Highly efficient route to functionalized tetrahydrocarbazoles using a tandem cross-metathesis/intramolecular-hydroarylation sequence

Article abstract of DOI:10.1002/asia.201000315

The scope of the novel ruthenium-catalyzed tandem cross-metathesis/ intramolecular-hydroarylation sequence is described. This methodology offers a practical and efficient synthesis of structurally diverse and complex tetrahydrocarbazoles in good to excellent yields (up to 98%). Moreover, preliminary efforts towards the development of an enantioselective version of the current process by sequential catalysis with ruthenium complex and chiral amine are presented, with high yields and enantioselectivities (up to 88% yield and 91% ee).

Full text of DOI:10.1002/asia.201000315

FULL PAPERS
DOI: 10.1002/asia.201000315
Highly Efficient Route to Functionalized Tetrahydrocarbazoles Using a
Tandem Cross-Metathesis/Intramolecular-Hydroarylation Sequence
Xiao-Lei An, Jia-Rong Chen,* Chang-Feng Li, Fu-Gen Zhang, You-Quan Zou,
Ying-Cen Guo, and Wen-Jing Xiao*[a]
Abstract: The scope of the novel ruthenium-catalyzed tandem cross-metathesis/in-
tramolecular-hydroarylation sequence is described. This methodology offers a
practical and efficient synthesis of structurally diverse and complex tetrahydrocar-
bazoles in good to excellent yields (up to 98%). Moreover, preliminary efforts to-
wards the development of an enantioselective version of the current process by se-
quential catalysis with ruthenium complex and chiral amine are presented, with
high yields and enantioselectivities (up to 88% yield and 91% ee).
Keywords: enantioselectivity
heterocycles · metathesis · ruthe-
nium · synthesis design
·
Introduction
thesis of 1-vinyl- and 4-vinyl-THCs in a highly enantioselec-
tive manner, which provided a new design concept for the
functionalization of indoles.[6] Shortly after, Youꢀs group in-
geniously developed a sequential olefin cross metathesis
(CM)/intramolecular asymmetric Friedel–Crafts alkylation
Polycyclic aromatic systems bearing a privileged indole core
are ubiquitous structural frameworks in chemical science,
with various applications identified throughout the pharma-
ceutical industry as well as among naturally occurring and
biologically active molecules.[1] Among this plethora of com-
pounds, polyfunctionalized tetrahydrocarbazoles (THCs)
and more-complex cyclic systems possess a wide variety of
therapeutic actions, such as antitumoural, cardiovascular ef-
fects, and treatment of atherosclerosis.[2] Consequently, the
development of new synthetic strategies that facilitate the
rapid and efficient construction of the molecules of such
types remains a preeminent goal in the chemical-synthesis
community.[3] In this endeavor, the intramolecular alkylation
of indoles promoted by Lewis acids[4] or transition-metal
complexes[5] has received much attention and been well-
documented recently. Notably, Bandini et al. reported an el-
egant gold-catalyzed allylic alkylation of indoles for the syn-
reactions,
which
provided
a
direct
route
to
tetrahydropyranoAHCTUNGTR[EUNNNG 3,4-b]indoles (THPIs) and tetrahydro-b-
carbolines (THBCs) in excellent yields and enantioselectivi-
ties.[7] More recently, MacMillan and co-workers designed a
novel tandem Diels–Alder cyclization reaction and success-
fully applied this methodology to the total synthesis of the
polycyclic natural product, (ꢀ)-Minfiensine.[8] We also dis-
closed an alternative hydrogen bonding-catalyzed double
Michael addition/aromatization cascade of 2-propenylin-
doles with nitroolefins.[9] This strategy allows efficient access
to a diverse range of THCs in high stereoselectivities. De-
spite these achievements, the development of more efficient
and practical catalytic systems for the synthesis of multifunc-
tional THCs is still challenging and highly desirable.
As part of our ongoing research program addressing het-
erocycle-oriented methodology development,[10] we recently
reported a single Ru-catalyzed tandem olefin CM/intramo-
lecular hydroarylation sequence of alkenyl indoles with a,b-
unsaturated carbonyl compounds (Scheme 1).[11] Such a pro-
tocol provided efficient access to racemic THCs in excellent
yields under mild conditions. Importantly, the Lewis acidic
ruthenium species generated in situ can act as a Lewis acid
to promote the intramolecular hydroarylation reaction. On
the basis of the success of the initial study, we further ex-
panded the synthetic utility of this approach to synthesize a
variety of polycyclic indole derivatives. In this article, we
[a] X.-L. An, Dr. J.-R. Chen, Dr. C.-F. Li, F.-G. Zhang, Y.-Q. Zou,
Dr. Y.-C. Guo, Prof. Dr. W.-J. Xiao
Key Laboratory of Pesticide & Chemical Biology
Ministry of Education, College of Chemistry
Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (China)
Fax : (+86)27-6786-2041
E-mail: wxiao@mail.ccnu.edu.cn
Homepage: http://chem-xiao.ccnu.edu.cn/default.aspx
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000315.
2258
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Chem. Asian J. 2010, 5, 2258 – 2265

Table 1. Optimization studies for the tandem reaction of 1-methyl-2-
(pent-4-enyl)-1H-indole 5a and phenyl vinyl ketone 6a.[a]
Scheme 1. Ruthenium-catalyzed tandem CM/intramolecular-hydroaryla-
tion reaction.
will document a full account of this investigation and the
preliminary study on the enantioselective version of this
transformation.
Entry
[Ru] catalyst
Solvent
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
1
2
3
4
4
4
4
4
DCE
DCE
DCE
DCE
DCM
40
40
40
1.5
6.5
25
6
ꢁ5
29
ꢁ5
82
67
74
68
66
Results and Discussion
Ruthenium-Catalyzed Tandem CM/Intramolecular-
Hydroarylation Reactions
toluene
chlorobenzene
DCE
Initially, we chose 1-methyl-2-(pent-4-enyl)-1H-indole 5a
and sterically bulky phenyl vinyl ketone 6a as the model
substrates for the tandem process and examined several
commercially available metathesis catalysts under our previ-
ous reaction conditions (Table 1). The ruthenium catalysts
were found to play an important role on the reaction effi-
ciency (Table 1, entries 1–4). For example, in the presence of
Hoveyda-Grubbs second-generation catalyst 4, the reaction
went to completion within 1.5 h to furnish the desired THC
7aa with an 82% yield (Table 1, entry 4). We then simply
examined the effects of other solvents on the reaction with
4 as the catalyst. The yield/solvent profile showed that DCE
was still the ideal reaction medium (Table 1, entry 4). Inter-
estingly, a significant decrease of yield was observed when
the reaction was run with a somewhat longer reaction time
(Table 1, entry 8).
Having established the optimal conditions, we investigat-
ed the scope of the tandem reaction with a variety of w-in-
dolyl alkenes and aryl vinyl ketones. As shown in Table 2,
the reaction displayed broad generality with respect to the
aryl-vinyl-ketone components. Substantial variation in the
steric and electronic demand of the aromatic ring of aryl
vinyl ketones can be well-tolerated without loss of reaction
efficiency, giving the corresponding THCs in good to high
yields (Table 2, entries 1–10). Heteroaromatic vinyl ketone
also proved to be a suitable substrate for this tandem reac-
7
[a] Conditions: 5a (0.3 mmol), 6a (1.5 mmol), [Ru] catalyst (3 mol%),
solvent (3 mL). DCE=1,2-dichloroethane. DCM=dichloromethane.
[b] Yield of isolated product after column chromatography on silica gel.
