Oxidative Pd(II)-catalyzed C-H bond amination to carbazole at ambient temperature

Article abstract of DOI:10.1021/ja806543s

We report a new Pd(II)-catalyzed C-H bond amination reaction to form carbazoles, an important motif that is prevalent in a range of systems. The catalytic amination process operates under extremely mild conditions and produces carbazole products in good to excellent yields. Carbazoles possessing complex molecular architecture can also be formed using this reaction, highlighting its potential in natural product synthesis applications. Preliminary mechanistic investigations reveal the reaction proceeds through a Pd(II)/Pd(IV) manifold and that reductive elimination from a high oxidation state Pd(IV) complex facilitates the mild conditions of this transformation. Copyright

Full text of DOI:10.1021/ja806543s

Published on Web 11/08/2008
Oxidative Pd(II)-Catalyzed C-H Bond Amination to Carbazole at Ambient
Temperature
James A. Jordan-Hore, Carin C. C. Johansson, Moises Gulias, Elizabeth M. Beck, and
Matthew J. Gaunt*
Department of Chemistry, UniVersity of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K.
Received August 18, 2008; E-mail: mjg32@cam.ac.uk
The ubiquity of aromatic C-N bonds in organic molecules has
made the development of novel amination methodologies an
important objective for chemical synthesis. Until recently, traditional
methods for diaryl-amine bond construction routinely focused on
variations of Cu-mediated Ullmann coupling between an aryl halide
and an aniline.1 However, these processes can sometimes be
problematic due to harsh conditions, therefore restricting their utility
in complex molecule synthesis applications. The limitations of
Ullmann-type amination reactions have now been marginalized
through the pioneering studies carried out in the Buchwald and
Hartwig laboratories.2 The advances made through these modern
day Pd(0) and Cu(I) catalyzed transformations mean that many
classes of amine are now accessible.2 Interestingly, the disconnec-
tion of the C-N bond in these processes, to an aryl halide and
aniline, remains the same as in the case of Ullmann’s seminal report
(eq 1a).1a With this mind, we considered a direct catalytic C-H
amination process could complement existing C-N bond forming
strategies. Herein, we describe a Pd(II)-catalyzed intramolecular
C-H bond amination strategy (eq 1b) and its application to direct
carbazole formation (eq 1c);3 this motif is common in bioactive
natural products,4a has demonstrated importance in a range of
therapeutics,4b and imparts novel properties in polymeric materials
(eq 2).4c This Pd(II)-catalyzed amination process does not require
prefunctionalization of the aryl group, operates under ambient
conditions, and can be applied to the assembly of complex
molecules.
through highly reactive metallo-nitreneoids,5a-f and π-allyl-type
species.5g-i More relevant to this study is the elegant Pd(II)-
catalyzed intramolecular amination of acetanilide derivatives.6 This
Pd(II)/Pd(0) process is proposed to occur via coordination of the
metal center to the amide, carbopalladation, and reductive elimina-
tion to form the C-N bond but requires rather forcing reaction
conditions.
As part of our blueprint for an ambient and general catalytic
C-H bond amination strategy, we reasoned that reductive elimina-
tion from a high oxidation state Pd(IV) center would more readily
facilitate C-N bond formation.8 To realize this process, an amine
bearing an electron-donating group (1) should coordinate strongly
to a Pd(II) catalyst, resulting in complex I that could then undergo
cyclopalladation to form II. Next, oxidation of the Pd(II) complex
II to a Pd(IV) species III would expedite C-N bond formation to
form 2 (Scheme 1). Following this design strategy, we anticipated
that both carbopalladation and oxidation, and hence the overall C-H
amination process, could occur under ambient conditions.
Scheme 1. Proposed Mechanistic Hypothesis for C-H Amination
Guided by this, we began our studies by testing the reaction of
N-Bn biphenyl 1a to carbazole 2a at room temperature, in the
presence of catalytic amounts of Pd(OAc)2 and an oxidant (Table
1).
Table 1. Optimization towards Catalytic C-H Bond Amination
catalyst
loading,
mol %
entry
R
solvent
oxidant
yield, %a
1
2
3
4
5
6
7
8
9
10
10
10
10
10
10
10
10
5
Bn
Bn
Bn
H
H
H
Ac
Ac
Bn
DMF
DMF
CH2Cl2
DMF
DMF
CH2Cl2
DMF
CH2Cl2
PhMe
t-BuOOBz
PhI(OAc)2
PhI(OAc)2
t-BuOOBz
PhI(OAc)2
PhI(OAc)2
t-BuOOBz
PhI(OAc)2
PhI(OAc)2
nr
18 (2a)
77 (2a)
<10 (2b)
34 (2b)
<10 (2b)
<10 (2c)
<10 (2c)
96 (2a)
a Isolated yield after chromatography.
In recent years, significant progress has been made in the area
After screening a variety of conditions, we found that reaction
of 1a (R ) Bn), with t-BuOOBz or phenyliodosyl diacetate
of metal-catalyzed amination of C-H bonds,5,6 for example,
9
16184 J. AM. CHEM. SOC. 2008, 130, 16184–16186
10.1021/ja806543s CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Scope of C-H Bond Amination: Aryl-Ring Substituents
(PhI(OAc)2) as oxidant and DMF as solvent, afforded carbazole
2a in low yield (entries 1 and 2). However, changing the solvent
to CH2Cl2, while maintaining PhI(OAc)2 as oxidant, led to the
formation of the desired product 2a in 77% yield (entry 3).
Interestingly, reaction of 1b (R ) H) under similar conditions
afforded carbazole 2b in poor yields (entries 4-6) that could not
be improved on. Little reaction was observed with acetamide 1c
(R ) Ac) at room temperature (entries 7 and 8), in contrast to related
studies under more forcing conditions.6a Subsequent optimization
on 1a (R ) Bn) revealed that reaction at room temperature with 5
mol % Pd(OAc)2 as catalyst, 1.2 equiv of PhI(OAc)2 as oxidant,
and PhMe as solvent afforded 96% of the carbazole 2a after 1 h
(entry 9).9a,b These results clearly demonstrate that N-alkyl amines
display enhanced reactivity in this Pd(II)-catalyzed C-H bond
amination process, under ambient conditions. Furthermore, they
suggest that key mechanistic differences exist between our Pd(II)-
catalyzed amination and related transformations of acetanilides.6a-d
No reaction was observed in the absence of the palladium catalyst.
With an optimized set of reaction conditions, attention was turned
to the exploration of the scope of this Pd(II)-catalyzed C-H
amination process. We first examined the effect of the nitrogen
substituent; mindful of the fact that we needed to demonstrate a
range of tolerant groups, we also need to be able to remove the
N-substituent if necessary. Simple alkyl, benzyl, and allyl motifs
all worked well in the reaction, providing the carbazoles 2a-g in
good yields (Table 2, entries 1-5).
catalyst
entry loading,
mol %
Ar (in 2)a
additive
time, h
yield, %b
1c
2
3
5
5
3-(OMe)-C6H4
3-(Me)-C6H4
3-(F)-C6H4
3-(Cl)-C6H4
3-(CO2Me)-C6H4 1 equiv of AcOH
3-(NO2)-C6H4
2-(OMe)-C6H4
2-(CO2Me)-C6H4
4-(Me)-C6H4
4-(OMe)-C6H4
R-C10H6
-
4
1
3
2
5
36
4
5
3
4
85 (2q)
86 (2l)d
72 (2m)e
80 (2k)
95 (2n)
72 (2r)
81 (2i)
94 (2s)
56 (2o)
75 (2f)
63 (2u)
1 equiv of AcOH
-
10
10
10
10
5
5
5
5
20
4
1 equiv of AcOH
5
6f
7
1 equiv of AcOH
-
-
8
9
10
11
1 equiv of AcOH
-
1 equiv of AcOH
3
a Standard
carbazole
numbering.
b Isolated
yield
after
chromatography. c Reaction at 5 °C. d 6:1 mixture of C10 and C4
carbazole isomers. e 3:1 mixture of C10 and C4 carbazole isomers.
f Reaction at 100 °C.
