Communications
tivity (g/a 62:38). An isolated air-stable NHC–CuCl complex
The enantioselective arylation of o-methylcinnamyl bro-
mide (1 f) with p-fluoro-, p-chloro-, and p-methylphenyl
Grignard reagents proceeded in high yield with excellent
regio- and enantioselectivity (up to 96% yield, g/a 97:3,
98% ee; Table 3, entries 1–3). High regio- and enantioselec-
C1 derived from L4 also gave comparable results to afford g-
2a with 96% ee and a g/a ratio of 67:33 (Table 1, entry 4). We
speculated that a ligand with bulky Ar groups might improve
the regioselectivity by enhancing the rate of the reductive
elimination step of the initially formed g-s-allyl–CuIII inter-
mediate.[14] As expected, an isolated air-stable NHC–CuCl C2
derived from L5, having an ortho-methyl group on the phenyl
moieties (Ar= 2-MeC6H4), dramatically increased the g se-
lectivity to 93:7 without affecting the high enantioselectivity
(95% ee; Table 1, entry 5).
Table 3: Copper-catalyzed asymmetric allylic arylation of 1c and 1 f using
various aryl Grignard reagents.
Having established the optimal catalyst for cinnamyl-type
substrates (Table 1, entry 5), we evaluated the arylation of
other substrates. The reaction of substrates with electron-
deficient aryl moieties, for example, a chloro substituent at
the ortho, meta, or para position or a para-trifluoromethyl
group, gave the g products g-2a–e with 92–96% ee and high
regioselectivity (ꢁ 93:7) in high yield (Table 2, entries 1–5).
Moreover, sterically demanding o-tolyl substrate 1 f gave an
Entry
1
Ar1
Ar2
2
Yield [%][a] g/a[b] ee [%][c]
1
2
3
1 f 2-MeC6H4 4-FC6H4
1 f 2-MeC6H4 4-ClC6H4
1 f 2-MeC6H4 4-MeC6H4
2i 96
2j 96
2k 94
97:3
94:6
96:4
97
97
98
4
1c 2-ClC6H4
2l 68[d]
97:3
92
[a] Yield of isolated product. [b] Determined by GC or 1H NMR analysis of
the crude reaction mixture. [c] Determined by HPLC analysis on a chiral
stationary phase after conversion into the corresponding terminal
alcohol by hydroboration/oxidation or GC analysis on a chiral stationary
phase. [d] Reaction run for 1 h. 1c was recovered in 22% yield.
Table 2: Copper-catalyzed asymmetric allylic arylation of cinnamyl-type
substrates using PhMgBr.
tivity (g/a 97:3, 92% ee) were also observed with the
methylenedioxyphenyl Grignard reagent leading to g-2l in
acceptable yield (68%) along with 22% recovery of the
starting material (Table 2, entry 4).
The ee value of g-2e was determined after transformation
into alcohol 3, the enantiomer of an alcohol with established
stereochemistry,[17] using a hydroboration/oxidation protocol
(Scheme 2). Product 3 is an intermediate in the synthesis of
sertraline, a major pharmaceutical for the treatment of
depression.
Entry
1
Ar1
2
Yield [%][a]
g/a[b]
ee [%][c]
1
2
3
4
5
6
1a
1b
1c
1d
1e
1 f
1 f
1 f
1 f
1g
1h
4-ClC6H4
3-ClC6H4
2-ClC6H4
2a
2b
2c
2d
2e
2 f
2 f
2 f
2 f
2g
2h
96
99
99
99
99
99
99
98
99
91
97
93:7
95:5
96:4
93:7
95:5
95:5
97:3
93:7
90:10
94:6
75:25
95
93
96
93
92
98
97
98
97
93
93
4-CF3C6H4
3,4-Cl2C6H3
2-MeC6H4
2-MeC6H4
2-MeC6H4
2-MeC6H4
2-MeOC6H4
1-naphthyl
7[d]
8[e]
9[f]
10
11[g]
[a] Yield of isolated product. [b] Determined by GC analysis on a chiral
1
stationary phase or by H NMR analysis of the crude reaction mixture.
[c] Determined by HPLC analysis on a chiral stationary phase after
conversion into the corresponding terminal alcohol by hydroboration/
oxidation or by chiral GC analysis. [d] Used 4 mol% of C2. [e] Used
1 mol% of C2. [f] Used 0.5 mol% of C2. [g] Reaction run for 1 h.
unprecedented high enantioselectivity (98% ee) and a high g/
a ratio (95:5; Table 2, entry 6). The catalyst amount affected
the selectivity of the reaction;[11] gradually decreasing the
catalyst loading from 4 to 0.5 mol% did not affect the
enantioselectivity, whereas the g/a ratio decreased from 97:3
to 90:10 (Table 2, entries 7–9). These results indicate that the
high catalyst loading accelerated the reaction, thereby
preventing the formation of the undesirable diphenylcuprate
intermediate, which might lead to an a product through p-
allyl equilibration.[15] The optimum amount of C2 was
determined to be 2 mol%. Allylic bromide 1g with an o-
methoxy group afforded g-2g with 93% ee and 94:6 g/a
selectivity (Table 2, entry 10). The more sterically hindered
naphthyl substrate 1h gave g-2h with 93% ee in 75:25
regioselectivity (Table 2, entry 11).[16]
Scheme 2. Conversion of g-2e into 3, a synthetic intermediate of
sertraline. 9-BBN=9-borabicyclo[3.3.l]nonane, THF=tetrahydrofuran.
In conclusion, we developed an air-tolerant monodentate
chiral NHC–CuCl catalyst for highly enantio- and g-selective
copper-catalyzed allylic arylation of cinnamyl bromides using
aryl Grignard reagents, which affords the versatile chiral
building blocks diarylvinylmethanes.
Experimental Section
Typical procedure for the AAAr reaction (Table 2, entry 1): A dry
10 mL tube was charged with NHC–CuCl catalyst C2 (7.1 mg,
8734
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2009, 48, 8733 –8735