Highly efficient alkylation to ketones and aldimines with Grignard reagents catalyzed by zinc(II) chloride

Article abstract of DOI:10.1021/ja0628405

A highly efficient alkylation to ketones and aldimines with Grignard reagents in the presence of catalytic trialkylzinc(II) ate complexes derived from ZnCl₂ (10 mol %) in situ was developed. This simple Zn(II)-catalyzed alkylation could minimize the well-known but serious problems with the use of only Grignard reagents, which leads to reduction and aldol side products, and the yield of desired alkylation products could be improved. Copyright

Full text of DOI:10.1021/ja0628405

Published on Web 07/14/2006
Highly Efficient Alkylation to Ketones and Aldimines with Grignard Reagents
Catalyzed by Zinc(II) Chloride
Manabu Hatano, Shinji Suzuki, and Kazuaki Ishihara*
Graduate School of Engineering, Nagoya UniVersity, Furo-cho, Chikusa, Nagoya 464-8603, Japan
Received April 24, 2006; E-mail: ishihara@cc.nagoya-u.ac.jp
Table 1. Ethylation to Benzophenone with Organometal
For carbon-carbon bond-forming reactions, the addition of
Reagentsa
organometal reagents to ketones is a versatile method for synthesiz-
ing tertiary alcohols.1,2 However, Grignard and alkyllithium reagents
for ketones (1) give the desired adducts (2) along with (1) com-
petitive reduction products (3) due to the â-hydride transfer of alkyl
groups and (2) aldol adducts (4) due to enolization by their strong
yield (%)
yield (%)
basicity (eq 1).3 Recently, the addition of stoichiometric or an excess
entry
EtMX
of 6b [7]
entry
EtMX
of 6b [7]
amount of CeCl3,3 LiCl,4 LiClO4,5 FeCl2,6 and LnCl3‚2LiCl7 with
Grignard reagents has shown good results with smooth alkylations
and minimum side products. These additive effects were based on
either a stoichiometric Lewis acid activation of carbonyl compounds
or enhancement of the nucleophilicity of stoichiometric alkylation
reagents (e.g., RCeCl2, RMgCl2‚Li, etc.), which were prepared in
situ from oligomeric Grignard reagents by binary metal complexa-
tions or transmetalations. While somewhat expensive LnCl3 (Ln
) La, Ce) salts have been the best alternatives to date, these stoichi-
ometric compounds must be synthesized prior to use.3,7 In our pre-
vious research, trialkylmagnesium(II) ate complexes, as good alkyl-
ation reagents with weak basicity, namely, R3MgLi, which can be
easily prepared from Grignard reagents (RMgX) and alkyllithiums
(RLi) in situ,8 have improved the efficiency of alkylation to ketones
(eq 1).9 However, in that case, more than equimolar amounts of
expensive RLi (1-2 equiv) were indispensable. To overcome these
problems, we report here the highly efficient alkylation to ketones
and aldimines with Grignard reagents in the presence of catalytic
trialkylzinc(II) ate complexes (R3ZnMgCl) derived from ZnCl2 in
situ. The catalytic use of simple and inexpensiVe ZnCl2 without
further purification, instead of above stoichiometric additives, would
offer significant advantage over the existing technologies.
1
2
3
4
5
6
EtLi
EtMgCl
EtMgBr
Et2Zn
64 [30]
25 [71]
20 [78]
5 [0]
7
8
9
EtMgCl + LiClO4
Et2Zn + LiCl
18 [57]
0 [0]
85 [6]
EtMgCl + Et2Zn
10b EtMgCl + cat. Et2Zn 84 [15]
EtMgCl + LiCl
22 [70] 11c EtMgCl + cat. ZnCl2 84 [15]
EtMgCl + LiOBut 22 [70] 12d EtMgCl + cat. ZnCl2 70 [28]
a EtMX (1.1 equiv) was used unless otherwise noted. b EtMgCl (1.1
equiv) and Et2Zn (10 mol %) were used. c EtMgCl (1.3 equiv) and ZnCl2
(10 mol %) were used. d EtMgCl (1.2 equiv) and ZnCl2 (5 mol %) were used.
