Heterocycle synthesis via direct C-H/N-H coupling

Article abstract of DOI:10.1021/ja210959p

A method for five- and six-membered heterocycle formation by palladium-catalyzed C-H/N-H coupling is presented. The method employs a picolinamide directing group, PhI(OAc)₂ oxidant, and toluene solvent at 80-120 °C. Cyclization is effective for sp² as well as aliphatic and benzylic sp³ C-H bonds.

Full text of DOI:10.1021/ja210959p

Communication
pubs.acs.org/JACS
Heterocycle Synthesis via Direct C−H/N−H Coupling
Enrico T. Nadres and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States
S
* Supporting Information
Scheme 1. Picolinic Acid Directing Group
ABSTRACT: A method for five- and six-membered
heterocycle formation by palladium-catalyzed C−H/N−
H coupling is presented. The method employs a
picolinamide directing group, PhI(OAc)2 oxidant, and
toluene solvent at 80−120 °C. Cyclization is effective for
sp2 as well as aliphatic and benzylic sp3 C−H bonds.
ransition-metal-catalyzed functionalization of carbon−
Thydrogen bonds is a topic of recent intense interest.
During the past few years, significant advances have been made
in the conversion of C−H bonds to C−C and C−O
functionalities.1 However, direct non-nitrene amination reac-
tions are rare. Most of the reports demonstrate functionaliza-
tion of either sp2 or activated (benzylic) sp3 C−H bonds.2a−k
Only a few papers describe palladium-catalyzed amination of
alkane C−H bonds. Functionalization of methyl groups
adjacent to quartenary centers is described in most cases. An
early paper by Sames describes amino acid cyclization under
platinum catalysis.3a Glorius has developed an elegant method
for intramolecular, palladium-catalyzed amination of unacti-
vated sp3 C−H bonds that results in the formation of
indolines.3b The reaction proceeds by an oxidative coupling
of an amide NH with a C(sp3)−H bond that is the most
straightforward way for generating a N−C bond. A
stoichiometric Ag(I) oxidant was employed, and no examples
of pyrrolidine formation were presented. Buchwald has shown
that palladium-catalyzed intermolecular amination of 2-bromo-
tert-butylbenzenes by using aryl amines as a nitrogen source is
possible. In this example, an ortho-C(sp2)−Br bond is used as
an internal oxidant.4 In two examples, palladium-catalyzed
formation of indolines has been accomplished by C−Br/sp3
C−H coupling.5 In these cases, functionalization of C−H
bonds that are not part of tert-butyl groups is also possible.
Several examples describe the formation of indolines or
carbazoles by a C(sp2)−H/NH coupling.6a−c,e Notably, Yu
has demonstrated palladium-catalyzed N-triflated phenethyl-
amine conversion to indolines by employing a range of
oxidants.6a Buchwald and Gaunt have formed carbazoles from
2-arylanilines by employing palladium catalysis and O2/
Cu(OAc)2 or PhI(OAc)2 oxidants.6b,c Copper-catalyzed and
transition-metal-free synthesis of carbazoles has been reporte-
Scheme 2. Activation of C−H Bonds in δ-Positions
pyrrolidine, indoline, and isoindoline synthesis by a C−H/N−
H coupling.
In 2005, we reported the β-arylation of carboxylic acid and γ-
arylation of amine derivatives by employing an 8-aminoquino-
line or picolinic acid auxiliary, catalytic Pd(OAc)2, stoichio-
metric AgOAc, and an aryl iodide coupling partner (Scheme
1).7 Subsequently, a number of auxiliaries were investigated for
carboxylic acid β-arylation and it was shown that silver salts can
be replaced by simple inorganic bases.8 Several other groups
have used this methodology for synthetic purposes. Corey has
used the 8-aminoquinoline auxiliary to arylate sp3 C−H bonds
in amino acid derivatives.9 Chen has employed the method-
ology in the total synthesis of Celogentin C.10a The picolinic
acid directing group has also been used by Chen in the
arylation of γ-positions of amines culminating in the synthesis
of obafluorin.10b Total syntheses of piperarborenines were
recently reported by Baran by employing a 2-thiomethylaniline
directing group.10c The arylation reactions proceed via a
favored double five-membered ring chelate (Scheme 1). If it
was possible for C−H activation in δ-positions to occur,
oxidation of the palladacycle 2 to form a high-valent palladium
species followed by C−N reductive elimination would afford a
d.2i,k Hofmann−Loffler reaction is a classical way to form
̈
pyrrolidines.6f,g A picolinamide directing group has been used
for acetoxylation of sp2 C−H bonds.6d A general method for
