Remote amide-directed palladium-catalyzed benzylic C-H amination with N-fluorobenzenesulfonimide

Article abstract of DOI:10.1039/c0cc02175j

An unprecedented remote amide-directed palladium-catalyzed intermolecular highly selective benzylic C-H amination with N-fluorobenzenesulfonimide is developed, which represents the first direct benzylic C-H amination with a non-nitrene nitrogen source. This methodology provides a novel approach to circumvent the common ortho aromatic C-H selectivity in directed palladium catalyzed C-H functionalization.

Full text of DOI:10.1039/c0cc02175j

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Remote amide-directed palladium-catalyzed benzylic C–H amination
with N-fluorobenzenesulfonimidew
Tao Xiong, Yan Li, Yunhe Lv and Qian Zhang*
Received 29th June 2010, Accepted 26th July 2010
DOI: 10.1039/c0cc02175j
An unprecedented remote amide-directed palladium-catalyzed
intermolecular highly selective benzylic C–H amination with
N-fluorobenzenesulfonimide is developed, which represents the
first direct benzylic C–H amination with a non-nitrene nitrogen
source. This methodology provides a novel approach to circumvent
the common ortho aromatic C–H selectivity in directed palladium
catalyzed C–H functionalization.
Initial studies focused on the amination reaction of N-p-
tolylpivalamide (1a) with NFSI. With Pd(OAc)2 (0.1 equiv.) as
catalyst, the reaction of 1a (0.4 mmol) and NFSI (2.5 equiv.)
was conducted at 90 1C in 1,2-dichloroethane (DCE) for 1.5 h,
surprisingly, instead of the usually formation of C(sp2)–H
amination product (Scheme 1A), a benzyl C(sp3)–H amination
product 2a was generated in 73% yield (Table 1, entry 1) and
17% N-(phenylsulfonyl)benzenesulfonamide was obtained.zy
However, when NBS was used instead of NFSI, the normal
C(sp2)–H bromination2 product N-(2-bromo-4-methylphenyl)-
pivalamide was obtained in 92% yield. When additive KF
(4.0 equiv.) was added, 2a was obtained in 86% yield with a
relatively longer reaction time (entry 2). No reaction occurred
in the absence of palladium catalyst (entry 3). NaHCO3 was as
effective as KF (entry 4). With solvents such as acetonitrile,
DMA, DMF and DMSO, no desired 2a was obtained. Other
solvents such as 1,4-dioxane, C6H5Cl and mesitylene were not
as effective as DCE (entries 5–7). In addition, the use of
Pd(TFA)2 as catalyst gave 2a in 72% yield (entry 8). With
Pd(dba)2 as catalyst, after 24 h, the reaction of 1a and NFSI
gave 2a in 23% yield, and 63% 1a was recovered (entry 9).
Whereas, the reaction employing catalyst Pd(PPh3)2Cl2 gave
no desired 2a and 80% 1a was recovered (entry 10). It should
be noted that the transformation from 1a to 2a represents
the first direct benzylic C–H amination with a non-nitrene
nitrogen source. In our experiment, starting from substrates
N-o-tolylpivalamide and N-m-tolylpivalamide, no reaction
occurred. On the contrary to benzylic C–H amination of
nitrenes,8,9 high selectivity toward benzylic C–H para to the
directed amide group of the present study is desirable.
Transition metal catalyzed direct carbon–hydrogen bond
functionalization appears highly appealing especially if
high selectivity for a unique C–H bond can be achieved.1
Accordingly, directed metallation,1,2 is a powerful approach
for selective functionalization of C–H bonds in complex
substrates. All previously reported directed palladium catalyzed
C–H functionalization of arenes provided ortho-C(sp)2–H
functionalized products via an ortho-arene substituted cyclo-
palladium intermediate (Scheme 1A, with C–H to C–N3 as an
example3a), which may restrict their potential synthetic appli-
cation. Therefore, development of a new directing paradigm
overriding the common ortho aromatic C–H selectivity to
realize remote meta/para aromatic or benzylic C–H activation
remains a challenge.4 Recently, a remarkably interesting
amide group5 directed copper-catalyzed meta aromatic C–H
arylation reaction was reported by Gaunt and Phipps.4a In this
communication, an unprecedented amide directed Pd(OAc)2
catalyzed benzylic C(sp3)–H6 amination with N-fluorobenzene-
sulfonimide (NFSI) was realized and a novel iminoquinone
methide was proposed as the key intermediate (Scheme 1B).
Nitrogen functionality is prevalent in synthetic and natural
small molecules with significant biological activities.7 Recently,
the area of catalytic C–H amination has led to significant
results both arising from the discovery of simple efficient
nitrene transfers8,9 and the combination of transition metal
catalyzed C–H activation with C–N bond formation.8
However, to date, benzylic C–H activation amination with a
non-nitrene nitrogen source had never been realized. Most
recently, the works of Michael10a,b and Liu10c showed that
NFSI could be efficiently utilized as nitrogen source as well as
oxidant. Combining with our continuing interest in the synthesis
of heterocyclic compounds from amide substrates,11 we
have attempted the amide directed palladium catalyzed C–H
amination of arenes with NFSI.
We next addressed reaction optimization with respect to
various N-p-tolylamide derivatives 1b–e (Table 2). We found
that changing the nature of the acyl group had a large effect on
the yield of the reaction without compromising the benzyl
C–H selectivity (entries 2–4). In addition, the reaction works
with carbamate (entry 5), although the yield was only moderate.
With the defined efficient directing group (Table 2, entry 1),
the scope of benzyl C–H amination reaction was explored. As
described in Table 3, N-p-tolylpivalamide derivatives 1f–j were
Department of Chemistry, Northeast Normal University, Changchun,
130024, P. R. China. E-mail: zhangq651@nenu.edu.cn;
Fax: +86-431-85099759; Tel: +86-431-85099759
w Electronic supplementary information (ESI) available: Experimental
procedures, full characterization data, copies of 1H and 13C NMR spectra
for all the new compounds. CCDC 779680. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0cc02175j
Scheme 1 Directed palladium catalyzed C–H amination.
Chem. Commun., 2010, 46, 6831–6833 6831
c
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Table 1 Benzylic C–H amination of 1a with NFSIa
Entry
Catalyst
Solvent
Additive (4.0 equiv.)
Time/h
Yield of 2ab (%)
1
2
3
4
5
6
7
8
9
10
Pd(OAc)2
Pd(OAc)2
None
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(dba)2
Pd(PPh3)2Cl2
DCE
DCE
DCE
DCE
1,4-dioxane
C6H5Cl
Mesitylene
DCE
DCE
DCE
None
KF
KF
NaHCO3
KF
KF
KF
KF
KF
KF
1.5
5.5
24.0
3.5
3.0
5.0
1.0
8.0
73
86
0
83
17
64
23
72
24.0
8.0
23
Trace
a
b
Reactions were carried out with 1 (0.4 mmol), 10 mol% palladium catalyst, NFSI (2.5 equiv.) in solvent (4 mL) at 90 1C. Yield of the isolated
product.
Table 2 Pd(OAc)2 catalyzed benzylic C–H amination of 1a–e with
NFSIa
OMe and phenyl at aromatic ring, 2n was obtained in 94%
yield (entry 9).
Although the mechanistic details of this transformation are
not clear at the moment,12 we propose the possible catalytic
cycle as shown in Scheme 2. The suggested initial step is
the formation of intermediate A with an O–Pd(II) bond.13
Oxidative addition of NFSI10a,b to intermediate A generates
Pd(IV) species B. The next elimination of benzenesulfonimide
gives a key iminoquinone methide intermediate C14 and
regenerates the active Pd(II) species. Finally, the nucleophilic
amination10b,15 of intermediate C and benzenesulfonimide
leads to the products 2.16
Entry
Substrate
X
Time/h
Product 2b (%)
1
2
3
4
5
1a
1b
1c
1d
1e
t-Bu
Me
Ph
PhCH2
OC(CH3)3
5.5
11.0
15.5
10.0
3.3
86
71
59
57
51c
a
Reactions were carried out with 1 (0.4 mmol), 10 mol% Pd(OAc)2,
b
NFSI (2.5 equiv.) and KF (4 equiv.) in DCE (4 mL) at 90 1C. Yield
of the isolated product. Without adding additive.
