Base-Controlled Completely Selective Linear or Branched Rhodium(I)-Catalyzed C?H ortho-Alkylation of Azines without Preactivation

Article abstract of DOI:10.1002/anie.201702409

A [Rh^I]/bisphosphine/base catalytic system for the ortho-selective C?H alkylation of azines by acrylates and acrylamides is reported. This catalytic system features an unprecedented complete linear or branched selectivity that is solely dependent on the catalytic base that is used. Complete branched selectivity is even achieved for ethyl methacrylate, which enables the introduction of a quaternary carbon center. Excellent functional group compatibility is demonstrated for both linear and branched alkylations. The operational simplicity and broad scope of this transformation allow for rapid access to functionalized azines of direct pharmaceutical and agrochemical relevance.

Full text of DOI:10.1002/anie.201702409

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International Edition: DOI: 10.1002/anie.201702409
German Edition: DOI: 10.1002/ange.201702409
Synthetic Methods
Base-Controlled Completely Selective Linear or Branched Rhodium-
À
(I)-Catalyzed C H ortho-Alkylation of Azines without Preactivation
Gaꢀl Tran, Kevin D. Hesp, Vincent Mascitti, and Jonathan A. Ellman*
Abstract: A [RhI]/bisphosphine/base catalytic system for the
cycles with unactivated alkenes [Eq. (1)].[7] This reaction was
also efficient for azines bearing an ortho steric blocking group,
but the absence of this substituent resulted in catalyst
poisoning. Finally, Chang described a [RhI]/dppe/CsOAc
catalytic system, but alkylation was only reported for azines
preactivated as N-oxides [Eq. (2)].[8,9]
À
ortho-selective C H alkylation of azines by acrylates and
acrylamides is reported. This catalytic system features an
unprecedented complete linear or branched selectivity that is
solely dependent on the catalytic base that is used. Complete
branched selectivity is even achieved for ethyl methacrylate,
which enables the introduction of a quaternary carbon center.
Excellent functional group compatibility is demonstrated for
both linear and branched alkylations. The operational sim-
plicity and broad scope of this transformation allow for rapid
access to functionalized azines of direct pharmaceutical and
agrochemical relevance.
H
eterocycles are found in more than 90% of the new
synthetic biologically active molecules reported in the liter-
ature.[1] The azine family, which includes pyridines, pyrimi-
dines, pyridazines and pyrazines, is one of the most exten-
sively used subclasses of heterocycles in the pharmaceutical
and agrochemical industry, and considerable efforts have
been dedicated to their synthesis and functionalization.[2] In
particular, the ability to directly access carboxylic acid
derivatives from unsubstituted heteroarenes would present
an exciting opportunity for achieving hepatoselective delivery
of drug-like molecules via organic-anion transporting poly-
peptides (OATPs)—a strategy for the hepatic uptake of drugs
that has been well validated.[3]
Herein, we report that unactivated azines with or without
an ortho blocking group can be efficiently alkylated with a,b-
unsaturated carboxylic acid derivatives using a [RhI]/bisphos-
phine catalytic system [Eq. (3)–(5)]. In an unprecedented
finding, complete selectivity for either the linear [Eq. (3)] or
branched [Eq. (4)] product can be achieved solely depending
on the catalytic base that is used. The branched conditions can
even be employed with methacrylates to provide the first
À
The direct regioselective C H functionalization of unsub-
stituted azines would represent a highly efficient method for
À
examples of azine C H alkylation with a Michael acceptor to
incorporating carboxylic acid functionality.[4,5] However, few
introduce a quaternary center [Eq. (5)].
À
methods are available for the ortho-selective C H alkylation
of azines. The seminal example made use of a [RhI]/PCy3/HCl
catalytic system for the ortho alkylation of pyridines and
À
quinolines by C H bond addition to unactivated alkenes
[Eq. (1)].[6] Although efficient alkylation occurred for pyr-
idines substituted with a steric blocking group at an ortho
position, no alkylation was observed for pyridines lacking this
substituent, presumably due to strong [RhI] coordination of
the unsubstituted pyridine. Subsequently, Hou et al. reported
the rare earth-catalyzed ortho alkylation of similar hetero-
[*] Dr. G. Tran, Prof. Dr. J. A. Ellman
Department of Chemistry, Yale University
225 Prospect St., New Haven, CT 06520 (USA)
E-mail: jonathan.ellman@yale.edu
Dr. K. D. Hesp, Dr. V. Mascitti
Pfizer, Inc., Medicinal Sciences
Groton, CT 06340 (USA)
After intensive optimization, alkylation of 3-trifluorome-
thylpyridine in 76% yield was achieved with ethyl acrylate in
the presence of [Rh(cod)Cl]2, dppe, and potassium pivalate
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201702409.
