C2 symmetric chiral NHC ligand for asymmetric quaternary carbon constructing copper-catalyzed conjugate addition of Grignard reagents to 3-substituted cyclohexenones

Article abstract of DOI:10.1021/jo800613h

(Chemical Equation Presented) The asymmetric construction of quaternary carbon centers by conjugate addition of Grignard reagents to 3-methyl- and 3-ethylcyclohexenones was realized in a maximum enantioselectivity of 80% by using a C₂ symmetric chiral N-heterocyclic carbene (NHC)-copper catalyst, generated from (4S,5S)-1,3-bis(2-methoxyphenyl)-4,5-diphenyl-4,5- dihydro-1H-imidazol-3-ium tetrafluoroborate and copper(II) triflate. The stereostructures of the NHC-Au complexes were analyzed by X-ray crystallography, which rationalized the good stereocontrolling ability of N-aryl NHCs.

Full text of DOI:10.1021/jo800613h

C2 Symmetric Chiral NHC Ligand for Asymmetric Quaternary
Carbon Constructing Copper-Catalyzed Conjugate Addition of
Grignard Reagents to 3-Substituted Cyclohexenones
Yasumasa Matsumoto, Ken-ichi Yamada, and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo, Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
ReceiVed March 18, 2008
The asymmetric construction of quaternary carbon centers by conjugate addition of Grignard reagents to
3-methyl- and 3-ethylcyclohexenones was realized in a maximum enantioselectivity of 80% by using a
C2 symmetric chiral N-heterocyclic carbene (NHC)-copper catalyst, generated from (4S,5S)-1,3-bis(2-
methoxyphenyl)-4,5-diphenyl-4,5-dihydro-1H-imidazol-3-ium tetrafluoroborate and copper(II) triflate. The
stereostructures of the NHC-Au complexes were analyzed by X-ray crystallography, which rationalized
the good stereocontrolling ability of N-aryl NHCs.
Introduction
We have been engaged in the development of chiral ligand-
metal-catalyzed1 or mediated asymmetric reactions. In the
asymmetric conjugate addition reaction,2 C2 symmetric chiral
diether 13 for lithiated nucleophiles and chiral phosphines 24
for the copper- and rhodium-catalyzed reactions have been
developed as representative examples of our successes (Figure
1). A phosphorus ligand 3 (Mes ) 2,4,6-trimethylphenyl) also
has been developed with limited success for the copper-catalyzed
conjugate addition of organozinc reagents to cycloalkenones.5
Since the C2 symmetry is one of the central motifs for the design
FIGURE 1. Chiral ligands and NHC precursor.
(1) Tomioka, K. Synthesis 1990, 541–549.
(2) A general reference on asymmetric conjugate addition reactions: Christoffers,
J.; Koripelly, G.; Rosiak, A.; Ro¨ssle, M. Synthesis 2007, 1279–1300.
(3) (a) Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989, 111,
8266–8268. (b) Fujieda, H.; Kanai, M.; Kambara, T.; Iida, A.; Tomioka, K. J. Am.
Chem. Soc. 1997, 119, 2060–2061. (c) Doi, H.; Sakai, T.; Iguchi, M.; Yamada,
K.; Tomioka, K. J. Am. Chem. Soc. 2003, 125, 2886–2887. (d) Sakai, T.;
Kawamoto, Y.; Tomioka, K. J. Org. Chem. 2006, 71, 4706–4709, and references
cited therein.
of efficient chiral ligands,6 we explored the carbene version of
3: replacement of its phosphorus moiety with a carbene leads
to C2 symmetric N-heterocyclic carbene (NHC) 4.7,8 By the
(6) (a) Dang, T. P.; Kagan, H. B. J. Chem. Soc., Chem. Commun. 1971,
481–482. (b) Noyori, R.; Ohkuma, T.; Kitamura, M.; Takaya, H.; Sayo, N.;
Kumobayashi, H.; Akutagawa, S. J. Am. Chem. Soc. 1987, 109, 5856–5858. (c)
Tomioka, K.; Nakajima, M.; Koga, K. J. Am. Chem. Soc. 1987, 109, 6213–
6215. (d) Bolm, C. Angew. Chem., Int. Ed. Engl. 1991, 30, 542–543. (e) Weber,
B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1992, 31, 84–86. (f) Nakajima,
M.; Tomioka, K.; Iitaka, Y.; Koga, K. Tetrahedron 1993, 49, 10793–10806. (g)
Pfaltz, A. Acc. Chem. Res. 1993, 26, 339–345.
