Direct alkylation of heteroaryls using potassium alkyl- and alkoxymethyltrifluoroborates

Article abstract of DOI:10.1021/ol2003572

A direct alkylation of various heteroaryls using stoichiometric potassium alkyl- and alkoxymethyltrifluoroborates has been developed. This method leads to the synthesis of complex substituted heterocycles, which have been obtained with yields up to 89%.

Full text of DOI:10.1021/ol2003572

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1852–1855
Direct Alkylation of Heteroaryls Using
Potassium Alkyl- and
Alkoxymethyltrifluoroborates
Gary A. Molander,* Virginie Colombel, and Valerie A. Braz
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of
Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States
gmolandr@sas.upenn.edu
Received February 7, 2011
ABSTRACT
A direct alkylation of various heteroaryls using stoichiometric potassium alkyl- and alkoxymethyltrifluoroborates has been developed. This
method leads to the synthesis of complex substituted heterocycles, which have been obtained with yields up to 89%.
Heteroaryl moieties are important components in
natural products and pharmaceutical drugs.1 In the
past decade, many publications have reported C-H
bond activations of heterocycles using base/copper
salts with subsequent coupling to aryl halides,2 and
direct C-H activation/arylation of heteroaromatics
through palladium activation of aryl and heteroaryl
halides has also been observed.3 Few examples of
carbon-carbon bond formation involving organobor-
on compounds have been reported. In these contribu-
tions, C-H bond activation of heteroarenes can be
performed with arylboronic acids in the presence of a
catalytic amount of palladium acetate and either stoi-
chiometric copper acetate or TEMPO.4 These transfor-
mations were postulated to proceed via organo-
palladium intermediates generated by transmetalation
from the boronic acids.
(1) For bioactive quinoline derivatives, see: (a) Kolasa, T.; Gunn,
D. E.; Bhatia, P.; Woolds, K. W.; Gane, T.; Stewart, A. O.; Bouska, J. B.;
Harris, R. R.; Hulkower, K. I.; Malo, P. E.; Bell, R. L.; Carter, G. W.;
Brooks, C. D. W. J. Med. Chem. 2000, 43, 690–705. (b) Narayanan, S.;
Vangapandu, S.; Jain, R. Bioorg. Med. Chem. Lett. 2001, 11, 1133–1136.
(c) Jain, R.; Vaitilingam, B.; Nayyar, A.; Palde, P. B. Bioorg. Med.
Chem. Lett. 2003, 13, 1051–1054. (d) Payne, J. E.; Bonnefous, C.;
Symons, K. T.; Nguyen, P. M.; Sablad, M.; Rozenkrants, N.; Zhang,
Y.; Wang, L.; Yazdani, N.; Shiau, A. K.; Noble, S. A.; Rix, P.; Rao,
T. S.; Hassig, C. A.; Smith, N. D. J. Med. Chem. 2010, 53, 7739–7755.
For active alkylated benzimidazoles, see: (e) Bali, A.; Bansal, Y.;
Sugumaran, M.; Singh Saggu, J.; Balakumar, P.; Kaur, G.; Bansal, G.;
Sharma, A.; Singh, M. Bioorg. Med. Chem. 2005, 15, 3962–3965. (f)
Capkauskaite, E.; Baranauskiene, L.; Golovenko, D.; Manakova, E.;
Grazulis, S.; Tumkevicius, S.; Matulis, D. Bioorg. Med. Chem. 2010, 18,
7357–7364. (g) Kumar, S.; Bawa, S.; Gupta, H. Mini-Rev. Med Chem.
2009, 9, 1648–1654.
(2) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404–
12405. (b) Do, H.-Q.; Kashif Khan, R. M.; Daugulis, O. J. Am. Chem.
