Synthesis of amidomethyltrifluoroborates and their use in cross-coupling reactions

Article abstract of DOI:10.1021/ol102039c

Amidomethyltrifluoroborates were successfully synthesized in a one-pot fashion and used in cross-coupling reactions with a wide variety of aryl and heteroaryl chlorides.

Full text of DOI:10.1021/ol102039c

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4876-4879
Synthesis of Amido-
methyltrifluoroborates and Their Use in
Cross-Coupling Reactions
Gary A. Molander* and Marie-Aude Hiebel
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104-6323, United States
gmolandr@sas.upenn.edu
Received August 27, 2010
ABSTRACT
Amidomethyltrifluoroborates were successfully synthesized in a one-pot fashion and used in cross-coupling reactions with a wide variety of
aryl and heteroaryl chlorides.
Amidomethylarenes are commonly found in a variety of
biologically active compounds (Figure 1).1 Several strategies
have been developed to obtain amidomethyl-containing
products such as nucleophilic displacement,2 reductive
N-alkylation,3 and more commonly amidation.4 These meth-
ods follow a consonant reactivity pattern based on the
nucleophilicity of the nitrogen. Recently, cross-coupling
reactions with N,N-dialkylaminomethyltrifluoroborates were
described to access the analogous aminomethyl moiety.5 This
(1) (a) French, K. J.; Zhuang, Y.; Maines, L. W.; Gao, P.; Wang, W.;
Beljanski, V.; Upson, J. J.; Green, C. L.; Keller, S. N.; Smith, C. D.
J. Pharmacol. Exp. Ther. 2010, 133, 129. (b) Belyk, K. M.; Morrison, H. G.;
Jones, P.; Summa, V. WO Patent 60,730, 2007. (c) McIntyre, J. A.; Castaner,
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Fumagalli, R.; Corsini, A. Eur. J. Pharmacol. 1998, 355, 77.
Figure 1. Biologically active molecules containing the amidomethyl
moiety.
(2) Gajda, T.; Zwierzak, A. Biochemistry 1981, 1, 1005.
(3) (a) Dube´, D.; Scholte, A. A. Tetrahedron Lett. 1999, 40, 2295. (b)
Oaki, Y.; Kobayashi, S. J. Comb. Chem. 1999, 1, 371.
approach provides access to amines using a C-C bond
connection strategy complementary to existing C-N bond-
forming approaches.
The N,N-dialkylaminomethyltrifluoroborates used in previ-
ous coupling efforts were obtained by a direct SN2 displace-
ment of the halides of potassium halomethyltrifluoroborates.
Unfortunately, amidomethyltrifluoroborates cannot be ac-
(4) (a) Han, S. Y.; Kim, Y. A. Tetrahedron 2004, 60, 2447. (b)
Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827. (c)
Huang, Z.; Reilly, J. E.; Buckle, R. N. Synlett 2007, 1026. (d) NordstrØm,
L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 17672. (e) Terada,
Y.; Ieda, N.; Komura, K.; Sugi, Y. Synlett 2008, 2318. (f) Bure´s, J.; Mart´ın,
M.; Urp´ı, F.; Vilarrasa, J. J. Org. Chem. 2009, 74, 2203.
(5) (a) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2031. (b) Molander,
G. A.; Sandrock, D. L. Org. Lett. 2007, 9, 1597. (c) Molander, G. A.;
Gormisky, P. E.; Sandrock, D. L. J. Org. Chem. 2008, 73, 2052.
10.1021/ol102039c  2010 American Chemical Society
Published on Web 09/29/2010

