β-Arylation of carboxamides via iron-catalyzed C(sp3)-H bond activation

Article abstract of DOI:10.1021/ja402806f

A 2,2-disubstituted propionamide bearing an 8-aminoquinolinyl group as the amide moiety can be arylated at the β-methyl position with an organozinc reagent in the presence of an organic oxidant, a catalytic amount of an iron salt, and a biphosphine ligand at 50 C. Various features of selectivity and reactivity suggest the formation of an organometallic intermediate via rate-determining C-H bond cleavage rather than a free-radical-type reaction pathway.

Full text of DOI:10.1021/ja402806f

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Communication
#-Arylation of Carboxamides via Iron-Catalyzed C(sp3)-H Bond Activation
Rui Shang, Laurean Ilies, Arimasa Matsumoto, and Eiichi Nakamura
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja402806f • Publication Date (Web): 12 Apr 2013
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β-Arylation of Carboxamides via Iron-Catalyzed C(sp3)–H Bond
Activation
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Rui Shang, Laurean Ilies, Arimasa Matsumoto,† and Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
†Present Address: Department of Applied Chemistry, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-
8601
Supporting Information Placeholder
amount of the zinc reagent, the catalyst, and longer reaction time
did not result in higher conversion. Addition of a catalytic amount
of water or the use of old Grignard reagent significantly lowered
the reaction yield, suggesting that the presence of alkoxide
impedes the reaction.
ABSTRACT: A 2,2-disubstituted propionamide bearing an 8-
aminoquinolinyl group as the amide moiety can be arylated at the
β-methyl position with an organozinc reagent in the presence of
an organic oxidant, a catalytic amount of an iron salt, and a
biphosphine ligand at 50 °C. Various features of selectivity and
Under similar conditions, the reaction of phenylmagnesium
bromide gave 3 in 80% yield together with the recovered 1 (14%)
and biaryl (15% based on PhMgBr) because of iron-mediated
homocoupling.14 Interestingly, most of the biaryl formed after the
product formation stopped. We found no products either from
arylation at the benzylic position7a of 1, from further reaction of
the product 2 or 3, or from arylation of the carboxamide
nitrogen.15
reactivity suggest the formation of an organometallic intermediate
via rate-determining C–H bond cleavage rather than a free-
radical-type reaction pathway.
Because of the potential economic and environmental merits1
compared with precious metals, iron catalysis2 for C(sp2)–H bond
activation3 to create a C–C bond has recently seen tremendous
development,4 and iron catalysis for C(sp3)–H activation5 , 6 is
expanding as well.7,8 Except for a few examples, these reactions
may be categorized as remote functionalization of the C–H bond,
where an organometallic intermediate is stabilized by chelation to
the nearby directing group (e.g., chelated metal homoenolate A in
Figure 1a). Having been interested in homoenolate chemistry for
some time,9 we conjectured that A in Figure 1a may serve as a
viable intermediate for the conversion of an aliphatic acid
derivative such as carboxamide 1 to a β-functionalized product (2
or 3). We report here an iron-catalyzed arylation of the β-methyl
position of a 2,2-disubstituted propionamide bearing an 8-
aminoquinolinyl group (NH-Q)6a,10 as the amide moiety in the
presence of an organic oxidant11 under mild thermal conditions.
The reaction has less of the radical character previously observed
in iron catalysis7 and a more organometallic character,12 because
the reaction is sensitive to the choice of the ligand and shows
complete preference toward C–H bond activation on the methyl
group over the benzyl group of 1 (Figure 1a).
Ar2Zn•MgBr2 (3 equiv)
ArMgBr (1 equiv)
Fe(acac)3 (10 mol %)
dppbz (10 mol %)
a
O
O
Ph
N
H
Ph
N
H
N
N
Cl
(2 equiv)
H
Ar
Cl
THF, 50 °C
Ar = p-MeOC6H4 2: 85% (1.40 g)
Ar = Ph 3: 80%; 1: 14%
1
O–
Ph
O
N
N
[Fe]
Ar
A
b
O
O
O
N
N
N
N
H
H
H
N
N
N
(90% recovery)
(87% recovery)
(99% recovery)
(99% recovery)
c
PPh2
Fe
PPh2
A
typical procedure optimized after considerable
Ph2P
dppbz
3: 80%; 1: 14%
PPh2 Ph2P
dppe
3: 9%; 1: 87%
PPh2
Ph2P
PPh2
dppp
dppf
experimentation is described first (Figure 1a). The NH-Q amide 1
(1.22 g, 4 mmol) was added to a THF solution of freshly prepared
p-anisylmagnesium (Ar) bromide (7 equiv), ZnBr2•TMEDA (3
equiv), then a solution of Fe(acac)3 (10 mol %) and 1,2-
bis(diphenylphosphino)benzene (dppbz, 10 mol %) in THF and
1,2-dichloroisobutane13 (DCIB, 2 equiv) were added, and the
mixture was heated at 50 °C for 36 h. Aqueous work-up followed
by column chromatography gave 1.40 g of arylated product 2
(85%, Figure 1a) together with the recovery of 1. Out of the 7
equiv of ArMgBr, 6 equiv form 3 equiv of Ar2Zn and 1 equiv
deprotonates the amide proton. A small amount of the Ar group
must have been consumed upon reaction with Fe(acac)3. The use
of a smaller amount of organometallic reagent resulted in a lower
yield (45% with 2 equiv of organozinc reagent) and slower
reaction. Omission of the zinc salt resulted in no formation of the
desired product. For reasons yet to be probed, increasing the
3: 0%; 1: 99%
3: 0%; 1: 98%
PPh2
PPh2
O
PPh2
Xantphos
3: 0%; 1: 95%
PPh2
2 PPh3
N
N
dtbpy
rac-BINAP
3: 0%; 1: 99%
3: 0%; 1: 98%
3: 0%; 1: 95%
Figure 1. Iron-catalyzed arylation of the β-methyl group of 2,2-
disubstituted propionamide. (a) Representative example of
conversion of 1 to 2 or 3 and a possible intermediate A. (b)
Representative unreactive substrates under the conditions shown
in (a). The recovery of the starting material is shown in
parentheses. (c) Representative ligands examined as an illustration
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of the unique effectiveness of dppbz. The yield of phenylated
product 3 and the recovery of 1 are shown.