In conclusion, an unprecedented remote amide-directed
palladium-catalyzed intermolecular highly selectively benzylic
C–H amination with NFSI is developed. This methodology
provides a novel approach to circumvent the common ortho
aromatic C–H selectivity in directed palladium catalyzed C–H
functionalization, although currently, this chemistry has
narrow scope limited to N-p-tolylamide derivatives. Further
studies of these transformations may lead to new paths for
developing efficient C–H activation methodologies.
c
successfully reacted with NFSI to afford 2f–j in 72–83% yield
(entries 1–5) and 1g–i with strong electron donating OR
group needed a relatively shorter reaction time (entries 2–4).
Interestingly, starting from biphenyl derivatives 1k–m, the
desired benzylic C–H amination products 2k–m could
also be obtained without the formation of carbazole deriva-
tives via possible intramolecular competing C–N formation
reaction5a,c (entries 6–8). From substrate 1n with both
Financial support of this research by the NCET-08-0756,
NNSFC (20772015 and 20972028), NENU-STC07006,
JLSDP (20080547 and 20082212) is greatly acknowledged.
Table 3 Pd(OAc)2 catalyzed benzylic C–H amination of 1f–n with NFSIa
Entry
Substrate 1
R1
R2
R3
Time/h
Yield of 2b (%)
1
2
3
4
5
6
7
8
9
1f
Me
OMe
OEt
OCH2Ph
H
H
H
H
H
H
H
H
H
Me
H
H
Me
Ph
H
H
H
H
19.0
1.0
0.5
0.3
20.0
0.5
0.6
75
83
77
73
72
70
81
58c
94
1g
1h
1i
1j
1k
1l
H
Ph
4-MeC6H4
Ph
OMe
1m
1n
13.0
4.0
a
b
Reactions were carried out with 1 (0.4 mmol), 10 mol% Pd(OAc)2, NFSI (2.5 equiv.) and NaHCO3 (4 equiv.) in DCE (4 mL) at 90 1C. Yield of
the isolated product. With 15% HN(SO2Ph)2 obtained.
c
c
6832 Chem. Commun., 2010, 46, 6831–6833
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Angew. Chem., Int. Ed., 2005, 44, 4046–4048; (c) W. C. P. Tsang,
N. Zheng and S. L. Buchwald, J. Am. Chem. Soc., 2005, 127,
14560–14561.
6 For
a
recent review on transition metal-mediated C(sp3)–H
functionalization reactions, see: R. Jazzar, J. Hitce, A. Renaudat,
J. Sofack-Kreutzer and O. Baudoin, Chem.–Eur. J., 2010, 16,
2654–2672.
7 (a) R. Hili and A. K. Yudin, Nat. Chem. Biol., 2006, 2, 284–287;
(b) T. Henkel, R. M. Brunne, H. Muller and F. Reichel, Angew.
Chem., Int. Ed., 1999, 38, 643–647.
¨
8 A recent review on catalytic C–H amination see: F. Collet,
R. H. Dodd and P. Dauban, Chem. Commun., 2009, 5061–5074,
and also see references therein.
9 See a recent review on catalytic C–H functionalization by metal
carbenoid and nitrenoid, and references therein: H. M. L. Davies
and J. R. Manning, Nature, 2008, 451, 417–424.
10 (a) P. A. Sibbald and F. E. Michael, Org. Lett., 2009, 11,
1147–1149; (b) P. A. Sibbald, C. F. Rosewall, R. D. Swartz and
F. E. Michael, J. Am. Chem. Soc., 2009, 131, 15945–15951;
(c) S. Qiu, T. Xu, J. Zhou, Y. Guo and G. Liu, J. Am. Chem.
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11 (a) Z. Zhang, Q. Zhang, Z. Ni and Q. Liu, Chem. Commun., 2010,
46, 1269–1271; (b) Z. Zhang, Q. Zhang, S. Sun, T. Xiong and
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Q. Zhang, Z. Yan and Q. Liu, J. Org. Chem., 2007, 72, 9808–9810;
(d) Q. Zhang, Z. Zhang, Z. Yan, Q. Liu and T. Wang, Org. Lett.,
2007, 9, 3651–3653.
Scheme 2 Proposed mechanism for formation of 2.
