Synthesis and Suzuki-Miyaura cross-coupling reactions of potassium Boc-protected aminomethyltrifluoroborate with aryl and hetaryl halides

Article abstract of DOI:10.1021/ol2014768

Potassium Boc-protected aminomethyltrifluoroborate, a primary aminomethyl equivalent, was synthesized successfully through a "one-pot" process. With this trifluoroborate, Suzuki-Miyaura cross-coupling reactions were investigated with a variety of both aryl and hetaryl chlorides in good to excellent yields.

Full text of DOI:10.1021/ol2014768

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3956–3959
Synthesis and SuzukiÀMiyaura
Cross-Coupling Reactions of Potassium
Boc-Protected Aminomethyltrifluoroborate
with Aryl and Hetaryl Halides
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 31, 2011
ABSTRACT
Potassium Boc-protected aminomethyltrifluoroborate, a primary aminomethyl equivalent, was synthesized successfully through a “one-pot”
process. With this trifluoroborate, SuzukiÀMiyaura cross-coupling reactions were investigated with a variety of both aryl and hetaryl chlorides in
good to excellent yields.
Aminomethyl moieties, especially aminomethylated
arenes, might be considered privileged substructures be-
cause they appear in many bioactive natural products,1
and they are also used as important intermediates in
synthetic organic chemistry (Figure 1).2
Aminomethylarenes are often synthesized by reduction
of either aryl cyanides3 or oximes4 (Scheme1, pathA). How-
ever, access to primary aminomethyl aryl and hetaryl
compounds with reducible functional groups would not
be compatible with this method. An alternative way to
Figure 1. Bioactive molecules containing the aminomethyl
moiety.
(1) (a) Musher, D. M.; Fainstein, V.; Young, E. J. Antimicrob. Agents
Chemother. 1980, 254. (b) Campoli-Richards, D.; Lackner, T.; Monk, J.
Drug 1987, 34, 411. (c) Kaczanowska, K.; Wiesmuller, K.-H.; Schaffner,
€
A.-P. ACS Med. Chem. Lett. 2010, 1, 530.
install the aminomethylarene moiety is the Staudinger
reaction5 of organic azides with trivalent phosphorus
compounds (Scheme 1, path B). Unfortunately, some aryl
(2) Miller, J. F.; Gudmundsson, K. S.; Richardson, L. D.; Jenkinson,
S.; Spaltenstein, A.; Thomson, M.; Wheelan, P. Bioorg. Med. Chem.
Lett. 2010, 20, 3026. (b) Aliabadi, A.; Shamsa, F.; Ostad, S. N.; Emami,
S.; Shafiee, A.; Davoodi, J.; Foroumadi, A. Eur. J. Med. Chem. 2010, 45,
5348. (c) Shukla, N. M.; Mutz, C. A.; Ukani, R.; Warshakoon, H. J.;
Moore, D. S.; David, S. A. Bioorg. Med. Chem. Lett. 2010, 20, 6384.
(d) Liu, G.-S.; Dong, Q.-L.; Yao, Y.-S.; Yao, Z.-J. Org. Lett. 2008, 10, 5393.
(3) (a) Nystrom, R. F.; Brown, W. G. J. Am. Chem. Soc. 1948, 70,
3738. (b) Soffer, L. M.; Katz, M. J. Am. Chem. Soc. 1956, 78, 1705.
(4) (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.
(5) (a) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F. Tetra-
hedron 1981, 37, 437. (b) Gololobov, Y. G.; Kaukhin, L. F. Tetrahedron
€
1992, 48, 1353. (c) Knolker, H.-J.; Filali, S. Synlett 2003, 11, 1752.
(6) (a) Agrawal, J. P.; Hodgson, R. In Organic Chemistry of Ex-
plosives; 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/ol2014768
Published on Web 07/06/2011
2011 American Chemical Society