reagents (entries 12, 13, and 18). A 2-naphthylzinc reagent also
gave a satisfactory yield (entry 19). Alkyl- and alkenylzinc
reagents did not react under these reaction conditions.
1
2
3
4
5
6
7
8
9
Table 1. Iron-Catalyzed Arylation of 2,2-Disubstituted
Propionamide with Organozinc Reagenta
The NH-Q directing group and the dppbz ligand were found to
be uniquely effective for the reaction (Figure 1). For instance, a 2-
methyl group on the quinoline entirely stops the reaction, and a 2-
picoline analogue and a simple N-phenylcarboxamide did not take
part in the reaction at all (Figure 1b). The N-methylated derivative
of 4 did not react at all (Figure 1b). The importance of the ligand
is illustrated in Figure 1c. The reaction did not proceed at all in
the absence of a ligand. A bidentate ligand, dppe, which is similar
to dppbz except for its slightly larger bite angle and a more
flexible backbone gave the product in 9% yield. Other bidentate
phosphine ligands with larger bite angles and various degrees of
flexibility were entirely inefficient. Bipyridine-type ligands that
are the ligand of choice for iron-catalyzed C(sp2)–H bond
activation13 were ineffective, and monophosphine ligands such as
PPh3 were also ineffective. Such high sensitivity to the ligand
structure is less consistent with either a pure radical mechanism or
sole inclusion of organozinc species than with a chelated iron
intermediate16,17 such as A.
entry
substrateb
O
productb
O
yield (%)c
1
2
3
4
79
74
71
73
2
X = H
X = F
X = Cl
X = Br
NH-Q
NH-Q
X
p-MeOC6H4
X
H
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O
O
5
6
7
8
MeO
MeO
71
83
NH-Q
NH-Q
NH-Q
H
p-MeOC6H4
O
O
NH-Q
p-MeOC6H4
H
O
H
O
O
As we found for the structures of the directing group and the
ligand, the reaction is sensitive also to the structure of the
substrate, as summarized in Table 1, at the bottom of which
unreactive substrates are listed. Carboxamides possessing 3-
phenyl and 3-naphthyl-2,2-dimethylpropionamide reacted
exclusively on one of the two methyl groups (entries 1–6) with
retention of fluorine, chlorine, and bromine groups. Pivalamide 4
(entry 7) gave a mixture of monoarylated and diarylated products
(1 and 3), and no further arylation of 3 occurred. Replacement of
one methyl group in the pivalamide with an ethyl group (entry 8)
resulted in selective monoarylation, but replacement with a phenyl
28+20d
(33+31)e
NH-Q
NH-Q Ph
NH-Q
4
1
3
Ph
Ph
O
O
NH-Q
53
NH-Q
O
p-MeOC6H4
H
O
9
NH-Q
75
69
NH-Q
p-MeOC6H4
H
5
group shut off the reaction (bottom of Table 1).
cyclohexanecarboxamide (5, entry 9)
A
and
O
O
10
NH-Q
cyclopentanecarboxamide (6, entry 10) reacted well, whereas the
corresponding cyclobutane- and cyclopropanecarboxamide (7 and
8) did not give the desired product at all. One key feature that one
might consider to be crucial for the efficient C–H activation may
be the <CH3–C–C(=O) bond angle (θ) shown below (Figure 2):
this angle is much wider for the unreactive substrates 7 and 8 than
for 5 and 6, making the distance between the β-H and amide
nitrogen (l) longer, and thus the formation of a chelate
intermediate A less feasible. However, a smaller θ angle may not
be sufficient, because most of the reactive substrates such as 1, 4,
and unreactive substrates including 2, 3, and propionamide
(bottom) have a θ angle of ca. 107–109° (data not shown). We
note that cyclopropanecarboxamide 8 was completely recovered
NH-Q
6
H
p-MeOC6H4
O
O
11
12
13
14
15
16
17
18
19
80
78
85
78
0
3
Ar = Ph
Ar = p-Tol
Ph
NH-Q
Ph
NH-Q
Ar
Ar = p-t-BuC6H4
Ar = m-Tol
H
Ar = o-Tol
56
51
Ar = p-FC6H4
Ar = m-FC6H4
Ar = p-Me2NC6H4
Ar = 2-Naphthyl
80
69
O
O
O
H
O
H
O
and
Cyclohexanecarboxamides not possessing the α-methyl group did
a
ring-opened product was not produced at all.
