Rapid nickel-catalyzed suzuki-miyaura cross-couplings of aryl carbamates and sulfamates utilizing microwave heating

Article abstract of DOI:10.1021/jo1024464

High-speed and scalable nickel-catalyzed cross-coupling of arylboronic acids with aryl carbamates and sulfamates is achieved by using sealed-vessel microwave processing.(Figure Presented)

Full text of DOI:10.1021/jo1024464

pubs.acs.org/joc
SCHEME 1. Nickel-Catalyzed Suzuki-Miyaura Cross-Cou-
plings of Aryl Carbamates and Sulfamates with Aryl Boronic
Rapid Nickel-Catalyzed Suzuki-Miyaura Cross-
Couplings of Aryl Carbamates and Sulfamates
Utilizing Microwave Heating
Acids9-11
Mostafa Baghbanzadeh,† Christian Pilger,‡ and
C. Oliver Kappe*,†
†Christian Doppler Laboratory for Microwave Chemistry
(CDLMC) and Institute of Chemistry, Karl-Franzens-
University, Graz, Heinrichstrasse 28, 8010 Graz, Austria, and
‡BASF SE, 67056 Ludwigshafen, Germany
oliver.kappe@uni-graz.at
far limited their use. To address this concern, other types
of phenol derivatives such as ethers,4 phosphoramides,5
carboxylates,6 phenolate,7 and sulfate8 derivatives have been
intensely investigated in the past few years in a variety of Ni-
catalyzed cross-coupling reactions.
Received December 10, 2010
Recently, the groups of Garg,9 Snieckus,10 and Shi11 have
independently introduced the use of aryl carbamates and/or
sulfamates as electrophilic coupling partners for Ni-cata-
lyzed Suzuki-Miyaura cross-coupling reactions (Scheme 1).
The ready availability, pronounced stability under a variety
of reaction conditions, and ease of preparation of these
phenolic substrates makes these coupling protocols highly
attractive from the synthetic point of view. In all three
reports the commercially available and air/moisture stable
Ni(PCy3)2Cl2 catalyst was employed.9-11
High-speed and scalable nickel-catalyzed cross-coupling
of arylboronic acids with aryl carbamates and sulfamates
is achieved by using sealed-vessel microwave processing.
While Garg9 used standard aryl boronic acids as nucleo-
philic coupling partners for carbamates and sulfamates, the
work of Snieckus10 and Shi11 described the use of aryl
boroxines for cross-couplings with carbamates. Despite the
advantages of these novel Suzuki-Miyaura protocols, the
coupling efficiency with aryl boronic acids in most of these
transformations (except for aryl sulfamates) is only moder-
ate for nonfused aromatic aryl substrates, even in the pres-
ence of a large excess of the boronic acid (Scheme 1).9-11
Most importantly, these methods suffer from exceedingly
long reaction times at an elevated temperature regime
(typically 5-24 h at 110-150 °C) and the necessity to employ
In recent years Ni-catalyzed carbon-carbon cross-cou-
pling transformations involving phenol derivatives as elec-
trophiles have attracted a substantial amount of interest.1 In
contrast to the more commonly used aryl halides, phenol
derivatives originate from different precursors and therefore
represent a valuable extension of the spectrum of electro-
philic cross-coupling partners. Of equal importance, re-
placement of the traditionally used Pd with less expensive
Ni-based catalyst systems can significantly lower costs for
cross-couplings of this type when performed on scale. Aryl
triflates2 and related sulfonates3 have frequently been inves-
tigated even at the early stages of Ni-catalyzed cross-cou-
pling chemistry, but their high cost and/or instability has so
(4) (a) Dankwardt, J. W. Angew. Chem., Int. Ed. 2004, 43, 2428. (b) Guan,
B.; Xiang, S.; Wu, T.; Sun, Z.; Wang, B.; Zhao, K.; Shi, Z. Chem. Commun.
2008, 12, 1437. (c) Tobisu, M.; Shimasaki, T.; Chatani, N. Angew. Chem., Int.
Ed. 2008, 47, 4866.
(5) Zhao, Y.-L.; Li, Y.; Li, Y.; Gao, L.-X.; Han, F.-S. Chem.;Eur. J.
2010, 16, 4991.
(6) (a) Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008,
130, 14422. (b) Guan, B.-T.; Wang, Y.; Li, B.-J.; Yu, D.-G.; Shi, Z.-J. J. Am.
Chem. Soc. 2008, 130, 14468. (c) Li, B.-J.; Li, Y.-Z.; Lu, X.-Y.; Liu, J.; Guan,
B.-T.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, 47, 10124. (d) Sun, C.-L.;
Wang, Y.; Zhou, X.; Wu, Z.-H.; Li, B.-J.; Guan, B.-T.; Shi, Z.-J. Chem.;
Eur. J. 2010, 16, 5844. (e) Shimasaki, T.; Tobisu, M.; Chatani, N. Angew.
Chem., Int. Ed. 2010, 49, 2929.
(7) Yu, D.-G.; Li, B.-J.; Zheng, S.-F.; Guan, B.-T.; Wang, B.-Q.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2010, 49, 4566.
(8) Guan, B.-T.; Lu, X.-Y.; Zheng, Y.; Yu, D.-G.; Wu, T.; Li, K.-L.; Li,
B.-J.; Shi, Z.-J. Org. Lett. 2010, 12, 396.
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Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. DOI:
10.1021/cr100259t. Published Online: Dec 6, 2010. (b) Yu, D.-G.; Li, B.-J;
Shi, Z.-J. Acc. Chem. Res. 2010, 43, 1486.
(2) (a) Quesnelle, C. A.; Familoni, O. B.; Snieckus, V. Synlett 1994, 349.
(b) Han, J. W.; Tokunaga, N.; Hayashi, T. Synlett 2002, 871. (c) Melzig, L.;
Gavryushin, A.; Knochel, P. Org. Lett. 2007, 9, 5529. (d) Liao, X.; Weng, Z.;
Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195. (e) Canivet, J.; Yamaguchi,
J.; Ban, I.; Itami, K. Org. Lett. 2009, 11, 1733.
(3) (a) Percec, V.; Bae, J. Y.; Hill, D. H. J. Org. Chem. 1995, 60, 1060. (b)
Ueda, M.; Saitoh, A.; Oh-tani, S.; Miyaura, N. Tetrahedron 1998, 54, 13079.
(c) Tang, Z.-Y.; Hu, Q.-S. J. Am. Chem. Soc. 2004, 126, 3058. (d) Molander,
G. A.; Beaumard, F. Org. Lett. 2010, 12, 4022. (e) Fan, X.-H.; Yang, L.-M.
(9) Quasdorf, K. W.; Reiner, M.; Petrova, K. V.; Garg, N. K. J. Am.
Chem. Soc. 2009, 131, 17748.
(10) Antoft-Finch, A.; Blackburn, T.; Snieckus, V. J. Am. Chem. Soc.
2009, 131, 17750.
€
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(11) Xu, L.; Li, B.-J.; Wu, Z.-H.; Lu, X.-Y.; Guan, B.-T.; Wang, B.-Q.;
Zhao, K.-Q.; Shi, Z.-J. Org. Lett. 2010, 12, 884.
DOI: 10.1021/jo1024464
r
Published on Web 01/20/2011
J. Org. Chem. 2011, 76, 1507–1510 1507
2011 American Chemical Society

Baghbanzadeh et al.
