Bronsted base-modulated Regioselective Pd-catalyzed intramolecular aerobic oxidative amination of alkenes: Formation of seven-membered amides and evidence for allylic C-H activation

Article abstract of DOI:10.1021/ol900941t

A novel palladium-catalyzed intramolecular aerobic oxidative allylic C-H amination of olefins has been developed. Bronsted base can modulate the regioselectivity, favoring the formation of 7-membered rings. Mechanistic studies using deuterium-labeled substrates as probes support a rate-determining allylic C-H activation/irreversible reductive elimination pathway.

Full text of DOI:10.1021/ol900941t

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2707-2710
Brønsted Base-Modulated Regioselective
Pd-Catalyzed Intramolecular Aerobic
Oxidative Amination of Alkenes:
Formation of Seven-Membered Amides
and Evidence for Allylic C-H Activation
Liang Wu, Shuifa Qiu, and Guosheng Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai, China, 200032
gliu@mail.sioc.ac.cn
Received April 29, 2009
ABSTRACT
A novel palladium-catalyzed intramolecular aerobic oxidative allylic C-H amination of olefins has been developed. Brønsted base can modulate
the regioselectivity, favoring the formation of 7-membered rings. Mechanistic studies using deuterium-labeled substrates as probes support
a rate-determining allylic C-H activation/irreversible reductive elimination pathway.
The prominence of nitrogen-containing heterocycles in
natural products and biologically active molecules has
prompted considerable efforts toward their synthesis.1 Among
transition-metal promoted cyclizations of alkenes, palladium-
catalyzed oxidative aminations represent one of the most
efficient synthetic routes for nitrogen-containing hetero-
cycles.2 An even more desirable approach for catalytic C-N
bond formation is the dioxygen-coupled oxidative amination
of olefins.3 While formations of five- and six-membered
heterocycles have dominated palladium-catalyzed oxidative
intramolecular aminations of alkenes, formations of seven-
membered nitrogen-containing heterocycles under oxidative
conditions are quite rare.4 Herein, we report a Brønsted base-
modulated regioselective Pd-catalyzed intramolecular aerobic
oxidative amination of alkenes for seven-membered amides
(4) (a) van der Schaaf, P. A.; Sutter, J.-P.; Grellier, M.; van Mier,
G. P. M.; Spek, A. L.; van Koten, G.; Pfeffer, M. J. Am. Chem. Soc. 1994,
116, 5134. (b) Grellier, M.; Pfeffer, M.; Van Koten, G. Tetrahedron Lett.
1994, 35, 2877.
(5) The seven-membered amides are important intermediates for the
synthesis of biological compounds and materials, see: (a) Proctor, G. R.;
Redpath, J. In Monocyclic Azepines; Taylor, E. C. Eds.; Wiley-VCH: New
York, 1996. (b) Hutchison, G. I.; Prager, R. H.; Ward, A. D. Austra.
J. Chem. 1980, 33, 2477. (c) Maier, S.; Loontjens, T.; Scholtens, B.;
Mu¨lhaupt, R. Angew. Chem., Int. Ed. 2003, 42, 5094, and reference therein.
(6) For palladium catalyzed aerobic allylic C-H functionalization, see:
(a) Mitsudome, T.; Umetani, T.; Nosaka, N.; Mori, K.; Mizugako, T.;
Ebitani, K.; Kaneda, K. Angew. Chem., Int. Ed. 2006, 45, 481. (b) Liu, G.;
Yin, G.; Wu, L. Angew. Chem., Int. Ed. 2008, 47, 4733. (c) Beccalli, E. M.;
Broggini, G.; Paladino, G.; Penoni, A.; Zoni, C. J. Org. Chem. 2004, 69,
5627. For single example, see: (d) Larock, R. C.; Hightower, T. R.; Hasvold,
L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584.
(1) Brown, E. G. In Ring Nitrogen and Key Biomolecules; Springer:
Boston, MA, 1998.
(2) For reviews on oxidative amination methods, see: (a) Zeni, G.;
Larock, R. C. Chem. ReV. 2006, 106, 4644. (b) Beccalli, E. M.; Broggini,
G.; Martinelli, M.; Sottocornola, S. Chem. ReV. 2007, 107, 5318.
(3) For reviews on oxidative amination of alkenes, see: (a) Stahl, S. S.
Angew. Chem., Int. Ed. 2004, 43, 3400. (b) Kotov, V.; Scarborough, C. C.;
Stahl, S. S. Inorg. Chem. 2007, 46, 1910.
10.1021/ol900941t CCC: $40.75
Published on Web 05/20/2009
 2009 American Chemical Society

