Transition-metal-free sonogashira-type coupling of ortho-substituted aryl and alkynyl grignard reagents by using 2,2,6,6-tetramethylpiperidine-N-oxyl radical as an oxidant

Article abstract of DOI:10.1021/ol1015702

Cross coupling of aryl, alkenyl, and alkynyl magnesium compounds by using 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO) as an environmentally benign organic oxidant is described. This coupling reaction can be performed without adding any transition

Full text of DOI:10.1021/ol1015702

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3878-3881
Transition-Metal-Free Sonogashira-Type
Coupling of ortho-Substituted Aryl and
Alkynyl Grignard Reagents by Using
2,2,6,6-Tetramethylpiperidine-N-oxyl
Radical as an Oxidant
Modhu Sudan Maji, Sandip Murarka, and Armido Studer*
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t, Corrensstraꢀe 40,
48149 Mu¨nster, Germany
studer@uni-muenster.de
Received July 8, 2010
ABSTRACT
Cross coupling of aryl, alkenyl, and alkynyl magnesium compounds by using 2,2,6,6-tetramethylpiperidine-N-oxyl radical (TEMPO) as an
environmentally benign organic oxidant is described. This coupling reaction can be performed without adding any transition metal on various
ortho-substituted aryl and alkynyl Grignard reagents. Importantly, functional groups such as esters, amides, and cyanides are shown to be
tolerated under the reaction conditions.
Transition-metal-catalyzed Sonogashira cross coupling of
terminal alkynes with aryl or alkenyl halides is one of the
most widely used methods to build up compounds bearing
an internal alkyne moiety.1 This structural motif can be found
in biologically active compounds, in fine chemicals, and also
in conjugated polymers.2 The original Sonogashira coupling
protocol uses two transition metal catalysts, a Pd(II)-salt and
CuI as the cocatalyst, along with a larger amount of an
amine.3 It is meanwhile well established that Sonogashira
couplings can also be accomplished with Pd catalysts in the
absence of any copper salt4 or by using non Pd-based
transition metal catalysts.5 An alternative method to
C(sp2)-C(sp) bond formation was developed by Knochel
who showed that at low temperature mixed aryl alkynyl
organocuprates undergo cross coupling to deliver the cor-
responding Sonogashira products by using chloranil as an
oxidant.6a However, a stoichiometric amount of Cu was
necessary for these reactions.
More recently, Cahiez reported on Mn-catalyzed Sono-
gashira-type couplings between aryl and alkynyl Grignard
reagents by using molecular oxygen as an oxidant.6b There
are only very few reports on transition-metal-free Sonogash-
(1) (a) Chinchilla, R.; Na´jera, C. Chem. ReV. 2007, 107, 874. (b) Doucet,
H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46, 834.
(5) (a) Son, S.; Jang, Y.; Park, J.; Na, H. B.; Park, H. M.; Yun, H. J.;
Lee, J.; Hyeon, T. J. Am. Chem. Soc. 2004, 126, 5026. (b) Arellano, C. G.;
Abad, A.; Corma, A.; Garcia, H.; Iglesias, M.; Sanchez, F. Angew. Chem.,
Int. Ed. 2007, 46, 1536. (c) Park, S.; Kim, M.; Koo, D. H.; Chang, S. AdV.
Synth. Catal. 2004, 346, 1638. (d) Mao, J.; Wu, M.; Xie, G.; Jia, S. AdV.
Synth. Catal. 2009, 351, 2101.
(2) Nielsen, M. B.; Diederich, F. Chem. ReV. 2005, 105, 1837.
(3) (a) Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975, 93, 259.
(b) Cassar, L. J. Organomet. Chem. 1975, 93, 253. (c) Sonogashira, K.;
Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467.
(4) (a) Anastasia, L.; Negishi, E.-i. Org. Lett. 2001, 3, 3111. (b)
Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I. Org. Lett.
2002, 4, 1691. (c) Li, J.-H.; Zhang, X.-D.; Xie, Y.-X. Eur. J. Org. Chem.
2005, 4256. (d) Liang, Y.; Xie, Y.-X.; Li, J.-H. J. Org. Chem. 2006, 71,
379.
(6) (a) Dubbaka, S. R.; Kienle, M.; Mayr, H.; Knochel, P. Angew. Chem.,
Int. Ed. 2007, 46, 9093. (b) Aerobic Mn-catalyzed heterocoupling of
Grignard reagents: Cahiez, G.; Duplais, C.; Buendia, J. Angew. Chem., Int.
Ed. 2009, 48, 6731.
10.1021/ol1015702  2010 American Chemical Society
Published on Web 08/12/2010