JOCNote
TABLE 1. Optimization Studies for Microwave-Assisted Cross-Coupling of 2-Naphthyl Carbamate 1a with PhB(OH)2 (2a)a
entry
2a (equiv)
catalyst (mol %)
K3PO4 (equiv)
T (°C)
time (min)
conv (%)b
1
2
3
4
5
4
4
10
10
10
5
5
2
7
4
7
7
7
7
7
7
180
180
180
180
150
180
180
180
10
10
10
10
10
10
10
10
94
75
94
2.5
2.5
2.5
2.5
2
95 (87)c
78
89
6
7
5
5
85
93 (86)c
8d
2.5
aReactions were performed with sealed vessel single-mode microwave heating (Monowave 300) with internal fiber-optic temperature control and
magnetic stirring on a 0.3 mmol scale of 1a, using 2 mL of toluene as solvent. bConversions were determined via peak area integration of the obtained
GC-MS spectra. cIsolated yield. dPerformed in a SiC reaction vessel.
additional quantitites of phosphine ligand to achieve high
conversions for difficult substrates.10,11
nonfused aryl carbamates has been reported to be challeng-
ing and sensitive to electronic factors,9,10 we find that in
addition to the naphthyl derivatives (Table 2, entries 1-4)
also nonfused aryl derivatives display a high reactivity under
these conditions and lead to the corresponding cross-coupled
biaryl products 3e-n in high yields (Table 2, entries 5-15).
In agreement with Snieckus10 we find that for simple aryl
substrates, electron-withdrawing group substituted systems
show somewhat higher reactivity (entries 5, 6, and 10) com-
pared to those having electron-donating groups (entries 7, 8,
9, 12, and 13). However, under controlled microwave con-
ditions at 180 °C the yields for these more challenging
substrates are significantly higher compared to experiments
performed with conventional heating.9,10 Furthermore, het-
eroaromatic carbamates (entries 14 and 15) as well as a steri-
cally highly congested 2,6-disubstituted substrate (entry 12)
also participate successfully in the desired cross-coupling
process with arylboronic acids. The optimized microwave
conditions thus provide high conversions also for aryl car-
bamates which have been previously reported as low-reactive
electrophiles in these Suzuki-Miyaura cross-coupling reac-
tions.9,10 In the case of aryl sulfamate substrates, the re-
ported yields using conventional heating (110 °C, 24 h) by
Garg9 are similar to the yields obtained with microwave heat-
ing (Table 2) under otherwise more or less identical reaction
conditions. Therefore, the main advantage here is a reduction
of the required reaction time. Apart from different aryl car-
bamates and sulfamates, arylboronic acids coupling partners
bearing electron-withdrawing (entries 2 and 3) and electron-
donating groups are also tolerated (entries 6, 7, 9, 13, and 15).
An example involving the preparation of 2-aminobiphenyl
derivatives 8 via the Ni-catalyzed Suzuki-Miyaura route is
highlighted in Scheme 2. To prevent N versus O selectivity
problems encountered during classical N-acetyl protection,
the amino group in 2-aminophenol (4) was protected with
succinic anhydride.14,15 In the next step, aryl sulfamate 6 was
prepared, which was subsequently subjected to the optimized
microwave-assisted Suzuki-Miyaura cross-coupling proto-
col (Table 2), providing;despite severe steric hindrance;
the desired biaryl substrates 7 in high yield. Finally, basic
Employing controlled sealed-vessel microwave heating we
herewith report an improved protocol that allows the execu-
tion of these intriguing coupling reactions in only 10 min
with use of standard aryl boronic acids as coupling partners.
Our method avoids the use of additional phosphine ligands10,11
and;in several cases;utilizes lower catalyst loadings and
reduced boronic acid stoichiometry. We also demonstrate
the scalability of these new microwave protocols up to a
0.375 mol scale in the context of the preparation of 2-(4-
tolyl)benzonitrile, a key intermediate in the synthesis of the
angiotensin II receptor antagonist losartan.
