Iron-Catalyzed Ortho C-H Methylation of Aromatics Bearing a Simple Carbonyl Group with Methylaluminum and Tridentate Phosphine Ligand

Article abstract of DOI:10.1021/jacs.6b06908

Iron-catalyzed C-H functionalization of aromatics has attracted widespread attention from chemists in recent years, while the requirement of an elaborate directing group on the substrate has so far hampered the use of simple aromatic carbonyl compounds such as benzoic acid and ketones, much reducing its synthetic utility. We describe here a combination of a mildly reactive methylaluminum reagent and a new tridentate phosphine ligand for metal catalysis, 4-(bis(2-(diphenylphosphanyl)phenyl)phosphanyl)-N,N-dimethylaniline (Me₂N-TP), that allows us to convert an ortho C-H bond to a C-CH₃ bond in aromatics and heteroaromatics bearing simple carbonyl groups under mild oxidative conditions. The reaction is powerful enough to methylate all four ortho C-H bonds in benzophenone. The reaction tolerates a variety of functional groups, such as boronic ester, halide, sulfide, heterocycles, and enolizable ketones.

Full text of DOI:10.1021/jacs.6b06908

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Communication
Iron-catalyzed ortho C–H Methylation of Aromatics Bearing a Simple
Carbonyl Group with Methylaluminum and Tridentate Phosphine Ligand
Rui Shang, Laurean Ilies, and Eiichi Nakamura
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b06908 • Publication Date (Web): 03 Aug 2016
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Iron-Catalyzed ortho C–H Methylation of Aromatics Bearing a
Simple Carbonyl Group with Methylaluminum and Tridentate
Phosphine Ligand
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Rui Shang, Laurean Ilies,* and Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, 7ꢀ3ꢀ1 Hongo, Bunkyoꢀku, Tokyo 113ꢀ0033
Supporting Information Placeholder
two equivalents of AlMe3 used, one equivalent was consumed for
acid deprotonation. Ketones also serve as good substrates, as
ABSTRACT: Ironꢀcatalyzed C–H functionalization of aromatics
has attracted widespread attention from chemists in recent years,
illustrated in Figure 1c for a gramꢀscale exclusive 5ꢀmethylation
while the requirement of an elaborate directing group on the
of 7,8ꢀbenzoflavone—a potent aromatase inhibitor.9
substrate has so far hampered the use of simple aromatic carbonyl
compounds such as benzoic acid and ketones, much reducing its
synthetic utility. We describe here a combination of a mildly
reactive methylaluminum reagent and a new tridentate phosphine
ligand
for
metal
catalysis,
4ꢀ(bis(2ꢀ
(diphenylphosphanyl)phenyl)phosphanyl)ꢀN,Nꢀdimethylaniline
(Me2NꢀTP), that allows us to convert an ortho C–H bond to a C–
CH3 bond in aromatics and heteroaromatics bearing simple
carbonyl groups under mild oxidative conditions. The reaction is
powerful enough to methylate all four ortho C–H bonds in
benzophenone. The reaction tolerates a variety of functional
groups, such as boronic ester, halide, sulfide, heterocycles and
enolizable ketones.
Two decades ago Murai demonstrated the feasibility of C–C
bond formation via catalytic C–H activation of aryl ketones as
reaction substrates.1 However, the focus of subsequent studies has
diverged from simple carbonyl groups to strongly coordinating
nitrogen directing groups,2,3,4 such as an amide of 8ꢀ
aminoquinoline (8Q, Figure 1a).3aꢀd,3h,4bꢀd The popularity of such
directing groups has originated partly from the difficulty of direct
functionalization of free carboxylic acids,2b and partly from an
assumption that strong metal coordination to the substrate
increases the efficacy of the catalytic reaction, although this idea
has frequently been challenged.5 In the iron catalysis using an 8Q
amide substrate,4bꢀd,6 the substrate acts as a tridentate ligand while
the remaining three coordination sites are occupied by a bidentate
ligand (e.g., dppen) and an incoming organic group (INTꢀA,
Figure 1a). We therefore conjectured that a strongly binding
tridentate phosphine7 may eliminate the need for the use of the 8Q
ligand, allowing us to utilize simple aromatic carbonyl
compounds (INTꢀB, Figure 1b). We report here an ironꢀcatalyzed
ortho C–H methylation of a wide variety of aromatics and
Figure 1. Ironꢀcatalyzed C–H functionalization: the contrast
between an 8Q directing group vs. simple carbonyl groups. (a)
Previous work: C–H activation of an 8Q amide via INTꢀA. (b)
This work: gramꢀscale C–H methylation of a boronꢀsubstituted 2ꢀ
naphthoic acid 1. (c) This work: gramꢀscale C–H methylation of
7,8ꢀbenzoflavone 3.
This catalytic system does not need any extraneous directing
group that has often impaired the simplicity of the C–H
functionalization strategy and limited the applicability. The
reaction conditions are mildly oxidative and Lewis acidic, and the
reaction tolerates functional groups sensitive to base and reductant,
such as boronic ester (Figure 1b), halide, sulfide, heterocycles and
enolizable ketones, enabling lateꢀstage structural modification of
molecules of biological and materials interest by the use of a
nontoxic metal.10 Inexpensive AlMe3 is the methyl group source
of choice, while the easyꢀtoꢀhandle bisꢀ(trimethylaluminum)ꢀ1,4ꢀ
diazabicyclo[2.2.2]octane adduct (DABALꢀMe3; Table 1, 11) can
be used at the expense of lower reactivity.
heteroaromatics bearing
a
simple carbonyl group—a
transformation found to be useful for probing the profound methyl
effects in pharmacology8 through lateꢀstage synthetic elaboration.
This transformation was enabled by a new tridentate phosphine
ligand
for
metal
catalysis,
4ꢀ(bis(2ꢀ
(diphenylphosphanyl)phenyl)phosphanyl)ꢀN,Nꢀdimethylaniline
(Me2NꢀTP), combined with a mildly reactive and readily available
AlMe3 as the methyl donor and 2,3ꢀdichlorobutane (2,3ꢀDCB) as
the oxidant.
Figure 1b illustrates a gramꢀscale monoꢀorthoꢀmethylation
of 2ꢀnaphthoic acid without affecting the boronate moiety. Of the
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was modestly or poorly effective for 8Q amide derivatives,
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3
4
suggesting that the ligand and the directing group compete for the
coordination sites on the metal center (see supplementary
information (SI)). Bipyridine ligands that are effective in some
iron catalysis were ineffective (bottom row of Figure 2a).13
The reaction is also highly sensitive to the organometallic
sources of the methyl group (Figure 2c). Trimethylaluminum was
the most effective among all of the reagents examined, while
dimethylaluminum chloride is modestly reactive. Triethylꢀ and
triphenylaluminum produced no desired product. Organozinc and
ꢀmagnesium reagents failed entirely, although they serve as good
donors for substrates bearing a strongly coordinating directing
group.4d,6b We ascribe the unique efficacy of the methyl aluminum
reagent to its weak reducing ability and facile transmetallation to
iron, undisturbed by βꢀH elimination that readily proceeds for
higher alkyl groups (Figure 1d).
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We illustrate the synthetic utility of the new catalytic system
for ortho-functionalization of aromatic and heteroaromatic
carboxylic acids and derivatives in Table 1. The reaction
produced only the desired methylated products, and the recovery
of the starting material accounted largely for the rest of the
material. Being sensitive to steric hindrance, orthoꢀmethylation of
metaꢀsubstituted benzoic acids and 2ꢀnaphthoic acids occurred
only on the less hindered site in high yield (7–11). The reaction of
11 with DABALꢀMe314 (1 equiv) afforded the desired methylation
product in 77% yield. However, without steric hindrance, a
second ortho-methylation quickly followed the first methylation
to give a dimethylation product (15, 16). Even when a less than
stoichiometric amount of AlMe3 was used, the reaction still
afforded a mixture of monoꢀ and dimethylated products with
recovery of the starting acid, suggesting therefore that a methylꢀ
groupꢀbearing catalytic intermediate stays on the monomethylated
molecule and undergoes the second methylation before it migrates
to another molecule.5c The secondary 4ꢀacetamide group on a
benzoic acid (17) did not activate the nearby C–H bond, and the
reaction proceeded selectively at the C–H nearby the carboxylate
group. The tertiary acetamide moiety in N-acetylindole promoted
methylation of the nearby C2–H bond (22).
aThe reaction was performed on a 0.2 mmol scale. Recovery of the starting
b
material is shown in parentheses. The yield was determined by 1H NMR
analysis using 1,1,2,2ꢀtetrachloroethane as an internal standard.
Figure 2. Effects of ligands and organometallic reagents on
methylation of m-toluic acid. (a) Ligand effects on yield. (b) Xꢀ
ray structure of NMe2-TP. Thermal ellipsoids correspond to 30%
probability. Hydrogen atoms are omitted for clarity. (c)
Organometallic reagent effects on yield.
