Pd-catalyzed Suzuki-Miyaura cross-coupling reactions between sulfamates and potassium Boc-protected aminomethyltrifluoroborates

Article abstract of DOI:10.1021/ol401021x

Sulfamates were studied as the electrophilic partners in the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction with potassium Boc-protected primary and secondary aminomethyltrifluoroborates. A broad range of substrates was successfully coupled to provide the desired products. Complex molecules containing a new carbon-carbon bond and an aminomethyl moiety could be prepared through this developed method.

Full text of DOI:10.1021/ol401021x

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Pd-Catalyzed SuzukiÀMiyaura
Cross-Coupling Reactions between
Sulfamates and Potassium Boc-Protected
Aminomethyltrifluoroborates
Gary A. Molander* and Inji Shin
Roy and Diana A. Vagelos Laboratories, Department of Chemistry, University of
Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States
gmolandr@sas.upenn.edu
Received April 12, 2013
ABSTRACT
Sulfamates were studied as the electrophilic partners in the palladium-catalyzed SuzukiÀMiyaura cross-coupling reaction with potassium Boc-
protected primary and secondary aminomethyltrifluoroborates. A broad range of substrates was successfully coupled to provide the desired
products. Complex moleculescontaining a newcarbonÀcarbon bond and anaminomethylmoietycouldbe preparedthroughthisdeveloped method.
Transition-metal-catalyzed cross-coupling reactions of
phenol derivatives, such as sulfonates1 and sulfamates,2À4
can complement procedures using more common aryl
halide electrophiles. Such substrates are inexpensive and
easy to prepare from the corresponding phenols. More-
over, phenolic moieties are readily found as intermediates
in many target-oriented syntheses and can thus be utilized
as coupling partners after activation when analogous
halides would be difficult to access.
The installation of functional groups via metalation ortho or
para to sulfamates have been reported, and the sulfamate
group can also remain intact during transformations of
other functional groups embedded within the molecules.
Subsequent to such transformations, sulfamates can serve
as electrophiles in cross-coupling reactions. Although sulfa-
mates have been utilized as partners in Kumada couplings,3
many functional groups, such as esters, ketones, and nitro
groups, are generally not compatible with the Grignard
reagents used in these protocols. Therefore, Kumada cou-
plings cannot be widely applied. More recently, SuzukiÀ
Miyaura reactions with sulfamates have been reported by
several research groups.2,3a,4 Boronic acids and neopentyl-
glycolboronates have been successfully coupled with sulfa-
mates in the presence of nickel catalysts. Only nickel-
catalyzed reactions have been studied because palladium
catalysts were thought to be inefficient for sulfamate cou-
pling reactions.2a By a combination of these developed
methods (functionalization and coupling reactions), the
complexity of the starting materials used in these transfor-
mations can be rapidly increased (Scheme 1).
Recently, sulfamates have gained interest because of their
facile preparation and ease of further functionalization.2,3a
(1) For recent examples of SuzukiÀMiyaura cross-coupling with sulfo-
nate derivatives, see: (a) Fan, X.-H.; Yang, L.-M. Eur. J. Org. Chem. 2011,
1467. (b) So, C. M.; Lau, C. P.; Chan, A. S. C.; Kwong, F. Y. J. Org. Chem.
2008, 73, 7731. (c) Petersen, M. D.; Boye, S. V.; Nielsen, E. H.; Willumsen,
J.; Sinning, S.; Wiborg, O.; Bols, M. Bioorg. Med. Chem. 2007, 15, 4159. (d)
Zhang, L. A.; Meng, T. H.; Wu, J. J. Org. Chem. 2007, 72, 9346. (e)
Lipshutz, B. H.; Butler, T.; Swift, E. Org. Lett. 2008, 10, 697.
(2) (a) Quasdorf, K. W.; Riener, M.; Petrova, K. V.; Garg, N. K.
J. Am. Chem. Soc. 2009, 131, 17748. (b) Quasdorf, K. W.; Antoft-Finch,
A.; Liu, P.; Silberstein, A. L.; Komaromi, A.; Blackburn, T.; Ramgren,
S. D.; Houk, K. N.; Snieckus, V.; Garg, N. K. J. Am. Chem. Soc. 2011,
133, 6352.
(3) (a) Macklin, T. K.; Snieckus, V. Org. Lett. 2005, 7, 2519. (b)
When, P. M.; Du Bois, J. Org. Lett. 2005, 7, 4685. (c) Silberstein, A. L.;
Ramgren, S. D.; Garg, N. K. Org. Lett. 2012, 14, 3796.
(4) (a) Baghbanzadeh, M.; Pilger, C.; Kappe, C. O. J. Org. Chem.
2011, 76, 1507. (b) Leowanawat, P.; Zhang, N.; Resmerita, A.-M.;
Rosen, B. M.; Percec, V. J. Org. Chem. 2011, 76, 9946.
As a continuation of our study on phenol coupling
partners5,6a and aminomethylating reagents,6,7 we were
interested in the use of sulfamates as the electrophilic
coupling partners in the SuzukiÀMiyaura reaction of
r
10.1021/ol401021x
XXXX American Chemical Society

Table 1. Cross-Coupling of Various Aryl Sulfamates with
Primary Aminomethyltrifluoroborate 1
Scheme 1
potassium Boc-protected aminomethyltrifluoroborates.
We envisioned that carbon(sp3)Àcarbon(sp2) bonds could
be formed by the development of SuzukiÀMiyaura coupling
reactions with sulfamates and aminomethyltrifluoroborates,
which were previously reported only with carbon(sp2)À
carbon(sp2) bond formation. To the best of our knowledge,
palladium-catalyzed SuzukiÀMiyaura coupling reactions
with potassium organotrifluoroborates and sulfamates have
not been reported.
First, coupling reactions were investigated with the
N,N-dimethylsulfamate derived from 1-naphthol and Boc-
protected primary aminomethyltrifluoroborate 1. Various
palladium catalysts, ligands, bases, solvents, concentrations,
temperatures, and reaction times were screened extensively
(see the Supporting Information for details). After this
process, the combination of 4 mol % of XPhos-Pd-G2
(Buchwald’s second-generation preformed catalyst, Figure 1)
and K2CO3 in t-BuOH/H2O (1:1, 0.5 M) at 85 °C for 3 h
emerged as the best conditions. Inexplicably, the amount of
base was not general to all substrates. Therefore, 3, 5, or 7 equiv
of K2CO3 were required, depending on the nature of the
sulfamates.
a Reaction conditions: 1.0 equiv of aryl sulfamate, 1.05 equiv of
trifluoroborate, 4 mol % of XPhos-Pd-G2, K2CO3, t-BuOH/H2O (1:1,
0.5 M), 85 °C, 3 h. b Isolated yield. c Calculated by 1H NMR with 30 μL
of CH2Cl2. d 3 equiv of K2CO3. e 5 equiv of K2CO3. f 7 equiv of K2CO3.
g n-PrOH/H2O. h 3 mmol of sulfamate, 2 mol % of XPhos-Pd-G2,
3 equiv K2CO3, t-BuOH/H2O (1:1, 0.5 M), 85 °C, 18 h.
coupled to provide the desired products in 93% and
85% isolated yields, respectively (Table 1, entries 1 and 2).
Unfortunately, the o- or p-methyl-substituted phenolic
derivatives were observed in low conversions and low yields
by 1H NMR with an internal standard (Table 1, entries 3
and 4). Moreover, electron-rich substrates in general proved
to be inefficient coupling partners under the same set of
reaction conditions (Table 1, entry 5). Interestingly, the
aryl sulfamate with both electron-donating and electron-
withdrawing groups on the aryl ring gave the desired product
2f in a high yield, 90%, with full conversion (Table 1, entry 6).
In the case of fluoro-substituted aryl sulfamates, a mixture of
t-BuOH/H2O was not efficient because low conversion
and yields were observed. After the solvents were screened
again, a mixture of n-PrOH/H2O emerged as a better solvent
system for the fluoro substrate to obtain the desired product
in a higher yield with a better conversion (Table 1, entry 9).
Several functional groups, such as ketones, esters, nitriles,
and nitro groups were compatible throughout the coupling
reactions performed. Moreover, the reaction was scalable to
3 mmol of sulfamate with a lower catalyst loading, 2 mol %
instead of 4 mol %, and the desired product was isolated in
93% yield (Table 1, entry 1).
Figure 1. Buchwald’s second-generation preformed catalyst.
With the optimized conditions in hand, we investigated
the scope of the coupling reactions with aryl sulfamates
(Table 1). 1-Naphthol and phenol sulfamates were successfully
(5) (a) Molander, G. A.; Beaumard, F. Org. Lett. 2011, 13, 3948. (b)
Molander, G. A.; Beaumard, F.; Niethamer, T. K. J. Org. Chem. 2011,
76, 8126. (c) Molander, G. A.; Beaumard, F. Org. Lett. 2011, 13, 1242.
(d) Molander, G. A.; Beaumard, F. Org. Lett. 2010, 12, 4022.
(6) (a) Molander, G. A.; Shin, I. Org. Lett. 2012, 14, 3138. (b)
Molander, G. A.; Shin, I. Org. Lett. 2011, 13, 3956. (c) Molander,
G. A.; Shin, I. Org. Lett. 2012, 14, 4458.
(7) (a) Molander, G. A.; Hiebel, M.-A. Org. Lett. 2010, 12, 4876. (b)
ꢀ
Molander, G. A.; Fleury-Bregeot, N.; Hiebel, M.-A. Org. Lett. 2011, 13,
ꢀ
16937. (c) Fleury-Bregeot, N.; Raushel, J.; Sandrock, D. L.; Dreher,
S. D.; Molander, G. A. Chem.ÀEur. J. 2012, 18, 9564. (d) Molander,
G. A.; Sandrock, D. L. Org. Lett. 2007, 9, 1597.
B
Org. Lett., Vol. XX, No. XX, XXXX

product 5f in lower yield compare to 3-pyridyl sulfamate
(Table 2, entries 5 and 6).
Table 2. Cross-Coupling of Various Hetaryl Sulfamates with
Primary Aminomethyltrifluoroborate 1
Based on the reaction conditions with Boc-protected
primary aminomethyltrifluoroborate, we screened the cou-
pling reactions of Boc-protected secondary aminomethyltri-
fluoroborate 6 with different bases, solvents, and times. The
optimal conditions were a combination of 4 mol % of
XPhos-Pd-G2 and 7 equiv of K2CO3 in t-BuOH/H2O (1:1,
0.5 M) at 85 °C for 18 h. Although the amount of base was
varied with primary aminomethyltrifluoroborate 1, 7 equiv
of base was more efficient for secondary aminomethyltri-
fluoroborate 6. Moreover, a longer reaction time, 18 h rather
than 3 h, was required for the reactions to go to completion.
We applied these optimized conditions to coupling
reactions with various aryl sulfamates (Table 3). Unfortu-
nately, many of the substrates did not give as high yields as
the coupling reactions with the primary aminomethyltri-
fluoroborate 1. 1-Naphthol sulfamate was successfully cou-
pled to provide the desired products in 92% isolated yield, but
the substrate derived from phenol gave the correspond-
ing product in only 33% yield (Table 1, entries 1 and 2). A
sulfamate with both electron-rich and electron-poor func-
tional groups on the aryl ring provided the desired product in
63% isolated yield, while lower yields and lower conversions
a Reaction conditions: 1.0 equiv of hetaryl sulfamate, 1.05 equiv of
trifluoroborate, 4 mol % of XPhos-Pd-G2, K2CO3, t-BuOH/H2O (1:1,
0.5 M), 85 °C, 3 h. b Isolated yield. c Calculated by 1H NMR with 30 μL
of CH2Cl2. d 3 equiv of K2CO3. e 5 equiv of K2CO3. f 7 equiv of K2CO3.
1
were observed by H NMR in the case of an electron-
rich sulfamate (Table 3, entries 3 and 4). Several functional
groups, such as nitriles, ketones, and esters, were tolerated.
Subsequently, 4-chlorophenyl N,N-dimethylsulfamate 3
was examined as the electrophilic coupling partner using
the same set of conditions (eq 1). Perhaps not unexpect-
edly, the product that was isolated resulted from coupling
of the chloride site, and no trace of product resulting from
coupling at the sulfamate could be detected by 1H NMR.
Conditions that had been previously developed for cou-
pling of aryl chlorides with Boc-protected primary amino-
methyltrifluoroborate were also applied to this substrate,
with essentially the same result. Therefore, oxidative addi-
tion to chlorides is evidently faster than that of sulfamates
when the two substrates are on the same aryl ring. In fact,
nickel-catalyzed SuzukiÀMiyaura cross-coupling reac-
tions provide the same result with competing sulfamate/
halide electrophilic sites, albeit using aniodide as the halide
as opposed to a chloride as in the present study.2b
Table 3. Cross-Coupling of Various Aryl Sulfamates with
Secondary Aminomethyltrifluoroborates 6
To expand the array of electrophiles, hetaryl sulfamates
were employed as the coupling partners using the same
reaction conditions (Table 2). Various hetaryl sulfamates
containing nitrogen and sulfur proved to be good electro-
philic coupling counterparts. However, the desired product
was not detected with indazole derivatives (Table 2, entry 7).
In the case of indole, the reaction proceeded to give the
corresponding product 5c without protection in 68% iso-
lated yield (Table 2, entry 3). 2-Pyridyl sulfamate gave the
a Reaction conditions: 1.0 equiv of aryl sulfamate, 1.05 equiv of
trifluoroborate, 4 mol % of XPhos-Pd-G2, 7 equiv of K2CO3, t-BuOH/
H2O (1:1, 0.5 M), 85 °C, 18 h. b Isolated yield. c Calculated by 1H NMR
with 30 μL of CH2Cl2. d 5 equiv of K2CO3.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Cross-Coupling of Various Hetaryl Sulfamates with
Secondary Aminomethyltrifluoroborates 6
Table 5. Cross-Coupling of 1-Naphthol Sulfamate with Various
Secondary Aminomethyltrifluoroborates 9aÀf
a Reaction conditions: 1.0 equiv of hetaryl sulfamate, 1.05 equiv of
trifluoroborate, 4 mol % of XPhos-Pd-G2, 7 equiv of K2CO3, t-BuOH/
H2O (1:1, 0.5 M), 85 °C, 18 h. b Isolated yield. c Calculated by 1H NMR
with 30 μL of CH2Cl2.
a Reaction conditions: 1.0 equiv of hetaryl sulfamate, 1.05 equiv of
trifluoroborate, 4 mol % of XPhos-Pd-G2, 7 equiv of K2CO3, t-BuOH/
H2O (1:1, 0.5 M), 85 °C, 18 h. b Isolated yield. c Calculated by 1H NMR
with 30 μL of CH2Cl2.
In the case of the nitrile-containing substrate, a lower amount
of base, 5 equiv of K2CO3, was required (Table 3, entry 5). An
acyl-substituted sulfamate gave a lower yield compared to
other substrates (Table 3, entry 6). Even though the expected
products were obtained with fluoro and trifluoromethyl
substituted aryl sulfamates, the yields, 47% and 42%, respec-
tively, were lower (Table 3, entries 8 and 9). Unfortunately,
the desired product was not observed with a nitro group-
containing aryl sulfamate (Table 3, entry 10).
cyclopropyl group (Table 5, entry 3). Benzyl groups on the
nitrogen, even with electron-donating groups on an aryl ring,
afforded the desired products in good yields (Table 5, entries
4 and 5). Moreover, the trifluoroborate with an embedded
acetal also proved to be an effective coupling partner,
providing the corresponding product 10f in 86% isolated
yield with full conversion (Table 5, entry 6).
We also studied hetaryl sulfamates as the electrophilic
coupling partners in the coupling with secondary amino-
methyltrifluoroborate 6 (Table 4). Unfortunately, the
reactions were limited to only a few hetaryl sulfamates.
Quinoline, isoquinoline, and thiazole derivatives provided
the desired products in good yields (Table 4, entries 1À3).
However, pyridine derivatives were inefficient coupling
partners under the same set of conditions (Table 4, entries
4 and 5). No conversion was observed in the case of the
2-pyridyl sulfamate, and with the 3-pyridyl sulfamate a
complex mixture of products was formed. Moreover, the
expected product was not detected when the indole derivative
was applied (Table 4, entry 6), with again unreacted starting
material being observed. Even though expanded studies were
conducted with these substrates, all efforts were unsuccessful.
Next, we employed various Boc-protected secondary
aminomethyltrifluoroborates 9aÀf as the nucleophilic cou-
pling partners with N,N-dimethylsulfamated 1-naphthol
using the same set of conditions (Table 5). An aliphatic
alkyl group on the amine nitrogen was effectively coupled to
give the desired product 10a in good yield (Table 5, entry 1).
In the case of the substrates possessing cyclic alkyl groups on
the nitrogen, only a cyclohexyl group provided the corre-
sponding product 10b in 68% isolated yield (Table 5, entry 2).
Unfortunately, the expected product was not observed with a
In conclusion, a method has been developed to couple
sulfamates as the electrophilic coupling partners with
various potassium Boc-protected aminomethyltrifluo-
roborates, primary and secondary aminomethylating re-
agents, in the presence of palladium catalyst. By this
method, new carbon(sp3)Àcarbon(sp2) bonds could be
efficiently forged, and the complexity of the molecules
could be readily increased. This study provides evidence
that potassium alkyltrifluoroborates can be utilized to
expand the scope of cross-coupling to diverse electrophilic
partners, thus complementing similar methods that em-
ploy less advantageous nucleophilic partners.
Acknowledgment. We thank the NIH (NIGMS R01-
GM-081376) for support of this research. We also ac-
knowledge Dr. Rakesh Kohli (University of Pennsylvania)
for obtaining HRMS data.
Supporting Information Available. Experimental pro-
cedures and spectral data of all compounds synthesized.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX