Angewandte
Chemie
Table 3: Addition of aryl- and benzylzinc reagents complexed with MgCl2
to carbon dioxide.
dicyclopropyl ketone (2h) and cyclopentanone (2i) pro-
ceeded in 2 h and 12 h, respectively, leading to the alcohols
3h,i in 84% and 87% yield (entries 4 and 5 in Table 1).[18]
Entry
Zinc reagent[a]
Product[b,c]
Bis(2-trifluoromethylphenyl)zinc·2MgX2
(6b)
reacted
1
2
3
4
5
(p-MeOC6H4)2Zn·2MgX2
p-MeOC6H4CO2H
12a: 84% (258C, 3 h)
p-Me3SiC6H4CO2H
12b: 73% (258C, 6 h)
p-MeOC6H4CH2CO2H
12c: 98% (258C, 2 h)
m-CF3C6H4CH2CO2H
12d: 86% (508C, 12 h)
o-FC6H4CH2CO2H
smoothly with a heterocyclic aldehyde such as 2j furnishing
the pyridyl alcohol 3j in 82% yield (entry 6 in Table 1). The
electron-rich arylzinc reagent bis(4-trimethylsilylphenyl)-
zinc·2MgX2 (6c) added to 4-cyanobenzaldehyde (2g) in
almost quantitative yield giving the benzhydryl alcohol 3k
(entry 7 in Table 1). Also, bis(4-N,N-dimethylaminophenyl)-
zinc·2MgX2 (6d) reacted with the ketone 2h in 24 h leading to
the desired product 3l (74%; entry 8 in Table 1). The bis(5-
pyrazolyl)zinc species[19] 6e as well as the bis(1,2-oxazol-4-
yl)zinc compound 6 f added to substituted benzaldehydes 2k,l
providing heterocyclic secondary alcohols 3m,n in 83% and
91% yield, respectively (entries 9 and 10 in Table 1).
6a[d]
(p-Me3SiC6H4)2Zn·2MgX2
6c[d]
(p-MeOC6H4CH2)2Zn·2MgCl2
9b
(m-CF3C6H4CH2)2Zn·2MgCl2
9c
(o-FC6H4CH2)2Zn·2MgCl2
9d
12e: 98% (258C, 12 h)
[a] Complexed LiCl has been omitted for clarity. [b] Yield of isolated,
analytically pure product. [c] The reaction conditions with CO2 are
indicated. [d] X=Cl, Br.
Benzylic zinc reagents are similarly activated by the
presence of MgCl2. Thus, the ester-substituted benzylic zinc
reagent 8a smoothly added within 16 h to trifluoromethyl
phenyl ketone (2d) leading to the tertiary alcohol 3o in 87%
yield (entry 1 in Table 2). Various electron-poor benzylic zinc
reagents such as 8b,c added to cyclohexanecarbaldehyde
(2m), a-tetralone (2n), and benzophenone 2o providing the
products 3p–r in 74–97% yield (entries 2—4 in Table 2).
4-Methoxybenzylzinc chloride·MgCl2 (8d) reacted well with
4-acetylbenzonitrile (2p) furnishing the benzylic alcohol 3s in
74% yield (entry 5 in Table 2).
to the benzoic acid 12b in 73% yield (entry 2 in Table 3).
Dibenzylzinc reagents of type 9 reacted especially well and
smoothly provided the corresponding phenylacetic acids 12c–
e in 86–98% yield (entries 3–5 in Table 3).
Substituted phenylacetic acids often have useful pharma-
ceutical properties.[23] As an application of our method, we
report a short four-step synthesis of ibuprofen (13)[24] from the
commercially available ketone 2b without transition-metal
catalysis and purification steps (Scheme 2). Thus, the reduc-
tion of 2b with NaBH4 followed by chlorination using thionyl
chloride provided the benzylic chloride 14 in 94% yield over
two steps. The corresponding benzylzinc reagent 15 was
readily obtained in 70% yield. This secondary benzylic zinc
halide of type 8 was sufficiently reactive to undergo addition
to CO2 to produce ibuprofen (13) in 89% yield.[25]
The acceleration effect of MgCl2 may be rationalized by
assuming that the usual six-membered transition-state 16 is
modified by the presence of MgCl2.[26] Thus, R3ZnCl, which
complexes the carbonyl group, is replaced by MgCl2 (see
transition-state 17; Scheme 3). Since MgCl2 is a stronger
Lewis acid than R3ZnCl, more effective activation of the
carbonyl group towards the addition of the zinc reagent is
expected. Our results show that the addition of an organo-
Instead of benzylic zinc chlorides of type
8
(ArCH2ZnCl·MgCl2; 1.2 equiv) it is also beneficial to use
dibenzylzinc compounds of type 9 ((ArCH2)2Zn·2MgCl2;
0.6 equiv). Usually both benzylic groups are transferred to the
electrophile. Recently, it has been reported by Arrayas,
Carretero,[20a] and Charette[20b] that both aryl N-(2-pyridyl-
sulfonyl)aldimines and CuII catalysis are required for the
addition of various zinc reagents. However, the presence of
MgCl2 allows direct addition of organozincs to N-tosylimines.
Thus, the reaction of the benzylic zinc reagent 9a with the N-
tosylimine 2q afforded the expected N-tosylamine derivative
3t in 86% yield within 24 h at 258C (entry 6 in Table 2).[20c] As
already shown in Equation (4) of Scheme 1, functionalized
alkylzinc bromides prepared by the Mg/ZnCl2/LiCl method[12]
readily add to aldehydes and ketones. Thus, EtO2C-
(CH2)3ZnBr·MgCl2 (11b) added to the aldehyde 2g and a-
tetralone (2n) in 6 h and 12 h, respectively, leading to the
lactones 3u,v in 65% and 70% yield (entries 7 and 8 in
Table 2). The related zinc reagent EtO2C(CH2)5ZnBr·MgCl2
(11c) added to the trifluoromethyl ketone 2d within 24 h at
258C leading to the tertiary alcohol 3w in 60% yield (entry 9
in Table 2).
Scheme 2. Synthesis of ibuprofen (13) by carboxylation of the benzyl-
zinc reagent 15. Reagents and conditions: a) NaBH4 (1.5 equiv),
MeOH, reflux, 2 h; b) SOCl2 (1.0 equiv), CH2Cl2, 258C, 12 h; c) Mg
turnings (2.5 equiv), LiCl (1.25 equiv), ZnCl2 (1.1 equiv), THF, 258C,
2 h; d) CO2 (1 bar), THF, 258C, 12 h then 508C, 12 h.
Remarkably, the presence of MgCl2 allows the addition of
aryl and benzylic zinc reagents to CO2 (1 bar) at 25–508C in
THF without the use of a polar solvent.[21] It is advantageous
to use diorganozinc reagents of type 6 (Ar2Zn·2MgX2) and 9
((ArCH2)2Zn·2MgCl2). With these reagents, both organic
groups are transferred to CO2. Thus, bis(4-methoxyphenyl)-
zinc·2MgX2 (6a) added in THF to CO2 (1 bar, 258C, 3 h)
providing 4-methoxybenzoic acid (12a) in 84% yield (entry 1
in
Table 3).[22]
Similarly,
bis(4-trimethylsilylphenyl)-
Scheme 3. Tentative MgCl2-modified six-membered transition state for
zinc·2MgX2 (6c) was carboxylated within 6 h at 258C leading
the addition of R3ZnCl to a carbonyl substrate R1R2CO.
Angew. Chem. Int. Ed. 2010, 49, 4665 –4668
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim