Iron-catalyzed C(sp2)-H alkylation of carboxamides with primary electrophiles

Article abstract of DOI:10.1002/anie.201406594

The direct ortho alkylation of 8-aminoquinoline-based aryl amides was achieved with primary alkyl bromides in high yields in the presence of an iron catalyst 1,2-bis(diphenylphosphino)ethane (dppe) and PhMgBr in 2-MeTHF.

Full text of DOI:10.1002/anie.201406594

Angewandte
Chemie
DOI: 10.1002/anie.201406594
ortho Alkylation
Hot Paper
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Iron-Catalyzed C(sp ) H Alkylation of Carboxamides with Primary
Electrophiles**
Brendan M. Monks, Erin R. Fruchey, and Silas P. Cook*
Transition-metal-catalyzed cross-coupling reactions have
emerged as workhorse reactions in both medicinal chemistry
and drug manufacturing.[1] Although palladium catalysis
enables the majority of these transformations, concerns over
costs, environmental impact, and human health[2] have
prompted interest in alternative metals. Specifically, cost-
effective catalyst systems that enable difficult couplings to
take place easily are highly valuable. Moreover, with organic
solvents comprising up to 85% of the waste produced from
a drug synthesis,[3] the ability to efficiently carry out cross-
coupling reactions in more environmentally friendly solvents
at high concentration[4] remains an important goal of green
chemistry.[5]
Recently, iron-catalyzed cross-coupling reactions have
gained considerable attention because of the low cost, low
toxicity, and favorable environmental profile of iron.[6] This
metal also offers impressive reactivity and complementary
selectivity relative to the noble metals and nickel.[7] While
iron catalysis works well for a range of traditional nucleo-
phile/electrophile cross-coupling reactions,[8] the direct cou-
often suffer from long reaction times, high temperatures, or
moderate selectivity. As a result of the pioneering work by
Nakamura and co-workers, two classes of electrophiles have
À
been used in iron-catalyzed C H functionalization, allyl
ethers and chloramines.[16] Consequently, many important
electrophiles remain unexplored. Based on our recent expe-
rience with the superior performance of iron in a range of
transition-metal-catalyzed transformations,[17] we reasoned
that low-valent iron might prove superior for the direct
À
coupling of unactivated alkyl bromides with C H groups.
Considering the need to make industrial processes more
environmentally friendly, we explored coupling reactions in
2-methyltetrahydrofuran (2-MeTHF). Here we report the
directed ortho alkylation of 8-aminoquinoline-based aryl
amides 1 to alkylated products 2 using inexpensive and
benign iron salts under mild conditions (Scheme 1c). The
reaction does not require a co-oxidant and proceeds in less
than 10 min.
À
pling of C H bonds with electrophiles remains largely
undeveloped. Consequently, the development of iron-based
À
systems for C H functionalization reactions represents a crit-
ical goal in coupling chemistry.
Currently, few strategies exist for the ortho alkylation of
carboxylate derivatives. The Friedel–Crafts alkylation offers
the potential to use primary halides for aryl alkylations, but
poor regioselectivity, carbocation rearrangements, and the
requirement for electron-rich aromatics significantly limit this
approach (Scheme 1a).[9] Alternatively, ortho lithiation offers
greater selectivity, but the harsh, cryogenic reaction condi-
tions and poor functional-group compatibility restrict its
application (Scheme 1b).[10] Transition-metal-catalyzed,
À
directed C H bond functionalization, however, represents
a more modern approach to the same bond disconnection.[11]
2
À
The currently known C(sp ) H alkylation examples with
À
Scheme 1. Select examples of aryl C H functionalization methods.
unactivated alkyl halides using Pd,[12] Ru,[13] Co,[14] and Ni,[15]
a) Friedel–Crafts reaction;[9a] b) ortho lithiation/alkylation;[10d] c) Fe-cata-
lyzed alkylation (this work).
[*] B. M. Monks,[+] E. R. Fruchey,[+] Prof. S. P. Cook
Department of Chemistry, Indiana University
800 East Kirkwood Avenue, Bloomington, IN 47405 (USA)
E-mail: sicook@indiana.edu
Homepage: http://www.indiana.edu/~cooklab/
[+] These authors contributed equally to this work.
The iron-catalyzed ortho alkylation of aryl amides was
optimized through the systematic evaluation of the pertinent
reaction parameters (see the Supporting Information).
