I -PrI acceleration of Negishi cross-coupling reactions

Article abstract of DOI:10.1021/ol1007026

(Figure presented) The Negishi cross-coupling of arylzinc reagents with various bromoanilines is accelerated by the presence of i-PrI (1 equiv) and furnished the expected biaryls within 5-12 min reaction time at 25 °C. Arylzinc reagents can also be cross-coupled under these conditions with a range of aryl bromides bearing an enolizable ester or acidic benzylic protons.

Full text of DOI:10.1021/ol1007026

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2702-2705
i-PrI Acceleration of Negishi
Cross-Coupling Reactions
Marcel Kienle and Paul Knochel*
Department Chemie, Ludwig-Maximilians-UniVersita¨t, Butenandtstrasse 5-13,
81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received March 29, 2010
ABSTRACT
The Negishi cross-coupling of arylzinc reagents with various bromoanilines is accelerated by the presence of i-PrI (1 equiv) and furnished the
expected biaryls within 5-12 min reaction time at 25 °C. Arylzinc reagents can also be cross-coupled under these conditions with a range of
aryl bromides bearing an enolizable ester or acidic benzylic protons.
The Suzuki and the Negishi cross-coupling reactions are the
most powerful and widely used methods for making
Csp2-Csp2 bonds.1 In contrast to organoboronates (Suzuki
reaction), organozinc reagents usually undergo cross-
couplings under very mild conditions; however, arylboronates
are usually air- and water-stable reagents.2 Recently, we
reported that primary and secondary amines, alcohols,
phenols and amides are compatible with the Negishi cross-
coupling conditions, when the zinc reagent is slowly added
(over 90 min) to the electrophile.3 Furthermore, we reported
a new i-PrI-accelerated Kumada cross-coupling, allowing a
reaction of aryl bromides and magnesium reagents within
5-10 min.4 A radical reaction pathway has been proposed
for this reaction.4,5 Herein, we report that the Negishi cross-
coupling can similarly be accelerated by the presence of i-PrI.
These new reaction conditions allow the use of aryl bromides
bearing various acidic protons without the need of protection.
Thus, a Br/Mg exchange on 3-bromobenzonitrile (1a) and
subsequent transmetalation with the THF-soluble complex
ZnCl2·2LiCl6 afforded the diarylzinc reagent 2 (Scheme 1).
Negishi cross-coupling of 2 with 4-bromoaniline (3a) in the
presence of Pd(dba)2 (1 mol %) and RuPhos7 (2 mol %)
gave only 37% conversion after 10 min at 25 °C. However,
(1) (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 2004. (b) Beller, M.; Bolm, C.
Transition Metals for Organic Synthesis; Wiley-VCH: Weinheim, 1998.
(c) Tsuji, J. Transition Metal Reagents and Catalysts; Wiley: New York,
1995. (d) Ackermann, L. Modern Arylation Methods; Wiley-VCH: Wein-
heim, 2009. (e) Terao, J.; Kambe, N. Acc. Chem. Res. 2008, 41, 1545.
(2) (a) Negishi, E.; King, A. O.; Okudado, N. J. Org. Chem. 1977, 42,
1821. (b) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (c) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (d) Han,
C.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 7532. (e) Sase, S.; Jaric,
M.; Metzger, A.; Malakhov, V.; Knochel, P. J. Org. Chem. 2008, 73, 7380.
(f) Son, S.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 2756. (g) Zeng, X.;
Quian, M.; Hu, Q.; Negishi, E. Angew. Chem., Int. Ed. 2004, 43, 2259.
(3) (a) Manolikakes, G.; Dong, Z.; Mayr, H.; Li, J.; Knochel, P.
Chem.sEur. J. 2009, 15, 1324. (b) Manolikakes, G.; Schade, M. A.; Munoz
Hernandez, C.; Mayr, H.; Knochel, P. Org. Lett. 2008, 10, 2765. (c)
Manolikakes, G.; Munoz Hernandez, C.; Schade, M. A.; Metzger, A.;
Knochel, P. J. Org. Chem. 2008, 73, 8422.