Table 2. Scope of the ruthenium-catalyzed tandem CM/intramolecular-
hydroarylation between w-indolyl alkene 5 with aryl vinyl ketones 6.[a]
Entry
R
Ar
Product t [h] Yield [%][b]
1
2
3
4
5
6
7
8
H (5a)
H (5a)
H (5a)
H (5a)
H (5a)
H (5a)
H (5a)
H (5a)
Ph (6a)
7aa
7ab
7ac
7ad
7ae
7af
7ag
7ah
7ai
1.5 82
p-Me-C6H4 (6b)
p-MeO-C6H4 (6c)
p-F-C6H4 (6d)
p-Cl-C6H4 (6e)
p-Br-C6H4 (6 f)
m-MeO-C6H4 (6g)
5
5
7
6
3
3
3
6
8
7
5
4
4
8
6
93
88
87
69
60
86
84
74
85
85
77
81
81
48
92
m-Br-C6H4 ACTHUGNETRNNU(G 6h)
9
H (5a)
H (5a)
H (5a)
o-MeO-C6H4 (6i)
o-Br-C6H4 (6j)
2-furyl (6k)
10
11
12
13
14
15
16
17
18
19
20
21
7aj
7ak
7bb
7cb
7 db
7eb
7 fb
7gb
7hb
7ib
4-Me (5b)
5-Me (5c)
6-Me (5d)
7-Me (5e)
4-F (5 f)
4-Cl (5g)
5-F (5h)
6-Cl (5i)
p-Me-C6H4 (6b)
p-Me-C6H4 (6b)
p-Me-C6H4 (6b)
p-Me-C6H4 (6b)
p-Me-C6H4 (6b)
p-Me-C6H4 (6b)
p-Me-C6H4 (6b)
p-Me-C6H4 (6b)
5.5 96
8
4
5
8
71
93
88
40
Abstract in Chinese:
5-Me-7-Cl (5j) p-Me-C6H4 (6b)
5-Me-7-Me (5k) p-Me-C6H4 (6b)
7jb
7kb
[a] Conditions: 5 (0.3 mmol), 6 (1.5 mmol), 4 (3 mol%), DCE (3 mL).
[b] Yield of isolated product after column chromatography on silica gel.
tion; product 7ak was obtained with an 85% yield (Table 2,
entry 11). Notably, this tandem process is also general with
respect to the w-indolyl alkene moiety.
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J.-R. Chen, W.-J. Xiao et al.
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For instance, with para-methyl phenyl vinyl ketone 6b as
the reaction partner, the incorporation of methyl, fluoro, or
chloro groups at positions C4–C6 of the indole architecture
were well-tolerated, and revealed that the steric and elec-
tronic modification of the indole architecture can be ach-
ieved without significant loss in reaction yield or efficiency
(Table 2, entries 12–19). These halogenated THC products
should be suitable for further functionalization.[12] Impor-
tantly, the multi-substituted w-indolyl alkenes, such as 5j
and 5k, can also be employed to construct the THC core, a
structural motif commonly found among natural alkaloids
and drug candidates (Table 2, entries 20 and 21).
Scheme 2. Preparation of the N-1 phenyl-substituted THCs by rutheni-
um-catalyzed tandem CM/intramolecular-hydroarylation reaction.
DCE=1,2-dichloroethane.
Further to aryl vinyl ketones, aliphatic vinyl ketones, such
as methyl vinyl ketone 8, were then examined. As illustrated
in Table 3, the reactions showed generally superior efficien-
Stereoselective Sequential CM/Intramolecular-
Hydroarylation: Towards the Synthesis of Enantiomerically
Enriched THCs
In the past few years, the concept of combining two distinct
catalytic entities has become a powerful tool in asymmetric
synthesis, because of their superior activity and stereoselec-
tivity than the individual components.[14,15] In the field of
olefin metathesis, the ruthenium-alkylidene system has been
successfully utilized for several tandem processes wherein
the ruthenium complexes are highly compatible with other
transition metals and Lewis acids.[16] Therefore, we decided
to examine the enantioselective variant of this reaction by
combining the ruthenium catalyst with the chiral Lewis acid
complex (Scheme 3). However, in initial experiments we did
Table 3. Scope of the ruthenium-catalyzed tandem reaction of w-indolyl
alkenes 5 with MVK 8.[a]
Entry
R
Product
t [h]
Yield [%][b]
1[c]
2
3
4
5
H (5a)
9a
9b
9c
9d
9e
9 f
9g
0.5
1.0
1.0
1.5
3.5
3.5
8.5
98
64
82
78
87
85
90
4-Me (5b)
5-Me (5c)
6-Me (5d)
4-F (5 f)
6-Cl (5i)
5-Me-7-Cl (5j)
6
7
[a] Conditions: 5 (0.3 mmol), 8 (1.5 mmol), 4 (3 mol%), DCE (3 mL).
[b] Yield of isolated product after column chromatography on silica gel.
[c] See Ref. [11].
Scheme 3. Concept of sequential CM/intramolecular-hydroarylation.
cy and chemical yield to the aryl vinyl ketones used above.
Under our optimal conditions, the w-indolyl alkenes bearing
electron-donating or electron-withdrawing groups at C4, C5,
and C6 positions reacted smoothly with methyl vinyl ketone
8, giving the THC products in a yield range of 64–98%
(Table 3, entries 1–6). Similarly, the 5-Me-7-Cl-substituted
w-indolyl alkene also readily took part in the reaction and
gave rise to the desired product 9g with a 90% yield
(Table 3, entry 7).
It was documented that the substituents on the N-1 posi-
tion of polycyclic indoles had great effects on their biologi-
cal activity.[13] Accordingly, we investigated the tandem reac-
tion between N-1 phenyl substituted w-indolyl alkene and
representative electron-deficient olefin components, such as
phenyl vinyl ketone 6a, methyl vinyl ketone 8, and acrolein
11 (Scheme 2). Again, high yields of the cyclized products
were obtained (81–86%).
not obtain satisfactory enantioselectivity, probably because
of the low catalyst turnover. Based on our previous success-
ful use of iminium catalysis in intramolecular Friedel–
Crafts-type alkylation,[10a,e] we decided to investigate an al-
ternative strategy of chiral amine as the organocatalyst for
the intramolecular hydroarylation.
A simple optimization of the reaction conditions led to ef-
ficient sequential catalysis: when the N-Boc w-indolyl
alkene 13a and crotonaldehyde (10 equiv; Boc=tert-butoxy-
carbonyl) were refluxed in dichloromethane with the ruthe-
nium catalyst 4 (5 mol%) for 12 hours, the solvent was re-
placed with a mixture of diethyl ether and iso-propanol as
the reaction medium; then, the resulting CM product under-
went intramolecular hydroarylation smoothly in the pres-
ence of a catalytic amount of an imidazolidinone reported
by MacMillan and co-workers and trifluoroacetic acid, af-
fording the corresponding product in 65% overall yield with
91% ee (Scheme 4). Significant structural variation in the w-
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Highly Efficient Route to Functionalized Tetrahydrocarbazoles
2-(9-Methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-1-p-tolylethanone
(7ab): Following the general procedure with catalyst 4, compound 7ab
(93%) was isolated by FC on silica gel (petroleum ether/ethyl acetate=
1
30:1 then 20:1). H NMR (600 MHz, CDCl3): d=7.90 (d, J=7.8 Hz, 2H),
7.51 (d, J=7.8 Hz, 1H), 7.25–7.22 (m, 3H), 7.15 (t, J=7.5 Hz, 1H), 7.05
(t, J=7.5 Hz, 1H), 3.79 (d, J=7.2 Hz, 1H), 3.57 (s, 3H), 3.54 (d, J=
16.8 Hz, 1H), 3.14 (dd, J=10.8, 16.8 Hz, 1H), 2.73–2.61 (m, 2H), 2.38 (s,
3H), 1.94–1.86 (m, 3H), 1.76–1.70 ppm (m, 1H); 13C NMR (150 MHz,
CDCl3): d=199.5, 143.6, 136.8, 136.1, 134.8, 129.6, 129.2, 128.1, 126.1,
118.6, 118.1, 117.7, 111.7, 43.6, 28.8, 27.9, 27.9, 22.0, 21.9, 21.1 ppm; MS
(EI): m/z (%): 317 (rel. intensity) [M+]; elemental analysis: calcd (%)
for (C22H23NO): C 83.24, H 7.30, N 4.41; found: C 83.38, H 7.26, N 4.38.
