Cu-Catalyzed Aerobic Oxidative N-N Coupling of Carbazoles and Diarylamines Including Selective Cross-Coupling

Article abstract of DOI:10.1021/jacs.8b05245

A Cu-catalyzed method has been identified for aerobic oxidative dimerization of carbazoles and diarylamines to the corresponding N-N coupled bicarbazoles and tetraarylhydrazines. The reactions proceed under mild conditions (1 atm O₂, 60-80 °C)

Full text of DOI:10.1021/jacs.8b05245

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Communication
Cu-Catalyzed Aerobic Oxidative N–N Coupling of Carbazoles
and Diarylamines Including Selective Cross-Coupling
Michael Ryan, Joseph R Martinelli, and Shannon S. Stahl
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b05245 • Publication Date (Web): 10 Jul 2018
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Cu-Catalyzed Aerobic Oxidative N–N Coupling of Carbazoles
and Diarylamines Including Selective Cross-Coupling
Michael C. Ryan,† Joseph R. Martinelli,‡ and Shannon S. Stahl*,†
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† Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, United
States
‡ Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana
46285, United States
Supporting Information Placeholder
tetrasubstituted hydrazines (i.e., carbazole-diarylamines in
Scheme 1B) in preference to the homocoupled dimers. The
origin of this unusual selectivity is elucidated.
ABSTRACT: A Cu-catalyzed method has been identified
for aerobic oxidative dimerization of carbazoles and
diarylamines to the corresponding N–N coupled
bicarbazoles and tetraarylhydrazines. The reactions proceed
under mild conditions (1 atm O2, 60–80 °C) with a catalyst
composed of CuBr·dimethylsulfide and N,N-dimethyl-
aminopyridine. Reactions between carbazole and
diarylamines show unusually selective cross-coupling, even
with a 1:1 ratio of the two substrates. This behavior was
found to arise from reversible formation of the
tetraarylhydrazine. Formation of this species is kinetically
favored, but cleavage of the N–N bond under the reaction
conditions leads to selective formation of the
thermodynamically favored cross-coupling product.
Scheme 1. A) N–N bonds found naturally and synthetically
B) Intermolecular cross-coupling of nitrogen atoms.
A) Important Examples of Compounds with N–N Bonds
Natural Products
Pharmaceuticals
Materials and Dyes
HO
Me
HO2C
NO2
O
S
NH2
Me
H
O
N
N
F3C
N N
N
N
Me
PhHN
H
CO2H
Me
Me
Dixiamycin B
Antibacterial activity
Disperse Orange 1
azo dye
Celecoxib
NSAID
OH
Nitrogen-nitrogen bonds are prevalent in natural
products,1 pharmaceuticals,2 and organic materials3 (Scheme
1A). Various methods are available to prepare these bonds,
with classical methods including diazotization of anilines
with sodium nitrite and a Brønsted acid, and the use of N-
chlorinated reagents or related electrophilic nitrogen
species.4 Amidst growing interest in "green" oxidation
methods for organic synthesis, catalytic methods have been
identified for N–N coupling that are capable of using O2 as
the terminal oxidant.5 Recent examples include
intramolecular reactions for the formation of pyrazoles and
related heterocycles5d,g and Au- and Cu-catalyzed methods
for aerobic oxidative coupling of anilines to azo
compounds.5b,e These precedents and our interest in Cu-
catalyzed aerobic oxidation reactions6,7 prompted us to
consider intermolecular N–N coupling reactions of N-
substituted anilines, including carbazoles. Homodimeric
9,9'-bicarbazoles, such as Dixiamycin B8 (cf. Scheme 1A),
are found in nature and are also of interest in materials
chemistry.9 Previously reported methods for the preparation
of these compounds feature stoichiometric oxidants, such as
KMnO4,10 Ag2O,11 or dichromate,12 in addition to a recent
electrolysis method.13 Here, we report a Cu-catalyzed
aerobic oxidation method to access these molecules, as well
as tetraarylhydrazines derived from diarylamines. Reactions
between carbazole and diarylamine substrates undergo
selective cross-coupling to afford unsymmetrical
B) Utilization of Carbazoles and Diarylamines in Oxidative N–N bond Formation
cat. [Cu],
O2
N
N
N
N
N
N
N H
N–N
bond formation
Carbazole-
Diarylamines
9,9'-Bicarbazoles
Tetraarylhydrazines
We began our studies by using 3,6-di(tert-butyl)-
carbazole 1a as a model substrate, and a summary of results
obtained from reactions performed with 20 mol% of a
copper salt in combination with an ancillary ligand are
provided in Table 1. Copper(II) salts were ineffective
precatalysts (Table 1, entries 1 and 2), but moderate yields
of 9,9'-bicarbazole 2a were obtained when CuCl or CuBr
was used in combination with 1,10-phenanthroline (entries
3 and 4). Use of CuBr·DMS instead of CuBr led to further
improvement (entry 5). Assessment of other bidentate
ligands revealed improved results with 2,2'-bipyridine (bpy;
cf. entries 5-7), but two equivalents of an electron- rich
monodentate ligand proved even more effective (entries 8-
11), with the best results obtained with N,N-
dimethylaminopyridine (DMAP) and N-methylimidazole
(NMI) (entries 10 and 11). Further optimization of the
CuBr·DMS/DMAP catalyst system led to formation of
bicarbazole 2a in 85% yield (70% isolated; cf. entry 12),
with 10 mol% Cu loading at 60 °C. Good yields were also
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Journal of the American Chemical Society
observed in other solvents, including 1,2-dichloroethane
(78%, entry 13) (see Supporting Information for full
screening data).
