Syntheses of N-alkylated carbazolones via Pd(OAc)2-mediated intramolecular coupling of N-substituted 3-(arylamino)cyclohex-2-enones

Article abstract of DOI:10.1055/s-0030-1259027

A variety of functionalized N-alkylated carbazolones were prepared via N-alkylation of 3-(arylamino)cyclohex-2-enones followed by an intramolecular oxidative coupling mediated by Pd(OAc)₂ under an oxygen atmosphere. This approach adopts an inverted sequence, consisting of the conventional annulation and subsequent N-alkylation. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259027

LETTER
2899
Syntheses of N-Alkylated Carbazolones via Pd(OAc)2-Mediated
Intramolecular Coupling of N-Substituted 3-(Arylamino)cyclohex-2-enones
S
ynthese
s
of N-Alkylate
e
d
C
arbazol
n
one
s
ying Bi, Xiliu Yun, Yanfeng Fan, Xiuxiang Qi, Yunfei Du,* Jianhui Huang*
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology,
Tianjin University, Tianjin 300072, P. R. of China
Fax +86(22)27404031; E-mail: duyunfeier@tju.edu.cn; E-mail: jhuang@tju.edu.cn
Received 5 September 2010
yields (Table 1, entry 2–4). On the hypothesis that the ba-
Abstract: A variety of functionalized N-alkylated carbazolones
sic conditions might be substantially ineffective for the
conversion, we performed the reaction in the presence of
acetic acid and in the absence of a base. To our delight, we
were prepared via N-alkylation of 3-(arylamino)cyclohex-2-enones
followed by an intramolecular oxidative coupling mediated by
Pd(OAc)2 under an oxygen atmosphere. This approach adopts an in-
verted sequence, consisting of the conventional annulation and sub- discovered that the desired cyclized 3a could be obtained
sequent N-alkylation.
in good yield without any basic or acid additive. Further
screening of other solvents shows that MeCN, toluene,
and acetic acid were not superior to DMF. Very recently,
Weng and coworkers3a reported that N-unsubsituted car-
bazolones could be achieved via palladium annulation of
3-(arylamino)cyclohex-2-enones in the presence of 40
mol% of Cu(OAc)2·H2O in combination with an oxygen
balloon as oxidant in ethanol at 80 °C. However, when the
identical conditions were used to treat 2a, only a trace
amount of the desired 3a was observed. Anyhow, it is ev-
ident that the application of the environmentally benign
oxygen as an oxidant7 is a highlighted feature for such an-
nulation reaction. So we are interested in studying wheth-
er Cu(OAc)2 can be partially or wholly replaced by
oxygen. Carrying out the reactions with the combination
of Cu(OAc)2 and oxygen as oxidants in MeCN or DMF
led to unsatisfactory results (Table 1, entries 11 and 12).
The reaction in dry DMF in the presence of oxygen at
100 °C for 12 hours gave our desired product 2a with a
rather poor yield, with the majority of the starting material
unconsumed along with formation of some unidentified
byproducts (Table 1, entry 13). Finally, we were delighted
to find out that the operation of the reaction in acetic acid
at 100 °C gave the desired product 3a in a satisfactory
81% yield within one hour. In this process oxygen can be
used as the only oxidant, and Cu(OAc)2 was shown to be
less efficient.
Key words: N-substituted 3-(arylamino)cyclohex-2-enones, N-
alkylated carbazolones, Pd(OAc)2, oxygen, CH activation
The carbazolone moiety represents a key substructure as-
sociated with many biologically active natural products
and medicinal entities.1 For example, the N-methylated
carbazolone is an important intermediate for the synthesis
of ondansetron,1a,d,h a selective serotonin 5-HT3 receptor
antagonist. Many methods have been reported for the syn-
thesis of N-unsubstituted carbazolones and their deriva-
tives.2,3 Generally, N-alkylated carbazolones can be
achieved via the N-alkylation of carbazolones with alkyl
halides in the presence of a base (Scheme 1).4 To the best
of our knowledge, there is no report of constructing the N-
alkylated carbazolone skeleton via the direct intramolecu-
lar oxidative coupling of N-alkylated 3-(arylamino)cyclo-
hex-2-enones, although the synthesis of N-unsubstituted
carbazolone through palladium-catalyzed oxidative cou-
pling of two sp2 C–H bonds of N-arylenaminones has
been well established.5 Herein, we describe an alternative
approach to the N-alkylated carbazolone via an early N-
alkylation of N-arylenaminone followed by palladium-
mediated intramolecular coupling.
We assumed that the palladium-mediated oxidative con-
ditions, which have been well established for the synthe-
ses of N-unsubstituted indoles6 and carbazolones,3 might
also be applicable to the syntheses of N-alkylated carba-
zolones. Initially, N-methyl-N-phenyl-3-amino-2-cyclo-
hexen-1-one (2a) was subjected to the identical conditions
as applied in the palladium-catalyzed oxidative cycliza-
tion of N-aryl enamines reported by Glorius.6b However,
it was found that the reaction afforded a complex mixture,
with the desired 3a being isolated in only 18% yield
(Table 1, entry 1). Next, the applicability of other bases,
that is, other than K2CO3, was also evaluated. However,
the desired coupled product was formed in fairly poor
conventional strategy
O
O
R2X, base
R1
R1
N-alkylation
N
R2
N
H
Pd(II), O2
This approach
O
O
R2X, base
R1
R1
N-alkylation
N
R2
N
SYNLETT 2010, No. 19, pp 2899–2904
x
x
.x
x
.2
0
1
0
H
Advanced online publication: 03.11.2010
DOI: 10.1055/s-0030-1259027; Art ID: W13810ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

2900
W. Bi et al.
LETTER
Table 1 Condition Screening for the Intramolecular Cyclization of N-Substituted 3-(Arylamino)cyclohex-2-enones 2aa
O
O
catalyst, oxidant, additive
solvent, temp
N
N
Me
Me
2a
3a
Entry
1
Catalyst (equiv)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.15)
Pd(OAc)2 (0.2)
Pd(OAc)2 (0.2)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Oxidant (equiv)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Cu(OAc)2 (3.0)
Solvent
DMF
Additiveb
Temp (°C)
100
100
100
100
100
100
80
Yield (%)c
18
K2CO3
2
DMF
Cs2CO3
<10e
<10e
20
3
DMF
pyridine
4
DMF
Et3N
5
DMF
AcOH
41
6
DMF
–
–
–
–
–
–
–
–
–
72
7
MeCN
AcOHd
toluene
EtOH
MeCN
DMF
<10e
<10e
<10e
trace
51
8
110
110
80
9
10
11
12
13
14
Cu(OAc)2·H2O (0.4) and O2
Cu(OAc)2 (0.3) and O2
80
Cu(OAc)2 (0.3) and O2
100
100
100
25
O2
O2
DMF
13
AcOH
81
a Reaction conditions: 2a (1.0 mmol), catalyst, oxidant, and additive in 15 mL of solvent.
b The base or acid was added as additive (1.2 equiv).
c Isolated yields after flash column chromatography.
d The temperature was elevated from 80–110 °C over 1 h.
e Estimated from the 1H NMR of the crude reaction mixture.
By applying the optimal conditions, a great variety of N- strates hardly underwent the palladium-mediated
disubstituted enaminones, which could be obtained annulation.3a
through a general and efficient N-alkylation of 3-(ary-
Unsurprisingly, when an ortho-bromo-substituted N-
arylenaminone (Table 2, entry 7) was subjected to the op-
timized reaction conditions, both 3g and 3a were obtained
in nearly same yields. The formation of 3a was due to
lamino)cyclohex-2-enones with methyl iodide8 or benzyl
chloride,9 were transformed into the corresponding N-
alkylated carbazolones (Table 2). Both the electron-
donating (Table 2, entries 4, 5, 9, and 14) and electron-
withdrawing substituents (Table 2, entries 2, 3, 6–8, 10–
13) can be well tolerated in the process and afford the de-
sired N-alkylated carbazolones 3 in good overall yields.