1-(4-Methoxyphenyl)-2-(9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)e-
thanone (7ac): Following the general procedure with catalyst 4, com-
pound 7ac (88%) was isolated by FC on silica gel (petroleum ether/ethyl
acetate=30:1 then 20:1). 1H NMR (600 MHz, CDCl3): d=7.98 (d, J=
9.0 Hz, 2H), 7.51 (d, J=7.8 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.15 (t, J=
7.5 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 6.90 (d, J=9.0 Hz, 2H), 3.82 (s,
3H), 3.79 (d, J=7.2 Hz, 1H), 3.58 (s, 3H), 3.50 (dd, J=3.0, 16.8 Hz, 1H),
3.12 (dd, J=10.2, 16.2 Hz, 1H), 2.73–2.61 (m, 2H), 1.95–1.87 (m, 3H),
1.77–1.73 ppm (m, 1H); 13C NMR (150 MHz, CDCl3): d=198.5, 163.3,
136.8, 136.1, 130.4, 130.3, 126.1, 120.5, 118.7, 117.9, 113.6, 111.8, 108.7,
55.4, 43.4, 28.9, 28.2, 22.0, 19.4 ppm; MS (EI): m/z (%): 333 (rel. intensi-
ty) [M+]; elemental analysis: calcd (%) for (C22H23NO2): C 79.25, H 6.95,
N 4.20; found: C 79.21, H 6.96, N 4.27.
Scheme 4. Asymmetric sequential CM/intramolecular-hydroarylation in-
volving CM and iminium catalysis.
indolyl alkene component can be well-tolerated. For exam-
ple, the reaction with 5-Me and 6-Me-substituted w-indolyl
alkenes gave the desired products in 84–88% yield and with
84–86% ee. Further optimization of the reaction conditions
to improve the enantioselectivity and extension of the sub-
strate scope are underway in our laboratory.
1-(4-Fluorophenyl)-2-(9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)etha-
none (7ad): Following the general procedure with catalyst 4, compound
7ad (87%) was isolated by FC on silica gel (petroleum ether/ethyl ace-
Conclusions
1
tate=30:1). H NMR (600 MHz, CDCl3): d=8.00 (t, J=7.5 Hz, 2H), 7.48
(d, J=7.8 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.15 (t, J=7.5 Hz, 1H), 7.10–
7.03 (m, 3H), 3.79 (d, J=6.0 Hz, 1H), 3.59 (s, 3H), 3.53 (dd, J=3.0,
17.4 Hz, 1H), 3.13 (dd, J=10.8, 17.4 Hz, 1H), 2.74–2.62 (m, 2H), 1.95–
1.90 (m, 3H), 1.75–1.70 ppm (m, 1H); 13C NMR (150 MHz, CDCl3): d=
198.2, 166.4, 164.7, 136.8, 136.2, 133.8, 130.6, 130.6, 126.0, 120.6, 118.7,
117.9, 115.6, 115.5, 111.7, 108.7, 43.7, 28.9, 28.2, 27.8, 22.0, 19.4 ppm; MS
(EI): m/z (%): 321 (rel. intensity) [M+]; elemental analysis: calcd (%)
for (C21H20FNO): C 78.48, H 6.27, N 4.36; found: C 78.44, H 6.28, N 4.43.
In conclusion, we have developed an efficient and mild ap-
proach to THCs through a single ruthenium-complex-cata-
lyzed CM/intramolecular hydroarylation sequence. The easy
availability of the alkenyl-indole precursors and broadness
of scope make this methodology suitable for the preparation
of a wide range of multifunctional polycyclic-indole deriva-
tives.
1-(4-Chlorophenyl)-2-(9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)etha-
none (7ae): Following the general procedure with catalyst 4, compound
7ae (69%) was isolated by FC on silica gel (petroleum ether/ethyl ace-
tate=30:1). 1H NMR (600 MHz, CDCl3): d=7.91 (d, J=8.4 Hz, 2H),
7.48 (d, J=7.8 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H),
7.15 (t, J=7.5 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 3.79 (d, J=6.0 Hz, 1H),
3.60 (s, 3H), 3.52 (dd, J=1.8, 16.8 Hz, 1H), 3.13 (dd, J=10.8, 16.8 Hz,
1H), 2.75–2.64 (m, 2H), 1.95–1.91 (m, 3H), 1.74 ppm (t, J=5.1 Hz, 1H);
13C NMR (150 MHz, CDCl3): d=198.7, 139.3, 136.8, 136.2, 135.6, 129.5,
128.6, 126.0, 120.6, 118.8, 117.9, 111.5, 108.8, 43.8, 28.9, 28.2, 27.8, 22.0,
19.4 ppm; MS (EI): m/z (%): 339 (rel. intensity) [M++2]; elemental anal-
ysis: calcd (%) for (C21H20ClNO): C 74.66, H 5.97, N 4.15; found:
C 74.55, H 5.91, N 4.28.
Experimental Section
General Procedure for the Ru-catalyzed Tandem CM/Intramolecular
Hydroarylation Between w-Indolyl Alkene and a,b-Unsaturated Carbonyl
Compounds (Tables 2, 3, and Scheme 2):
The w-indolyl alkenes 5 or 10 (0.3 mmol) and a,b-unsaturated ketones 6,
8, or 11 (1.5 mmol, 5 equiv) were dissolved in DCE (3.0 mL), followed by
the addition of the Ru catalyst 4 (9.0 mmol, 3 mol% based on 5 or 10).
Then, the mixture was heated to reflux. The stirring was maintained at
reflux until the completion of the reaction as determined by TLC. The
reaction mixture was then cooled to room temperature, and the solvent
was removed under reduced pressure. The crude product was purified by
flash chromatography (FC) on silica gel to afford the corresponding pure
adduct.
1-(4-Bromophenyl)-2-(9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)etha-
none (7af): Following the general procedure with catalyst 4, compound
7af (60%) was isolated by FC on silica gel (petroleum ether/ethyl ace-
tate=30:1 then 20:1). 1H NMR (600MHz, CDCl3): d=7.73 (d, J=
7.8 Hz, 2H), 7.46 (d, J=8.4 Hz, 1H), 7.38 (d, J=7.2 Hz, 1H), 7.16 (d, J=
7.8 Hz, 1H), 7.06 (t, J=6.6 Hz, 1H), 6.95 (t, J=7.2 Hz, 1H), 3.68 (d, J=
5.4 Hz, 1H), 3.50 (s, 3H), 3.42 (d, J=16.8 Hz, 1H), 3.02 (dd, J=10.8,
16.8 Hz, 1H), 2.65–2.56 (m, 2H), 1.83 (t, J=12.6 Hz, 3H), 1.64 ppm (d,
J=10.8 Hz, 1H); 13C NMR (150MHz, CDCl3): d=198.8, 136.8, 136.2,
136.0, 131.8, 129.6, 128.0, 126.0, 120.7, 118.8, 117.8, 111.5, 108.7, 43.8,
28.9, 28.2, 27.8, 22.0, 19.4 ppm; MS (EI): m/z (%): 382 (rel. intensity)
[M+]; elemental analysis: calcd (%) for (C21H20BrNO): C 65.98, H 5.27,
N 3.66; found: C 65.95, H 5.23, N 3.74.
2-(9-Methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-1-phenylethanone
(7aa): Following the general procedure with catalyst 4, compound 7aa
(82%) was isolated by FC on silica gel (petroleum ether/ethyl acetate=
1
50:1 then 30:1). H NMR (600 MHz, CDCl3): d=7.99 (d, J=7.2 Hz, 2H),
7.54–7.50 (m, 2H), 7.43 (t, J=7.8 Hz, 2H), 7.25 (d, J=8.4 Hz, 1H), 7.15
(t, J=13.8 Hz, 1H), 3.58 (s, 3H), 3.55 (d, J=3.0 Hz, 1H), 3.17 (dd, J=
10.2, 16.8 Hz, 1H), 2.73–2.62 (m, 2H), 1.97–1.69 (m, 3H), 1.77–1.74 ppm
(m, 1H); 13C NMR (150 MHz, CDCl3): d=199.9, 137.3, 136.8, 136.2,
132.9, 128.5, 128.0, 126.1, 120.5, 118.7, 117.9, 111.7, 108.7, 43.8, 28.9, 28.2,
27.8, 22.0, 18.4 ppm; MS (EI): m/z (%): 303 (rel. intensity) [M+]; elemen-
tal analysis: calcd (%) for (C21H21NO): C 83.13, H 6.98, N 4.62; found:
C 83.02, H 6.88, N 4.74.
