Zr-catalyzed coupling reaction of alkyl halides, tosylates, and sulfates with β-phenethyl Grignard reagents via styrene-zirconate intermediates

Article abstract of DOI:10.1055/s-2005-871572

β-Phenethylmagnesium chlorides react with alkyl halides, tosylates, and sulfates in the presence of a catalytic amount of Cp₂ZrCl ₂ to afford 2-arylalkanes via alkylation of styrene-zirconate intermediates at the benzylic position. Competitive reaction using mixtures of alkyl halides (alkyl-X; X = F, Cl, Br) showed that the reactivities of the halides increase in the order of alkyl-Cl < alkyl-F < alkyl-Br with the relative rates of 1:19:428. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871572

CLUSTER
1783
Zr-Catalyzed Coupling Reaction of Alkyl Halides, Tosylates, and Sulfates with
b-Phenethyl Grignard Reagents via Styrene–Zirconate Intermediates
Z
r-Catalyz
u
e
d
Couplingnof 2
A
rCH C
H
MgC
T
l
w
ith Alkyl
H
e
alides rao, Shameem Ara Begum, Akihiro Oda, Nobuaki Kambe*
2
Department of Applied Chemistry & Science and Technology Center for Atoms, Molecules and Ions Control, Graduate School of
Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
Fax +81(6)68797390; E-mail: kambe@chem.eng.osaka-u.ac.jp
Received 2 May 2005
benzene, which can be generated by the direct coupling of
Abstract: b-Phenethylmagnesium chlorides react with alkyl ha-
ethyl tosylate with the Grignard reagent, was obtained.
Table 1 summarizes representative results of the reaction
using various alkylating reagents and b-phenethyl
lides, tosylates, and sulfates in the presence of a catalytic amount of
Cp2ZrCl2 to afford 2-arylalkanes via alkylation of styrene–zirconate
intermediates at the benzylic position. Competitive reaction using
mixtures of alkyl halides (alkyl-X; X = F, Cl, Br) showed that the Grignard reagents. Under the same conditions, methyl and
reactivities of the halides increase in the order of alkyl-Cl < alkyl-F
< alkyl-Br with the relative rates of 1:19:428.
octyl tosylates afforded cumene and 2-phenyldecane in
61% and 65% yields, respectively (entries 2 and 3). The
Key words: zirconocene, b-phenethyl Grignard reagent, coupling
reaction, alkyl halide, alkyl tosylate
reaction failed when ethyl triflate was used as the alkylat-
ing reagent due to its high reactivity toward b-phenethyl
Grignard reagent resulting in the formation of n-butylben-
zene, whereas ethyl sulfate afforded s-butylbenzene (1) in
Coupling reaction of alkylmetals with alkyl halides or 84% yield (entry 4). b-Phenethyl Grignard reagents hav-
pseudo halides provides a straightforward method for ing p-chloro and p-methyl substituents also gave the cor-
constructing methylene chains. For such transformations, responding products in 63% and 74% yields, respectively
Cu1 or the late transition metal catalysts2 have often been (entries 5 and 6). 2,2-Diphenylethylmagnesium chloride
employed. We and another group have revealed that underwent alkylation to yield 6 in 70% yield (entry 7).
zirconocene catalyzes hydroalkylation of styrenes in the Primary octyl bromide afforded the corresponding prod-
presence of n-BuMgCl (Scheme 1).3
uct 3 in 52% yield along with octane (29%) as a by-prod-
uct (entry 8), whereas only a trace amount of 3 (2%) was
obtained when 1-chlorooctane was used under the same
conditions. This difference in reactivities explains the se-
lective formation of 1-chloro-7-(4-methylphenyl)octane 5
from 6-chlorohexyl tosylate (entry 6).
cat. Cp2ZrCl2
– butene
Ar
alkyl
Ar
nBu-MgCl
+
X
alkyl
+
H
(X = OTs, OSO3R, Br)
Scheme 1
It should be noted that the present reaction proceeds
efficiently using alkyl fluorides to afford 3 in 80% yield
with suppression of octane formation (<1%, entry 9).6
When cyclohexyl tosylate was employed as an alkylating
reagent, the corresponding coupling product was formed
in 70% yield (entry 10), indicating that secondary alkyl
groups can be manipulated by this reaction.
During the course of this study, we have found that b-
phenethyl Grignard reagents4 react with alkyl halides, to-
sylates, and sulfates to give the same products 2-aryl-
alkanes (Scheme 2).5
Ar
Ar
alkyl
cat. Cp2ZrCl2
+
X
alkyl
XMg
H
In order to examine the reactivity of alkyl halides (R–X;
X = F, Cl, Br) in the present catalytic system, we carried
out following competitive experiments. To a mixture of
equimolar amounts of 1-fluorooctane, 1-chlorohexane,
and 1-bromoheptane were added a THF solution of
PhCH2CH2–MgCl and 5 mol% Cp2ZrCl2 (Scheme 3). GC
analysis of the resulting mixture revealed that the reactiv-
ity of alkyl halides increased in the order of chloride < flu-
oride < bromide.6a
(X = OTs, OSO3R, Br, F)
Scheme 2
For example, into a mixture of ethyl tosylate (2 mmol) and
b-phenethylmagnesium chloride (1.5 equiv) was added a
catalytic amount of zirconocene dichloride (0.05 equiv) at
0 °C, and the solution was stirred at 50 °C for 6 hours. GC
analysis of the crude mixture indicated the formation of s-
butylbenzene (1) in 76% yield (Table 1, entry 1). The
product was obtained in 70% yield by a recycling prepar-
ative HPLC. No evidence for the formation of n-butyl-
To determine the relative reactivities of alkyl halides
quantitatively, we carried out the competitive reaction
between 1-fluorooctane and 1-bromoheptane and the
product ratios of 3 over 9 were plotted against the ratios of
1-fluorooctane:1-bromoheptane in Figure 1. The result
that a linear line was obtained indicates that the reaction
obeys pseudo first order kinetics on the concentration of
SYNLETT 2005, No. 11, pp 1783–1786
0
7
.0
7
.2
0
0
5
Advanced online publication: 27.06.2005
DOI: 10.1055/s-2005-871572; Art ID: Y01105ST
© Georg Thieme Verlag Stuttgart · New York

1784
J. Terao et al.
CLUSTER
Table 1 Zr-Catalyzed Coupling of Alkylating Reagents with b-Phenethyl Grignard Reagentsa
Entry
1
Alkyl–X
Et-OTs
Grignard reagent
Product
Yield (%)b
Ph
70
Ph
ClMg
1
2
Et
2
3
Me-OTs
61
Ph
n-C8H17-OTs
65c
Ph
3
1
n-C8H17
4
5
Et2SO4
Et-OTs
84
63
p-ClC6H4
p-ClC6H4m
ClMg
4
Et
p-MeC6H4m
6
7
Cl(CH2)6-OTs
Et-OTs
74
70
p-MeC6H4
ClMg
ClMg
5
Cl(CH2)6
Ph
Ph
6
Ph
Et
Ph
52c
80c
70
3
3
8
9
n-C8H17Br
n-C8H17F
Ph
Ph
ClMg
ClMg
10
Ph
OTs
7
c-Hex
a Alkylating reagents (2 mmol), b-phenethyl Grignard reagents (3 mmol), and Cp2ZrCl2 (0.1 mmol) were used.
b Isolated yield based on alkyl electrophiles unless otherwise stated.
c GC yield.
Ph
n-C8H17-F
5 mol% Cp2ZrCl2
50 °C, 2 h
n-C6H13-Cl n-C H -Br +
+
+
ClMg
7
15
2 mmol
Ph
2 mmol
2 mmol
2 mmol
Ph
Ph
+
+
n-C8H17
3; 4%
n-C6H13
8; <1%
n-C7H15
9; 27%
Scheme 3
1-fluorooctane. Figure 2 shows a similar result of compet-
itive experiments between 1-fluorooctane and 1-chloro-
hexane. With the slopes of these figures, the relative
reactivities of alkyl-F, alkyl-Cl, and alkyl-Br in the
present reaction were found to be 19:1:428.
Figure 1 Plots of product ratios 3:9 against the ratios of 1-fluorooc-
tane:1-bromoheptane. The reactions were run in the presence of 0.1
mmol of Cp2ZrCl2, 2 mmol of PhCH2CH2MgCl, 2 mmol of 1-bromo-
heptane, and 2 mmol, 4 mmol, 6 mmol, or 10 mmol of 1-fluorooctane
at 25 °C for 1 h. Conversions of alkyl halides were less than 10%.
A plausible reaction pathway is shown in Scheme 4. The
reaction of Cp2ZrCl2 with three equivalents of b-pheneth-
yl Grignard reagent affords a zirconate complex 127 or a
benzylmagnesium complex 13 via bis(b-phenethyl)zir-
conocene complex 10 and styrene–zirconocene complex
11. The intermediates 12 and/or 13 react with alkylating We carried out several control experiments in order to
reagents at the benzylic position giving rise to dialkyl- confirm the validity of this reaction pathway. Firstly, we
zirconocene complex 14.8 The successive intramolecular conducted a stoichiometric reaction of ethyl tosylate with
hydrogen shift affords 15 along with regeneration of 11, styrene–zirconocene complex 11, prepared from
where a b-hydrogen at the less hindered benzylic position Cp2ZrCl2 and two equivalents of b-phenethyl Grignard re-
selectively migrates.9
agent,10 but no s-butylbenzene (1) was formed. On the
Synlett 2005, No. 11, 1783–1786 © Thieme Stuttgart · New York

CLUSTER
Zr-Catalyzed Coupling of ArCH2CH2MgCl with Alkyl Halides
1785
Ph
MgCl
n-Bu3P
Ph
Et
Et
Cp2Zr(H)Cl
Ph
Cp2Zr
Cp2Zr
Ph
Et
Ph
17
Cl
16
Et
Et
+
+
Ph
H
Ph
Ph
1; 94%
93%
<1%
Scheme 6
sult strongly supports the proposed process from 14 to 15
and 11 in Scheme 4 and also explains the site-selectivity
of intramolecular hydrogen shift.
Figure 2 Plots of product ratios of 8:3 against the ratios of 1-chlo-
rohexane:1-fluorooctane. The reactions were run in the presence of
0.1 mmol of Cp2ZrCl2, 2 mmol of PhCH2CH2MgCl, 2 mmol of 1-
fluorooctane, and 2 mmol, 4 mmol, 6 mmol, or 10 mmol of 1-chloro-
hexane at 25 °C for 2.5 h. Conversions of alkyl halides were less than
10%.
In order to confirm the intermediary of styrene complex
11, we carried out a coupling reaction in the presence of
p-methylstyrene and quenched this reaction at early stages
(Scheme 7). The result that coupling product 18 arising
from added p-methylstyrene was formed in similar yields
as those of 3 would suggest that the ligand exchange be-
tween 11 with p-methylstyrene is involved in the present
catalytic reaction system and that the ligand exchange rate
is similar to that of the successive C–C bond forming
process.
MgCl
Ph
MgCl
Cp2Zr
Ph
Cp2ZrCl2
Ph
Ph
Ph
Cp2Zr
– Et–Ph
11
10
–
ClMg Ph
Cp2Zr
Ph
Ph
alkyl
15
H
Cp2Zr
Ph
+
5 mol % Cp2ZrCl2
Ph
MgCl
Ph
n-C8H17-OTs
+
C6H4-Me-p
+
ClMg
2 mmol
50 °C
Ph
12
13
H
Cp2Zr
H
2 mmol
2 mmol
alkyl
alkyl–X
Ph
C6H4-Me-p
+
Ph
H
n-C8H17
n-C8H17
14
3; 9%
18; 12%
5 min
Scheme 4
35%
28%
15 min
Scheme 7
contrary, 1 was obtained in 66% yield when the reaction
was performed in the presence of one equivalent of b-
phenethyl Grignard reagent (Scheme 5). These results
suggest that a key intermediate for the C–C bond-forming
step is not styrene–zirconocene complex 11 but probably
a zirconate complex 12 or a benzylmagnesium halide 13.
In conclusion, we have developed a unique coupling reac-
tion of alkyl tosylates, sulfates, bromides, and fluorides
with b-phenethyl Grignard reagents catalyzed by a zir-
conocene complex. The present reaction provides a new
method for the formation of 2-arylalkanes via C–C bond
formation between a benzylic sp3-carbon and an alkyl sp3-
carbon. The present reaction demonstrates superiority of
alkyl fluorides as alkylating reagents over the correspond-
ing bromides and chlorides, where the latter substrates
may undergo oxidative addition toward ‘Cp2Zr(II)’ lead-
ing to the formation of reduction product.11
Et-OTs
Ph
Ph
Et
1
Cp2Zr
Ph
11
ClMg
Et-OTs
1; 66%
Scheme 5
General Experimental Procedure for the Synthesis of s-Butyl-
benzene (1).