formation.5,6 Mechanistic studies support the allylic C-H
activation pathway.
Table 1. Pd-Catalyzed Intramolecular Oxidative Amination of
Recently, significant progress has been made in the area
of metal-catalyzed amination of C-H bonds;7,8 for instance,
Rh-catalyzed C-H amination through highly reactive met-
allo-niteneoids,7a-d Pd- or Cu-mediated C-H oxidative
amination assisted by directing groups,7e-g,8 and Pd-
catalyzed allylic C-H oxidative amination.6b,c,9 The latter
have proposed a π-allylpalladium species as key intermedi-
ates. For intramolecular cyclizations, since the π-allylpalla-
dium intermediate normally exists as an equilibrium mixture
of syn (I-A) and anti (I-B and I-C), the subsequent
nucleophilic attack may afford five- and/or seven-membered
rings depending on whether the attack proceeds through exo
or endo fashion (Scheme 1). We hypothesized that Brønsted
1aa
entry
additive
yield (2a:3a)b
1
2
none
20% (<3:97)
44% (82:18)
NaOBz (100 mol %)
3c NaOBz (100 mol %), 4 Å MS (15 mg), MA
(40 mol %) [Condition A]
(salen)Cr(III)Cl (10 mol %) [Condition
B]
NaOBz (100 mol %), (salen)Cr(III)Cl (10
mol %)
91% (86:14)
65% (<3:97)
54% (80:20)
4
5
a Reactions were conducted at 0.1 mmol scale at 1 mL DMA under 1
atm dioxygen, 50 °C. b 1H NMR yield, 1,3,5-trimethoxybenzene as internal
standard. c At 70 °C.
Scheme 1
.
Pd|-Mediated Intramolecular Oxidative Allylic C-H
Amination of Alkenes
membered ring 2a was formed as the major product in the
presence of a base additive (NaOBz, 1 equivalent) under
otherwise identical conditions (entry 2). The formation of
2a can be further enhanced by adding maleic anhydride (MA,
40 mol %) and 4 Å molecular sieves (condition A, entry
3).11 On the other hand, 3a can also be obtained in good
yield by adding (salen)CrIIICl, an additive first reported by
White and co-workers (condition B, entry 4).9a,12 However,
when base is added to the system containing (salen)CrIIICl,
the regioselectivity of the reaction was reverted with the
generation of 7-membered ring 2a again (entry 5). The
above results indicated that the use of base additive is
crucial for the formation of 7-membered ring, as proposed
in Scheme 1.13
The base-promoted regioselective formation of 7-mem-
bererd rings is general with respect to monosubstituted
alkenes (Table 2). For substrates 1a-1f tested in our
experiments, the optimal condition described above (condi-
tion A) favored 7-membered rings 2a-2f formation (selec-
tivity ranging from 79:21 to 86:14, odd entries). In cases
where no base was added (Condition B), 5-membered rings
3a-3f were formed selectively (even entries). It is worth
noting that reactions of 1b-1e exhibited high stereoselec-
tivity to afford trans products 3b-3e (entries 4, 6, 8 and
10).
base can promote the Pd-N bond formation10 to favor
intermediate I-C, leading to selective generation of seven-
membered rings (Scheme 1, bottom).
Our experiments were initiated with the intramolecular
allylic amination reaction of monosubstituted olefine 1a. The
reaction mediated by Pd (OAc)2 under aerobic condition
yielded 20% five-membered ring product 3a with high
regioselectivity (Table 1, entry 1). To our surprise, the seven-
(7) C-H amination via nitrenes: (a) Espino, C. G.; Fiori, K. W.; Kim,
M.; Du Bois, J. J. Am. Chem. Soc. 2004, 126, 15378. (b) Lebel, H.; Huard,
K.; Lectard, S. J. Am. Chem. Soc. 2005, 127, 14198. (c) Liang, C.; Robert-
Peillard, F.; Fruit, C.; Mu¨ller, P.; Dodd, R. H.; Dauban, P. Angew. Chem.,
Int. Ed. 2006, 45, 4641. (d) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey,
A. L.; Driver, T. G. J. Am. Chem. Soc. 2007, 129, 7500. (e) Thu, H.-Y.;
Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048 For Cu-catalyzed
aminations, see. (f) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed.
2008, 47, 1932. (g) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am.
Chem. Soc. 2006, 128, 6790. (h) Hamada, T.; Ye, X.; Stahl, S. S. J. Am.
Chem. Soc. 2008, 130, 833
.
(8) (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc.
2005, 127, 14560. (b) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.;
Hiroya, K. Org. Lett. 2007, 9, 2931. (c) Tsang, W. C. P.; Munday, R. H.;
Brasche, G.; Zheng, N.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7603.
(d) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058. (e) Jordan-
Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J.
J. Am. Chem. Soc. 2008, 130, 16184
.
(9) (a) Reed, S. A.; White, M. C. J. Am. Chem. Soc. 2008, 130, 3316.
(b) Fraunhoffer, K. J.; White, M. C. J. Am. Chem. Soc. 2007, 129, 7274.
(c) Wang, B.; Du, H.; Shi, Y. Angew. Chem., Int. Ed, 2008, 47, 8224. For
allylic C-H alkylation, see: (d) Lin, S.; Song, C.-X.; Cai, G.-X.; Wang,
W.-H.; Shi, Z.-J. J. Am. Chem. Soc. 2008, 130, 12901. (e) Young, A. J.;
White, M. C. J. Am. Chem. Soc. 2008, 130, 14090. (f) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2006, 128, 56
.
The regioselectivity of 7- over 5-membered rings may be
further enhanced by using substrates with a methyl group
installed at an internal vinyl position. This is because the
(10) For the N-Pd bond formation promoted by Brønsted base, see: (a)
Mun˜iz, K.; Ho¨velmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130,
763. (b) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328.
2708
Org. Lett., Vol. 11, No. 12, 2009