Table 2. Alkylation to Benzophenone Catalyzed by ZnCl2
Yield (%)
Yield (%)
of 6 [7]
of 6 [7]
entry
R
with Zn
without Zn entry
R
with Zn
without Zn
1
2
Me
Et
6a 94 [0] 91 [0]
6
s-Bu 6f 50 [23] 43 [26]
6b 84 [15] 25 [72] 7a c-Hex 6g 57 [9]
51 [14]
92 [0]
6i >99 [0] >99 [0]
6j >99 [0] 90 [0]
3a n-Pr 6c 71 [29] 14 [86]
8
9
vinyl 6h 96 [0]
allyl
4
i-Pr 6d 75 [10] 62 [14]
5b n-Bu 6e 74 [24] 11 [81] 10 Bn
a Solvent was Et2O. b ZnCl2 (30 mol %) and n-BuMgCl (1.7 equiv) were
used.
next examined other alkylations to 5 with various Grignard reagents
(1.3 equiv) in the presence of 10 mol % of ZnCl2 (Table 2). As
expected, some alkylations with only Grignard reagents gave rise
to reduction product 7 in considerable yield. In contrast, with the
use of 10 mol % of ZnCl2, not only Et adduct 6b but also Me,
n-Pr, i-Pr, n-Bu, s-Bu, and c-Hex adducts (6a,c-g) were obtained
with improvements in decreasing side product 7 (entries 1 and 3-7).
Vinyl, allyl, and Bn addition, in which â-H transfer (i.e., reduction)
is not probable, also proceeded with slight improvements in yield
for 6h-j when 10 mol % of ZnCl2 was added (entries 8-10).
Next, isopropylation to ketone 8 with i-PrMgCl (1.3 equiv) in the
presence of 10 mol % of ZnCl2 was examined because sec-RMgX
often prefers reduction to the desired alkylation (Table 3). For aryl
or heteroaryl ketones, the reactions proceeded smoothly to give the
desired i-Pr adducts (9) in >75% yield (entries 1-3 and 5-11).
Double isopropylation to an ester gave 9c in 80% yield (entry 4).
Aliphatic ketones, such as cyclohexanone and 2-adamantanone, were
also suitable for this alkylation system using catalytic ZnCl2, and iso-
propylation was improved to 51-52% yield (entries 12 and 13).
Particularly, 2-alkyl-2-adamantanol is a useful photoresistant mate-
rial,12 but the reduction occurs in preference to the desired alkylation
when only Grignard reagents are used.13 In our method, a 100 mmol
First, ethylation to benzophenone (5) with organometal reagents
(1.1 equiv) was examined in THF at 0 °C for 2 h. EtLi, EtMgCl,
EtMgBr, and Et2Zn were ineffective, and the Et adduct (6b) was
obtained in 0-64% yield along with a large amount (up to 78%)
of the undesired reduction product (7) (Table 1, entries 1-4). A
salt effect of LiCl, LiOBut, or LiClO4 with EtMgCl or Et2Zn for 5
was not clearly observed (entries 5-8). However, the combined
use of EtMgCl (1.1 equiv) and Et2Zn (1.1 equiv), that is, in situ
preparation of stoichiometric Et3ZnMgCl, promoted the Et addition
reaction, and 6b was obtained in 85% yield as a major product
(entry 9). Interestingly, a catalytic amount of Et2Zn (10 mol %),
which led to 10 mol % of Et3ZnMgCl, was still effective and gave
6b in 84% yield (entry 10). Preparation of Et3ZnMgCl from ZnCl2
(10 or 5 mol %) and EtMgCl (1.3 or 1.2 equiv) also gave the desired
tertiary alcohol 6b in 84 or 70% yield, respectively (entries 11 and
12).10,11 We thus can come to use convenient RMgX independent
of the availability of dialkylzinc reagents (R2Zn). Therefore, we
9
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J. AM. CHEM. SOC. 2006, 128, 9998-9999
10.1021/ja0628405 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Isopropylation to Ketones Catalyzed by ZnCl2
Yield (%) of 9 [10]
entry
ketone (8)
with ZnCl2
without ZnCl2
1
2
PhC(dO)Me (8a)
9a
9b
9c
9c
9d
9e
9f
9g
9h
9i
85 [0]
95 [0]
87 [12]
80 [12]
78b [20]
76 [0]
76 [0]
80 [6]
91 [0]
86 [0]
80 [7]
60 [-]
52b [27]
31 [11]
56 [38]
38 [59]
61 [29]
23c [73]
33 [12]
35 [12]
20 [36]
40 [0]
PhC(dO)Et (8b)
3
PhC(dO)Pri (8c)
4a
5
PhC(dO)OEt
Figure 1. Proposed catalytic cycle and transition-state assembly.
