Generation of bromophenyllithium reagents from dibromobenzenes and addition to carbonyl and nitrile electrophiles

Article abstract of DOI:10.1055/s-2004-825611

An evaluation of the mono-lithiation of all three regioisomers of dibromobenzene using n-butylithium was performed. The resulting aryllithium reagents were added to electrophiles such as ketones, aldehydes, nitriles and amides to afford the desired benzylic alcohols or ketones.

Full text of DOI:10.1055/s-2004-825611

1440
LETTER
Generation of Bromophenyllithium Reagents from Dibromobenzenes and
Addition to Carbonyl and Nitrile Electrophiles
Generation of
t
Bromo
é
phenyllithi
p
Chemical R & D, Pfizer Global Research & Development, MS-8118D/4002, Groton, CT 06340, USA
Fax +1(860)7158584; E-mail: Stephane_caron@groton.pfizer.com
Received 25 March 2004
Dedicated to Professor Clayton H. Heathcock in appreciation of his teaching and many contributions to organic synthesis on the occasion
of his retirement from the University of California at Berkeley
pared using n-BuLi in Et2O7–9 or THF10 or sec-BuLi in
Abstract: An evaluation of the mono-lithiation of all three regio-
THF.11 It is interesting that even when using two equiva-
isomers of dibromobenzene using n-butylithium was performed.
The resulting aryllithium reagents were added to electrophiles such
as ketones, aldehydes, nitriles and amides to afford the desired
lents of n-BuLi, it appears that only one halogen-metal ex-
change occurs.8 Similarly, 1,3-dibromobenzene (5) has
benzylic alcohols or ketones.
been converted to the mono-lithio reagent using n-BuLi in
Et2O12 or THF.13 In the case of 1,2-dibromobenzene (6),
the situation is further complicated by the ability of the
lithiated species to eliminate LiBr and generate ben-
zyne.14,15 Nonetheless, the halogen-metal exchange reac-
tion has been conducted and the resulting organolithium
reagent was added to a few electrophiles.16,17 Our goal was
to identify a general procedure for the lithiation which
could be carried out on any of the three dibromobenzenes
and provide an efficient addition to a carbonyl reagent.
Key words: dibromobenzene, organolithium, halogen-metal ex-
change, addition, aryllithium
The halogen-metal exchange reaction continues to gener-
ate much interest and remains an efficient and simple way
to prepare organometallic reagents.1,2 The availability of a
large number of aryl bromides and chlorides add to the
utility of this method for preparation of aryllithium and
magnesium reagents.
As shown in Table 1, a rapid solvent screen was first con-
ducted on 4 using n-BuLi and trapping the lithiated re-
agent with cyclobutanone (7). It is noteworthy that while
Et2O has historically been the solvent of choice for this re-
action, it was omitted from our evaluation because of its
lack of practicality and safety concerns on scale. We also
looked at the effect of temperature on the stability of the
We were recently asked to identify a procedure for the
preparation of derivatives of the general structure 1. The
dihalo-arene 2 and ketone or aldehyde 3 were targeted as
attractive precursors to 1 (Scheme 1).
OH
R1
R2
X
O
Table 1 Evaluation of the Solvent and Temperature Effects in the
Halogen-Metal Exchange of 4 Followed by Addition of 7
Br
R1
R2
Br
HO
Br
i) n-BuLi
1
2
3
ii)
Scheme 1 Retrosynthesis of 1
Br
Br
O
4
8
The original procedure relied on the preparation of the
Grignard reagent using i-PrMgCl3 and iodobromoben-
zene. While the procedure worked reliably and in high
yield, it had the disadvantage of using a costly aryl iodide
and an excess of both organomagnesium and iodide re-
agents in order to achieve high conversion. A practical
method allowing use of any regioisomers of dibromo-
benzene was especially sought.
7
Entry
Solvent
THF
Temp (°C)
–78
–78
–78
–78
–40
–20
0
Yield of 8 (%)
1
2
3
4
5
6
7
8
9
98
Toluene
IPE
No reaction
15
MTBE
THF
46
The halogen-magnesium exchange of 1,4-dibromo-
benzene (4) via a trialkylmagnesate reagent4 or Rieke
magnesium5 is precedented. Gilman first reported the
mono-halogen metal exchange of general polyhaloben-
zenes in 1940.6 4-Lithiobromobenzene has since been pre-
80
THF
Decomposition
Decomposition
No reaction
No reaction
THF
Toluene
Toluene
–40
0
SYNLETT 2004, No. 8, pp 1440–1442
0
1.
0
7.
2
0
0
4
Advanced online publication: 18.05.2004
DOI: 10.1055/s-2004-825611; Art ID: Y02504ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Generation of Bromophenyllithium Reagents
1441
anion in THF and toluene. No halogen-metal exchange (2.15 mmol) keeping the temperature below –70 °C. The
was observed in toluene over the temperature range stud- resulting reaction mixture was stirred at –78 °C for 30
ied. However, THF was an acceptable solvent. An operat- minutes followed by addition of the electrophile (1.93
ing temperature of about –78 °C was adequate and far mmol). Upon completion, the reaction was quenched with
from the edge of failure as the yield changed significantly saturated NH4Cl and allowed to warm to room tempera-
only above –40 °C.
ture. The mixture was extracted with MTBE, dried over
Na2SO4, filtered and concentrated. The crude product was
purified by chromatography (20% EtOAc–hexane) to
give the desired material.
Generation of the bromophenylithium species starting
from 1,4- (4), 1,3- (5), or 1,2-dibromobenzene (6) fol-
lowed by addition to several electrophiles was next eval-
uated (Table 2). As expected, the yields of alcohol 9 Electrophiles, which would allow for the production of
starting from 4 and 5 (entries 1–10) proved to be superior ketones 10, namely nitriles and amides, were also evalu-
to 6 (entries 11–15), mainly due to the stability of the lithi- ated (Table 3). Benzonitrile and p-tolunitrile proved to be
ated species. Furthermore, the yields using cyclohex- poor reagents for the addition of the organolithium
anone or hexanal were lower due to competitive (entries 1, 2, 6, 7, 12 and 13). Morpholine acetamide18 be-
enolization (entries 2, 4, 7, 9). This appeared not to be a haved similarly to the nitriles and fairly low yields of the
problem for a-tetralone (entry 15). While a-tetralone re- desired ketone were isolated (entries 4, 9, 14). Weinreb
acted with the anion generated from 4 or 5, it proved to be amides19 were the preferred option for this transformation,
unreactive towards 2-lithiobromobenzene, which decom- and yields as high as 95% (entry 8) could be achieved. N-
posed prior to addition.
Methoxy-N-methylbenzamide was sufficiently reactive to
allow for a 50% yield of product even with 2-lithio-
bromobenzene (entry 13).
General procedure: To a –78 °C solution of dibromo-
benzene (2.15 mmol) in THF (5 mL) was added n-BuLi
Table 2 Halogen-metal Exchange of 4, 5 and 6 and Addition to a
Carbonyl Derivative
Table 3 Halogen-Metal Exchange of 4, 5 and 6 and Addition to
Nitriles or Amides
HO R2
O
i) n-BuLi, THF
–78 °C
Br
i) n-BuLi, THF
–78 °C
Br
Br
Br
Br
Br
R1
R1
O
ii)
O
ii)
R1
R2
para (4)
meta (5)
ortho (6)
R1 NR2R3
or R1CN
para (4)
meta (5)
ortho (6)
9
10
Entry
1
Bromide
Electrophile
Yield of 9 (%)
Entry
1
Bromide
Electrophile
Yield of 10 (%)
4
4
4
4
4
5
5
5
5
5
6
6
6
6
6
Cyclobutanone (7)
Cyclohexanone
Benzaldehyde
Hexanal
98
70
85
43
94
89
86
89
49
95
51
47
Trace
11
4
4
4
4
4
5
5
5
5
5
6
6
6
6
6
Benzonitrile
p-Tolunitrile
PhCONMeOMe
MorphCOMe
22
50
71
36
65
26
27
95
46
74
13
18
50
0
2
2
3
3
4
4
5
a-Tetralone
5
MeCONMeOMe
Benzonitrile
6
Cyclobutanone (7)
Cyclohexanone
Benzaldehyde
Hexanal
6
7
7
p-Tolunitrile
8
8
PhCONMeOMe
MorphCOMe
MeCONMeOMe
Benzonitrile
9
9
10
11
12
13
14
15
a-Tetralone
10
11
12
13
14
15
Cyclobutanone (7)
Cyclohexanone
Benzaldehyde
Hexanal
p-Tolunitrile
PhCONMeOMe
MorphCOMe
MeCONMeOMe
a-Tetralone
Recovered a-
Tetralone
0
Synlett 2004, No. 8, 1440–1442 © Thieme Stuttgart · New York

