Modifications to the Vilsmeier-Haack formylation of 1,4-dimethylcarbazole and its application to the synthesis of ellipticines

Article abstract of DOI:10.1002/jhet.598

Figure represented. An improved method for the preparation of 3-formyl-1,4-dimethylcarbazole, a key intermediate in the synthesis of ellipticine, is presented. Conditions of the Vilsmeier-Haack reaction have been modified to facilitate the production of 3-formyl-1,4-dimethylcarbazole as a major product leading to an overall improvement in yield of ellipticine from 3% to 14%. This approach was also applied to the synthesis of 6-methylellipticine and 9-methoxyellipticine.

Full text of DOI:10.1002/jhet.598

814
Modifications to the Vilsmeier-Haack Formylation of 1,4-
Dimethylcarbazole and Its Application to the Synthesis of
Ellipticines
Vol 48
Fiona M. Deane, Charlotte M. Miller, Anita R. Maguire,
and Florence O. McCarthy*
Department of Chemistry, School of Pharmacy and Analytical and Biological Chemistry Research
Facility, University College Cork, Cork, Ireland
*E-mail: f.mccarthy@ucc.ie
Received May 24, 2010
DOI 10.1002/jhet.598
Published online 12 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
An improved method for the preparation of 3-formyl-1,4-dimethylcarbazole, a key intermediate in the
synthesis of ellipticine, is presented. Conditions of the Vilsmeier-Haack reaction have been modified to
facilitate the production of 3-formyl-1,4-dimethylcarbazole as a major product leading to an overall
improvement in yield of ellipticine from 3% to 14%. This approach was also applied to the synthesis of
6-methylellipticine and 9-methoxyellipticine.
J. Heterocyclic Chem., 48, 814 (2011).
INTRODUCTION
versatile ‘‘D-type’’ routes to ellipticine starting from
appropriately substituted indoles or carbazoles is due to
Cranwell and Saxton [11], and subsequently, a number
of important modifications have increased the utility of
this route further [12–14]. Although these modifications
have decreased the difficulty and length of the original
synthesis, one main disadvantage still exists. The prob-
lematic Vilsmeier-Haack formylation of 1,4-dimethyl-
carbazole 5 typically affords the desired 3-formyl-1,4-
dimethylcarbazole 6 in low yields (<30%) along with
unwanted side products. The formylation reaction is a
critical step as the success of the Cranwell–Saxton route
depends on the efficient introduction of a suitable sub-
stituent at the 3-position of 1,4-dimethylcarbazole 5
(which then permits the construction of pyridine ring
D). This article describes a simple modification of the
Vilsmeier-Haack reaction, which increases the yield of
3-formyl-1,4-dimethylcarbazole 6 dramatically leading
to an increased overall yield of ellipticine (14%) by this
route.
Since the 1950s, the natural product ellipticine (5,11-
dimethyl-6H-pyrido[4,3-b]carbazole, 1; Figure 1) has
engendered interest due to its antineoplastic properties
and limited side effects [1]. The synthetic drug Celip-
tium 2 has been used clinically as an anti-cancer drug,
including treatment of breast cancer, myeloblastic leuke-
mia, and solid tumors [2]. More recently, studies have
also indicated activity against HIV [3]. Ellipticine is
seen to display its activity via a multimodal mechanism
of action of which DNA intercalation, inhibition of to-
poisomerase II, oxidative bioactivation, and inhibition of
p53 phosphorylation and c-kit kinase have all been
implicated [4–6].
Synthetic strategies leading to ellipticine are usually
classified according to the construction of the last ring
as B, C, D, and B þ C types [7–10]. One of the most
RESULTS AND DISCUSSION
Formylation of 1,4-dimethylcarbazole 5. As part of
an ongoing research program in our laboratory, a modified
Cranwell–Saxton route was investigated toward the syn-
thesis of ellipticine 1 [15,16]. From our experience of the
Dalton method of formylation, the reaction afforded low
Figure 1. Structures of ellipticine and Celiptium.
