Suzuki-Miyaura cross-coupling reactions of potassium boc-protected aminomethyltrifluoroborate with aryl and hetaryl mesylates

Article abstract of DOI:10.1021/ol301221p

Palladium-catalyzed Suzuki-Miyaura cross-coupling reactions were studied with potassium Boc-protected aminomethyltrifluoroborate through C-O activation of various mesylate derivatives to afford the corresponding products in moderate to good yields.

Full text of DOI:10.1021/ol301221p

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3138–3141
SuzukiÀMiyaura Cross-Coupling
Reactions of Potassium Boc-Protected
Aminomethyltrifluoroborate with Aryl and
Hetaryl Mesylates
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 May 4, 2012
ABSTRACT
Palladium-catalyzed SuzukiÀMiyaura cross-coupling reactions were studied with potassium Boc-protected aminomethyltrifluoroborate through
CÀO activation of various mesylate derivatives to afford the corresponding products in moderate to good yields.
Aminomethylarenes are encountered in many bioactive
materials.1 Primary aminomethyl subunits are particularly
important targets for synthesis because they exhibit useful
Scheme 1
properties as drugs and inhibitors. Despite their impor-
tance, syntheses of aminomethyl substructures are not
general. Reduction of aryl cyanides2 or oximes3 and the
Staudinger reaction4 of azides have often been used to
build aminomethyl moieties (Scheme 1). However, these
approaches have limitations because of their sensitivity to
reducible functional groups and the instability of azides,5
aminomethyl moieties. To the best of our knowledge, three
methods of SuzukiÀMiyaura cross-coupling reactions to
respectively.
afford primary aminomethyl arenes using different pro-
tecting groups have been reported (Scheme 2).6 Among
them, p-toluenesulfonyl (Ts)6a or N-phthalimido (Phth)6b,c
groups have been utilized but are not ideal because
the amine protecting groups are difficult to remove, re-
quiring relatively harsh reaction conditions.7 Recently, we
Transition metal mediated cross-coupling reactions
of aminomethylmetallic species are one of the most
straightforward strategies for preparation of primary
(1) (a) Musher, D. M.; Fainstein, V.; Young, E. J. Antimicrob. Agents
Chemother. 1980, 254. (b) Campoli-Richards, D.; Lackner, T.; Monk, J.
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(3) (a) Chandrasekharan, J.; Ramachandran, P. V.; Brown, H. C.
J. Org. Chem. 1985, 50, 5448. (b) Bair, K. W.; Tuttle, R. L.; Knick, V. C.;
Cory, M.; McKee, D. D. J. Med. Chem. 1990, 33, 2385.
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(6) (a) Molander, G. A.; Fleury-Bregeot, N.; Hiebel, M.-A. Org. Lett.
2011, 13, 1694. (b) Tanaka, K. PCT Int. Appl. WO 2008007670, 2008.
(c) Devulapally, R.; Fleury-Bregeot, N.; Molander, G. A.; Seapy, D. G.
Tetrahedron Lett. 2012, 53, 1051. (d) Molander, G. A.; Shin, I. Org. Lett.
2011, 13, 3956.
(7) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999. (b) Kocienski, P. J.
Protecting Groups, 3rd ed.; Georg Thieme: Stuttgart, NY, 2005. (c) Hasan, I.;
Marinelli, E. R.; Lin, L.-C. C.; Fowler, F. W.; Levy, A. B. J. Org. Chem.
1981, 46, 157. (d) Ravinder, K.; Reddy, V.; Mahesh, K. C.; Narasimhulu,
M.; Venkateswarlu, Y. Synth. Commun. 2007, 37, 281.
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(4) (a) Knolker, H.-J.; Filali, S. Synlett 2003, 11, 1752. (b) Gololobov,
Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetrahedron 1981, 37, 437.
(c) Gololobov, Y. G.; Kaukhin, L. F. Tetrahedron 1992, 48, 1353.
(5) (a) Agrawal, J. P.; Hodgson, R. Organic Chemistry of Explosives;
Wiley: Chichester, 2007. (b) Huynh, M.-H. V.; Hiskey, M. A.; Chavez, D. E.;
Naud, D. L.; Gilardi, R. D. J. Am. Chem. Soc. 2005, 127, 12537.
r
10.1021/ol301221p
Published on Web 05/31/2012
2012 American Chemical Society

demonstrated that potassium Boc-protected amino-
methyltrifluoroborate can be used as the coupling partner
in SuzukiÀMiyaura reactions.6d In that contribution, we
reported the synthesis and cross-coupling reactions of
potassium Boc-protected aminomethyltrifluoroborate 2.
Potassium Boc-protected aminomethyltrifluoroborate,
which is a primary aminomethyl equivalent, was synthe-
sized through a ‘one-pot’ synthesis in good yield and isnow
commercially available. Primary aminomethylarenes are
readily available using this method after deprotection of
the Boc group. The Boc protecting group is known to be
easier to deprotect, compared to Ts or Phth groups, in
acidic or even basic conditions.8 Therefore, using the Boc
group is a more general approach to the primary amines.
Figure 1. SPhos and RuPhos.
Table 1. Cross-Coupling of Aminomethyltrifluoroborate 2 with
Various Electron-Neutral and Electron-Rich Aryl Mesylates
Scheme 2
All of the previous reports employed aryl and hetaryl
halides as electrophilic partners in cross-coupling reac-
tions. As alternative coupling partners, aryl and hetaryl
sulfonate derivatives have been utilized in SuzukiÀ
Miyaura couplings.9À11 Sulfonate groups are generally
easy to handle and are derived from a complementary set
of starting materials. Mesylates are of special interest in
terms of atom economy, low cost, and stability, even
though they show the lowest reactivity among sulfonate
derivatives.10 Recently, our group has demonstrated the
feasibility of SuzukiÀMiyaura cross-coupling reactions of
aryl and hetaryl mesylates with tertiary ammoniomethyl-
trifluoroborates and amidomethyltrifluoroborates.11c
To extend the scope of this transformation, we investi-
gated the SuzukiÀMiyaura cross-coupling reaction of
(8) (a) du Vigneaud, V.; Behrens, O. K. J. Biol. Chem. 1937, 117, 27.
(b) Kharasch, M. S.; Priestley, H. M. J. Am. Chem. Soc. 1939, 61, 3425.
(c) Snyder, H. R.; Heckert, R. E. J. Am. Chem. Soc. 1952, 74, 2006. (d) Li,
S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson, W. D.;
Wriede, P. J. Am. Chem. Soc. 1967, 89, 5311.
(9) For recent examples of SuzukiÀMiyaura cross-coupling with
sulfonate 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.
a Reaction conditions: 1.0 equiv of aryl mesylate, 1.1 equiv of
trifluoroborate, 5 mol % of PdCl2(cod), 10 mol % of ligand, 7 equiv
of K3PO4, t-BuOH/H2O (1:1, 0.2 M), 95 °C, 22 h. b 4.0 mmol of mesylate,
3 mol % of PdCl2(cod), 6 mol % of RuPhos.
(10) For recent examples of SuzukiÀMiyaura cross-coupling with
mesylates, see: (a) Leowanawat, P.; Zhang, N.; Resmerita, A.-M.;
Rosen, B. M.; Percec, V. J. Org. Chem. 2011, 76, 9946. (b) Chow,
W. K.; So, C. M.; Lau, C. P.; Kwong, F. Y. J. Org. Chem. 2010, 75, 5109.
(c) Molander, G. A.; Beaumard, F. Org. Lett. 2010, 12, 4022. (d)
Kuroda, J. I.; Inamoto, K.; Hiroya, K.; Doi, T. Eur. J. Org. Chem.
2009, 2251. (e) Bhayana, B.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2009,
11, 3954. (f) So, C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed.
2008, 47, 8059. (g) So, C. M.; Kwong, F. Y. Chem. Soc. Rev. 2011, 40,
4963–4972.
potassium Boc-protected primary aminomethyltrifluoro-
borate with various aryl and hetaryl mesylates, providing
an alternative entry to primary aminomethyl-substituted
aromatics.
Initially, when the optimal conditions [Pd(OAc)2, SPhos
or XPhos, K2CO3, and toluene/H2O, 85 °C, 22 h] for
aryl and hetaryl chlorides with potassium Boc-protected
aminomethyltrifluoroborate 2 were applied to mesylates,
(11) (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.
Org. Lett., Vol. 14, No. 12, 2012
3139