C−H/N−H bond coupling that could utilize both sp2 and sp3
C−H bonds has not yet been disclosed. We report here a
method for picolinamide auxiliary assisted, palladium-catalyzed
Received: November 21, 2011
Published: December 29, 2011
© 2011 American Chemical Society
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Communication
pyrroline derivative 3 (Scheme 2). Treatment of 1 with 5%
Pd(OAc)2 in toluene/CD3CO2D at 120 °C showed 33%
deuterium incorporation at the terminal methyl groups. No
other C−H bonds were deuterated. Hence, C−H δ-activation is
Scheme 3. Optimization of Oxidant
possible by employing a picolinic acid directing group.3b,11,12
Subsequent reaction steps require an oxidant capable of
converting palladium to a higher oxidation state followed by
reductive elimination that would afford a cyclized product and
regenerate the Pd(II) catalyst. Several oxidants were inves-
tigated, and the best results were obtained by employing
PhI(OAc)2 in toluene (Scheme 3).
Cyclization results are presented in Table 1. Direct sp2 C−
H/N−H coupling is possible, generating indolines in fair to
a
Table 1. Cyclization of Aryl and Alkyl Picolinamides
a
b
Yields are isolated yields. See Supporting Information for details. 5,6-Dimethoxyindole picolinamide (18%) and 2-acetoxy-4,5-
c
d
e
dimethoxyphenethylamine picolinamide (59%) also isolated. 7-Phenylphenanthridine (7%) also isolated. Toluene/acetonitrile solvent. Trans/
cis ratio 9/1. >10/1 trans/cis. Toluene/DMF solvent. Entries 1, 3−7, 13 were run at 80 °C; 2, 9 at 100 °C, and 10−12, 14 at 120 °C.
f
g
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Journal of the American Chemical Society
Communication
good yields (entries 1−5, 13). Chloro substitution on an
aromatic ring is tolerated (entry 2), as is ester on indoline
(entries 3, 13). 2,2-Diphenylethylamine picolinamide is cyclized
in a good yield affording 3-phenylindoline (entry 4). A low
yield is observed for cyclization of 3,4-dimethoxyphenetylamine
picolinamide (entry 5). In addition to the cyclized product, the
corresponding indole and sp2 C−H bond acetoxylation
products are obtained. Interestingly, formation of a six-
membered ring structure is also possible in a good yield
(entry 6), showing that cyclopalladation via a seven-membered
ring is feasible.3b,12 In addition to a dihydrophenanthridine
derivative, a minor amount of 7-phenylphenanthridine was also
isolated.
In conclusion, we have developed a palladium-catalyzed
method for pyrrolidine, indoline, and isoindoline formation by
a C−H/N−H coupling. The method employs a picolinamide
directing group, PhI(OAc)2 oxidant, and toluene solvent at 80−
120 °C. Cyclization is effective for sp2 as well as aliphatic and
benzylic sp3 C−H bonds.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and characterization data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
More challenging sp3 C−H/N−H cyclizations also proceed
smoothly (entries 7−12, 14). tert-Octylamine picolinamide is
cyclized in a good yield (entry 7), and a 3,3-dimethylbutyl-
amine derivative affords the product in moderate yield (entry
8). Leucine picolinamide gives a cyclized product in fair yield
(entry 9). 4-Methyl-2-aminopentane picolinamide cyclizes in
59% yield (entry 10). Benzylic sp3 C−H bonds are also
reactive. 2,6-Dimethylbenzylamine picolinamide affords a 4-
methylisoindoline derivative (entry 11). A 2,4,6-trisubstituted
isoindoline can be obtained if 2,6-dimethyl-4-bromo-α-
methylbenzylamine picolinamide is cyclized (entry 12). A 2-
tert-butylaniline derivative is cyclized in a modest yield (entry
14). For sp3 C−H bond amination, addition of acetonitrile
solvent is sometimes beneficial (entries 8, 9, 11). Reasonable
functional group tolerance is observed, with tert-butyl and
methyl esters (entries 3 and 13) as well as aromatic chloride
and bromide substituents (entries 2 and 12) tolerated. The
directing group can be removed by LiEt3BH (eq 1). In general,
amination is preferable to acetoxylation which is observed if a
six-membered chelate such as 2 cannot be formed. Amination
of methylene groups was not successful.
AUTHOR INFORMATION
Corresponding Author
olafs@uh.edu
■
ACKNOWLEDGMENTS
■
We thank the Welch Foundation (Grant No. E-1571), National
Institute of General Medical Sciences (Grant No.
R01GM077635), A. P. Sloan Foundation, and Camille and
Henry Dreyfus Foundation for supporting this research.
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