(4) (a) Kanai, M.; Koga, K.; Tomioka, K. Tetrahedron Lett. 1992, 33, 7193–
7196. (b) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1995, 36, 4273–4274. (c)
Kuriyama, M.; Tomioka, K. Tetrahedron Lett. 2001, 42, 921–923. (d) Soeta,
T.; Kuriyama, M.; Tomioka, K. J. Org. Chem. 2005, 70, 297–300. (e) Selim,
K.; Soeta, T.; Yamada, K.; Tomioka, K. Chem. Asian J. 2008, 3, 342–350, and
references cited therein.
(5) Mori, T.; Kosaka, K.; Nakagawa, Y.; Nagaoka, Y.; Tomioka, K.
Tetrahedron: Asymmetry 1998, 9, 3175–3178.
(7) Nolan, S. P. N-Heterocyclic Carbenes in Synthesis; Wiley-VHC: Wein-
heim, Germany, 2006.
4578 J. Org. Chem. 2008, 73, 4578–4581
10.1021/jo800613h CCC: $40.75 2008 American Chemical Society
Published on Web 05/20/2008

Cu-Catalyzed Conjugate Addition of Grignard Reagents
TABLE 1. The 6-Cu(OTf)2-Mediated Asymmetric Conjugate
Ethylation
FIGURE 2. Successful NHC precursors 7 and 8.
conformational fixation of N-substituent, an asymmetric space
would be created around the carbene moiety of 5, and thus the
asymmetric space of 4 appears to be more rigid than that of 3
due to lack of a substituent on the carbene. Consequently 4
should afford a more efficient asymmetric induction than 3. We
have also investigated the design and application of C2 sym-
metric carbene 49 as an organocatalyst for asymmetric Stetter
reaction.10
Recent brilliant successes in chiral NHC-copper(I)-
catalyzed conjugate addition reactions,11 especially asym-
metric construction of a quaternary carbon,12 stimulated us
to explore the reaction by using C2 symmetric carbene 4. In
this report, we describe the chiral NHC-copper(I)-catalyzed
asymmetric quaternary carbon constructing conjugate addition
reaction of Grignard reagents with 3-methyl- and 3-ethyl-
cyclohexenones giving enantioenriched 3,3-disubstituted
cyclohexanones.
Cu(OTf)2,
mol %
M,a
mol/L 10a:12b 10a, % ee, %
yield of
entry
6
X
1
2
3
4
5
6
none
6a
6a
6b
6b
0
0
6
6
6
6
1:99
1:99
trace
trace
34
nd
nd
21
20
19
21
BF4
BF4
Cl
Cl
PF6
0.012
0.012
0.008
0.024
0.012
42:58
45:55
55:45
41:59
45
52
34
6c
a Molar concentration of 6. b The molar ratio determined by 1H NMR
(the triplet Me of 10a:singlet Ha of 12).
was determined by a chiral gas chromatography (Gamma Dex
225, 90 °C, helium gas flow of 4 mL/min, rt: 17.7 min (R),
20.2 min (S)). The production of 12 was ascribable to almost
complete dehydration of 11 by 10% hydrochloric acid
treatment of the reaction mixture. The catalysis by an NHC-
copper complex was apparent from the reactions that gave
no conjugate addition product 10a in the absence of both or
a copper source (entries 1 and 2). The counteranion species,
tetrafluoroborate (6a), chloride (6b), and hexafluorophosphate
(6c), were not a critical factor in determining 1,4- versus
1,2-addition ratio and also percent ee (entries 3-6). Molar
concentration of 6 was not decisive (entries 4 vs 5).
Asymmetric Reaction by Using Variously Modified NHC.
