Pd-catalyzed Semmler-Wolff reactions for the conversion of substituted cyclohexenone oximes to primary anilines

Article abstract of DOI:10.1021/ja4073172

Homogeneous Pd catalysts have been identified for the conversion of cyclohexenone and tetralone O-pivaloyl oximes to the corresponding primary anilines and 1-aminonaphthalenes. This method is inspired by the Semmler-Wolff reaction, a classic method that exhibits limited synthetic utility owing to its forcing conditions, narrow scope, and low product yields. The oxime N-O bond undergoes oxidative addition to Pd⁰(PCy₃)₂, and the product of this step has been characterized by X-ray crystallography and shown to undergo dehydrogenation to afford the aniline product.

Full text of DOI:10.1021/ja4073172

Communication
pubs.acs.org/JACS
Pd-Catalyzed Semmler−Wolff Reactions for the Conversion of
Substituted Cyclohexenone Oximes to Primary Anilines
Wan Pyo Hong, Andrei V. Iosub, and Shannon S. Stahl*
Department of Chemistry, University of WisconsinMadison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S
* Supporting Information
Scheme 2. Known Pd-Catalyzed Aerobic Dehydrogenation
Routes to Substituted Phenols and Anilines
ABSTRACT: Homogeneous Pd catalysts have been
identified for the conversion of cyclohexenone and
tetralone O-pivaloyl oximes to the corresponding primary
anilines and 1-aminonaphthalenes. This method is inspired
by the Semmler−Wolff reaction, a classic method that
exhibits limited synthetic utility owing to its forcing
conditions, narrow scope, and low product yields. The
oxime N−O bond undergoes oxidative addition to
Pd0(PCy3)2, and the product of this step has been
characterized by X-ray crystallography and shown to
undergo dehydrogenation to afford the aniline product.
molecules, and we envisioned that analogous methods could
be used to prepare anilines. Dehydrogenation of preformed
cyclohexanone-derived enamines has been used to prepare
tertiary anilines, but these reactions exhibit relatively narrow
scope and often use undesirable stoichiometric oxidants.11,12 Our
preliminary efforts focused on in situ condensation of an amine
with the ketone, followed by dehydrogenation of the imine or
enamine intermediate (Scheme 2B). These reactions were
complicated by parallel dehydrogenation of the ketone and
imine/enamine and led to mixtures of phenol and aniline
products. Independently, however, the groups of Yoshikai and Li
identified suitable Pd catalysts and substrate partners for this
transformation, enabling good yields of various secondary and
tertiary aryl amines via this strategy.13 The condensation of
ammonia with ketones is not strongly favored, and it is unlikely
that primary anilines could be prepared by a similar approach.
Oximes are quite stable, however, and the Semmler−Wolff
precedent raised the prospect of identifying Pd catalysts to
enhance the synthetic utility of this transformation. Oxidative
romatic amines are prevalent in pharmaceuticals, agro-
A
chemicals, and functional organic materials.1 Of such
structures, primary anilines (ArNH2) are among the most
difficult to access via metal-catalyzed C−N coupling with aryl
halides or arylboronic acid derivatives (e.g., Ullmann−Goldberg,
Buchwald−Hartwig, Chan−Lam). Strategies to address this
challenge include the use of ammonia surrogates, such as benzyl
amine and tert-butyl carbamate,2 which can undergo C−N
coupling and yield the parent aniline upon deprotection. Recent
efforts have identified catalytic methods compatible with
ammonia as the nitrogen nucleophile,3 as well as uncatalyzed
reactions of aryl boron reagents with methoxy- or aryloxy-
amines.4 The Semmler−Wolff reaction is a classic but rarely used
method for the synthesis of aromatic primary amines involving
dehydration of cyclohexenone- and tetralone-derived oximes.
This reaction is typically carried out under harsh conditions with
anhydrous HCl gas in refluxing AcOH/Ac2O (Scheme 1).5−8 It
addition of N−O bonds has been exploited in various Pd0/II
-
catalyzed reactions,14 and the oxime could therefore serve as an
internal oxidant to promote Pd-mediated dehydrogenation of the
substrate.
