Copper(II) carboxylate-promoted intramolecular carboamination of alkenes for the synthesis of polycyclic lactams

Article abstract of DOI:10.1021/ol702401w

The copper(II) carboxylate-promoted intramolecular carboamination reactions of variously substituted y-alkenyl amides have been investigated. These oxidative cyclization reactions efficiently provide polycyclic lactams, useful intermediates in nitrogen he

Full text of DOI:10.1021/ol702401w

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5477-5480
Copper(II) Carboxylate-Promoted
Intramolecular Carboamination of
Alkenes for the Synthesis of Polycyclic
Lactams
Peter H. Fuller and Sherry R. Chemler*
Department of Chemistry, Natural Science Complex, UniVersity at Buffalo, The State
UniVersity of New York, Buffalo, New York 14260
schemler@buffalo.edu
Received October 2, 2007
ABSTRACT
The copper(II) carboxylate-promoted intramolecular carboamination reactions of variously substituted
γ-alkenyl amides have been investigated.
These oxidative cyclization reactions efficiently provide polycyclic lactams, useful intermediates in nitrogen heterocycle synthesis, in good to
excellent yields. The efficiency of the carboamination process is dependent upon the structure of the amide backbone as well as the nitrogen
substituent.
Nitrogen heterocycles are useful intermediates in complex
molecule synthesis, as well as an abundant class of biologi-
cally active molecules. The rapid assembly of such molecules
and the search for new molecular scaffolds provides a
constant challenge to the synthetic and medicinal chemist;
thus, new methods of entry into these systems are especially
useful.1 One particularly attractive method is the intramo-
lecular carboamination reaction of alkenes.2
In 2004, our lab disclosed the first copper(II) carboxylate-
promoted intramolecular carboamination reaction of N-
arylsulfonyl 2-allyl anilines (eq 1).2c
(1) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285.
(2) (a) Larock, R. C.; Yang, H.; Weinreb, S. M.; Herr, R. J. J. Org.
Chem.1994, 59, 4172. (b) Harayama, H.; Abe, A.; Sakado, T.; Kimura,
M.; Fugami, K.; Tanaka, S.; Tamaru, Y. J. Org. Chem. 1997, 62, 2113. (c)
Sherman, E. S.; Chemler, S. R.; Tan, T. B.; Gerlitis, O. Org. Lett. 2004, 6,
1573. (d) Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am.
Chem. Soc. 2006, 8, 3130. (e) Scarborough, C. C.; Stahl, S. S. Org. Lett.
2006, 8, 3251. (f) Sherman, E. S.; Fuller, P. H.; Kasi, D.; Chemler, S. R.
J. Org. Chem. 2007, 72, 3896. (g) Peng, J.; Lin, W.; Yuan, S.; Chen, Y. J.
Org. Chem. 2007, 72, 3145. (h) Nakhla, J. S.; Wolfe, J. P. Org. Lett. 2007,
9, 3279. (i) Bertrand, M. B.; Leathen, M. L.; Wolfe, J. P. Org. Lett. 2007,
9, 457. (j) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571 and references therein.
More recently we reported further substrate versatility and
diastereoselectivity, and provided an experimental analysis
of the reaction mechanism.2f
In both of these accounts, a variety of γ- and δ-alkenyl
N-aryl sulfonamides were shown to undergo the oxidative
cyclization in the presence of copper(II) carboxylates to
produce the corresponding polycyclic sultams in modest to
good yield.2c,2f In an effort to expand the utility of the method,
10.1021/ol702401w CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/29/2007

a variety of aryl-, vinyl-, and aliphatic γ-alkenyl amides were
investigated in the copper(II)-promoted carboamination reac-
tion. The results of our findings are described in this report.
Under our original reaction conditions (e.g., eq 1), 2-allyl
aniline amides were poor substrates for the copper(II)
carboxylate-promoted intramolecular carboamination reac-
tion, significantly less reactive in comparison to their aryl
sulfonamide counterparts (Table 1, entries 1 and 2).2f Success
Table 2. Carboamination of Aryl Amidesa
Table 1. Reaction Optimizationa
entry
copper salt
temperature (°C)
yieldb (%)
1c
2c
3
Cu(OAc)2
Cu(OAc)2
Cu(ND)2
Cu(EH)2
170
190
190
190
16
39
59
61
4
a Conditions: Substrate in DMF (0.1 M) was treated with Cu(OR)2 (3
equiv) and Cs2CO3 (1 equiv). The mixture was heated to the indicated
temperature for 24 h in a pressure tube. b Yields refer to product isolated
by chromatography on SiO2. c DMSO (4 equiv) was used. The remainder
of the material was either starting olefin or olefin-isomerized starting
material. Cu(EH)2 ) copper(II) 2-ethylhexanoate, Cu(ND)2 ) copper(II)
neodecanoate.
a Conditions: Substrate in DMF (0.1 M) was treated with Cu(EH)2 (3
equiv) and Cs2CO3 (1 equiv). The mixture was heated to 190 °C for 24 h
in a pressure tube. b Yields refer to the sum of products isolated by
chromatography on SiO2. The remainder of the material was either starting
olefin or olefin-isomerized starting material. c tert-Butyl benzene was used
as solvent. The structures of the products (e.g., regioisomer) were assigned
1
by analysis of the aromatic region of the H NMR spectra.
in this matter was subsequently realized when N-benzoyl-
2-allyl aniline was treated with more organic soluble copper-
(II) salts and slightly higher reaction temperatures, providing
polycyclic lactam 2a in moderate yield (Table 1). The organic
soluble copper salts, Cu(II) neodecanoate [Cu(ND)2] and Cu-
(II) 2-ethylhexanoate [Cu(EH)2], were shown to be more
reactive than Cu(OAc)2 (Table 1, entries 3 and 4).2f,3 Cu-
(EH)2 was subsequently used throughout the substrate
screening because of its lower cost and ease of use [Cu-
(EH)2 is purchased as a solid, whereas Cu(ND)2 is purchased
as a solution in toluene].
A variety of 2-allyl aniline-derived aryl amides were
oxidatively cyclized in an efficient manner using the
optimized reaction conditions (Table 2). The mildly electron-
deficient halogenated substrates 1b and 1c reacted efficiently
(Table 2, entries 2-4 and 7). Worth noting, the flourine was
displaced with dimethylamine when the reaction was run in
DMF (Table 2, entry 3) (dimethylamine presumably arises
from thermally decomposed DMF). When tert-butyl benzene
was used as solvent, the carboamination adduct was obtained
in good yield with the fluorine intact (Table 2, entry 4).
4-Cyano and 4-methoxy arylamides displayed comparatively
lower reactivity (Table 2, entries 5 and 6). Meta-substituted
aryl amides demonstrated a preference (ca. 1.8:1) for the
ortho addition product over the para (Table 2, entries 7 and
8). This ortho preference is consistent with that of meta-
substituted aryl sulfonamides2c,f and provides evidence for
C-C bond formation via the addition of a carbon radical to
an aromatic ring.2f,4
2-Allyl aniline-derived vinyl amides are reactive car-
boamination substrates as well (Table 3). Interestingly, the
unsubstituted vinyl amides 9a-c cyclized in 6-endo fashion
at 140 °C to provide the polycyclic R,â-unsaturated lactones
10a-c in good yield (Table 3, entries 1-3). These observa-
tions are in contrast to similar palladium-catalyzed processes
where the 5-exo cyclization product (similar to 11) was the
only observed regioisomer.2d,5 Increasing the reaction tem-
perature to 190 °C, however, resulted in a 1.2:1 mixture of
the 6-endo to 5-exo carboamination adducts (Table 3, entry
4). The 5-exo product 11a terminated in hydrogen-atom
capture rather than olefin formation. This observation
presents an intriguing example of temperature control of
regiochemistry.
Disappointingly, the more substituted vinyl amides 12 and
14 were less reactive (Table 3, entries 5 and 6). These
substrates required higher reaction temperature (190 °C) in
order to consume most of the substrate, but in doing so,
resulted in the concomitant formation of a mixture of
5-exo cyclization products and isomerized olefin starting
material.
(4) (a) Ito, R.; Migita, T.; Morikawa, N.; Simamura, O. Tetrahedron
1965, 21, 955. (b) Pryor, W. A.; Davis, W. H.; Gleaton, J. H. J. Org. Chem.
1975, 40, 2099.
(5) (a) Hegedus, L. S.; McKearin, J. M. J. Am. Chem. Soc. 1982, 104,
2444. (b) Danishefsky, S.; Taniyama, E. Tetrahedron Lett. 1983, 24, 15.
(3) (a) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077. (b) Baran,
P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450. (c) For a review
of copper-facilitated C-N and C-C bond formation, see Chemler, S. R.;
Fuller, P. H. Chem. Soc. ReV. 2007, 36, 1153 and references therein.
5478
Org. Lett., Vol. 9, No. 26, 2007