Pd(0)-mediated Heck reaction as the background reaction
during the process.4c,d While for the ortho-chloro, the re-
action mainly afforded the desired chlorinated N-alkylat-
ed carbazolone (Table 2, entry 8) with a trace amount of
The reactions with the substrates bearing electron-donat- Heck byproduct 3a.
ing groups proceed more rapidly than these bearing elec-
tron-withdrawing groups. For para-nitro-substituted N-
arylenaminone 2f, the reaction temperature needs to be
raised to 120 °C for an efficient conversion.
Aromatics with meta-substituted substrates have the pos-
sibility of producing two regioisomeric products. When
the m-fluoroaniline (2j) was applied, both the two 5-fluo-
ro- and 7-fluoro-substituted regioisomeric carbazolones
It is worth noting that when the aromatic ring of the sub- were formed (Table 2, entry 10), however, for the m-
strates bearing strong electron-withdrawing substituents, nitroaniline (2k) and trifluoromethylaniline (2l), only a
such as nitro and trifluoromethyl groups, the reaction single regioisomeric product (Table 2, entries 11 and 12),
could also give the desired annulated products in good was observed in both cases. We tentatively proposed that
yields (Table 2, entries 6, 11, and 12). While in the previ- the steric hindrance of the relatively bulky meta-substitu-
ous syntheses of carbazolones, such deactivated sub- ent in 2k,l and 2n might be the reason for preventing the
formation of the other regioisomers.
Synlett 2010, No. 19, 2899–2904 © Thieme Stuttgart · New York

LETTER
Syntheses of N-Alkylated Carbazolones
2901
Table 2 Synthesis of N-Substituted Carbazolones via Intramolecular Annulation Mediated by Pd(OAc)2 under Oxygen Atmospherea
O
O
O
R2X, NaH
DMF, r.t.
Pd(OAc)2, O2
AcOH, 100 °C
R1
R1
R1
N
R2
N
N
R2
H
1
2a–n
3a–n
Entry
1
Substrate 2
Product 3
Time (h)
Yield (%)b
O
O
1
81
N
N
Me
Me
2a
3a
O
O
Br
Br
2
3
4
5
6
7
8
11
12
4
79
N
N
Me
Me
2b
3b
O
O
Cl
Cl
62
N
N
Me
Me
2c
3c
O
O
85
N
N
Me
Me
2d
3d
O
O
MeO
MeO
3.5
24
12
7
83
N
N
Me
Me
2e
3e
O
O
O2N
O2N
65c
40/40
25
N
N
Me
Me
2f
3f
O
O
+ 3a
N
N
Br
Me
Me
Br
2g
3g
O
O
N
N
Cl
Me
Cl
Me
2h
3h
Synlett 2010, No. 19, 2899–2904 © Thieme Stuttgart · New York

2902
W. Bi et al.
LETTER
Table 2 Synthesis of N-Substituted Carbazolones via Intramolecular Annulation Mediated by Pd(OAc)2 under Oxygen Atmospherea (continued)
O
O
O
R2X, NaH
DMF, r.t.
Pd(OAc)2, O2
AcOH, 100 °C
R1
R1
R1
N
R2
N
N
R2
H
1
2a–n
3a–n
Entry
9
Substrate 2
Product 3
Time (h)
12
Yield (%)b
O
O
34
N
N
Me
Me
2i
3i
O
O
7-F 39c
5-F 30c
F
10
11
12
13
14
8
22
27
16
8
F
N
N
Me
Me
2j
3j
O
O
61
55
63
77
O2N
N
O2N
N
Bn
Bn
3k
2k
O
O
F3C
N
F3C
N
Me
Me
2l
3l
F
O
O
F
N
N
F
Me
F
Me
2m
3m
O
O
N
N
Bn
Bn
2n
3n
a Reaction conditions: substrates 2 (1.0 mmol), Pd(OAc)2 (0.1 mmol), oxygen flow (1.0 L/min), dry AcOH (15 mL), 100 °C except that the
reaction in entry 6 was carried out at 120 °C.
b Isolated yields after silica gel chromatography.
c The regioisomers were determined by NMR analysis.