ira-type coupling processes,7 and to the best of our knowl-
edge, transition-metal-free cross coupling between aryl and
alkynyl Grignard reagents are not known. Herein we describe
the first results on highly efficient coupling reactions of aryl
with alkynyl Grignard reagents by using the 2,2,6,6-tetram-
ethylpiperidine-N-oxyl radical (TEMPO)8 as an environ-
mentally benign commercially available oxidant.
benzene with i-PrMgCl·LiCl,12 and Mg-acetylide 2a was
readily obtained via deprotonation of phenylacetylene with
i-PrMgCl·LiCl.10 Both yield and 3a/4a selectivity were
improved by using 1.6 equiv of aryl Grignard reagent 1a
(Table 1, entry 2). Upon increasing the amount of 1a to 2.0
Transition-metal-free oxidative homocoupling of Grignard
reagents has recently gained attention.9 Along this line, we
reported on homocoupling reactions of aryl, alkenyl, and
alkynyl Grignard reagents by using TEMPO as an oxidant
(Scheme 1).10 More recently, we have also successfully
Table 1. Oxidative Coupling between 1a and 2a at 66 °C under
Different Conditions
Scheme 1. Oxidative Homocoupling of Aryl and Alkynyl
Grignard Reagents Using TEMPO and Planned Cross Coupling
entry 1a (equiv) tempo (equiv) time [h] 3aa [%] 4a [%]
of 1 and 2
1
2
3
4
5
6
1
2.20
2.86
3.30
3.30
3.85
2.16
3.85
3.85
3.85
3.85
1.5
3.0
0.75
2.5
2.5
2.5
60b
79b
71
84
90
61
76
40
75
45
18c
1.6
2.0
2.0
2.5
2.5
2.5
2.5
2.5
2.5
7c
<2%d
<2%d
<2%d
<2%d
<2%d
<2%d
<2%d
<2%d
7e
8f
9g
10h
72
2.5
2.5
2.5
a Isolated yield. b Isolated as a mixture of 3a and 4a. c Yield was
calculated by H NMR analysis from the 3a/4a mixture. d In GC, 4a was
1
identified in traces. e Run at 25 °C. f Aryl Grignard was generated from
2,6-dimethylbromobenzene by using Mg-turnings, and phenyl alkynyl
Grignard was generated by using i-PrMgCl. g Aryl Grignard was generated
from 2,6-dimethylbromobenzene by using Mg-turnings in the presence of
1.0 equiv of LiCl. h Aryl Grignard 1a was prepared from 2,6-dimethylbro-
mobenzene via Br-Li exchange with t-BuLi followed by Li-Mg exchange
by using MgBr2.
applied these processes for preparation of various conjugated
polymers.11
During these studies, we made the important observation
that TEMPO-mediated homocoupling of aryl Grignard
reagents occurs far faster as compared to the analogous
reaction with alkynyl Grignard reagents.10 Moreover, we
found that sterically demanding aryl Grignard reagents either
react slowly or do not react at all with TEMPO.10b On the
basis of these two observations, we assumed that transition-
metal-free cross coupling reactions between aryl 1 and
alkynyl Grignard reagents 2 to form Sonogashira products
3 by using TEMPO as an oxidant should be feasible.
equiv, yield further increased to 71% without diminishing
the 3a/4a selectivity (45 min, entry 3). A slightly better yield
was noted by extending the reaction time to 2.5 h (entry 4).
The best result was obtained when 2.5 equiv of 1a and 3.85
equiv of TEMPO were used in the coupling reaction (90%,
entry 5). Decreasing the amount of TEMPO provided a worse
result (61%, entry 6). Selective cross coupling could also
be achieved at room temperature (entry 7). However, reaction
time had to be extended to 72 h. To check whether aryl
bromides can also be used as precursors, we generated
Grignard 1a from 2,6-dimethylbromobenzene by using Mg-
turnings. Oxidative cross coupling with 2a occurred with
excellent 3a/4a selectivity; however, yield was moderate
(40%, entry 8). Importantly, yield was improved to 75%
when Grignard generation was performed in the presence
of LiCl, clearly showing that also the cheaper aryl bromides
are suitable substrates for our oxidative coupling (entry 9).13
However, when Grignard 2a was generated via Br-Li
exchange followed by transmetalation with MgBr2·OEt2,11
The Grignard reagent 1a used in our initial studies was
generated via I-Mg-exchange reaction of 2,6-dimethyliodo-
(7) (a) Luque, R.; Macquarrie, D. J. Org. Biomol. Chem. 2009, 7, 1627.
(b) Pru¨ger, B.; Hofmeister, G. E.; Jacobsen, C. B.; Alberg, D. G.; Nielsen,
M.; Jørgensen, K. A. Chem.sEur. J. 2010, 16, 3783. (c) Protti, S.; Fagnoni,
M.; Albini, A. Angew. Chem., Int. Ed. 2005, 44, 5675. (d) DeRoy, P. L.;
Surprenant, S.; Laperle, M. B.; Yoakim, C. Org. Lett. 2007, 9, 2741. (e)
Borah, H. N.; Prajapati, D.; Boruah, R. C. Synlett 2005, 2823. (f)
Appukkuttan, P.; Dehaen, W.; Eycken, E. V. Eur. J. Org. Chem. 2003,
4713. (g) Leadbeater, N. E.; Marco, M.; Tominack, B. J. Org. Lett. 2003,
5, 3919.
(8) Review: (a) Vogler, T.; Studer, A. Synthesis 2008, 1979. See also:
(b) Vogler, T.; Studer, A. Org. Lett. 2008, 10, 129. (c) Guin, J.; De Sarkar,
S.; Grimme, S.; Studer, A. Angew. Chem., Int. Ed. 2008, 47, 8727. (d)
Kirchberg, S.; Vogler, T.; Studer, A. Synlett 2008, 18, 2841. (e) Vogler,
T.; Studer, A. AdV. Synth. Catal. 2008, 350, 1963. (f) Kirchberg, S.; Fro¨hlich,
R.; Studer, A. Angew. Chem., Int. Ed. 2009, 48, 4235.
(9) (a) Krasovskiy, A.; Tishkov, A.; del Amo, V.; Mayr, H.; Knochel,
P. Angew. Chem., Int. Ed. 2006, 45, 5010. (b) Woltermann, C. J.; Shechter,
H. HelV. Chim. Acta 2005, 88, 354.
(12) 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.
(10) (a) Maji, M. S.; Pfeifer, T.; Studer, A. Angew. Chem., Int. Ed. 2008,
47, 9547. (b) Maji, M. S.; Studer, A. Synthesis 2009, 2467.
(13) Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.
2010, 49, 2219.
(11) Maji, M. S.; Pfeifer, T.; Studer, A. Chem.sEur. J. 2010, 16, 5872.
Org. Lett., Vol. 12, No. 17, 2010
3879

