Mild palladium-catalyzed C-H alkylation using potassium alkyltrifluoroborates in combination with MnF3

Article abstract of DOI:10.1021/ol400888r

A Pd-catalyzed method for ligand-directed C-H alkylation with organoboron reagents is described. The combination of potassium organotrifluoroborates, MnF₃, and a Pd^II catalyst effects pyridine and amide-directed C-H alkylation. These reactions proceed under mild conditions (25-40 C in weakly acidic media), are effective for installing methyl and 1 alkyl groups, and do not require promoters such as benzoquinone.

Full text of DOI:10.1021/ol400888r

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Mild Palladium-Catalyzed CꢀH Alkylation
Using Potassium Alkyltrifluoroborates in
Combination with MnF3
Sharon R. Neufeldt, Cydney K. Seigerman, and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 North University Avenue,
Ann Arbor, Michigan 48109, United States
mssanfor@umich.edu
Received April 1, 2013
ABSTRACT
A Pd-catalyzed method for ligand-directed CꢀH alkylation with organoboron reagents is described. The combination of potassium organo-
trifluoroborates, MnF3, and a PdII catalyst effects pyridine and amide-directed CꢀH alkylation. These reactions proceed under mild conditions
(25ꢀ40 °C in weakly acidic media), are effective for installing methyl and 1° alkyl groups, and do not require promoters such as benzoquinone.
Palladium-catalyzed CꢀH functionalization is an atom-
economical alternative to more traditional cross-coupling
reactions for the formation of CꢀC bonds.1 Numerous
reports have demonstrated Pd-catalyzed ligand-directed
CꢀH arylation using diaryliodonium salts, aryl halides,
and arylboronic acids.1 In contrast, examples of analogous
Pd-catalyzed ligand-directed CꢀH alkylations remain
much more limited.2ꢀ6
Organoboron compounds are particularly attractive
reagents for CꢀH alkylation due to their low toxicity,
low cost, and synthetic accessibility.7 Seminal work by Yu
established the feasibility of PdII/0-catalyzed CꢀH alkyla-
tion with alkylboronic acids.2 However, these transfor-
mations have limitations with respect to generality, practi-
cality, andefficiency.2 For example, relativelyfewdirecting
groups are effective, and extensive optimization of addi-
tives, solvent, and oxidant is typically required for each
substrate class. In addition, these transformations gener-
allyrequire high temperatures(g100 °C), along withbases,
silver salts, and other additives/promoters. In particular,
stoichiometricquantitiesof benzoquinone(BQ) are used in
all such reactions reported to date.
(1) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174. (b) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (c) McGlacken,
G. P.; Bateman, L. Chem. Soc. Rev. 2009, 38, 2447. (d) Chen, X.; Engle,
K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (e)
Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (f) Daugulis,
O. Top. Curr. Chem. 2010, 292, 57. (g) Chiusoli, G. P.; Catellani, M.;
Costa, M.; Motti, E.; Ca’, N. D.; Maestri, G. Coord. Chem. Rev. 2010,
254, 456.
(2) (a) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006,
128, 12634. (b) Giri, R.; Maugel, N.; Li, J.-J.; Wang, D. H.; Breazzano,
S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc. 2007, 129, 3510. (c)
Wang, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130,
7190. (d) Dai, H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang, Y.-H.; Yu,
J.-Q. J. Am. Chem. Soc. 2011, 133, 7222. (e) Romero-Revilla, J. A.;
Garcia-Rubia, A.; Arrayas, R.; Fernandez-Ibanez, M. A.; Carretero,
J. C. J. Org. Chem. 2011, 76, 9525. (f) Wasa, M.; Engle, K. M.; Lin,
D. W.; Yoo, E. J.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19598. (g)
Wasa, M.; Chan, K. S. L.; Yu, J.-Q. Chem. Lett. 2011, 40, 1004.
(3) CꢀH alkylation with alkylstannanes: Chen, X.; Li, J.-J.; Hao,
X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 78.
(4) CꢀH methylation with MeI: Tremont, S. J.; Rahman, H. U.
J. Am. Chem. Soc. 1984, 106, 5759.
(5) CꢀH alkylation with alkyl halides: (a) Catellani, M.; Frignani,
F.; Rangoni, A. Angew. Chem., Int. Ed. 1997, 36, 119. (b) Rudolph, A.;
Rackelmann, N.; Lautens, M. Angew. Chem., Int. Ed. 2007, 46, 1485. (c)
Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
6097. (d) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132,
3965. (e) Zhao, Y.; Chen, G. Org. Lett. 2011, 13, 4850. (f) Tran, L. D.;
Daugulis, O. Angew. Chem., Int. Ed. 2012, 51, 5188. (g) Zhang, S. Y.; He,
G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013, 135,
2124.