NH-Q
NH-Q Ph
NH-Q
NH-Q
NH-Q
not give the desired product, as shown at the bottom of the table.
H
H
H
H
7
8
O-
aThe reaction was performed under the conditions in Figure 1a
using 0.5 mmol of substrate. Unreactive substrates (<5% yield)
are shown at the bottom. bQ = 8-quinolinyl. cDetermined by
! = 106.13°; l = 1.905 Å
! = 108.03°; l = 1.956 Å
! = 111.00°; l = 2.163 Å
! = 116.12°; l = 2.187 Å
5: (H2C)3
6: (H2C)2
7: (H2C)1
8: (H2C)0
(H2C)n
Q
N
!
l
d
H
isolation. Determined by GC in the presence of tridecane as an
internal standard. e20 mol % of catalyst was used.
Figure 2. Bond angle and atomic distance for
cycloalkylcarboxamides 5–8. MMFF-optimized with H–C–C–
C=N fixed in the plane.
Kinetic isotope effect (KIE) experiments indicated that the
cleavage of the C–H bond is the rate-determining step of the
reaction. As depicted in Scheme 1, competition experiments
between the deuterated substrate 5-D and the protio 5 showed a
primary KIE of 2.4 when the reactions were performed in parallel,
and an intermolecular KIE of 4.0 (at 19% conversion). The
Para-substituted arylzinc reagents (entries 12, 13, 16, and 18)
reacted well, and meta-substitution (entries 14 and 17) resulted in
satisfactory yields, while ortho-substitution totally shut off the
reaction (entry 15). Electron-deficient organometallic reagents
(entries 16 and 17) tend to give lower yield than electron-rich
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organometallic reagent takes up the β-hydrogen, as demonstrated
by partial deuterium incorporation into the recovered
1
2
3
4
5
6
7
8
9
organometallic reagent for the reaction of 5-D (SI). Deuterium
scrambling on the product 9-D or on the recovered 5-D was not
observed.
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Scheme 1. KIE Experiments
O
O
Ar2Zn (3 equiv)
NH-Q
ArMgBr (1 equiv)
Fe(acac)3 (10 mol %)
dppbz (10 mol %)
NH-Q + 5-D
>99% d
CD3
D2C
Ar
(3) Dyker, G. Ed.; Handbook of C–H Transformations; Wiley-VCH:
Weinheim, Germany, 2005.
5-D (>99% d)
9-D (>99% d)
10
11
12
13
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DCIB (2 equiv)
THF, 50 °C
O
O
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NH-Q
NH-Q
Ar = p-MeOC6H4
H2C
CH3
Ar
5
9
KIE determined from two parallel reactions: 2.4 ± 0.3 (at 50.0 ± 1.5) °C
KIE determined from an intermolecular competition: 4.0 (19% conversion)
In conclusion, we have found the reaction conditions for
replacing a C(sp3)–H bond with a new C–aryl bond at the β-
position of
a
2,2-disubstituted carboxamide, where the
quinolineamide group acts as a uniquely effective directing group
for iron. The overwhelmingly higher reactivity of a methyl group
over a benzylic group excludes a radical mechanism, and the high
sensitivity of the yield to the structure of the substrate and the
ligand suggests involvement of organoiron intermediates in some
crucial steps. Further understanding of the reaction parameters in
the present reaction will uncover guidelines for designing efficient
iron catalysts.
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
*nakamura@chem.s.u-tokyo.ac.jp
ACKNOWLEDGMENT
This paper is dedicated to Prof. Irina Petrovna Beletskaya for her
contribution to metal-catalyzed reactions. We thank MEXT for
financial support (KAKENHI Specially Promoted Research No.
22000008 to E.N.; Grant-in-Aid for Young Scientists (B) No.
23750100 and Grant-in-Aid for Scientific Research on Innovative
Areas No. 25105711 to L.I.) and to the Chinese Scholarship
Council for a scholarship for R.S. to visit Tokyo from the
University of Science & Technology of China. A.M. thanks the
Japan Society for the Promotion of Science for Young Scientists
for a Research Fellowship (No. 21-8684).
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REFERENCES
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1
2
3
4
5
cat. Fe(acac)3/
dppbz
N
N
Ar2Zn•MgBr2
+
O
NH
O
NH
Ar
1.40 g (85%)
ArMgBr
Cl
Cl
THF, 50 °C
Ph
H
Ph
6
7
8
1.22 g
Ar = p-MeOC6H4
9
10
11
12
13
14
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