Scheme 1. Semmler−Wolff Reaction
A number of different 1-tetralone oxime derivatives (1a−h)
were synthesized and tested under a variety of catalytic
conditions (Chart 1, Table 1). The O-pentafluorobenzoyl and
O-pivaloyl derivatives 1a and 1c led to the highest yield of 1-
aminonaphthalene 2. Lower yields were obtained with the
benzoyl and acetyl derivatives, and very low yields were obtained
with the carbonate, siloxy, and sulfonate derivatives 1e−h. The
reaction with the O-acetyl derivative (1d) led to a 7% yield of N-
acetyl-1-aminonaphthalene as a side product. On the basis of
these observations, we opted to proceed with pivaloyl oxime
exhibits limited functional group compatibility, and it typically
affords products in moderate to low (≤60%) yields, with the
Beckmann rearrangement as a common side reaction. Here, we
show that homogeneous Pd catalysts overcome many of these
limitations in the conversion of cyclohexenone and tetralone O-
acyl oximes to the corresponding primary aromatic amines.
We recently reported Pd-catalyzed methods for aerobic
dehydrogenation of diverse substituted cyclohexanones and
cyclohexenones to phenols (Scheme 2A).9,10 These reactions
complement metal-catalyzed cross-coupling routes to such
Received: July 20, 2013
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
Chart 1. Comparison of O-Substituents in the Conversion of
Tetralone Oximes to 1-Aminonaphthalene (2)
Table 2. Aromatization of Substituted Tetralone Pivaloyl
Oximes
ab
,
a
a
Reaction conditions: 1a−h (0.2 mmol), Pd(OAc)2 (0.02 mmol),
tricyclopentylphosphine (0.04 mmol), K2CO3 (0.8 mmol), toluene
b
(2.2 mL). 1H NMR yield; internal standard = tetrachloroethane.
c
Yield of N-acetyl-1-aminonaphthalene.
Table 1. Reaction Optimization for Conversion of Tetralone
Pivaloyl Oxime to 1-Aminonaphthalene (2)
% conv/
b
entry
palladium
ligand
additive
% yield
1
2
3
4
5
6
7
8
9
10
10% Pd(P(o-tol)3)2
5% Pd2(dba)3
50/24
56/23
96/70
99/63
99/68
97/82
97/80
74/37
73/62
78/44
99/87
10% Pd(PPh3)4
5% Pd2(dba)3
a
Reaction conditions: pivaloyl oxime (0.2 mmol), Pd(OAc)2 (0.02
20% PPh3
20% PCy3
20% PCyp3
20% PCy3
20% PPh3
20% dppe
20% dppf
mmol), tricyclopentylphosphine (0.04 mmol), PivOH (0.06 mmol),
b
5% Pd2(dba)3
toluene (2.2 mL). Structural data were analyzed after acetylation.
c
10% Pd(OAc)2
10% Pd(OAc)2
10% Pd(OAc)2
10% Pd(OAc)2
10% Pd(OAc)2
10% Pd(OAc)2
Reaction temperature, 120 °C.
shown to react with good yields (Table 2). The formation of 5 is
noteworthy because of the presence of a sensitive nitro group,
which is not tolerated under Semmler−Wolff aromatization
conditions. Formation of 7 was successfully reproduced on 2.2 g
scale. Several aminonaphthalene products (9, 10, and 11)
represent key intermediates in the synthesis of pharmaceutically
active compounds. A previously reported synthesis of the 3α-
hydroxysteroid dehydrogenase inhibitor HKI0231B prepared
aminonaphthalene 9 in 50% yield via aromatization of the
tetralone tosyl oxime in the presence of strong base (KOH,
refluxing MeOH).6d The Pd-catalyzed method described here
generates 9 in 80% isolated yield. Aminonaphthalene 10 is the
central intermediate in the preparation of benzo[c]-
phenanthridine alkaloids such as chelerythrine, fagaridine, and
decarine. The yield of 10 is only 58% under the present
conditions, but this result is significantly better than the 28%
yield obtained under classical Semmler−Wolff conditions.17
Compound 11 is an intermediate in the synthesis of the anti-
tumor/anti-viral alkaloid, norallonitidine.18 Efficient access to 11
via this Pd-catalyzed method (79% yield) may be compared to a
previously reported route (Scheme 3), in which classical
electrophilic nitration affords a mixture of difficult-to-separate
nitronaphthalene products,19,20 and only 17% of this mixture
consists of the nitronaphthalene precursor to 11. These results
highlight the regioselectivity advantage of (catalytic) Semmler−
Wolff methods relative to nitration/reduction routes to
substituted anilines. Complications were encountered in the
a
11
20% PCyp3 30% PivOH
a
Reaction conditions of entry 11: 1c (0.2 mmol), Pd(OAc)2 (0.02
mmol), tricyclopentylphosphine (0.04 mmol), PivOH (0.06 mmol),
b
K2CO3 (0.8 mmol), toluene (2.2 mL). 1H NMR yield; internal
standard, tetrachloroethane.
derivatives rather than the more expensive pentafluorobenzoyl
derivatives.