1-(3-Methoxyphenyl)-2-(9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-
ethanone (7ag): Following the general procedure with catalyst 4, com-
pound 7ag (86%) was isolated by FC on silica gel (petroleum ether/ethyl
acetate=30:1 then 20:1). 1H NMR (400 MHz, CDCl3): d=7.59 (d, J=
7.6 Hz, 1H), 7.54–7.51 (m, 2H), 7.37 (t, J=7.8 Hz, 1H), 7.29 (d, J=
Chem. Asian J. 2010, 5, 2258 – 2265
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J.-R. Chen, W.-J. Xiao et al.
FULL PAPERS
8.4 Hz, 1H), 7.19–7.14 (m, 1H), 7.12–7.05 (m, 2H), 3.86 (s, 4H), 3.64 (s,
3H), 3.56 (dd, J=2.8, 16.8 Hz, 1H), 3.19 (dd, J=10.4, 16.8 Hz, 1H),
2.79–2.64 (m, 2H), 1.98–1.92 (m, 3H), 1.79–1.74 ppm (m, 1H); 13C NMR
(100 MHz, CDCl3): d=199.7, 159.7, 138.6, 136.8, 136.2, 129.5, 126.0,
120.7, 120.6, 119.5, 118.7, 117.9, 112.1, 111.6, 108.7, 55.3, 43.9, 28.9, 28.1,
27.8, 22.0, 19.3 ppm; MS (EI): m/z (%): 333 (rel. intensity) [M+]; elemen-
tal analysis: calcd (%) for (C22H23NO2): C 79.25, H 6.95, N 4.20; found:
C 79.23, H 6.99, N 4.22.
28.9, 27.3, 27.2, 22.0, 21.6, 19.8, 17.6 ppm; MS (EI): m/z (%): 331 (rel. in-
tensity) [M+]; elemental analysis: calcd (%) for (C23H25NO): C 83.34,
H 7.60, N 4.23; found: C 83.39, H 7.55, N 4.18.
2-(6,9-Dimethyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-1-p-tolylethanone
(7cb): Following the general procedure with catalyst 4, compound 7cb
(81%) was isolated by FC on silica gel (petroleum ether/ethyl acetate=
1
50:1). H NMR (400 MHz, CDCl3): d=7.92 (d, J=8.0 Hz, 2H), 7.33–7.24
(m, 3H), 7.16 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 3.77 (d, J=
10.0 Hz, 1H), 3.60 (s, 3H), 3.51 (dd, J=3.2, 17.2 Hz, 1H), 3.17 (dd, J=
11.2, 17.2 Hz, 1H), 2.75–2.65 (m, 2H), 2.42 (s, 3H), 2.41 (s, 3H), 1.96–
1.89 (m, 3H), 1.77–1.69 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=
199.7, 143.6, 136.2, 135.2, 134.9, 129.2, 128.2, 127.8, 126.2, 122.0, 117.7,
111.2, 108.4, 43.6, 28.9, 28.1, 27.8, 22.1, 21.6, 21.4, 19.3 ppm; MS (EI): m/z
(%): 331 (rel. intensity) [M+]; elemental analysis: calcd (%) for
(C23H25NO): C 83.34, H 7.60, N 4.23; found: C 83.30, H 7.67, N 4.29.
1-(3-Bromophenyl)-2-(9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)etha-
none (7ah): Following the general procedure with catalyst 4, compound
7ah (84%) was isolated by FC on silica gel (petroleum ether/ethyl ace-
1
tate=30:1 then 20:1). H NMR (400 MHz, CDCl3): d=8.12 (t, J=1.6 Hz,
1H), 7.91 (d, J=7.2 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz,
1H), 7.30 (t, J=8.2 Hz, 1H), 7.18 (t, J=7.4 Hz, 1H), 7.07 (t, J=8.2 Hz,
1H), 3.80 (d, J=10.4 Hz, 1H), 3.64 (s, 3H), 3.54 (dd, J=2.8, 17.2 Hz,
1H), 3.16 (dd, J=10.8, 17.2 Hz, 1H), 2.78–2.66 (m, 2H), 1.99–1.91 (m,
3H), 1.78–1.73 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=198.5,
138.9, 136.8, 136.2, 135.7, 131.2, 130.2, 126.5, 125.9, 122.9, 120.6, 118.8,
117.8, 111.4, 108.8, 43.9, 29.0, 28.1, 27.6, 22.0, 19.3 ppm; MS (EI): m/z
(%): 382 (rel. intensity) [M+]; elemental analysis: calcd (%) for
(C21H20BrNO): C 65.98, H 5.27, N 3.66; found: C 65.87, H 5.33, N 3.61.
2-(7,9-Dimethyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-1-p-tolylethanone
(7 db): Following the general procedure with catalyst 4, compound 7 db
(81%) was isolated by FC on silica gel (petroleum ether/ethyl acetate=
50:1). 1H NMR (400 MHz, CDCl3): d=7.90 (d, J=8.4 Hz, 2H), 7.39 (d,
J=8.0 Hz, 1H), 7.30–7.23 (m, 2H), 7.08 (s, 1H), 6.89 (d, J=8.0 Hz, 1H),
3.76 (d, J=10.8 Hz, 1H), 3.59 (s, 3H), 3.54 (dd, J=3.2, 17.2 Hz, 1H),
3.13 (dd, J=10.8, 16.8 Hz, 1H), 2.74–2.64 (m, 2H), 2.48 (s, 3H), 2.41 (s,
3H), 1.97–1.88 (m, 3H), 1.78–1.70 ppm (m, 1H); 13C NMR (100 MHz,
CDCl3): d=199.7, 143.6, 137.2, 135.5, 134.8, 130.2, 129.2, 128.2, 123.9,
120.3, 117.6, 111.5, 108.9, 43.7, 28.8, 28.2, 29.0, 22.0, 21.8, 21.6, 19.5 ppm;
MS (EI): m/z (%): 331 (rel. intensity) [M+]; elemental analysis: calcd
(%) for (C23H25NO): C 83.34, H 7.60, N 4.23; found: C 83.28, H 7.63,
N 4.25.
1-(2-Methoxyphenyl)-2-(9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-
ethanone (7ai): Following the general procedure with catalyst 4, com-
pound 7ai (74%) was isolated by FC on silica gel (petroleum ether/ethyl
acetate=30:1 then 20:1). 1H NMR (400 MHz, CDCl3): d=7.70 (dd, J=
1.6, 7.6 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.48–7.43 (m, 1H), 7.27 (d, J=
8.0 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.09–7.01 (m, 2H), 6.95 (d, J=
8.4 Hz, 1H), 3.87 (s, 3H), 3.70 (d, J=8.0 Hz, 1H), 3.67 (d, J=2.8 Hz,
1H), 3.62 (s, 3H), 3.13 (dd, J=12.0, 17.6 Hz, 1H), 2.76–2.63 (m, 2H),
1.97–1.86 (m, 3H), 1.80–1.72 ppm (m, 1H); 13C NMR (100 MHz, CDCl3):
d=203.0, 158.1, 136.7, 136.1, 133.1, 130.1, 128.9, 126.2, 120.5, 120.3, 118.5,
118.1, 111.8, 111.3, 108.6, 55.4, 48.9, 28.9, 28.3, 28.0, 22.0, 19.5 ppm; MS
(EI): m/z (%): 333 (rel. intensity) [M+]; elemental analysis: calcd (%)
for (C22H23NO2): C 79.25, H 6.95, N 4.20; found: C 79.35, H 6.93, N 4.18.