A range of N-variant precursors of NHC 6 and 27-38 were
readily prepared starting from chiral 1,2-diamino-1,2-diphe-
nylethane (13) by standard imidazolium forming procedure of
N-alkylation 14-19 and N-arylation products 20-26 as shown
in Scheme 1.14
Results and Discussion
Asymmetric Conjugate Addition of Ethylmagnesium Bro-
mide in the Presence of 6. We followed the reaction
procedure reported by Alexakis and Mauduit where an
efficient quaternary carbon constructing conjugate addition
reaction of Grignard reagents has been realized by using
chiral NHC precursors 7 and 8 (Figure 2).12b The reaction
of 2 equiv of ethylmagnesium bromide with 3-methylcyclo-
hexenone (9a) in the presence of 8 mol % of 6a (X ) BF4)
and 6 mol % of copper(II) triflate in diethyl ether at 0 °C for
0.5 h gave a 42:58 mixture of desired 10a and diene 12
derived from 1,2-adduct 11 (Table 1, entry 3). The absolute
configuration of 10a was assigned to be S based on the
specific rotation.13 The enantioselectivity (21% ee) of 10a
It became apparent from our investigation that NHCs
bearing RCH2 or R2CH N-substituents 6 and 29-31 gave
poor yields of 10a (20-51%) (Table 2, entries 1 and 4-6).
Exceptions are NHCs 27 and 28 bearing a coordinatable
heteroatom group, F and MeO, at the ortho position of a
phenyl ring that gave good yields (81% and 70%) (entries 2
and 3), while ee was not satisfactory (24% and 35% ee).
On the contrary, the NHCs bearing an aryl group directly
attached to the amino nitrogen, 32-38, exerted relatively
satisfactorily higher efficiency in chemical yield and ee
(entries 7-13). It is surprising to find that even unsubstituted
phenyl group 32 exerted a better activation behavior to give
10a with 64% ee in 60% yield. The ratio of 1,4-addition
versus 1,2-addition was improved up to 80:20 (entry 7). Both
ortho 2,6-dimethyl and diethyl substitutions on a phenyl ring,
33 and 34, exerted profound effect on yield to give 10a in
93% and 62% yields, respectively, although ee values, 64%
and 59%, were not affected much (entries 8 and 9).
(8) For reviews on carbene ligands, see: (a) Ce´sar, V.; Bellemin-Laponnaz,
S.; Gade, L. H. Chem. Soc. ReV. 2004, 33, 619–636. (b) Perry, M. C.; Burgess,
K. Tetrahedron: Asymmetry 2003, 14, 951–961. (c) Herrmann, W. A. Angew.
Chem., Int. Ed. 2002, 41, 1290–1309.
(9) Matsumoto, Y.; Tomioka, K. Tetrahedron Lett. 2006, 47, 5843–5846.
(10) For reviews on carbene organocatalysts, see: (a) Enders, D.; Niemeier,
O.; Henseler, A. Chem. ReV. 2007, 107, 5606–5655. (b) Marion, N.; Die´z-
Gonza´les, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988–3000. (c)
Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534–541.
(11) (a) Clavier, H.; Guillemin, J. H.; Mauduit, M. Chirality 2007, 19, 471–
476. (b) Clavier, H.; Coutable, L.; Guillemin, J. C.; Mauduit, M. Tetrahedron:
Asymmetry 2005, 16, 921–924. (c) Winn, C. L.; Guillen, F.; Pytkowicz, J.;
Roland, S.; Mangeney, P.; Alexakis, A. J. Organomet. Chem. 2005, 690, 5672–
5695. (d) Clavier, H.; Coutable, L.; Toupet, L.; Guillemin, J. C.; Mauduit, M. J.
Organomet. Chem. 2005, 690, 5237–5254. (e) Arnold, P. L.; Rodden, M.; Davis,
K. M.; Scarisbrick, A. C.; Blake, A. J.; Wilson, C. Chem. Commun. 2004, 1612–
1613. (f) Alexakis, A.; Winn, C. L.; Guillen, F.; Pytkowicz, J.; Roland, S.;
Mangeney, P. AdV. Synth. Catal. 2003, 345, 345–348. (g) Fraser, P. K.;
Woodward, S. Tetrahedron Lett. 2001, 42, 2747–2749. (h) Pytkowicz, J.; Roland,
S.; Mangeney, P. Tetrahedron: Asymmetry 2001, 12, 2087–2089. (i) Guillen,
F.; Winn, C. L.; Alexakis, A. Tetrahedron: Asymmetry 2001, 12, 2083–2086.