and hetaryl azides exhibit significant thermal or shock
sensitivity.6 Moreover, the benzylic or pseudobenzylic
halide precursors required to prepare the azides are often
not readily available.
is the synthetic equivalent of a primary aminomethyl unit, and
the development of SuzukiÀMiyaura cross-coupling reactions
of this trifluoroborate with various aryl and hetaryl chlorides.
The requisite potassium Boc-protected aminomethyl-
trifluoroborate 2 was prepared in 75% yield over four
steps in a “one-pot” process from 2-(chloromethyl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1 by applying
our recently published protocol (eq 1).7,12 Pleasingly, the
prepared aminomethyltrifluoroborate 2 was air stable
and could be stored indefinitely on the bench without
decomposition.
Scheme 1
With Boc-protected aminomethyltrifluoroborate suc-
cessfully prepared, we first investigated its application in
SuzukiÀMiyaura cross-coupling reactions with 4-chlor-
obenzonitrile and 4-chloroanisole as coupling partners
to determine optimal conditions. After screening several
catalysts, ligands, bases, and reaction times, the combi-
nation of 5 mol % of Pd(OAc)2, 10 mol % of SPhos or
XPhos (Figure 2), and 3 equiv of K2CO3 in toluene/H2O
(4:1, 0.25 M) for 22 h emerged as the best reaction
conditions. Indeed, we decided to use two different
ligands, SPhos and XPhos, because they were often
complementary in their reactivity with various aryl
and hetaryl chlorides. Importantly, the trifluoroborate
could be employed in virtually a stoichiometric quantity
in the cross-coupling reactions. We employed these
conditions to explore cross-couplings with diverse aryl
chlorides as electrophiles (Table 1).
Interestingly, reported syntheses and transition metal
catalyzed cross-coupling reactions of primary aminomethyl
organometallics or their equivalents are rare (Scheme 1,
path C). Recently, we demonstrated the synthesis and cross-
coupling reactions of amidomethyltrifluoroborates7 and
tertiary aminomethyltrifluoroborates.8 Among these, the
sulfonamidomethyl derivatives could be utilized to generate
primary amines [e.g., using the p-toluenesulfonyl (tosyl)
group as the amine protecting group].7b However, the
removal of tosyl groups requires the use of harsh conditions9
compared to the Boc group, for example, which can be
easily removed under either acidic or basic conditions.10
Although a patent exists that refers to the use of the
N-phthalimido group as an amine protecting group in
SuzukiÀMiyaura coupling reactions,11 the scope of that
process has not been widely disseminated, and we have
been unable to develop a broadly applicable procedure
based on such a protocol. Furthermore, hydrazine is often
used to remove the phthalimido group, and its toxicity and
instability to storage and handling prevent its routine use
in this capacity.
The development of the aminomethylating and amido-
methylating procedures in our laboratory7 ledustoinvestigate
the synthesis of alternative protected primary aminomethyl-
trifluoroborates. Herein, we disclose a successful synthesis of
potassium Boc-protected aminomethyltrifluoroborate, which
Figure 2. SPhos and XPhos.
Electron-neutral (entries 1À3), electron-donating (entries
4À7), and electron-withdrawing groups (entries 8À12) were
suitable coupling partners in SuzukiÀMiyaura cross-cou-
pling reactions. Surprisingly, sterically hindered di-ortho
substituted electrophiles provided as high a yield as the less
hindered monosubstituted electrophiles (compare entries 2
and 3). The cross-coupling reactions using 4-chloroanisole
as an electrophile furnished the product 3d in 78% yield on a
larger scale (4.0 mmol) with a lower catalyst loading (2 mol
%, entry 4). Of particular note, access to aminomethylated
(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.
(8) (a) Molander, G. A.; Sandrock, D. L. Org. Lett. 2007, 9, 1597.
(b) Hasnık, Z; Pohl, R.; Hocek, M. Synthesis 2009, 8, 1309.
´
(9) (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.
(10) (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.
ꢀ
(12) (a) Matteson, D. S. Chem. Rev. 1989, 89, 1535. (b) Matteson,
D. S. Tetrahedron 1989, 45, 1859. (c) Matteson, D. S. Tetrahedron 1998,
54, 10555.
(11) Tanaka, K. PCT Int. Appl. WO 2008007670, 2008.
Org. Lett., Vol. 13, No. 15, 2011
3957