(4) Manolikakes, G.; Knochel, P. Angew. Chem., Int. Ed. 2009, 48, 205.
(5) (a) Corey, E. J.; Semmelhack, M. F.; Hegedus, L. S. J. Am. Chem.
Soc. 1968, 90, 2416. (b) Corey, E. J.; Semmelhack, M. F.; Hegedus, L. S.
J. Am. Chem. Soc. 1968, 90, 2417. (c) Hegedus, L. S.; Waterman, E. L.
J. Am. Chem. Soc. 1974, 96, 6789. (d) Hegedus, L. S.; Miller, L. L. J. Am.
Chem. Soc. 1975, 97, 459. (e) Hegedus, L. S.; Thompson, D. H. P. J. Am.
Chem. Soc. 1985, 107, 5663. (f) Elson, I. H.; Morrell, D. G.; Kochi, J. K.
J. Organomet. Chem. 1975, 84, C7. (g) Tsou, T. T.; Kochi, J. K. J. Am.
Chem. Soc. 1979, 101, 6319. (h) Tsou, T. T.; Kochi, J. K. J. Am. Chem.
Soc. 1979, 101, 7547. (i) Labinger, J. A.; Kramer, A. V.; Osborn, J. A.
J. Am. Chem. Soc. 1973, 95, 7908. (j) Kramer, A. V.; Labinger, J. A.;
Bradley, J. S.; Osborn, J. A. J. Am. Chem. Soc. 1974, 96, 7145. (k) Kramer,
A. V.; Osborn, J. A. J. Am. Chem. Soc. 1974, 96, 7832
.
(6) The presence of LiCl from ZnCl2·2LiCl leads to an additional rate
enhancement.
(7) For aryl-aryl Negishi cross-coupling reactions using RuPhos, see:
Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 13028.
10.1021/ol1007026  2010 American Chemical Society
Published on Web 05/18/2010

Scheme 1
.
Negishi Cross-Coupling of Zinc Reagents with Aryl
Table 1. Palladium-Catalyzed Cross-Coupling of Zinc Reagents
2 with Aniline Derivatives of Type 3
Bromides Accelerated by i-PrI
when the same reaction is performed with the diarylzinc 2,
generated from the corresponding 3-iodobenzonitrile (1b),
full conversion was obtained after 10 min, and the desired
biaryl 4a was isolated in 89% yield. Other alkyl iodides gave
also an acceleration in this reaction. However, this effect
strongly depends on the nature of the used alkyl halide.
Secondary alkyl iodides gave the best results.8 The same
rate enhancement can also be achieved by addition of i-PrI
(1.1 equiv) to a Grignard reagent obtained by Br/Mg-
exchange and subsequent transmetalation with the THF-
soluble complex ZnCl2·2LiCl.
Encouraged by these results, we studied the scope of this
new protocol, emphasizing the compatibility with amines and
various other functional groups bearing acidic protons. Thus,
the reaction of bis(3-cyanophenyl)zinc (2b) with 4-bromo-
2-chloroaniline (3b) in the presence of Pd(dba)2 (1 mol %)
and RuPhos7 (2 mol %) furnished the biphenyl 4b within 5
min at 25 °C in 97% yield (Table 1, entry 1). In a similar
manner, 1-iodo-3-(trifluoromethyl)benzene was converted to
the corresponding biarylzinc 2c. This reagent was success-
fully coupled with various bromoanilines 3a,b, furnishing
the amines (4c,d) in 89-92% yield (entries 2 and 3).
Furthermore, the zinc compound 2c was reacted with the
sterically hindered 2-bromoaniline (3c), providing the biaryl
4e within 10 min in 80% yield (entry 4). Interestingly, this
reaction also proceeds smoothly at larger scales (10 mmol),
furnishing the aniline derivative 4e after the same reaction
time in 81% yield.