Table 2. Cross-Coupling of Aminomethyltrifluoroborate 2 with
Various Electron-Poor Aryl Mesylates
Table 3. Cross-Coupling of Aminomethyltrifluoroborate 2 with
Various Hetaryl Mesylates
a Reaction conditions: 1.0 equiv of aryl mesylate, 1.1 equiv of
trifluoroborate, 5 mol % of PdCl2(cod), 10 mol % of ligand, 7 equiv
of K3PO4, t-BuOH/H2O (1:1, 0.2 M), 95 °C, 22 h.
a Reaction conditions: 1.0 equiv of hetaryl mesylate, 1.1 equiv of
trifluoroborate, 5 mol % of PdCl2(cod), 10 mol % of ligand, 7 equiv of
K3PO4, t-BuOH/H2O (1:1, 0.2 M), 95 °C, 22 h.
only trace amounts of products were obtained.6d Keeping
these results in mind, we screened the SuzukiÀMiyaura
cross-coupling with the mesylated 1-naphthol 1a based on
the conditions related to CÀO activation with potassium
organotrifluoroborates reported previously.11 Potassium
phosphate tribasic was chosen as a base in a mixture of
t-BuOH/H2O. The coupling reactions were screened with
different sources of palladium catalysts and ligands. More-
over, the reaction concentrations, ratio of two solvents,
and temperature were studied extensively. After the opti-
mization process, the combination of 1 equiv of mesylate,
1.1 equivoftrifluoroborate, 5mol % ofPdCl2(cod), 10mol
% of SPhos or RuPhos (Figure 1), and 7 equiv of K3PO4
in t-BuOH/H2O (1:1, 0.2 M) at 95 °C for 22 h turned out
to be the best reaction conditions. Two different ligands
were used because neither was general across the entire
range of substrates.
Withthese optimized conditions inhand, wefirst studied
the scope of the coupling reactions with various aryl
mesylates (Tables 1 and 2).
Electrophiles with both electron-neutral and electron-
rich substituents on the aryl rings represented good
coupling partners in the desired reactions (Table 1). The
reactions revealed that RuPhos was the most efficient
ligand for all substrates containing electron-neutral and
electron-donating groups on the aryl ring. With more
sterically demanding substituents ortho to the mesylate
group, the coupling yields dropped dramatically (Table 1,
entries 4 and 5). The more sterically encumbered di-ortho
substituted electrophile gave only a 22% isolated yield,
perhaps because of a slow oxidative addition step (Table 1,
entry 5).12 The reactions were also successful with electron-
donating groups on the aryl ring (Table 1, entries 7 and 8).
By increasing the reaction scale to 4 mmol of mesylated
1-naphthol 1a, the reaction could be carried out with a
lower catalyst loading [3 mol % of PdCl2(cod), and 6 mol
% of RuPhos] toobtain the corresponding product3awith
an 87% isolated yield (Table 1, entry 1).
We then investigated electron-poor aryl mesylates as
electrophilic coupling partners (Table 2). All electron-
deficient aryl mesylates gave the desired products 3iÀp in
moderate to good yields. In these cases, two different
ligands (RuPhos and SPhos) were utilized to obtain the
products, the yields of which depended on the nature of the
(12) Alami, M.; Amatore, C.; Bensalem, S.; Choukchou-Brahim, A.;
Jutand, A. Eur. J. Inorg. Chem. 2001, 2675.
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Org. Lett., Vol. 14, No. 12, 2012

functional groups and ligand utilized. As shown, a wide
variety of functional groups, such as nitriles, aldehydes,
esters, and ketones, were compatible with the reaction
conditions (Table 2). However, lower yields were observed
with the aldehyde and methyl ester substituents on the
aryl ring compared to other substrates (Table 2, entries
2 and 3).
We next expanded the array of electrophiles to hetaryl
mesylates (Table 3). Various hetaryl mesylates were
coupled with potassium Boc-protected aminomethyltri-
fluoroborate 2 in moderate to good yields. Again, two
ligands (RuPhos and SPhos) were required to give better
results depending on the nature of the hetaryl coupling
partners. Nitrogen-containing hetaryl mesylates, such as
pyridine, quinoline, isoquinoline, indole, and thiazole, all
provided the expected products in good yields (Table 3,
entries 1À7). Interestingly, indole was successfully coupled
without any protecting group in a 75% isolated yield
(Table 3, entry 6). Moreover, sulfur-containing hetaryls
also proved to be good coupling partners under the set of
reaction conditions developed (Table 3, entries 7 and 8).
In summary, we have shown that potassium Boc-
protected aminomethyltrifluoroborate, an equivalent of a
primary aminomethyl subunit, was a good coupling part-
ner in SuzukiÀMiyaura cross-coupling reactions with aryl
and hetaryl mesylates. A broad array of electrophiles, such
as functionalized aryl mesylates and hetaryl mesylates,
were coupled efficiently in standard coupling reactions.
Further efforts to expand the scope of aminomethyl
moieties are currently under study.
Acknowledgment. We thank the National Institutes of
Health (NIGMS R01 81376) for their support of this
research. We acknowledge 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.
Org. Lett., Vol. 14, No. 12, 2012
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