Page 2 of 5
and oxidative coupling of bis(4-tert-butylphenyl)amine to
2k was conducted on 1 g scale without impact on the isolated
yield (98%). Good yields were observed with a number of
the other substrates, including those with electron-donating
and electron-withdrawing substituents (cf. 2j, 2k and 2n, 2o,
2p, respectively), and the reactions were less affected by the
lack of an aryl substituent para to the nitrogen atom (cf. 2i,
2l, 2m). The unsymmetrical diarylamine, 1q, required
elevated temperature (60 °C) to reach completion.
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2
3
4
5
6
7
8
Table 1. Optimization of carbazole dimerization.
t-Bu
t-Bu
t-Bu
X mol% [Cu],
Y mol% Ligand
N
N
NH
DMF (0.2 M), O2 (1 atm),
80 ºC, 6 h
t-Bu
t-Bu
t-Bu
9
1a
2a
Table 2. Substrate scope of carbazole and diarylamine
dimerization.
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60
Liganda (mol%)
Conversion (%)b
Yield (%)b
entry
Cu Source (mol%)
1
2
3
4
5
6
7
Cu(OAc)2•H2O (20)
CuBr2 (20)
phen (20)
phen (20)
phen (20)
phen (20)
phen (20)
TMEDA (20)
bpy (20)
18
2
2
a Numbers below refer to isolated yields. b 20 mol% CuBr·DMS, 40 mol%
0
DMAP, DCE, 60 ºC c 10 mol% CuBr·DMS, 20 mol% DMAP, DCM, r.t. d
CuCl (20)
76
70
64
63
66
26
39
43
38
50
R
R
R
CuBr (20)
10-20 mol% CuBr•DMS,
20-40 mol% DMAP,
CuBr•DMS (20)
CuBr•DMS (20)
CuBr•DMS (20)
N
N
N H
DCM or DCE, O2 (1 atm),
r.t. or 60 ºC, 17 h
1a-q
A. Carbazoleb
2a-qa
8
9
pyridine (40)
4-methoxypyridine (40)
DMAP (40)
41
44
87
88
18
33
72
71
CuBr•DMS (20)
CuBr•DMS (20)
CuBr•DMS (20)
CuBr•DMS (20)
B. Diarylaminec
10
11
Me
t-Bu
t-Bu
Cl
Br
NMI (40)
12c
13c,d
CuBr•DMS (10)
DMAP (20)
94
85 (70)
N
N
N
2
N
N
N
2
CuBr•DMS (10)
DMAP (20)
100
78
2
2
2
2
a phen = 1,10-phenanthroline, TMEDA = tetramethylethylenediamine, bpy
2,2'-bipyridine, DMAP 4-dimethylaminopyridine, NMI N-
Conversion and yield determined by 1H NMR
t-Bu
Cl
Br
Me
2j
99%
t-Bu
2k
98%
=
=
=
2a
74%d,e
2b
72%
2c
69%f
2i
63%
b
methylimidazole.
Br
integration, using 1,3,5-trimethoxybenzene as an internal standard. Isolated
I
MeO
Ph
Ph
yield in parentheses. c Performed at 60 ºC for 17 h. d Performed in DCE.
N
N
2
N
N
N
2
N
2
Application of these catalytic conditions to other
substrates showed that good yields of bicarbazoles could be
obtained from carbazoles bearing both electron-withdrawing
and electron-donating groups in the 3- and 6-positions (i.e.,
para to the nitrogen atom of the carbazole; cf. 2b-f, Table
2A). 1,2-Dichloroethane proved to be the most effective
solvent in these cases. Substrates lacking substitution in one
or both of the 3- and 6-positions are susceptible to side
reactions leading to C–N and C–C-coupled carbazole dimers
and oligomers.14 For example, the parent bicarbazole was
obtained in < 30% yield (See Supporting Information, Table
S7). Even in these cases, however, the desired N–N-coupled
bicarbazoles could be readily isolated from side products,
and products 2g and 2h were obtained in moderate yields
(35% and 54%, respectively). The latter compound is
noteworthy because it represents a structural analog of
Dixiamycin B (cf. Scheme 1). The recently reported
synthesis of this natural product by Baran and coworkers
provides important context for the challenge associated with
this type of N–N coupling.13
2
2
2
Me
Me
Me
I
MeO
MeO
2m
76%
Me
2d
63%
2e
79%
2f
69%g
2l
89%
2n
84%
Me
F
Br
N
N
2
2
N
N
N
2
2
2
Br
F
Br
EtO2C
2g
35%
2p
99%e
2q
69%h
2h
54%
2o
81%
10 mol% CuBr·DMS, 20 mol% DMAP, DMF, 60 ºC. e Average isolated
yield over three runs. f 80 ºC. g 10 mol% CuBr·DMS, 20 mol% DMAP. h 60
ºC, DCE.
After demonstrating these homocoupling reactions, we
evaluated prospects for cross-coupling. N–N cross-coupling
reactions are rare, with precedents typically requiring use of
one of the reaction partners in large excess to achieve
formation of the desired product.5e A reaction of carbazole
1a and diarylamine 1p was tested in 1:1 stoichiometry under
standard conditions (eq 1). A 72% yield of the cross-coupled
product 3a was observed, with a 10% yield of each
homocoupled dimer. Use of a small excess of the carbazole
(1a:1p = 1.5:1) led to formation of the cross-coupled product
in 86% yield. In both cases, the cross-coupling selectivity far
exceeds that expected from statistical product ratios.
In general, aerobic oxidative dimerization of
diarylamines proved to proceed under milder conditions and
afford higher yields than the reactions of carbazoles (Table
2B). Precedents for this reaction are limited. Kajimoto et al.
showed that N–N coupling of the parent diphenylamine
could be achieved under aerobic conditions with
stoichiometric CuCl,15 and Knölker recently described an
Fe(phthalocyanin) catalyst for aerobic oxidative N–N
coupling of diarylamines.5h,16,17 The present reactions were
conducted at room temperature in DCM with 10 mol%
CuBr·DMS and 20 mol% DMAP. Several substrates
Br
Br
t-Bu
t-Bu
10 mol% CuBr•DMS,
20 mol% DMAP
+
(1)
N
N
HN
NH
DCE, O2 (1 atm)
60 ºC, 17 h
t-Bu
t-Bu
Br
Br
1a
1p
3a
1a:1p = 1:1, 72% (NMR)
1a:1p = 1.5:1, 86% (NMR)
underwent
conversion
to
the
corresponding
tetrarylhydrazine in near-quantitative yield (cf. 2j, 2k, 2p),
2
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Journal of the American Chemical Society
Due to the paucity of synthetic methods available to
relatively insensitive to the ratio of the coupling partners
(Figure 1, red trace), showing significantly greater-than-
statistical selectivity for cross-coupling under conditions
with a 1:1 substrate ratio (73% yield of 3a; the dashed line
in Figure 1 shows the yield expected from a statistical ratio
of products). Only a small excess of either substrate was
needed to observe 80–90% yield of the cross-coupled
product. The reaction of two different diarylamines also
achieved greater-than-statistical selectivity (Figure 1, blue
trace), albeit not as high as that observed in the
carbazole/diarylamine coupling reaction (56% yield of 4a at
1:1 ratio). Excellent yields of the tetraarylhydrazine cross-
coupling product were obtained when excess of either
partner was used (i.e., at 1:5 or 5:1 ratio).
create N–N cross-coupled products,18 we explored the
substrate scope of this reaction (Table 3). A 1.5:1 ratio of
substrates was used to facilitate purification of the cross-
coupled product. For example, product 3a was obtained in a
69% isolated yield when using a 1:1.5 ratio of 1a:1p. The
parent carbazole was a poor substrate for oxidative
homocoupling (see above), but it performed well as a cross-
coupling partner, affording 3b and 3l in 64% and 62% yield,
respectively. Product 3b could be isolated in an improved
77% yield when the reaction was performed on a larger scale
(1 g, 6 mmol carbazole). Both electron-rich and electron-
deficient carbazoles were effective with bis(4-
bromophenyl)amine 1p as the coupling partner (cf. 3c–3f).
Halogen substituents are well-tolerated on both coupling
partners (3a–3k), and the unsymmetrical diarylamine 1n
was an excellent cross-coupling partner, affording 3g and 3h
in a 75% and 61% yields, respectively.
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t-Bu
Br
Br
Br
t-Bu
t-Bu
cat. Cu/O2
or
N
N
N
N
HN
+
NH
t-Bu
t-Bu
t-Bu
Br
Br
Br
1a (carbazole)
or 1k (diarylamine)
1p
3a
4a
Table 3. Cross-coupling of carbazoles and diarylamines.
R
R
R
R
10 mol% CuBr•DMS,
20 mol% DMAP
+
NH
HN
N N
DCE, O2 (1 atm),
60 ºC, 17 h
(1.5 equiv)
Br
3a-ja
Br
Br
Br
MeO
t-Bu
N N
N N
N N
N N
t-Bu
MeO
Br
Br
Br
Br
3a
69%b,c ,72%b,c,d
Br
3b
64%c,e,77%c,f
3c
62%g
3d
67%c
Br
Br
Br
Cl
Br
Br
t-Bu
t-Bu
F
N N
N N
N N
N N
Me
Me
Figure 1. Dependence of cross-coupling yield on substrate
stoichiometry. 1H NMR yields, average of three runs.
Conditions: (3a) 10 mol% CuBr·DMS, 20 mol% DMAP, DCE,
O2 (1 atm) 60 ºC, 17 h; (4a) 10 mol% CuBr·DMS 20 mol%
DMAP, DCM, O2 (1 atm) r.t., 17 h.
Cl
F
Br
Br
Me
Me
3e
55%
3f
46%
3g
75%c
3h
61%c
t-Bu
t-Bu
t-Bu
t-Bu
Cl
Br
Br
In order to gain further insight into the origin of the
N N
N N
N N
N N
selectivity for 3a in Figure 1, we analyzed a time course for
1
the reaction between 1a and 1p by H NMR spectroscopy
Cl
Br
t-Bu
t-Bu
t-Bu
t-Bu
(Figure 2). The diarylamine 1p is consumed rapidly,
generating the homocoupled tetraarylhydrazine 2p. Initial
formation of 2p is consistent with the milder reaction
conditions observed with diarylamines relative to carbazoles
(cf. Table 2). The tetraarylhydrazine 2p reaches a maximum
concentration at ~40 minutes and then disappears with
concomitant formation of the cross-coupling product 3a.
This observation indicates that formation of the N–N bond
in 2p is reversible under the reaction conditions, and 2p is
consumed by irreversible formation of the cross-coupled
product 3a. Control experiments reveal that N–N cleavage
in 2p is not promoted by copper and that N–N bond
formation in 3a is irreversible under the reaction conditions
(Figure S6). The N–N bond in tetraarylhydrazines is quite
weak (e.g., BDE = 23.5 kcal/mol for Ph2N–NPh220), and
homolytic cleavage of the tetraarylhydrazine N–N bond will
generate aminyl radicals21 capable of undergoing cross-
coupling with the carbazole coupling partner. Irrespective of
3j
61%
3i
59%
3k
80%
3l
62%
Isolated yields. 20 mol% CuBr·DMS, 40 mol% DMAP. c 1.5 equiv
a
b
diarylamine. d Reaction performed in air. e Average isolated yield over three
runs. f Isolated yield, 1 g (6 mmol) carbazole scale. g 0.1 mmol scale.
The selectivity observed in the carbazole/diarylamine
cross-coupling reactions is generally better than that
observed from the cross-coupling of two different
diarylamines (Figure 1), and much higher than that observed
in previously reported reactions of primary anilines.5e The
latter reactions required a 5:1 ratio of aniline substrates to
obtain moderate-to-good yields (42–73%) of cross-coupled
azo compounds, ArN=NAr'. More systematic assessment of
the different selectivities observed in the present cross-
coupling reactions was probed by varying substrate ratios
from 5:1 to 1:5 in each case (Figure 1).19 In the reaction of
carbazole 1a with diarylamine 1p, the yield of 3a was
3
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mechanism, the observations show that preferential
formation of the cross-coupled product 3a over 2p is
thermodyanamically controlled. The cross-coupling
selectivity for 4a obtained from the reaction of 1k and 1p
reflects an equilibrium preference for formation of the cross-
coupled over the homocoupled tetraarylhydrazines.22
Page 4 of 5
In conclusion, we have developed the first catalytic
method for aerobic N–N coupling of carbazoles to 9,9´-
bicarbazoles, and showed that similar conditions may be
used for the coupling of diarylamines. Moreover, we have
identified selective cross-coupling reactions of carbazoles
and diarylamines, wherein the selectivity arises from
reversible cleavage of the N–N bond in kinetically favored
tetraarylhydrazine intermediates, ultimately generating the
more stable carbazole-diarylamine products. The latter
compounds have little precedent and warrant attention in
medicinal and materials applications.
1
2
3
4
5
6
7
8
Br
Br
t-Bu
t-Bu
t-Bu
t-Bu
10 mol% CuBr•DMS,
20 mol% DMAP
9
NH + HN
N
N
N
DCE, O2 (1 atm),
60 ºC, 3 h
2
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t-Bu
t-Bu
Br
1p
(1 equiv)
Br
1a
(1 equiv)
3a
2a
ASSOCIATED CONTENT
Br
Br
Br
Br
The Supporting Information is available free of charge on
the ACS Publications website.
Experimental Procedures and compound characterization
data (PDF)
N
N
2p
AUTHOR INFORMATION
Corresponding Author
*stahl@chem.wisc.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We would like to thank Eli Lilly and Company for funding
through the Lilly Research Award Program (LRAP). We also
thank the DOE (DE-FG02-05ER15690) for funding.
Spectroscopic instrumentation was partially supported by
the NIH (1S10 OD020022) and the NSF (CHE-1048642).
1
Figure 2. H NMR time course of the cross-coupling of
carbazole 1a and diarylamine 1p.
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14. Baran and coworkers have observed similar products from the
electrochemical oxidative dimerization of carbazoles, originating from
unselective coupling of a carbazolyl radical intermediate (See ref. 13).
15. Kajimoto, T.; Takahashi, H.; Tsuji, J., Bull. Chem. Soc. Jpn. 1982,
55, 3673.
16 . Cu-catalyzed methods using oxidants other than O2: (a) Zhu, Y.;
Shi, Y., Org. Lett. 2013, 15, 1942. (b) Reddy, C. B. R.; Reddy, S. R.;
Naidu, S., Catal. Commun. 2014, 56, 50.
17 . Non-catalytic methods: (a) Naimi-Jamal, M. R.; Hamzeali, H.;
Mokhtari, J.; Boy, J.; Kaupp, G., ChemSusChem 2009, 2, 83. (b)
Zhang, L.; Xia, J.; Li, Q.; Li, X.; Wang, S., Organometallics 2011, 30,
375.
18. (a) Benati, L.; Placucci, G.; Spagnolo, P.; Tundo, A.; Zanardi, G.,
J. Chem. Soc., Perkin Trans. 1 1977, 1684. (b) Benati, L.; Spagnolo,
P.; Tundo, A.; Zanardi, G., J. Chem. Soc., Perkin Trans. 1 1979, 1536.
19. Cross-coupling between two differently-substituted carbazoles 1a
and 1c was also attempted, but formation of considerable amounts of
side products complicated analysis.
7. For a comprehensive review: Allen, S. E.; Walvoord, R. R.; Padilla-
Salinas, R.; Kozlowski, M. C. Chem. Rev. 2013, 113, 6234.
8. Zhang, Q.; Mándi, A.; Li, S.; Chen, Y.; Zhang, W.; Tian, X.; Zhang,
H.; Li, H.; Zhang, W.; Zhang, S.; Ju, J.; Kurtán, T.; Zhang, C., Eur. J.
Org. Chem. 2012, 2012, 5256.
9. (a) Pandit, P.; Yamamoto, K.; Nakamura, T.; Nishimura, K.;
Kurashige, Y.; Yanai, T.; Nakamura, G.; Masaoka, S.; Furukawa, K.;
Yakiyama, Y.; Kawano, M.; Higashibayashi, S., Chem. Sci. 2015, 6,
20. (a) Franzen, V., Justus Liebigs Ann. Chem. 1957, 604, 251. (b)
Cain, C. K.; Wiselogle, F. Y., J. Am. Chem. Soc. 1940, 62, 1163.
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22. See Section IX in the Supporting Information for equilibration
studies.
1
2
3
4
21. Evidence for N-centered radical formation under catalytic reaction
conditions has been confirmed by EPR spectroscopy. See section X in
the Supporting Information.
5
6
TOC Graphic
7
8
9
cat. Cu/O2
NH
N
N
HN
+
Selective
Cross-Coupling
Kinetically
Facile and
Reversible
cat. Cu/O2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
N
N
carbazole
homocoupling
diarylamine
homocoupling
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