the cross coupling product was formed with moderate yield
(45%, entry 10).
Table 3. Oxidative Coupling of Various Aryl Grignard Reagents
(2.5 equiv) with 2a by Using TEMPO (3.85 equiv) in THF
It is important to note that the side product of our cross
coupling reaction derived from the organic oxidant is the
TEMPOMgX salt which could readily be reoxidized to
TEMPO by purging the reaction mixture with dioxygen.10a
The mechanism of our TEMPO-mediated oxidative cross
coupling reaction between aryl and alkynyl Grignard deriva-
tives is currently not known.
We next studied substrate scope by reacting various
alkynyl Grignard reagents 2 with 2.5 equiv of aryl Grignard
reagent 1a under optimized conditions (Table 2). Mg-
acetylides 2 were generated from the corresponding terminal
alkynes via deprotonation with i-PrMgCl·LiCl.10 Arylalkynyl
Table 2. Oxidative Coupling of 1a (2.5 equiv) with Various
Alkynyl Grignard Reagents by Using TEMPO (3.85 equiv) in
Refluxing THF
a Isolated as a mixture with 9% of biaryl homocoupling product. b 4
equiv of aryl Grignard reagent was used. c 62% of biaryl product, which
was readily separated, was formed. d The biaryl product was observed
by TLC. e 3,5-Dimethyl cyano benzene derived from hydrolysis could
not be separated from the product. f 44% of 4a and 30% of biphenyl
(yield calculated from used amount of phenyl Grignard reagent) were
formed. Yield was determined by GC using decane as an internal
standard.
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Org. Lett., Vol. 12, No. 17, 2010