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electron-withdrawing functional groups such as sulfone (3e)
or phenyl (3 f) were also compatible. With an electron-
donating group such as isobutyl (3g) the reaction was
significantly slower, but some product could be obtained
when the reaction time was extended to 10 h. Notably,
pyridines combining both an electron-donating and an
electron-withdrawing group did not require more forcing
conditions, and good to excellent yields were obtained
regardless of the substitution pattern (3h–k).
The presence of a substituent at the C2-position of the
pyridine ring, such as in quinoline, did not hamper the
reaction with product 3l obtained in 74% yield. While 2-
picoline gave 27% yield (3m), significant improvement was
obtained when adjoining an electron-withdrawing group to
the ring (3n,o).
All of the previous reactions featured complete selectivity
for mono-alkylation. However, when pyridine was substituted
with a trifluoromethyl group at the para-position, the mono-
alkylated product 3p was obtained in 42% yield along with
the dialkylation product 3p’ in 36% yield. Better selectivity
was observed for 3-chloro-4-trifluoromethylpyridine (3q)
when milder conditions were used (1208C, 10 h). Parent
pyridine also provided good selectivity in favor of the mono-
alkylated product (3r), although with a modest yield. For 2-
methylnicotinonitrile, the C2-alkylated product 3s was
obtained in 62% yield along with the C3,C6-dialkylated
product 3s’ in 22% yield. This was the only example where
alkylation did not occur solely at the position ortho to the
pyridine nitrogen.
We next evaluated diazines, which are also highly
represented in biologically active compounds.[1] Diazines
were sufficiently reactive that the reaction time was decreased
to minimize over-alkylation (Scheme 2). Complete regiose-
lectivity in favor of the C6-position was observed with 4-
methylpyrimidine, though a small amount of C2,C6-dialky-
lated product 5a’ was also obtained. A good yield of
monoalkylated 5b was also obtained from 2,3-dimethylpyr-
azine, again with a small amount of dialkylated product 5b’.
In contrast, 4-methylpyridazine led to significant amounts of
by-products and the desired monoalkylated product 5c was
obtained in 31% yield.
À
Scheme 1. Substrate scope for linear C H alkylation of pyridines.
[a] 1608C instead of 1908C. [b] 10 h reaction time instead of 5 h.
[c] 1208C instead of 1908C.
In addition to ethyl acrylate, other acrylate derivatives
such as tert-butyl acrylate, 2b, and N,N-dimethylacrylamide,
2c, were suitable alkene partners (Scheme 3). Significantly, 4-
(KOPiv) with microwave heating at 1908C in toluene for 5 h
(3a, Scheme 1). Significantly, the reaction proceeded with
complete selectivity for linear mono-alkylation at the C6-
position. KOPiv proved superior to all other bases, including
CsOAc initially used by Chang, which gave a 22% yield (see
Table S1).[9] The stability of the [Rh(cod)Cl]2 pre-catalyst to
air and the low hygroscopicity of the KOPiv base enabled the
reaction to be readily set up on the bench-top.
Broad scope for this reaction was observed for the
pyridine coupling partner (Scheme 1). Carbonyl-containing
functional groups, such as an ester (3b) or an amide (3c) led
to the desired products in good to excellent yields. On the
other hand, significant amounts of by-products were formed
at 1908C when 3-acetylpyridine was used, presumably due to
enolate-mediated side reactions. This could be avoided by
reducing the reaction temperature to 1608C (3d). Other
À
Scheme 2. Substrate scope for linear C H alkylation of diazines.