Soc. 2008, 130, 15185–15192. (c) Yoshizumi, T.; Tsurugi, H.; Satoh, T.;
Miura, M. Tetrahedron Lett. 2008, 49, 1598–1600. (d) Zhao, D.; Wang,
W.; Lian, S.; Yang, F.; Lan, J.; You, J. Chem.;Eur. J. 2009, 15, 1337–
1340. (e) Barbero, N.; SanMatin, R.; Dominguez, E. Org. Biomol. Chem.
2010, 8, 841–845.
The Minisci reaction and related processes provide
another useful means to alkylate or arylate various hetero-
arenes via C-H bond substitution5 in which radical inter-
mediates add to activated aromatic systems (Scheme 1).6
Within this context, the reactivity of a variety of radical
precursors has been studied with quinolines7 and deriva-
tives such as lepidine,8 but the conditions often involve the
use of the heteroaryl substrate as a solvent.
(4) (a) Liu, B.; Qin, X.; Li, K.; Li, X.; Guo, Q.; Lan, J.; You, J.
Chem.;Eur. J. 2010, 16, 11836–11839. (b) Kirchberg, S.; Tani, S.; Ueda,
K.; Yamagushi, J.; Studer, A.; Itami, K. Angew. Chem., Int. Ed. 2011,
DOI: 10.1002/anie.201007060.
(5) (a) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28,
489–519. (b) Harrowven, D. C.; Sutton, B. J. Prog. Heterocycl. Chem.
2004, 16, 27–53.
(6) (a) Minisci, F.; Galli, R.; Cecere, M.; Malatesta, V.; Caronna, T.
Tetrahedron Lett. 1968, 5609–5612. (b) Bowman, W. R.; Storey, J. M. D.
Chem. Soc. Rev. 2007, 36, 1803–1822. (c) Vaillard, S. E. ; Schulte, B. ;
Studer, A. In Modern Arylation Methods; Ackermann, L., Ed.; Wiley-
VCH: Weinheim, 2009; pp 475-511.
(7) (a) Minisci, F.; Vismara, E.; Fontana, F.; Morini, G.; Serravalle,
M. J. Org. Chem. 1986, 51, 4411–4416. (b) Minisci, F.; Vismara, E.;
Fontana, F. J. Org. Chem. 1989, 54, 5224–5227.
(3) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174–238. (b) Beck, E. M.; Gaunt, M. J. Top. Curr. Chem. 2009, 292, 85–
121. (c) Fall, Y.; Reynaud, C.; Doucet, H.; Santelli, M. Eur. J. Org.
Chem. 2009, 4041–4050 and references therein.
r
10.1021/ol2003572
Published on Web 03/10/2011
2011 American Chemical Society

Scheme 1. Overviewa
Table 1. Optimization of C-H Alkylation
GCMS
entry
oxidant
additive
solvent
conversion
a Route A: Minisci reaction using alkyl halides. Route B: direct
alkylation with potassium alkyltrifluoroborates.
