Suzuki-Miyaura cross-coupling of aryl carbamates and sulfamates: Experimental and computational studies

Article abstract of DOI:10.1021/ja200398c

The first Suzuki-Miyaura cross-coupling reactions of the synthetically versatile aryl O-carbamate and O-sulfamate groups are described. The transformations utilize the inexpensive, bench-stable catalyst NiCl ₂(PCy₃)₂ to furnish biaryls in good to excellent yields. A broad scope for this methodology has been demonstrated. Substrates with electron-donating and electron-withdrawing groups are tolerated, in addition to those that possess ortho substituents. Furthermore, heteroaryl substrates may be employed as coupling partners. A computational study providing the full catalytic cycles for these cross-coupling reactions is described. The oxidative addition with carbamates or sulfamates occurs via a five-centered transition state, resulting in the exclusive cleavage of the aryl C-O bond. Water is found to stabilize the Ni-carbamate catalyst resting state, which thus provides rationalization of the relative decreased rate of coupling of carbamates. Several synthetic applications are presented to showcase the utility of the methodology in the synthesis of polysubstituted aromatic compounds of natural product and bioactive molecule interest.

Full text of DOI:10.1021/ja200398c

ARTICLE
pubs.acs.org/JACS
SuzukiÀMiyaura Cross-Coupling of Aryl Carbamates and Sulfamates:
Experimental and Computational Studies
Kyle W. Quasdorf,† Aurora Antoft-Finch,‡ Peng Liu,† Amanda L. Silberstein,† Anna Komaromi,†
Tom Blackburn,‡ Stephen D. Ramgren,† K. N. Houk,*,† Victor Snieckus,*,‡ and Neil K. Garg*,†
†Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States
‡Department of Chemistry, Queen’s University, Kingston, Ontario K7L 3N6, Canada
S Supporting Information
b
ABSTRACT: The first SuzukiÀMiyaura cross-coupling reactions of the
synthetically versatile aryl O-carbamate and O-sulfamate groups are de-
scribed. The transformations utilize the inexpensive, bench-stable catalyst
NiCl2(PCy3)2 to furnish biaryls in good to excellent yields. A broad scope
for this methodology has been demonstrated. Substrates with electron-
donating and electron-withdrawing groups are tolerated, in addition to
those that possess ortho substituents. Furthermore, heteroaryl substrates
may be employed as coupling partners. A computational study providing
the full catalytic cycles for these cross-coupling reactions is described. The
oxidative addition with carbamates or sulfamates occurs via a five-centered
transition state, resulting in the exclusive cleavage of the aryl CÀO bond.
Water is found to stabilize the Ni-carbamate catalyst resting state, which thus provides rationalization of the relative decreased rate of
coupling of carbamates. Several synthetic applications are presented to showcase the utility of the methodology in the synthesis of
polysubstituted aromatic compounds of natural product and bioactive molecule interest.
’ INTRODUCTION
Transition metal-catalyzed cross-coupling reactions provide a
powerful means to assemble carbonÀcarbon (CÀC) and carbonÀ
heteroatom (CÀX) bonds.1 Although halides are most commonly
employed as the electrophilic partner,1,2 phenolic derivatives
(Figure 1), or “pseudohalides”, offer a valuable alternative given
that phenols are typically inexpensive and readily available
materials.3 Cross-couplings of aryl sulfonates have been most
widely studied, and a range of CÀC and CÀX bond forming
reactions are now established.1,4,5 Recent studies have focused on
the development of less common phenol-based electrophiles,6
such as ethers,7 esters,8 carbamates,9 and sulfamates9b,10 since
they are commonly more robust, typically unreactive toward Pd
catalysis, and show synthetic advantage for the regioselective
Figure 1. Phenol-based cross-coupling partners.
construction of aromatics by CÀH activation and directed ortho
metalation (DoM) chemistry.11À14
SuzukiÀMiyaura cross-coupling reactions of aryl O-carbamates
Inspired by the reasons outlined above, our laboratories have
and O-sulfamates, (b) the broad scope of these transformations,
which includes the cross-coupling of heterocyclic substrates, (c)
computational studies that elucidate the complete catalytic cycle of
these couplings, and (d) a variety of synthetic applications,
including DoM-linked tactics and a concise synthesis of the anti-
inflammatory drug flurbiprofen.16
pursued the development of cross-coupling reactions involving
phenol-derived carbamates and sulfamates (Scheme 1). Previous
studies have demonstrated the utility of these reaction partners in
nickel-catalyzed Kumada couplings.9d,e,10 However, the corre-
sponding SuzukiÀMiyaura couplings of these substrates have
remained elusive, despite the numerous benefits of organoboro-
nate coupling methodologies. Such advantages include the low
toxicity, wide availability, and pronounced stability of organobor-
onates, in addition to their broad functional group tolerance.1,15 In
this article, we report (a) the development of the Ni-catalyzed
Received: January 14, 2011
Published: April 01, 2011
r
2011 American Chemical Society
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Scheme 1
Table 2. Optimization Studies for Naphthyl 2-O-Carbamate
Coupling
Table 1. Cross-Coupling of Aryl Carbamates with
Arylboronic Acidsa
a Yield by GC/MS analysis (yield of isolated product). b All reactions
were run for 20 h with the exception of entry 4, which was run for 5 h. c 10
mol % NiCl2(PCy3)2.
