Construction of a new type of chiral bidentate NHC ligands: copper-catalyzed asymmetric conjugate alkylation

Article abstract of DOI:10.1016/j.tetlet.2009.06.026

We synthesized in three steps simple chiral bidentate NHC compounds that carry an achiral coordinating group as N-substituent and revealed that they serve as efficient chiral auxiliaries for the copper-catalyzed asymmetric conjugate addition of dialkylzin

Full text of DOI:10.1016/j.tetlet.2009.06.026

Tetrahedron Letters 50 (2009) 4741–4743
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Construction of a new type of chiral bidentate NHC ligands: copper-catalyzed
asymmetric conjugate alkylation
*
Tatsuya Uchida, Tsutomu Katsuki
Department of Chemistry, Faculty of Science, Graduate School, Kyushu University, Hakozaki, Higashi-Ku, Fukuoka 812-8581, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We synthesized in three steps simple chiral bidentate NHC compounds that carry an achiral coordinating
group as N-substituent and revealed that they serve as efficient chiral auxiliaries for the copper-catalyzed
asymmetric conjugate addition of dialkylzinc to acyclic enones (up to 97% ee).
Ó 2009 Elsevier Ltd. All rights reserved.
Received 29 April 2009
Revised 29 May 2009
Accepted 5 June 2009
Available online 9 June 2009
Recently, optically active N-heterocyclic carbene compounds
(NHC compounds) have attracted significant attention for their
application in asymmetric synthesis.1,2 In 1962, Wanzlick reported
the seminal study on the unique catalytic performance of NHC
compounds3 and, in 1968, Öfele reported the synthesis of NHC–
transition metal complexes.4 Subsequent to these studies, a stable
NHC was synthesized5 and the catalysis of NHCs has been inten-
sively studied.2,6,7 Furthermore, the ligating properties of NHC
compounds have attracted increasing attention because of the dis-
covery of unprecedented catalysis by transition-metal NHC com-
plexes, such as the ruthenium catalyst for olefin metathesis1c and
the palladium catalyst for C–C bond formation.1e Moreover, Bur-
gess and co-workers reported the asymmetric hydrogenation of al-
kenes using a Ir-chiral NHC complex as the catalyst.8a Since then,
various chiral-NHC ligands have been introduced, and their transi-
tion-metal complexes have been used as the catalysts for asym-
metric reactions such as hydrogenation,1b,8 olefin metathesis,1c,9
allylic substitution,1a,10 and the aerobic oxidation of alcohols.11
Conjugate addition to enones is a useful method not only for C–
C bond formation but also for the generation of a stereogenic cen-
ter. Thus, the asymmetric version of the conjugate addition has
been extensively studied,12 and chiral NHC–transition metal com-
plexes have also been found to be efficient catalysts for conjugate
addition reactions.13 Among the NHC ligands, bidentate NHC li-
gands bearing a chiral or dynamically induced chiral coordinating
N-substituent generally induce high asymmetry. Mauduit’s group
has reported that the addition of various dialkylzinc to cyclic enon-
es in the presence of 1a proceeds with high enantioselectivity (up
to 93% ee).13a,b Alexakis and co-workers have also reported that the
copper-mediated addition of Grignard reagents to b-substituted
cyclic enones in the presence of 1b proceeds with high enantiose-
lectivity.13e Moreover, Hoveyda and co-workers reported the
highly enantioselective addition of alkyl- and aryl-zincs and alkyl-
and aryl-aluminums to b-substituted cyclic enones in the presence
of NHC derivatives 2 and 3, respectively (up to 97% ee).13c,d The N-
substituent of 3 is achiral but it is conformationally fixed to induce
an axial chirality upon the chelate formation.13d However, good
substrates for these addition reactions are mostly limited to cyclic
enones (Fig. 1).