This procedure was extended to functionalized zinc
reagents bearing an ester function. This may be of practical
interest since the corresponding magnesium reagents show
a low stability at room temperature. Therefore, the zinc
species 2d was chemoselectively coupled with 4-bromo-2-
chloroaniline (3b), affording the chlorobiphenyl derivative
4f in 91% yield (entry 5). After reaction of 2d with the
a Isolated, analytically pure product. Reaction conditions: 5 min at 25
°C. b The zinc reagent was obtained by an I/Mg exchange and subsequent
transmetalation with ZnCl2·2LiCl (0.55 equiv). c The reaction was performed
on a 10 mmol scale. d The zinc reagent was obtained by a Br/Mg exchange
and subsequent transmetalation with ZnCl2·2LiCl (0.55 equiv) and addition
of i-PrI (1.1 equiv). e 10 min reaction time. f The zinc reagent was obtained
after a Br/Mg insertion and subsequent transmetalation with ZnCl2·2LiCl
(0.55 equiv) and addition of i-PrI (1.1 equiv).
(8) The use of the other secondary alkyl iodides instead of i-PrI led to
comparable conversions. n-BuI and cHexI gave under similar conditions
after 10 min 88% and 85% conversion, respectively. In contrast, MeI resulted
in a conversion of 18%.
Org. Lett., Vol. 12, No. 12, 2010
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methyl ester derivative 3d the corresponding biaryl 4g was
obtained in 94% yield (entry 6). 2-Bromoaniline (3c) was
reacted with the ester-substituted organozinc compound 2e,
furnishing the aniline derivative 4h within 10 min in 79%
yield (entry 7). Additionally, we have applied this procedure
to zinc reagents prepared by transmetalation from the
corresponding arylmagnesium bromides. Thus, the reaction
of the zinc reagent 2f in the presence of i-PrI (1.1 equiv)
with 4-bromo-2-methylaniline (3e) gave within 10 min the
amine 4i in 94% yield (entry 8). In a similar sequence, the
reaction of the dichlorophenylzinc reagent 2g with 4-bro-
moaniline (3a) furnished the biaryl 4j in 76% yield (entry
9).
Table 2. Palladium-Catalyzed Cross-Coupling of Zinc Reagents
2 with Arylbromoketones of Type 5
We used also this protocol for the reaction of enolizable
bromoaryl ketones. Therefore, ethyl 3-iodobenzoate (1c) was
smoothly exchanged using iPrMgCl·LiCl (30 min, -20 °C).
Transmetalation with ZnCl2·2LiCl (0.55 equiv) furnished the
diarylzinc 2e (Scheme 2). Subsequent palladium-catalyzed
Scheme 2
.
Negishi Cross-Coupling of a Biarylzinc Reagent 2e
with 3-Bromoacetophenone (5a)
cross-coupling with 3-bromoacetophenone (5a) yielded the
biaryl ketone 6a in 86% yield.
By applying this procedure, various arylzinc reagents were
efficiently coupled with several bromoaryl ketones. Thus,
the reaction of 2d with 4-bromovalerophenone (5b) furnished
the ester 6b in 92% yield (Table 2, entry 1). Further-
more, the Pd-catalyzed cross-couplings of the zinc com-
pounds 2c and 2h with 3-bromoacetophenone (5a) resulted
a Isolated, analytically pure product. Reaction conditions: 5 min at 25
°C. b The zinc reagent was obtained by an I/Mg exchange and subsequent
transmetalation with ZnCl2·2LiCl (0.55 equiv). c The zinc reagent was
obtained after a Br/Mg insertion and subsequent transmetalation with
ZnCl2·2LiCl (0.55 equiv) and addition of i-PrI (1.1 equiv). d 12 min reaction
time.
