Palladium-Catalyzed Synthesis of Diarylamines and 1- and 2-Oxygenated Carbazoles: Total Syntheses of Natural Alkaloids Clauraila A, Clausenal, Clausine P, and 7-Methoxy- O -methylmukonal

Article abstract of DOI:10.1055/s-0036-1588467

The scope and limitations of the strategy for the conversion of 2-anilinocyclohexenones and N -arylcyclohexane enaminones into the 1- and 2-oxygenated carbazole scaffolds, respectively, were evaluated. The one-pot palladium(0)-catalyzed aromatization/meth

Full text of DOI:10.1055/s-0036-1588467

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–O
paper
A
en
R. I. Hernández-Benitez et al.
Paper
Synthesis
Palladium-Catalyzed Synthesis of Diarylamines and 1- and 2-Oxy-
genated Carbazoles: Total Syntheses of Natural Alkaloids Clauraila
A, Clausenal, Clausine P, and 7-Methoxy-O-methylmukonal
R. Israel Hernández-Benitez
Pd(II)-catalyzed
diaryl coupling
Pd(II)-catalyzed
diaryl coupling
Pd(II)-catalyzed
thermal aromatization
Pd(0)-catalyzed
thermal aromatization
Daniel Zárate-Zárate
Francisco Delgado
Joaquín Tamariz*
R3
R2
OHC
R2
O
OMe
O
N
R1
H
OMe
N
H
H+/MW-promoted
condensation
O
R1
O
H+/MW-promoted
condensation
Departamento de Química Orgánica, Escuela Nacional
de Ciencias Biológicas, Instituto Politécnico Nacional,
Prol. Carpio y Plan de Ayala, 11340 Mexico City, Mexico
jtamarizm@gmail.com
Clauraila A, R1 = OMe, R2 = H
7-Methoxy-O-methylmukonal, R1 = H, R2 = OMe
Clausenal, R1 = OMe, R2 = H, R3 = CHO
Clausine P, R1 = H, R2 = OMe, R3 = Me
Received: 07.04.2017
Accepted after revision: 22.05.2017
Published online: 05.07.2017
Murraya siamensis15a as well as the rhizomes and roots of
Clausena excavata15b and from Clausena wallicchii roots,15c
which has anti-HIV-1 activity (Figure 1).
DOI: 10.1055/s-0036-1588467; Art ID: ss-2017-m0232-op
CHO
CHO
Abstract The scope and limitations of the strategy for the conversion
of 2-anilinocyclohexenones and N-arylcyclohexane enaminones into
the 1- and 2-oxygenated carbazole scaffolds, respectively, were evaluat-
ed. The one-pot palladium(0)-catalyzed aromatization/methylation
process of the aforementioned substrates provided a diversity of the
corresponding diarylamines. A subsequent palladium(II)-catalyzed cy-
clization of the latter delivered the desired 1- and 2-oxygenated carba-
zoles in good overall yields. Special attention was given to the synthesis
of the uncommon 1,8-disubstituted carbazoles. This methodology was
employed for the total synthesis of the naturally occurring clauraila A,
clausenal, clausine P, and 7-methoxy-O-methylmukonal.
MeO
N
H
N
H
OMe
MeO
OMe
1
2
Me
CHO
MeO
OMe
OMe
N
H
N
H
MeO
3
4
Figure 1 Clauraila A (1), clausenal (2), clausine P (3), and 7-methoxy-
O-methylmukonal (4)
Key words 1- and 2-oxygenated carbazoles, diarylamines, palladi-
um(II) coupling, clausenal, clausine P
Naturally occurring 1- and 2-oxygenated tricyclic carba-
zole alkaloids constitute a broad family of natural prod-
ucts.1 Whereas 1-oxygenated carbazole alkaloids have been
isolated from leaves, stem bark, and roots of higher plant
species of the genera Clausena, Glycosmis, and Murraya,2 2-
oxygenated carbazoles have been extracted from the same
genera,3 as well as others, such as Micromelum, Malassezia,
and Bergera.1,4 Both isomeric alkaloids exhibit significant
and diverse biological activity, acting as antibacterial,4c,5
antiplatelet aggregative,6 anticonvulsant,7 antifungal,8 anti-
plasmodial,9 anticancer,2d,10 and antiviral11 agents.
Among 1-oxygenated carbazoles, clauraila A (1) (isolat-
ed from Clausena harmandiana) shows cytotoxicity against
the NCI-H187 cell lines,12 and clausenal (2) (from Clausena
heptaphylla and Murraya koenigii) displays antibiotic activ-
ity.13 Examples of the 2-oxygenated alkaloids are clausine
P (3), isolated from the root bark of Clausena excavata,14
and 7-methoxy-O-methylmukonal (4), from the roots of
There has been growing interest in designing and devel-
oping new and more efficient synthetic approaches to
building the carbazole skeleton and achieving the total syn-
thesis of these natural alkaloids due to their potential ther-
apeutic profile and the challenge of constructing a structur-
al scaffold with such variety.1,16 In particular, clauraila A
(1),17 clausenal (2),17b,c clausine P (3),18 and 7-methoxy-O-
methylmukonal (4)19 are carbazoles that represent proto-
types for the total synthesis of tricyclic 1- and 2-oxygenat-
ed carbazole alkaloids.
Diverse synthetic protocols have been described for the
preparation of the carbazole scaffold.1 Of particular rele-
vance are the Fischer indolization,20 the iron-mediated oxi-
dative cyclization of arylamine tricarbonyl(cyclohexadiene)
complexes,21 the electrocyclic benzannulation of 2,3-substi-
tuted indoles,22 and the very efficient and versatile palladi-
um-catalyzed diarylamine intramolecular coupling.21,23
Having been inspired by the latter, we previously developed
a novel approach for the synthesis of diarylamines via a re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O

B
R. I. Hernández-Benitez et al.
Paper
Synthesis
gioselective Diels–Alder cycloaddition of 2-oxazolidinone-
grafted exocyclic dienes,24 which was applied in the total
synthesis of several natural carbazoles,25 including clauraila
A (1).26 More recently, a new strategy for the preparation of
polysubstituted diarylamines 6 and 9 was achieved by
starting from captodative enamines 2-anilinocyclohexen-
ones 727 and push-pull enamines 3-anilinocyclohexene
enaminones 10,28 respectively, which were used for the
synthesis of 1-oxygenated 5 and 2-oxygenated 8 carbazoles,
respectively (Scheme 1).
Table 1 Reaction between Anilines 11a–j and Cyclohexane-1,2-dione
(12a)a
R4
R4
R3
R2
R3
R2
p-TsOH, PhMe
+
MW (100 W)
130 °C, 4.5 h
NH2
O
N
H
R1
O
R1
O
11a–j
12a
7a–j
Entry
11
11a
R1
R2
Me
R3
R4
7
Yield (%)b
1
2
Me
H
H
7a
7b
7c
7d
7e
7f
91
80
95
80
98
89
94
86
65
72
R
R
R
11b
11c
11d
11e
11f
11g
11h
11i
Me
Me
H
H
H
Me
H
H
N
H
N
H
N
H
3
Me
H
OR'
OR'
O
5
6
7
4
OMe
H
Me
5
OMe
H
Me
H
R
R
6
OMe
H
OMe
OMe
OMe
OBn
OMe
H
OR'
N
H
OR'
N
H
7
OMe
OMe
H
H
7g
7h
7i
8
9
8
H
OMe
H
9
H
R
N
H
O
10
11j
H
H
H
7j
a Standard conditions: 11 (1.00–4.06 mmol), 12a (1.0 equiv), p-TsOH (10–
30 mol%), MS 4Å, MW (100 W), 130 °C, 4.5 h.
b Isolated yields.
10
Scheme 1 Strategy for the synthesis of carbazoles 5 and 8 starting
from captodative enamines 7 and push-pull enaminones 10
Table 2 Preparation of Diarylamines 6a–ja
Owing to the success of these preliminary works, and in
order to gain insight into the scope and limitations of this
strategy, we herein explored the preparation of a new series
of tricyclic 1- and 2-oxygenated polysubstituted carbazoles.
There was a special emphasis on the cyclization of bis-
ortho-substituted diarylamines, leading to the uncommon
1,8-disubstituted carbazoles,29 and to the total synthesis of
natural carbazoles 1–4.
R4
R4
1) Pd(OAc)2, MeCN
80 °C, 24 h
R3
R2
R3
R2
2) MeI or BnBr, K2CO3
acetone, reflux, 12 h
N
H
N
H
R1
O
R1
OR5
7a–j
6a–j
In the previous report,27 the method of preparation of 2-
anilinocyclohex-2-en-1-ones 7 was carried out under catal-
ysis-free condensation of cyclohexane-1,2-dione (12a) with
a series of mostly monosubstituted anilines, applying con-
ventional heating (refluxing toluene for 12 h), to produce
the expected products 7 in high yields (82–95%). However,
in the current contribution, this procedure was less effi-
cient when using di- and trisubstituted anilines 11a–h,
which exhibited longer reaction times and lower yields or
no reaction. In contrast, Brønsted acid catalysis (p-TsOH)
and microwave (MW) irradiation treatment furnished the
series of 2-anilinocyclohexenones 7a–h in high yields (80–
98%) and the monosubstituted derivatives 7i–j in lower
yields (65–72%, Table 1).
Entry
7
R1
R2
R3
R4
Method 6
Yield
(R5)
(%)b
1
2
3
4
5
6
7
8
9
10
7a
7b
7c
7d
7e
7f
Me
Me
H
H
A
A
A
A
A
A
A
A
A
B
6a (Me)
6b (Me)
6c (Me)
6d (Me)
6e (Me)
6f (Me)
6g (Me)
6h (Me)
6i (Me)
6j (Bn)
86
88
89
86
82
89
87
92
70
69
Me
Me
OMe
H
H
Me
H
H
H
Me
H
H
Me
OMe
H
Me
H
OMe
H
OMe
OMe
OMe
OBn
OMe
H
7g
7h
7i
OMe
OMe
H
H
H
OMe
H
H
7j
H
H
H
a Standard conditions: Method A: (i) 7 (0.41–4.61 mmol), Pd(OAc)2 (30
mol%), MeCN, 80 °C, 24 h; (ii) MeI (2.0 equiv), K2CO3 (2.0 equiv), acetone,
60 °C, 12 h. Method B: (i) 7 (2.30 mmol), Pd(OAc)2 (30 mol%), 80 °C, 24 h;
(ii) BnBr (2.0 equiv), K2CO3 (2.0 equiv), acetone, 60 °C, 12 h.
b Isolated yields.
Aromatization of the series 7a–j was readily accom-
plished with the reported one-pot two-step protocol.27
Thus, when this series was subjected to palladium(II)-cata-
lyzed (30 mol%) treatment in acetonitrile at 80 °C for 24
hours, followed by methylation or benzylation of the result-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O

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R. I. Hernández-Benitez et al.
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Synthesis
ing phenols with methyl iodide or benzyl bromide, respec-
tively, in basic medium, the diarylamines 6a–j were ob-
tained in good yields (Table 2).
ficient for the preparation of 1,8-dimethoxy-3-methyl-9H-
carbazole (5d), which was the precursor for the total syn-
thesis of clausenal (2).17c Consequently, these optimized
conditions (Method B) were applied to oxidative cyclization
for the preparation of 1,8-disubstituted carbazoles 5a,b, 5d,
and 5e, leading to a conversion in good yields, except for the
ring closure of 6c, which did not proceed to give the expect-
ed 8-methoxy-1,4-dimethyl-9H-carbazole (5c). The pres-
ence of methyl groups at the ortho- and meta-positions of
the aniline unit in 6c seems to impede the formation of the
palladacycle, which is the intermediate species toward the
biaryl C–C bond formation.35
In the synthesis of clausine P (3), the yield obtained via
ring-closure with method A was slightly improved when
adopting method B (Table 3, entries 6, 7). It is noteworthy
that this novel approach is one of the few total syntheses
that has been reported for natural alkaloid 3.18 The spectro-
scopic data agree with those previously described for the
natural14 and synthetic18 products.
The palladium(II)-catalyzed diarylamine intramolecular
coupling30 by double C–H activation has proven to be highly
efficient for the conversion of diarylamines to carbazoles.31
This strategy was optimized with the procedure developed
by Knölker23a–c and applied by other researchers,23d,e,32 in-
cluding our group,25 under MW irradiation and in the pres-
ence of copper acetate to oxidize and convert the in situ
formed palladium(0) into palladium(II) as the active species
of the process. These reaction conditions worked well for
the conversion of 6e into the respective natural carbazole
clausine P (3) (Table 3, entry 6), but were not successful for
closing diarylamines 6a–d and 6f, whose aryl rings are bis-
ortho substituted by methyl or methoxyl groups. This draw-
back probably explains why there are few reports for the
synthesis of 1,8-disubstituted carbazoles starting from this
type of diarylamines.17c
On the other hand, carbazole 5d was converted into
clausenal (2) through an improved oxidation method using
DDQ, quite similar to that already described.17c Thus, the re-
actants were dissolved in a mixture of MeOH–acetone–H2O
(6:3:1) and the solution was stirred at room temperature
for 15 minutes (instead of heating to 50 °C) to afford 2 in a
higher yield (89%) (Scheme 2).
Table 3 Preparation of Carbazoles 3 and 5a–ia
R4
R4
R3
R2
R3
R2
Pd(OAc)2
Cu(OAc)2 or pivalic acid
130–140 °C, 70 min to 12 h
N
H
N
R1
OR5
H
OR5
R1
6a–j
3, 5a–i
CHO
DDQ
Entry
6
R1
R2
Me
R3
R4
R5
Me
Method 3, 5 Yield (%)b
MeOH/acetone/H2O
N
H
N
H
1
2
6a Me
6b Me
H
H
B
5a
5b
5c
5d
5d
3
72
60
NR
52
78
89
94
79
86
72
65
80
r.t., 15 min
89%
MeO
OMe
MeO
OMe
H
H
H
H
Me
H
H
Me
Me
Me
Me
Me
Me
Me
Me
B
5d
clausenal (2)
3
6c
Me
Me
H
A, B
C
B
Scheme 2 Preparation of clausenal (2) by oxidation of 5d
4
6d OMe
6d OMe
Me
Me
5
H
We decided to investigate the synthesis of carbazoles
5h,i due to the presence of hydroxy groups at the C-1 and
C-6 positions of the carbazole core in many biologically ac-
tive natural alkaloids,34a such as clausine I (13b),6a clausenol
(13c),2c and clausine Z (13d),36 and also because these
groups can be readily obtained by hydrogenolysis of the
benzyloxy group or by removing the methoxy group with
boron tribromide.34a Hence, after aromatization of the anili-
no enamines 7i,j, the resulting phenols were protected with
methyl iodide or benzyl bromide to deliver diarylamines
6i,j, respectively (Table 2, entries 9, 10). Upon applying
method B for the palladium(II)-catalyzed oxidative cycliza-
tion, carbazoles 5h,i were obtained in 65% and 80% yield,
respectively (Table 3, entries 11, 12).
6
6e
6e
6f
H
OMe Me
OMe Me
H
A
B
7
H
H
3
8
OMe
H
H
OMe
H
B
5e
5f
5g
5h
5i
9
6g
6h
6i
OMe OMe
H
A
B
10
11
12
H
OMe OMe OMe Me
H
H
H
OBn
H
H
Me
Bn
B
6j
H
OMe
B
a Standard conditions: Method A: 6 (0.19–0.21 mmol), Pd(OAc)2 (30 mol%),
Cu(OAc)2 (2.5 equiv), DMF, MW (100 W), 130 °C, 70 min. Method B: 6 (0.21–
1.31 mmol), Pd(OAc)2 (10 mol%), pivalic acid (14.0 equiv), K2CO3 (10 mol%),
air, 140 °C, 12–48 h. Method C: 6d (0.25 mmol), Pd(OAc)2 (10 mol%), pivalic
acid (14.0 equiv), K2CO3 (10 mol%), N2, 140 °C, 48 h.
b Isolated yields. NR: No reaction.
In the search for a more versatile synthon than 5i, a
highly regioselective formylation of this carbazole was car-
ried out under Vilsmeier–Haack conditions, furnishing 3-
formylcarbazole 13a in 72% yield (Scheme 3). Interestingly,
the latter is a known precursor of several natural alkaloids:
clausine I (13b), clausenol (13c), and clausine Z (13d),
whose total syntheses were efficiently accomplished by
Fagnou et al.33 demonstrated that the use of pivalic acid
as the solvent improves such a synthesis, a finding that has
been widely applied to the total synthesis of natural carba-
zole alkaloids.17c,34 Indeed, we observed better yields by us-
ing pivalic acid, and an ever greater yields in the presence of
air (Table 3, entries 4, 5). This procedure was particularly ef-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O