1
Mn(OAc)3
Cu(OAc)2
KMnO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
TFA
AcOH:H2O 1:1
AcOH:H2O 1:1
AcOH:H2O 1:1
AcOH:H2O 1:1
AcOH:H2O 1:1
AcOH:H2O 1:1
AcOH:H2O 1:1
AcOH:H2O 1:1
AcOH:H2O 1:1
71%
1%
2
3
20%
54%
26%
6%
Interestingly, there is a relatively recent recognition that
arylborons can serve as radical precursors in C-C bond-
forming reactions via oxidative carbon-boron bond
cleavage.9 Among the different metal oxidants that can
be employed for this reaction, manganese(III) acetate has
proven to be efficient for the C-H arylation of olefins,10
arenes, and heteroarenes using arylboronic acids.11 How-
ever, in the latter cases either the substrate was used as a
solvent or the reaction was performed with a 10-fold excess
of the arene/heteroarene at 170 °C under microwave
conditions. During the course of our investigations, Baran
and co-workers reported a method for direct arylation of
heterocycles using a 50% excess of arylboronic acids,
employing potassium persulfate and catalytic silver nitrate
as oxidants.12
Because of their lack of an empty p-orbital, potassium
organotrifluoroborates are more stable toward numerous
reagents than their corresponding boronic acids. This
important characteristic facilitates their ease of handling,
storability, and robustness under harsh reaction condi-
tions. Over the past decade, these compounds have proven
tobeexcellent partners inSuzuki-Miyaura cross-coupling
and other transition metal catalyzed reactions.13 As is the
case with boronic acids, there has been a recognition that
trifluoroborates can also serve as radical precursors. In-
deed, Fensterbank et al. recently reported that potassium
alkyltrifluoroborates serve as precursors to radicals in a
variety of reactions under oxidative conditions employing
copper acetate or copper chloride and TEMPO.14
4
Ce(SO4)2
5
K2Cr2O7
6
Fe(SO4)2•7H2O
(NH4) 2S2O7
benzoquinone
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
7
12%
3%
8
9
6%
10
11
12
13
14
15
16
17
18
19
AcOH:H2O 1:1 78% (60%)a
TFAb
KHF2
-
AcOH:H2O 1:1
AcOH:H2O 1:1
AcOH:H2O 1:1
AcOH
71%
71%
65%
48%
4%
TFA
TFA
DMSO
TFA
CH3CN
41%
54%
51%
31%
TFA
MeOH
TFA
ClCH2CH2Cl
acetone
TFA
a Reaction performed at room temperature. b Reaction performed
with only 0.2 equiv of trifluoroacetic acid.
potassium alkyl- and alkoxymethyltrifluoroborates. We
chose to optimize this reaction by testing the direct alkyla-
tion of benzothiazole with potassium cyclobutyltrifluoro-
borate. First, different metal and nonmetal oxidants were
tried (Table 1, entries 1-8). Next, different additives
(entries 9-13) and various solvents (entries 14-19) were
tested, and from these studies it appeared that the highest
conversion was obtained with manganese(III) acetate in
the presenceof trifluoroaceticacidina 1:1 mixtureofacetic
acid/water (entry 10).
Using these conditions a variety of heteroaryl substrates
have been engaged in reactions with potassium cyclobutyl-
trifluoroborate (Table 2). Reactions with quinoline and
derivatives 1a-k afford yields up to 65% (entries 1-8).
As reported in the literature,15 quinoline 1a presents two
electron-deficient positions, so both regioisomers were isolated
in a 44% combined yield, and 1H NMR analysis of the crude
mixture indicated the presence of a 70:30 ratio of 2aa/2ab.
Isoquinoline 1d gives not only the expected heteroaryl 2d but
also the corresponding dimer. This side product is obtained
by reaction between two radical intermediate species.16
Azole compounds 1l-r also gave good conversions
(entries 9-12), but the yields are low because of the
difficulty in separating compounds 2o-r from the corre-
sponding starting material (entries 11-12).
Herein, we reveal our initial investigations on the use of
stoichiometric organotrifluoroborates as radical precur-
sors in the first direct C-H alkylation of heteroaryls with
(8) (a) Minisci, F.; Giordano, C.; Vismara, E.; Levi, S.; Tortelli, V. J.
Am. Chem. Soc. 1984, 106, 7146–7150. (b) Minisci, F.; Fontana, F.;
Pianese, G.; Ming Yan, Y. J. Org. Chem. 1993, 58, 4207–4211.
(9) (a) Ollivier, C.; Renaud, P. Chem. Rev. 2001, 101, 3415–3434. (b)
Darmency, V.; Renaud, P. Top. Curr. Chem. 2006, 263, 71–106. (c)
Vogler, T.; Studer, A. Org. Lett. 2008, 10, 129–131. (d) Pouliot, M.;
Renaud, P.; Schenk, K.; Studer, A.; Vogler, T. Angew. Chem., Int. Ed.
2009, 48, 6037–6040.
(10) Dickschat, A.; Studer, A. Org. Lett. 2010, 12, 578–580.