cessed in this manner, and thus it was necessary to develop
a different approach to the trifluoroborate starting materials.
The strategy chosen was based on previous work pioneered
by Matteson,6 in which substituted boronate esters were
obtained from halomethylboronate esters via intramolecular
nucleophilic displacement and one carbon homologation of
in situ generated LiCHX2 or LiCH2X species (X ) Cl, Br,
I).7 The “ate” complex resulting from initial attack of the
nucleophile at the boron atom is followed by R-transfer to
the neighboring carbon to form the elaborated boronate ester
(Figure 2).8
success as Suzuki-Miyaura cross-coupling partners.11 We
disclose herein the formation of amidomethyltrifluoroborates
synthesized in an original one-pot process from halometh-
ylboronate esters. Additionally we report their palladium-
catalyzed coupling with various aryl and heteroaryl chlorides,
which constitutes the first successful example of amido-
methylation by a cross-coupling protocol.12,13
The current study began with the preparation of amido-
methyltrifluoroborates 4a-m using an adaptation of the
Matteson procedure (Scheme 1).9
Scheme 1. One-Pot Process To Synthesize 4a-m
Thus 2-(chloromethyl)-4,4,5,5-tetramethyl-1,3,2-diox-
aborolane 1 in the presence of potassium hexamethyldisi-
lazide gave the expected disilylated aminoboronate ester 2a,
Figure 2. Reaction mechanism of the one-carbon homologation of
boronate esters and the intramolecular nucleophilic displacement
of R-halo boronate esters with various nucleophiles.
Amidomethylboronate esters have been synthesized fol-
lowing this strategy,9 but only a few examples were reported,
and poor to moderate yields were observed for the formation
of R-unsubstituted products in a process that required two
to three steps.9f,10 Furthermore, apart from their biological
evaluations, amidomethylborons have not been used with
Table 1. Preparation of Amidomethyltrifluoroborates
(6) For reviews on R-halo boronate esters see: (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.
(7) (a) Brown, H. C.; Rogic, M. M.; Rathke, M. W.; Kabalka, G. W.
J. Am. Chem. Soc. 1968, 90, 818. (b) Matteson, D. S.; Mah, R. W. H. J. Am.
Chem. Soc. 1963, 85, 2599. (c) Brown, H. C.; De Lue, N. R.; Yamamoto,
Y.; Maruyama, K.; Kasahara, T.; Murahashi, S.; Sanoda, A. J. Org. Chem.
1977, 42, 4088.
(8) (a) Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687.
(b) Sadhu, K. M.; Matteson, D. S. Tetrahedron Lett. 1986, 27, 795. (c)
Brown, H. C.; Phadke, A. S.; Rangaishenvi, M. V. J. Am. Chem. Soc. 1998,
110, 6263. (d) Brown, H. C.; Singh, S. M. Organometallics 1986, 5, 994.
(e) Brown, H. C.; Singh, S. M.; Rangaishenvi, M. V. J. Org. Chem. 1986,
51, 3150. (f) Wallace, R. H.; Zong, K. K. Tetrahedron Lett. 1992, 33, 6941.
(g) Soundararajan, R.; Li, G.; Brown, H. C. Tetrahedron Lett. 1994, 35,
8957. (h) Davoli, P.; Fava, R.; Morandi, S.; Spaggiari, A.; Prati, F.
Tetrahedron 1993, 49, 177.
(9) (a) Matteson, D. S.; Sadhu, K. M.; Lienhard, G. E. J. Am. Chem.
Soc. 1981, 103, 5241. (b) Matteson, D. S.; Jesthi, P. K.; Kizhakethil, M. S.
Organometallics 1984, 3, 1284. (c) Matteson, D. S.; Sadhu, K. M.
Organometallics 1984, 3, 614. (d) Verleijen, J. P. G.; Faber, P. M.; Bodewes,
H. H.; Braker, A. H.; Van Leusen, D.; van Leusen, A. M. Tetrahedron
Lett. 1995, 36, 2109. (e) Matteson, D. S.; Singh, R. P.; Sutton, C. H.;
Verheyden, J. D.; Lu, J.-H. Heteroat. Chem. 1997, 8, 487. (f) Matteson,
D. S. Pure Appl. Chem. 2003, 75, 1249. (g) Lai, J. H.; Liu, Y.; Wu, W.;
Zhou, Y.; Maw, H. H.; Bachovchin, W. W.; Bhat, K. L.; Bock, C. W. J.
Org. Chem. 2006, 71, 512. (h) Inglis, S. R.; Woon, E. C. Y.; Thompson,
A. L.; Schofield, C. J. J. Org. Chem. 2010, 75, 468.
(10) (a) Caselli, E.; Powers, R. A.; Blasczcak, L. C.; Wu, C. Y. E.;
Prati, F.; Shoicher, B. K. Chem. Biol. 2001, 8, 17. (b) Kinder, D. H.;
Katzenellenbogen, J. A. J. Med. Chem. 1985, 28, 1917. (c) Pechenov, A.;
Stefanova, M. E.; Nicholas, R. A.; Peddi, S.; Gutheil, W. G. Biochemistry
2003, 42, 579.
a Reaction for 12 h at rt in the presence of RCOCl.
Org. Lett., Vol. 12, No. 21, 2010
4877

which was deprotected in situ by the addition of methanol.
The revealed free amine 2b was then reacted with various
acyl chlorides to form the corresponding amides. The crude
boronate esters 3 obtained in this one-pot fashion were
directly treated with a saturated solution of KHF2 to afford
4a-m in good to excellent overall yields (Table 1).
This method provided access to aromatic substituted
carbamides 4a-f that contained electron-withdrawing and
electron-donating groups (Table 1, entries 1 and 2). Saturated
carbocycles (entries 3-5) as well as alkyl side chains (entries
6-8) could also be incorporated.
coupling conditions were found to be 2.5 mol % of
Pd(OAc)2, 5 mol % of XPhos, and 3 equiv of Cs2CO3 in a
10:1 cyclopentyl methyl ether (CPME) and water mixture
at 85 °C for 6 h with a stoichiometric amount of potassium
trifluoroborate. On a larger scale reaction (1 g of product),
the catalyst loading could be lowered to 1 mol % with similar
results (entry 6). The generality of the method was then
investigated by using structurally and electronically diverse
aryl chlorides. Throughout the series of reaction partners
studied, the expected coupling products were obtained in
good to excellent yields, and a variety of functional groups
including nitriles, ketones, aldehydes, esters, and alcohols
were tolerated under these conditions. Sterically hindered
electrophiles (Table 2, entries 2, 3, 7, and 10) were found to
couple in excellent yields, although an increase in the catalyst
loading or in the reaction time was required.
Table 2. Cross-Coupling of 4a with Diverse Aryl Chloridesd
Table 3. Cross-Coupling of 4a with Various Heteroaryl
Chloridesc
a 5 mol % Pd(OAc)2, 10 mol % XPhos. b Reaction heated for 14 h.
c Reaction performed on 4.1 mmol scale with 1 mol % Pd(OAc)2 and 2
mol % XPhos, 24 h at 85 °C. d All reactions were carried out with 0.3
mmol of 4a and aryl chloride, 2.5 mol % Pd(OAc)2, 5 mol % XPhos, 0.9
mmol of Cs2CO3, 10:1 CPME/H2O (0.09 M), 85 °C, 6 h.
a Heated for 24 h with 5 mol % Pd(OAc)2, 10 mol % XPhos. b Reaction
heated for 14 h. c All reactions were carried out with 0.3 mmol of 4a and
heteroaryl chloride, 2.5 mol % Pd(OAc)2, 5 mol % XPhos, 0.9 mmol of
Cs2CO3, 10:1 CPME/H2O (0.09 M), 85 °C, 6 h.
With these compounds in hand, the cross-coupling condi-
tions were first optimized with 4a and p-chloroanisole as
the electrophilic partner (Table 2, entry 6). The most effective
To investigate the method further, the array of electrophiles
was expanded to heteroaryl chlorides (Table 3). Chloropy-
ridines bearing the halogen in the 3 or 4 position and other
4878
Org. Lett., Vol. 12, No. 21, 2010

heteroaryl chlorides such as quinoline, thiophene, or furan
derivatives were successfully coupled with 4a under our
previously described conditions in moderate to excellent
yields. Unfortunately, despite attempting to increase the
reaction temperature and increase or decrease the catalyst
loading, 2-chloropyridine (6d) and 2-chloro-4-methoxypy-
rimidine (6g) gave rise to a significant amount of homo-
coupled product (entries 3 and 6).
and acyclic carbamides gave the expected coupling product
in good to excellent yields except for the biphenyl and the
pentafluorophenyl substrates (7d and 7f) (Table 4, entries 1
and 2), where degradation products were mostly recovered.
Table 5. Electrophile Compatibilitya
Table 4. Cross-Coupling with Various Potassium
Amidomethyltrifluoroboratesb
entry
aryl electrophile
% isolated yield
1
2
3
4
I
Br
OTf
OTs
31
85
93
traces
a All reactions were carried out with 0.3 mmol of 1a and aryl chloride,
2.5 mol % Pd(OAc)2, 5 mol % XPhos, 0.9 mmol of Cs2CO3, 10:1 CPME/
H2O (0.09 M), 85 °C, 6 h.
Finally, the electrophile compatibility was examined (Table
5). Surprisingly, the aryl iodide gave low yields, indicating
that the oxidative addition is not the limiting step of the
catalytic cycle under these conditions. Aryl triflates and aryl
bromides coupled cleanly in high yields. Unfortunately,
tosylate derivatives exhibited no reactivity.
In summary, an efficient one-pot synthetic protocol suc-
cessfully delivered R-unsubstituted amidomethyltrifluorobo-
rates. These trifluoroborates proved to be suitable reagents
to introduce the amidomethyl functional group into substrates
via a unique bond construction. Various electron-rich and
electron-poor aryl and heteroaryl electrophiles were used,
demonstrating the generality of this method.
Acknowledgment. This research was supported by a
National Priorities Research Program (NPRP) grant from the
Qatar National Research Fund (Grant no. 08-035-1-008) and
the NIH (R01 GM-081376). We thank Frontier Scientific
for a generous gift of Pd(OAc)2. Dr. Rakesh Kohli (Univer-
sity of Pennsylvania) is acknowledged for obtaining HRMS
data.
a Used 5 mol % Pd(OAc)2, 10 mol % XPhos. b All reactions were carried
out with 0.3 mmol of 1a and aryl chloride, 2.5 mol % Pd(OAc)2, 5 mol %
XPhos, 0.9 mmol of Cs2CO3, 10:1 CPME/H2O (0.09 M), 85 °C, 6 h.
Supporting Information Available: Experimental pro-
cedures, spectral characterization, and copies of 1H, 13C, 19F,
and 11B NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
We next examined the efficiency of the reaction with
different amidomethyltrifluoroborates (Table 4). Both cyclic
OL102039C
(11) Tanaka, K. US Patent 15,351 A1, 2008.
(12) For reviews on organotrifluoroborate salts see: (a) Molander, G. A.;
Figueroa, R. Aldrichim. Acta 2005, 38, 49. (b) Molander, G. A.; Ellis, N.
Acc. Chem. Res. 2007, 40, 275. (c) Stefani, H. A.; Cella, R.; Adriano, S.
Tetrahedron 2007, 63, 3623. (d) Darses, S.; Geneˆt, J.-P. Chem. ReV. 2008,
108, 288.
(13) (a) Molander, G. A.; Biolatto, B. J. Org. Chem. 2007, 68, 4302.
(b) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem. 2009, 74,
973.
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