When a stoichiometric reaction of b-phenethyl Grignard
reagent (1 mmol) with monoalkylated zirconocene com-
plex 16, prepared from Cp2Zr(H)Cl and a-ethylstyrene,
was conducted in the presence of n-Bu3P (3 mmol) at
50 °C for 15 minutes, s-butylbenezene was formed in
94% yield along with the equimolar amount of styrene
and a trace amount of a-ethylstyrene (Scheme 6). This re-
To a mixture of EtOTs (401 mg, 2.0 mmol) and PhCH2CH2MgCl
(0.80 M in THF, 3.75 mL, 3.0 mmol) was added Cp2ZrCl2 at 0 °C
under nitrogen. After stirring for 6 h at 50 °C, 1 N HCl (aq) was add-
ed to the solution at 0 °C, and the mixture was again warmed to
25 °C. A sat. NaHCO3 solution (50 mL) was added, and the product
was extracted with Et2O (50 mL), dried over MgSO4, and evaporat-
ed to give a yellow crude product (76% GC yield). Purification by
HPLC with CHCl3 as the eluent afforded 188 mg (70%) of 1.
Synlett 2005, No. 11, 1783–1786 © Thieme Stuttgart · New York

1786
J. Terao et al.
CLUSTER
1-Chloro-7-(4-methylphenyl)octane (6).
(4) Nii, S.; Terao, J.; Kambe, N. J. Org. Chem. 2000, 65, 5291.
(5) It is known that Ni-catalyzed cross-coupling reaction of aryl
halides with isopropyl Grignand reagent affords n-propyl-
benzene as the major product via isomerization of isopropyl
group, see: Kiso, Y.; Tamao, K.; Kumada, K. J. Organomet.
Chem. 1973, 50, C12.
(6) Ni-catalyzed coupling reactions using alkyl fluorides, see:
(a) Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am.
Chem. Soc. 2003, 125, 5646. (b) Terao, J.; Todo, H.;
Watanabe, H.; Kambe, N. Angew. Chem. Int. Ed. 2004, 43,
6180. (c) Terao, J.; Watabe, H.; Kambe, N. J. Am. Chem.
Soc. 2005, 127, 3656.
IR (neat): 2956, 2928, 2856, 1514, 1456, 816 cm–1. 13C NMR (100
MHz, CDCl3): d = 144.5, 135.0, 128.8, 126.7, 45.2, 39.6, 38.4, 32.7,
29.1, 27.7, 26.9, 22.6, 21.1. 1H NMR (400 MHz, CDCl3): d = 7.11–
7.05 (m, 4 H), 3.50 (t, J = 6.7 Hz, 2 H), 2.63 (m, 1 H), 2.32 (s, 3 H),
1.72 (tt, J = 6.7, 7.4 Hz, 2 H), 1.56–1.23 (m, 8 H), 1.21 (d, J = 7.1
Hz, 3 H). MS (El): m/z (relative intensity, %, 35Cl) = 238 (14) [M+],
120 (10), 119 (100), 117 (16), 91 (14). Anal. Calcd for C15H23Cl: C,
75.44; H, 9.71. Found: C, 75.40; H, 9.59.
Acknowledgment
(7) As the similar pathways leading to 12, it has been proposed
that zirconate complex [Cp2ZrEt(CH2=CH2)MgBr] are
formed by the reaction of Cp2ZrCl2 with 3 equiv of EtMgBr,
see: Takahashi, T.; Suzuki, N.; Kageyama, M.; Nitto, Y.;
Saburi, M.; Negishi, E. Chem. Lett. 1991, 1579.
(8) s-Butylbenzene was formed in 81% yield by the direct
reaction of EtOTs with PhCHMeMgBr in THF for 5 min at
50 °C. This result indicates that a-substituted benzyl
Grignard reagents readily react with alkyl electrophiles, see
also: Terao, J.; Saito, K.; Nii, S.; Kambe, N.; Sonoda, N. J.
Am. Chem. Soc. 1998, 120, 11822.
(9) Reactivities of alkyl groups on Zr as b-hydrogen donors, see:
Negishi, E.; Nguyen, T.; Maye, J. P.; Choueiri, D.; Suzuki,
N.; Takahashi, T. Chem. Lett. 1992, 2367.
(10) Negishi, E.; Swanson, D. R.; Takahashi, T. Chem. Commun.
1990, 1254.
This research was supported in part by a grant from the Ministry of
Education, Culture, Sports, Science and Technology of Japan.
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Synlett 2005, No. 11, 1783–1786 © Thieme Stuttgart · New York