Table 1. Cross-Coupling of Trifluoroborate 2 with Various Aryl
Chloridesa
Figure 3. Dimeric metalated pyridine.
Table 2. Cross-Coupling of Trifluoroborate 2 with Various
Hetaryl Chloridesa
a Reaction conditions: 1.0 equiv of aryl halide, 1.05 equiv of
trifluoroborate, 5 mol % of Pd(OAc)2, 10 mol % of ligand, 3 equiv
of K2CO3, 4:1 toluene/H2O (0.25 M), 85 °C, 22 h. b SPhos. c XPhos.
d 4.0 mmol of 4-chloroanisole, 2 mol % of Pd(OAc)2, 4 mol % of
XPhos.
aromatics by this cross-coupling protocol complements the
nitrile reduction method. Thus nitrile, aldehyde, ketone,
ester, and nitro functional groups are accommodated by the
cross-coupling route (entries 8À12), but these substituents
would have to be protected or alternate routes employed if a
nitrile reduction strategy was employed.
(13) (a) Chin, C. C. H.; Yeo, J. S. L.; Loh, Z. H.; Vittal, J. J.;
Henderson, W.; Hor, T. S. A. J. Chem. Soc., Dalton Trans. 1998, 3777.
(b) Beeby, A.; Bettington, S.; Fairlamb, I. J. S.; Goeta, A. E.; Kapdi,
A. R.; Niemela, E. H.; Thompson, A. L New J. Chem. 2004, 28, 600.
(c) Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036.
a Reaction conditions: 1.0 equiv of aryl halide, 1.05 equiv of trifluor-
oborate, 5 mol % of Pd(OAc)2, 10 mol % of ligand, 3 equiv of K2CO3,
4:1 toluene/H2O (0.25 M), 85 °C, 22 h. b SPhos. c XPhos.
3958
Org. Lett., Vol. 13, No. 15, 2011

To expand the array of electrophiles, various hetaryl
chlorides were investigated as coupling partners (Table 2).
Thiophene, furan, pyridine, quinoline, and indole derivatives
were successfully coupled to afford the expected products in
moderate to good yields. Interestingly, 2-chloropyridine and
structurally related quinoline and isoquinoline derivatives
(entries 8À10) provided a much lower yield compared to
other hetaryl chlorides. Oxidative addition of Pd(0) to
2-halopyridines generates a well-characterized dimeric spe-
cies (Figure 3).13 Although this complex has served as an
effective precatalyst in SuzukiÀMiyaura cross-coupling re-
actions with boronic acid derivatives, it may be the case that
in the current protocol this type of complex in some way
inhibits effective cross-coupling.
Table 3. Electrophile Compatibilitya
Once again, sensitive functional groups such as alde-
hydes and ketones were tolerated under these conditions,
providing the desired products in good to excellent yields
(entries 2, 3, and 5). Of additional note, unprotected
indolescouldalso be coupled effectively(entries 14and 15).
Next, we examined other electrophilic partners employ-
ing the same conditions [Pd(OAc)2, SPhos, Table 3].
Interestingly, phenyl bromide and triflate gave moderate
yields (entries 2 and 4). However, iodobenzene furnished
the desired product in only 41% yield (entry 3). Moreover,
phenyl mesylate and tosylate were not effective coupling
partners under these reactions conditions (entries 5 and 6).
Because the oxidative addition step is undoubtedly not the
rate-determining step among some of the substrates tested
and because the reactions were optimized for aryl chlor-
ides, a different set of conditions would have to be devel-
oped to couple substrates with other nucleofugic groups
effectively.
a Reaction conditions: 1.0 equiv of aryl halide, 1.05 equiv of trifluor-
oborate, 5 mol % of Pd(OAc)2, 10 mol % of SPhos, 3 equiv of K2CO3,
4:1 toluene/H2O (0.25 M), 85 °C, 22 h.
this potassium Boc-aminomethyltrifluoroborate, SuzukiÀ
Miyaura cross-coupling reactions were investigated with a
variety of aryl and hetaryl chlorides. Studies to expand the
scope of this protocol continue in our laboratory.
Acknowledgment. We thank the NIGMS (R01 GM-
081376) for their support of this research. We thank Dr.
Marie-Aude Hiebel (University of Pennsylvania) for initial
work on the synthesis of potassium Boc-protected amino-
methyltrifluoroborate. We also acknowledge Dr. Rakesh
Kohli (University of Pennsylvania) for obtaining HRMS
data.
In summary, we successfully synthesized the air stable
potassium Boc-protected aminomethyltrifluoroborate, which
is an equivalent of the primary aminomethyl unit, through
a “one-pot” synthetic process from 2-(chloromethyl)-4,4,
5,5-tetramethyl-1,3,2-dioxaborolane in good yield. With
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.
Org. Lett., Vol. 13, No. 15, 2011
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