ingly, competition experiments between 1n (R ) CO2Me) and 1q
(R ) OMe) showed a preference for the formation of 2q (R )
OMe). This could support an electrophilic mechanism,10 but it is
possible that it could be the result of a stronger interaction of the
more electron-rich C-H bond with the metal.11,12
Table 2. Scope of C-H Bond Amination: Aniline Substituents
To probe the structure of the carbopalladation complex, we
prepared palladacycle IIa from amine 1a and Pd(OAc)2 in PhMe
at room temperature. We anticipated that the palladacycle IIa would
be dimeric;7 however, X-ray diffraction revealed that the pallada-
cycle IIa was a trinuclear complex, comprising two cyclopalladated
aminobiphenyl 1a units linked through bridging acetates to a third
Pd(II) center (Scheme 2).13
catalyst
loading,
mol %
entry
R1
Ar (in 2)a
time h
yield, %b
Scheme 2. Isolation of a Trinuclear Carbopalladation Complex
1
2
3
4
5
5
5
5
10
5
5
5
10
5
5
5
Bn
(C6H4)
(C6H4)
(C6H4)
(C6H4)
1
4
2
2
1.5
5
3
1.5
2
1
3
96 (2a)
96 (2a)
80 (2d)
79 (2e)
80 (2f)
81 (2g)
89 (2h)
85 (2i)
64 (2j)
89 (2k)
70 (2l)
60 (2n)
71 (2o)
83 (2p)
i-Pr
Me
allyl
t-bu
Bn
Bn
Bn
Bn
Bn
Bn
Bn
i-Pr
Bn
(C6H4)
6
1-Me-(C6H3)
2-OMe-(C6H3)
2-CF3-(C6H3)
3-Cl-(C6H3)
3-Me-(C6H3)
3-F-(C6H3)
3-CO2Me-(C6H3)
3-I-(C6H3)
4-Me-(C6H3)
7
8c
9
10c
11
12
13
14c
10
10
10
24
12
3
The existence and stability of IIa suggests that oxidation to
Pd(IV) must promote reductive elimination; this is a rare example
of C/N reductive elimination from a high oxidation state transition
metal complex.8 In confirming this, we found IIa can be smoothly
converted to carbazole 2a on treatment with PhI(OAc)2 in PhMe.
It is also possible that IIa breaks down to a monomeric species
prior to oxidation. However, we observed that the complex IIa
shows no crossover when mixed with 5 equiv of a different amine,
suggesting that the complex is stable under pseudo-catalytic
conditions. Furthermore, the oxidation of IIa does not proceed in
highly coordinating solvents, such as DMSO, or in the presence of
coordinating additives (pyridine). These solvents are known to break
di- and trinuclear palladacycles to monomeric species. Taken
together, these results indicate that the reaction does not proceed
through a monomeric palladacycle and, more importantly, that a
higher order complex is essential for catalytic activity and amination
under such mild conditions.
a Standard carbazole numbering. b Reaction with 1 equiv of AcOH.
c Isolated yield after chromatography.
The reaction was also amenable to a range of groups on the
aniline ring with varied electronic and steric properties (Table 2,
entries 6-13). Importantly, the 3-iodo derivative (entry 13)
smoothly forms the carbazole 2o in good yield without compromis-
ing the C-I bond, highlighting the compatibility of this reaction
with the functionality used in other metal-catalyzed coupling
processes. Substitution on the aryl donor portion of the molecule
was next tested (Table 3), and again it was found that the reaction
tolerated a range of electronic and steric groups, providing the
carbazoles in good to excellent yields under mild conditions.9c
During our scope studies we had noticed that electron-rich
substrates reacted faster than electron-deficient molecules. Accord-
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C O M M U N I C A T I O N S
Finally, we sought to test the amination reaction in more complex
systems (Scheme 3). In particular, we were attracted to N-glycosyl
carbazoles, due to the prevalence of this motif in a range of natural
products.4a We were pleased to find that 1v underwent smooth C-H
bond amination to form carbazole 2v in good yield. Despite the
sensitivity and the steric encumbrance at the N-glycosyl linkage,
the successful outcome demonstrates the potential for this C-H
bond amination process in more challenging situations.
References
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Scheme 3. Formation of N-Glycosyl Carbazoles
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We also found that if we changed the oxidation system to
I2-PhI(OAc)2,8e we were able to affect a tandem reaction wherein
1a is first iodinated in the para-position to the electron-donating
amino group, before undergoing C-H bond amination giving 2o.14
The product of this reaction can be further elaborated to 3 using a
Suzuki cross coupling reaction allowing a facile method for the
generation of highly functionalized carbazoles (Scheme 4).
