complex,
derived from carbene 7 (Scheme 2), as effective as the first
Cu-Catalyzed Asymmetric Alkylations of Trisubstituted
Olefins. Enantioselective Synthesis of All-Carbon Quater-
nary Stereogenic Centers. As the data in Table 3 indicate,
(15) Ag-based complexes of heterocyclic carbenes readily undergo exchange
with a variety of late transition metals. See: (a) Wang, H. M. J.; Lin, I. J.
B. Organometallics 1998, 17, 972-975. (b) Arnold, P. L. Heteroat. Chem.
2002, 13, 534-539 and references therein.
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Chiral Ag-Based N-Heterocyclic Carbene Complex
A R T I C L E S
Scheme 4. Synthesis, X-ray Structure, and Catalytic Activity of Cu Complex 24
Table 3. Enantioselective Synthesis of Quaternary Carbons by
Several additional points regarding the Cu-catalyzed allylic
alkylations in the presence of Ag(I) complex 8 are worthy of
note:
Cu-Catalyzed Asymmetric Allylic Alkylation Promoted by
Ag(I)-Complex 8a
a See the Supporting Information for details. >98% regioisomeric excess
(re; SN2′:SN2) in all cases. b Determined by GLC analysis; details in the
Supporting Information. c Isolated yield of purified product. d Determined
by chiral GLC analysis; details in the Supporting Information. e 1 mol %
(S,S)-8 and 2 mol % Cu salt were used.
(a) As shown in eq 1, when the corresponding cis and Z allylic
phosphates (e.g., 20a,b) are used as the substrate, Cu-catalyzed
allylic alkylations are slower and proceed with lower enantio-
selectivity to afford the opposite product enantiomer (as com-
pared to trans and E substrates). It should however be noted
that, as indicated by the example in eq 1, even in instances where
a trisubstituted olefin bears sterically hindered substituents, ap-
preciable reactivity and high asymmetric induction are attained.
The Cu-catalyzed asymmetric synthesis of the quaternary carbon
stereogenic center in eq 2 is especially noteworthy, as it
constitutes stereodifferentiation of two aryl groups in 2217 that
differ almost exclusively in their electronic properties.
(b) As illustrated in Scheme 4, treatment of Ag(I) complex 8
with CuCl2‚2H2O leads to the formation of air-stable Cu(II)
complex 24 in 95% yield; the X-ray structure of 24 is depicted
in Scheme 4.18 As the representative examples in Scheme 4
and Table 4 indicate, the Cu(II) complex can be employed
directly to catalyze highly enantioselective allylic alkylation
reactions.
complex 8 is particularly effective when used to promote Cu-
catalyzed alkylations that lead to enantioselective synthesis of
all-carbon quaternary stereogenic centers (94-98% ee).16 In all
cases, >98% regioisomeric excess (re) in favor of the SN2′ mode
of addition is observed. Even when the sterically demanding
(i-Pr)2Zn is used, formation of the quaternary carbon stereogenic
center proceeds efficiently (1 mol % 8 in 12 h at -15 °C) to
afford the desired product in 98% ee and >98% re. It should
be noted that higher asymmetric induction can be obtained with
the new complex; Cu-catalyzed alkylations in entries 1 and 3
of Table 3 proceed to afford the desired alkylation products in
91% and 93% ee when chiral complex 2 is used in the presence
of CuCl2‚2H2O (vs 97% ee in both cases with 8).5
(16) For reviews on enantioselective synthesis of quaternary carbon stereogenic
centers, see: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed.
1998, 37, 388-401. (b) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed.
2001, 40, 4591-4597. (c) Denissova, I.; Barriault, L. Tetrahedron 2003,
59, 10105-10146. (d) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363-6367.
(17) For stereoselective synthesis of 22, see: Havranek, M.; Dvorak, D. J. J.
Org. Chem. 2002, 67, 2125-2130.
(18) For a related dimeric Cu complex, see: Arnold, P. L.; Scarisbrick, A. C.;
Blake, A. J.; Wilson, C. Chem. Commun. 2001, 2340-2341.
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J. AM. CHEM. SOC. VOL. 127, NO. 18, 2005 6881

A R T I C L E S
Van Veldhuizen et al.
Table 4. Comparison of Enantioselective Cu-Catalyzed
Asymmetric Allylic Alkylation Promoted by Ag(I)-Complex 8 and
Cu(II)-Complex 24a
Conclusions
We report the design, synthesis, characterization, and devel-
opment of a new class of chiral NHC ligand. Preparation of the
ligand does not require the availability of an optically pure
binaphthyl-based amino alcohol, the synthesis of which would
require longer synthesis routes and inefficient resolution pro-
cedures.4 Chirality is transferred by the stereogenic centers in
the diamine backbone that in turn induce the achiral biphenyl
amino alcohol moiety to coordinate to the metal center to form
a single atropisomer. The resulting enantiomerically and dias-
tereomerically pure Ag(I) complex 8, the X-ray structure of
which is disclosed, can be used in the preparation of the
corresponding Ru-based and Cu-based complexes that readily
promote efficient enantioselective olefin metathesis and allylic
alkylation reactions. In all cases, whether it is the Cu complex
24, the sensitive but reactive chiral Ru-chloride 10, or the more
robust Ru-iodide 11, chiral catalysts can be prepared and
employed in situ to promote highly enantioselective C-C bond
forming reactions.
In the presence of air-stable CuCl2‚2H2O, the optically pure
NHC-Ag(I) complex can be utilized to generate a Cu(I)
complex that serves as an exceptionally effective chiral alky-
lation catalyst. Particularly noteworthy is the facility and
enantioselectivity with which even sterically hindered alkylzincs
are induced to add to trisubstituted olefins to generate all-carbon
quaternary stereogenic centers with high optical purity. The
derived Cu(II) complex (24) has been synthesized and charac-
terized by X-ray crystallography; this air-stable Cu complex can
be used to effect catalytic alkylations.
a See the Supporting Information for details. b Determined by GLC
analysis; details in the Supporting Information. c Determined by chiral GLC
analysis; details in the Supporting Information.
As shown by the data summarized in Table 4, Cu(II) complex
24 delivers levels of reactivity and enantioselectivity similar to
those observed with the combination of Ag(I) complex 8 and
CuCl2‚2H2O. These findings support the contention that similar
(if not identical) Cu-based NHC complexes are involved in
initiating C-C bond formation when Ag(I) complexes such as
8 are used in the presence of various Cu salts.
Comparison with Cu-Catalyzed Alkylations Promoted
by Amino Acid-Based Ligands. Recent reports from these
laboratories have introduced various peptide-based ligands
that promote Cu-catalyzed asymmetric allylic alkylations in-
volving the same allylic phosphate substrates that are discussed
above.6m In general, in cases involving di- and trisubstituted
olefins, the NHC-based catalysts presented herein are signifi-
cantly more effective in promoting enantioselective alkylations
(0.5-1 mol % vs 10 mol % catalyst loading required with
peptidic ligands).
The readily available chiral NHC ligand 7 as well as the
corresponding Ag(I) complex 8 are expected to give rise to a
range of chiral complexes that promote other synthetically useful
C-C bond forming reactions. Studies toward the development
of such catalytic asymmetric methods, as well as mechanistic
studies elucidating the mode of action of this class of bidentate
NHC ligands and the related applications to target-oriented
synthesis, are in progress.
It should be noted that with chiral Ag(I) complex 8 and
CuCl2‚2H2O, catalyst loading may be as low as 0.25 mol %.
As an example, Cu-catalyzed alkylation shown in entry 2 of
Table 2 proceeds to >98% conv within 15 h in the presence of
0.25 mol % 8 to afford the desired product in 89% ee and 67%
isolated yield; with 0.05 mol % 8, alkylation proceeds to 80%
conv after 24 h (desired product formed in 86% ee).
Acknowledgment. This research was supported by the
National Institutes of Health (GM-47480) and the National
Science Foundation (CHE-0213009). We thank A. W. Hird for
the X-ray structure of Cu complex 24. We are grateful to A. O.
Larsen, K. E. Murphy, M. A. Kacprzynski, D. G. Gillingham,
and O. Kataoka for helpful discussions. Schering-Plough
provided generous support for X-ray facilities at the Department
of Chemistry at Boston College.
In contrast to peptidic systems, NHC-based catalysts readily
promote highly enantioselective reactions with the less reactive
alkylzinc reagents such as Me2Zn and i-Pr2Zn. It is particularly
important to note that complexes 8 and 24 are by far the most
efficient chiral catalysts for enantioselective synthesis of all-
carbon quaternary stereogenic centers through allylic alkylations
with (hard) alkylmetal reagents.19 Finally, NHC-based catalysts
require the use of air-stable (and commercially available) CuCl2‚
2H2O, whereas peptidic ligands demand the presence of air-
sensitive (CuOTf)2‚C6H6.
Supporting Information Available: Experimental procedures
and spectral data for the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
JA050179J
(19) For a review, see: Hoveyda, A. H.; Heron, N. M. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999; pp 431-454.
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6882 J. AM. CHEM. SOC. VOL. 127, NO. 18, 2005