C
V
2011 HeteroCorporation

July 2011
Modifications to the Vilsmeier-Haack Formylation of 1,4-Dimethylcarbazole and Its
Application to the Synthesis of Ellipticines
815
Scheme 1
yields of 3-formyl-1,4-dimethylcarbazole 6 but the major
product was shown to be undesired 9-formyl-1,4-dime-
thylcarbazole 7 with typical yields of >50% (Scheme 1
Use of less than 1 equiv of POCl3 afforded 9-formyl-
1,4-dimethylcarbazole 7 as a sole product with very
poor yields (Entry 2, Table 1). The reaction time was
lengthened to improve the yield of 3-formyl-1,4-dime-
thylcarbazole 6; however, no appreciable difference was
observed (Entry 3). It is clear that increasing the equiva-
lents of POCl3 and DMF was seen to increase the yield
of 6 (entries 4 and 5) with the most significant yield
observed for entry 5. Regarding entry 5, the reaction
was initiated with 1 equiv of POCl3 and 1 equiv of
DMF. TLC analysis of the reaction mixture after 3.5 h
showed that only trace amounts of 6 and 8 (identical Rf
value) had formed. At this stage, a further 0.2 equiv of
each reagent was added, and the heating of the reaction
was increased to afford a more vigorous reflux.
1
and Table 1), which was previously unreported. H-NMR
spectroscopic analysis after column chromatography deter-
mined that 3-formyl-1,4-dimethylcarbazole 6 was conta-
minated with 6-formyl-1,4-dimethylcarbazole 8, which
could not be separated from the desired product by chro-
matography (Scheme 1). It was observed that multiple
recrystallizations of the isomeric mixture greatly reduced
the amount of the 6-formyl derivative 8 present; however,
it also led to decreased overall yields of 3-formyl-1,4-
dimethylcarbazole 6 with consequent effects on the route
to ellipticine 1. Although other groups have investigated
the formylation reaction with substituents blocking the 6-
and 9-positions of the carbazole, the formylation of 1,4-
dimethylcarbazole 5 has remained essentially unchanged
from Daltons original paper [10]. The Vilsmeier-Haack
reaction was subsequently studied comprehensively using
1,4-dimethylcarbazole 5 as the initial substrate. Initially,
the reaction was undertaken using various molar ratios of
POCl3 and DMF, and reaction times (Table 1).
Because of the high yield of 6 obtained using method
C, it appeared that prolonged heating was an important
parameter of the reaction. Further evidence of this was
1
seen in a H-NMR spectroscopic study at elevated tem-
perature. Starting with 7 in d6-DMSO, the temperature
was increased in 10ꢀC increments and the formyl peak
at 10.46 ppm was monitored. This peak diminished
gradually until the temperature reached 110ꢀC where it
disappeared completely. Further testament to the lability
of the amide bond of compound 7 was observed by the
ease in which the compound could by recycled back to
Using 1 equiv of POCl3 and 1 equiv of DMF afforded
9-formyl-1,4-dimethylcarbazole 7 as a major product
(66% yield) with only a minor amount of the isomeric
mixture of 6 and 8 formed (10%) (Entry 1, Table 1).
Table 1
Effect of varying the stoichiometry of reagents and conditions on the formation of 6 and 8 from 1,4-dimethylcarbazole 5 in trichloroethylene.
Reaction conditions
% Yield
6 and 8b
7
DMFa
Time
Temperature (ꢀC)
Method
Ratio of 6 and 8c
a
Entry
POCl3
1
2
3
4
5
1 equiv
0.66 equiv
1 equiv
1 equiv
1 equiv
1 equiv
3.5 h
3.5 h
6 h
87.5
87.5
87.5
87.5
87.5
A
A
B
A
C
10
0
12
30
51
66
8
44
51
8
1.00:0.23
–
1.00:0.17
1.00:0.23
1.00:0.19
4.5 equiv
1.2 equiv
4.5 equiv
1.2 equiv
3.5 h
6.5 h
Reaction conditions: See Experimental for conditions A–C. A, heat under gentle reflux for 3.5 h; B, heat under gentle reflux for 6 h; C, heat under
vigorous reflux for 3.5 h, extra equivalents of POCl3 and DMF are added and the reaction mixture is heated under reflux for a further 3 h. Initial
experiments using the original Cranwell–Saxton conditions (o-dichlorobenzene as solvent) yielded no improvement in yield of compound 6.
a Equivalents of DMF and POCl3 are relative to 1 equiv of starting material 1,4-dimethylcarbazole 5.
b The ‘‘combined yield’’ of 6 and 8 refers to an isolated yield of 3-formyl-1,4-dimethylcarbazole and 6-formyl-1,4-dimethylcarbazole after
chromatography.
c Determined from 1H-NMR spectroscopic analysis of the singlet peaks corresponding to the formyl protons at 10.10–10.50 ppm.