Notes and references
z General procedure for the preparation of 2 (with 2a as an example):
To a solution of the N-p-tolylpivalamide (1a, 0.40 mmol) in 1,2-
dichloroethane (4.0 ml) was added the N-fluorobenzenesulfonimide
(315 mg, 1.0 mmol), KF (93 mg, 1.6 mmol) and Pd(OAc)2 (9.0 mg,
0.04 mmol). The reaction was stirred for the 5.5 h at 90 1C under
air. After completion of the reaction (TLC monitoring) the mixture
was poured onto ice–water and extracted with dichloromethane
(3 ꢀ 15 mL). The combined organic layers were dried (Na2SO4), filtered
over Celite, evaporated in vacuo, and the residue was purified by column
chromatography to give the compound N-(4-((N-(phenylsulfonyl)-
phenylsulfonamido)methyl)phenyl)pivalamide (2a, 167 mg, 86%).
1
y Selected data for 2a: White solid. mp: 151 1C; H NMR (500 MHz;
CDCl3): d = 1.34 (s, 9H), 4.88 (s, 2H), 7.30 (s, 1H), 7.33 (d, J = 8.5 Hz,
2H), 7.41–7.47 (m, 6H), 7.59 (t, J = 7.5 Hz, 2H), 7.80 (d, J = 7.5 Hz,
4H). 13C NMR (125 MHz; CDCl3): d = 27.6, 39.7, 51.9, 119.7, 128.1,
128.9, 129.9, 130.2, 133.7, 137.9, 139.8, 176.6. IR (KBr, cmꢁ1): 1676,
1394, 1170, 788, 582. MS calcd m/z 486.6036, [M]+ found 486.6041;
Anal. Calcd for: C24H26N2O5S2: C, 59.24; H, 5.39; N, 5.76. Found: C,
59.27; H, 5.34; N, 5.75%.
12 There is no obvious effect on the benzylic C–H amination by
addition of 2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPO) which
suggests against a radical mechanism.
13 No reaction occurred starting from substrate N-methyl-N-p-
tolylacetamide. In addition, high yields could be achieved
by adding base such as NaHCO3 or KF to facilitate proton
abstraction. These results may support the formation of anionic-
typecoordination intermediate A.
14 (a) P. V. Chang, D. H. Dube, E. M. Sletten and C. R. Bertozzi,
J. Am. Chem. Soc., 2010, 132, 9516–9518; (b) A. N. Dinant and
S. D. Taylor, Chem. Commun., 2001, 1386–1387.
15 S. L. Marquard, D. C. Rosenfeld and J. F. Hartwig, Angew.
Chem., Int. Ed., 2010, 49, 793–796.
16 An ortho-substituted cyclopalladium (II) intermediate E was
1 For selected reviews, see: (a) J. A. Labinger and J. E. Bercaw,
Nature, 2002, 417, 507–514; (b) K. Godula and D. Sames, Science,
2006, 312, 67–72.
2 A recent review for palladium catalyzed ligand-directed C–H
functionalization reactions, see: T. W. Lyons and M. S. Sanford,
Chem. Rev., 2010, 110, 1147–1169.
3 We aware of only two examples of intermolecular C–H activation
aminations via directed metallation: (a) H.-Y. Thu, W.-Y. Yu and
C.-M. Che, J. Am. Chem. Soc., 2006, 128, 9048–9049; (b) X. Chen,
X. -S. Hao, C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc., 2006,
128, 6790–6791.
4 For meta-C–H functionalization, see: (a) R. J. Phipps and
M. J. Gaunt, Science, 2009, 323, 1593–1597; (b) Y.-H. Zhang,
B.-F. Shi and J.-Q. Yu, J. Am. Chem. Soc., 2009, 131, 5072–5074.
5 For selected examples of amide directed C(sp2)–H functionaliza-
tion, see: (a) B. Li, S. -L. Tian, Z. Fang and Z. Shi, Angew. Chem.,
Int. Ed., 2008, 47, 1115–1118; (b) O. Daugulis and V. G. Zaitsev,
prepared from 1a (eqn (1)). No desired 2a was obtained when
the reaction of E and NFSI was performed under identical condi-
tions described in Table 2, entry 1. For preparation and X-ray
diffraction analysis of intermediate E (CCDC-776890), please see
Supporting Informationw
ð1Þ
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6831–6833 6833