Zinc chloride enhanced arylations of secondary benzyl trifluoroacetates in the presence of b-hydrogen atoms

Article abstract of DOI:10.1002/anie.201002116

Zinc or swim: Arylation of benzyl trifluoroacetates with arylzinc reagents in the presence of β- hydrogen atoms were realized under mild conditions. Both electron-rich and electron-deficient arene substrates were successfully arylated. This arylation method could offer a very versatile synthetic route to access a series of diversity-oriented diarylalkane motifs. TFA = trifluoroacetyl. Copyright

Full text of DOI:10.1002/anie.201002116

Angewandte
Chemie
DOI: 10.1002/anie.201002116
Cross-Coupling
Zinc Chloride Enhanced Arylations of Secondary Benzyl
Trifluoroacetates in the Presence of b-Hydrogen Atoms**
Hui Duan, Lingkui Meng, Denghui Bao, Heng Zhang, Yao Li, and Aiwen Lei*
À
During the past three decades, carbon carbon bond forma-
tion has been one of the central themes in synthetic chemistry.
electrophile and an aryl nucleophile, were mainly produced
using transition-metal-catalyzed reactions.[30,41–53] Beller and
À
Among the variety of C C bond-formation reactions, tran-
co-workers described two elegant benzylation reactions using
a Friedel–Crafts arylation strategy of secondary benzyl
sition-metal-catalyzed coupling reactions have been exten-
sively studied and widely applied.[1–9] However, those tran-
sition-metal-catalyzed reactions involving alkyl groups have
encountered inherent problems owing to the sluggish reduc-
tive elimination and facile b-hydride elimination steps.[10,11]
Many efforts have been made to overcome this difficulty with
some success.[12–36] However, as shown in Figure 1, the
arylation of secondary benzyl derivatives, especially in the
derivatives with electron-rich arene nucleophiles.[54,55]
A
cobalt-catalyzed arylation of benzyl chloride derivatives
with aryl zinc reagents has also been described.[49,50] In
general, there is still a lack of efficient methods to build new
À
C C bonds between secondary benzyl derivatives and arenes.
In order to investigate the capability of the phosphine-
olefin ligands,[56,57] our research interest focused on exploring
the potential reaction between secondary benzyl derivatives
and aryl zinc reagents. Unexpectedly, all of the reactions
employing palladium catalysts failed. Interestingly, the reac-
tion did work without palladium catalysts. After further
investigation, we found that ZnCl2 played a key role in the
reaction. Herein, we report these observations.
To examine the bond formation between a secondary
benzyl electrophile and aryl zinc reagents, we initially tested
the reaction of 1 with 2a (prepared from PhLi with 1.4 equiv
of ZnCl2) in the presence of a Pd(OAc)2/dppf catalyst. No
conversion of starting material was identified by GC for the
reaction of 1a with 2a (Table 1, entry 1). The reactions of 1b
and 1c with 2a in the presence of Pd(OAc)2/dppf and toluene
as the solvent led to consumption of the electrophiles with
only trace amounts of the desired arylation product 3aa
observed (Table 1, entries 3 and 4). To our delight, when
À
Figure 1. The theme of C C bond formations.
presence of b-hydrogen atoms, remains a challenge in this
field.
Diarylalkane fragments are key components of several
pharmacologically active compounds, such as Phenindamine
and Fluspirilene.[37] Theoretically, an aryl nucleophile could
undergo a nucleophilic substitution with primary benzyl
derivatives in the traditional manner. However, owing to
steric hindrance, it is less effective when the electrophiles are
secondary benzyl derivatives. Only a few results have been
reported in the literature.[38–40] In fact, even the most simple
diarylmethanes, involving a primary benzyl derivative as the
Table 1: Arylation of 1 with phenylzinc chloride 2a.[a]
Entry LG
Solvent
Catalyst
Conv. 1 [%] Conv. 3aa [%]
1
2
3
4
5
6
7
8
9
OH 1a
THF dppf, Pd(OAc)2
0
0
0
0
OAc 1d toluene dppf, Pd(OAc)2
OMs 1b
OTFA 1c THF dppf, Pd(OAc)2 80
OTFA 1c toluene dppf, Pd(OAc)2 100
OH 1a
OTFA 1c toluene
OTFA 1c THF
OAc 1d toluene
THF dppf, Pd(OAc)2 100
trace[b]
<1[c]
84
[*] H. Duan, L. Meng, D. Bao, Prof. H. Zhang, Y. Li, Prof. A. Lei
College of Chemistry and Molecular Sciences, Wuhan University
Wuhan, Hubei, 430072 (P. R. China)
toluene dppf, Pd(OAc)2
0
100
54
0
95
36
0
none
none
none
Fax: (+86)27-6875-4067
E-mail: aiwenlei@whu.edu.cn
0
Homepage: http://www.chem.whu.edu.cn/GCI_WebSite/
main.htm
[a] Reaction conditions: 1 (1.8 mmol), 2a (2.5 mmol; prepared from
PhLi with 1.4 equiv of ZnCl2), solvent (4.0 mL), 508C, 24 h; conversion
was determined by GC with biphenyl as an internal standard. [b] 1-
Chloroethyl-benzene was the major product. [c] Styrene was the major
product. LG=leaving group, THF=tetrahydrofuran, Ac=acetyl, TFA=
trifluoroacetyl, dppf=1,1’-bis(diphenylphosphino)ferrocene.