2-(8,9-Dimethyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-1-p-tolylethanone
(7eb): Following the general procedure with catalyst 4, compound 7eb
(48%) was isolated by FC on silica gel (petroleum ether/ethyl acetate=
1
30:1 then 20:1). H NMR (400 MHz, CDCl3): d=7.89 (d, J=8.0 Hz, 2H),
7.33 (d, J=7.6 Hz, 1H), 7.24 (d, J=8.0 Hz, 2H), 6.92 (t, J=7.6 Hz, 1H),
6.85 (s, 1H), 3.86 (s, 3H), 3.76 (d, J=10.4 Hz, 1H), 3.49 (dd, J=2.4,
16.8 Hz, 1H), 3.14 (dd, J=10.8, 16.8 Hz, 1H), 2.75 (s, 3H), 2.69–2.58 (m,
2H), 2.39 (s, 3H), 1.95–1.75 ppm (m, 4H); 13C NMR (100 MHz, CDCl3):
d=199.6, 143.6, 136.5, 135.6, 134.9, 129.2, 128.2, 126.9, 123.8, 120.7, 118.9,
115.9, 112.0, 43.4, 32.0, 27.8, 27.6, 22.3, 21.6, 20.2, 19.3 ppm; MS (EI): m/z
(%): 331 (rel. intensity) [M+]; elemental analysis: calcd (%) for
(C23H25NO): C 83.34, H 7.60, N 4.23, found: C 83.37, H 7.66, N 4.34.
1-(2-Bromophenyl)-2-(9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)etha-
none (7aj): Following the general procedure with catalyst 4, compound
7aj (85%) was isolated by FC on silica gel (petroleum ether/ethyl ace-
tate=50:1 then 30:1). 1H NMR (400 MHz, CDCl3): d=7.61 (d, J=
8.0 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H), 7.43–7.35 (m, 2H), 7.30 (t, J=5 Hz,
2H), 7.16 (t, J=7.4 Hz, 1H), 7.07 (t, J=7.4 Hz, 1H), 3.74 (dd, J=2.8,
10.0 Hz, 1H), 3.61 (s, 3H), 3.56 (d, J=2.8 Hz, 1H), 3.10 (dd, J=10.8,
17.2 Hz, 1H), 2.77–2.62 (m, 2H), 1.96–1.92 (m, 3H), 1.87–1.82 ppm (m,
1H); 13C NMR (100 MHz, CDCl3): d=204.1, 141.8, 136.7, 136.2, 133.6,
131.4, 128.2, 127.3, 125.9, 120.5, 118.7, 118.5, 117.8, 111.1, 108.7, 48.0,
28.9, 28.0, 27.8, 21.9, 19.3 ppm; MS (EI): m/z (%): 382 (rel. intensity)
[M+]; elemental analysis: calcd (%) for (C21H20BrNO): C 65.98, H 5.27,
N 3.66; found: C 65.91, H 5.38, N 3.64.
2-(5-Fluoro-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-1-p-tolyletha-
none (7 fb): Following the general procedure with catalyst 4, compound
7 fb (92%) was isolated by FC on silica gel (petroleum ether/ethyl ace-
tate=30:1). 1H NMR (400 MHz, CDCl3): d=7.96 (d, J=8.4 Hz, 2H),
7.32 (t, J=11.2 Hz, 2H), 7.07–7.05 (m, 2H), 6.75–6.71 (m, 1H), 4.83 (d,
J=11.2 Hz, 1H), 3.66 (dd, J=2.8, 16.4 Hz, 1H), 3.62 (s, 3H), 3.04 (dd,
J=11.2, 16.0 Hz, 1H), 2.76–2.59 (m, 2H), 2.41 (s, 3H), 1.92–1.82 ppm (m,
4H); 13C NMR (100 MHz, CDCl3): d=199.6, 157.4, 155.0, 143.5, 139.7,
139.5, 136.1, 134.7, 129.5, 129.1, 128.3, 121.0, 120.9, 110.6, 104.8, 104.2,
104.0, 44.8, 29.3, 28.6, 27.1, 22.0, 21.5, 18.4 ppm; MS (EI): m/z (%): 335
(rel. intensity) [M+]; elemental analysis: calcd (%) for (C22H22FNO):
C 78.78, H 6.61, N 4.18; found: C 78.71, H 6.56, N 4.29.
1-(Furan-2-yl)-2-(9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)ethanone
(7ak): Following the general procedure with catalyst 4, compound 7ak
(85%) was isolated by FC on silica gel (petroleum ether/ethyl acetate=
1
30:1 then 20:1). H NMR (400 MHz, CDCl3): d=7.73 (d, J=3.6 Hz, 1H),
7.64 (d, J=4.8 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H),
7.19–7.06 (m, 3H), 3.81–3.78 (m, 1H), 3.63 (s, 3H), 3.51 (dd, J=3.2,
16.4 Hz, 1H), 3.11 (dd, J=10.8, 16.0 Hz, 1H), 2.78–2.67 (m, 2H), 1.98–
1.91 (m, 3H), 1.85–1.77 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=
192.9, 144.9, 136.7, 136.2, 133.6, 131.8, 128.1, 126.0, 120.6, 118.8, 117.9,
111.4, 108.7, 44.5, 29.0, 28.04, 28.0, 22.0, 19.3 ppm; MS (EI): m/z (%): 293
(rel. intensity) [M+]; elemental analysis: calcd (%) for (C19H19NO2):
C 77.79, H 6.53, N 4.77; found: C 77.71, H 6.56, N 4.69.
2-(5-Chloro-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-1-p-tolyletha-
none (7gb): Following the general procedure with catalyst 4, compound
7gb (96%) was isolated by FC on silica gel (petroleum ether/ethyl ace-
tate=50:1 then 30:1). 1H NMR (400 MHz, CDCl3): d=7.91 (d, J=
8.0 Hz, 2H), 7.25 (t, J=10.4 Hz, 2H), 7.15 (d, J=7.6 Hz, 1H), 7.06–7.00
(m, 2H), 4.22 (d, J=8.4 Hz, 1H), 3.62 (dd, J=0.8, 15.2 Hz, 1H), 3.61 (s,
3H), 3.22 (dd, J=10.8, 17.6 Hz, 1H), 2.81–2.40 (m, 2H), 2.40 (s, 3H),
1.97–1.85 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=199.0, 143.4,
138.1, 136.9, 134.9, 129.1, 128.0, 125.0, 123.4, 121.0, 119.5, 112.4, 107.2,
45.0, 29.1, 26.8, 26.8, 22.0, 21.2, 17.6 ppm; MS (EI): m/z (%): 351 (rel. in-
tensity) [M++2]; elemental analysis: calcd (%) for (C22H22ClNO):
C 75.09, H 6.30, N 3.98; found: C 75.07, H 6.31, N 3.97.