(12) (a) Brown, M. K.; May, T. L.; Baxter, C. A.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2007, 46, 1097–1100. (b) Martin, D.; Kehrli, S.; d’Augustin,
M.; Clavier, H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006, 128, 8416–
8417. (c) Lee, K. S.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem.
Soc. 2006, 128, 7182–7184.
(14) (a) Saba, S.; Brescia, A.; Kaloustian, M. K. Tetrahedron Lett. 1991,
32, 5031–5034. (b) Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R.
Tetrahedron 1999, 55, 14523–14534.
(13) D’Augustin, M.; Palais, L.; Alexakis, A. Angew. Chem., Int. Ed. 2005,
44, 1376–1378.
J. Org. Chem. Vol. 73, No. 12, 2008 4579

Matsumoto et al.
SCHEME 1. Synthesis of Various NHC Precursors 6 and 27-38 from 13
TABLE 2. The 6 and 27-38-Copper-Catalyzed Asymmetric
Conjugate Ethylation
promoted by 36 at lower temperatures gave 10a with 77%
and 80% ee values in nearly quantitative yields (entries 14
and 15).
The Reaction with Other Grignard Reagents. The reactions
of various Grignard reagents (R2MgBr) with 9a were also
successfully catalyzed by 36-copper triflate complex to give the
products with good ee (74-80%) in high yields (89-99%)
(Figure 3, 10b-e), except phenylation product 10f. 3-Ethylcy-
clohexenone (9b) was also converted to the quaternary carbon-
containing product 10g with good 65% ee by the reaction with
isobutylmagnesium bromide. Unfortunately, methylmagnesium
bromide was not a good nucleophile to give methylation product
ent-10a with 18% ee. With the exception of 10c with unknown
absolute configuration, nucleophiles attacked from the Si-face
of cyclohexenones.
entry 6, 27-38
X
10a:11 (10a:12)a yield, % ee, % R/S
1b
2
6a
27
28
29
30
31
32
33
34
35
36
37
38
36
36
BF4
Cl
Cl
(42:58)
(81:19)
(74:26)
(30:70)
(59:41)
29:71
80:20
95:5
34
81
70
20
51
27
64
93
62
93
94
74
40
99
98
21
24
35
10
29
8
60
64
59
50
71
57
49
77
80
S
S
S
R
R
S
S
S
S
S
S
S
S
S
S
The Reaction with Cyclohexenone. The reaction of cyclo-
hexenone 9c in place of 3-substituted cyclohexenones 9a,b with
ethylmagnesium bromide was also successfully catalyzed by
3
4
5
6
7
8
9
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
64:36
93:7
96:4
10
11
12
13
14c
15d
79:21
54:46
>99:1
98:2
a The reaction was quenched with 10% HCl in entries 1-5, while sat.
NH4Cl was used for quenching in entries 6-15 to avoid the formation
of 12 from 11. b Table 1, entry 3. c Reaction was performed at -40 °C
for 0.5 h d Reaction was performed at -60 °C for 1.5 h.
Dimethoxy substitution of 35 was also effective to give 93%
yield of 10a with 50% ee (entry 10). Monosubstitution with
a methoxy group as in 36 was much more effective to give
94% yield of 10a with improved enantioselectivity (71% ee),
while more bulky isopropoxy-substituted 37 and methoxym-
ethyl-substituted 38 were not effective, 74% yield with 57%
ee and 40% yield with 49% ee (entries 11-13). The reactions
FIGURE 3. The asymmetric reaction products.
4580 J. Org. Chem. Vol. 73, No. 12, 2008

Cu-Catalyzed Conjugate Addition of Grignard Reagents
SCHEME 2. Asymmetric Conjugate Ethylation of
Cyclohexenone
36-copper triflate complex to give (S)-10h15 (Scheme 2) with
43% ee in 98% yield. The sense of asymmetric induction is the
same as that of 9a and 9b, indicating the same type of
stereochemical control by the NHC-copper derived from 36.