[**] This work was supported by the National Natural Science
Foundation of China (20702040, 20832003, and 20972118).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002116.
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Table 3: Substrate scope of the arylation of benzyl trifluoroacetates.[a]
toluene was used as the solvent, the reaction of 1c with 2a
gave 84% conversion to 3aa (Table 1, entry 5). The reactions
of 1a and 1d with 2a were then re-examined in toluene;
however, no desired product was observed when 1a and 1d
were employed as electrophilic components (Table 1,
entries 6 and 2, respectively). Unexpectedly, the reaction of
1c with 2a in toluene produced 95% arylation of 3aa without
a palladium catalyst (Table 1, entry 7), whilst the reaction of
1c with 2a in tetrahydrofuran afforded only 36% 3aa
(Table 1, entry 8). There was almost no reaction between 1d
and 2a in toluene without a palladium catalyst (Table 1,
entry 9).
Entry
1
2
1g 2a
1g 2b
3
Yield
[%]
1
2
3ga
3gb
98
77
Table 2 shows the results of the reactions of 1c with
various organozinc reagents 2 under the same conditions as
shown in Table 1, entry 7. Good to excellent yields were
3
4
5
6
1g 2c
1g 2e
1h 2a
1h 2d
3gc
3ge
3ha
3hd
80
81
92
83
Table 2: Arylation of secondary benzyl trifluoroacetate 1c with different
arylzinc reagents 2.[a]
Entry
1
2
3
Yield [%]
76
2a
2b
3aa
3ab
7
1h 2e
1e 2a
1e 2d
1e 2e
3he
3ea
3ed
3ee
75
94
73
84
2
90
8
3
4
5
2c
2d
2e
3ac
3ad
3ae
88
88
92
9
10
6
7
2 f
3af
75
79
11
1 f 2b
3 fb
68
2g
3ag
12
13
1 f 2e
1g 2e
3 fe
3ge
46
80
[a] Reaction conditions: 1 (1.8 mmol), 2 (2.5 mmol; prepared from the
ArLi with 1.4 equiv of ZnCl2), toluene (4.0 mL), 508C, 24 h, yield of
isolated product.
obtained from a variety of substituted arylzinc reagents
(Table 2, entries 1–5, and 7). Particularly noteworthy was that
an alkenylzinc reagent 2 f provided 75% of the corresponding
alkenylation product 3af (Table 2, entry 6). When optically
pure electrophile 1c was investigated, complete racemization
was observed.
The substrate scope was then investigated further, and the
arylation reactions of various aryl zinc reagents proceeded
smoothly, providing the products in good to high yields
(Table 3). Not only CH3-substituted but also n-C3H7 (1h)- and
[a] Reaction conditions: 1 (1.8 mmol), 2 (2.5 mmol; prepared from the
ArLi with 1.4 equiv of ZnCl2), toluene (4.0 mL), 508C, 24 h, yield of
isolated product.
n-C7H15 (1e)-substituted benzyl derivatives were examined as
electrophiles in the reaction, and afforded their correspond-
ing products in high yields. Electron-withdrawing groups were
À
also tolerated. Meanwhile, C Br bonds on the phenyl ring
remained intact, and olefin functional groups were also
tolerated under the reaction conditions.
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It is noteworthy that only the arylzinc reagents generated
from the reaction of aryllithiums with ZnCl2 afforded the
desired arylation products in high yields (Table 4, entry 1).
When TMEDA (N,N,N’,N’-tetramethylethylenediamine) was
added as an additive or the arylzinc reagent was prepared
from ArMgX, no arylation reaction took place (Table 4,
Table 4: Arylation of benzyl trifluoroacetate 1c with phenylzinc reagents
prepared by different methods.
Entry
“PhZnCl”
Yield [%]
1
2
3
4
PhLi+ZnCl2
PhLi+TMEDA·ZnCl2
PhMgBr+ZnCl2
76
0
trace[a]
0
Figure 2. Kinetic profiles of the arylation of 1c with (4-FC6H6)2Zn in
the presence of different amounts of ZnCl2.