1442
S. Caron, N. M. Do
LETTER
(6) Gilman, H.; Langham, W.; Moore, F. W. J. Am. Chem. Soc.
1940, 62, 2327.
(7) Chauret, N.; Guay, D.; Li, C.; Day, S.; Silva, J.; Blouin, M.;
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6023.
In conclusion, generation of the organolithium reagent
starting from all three regioisomers of dibromobenzene
(4, 5, 6) and addition to several carbonyl and nitrile elec-
trophiles was evaluated. In general, the reaction proceed-
ed smoothly at low temperature with 1,4- and 1,3-
dibromobenzene, adding to ketones, Weinreb amides and
non-enolizable aldehydes. The reaction proved to be more
capricious starting from 1,2-dibromobenzene or when us-
ing a nitrile or a less reactive amide as the electrophile.
This reaction leads to useful products since the resulting
aryl bromides can be used further in a variety of metal-
mediated processes.
(12) Rajca, A. J. Org. Chem. 1991, 56, 2557.
(13) Klusener, P. A. A.; Hanekamp, J. C.; Brandsma, L.; von
Ragué Schleyer, P. J. Org. Chem. 1990, 55, 1311.
(14) Leroux, F.; Schlosser, M. Angew. Chem. Int. Ed. 2002, 41,
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Synlett 2004, No. 8, 1440–1442 © Thieme Stuttgart · New York