A practical non-cryogenic process for the selective functionalization of bromoaryls

Article abstract of DOI:10.1016/j.tetlet.2008.06.046

A selective and practical bromine-metal exchange process under non-cryogenic conditions was developed by a simple modification of an existing protocol. By directly adding an alkyl lithium RLi reagent to a solution of a bromoaryl substrate ArBr and an alkylmagnesium reagent RMgX, a lithium triarylmagnesiate Ar₃MgLi complex formed that allowed for various types of functionalization and more elaborate cross-coupling reactions. The simplicity and improved safety of the method represent a significant improvement over current state of the art that uses lithium trialkylmagnesiate R₃MgLi complexes, and is especially advantageous for large-scale synthesis.

Full text of DOI:10.1016/j.tetlet.2008.06.046

Tetrahedron Letters 49 (2008) 5024–5027
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A practical non-cryogenic process for the selective functionalization
of bromoaryls
*
Fabrice Gallou , Ruedi Haenggi, Hans Hirt, Wolfgang Marterer, Frank Schaefer, Manuela Seeger-Weibel
Novartis Pharma AG, Chemical and Analytical Development, CH-4002 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
A selective and practical bromine–metal exchange process under non-cryogenic conditions was devel-
oped by a simple modification of an existing protocol. By directly adding an alkyl lithium RLi reagent
to a solution of a bromoaryl substrate ArBr and an alkylmagnesium reagent RMgX, a lithium triarylmag-
Received 15 May 2008
Revised 5 June 2008
Accepted 10 June 2008
Available online 14 June 2008
nesiate Ar
3
MgLi complex formed that allowed for various types of functionalization and more elaborate
cross-coupling reactions. The simplicity and improved safety of the method represent a significant
improvement over current state of the art that uses lithium trialkylmagnesiate R
is especially advantageous for large-scale synthesis.
3
MgLi complexes, and
Keywords:
Bromine–magnesium exchange
Magnesiate
Ó 2008 Elsevier Ltd. All rights reserved.
Selective
Non-cryogenic
The halogen–metal exchange reaction is an often used and well
established transformation prior to functionalization by either
direct electrophilic quench or more elaborate metal-mediated
cross-coupling reaction. In the course of our development of a
robust and practical process for C–C bond forming reactions from
aryl halides, we evaluated variations of commonly used halogen–
metal exchange processes and their impact on the efficiency (yield,
productivity) and the outcome (formation of regioisomers) of the
transformation.
More recently, Knochel has developed attractive alternatives to
prepare functionalized aryl magnesium compounds with activated
forms of Grignard reagents. These reagents proceed particularly
5
well for aryl iodides and aryl bromides having electron-deficient
or chelating groups, under non-cryogenic conditions and with high
selectivity. In the case of aryl bromides with electron-donating
groups, specific functionalization patterns, such as aromatic ethers,
for example, can be reached only with difficulty and recourse to
5
a,b
more elaborate conditions is required.
magnesiate complexes, for example, R
The use of higher-order
3
MgLi that can be conve-
Numerous methods have been reported for halogen–metal
1
exchange reactions, but it still remains a challenge and an interest
niently prepared by premixing of alkyl lithium and alkylmagne-
sium reagents, has here proven to be a particularly powerful
to the synthetic community, more particularly to process chemists.
Direct metalation of aryl bromides with metallic magnesium is a
strategy that is often used for the formation of aryl Grignard
6
solution. Their enhanced reactivity generally allows a smooth
bromine–magnesium exchange even in the most unfavored cases,
under non-cryogenic conditions. In addition, the absence of regio-
isomer usually observed even in the case of densely substituted
aromatic systems bearing directing groups makes it very attractive
for industrial processes. However, a major drawback of this
methodology is the need for the preformation of a lithium trialkyl-
magnesiate complex, thus requiring longer process cycle times and
additional in-process controls.
The state of the art for magnesium–bromine exchange reactions
prompted us to look for a new methodology which would address
simultaneously the selectivity issues, the low temperature require-
ment, the practicality, and the safety of the process. This Letter
details our recent progress in the design of a simple process that
consists of a selective, net halogen–magnesium exchange reaction
under non-cryogenic conditions. The scope of the new simplified
and practical protocol is then illustrated.