On the other hand, it is known that, when the N-substituent in
4,5-trans-1,3,4,5-tetrasubstituted 4,5-dihydroimidazolium salts is
an arylmethyl group, the aryl group is anti to the vicinal C-substi-
tuent.13f,g,14 Thus, we expected that the NHC ligands 4, bearing an
achiral N1-(m-substituted o-hydroxy)benzyl and N3-aryl groups,
would form a broad chiral coordination sphere around the metal
center upon complex formation (Fig. 2 and Scheme 1) and that
the complex, dialkylzinc, and enone would combine therein to give
a postulated bimetallic intermediate in the conjugate addition.12,15
Moreover, it was expected that the ligands 4 could be synthesized
in a modular manner. Indeed, the ligands 4a–f were synthesized in
three steps from (1R,2R)-1,2-diphenylethyrenediamine (Scheme
1): (i) Buchwald amination,16 (ii) reductive amination, and (iii) imi-
dazolium formation.14b
R
R
R
N
N
N
N
Mes
Mes
OH
OH
1a: R=i-Pr
1b: R=t-Bu
Ph
2a: R=H, Binaphthyl
2b: R=Ph, Biphenyl
N
N
C6H3-2,6-Et2
O
S
O
OH
3
* Corresponding author. Tel.: +81 92 642 2586.
E-mail address: katsuscc@chem.kyushu-univ.jp (T. Katsuki).
Figure 1. Previous examples of chiral bidentate NHC ligands.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.026

4742
T. Uchida, T. Katsuki / Tetrahedron Letters 50 (2009) 4741–4743
vent remarkably improved both the enantioselectivity and the
chemical yield (run 5). Moreover, the reaction at ꢀ10 °C provided
a better result (97% ee, 95%) (run 6). The reactions at room temper-
ature reduced the enantioselectivity and yield (run 7). The reac-
tions were further examined using 4c–f as the ligands at ꢀ10 °C,
but no improvement was observed in enantioselectivity and
chemical yield (runs 8–11). We next examined the reaction using
reduced catalyst loading (runs 12–14). The reactions proceeded
without diminishing enantioselectivity even at 1 mol% catalyst
loading (run 13). The reaction could be carried out even on a
5 mmol scale.17 However, further reduction of catalyst loading
diminished both the enantioselectivity and yield (run 14). The
reaction in the absence of copper salt was slow and less enantiose-
lective (run 15).
Under the optimized reaction conditions, we examined the con-
jugate addition reaction of dialkylzinc to various acyclic enones
(Table 2). The reactions with chalcone derivatives proceeded with
high enantioselectivities (up to 97% ee), irrespective of dialkylzinc
(runs 1–6). The reactions of E-alkenyl phenyl ketones (R1 = alkyl)
also proceeded with high enantioselectivities (94–95% ee) and
yields (90–>99%) (runs 7–9). In contrast, the conjugate addition
to benzal acetone (R2 = Me) showed almost no enantioselectivity
(run 10). However, the use of n-BuLi as the base was found to in-
duce a reversed enantioselectivity, albeit with low selectivity
(run 11). Thus, we examined the reaction using ligands 4c–f in
the presence of n-BuLi in THF, and a moderate enantioselectivity
of 69% was obtained when 4f was used (run 12). An identical
enantioselectivity was also obtained in the reaction of 5-methyl-
3-hexen-2-one (run 13).
R
N
R'
O
M
N
Ar
R
Figure 2. An expected structure of a metal–NHC complex
Ph
Ph
Ph
Ph
ArBr
Pd(OAc)2, BINAP,
tBuONa
(Buchwald method)
H2N
NH2
H2N HN Ar
Ph Ph
O
NH HN Ar
OH
OH
R'
then, NaBH3CN
(reductive amination)
R'
Ph
Ph
NH4BF4, HC(OEt)3
N
N
Ar
6'
R'
-
BF4
OH
4
4'
4a: R'= 4', 6'-di-t-Bu, Ar= mesityl
4b: R'= 4'-Ph, Ar= mesityl
4c: R'= 4'-Ph, Ar= Ph
4d: R'= 4'-Ph, Ar= 2-iso-propylphenyl
4e: R'= 4'-Ph, Ar= 3,5-xylyl
4f: R'= 4'-Ph, Ar= 3,5-dicholorophenyl
Scheme 1. Synthesis of NHC ligands 4.