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F. M. Deane, C. M. Miller, A. R. Maguire, and F. O. McCarthy
Vol 48
1,4-dimethylcarbazole 5 via mild hydrolysis conditions
(See Experimental section). Therefore, it was decided to
use a higher boiling point solvent in the reaction to
exploit the lability of the CAN amide bond of 7 leading
to the production of greater yields of 6 (Table 2).
had formed. We found that far greater yields of 6 were
obtained using longer reflux times (6.5 h) and increased
equivalents of POCl3 and DMF (entries 6 and 7, Table 2).
Regarding entries 6–8, the reactions were initiated using 1
equiv of POCl3 and 1 equiv of DMF; however, after 3.5 h,
addition of extra equivalents of POCl3 and DMF was seen
to produce improved yields of 6 and 8.
Finally, a large scale synthetic batch using method C
with just 1.01 equiv of POCl3 and DMF was undertaken
leading to the formation of 6 and 8 with a yield of 64%.
This result shows prolonged heating together with a sec-
ond addition of POCl3 and DMF after 3.5 h to be the
key criteria in the reaction with significantly improved
yields and product ratio (<10% of undesired 8 in prod-
uct mixture). This improvement in selectivity has evi-
dent synthetic advantages.
A panel of solvents including DMF, toluene, nitroben-
zene, and chlorobenzene were used to test this effect.
The initial reaction involving DMF was heated to 70ꢀC
for 2 h to determine if the choice of solvent would
affect the production of formylated products at tempera-
tures below reflux. At this temperature, the reaction did
not go to completion as starting material 5 (24%) was
isolated from the reaction following column chromatog-
raphy along with undesired 7 as the sole product (Entry
1, Table 2). Increasing the temperature of DMF (Entry
2, Table 2) led to an increased yield of 7; however, no
formation of isomers 6 and 8 was observed. Starting
material 5 (31%) was also isolated from the reaction fol-
lowing chromatography. Encouraging results were seen
when toluene was used as solvent for the formylation
reaction (Entry 3, Table 2), as formation of 7 was not
detected, however, yields of desired 6 were still low.
Use of nitrobenzene as solvent again demonstrated the
lability of the amide bond at higher temperature as none
of the 9-formyl derivative 7 was isolated from the reac-
tion mixture (Entry 4, Table 2). However, the reaction
led to the production of poor yields of compound 6
along with the formation of a blue polymeric side prod-
uct. As a consequence of this, we next looked at chloro-
benzene as another high-boiling point solvent.
Another method of formylation explored was the
Duff reaction, which was shown by Plug et al. to regio-
specifically formylate at position 9 of ellipticine 1 [17].
Using this protocol on 1,4-dimethylcarbazole 5, only
starting material 5 and polyformylated carbazoles were
obtained.
Formylation of 1,4,9-trimethylcarbazole 9. Given
the success of our modified formylation conditions with
6, we trialed a series of reaction conditions on the for-
mylation of 1,4,9-trimethylcarbazole 9 toward the syn-
thesis of 6-methylellipticine 3. Because of the protection
of the indole nitrogen by a methyl group, formylation at
position 9 would not be an issue in this case with the
synthetic challenge to affect selective formylation at C3
rather than C6 Scheme 2 [18]. Given the effect of
increased equivalents of phosphorus oxychloride in the
formylation of 1,4-dimethylcarbazole 5, 2 equiv were
used toward the formylation of 9 as standard conditions.
Initial results were promising as work up of the reaction
after 3.5 h afforded compounds 6–8 with no trace of the
polymeric impurity (Entry 5, Table 2). However, after 3.5
h a substantial amount of undesired N-formyl derivative 7
Table 2
Effect of varying solvents on the formation of 6 and 8 from 1,4-dimethylcarbazole 5.
Reaction conditions
% Yielda
b
Entry
POCl3
DMFb
Solvent
Time
Temperature (ꢀC)
Method
5
6 and 8
7
Ratio of 6 ans 8c
1
2
3
4
5
6
7
8
1 equiv
1.01 equiv
1.01 equiv
1 equiv
–
–
DMF
DMF
2 h
70
153
111
150
131
131
131
131
D
C
C
B
A
C
C
C
24
31
0
23
0
0
0
32
54
0
0
0
6.5 h
6.5 h
6 h
1.01 equiv
1 equiv
1 equiv
1.5 equiv
1.15 equiv
1.01 equiv
C6H5CH3
C6H5NO2
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
26
18
12
52
54
64
1.00:0.12
1.00:0.14
1.00:0.21
1.00:0.09
1.00:0.08
1.00:0.09
0
1 equiv
3.5 h
6.5 h
6.5 h
6.5 h
33
4
1.5 equiv
1.15 equiv
1.01 equiv
0
0
3
0
6
Reaction conditions: See Experimental for conditions A–D. A, heat under reflux for 3.5 h; B, heat under gentle reflux for 6 h; C, heat under
reflux for 3.5 h, extra equivalents of POCl3 and DMF are added and the reaction mixture is heated under reflux for a further 3 h; D, heat to
70ꢀC for 2 h.