2-(5,9-Dimethyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-1-p-tolylethanone
(7bb): Following the general procedure with catalyst 4, compound 7bb
(77%) was isolated by FC on silica gel (petroleum ether/ethyl acetate=
50:1). 1H NMR (400 MHz, CDCl3): d=7.88 (d, J=8.0 Hz, 2H), 7.25 (t,
J=4.0 Hz, 2H), 7.13–7.03 (m, 2H), 6.80 (d, J=6.8 Hz, 1H), 4.14 (d, J=
9.2 Hz, 1H), 3.60 (s, 3H), 3.41 (dd, J=10.8, 18.4 Hz, 1H), 3.28 (dd, J=
2.0, 18.4 Hz, 1H), 2.84–2.63 (m, 2H), 2.61 (s, 3H), 2.40 (s, 3H), 1.94–
1.84 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=198.7, 143.7, 137.0,
135.2, 134.8, 129.4, 129.2, 128.0, 124.8, 120.6, 120.5, 112.8, 106.3, 45.0,
2-(6-Fluoro-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-1-p-tolyletha-
none (7hb): Following the general procedure with catalyst 4, compound
7hb (71%) was isolated by FC on silica gel (petroleum ether/ethyl ace-
tate=50:1 then 30:1). 1H NMR (600 MHz, CDCl3): d=7.89 (d, J=
2262
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Highly Efficient Route to Functionalized Tetrahydrocarbazoles
7.8 Hz, 2H), 7.24 (d, J=7.8 Hz, 2H), 7.15–7.13 (m, 2H), 6.89–6.85 (m,
1H), 3.73 (d, J=7.2 Hz, 1H), 3.58 (s, 3H), 3.44 (dd, J=3.0, 16.8 Hz, 1H),
3.13 (dd, J=10.2, 16.8 Hz, 1H), 2.73 (t, J=10.2 Hz, 1H), 2.65–2.62 (m,
1H), 2.40 (s, 3H), 1.94–1.87 (m, 3H), 1.76–1.73 ppm (m, 1H); 13C NMR
(100 MHz, CDCl3): d=199.4, 158.2, 156.7, 143.7, 138.0, 134.8, 133.5,
129.2, 128.2, 126.3, 126.2, 111.9, 109.1, 109.0, 108.3, 103.2, 103.0, 43.4,
29.1, 28.2, 27.8, 22.2, 21.6, 19.3 ppm; MS (EI): m/z (%): 335 (rel. intensi-
ty) [M+]; elemental analysis: calcd (%) for (C22H22FNO): C 78.78,
H 6.61, N 4.18; found: C 78.75, H 6.58, N 4.24.
1-(7,9-Dimethyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)propan-2-one (9d):
Following the general procedure with catalyst 4, compound 9d (78%)
was isolated by FC on silica gel (petroleum ether/ethyl acetate=10:1
then 5:1). 1H NMR (400 MHz, CDCl3): d=7.33 (d, J=7.6 Hz, 1H), 7.06
(s, 1H), 6.89 (d, J=8.0 Hz, 1H), 3.59–3.55 (m, 4H), 3.05 (dd, J=3.6,
16.8 Hz, 1H), 2.72–2.55 (m, 3H), 2.45 (s, 3H), 2.19 (s, 3H), 1.94–1.86 (m,
3H), 1.68–1.63 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=209.0,
137.2, 135.3, 130.2, 123.9, 120.3, 117.5, 111.1, 108.8, 49.2, 30.6, 28.8, 28.3,
27.7, 21.9, 21.7, 19.4 ppm; MS (EI): m/z (%): 255 (rel. intensity) [M+]; el-
emental analysis: calcd (%) for (C17H21NO): C 79.96, H 8.29, N 5.49;
found: C 79.90, H 8.33, N 5.39.
2-(7-Chloro-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-1-p-tolyletha-
none (7ib): Following the general procedure with catalyst 4, compound
7ib (93%) was isolated by FC on silica gel (petroleum ether/ethyl ace-
tate=30:1). 1H NMR (400 MHz, CDCl3): d=7.89 (d, J=8.0 Hz, 2H),
7.38 (d, J=8.4 Hz, 1H), 7.25 (d, J=6.0 Hz, 3H), 7.01 (dd, J=1.6, 8.4 Hz,
1H), 3.76 (d, J=6.8 Hz, 1H), 3.59 (s, 3H), 3.43 (dd, J=3.2, 16.8 Hz, 1H),
3.15 (dd, J=10.4, 16.8 Hz, 1H), 2.72–2.65 (m, 2H), 2.41 (s, 3H), 1.99–
1.90 (m, 3H), 1.78–1.72 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=
199.3, 143.7, 137.3, 137.0, 134.7, 129.2, 128.1, 126.4, 124.7, 119.1, 118.7,
112.0, 108.7, 43.6, 29.0, 28.1, 27.7, 22.0, 21.6, 19.2 ppm; MS (EI): m/z (%):
351 (rel. intensity) [M++2]; elemental analysis: calcd (%) for
(C22H22ClNO): C 75.09, H 6.30, N 3.98; found: C 75.13, H 6.34, N 3.90.
1-(5-Fluoro-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)propan-2-one
(9e): Following the general procedure with catalyst 4, compound 9e
(87%) was isolated by FC on silica gel (petroleum ether/ethyl acetate=
10:1 then 5:1). 1H NMR (400 MHz, CDCl3): d=7.07–7.01 (m, 2H), 6.74–
6.69 (m, 1H), 3.68–3.65 (m, 1H), 3.60 (s, 3H), 3.10 (dd, J=2.0, 16.0 Hz,
1H), 2.73–2.53 (m, 3H), 2.22 (s, 3H), 1.91–1.77 ppm (m, 4H); 13C NMR
(100 MHz, CDCl3): d=208.9, 157.4, 155.0, 139.7, 139.6, 136.0, 121.0,
120.9, 114.6, 110.4, 104.8, 104.2, 104.0, 50.0, 29.9, 29.3, 28.1, 27.2, 22.0,
18.4 ppm; MS (EI): m/z (%): 259 (rel. intensity) [M+]; elemental analy-
sis: calcd (%) for (C16H18FNO): C 74.11, H 7.00, N 5.40; found: C 74.16,
H 7.07, N 5.34.
2-(8-Chloro-6,9-dimethyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)-1-p-tolyl-
ethanone (7jb): Following the general procedure with catalyst 4, com-
pound 7jb (88%) was isolated by FC on silica gel (petroleum ether/ethyl
acetate=30:1). 1H NMR (400 MHz, CDCl3): d=7.90 (d, J=7.2 Hz, 2H),
7.25 (d, J=8.4 Hz, 2H), 7.12 (s, 1H), 6.91 (s, 1H), 3.95 (s, 3H), 3.74 (d,
J=8.8 Hz, 1H), 3.37 (dd, J=2.0, 16.8 Hz, 1H), 3.19 (dd, J=10.4, 16.0 Hz,
1H), 2.75–2.56 (m, 2H), 2.42 (s, 3H), 2.35 (s, 3H), 1.94–1.85 (m, 3H),
1.81–1.75 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=199.4, 143.7,
138.0, 134.6, 130.5, 129.3, 129.2, 128.9, 128.1, 123.7, 116.3, 115.9, 111.9,
43.1, 31.7, 27.7, 27.3, 22.2, 21.5, 20.9, 19.0 ppm; MS (EI): m/z (%): 365
(rel. intensity) [M++2]; elemental analysis: calcd (%) for (C23H24ClNO):
C 75.50, H 6.61, N 3.83; found: C 75.43, H 6.64, N 3.90.
1-(7-Chloro-9-methyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)propan-2-one
(9 f): Following the general procedure with catalyst 4, compound 9 f
(85%) was isolated by FC on silica gel (petroleum ether/ethyl acetate=
10:1 then 5:1). 1H NMR (400 MHz, CDCl3): d=7.34 (d, J=8.4 Hz, 1H),
7.25 (d, J=6.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 3.60–3.54 (m, 4H), 2.98
(dd, J=3.6, 16.8 Hz, 1H), 2.72–2.56 (m, 3H), 2.18 (s, 3H), 1.96–1.88 (m,
3H), 1.70–1.65 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=208.6,
137.2, 136.9, 126.4, 124.6, 119.1, 118.6, 111.7, 108.7, 49.0, 30.6, 28.9, 28.2,
27.4, 21.9, 19.2 ppm; MS (EI): m/z (%): 277 (rel. intensity) [M++2]; ele-
mental analysis: calcd (%) for (C16H18ClNO): C 69.68, H 6.58, N 5.08;
found: C 69.65, H 6.64, N 5.17.