2
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Scheme 3. Evaluation of acrylate esters and amides.
acryloylmorpholine, 2d, led to acceptable yields of the
alkylated pyridine 3ad, which can potentially be converted
to a wide range of ketones by reaction with the corresponding
organometallic reagents.[10]
All of the reactions presented in this study so far feature
complete linear selectivity as assessed by 1H NMR of the
crude reaction mixtures, consistent with virtually all of the
À
intermolecular C H bond additions to Michael acceptors
whether catalyzed by [Co], [Ir], [Ru], [Rh], or [Pd].[5,11,12] It
was therefore exciting for us to discover that the alkylation of
3-trifluoromethylpyridine, 1a, by acrylamide 2c led to a good
yield of product 6ac through the use of a [Rh(cod)Cl]2/dppe
catalyst system with K3PO4 as the catalytic base instead of
KOPiv [Eq. (6)].[13] In contrast, the linear product 3ac was the
À
Scheme 4. Substrate scope for branched C H alkylation using acryl-
amides.
and conditions B with dArFpe instead of dppe at 1208C
(Scheme 4). Very good scope with complete retention of the
branched selectivity was observed for both of these con-
ditions, though the broadest scope was achieved for con-
ditions B. Alkylations of 3-trifluoromethylpyridine (6ac),
ethyl nicotinate (6bc), quinoline (6lc) and 4-trifluoromethyl-
pyridine (6pc) by acrylamide 2c were accomplished in good
yields with conditions A, and in excellent to quantitative
yields with conditions B. Even when modest yields are
obtained with conditions A, as with 3-methylsulfonylpyridine
(6ec) or 3-trifluoromethyl-4-morpholinepyridine (6jc),
almost quantitative yields are obtained with conditions B.
The superiority of conditions B over conditions A was also
apparent when 3-phenylpyridine (6 fc), 3-chloro,4-trifluoro-
methylpyridine (6qc) or ethyl isonicotinate (6tc) were used.
While only traces of the desired products could be observed
with conditions A, moderate to good yields could be obtained
with conditions B. Finally, the alkylation of 3-trifluorome-
thylpyridine by 4-acryloylmorpholine also led to a good to
excellent yield of the corresponding branched product (6ad)
with both conditions.
sole alkylation product of the reaction when KOPiv was used
as base under otherwise identical conditions. Such a switch in
regioselectivity in metal-catalyzed hydroarylation of alkenes
is unprecedented, not only due to the very simple change in
reaction conditions under which it is operated (K3PO4 vs.
KOPiv), but also due to its complete selectivity.
Satisfying yields of branched product 6ac could be
obtained using the [Rh(cod)Cl]2/dppe/K3PO4 catalytic
system depicted in Equation (6), but some limitations in the
scope were observed after further investigation (vide infra). A
second screening campaign established that replacing dppe
with its electron-deficient analog d(3,5-(CF3)2Ph)pe (dArFpe)
resulted in a significant increase in yield (see Table S2). With
this more efficient catalyst system, the reaction temperature
could be lowered to 1208C. The nature of the base was still
crucial for branched/linear selectivity and reaction efficiency,
as the use of KOPiv as well as a number of other bases instead
of K3PO4 resulted in only trace amounts of the linear product
(see Table S2).
Methacrylate derivatives were also explored for the direct
incorporation of quaternary centers. While N,N-dimethyl
methacrylamide was insufficiently reactive and did not
couple, ethyl methacrylate, 2e, was a highly effective sub-
strate for branched alkylation, leading to azines 7ae, 7be and
7ee, diazine 7ue and quinoline 7le in excellent yields
We evaluated the scope of the reaction under conditions
A, with a [Rh(cod)Cl]2/dppe/K3PO4 catalytic system at 1608C,
À
(Scheme 5). These are the first examples of azine C H
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À
A number of Rh-catalyzed C C bond cleavage reactions
have recently been reported.[16] It is therefore conceivable
that deuterium could be incorporated into acrylamide 2c and
the linear and branched products 3ac and 6ac by reversible
À
C C bond formation. However, this pathway was ruled out by
the complete lack of crossover upon submitting linear product
3ac to the branched alkylation conditions and branched
product 6ac to the linear alkylation conditions (see
Scheme S2). A detailed discussion is provided in the Support-
ing Information for possible mechanistic scenarios that
explain the complete turnover in selectivity under the linear
and branched reaction conditions.
À
Scheme 5. Branched C H alkylation using ethyl methacrylate.
alkylation with a Michael acceptor to introduce a quaternary
center.
To probe mechanistic differences between the KOPiv-
catalyzed linear and K3PO4-catalyzed branched alkylations, 2-
deutero-5-trifluoromethylpyridine, 1a-D, was reacted with
In summary, we have developed a [RhI]-catalyzed ortho-
selective alkylation of azines with acrylates and acrylamides
with complete linear or branched selectivity controlled
exclusively by catalytic base. This transformation has excel-
lent functional group tolerance and is operationally simple
thereby making it useful for drug discovery applications. The
base-controlled switch in linear/branched selectivity is com-
pletely unprecedented and may be symptomatic of a novel
mode of reactivity in [RhI]-catalytic systems. Further studies
on extending the reaction scope to broader classes of nitrogen
heterocycles and to asymmetric transformations is underway
in our laboratories.
Acknowledgments
Financial support for this work was provided by Pfizer Inc,
GM069559 and GM122473. We appreciate helpful discussions
with and suggestions by Nilay Hizari (Yale).
Conflict of interest
The authors declare no conflict of interest.
À
acrylamide 2c using both the linear and branched protocols
Keywords: C H activation · homogeneous catalysis ·
nitrogen heterocycles · regioselectivity
À
and halted at early conversion [Eqs. (7) and (8)]. C H
activation under the linear conditions is highly reversible as
evidenced by significant H/D scrambling of 1a-D [Eq. (7)]. In
À
contrast, C H activation for the branched conditions is
irreversible as evidenced by the complete absence of H/D
scrambling of 1a-D [Eq. (7)]. The lack of deuterium exchange
for branched alkylation of 1a-D, enabled initial rates to be
determined for protio and deuterio 1a under the branched
alkylation conditions (see Scheme S1). A modest kinetic
isotope effect (KIE) of 1.34 was observed.
Under both linear and branched reaction conditions
[Eqs. (7) and (8)], deuterium incorporation was observed
not only at both the a and the b alkyl sites in products 3ac-D/
H and 6ac-D/H, but also at the a and b vinyl sites in the
recovered acrylamide 2c. Deuterium incorporation in the
products and in acrylamide 2c could occur by RhI-catalyzed
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Med. Chem. 2014, 57, 10257.
[2] For the synthesis and functionalization of azines, see: Modern
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Vaquero, J. Barluenga), Wiley-VCH, Weinheim, 2011.
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selective delivery with reduced risk of off target pharmacology.
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genomics 2007, 8, 787.
À
oxidative addition of the azine C H bond followed by
reversible RhIII-hydride migratory insertion of acrylamide
2c. This pathway is consistent with well-documented highly
reversible migratory insertions for Rh-hydrides.[14,15]
À
[4] For reviews on transition-metal-catalyzed C H functionaliza-
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124, 9092; c) R. Rossi, F. Bellina, M. Lessi, C. Manzini, Adv.
Synth. Catal. 2014, 356, 17.
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À
[5] For a comprehensive review on transition-metal-catalyzed C H
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chemrev.6b00574.
[13] Complete branched selectivity was observed with acrylates
instead of acrylamides; however, over-alkylation at the newly
formed benzylic position occurred, likely due to deprotonation
by K3PO4 followed by 1,4-addition to another acrylate.
[14] a) C. P. Lenges, M. Brookhart, J. Am. Chem. Soc. 1999, 121,
6616; b) also see Ref.[5].
[15] Deuterium incorporated could also occur through a CMD
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[6] J. C. Lewis, R. G. Bergman, J. A. Ellman, J. Am. Chem. Soc.
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[9] For application of a similar catalytic system to the enantiose-
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Manuscript received: March 7, 2017
Final Article published: && &&, &&&&
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Communications
Synthetic Methods
G. Tran, K. D. Hesp, V. Mascitti,
J. A. Ellman*
&&&& — &&&&
Base-Controlled Completely Selective
Linear or Branched Rhodium(I)-Catalyzed
À
C H ortho-Alkylation of Azines without
Preactivation
A basic choice: The linear/branched
carbon centers can be introduced. Excel-
lent functional group compatibility is
demonstrated for both linear and
branched alkylations with acrylate deriv-
atives.
À
selectivity of an ortho-selective C H alky-
lation of azines without preactivation is
completely controlled by a simple switch
between base catalysts. Under the
“branched” conditions even quaternary
6
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