Table 3. Carboamination of Vinyl Amidesa
Table 4. Carboamination of Aliphatic Imides and Amidesa
a Conditions: Substrate in DMF (0.1 M) was treated with Cu(EH)2 (3
equiv) and Cs2CO3 (1 equiv). The mixture was heated to 140 °C for 24 h
in a pressure tube. b Yields refer to the sum of products isolated by
chromatography on SiO2. The remainder of the material was either starting
olefin or olefin-isomerized starting material. c Heated to 190 °C for 24 h.
a Conditions: Substrate in DMF (0.1 M) was treated with Cu(EH)2 (3
equiv) and Cs2CO3 (1 equiv). The mixture was heated to 120 °C for 24 h
in a pressure tube. b Yields refer to the sum of products isolated by
chromatography on SiO2. The remainder of the material was either starting
olefin or olefin-isomerized starting material. c Heated to 190 °C. d Reaction
run for 72 h. e tert-Butyl benzene was used as solvent.
Our previous studies showed that the copper(II) carboxy-
late-promoted intramolecular carboamination reaction is
effective in cyclizing a variety of aliphatic N-aryl sulfona-
mides (e.g., eq 2).2f
its benzyl amide counterpart 19 (Table 4, entries 1 and 2).
Thus, the imide is more reactive than the alkyl amide.
Substrates with geminally disubstituted carbon backbones
cyclized more efficiently due to the Thorpe-Ingold effect
(compare entries 6 and 7, Table 4).6
This prompted us to investigate the cyclization reaction
of a corresponding N-benzoyl aliphatic amide (eq 3).
Unfortunately, this substrate was shown to be unreactive
upon heating at 190 °C for 24 h.
The aryl amides 22 and 25 were able to undergo the
cyclization in an efficient manner albeit with the formation
of the hydroamination byproducts (Table 4, entries 3 and
4). In order to reduce hydroamination and maximize car-
boamination, a less hydrogen-atom-donating solvent, i.e.,
tert-butyl benzene, was used. Although increased selectivity
for carboamination was observed, formation of the hy-
droamination byproduct still occurred. Regardless, these are
the first examples where two fused five-membered rings are
formed in the copper(II) carboxylate-promoted intramolecular
carboamination reaction. Substrate 28, which lacks the
geminal methyl groups in the backbone, only produced
hydroamination adduct 29 (Table 4, entry 5). Because of the
apparent difficulty in forming a five-membered ring with
the aryl substituent7 (vide supra), naphthalene substrates 30
and 32 were investigated. Gratifyingly, both substrates
This result led us to examine a variety of structurally
different imides and amides as shown Table 4. Imide 17
cyclized in high yield while the amide substrate in eq 3 did
not react. This indicates that an sp2 hybridized carbon in the
substrate’s backbone decreases the activation energy for
cyclization. (This could be due to lower relative torsional
strain in the five-membered ring of the transition state and
product for substrate 17.) In addition, imide 17 cyclized at
lower temperature and in higher yield and selectivity than
(6) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Am. Chem. Soc. 1915,
107, 1080.
Org. Lett., Vol. 9, No. 26, 2007
5479

underwent the oxidative cyclization in good yield without
the simultaneous formation of the hydroamination byproduct
(Table 4, entries 6 and 7).
Scheme 1. Mechanistic Rationale for Carboamination Product
36c
During the synthesis of naphthalene substrate 30, an
interesting observation was made. When the corresponding
amide was treated under the coupling reaction conditions
developed by Buchwald et al.8 (5 mol % CuI, DMDA,
iodonaphthalene, K3PO4, in DMF at 120 °C), trace amounts
of carboamination (ca. 2-3%) product (31) are observed in
1
the H NMR. This occurrence is easily explained by the
ability of Cu(I) to disproportionate into Cu(II) and Cu(0).9
Thus, in an effort to exploit this reactivity, a one-pot
arylation/carboamination reaction was performed. Upon
completion of the coupling reaction, 3 equiv of Cu(EH)2 was
added to the reaction mixture. After 24 h the carboamination
adduct was obtained in 71% yield (eq 4).
add 1,6 to give the carboamination product 35c after
oxidation of the aryl radical intermediate B, or 1,5 (ipso),
giving rise to carboamination product 36c via intermediate
C, radical migration, and oxidative re-aromatization as shown
in Scheme 1.10 Rearrangement of intermediate C via a
carbocation is also possible.
In conclusion, the intramolecular copper(II) carboxylate-
promoted carboamination reaction is an efficient method to
form a variety of polycyclic lactams. The substrate scope
has been expanded from sulfonamides, to include not only
aryl amides, but vinyl amides and alkyl imides as well.
Furthermore, a simple one-pot arylation/carboamination
reaction sequence was achieved. The synthetic utility of this
methodolgy and its application in natural product as well as
biologically active molecule synthesis is currently ongoing
in our lab and will be reported in due course.
Another interesting observation was made when perform-
ing the carboamination reaction on heteroaromatic ring
amides. Both the amido furan 34a and the amido pyrrole
34b derivatives of 2-allyl aniline were unreactive substrates.
The amido thiophene 34c cyclized in 43% yielding two
carboamination products 35c and 36c in a 1:1 ratio (eq 5).
This observation can be rationalized on the basis of the
Acknowledgment. We thank Mr. Dov Shalman (North-
western University), Ms. Fatima Sequiera (University at
Buffalo, ACS administered PRF Summer Scholar 40968-
G1), and Ms. Melantha Jackson (from Utica College, NSF
REU Fellowship at SUNY, Buffalo, CHE-0453206) for
preliminary studies. This work was supported by the National
Institutes of Health (NIGMS R01-GM078383).
Supporting Information Available: Procedures and
characterization data and NMR spectra for all new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
mechanism shown in Scheme 1. Thus, syn aminocupration
followed by homolysis of the resulting unstable organocopper
intermediate gives primary radical A.2f This radical can either
OL702401W
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5480
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