Among several well-known directing groups, few provided
any product at all, and Daugulisꢀ 8-aminoquinoline[18] proved
to be significantly better (68% yield) than either 2-methyl-
aminopyridine[19] (19% yield) or 2-thiomethylaniline[12d] (3%
yield). We optimized the reaction to use inexpensive and
widely available 1,2-bis(diphenylphosphino)ethane (dppe) as
the requisite ligand. Although several Grignard reagents were
[**] We acknowledge start-up funds from Indiana University. We also
gratefully acknowledge the American Chemical Society Petroleum
Research Fund (PRF52233-DNI1) and Eli Lilly & Co. for the Lilly
Grantee Award. We would also like to thank Prof. Gojko Lalic for
insightful discussions on kinetics.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406594.
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Table 1: The C(sp ) H alkylation of carboxamides with n-butyl bromide.
viable in the reaction, phenylmagnesium bromide offered the
highest conversion to product, while minimizing the direct
coupling of Grignard and benzamide substrate.[20] The rate of
Grignard addition was critical to the success of the reaction
(i.e., dropwise additions over less than nine minutes compro-
mised the yield of the reaction). With these observations
taken into account, the reaction is performed by combining
[Fe(acac)3] (10 mol%), dppe (15 mol%), and primary bro-
mide (3 equiv) in reagent-grade 2-MeTHF (1m) at 658C,
followed by the slow addition of Grignard (9 min).
With a robust set of reaction conditions available for the
ortho alkylation of aryl amides, a variety of substrates were
evaluated (Table 1). In contrast to Pd-,[12a,b,d,e] Co-,[14a] and Ni-
catalyzed[15a,b] C H alkylations, the reaction provides exclu-
À
sively the monosubstituted products without any detectable
bis(alkylation) (entries 1–12, 14, and 15, Table 1). Moreover,
the presence of a meta substituent provided very high levels of
regioselectivity, favoring the less-hindered position
(entries 1–7, 14, and 15, Table 1). Remarkably, even
m-fluorobenzamide 7 provided product 27 with more than
20:1 regioselectivity (entry 5, Table 1). As would be expected,
this high monoselectivity precludes the use of ortho-substi-
tuted benzamides (see the Supporting Information), except
for the relatively small o-fluorobenzamide 18 (entry 16,
Table 1). Finally, the reaction proceeds well on gram scale,
providing 24 in 80% yield with 88% conversion (entry 2,
Table 1).
Next, various alkyl bromide derivatives were evaluated in
the reaction (Table 2). Interestingly, the transformation
tolerated sterically hindered electrophiles (entries 4, 5, 9,
and 10, Table 2). Even neopentyl bromide, a generally
recalcitrant electrophile under other conditions,[13,14b] pro-
vided synthetically useful yields of 52 (entry 10, Table 2). One
major concern with the use of phenylmagnesium bromide as
the base and reductant in this chemistry is the potential for
cross-reactivity. Fortunately, the phenylmagnesium bromide
reacts with sufficient rate as to allow the use of esters in the
reaction with no evidence of Grignard addition into the
product ester (entry 8, Table 2). Unfortunately, the use of
À
unactivated primary chlorides and unactivated C O-based
electrophiles, such as tosylates and phosphinates, failed under
these reaction conditions. Primary iodides, however, proved
competent in the transformation, albeit in diminished yield
(entry 14, Table 2). Attempts to employ secondary electro-
philes in this reaction resulted in complex reaction mixtures
containing polyalkylated products.
Interestingly, the use of cyclopropylmethyl bromide
provides homoallyl product 49 in 75% yield, and the addition
of free-radical inhibitor butylhydroxytoluene (BHT) com-
promised the yield somewhat (Scheme 2a). Additionally,
subjecting 6-bromo-1-hexene to the optimized reaction con-
ditions produced a mixture of linear product 56 and cyclized
product 57 in 60% combined yield and 1.0:4.9 ratio of 56:57
(Scheme 2b). The addition of BHT both increased the yield
slightly and caused a detectable reduction in the formation of
cyclized product 57 (Scheme 2b). While consistent with
primary radical formation,[21] these results can also be
explained by organometallic b-carbon elimination (in Sche-
me 2a) and migratory insertion (in Scheme 2b).[22]
An intermolecular competition experiment between 3 and
[D5]-3 provided a kinetic isotope effect (KIE) of 1.5
(Scheme 3a). While higher than other reported isotope
[12f,16a]
À
effects for C H alkylation reactions,
this value is
lower than the expected 1.8 to 3.4 for a primary KIE.[20e,j]
An intramolecular KIE experiment with monodeuterated
[D1]-3 provided a significant primary KIE of 2.9 (Scheme 3b).
The observed difference in the KIE for the inter- and
À
intramolecular reactions indicates that C H cleavage is not
the sole contributor to product selectivity in the intermolec-
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Table 2: The ortho C H functionalization of m-tolylbenzamide 4 with
alkyl bromide derivatives.
Scheme 2. Formation of rearranged products. Q=8-quinolinyl.
Scheme 3. Experiments on a) intermolecular and b) intramolecular
kinetic isotope effects. Q=8-quinolinyl.
observed minimal isotopic selectivity. The significant intra-
À
molecular KIE (kH/kD = 2.9) indicates that C H cleavage is
involved in the product-determining step for the intramolec-
ular case. Together, the small intermolecular KIE and the
large intramolecular KIE imply that substrate coordination is
irreversible and occurs prior to C H cleavage.[23] A plausible
À
explanation would be turnover-limiting binding of the sub-
[a] Yields of isolated products after column chromatography on silica gel.
[b] PhMgBr (4.44 equiv) [Fe(acac)3] (20 mol%), dppe (30 mol%), alkyl
halide (3.5 equiv). [c] Yields based on 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as internal standard. Q=8-quinolinyl.
À
strate to iron, followed by rapid, irreversible C H cleavage.
During the exploration of this reaction, we noticed that
aryl amides with electron-withdrawing groups appeared to
react at slower rates or with lower conversions per time unit.
To examine the electronic effects of the ring more closely, we
performed a series of competition experiments (Table 3). In
these experiments, a methoxy or trifluoromethyl group was
ular competition reaction (Scheme 3a). The small intermo-
lecular KIE (kH/kD = 1.5) suggests that the product-determin-
À
À
ing step(s) occurs prior to C H cleavage, producing the
installed either in para position to the amide or the C H bond
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Table 3: Reactivity effects for electron-donating and electron-withdraw-
ing substituents.
Experimental Section
General procedure for the alkylation reaction: An oven-dried 8 mL
screw thread culture tube (Kimberly-Chase) was purged with N2, then
charged with [Fe(acac)3] (0.1 equiv), dppe (0.15 equiv), and the
benzamide (1.0 equiv). Subsequently the solids were dissolved by the
addition of reagent-grade 2-MeTHF (1m) and alkyl electrophile
(3.0 equiv) under N2. The mixture was then placed in an oil bath at
658C and PhMgBr in 2-MeTHF (1.1 equiv) was added in a single
portion. Following the first addition of Grignard, an additional
portion of PhMgBr in 2-MeTHF (2.35 equiv) was added dropwise to
the reaction at 658C over 9 min. Upon completion of Grignard
addition, the reaction was stirred at 658C for 1 min, brought to RT,
and allowed to cool for an additional 2 min. Subsequently the reaction
was quenched with saturated ammonium chloride (0.02m) and
extracted with DCM (3 ꢁ 0.1m). The combined organic extracts
were dried (MgSO4), filtered, and concentrated to give a residue. The
residue was purified by flash chromatography on silica gel using
hexanes and ethyl acetate in appropriate combination based on the Rf
of the desired product.
[a] Yields based on 1H NMR spectroscopy using 1,3,5-trimethoxyben-
zene as internal standard. Q=8-quinolinyl.
Received: June 25, 2014
Published online: && &&, &&&&
À
Keywords: 8-aminoquinoline · alkyl bromides · C H activation ·
iron
.
to be coupled. Interestingly, an electron-rich group (OMe) in
À
meta position to the amide (para to the C H bond) results in
significantly more alkylation than the CF3 group in the same
position (entry 1, Table 3). Meanwhile, having either
a methoxy or trifluoromethyl group in para position to the
amide has no effect on the product ratio (entry 2, Table 3).
Comparing the methoxy group at either the meta or para
positions shows a slight preference for product formation in
the case where the electron-donating group is in meta position
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À
a reaction profile unique among the reported C H function-
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À
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À
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Communications
ortho Alkylation
B. M. Monks, E. R. Fruchey,
S. P. Cook*
&&&& — &&&&
2
À
Iron-Catalyzed C(sp ) H Alkylation of
Carboxamides with Primary Electrophiles
The direct ortho alkylation of 8-amino-
quinoline-based aryl amides was ach-
ieved with primary alkyl bromides in high
yields in the presence of an iron catalyst,
1,2-bis(diphenylphosphino)ethane
(dppe), and PhMgBr in 2-MeTHF.
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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