D
R. I. Hernández-Benitez et al.
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Synthesis
MeO
MeO
MeO
CHO
CHO
POCl3, DMF
1 step
60 °C, 1 h
72%
(ref. 34a)
N
H
N
N
H
H
OBn
OBn
OH
5i
13a
clausine I (13b)
2 steps
1 step
(ref. 34a)
HO
(ref. 34a)
CHO
MeO
MeO
Me
CO2Me
N
N
N
H
H
OH
H
OH
OH
clausine Z (13d)
clausenol (13c)
clausine G (13e)
Scheme 3 Preparation of 13a as precursor in the formal synthesis of clausine I (13b), clausenol (13c), clausine Z (13d), and clausine G (13e)
Knölker and co-workers.34a Thus, the C-1 benzyloxy group
could be removed through hydrogenolysis to deliver
clausine I (13b), while clausenol (13c) resulted from reduc-
tion of the formyl group and subsequent debenzylation. In
addition, the transformation of carbazole 13a into the car-
bazole alkaloid clausine Z (13d) took place by one-pot dou-
ble deprotection of the C-1 benzyloxy and C-6 methoxy
groups. On the other hand, clausine G (13e)37 may be pre-
pared from 13a by conversion of the C-3 formyl group into
the methyl carboxylate according to the known meth-
od,19b,28 followed by debenzylation. Of course, 6-benzyloxy-
1-methoxycarbazole (5h) is in turn a potential precursor of
1,6-dihydroxycarbazoles, such as 13d, isoclausine G,38 or
der vacuum. Then the residue was dissolved in the solvent
mixture MeOH–acetone–H2O (6:3:1) with DDQ and stirred
at room temperature for 45 minutes to provide the desired
natural carbazoles 1 and 4 in excellent overall yields (78%
for both) and in only three steps.
The preparation of the series of carbazoles 8c–f
(Scheme 5) was carried out with the aim of evaluating the
scope of this methodology for synthesizing 2-oxygenated
carbazoles substituted with methoxy and hydroxy groups,
as potential precursors of natural tricyclic carbazoles that
are characterized by these groups.6a,40
Me
methyl
1,6-dihydroxy-9H-carbazole-3-carboxylate39
R2
NH2
through similar deprotection pathways.
R1
Clauraila A (1) and 7-methoxy-O-methylmukonal (4)
were synthesized by utilizing the methodology that in-
volves the preparation of push-pull enaminones 10a,b
(Scheme 4). The acid-catalyzed reaction of anilines 11d,e
with 1,3-cyclohexanedione (12b) under MW irradiation af-
forded enaminones 10a,b in excellent yields. Unlike enam-
ines 7a–i, the aromatization of 10a,b took place only under
more severe conditions (300 °C, 48 h) and by using 10%
Pd/C (50 mol%) as the catalyst. After filtration and removal
of the solvent, without isolating the resulting phenol inter-
mediates, the residues were treated with methyl iodide in
the presence of potassium carbonate, and the acetone solu-
tion was refluxed to furnish the respective diarylamines
9a,b in high yields.
We explored the possibility of carrying out the final oxi-
dative cyclization and the oxidation of the C-3 methyl
group to the formyl group of the natural carbazoles 1 and 4
via a similar sequenced procedure. Rather than isolating the
C-3 methylcarbazole, we proceeded directly to oxidation.
Thus, after concluding the reaction of the palladium ace-
tate-catalyzed (10 mol%) five-membered-ring closure, the
reaction mixture was filtered and the solvent removed un-
Me
R2
11d, R1 = OMe, R2 = H
11e, R1 = H, R2 = OMe
+
p-TsOH, PhMe
MS (4 Å)
N
O
H
MW (100 W)
130 °C, 4.5 h
R1
10a, R1 = OMe, R2 = H (96%)
10b, R1 = H, R2 = OMe (99%)
O
O
12b
1) Pd/C (10%), xylene
300 °C, 48 h
2) MeI, K2CO3
acetone, r.t., 12 h
1) Pd(OAc)2
pivalic acid, K2CO3
140 °C, 12 h
Me
R2
N
OMe
2) DDQ
H
R1
MeOH/acetone/H2O
r.t., 45 min
9a, R1 = OMe, R2 = H (85%)
9b, R1 = H, R2 = OMe (89%)
OHC
R2
OMe
N
R1
H
1, R1 = OMe, R2 = H (96%)
4, R1 = H, R2 = OMe (89%)
Scheme 4 Total synthesis of clauraila A (1) and 7-methoxy-O-methyl-
mukonal (4)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O

E
R. I. Hernández-Benitez et al.
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Synthesis
bered rings with each other to adopt a nonplanar confor-
mation [C(9)–C(8)–N(7)–C(6), –36.1(3)°; C(13)–C(8)–N(7)–
C(1), 147.31(19)°]. As expected for a push-pull enamine, the
nitrogen atom is coplanar to the enone unit [C(1)–C(6)–
N(7)–C(8), –2.0(3)°; C(5)–C(6)–N(7)–C(8), 179.35(18)°].
However, a conformational disorder of the cyclohexenone
moiety was also observed [C(6)–C(1)–C(2)–O(14a), –170.5(6)°;
C(6)–C(1)–C(2)–O(14b), 160.0(7)°; O(14a)–C(2)–C(3)–
C(4a), –143.5(10)°; O(14b)–C(2)–C(3)–C(4b), –149.8(8)°].
Figure 2 shows only one of the two conformers.
R3
MeO
R2
R3
NH2
MeO
R1
11f, R1 = OMe, R2 = R3 = H
11g, R1 = R3 = H, R2 = OMe
11h, R1 = H, R2 = R3 = OMe
+
R2
N
O
p-TsOH, PhMe
H
R1
MS (4 Å)
130 °C, 24 h
10c, R1 = OMe, R2 = R3 = H (96%)
10d, R1 = R3 = H, R2 = OMe (94%)
10e, R1 = H, R2 = R3 = OMe (99%)
O
O
1) Pd/C (10%), xylene
12b
300 °C, 48 h
2) R4X, K2CO3
acetone, r.t., 12 h
R3
MeO
Pd(OAc)2 (10 mol%)
pivalic acid, K2CO3
140 °C, 24 h
R2
N
OR4
H
R1
9c, R1 = OMe, R2 = R3 = H, R4 = Me (96%)
9d, R1 = OMe, R2 = R3 = H, R4 = Bn (90%)
9e, R1 = R3 = H, R2 = OMe, R4 = Me (80%)
9f, R1 = H, R2 = R3 = OMe, R4 = Me (96%)
R3
MeO
R2
OR4
N
H
R1
8c, R1 = OMe, R2 = R3 = H, R4 = Me (80%)
8d, R1 = OMe, R2 = R3 = H, R4 = H (95%)
8e, R1 = R3 = H, R2 = OMe, R4 = Me (97%)
8f, R1 = H, R2 = R3 = OMe, R4 = Me (91%)
Figure 2 Molecular structure of 10e (ellipsoids with 30% probability
level)
Scheme 5 Synthesis of the series of carbazoles 8c–f
In summary, an extensive series of 1- and 2-oxygenated
carbazoles 5 and 8 were synthesized, including naturally
occurring alkaloids clauraila A (1), clausenal (2), clausine P
(3), and 7-methoxy-O-methylmukonal (4). The strategy
employed consisted of a short and simple three-step ap-
proach starting from the preparation of captodative enam-
ines 7 or push-pull enaminones 10. The number and variety
of substituents incorporated in the prepared carbazoles,
even in the uncommon 1,8-disubstituted derivatives,
demonstrated the wide scope of these methodologies.
However, the final palladium(II)-catalyzed ring-closing step
seems to be limited to 2,2′,5-trisubstituted diarylamines,
such as 6c. In addition to the total syntheses of carbazole
alkaloids 1–4, a formal synthesis of clausine I (13b), clause-
nol (13c), and clausine Z (13d) is also described via the effi-
cient preparation of their carbazole precursor 13a.
A series of substituted anilines 11f–h bearing a me-
thoxy group at the para-position was chosen to prepare the
respective enaminones 10c–e (Scheme 5). High yields were
provided when using a heating mantle to carry out the re-
action at 130 °C for 24 hours. Again, aromatization was
achieved during catalysis with Pd/C under thermal condi-
tions, and the subsequent addition of methyl iodide or ben-
zyl bromide with potassium carbonate gave rise to the se-
ries of diarylamines 9c–f in high to excellent yields. Finally,
by following the previously described procedure for prepar-
ing carbazoles in the presence of palladium acetate and piv-
alic acid, the corresponding series of carbazoles 8c–f was
obtained in high overall yields (72–86%) in three steps. For
diarylamine 9d, the benzyl group was removed at the same
time that the five-membered-ring closure took place to af-
ford 1,3,7-trihydroxycarbazole (8d). In contrast, a similar
debenzylation was not detected during the carbazole core
formation step of benzyl derivatives 6i,j (Table 3, entries 11,
12).
Melting points were determined with an Electrothermal capillary
melting point apparatus. IR spectra were recorded on a PerkinElmer
2000 spectrophotometer. 1H (300 or 500 MHz) and 13C (75 or 125
MHz) NMR spectra were recorded on Varian Mercury-300 or Varian
VNMR System instruments, with TMS as internal standard. HRMS
were obtained in EI mode (70 eV) on a Jeol JSM-GcMateII spectrome-
ter. Microwave (MW) irradiation was performed on a CEM MW reac-
tor and CEV-MIC-1 from SEV (Mexico).41 Analytical TLC was carried
out with silica gel 60 F254 coated 0.25 plates (E. Merck), and visual-
ized by a long- and short-wavelength UV lamp. Flash column chroma-
tography was done over silica gel (230–400 mesh, Natland Interna-
All the structures of intermediates and products in-
volved in these synthetic pathways were characterized by
1H and 13C NMR spectroscopy, assisted by 2D (HMQC and
HMBC) experiments, and high resolution mass spectrome-
try (HRMS). In the case of 10e, the structure was estab-
lished by single-crystal X-ray diffraction (Figure 2). The
analysis of this structure revealed a folding of the six-mem-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O

F
R. I. Hernández-Benitez et al.
Paper
Synthesis
tional Co.). All air moisture sensitive reactions were conducted under
a N2 atmosphere in oven-dried glassware. DMF was freshly distilled
over CaH2 prior to use. Acetone was dried through distillation after
treatment with KMnO4, followed by a second distillation over anhyd
Na2SO4. Toluene, xylene, acetone, and MeCN were taken from re-
agent-grade bottles without distillation. K2CO3and molecular sieves
(MS 4Å) were dried overnight at 200 °C prior to use. All other re-
agents were utilized without further purification.
13C NMR (125 MHz, CDCl3): δ = 17.3 (CH3Ar-C2′), 21.1 (CH3Ar-C5′),
23.1 (C5), 24.5 (C4), 37.7 (C6), 115.7 (C3), 120.5 (C6′), 122.9 (C4′),
126.3 (C2′), 130.6 (C3′), 136.1 (C5′), 136.9 (C2), 139.7 (C1′), 195.6 (C1).
HRMS (EI): m/z [M+] calcd for C14H17NO: 215.1310; found: 215.1310.
2-[(2-Methoxy-4-methylphenyl)amino]cyclohex-2-en-1-one (7d)
Following the procedure for 7a, 11d (0.206 g, 1.50 mmol), 12a (0.168
g, 1.50 mmol), and p-TsOH (0.069 g, 0.40 mmol) were reacted to af-
ford 7d (0.28 g, 80%) as a yellow solid; mp 68–69 °C; Rf = 0.65 (hex-
ane–EtOAc, 7:3).
2-[(2,3-Dimethylphenyl)amino]cyclohex-2-en-1-one (7a); Typical
Procedure
IR (film): 3383, 2939, 1672, 1612, 1525, 1486, 1464, 1329, 1264,
In a threaded ACE glass pressure tube with a sealed Teflon screw cap
equipped with a magnetic stirring bar, a mixture of 11a (0.200 g, 1.65
mmol), 12a (0.185 g, 1.65 mmol), p-TsOH (0.028 g, 0.16 mmol), and
MS 4Å (0.20 g) in toluene (10 mL) was stirred and heated at 130 °C for
4.5 h under microwave irradiation (100 W). The solvent was removed
under vacuum and the residue purified by column chromatography
(silica gel, hexane–EtOAc, 98:2) to give 7a (0.32 g, 91%) as a brownish
oil; Rf = 0.75 (hexane–EtOAc, 7:3).
1252, 1147, 1036, 910, 795 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.00 (qu, J = 6.3 Hz, 2 H, H5), 2.30 (s, 3
H, CH3Ar), 2.43 (dt, J = 6.3, 4.9 Hz, 2 H, H4), 2.55 (t, J = 6.3 Hz, 2 H, H6),
3.83 (s, 3 H, CH3O), 6.34 (t, J = 4.9 Hz, 1 H, H3), 6.65 (br s, 1 H, NH),
6.67–6.70 (m, 2 H, H3′, H5′), 7.07 (d, J = 8.5 Hz, 1 H, H6′).
13C NMR (125 MHz, CDCl3): δ = 21.1 (CH3Ar), 23.0 (C5), 24.6 (C4), 37.9
(C6), 55.5 (CH3O), 111.6 (C3′), 115.7 (C3), 116.9 (C6′), 120.6 (C5′),
128.9 (C1′), 130.4 (C4′), 136.4 (C2), 149.4 (C2′), 195.6 (C1).
IR (film): 3384, 2923, 1673, 1586, 1474, 1333, 1315, 1146, 1124, 764
cm–1
.
HRMS (EI): m/z [M+] calcd for C14H17NO2: 231.1259; found: 231.1252.
1H NMR (500 MHz, CDCl3): δ = 1.95–2.03 (m, 2 H, H5), 2.11 (s, 3 H,
CH3Ar-C2′), 2.28 (s, 3 H, CH3Ar-C3′), 2.37 (dt, J = 5.5, 4.5 Hz, 2 H, H4),
2.55 (t, J = 6.5 Hz, 2 H, H6), 5.87 (t, J = 4.5 Hz, 1 H, H3), 6.02 (br s, 1 H,
NH), 6.86 (br d, J = 6.5 Hz, 1 H, H4′), 6.99–7.07 (m, 2 H, H5′, H6′).
13C NMR (125 MHz, CDCl3): δ = 13.5 (CH3Ar-C2′), 20.6 (CH3Ar-C3′),
23.1 (C5), 24.4 (C4), 37.7 (C6), 115.3 (C3), 119.4 (C6′), 124.7 (C4′),
125.7 (C5′), 129.3 (C1′), 137.6 (C2), 137.7 (C2′), 139.7 (C3′), 195.6 (C1).
2-[(3-Methoxy-4-methylphenyl)amino]cyclohex-2-en-1-one (7e)
Following the procedure for 7a, 11e (0.206 g, 1.50 mmol), 12a (0.168
g, 1.50 mmol), and p-TsOH (0.069 g, 0.40 mmol) were reacted to af-
ford 7e (0.34 g, 98%) as a yellow oil; Rf = 0.77 (hexane–EtOAc, 7:3).
IR (film): 3370, 2939, 1671, 1611, 1591, 1511, 1453, 1409, 1316,
1214, 1167, 1130, 1038, 807, 737 cm–1
.
HRMS (EI): m/z [M+] calcd for C14H17NO: 215.1310; found: 215.1310.
1H NMR (300 MHz, CDCl3): δ = 2.01 (qu, J = 6.2 Hz, 2 H, H5), 2.15 (s, 3
H, CH3Ar), 2.44 (dt, J = 6.2, 4.8 Hz, 2 H, H4), 2.56 (t, J = 6.2 Hz, 2 H, H6),
3.79 (s, 3 H, CH3O), 6.29 (br s, 1 H, NH), 6.35 (t, J = 4.8 Hz, 1 H, H3),
6.50 (d, J = 2.1 Hz, 1 H, H2′), 6.59 (dd, J = 7.8, 2.1 Hz, 1 H, H6′), 7.00 (d,
J = 7.8 Hz, 1 H, H5′).
13C NMR (75 MHz, CDCl3): δ = 15.5 (CH3Ar), 22.9 (C5), 24.5 (C4), 37.7
(C6), 55.2 (CH3O), 102.4 (C2′), 110.6 (C6′), 115.6 (C3), 119.6 (C4′),
130.7 (C5′), 136.7 (C2), 140.7 (C1′), 158.2 (C3′), 195.6 (C1).
2-[(2,4-Dimethylphenyl)amino]cyclohex-2-en-1-one (7b)
Following the procedure for 7a, 11b (0.200 g, 1.65 mmol), 12a (0.185
g, 1.65 mmol), and p-TsOH (0.028 g, 0.16 mmol) were reacted to af-
ford 7b (0.28 g, 80%) as a brownish yellow oil; Rf = 0.51 (hexane–
EtOAc, 8:2).
IR (film): 3386, 2925, 1673, 1495, 1451, 1050, 876, 824 cm–1
.
HRMS (EI): m/z [M+] calcd for C14H17NO2: 231.1259; found: 231.1261.
1H NMR (500 MHz, CDCl3): δ = 1.96–2.02 (m, 2 H, H5), 2.17 (s, 3 H,
CH3Ar-C2′), 2.27 (s, 3 H, CH3Ar-C4′), 2.38 (dt, J = 5.5, 5.0 Hz, 2 H, H4),
2.55 (t, J = 6.5 Hz, 2 H, H6), 5.93 (t, J = 5.0 Hz, 1 H, H3), 5.96 (br s, 1 H,
NH), 6.94 (br d, J = 8.0 Hz, 1 H, H5′), 6.99 (br s, 1 H, H3′), 7.04 (d, J = 8.0
Hz, 1 H, H6′).
13C NMR (125 MHz, CDCl3): δ = 17.7 (CH3Ar-C2′), 20.6 (CH3Ar-C4′),
23.1 (C5), 24.4 (C4), 37.7 (C6), 114.9 (C3), 121.0 (C6′), 126.9 (C5′),
130.1 (C2′), 131.5 (C3′), 132.0 (C4′), 137.1 (C1′), 137.3 (C2), 195.6 (C1).
2-[(2,4-Dimethoxyphenyl)amino]cyclohex-2-en-1-one (7f)
Following the procedure for 7a, 11f (0.200 g, 1.31 mmol), 12a (0.147
g, 1.31 mmol), and p-TsOH (0.022 g, 0.13 mmol) were reacted to af-
ford 7f (0.29 g, 89%) as a pale yellow oil; Rf = 0.56 (hexane–EtOAc,
7:3).
IR (film): 3379, 2923, 1672, 1629, 1522, 1456, 1284, 1206, 1156,
HRMS (EI): m/z [M+] calcd for C14H17NO: 215.1310; found: 215.1308.
1032, 831 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.00 (qu, J = 6.1 Hz, 2 H, H5), 2.41 (dt, J
= 6.1, 5.3 Hz, 2 H, H4), 2.55 (t, J = 6.1 Hz, 2 H, H6), 3.79 (s, 3 H, CH3O),
3.82 (s, 3 H, CH3O), 6.18 (t, J = 5.3 Hz, 1 H, H3), 6.38 (br s, 1 H, NH),
6.43 (dd, J = 8.5, 2.5 Hz, 1 H, H5′), 6.50 (d, J = 2.5 Hz, 1 H, H3′), 7.09 (d,
J = 8.5 Hz, 1 H, H6′).
13C NMR (125 MHz, CDCl3): δ = 23.1 (C5), 24.6 (C4), 37.9 (C6), 55.5
(CH3O), 55.6 (CH3O), 99.4 (C3′), 103.5 (C5′), 114.5 (C3), 119.6 (C6′),
124.8 (C1′), 137.3 (C2), 151.4 (C2′), 155.0 (C4′), 195.7 (C1).
2-[(2,5-Dimethylphenyl)amino]cyclohex-2-en-1-one (7c)
Following the procedure for 7a, 11c (0.200 g, 1.65 mmol), 12a (0.185
g, 1.65 mmol), and p-TsOH (0.028 g, 0.16 mmol) were reacted to af-
ford 7c (0.34 g, 95%) as a white solid; mp 61–62 °C; Rf = 0.74 (hexane–
EtOAc, 7:3).
IR (film): 3373, 2922, 1663, 1635, 1578, 1482, 1445, 1292, 1189,
1144, 874, 796 cm–1
.
HRMS (EI): m/z [M+] calcd for C14H17NO3: 247.1208; found: 247.1204.
1H NMR (500 MHz, CDCl3): δ = 2.00 (qu, J = 6.5 Hz, 2 H, H5), 2.17 (s, 3
H, CH3Ar-C2′), 2.29 (s, 3 H, CH3Ar-C5′), 2.41 (dt, J = 6.5, 5.0 Hz, 2 H,
H4), 2.55 (t, J = 6.5 Hz, 2 H, H6), 6.05 (br s, 1 H, NH), 6.06 (t, J = 5.0 Hz,
1 H, H3), 6.73 (br d, J = 7.5 Hz, 1 H, H4′), 6.98 (br s, 1 H, H6′), 7.05 (d, J
= 7.5 Hz, 1 H, H3′).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O

G
R. I. Hernández-Benitez et al.
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Synthesis
2-[(3,4-Dimethoxyphenyl)amino]cyclohex-2-en-1-one (7g)
N-(2-Methoxyphenyl)-2,3-dimethylaniline (6a); Typical Procedure
Following the procedure for 7a, 11g (0.200 g, 1.31 mmol), 12a (0.147
g, 1.31 mmol), and p-TsOH (0.022 g, 0.13 mmol) were reacted to af-
ford 7g (0.304 g, 94%) as a pale yellow solid; mp 88–89 °C; Rf = 0.51
(hexane–EtOAc, 7:3).
In a threaded ACE glass pressure tube with a sealed Teflon screw cap
equipped with a magnetic stirring bar, a mixture of 7a (0.100 g, 0.47
mmol) and Pd(OAc)2 (0.031 g, 0.14 mmol) in MeCN (2.0 mL) was
stirred at 80 °C for 24 h under a N2 atmosphere. After removing the
solvent under vacuum, the residue was mixed with anhyd K2CO3
(0.128 g, 0.93 mmol) and MeI (0.132 g, 0.93 mmol) in acetone (5 mL)
and heated at 60 °C for 12 h. The solvent was removed under vacuum
and the residue purified by column chromatography (silica gel, hex-
ane–EtOAc, 98:2) to give 6a (0.09 g, 86%) as a dark oil; Rf = 0.80 (hex-
ane–EtOAc, 7:3).
IR (film): 3350, 2937, 1668, 1596, 1518, 1451, 1410, 1336, 1252,
1212, 1149, 1146, 1124, 1026, 850, 786 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 1.95 (qu, J = 6.2 Hz, 2 H, H5), 2.36 (dt,
J = 6.2, 5.1 Hz, 2 H, H4), 2.50 (t, J = 6.2 Hz, 2 H, H6), 3.791 (s, 3 H,
CH3O), 3.793 (s, 3 H, CH3O), 6.09 (br s, 1 H, NH), 6.15 (t, J = 5.1 Hz, 1 H,
H3), 6.53–6.61 (m, 2 H, H2′, H6′), 6.74 (d, J = 8.1 Hz, 1 H, H5′).
13C NMR (75 MHz, CDCl3): δ = 22.9 (C5), 24.4 (C4), 37.6 (C6), 55.7
(CH3O), 56.0 (CH3O), 105.4 (C2′), 111.7 (C5′), 111.9 (C6′), 114.4 (C3),
135.2 (C1′), 137.3 (C2), 144.2 (C4′), 149.3 (C3′), 195.5 (C1).
IR (film): 3415, 2938, 1602, 1584, 1509, 1464, 1337, 1297, 1241,
1214, 1117, 1029, 769, 739 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.17 (s, 3 H, CH3Ar-C2), 2.31 (s, 3 H,
CH3Ar-C3), 3.89 (s, 3 H, CH3O), 5.86 (br s, 1 H, NH), 6.77 (td, J = 7.3, 2.0
Hz, 1 H, H4′), 6.80 (td, J = 7.3, 1.5 Hz, 1 H, H5′), 6.84 (dd, J = 7.3, 2.0 Hz,
1 H, H6′), 6.86 (dd, J = 7.3, 1.5 Hz, 1 H, H3′), 6.89 (d, J = 7.5 Hz, 1 H, H4),
7.04 (t, J = 7.3 Hz, 1 H, H5), 7.14 (d, J = 7.3 Hz, 1 H, H6).
HRMS (EI): m/z [M+] calcd for C14H17NO3: 247.1208; found: 247.1202.
2-[(3,4,5-Trimethoxyphenyl)amino]cyclohex-2-en-1-one (7h)
Following the procedure for 7a, 11h (0.201 g, 1.10 mmol), 12a (0.123
g, 1.10 mmol), and p-TsOH (0.017 g, 0.10 mmol) were reacted to af-
ford 7h (0.26 g, 86%) as a yellow oil; Rf = 0.43 [hexane–EtOAc, 8:2 (2
×)].
13C NMR (125 MHz, CDCl3): δ = 13.6 (CH3Ar-C2), 20.6 (CH3Ar-C3), 55.5
(CH3O), 110.2 (C3′), 113.7 (C6′), 118.6 (C4′), 119.4 (C6), 120.9 (C5′),
124.8 (C4), 125.8 (C5), 129.4 (C2), 134.8 (C1′), 137.8 (C3), 140.6 (C1),
147.6 (C2′).
IR (film): 3436, 2926, 1606, 1494, 1452, 1127, 1050, 876, 824 cm–1
.
HRMS (EI): m/z [M+] calcd for C15H17NO: 227.1310; found: 227.1307.
1H NMR (500 MHz, CDCl3): δ = 2.03 (qu, J = 6.3 Hz, 2 H, H5), 2.45 (dt,
J = 6.3, 4.4 Hz, 2 H, H4), 2.57 (t, J = 6.3 Hz, 2 H, H6), 3.80 (s, 3 H, CH3O),
3.83 (s, 6 H, 2 × CH3O), 6.25 (br s, 1 H, NH), 6.28 (s, 2 H, H2′, H6′), 6.34
(t, J = 4.4 Hz, 1 H, H3).
13C NMR (125 MHz, CDCl3): δ = 22.9 (C5), 24.5 (C4), 37.6 (C6), 56.1 (2
× CH3O), 61.0 (CH3O), 97.3 (C2′, C6′), 115.6 (C3), 132.9 (C4′), 136.8
(C2), 137.9 (C1′), 153.6 (C3′, C5′), 195.4 (C1).
N-(2-Methoxyphenyl)-2,4-dimethylaniline (6b)
Following the procedure for 6a, 7b (0.100 g, 0.47 mmol), Pd(OAc)2
(0.031 g, 0.14 mmol), K2CO3 (0.128 g, 0.93 mmol), and MeI (0.132 g,
0.93 mmol) were reacted to afford 6b (0.093 g, 88%) as a dark green
oil; Rf = 0.71 (hexane–EtOAc, 8:2).
IR (film): 3430, 2926, 1600, 1496, 1452, 1339, 1240, 1114, 1030, 876,
HRMS (EI): m/z [M+] calcd for C15H19NO4: 277.1314; found: 277.1313.
824, 740 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.22 (s, 3 H, CH3Ar-C2), 2.30 (s, 3 H,
CH3Ar-C4), 3.89 (s, 3 H, CH3O), 5.78 (br s, 1 H, NH), 6.77 (td, J = 7.5, 1.5
Hz, 1 H, H4′), 6.81 (td, J = 7.5, 1.5 Hz, 1 H, H5′), 6.84–6.89 (m, 2 H, H3′,
H6′), 6.96 (br d, J = 8.0 Hz, 1 H, H5), 7.03 (br s, 1 H, H3), 7.18 (d, J = 8.0,
Hz, 1 H, H6).
13C NMR (125 MHz, CDCl3): δ = 17.8 (CH3Ar-C2), 20.7 (CH3Ar-C4), 55.5
(CH3O), 110.1 (C3′), 113.3 (C6′), 118.5 (C4′), 120.8 (C5′), 121.3 (C6),
127.1 (C5), 130.5 (C2), 131.6 (C3), 132.3 (C4), 134.7 (C1′), 137.8 (C1),
147.5 (C2′).
2-{[4-(Benzyloxy)phenyl]amino}cyclohex-2-en-1-one (7i)
Following the procedure for 7a, 11i (0.200 g, 1.00 mmol), 12a (0.112
g, 1.00 mmol), and p-TsOH (0.017 g, 0.10 mmol) were reacted to af-
ford 7i (0.191 g, 65%) as a dark yellow solid; mp 87–88 °C; Rf = 0.67
(hexane–EtOAc, 7:3).
IR (film): 3363, 2918, 1508, 1455, 1379, 1234, 1174, 1024, 827, 739,
696 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.98 (qu, J = 6.5 Hz, 2 H, H5), 2.38 (q, J =
6.5 Hz, 2 H, H4), 2.53 (t, J = 6.5 Hz, 2 H, H6), 5.01 (s, 2 H, CH2Ph), 6.10
(br s, 1 H, NH), 6.14 (t, J = 5.0 Hz, 1 H, H3), 6.85–6.93 (m, 2 H, H3′),
6.95–7.00 (m, 2 H, H2′), 7.28–7.33 (m, 1 H, H4′′), 7.33–7.39 (m, 2 H,
H3′′), 7.39–7.44 (m, 2 H, H2′′).
13C NMR (125 MHz, CDCl3): δ = 23.1 (C5), 24.4 (C4), 37.7 (C6), 70.4
(CH2Ph), 114.2 (C3), 115.6 (C3′), 121.9 (C2′), 127.4 (C2′′), 127.9 (C4′′),
128.5 (C3′′), 135.2 (C1′), 137.1 (C1′′), 137.6 (C2), 154.0 (C4′), 195.6
(C1).
HRMS (EI): m/z [M+] calcd for C15H17NO: 227.1310; found: 227.1313.
N-(2-Methoxyphenyl)-2,5-dimethylaniline (6c)
Following the procedure for 6a, 7c (0.100 g, 0.47 mmol), Pd(OAc)2
(0.031 g, 0.14 mmol), K2CO3 (0.128 g, 0.93 mmol), and MeI (0.132 g,
0.93 mmol) were reacted to afford 6c (0.093 g, 89%) as a green oil; Rf =
0.80 (hexane–EtOAc, 7:3).
IR (film): 3411, 2921, 1598, 1526, 1500, 1454, 1341, 1244, 1220,
HRMS (EI): m/z [M+] calcd for C19H19NO2: 293,1416; found: 293.1411.
1114, 1048, 1030, 807, 739 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.22 (s, 3 H, CH3Ar-C2), 2.28 (s, 3 H,
CH3Ar-C5), 3.89 (s, 3 H, CH3O), 5.82 (br s, 1 H, NH), 6.76 (br d, J = 8.0
Hz, 1 H, H4), 6.81 (td, J = 7.5, 1.5 Hz, 1 H, H4′), 6.84 (td, J = 7.5, 2.0 Hz,
1 H, H5′), 6.88 (dd, J = 7.5, 2.0 Hz, 1 H, H3′), 7.01 (dd, J = 7.5, 1.5 Hz, 1
H, H6′), 7.08 (d, J = 8.0 Hz, 1 H, H3), 7.13 (br s, 1 H, H6).
2-[(4-Methoxyphenyl)amino]cyclohex-2-en-1-one (7j)27
Following the procedure for 7a, 11j (0.500 g, 4.06 mmol), 12a (0.455
g, 4.06 mmol), and p-TsOH (0.069 g, 0.40 mmol) were reacted to af-
ford 7j (0.635 g, 72%) as a reddish oil; Rf = 0.49 (hexane–EtOAc, 8:2).
The analytical and spectral data were in agreement with the reported
values.27
13C NMR (125 MHz, CDCl3): δ = 17.4 (CH3Ar-C2), 21.2 (CH3Ar-C5), 55.6
(CH3O), 110.4 (C3′), 114.4 (C6′), 119.1 (C4′), 120.3 (C6), 120.8 (C5′),
123.0 (C4), 126.3 (C2), 130.7 (C3), 134.0 (C1′), 136.3 (C5), 140.6 (C1),
148.0 (C2′).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O

H
R. I. Hernández-Benitez et al.
Paper
Synthesis
HRMS (EI): m/z [M+] calcd for C15H17NO: 227.1310; found: 227.1310.
2-Methoxy-N-(2-methoxyphenyl)-4-methylaniline (6d)
1H NMR (500 MHz, CDCl3): δ = 3.83 (s, 3 H, CH3O), 3.85 (s, 3 H, CH3O),
3.88 (s, 3 H, CH3O), 5.99 (br s, 1 H, NH), 6.72 (dd, J = 8.5, 2.5 Hz, 1 H,
H6), 6.74 (d, J = 2.5 Hz, 1 H, H2), 6.76–6.84 (m, 2 H, H4′, H5′), 6.81 (d,
J = 8.5 Hz, 1 H, H5), 6.86 (dd, J = 8.0, 1.5 Hz, 1 H, H3′), 7.09 (dd, J = 8.0,
1.5 Hz, 1 H, H6′).
13C NMR (125 MHz, CDCl3): δ = 55.5 (CH3O), 55.8 (CH3O), 56.2 (CH3O),
105.9 (C2), 110.2 (C3′), 112.1 (C5), 112.6 (C6), 113.0 (C6′), 118.7 (C4′),
120.8 (C5′), 134.6 (C1′), 135.9 (C1), 144.6 (C4), 147.4 (C2′), 149.5 (C3).
Following the procedure for 6a, 7d (0.100 g, 0.43 mmol), Pd(OAc)2
(0.029 g, 0.13 mmol), K2CO3 (0.119 g, 0.86 mmol), and MeI (0.122 g,
0.86 mmol) were reacted to afford 6d (0.09 g, 86%) as a pale yellow
oil; Rf = 0.71 (hexane–EtOAc, 7:3).
IR (film): 3423, 2934, 1602, 1531, 1503, 1455, 1342, 1284, 1244,
HRMS (EI): m/z [M+] calcd for C15H17NO3: 259.1208; found: 259.1215.
1131, 1115, 1034, 805, 741 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.32 (s, 3 H, CH3Ar), 3.85 (s, 3 H, CH3O),
3.88 (s, 3 H, CH3O), 6.35 (br s, 1 H, NH), 6.68–6.74 (m, 2 H, H3, H5),
6.78–6.90 (m, 3 H, H3', H4', H5'), 7.22–7.30 (m, 2H, H6, H6').
13C NMR (75 MHz, CDCl3): δ = 21.2 (CH3Ar), 55.5 (2 CH3O), 110.3 (C3′),
111.6 (C3), 114.3 (C6′), 116.7 (C6), 119.3 (C4′), 120.7 (C5′), 120.8 (C5),
129.4 (C1), 130.4 (C4), 133.2 (C1′), 148.5 (C2′), 149.3 (C2).
3,4,5-Trimethoxy-N-(2-methoxyphenyl)aniline (6h)
Following the procedure for 6a, 7h (0.25 g, 0.9 mmol), Pd(OAc)2
(0.061 g, 0.27 mmol), K2CO3 (0.244 g, 1.77 mmol), and MeI (0.251 g,
1.77 mmol) were reacted to afford 6h (0.24 g, 92%) as a pale yellow
solid; mp 79–80 °C; Rf = 0.46 [hexane–EtOAc, 8:2 (2 ×)].
IR (film): 3369, 2934, 1595, 1495, 1464, 1235, 1128, 1008, 824, 749
HRMS (EI): m/z [M+] calcd for C15H17NO2: 243.1259; found: 243.1254.
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 3.81 (s, 6 H, 2 × CH3O), 3.82 (s, 3 H,
CH3O), 3.88 (s, 3 H, CH3O), 6.07 (br s, 1 H, NH), 6.40 (s, 2 H, H2, H6),
6.82–6.90 (m, 3 H, H3′, H4′, H5′), 7.24–7.27 (m, 1 H, H6′).
13C NMR (75 MHz, CDCl3): δ = 55.5 (CH3O), 55.9 (2 × CH3O), 60.9
(CH3O), 96.7 (C2, C6), 110.4 (C3′), 114.3 (C6′), 119.6 (C4′), 120.8 (C5′),
132.7 (C4), 133.2 (C1′), 138.7 (C1), 147.9 (C2′), 153.6 (C3, C5).
3-Methoxy-N-(2-methoxyphenyl)-4-methylaniline (6e)
Following the procedure for 6a, 7e (0.100 g, 0.43 mmol), Pd(OAc)2
(0.029 g, 0.13 mmol), K2CO3 (0.119 g, 0.86 mmol), and MeI (0.122 g,
0.86 mmol) were reacted to afford 6e (0.086 g, 82%) as a yellow oil; Rf
= 0.66 (hexane–EtOAc, 7:3).
IR (film): 3412, 2935, 1618, 1597, 1509, 1460, 1340, 1243, 1218,
HRMS (EI): m/z [M+] calcd for C16H19NO4: 289.1314; found: 289.1322.
1128, 1113, 1029, 828, 810, 740 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.17 (s, 3 H, CH3Ar), 3.78 (s, 3 H, CH3O),
3.87 (s, 3 H, CH3O), 6.10 (br s, 1 H, NH), 6.65–6.70 (m, 2 H, H2, H6),
6.77–6.90 (m, 3 H, H3′, H4′, H5′), 7.02 (d, J = 8.0 Hz, 1 H, H5), 7.30 (d,
J = 8.0 Hz, 1 H, H6′).
13C NMR (75 MHz, CDCl3): δ = 15.6 (CH3Ar), 55.2 (CH3O), 55.5 (CH3O),
102.4 (C2), 110.3 (C3′), 111.0 (C6), 113.8 (C6′), 119.2 (C4′), 119.7 (C4),
120.8 (C5′), 130.8 (C5), 133.6 (C1′), 141.4 (C1), 147.8 (C2′), 158.2 (C3).
N-[4-(Benzyloxy)phenyl]-2-methoxyaniline (6i)
Following the procedure for 6a, 7i (0.180 g, 0.61 mmol), Pd(OAc)2
(0.041 g, 0.18 mmol), K2CO3 (0.170 g, 1.23 mmol), and MeI (0.175 g,
1.23 mmol) were reacted to afford 6i (0.131 g, 70%) as a green oil
(which turns black after a few min at r.t.); Rf = 0.62 (hexane–EtOAc,
8:2).
IR (film): 3409, 2933, 1599, 1506, 1456, 1381, 1292, 1233, 1172,
HRMS (EI): m/z [M+] calcd for C15H17NO2: 243.1259; found: 243.1267.
1113, 1024, 817, 737, 696 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.84 (s, 3 H, CH3O), 5.01 (s, 2 H, CH2Ph),
5.97 (br s, 1 H, NH), 6.76 (td, J = 7.8, 1.5 Hz, 1 H, H4), 6.80 (td, J = 7.8,
1.5 Hz, 1 H, H5), 6.83 (dd, J = 7.8, 1.5 Hz, 1 H, H3), 6.89–6.91 (m, 2 H,
H3′), 7.05 (dd, J = 7.8, 1.5 Hz, 1 H, H6), 7.06–7.10 (m, 2 H, H2′), 7.27–
7.32 (m, 1 H, H4′′), 7.33–7.39 (m, 2 H, H3′′), 7.39–7.43 (m, 2 H, H2′′).
13C NMR (125 MHz, CDCl3): δ = 55.4 (CH3O), 70.4 (CH2Ph), 110.2 (C3),
112.7 (C6), 115.6 (C3′), 118.6 (C4), 120.8 (C5), 122.3 (C2′), 127.4 (2′′),
127.8 (C4′′), 128.5 (C3′′), 134.8 (C1), 135.7 (C1′), 137.2 (C1′′), 147.4
(C2), 154.3 (C-4′).
2,4-Dimethoxy-N-(2-methoxyphenyl)aniline (6f)
Following the procedure for 7a, 7f (0.100 g, 0.405 mmol), Pd(OAc)2
(0.027 g, 0.12 mmol), K2CO3 (0.112 g, 0.81 mmol), and MeI (0.115 g,
0.81 mmol) were reacted to afford 6f (0.093 g, 89%) as a yellow oil; Rf
= 0.57 (hexane–EtOAc, 8:2).
IR (film): 3418, 2937, 1592, 1519, 1501, 1454, 1337, 1281, 1243,
1206, 1176, 1156, 1115, 1029, 832, 740 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 3.79 (s, 3 H, CH3O), 3.82 (s, 3 H, CH3O),
3.88 (s, 3 H, CH3O), 6.13 (br s, 1 H, NH), 6.45 (dd, J = 8.6, 2.7 Hz, 1 H,
H5), 6.53 (d, J = 2.7 Hz, 1 H, H3), 6.74–6.90 (m, 3 H, H3′, H4′, H5′), 7.11
(dd, J = 7.5, 2.1 Hz, 1 H, H6′), 7.26 (d, J = 8.6 Hz, 1 H, H6).
13C NMR (75 MHz, CDCl3): δ = 55.4 (CH3O), 55.51 (CH3O), 55.53
(CH3O), 99.3 (C3), 103.5 (C5), 110.1 (C3′), 112.9 (C6′), 118.7 (C4′),
119.8 (C6), 120.7 (C5′), 125.0 (C1), 134.3 (C1′), 147.9 (C2′), 151.6 (C2
or C4), 155.1 (C4 or C2).
HRMS (EI): m/z [M+] calcd for C20H19NO2: 305.1416; found: 305.1417.
2-(Benzyloxy)-N-(4-methoxyphenyl)aniline (6j)
Following the procedure for 6a, 7j (0.500 g, 2.30 mmol), Pd(OAc)2
(0.152 g, 0.69 mmol), K2CO3 (0.636 g, 4.61 mmol), and BnBr (0.788 g,
4.61 mmol) were reacted to afford 6j (0.485 g, 69%) as a green oil
(which turns to black after a few min at r.t.); Rf = 0.63 (hexane–EtOAc,
8:2).
HRMS (EI): m/z [M+] calcd for C15H17NO3: 259.1208; found: 259.1204.
IR (film): 3413, 2931, 1600, 1509, 1453, 1292, 1239, 1114, 1035, 819,
3,4-Dimethoxy-N-(2-methoxyphenyl)aniline (6g)
740, 697 cm–1
.
Following the procedure for 6a, 7g (0.100 g, 0.405 mmol), Pd(OAc)2
(0.027 g, 0.12 mmol), K2CO3 (0.112 g, 0.81 mmol), and MeI (0.115 g,
0.81 mmol) were reacted to afford 6g (0.09 g, 87%) as a green oil; Rf =
0.64 (hexane–EtOAc, 7:3).
1H NMR (500 MHz, CDCl3): δ = 3.73 (s, 3 H, CH3O), 5.06 (s, 2 H, CH2Ph),
5.99 (br s, 1 H, NH), 6.72 (td, J = 8.0, 1.5 Hz, 1 H, H4), 6.81 (td, J = 8.0,
1.5 Hz, 1 H, H5), 6.82–6.85 (m, 2 H, H3′), 6.89 (dd, J = 8.0, 1.0 Hz, 1 H,
H3), 7.04 (dd, J = 8.0, 1.5 Hz, 1 H, H6), 7.05–7.09 (m, 2 H, H2′), 7.27–
7.32 (m, 1 H, H4′′), 7.33–7.37 (m, 2 H, H3′′), 7.39–7.43 (m, 2 H, H2′′).
IR (film): 3381, 2933, 1724, 1599, 1513, 1460, 1340, 1234, 1162,
1027, 806, 743 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O

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R. I. Hernández-Benitez et al.
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Synthesis
13C NMR (125 MHz, CDCl3): δ = 55.4 (CH3O), 70.6 (CH2Ph), 111.9 (C3),
112.6 (C6), 114.5 (C3′), 118.3 (C4), 121.3 (C5), 122.9 (C2′), 127.6 (C2′′),
128.0 (C4′′), 128.5 (C3′′), 135.2 (C1′), 135.4 (C1), 136.9 (C1′′), 146.4
(C2), 155.3 (C4′).
13C NMR (125 MHz, CDCl3): δ = 21.9 (CH3Ar), 55.4 (CH3O), 55.5
(CH3O), 105.5 (C7), 107.5 (C2), 112.6 (C4), 113.0 (C5), 119.4 (C6),
124.5 (C4a), 124.6 (C4b), 127.8 (C9a), 129.3 (C3), 129.8 (C8a), 145.6
(C1), 145.9 (C8).
HRMS (EI): m/z [M+] calcd for C20H19NO2: 305.1416; found: 305.1406.
HRMS (EI): m/z [M+] calcd for C15H15NO2: 241.1103; found: 241.1100.
8-Methoxy-1,2-dimethyl-9H-carbazole (5a); Typical Procedure
1,7-Dimethoxy-6-methyl-9H-carbazole (Clausine P, 3)
In a threaded ACE glass pressure tube with a sealed Teflon screw cap
equipped with a magnetic stirring bar, a mixture of 6a (0.059 g, 0.26
mmol), Pd(OAc)2 (0.0045 g, 0.02 mmol), K2CO3 (0.0028 g, 0.020
mmol), and pivalic acid (0.300 g, 2.94 mmol) was stirred and heated
to 140 °C for 48 h. The mixture was cooled to r.t. and CH2Cl2 (20 mL)
was added. The organic layer was washed with sat. aq Na2CO3 (2 × 10
mL), dried (Na2SO4), and concentrated under vacuum. The residue
was purified by column chromatography (silica gel, hexane–EtOAc,
98:2) to give 5a (0.043 g, 72%) as an amber solid; mp 95–97 °C; Rf =
0.74 (hexane–EtOAc, 7:3).
Method A: A mixture of 6e (0.050 g, 0.21 mmol), Pd(OAc)2 (0.014 g,
0.06 mmol), and Cu(OAc)2 (0.093 g, 0.51 mmol) in DMF (0.05 mL) was
stirred and heated to 130 °C for 70 min under microwave irradiation
(100 W). The solvent was removed under vacuum and the residue pu-
rified by column chromatography (silica gel, hexane–EtOAc, 98:2) to
give 3 (0.044 g, 89%) as a pale yellow solid.
Method B: Following the procedure for 5a, 6e (0.050 g, 0.21 mmol),
Pd(OAc)2 (0.0045 g, 0.020 mmol), K2CO3 (0.0028 g, 0.02 mmol), and
pivalic acid (0.300 g, 2.94 mmol) were mixed and heated for 12 h, af-
fording 3 (0.047 g, 94%) as a pale yellow solid; mp 147–148 °C (Lit.18
mp 142–144 °C); Rf = 0.62 (hexane–EtOAc, 7:3).
IR (film): 3423, 2927, 1720, 1581, 1508, 1463, 1442, 1383, 1315,
1256, 1063, 776, 729, cm–1
.
IR (film): 3414, 2939, 1636, 1579, 1473, 1445, 1302, 1266, 1245,
1H NMR (500 MHz, CDCl3): δ = 2.46 (s, 6 H, 2 × CH3Ar), 4.02 (s, 3 H,
CH3O), 6.87 (d, J = 8.0 Hz, 1 H, H7), 7.05 (d, J = 8.0 Hz, 1 H, H3), 7.13 (t,
J = 8.0 Hz, 1 H, H6), 7.62 (d, J = 8.0 Hz, 1 H, H5), 7.78 (d, J = 8.0 Hz, 1 H,
H4), 8.07 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): δ = 13.3 (CH3Ar-C2), 19.7 (CH3Ar-C1), 55.5
(CH3O), 105.4 (C7), 112.8 (C5), 117.5 (C4), 118.1 (C1), 119.6 (C6),
121.4 (C4a), 122.0 (C3), 125.1 (C4b), 129.7 (C8a), 133.5 (C2), 139.2
(C9a), 145.6 (C8).
1149, 1092, 892, 781, 739 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.35 (s, 3 H, CH3Ar), 3.85 (s, 3 H, CH3O-
C7), 3.98 (s, 3 H, CH3O-C1), 6.79 (s, 1 H, H8), 6.80 (d, J = 7.8 Hz, 1 H,
H2), 7.10 (t, J = 7.8 Hz, 1 H, H3), 7.55 (d, J = 7.8 Hz, 1 H, H4), 7.75 (s, 1
H, H5), 8.12 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): δ = 16.8 (CH3Ar), 55.4 (2 × CH3O), 92.5 (C8),
104.5 (C2), 112.0 (C4), 116.5 (C4b), 119.2 (C6), 119.5 (C3), 121.6 (C5),
124.5 (C4a), 129.2 (C9a), 138.8 (C8a), 145.4 (C1), 157.3 (C7).
HRMS (EI): m/z [M+] calcd for C15H15NO: 225.1154; found: 225.1155.
HRMS (EI): m/z [M+] calcd for C15H15NO2: 241.1103; found: 241.1107.
8-Methoxy-1,3-dimethyl-9H-carbazole (5b)
1,3,8-Trimethoxy-9H-carbazole (5e)
Following the procedure for 5a, 6b (0.075 g, 0.33 mmol), Pd(OAc)2
(0.0074 g, 0.033 mmol), K2CO3 (0.0046 g, 0.033 mmol), and pivalic
acid (0.300 g, 2.94 mmol) were reacted to afford 5b (0.045 g, 60%) as a
white solid; mp 118–120 °C; Rf = 0.57 (hexane–EtOAc, 8:2).
Following the procedure for 5a, 6f (0.070 g, 0.27 mmol), Pd(OAc)2
(0.0067 g, 0.03 mmol), K2CO3 (0.004 g, 0.03 mmol), and pivalic acid
(0.300 g, 2.94 mmol) were reacted to afford 5e (0.055 g, 79%) as a yel-
low oil; Rf = 0.43 (hexane–EtOAc, 8:2).
IR (film): 3428, 2918, 1579, 1508, 1434, 1390, 1330, 1306, 1256,
IR (film): 3369, 2933, 1591, 1495, 1454, 1433, 1310, 1253, 1204,
1226, 1075, 849, 783, 729 cm–1
.
1142, 1029, 780, 730 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.49 (s, 3 H, CH3Ar-C3), 2.53 (s, 3 H,
CH3Ar-C1), 4.01 (s, 3 H, CH3O), 6.87 (dd, J = 7.8, 0.5 Hz, 1 H, H7), 7.05
(br s, 1 H, H2), 7.13 (t, J = 7.8 Hz, 1 H, H6), 7.63 (dd, J = 7.8, 0.5 Hz, 1 H,
H5), 7.69 (br s, 1 H, H4), 8.07 (br s, 1 H, NH).
1H NMR (500 MHz, CDCl3): δ = 3.92 (s, 3 H, CH3O), 3.97 (s, 3 H, CH3O),
4.00 (s, 3 H, CH3O), 6.58 (d, J = 2.0 Hz, 1 H, H2), 6.86 (d, J = 8.0 Hz, 1 H,
H7), 7.09 (d, J = 2.0 Hz, 1 H, H4), 7.11 (t, J = 8.0 Hz, 1 H, H6), 7.60 (d, J =
8.0 Hz, 1 H, H5), 8.30 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): δ = 16.8 (CH3Ar-C1), 21.4 (CH3Ar-C3), 55.4
(CH3O), 105.5 (C7), 113.0 (C5), 117.9 (C4), 119.5 (C6), 119.8 (C1),
123.3 (C4a), 124.6 (C4b), 127.8 (C2), 128.8 (C3), 129.9 (C8a), 136.8
(C9a), 145.7 (C8).
13C NMR (125 MHz, CDCl3): δ = 55.5 (CH3O), 55.7 (CH3O), 56.0 (CH3O),
94.1 (C4), 97.4 (C2), 105.5 (C7), 112.9 (C5), 119.3 (C6), 123.9 (C4a),
124.6 (C4b), 124.8 (C9a), 130.0 (C8a), 146.1 (C3), 146.4 (C8), 154.6
(C1).
HRMS (EI): m/z [M+] calcd for C15H15NO: 225.1154; found: 225.1156.
HRMS (EI): m/z [M+] calcd for C15H15NO3: 257.1052; found: 257.1056.
1,8-Dimethoxy-3-methyl-9H-carbazole (5d)
1,6,7-Trimethoxy-9H-carbazole (5f)
Following the procedure for 5a, 6d (0.060 g, 0.26 mmol), Pd(OAc)2
(0.0045 g, 0.02 mmol), K2CO3 (0.0028 g, 0.02 mmol), and pivalic acid
(0.30 g, 2.94 mmol) were reacted to afford 5d (0.046 g, 78%) as an or-
ange solid; mp 87–89 °C; Rf = 0.53 (hexane–EtOAc, 8:2).
Following method A for 3, 6g (0.049 g, 0.19 mmol), Pd(OAc)2 (0.014 g,
0.06 mmol), and Cu(OAc)2 (0.087 g, 0.48 mmol) were reacted to afford
5f (0.042 g, 86%) as an orange solid; mp 164–165 °C; Rf = 0.36 (hex-
ane–EtOAc, 7:3).
IR (film): 3362, 2934, 1585, 1492, 1442, 1393, 1340, 1308, 1254,
IR (film): 3369, 2936, 1620, 1578, 1507, 1481, 1462, 1443, 1303,
1134, 1087, 1035, 828, 782, 731 cm–1
.
1270, 1208, 1173, 1153, 1098, 1030, 898, 781, 735 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.51 (s, 3 H, CH3Ar), 3.95 (s, 3 H, CH3O),
3.96 (s, 3 H, CH3O), 6.69 (s, 1 H, H2), 6.84 (d, J = 7.5 Hz, 1 H, H7), 7.10
(t, J = 7.5 Hz, 1 H, H6), 7.43 (s, 1 H, H4), 7.60 (d, J = 7.5 Hz, 1 H, H5),
8.38 (br s, 1 H, NH).
1H NMR (500 MHz, CDCl3): δ = 3.94 (s, 3 H, CH3O-C7), 3.99 (s, 6 H, 2 ×
CH3O), 6.82 (d, J = 7.8 Hz, 1 H, H2), 6.93 (s, 1 H, H8), 7.12 (t, J = 7.8 Hz,
1 H, H3), 7.47 (s, 1 H, H5), 7.55 (d, J = 7.8 Hz, 1 H, H4), 8.14 (br s, 1 H,
NH).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O

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R. I. Hernández-Benitez et al.
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Synthesis
13C NMR (125 MHz, CDCl3): δ = 55.5 (CH3O), 56.1 (CH3O), 56.5 (CH3O),
94.4 (C8), 102.8 (C5), 104.6 (C2), 111.9 (C4), 115.7 (C4b), 119.5 (C3),
124.7 (C4a), 129.5 (C9a), 133.9 (C8a), 144.4 (C6), 145.6 (C1), 149.4
(C7).
3-Formyl-1,8-dimethoxy-9H-carbazole (Clausenal, 2)
After adding 5d (0.047 g, 0.19 mmol) and DDQ (0.111 g, 0.49 mmol)
to a mixture of MeOH–acetone–H2O (6:3:1, 10 mL), the solution was
stirred at r.t. for 15 min. The solvent was removed under vacuum and
the residue purified by column chromatography (neutral alumina,
hexane–EtOAc, 95:5) to furnish 2 (0.044 g, 89%) as a pale yellow solid;
mp 166–168 °C (Lit.13a mp 198 °C; Lit.17b mp 165–170 °C); Rf = 0.26
(hexane–EtOAc, 8:2).
HRMS (EI): m/z [M+] calcd for C15H15NO3: 257.1052; found: 257.1052.
1,5,6,7-Tetramethoxy-9H-carbazole (5g)
Following the procedure for 5a, 6h (0.065 g, 0.22 mmol), Pd(OAc)2
(0.0157 g, 0.07 mmol), K2CO3 (0.0028 g, 0.02 mmol), and pivalic acid
(0.300 g, 2.94 mmol) were reacted to afford 5g (0.046 g, 72%) as a pale
orange solid; mp 139–141 °C; Rf = 0.14 (hexane–EtOAc, 8:2).
IR (film): 3332, 2936, 1678, 1583, 1510, 1487, 1344, 1248, 1135,
1086, 1032, 851, 784, 724 cm–1
.
1H NMR (500 MHz, acetone-d6): δ = 4.01 (s, 3 H, CH3O), 4.08 (s, 3 H,
CH3O), 7.04 (d, J = 7.8 Hz, 1 H, H7), 7.22 (t, J = 7.8 Hz, 1 H, H6), 7.45 (d,
J = 1.0 Hz, 1 H, H2), 7.78 (dd, J = 7.8, 1.0 Hz, 1 H, H5), 8.31 (d, J = 1.0 Hz,
1 H, H4), 10.05 (s, 1 H, CHO), 10.75 (br s, 1 H, NH).
13C NMR (125 MHz, acetone-d6): δ = 56.6 (CH3O), 56.7 (CH3O), 104.6
(C2), 108.3 (C7), 114.2 (C5), 121.2 (C4), 122.4 (C6), 125.5 (C4b), 126.2
(C4a), 131.86 (C8a), 136.87 (C3), 135.4 (C9a), 148.1 (C8), 148.3 (C1),
192.4 (CHO).
IR (film): 3436, 2926, 1609, 1578, 1494, 1451, 1300, 1257, 1111,
1050, 824 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.91 (s, 3 H, CH3O), 3.92 (s, 3 H, CH3O),
3.99 (s, 3 H, CH3O), 4.15 (s, 3 H, CH3O), 6.69 (s, 1 H, H8), 6.83 (d, J = 8.0
Hz, 1 H, H2), 7.13 (t, J = 8.0 Hz, 1 H, H3), 7.78 (d, J = 8.0 Hz, 1 H, H4),
8.20 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): δ = 55.5 (CH3O), 56.2 (CH3O), 60.9 (CH3O),
61.6 (CH3O), 89.7 (C8), 104.7 (C2), 110.4 (C4b), 114.4 (C4), 119.9 (C3),
123.6 (C4a), 129.1 (C9a), 135.9 (C8a), 136.1 (C6), 145.1 (C1), 148.5
(C5), 153.5 (C7).
HRMS (EI): m/z [M+] calcd for C15H13NO3: 255.0895; found: 255.0899.
1-Benzyloxy-6-methoxy-3-formyl-9H-carbazole (13a)
HRMS (EI): m/z [M+] calcd for C16H17NO4: 287.1158; found: 287.1151.
In a round-bottomed flask, a mixture of anhyd DMF (0.017 g, 0.23
mmol) and POCl3 (0.035 g, 0.23 mmol) was stirred at 0 °C for 15 min
under N2 atmosphere. A solution of 5i (0.069 g, 0.23 mmol) in anhyd
DMF (1.0 mL) was added via cannula, and the mixture stirred at r.t. for
15 min, then at 60 °C for 1 h. The mixture was diluted with CH2Cl2 (10
mL) and washed with aq NaOH (5%) until neutral. The organic layer
was dried (Na2SO4), the solvent removed under vacuum, and the resi-
due purified by column chromatography (silica gel, hexane–EtOAc,
95:5) to give 13a (0.054 g, 72%) as a red-orange solid; mp 207–208 °C
(Lit.34a mp 209.5–210.0 °C); Rf = 0.2 (hexane–EtOAc, 8:2).
6-(Benzyloxy)-1-methoxy-9H-carbazole (5h)
Following the general procedure for 5a, 6i (0.080 g, 0.26 mmol),
Pd(OAc)2 (0.018 g, 0.08 mmol), K2CO3 (0.004 g, 0.03 mmol), and pival-
ic acid (0.300 g, 2.94 mmol) were reacted to afford 5h (0.052 g, 65%)
as a white solid; mp 94.5–95.5 °C; Rf = 0.49 (hexane–EtOAc, 8:2).
IR (film): 3435, 2925, 1609, 1494, 1451, 1260, 1050, 875, 824 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.01 (s, 3 H, CH3O), 5.17 (s, 2 H, CH2Ph),
6.88 (dd, J = 8.0, 0.5 Hz, 1 H, H2), 7.12 (t, J = 8.0 Hz, 1 H, H3), 7.13 (dd,
J = 8.5, 2.5 Hz, 1 H, H7), 7.31–7.35 (m, 1 H, H4′), 7.36 (d, J = 8.5 Hz, 1 H,
H8), 7.38–7.42 (m, 2 H, H3′), 7.49–7.52 (m, 2 H, H2′), 7.61 (d, J = 2.5
Hz, 1 H, H5), 7.62 (dd, J = 8.0, 0.5 Hz, 1 H, H4), 8.11 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): δ = 55.5 (CH3O), 71.1 (CH2Ph), 104.8 (C5),
105.7 (C2), 111.6 (C8), 112.8 (C4), 115.8 (C7), 119.3 (C3), 124.0 (C4b),
124.2 (C4a), 127.6 (C2′), 127.8 (C4′), 128.5 (C3′), 130.6 (C9a), 134.3
(C8a), 137.5 (C1′), 145.7 (C1), 153.0 (C6).
IR (film): 3345, 2926, 1726, 1679, 1609, 1579, 1498, 1464, 1261,
1219, 1124, 1072, 741, 706 cm–1
.
1H NMR (500 MHz, acetone-d6): δ = 3.92 (s, 3 H, CH3O), 5.41 (s, 2 H,
CH2Ph), 7.11 (dd, J = 8.5, 2.5 Hz, 1 H, H7), 7.36–7.40 (m, 1 H, H4′),
7.42–7.46 (m, 2 H, H3′), 7.55 (d, J = 8.5 Hz, 1 H, H8), 7.56 (d, J = 1.0 Hz,
1 H, H2), 7.61–7.64 (m, 2 H, H2′), 7.79 (d, J = 2.5 Hz, 1 H, H5), 8.35 (d,
J = 1.0 Hz, 1 H, H4), 10.03 (s, 1 H, CHO), 10.89 (br s, 1 H, NH).
13C NMR (125 MHz, acetone-d6): δ = 56.1 (CH3O), 71.0 (CH2Ph), 103.7
(C5), 105.1 (C2), 113.7 (C8), 116.9 (C7), 121.0 (C4), 124.7 (C4a), 124.8
(C4b), 128.9 (C2′), 129.0 (C-4′), 129.4 (C3′), 130.6 (C3), 135.9 (C9a),
136.1 (C8a), 137.9 (C1′), 146.5 (C1), 155.6 (C6), 191.8 (CHO).
HRMS (EI): m/z [M+] calcd for C20H17NO2: 303.1259; found: 303.1255.
1-Benzyloxy-6-methoxy-9H-carbazole (5i)
HRMS (EI): m/z [M+] calcd for C21H17NO3: 331.1208, found: 331.1199.
Following the procedure for 5a, 6j (0.400 g, 1.31 mmol), Pd(OAc)2
(0.029 g, 0.13 mmol), K2CO3 (0.018 g, 0.13 mmol), and pivalic acid
(0.300 g, 2.94 mmol) were reacted to afford 5i (0.318 g, 80%) as an or-
ange oil; Rf = 0.46 (hexane–EtOAc, 8:2).
3-[(2-Methoxy-4-methylphenyl)amino]cyclohex-2-en-1-one (10a)
Following the procedure for 7a, 11d (0.500 g, 3.65 mmol), 12b (0.409
g, 3.65 mmol), and p-TsOH (0.062 g, 0.36 mmol) were reacted to af-
ford 10a (0.809 g, 96%) as a white solid; mp 139–141 °C; Rf = 0.12
(hexane–EtOAc, 1:1).
IR (film): 3421, 2927, 1615, 1578, 1509, 1485, 1461, 1379, 1297,
1255, 1209, 1176, 1031, 804, 781, 739 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.91 (s, 3 H, CH3O), 5.23 (s, 2 H, CH2Ph),
6.94 (d, J = 7.8 Hz, 1 H, H2), 7.04 (dd, J = 8.7, 2.5 Hz, 1 H, H7), 7.11 (t,
J = 7.8 Hz, 1 H, H3), 7.31 (d, J = 8.7 Hz, 1 H, H8), 7.34–7.38 (m, 1 H,
H4′), 7.38–7.44 (m, 2 H, H3′), 7.48–7.51 (m, 2 H, H2′), 7.52 (d, J = 2.5
Hz, 1 H, H5), 7.64 (td, J = 7.8 Hz, 1 H, H4), 8.15 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): δ = 56.0 (CH3O), 70.4 (CH2Ph), 103.2 (C5),
107.1 (C2), 111.6 (C8), 113.1 (C4), 115.1 (C7), 119.3 (C3), 124.0 (C4b),
124.5 (C4a), 127.8 (C2′), 128.2 (C4′), 128.6 (C3′), 130.8 (C9a), 134.1
(C8a), 137.0 (C1′), 145.0 (C1), 153. 8 (C6).
IR (film): 3243, 2942, 1576, 1525, 1463, 1412, 1364, 1285, 1247,
1186, 1139, 1035, 808 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.04 (qu, J = 6.5 Hz, 2 H, H5), 2.33 (s, 3
H, CH3Ar), 2.36 (t, J = 6.5 Hz, 2 H, H6), 2.51 (t, J = 6.5 Hz, 2 H, H4), 3.83
(s, 3 H, CH3O), 5.66 (s, 1 H, H2), 6.16 (br s, 1 H, NH), 6.71–6.74 (m, 2 H,
H3′, H5′), 7.20 (d, J = 8.0 Hz, 1 H, H6′).
13C NMR (125 MHz, CDCl3): δ = 21.4 (CH3Ar), 21.9 (C5), 30.1 (C4), 36.5
(C6), 55.5 (CH3O), 100.1 (C2), 111.9 (C3′), 121.0 (C5′), 123.2 (C6′),
124.7 (C1′), 135.5 (C4′), 150.9 (C2′), 161.2 (C3), 198.2 (C1).
HRMS (EI): m/z [M+] calcd for C20H17NO2: 303.1259; found: 303.1252.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O

K
R. I. Hernández-Benitez et al.
Paper
Synthesis
HRMS (EI): m/z [M+] calcd for C14H17NO2: 231.1259; found: 231.1258.
1,7-Dimethoxy-3-formyl-9H-carbazole (Clauraila A, 1); Typical
Procedures
3-[(3-Methoxy-4-methylphenyl)amino]cyclohex-3-en-1-one (10b)
Method A: A mixture of 9a (0.050 g, 0.21 mmol), Pd(OAc)2 (0.014 g,
0.06 mmol), and Cu(OAc)2 (0.093 g, 0.51 mmol) in DMF (0.05 mL) was
stirred and heated to 130 °C for 70 min under MW irradiation (100
W). The solvent was removed under vacuum and the residue dis-
solved in a mixture of MeOH–acetone–H2O (6:3:1, 10 mL) at r.t. before
adding DDQ (0.187 g, 0.82 mmol) and stirring for 45 min. The solvent
was removed under vacuum and the residue purified by column chro-
matography (silica gel, hexane–EtOAc, 95:5) to give 1 (0.045 g, 86%) as
a pale yellow solid.
Following the procedure for 7a, 11e (0.500 g, 3.65 mmol), 12b (0.409
g, 3.65 mmol), and p-TsOH (0.062 g, 0.36 mmol) were reacted to af-
ford 10b (0.835 g, 99%) as a colorless oil; Rf = 0.08 (hexane–EtOAc,
1:1).
IR (film): 3254, 2944, 1572, 1504, 1454, 1408, 1246, 1194, 1183,
1128, 1034, 813, 733, 681 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.95 (qu, J = 6.5 Hz, 2 H, H5), 2.16 (s, 3
H, CH3Ar), 2.30 (t, J = 6.5 Hz, 2 H, H6), 2.49 (t, J = 6.5 Hz, 2 H, H4), 3.71
(s, 3 H, CH3O), 5.52 (s, 1 H, H2), 6.58–6.62 (m, 2 H, H2′, H6′), 6.99 (d, J
= 7.5 Hz, 1 H, H5′), 7.62 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): δ = 15.7 (CH3Ar), 21.7 (C5), 29.4 (C4), 36.3
(C6), 55.2 (CH3O), 98.8 (C2), 106.3 (C2′), 115.7 (C6′), 124.0 (C4′), 130.6
(C5′), 136.8 (C1′), 158.0 (C3′), 163.8 (C3), 198.3 (C1).
Method B: A mixture of 9a (0.050 g, 0.21 mmol), Pd(OAc)2 (0.005 g,
0.02 mmol), K2CO3 (0.003 g, 0.02 mmol), and pivalic acid (0.300 g,
2.94 mmol) was stirred and heated to 140 °C for 12 h. The mixture
was cooled to r.t. before adding CH2Cl2 (20 mL), then washed with sat.
aq Na2CO3 (2 × 20 mL). The organic layer was dried (Na2SO4) and con-
centrated under vacuum. The residue was dissolved in a mixture of
MeOH–acetone–H2O (6:3:1, 10 mL) at r.t., and then DDQ (0.186 g,
0.82 mmol) was added and the solution stirred for 45 min. The sol-
vent was removed under vacuum and the residue purified by column
chromatography (silica gel, hexane–EtOAc, 95:5) to give 1 (0.05 g,
96%) as a pale yellow solid; mp 178–179 °C (Lit.17b mp 177–180 °C;
Lit.12 mp 175–177 °C; Lit.26 mp 183–184 °C); Rf = 0.25 (hexane–EtOAc,
1:1).
HRMS (EI): m/z [M+] calcd for C14H17NO2: 231.1259; found: 231.1264.
2-Methoxy-N-(3-methoxyphenyl)-4-methylaniline (9a); Typical
Procedure
In a threaded ACE glass pressure tube with a sealed Teflon screw cap
equipped with a magnetic stirring bar, a mixture of 10a (0.100 g, 0.43
mmol) and Pd/C (10%, 0.011 g, 0.09 mmol) in xylene (0.2 mL) was
heated to 300 °C for 48 h. The mixture was filtered over Celite and the
solvent removed under vacuum. The residue was mixed with anhyd
K2CO3 (0.119 g, 0.86 mmol) and MeI (0.122 g, 0.86 mmol) in acetone
(5.0 mL) and stirred at r.t. for 12 h. The solvent was removed under
vacuum and the residue purified by column chromatography (silica
gel, hexane–EtOAc, 95:5) to give 9a (0.089 g, 85%) as a dark oil; Rf =
0.56 (hexane–EtOAc, 8:2).
IR (film): 3159, 2923, 1655, 1609, 1577, 1488, 1462, 1339, 1278,
1239, 1220, 1159, 1136, 800, 702, 671 cm–1
.
1H NMR (500 MHz, acetone-d6): δ = 3.93 (s, 3 H, CH3O), 4.12 (s, 3 H,
CH3O), 6.96 (dd, J = 8.5, 2.5 Hz, 1 H, H6), 7.19 (d, J = 2.5 Hz, 1 H, H8),
7.45 (d, J = 1.3 Hz, 1 H, H2), 8.12 (d, J = 8.5, 0.5 Hz, 1 H, H5), 8.28 (d, J =
1.3 Hz, 1 H, H4), 10.07 (s, 1 H, CHO), 10.82 (br s, 1 H, NH).
13C NMR (125 MHz, acetone-d6): δ = 56.4 (CH3O), 56.7 (CH3O), 96.7
(C8), 104.2 (C2), 111.0 (C6), 118.4 (C4b), 120.0 (C4), 122.7 (C5), 125.5
(C4a), 131.8 (C3), 135.4 (C9a), 143.3 (C8a), 147.6 (C1), 161.2 (C7),
192.4 (CHO).
IR (film): 3403, 2924, 1599, 1523, 1497, 1463, 1260, 1224, 1158,
1038, 807, 764, 687 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.31 (s, 3 H, CH3Ar), 3.77 (s, 3 H, CH3O),
3.85 (s, 3 H, CH3O), 5.99 (br s, 1 H, NH), 6.44 (ddd, J = 8.5, 2.5, 1.0 Hz, 1
H, H4′), 6.65–6.72 (m, 4 H, H3, H5, H2′, H6′), 7.14 (br t, J = 8.5 Hz, 1 H,
H5′), 7.22 (d, J = 8.0 Hz, 1 H, H6).
HRMS (EI): m/z [M+] calcd for C15H13NO3: 255.0895; found: 255.0896.
2,7-Dimethoxy-3-formyl-9H-carbazole (7-Methoxy-O-methylmu-
13C NMR (125 MHz, CDCl3): δ = 21.1 (CH3Ar), 55.2 (CH3O), 55.6
(CH3O), 103.1 (C2′), 105.8 (C4′), 110.1 (C6′), 111.7 (C3), 116.6 (C6),
120.9 (C5), 129.7 (C1), 129.9 (C5′), 130.4 (C4), 144.9 (C1′), 148.9 (C2),
160.6 (C3′).
konal, 4)
Method A: Following method A for 1, 9b (0.050 g, 0.21 mmol),
Pd(OAc)2 (0.014 g, 0.06 mmol), Cu(OAc)2 (0.093 g, 0.51 mmol), and
DDQ (0.187 g, 0.82 mmol) were reacted to afford 4 (0.042 g, 80%) as a
pale yellow solid.
HRMS (EI): m/z [M+] calcd for C15H17NO2: 243.1259; found: 243.1263.
Method B: Following method B for 1, 9b (0.050 g, 0.21 mmol),
Pd(OAc)2 (0.0045 g, 0.020 mmol), K2CO3 (0.003 g, 0.02 mmol), pivalic
acid (0.300 g, 2.94 mmol), and DDQ (0.187 g, 0.82 mmol) were react-
ed to afford 4 (0.047 g, 89%) as a pale yellow solid; mp 225–227 °C
(Lit.19c mp 222–223 °C; Lit.15a mp 219–220 °C); Rf = 0.25 (hexane–EtO-
Ac, 1:1).
3-Methoxy-N-(3-methoxyphenyl)-4-methylaniline (9b)
Following the procedure for 9a, 10b (0.100 g, 0.43 mmol), Pd/C (10%,
0.011 g, 0.09 mmol), K2CO3 (0.119 g, 0.86 mmol), and MeI (0.122 g,
0.86 mmol) were reacted to afford 9b (0.094 g, 89%) as an amber oil;
Rf = 0.51 (hexane–EtOAc, 8:2).
IR (film): 3383, 2933, 1714, 1615, 1454, 1342, 1268, 1233, 1197,
IR (film): 3388, 2930, 1599, 1511, 1463, 1271, 1211, 1155, 1129,
1144, 1026, 822 cm–1
.
1039, 831, 764, 688 cm–1
.
1H NMR (500 MHz, acetone-d6): δ = 3.86 (s, 3 H, CH3O), 4.00 (s, 3 H,
CH3O), 6.85 (dd, J = 8.5, 2.2 Hz, 1 H, H6), 7.04 (d, J = 2.2 Hz, 1 H, H8),
7.12 (s, 1 H, H1), 8.00 (d, J = 8.5 Hz, 1 H, H5), 8.38 (s, 1 H, H4), 10.45 (s,
1 H, CHO), 10.57 (br s, 1 H, NH).
1H NMR (500 MHz, CDCl3): δ = 2.16 (s, 3 H, CH3Ar), 3.76 (s, 3 H, CH3O),
3.78 (s, 3 H, CH3O), 5.64 (br s, 1 H, NH), 6.44 (ddd, J = 8.3, 2.5, 0.5 Hz, 1
H, H4′), 6.59–6.64 (m, 4 H, H2, H6, H2′, H6′), 7.02 (d, J = 8.0 Hz, 1 H,
H5), 7.14 (t, J = 8.3 Hz, 1 H, H5′).
13C NMR (125 MHz, acetone-d6): δ = 55.9 (CH3O), 56.4 (CH3O), 93.9
(C1), 96.3 (C8), 109.6 (C6), 117.9 (C4b), 118.4 (C4a), 119.5 (C3), 120.2
(C4), 121.6 (C5), 143.1 (C8a), 146.7 (C9a), 160.1 (C7), 161.8 (C2), 188.7
(CHO).
13C NMR (125 MHz, CDCl3): δ = 15.6 (CH3Ar), 55.2 (CH3O), 55.3
(CH3O), 102.2 (C2), 102.5 (C2′), 105.7 (C4′), 109.5 (C6), 111.0 (C6′),
120.0 (C4), 130.0 (C5′), 130.9 (C5), 141.5 (C1), 145.3 (C1′), 158.3 (C3),
160.7 (C3′).
HRMS (EI): m/z [M+] calcd for C15H13NO3: 255.0895; found: 255.0894.
HRMS (EI): m/z [M+] calcd for C15H17NO2: 243.1259; found: 243.1254.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O

L
R. I. Hernández-Benitez et al.
Paper
Synthesis
3-[(2,4-Dimethoxyphenyl)amino]cyclohex-2-en-1-one (10c)
and stirred at r.t. for 12 h. The solvent was removed under vacuum
and the residue purified by column chromatography (silica gel, hex-
ane–EtOAc, 97:3) to give 9c (0.101 g, 96%) as a colorless oil; Rf = 0.63
(hexane–EtOAc, 7:3).
Following the procedure for 7a, 11f (0.200 g, 1.31 mmol), 12b (0.147
g, 1.31 mmol), and p-TsOH (0.022 g, 0.13 mmol) were mixed and
heated in a heating mantle to 130 °C for 24 h to give 10c (0.31 g, 96%)
as a pale purple solid; mp 139.0–140.5 °C; Rf = 0.14 (hexane–EtOAc,
1:1).
IR (film): 3392, 2937, 1598, 1522, 1500, 1464, 1284, 1208, 1156,
1037, 832, 764, 689 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.75 (s, 3 H, CH3O-C3′), 3.78 (s, 3 H,
CH3O-C4), 3.81 (s, 3 H, CH3O-C2), 5.75 (br s, 1 H, NH), 6.40 (ddd, J =
8.0, 2.3, 0.5 Hz, 1 H, H4′), 6.43 (dd, J = 8.5, 2.5 Hz, 1 H, H5), 6.52 (d, J =
2.5 Hz, 1 H, H3), 6.55 (t, J = 2.3 Hz, 1 H, H2′), 6.57 (ddd, J = 8.0, 2.3, 0.5
Hz, 1 H, H6′), 7.11 (t, J = 8.0 Hz, 1 H, H5′), 7.23 (d, J = 8.5 Hz, 1 H, H6).
13C NMR (125 MHz, CDCl3): δ = 55.1 (CH3O), 55.5 (2 × CH3O), 99.3
(C3), 101.8 (C2′), 103.6 (C5), 104.9 (C4′), 108.9 (C6′), 119.6 (C6), 125.2
(C1), 129.8 (C5′), 146.0 (C1′), 151.1 (C2), 155.1 (C4), 160.6 (C3′).
IR (film): 3236, 2943, 1575, 1512, 1466, 1247, 1209, 1186, 1031, 825
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.03 (qu, J = 6.3 Hz, 2 H, H5), 2.35 (t, J =
6.3 Hz, 2 H, H6), 2.51 (t, J = 6.3 Hz, 2 H, H4), 3.80 (s, 3 H, CH3O), 3.81 (s,
3 H, CH3O), 5.51 (s, 1 H, H2), 6.10 (br s, 1 H, NH), 6.43 (dd, J = 8.5, 2.5
Hz, 1 H, H5′), 6.48 (d, J = 2.5 Hz, 1 H, H3′), 7.19 (d, J = 8.5 Hz, 1 H, H6′).
13C NMR (125 MHz, CDCl3): δ = 21.8 (C5), 29.8 (C4), 36.4 (C6), 55.5
(CH3O), 55.6 (CH3O), 99.2 (C3′), 99.3 (C2), 103.8 (C5′), 120.1 (C1′),
125.4 (C6′), 152.9 (C2′), 158.1 (C4′), 162.4 (C3), 198.1 (C1).
HRMS (EI): m/z [M+] calcd for C15H17NO3: 259.1208; found: 259.1202.
HRMS (EI): m/z [M+] calcd for C14H17NO3: 247.1208; found: 247.1211.
N-[3-(Benzyloxy)phenyl]-2,4-dimethoxyaniline (9d)
3-[(3,4-Dimethoxyphenyl)amino]cyclohex-2-en-1-one (10d)
Following the procedure for 9c, 10c (0.100 g, 0.41 mmol), Pd/C (10%,
0.024 g, 0.20 mmol), K2CO3 (0.112 g, 0.81 mmol), and BnBr (0.139 g,
0.81 mmol) were reacted to afford 9d (0.122 g, 90%) as a yellow oil; Rf
= 0.57 (hexane–EtOAc, 7:3).
Following the procedure for 10c, 11g (0.200 g, 1.31 mmol), 12b (0.147
g, 1.31 mmol), and p-TsOH (0.022 g, 0.13 mmol) were reacted to af-
ford 10d (0.304 g, 94%) as a white solid; mp 199–201 °C; Rf = 0.10
(hexane–EtOAc, 1:1).
IR (film): 3401, 2936, 1596, 1520, 1499, 1454, 1283, 1208, 1156,
1033, 833, 751, 697 cm–1
.
IR (KBr): 3255, 3057, 2945, 1579, 1549, 1509, 1446, 1411, 1362, 1249,
1201, 1138, 1025, 851, 810, 764, 747 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.79 (s, 3 H, CH3O), 3.80 (s, 3 H, CH3O),
5.01 (s, 2 H, CH2Ph), 5.74 (br s, 1 H, NH), 6.41 (dd, J = 9.0, 2.5 Hz, 1 H,
H5), 6.47 (br dd, J = 8.0, 2.3 Hz, 1 H, H4′), 6.51 (d, J = 2.5 Hz, 1 H, H3),
6.57 (ddd, J = 8.0, 2.3, 0.5 Hz, 1 H, H6′), 6.63 (t, J = 2.3 Hz, 1 H, H2′),
7.11 (t, J = 8.0 Hz, 1 H, H5′), 7.17 (d, J = 9.0 Hz, 1 H, H6), 7.28–7.33 (m,
1 H, H4′′), 7.34–7.39 (m, 1 H, H3′′), 7.39–7.43 (m, 1 H, H2′′).
1H NMR [500 MHz, acetone-d6/DMSO-d6 (3:1)]: δ = 1.92 (qu, J = 6.4
Hz, 2 H, H5), 2.16 (t, J = 6.4 Hz, 2 H, H6), 2.52 (t, J = 6.4 Hz, 2 H, H4),
3.77 (s, 3 H, CH3O), 3.78 (s, 3 H, CH3O), 5.27 (s, 1 H, H2), 6.74 (dd, J =
8.5, 2.5 Hz, 1 H, H6′), 6.79 (d, J = 2.5 Hz, 1 H, H2′), 6.95 (d, J = 8.5 Hz, 1
H, H5′), 8.46 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): δ = 55.5 (CH3O), 55.6 (CH3O), 69.7
(CH2Ph), 99.3 (C3), 102.6 (C2′), 103.7 (C5), 105.8 (C4′), 109.2 (C6′),
119.7 (C6), 125.2 (C1), 127.4 (C2′′), 127.8 (C4′′), 128.5 (C3′′), 129.9
(C5′), 137.1 (C1′′), 146.1 (C1′), 151.2 (C2), 155.2 (C4), 159.8 (C3′).
13C NMR [125 MHz, acetone-d6/DMSO-d6 (3:1)]: δ = 13.6 (C5), 20.4
(C4), 28.3 (C6), 47.1 (CH3O), 47.2 (CH3O), 89.5 (C2), 100.4 (C2′), 103.9
(C5′), 107.7 (C6′), 124.2 (C1′), 138.3 (C4′), 141.2 (C3′), 154.3 (C3),
187.0 (C1).
HRMS (EI): m/z [M+] calcd for C21H21NO3: 335.1521; found: 335.1523.
HRMS (EI): m/z [M+] calcd for C14H17NO3: 247.1208; found: 247.1210.
3,4-Dimethoxy-N-(3-methoxyphenyl)aniline (9e)
3-[(3,4,5-Trimethoxyphenyl)amino]cyclohex-2-en-1-one (10e)
Following the procedure for 9c, 10d (0.100 g, 0.41 mmol), Pd/C (10%,
0.024 g, 0.20 mmol), K2CO3 (0.112 g, 0.81 mmol), and MeI (0.175 g,
1.23 mmol) were reacted to afford 9e (0.083 g, 80%) as a colorless oil;
Rf = 0.51 (hexane–EtOAc, 7:3).
Following the procedure for 10c, 11h (0.500 g, 2.73 mmol), 12b
(0.306 g, 2.73 mmol), and p-TsOH (0.046 g, 0.27 mmol) were reacted
to afford 10e (0.75 g, 99%) as a pale orange solid; mp 202.0–203.5 °C;
Rf = 0.10 (hexane–EtOAc, 1:1).
IR (film): 3370, 2935, 1598, 1514, 1464, 1232, 1211, 1154, 1026, 835,
IR (KBr): 3271, 2956, 2931, 1584, 1506, 1462, 1413, 1352, 1254, 1237,
766, 739, 689 cm–1
.
1197, 1130, 1184, 1011, 827, 719 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.75 (s, 3 H, CH3O), 3.82 (s, 3 H, CH3O),
3.86 (s, 3 H, CH3O), 5.59 (br s, 1 H, NH), 6.40 (ddd, J = 8.5, 2.5, 0.5 Hz, 1
H, H4′), 6.50 (t, J = 2.5 Hz, 1 H, H2′), 6.52 (ddd, J = 8.5, 2.5, 0.5 Hz, 1 H,
H6′), 6.67 (dd, J = 8.5, 2.5 Hz, 1 H, H6), 6.72 (d, J = 2.5 Hz, 1 H, H2), 6.80
(d, J = 8.5 Hz, 1 H, H5), 7.12 (t, J = 8.5 Hz, 1 H, H5′).
13C NMR (125 MHz, CDCl3): δ = 55.0 (CH3O), 55.7 (CH3O), 56.1 (CH3O),
101.4 (C2′), 104.8 (C4′), 105.5 (C2), 108.4 (C6′), 111.9 (C5), 112.5 (C6),
130.0 (C5′), 135.7 (C1), 144.7 (C4), 146.3 (C1′), 149.4 (C3), 160.6 (C3′).
1H NMR (500 MHz, CD3OD): δ = 2.02 (qu, J = 6.3 Hz, 2 H, H5), 2.34 (t,
J = 6.3 Hz, 2 H, H6), 2.59 (t, J = 6.3 Hz, 2 H, H4), 3.76 (s, 3 H, CH3O), 3.83
(s, 6 H, 2 × CH3O), 5.52 (s, 1 H, H2), 6.52 (s, 2 H, H2′, H6′).
13C NMR (125 MHz, CD3OD): δ = 23.1 (C5), 30.1 (C4), 36.9 (C6), 56.8 (2
× CH3O), 61.3 (CH3O), 98.7 (C2), 103.2 (C2′, C6′), 135.8 (C1′), 137.2
(C4′), 155.1 (C3′, C5′), 168.1 (C3), 201.3 (C1).
HRMS (EI): m/z [M+] calcd for C15H19NO4: 277.1314; found: 277.1319.
HRMS (EI): m/z [M+] calcd for C15H17NO3: 259.1208; found: 259.1206.
2,4-Dimethoxy-N-(3-methoxyphenyl)aniline (9c); Typical Proce-
dure
3,4,5-Trimethoxy-N-(3-methoxyphenyl)aniline (9f)
In a threaded ACE glass pressure tube with a sealed Teflon screw cap
equipped with a magnetic stirring bar, a mixture of 10c (0.100 g, 0.41
mmol) and Pd/C (10%, 0.024 g, 0.20 mmol) in xylene (0.2 mL) was
stirred at 300 °C for 48 h. The mixture was filtered and the solvent
removed under vacuum. The residue was mixed with anhyd K2CO3
(0.112 g, 0.81 mmol) and MeI (0.115 g, 0.81 mmol) in acetone (5 mL)
Following the procedure for 9c, 10e (0.100 g, 0.36 mmol), Pd/C (10%,
0.021 g, 0.18 mmol), K2CO3 (0.099 g, 0.72 mmol), and MeI (0.102 g,
0.72 mmol) were reacted to afford 9f (0.10 g, 96%) as a colorless oil;
Rf = 0.28 (hexane–EtOAc, 7:3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O

M
R. I. Hernández-Benitez et al.
Paper
Synthesis
IR (film): 3364, 2933, 1596, 1507, 1465, 1234, 1128, 1009, 818, 771,
707, 688 cm–1
1H NMR (500 MHz, CDCl3): δ = 3.77 (s, 3 H, CH3O), 3.79 (s, 6 H, 2 ×
CH3O), 3.82 (s, 3 H, CH3O), 5.72 (br s, 1 H, NH), 6.35 (s, 2 H, H2, H6),
6.46 (ddd, J = 8.0, 2.5, 1.0 Hz, 1 H, H4′), 6.60–6.64 (m, 2 H, H2′, H6′),
7.16 (t, J = 8.0 Hz, 1 H, H5′).
13C NMR (125 MHz, acetone-d6): δ = 55.7 (CH3O), 56.3 (CH3O), 57.0
(CH3O), 95.5 (C8), 96.0 (C1), 104.2 (C4), 108.3 (C6), 116.4 (C4a), 118.4
(C4b), 120.6 (C5), 135.8 (C9a), 142.1 (C8a), 145.5 (C3), 149.8 (C2),
158.9 (C7).
.
HRMS (EI): m/z [M+] calcd for C15H15NO3: 257.1052; found: 257.1056.
13C NMR (125 MHz, CDCl3): δ = 55.1 (CH3O), 55.9 (2 × CH3O), 60.9
(CH3O), 96.5 (C2, C6), 102.7 (C2′), 105.7 (C4′), 109.7 (C6′), 130.1 (C5′),
132.7 (C1), 138.8 (C4), 145.0 (C1′), 153.6 (C3), 160.6 (C3′).
2,3,4,7-Tetramethoxy-9H-carbazole (8f)
Following the procedure for 8c, 9f (0.064 g, 0.22 mmol), Pd(OAc)2
(0.005 g, 0.022 mmol), K2CO3 (0.003 g, 0.022 mmol), and pivalic acid
(0.300 g, 2.94 mmol) were reacted to afford 8f (0.057 g, 91%) as a
greenish-yellow solid; mp 143.5–145.0 °C; Rf = 0.49 (hexane–EtOAc,
1:1).
HRMS (EI): m/z [M+] calcd for C16H19NO4: 289.1314; found: 289.1315.
1,3,7-Trimethoxy-9H-carbazole (8c)
IR (film): 3400, 2931, 1616, 1497, 1466, 1260, 1198, 1156, 1113,
Following the procedure for 5a, 9c (0.060 g, 0.23 mmol), Pd(OAc)2
(0.005 g, 0.022 mmol), K2CO3 (0.003 g, 0.022 mmol), and pivalic acid
(0.300 g, 2.94 mmol) were mixed and heated for 24 h to give 8c (0.048
g, 80%) as a yellow solid; mp 90.0–91.5 °C; Rf = 0.51 (hexane–EtOAc,
8:2).
1070, 1006 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.89 (s, 3 H, CH3O), 3.92 (s, 3 H, CH3O),
3.93 (s, 3 H, CH3O), 4.14 (s, 3 H, CH3O), 6.67 (s, 1 H, H1), 6.84 (dd, J =
8.5, 2.0 Hz, 1 H, H6), 6.87 (d, J = 2.0 Hz, 1 H, H8), 7.86 (br s, 1 H, NH),
8.02 (d, J = 8.5 Hz, 1 H, H5).
13C NMR (125 MHz, CDCl3): δ = 55.6 (CH3O), 56.3 (CH3O), 60.7 (CH3O),
61.6 (CH3O), 89.7 (C1), 94.7 (C8), 107.9 (C6), 110.1 (C4a), 116.6 (C4b),
122.3 (C5), 135.9 (C9a), 136.3 (C3), 140.3 (C8a), 148.0 (C4), 152.5 (C2),
157.8 (C7).
IR (film): 3401, 2932, 1630, 1595, 1503, 1452, 1281, 1201, 1158,
1104, 1022, 822 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.87 (s, 3 H, CH3O), 3.91 (s, 3 H, CH3O),
3.95 (s, 3 H, CH3O), 6.52 (d, J = 2.3 Hz, 1 H, H2), 6.81 (dd, J = 8.5, 2.0 Hz,
1 H, H6), 6.88 (d, J = 2.0 Hz, 1 H, H8), 7.04 (d, J = 2.3 Hz, 1 H, H4), 7.85
(d, J = 8.5 Hz, 1 H, H5), 8.02 (br s, 1 H, NH).
HRMS (EI): m/z [M+] calcd for C16H17NO4: 287.1158; found: 287.1158.
13C NMR (125 MHz, CDCl3): δ = 55.51 (CH3O), 55.54 (CH3O), 56.0
(CH3O), 93.7 (C4), 94.7 (C8), 96.3 (C2), 108.1 (C6), 117.6 (C4b), 121.0
(C5), 123.8 (C4a), 124.5 (C9a), 140.8 (C8a), 145.8 (C1), 154.8 (C3),
158.9 (C7).
Single-Crystal X-ray Crystallography42
Enaminone 10e was obtained as pale orange crystals (CH2Cl2), which
were mounted on glass fibers. Crystallographic measurements were
performed on an Oxford XCalibur diffractometer with Mo Kα radia-
tion (λ = 0.71073 Å; graphite monochromator) at r.t. Two standard re-
flections were monitored periodically, showing no change during
data collection. Unit cell parameters were obtained from a least-
squares refinement and intensities were corrected for Lorentz and
polarization effects. No absorption correction was applied. Anisotro-
pic temperature factors were introduced for all non-hydrogen atoms,
while hydrogen atoms were placed in idealized positions and their
atomic coordinates refined. Unit weights were used in the refine-
ment. After being solved with SHELXT,43 the structure was visualized
and plotted with the MERCURY program package.44 Data from 10e:
Formula: C15H19NO4: molecular weight: 277.31; cryst. syst.: triclinic;
space group: P-1; unit cell parameters: a, 7.1750(5), b, 10.2584(6), c,
11.3201(6) (Å); α 113.604(5)°, β 107.536(5)°, γ 93.826(5)°; temp (K):
293(2); Z: 2; No. of reflections collected: 15063; No. of independent
reflections: 4730; No. of observed reflections: 3332; data collection
range: 3.364 < θ < 32.454°; R: 0.0694; wR: 0.1868; GOF: 1.039.
HRMS (EI): m/z [M+] calcd for C15H15NO3: 257.1052; found: 257.1045.
1,3-Dimethoxy-7-hydroxy-9H-carbazole (8d)
Following the procedure for 8c, 9d (0.070 g, 0.21 mmol), Pd(OAc)2
(0.005 g, 0.022 mmol), K2CO3 (0.003 g, 0.022 mmol), and pivalic acid
(0.300 g, 2.94 mmol) were reacted to afford 8d (0.048 g, 95%) as a
green oil; Rf = 0.23 (hexane–EtOAc, 7:3).
IR (film): 3401, 2934, 1630, 1594, 1503, 1433, 1291, 1202, 1142, 820
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 3.91 (s, 3 H, CH3O), 3.95 (s, 3 H, CH3O),
5.11 (br s, 1 H, OH), 6.52 (d, J = 2.0 Hz, 1 H, H2), 6.71 (dd, J = 8.5, 2.0
Hz, 1 H, H6), 6.84 (d, J = 2.0 Hz, 1 H, H8), 7.03 (d, J = 2.0 Hz, 1 H, H4),
7.81 (d, J = 8.5 Hz, 1 H, H5), 7.98 (br s, 1 H, NH).
13C NMR (125 MHz, CDCl3): δ = 55.5 (CH3O), 56.0 (CH3O), 93.7 (C4),
96.3 (C2), 97.0 (C8), 108.4 (C6), 117.9 (C4b), 121.1 (C5), 123.8 (C4a),
124.5 (C9a), 140.9 (C8a), 145.8 (C1), 154.6 (C7), 154.8 (C3).
HRMS (EI): m/z [M+] calcd for C14H13NO3: 243.0895; found: 243.0891.
Funding Information
2,3,7-Trimethoxy-9H-carbazole (8e)
J.T. acknowledges SIP/IPN (Grants 20150917, 20161791 and
20170902) and CONACYT (Grant 178219) for financial support. R.I.H.-B.
and D.Z.-Z. thank CONACYT for graduate scholarships awarded, and
SIP/IPN (BEIFI) for scholarship complements. F.D. and J.T. are fellows
Following the procedure for 8c, 9e (0.050 g, 0.19 mmol), Pd(OAc)2
(0.0045 g, 0.020 mmol), K2CO3 (0.0028 g, 0.020 mmol), and pivalic
acid (0.300 g, 2.94 mmol) were reacted to afford 8e (0.047 g, 97%) as a
green solid; mp 189–190 °C; Rf = 0.60 (hexane–EtOAc, 1:1).
of the EDI-IPN and COFAA-IPN programs.
S
PI/N
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0
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1
6
1
7
9
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0
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1
9)
IR (KBr): 3389, 2944, 1612, 1578, 1487, 1450, 1346, 1273, 1222, 1197,
1151, 1106, 1021, 826, 809 cm–1
.
1H NMR (500 MHz, acetone-d6): δ = 3.87 (s, 3 H, CH3O), 3.89 (s, 3 H,
CH3O), 3.91 (s, 3 H, CH3O), 6.78 (dd, J = 8.5, 2.5 Hz, 1 H, H6), 7.01 (d, J =
2.5 Hz, 1 H, H8), 7.09 (s, 1 H, H1), 7.61 (s, 1 H, H4), 7.88 (d, J = 8.5 Hz, 1
H, H5), 9.98 (br s, 1 H, NH).
Acknowledgment
We thank Vanessa Pelayo for her assistance in the experimental sec-
tion, Edson Barrera and Dr. Hugo A. Jiménez-Vázquez for their sup-
port in the X-ray diffraction analysis, and Bruce A. Larsen for
proofreading.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–O

N
R. I. Hernández-Benitez et al.
Paper
Synthesis
Supporting Information
(13) (a) Chakraborty, A.; Saha, C.; Podder, G.; Chowdhury, B. K.;
Bhattacharyya, P. Phytochemistry 1995, 38, 787. (b) Intekhab, J.;
Aslam, M. J. Saudi Chem. Soc. 2008, 12, 515.
(14) Wu, T.-S.; Huang, S.-C.; Wu, P.-L.; Kuoh, C.-S. Phytochemistry
1999, 52, 523.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588467.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(15) (a) Ruangrungsi, N.; Ariyaprayoon, J.; Lange, G. L.; Organ, M. G.
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S.; Promgool, T.; Yossathera, K.; Deachathai, S.; Phakhodee, W.;
Laphookhieo, S. J. Nat. Prod. 2012, 75, 741.
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