These limitations are due, in large part, to the reaction
mechanism, which is believed to involve (i) ligand-directed
CꢀH activation at PdII, (ii) transmetalation from boron to
PdII, (iii) CꢀC reductive elimination from PdII, and (iv)
(6) CꢀH methylation with TBHP: Zhang, Y.; Feng, J.; Li, C.-J.
J. Am. Chem. Soc. 2008, 130, 2900.
(7) (a) Darses, S.; Genet, J.-P. Chem. Rev. 2008, 108, 288. (b)
Molander, G. A.; Sandrock, D. L. Curr. Opin. Drug Discovery Dev.
2009, 12, 811.
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10.1021/ol400888r
XXXX American Chemical Society

oxidationofPd0 toPdII byCuII or AgI (Scheme 1A). Inthis
sequence, the reductive elimination (step iii) is typically
slow, thus requiring BQ as a promoter.2 The oxidation of
Pd0 (step iv) can also be challenging, since aggregation of
Pd black is a competing side reaction. As a result, extensive
optimization and complex mixtures of additives are often
required to facilitate this step.8
Table 1. Oxidant Screen for Methylation of 1a
entry
oxidant
PhI(OAc)2
yield 2 (%)
yield 3 (%)
Scheme 1. Potential Pathways for Pd-Catalyzed CꢀH
1
e2
e2
4
4
Alkylation with Alkyl Boron Reagents
2
PhI(O2CCF3)2
N-chlorosuccinimide
K2S2O8
16
ndb
e2
e2
e2
3
3
4
7
5
Mn(OAc)3
t-BuOOH
MnF3
20
33
60
80
89
51
nd
e2
e2
e2
e2
e2
6
7
8c
MnF3
nd
nd
nd
nd
nd
nd
nd
nd
nd
9c,d
10c,d,e
11c,d,f
12
13
14
15
16
MnF3
MnF3
MnF3
benzoquinone
Cu(OAc)2
Ag2O
AgOAc
Ag2CO3
a Yields determined by GC analysis of the crude reaction mixture;
nd = not detected. b CꢀH chlorination product (∼7%) formed.
c In TFE/H2O/AcOH (8:1:1), 6 h. d 40 °C e With 1 equiv of CH3BF3K
and 2 equiv of MnF3. f Control reaction without Pd.
We sought to address these challenges by targeting a
complementarypathway for Pd-catalyzed CꢀH alkylation
with organoboron reagents (Scheme 1B). The proposed
sequence would involve the use of strong oxidants that are
capable of oxidizing PdII intermediates to high-valent Pd
species. Under these conditions CꢀC coupling should
occur at a PdIII or PdIV center, where it is known to
proceed under mild conditions without the requirement
for promoters such as benzoquinone.9,10 This pathway
also circumvents the intermediacy of Pd0, thereby avoiding
the challenging oxidation of Pd0 to PdII.
We first evaluated the Pd(OAc)2-catalyzed methylation
of 1 with CH3BF3K in AcOH at room temperature in the
presence of oxidants that are capable of oxidizing PdII to
high valent Pd (Table 1).9 While ortho-acetoxylation to
form 3 was a major side product in some cases, a number of
these oxidants provided modest to good yields of 2 after
16 h (entries 4ꢀ7). The highest yield of 2 was obtained with
MnF3 (entry 7). Further optimization of the solvent
[changing to TFE/H2O/AcOH (8:1:1)] and temperature
(moving to 40 °C) resulted in an 89% yield of 2 in just
6 h (entry 9).11,12 Importantly, no methylation occurred in
the absence of Pd (entry 11). Further, only traces (e2%)
of 2 were detected with PdII/0 oxidants such as benzoqui-
none, Cu(OAc)2, Ag2O, AgOAc, or Ag2CO3 under these
conditions.
The optimal conditions were next applied to the CꢀH
methylation of diverse arylpyridine and anilide substrates
(Figure 1). Products derived from the ortho-CꢀH methy-
lation of acetanilide (5ꢀ8), pyrrolidinone (9), acetylindo-
line (10), and tetrahydroacetylquinoline (11) derivatives
were all obtained in good to excellent yields. Notably, the
presence of an aryl iodide was well tolerated (8).
Other 1° alkyl groups were installed using the corre-
sponding alkyltrifluoroborates (Figure 2). Alkylation of
both arylpyridine 1 and 30-methylacetanilide with ethyl,
n-butyl, and n-hexyl groups proceeded efficiently to afford
12, 13, 14, and 21. The sterically hindered neopentyl group
was introduced in 40% yield (16), and alkyl chains bearing
phenyl, ester, ketone, and trifluoromethyl substituents
were compatible with the reaction conditions. The major
current limitation of this method is that 2° alkyl trifluoro-
borates afford low yields (typically e10%).
We envisioned at least two possible roles for MnF3 in
these reactions, both of which would lead to the formation
of high valent Pd intermediates. The first would involve
MnIII oxidizing RBF3K to an alkyl radical (R•); subse-
quent reaction of R• with palladacycle I would then form
PdIII intermediate II (Scheme 2A). A number of recent
(8) Engle, K. M.; Thuy-Boun, P. S.; Dang, M.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 18183.
~
(9) Reviews on high valent Pd: (a) Muniz, K. Angew. Chem., Int. Ed.
2009, 48, 9412. (b) Canty, A. J. Dalton Trans. 2009, 47, 10409. (c) Xu,
L.-M.; Li, B.-J.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712. (d)
Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177.
(10) CꢀC reductive elimination from high valent Pd is well-known to
be facile. For examples, see: (a) Lanci, M. P.; Remy, M. S.; Kaminsky,
W.; Mayer, J. M.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 15618. (b)
Canty, A. J.; Ariaford, A.; Sanford, M. S.; Yates, B. F. Organometallics
2013, 32, 544.
(11) Methylboronic acid and trimethylboroxine performed nearly as
well as MeBF3K (80 and 83% yield, respectively); however, these reagent
classes are not as convenient to prepare and handle as trifluoroborate
salts (see ref 7).
(12) The composition of the reaction vessel (glass vs PTFE) and the
size of the reaction vessel (4 mL vs 20 mL) did not have a significant
influence on the yield of the reaction at an early time point (see
Supporting Information for details). Lennox, A. J. J.; Lloyd-Jones,
G. C. J. Am. Chem. Soc. 2012, 134, 7431.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Two Possible Roles for MnF3
fluorination of organic substrates.15 Furthermore, recent
publications have demonstrated PdII/IV catalysis with
other electrophilic fluorinating reagents.16
Figure 1. Substrate scope for CꢀH methylation. Conditions:
Substrate (1 equiv), Pd(OAc)2 (0.10 equiv), CH3BF3K (2 equiv),
MnF3 (4 equiv), TFE/H2O/AcOH (0.067 M in substrate),
25ꢀ40 °C, 3 h. Yields are of isolated products.
We initially favored the free radical mechanism in
Scheme 2A based on several pieces of circumstantial
evidence. First, Minisci-type radical aromatic substitution
products were detected in several of the pyridine alkylation
reactions.17 For example, the reaction of 23 with CyBF3K
afforded alkylated pyridine 25 in 5% yield, along with 9%
of the desired product 24 (Table 2, entry 1). Formation of
25 did not require Pd (entry 2) but did require MnF3 (entry3),
consistent with a Mn-promoted radical pathway to this
product.
Table 2. Products Obtained with CyBF3Ka
entry
conversion (%)
yield 24 (%)
yield 25 (%)
1
42
35
18
9
nd
nd
5
6
2b
3c
nd
a Determined by GC analysis of the crude reaction mixture. b Control
reaction without Pd; nd = not detected. c Control reaction without Mn.
Figure 2. Scope of alkyl trifluoroborates. General conditions: 1
or 30-methylacetanilide (1 equiv), Pd(OAc)2 (0.10 equiv),
alkylꢀBF3K (2ꢀ4 equiv), MnF3 (3ꢀ4 equiv), TFE/H2O/AcOH,
25ꢀ40 °C, 3ꢀ6 h. Yields are of isolated products.
A second piece of circumstantial evidence consistent
with a radical pathway is the observation of dose-dependent
inhibition of CꢀH methylation by the radical inhibitor
galvinoxyl (Table 3).
reports have shown the feasibility of both the oxidation of
organoboron compounds with MnIII to generate radicals13
and the oxidation of palladacycles by radicals.14
A second potential pathway would involve oxidation of
a PdII intermediate by MnIII. This oxidation could occur
by Fþ transfer from MnF3 to PdII either after (shown in
Scheme 2B) or before transmetalation from boron to
palladium. Importantly, MnF3 is a known Fþ source for
(14) Selected examples: (a) Yu, W.-Y.; Sit, W. N.; Lai, K.-M.; Zhou,
Z.; Chan, A. S. C. J. Am. Chem. Soc. 2008, 130, 3304. (b) Yu, W.-Y.; Sit,
W. N.; Zhou, Z.; Chan, A. S.-C. Org. Lett. 2009, 11, 3174. (c) Kalyani,
D.; McMurtrey, K. B.; Neufeldt, S. R.; Sanford, M. S. J. Am. Chem. Soc.