Using the conditions reported by Garg9 as an initial
reference point (5-10 mol % of Ni(PCy3)2Cl2, 2.5-4 equiv
of boronic acid, and 4-7.2 equiv of K3PO4), a series of
coupling experiments involving 2-naphthyl carbamate 1a
and phenylboronic acid (2a) were performed in a single-
mode microwave reactor with accurate internal temperature
monitoring.12 After considerable experimentation varying
reaction times and temperatures we discovered that nearly
full conversion in this cross-coupling reaction could be
obtained in toluene at 180 °C within <1 h. Fine-tuning of
the reaction parameters ultimately led to conditions that
utilized 5 mol % of the Ni catalyst and 2.5 equiv of boronic
acid at 180 °C for 10 min, resulting in a 87% isolated yield of
desired biaryl product 3a (Table 1, entry 4). This outcome is
comparable to the yields reported by Garg,9 Snieckus,10 and
Shi11 for similar substrates, albeit requiring reaction times of
20-24 h. Control experiments employing a reaction vial
made out of strongly microwave absorbing silicon carbide
(SiC)13 demonstrated that the improvements in reaction rate
are the result of a purely thermal effect (Table 1, entry 8).
To explore the scope and limitations of this microwave-
assisted cross-coupling protocol a series of aryl carbamate
and sulfamate substrates 1 were reacted with arylboronic
acids 2a-e utilizing the optimized reaction conditions shown
in Table 1. Gratifyingly, although the coupling reaction of
(12) For the importance of internal temperature measurement in micro-
wave chemistry and a description of the microwave reactor, see: Obermayer,
D.; Kappe, C. O. Org. Biomol. Chem. 2010, 8, 114 and references cited
therein. See also ref 13.
(14) Caulfield, M. J.; Looney, M. G.; Pittard, R. A.; Solomon, D. H.
Polymer 1998, 39, 6541.
(13) Obermayer, D.; Gutmann, B.; Kappe, C. O. Angew. Chem., Int. Ed.
2009, 48, 8321.
(15) Attempts to perform cross-coupling experiments with the cyclic
carbamate derivative of 2-hydroxyaniline were unsuccessful.
1508 J. Org. Chem. Vol. 76, No. 5, 2011

Baghbanzadeh et al.
JOCNote
TABLE 2. Aryl Carbamates and Sulfamates in Microwave-Assisted
SCHEME 2. Preparation of 2-Aminobiphenyl Derivatives 8 via
Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling
Suzuki-Miyaura Cross-Coupling Reactionsa
SCHEME 3. Preparation of the Sartan Precursor 2-(4-Tolyl)-
benzonitrile (10)
a limitation of these cross-coupling reactions involving C-O
bond activation in phenolic substrates became evident.
Using 4-chloroboronic acid as nucleophilic substrate in the
coupling step (6 f 7) resulted in a complex mixture of
products, including polymeric materials. Since aryl chlorides
are known to undergo Suzuki-Miyaura cross-coupling with
boronic acids in the presence of Ni catalysts, this is not
surprising.18 Competition experiments have demonstrated
that aryl chlorides are far more reactive compared to the
corresponding carbamates and sulfamates, and that very
efficient cross-couplings of a diverse range of aryl chloride
substrates with boronic acids could be achieved by using only
slightly modified microwave reaction conditions (see the
Supporting Information, including Table S1, for details).
Finally, in order to highlight the synthetic usefulness of
these high-speed microwave protocols and to investigate the
scalability of these reactions, the preparation of 2-(4-tolyl)-
benzonitrile (10), a key intermediate in the synthesis of the
angiotensin II receptor antagonist losartan (and related
compounds), was performed (Scheme 3).19 Using both types
of electrophilic coupling precursors (aryl chloride 9a and aryl
carbamate/sulfamate 9b,c) high yields (85-90%) of the
corresponding ortho-substiuted biaryl derivative 10 were
aReaction conditions: sealed vessel single-mode microwave heating
(Monowave 300) with internal fiber-optic temperature control and
magnetic stirring; 0.3 mmol of 1, 0.75 mmol of 2, 0.015 mmol of
Ni(PCy3)2Cl2, 2.1 mmol of K3PO4 in 2 mL of toluene; 180 °C for 10 min.
deprotection of the imide16 furnished the corresponding
2-aminobiphenyl derivatives 8a,b in 52% overall yield.
In an attempt to apply the above method for the pre-
parationof 2-amino-40-chlorobiphenyl (8c: R=Cl), a key inter-
mediate in the industrial synthesis of the fungicide Boscalid,17
(18) (a) Saito, S.; Sakai, M.; Miyaura, N. Tetrahedron Lett. 1996, 37,
2993. (b) Lipshutz, B. H.; Sclafani, J. A.; Blomgren, P. A. Tetrahedron 2000,
56, 2139. (c) Zhou, J.-R.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340. (d)
Lee, C.-C.; Ke, W.-C.; Chan, K.-T.; Lai, C.-L.; Hu, C.-H.; Lee, H. M.
Chem.;Eur. J. 2007, 13, 582. (e) Zhou, L.; Miao, Q.; He, R.; Feng, X.; Bao,
M. Tetrahedron Lett. 2007, 48, 7899.
(16) Martin, S. F.; Limberakis, C. Tetrahedron Lett. 1997, 38, 2617.
(17) (a) Kuck, K.-H.; Gisi, U. Modern Crop Protection Compounds;
(19) (a) Daugherty, A.; Cassis, L. Trends Cardiovasc. Med. 2004, 14, 117.
€
ꢀ
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n, R.; Serrano, I.; Sanchez-
Kramer, W., Schrimer, U., Eds.; Wiley-VCH: Weinheim, Germany, 2007;
(b) Garcı
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a, G.; Rodrı
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guez-Puyol, M.; Alajarı
guez-Puyol, D.; Alvarez-Builla,
´
ez-Marques, M. L. J. Med. Chem. 2009, 52, 7220.
Vol. 2, pp 415-432. (b) For a recent Pd-catalyzed route toward the synthesis
of 8c, see: Glasnov, T. N.; Kappe, C. O. Adv. Synth. Catal. 2010, 352, 3089.
Alonso, P.; Griera, M.; Vaquero, J. J.; Rodrı
´
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J.; Dı
J. Org. Chem. Vol. 76, No. 5, 2011 1509

Baghbanzadeh et al.
JOCNote
obtained applying the appropriate cross-coupling conditions
(Scheme 3).
Experimental Section
General Procedure for the Cross-Coupling Reaction of Aryl
Carbamate and/or Aryl Sulfamates with Aryl Boronic Acids
(Table 2). Aryl carbamate and/or aryl sulfamate (0.3 mmol),
arylboronic acid (0.75 mmol, 2.5 equiv), potassium phosphate
(2.1 mmol, 450 mg, 7 equiv), and bis(tricyclohexylphosphine)-
nickel(II) chloride (10.3 mg, 0.015 mmol, 5 mol %) were added
to a 10 mL flame-dried microwave vial containing a Teflon-
coated stir bar. After the vial was sealed dry toluene (2 mL) was
transferred to the vial and the mixture was purged with Ar for 2
min. The mixture was subsequently placed in the microwave
cavity and irradiated for 10 min at 180 °C (hold time). After
cooling, ethyl acetate (10 mL) was added and the crude reaction
mixture was subsequently washed with 25% aqueous ammonia
(2 ꢀ 10 mL). The aqueous ammonium layer was extracted again
with ethyl acetate (2 ꢀ 10 mL). The combined organic phases
were dried over MgSO4 and the residue after evaporation
purified by flash chromatography by using a mixture of petro-
leum ether and ethyl acetate as eluent solvent. All compounds
are literature known and NMR data are in good agreement with
published data.