carbamate substrate led only to trace amounts of cross-coupled
product. By raising the temperature to 110 °C, however, the desired
biaryl was obtained in 51% yield (entry 1). Further optimization
ultimately established more forcing conditions that delivered the
targeted product in 86% yield (entry 2).
Additional carbamate substrates were examined under our Ni-
catalyzed reaction conditions (Table 1).20 2-Naphthyl carba-
mates gave products in lower yields (entries 3 and 4). The
reaction proved tolerant of an electron-withdrawing group
(EWG; ÀCO2Me, entry 4) and an electron-donating group
(EDG; ÀOMe, entry 5) on the naphthyl ring. The correspond-
ing reactions of phenyl carbamates was more challenging. None-
theless, carbamates derived from phenol and p-methoxyphenol
were converted to the corresponding cross-coupled products in
52% and 41% yield, respectively (entries 6 and 7).
Further studies were undertaken to uncover higher yielding and
more generally useful reaction conditions. The N,N-diethyl carba-
mate of 2-naphthol was subjected to NiCl2(PCy3)2 with variations
in temperature, solvent, ligand additive, and organoboron species
(Table 2). When employing o-xylenes at 150 °C, cross-coupling
with boroxine 3b proceeded sluggishly but nevertheless furnished
the desired biaryl in 61% yield (entry 1). Mixtures of boronic acids
and boroxines were also examined. Using a 1:1 mixture of 3a:3b,
the desired biaryl was obtained in only 26% yield (entry 2). These
results, coupled with the observation that 3a liberates excessive
water in organic solvents, led us to hypothesize that, although
some water is necessary to generate the catalytically active
boronate species, excessive water can be detrimental to the
carbamate cross-coupling reaction.21 Furthermore, Shi had previously
reported the critical role of water in the SuzukiÀMiyaura coupling of
aryl pivalate esters.8b By using a 1:10 ratio of 3a:3b,22 and thereby
minimizing the water content, a quantitative yield of cross-coupled
product was obtained (entry 3). Conducting the reaction at 120 °C,
with toluene as solvent and 10 mol % Ni catalyst, gave a lower yield of
the biaryl adduct (entry 4).23
a Conditions: NiCl2(PCy3)2 (10 mol %), ArB(OH)2 (4 equiv), K3PO4
(7.2 equiv), toluene (0.3 M), 130 °C for 24 h. b Conditions: NiCl2-
(PCy3)2 (5 mol %), ArB(OH)2 (2.5 equiv), K3PO4 (4.5 equiv), toluene
(0.3 M), 110 °C, 24 h. c Yields of isolated products.
’ RESULTS AND DISCUSSION
SuzukiÀMiyaura Cross-Coupling Reactions of Aryl O-Car-
bamates. A key challenge in achieving the SuzukiÀMiyaura cross-
coupling of aryl carbamates lies in activating the fairly inert aryl
carbonÀoxygen bond of these substrates. A similar obstacle had
been overcome in our previously reported SuzukiÀMiyaura cou-
pling of aryl pivalates.8a Encouraged by our prior success, we explored
NiCl2(PCy3)2-promoted conditions to effect the desired SuzukiÀ
Miyaura coupling of aryl carbamates (Table 1). Of note, NiCl2-
(PCy3)2 is readily available, is considerably stable to air and water,
and can be used on the benchtop rather than in a glovebox.17À19
Initial studies were directed toward the coupling of fused-aromatic
systems, which are typically superior substrates in Ni-catalyzed
couplings of phenolic derivatives.7À9 Unfortunately, applying our
optimal conditions for pivalate coupling (i.e., NiCl2(PCy3)2 (5 mol
%) and K3PO4 (4.5 equiv) in toluene at 80 °C) to a 1-naphthyl
Having found optimal and reproducible conditions, we turned
our attention to defining the scope and functional group tolerance of
the carbamate cross-coupling reaction (Table 3).20 Substrates
derived from 2-naphthol, 1-naphthol, and phenol underwent
smooth coupling (entries 1À3). Furthermore, although a substrate
bearing the electron-withdrawing fluoro substituent was tolerated
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Table 3. Cross-Coupling of Aryl Carbamates under
Improved Conditionsa
Table 5. Cross-Coupling of Heterocyclic Aryl O-Carbamates
and Scope of Aryl Boronatesa
a Conditions: NiCl2(PCy3)2 (5 mol %), PCy3HBF4 (10 mol %), ArB-
(OR)2 (2.5 equiv), ratio of Ar3B3O3:ArB(OH)2 = 10:1 (4 equiv),
K3PO4 (5 equiv). b Yield by GC/MS analysis (yield of isolated product).
a Conditions: NiCl2(PCy3)2 (5 mol %), PCy3HBF4 (10 mol %), ArB-
(OR)2 (2.5 equiv), ratio of Ar3B3O3:ArB(OH)2 = 10:1 (4 equiv),
K3PO4 (5 equiv). b Yield by GC/MS analysis (yield of isolated product).
Table 4. Cross-Coupling of Ortho-Substituted Aryl
O-Carbamatesa
cross-coupling at the cyano group, a transformation reported
recently by Shi.24 Finally, an electron-rich substrate gave only low
yields of product (entry 6).
Several ortho-substituted aryl carbamates were tested in the
SuzukiÀMiyaura coupling (Table 4). Substrates of this type can
be readily synthesized by DoM12 or transition metal-catalyzed CÀH
functionalization.14bÀe Substrates with o-benzyl, -alkenyl, and -phenyl
groups were all tolerated (entries 1À3). Coupling of the o-methoxy
substrate proceeded in modest yield (entry 4), whereas coupling of
a 2,4-dimethylated substrate was unsuccessful (entry 5). In view of
the coupling of other ortho-substituted systems to afford good to
excellent yields of products (entries 1À3), rationalization of these
results based on steric effects is premature.
As shown in Table 5, the carbamate cross-coupling methodology
is also applicable to heterocyclic substrates. Thus, the 3-pyridyl
carbamate was efficiently cross-coupled with a variety of organobor-
on species (entries 1À5). In addition, a quinoline-derived substrate
was tolerated (entry 6), and a carbazole-containing substrate under-
went conversion to the desired biaryl under our optimal reaction
conditions albeit in modest yield (entry 7).
SuzukiÀMiyaura Cross-Coupling Reactions of Aryl Sulfa-
mates. Concurrent with the above studies on aryl carbamates, aryl
sulfamates were targeted as substrates for the Ni-catalyzed SuzukiÀ
Miyaura cross-coupling reactions. Although early efforts to effect this
transformation with dppp as ligand gave initial encouragement,10a
employing the tricyclohexylphosphine ligand led to improved results,
ultimately rendering aryl sulfamates superior SuzukiÀMiyaura
coupling partners to the corresponding carbamates (Table 6).20
Naphthyl substrates were smoothly converted to biaryl products,25
a Conditions: NiCl2(PCy3)2 (5 mol %), PCy3HBF4 (10 mol %), 2 (2.5
equiv), ratio of Ph3B3O3:PhB(OH)2 = 10:1 (4 equiv), K3PO4 (5 equiv).
b Yield by GC/MS analysis (yield of isolated product).
(entry 4), coupling in the presence of a cyano derivative was less
fruitful (entry 5). The latter result can be explained by competitive
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Table 6. Cross-Coupling of Aryl Sulfamatesa
Table 7. Cross-Coupling of Ortho-Substituted Aryl
Sulfamatesa
a Conditions: NiCl2(PCy3)2 (5 mol %), ArB(OH)2 (2.5 equiv), K3PO4
(4.5 equiv), toluene (0.3 M), 110 °C for 24 h. b Yields of isolated
products. c Conditions: NiCl2(PCy3)2 (10 mol %), ArB(OH)2 (4
equiv), K3PO4 (7.2 equiv), toluene (0.3 M), 130 °C for 24 h.
Scheme 2
a Conditions: NiCl2(PCy3)2 (5 mol %), ArB(OH)2 (2.5 equiv), K3PO4
(4.5 equiv), toluene (0.3 M), 110 °C for 24 h. b Yields ofisolatedproducts.
even in the presence of an EWG or EDG (entries 1À3). Most
strikingly, the reaction proceeded comparably well when operating on
aryl derivatives (entries 4À9). Methyl and the electron-withdrawing
CF3 substituents are tolerated (entries 5À7). Substrates bearing
electron-rich methoxy or amino substituents also afforded very good
yields of coupled products (entries 8 and 9). Moreover, a vinyl
sulfamate participated in the SuzukiÀMiyaura cross-coupling reac-
tion (entry 10).
In view of the availability of many ortho-substituted aryl sulfamates
by DoM chemistry, such derivatives were also evaluated in the
SuzukiÀMiyaura cross-coupling reaction (Table 7).20,26 The trans-
formation was found to be tolerant of an o-cresol-derived substrate, in
addition to the sterically burdened sulfamate prepared from 2,6-
dimethylphenol (entries 1 and 2). Furthermore, substrates bearing
o-trimethylsilyl, -phenyl, and -methoxy substituents underwent cross-
coupling to give the corresponding products in excellent yields (entries
3À5). Interestingly, a substrate possessing a bulky o-tert-butylketone
substitutent could also be utilized in this methodology (entry 6).
Although the DoM chemistry of aryl sulfamates was initially
reported using N,N-diethyl substrates,10a the corresponding N,N-
dimethyl aryl sulfamates were found to undergo metalation under
the identical reported reaction conditions. Scheme 2 highlights
syntheses of substrates 8À11 beginning from phenyl sulfamate 6,
which, in turn, is easily prepared from phenol and commercially
available dimethylsulfamoyl chloride27 in quantitative yield. Com-
pounds 9 and 10 were obtained by lithiation of phenyl sulfamate 6,
followed by quenching with TMSCl and PivCl, respectively. Simi-
larly, the boronate 7 was derived by quenching the intermediate
lithio species with B(OMe)3, followed by treatment with pinacol.10a
Boronate 7 served as the common precursor to substituted sulfa-
mates 8 and 11. Whereas methoxysulfamate 11 was prepared by a
straightforward oxidation28/methylation sequence, o-phenyl sulfa-
mate 8 was accessed by a Pd-catalyzed SuzukiÀMiyaura cross-
coupling. It is notable that the sulfamate remains undisturbed under
the Pd-mediated reaction conditions.
The scope of the sulfamate cross-coupling reaction was also
found to be broad with respect to the boronic acid component
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Table 8. Scope of Arylboronic Acid in the SuzukiÀMiyaura
Cross-Coupling of Aryl O-Sulfamatesa
Table 9. Cross-Coupling of Heterocyclic Aryl O-Sulfamates
with Phenylboronic Acida
a Conditions: NiCl2(PCy3)2 (5 mol %), 2a (2.5 equiv), K3PO4 (4.5
equiv), toluene (0.3 M), 110 °C, 24 h. b Yields of isolated products.
c Conditions: NiCl2(PCy3)2 (10 mol %), 2a (4 equiv), K3PO4 (7.2
equiv), toluene (0.3 M), 130 °C for 24 h.
addition to indole and carbazole (entries 2 and 3), the pyridine
and quinoline heterocycles, each possessing basic amine function-
ality, were also tolerated (entries 4À6).
The scope of the sulfamate cross-coupling reaction with respect
to heteroaryl boronic acids is summarized in Table 10. Benzofuran-
and furan-containing substrates underwent smooth cross-coupling
under our standard reaction conditions (entries 1 and 2). Further-
more, a sulfur-containing heterocyclic boronic acid could be em-
ployed (entry 3). A pyridine 3-boronic acid derivative was also
tolerated in our SuzukiÀMiyaura coupling methodology (entry 4).
As an additional important test of the sulfamate coupling
methodology, we attempted a SuzukiÀMiyaura reaction wherein
both coupling partners were heterocyclic substrates (Scheme 3).29
We were delighted to find that the desired cross-coupling between
quinoline-derived sulfamate 12 and pyridinylboronic acid 13 pro-
ceeded smoothly to furnish biaryl 14 in 97% yield. This result
underscores the critical tolerance of the sulfamate cross-coupling
process to basic nitrogen substituents.
Mechanistic Studies. Pd-catalyzed SuzukiÀMiyaura cross-cou-
plings have been studied computationally by various groups.30,31
The three key steps in the catalytic cycle, oxidative addition,32
transmetalation,31 and reductive elimination,33 have been studied
carefully for reactions involving a variety of substrates. The mechan-
ism of the Ni-catalyzed SuzukiÀMiyaura cross-coupling with aryl
acetates has been recently investigated theoretically by Li et al.34 Here
we report the first theoretical study of the catalytic cycles of the Ni-
catalyzed SuzukiÀMiyaura cross-coupling with O-carbamates and O-
sulfamates using density functional theory (DFT). The selectivities
between couplings with the ArÀO bond and the OÀcarbonyl/
a Conditions: NiCl2(PCy3)2 (5 mol %), ArB(OH)2 (2.5 equiv), K3PO4
(4.5 equiv), toluene (0.3 M), 110 °C for 24 h. b Yields of isolated
products. c Conditions: NiCl2(PCy3)2 (10 mol %), ArB(OH)2 (4
equiv), K3PO4 (7.2 equiv), toluene (0.3 M), 130 °C for 24 h. d Condi-
tions: NiCl2(PCy3)2 (5 mol %), ArB(OH)2 (2.5 equiv), K3PO4 (4.5
equiv), toluene (0.3 M), 120 °C for 24 h.