2
reagents. However, the relatively limited substrate scope and
the inherent safety liability of the reaction constitute process
limitations. Alternatively, the bromine–lithium exchange reaction
under cryogenic conditions is a strategy which relies on the rapid
exchange even at low temperature and the possibility to prepare
3
compounds that are not readily available by direct metalation.
The reactivity and stability of the lithiated species under the reac-
tion conditions usually require cryogenic conditions to minimize
undesired side-reactions. This becomes all the more important,
for example, with aryl bromides bearing directing groups, and thus
exhibiting a propensity to isomerize the lithiated intermediate
4
6i
species generated or when aryne formation is likely to occur.
*
Corresponding author. Tel.: +41 61 696 3491; fax: +41 61 6962711.
E-mail address: fabrice.gallou@novartis.com (F. Gallou).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.046

F. Gallou et al. / Tetrahedron Letters 49 (2008) 5024–5027
5025
Our study started by a direct comparison of existing methods of
Table 1
bromine–metal exchange reactions on 4-bromoanisole 1, known to
be a poor substrate for bromine–magnesium exchange reactions
O
Br
with RMgX and R
2
Mg (R = alkyl) (e.g., Refs. 5a,f). We hoped that
M-X
CO2
OH
careful monitoring of the kinetics and purity profiles for the known
bromine–metal exchange reactions would lead us to an improved
process. The unambiguous assignment of the product and by-prod-
ucts formed in the course of the reaction was made by conversion
of the metalated intermediate into the corresponding benzoic acid
MeO
MeO
1
2
Entry
Conditions
Conversion to 2 (%)
2
with addition of carbon dioxide.
1
2
3
4
5
6
7
8
nBuLi (1.1 equiv), THF, ꢀ78 °C, 1 h
nBuLi (1.1 equiv), THF, ꢀ40 °C, 1 h
iPrMgCl (1.1 equiv), THF, ꢀ10 °C, 24 h
iPrMgClꢁLiCl (1.1 equiv), ꢀ10 °C, 24 h
92
80
10
55
72
78
80
86
All experiments were run in THF in order to promote a potential
7
isomerization. HPLC-conversion was monitored and results are
shown in Graph 1 with the optimal conversions summarized in
Table 1. The bromine–lithium exchange reaction using nBuLi at
iPr MgꢁLiCl (0.55 equiv), THF, ꢀ10 °C, 6 h
2
ꢀ
78 °C proceeded very rapidly, selectively, and with high conver-
iBu
nBu
iPrnBu
2
MgꢁLiCl (0.55 equiv), THF, ꢀ10 °C, 20 h
3
MgLi (0.37 equiv), THF, ꢀ10 °C, 1 h
MgLi (0.37 equiv), THF, ꢀ10 °C, 1 h
sion to 4-methoxy benzoic acid 2 (92%, entry 1). An increase of
the temperature to ꢀ40 °C resulted in a significant drop of effi-
ciency (80% conversion, entry 2) mostly due to numerous subse-
2
8
quent side-reactions. In the case of Grignard reagents, iPrMgCl
proved to be poorly reactive with only ca. 10% conversion after
the need for preforming the lithium trialkyl magnesiate com-
6
a–c
2
4 h at 10 °C (entry 3). The presence of lithium chloride additive
only resulted in a marginal improvement of the reactivity to 55%
conversion after 24 h (entry 4). The more reactive iPr
MgꢁLiCl
reacted much faster with a maxi-
plex.
Based on the observations described above, we envisioned
that a branched alkyl magnesium halide (used here to minimize
the hetero-coupling product formation) would be poorly reactive
when added under non-cryogenic conditions to the solution of
the aryl bromide. The addition of an alkyl lithium at a controlled
rate would then result in a transient aryl lithium compound that
would rapidly be transmetalled by the Grignard reagent present
2
5a,b
and iBu
2
MgꢁLiCl complexes
mum conversion at ꢀ10 °C of 72% and 78%, respectively, after 6 h
and 20 h (entries 5 and 6). The lithium trialkylmagnesiate com-
3 2
plexes nBu MgLi and iPrnBu
MgLi6 gave the fastest and best con-
a,b
1
2
versions after less than an hour in 80% and 86% yield, respectively
entries 7 and 8, respectively). In the latter four entries 5–8, a
in solution. Thus, the lithium triarylmagnesiate complex would
form at the end in a process that is a net bromine–magnesium
exchange reaction. We evaluated this concept on the model
4-bromoanisole 1 and were delighted to find that it proceeded very
efficiently at 0–5 °C in 98% conversion without formation of the
regioisomer. Compared to prior state of the art, the revised proto-
col displays similar efficiency; however, it is now operationally
simpler and displays significant safety advantages for large-scale
(
decomposition of the formed aryl magnesium species was ob-
served that reduced the conversion to 4-methoxy benzoic acid.
A careful examination of the purity profile and nature of impu-
rities for all these conditions showed that decomposition resulted
mostly in the reduced product (3), alkyl–aryl (4 and 5), aryl–aryl
coupling (6), and the bis-functionalized acid (7) side-products
9
,10
13
(
see Fig. 1).
Interestingly, only in the case of the bromine–lith-
processes.
ium exchange with nBuLi did we observe migration of the lithium
In order to demonstrate the practicality of this simplified proto-
col, we wanted to utilize the selectively obtained lithium triaryl-
magnesiate complexes in a known cross-coupling reaction such
as, for example, a nickel-catalyzed Kumada–Corriu cross-coupling
reaction For example, 4-bromoanisole 1 under our conditions
after the net bromine–magnesium exchange reaction was cross-
coupled efficiently with bromobenzene in the presence of NiCl2-
dppp at 0 °C in 90% overall yield (Scheme 1). The interest of the
method becomes clearly apparent here in view of the importance
of the biphenyl unit in pharmaceutical drugs.
to the ortho position in up to 3% (compound 8).11
Overall, these preliminary data showed that a bromine–magne-
sium exchange with Grignard reagent was not kinetically favored
while bromine–lithium exchange was rapid, even at ꢀ78 °C. The
high order magnesiates clearly exhibited the best purity profiles
with only Wurtz-type coupling products, which could be further
reduced by using branched alkyl Grignard reagents.
1
4
We therefore decided to design a system that could lead to a
highly reactive lithium triaryl magnesiate intermediate without
1
00
9
8
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
0
0
entry 3
x
entry 4
entry 5
entry 6
entry 7
entry 8
+
0
5
10
15
20
25
Time
Graph 1. Conversion of 4-bromoanisole 1 to 4-methoxy benzoic acid 2.

5
026
F. Gallou et al. / Tetrahedron Letters 49 (2008) 5024–5027
Br
n
BuLi
Br
(1 eq)
(
0.74 eq)
NiCl -dppp (1 mol%)
2
+
MgCl
[
(pMeO-C H ) MgLi]
6
4 3
MeO
THF
THF
0-5 C
1 h
MeO
o
o
0
-5 C
(
0.37 eq)
1
h
9
1
Scheme 1.
CH O
H
CH O
CH O
OCH3
3
3
CH O
3
3
3
4
5
6
CH O
COOH CH O
3
3
HOOC
HOOC
7
8
Figure 1. Observed impurities in the bromine–metal exchange reaction.
Encouraged by these results, we then investigated the scope of
ing from 80% to 95%) and low to mediocre for the ortho substitu-
tion pattern (yield from 12% to 48%) probably due to benzyne
formation as observed by analysis of side-products. The highly
selective results obtained in the fluoro series, demonstrated by
the revised net bromine–magnesium exchange protocol. We
decided here to functionalize the aryl bromides into the corre-
sponding aldehydes after quenching with dimethylformamide.
The benzaldehyde products formed can be easily compared to
1
19
careful H and F NMR analyses, were particularly remarkable in
view of the known pronounced directing effect of the fluoride
atom. Another illustration of the value of our method is the known
commercially available reference samples. Besides, all benzalde-
1
hydes exhibit a well-resolved aldehydic proton signal on the
H
0
6d
NMR spectra, which allow for the unambiguous assignment of
the isomer formed and the extent of the isomerization. The results
are summarized in Table 2.
formylation of 4,4 -bis-bromobiphenyl (entry 17).
With our
revised protocol, we obtained for the selective functionalization
8
,15
of the dibrominated substrate
the same result as those reported
Bromotoluenes (entries 1–3) and bromoanisoles (entries 5–7)
reacted smoothly in high yield (yields ranging from 82% to 96%)
and with high selectivity as demonstrated by 1H NMR. Only in
the case of 3-bromoanisole did we detect formation of an isomer
in less than 0.5%. The more substituted 2,6-dimethylbromo-
benzene (entry 4) gave results consistent with the bromotoluene
series. For halobenzene bromides (entries 8 through 16), high
selectivity was again observed in all cases. High yields were
obtained for the meta and para substitution patterns (yields rang-
with the lithium trialkylmagnesiate complex (Ref. 6d, 82% yield).
We then turned our attention to the effect of the trifluoromethyl
substituent, also reported to be an effective directing group in
halogen–metal exchange reactions (entries 18–20). The series
proceeded here with the same trend as for the halobenzene
bromides and resulted in modest to good yields (48–72%), and high
selectivity. The more functionalized 3,5-bistrifluoromethylbromo-
benzene (entry 21) also reacted without formation of isomer in
1
6
55% yield. The bromophenol series bearing an acidic proton
Table 2
n
BuLi
(
0.74 eq)
DMF
MgCl
[(R-C H ) MgLi]
R-C H -CHO
R-C H -Br
+
6
4 3
6
4
6
4
o
THF
0 C
o
1 h
0
-5 C
(
0.37 eq)
10
11
1
h
Entry
R
Yield (%)
Entry
R
Yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
2-Me
3-Me
4-Me
2,6-Me
2-OMe
3-OMe
4-OMe
2-F
3-F
4-F
2-Cl
3-Cl
82
89
95
94
90
96
95
47
81
82
48
80
84
12
90
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
4-Br
4(p-BrPh)
95
82
48
70
72
55
21
64
56
<5
<5
<5
<5
<5
<5
2-CF
3-CF
4-CF
3,5-CF
2-OH
3-OH
4-OH
2-COOEt
3-COOEt
4-COOEt
2-CN
3
3
3
3
1
1
1
1
1
1
4-Cl
2-Br
3-Br
3-CN
4-CN

F. Gallou et al. / Tetrahedron Letters 49 (2008) 5024–5027
5027
(
2
entries 22–24) gave modest to good yields (yields ranging from
8. Caron, S.; Do, N. M. Synlett 2004, 1440.
9. Merrill, R. E.; Negishi, E. J. Org. Chem. 1974, 39, 3452.
1
1% to 64%) in addition to high selectivity.17 In our hands, sodium
0. Formation of Wurtz-type coupling by-products is well-precedented and results
from the presence of the alkyl bromide cogenerated in the process. In our
study, we found that the amount of these side-products was mostly a function
of the temperature. The reduced aryl by-product arises from proton abstraction
on the alkyl bromide via b-elimination. Recourse to tBuLi would completely
avoid its formation, but it is not an option for large-scale applications. see, for
example: Bailey, W. F.; Luderer, M. R.; Jordan, K. P. J. Org. Chem. 2006, 71, 2825–
hydride appeared to be a good sacrificial base to sequester the
acidic proton. Finally, the bromo-methylbenzoate (entries 25–27)
and the bromobenzonitrile (entries 28–30) series gave no product,
presumably due to the incompatibility of the alkyl lithium with the
functional groups.
In summary, we have developed a selective and practical net
bromine–magnesium exchange process under non-cryogenic con-
ditions by a simple modification of an existing protocol.1 The lith-
ium triarylmagnesiate complex formed allows for various types of
functionalization and more elaborate cross-coupling.18 Overall, no
migration to an extent of more than 0.5% was observed in all our
substrates, which compares well to the selectivity observed with
2828. As an alternative, the branched iPrLi offers relatively similar advantages
and is therefore preferred for such applications.
11. Careful monitoring of the purity profile in the previously described entries is
9
summarized in the table below (see structures 3–8 in the text).
Entry Conditions Reactant Product
By-products
T
t
1
2
3
4
5
6
7
8
(
°C)
(h)
6
lithium trialkylmagnesiate complexes. The method is particularly
3
4
5
6
7
8
20
20
20
20
20
20
24
24
24
24
24
24
2.3
3.6
5.4
11.1
6.8
13.5
50.9
75.3
16.3
50.8
65.0
<0.1 <0.1
0.4 79.9 1.2 <0.1
0.5 41.7 1.0 <0.1
0.8 14.6 1.0 <0.1
suitable for poorly reactive aryl bromides but suffers from a poorer
substrate scope as expected from the presence of a highly reactive
alkyllithium and a functionalized aryl bromide at temperatures
above 0 °C, in addition to modest to mediocre efficiency in the case
of the ortho substituted substrates. The simplicity of the method
nevertheless represents a significant improvement over current
methodology and is especially advantageous for large-scale
synthesis.
<0.1
<0.1
0.4
0.3
<0.1 <0.1
23.8 <0.1
16.1 <0.1
1.5 65.8 1.2 <0.1
3.7
2.8
5.4 5.8 <0.1
3.2 4.0 <0.1
5.8
7
8
0–5
0–5
2
2
2.8
1.8
80.4
92.2
8.6 <0.1
0.9 <0.1 <0.1
0.4
1.9 2.9 <0.1
1.1 0.9 <0.1
Results reported in HPLC Area % at 210 nm.
Limit of quantitation: 0.1%.
References and notes
1
2. For in situ trapping of organolithiated species, see, for example: Kristensen, J.;
Lysén, M.; Vedsø, P.; Begtrup, M. Org. Lett. 2001, 3, 1435–1437; ElSheikh, S.;
Schmalz, H.-G. Curr. Opin. Drug Discovery Dev. 2004, 7, 882–895.
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.
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1
3. The current process indeed avoids forming
a highly reactive lithium
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T.; Houpis, I. N.; Akao, A.; Dorziotis, I.; Emerson, K.; Hoang, T.; Iida, T.; Itoh, T.;
Kamei, K.; Kato, S.; Kato, Y.; Kawasaki, M.; Lang, F.; Lee, J.; Lynch, J.; Maligres,
P.; Molina, A.; Nemoto, T.; Okada, S.; Reamer, R.; Song, J. Z.; Tschaen, D.; Wada,
T.; Zewge, D.; Volante, R. P.; Reider, P. J.; Tomimoto, K. J. Org. Chem. 2001, 66,
19. General procedure: To a solution of aryl bromide (12 mmol, 1.2 equiv) in dry
THF (12 mL) at 0 °C was added a 2 M solution of iPrMgCl in THF (5 mmol,
0.5 equiv) in 5 min. The clear solution was stirred at that temperature for an
additional 10 min, and a 30% solution of nBuLi in hexanes(10 mmol, 1.0 equiv)
was added dropwise in 10 min, while maintaining the temperature below 5 °C.
The resulting mixture was stirred at that temperature for 1 h, cooled to ꢀ10 °C,
and dry DMF (13 mmol, 1.3 equiv) in dry THF (13 mL) was added dropwise in
6
775–6786; See also early reactivity investigations of organo magnesiates: (n)
10 min. The resulting mixture was warmed to rt in 1 h, and added to a 0.5 M
Richey, H. G., Jr.; King, B. A. J. Am. Chem. Soc. 1982, 104, 4672–4674.
The enhanced basic character of organolithium species in THF compared to
other solvents such as diethyl ether or TBME makes them more susceptible to
isomerization. Such isomerizations are less likely to be observed in diethyl
ether where the organolithium species are more aggregated and thus rendered
less reactive.
citric acid solution at rt. After 10 min stirring, the phases were separated and
the water phase was extracted one additional time with toluene. The combined
organic phases were concentrated and water was removed azeotropically with
toluene to obtain the desired aldehyde. All benzaldehyde products were
compared to commercially available reference samples.
7
.