We describe the reaction conditions for the methylation of
6ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)ꢀ2ꢀnaphthoic acid
(1), illustrating retention of the boronate moiety—a commonly
used donor of aromatic groups under palladiumꢀcatalyzed C–H
functionalization.11 A toluene solution of AlMe3 (2.0 equiv) was
added dropwise to a mixture of 1 (1.19 g, 4.0 mmol), Fe(acac)3
(5.0 mol %) and Me2NꢀTP (5.0 mol %) in 10:1 anhydrous
THF/1,2ꢀdimethoxyethane (DME) under nitrogen at room
temperature. After methane formation subsided, 2,3ꢀDCB (3.0
equiv) was added and the mixture was stirred at 70 °C for 24 h to
achieve full conversion of 1 without any byꢀproducts detected by
1H NMR. Aqueous acid workup afforded 1 in 89% isolated yield
after recrystallization. DME is beneficial for solubilization of
aluminum carboxylate intermediates. Catalyst loading can be
reduced to 3 mol% at the expense of reaction rate. 2,3ꢀDCB is the
reagent of choice for its efficacy and low cost.
We found a marked correlation between the ligand structure
and the reaction outcome, as summarized in Figure 2a: effective
ligands need at least three phosphine groups, among which the
central one bears a phenyl group. Of these, Me2NꢀTP was found
to be the best. The beneficial effect of the Me2Nꢀ group here (cf.
TP) was also found in an ironꢀcatalyzed C–H activation reported
by us previously.4b,12 As seen in a crystal structure of Me2NꢀTP
(Figure 2b) and of a recently reported Fe(II)/TP complex,7 the
three phosphine groups are so oriented as to be suitable for
tridentate coordination. Interestingly, the reaction with Me2NꢀTP
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newly introduced orthoꢀmethyl groups hinders the necessary
Table 1. Methylation of Aromatic Carboxylic Acids, Esters
and Amidesa
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rotation of the carbonyl group and prevents the second C–H
activation. We did not detect any C(sp3)–H methylation on the
tertꢀbutyl group. A KIE experiment for parallel reactions using
this substrate gave a kH/kD value of 1.23, suggesting that either the
C–H cleavage step occurs via a transition state of low symmetry,
or that it is not directly involved in the turnoverꢀlimiting step. A
sterically unencumbered methyl ketone gave 32 in low yield
because of a carbonyl addition side reaction to give the
corresponding alcohol.
9
Benzophenone, where four ortho C–H bonds are available,
underwent remarkably smooth tetramethylation in 63% yield (33).
A contrasting result shown in eq. 1 for AlEt3 is remarkable—
occurrence of carbonyl reduction, addition and dimerization
products suggestive of the concurrent occurrence of catalytic
cycles including reduced iron species and a ketyl radical, when
the desired C–H activation is a slow reaction.
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Flavone (34) and αꢀnaphthoflavone (4) underwent exclusive
methylation at the 5ꢀposition, which was confirmed by the singleꢀ
crystal structure (see SI). Xanthone and thioxanthone afforded
dimethylated products 36 and 37 exclusively, and so did
dibenzosuberenone (35). On the other hand, fluorenone (38) gave
none of the desired methylation product, probably because the
large bond angle of CH–C–CO prevented the formation of a
ferracycle intermediate (cf. the small atomic radius of iron).4b The
reactions of the diaryl ketones 33, 35–38 underwent full
conversion of the starting material, but were accompanied by
dimerization products (cf. eq. 1).
Table 2. Methylation of Aryl Ketonesa
aThe methyl groups in bold indicate those introduced by the reaction.
The reaction was performed on a 0.8 mmol scale using Fe(acac)3/NMe2ꢀ
TP (5–10 mol%) and AlMe3 (200 mol%) following the procedure
described in the text for a gramꢀscale experiment. Yields of isolated
b
products are shown. See the SI for details. DABALꢀMe3 was used as the
methyl source. cIsolated as methyl ester by treatment with
SOCl2/Et3N/MeOH. d1H NMR yield using 1,1,2,2ꢀtetrachloroethane as an
internal standard. eIsolated as the methyl ester by treating with
TMSCH2N2/Et2O/MeOH. fYield of 2ꢀmethyl indole.
Functional group tolerance is noteworthy, as already pointed
out in Figure 1b (boronate group). The sulfide group (10) as well
as a remote bromide (9, 13) and ortho-fluoride (18) are tolerated,
while ortho-chloride was substituted by a methyl group (19).