PhC(dO)CF3 (8d)
R-NaphC(dO)Me (8e)
â-NaphC(dO)Me (8f)
R-tetralone (8g)
2-thienylC(dO)Me (8h)
3-thienylC(dO)Me (8i)
4-pyridylC(dO)Me (8j)
cyclohexanone (8k)
2-adamantanone (8l)
6
7
8
9
10
11
12
13
mation,16,17 and then [R2Zn-R]- would attack the activated sub-
strate followed by release of the corresponding adduct and the re-
generation of R3ZnMgCl. The key to promoting this catalytic system
was the careful control of R3ZnMgCl reagent between the decreased
basicity and the increased nucleophilicity from the original Grignard
reagent.
29 [8]
9j
9k
9l
73 [11]
43 [-]
16c [78]
In summary, we have developed a highly efficient alkylation to
ketones and aldimines with Grignard reagents using catalytic ZnCl2.
This simple Zn(II)-catalyzed alkylation via trialkylzinc(II) ate
reagents could relieve the serious problems of reduction and aldol
reactions and give the desired alkylation products in high yield.
Further applications to other reactions mediated by trialkylzinc(II)
ate compounds are now under investigation.
a i-PrMgCl (2.5 equiv) was used. b ZnCl2 (30 mol %), LiCl (1.1 equiv),
and i-PrMgCl (1.7 equiv) were used. c LiCl (1.1 equiv) was added.
a
Table 4. Alkylation to Aldimine Catalyzed by ZnCl2
Acknowledgment. Financial support for this project was
provided by the JSPS, KAKENHI (15205021), and the 21st Century
COE Program of MEXT.
Supporting Information Available: Experimental procedures. This
material is available free of charge via the Internet at http://pubs.acs.org.
Yield (%) of 13
with without
Zn Zn
Yield (%) of 13
with
Zn
without
Zn
entry
R
entry
R
1b
Et
13a 81 41
13b 89 65
13c 82 28
7
8
9
n-Oct 13g 73
vinyl 13h 86
54
51
2b,c n-Pr
References
3
4
i-Pr
allyl
Bn
13i >99
13j >99
>99
>99
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examined aldimine 12 with Grignard reagents in the presence of
10 mol % of ZnCl2 (Table 4). In principle, aldimines are less
reactive than ketones due to their weak electrophilic nature, and
alkylation with Grignard reagents has not been easy.2,14 As expected,
the alkylation of 12 with only Grignard reagent at room temperature
was slow as it progressed to full conversion. In contrast, ZnCl2
promoted the alkylation, and the desired amines 13a-j were
obtained in high yield (73-99%) for 2-24 h. Alkylation to N-Ts
imines also proceeded selectively (entries 11 and 12).15
Finally, a plausible catalytic cycle including transition-state as-
sembly in this ZnCl2-catalyzed alkylation to ketones and aldimine
with Grignard reagents is shown in Figure 1. Interestingly, Zn(OTf)2
(g10 mol %) as a strong Lewis acid was not effective. Thus, this
unique catalytic system should be based on trialkylzinc(II) ate com-
plexes, R3ZnMgCl. First, R3ZnMgCl is generated via R2Zn from
ZnCl2 and RMgCl. R3ZnMgCl reagent coordinates to ketone (or aldi-
mine) at the [MgCl]+ moiety by a six-membered ring chair confor-
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(15) Et addition to less reactive PhCHdNBn proceeded in 27% yield with
catalyst ZnCl2 and in 12% yield without ZnCl2.
(16) When LiCl is used as a co-additive, the [MgCl]+ moiety may change to
[Li]+. Further investigations for the mechanistic aspects are underway.
(17) Six-membered ring assembly was proposed as in (CH3)nMLi ate complexes
(M ) Mg, Al, and Zn): Ashby, E. C.; Chao, L.-C.; Laemmle, J. J. Org.
Chem. 1974, 39, 3677. Also see ref 8f.
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