2011, 133, 18566. (d) Neufeldt, S. R.; Sanford, M. S. Adv. Synth. Catal.
2012, 354, 3517.
(15) Selected examples: (a) Fowler, R. D.; Anderson, H. C.; Hamilton,
J. M.; Burford, W. B.; Spadetti, A.; Bitterlich, S. B.; Litant, I. Ind. Eng.
Chem. 1947, 39, 343. (b) Boltalina, O. V.; Borschevskii, A. Ya.; Sidorov,
L. N.; Street, J. M.; Taylor, R. Chem. Commun. 1996, 529.
(16) Vigalok, A. Organometallics 2011, 30, 4802.
€
(13) (a) Demir, A. S.; Reis, O.; Emrullahoglu, M. J. Org. Chem. 2003,
68, 578. (b) Guchhait, S. K.; Kashyap, M.; Saraf, S. Synthesis2010, 1166.
(c) Dickschat, A.; Studer, A. Org. Lett. 2010, 12, 3972. (d) Molander,
G. A.; Colombel, V.; Braz, V. A. Org. Lett. 2011, 13, 1852.
(17) Minisci, F.; Bernardi, R.; Bertini, F.; Galli, R.; Perchinummo,
M. Tetrahedron 1971, 27, 3575.
Org. Lett., Vol. XX, No. XX, XXXX
C

We reasoned that if MnF3 and CH3BF3K react directly
to generate CH3• (Scheme 2A), then prestirring these two
reagents with 1 for 3 h prior to the addition of Pd(OAc)2
should lead to a dramatically diminished yield of product
2. However, as shown in eq 1, this prestirring protocol
resulted in only a minor drop in the yield of 2 (83%
compared to 89% without the prestir). This strongly
suggests against the direct oxidation of CH3BF3K by MnIII
to generate CH3• in this transformation. Thus, the results in
Tables 2 and 3 appear to be ‘red herrings’. They may reflect
radical side reactions that are not mechanistically con-
nected to the Pd-catalyzed conversion of 2 to 3 (Table 2)
and/or the interaction of galvinoxyl with the oxidant or
some other intermediate in the catalytic cycle (Table 3).
NFTPT is consistent with the feasibility of a ‘Fþ’-mediated
pathway such as that shown in Scheme 2B.
In summary, this manuscript describes a new approach
to Pd-catalyzed ligand-directed CꢀH alkylation that uses
MnF3 in conjunction with potassium organotrifluorobo-
rates. This method has enabled us to address several of the
key limitations of prior CꢀH alkylation processes. The
current transformations proceed under mild conditions
(25ꢀ40 °C in weakly acidic media) and are effective for the
installation of methyl and 1°-alkyl substituents into sub-
strates bearing both pyridine and amide directing groups.
The detailed mechanism remains to be elucidated, but
preliminary studies suggest that the MnF3 likely serves to
oxidize a PdII intermediate, rather than the organotrifluor-
oborate. Ongoing investigations are focused on gaining a
deeper mechanistic understanding of this transformation,
as well as expanding the scope with respect to both CꢀH
substrate and alkyl groups.
Table 3. Inhibition by Galvinoxyla
entry
galvinoxyl (equiv)
conversion (%)
yield 2 (%)
1
2
3
0
94
76
13
87
67
3
0.5
1
a Yields determined by GC analysis of the crude reaction mixture.
We next sought to probe whether the MnF3 is serving as
an Fþ oxidant in this system (Scheme 2B). To preliminarily
test this possibility, we substituted MnF3 with N-fluoro-
2,4,6-trimethylpyridinium triflate (NFTPT), a reagent that
has been used as a Fþ source to generate high valent Pd
intermediates.16 As shown in eq 2, NFTPT provided a
56% yield of 2 under the optimal conditions.18 While
further studies will be required to fully elucidate the details
of the reaction mechanism, the observed efficacy of
Acknowledgment. Thisworkwas supportedbythe NIH
NIGMS (GM073836).
Supporting Information Available. Experimental de-
tails and spectroscopic and analytical data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) All other oxidants screened under the optimized reaction con-
ditions afforded e10% yield; see Supporting Information for details.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX