Noncryogenic I/Br-Mg exchange of aromatic halides bearing sensitive functional groups using i-PrMgCl-Bis[2-(N,N-dimethylamino)ethyl] ether complexes

Article abstract of DOI:10.1021/ol052704p

Iodo- and bromoaromatics bearing sensitive carboxylic ester and cyano groups underwent a selective halide-magnesium exchange with isopropylmagnesium chloride at ambient temperature in the presence of bis[2-(N,N-dimethylamino) ethyl] ether to afford the corresponding Grignard reagents. The newly formed reactive Grignard reagents were allowed to react with electrophiles such as trimethylborate to afford arylboronic acids in good to excellent yields.

Full text of DOI:10.1021/ol052704p

ORGANIC
LETTERS
2006
Vol. 8, No. 2
305-307
Noncryogenic I/Br−Mg Exchange of
Aromatic Halides Bearing Sensitive
Functional Groups Using
i-PrMgCl−Bis[2-(N,N-dimethylamino)ethyl]
Ether Complexes
Xiao-jun Wang,* Xiufeng Sun, Li Zhang, Yibo Xu,
Dhileepkumar Krishnamurthy, and Chris H. Senanayake
Department of Chemical DeVelopment, Boehringer Ingelheim Pharmaceuticals Inc.,
Ridgefield, Connecticut 06877
xwang@rdg.boehringer-ingelheim.com
Received November 8, 2005
ABSTRACT
Iodo- and bromoaromatics bearing sensitive carboxylic ester and cyano groups underwent a selective halide−magnesium exchange with
isopropylmagnesium chloride at ambient temperature in the presence of bis[2-(N,N-dimethylamino)ethyl] ether to afford the corresponding
Grignard reagents. The newly formed reactive Grignard reagents were allowed to react with electrophiles such as trimethylborate to afford
arylboronic acids in good to excellent yields.
The halogen-magnesium exchange has provided a general
and chemoselective method for the preparation of function-
alized arylmagnesium reagents of considerable synthetic
utility.1 This method tolerates a wide range of sensitive
functional groups such as ester and cyano groups.2 However,
most iodine-magnesium exchanges are performed under
cryogenic conditions (e20 °C) to suppress the competing
side reactions of sensitive functional groups.3 Recently, we
disclosed an efficient synthesis of aryl ketones from aryl acid
chlorides and Grignard reagents that involved moderating
the reactivity of the organomagnesium reagents by com-
plexation with a simple organic ligand, bis[2-(N,N-dimethyl-
aminoethyl)] ether (1).4 A possible formation of complex 2
(Scheme 1) by the tridentate interaction between 1 and
Scheme 1
(1) For a review, see: Knochel, P.; Dohle, W.; Gommermann, N.;
Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem.,
Int. Ed. 2003, 42, 4302.
(2) (a) Knochel, P.; Krasovskiy, A. Angew. Chem., Int. Ed. 2004, 43,
3333. (b) Yang, X.; Rotter, T.; Piazza, C.; Knochel, P. Org. Lett. 2003, 5,
1229. (c) Abarbri, M.; Thibonnet, J.; Be´rillon, L.; Dehmel, F.; Rottlander,
M.; Knochel, P. J. Org. Chem. 2000, 65, 4618.
(3) For example, see: (a) Boymond, L.; Rottla¨nder, M.; Cahiez, G.;
Knochel, P.; Krasovskiy, A. Angew. Chem., Int. Ed. Engl. 1998, 37, 1701.
(b) Jensen, A. E.; Dohle, W.; Sapountzis, I.; Lindsay, D. M.; Vu, V. A.;
Knochel, P. Synthesis 2002, 565. (c) Varchi, G.; Ricci, A.; Cahiez, G.;
Knochel, P. Tetrahedron 2000, 56, 2727.
Grignard reagents deactivates Grignard reagents, therefore,
preventing the resulting ketone functionality from attack by
(4) Wang, X.-j.; Zhang, L.; Sun, X.; Xu, Y.; Krishnamurthy, D.;
Senanayake, C. H. Org. Lett. 2005, 7, 5593.
10.1021/ol052704p CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/23/2005

organomagnesium species. Diamines and polyethers have
been used to complex Grignard reagents, and the resulting
complexes, where Mg coordination ranged from four to six,
were characterized spectroscopically and by X-ray crystal-
lography.5
Table 1. Br or I/Mg Exchange at 10-25 °C in THF Followed
by Addition of B(OMe)3
Herein, we wish to report application of the concept of
moderating the reactivity of Grignard reagents to the
halogen-magnesium exchange. Aryl and heteroaryl iodides/
bromides containing sensitive ester and cyano groups
underwent a mild and selective halogen-magnesium ex-
change with i-PrMgCl in the presence of 1 at ambient
temperature, and addition of the newly formed arylmagne-
sium species to trimethylborate afforded boronic acids in
good to excellent yields.
In an initial experiment, 4-iodo-3-methoxybenzoate 3a was
treated with a mixture of isopropylmagnesium chloride (1.2
equiv) and 1 (1.2 equiv) in THF at 22 °C (Table 1). Within
15 min, a complete I-Mg exchange was observed to give
arylmagnesium chloride 3b in a remarkable 95% yield, as
indicated by quantitative HPLC analysis of the reaction
mixture for the protonated product, ethyl 3-methoxybenzoate.
In contrast to this excellent result, in the absence of 1, the
same exchange of 3a with i-PrMgCl (1.2 equiv) at 10-22
°C proceeded to completion in less than 5 min and gave
rise to 3b in only 43% yield, as indicated by quantitative
HPLC analysis, along with many unidentified byproducts.
In both cases, the resulting arylmagnesium chloride was
quenched with trimethylborate to afford boronic acid 3c in
86% and 28% isolated yields, respectively.6 Significant
improvement was also observed for the I-Mg exchange of
other iodobenzoates 4-6a with i-PrMgCl at ambient tem-
perature (Table 1). Generally, the presence of 1 for I-Mg
exchange minimized side reactions to give arylmagnesium
reagents and subsequent addition products, exemplified as
boronic acids in Table 1, in good to excellent yields. The
absence of 1 usually gave a moderate yield of arylmagnesium
intermediates and a poor isolated yield of the corresponding
boronic acids. A similar result was obtained for Br-Mg
exchange of electron-deficient bromides 7-8a. Interestingly,
it was found that the absence of 1 for I-Mg exchange of
o-iodobenzoate 10a with i-PrMgCl at 22 °C afforded
arylmagnesium chloride 10b in 90% yield, a result very
similar to the one in the presence of 1. This excellent
chemoselectivity can be explained by a chelation effect of
the ortho-carbonyl group that facilitates the formation of 10b
and possibly stabilizes it.7 On the other hand, the absence
of 1 for I-Mg exchange of para-iodobenzoate 9a, benzoni-
triles 11-12a, and iodobenzamide 13a gave 9b and 11-
13b and subsequent boronic acids 9c and 11-13c in good
to excellent yields, whereas the presence of 1 gave a slightly
better or similar result.8,9
a >97% conversion in 15-30 min. Because of the deactivation of
i-PrMgCl and I/Br-Mg, exchange in the presence of 1 was slower than
that in the absence of 1. b Wt % assay of protonated product by HPLC.c In
the absence of 1. d Isolated yield by crystallization. e In the absence of 1.
f Reaction run for 2-3 hours in the presence of 1.
(5) Uhm, H. L. In Handbook of Grignard Reagents; Silverman, G. S.,
Rakita, P. E., Eds.; Marcel Dekker: New York, 1996; p 117.
(6) For synthetic applications of boronic acids, see: (a) Miyaura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457. (b) Suzuki, A. J. Organomet. Chem.
1999, 576, 147. (c) Suzuki, A. Pure Appl. Chem. 1994, 66, 213. (d) Suzuki,
A. Pure Appl. Chem. 1991, 63, 419.
We next studied the stability of magnesium reagents 3b
and 7b (Table 2). After a complete I/Br-Mg exchange of
(7) (a) Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2002, 41, 1610.
(b) Kneisel, F. F.; Knochel, P. Synlett 2002, 11, 1799.
(8) Varchi, G.; Kofink, C.; Lindsay, D. M.; Ricci, A.; Knochel, P. Chem.
Commun. 2003, 396.
306
Org. Lett., Vol. 8, No. 2, 2006

Table 2. Stability of the Resulting Organomagnesium Species
after Br or I/Mg Exchange at 10-25 °C in THF
entry
substratea
0.2 h
1 h
2 h
1
2
3
4
3b-1b
3bb
7b-1b
7bb
95%
43%
95%
61%
89%
36%
93%
50%
88%
20%
92%
39%
Figure 1.
a >98% conversion after 0.2 h. b Wt % assay of protonated product by
HPLC.
result, the reaction of the 14b-1 complex with trimethyl
borate and benzaldehyde furnished the expected addition
products 14c (70%) and 14d (62%), respectively.
In summary, we have shown that iodo- and bromoaro-
matics bearing sensitive ester, cyano, and amide groups can
undergo a chemoselective I/Br-Mg exchange with isopro-
pylmagnesium chloride in the presence of bis[2-(N,N-
dimethylaminoethyl)] ether11 at ambient temperature.12 Al-
though direct evidence of the interaction between i-PrMgCl
and 1 postulated here is not yet at hand, this concept of
altering the reactivity of Grignard reagents can be utilized
in a number of other instances. In this preliminary report,
we have shown the application of the new protocol to the
preparation of a variety of aryl boronic acids, key reagents
for Suzuki coupling reactions.6
3a and 7a in 15 min at 22 °C, quantitative HPLC wt % assay
indicated about 95% of the resulting 3b and 7b in the
presence of 1. After being kept at 22 °C for 2 h, only a slight
degradation was observed for both cases. However, signifi-
cant decomposition of 3b and 7b was observed in the absence
of 1. This result suggests that possible tridentate interaction
between the resulting 3b/7b after I/Br-Mg exchange and 1
stabilizes these sensitive arylmagnesium reagents.
It was known that I-Mg exchange of iodide 14a with
i-PrMgCl at -30 °C produced magnesiated 1,3-oxazin-4-
one 14b.10 The stability of 14b was found to be limited with
a half-life of ca. 1 h at -30 °C. To further test our conditions,
I-Mg exchange of iodide 14a with i-PrMgCl in the presence
of 1 was performed. Treatment of 14a with a slight excess
of i-PrMgCl-bis[2-(N,N-dimethylamino)ethyl] ether (1)
complex in THF at -5 to 0 °C resulted in complete
conversion to the corresponding Grignard 14b in 10 min
(Figure 1). Quantitative HPLC analysis indicated only <10%
degradation of 14b when being kept at -5 °C for 1 h.
Clearly, the presence of 1 prevented the resulting Grignard
14b from fast degradation even at higher temperature. As a
Supporting Information Available: Spectroscopic data
for new compounds 3c-8c and 14c. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL052704P
(11) Preliminary experiments indicated that TMEDA as an alternative
ligand was less effective for this exchange, and N-methylmorpholine had
no effect at all.
(12) A typical experimental procedure is as follows: To a solution of 1
(0.22 mL, 1.2 mmol) in THF (5 mL) was added isopropylmagnesium
chloride (0.60 mL, 1.2 mmol, 2 M solution in THF) at 15 °C. The mixture
was stirred at this temperature for 20 min. Methyl 3-methoxy-4-iodobenzoate
(290 mg, 1.0 mmol) was added. After the resulting mixture was stirred at
22-25 °C for 10 min, trimethylborate (0.23 mL, 2.0 mmol) was added at
0 °C. The mixture was then quenched with 0.1 N HCl and extracted with
EtOAc. The extract was dried over MgSO4 and concentrated. The residue
was purified by crystallization in hexane to give 3c (187 mg, 89%).
(9) The nitro group is generally not compatible under these conditions
except for highly electron-deficient aryl iodides such as 2,4-dinitro-
phenyliodide.7a
(10) Vu, V. A.; Be´rillon, L.; Knochel, P. Tetrahedron Lett. 2001, 42,
6847.
Org. Lett., Vol. 8, No. 2, 2006
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