Table 2. Palladium-Catalyzed Oxidative Allylic C-H Aminationa
entry
substrate
condition
major
product
yield (2:3)b
1
2
3
4
5
6
7
8
1a R1 ) H, R2 ) H
A
B
A
B
A
B
A
B
A
B
A
B
2a
88% (86:14)
61% (<3:97)
83% (82:18)
66% (<3:97)
64% (81:19)
71% (6:94)
56% (81:19)
41% (<3:97)
67% (79:21)
61% (5:95)
74% (84:16)
71% (<3:97)
1a
3a
1b R1 ) Me, R2 ) H
2b
2c
2d
2e
2f
1b
3b (10:1)c
3c (6:1)c
3d (9:1)c
3e (17:1)c
3f
1c R1 ) C5H11, R2 ) H
1c
i
1d R1 ) Pr, R2 ) H
1d
9
1e R1 ) CH2OBn, R2 ) H
10
11
12
1e
1f R1 ) Me, R2 ) Me
1f
a Reaction was conducted at 0.2 mmol scale at 2 mL DMA under 1 atm dioxygen. Condition A: Pd(OAc)2 (10 mol %), NaOBz (1 equiv), MA (40 mol
%), 4 A MS (30 mg), 70 °C; Condition B: Pd(OAc)2 (10 mol %), (salen)Cr(III)Cl (10 mol %), 50 °C. b Isolated yield, the data in parentheses is the ratio
of 2 and 3. c Ratio of trans-3 and cis-3.
reaction of 4a is expected to favor π-allylpalladium inter-
mediates II over III due to the higher activity of the terminal
methyl over the internal methylene group.14 The intermediate
II should exclusively give seven-membered product 5a (eq
1). We found when substrate 4a was submitted to condition
A, similar ring-sized selectivity (5a/6a ) 87:13) was
achieved as in the cyclization of 1a (eq 1). The fact that 5a′
was not observed indicated that intermediate III afforded
five-membered ring 6a as the only product.15 However, for
the substrate 4a, no reaction occurred under condition B.
proceeded smoothly to six-membered rings with good yields
(entries 14-15).
We then conducted preliminary mechanistic studies. The
reaction may proceeds through an allylic C-H activation/
reductive elimination pathway, or an aminopalladation/ꢀ-H
elimination pathway. The deuterium labeled experiments can
be used to differentiate the above two scenarios. If the
reaction involves allylic C-H activation, both the reactions
Subsequent studies of substrate scope were conducted.
Interestingly, for substrates 4b-4i, which featured one or
two substituents at ꢀ-position of carbonyl groups, the
reactions afforded the seven-membered products 5b-5i in
good yields and excellent regioselectivities (Table 3, entries
2-10). This can be attributed to complete elimination of the
activation of allylic C-H bond of the methylene group
probably due to steric effect. Product 5f was successfully
prepared on a 1.5 mmol scale in yield comparable to that on
small scale (entry 7).16 The seven-membered rings 5j-5l
containing two hetereoatoms were also prepared using our
methods in moderate yields (entries 11-13). Finally, for the
one methylene less substrates 4m and 4n, the reactions
Table 3. Palladium-Catalyzed Oxidative Allylic C-H
Amination of 4a
(11) For the screening results, see Supporting Information Table S1.
(12) Covell, D. J.; White, M. C. Angew. Chem., Int. Ed. 2008, 47, 6448
(Salen ) 1,2-cyclohexanediamino-N,N′-bis(3,5-di-tert-butyl-sali-cylidene).
(13) For Brønsted base-modulated regioselectivity of oxidative amination
of styrene, see: Timokhin, V. I.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127,
17888.
(14) Maitlis, P. M. In The Organic Chemistry of Palladium; Academic
Press: New York, 1971; Vol. I, p 175.
(15) The isomerization from 5a′ to 5a is unlikely due to relative
thermodynamic stability, see: Eskola, P.; Hirsch, J. A. J. Org. Chem. 1997,
62, 5732. On the other hand, no observation of the double bond isomers
within the recovered 4a-A in eq 2also excludes this possibility.
(16) The product 5f was treated with Na/Naphthylene and hydrogen-
ation to afford 4,4,6-trimethyl carprolactam in 85% yield.
a Reaction condition: 4 (0.2 mmol), Pd(OAc)2 (10 mol %), NaOBz (1
equiv), MA (40 mol %), 4 A MS (30 mg) in DMA (2 mL) under 1 atm O2,
70 °C. b Isolated yield. c NaOBz (2.5 equiv). d NaOBz (1.5 equiv), 20 h.
e Scale: 1.5 mmol. f Ratio of 5a:6a.
Org. Lett., Vol. 11, No. 12, 2009
2709

of 4a-A and 4a-B will result the same π-allyl-PdII intermedi-
ate II-d and afford the similar results containing the mixture
of equal amounts of 5a-A and 5a-B (with negligible
secondary isotope effect, see Scheme 2, path a). Otherwise,
Scheme 2
.
Hypothesis of Two Possible Mechanisms (AMP )
Aminopalladation)
In conclusion, we have developed a new palladium-
catalyzed intramolecular aerobic oxidative allylic amination
of unactivated olefins. Brønsted base can modulate the
regioselectivity, favoring the formation of 7-membered
products. This methodology provides an efficient route for
the synthesis of seven-membered cyclic amides. Mechanistic
studies support that the reaction proceeds through a rate-
determining allylic C-H activation/irreversible reductive
elimination pathway to form the C-N bond.
Acknowledgment. This work was supported by the
Chinese Academy of Science, the National Natural Science
Foundation of China (20821002, 20872155), the National
Basic Research Program of China (973-2009CB825300) and
the Science and Technology Commission of the Shanghai
Municipality (Pujiang Program, 08PJ1411600). G.L. thanks
Prof. S. S. Stahl at Unversity of Wisconsin-Madison for
helpful discussion.
if the reaction goes through aminopalladation/ꢀ-H elimination
pathway, the reactions of 4a-A and 4a-B would be formed
seven-membered products 5a-A and 5a-B respectively
(path b).
The reactions with D-labeled substrate 4a-A afforded a
mixture of 5a-A and 5a-B with a ratio of 48:52 in low yield
(16%), and the five-membered product 6a-A (10%)17 (eq 2).
Substrate 4a-A was recovered in 52% yield without alkene
isomerization. For the substrate 4a-B, the reaction also
produced the mixture of 5a-A and 5a-B with the ratio 46:54
in 61% yield, and 6a-B in 9% yield (eq 3). The formations
of mixtures of 5a-A and 5a-B with roughly 1:1 ratio in both
reactions exclude the aminopalladation/ꢀ-H elimination
pathway. Furthermore, the lower conversion of 4a-A is
probably resulted from a higher energy barrier of the allylic
C-D activation. The kinetic isotopic effect (KIE) of allylic
C-H activation was obtained with a 1:1 mixture of 4a and
4a-A, and the large primary KIE value (kH/kD ) 5.75)
supports our hypothesis of a turnover-limiting allylic C-H
activation pathway (eq 4).18,19
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL900941T
(18) For the stoichiometric reaction of PdCl2 and methylenecyclo-hexane,
the KIE values (4.55-5.45) of allylic C-H activation were observed, see:
(a) Chrisope, D. R.; Beak, P. J. Am. Chem. Soc. 1986, 108, 334. (b)
Chrisope, D. R.; Beak, P.; Saunders, W. H. J. Am. Chem. Soc. 1988, 110,
230.
(19) The formation of seven-membered product 2a is the kinetically
preferred product formation and the C-N bond formation is irreversible
step, for more detail see Supporting Information.
(17) The formation of 6a-A also supports the allylic C-H activation
pathway, see Supporting Information Scheme S2 for details.
2710
Org. Lett., Vol. 11, No. 12, 2009