The X-ray Crystal Structure Analysis of NHC-Au. The
realization of the asymmetric space concept shown as 5 was
confirmed by the X-ray crystal structure of NHC-Au complexes.
Although copper complexes failed to give crystals suitable for
X-ray analysis, gold-NHC complexes gave suitable crystals.16
As shown in Figure 4, the two mesityl groups of 4-AuCl are
placed down- and up-sides of the 5-membered NHC ring plane,
avoiding steric repulsion with the adjacent phenyl groups.
However, it is impressive to find that the two mesityl groups
are folded like an umbrella blown inside out against the
carbene-Au bond, placing both phenyl and mesityl rings
parallel. On the other hand, the two 2-methoxyphenyl groups
of the 36-derived carbene-Au complex are stuck out according
to the carbene-Au bond, placing the methoxy groups down-
and up-sides of the NHC plane and hence creating a more
efficient asymmetric environment around the reaction site.
The chiral environment around the gold atom in the 36-
derived carbene-Au complex is surrounded by two 2-methox-
yphenyl groups potentially making it much more effective than
the 4-Au complex. Presumably, this is responsible for the higher
asymmetric induction by the NHC derived from 36.
FIGURE 4. The X-ray crystal structure analysis (ORTEP views).
min at 0 °C and the mixture was stirred at 0 °C for 0.5 h. Then the
mixture was cooled to -60 °C and a solution of 3-methylcyclohex-
2-enone (9a) (0.23 mL, 2.0 mmol) in diethyl ether (10 mL) was
added over 10 min. After being stirred for 1.5 h at -60 °C, the
reaction was quenched with satd NH4Cl (15 mL) and 25% NH3
(15 mL). The aqueous layer was separated and extracted with
diethyl ether (3 × 10 mL). The combined organic layers were
washed with brine (20 mL) and dried over sodium sulfate.
Concentration and column chromatography (hexane/Et2O ) 19/1)
Conclusion
Thirteen C2 symmetric chiral NHCs derived from 1,2-
diamino-1,2-diphenylethane were examined on their abilities in
mediating the asymmetric quaternary carbon constructing
conjugate addition reaction. Efficient construction of a chiral
space around the metallic active site was vital to the realization
of high asymmetric induction such as the 80% ee obtained by
the use of 36. The origin of the high stereocontrolling ability
of the NHC derived from 36 can be deduced from the X-ray
crystal structure analysis of NHC-metal complexes.
gave (S)-10a12b (277 mg, 98%) of [R]20 -6.57 (c 1.10, CHCl3).
D
Chiral GC (Gamma Dex 225, 90 °C, helium gas constant flow of
4 mL/min, Rt ) 17.7 min (R), 20.2 min (S)) indicated 80% ee.
The absolute configuration was determined by the specific
rotation.12b
Acknowledgment. This research was partially supported by
the 21st Century COE (Center of Excellence) Program “Knowl-
edge Information Infrastructure for Genome Science”, a Grant-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations”, and Target Proteins Research
Program from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
Experimental Section
The Asymmetric Conjugate Addition of Ethylmagnesium
Bromide to 3-Methylcyclohexenone (9a) (Table 2, entry 15).
Under argon atmosphere, to a suspension of copper(II) triflate (43
mg, 6 mol %) and imidazolinium tetrafluoroborate 36 (84 mg, 8
mol %) in diethyl ether (15 mL) was added a 3.0 M diethyl ether
solution of ethylmagnesium bromide (0.67 mL, 2.0 mmol) over 3
Supporting Information Available: Synthesis of diamines
14-26 and imidazolinium salts 6a, 6b, 6c, and 27-38, 1H NMR
and 13C NMR charts for the products, and the CIF of the
gold-carbene complexes 4-Au and 36-Au. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Posner, G. H.; Frye, L. Isr. J. Chem. 1984, 24, 88–92.
(16) The crystal structure of 4-Au was refined by SHELX-97 with WinGX
interface.
JO800613H
J. Org. Chem. Vol. 73, No. 12, 2008 4581