Scheme 3. Negishi Cross-Coupling of a Diarylzinc Reagent 2a
with (4-Bromophenyl)acetonitrile (7a)
in the biaryls 6c,d in 85-86% yield (entries 2 and 3). The
coupling of 2b with the sterically hindered 3-bromo-4-
fluoropropiophenone (5c) gave the desired product 6e within
12 min in 73% yield (entry 4). This reaction was also
applicable toward the reaction of zinc reagents obtained from
the corresponding arlymagnesium bromides and addition of
i-PrI (1.1 equiv). Thus, the reaction of 2f in the presence of
i-PrI, Pd(dba)2, and RuPhos with various bromoarylketones
provided the biaryls 6f-h in 91% yield (entries 5-7).
2704
Org. Lett., Vol. 12, No. 12, 2010

Furthermore, we used this method for the coupling of
arylzinc reagents with aryl bromides bearing acidic benzylic
protons. Thus, the I/Mg exchange of 3-iodobenzonitrile (1a)
with iPrMgCl·LiCl and transmetalation with ZnCl2·2LiCl
(0.55 equiv) yielded the diarylzinc 2a (Scheme 3).
Subsequent Pd(0)-catalyzed cross-coupling with (4-bro-
mophenyl)acetonitrile (7a) furnished the dinitrile 8a in 86%
yield.
reaction of the dichlorophenylzinc reagent 8d with (4-
bromophenyl)acetic acid ethyl ester (7c) in the presence of
i-PrI leads to the dichlorobiaryl 8d in 83% yield (entry 3).
The coupling of the zinc compounds 2c,d with aryl bromide
7c furnished the esters 8e,f in 85-94% yield.
This protocol was extended to alkylzinc reagents. Thus,
OctMgBr (9) was smoothly transmetalated with ZnCl2·2LiCl
(0.55 equiv) furnishing Oct2Zn (10a). Subsequent Pd-
catalyzed cross-coupling in the presence of i-PrI with various
bromoanilines provided within 10 min the amines 11a,b in
67-79% yield. In a similar manner, the reaction of 10a with
3-bromoacetophenone (5a) furnished within 10 min the
ketone 12 in 72% yield (Scheme 4).
Also, the reaction of the chloroarylzinc reagent 2h with
7a yielded the biaryl 8b in 97% yield (Table 3, entry 1).
Table 3. Cross-Coupling of Arylzinc Reagents with Various
Aryl Bromides Bearing Acidic Benzylic Protons
Scheme 4. Cross-Coupling of an Alkylzinc Reagent with
Various Aryl Bromides Bearing Acidic Protons
In conclusion, we have reported a new protocol for the
Negishi cross-coupling of organozinc reagents with aryl
bromides bearing acidic protons in the presence of i-PrI and
an active Pd-catalyst system such as RuPhos, enhancing the
yield of application of this valuable ligand.7 This new
procedure allows remarkably fast coupling reactions, thereby
allowing in several cases to avoid protecting groups.
Acknowledgment. We thank the Fonds der Chemischen
Industrie, the ERC (European Research Council), and the
Deutsche Forschungsgemeinschaft (DFG: SFB 749) for
financial support. We also thank BASF AG (Ludwigshafen),
W. C. Heraeus GmbH, and Chemetall GmbH (Frankfurt) for
the generous gift of chemicals.
a Isolated, analytically pure product. Reaction conditions: 5 min at 25
°C. b The zinc reagent was obtained by an I/Mg exchange and subsequent
transmetalation with ZnCl2·2LiCl (0.55 equiv). c The zinc reagent was
obtained by a Br/Mg exchange and subsequent transmetalation with
ZnCl2·2LiCl (0.55 equiv) and addition of i-PrI (1.1 equiv).
Note Added after ASAP Publication. The abstract
graphic contained an error in the version published ASAP
May 18, 2010; the correct version reposted May 21, 2010.
Supporting Information Available: Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
Furthermore, the coupling of the zinc compound 2e bearing
an ester function with (3-bromophenyl)acetonitrile (7b)
provided the desired product 8c in 89% yield (entry 2). The
OL1007026
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