Heterocycles in 14, 20, 21 and an indoleamine 2,3ꢀdioxygenaseꢀ1
inhibitor15 26 as well as sulfide in 10 did not disturb the catalytic
cycle, showing that our iron catalytic system is resistant to the
heterocycleꢀ and sulfurꢀpoisoning effects.16 Ester and amide
groups also act as good directing groups (23, 24 and 25).
aThe methyl groups in bold indicate those introduced by the reaction.
The reaction was performed on a 0.8 mmol scale using Fe(acac)3/NMe2ꢀ
TP (5 mol%) and AlMe3 (150 mol%) following the procedure described in
the text for a gramꢀscale experiment. Yields of isolated products are
Alkyl aryl ketones are very good substrates (27–30, Table 2
top two rows; full conversions of reactants were observed in most
of the cases), and underwent ortho-methylation without any
carbonyl addition side reaction (except for a methyl ketone, 32).
Exclusive monomethylation of tertꢀbutyl phenyl ketone (31)
suggests that steric interaction between the tertꢀbutyl and the
b
shown. See the SI for details. Fe(acac)3/NMe2ꢀTP (10 mol%) and AlMe3
(110 mol%) were used. cFe(acac)3/NMe2ꢀTP (10 mol%), AlMe3 (300
mol%) and 2,3ꢀDCB (600 mol%) were used.
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Res. 2015, 48, 1053–1064. (c) Rouquet, G.; Chatani, N. Angew. Chem., Int.
Ed. 2013, 52, 11726–11743.
1
(3) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154–13155. (b) Truong, T.; Klimovica, K.; Daugulis, O. J.
Am. Chem. Soc. 2013, 13, 9342–9345. (c) Shabashov, D.; Daugulis, O. J.
Am. Chem. Soc. 2010, 132, 3965–3972. (d) Zhang, S. Y.; Li, Q.; He, G.;
Nack, W. A.; Chen G. J. Am. Chem. Soc. 2015, 137, 531–539. (e) Inoue,
S.; Shiota, H.; Fukumoto Y.; Chatani N. J. Am. Chem. Soc. 2009, 131,
6898–6899. (f) Shiota, H.; Ano, Y.; Aihara, Y.; Fukumoto, Y.; Chatani, N.
J. Am. Chem. Soc. 2011, 133, 14952–14955. (g) Hasegawa, N.; Charra, V.;
Inoue, S.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc. 2011, 133, 8070–
8073. (h) Aihara Y.; Chatani N. J. Am. Chem. Soc. 2013, 135, 5308–5311.
(4) (a) Norinder, J.; Matsumoto, A.; Yoshikai N.; Nakamura E. J. Am.
Chem. Soc. 2008, 130, 5858–5859. (b) Shang, R.; Ilies, L.; Matsumoto, A.;
Nakamura, E. J. Am. Chem. Soc. 2013, 135, 6030–6032. (c) Asako, S.;
Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2013, 135, 17755–17757. (d)
Shang, R.; Ilies, L.; Asako, S.; Nakamura, E. J. Am. Chem. Soc. 2014, 136,
14349–14352. (e) Graczyk, K.; Haven, T.; Ackermann, L. Chem. Eur. J.
2015, 21, 8812–8815.
(5) (a) Engle, K. M.; Mei, T.ꢀS.; Wasa, M.; Yu, J.ꢀQ. Acc. Chem. Res.
2012, 45, 788–802. (b) Musaev, D. G.; Froese, R. D. J.; Svensson, M.;
Morokuma, K. J. Am. Chem. Soc. 1997, 119, 367–374. (c) Yoshikai, N.;
Matsuda, H.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 15258–15259.
(d) Deng, L.; Woo, T. K.; Cavallo, L.; Margl, P. M.; Ziegler, T. J. Am.
Chem. Soc. 1997, 119, 6177–6186. (e) Li, G.; Wan, L.; Zhang, G.; Leow,
D.; Spangler, J.; Yu, J.ꢀQ. J. Am. Chem. Soc. 2015, 137, 4391–4397.
(6) (a) Shang, R.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2015, 137,
7660–7663. (b) Ilies, L.; Ichikawa, S.; Asako, S.; Matsubara, T.;
Nakamura, E. Adv. Synth. Catal. 2015, 357, 2175ꢀ2179. (c) Sun, Y.; Tang,
H.; Chen, K.; Hu, L.; Yao, J.; Shaik, S.; Chen, H. J. Am. Chem. Soc. 2016,
138, 3715–3730.