Grignard reagents bearing electron-donating as well as
electron-withdrawing substituents at the aryl moiety reacted
with 1a to give the cross coupling products 3b-e with
excellent yields and selectivities (Table 2, entries 1-4). None
of the bisalkyne homocoupling products were identified in
these and all following reactions. 1-Naphthylalkynyl and (6-
methoxy-2-naphthyl)alkynyl Mg compounds underwent
smooth transformation to internal alkynes 3f and 3g (entries
5 and 6). Also, heteroarenes were tolerated as shown for the
cross coupling of the 2-pyridylalkynyl Grignard with 1a to
give 3h (entry 7). Interestingly, magnesiated eneynes turned
out to be good substrates for our oxidative cross coupling
reaction as documented by the preparation of 3i (80%, entry
8). Less reactive alkylalkynyl Grignard reagents afforded the
corresponding cross coupling products 3j,k in slightly lower
yields (entries 9 and 10). However, with the benzyloxym-
ethylalkynyl Mg derivative, a good yield for the cross
coupling reaction was achieved (see 3l, entry 11).
Reaction scope was further explored by testing a series
of structurally and electronically diverse aryl Grignard
reagents in the oxidative cross coupling with 2a. In all cases,
aryl Grignard reagents were generated from the correspond-
ing aryl iodides via I-Mg-exchange reaction by using
i-PrMgCl·LiCl (Table 3).12 The 2-ethylphenyl Grignard
compound underwent smooth cross coupling to provide 3m
with excellent yield (91%, Table 3, entry 1). Phenyl
Grignards bearing the sterically more demanding 2-tert-butyl
or two ortho-ethyl groups provided products 3n and 3o with
87% and 80% yield, respectively (entries 2 and 3). Phenyl
Grignard reagents with an ortho-trifluoromethyl or ortho-
or para-methoxy groups were also suitable coupling partners
in the reaction with 2a (entries 4-6). Sterically hindered
aryl Grignards bearing a chloro or bromo substituent at the
para position also underwent efficient cross coupling to
provide 3s and 3t with 95% and 92% yield (entries 7 and
8).
10).14 With the phenyl Grignard reagent containing an ortho-
amide functionality, a very fast cross coupling reaction with
2a was achieved at room temperature providing a 75% yield
of the desired alkyne 3w (entry 11) besides the corresponding
biaryl product derived from oxidative homocoupling of the
aryl-Mg compound (62%). However, by conducting cross
coupling at 0 °C, formation of biaryl could be largely
suppressed, and the internal alkyne 3w was isolated in 85%
yield (entry 12). As expected, by installing a methyl group
at the ortho′ position of the ortho-amide functionalized
phenyl Grignard reagent, homocoupling of the aryl Grignard
did not occur even at room temperature, and the targeted 3x
was isolated in excellent yield (93%, entry 13). A cyano
group at the arene was also tolerated under our reaction
conditions as shown for the preparation of 3y which was
formed in quantitative yield (entry 14). As expected, an ortho
substituent is necessary to get high selectivity in these cross
coupling processes as documented for the reaction of
PhMgCl·LiCl with 2a (entry 15). In that case, homocoupling
of the phenyl-Mg derivative and 2a was not suppressed.
In conclusion, we have described a highly efficient
transition-metal-free cross coupling reaction between aryl and
alkynyl Grignard reagents by using TEMPO as a mild
organic oxidant. These coupling reactions can be performed
on various aryl and alkynyl Grignard reagents. To suppress
the unwanted oxidative homocoupling reaction of aryl
Grignard reagents, substituents at the ortho position of the
aryl-Mg derivative are installed. Importantly, functional
groups such as esters, amides, and cyanides are tolerated.
These reactions are very easy to perform, and products are
obtained with high yields.
Acknowledgment. We thank the SFB 858 for supporting
our work (stipend to SM).
Supporting Information Available: Experimental details
and characterization data for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
Importantly, functionalized aryl Grignard reagents were
also suitable candidates for our oxidative coupling reaction.
These functional groups bearing aryl-Mg derivatives were
generated at 0 °C, and cross coupling was performed at room
temperature. Grignard reagents bearing an ortho-ester func-
tionality underwent smooth transformation to 3u and 3v with
excellent yields and selectivities (94 and 99%, entries 9 and
OL1015702
(14) Reaction did not work on the corresponding methyl esters and for
the aryl-Mg derivative derived from 4-iodo-3,5-dimethylphenylpivalate. This
is probably due to the instability of the corresponding Ar-Mg species at
room temperature.
Org. Lett., Vol. 12, No. 17, 2010
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