Representative catalyst screening data for the conversion of of
1-tetralone pivaloyl oxime to 1-aminonaphthalene are summar-
ized in Table 1 (see Supporting Information for additional
data).15 Pd(PPh3)4 gave full conversion and 70% yield (entry 3),
while other Pd0 sources, including Pd(P(o-tol)3)2 or Pd2(dba)3,
were less effective (entries 1 and 2). Good yields could be
obtained by combining Pd2(dba)3 with an appropriate phosphine
ligand (entries 4 and 5), and even better results were obtained by
using Pd(OAc)2 with 2 equiv of a phosphine ligand (entries 6−
11). Further screening studies revealed that the optimal result
could be obtained with a Pd(OAc)2/tricyclopentylphosphine
(PCyp3) catalyst system, containing pivalic acid (30 mol %; entry
11, 87% yield of 2). The idea of testing pivalic acid as an additive
was inspired by precedents in which pivalate/pivalic acid serves
as a proton shuttle in C−H activation.16
Upon the identification of suitable reaction conditions, a
variety of substituted tetralone-derived oximes were tested and
B
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Journal of the American Chemical Society
Communication
Scheme 3. Previously Reported Route to 1119
Semmler−Wolff conditions, which result in a product with
both N- and O-acetyl groups.6a Cyclohexenone oximes bearing
sulfone substituents were compatible with the reaction
conditions, and the corresponding sulfone-substituted anilines
23 and 24 were obtained in good yield. Reactions of 4-
alkoxycarbonyl-cyclohexenone derivatives afforded the corre-
sponding anilines 25 and 26.21
Oxidative addition of oxime N−O bonds to Pd0 has been
utilized in a number of catalytic transformations, including aza-
Heck coupling and directed C−H activation/C−N reductive
elimination reactions.14 Several different oxime and LnPd0
derivatives were evaluated in an effort to probe the viability of
this fundamental step as a prelude to aniline formation in the
present catalytic reactions.22 The reaction of tetralone pivaloyl
oxime with a stoichiometric amount of Pd(PPh3)4 led to a
complex product mixture, but the combination of tetralone
pentafluorobenzoyl oxime 1a and Pd(PCy3)2 afforded the N−O
oxidative addition product 27, which was characterized by NMR
spectroscopy and X-ray crystallography (Scheme 4). Upon
reaction of 6-bromo-1-tetralone; unsuccessful reaction of this
substrate (not shown) suggests that competing oxidative
addition of Ar−Br to Pd0 can initiate unwanted side reactions.
Efforts to engage 2-tetralone pivaloyl oxime in this reaction
resulted in only low yield (32%).
The catalytic conditions also proved to be successful for the
aromatization of cyclohexenone-derived pivaloyl oximes (Table
3). An array of primary anilines was obtained, including products
with cyano, trifluoromethyl, and chloro substituents. The more
sterically hindered 2-phenyl- and 6-phenylcyclohexenone oximes
proceed effectively to 2-aminobiphenyl (20) in 70% yield, and
even the 2,5,6-triphenyl derivative affords the corresponding
aniline 21 in 46% yield. A silyl ether group (in 22) was retained
under the catalytic reaction conditions, unlike traditional
Scheme 4. Stoichiometric Oxidative Addition/Aromatization
Sequence and X-ray Crystal Structure of 27
Table 3. Aromatization of Substituted Cyclohexenone
a
Pivaloyl Oximes
heating in toluene, 27 reacts to afford 1-aminonaphthalene in
46% yield. The reaction proceeds with somewhat faster rate and
in higher yield (59%) if it is carried out in the presence of pivalic
acid and K2CO3, which are valuable additives in the catalytic
reaction.
On the basis of these observations, we propose the mechanism
shown in Scheme 5. Oxidative addition of the tetralone oxime 1c
affords intermediate 27, which can undergo tautomerization to
afford the enamine-derived amido-PdII species A. Further
isomerization of this species results in coversion of this N-
bound enamido−PdII species to its C-bound isomer B. β-
Hydride elimination from C generates the primary enimine,
which can tautomerize to its more stable isomer, 1-amino-
naphthalene (2). We speculate that the beneficial effect of the
pivalic acid under catalytic and stoichiometric conditions (Table
1 and Scheme 5, respectively) reflects its ability to facilitate
proton-transfer reactions involved in the tautomerization step.