1-(8-Chloro-6,9-dimethyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)propan-2-
one (9g): Following the general procedure with catalyst 4, compound 9g
(90%) was isolated by FC on silica gel (petroleum ether/ethyl acetate=
10:1 then 5:1). 1H NMR (400 MHz, CDCl3): d=7.07 (s, 1H), 6.91 (s,
1H), 3.93 (s, 3H), 3.53 (dd, J=3.2, 10.4 Hz, 1H), 2.93 (dd, J=3.2,
16.8 Hz, 1H), 2.71–2.57 (m, 3H), 2.38 (s, 3H), 2.20 (s, 3H), 1.91–1.84 (m,
3H), 1.73–1.67 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=208.6,
137.9, 130.4, 129.2, 128.9, 123.7, 116.2, 115.9, 111.5, 48.7, 31.6, 30.6, 27.8,
27.1, 22.2, 20.9, 19.0 ppm; MS (EI): m/z (%): 391 (rel. intensity) [M++2];
elemental analysis: calcd (%) for (C17H20ClNO): C 70.46, H 6.96, N 4.83;
found: C 70.43, H 6.91, N 4.90.
1-p-Tolyl-2-(6,8,9-trimethyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)ethanone
(7kb): Following the general procedure with catalyst 4, compound 7kb
(40%) was isolated by FC on silica gel (petroleum ether/ethyl acetate=
1
50:1). H NMR (400 MHz, CDCl3): d=7.91 (d, J=8.4 Hz, 2H), 7.27–7.25
(m, 3H), 7.10 (s, 1H), 6.67 (s, 1H), 3.85 (s, 3H), 3.72 (t, J=5.6 Hz, 1H),
3.43 (dd, J=2.4, 16.4 Hz, 1H), 3.14 (dd, J=11.2, 17.2 Hz, 1H), 2.72 (s,
3H), 2.41ACHTUNGTRENNUNG(s, 3H), 2.35 (s, 3H), 1.91–1.89 (m, 3H), 1.78–1.76 ppm (m,
1H); 13C NMR (100 MHz, CDCl3): d=199.7, 143.7, 136.6, 135.0, 134.0,
129.2, 128.2, 128.1, 127.2, 125.5, 120.4, 115.6, 111.6, 43.3, 32.0, 27.8, 27.5,
22.4, 21.6, 21.1, 20.1, 19.3 ppm; MS (EI): m/z (%): 345 (rel. intensity)
[M+]; elemental analysis: calcd (%) for (C24H27NO): C 83.44, H 7.88,
N 4.05; found: C 83.32, H 7.96, N 4.08.
1-Phenyl-2-(9-phenyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)ethanone
(12a): Following the general procedure with catalyst 4, compound 12a
(81%) was isolated by FC on silica gel (petroleum ether/ethyl acetate=
10:1). 1H NMR (600 MHz, CDCl3): d=8.02 (d, J=7.8 Hz, 2H), 7.55 (dd,
J=7.8, 15.0 Hz, 2H), 7.49 (t, J=7.8 Hz, 2H), 7.22 (t, J=4.5 Hz, 1H),
7.45 (t, J=7.5 Hz, 2H), 7.39 (d, J=7.2 Hz, 1H), 7.35 (d, J=7.8 Hz, 2H),
7.22 (dd, J=2.4, 6.0 Hz, 1H), 7.10 (dd, J=3.0, 6.0 Hz, 2H), 3.90 (d, J=
3.0 Hz, 1H), 3.63 (d, J=16.8 Hz, 1H), 3.26 (dd, J=4.2, 16.8 Hz, 1H),
2.57 (d, J=5.4 Hz, 2H), 2.06–2.01 (m, 1H), 1.89–1.78 ppm (m, 3H);
13C NMR (150 MHz, CDCl3): d=199.8, 137.6, 137.4, 137.3, 136.4, 132.9,
129.3, 128.5, 128.0, 127.2, 127.1, 126.6, 121.3, 119.7, 118.0, 113.3, 110.1,
43.7, 28.3, 27.8, 23.2, 19.6 ppm; MS (EI): m/z (%): 365 (rel. intensity)
[M+]; elemental analysis: calcd (%) for (C26H23NO): C 85.45, H 6.34,
N 3.83; found: C 85.42, H 6.38, N 3.78.
1-(5,9-Dimethyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)propan-2-one (9b):
Following the general procedure with catalyst 4, compound 9b (64%)
was isolated by FC on silica gel (petroleum ether/ethyl acetate=10:1
then 5:1). 1H NMR (400 MHz, CDCl3): d=7.09 (d, J=8.0 Hz, 1H), 7.04
(t, J=7.6 Hz, 1H), 6.81 (d, J=7.2 Hz, 1H), 3.91–3.88 (m, 1H), 3.57 (s,
3H), 2.87 (dd, J=2.4, 7.6 Hz, 1H), 2.81–2.73 (m, 2H), 2.66–2.58 (m, 4H),
2.19 (s, 3H), 1.98–1.90 (m, 1H), 1.87–1.80 ppm (m, 3H); 13C NMR
(100 MHz, CDCl3): d=208.1, 137.0, 135.1, 129.2, 124.8, 120.6, 120.6,
112.4, 106.4, 50.6, 30.4, 28.9, 27.5, 27.0, 21.9, 19.8, 17.4 ppm; MS (EI): m/z
(%): 255 (rel. intensity) [M+]; elemental analysis: calcd (%) for
(C17H21NO): C 79.96, H 8.29, N 5.49; found: C 79.94, H 8.21, N 5.53.
1-(6,9-Dimethyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)propan-2-one (9c):
Following the general procedure with catalyst 4, compound 9c (82%)
was isolated by FC on silica gel (petroleum ether/ethyl acetate=10:1
then 5:1). 1H NMR (400 MHz, CDCl3): d=7.23 (s, 1H), 7.14 (d, J=
8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H), 3.57 (s, 1H), 3.57 (s, 3H), 3.05 (dd,
J=3.6, 16.8 Hz, 1H), 2.73–2.56 (m, 3H), 2.44 (s, 3H), 2.20 (s, 3H), 1.93–
1.86 (m, 3H), 1.69–1.64 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=
208.9, 136.1, 135.2, 127.8, 126.2, 122.0, 117.6, 110.8, 108.4, 49.1, 30.6, 28.9,
28.2, 27.6, 22.0, 21.4, 19.3 ppm; MS (EI): m/z (%) 255 (rel. intensity) [M+
]; elemental analysis: calcd (%) for (C17H21NO): C 79.96, H 8.29, N 5.49;
found: C 79.99, H 8.37, N 5.46.
1-(9-Phenyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)propan-2-one (12b): Fol-
lowing the general procedure with catalyst 4, compound 12b (88%) was
isolated by FC on silica gel (petroleum ether/ethyl acetate=20:1, 10:1
then 5:1). 1H NMR (600 MHz, CDCl3): d=7.50 (t, J=7.5 Hz, 3H), 7.39
(t, J=7.5 Hz, 1H), 7.34 (d, J=7.2 Hz, 2H), 7.23–7.21 (m, 1H), 7.10 (t,
J=7.8 Hz, 2H), 3.68 (t, J=4.8 Hz, 1H), 3.13 (dd, J=3.0, 16.8 Hz, 1H),
2.67 (dd, J=10.2, 16.8 Hz, 1H), 2.55 (t, J=7.2 Hz, 2H), 2.22 (s, 3H),
2.02–1.97 (m, 1H), 1.87–1.79 (m, 2H), 1.73–1.69 ppmACTHNUTRGNEUNG
(m, 1H); 13C NMR
(100 MHz, CDCl3): d=208.7, 137.7, 137.4, 136.3, 129.3, 127.3, 127.2,
126.5, 121.3, 119.6, 117.9, 113.0, 110.1, 49.0, 30.7, 28.4, 27.6, 23.2,
Chem. Asian J. 2010, 5, 2258 – 2265
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2263

J.-R. Chen, W.-J. Xiao et al.
FULL PAPERS
19.6 ppm; MS (EI): m/z (%): 303 (rel. intensity) [M+]; elemental analy-
sis: calcd (%) for (C21H21NO): C 83.13, H 6.98, N 4.62; found: C 83.19,
H 6.96, N 4.59.