A postulated mechanism for the above annulation process matic palladation might not occur in the CH activation
is shown in Scheme 2.3a,c,6b Firstly, an electrophilic attack step since the corresponding carbocation intermediates
of Pd(II) on the nucleophilic enaminone gives intermedi- generated are not stable. In light of the recent explana-
ate I, which is converted to palladium complex III after tions, the activation of the aromatic CH bond of the
deprotonation. Based on the experimental fact that sub- aniline moiety may potentially occur via s-bond metathe-
strates bearing the electron-withdrawing groups (NO2 and sis, which then leads to the six-membered palladacycle II,
CF3) can also afford the desired carbazolones, we tenta- with the release of HX. It is worth noting that no base is
tively propose that a pathway involving electrophilic aro- needed for this step. Finally, a reductive elimination reac-
Synlett 2010, No. 19, 2899–2904 © Thieme Stuttgart · New York

LETTER
Syntheses of N-Alkylated Carbazolones
2903
(2) (a) Bunce, R. A.; Nammalwar, B. J. Heterocycl. Chem.
2009, 46, 172. (b) Scott, T. L.; Burke, N.; Carrero-Martínez,
G.; Söderberg, B. C. G. Tetrahedron 2007, 63, 1183.
(c) Scott, T. L.; Yu, X.; Gorugantula, S. P.; Carrero-
Martinez, G.; Soederberg, B. C. G. Tetrahedron 2006, 62,
10835. (d) Czeskis, B. A.; Wheeler, W. J. J. Labelled
Compd. Radiopharm. 2005, 48, 407. (e) Sissouma, D.;
Collet, S. C.; Guingant, A. Y. Synlett 2004, 2612. (f) Scott,
T. L.; Söderberg, B. C. G. Tetrahedron 2002, 43, 1621.
(g) Tietcheu, C.; Garcia, C.; Gardette, D.; Dugat, D.;
Gramain, J. J. Heterocycl. Chem. 2002, 39, 965.
O
O
R1
R1
N
R2
2
O2
N
R2
PdX2
Pd(0)
3
O
X
O
H
Pd
Pd
R1
R1
(h) Dubois, E. A.; van den Bos, J. C.; Doornbos, T.; van
Doremalen, P.; Somsen, G. A.; Vekemans, J.; Janssen, A.;
Batink, H. D.; Boer, G. J.; Pfaffendorf, M.; van Royen, E.
A.; van Zwieten, P. A. J. Med. Chem. 1996, 39, 3256.
(i) Caubère, C.; Caubère, P.; Renard, P.; Bizot-Espiart, J.-G.;
Jamart-Grégoire, B. Tetrahedron Lett. 1993, 34, 6889.
(j) Oikawa, Y.; Yonemitsu, O. J. Org. Chem. 1977, 42,
1213. (k) Kawai, H.; Nagasu, T.; Takeda, T.; Fujiwara, K.;
Tsuji, T.; Ohkita, M.; Nishida, J.; Suzuki, T. Tetrahedron
Lett. 1975, 45, 4533.
+
N
R2
N
R2
X–
III
I
σ-bond
metathesis
X
HX
O
H
Pd
HX
R1
N
R2
II
(3) (a) Weng, B.; Liu, R.; Li, J.-H. Synthesis 2010, in press.
(b) Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. Rev.
2005, 105, 2329. (c) Knölker, H.-J.; Reddy, K. R. Chem.
Rev. 2002, 102, 4303. (d) Hagelin, H.; Oslob, J. D.;
Åkermark, B. Chem. Eur. J. 1999, 5, 2413. (e) Knölker,
H.-J.; Fröhner, W. J. Chem. Soc., Perkin Trans. 1 1998, 173.
(4) (a) Kudzma, L. V. Synlett 2003, 1661. (b) Osuka, A.; Mori,
Y.; Suzuki, H. Chem. Lett. 1982, 2031. (c) Iida, H.; Yuasa,
Y.; Kibayashi, C. J. Org. Chem. 1980, 45, 2938. (d) Iida,
H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1979, 44, 1236.
(5) (a) Ge, H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc.
2008, 130, 3708. (b) Rakshit, S.; Patureau, F. W.; Glorius, F.
J. Am. Chem. Soc. 2010, 132, 9585. (c) Neumann, J. J.;
Suri, M.; Glorius, F. Angew. Chem. Int. Ed. 2010, 49, In
press.
(6) (a) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao,
N. Angew. Chem. Int. Ed. 2009, 48, 4572. (b) Würtz, S.;
Rakshit, S.; Neumann, J. J.; Dröge, T.; Glorius, F. Angew.
Chem. Int. Ed. 2008, 47, 7230. (c) Humphrey, G. R.;
Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (d) Cacchi, S.;
Fabrizi, G. Chem. Rev. 2005, 105, 2873. (e) Chen, C.;
Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider,
P. J. J. Org. Chem. 1997, 62, 2676. (f) Koerber-Plé, K.;
Massiot, G. Synlett 1994, 759. (g) Sakamoto, T.; Nagano,
T.; Kondo, Y.; Yamanaka, H. Synthesis 1990, 215.
(7) For recent selected examples using oxygen as oxidant, see:
(a) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008,
130, 833. (b) Jiao, N.; Zhang, C. J. Am. Chem. Soc. 2010,
132, 28. (c) Shi, Z.; Zhang, B.; Cui, Y.; Jiao, N. Angew.
Chem. Int. Ed. 2010, 49, 4036. (d) Jiao, N.; Zhang, C.
Angew. Chem. Int. Ed. 2010, 49, 6174.
Scheme 2
tion generates the carbazolones and active Pd(0) species
which can be reoxidized to Pd(II) species by oxygen.
In summary, we have developed an alternative route for
the synthesis of N-alkylated carbazolones via N-alkyla-
tion and the subsequent intramolecular oxidative coupling
reaction.10 In the Pd(II)-mediated oxidative coupling pro-
cess, molecular oxygen was used to regenerate Pd(II) spe-
cies, and the use of stoichiometric amount of metal based
oxidants was avoided. A range of carbazolones were suc-
cessfully prepared in good over all yields. Further mecha-
nistic studies are currently in progress.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We acknowledge the National Natural Science Foundation of China
(#20802048) and Cultivation Foundation (B) for Young Faculty of
Tianjin University (TJU-YFF-08B68) for financial support.
References and Notes
(1) (a) Gant, T. G.; Sarshar, S. US 2010119623, 2010.
(b) Barta, T. E.; Barabasz, A. F.; Foley, B. E.; Geng, L.; Hall,
S. E.; Hanson, G. J.; Jenks, M.; Ma, W.; Rice, J. W.; Veal, J.
Bioorg. Med. Chem. Lett. 2009, 19, 3078. (c) Barta, T. E.;
Veal, J. M.; Rice, J. W.; Partridge, J. M.; Fadden, R. P.; Ma,
W.; Jenks, M.; Geng, L.; Hanson, G. J.; Huang, K. H.;
Barabasz, A. F.; Foley, B. E.; Otto, J.; Hall, S. E. Bioorg.
Med. Chem. Lett. 2008, 18, 3517. (d) Yan, S.; Wu, H.; Wu,
N.; Jiang, Y. Synlett 2007, 2699. (e) Romeo, G.; Materia,
L.; Pittala, V.; Modica, M.; Salerno, L.; Siracusa, M.; Russo,
F.; Minneman, K. P. Bioorg. Med. Chem. 2006, 14, 5211.