The base (K2CO3) is heterogeneous under the reaction
conditions, but it could play a similar role, in addition to
promoting the reductive elimination step, which forms carboxylic
acid as a stoichiometric byproduct.
a
Reaction conditions: pivaloyl oxime (0.2 mmol), Pd(OAc)2 (0.02
mmol), tricyclopentylphosphine (0.04 mmol), PivOH (0.06 mmol),
K2CO3 (0.8 mmol), toluene (2.2 mL). Structural data were analyzed
after acetylation. Derived from 2-phenylcyclohexenone. Derived
from 6-phenylcyclohexenone. Reaction temperature, 120 °C.
b
c
d
In summary, these results show that homogeneous Pd catalysts
promote efficient Semmler−Wolff-type reactions for conversion
e
C
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Journal of the American Chemical Society
Communication
(6) Modified conditions have been investigated; for leading references,
see: (a) Newman, M. S.; Hung, W. M. J. Org. Chem. 1973, 38, 4073.
(b) Tamura, Y.; Yoshimoto, Y.; Sakai, K.; Kita, Y. Synthesis 1980, 483.
(c) Tamura, Y.; Yoshimoto, Y.; Sakai, K.; Haruta, J.; Kita, Y. Synthesis
1980, 887. (d) Scopton, A.; Kelly, T. R. J. Org. Chem. 2005, 70, 10004.
(7) Traditional Semmler−Wolff reactions often lead to mixtures of
mono- and diacetylated anilines, which are treated with aqueous base to
afford the primary aniline. Kelly, T. R.; Chandrakumar, N. S.; Saha, J. K.
J. Org. Chem. 1989, 54, 980.
Scheme 5. Proposed Catalytic Cycle
(8) Heterogeneous Pd catalysts (Pd/C) can promote the Semmler−
Wolff reaction; however, very high temperatures (e.g., 200 °C) are
required. (a) Horning, E. C.; Horning, M. G. J. Am. Chem. Soc. 1947, 27,
1907. (b) Matsumoto, M.; Tomizuka, J.; Suzuki, M. Synth. Commun.
1994, 24, 1441. (c) Matsumoto, M.; Tomizuka, J. ITE Lett. 2000, 1, 127.
(9) (a) Izawa, Y.; Pun, D.; Stahl, S. S. Science 2011, 333, 209. (b) Izawa,
Y.; Zheng, C.; Stahl, S. S. Angew. Chem., Int. Ed. 2013, 52, 3672. (c) Pun,
D.; Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 8213.
(10) For related transformations, see: (a) Diao, T.; Stahl, S. S. J. Am.
Chem. Soc. 2011, 133, 14566. (b) Simon, M. O.; Girard, S. A.; Li, C.-J.
Angew. Chem., Int. Ed. 2012, 51, 7537. (c) Gao, W.; He, Z.; Qian, Y.;
Zhao, J.; Huang, Y. Chem. Sci. 2012, 3, 883. (d) Diao, T.; Wadzinski, T.
J.; Stahl, S. S. Chem. Sci. 2012, 3, 887. (e) Imahori, T.; Tokuda, T.;
Taguchi, T.; Takahata, H. Org. Lett. 2012, 14, 1172. (f) Sutter, M.; Sotto,
of readily accessible tetralone and cyclohexenone pivaloyl oxime
derivatives to the corresponding primary anilines. These
reactions provide an important demonstration of the comple-
mentarity of dehydrogenation and cross-coupling methods to
access valuable substituted aromatic molecules.
́
N.; Raoul, Y.; Metay, E.; Lemaire, M. Green Chem. 2013, 15, 347.
(g) Xie, Y.; Liu, S.; Liu, Y.; Wen, Y.; Deng, G.-J. Org. Lett. 2012, 14, 1692.
(h) Kim, D.; Min, M.; Hong, S. Chem. Commun. 2013, 49, 4021.
(11) (a) Ishikawa, T.; Uedo, E.; Tani, R.; Saito, S. J. Org. Chem. 2001,
66, 186. (b) Cossy, J.; Belotti, D. Org. Lett. 2002, 4, 2557. (c) Horillo-
Martinez, P.; Virolleaud, M. A.; Jaekel, C. ChemCatChem 2010, 2, 175.
(d) Bigdelli, M. A.; Rahmati, A.; Abbasi-Ghadim, H.; Mahdavinia, G. H.
Tetrahedron Lett. 2007, 48, 4575.
ASSOCIATED CONTENT
* Supporting Information
Additional catalyst screening data, experimental procedures, and
full compound characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
(12) Primary anilines have been accessed via dehydrogenation of
amino cyclohexene derivatives obtained via Diels−Alder cycloaddition
of Cbz-protected dienamines and activated dienophiles, such as N-
methyl maleimide. Neumann, H.; von Wangelin, A. J.; Klaus, S.;
AUTHOR INFORMATION
Corresponding Author
stahl@chem.wisc.edu
■
Strubing, D.; Gordes, D.; Beller, M. Angew. Chem., Int. Ed. 2003, 42,
̈
̈
4503.