All cross-coupling transformations described herein were
initially performed on a 0.3 mmol scale with 2 mL of solvent
in a single-mode microwave reactor employing a 10 mL
Pyrex reaction vial. Since microwave-assisted transforma-
tions are not always easy to scale,20 the cross-coupling of the
chloro and carbamate precursors (9a and 9b) with 4-tolyl-
boronic acid (2e) was additionally evaluated on a 10 times
higher scale employing the same microwave instrument
(Monowave 300), albeit with a larger vessel.12 In the event,
nearly identical yields compared to the small scale experi-
ment were obtained. To obtain sufficient quantities of 2-(4-
tolyl)benzonitrile (10) for further chemical manipulation, the
coupling of aryl chloride 9a with 4-tolylboronic acid (2e) was
ultimately performed in a recently developed multimode
benchtop microwave reactor (Masterwave) that allows batch
processing of up 700 mL volume in a 1 L PTFE reactor.21
Gratifyingly, performing this cross-coupling reaction on a
0.375 mol scale (∼700 mL volume) provided very similar
results in terms of yield and product purity as in the smaller
scale experiments (see the Supporting Information for fur-
ther details).
In conclusion, a rapid and highly efficient microwaveas-
sisted procedure for the Ni-catalyzed Suzuki-Miyaura cross-
coupling of aryl carbamates and sulfamates with boronic acids
was developed. Compared to the originally published meth-
ods by Garg,9 Snieckus,10 and Shi,11 this improved pro-
tocol features coupling times of only 10 min, and in a number
of instances allows a reduction in catalyst loading and
boronic acid stoichiometry, while retaining high coupling effi-
ciency. The improved conditions presented herein make these
intriguing carbon-carbon cross-coupling transformations in-
volving phenol derivatives as electrophiles significantly more
practical, and will stimulate the further development of this
area. We have also established that the microwave condi-
tions work exceedingly well with aryl chlorides as electro-
philic cross-coupling partners, and have additionally demon-
strated the scalability of the coupling process up to 700 mL scale.
2-Phenylnaphthalene (3a):9. H NMR (300 MHz, CDCl3) δ
1
7.42-7.48 (m, 1H), 7.53-7.60 (m, 4H), 7.78-7.83 (m, 3H),
7.91-7.99 (m, 3H), 8.11 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
141.2, 138.6, 133.7, 132.6, 128.9, 128.4, 128.2, 127.7, 127.5,
127.4, 126.3, 126.0, 125.8, 125.6.
3-Phenylpyridine (3m):10. 1H NMR (300 MHz, CDCl3) δ
7.35-7.52 (m, 4H), 7.57-7.61 (m, 2H), 7.89 (dt, J = 7.5, 1.8
Hz, 1H), 8.60 (dd, J = 4.8, 1.8 Hz, 1H), 8.87 (d, J = 1.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 148.4, 148.2, 137.8, 136.6, 134.4,
129.1, 128.1, 127.1, 123.5.
3-(4-Methoxyphenyl)pyridine (3n):10. 1H NMR (300 MHz,
CDCl3) δ 3.87 (s, 3H), 7.03 (d, J = 8.7 Hz, 2H), 7.32-7.37 (m,
1H), 7.53 (d, J = 9 Hz, 2H), 7.82-7.86 (m, 1H), 8.56 (dd, J =
4.8, 1.5 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 159.7, 148.0, 147.8, 136.2, 133.8, 130.2, 128.2, 123.5,
114.5, 55.4.
Acknowledgment. This work was supported by a grant
from the Christian Doppler Research Foundation (CDG).
We thank Anton Paar GmbH for the provision of the
Masterwave BTR.
(20) (a) Moseley, J. D. In Microwave Heating as a Tool for Sustainable
Chemistry; Leadbeater, N. E., Ed.; CRC Press: Boca Raton, FL, 2011;
Chapter 5, pp 105-147. (b) Strauss, C. R. Org. Process Res. Dev. 2009, 13,
915.
(21) For further details on this instrument, see the Supporting Informa-
tion and www.anton-paar.com.
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1510 J. Org. Chem. Vol. 76, No. 5, 2011