PhMgBr+TMEDA·ZnCl2
[a] ca. 60% conversion, although a complicated mixture of products was
obtained.
ZnCl2 was present. These important experiments revealed
that ArZnCl could not efficiently react with 1c to form 3ae
under these conditions. The kinetic profiles in Figure 2 clearly
showed that the more ZnCl2 was left, the faster the reaction
proceeded.
LiCl had no effect on the arylation reaction (Table 5,
entry 2); in addition, Zn(OTFA)2 was also not able to
facilitate the reactions (Table 5, entry 3 and 4). When the
reaction was carried out in polar, coordinating solvents, such
as tetrahydrofuran, dimethylacetamide, acetonitrile etc., no
arylation reactions were observed (see the Supporting
Information).
In addition, the zero-order kinetic profiles indicated that
the reaction underwent a ZnCl2-enhanced process, and that
the rate-limiting step was the step after the interactions
between 1c and 2e with the ZnCl2 salt (see the Supporting
Information).
entries 2–4). Indeed, we recently disclosed the potential
differences between the structure and reactivity of
“PhZnCl” reagents.[58] If the “PhZnCl” was prepared from
PhMgBr with ZnCl2, the co-product MgCl2 would aggregate
with PhZnCl in tetrahydrofuran. The detrimental effects of
MgCl2 in this reaction probably indicated that the vacant
coordination site in “PhZnCl” was important for the arylation
of benzyl trifluoroacetate.
The reactions of 1c with 2e in the presence of different
amounts of ZnCl2 were further monitored by in situ IR
spectroscopy (see the Supporting Information); Table 5 and
Figure 2 show the critical role of ZnCl2 in this transformation.
Table 5: Effect of salts on the arylation of benzyl trifluoroacetate with
arylzinc reagents.
In conclusion, a ZnCl2-enhanced arylation of benzyl
trifluoroacetate with arylzinc reagents was investigated. The
b-hydrogen atoms could be tolerated in the substrates. Both
electron-rich and electron-deficient arene substrates were
arylated under the mild reaction conditions. Moreover, the
role of ZnCl2 was unambiguously identified. The newly
developed arylation method could offer a very versatile
synthetic route to access a series of diverse diarylalkanes
motifs. Detailed mechanistic and kinetic investigations are
currently underway in our laboratory.
Entry
Additives (equiv)
Yield [%]
1
2
3
4
5
6
7
–
LiCl
trace
trace
6
2
3
27
88
Zn(OTFA)2 (0.4)
Zn(OTFA)2 (1.2)
ZnCl2 (0.1)
ZnCl2 (0.4)
ZnCl2 (1.2)
Experimental Section
Zn(4-FC6H4)2 did not react with 1c to produce 3ae (Table 5,
entry 1). 0.1 or 0.4 equivalents of ZnCl2 did not efficiently
promote the reaction (Table 5, entry 5 and 6, respectively).[59]
Delightfully, arylation product 3ae was isolated in 88% yield
when ZnCl2 (1.2 equiv) was added to the reaction (Table 5,
entry 7). One could reasonably speculate that the reaction of
Zn(4-FC6H4)2 with ZnCl2 would spontaneously generate 4-
FC6H4ZnCl. When less than 1.0 equivalent of ZnCl2 reacted
with Zn(4-FC6H4)2, only 4-FC6H4ZnCl and excess Zn(4-
FC6H4)2 was expected to form in the reaction mixture, and no
General procedure: A Schlenk tube was charged with 4-fluoro
bromobenzene (2.5 mmol) and 3.0 mL of THF under an argon
atmosphere at room temperature. After cooling to À788C, 1.0 mL of
nBuLi (2.5m) was slowly added to the reaction mixture, and stirred at
À788C for 30 min, then 3.5 mL of a ZnCl2 solution (1.0m in THF) was
slowly added at À788C. After slowly warming to room temperature,
the solution was stirred for one hour, and the solvent was removed
under reduced pressure. Toluene (4.0 mL) was added to the residue.
After the zinc reagent was dispersed, 1c (1.8 mmol) was added to the
mixture. The resulting solution was stirred at 508C for 12 h, then was
quenched with 1m HCl, diluted the mixture with 5 mL of diethyl ether.
Angew. Chem. Int. Ed. 2010, 49, 6387 –6390
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Received: April 9, 2010
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À
Keywords: arylation · C C coupling · cross-coupling ·
diarylalkanes · zinc
.
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[59] The observation that using 0.4 equiv of ZnCl2 produced 27%
yield of desired product may be ascribed to the Schlenk
equilibrium and the remaining ZnCl2 converted the arylzinc
reagent into the cross-coupling product.
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