(Table 8). A methyl substituent was tolerated at the para, meta,
and ortho positions (entries 1À3), as was a 4-methoxymethyl
group (entry 4). Cross-coupling of a boronic acid bearing the
electron-donating methoxy group proceeded in 95% yield (entry
5). Finally, electron-withdrawing trifluoromethyl, fluoro, and
acetyl substituents were compatible with the sulfamate coupling
methodology (entries 6À8).
SuzukiÀMiyaura Cross-Coupling Reactions of Heterocyclic
O-Sulfamates. Given the importance of heterocycles in medicinal
agents, we probed the use of heterocyclic partners in the sulfamate
SuzukiÀMiyaura cross-coupling process.29 As shown in Table 9, a
variety of heterocyclic aryl sulfamates were suitable for this meth-
odology, although more forcing reaction conditions were often
required to achieve synthetically useful yields. Coupling of a
dihydrobenzofuran-derived substrate afforded the desired biaryl in
88% yield (entry 1). Similar success was observed in the coupling
of nitrogen-containing heteroaryl sulfamates (entries 2À6). In
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Table 10. Cross-Coupling of Naphthyl Sulfamates with Het-
erocyclic Aryl Boronic Acidsa
oxidative addition may occur at the PhÀO bond or the OÀcarbonyl
bond of the carbamates. Previous theoretical studies suggested that
the oxidative addition of aryl halides to Pd(0) catalysts involves
formation of an η2 LPd(ArX) pre-reaction complex.32 The η2
LPd(ArX) complex may be generated through ligand dissociation
from PdL2 followed by coordination with aryl halide or through a
concerted or stepwise associative displacement pathway.39 Recent
density functional calculations by Li et al. suggested that the
oxidative addition of phenylacetates in Ni-catalyzed SuzukiÀ
Miyaura couplings also involves an η2 LNi(ArX) pre-reaction
complex.8c Upon dissociation of a PCy3 ligand, the Ni catalyst
coordinates with the substrate to generate an η2 complex 16,
which is slightly less stable than Ni(PCy3)2.40 Li et al. suggested
that the oxidative addition of phenylacetates occurs via a three-
centered transition state, and the weaker PhOÀcarbonyl bond is
more reactive compared to the PhÀO bond.8c We investigated the
possible pathways in the oxidative additions with phenyl carbamates
(Figures 2 and 4) and found that the preferred pathway involves
oxidative addition at the PhÀO bond via a five-centered transition
state (TS17, Figures 2 and 4) in which Ni is monoligated and
coordinated with the carbonyl oxygen.41,42 The corresponding
three-centered transition state (TS30) that uses a single oxygen
of the carboxylate to bridge requires 7.4 kcal/mol higher activation
energy. In contrast to previous theoretical studies by Li et al., the
PhÀO bond in carbamates is more reactive in oxidative addition
than the PhOÀcarbonyl bond, although the former is a stronger
bond in terms of bond dissociation energies.43 Oxidative addition at
the OÀcarbonyl bond can only occur via a three-centered transition
state (TS31) and requires 3.9 kcal/mol higher energy than the
oxidative addition at the PhÀO bond (TS17). Thus, the oxidative
addition occurs exclusively at the PhÀO bond due to a favorable
five-centered transition state. The carbonyl group is acting as a
directing group to activate the PhÀO bond in the oxidative addition.
It is conceivable that such activating effects by adjacent oxygenation
is also present in oxidative additions with carbonates, sulfonates, and
sulfamates, etc.
a Conditions: NiCl2(PCy3)2 (5 mol %), HetArB(OH)2 (2.5 equiv),
K3PO4 (4.5 equiv), toluene (0.3 M), 110 °C, 24 h. b Yields of isolated
products.
Scheme 3
sulfonyl bond and the effects of water on the reactivities are also
described.
A stable phenyl Ni(II)-carbamate complex 18 is formed after
the oxidative addition (Figure 2). The carbamate is κ2-coordi-
nated with Ni. Subsequent ligand exchange of the carbamate
complex 18 with phenylboronate leads to phenyl Ni(II)-bor-
onate complex 20, which is 5.5 kcal/mol less stable than the Ni-
carbamate complex. The detailed mechanism of this ligand
exchange step has been suggested to be stepwise.15a,44 Previous
theoretical studies suggested that the ligand exchange does not
have a large barrier.8c,31b,31g Thus, we assume the transformation
from 18 to 20 is facile.
The following transmetalation (TS21) is the rate-determining
step of the catalytic cycle, and requires an activation energy of 30.2
kcal/mol from the catalyst resting complex 18. The transmetalation
transition state (TS21) is consistent with the four-center transition
state proposed in previous theoretical studies of Pd- and Ni-
catalyzed SuzukiÀMiyaura couplings.31,8c The two aryl groups are
cis to each other in the transmetalation transition state. The trans
transition state is 3.5 kcal/mol less stable, presumably due to greater
steric repulsions between the ligand and the aryl groups. Subsequent
reductive elimination of the diphenyl Ni(II) complex (23 f TS24)
is facile, requiring only a 2.9 kcal/mol activation energy.
Figures 2 and 3 depict the catalytic cycles for the SuzukiÀMiyaura
cross-coupling of aryl carbamates and sulfamates, respectively, as
determined by DFT calculations. The geometries of important
transition structures are shown in Figure 4 for the couplings of N,
N-dimethyl phenyl carbamate and N,N-dimethyl phenyl sulfamate
with phenylboronic acid. The PCy3 ligand used in the experiments
was also used in the calculations. Geometry optimizations and
frequency calculations were performed using B3LYP35 and a mixed
basis set employing LANL2DZ for metal and 6-31G(d) for other
atoms. Conformational searches of the PCy3 ligand were performed.
The initial geometry of PCy3 was taken from the crystal structure of
Ni(PCy3)(C2H4)2.36 Several rotamers of the PCy3 ligands in the Ni
complexes were tested as the initial geometry in the optimizations.
Energies reported are Gibbs free energies in solution, which involve
zero-point vibrational energy corrections, thermal corrections to
Gibbs free energy at 298 K, and solvation free energy corrections
computed by singlet point CPCM37 calculations on gas-phase
optimized geometries (toluene was used as solvent). The molecular
cavities were built up using the United Atom Topological Model
(UAHF). Vibrational frequencies were calculated for all optimized
structures to confirm the nature of the stationary points. All calcula-
tions were performed using Gaussian 03.38
Similarly, the oxidative addition of N,N-dimethyl phenyl
sulfamate occurs via a monoligated five-membered transition
state (TS27).41 Three-center transition states TS32 and TS33
are both much higher in energy (Figure 4). The activation barrier
for oxidative addition of sulfamate 6 is 10.4 kcal/mol with respect
The oxidative addition of aryl carbamates may occur via several
different pathways: the Ni may be mono- or bis-ligated, and the
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Figure 2. Gibbs free energy profile of Ni-catalyzed SuzukiÀMiyaura cross-coupling reaction of phenyl N,N-dimethyl O-carbamate 15 with
phenylboronic acid. PCy3 was used as ligand in the calculations. For clarity, the cyclohexyl groups on the ligand are not shown.
Figure 3. Gibbs free energy profile of the Ni-catalyzed SuzukiÀMiyaura cross-coupling reaction of N,N-dimethyl phenyl O-sulfamate with
phenylboronic acid. PCy3 was used as ligand in the calculations. For clarity, the cyclohexyl groups on the ligand are not shown.
to the Ni(PCy3)2 complex, which is 3.1 kcal/mol lower than that
of the oxidative addition of N,N-dimethyl phenyl carbamate 15.
The higher reactivity of the sulfamate in oxidative addition is due
to the weaker PhÀO bond in sulfamate than the corresponding
PhÀO bond in the carbamate group. Nonetheless, the oxidative
addition with aryl carbamates or aryl sulfamates are both
predicted to be very facile. The differences of their reactivities
are attributed to the different activation barriers in the rate-
determining transmetalation step. After the oxidative addition of
the carbamate, a stable phenyl Ni(II)-carbamate complex 18 is
formed. Subsequent ligand exchange with phenyl boronate
requires 5.5 kcal/mol energy to form the Ni(II)-boronate com-
plex 20. In contrast, since sulfamate is a better leaving group, the
Ni(II)-boronate complex 20 is formed spontaneously from the
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Figure 4. Transition-state structures of Ni-catalyzed oxidative additions of (a) N,N-dimethyl phenyl O-carbamate and (b) N,N-dimethyl phenyl O-
sulfamate. PCy3 was used as ligand in the calculations. For clarity, the cyclohexyl groups on the ligand are not shown.
role of water computationally. In the coupling with phenyl carbamate,
water can coordinate with Ni and stabilize the catalyst resting state, the
Ni-carbamate complex 18. A six-membered cyclic Ni(II)-water-
carbamate complex 19 is formed and is 1.1 kcal/mol more stable
than 18 (Figure 2).47 Coordination with water increases the barrier of
transmetalation to 31.3 kcal/mol (19 f TS21), and thus decreases
the reactivity of the coupling for the carbamate. In the coupling with
phenyl sulfamate, the catalyst resting state is the Ni(II)-boronate
complex 20. Upon coordination with a water molecule, a similar six-
membered cyclic complex 29 is formed in equilibrium. However, 29 is
7.7 kcal/mol less stable than 20. This suggests that coordination with
water does not affect the barrier of transmetalation in the coupling
reaction of the sulfamate. This agrees with the experimental observa-
tion that SuzukiÀMiyaura cross-couplings of aryl sulfamates are less
sensitive to water than couplings of aryl carbamates.
In contrast to the high reactivity of the Ni catalyst in oxidative
addition with carbamates and sulfamates, Pd catalysts are much less
reactive in the oxidative addition step. Oxidative addition of phenyl
N,N-dimethylcarbamate with Pd also prefers a five-membered
monoligated transition state. The activation barrier is 42.2 kcal/
mol with respect to the Pd(PCy3)2 complex, much higher than that
of the corresponding Ni catalyst. Similarly, oxidative addition of
phenyl N,N-dimethylsulfamate also requires a very high activation
barrier of 39.7 kcal/mol. These observations are in agreement with
previous mechanistic and theoretical studies that the oxidative
addition step to Ni(0) is more facile than that to Pd(0).32,40
Therefore, due to the extremely high activation barriers for oxidative
addition, Pd catalysts are not effective in couplings with carbamates
and sulfamates.
Figure 5. Qualitative relative rates of cross-coupling depending on
boronic acid.
Ni(II)-sulfamate complex 28. The activation barrier of the rate-
determining transmetalation step for the cross-coupling with the
sulfamate (ΔGq = 24.7 kcal/mol) is much lower than that for the
corresponding carbamate (ΔGq = 30.2 kcal/mol). The subse-
quent steps after transmetalation are identical for the coupling
reactions for carbamates and sulfamates.
To support the computational finding that transmetalation is
the rate-determining step in the cross-coupling reactions de-
scribed above, a series of experiments were carried out. Sulfamate
34 was independently subjected to reactions with boronic acids
1a, 2a, and 4a in the presence of NiCl2(PCy3)2 and K3PO4 in
toluene at 80 °C (Figure 5). In each case, reaction progress was
1
monitored by H NMR analysis using hexamethylbenzene as
internal standard. The relative rate of cross-coupling was found
to be dependent on the individual boronic acid employed, with a
direct correlation between electron-richness of the boronic acid
and reaction rate (i.e., relative rate of conversion: 1a > 2a > 4a).45
These findings are consistent with a rate-determing transmetala-
tion step for the sulfamate cross-coupling process.46
Similar to the reports by Shi in related Ni-catalyzed SuzukiÀ
Miyaura cross-couplings,8b we have observed that water can play a
critical role in the success or failure of a coupling reaction (vide supra).
To better understand these experimental findings, we examined the
Synthetic Applications. The scope and limitations of our
sulfamate and carbamate coupling methodologies were further
6359
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Journal of the American Chemical Society
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Scheme 4
Scheme 6
Scheme 5
Scheme 7
examined by way of a variety of synthetic applications. In each of
the studies undertaken, the synthetically useful capability of
carbamates and sulfamates to function as directed metalation
groups (DMGs) and SuzukiÀMiyaura coupling partners was
exploited. These studies showcase the utility of our methodology
in the synthesis of polysubstituted aromatic compounds, with
relevance to natural product and bioactive molecule synthesis.
Scheme 4 depicts a concise synthesis of 5-phenyl-2H-chro-
mene 38 beginning from bis(carbamate) precursor 36. Thus, in a
one-pot procedure involving sequential treatment with t-BuLi,
3-methylbut-2-enal, and AcOH, compound 36 was converted
into 2H-chromene carbamate 37.48,49 Subsequent SuzukiÀ
Miyaura cross-coupling provided biaryl 38 in 56% yield. Biaryl
38 possesses a heterocyclic framework of bioactivity50 and natural
product interest.51
In another application, the unique heterotriaryl 43 was con-
structed using carbamate DoM and cross-coupling methodology
(Scheme 5). o-Methoxy carbamate 39 was first transformed into
boronic acid 40 in 88% yield using a standard lithiation/borylation
protocol. Subsequent Pd-catalyzed SuzukiÀMiyaura cross-coupling
with iodobenzofuran 41 delivered arylated product 42 without
disturbance of the aryl carbamate under these conditions.52 The
subsequent Ni-catalyzed carbamate cross-coupling with phenyl-
boronic acid provided the targeted heterotriaryl 43.53
An illustration of the DoM/cross-coupling protocol beginning
from a heteroaryl carbamate is presented in Scheme 6. Lithiation/
borylation of 44 afforded the boropinacolate 45, which was
subjected to standard SuzukiÀMiyaura cross-coupling conditions
with bromide 46 using Pd catalysis to furnish heterobiaryl 47.54
Heteroaryl carbamate 47 was found to be an excellent substrate for
the Ni-catalyzed cross-coupling using our standard conditions, to
afford the heterotriaryl product 48 in 91% yield. Compound 48
represents a class of pyridines with nonidentical diaryl substitution
for which only two synthetic methods are available.55
As an application to bioactive molecule synthesis, the anti-
inflammatory drug flurbiprofen56 was prepared using sulfamate
methodology (Scheme 7). Boronic acid 49, derived from o-lithia-
tion/borylation of N,N-dimethyl phenyl sulfamate, was fluorinated
using the conditions described by Furuya and Ritter57 to provide
fluorosulfamate 50. Alternative routes to generate 50 by direct
lithiation/fluorination of N,N-dimethyl phenyl sulfamate were un-
successful despite numerous attempts.58 Nonetheless, para-selective
electrophilic iodination of 50 furnished 51 in 64% yield. With the
aryl sulfamate being inert to Pd catalysis, we carried out a site-
selective enolate coupling to install the necessary propionate side
chain. Whereas enolate coupling of aryl iodide 51 under Buchwald’s
Pd-based conditions was feasible,59 higher yields of 52 were
obtained using a Ni-catalyzed variant.60 With the sulfamate remain-
ing undisturbed, exposure of 52 to our Ni-catalyzed conditions
facilitated the key sulfamate cross-coupling and delivered the biaryl
53. Acid-mediated hydrolysis furnished flurbiprofen (54) in 84%
yield over the two steps. It should be emphasized that the aryl
fluoride of 52 was chemically inert under our Ni-catalyzed cross-
coupling conditions.61
We have observed that aryl carbamates amd sulfamates are
unreactive toward Pd(0) catalysis (vide supra) and related
processes.62 This feature allows the sequential cross-coupling of an
aryl halide, followed by either an aryl sulfamate or carbamate
coupling process (see Scheme 7). To further probe related issues
of orthogonality, we questioned if it would be possible to couple aryl
sulfamates in the presence of aryl carbamates. Although aryl
sulfamates generally provide higher yields of cross-coupled products
compared to aryl carbamates, the relative reactivity of these
substrates had not been determined previously. As shown in
Figure 6, an equimolar mixture of phenyl carbamate 55 and phenyl
sulfamate 6 was treated with an excess of boronic acid 3a under
Ni-catalyzed cross-coupling conditions. Although significant selec-
tivity was observed at elevated temperatures, complete selectivity for
6360
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Journal of the American Chemical Society
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’ ACKNOWLEDGMENT
The authors are grateful to NSERC Canada (Discovery Grant
program) (V.S.), the NIH-NIGMS Grant R00-GM079922 (N.K.
G.), BoehringerIngelheim(N.K.G.), DuPont(N.K.G.), Eli Lilly(N.
K.G.), and the National Science Foundation Grant CHE-0548209
(K.N.H.) for financial support. The Chemistry-Biology Interface
training program (A.L.S., USPHS National Research Service Award
GM08496), the Hungarian Scholarship Board Office (A. K.), the
ACS Division of Organic Chemistry (K.W.Q.), and the Foote family
(K.W.Q.), are acknowledged for graduate student fellowships. We
thank the Garcia-Garibay laboratory (UCLA) for access to instru-
mentation, Michelle Riener and Krastina Petrova for experimental
assistance, Dr. Franc-oise Sauriol (Queen’s) for NMR, and Dr. John
Greaves (UC Irvine) and Dr. Lina Yuan (Queen’s) for mass spectral
assistance. We express our gratitude to Frontier, Inc. for provision of
samples of boronic acids. Calculations were performed on the
National Science Foundation Terascale Computing System at
the NCSA.
Figure 6. Intermolecular competition experiments of aryl sulfamates
and aryl carbamates.
’ REFERENCES
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In summary, we have discovered the first SuzukiÀMiyaura cross-
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’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental details,
b
compound characterization data, optimized Cartesian coordi-
nates and energies, and complete ref 38. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
houk@chem.ucla.edu; snieckus@chem.queensu.ca; neilgarg@
chem.ucla.edu
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Journal of the American Chemical Society
ARTICLE
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(39) The exact mechanism of the formation of the η2 LPd(ArX)
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