1H NMR (600 MHz, CDCl3): d=9.74 (s, 1H), 7.93 (s, 1H), 7.15 (d, J=
7.8 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 3.44 (d, J=3.8 Hz, 1H), 2.95 (d, J=
17.9 Hz, 1H), 2.82–2.74 (m, 2H), 2.55 (dd, J=11.1, 16.1 Hz, 1H), 2.36 (s,
3H), 1.81–1.76 (m, 3H), 1.61–1.59 (m, 1H), 1.56 ppm (s, 9H); 13C NMR
(150 MHz, CDCl3): d=202.1, 150.5, 136.3, 135.4, 133.3, 126.0, 123.7,
117.7, 117.1, 115.9, 83.3, 48.2, 28.2, 27.4, 26.1, 25.7, 21.9, 19.4 ppm; MS
(EI): m/z (%): 327 (rel. intensity) [M+]; elemental analysis: calcd (%)
for (C20H24NO3): C 73.59, H 7.41, N 4.29; found: C 73.64, H 7.38, N 4.20.
The ee was determined by HPLC analysis of the corresponding alcohol,
obtained by NaBH4 reduction of the aldehyde: Chiralpak AD-H, iso-
2-(9-Phenyl-2,3,4,9-tetrahydro-1H-carbazol-4-yl)acetaldehyde (12c): Fol-
lowing the general procedure with catalyst 4, compound 12c (86%) was
isolated by FC on silica gel (petroleum ether/ethyl acetate=10:1).
1H NMR (600 MHz, CDCl3): d=9.94 (s, 1H), 7.53–7.50 (m, 3H), 7.41 (t,
J=7.5 Hz, 1H), 7.35 (d, J=7.8 Hz, 2H), 7.22 (t, J=4.5 Hz, 1H), 7.12 (t,
J=3.9 Hz, 2H), 3.73 (dd, J=4.2, 9.0 Hz, 1H), 3.10 (dd, J=2.4, 16.8 Hz,
1H), 2.77–2.72ACHTUNGTRENNUNG(m, 1H), 2.58 (t, J=6.0 Hz, 2H), 2.08–2.03 (m, 1H), 1.90–
propanol/hexanes=10:90, 254 nm, 1 mLminꢀ1
; tmajor =7.2 min, tminor =
1.83 (m, 2H), 1.78–1.73 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=
202.7, 137.4, 137.3, 136.3, 129.3, 127.2, 127.1, 126.4, 121.3, 119.7, 117.8,
112.1, 110.0, 49.0, 28.7, 26.7, 23.0, 19.6 ppm; MS (EI): m/z (%): 289 (rel.
intensity) [M+]; elemental analysis: calcd (%) for (C20H19NO): C 83.01,
H 6.98, N 4.62; found: C 83.08, H 7.01, N 4.64.
8.5 min.
General procedure for the preparation and characterization of the sub-
strates, NMR spectroscopy, and HPLC data can be found in the Support-
ing Information.
General Procedure for the Sequential CM/Intramolecular Hydroarylation
Involving CM and Iminium Catalysis (Scheme 4):
A three-necked flask was charged with freshly distilled CH2Cl2, w-indolyl
alkenes 13 (0.3 mmol), crotonaldehyde (3.0 mmol, 10 equiv), and Ru cat-
alyst 4 (0.015 mmol, 5 mol% based on 13). The resulting reaction mixture
was heated to reflux. Upon the completion of the reaction as monitored
by TLC, the reaction mixture was then cooled to room temperature, and
the solvent was removed under reduced pressure.
Acknowledgements
We are grateful to the National Science Foundation of China (20872043)
and the Program for Academic Leaders in Wuhan Municipality
(200851430486) for the support of this research. We thank Materia, Inc.,
Pasadena, CA, USA for the generous gift of ruthenium catalysts.
The resulting crude indolyl a,b-unsaturated aldehyde was dissolved in
Et2O/iPrOH (2.25 mL +0.75 mL, 0.1m) and cooled to ꢀ408C. After stir-
ring for 20 min, (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one
14 (20 mol%) and trifluoroacetic acid (0.06 mmol, 20 mol% based on 13)
were added in one portion. The resulting mixture was stirred at ꢀ408C
until the complete consumption of the indolyl a,b-unsaturated aldehyde
as determined by TLC. The resulting residue was purified by silica gel
chromatography (petroleum ether/ethyl acetate=5:1) to afford 15. The
enantioselectivity was determined by subjecting 15 (approximately
10 mg) to an excess of NaBH4 in methanol (1 mL). After 15 min, the so-
lution was treated with saturated aqueous NaHCO3, and the mixture was
extracted with CH2Cl2. The organic layer was separated, filtered through
a silica-gel plug, and subjected to chiral HPLC analysis.
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4-(2-oxoethyl)-3,4-dihydro-1H-carbazole-9ACHTNGUTERNNU(G 2H)-carboxylate
(15a): Following the general procedure, compound 15a (65%, 91% ee)
was isolated by FC on silica gel. ½aꢂ2D7 =2.38 (c=2.0, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=9.87 (d, J=1.2 Hz, 1H), 8.14 (d, J=7.6 Hz, 1H),
7.38 (d, J=6.8 Hz, 1H), 7.18–7.26 (m, 2H), 3.59 (d, J=4.0 Hz, 1H), 3.06–
3.13 (m, 1H), 2.85–2.96 (m, 2H), 2.64–2.71 (m, 1H), 1.69–1.96 (m, 4H),
1.66 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=202.0, 150.4, 136.4,
135.9, 128.3, 123.4, 122.4, 117.8, 117.4, 115.5, 83.4, 48.2, 28.1, 27.3, 26.0,
25.9, 19.3 ppm; MS (EI): m/z (%): 313 (rel. intensity) [M+]; elemental
analysis: calcd (%) for (C19H23NO3): C 72.82, H 7.40, N 4.47; found:
C 72.92, H 7.48, N 4.39. The ee was determined by HPLC analysis of the
corresponding alcohol, obtained by NaBH4 reduction of the aldehyde:
Chiralpak AD-H, iso-propanol/hexanes=10:90, 254 nm, 1 mLminꢀ1
major =5.2 min, tminor =5.9 min.
tert-Butyl 6-methyl-4-(2-oxoethyl)-3,4-dihydro-1H-carbazole-9ACHTNUGTRNE(GUN 2H)-car-
;
t
boxylate (15b): Following the general procedure, compound 15b (88%,
84% ee) was isolated by FC on silica gel. ½aꢂ1D6 =0.47 (c=2.0, CH2Cl2);
1H NMR (600 MHz, CDCl3): d=9.78 (s, 1H), 7.92 (d, J=8.4 Hz, 1H),
7.06 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 3.46 (d, J=3.6 Hz, 1H), 2.99 (d, J=
18.0 Hz, 1H), 2.85–2.76 (m, 2H), 2.59–2.54 (m, 1H), 2.33 (s, 3H), 1.84–
1.61 (m, 4H), 1.56 ppm (s, 9H); 13C NMR (150 MHz, CDCl3): d=202.2,
150.4, 136.4, 134.1, 131.9, 128.5, 124.7, 117.6, 117.5, 115.2, 83.2, 48.1, 28.2,
28.2, 27.3, 26.0, 25.7, 21.3, 19.3, 19.3 ppm; MS (EI): m/z (%): 327 (rel. in-
tensity) [M+]; elemental analysis: calcd (%) for (C20H24NO3): C 73.59,
H 7.41, N 4.29; found: C 73.52, H 7.51, N 4.23. The ee was determined by
HPLC analysis of the corresponding alcohol, obtained by NaBH4 reduc-
tion of the aldehyde: Chiralpak AD-H, iso-propanol/hexanes=10:90,
254 nm, 1 mLminꢀ1; tmajor =5.2 min, tminor =6.1 min.
tert-Butyl 7-methyl-4-(2-oxoethyl)-3,4-dihydro-1H-carbazole-9ACHTNUTGRNEUNG(2H)-car-
boxylate (15c): Following the general procedure, compound 15c (84%,
86% ee) was isolated by FC on silica gel. ½aꢂ1D5 =ꢀ6.82 (c=2.0, CH2Cl2);
2264
www.chemasianj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2010, 5, 2258 – 2265

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