[Cp*RhCl2]2-catalyzed ortho-C-H bond amination of acetophenone o-methyloximes with primary N-chloroalkylamines: Convenient synthesis of N-alkyl-2-acylanilines

Article abstract of DOI:10.1039/c3cc42937g

Rh(iii)-catalyzed aromatic C-H amination of acetophenone o-methyloximes with primary N-chloroalkylamines was developed, and the arylamine products were obtained in up to 92% yield. The reaction probably involves rate-limiting electrophilic C-H bond cleavage (k_H/k_D = 2).

Full text of DOI:10.1039/c3cc42937g

Chemical Communications
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Volume 49 | Number 63 | 14 August 2013 | Pages 7015–7096
ISSN 1359-7345
COMMUNICATION
Wing-Yiu Yu et al.
[Cp*RhCl2]2-catalyzed ortho-C–H bond amination of acetophenone o-methyloximes with
primary N-chloroalkylamines: convenient synthesis of N-alkyl-2-acylanilines

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[Cp*RhCl2]2-catalyzed ortho-C–H bond amination
of acetophenone o-methyloximes with primary
N-chloroalkylamines: convenient synthesis of
N-alkyl-2-acylanilines†
Cite this: Chem. Commun., 2013,
49, 7031
Received 20th April 2013,
Accepted 29th May 2013
DOI: 10.1039/c3cc42937g
Ka-Ho Ng, Zhongyuan Zhou and Wing-Yiu Yu*
www.rsc.org/chemcomm
Rh(III)-catalyzed aromatic C–H amination of acetophenone o-methyl-
oximes with primary N-chloroalkylamines was developed, and the aryl-
amine products were obtained in up to 92% yield. The reaction probably
involves rate-limiting electrophilic C–H bond cleavage (kH/kD = 2).
Transition metal catalyzed aromatic C–H activation1 for C–N
bond formation2 is of fundamental importance for developing
straightforward and sustainable synthesis of arylamines.
Pioneered by the research groups of Buchwald,3g Hartwig3b and
Yu,3c,e,f aromatic amides are known to undergo intramolecular
ortho-C–H amidation using a variety of oxidizing agents [e.g.
Cu(OAc)2/O2; F+ oxidants].3 Recently, we4 and others5–8 achieved
the Pd-catalyzed intermolecular ortho-C–H amidation of arenes
with N-sulfonyloxycarbamates4b,c and other derivatives. Despite
Scheme 1 Synthetic routes to 2-acylanilines via C–H functionalizations.
these advances, the Pd-catalyzed direct C–H activation/C–N bond ketones with arylsulfonamides.5b However, the substrates are con-
formation is limited to amides as coupling partners, and the fined to aromatic ketones in which bulky tertiary alkyl groups are
direct C–H amination remains a challenge.9
needed for success.
[Cp*RhCl2]2-catalyzed arene C–H functionalizations for C–C
To begin, oxime 1a was treated with N-chlorocyclopentyl-
bond formation are currently receiving attention.10 With regard to amine (2a: 2.2 equiv., prepared in situ by reacting N-chloro-
C–N bond formation, we4a and Glorius et al.11b have independently succinimide with cyclopentylamine), [Cp*RhCl2]2 (5 mol%),
reported the [Cp*RhCl2]2-catalyzed direct electrophilic arene AgSbF6 (1.5 equiv.) and CsOAc (0.3 equiv.) in THF at room
aminations with N-chloromorpholine. Chang and co-workers11a,c temperature for 3 h, which afforded 3aa in 28% yield (Table 1,
recently reported the analogous C–H amination using arylazides to entry 1). Apart from the C–N coupling, aromatic chlorination of
afford diarylamines. Prompted by these investigations, we antici- 3aa was also observed [3ma (5-Cl, 40%) and 3ma0 (3-Cl, 22%)].
pated that the C–H aminations of acetophenone o-methyloximes Notably, neither 3aa nor any chlorination products were formed
with primary N-chloroalkylamines12 should furnish N-alkyl-2-acyl- in the absence of the Rh catalyst. Our previous study on the
anilines, which are key precursors to some medicinally important direct arene amination by N-chloromorpholine4a showed that
heterocycles such as 1,4-benzodiazepine-2-ones, 4-quinolones and HSbF6 should be formed as a side-product. According to the
quinazolin-2-ones.13 Indeed, Pd-catalyzed oxidative C–H acylation of literature,12b primary N-chloroalkylamines are poor aminating
anilides has been extensively investigated by us4e and others14 reagents and would undergo aromatic chlorination in acidic
for the synthesis of 2-acylanilines (Scheme 1). Previously, Liu and medium (e.g. aq. HCl). Thus, the observed chlorination of 3aa is
co-workers described the Pd-catalyzed C–H amidation of aromatic likely associated with the stoichiometric formation of HSbF6.
To suppress the acid-promoted chlorination, 1.3 equivalents
State Key Laboratory for Chirosciences and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon,
Hong Kong. E-mail: wing-yiu.yu@polyu.edu.hk; Tel: +852 3400 8725
† Electronic supplementary information (ESI) available. General and experi-
mental information on optimisation studies and procedures for amination.
CCDC 934929. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c3cc42937g
of CsOAc were employed for the amination of 1a. We were
gratified that 3aa was formed in 73% yield with negligible
chlorination being observed (entry 2). Compared to CsOAc,
AgOAc was a poor additive for the coupling reaction with poor
substrate turnovers (entry 3); other inorganic bases such as K2CO3
and K3PO4 gave inferior results (entries 4 and 5). Organic base such
c
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Table 1 Reaction optimizationa
Table 2 Scope of the acetophenone o-methyloximesa,b
Entry
Base (equiv.)
CsOAc (equiv.)
Yield (%)
1b
2
—
—
0.3
1.3
—
0.3
0.3
0.3
0.6
2.0
1.3
28
73
o5
35
33
39
20
18
80
3c
4
AgOAc (1.5)
K2CO3 (1.3)
K3PO4 (1.3)
NEt3 (1.3)
—
—
—
5
6
7b
8
9d
a
b
See ESI for detailed reaction conditions. Chlorination of 3aa was
observed, and products (3ma and 3ma0) were quantified by 1H NMR.
c
d
No AgSbF6 was employed. 2a addition rate = 2.2 equiv. per h,
reaction run for 2 h.
as triethylamine is less effective for the coupling reaction
(entry 6). After several trials, 3aa was obtained in 80% yield
(entry 9) by employing an optimized protocol: [Cp*RhCl2]2
(5 mol%), 1a (0.2 mmol), 2a (syringe-pump addition: 2.2 equiv.
per h), AgSbF6 (1.5 equiv.) and CsOAc (1.3 equiv.) in THF (2 mL)
for 2 h.
a
b
c
In general, successful aminations were achieved for sub-
strates bearing electron-donating and electron-withdrawing
groups (Table 2), and 3ba–3ja were obtained in 36–92% yields.
Yet, some fine tuning of the quantity of the CsOAc additive was
performed during our substrate scope study. For example,
amination of the substrates bearing electron-withdrawing
groups (including halogen, ester, –SO2Me, –NO2 and –CF3)
afforded 3ba–3ga in 76–92% with negligible chlorination when
one equivalent of CsOAc was employed as an additive. However,
employing 1.3 equivalents of CsOAc for the aminations of these
substrates resulted in moderate yields (o40%).15
See ESI for detailed reaction conditions. Isolated yields. CsOAc
d
(1 equiv.) was used. C-5 chlorination products (yield in parentheses)
of the arylamines were detected by 1H NMR.
Table 3 Scope of N-chloroalkylaminesa,b
With 1.3 equivalents of CsOAc, the aminations of acetophenone
oximes with electron-donating para-substituents (e.g. methyl,
methoxy) gave lower product yields (3ha–3ja: 36–64%), accom-
panied by aromatic chlorination. Employing 1.5 equiv. of
CsOAc seemed to suppress the chlorination reaction but the
amination product yields were not improved.15 meta-Substituted
oximes were also effective substrates; exclusive C–N coupling
a
b
c
See ESI for detailed reaction conditions. Isolated yields. CsOAc
(1.1 equiv.) was used. Yield was determined by 1H NMR; similar
d
occurred at the less hindered ortho-C–H bond (3ka–3la) with up product 3ag from o-methyloxime (1a) was produced and isolated in
66% yield.
to 78% yield for the amination of meta-CF3-substituted aceto-
phenone oximes. For the amination of 1n featuring a naphthalene
moiety, aromatic chlorination was observed with 3na–3Cl iso- from sec-butylamine and isopropylamine are effective for the
lated in 43% yield. However, the analogous 1o with a tetralone C–N coupling reaction with 3fe and 3ff obtained in 85% and
scaffold were converted to 3oa in 60% yield without apparent 84% yields. Yet, the analogous reactions with N-chloroalkyl-
chlorination.
amines of a-methylbenzylamine and 1-cyclohexylethylamine
Table 3 shows the scope of the primary amines. With 1f as afforded moderate product yields (3fg and 3fh: 55% and 42%),
the substrate, effective coupling of N-chlorocyclohexylamine presumably due to the increased steric hindrance of the chloro-
produced 3fb in 86% yield, and its structure has been char- amine skeletons. Consistent with this notion, N-chloro-tert-
acterized using X-ray crystallography.15 N-Chloroalkylamines butylamine and N-chloroadamantylamine are ineffective for
bearing a cycloalkyl group such as 4-aminotetrahydropyran the direct C–H amination. Moreover, reactions of N-chloro-1-
and exo-2-aminonorbornane reacted with 1f to give 3fc (66%) hexylamine with 1f were unsuccessful with almost complete
and 3fd (75%), respectively. Likewise, chloroamines derived recovery of the oxime (see ESI† for details).
c
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(e) M. Wasa and J.-Q. Yu, J. Am. Chem. Soc., 2008, 130, 14058;
( f ) J.-J. Li, T.-S. Mei and J.-Q. Yu, Angew. Chem., Int. Ed., 2008,
47, 6452; (g) W. C. P. Tsang, N. Zheng and S. L. Buchwald, J. Am.
Chem. Soc., 2005, 127, 14560.
4 Selected examples of catalytic C–H functionalizations; for amination–
amidation: (a) K.-H. Ng, Z. Zhou and W.-Y. Yu, Org. Lett., 2012,
14, 272; (b) K.-H. Ng, F.-N. Ng and W.-Y. Yu, Chem. Commun., 2012,
48, 11680; (c) K.-H. Ng, A. S. C. Chan and W.-Y. Yu, J. Am. Chem. Soc.,
2010, 132, 12862; (d) H.-Y. Thu, W.-Y. Yu and C.-M. Che, J. Am. Chem.
Soc., 2006, 128, 9048; for acylation: (e) C.-W. Chan, Z. Zhou and
W.-Y. Yu, Adv. Synth. Catal., 2011, 353, 2999; ( f ) C.-W. Chan, Z. Zhou,
A. S. C. Chan and W.-Y. Yu, Org. Lett., 2010, 12, 3926; (g) W.-Y. Yu,
W. N. Sit, K.-M. Lai, Z. Zhou and A. S. C. Chan, J. Am. Chem. Soc., 2008,
130, 3304; for arylation: (h) W.-Y. Yu, W. N. Sit, Z. Zhou and A. S. C.
Chan, Org. Lett., 2009, 11, 3174; for carbenoid insertion:
(i) W.-W. Chan, S.-F. Lo, Z. Zhou and W.-Y. Yu, J. Am. Chem. Soc.,
2012, 134, 13565; ( j) W.-W. Chan, T.-L. Kwong and W.-Y. Yu, Org.
Biomol. Chem., 2012, 10, 3749; (k) W.-W. Chan, S.-H. Yeung, Z. Zhou,
A. S. C. Chan and W.-Y. Yu, Org. Lett., 2010, 12, 604.
Scheme 2 Proposed mechanism.
5 For Pd-catalyzed intermolecular C–H amidations, see: (a) K. Sun,
Y. Li, T. Xiong, J. Zhang and Q. Zhang, J. Am. Chem. Soc., 2011,
133, 1694; (b) B. Xiao, T.-J. Gong, Z.-J. Liu and L. Liu, J. Am. Chem.
Soc., 2011, 133, 1466; (c) X.-Y. Liu, P. Gao, Y.-W. Shen and
Y.-M. Liang, Org. Lett., 2011, 13, 4196.
6 For some recent examples of Cu-mediated intermolecular C–H
amination on electron-rich arenes, see: (a) C. Tang and N. Jiao,
J. Am. Chem. Soc., 2012, 134, 18924; (b) N. Matsuda, K. Hirano,
T. Satoh and M. Miura, Org. Lett., 2011, 13, 2860; (c) A. John and
K. M. Nicholas, J. Org. Chem., 2011, 76, 4158; (d) T. Kawano,
K. Hirano, T. Satoh and M. Miura, J. Am. Chem. Soc., 2010,
132, 6900; (e) D. Monguchi, T. Fujiwara, H. Furukawa and A. Mori,
Org. Lett., 2009, 11, 1607; ( f ) Q. Wang and S. L. Schreiber, Org. Lett.,
2009, 11, 5178.
7 For recent examples of aromatic C–H amidation–amination under
metal-free conditions, see: (a) R. Samanta, J. O. Bauer, C. Strohmann
and A. P. Antonchick, Org. Lett., 2012, 14, 5518; (b) A. A. Kantak,
S. Potavathri, R. A. Barham, K. M. Romano and B. Deboef, J. Am.
Chem. Soc., 2011, 133, 19960; (c) S. Wertz, S. Kodama and A. Studer,
Angew. Chem., Int. Ed., 2011, 50, 11511; (d) H. J. Kim, J. Kim,
S. H. Cho and S. Chang, J. Am. Chem. Soc., 2011, 133, 16382.
8 For examples of intermolecular C–H activation–C–N bond formation
involving transition metal catalysts such as Au, Ag and Ru, see:
(a) M.-L. Louillat and F. W. Patureau, Org. Lett., 2013, 15, 164;
(b) L. Gu, B. S. Neo and Y. Zhang, Org. Lett., 2011, 13, 1872;
(c) S. H. Cho, J. Y. Kim, S. Y. Lee and S. Chang, Angew. Chem., Int.
Ed., 2009, 48, 9127.
The o-methyloxime group (QNOMe) can be removed by treating
the arylamine products in refluxing 6 M HCl for 2 h. For instance,
the acid deprotection of 3ca, 3fa, 3ga and 3ff afforded the corre-
sponding 2-acetyl-N-alkylanilines in 75–89% yields.15
Regarding the mechanism, the reaction should be initiated
by oxime-assisted C–H bond activation to form a rhodacyclic
complex (Scheme 2). Based on the two parallel reactions with 1a
and d5-1a as substrates, the kinetic isotope effect (kH/kD = 2) was
observed suggesting that cyclorhodation of the aryl C–H should
be rate-limiting. The Rh-catalyzed acetophenone aminations
exhibit a linear free energy relationship (r = ꢀ0.93) with the
Hammett spara constants. The small r value should not favor a
significant build-up of positive charge (e.g. Wheland intermediate)
at the cyclorhodation step. Furthermore, the stoichiometric
reactions of a cyclorhodated complex of 2-phenylpyridine with
a series of N-chloroalkylamines effected successful C–N coupling
reactions and afforded the arylamines being obtained in 79–93%
yields.15 Thus, the C–N bond formation step should proceed
by the coupling of the arylrhodium(III) complex with the
chloroamines.
In summary, Rh-catalyzed arene C–H bond amination using
monochlorinated primary amines was developed. This Rh-catalyzed
amination with monochlorinated primary amines comple-
ments the other related reactions with secondary amines and
amides as coupling partners. Application of the direct C–H
aminations for synthesis of natural products is under investiga-
tion and will be reported separately.
9 Recent example of Pd-catalyzed intermolecular direct aromatic C–H
amination, see: E. J. Yoo, S. Ma, T.-S. Mei, K. S. L. Chan and J.-Q. Yu,
J. Am. Chem. Soc., 2011, 133, 7652.
10 For recent reviews on Rh(III)-catalyzed C–H activation–C–C bond
formation, see: (a) F. W. Patureau, J. Wencel-Delord and F. Glorius,
Aldrichimica Acta, 2012, 45, 31; (b) G. Song, F. Wang and X. Li, Chem.
Soc. Rev., 2012, 41, 3651; (c) D. A. Colby, R. G. Bergman and
J. A. Ellan, Chem. Rev., 2010, 110, 624; (d) T. Satoh and M. Miura,
Chem.–Eur. J., 2010, 16, 11212. For selected recent examples, see:
˜
˜
˜
(e) N. Quinones, A. Seoane, R. Garcia-Fandino, J. L. Mascarenas and
M. Gulias, Chem. Sci., 2013, 4, 2874; ( f ) Y. Lian, R. G. Bergman,
L. D. Lavis and J. A. Ellman, J. Am. Chem. Soc., 2013, 135, 7122; (g) Z. Shi,
C. Grohmann and F. Glorius, Angew. Chem., Int. Ed., 2013, 52, 5393.
11 (a) J. Ryu, K. Shin, S. H. Park, J. Y. Kim and S. Chang, Angew. Chem.,
Int. Ed., 2012, 51, 9904; (b) C. Grohmann, H. Wang and F. Glorius,
Org. Lett., 2012, 14, 656; for a very recent example of Rh-catalyzed
intermolecular C–H amidation, see: (c) J. Y. Kim, S. H. Park, J. Ryu,
S. H. Cho, S. H. Kim and S. Chang, J. Am. Chem. Soc., 2012, 134, 9110.
12 For reviews on N-chloroamines, see: (a) E. Erdik and M. Ay, Chem.
Rev., 1989, 89, 1947; (b) L. Stella, Angew. Chem., Int. Ed., 1983,
22, 337; (c) P. Kovacic, M. K. Lowery and K. W. Field, Chem. Rev.,
1970, 70, 639.
We are grateful for the financial support from the Hong
Kong Research Grants Council (PolyU5017-07P; SEG_PolyU01).
Notes and references
1 Recent reviews on transition metal catalyzed arene C–H activation:
¨
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111, 1215; (c) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010,
110, 1147.
2 Recent reviews on catalytic C–H amidation–amination: (a) B. J.
Stokes and T. G. Driver, Eur. J. Org. Chem., 2011, 4071; (b) F. Collet,
R. H. Dodd and P. Dauban, Chem. Commun., 2009, 5061.
3 (a) J. Zhou, J. He, B. Wang, W. Yang and H. Ren, J. Am. Chem. Soc.,
2011, 133, 6868; (b) Y. Tan and J. F. Hartwig, J. Am. Chem. Soc., 2010,
13 For reviews, see: (a) A. Kamal, K. L. Reddy, V. Devaiah, N. Shankaraiah
and M. V. Rao, Mini-Rev. Med. Chem., 2006, 6, 71; (b) D. A. Horton,
G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103, 893.
132, 3676; (c) T.-S. Mei, X. Wang and J.-Q. Yu, J. Am. Chem. Soc., 2009, 14 (a) C. Li, L. Wang, P. Li and W. Zhou, Chem.–Eur. J., 2011, 17, 10208;
131, 10806; (d) J. A. Jordan-Hore, C. C. C. Johansson, M. Gulias, (b) Y. Wu, B. Li, F. Mao, X. Li and F. Y. Kwong, Org. Lett., 2011, 13, 3258.
E. M. Beck and M. J. Gaunt, J. Am. Chem. Soc., 2008, 130, 16184; 15 See ESI† for details.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 7031--7033 7033