(5) C-H amination via nitrenes: (a) Espino, C. G.; Fiori, K. W.; Kim, M.; Du
Bois, J. J. Am. Chem. Soc. 2004, 126, 15378, and references therein. (b)
Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127, 14198. (c)
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Scheme 4. Applications of Pd(II)-Catalyzed C-H Bond Amination
In summary, we have developed a new Pd(II)-catalyzed C-H
bond amination reaction to form carbazoles, an important motif
that is prevalent in a range of systems. The catalytic amination
process operates under extremely mild conditions, has a broad
substrate scope, and forms the carbazole products in good to
excellent yields. Carbazoles possessing complex molecular archi-
tecture can also be formed using this reaction, highlighting its
potential in natural product synthesis applications. Isolation of a
trinuclear cyclopalladation complex suggests that the mechanism
of the reaction proceeds through a Pd(II)/Pd(IV) manifold. More
detailed mechanistic investigations are ongoing, and these results
will be reported in due course. We are also investigating the
development of an intermolecular C-H bond amination process
using this concept.
(7) For a recent review on palladacycles see Dupont, J.; Consorti, C. S.; Spencer,
J. Chem. ReV. 2005, 105, 2527, and references therein.
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from Pd(IV), see: (a) Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2008, 130,
10060. (b) Fu, Y.; Li, Z.; Liang, S.; Guo, Q.-X.; Liu, L. Organometallics
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M. S. Organometallics 2007, 27, 1365. (e) Giri, R.; Chen, X.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2005, 44, 2112. For reductive elimination from
Pt(IV), see: (f) Pawlikowski, A. V.; Getty, A. D.; Goldberg, K. I. J. Am.
Chem. Soc. 2007, 129, 10382.
(9) (a) See Supporting Information for more details. (b) No reaction is observed
in the absence of Pd(OAc)2. (c) AcOH improved yield of 2.
(10) For electrophilic mechanism examples, see: (a) Parshall, G. W. Acc. Chem.
Res. 1970, 3, 139. (b) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res.
2001, 34, 633. For C-H abstraction mechanism examples, see: (c) Lafrance,
M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
8754. (d) Garcia-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren,
A. M. J. Am. Chem. Soc. 2006, 128, 1066. (e) Wang, X.; Lane, B. S.;
Sames, D. J. Am. Chem. Soc. 2005, 127, 4996.
Acknowledgment. We gratefully acknowledge AstraZeneca and
EPSRC for studentship (to J.J.H.), the EPSRC (C.C.C.J.), the
Spanish Government and Marie Curie Foundation for fellowship
(to M.G.), the Royal Society for University Research Fellowship
(to M.J.G.), Philip & Patricia Brown for Next Generation Fellow-
ship (to M.J.G.) and the EPSRC Mass Spectrometry service
(University of Swansea). We are also grateful to Barrie Martin
(AstraZeneca R&D Charnwood, U.K.) for useful discussion, and
Johnson Matthey for the loan of Pd(OAc)2. This paper is dedicated
to the memory of Dr. Jonathan Spencer.
(11) Ryabov, A. D. Chem. ReV. 1990, 90, 403. (b) Davies, D. L.; Donald,
S. M. A.; Macgregor, S. A J. Am. Chem. Soc. 2005, 127, 13754.
(12) For the monodeuterioamine d-1a we observed a kinetic isotope effect of
2.27; see Supporting Information for details.
(13) (a) Friedlein, F. K.; Kromm, K.; Hampel, F.; Gladysz, J. A. Chem.sEur.
J. 2006, 12, 5267. (b) Giri, R.; Liang, J.; Lei, J.; Li, J.; Wang, D.; Chen,
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(14) We do not believe that this reaction proceeds through a directed Pd(II)-
catalyzed iodination, followed by amination of the C-I bond. See : Mei,
T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47,
6452. Treatment of the corresponding iodo-biphenyl amine (1o) under the
oxidative Pd(II) conditions affords the same product, 2o, as seen in the
tandem reaction.
Supporting Information Available: Experimental data and proce-
dures for all compounds. The material is available free of charge via
the Internet at http://pubs.acs.org.
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