(11) (a) Demir, A. S.; Reis, O.; Emrullahoglu, M. J. Org. Chem. 2003,
68, 578–580. (b) Guchhait, S. K.; Kashyap, M.; Saraf, S. Synthesis 2010,
7, 1166–1170.
(12) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.; Fujiwara,
Y.; Sobel, A. L.; Baran, P. J. Am. Chem. Soc. 2010, 132, 13194–13196.
(13) (a) Stefani, H. A.; Cella, R.; Vieira, A. S. Tetrahedron 2007, 63,
3623–3658. (b) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–
^
€
286. (c) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288–325.
(15) Gebauer, M.; Heinisch, G.; Lotsch, G. Tetrahedron 1988, 44,
2449–2455.
(16) Minisci, F.; Galli, R.; Malatesta, V.; Caronna, T. Tetrahedron
1970, 26, 4083–4091.
(14) Sorin, G.; Malloquin, R. M.; Contie, Y.; Baralle, A.; Malacria,
M.; Goddard, J.-P.; Fensterbank, L. Angew. Chem., Int. Ed. 2010, 49,
8721–8723.
Org. Lett., Vol. 13, No. 7, 2011
1853

Table 2. Scope of Coupling with Diverse Heteroarylsa
Table 3. Scope of the Alkyltrifluoroboratesa
a Lepidine (1.0 mmol), potassium alkoxymethyltrifluoroborate (1.0
mmol), Mn(OAc)3 (2.5 mmol), TFA (1.0 mmol), AcOH/H2O 1:1
(0.08 M), 50 °C, 18 h. b Isolated yields and conversions (indicated in
parentheses) determined by 1H NMR spectroscopic analysis of the crude
mixture.
a Heterocycle (1.0 mmol), potassium cyclobutyltrifluoroborate (1.0
mmol), Mn(OAc)3 (2.5 mmol), TFA (1.0 mmol), AcOH/H2O 1:1 (0.08 M),
50 °C, 18 h. b Isolated yields and conversions (indicated in parentheses)
determined by 1H NMR spectroscopic analysis of the crude mix-
ture. c Heterocycle (1.0 mmol), potassium cyclobutyltrifluoroborate
(3.5 mmol), Mn(OAc)3 (5.0 mmol), TFA (1.0 mmol), AcOH/H2O 1:1
(0.08 M), 50 °C, 18 h.
alkyltrifluoroborates with 75% yields for both (entries 1,
2), but the tetrahydropyranyl derivative gave a lower yield
(entry 3). The hindered potassium isopinocampheyl-
trifluoroborate was also coupled to give substituted
lepidine 3d with complete stereoselectivity (entry 4). The
ease of alkyltrifluoroborate oxidation and the nucleo-
philic character of the in situ formed alkyl radicals could
combine toprovidethe drivingforce for the reaction, asthe
reactivity appears to increase on going from primary
to secondary and tertiary radicals.17 This could explain
the low yield obtained for compound 3e. Good yields are
observed for heteroaryls 3f-i, which are substituted by
We next evaluated the reactivity of lepidine toward
different primary, secondary, and tertiary potassium al-
kyltrifluoroborates (Table 3). The alkylated heteroaryls
3a-i were obtained with yields between 25 and 78%.
Cyclopentyl and cyclohexyl substituents were success-
fully added from the corresponding potassium cyclo-
1854
Org. Lett., Vol. 13, No. 7, 2011

Table 4. Scope of Alkoxymethyltrifluoroborates
Scheme 2. Proposed Mechanism with Lepidine
is tolerant of a range of functional groups present on the
boron reagent, including alkene, alkyne, and benzyl
groups (entries 5, 6, and 7).
In accord with precedents established in previous
studies,7b,8b,12,14 a possible mechanism can be proposed
(Scheme 2). The first step involves a homolytic cleavage of
the C-B bond using 1 equiv of manganese(III) acetate.
Subsequently, the alkyl radical adds to the protonated
heteroaryl to form the corresponding radical cation inter-
mediate, which leads to the protonated heteroaromatic
after a second oxidation. Basic workup leads to the final
observed product.
In summary, we have reported the first direct alkylation
of various heterocyles using potassium alkyl- and alkox-
ymethyltrifluoroborates as nucleophilic radical precur-
sors. Moderate to good yields are achieved, in most
cases, using a stoichiometric amount of both reacting
partners. This method fills an important void in that
Friedel-Crafts alkylations fail for nearly all heterocyclic
systems, and it also represents an efficient way to decorate
heteroaryl subunits with unique alkyl substituents (e.g.,
cyclobutyl and alkoxymethyl groups). Current research
efforts seek to expand the process to other distinctive
substrates and substituents.
a Isolated yields and conversions (indicated in parentheses) deter-
mined by 1H NMR spectroscopic analysis of the crude mixture.
b Lepidine (1.0 mmol), potassium alkoxymethyltrifluoroborate
(1.0 mmol), Mn(OAc)3 (2.5 mmol), TFA (1.0 mmol), AcOH/H2O
1:1 (0.08 M), 50 °C, 18 h. c 1.3 mmol of potassium alkoxy-
methyltrifluoroborate.
linear secondary and tertiary alkyls, respectively (entries
6-9).
For the third part of our investigation, it was of
interest to test the reactivity of various potassium
alkoxymethyltrifluoroborates toward lepidine, because
ethers induces a change in solubility that is important in
drug administration.18 Diverse potassium alkoxy-
methyltrifluoroborates were successfully coupled to
lepidine (Table 4) with yields between 58 and 89%.
Some of these organoborons were made by a process
that started with bromomethyltrifluoroborate and may
have contained some bromide salts.19 To counter that
possibility, in these cases the trifluoroborates were used
in excess (entries 4, 6). The alkoxymethylation reaction
Acknowledgment. We thank Frontier Scientific and
Aldrich for a donation of boronic acids. Financial support
has been provided by the NIH General Medical Sciences (R01
GM035249). Dr. Floriane Beaumard and Luciana Felix
(University of Pennsylvania) are acknowledged for making
potassium alkoxymethyltrifluoroborates and cyclobutyltri-
fluoroborate, respectively. Dr. Rakesh Kohli (University of
Pennsylvania) is acknowledged for obtaining HRMS data.
(17) Minisci, F.; Mondelli, R.; Gardini, G. P.; Porta, O. Tetrahedron
1972, 28, 2403.
(18) (a) Nudelman, A.; Elisheva, G.; Katz, Y.; Azulai, R.; Cohen-Ohana,
M.Zhuk, R.; Sampson, S. R.; Langzam, L.; Fibach, E.; Prus, E.; Pugach,
V.; Raphaeli, A. Eur. J. Med. Chem. 2001, 36, 63–74. (b) Shirasaki, Y.;
Miyashita, H.; Yamagushi, M.; Inoue, J.; Nakamura, M. Bioorg. Med.
Chem. 2005, 13, 4473–4484. (c) Hartz, R. A.; Ahuja, V. T.; Mattson, R. J.;
Denhart, D. J.; Deskus, J. A.; Vrudhula, V. M.; Pan, S.; Ditta, J. L.; Shu,
Y.-Z.; Grace, J. E.; Lentz, K. A.; Lelas, S.; Li, Y.-W.; Molski, T. F.;
Krishnananthan, S.; Wong, H.; Qian-Cutrone, J.; Schartman, R.; Denton,
R.; Lodge, N. J.; Zaczek, R.; Macor, J. E.; Bronson, J. J. J. Med. Chem.
2009, 52, 7653–7668.
Supporting Information Available. Experimental pro-
cedures and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(19) Raushel, J.; Sandrock, D. L.; Josyula, K. V.; Pakyz, D.; Molander,
G. A. Manuscript submitted.
Org. Lett., Vol. 13, No. 7, 2011
1855