(13) (a) Hajra, A.; Wei, Y.; Yoshikai, N. Org. Lett. 2012, 14, 5488.
(b) Girard, S. A.; Hu, X.; Knauber, T.; Zhou, F.; Simon, M. O.; Deng, G.
J.; Li, C.-J. Org. Lett. 2012, 14, 5606. (c) Wei, Y.; Deb, I.; Yoshikai, N. J.
Am. Chem. Soc. 2012, 134, 9098.
(14) For leading references, see: (a) Tsutsui, H.; Narasaka, K. Chem.
Lett. 1999, 45. (b) Kitamura, M.; Narasaka, K. Chem. Rec. 2002, 2, 268.
(c) Narasaka, K. Pure. Appl. Chem. 2003, 75, 19. (d) Zaman, S.;
Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn. 2003, 76, 1055.
(e) Narasaka, K.; Kitamura, M. Eur. J. Org. Chem. 2005, 4505. (f) Zaman,
S.; Mitsuru, K.; Abell, A. D. Org. Lett. 2005, 7, 609. (g) Tan, Y.; Hartwig,
J. F. J. Am. Chem. Soc. 2010, 132, 3676. (h) Faulkner, A.; Bower, J. F.
Angew. Chem., Int. Ed. 2012, 51, 1675.
(15) The reaction conditions in Table 1 often produced a dimeric
compound (up to 6% yield) arising from the condensation of 1-
aminonaphthalene with pivaloyl oxime 1c.
(16) Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496.
(17) Kessar, S. V.; Gupta, Y. P.; Balakrishnan, P.; Sawal, K. K.;
Mohammad, T.; Dutt, M. J. Org. Chem. 1988, 53, 1708.
(18) Geen, G. R.; Mann, I. S.; Mullane, M. V.; McKillop, A. J. Chem.
Soc., Perkin Trans. 1 1996, 1647.
(19) The distribution of products is 5-nitro-2,3-dimethoxynaphthalene
(17%), 6-nitro-2,3-dimethoxynaphthalene (36%), and 4-nitro-2,3-
dimethoxynaphthalene (47%).
(20) Stermitz, F. R.; Gillespie, J. P.; Amoros, L. G.; Romero, R.;
Stermitz, T. A.; Larson, K. A.; Earl, S.; Ogg, J. E. J. Med. Chem. 1975, 18,
708.
(21) Attempted aromatization of the parent oxime of 25 using
modified Semmler−Wolff conditions7 led to hydrolysis of the ester
followed by decarboxylation, with no formation of the desired aniline.
(22) Characterization of oxime N−O oxidative addition was recently
reported in the context of intramolecular C−H amination reactions.14g
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Dr. Ilia A. Guzei and Brian Dolinar for X-ray
crystallographic analysis of 27, and we thank the NIH for
financial support of this work (R01-GM100143). NMR
spectroscopy facilities were funded by NSF (CHE-1048642
and CHE-0342998).
REFERENCES
■
(1) (a) Rappoport, Z., Ed. The Chemistry of Anilines, Parts 1 and 2; John
Wiley & Sons: New York, 2007. (b) Negwer, M, Organic Chemical Drugs
and their Synonyms, 7th ed.; Akademie Verlag GmbH: Berlin, 1994.
(2) For leading references, see: (a) Wolfe, J. P.; Åhman, J.; Sadighi, J.
P.; Singer, R. A.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367.
(b) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575. (c) Shen, Q. L.;
Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 6586.
(3) For leading references, see: (a) Shen, Q.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 10028. (b) Xia, N.; Taillefer, M. Angew. Chem., Int. Ed.
2009, 48, 337. (c) Vo, G. D.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131,
11049. (d) Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto, M.
Angew. Chem., Int. Ed. 2010, 49, 4071. (e) Surry, D. S.; Buchwald, S. L.
Chem. Sci. 2011, 2, 27. (f) Ji, P. J.; Atherton, J. H.; Page, M. I. J. Org.
Chem. 2012, 77, 7471.
(4) (a) Mlynarski, S. N.; Karns, A. S.; Morken, J. P. J. Am. Chem. Soc.
2012, 134, 16449. (b) Zhu, C.; Li, G.; Ess, D. H.; Falck, J. R.; Kurti, L. J.
Am. Chem. Soc. 2012, 134, 18253.
(5) (a) Semmler, W. Ber. Dtsch. Chem. Ges. 1892, 25, 3352. (b) Wolff,
̈
L. Justus Liebigs Ann. Chem. 1902, 322, 351.
D
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