(7) Li, P.; Bruin, B.; Reek, J. N. H.; Dzik, W. I. Organometallics 2015, 34,
5009−5014.
(8) (a) Barreiro, E. J.; Kümmerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011,
111, 5215–5246. (b) Schçnherr, H.; Cernak, T. Angew. Chem., Int. Ed.
2013, 52, 12256–12267.
(9) Kellis Jr, J.ꢀT.; Vickery, L.ꢀE. Science 1984, 225, 1032ꢀ1034.
(10) (a) Nakamura, E.; Sato, K. Nat. Mater. 2011, 10, 158–161. (b) Yu, R.
P.; Hesk, D.; Rivera, N.; Pelczer I; Chirik, P. J. Nature 2016, 529, 195–
199. (c) Chen, M. S.; White, M. C. Science 2010, 327, 566ꢀ571. (d)
Sharma, A.; Hartwig, J. F. Nature 2015, 517, 600–604.
(11) (a) 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, 3510–3511. (b)
Rosen, B. R.; Simke, L. R.; ThuyꢀBoun, P. S.; Dixon, D. D.; Yu, J.ꢀQ.;
Baran, P. S. Angew. Chem., Int. Ed. 2013, 52, 7317–7320. (c) Chan, K. S.
L.; Wasa, M.; Chu, L.; Laforteza, B. N.; Miura, M.; Yu, J.ꢀQ. Nat. Chem.
2014, 6, 146–150.
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In summary, a new tridentate phosphine ligand, NMe2-TP,
was found to be very effective for ironꢀcatalyzed C–H
methylation of simple aromatic carbonyl compounds without
recourse to additional directing groups, which enhances the utility
of the C–H activation synthetic strategy. Wide substrate generality,
functional group tolerance and resistance to catalytic poisons are
additional attractive features of the new catalytic system, together
with the economical and environmental merits of iron catalysis.10
Although an iron(II) complex of TP was recently reported in the
literature,7 tridentate phosphines such as TP and NMe2-TP have
not, to our knowledge, been utilized for metal catalysis, and we
expect that their potential in catalysis is worthy of careful
investigations in the future.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and physical properties of the
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*laur@chem.s.uꢀtokyo.ac.jp; *nakamura@chem.s.uꢀtokyo.ac.jp.
ACKNOWLEDGMENTS
We thank MEXT for financial support (GrantꢀinꢀAid for Young
Scientists (A) No. 26708011 and JSPS KAKENHI Grant Number
JP16H01005 in Precisely Designed Catalysts with Customized
Scaffolding to L.I.). This work was supported by CREST, JST.
R.S. thanks the Japan Society for the Promotion of Science for a
Research Fellowship for Young Scientists (26ꢀ04342). We thank
Yi Zhou for synthesis of substrate 1, and assistance in synthesis of
NMe2-TP, Dr. Kazutaka Shoyama for the single crystal Xꢀray
analysis, and Prof. Yao Fu of USTC for kindly providing the
starting material for the synthesis of compound 26.
(12) Matsubara, T.; Asako, S.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc.
2014, 136, 646–649.
(13) (a) Asako, S.; Norinder, J.; Ilies, L.; Yoshikai, N.; Nakamura, E. Adv.
Synth. Catal. 2014, 356, 1481–1485. (b) Matsumoto, A.; Ilies, L.;
Nakamura, E. J. Am. Chem. Soc. 2011, 133, 6557–6559.
(14) Biswas, K.; Prieto, O.; Goldsmith, P. J.; Woodward, S. Angew. Chem.,
Int. Ed. 2005, 44, 2232–2234.
(15) Röhrig, U. F.; Majjigapu, S. R.; Vogel, P.; Zoete, V.; Michielin, O. J.
Med. Chem. 2015, 58, 9421−9437.
REFERENCES
(1) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529–531. (b) Kakiuchi, F.;
Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N.; Murai S.
Bull. Chem. Soc. Jpn. 1995, 68, 62–83. (c) Huang, Z.; Lim, H. N.; Mo, F.;
Young, M. C.; Dong, G. Chem. Soc. Rev. 2015, 44, 7764–7786.
(16) Liu, Y.ꢀJ.; Xu, H.; Kong, W.ꢀJ.; Shang, M.; Dai, H.ꢀX.; Yu, J.ꢀQ.
Nature 2014, 515, 389–393.
(2) Selected reviews, see: (a) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147–1169. (b) Daugulis, O.; Roane, J.; Tran, L. D. Acc. Chem.
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