As aforementioned, conjugate addition to cyclic enones often
proceeds with high enantioselectivity, while the selectivity of the
addition to acyclic substrates is generally lower due to the s-cis/
s-trans conformational flexibility.12,20,21 However, some of the
With a series of imidazolium salts in hand, we first examined
the reaction of chalcone using diethylzinc, triethylaluminum, or
ethylmagnesium chloride as the alkylating agent in the presence
of Cu(OTf)2 and the imidazolium salt 4a in tetrahydrofuran (THF)
at ꢀ20 °C (Table 1, runs 1–3). The reaction with diethylzinc gave
among the best results (run 1). The use of the imidazolium salt
4b improved the enantioselectivity to 94%, albeit with moderate
yield (run 4). The use of N,N-dimethylformamide (DMF) as the sol-
Table 2
Asymmetric conjugate reaction of dialkylzinc to acyclic enonesa
4b/Cu(OTf) 2/t-BuONa
R3
*
O
O
1/1/1.1 (1mol %), R 32Zn
R1
R2
R1
R2
R2
DMF, N 2, -10ºC
Table 1
Run
R1
R3
Time (h)
Yieldb (%)
ee (%)
Optimization of the asymmetric addition reaction of diethylzinc to chalcone using
in situ prepared NHC–Cu complexes as the catalysta
1
2
3
4
5
6
7
8
9
10
11i
12j
13j
p-Cl-C6H4
p-MeO-C6H4
Ph
Ph
Ph
Ph
Me
i-Pr
n-Pentyl
Ph
Ph
Ph
Et
Et
Et
Et
Me
i-Pr
Et
Et
Et
Et
Et
Et
Et
2
12
2
12
12
2
2
2
2
12
24
24
24
>99
62
>99
56
86
54
90
>99
90
62
67
97c,d
96c,d
97c
Run Ligand 4/Cu/base (mol %) Solvent Temp (°C) Yieldb (%) eec (%)
p-Cl-C6H4
p-MeO-C6H4
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
96d,e
95c
1
2e
3f
4
5
6
7
8
9
10
11
12
13g
14
15
4a
4a
4a
4b
4b
4b
4b
4c
4d
4e
4f
5/2.5/5.5
5/2.5/5.5
5/2.5/5.5
5/2.5/5.5
5/2.5/5.5
5/2.5/5.5
5/2.5/5.5
5/2.5/5.5
5/2.5/5.5
5/2.5/5.5
5/2.5/5.5
2.5/2.5/2.8
1/1/1.1
THF
THF
THF
THF
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ10
rt
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
ꢀ10
>99
28
24
35
81
95
47
52
81
69
52
93
89d
52
8
92c
95f
94
97
97
91
82
84
85
86
97d
94g
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
94f
2
Ph
Ph
i-Pr
ꢀ7
70
ꢀ69h,k
69m,n
39l
a
Reaction was carried out with a molar ratio of enone (0.5 mmol), dialkylzinc
4b
4b
4b
4b
(0.75 mmol), and DMF (2.5 mL) under N2 at ꢀ10 °C.
99 (98)d,h 97 (97)d,h
b
Isolated yield.
0.1/0.1/0.1
1/0/0
50
21
90
64
c
Determined by HPLC with DAICEL CHIRALCEL AD-H (hexane/i-PrOH = 99:1).
The absolute configuration of the product was S. (See Ref. 18.)
Determined by HPLC with DAICEL CHIRALPAC IA (hexane/i-PrOH = 90:10).
Determined by HPLC with DAICEL CHIRALCEL OD-H (hexane).
Determined by GLC with CP CP-CHIRASIL-DEX CB (30 m), 120 °C, 35 cm/s.
Determined by HPLC with DAICEL CHIRALCEL AD-H (hexane/i-PrOH = 99.5:0.5).
The reaction was run in THF with n-BuLi as the base.
The reaction was run in THF with n-BuLi as the base in the presence of 4f.
The absolute configuration of the product was R. (See Ref. 18.)
Determined by GLC using bicyclohexyl as the internal standard.
Determined by GLC with SUPELCO GAMMA-DEX 225 (30 m), 55 °C, 50 cm/s.
The configuration of the product has not been determined.
d
e
a
Reaction was carried out with a molar ratio of chalcone (0.1 mmol), diethylzinc
f
(0.15 mmol), and solvent (0.5 mL) in the presence of the described amounts of
ligand, Cu(OTf)2, and t-BuONa under N2.
g
h
b
Isolated yield.
i
c
Determined by HPLC with DAICEL CHIRALCEL AD-H (hexane/i-PrOH = 99:1).
The absolute configuration of the product was S. (See Ref. 18.)
Triethylaluminum was used.
Ethylmagnesium chloride was used.
The reaction was run on a 0.5-mmol scale.
The reaction was run on a 5.0-mmol scale.
j
d
k
e
l
f
m
g
n
h

T. Uchida, T. Katsuki / Tetrahedron Letters 50 (2009) 4741–4743
4743
10. Selected recent examples: (a) Tominaga, S.; Oi, Y.; Kato, T.; An, D. K.; Okamoto,
S. Tetrahedrone Lett. 2004, 45, 5585–5588; (b) Larsen, A. O.; Leu, W.; Oberhuber,
C. N.; Campbell, J. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 11130–11131.
11. Jensen, D. R.; Sigmann, M. S. Org. Lett. 2003, 5, 63–65.
reactions that proceed through a highly ordered transition state
proceed with high enantioselectivity.12,15,20 Although the mecha-
nism of the present reaction is unclear, it is likely that the reaction
also proceeds through an ordered transition state, from the catalyst
structure bearing a precoordinating substituent. Thus, we exam-
ined the reaction of 2-cyclohexen-1-one; however, the reaction
12. For recent reviews on asymmetric conjugate addition reaction, see: (a)
Alexakis, A.; Bäckvall, J. E.; Krause, N.; Pàmies, O.; Diéguez, M. Chem. Rev.
2008, 108, 2796–2823; (b) Christoffers, J.; Koripelly, G.; Rosiak, A.; Rössle, M.
Synthesis 2007, 1279–1300; (c) López, F.; Minnaard, A. J.; Feringa, B. L. Acc.
Chem. Res. 2007, 40, 179–188; (d) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem.
2002, 3221–3236; (e) Krause, N.; Hoffmann-Röder, A. Synthesis 2001, 171–196;
(f) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346–353; (g) Tomioka, K.; Nagaoka, Y.
In Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; pp 1105–1120; (h) Yamaguchi, M. In
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; pp 1121–1139.
13. For recent selected examples, see: (a) Clavier, H.; Coutable, L.; Toupet, L.;
Guillemin, J.-C.; Mauduit, M. J. Organomet. Chem. 2005, 690, 5237–5254; (b)
Clavier, H.; Coutable, L.; Guillemin, J.-C.; Mauduit, M. Tetrahedron: Asymmetry
2005, 921–924; (c) Lee, K.-S.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am.
Chem. Soc. 2006, 128, 7182–7184; (d) May, T. L.; Brown, M. K.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2008, 47, 7358–7362; (e) Martin, D.; Kehrli, S.;
d’Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006,
128, 8416–8417; (f) Matsumoto, Y.; Tomioka, K. Tetrahedron Lett. 2006, 47,
5843–5846; (g) Matsumoto, Y.; Yamada, K.-I.; Tomioka, K. J. Org. Chem. 2008,
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C. L.; Guillen, F.; Pytkowicz, J.; Roland, S.; Mangeney, P.; Alexakis, A. J.
Organomet. Chem. 2005, 690, 5672–5695.
15. (a) Ito, K.; Eno, S.; Saito, B.; Katsuki, T. Tetrahedron Lett. 2005, 46, 3981–3985;
(b) Hajra, A.; Yoshikai, N.; Nakamura, E. Org. Lett. 2006, 8, 4153–4155.
16. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805–818.
17. Typical experimental procedure for the asymmetric 1,4-conjugate addition of
diethylzinc to enones in the presence of imidazolium salt 4b: Imidazolium salt 4b
(3.5 mg, 0.05 mmol) and t-BuONa (0.5 mg, 0.055 mmol) were stirred in THF
(1.0 mL) under a nitrogen atmosphere at room temperature. After 30 min,
Cu(OTf)2 (1.8 mg, 0.05 mmol) was added to the mixture, and the whole
mixture was stirred for another 30 min. THF was removed in vacuo, and the
residue was re-dissolved in 25 mL of DMF. Chalcone (1.0 g, 5.0 mmol) was
added to the mixture, and the mixture was cooled to ꢀ10 °C. Then, a hexane
solution of diethylzinc (7.0 mL, 7.5 mmol) was slowly added to the reaction
mixture. After 90 min, the reaction was quenched with saturated NH4Cl aq
(5.0 mL), and the mixture was extracted twice with AcOEt (5.0 mL). The
combined organic phases were washed with saturated brine (2 ꢁ 5.0 mL) and
dried over MgSO4. After removal of the solvent, the residue was
chromatographed on silica gel (hexane/AcOEt = 50:1 to 20:1) to afford the
product (1.2 g, 98%). The enantiomeric excess of the product was determined
to be 97% by HPLC analysis using DAICEL CHIRALCEL AD-H (hexane/i-
PrOH = 99:1).
showed poor selectivity.22 This result suggests that a
p-complex
intermediate formed from the s-cis isomer of enone participates
in the present reaction.15b
In conclusion, we introduced new bidentate NHC ligands that
can be prepared in a modular fashion, and we revealed that they
serve as efficient chiral auxiliaries for the copper-catalyzed asym-
metric conjugate addition reaction of dialkylzinc to acyclic enones.
We believe that this study expands the utility of chiral bidentate
NHC ligands in asymmetric synthesis.
Acknowledgments
The authors acknowledge the financial support from a Grant-in-
Aid for Scientific Research on Priority Areas 18037056 ‘Advanced
Molecular Transformations of Carbon Resources’ and Specially Pro-
moted Research 18002011 from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
References and notes
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18. The specific rotations of the products are given below: (a) 1,3-Diphenyl-1-
pentanone (97% ee): ½a D24
ꢂ
+7.1 (c 2.0, EtOH); lit.19a [96% ee, (S)-isomer: ½a 2D4
ꢂ
+6.07
(c 5.85, EtOH)] (Table 1, run 13). (b) 3-(4-Chlorophenyl)-1-phenyl-1-pentanone
(97% ee): ½a 2D4
ꢂ
+1.9 (c 2.0, EtOH); lit.14a [99% ee, (S)-isomer: ½a 2D4
ꢂ
+1.5 (c 1.13,
EtOH)] (Table 2, run 1). (c) 3-(4-Methoxyphenyl)-1-phenyl-1-pentanone (96%
ee): ½a 2D4
ꢂ
+15.9 (c 2.0, EtOH); lit.19a [96% ee (S)-isomer: ½a 2D4
ꢂ
+15.5 (c 0.98, EtOH)]
(Table 2, run 2). (d) 1-(4-Methoxyphenyl)-3-phenyl-pentanone (96% ee): ½a D25
ꢂ
ꢀ2.3 (c 2.1, EtOH); lit.19a [97% ee (S)-isomer: ½a 2D4
ꢂ
-4.0 (c 2.2, EtOH)] (Table 2, run
4). (e) 1,3-Diphenyl-1-butanone (95 % ee): ½a D25
ꢂ
+13.4 (c 2.0, CCl4); lit.19b [82% ee
(R)-isomer: ½a 2D5
ꢀ13.5 (c 1.0, CCl4)] (Table 2, run 5). (f) 4-Phenyl-2-hexanone
ꢂ
(69% ee): ½a 2D4
ꢂ
ꢀ20.9 (c 2.0, EtOH); lit.15a [90% ee, (S)-isomer; ½a 2D4
ꢂ
+25.4 (c 0.16,
EtOH)] (Table 2, run 12).
19. (a) Shi, M.; Wang, C.-J.; Zhang, W. Chem. Eur. J. 2004, 10, 5507–5516; (b)
Kanazawa, Y.; Tsuchiya, Y.; Kobayashi, K.; Shiomi, T.; Itoh, J.-I.; Kikuchi, M.;
Yamamoto, Y.; Nishiyama, H. Chem. Eur. J. 2006, 12, 63–71; (c) Alexakis, A.;
Benhaim, C.; Rosset, S.; Humam, M. J. Am. Chem. Soc. 2002, 124, 5262–
5263.
20. (a) Harutyunyan, S. R.; López, F.; Browne, W. R.; Correa, A.; Peña, D.; Badorrey,
R.; Meetsma, A.; Minnaard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2006, 128, 9103–
9118; (b) García, J. M.; González, A.; Kardak, B. G.; Odriozola, J. M.; Oiarbide,
M.; Razkin, J.; Palomo, C. Chem. Eur. J. 2008, 14, 8768–8771.
21. With acyclic enones ees of conjugate addition are generally <90%. For
exceptions, see: (a) Hu, X.; Chen, H.; Zhang, X. Angew. Chem., Int. Ed. 1999,
38, 3518–3521; (b) Mizutani, H.; Degrado, S. J.; Hoveyda, A. H. J. Am. Chem. Soc.
2002, 124, 779–781; (c) Duncan, A. P.; Leighton, J. L. Org. Lett. 2004, 6, 4117–
4119; (d) Takahashi, Y.; Yamamoto, Y.; Katagiri, K.; Danjo, H.; Yamaguchi, K.;
Imamoto, T. J. Org. Chem. 2005, 70, 9009–9012.
22. The reaction of 2-cyclohexen-1-one and diethylzinc in the presence of 4f at
ꢀ10 °C for 24 h was poorly selective (3% ee, 54% yield).