(f) Li, X.; Vince, R. Bioorg. Med. Chem. 2006, 14, 2942.
(g) Kukushkin, S. Y.; Ivanov, P. Y.; Alekseeva, L. M.;
Levina, V. I.; Kobrakov, K. I.; Grigor’ev, N. B.; Granik,
V. G. Russ. Chem. Bull. 2005, 54, 1887. (h) Sorensen, U.
S.; Pombo-Villar, E. Helv. Chim. Acta 2004, 87, 82.
(8) For the most similar N-methylation of 1 using NaH and
methyl iodide in toluene, see: Aragon, P.-J.; Yapi, A.-D.;
Pinguet, F.; Chezal, J.-M.; Teulade, J.-C.; Chapat, J.-P.;
Blache, Y. Chem. Pharm. Bull. 2004, 52, 659.
(9) (a) Sissouma, D.; Collet, S. C.; Guingant, A. Y. Synlett 2004,
2612. (b) Dobbs, A. P.; Jones, K.; Veal, K. T. Tetrahedron
Lett. 1997, 38, 5379.
(10) General Procedure for the Synthesis of N-Substituted
Carbazolones 3
To a solution of N-substituted 3-(arylamino)cyclohex-
2-enones 2a–n (1 mmol) in AcOH (15 mL) was added
Pd(OAc)2 (0.1 mmol), and the resulting solution was heated
at 100 °C and passed through oxygen flow (1.0 L/min).
TLC was used to monitor the reaction progress. After the
consumption of starting material, the reaction mixture was
Synlett 2010, No. 19, 2899–2904 © Thieme Stuttgart · New York

2904
W. Bi et al.
LETTER
extracted by EtOAc (3 × 15 mL). The organic phase was
combined, dried (anhyd Na2SO4). After filtration, the
solvent was removed under reduced pressure to give the
crude product. The residue was purified by flash column
chromatography (EtOAc–PE, 1:3) on silica gel to give the
desired products 3a–n.
Compound 3b: brown solid; mp 230–231 °C. 1H NMR (400
MHz, CDCl3): d = 8.38 (d, J = 2.0 Hz, 1 H, ArH), 7.34 (dd,
J = 9.0, 2.0 Hz, 1 H, ArH), 7.18 (d, J = 9.0 Hz, 1 H, ArH),
3.68 (s, 3 H, NCH3), 2.92 (t, J = 6.0 Hz, 2 H, COCH2), 2.56
(t, J = 6.0 Hz, 2 H, CH2), 2.28–2.22 (m, 2 H, CH2). 13C NMR
(100 MHz, CDCl3): d = 193.8, 153.0, 137.6, 134.9, 127.2,
125.8, 124.4, 111.8, 110.8, 37.7, 35.6, 23.1, 21.9. ESI-
LRMS: m/z calcd for C13H1279BrNO+: 280.0 [M + H+];
found: 280.0. The spectroscopic data for all the new
Compound 3a:11 white solid; mp 195–196 °C. 1H NMR (400
MHz, CDCl3): d = 8.27–8.23 (m, 1 H, ArH), 7.33–7.27 (m,
3 H, ArH), 3.72 (s, 3 H, NCH3), 2.95 (t, J = 6.0 Hz, 2 H,
COCH2), 2.62 (t, J = 6.0 Hz, 2 H, CH2), 2.30–2.23 (m, 2 H,
CH2). ESI-LRMS: m/z calcd for C13H13NO+: 200.1 [M +
H+]; found: 200.1 [M + H+], 222 [M + Na+].
compounds can be found in the Supporting Information.
(11) Rodríguez, J. G.; del Valle, C.; Esteban-Calderón, C.;
Martinez-Ripoll, M. J. Chem. Crystallogr. 1995, 25, 249.
Synlett 2010, No. 19, 2899–2904 © Thieme Stuttgart · New York