a The ‘‘combined yield’’ of 6 and 8 refers to an isolated yield of 3-formyl-1,4-dimethylcarbazole and 6-formyl-1,4-dimethylcarbazole after
chromatography.
b Equivalents of DMF and POCl3 are relative to 1 equiv of starting material 1,4-dimethylcarbazole 5.
c Determined from 1H-NMR spectroscopic analysis from the singlet peaks corresponding to the formyl proton at 10.10–10.50 ppm.
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July 2011
Modifications to the Vilsmeier-Haack Formylation of 1,4-Dimethylcarbazole and Its
Application to the Synthesis of Ellipticines
817
Scheme 2
synthesis of 15 [19]. The formation of these side products
can be rationalized by the activating effect of the
methoxy group on the A ring.
The desired 3-formyl derivative 13 could efficiently
be separated from the 7-formyl and 8-formyl isomers,
14 and 15, by column chromatography and carried
through a modified Cranwell–Saxton route to afford 9-
methoxyellipticine 4 with an overall yield of 13%
´
´
[14,16]. It is worth noting that using the Dracınsky mod-
ification of the Cranwell–Saxton route (in which a ben-
zene sulfonamide 16 replaces a toluene sulfonamide as
the precursor to 4) would lead to a more efficient pro-
duction of 4 (Scheme 3) [14].
Once again, it could be seen that reaction solvents
greatly altered the yield of products formed. Similar to
its unmethylated derivative 5, use of higher boiling
point solvents were seen to lead to improved yields of
products. In this case, however, no reaction occurred
using the lower boiling point solvent trichloroethylene
(Entry 1, Table 3) with the greatest yields obtained
using DMF as solvent (Entry 3, Table 3). Moderate
yields were also obtained using chlorobenzene as sol-
vent. Disappointingly, the regioselectivity was lower for
the N-methyl carbazole derivative 10 than with the
NAH carbazole 6 with 20–30% of the undesired 6-
formyl regioisomer present in this instance.
Synthesis of ellipticine 1. On implementation of our
modified Vilsmeier-Haack conditions into ellipticine 1
synthesis, the overall yield from indole improved from
3% to 14% (Scheme 4). It was observed that the highest
overall yields were obtained when the isomeric mixture
of 3-formyl and 6-formyl carbazoles was carried through
the synthesis following the published routes until forma-
tion of the N-tosyl derivative, where purification by
recrystallization was seen to yield the 3-isomer as the
sole product.
Formylation of 6-methoxy-1,4-dimethylcarbazole
12. Because of high yields obtained for 3-formyl-1,4-
dimethylcarbazole 6 from use of chlorobenzene as solvent
and modified reaction conditions (Entry 8, Table 2), it
was decided that this protocol should be implemented to
the formylation of 6-methoxy-1,4-dimethylcarbazole 12, a
key precursor for 9-methoxyellipticine 4 and 9-hydroxyel-
lipticine. As reaction at C-6 was blocked in this case, the
Vilsmeier Haack reaction of 12 was previously shown to
formylate at position 3 with yields of 60% [15]. Interest-
ingly, conducting the Vilsmeier-Haack reaction in chloro-
benzene with the more activated carbazole 12 leads to
lower yields of the desired 3-formylcarbazole 13 (22%)
than seen with the less activated carbazoles. However,
formation of the 7- and 8-formyl derivatives, 14 and 15,
offer potentially useful synthetic intermediates for further
investigation (Scheme 3), in particular the new one-step
The 3-formyl derivatives, 6 and 8, were treated with
aminoacetaldehyde diethyl acetal in solvent free condi-
tions to afford the desired imine 17 and 18 in quantitative
yields. Platinium(IV) oxide-catalyed hydrogenation of 17
and 18 in ethanol furnished the corresponding amines 19
and 20 (98%) (3-isomer:6-isomer, 1.00:0.07). The 6-iso-
mer of the imine and the amine, 18 and 20, have not been
reported previously. Treatment of 19 and 20 with tosyl
chloride in pyridine afforded the N-tosyl derivative 21,
which was recyrstallized with dichloromethane and hex-
ane to afford 21 as the sole product (68%). Finally, cycli-
zation to ellipticine 1 was achieved by treatment of the
pure N-tosyl derivative 21 with concentrated hydrochloric
acid in dioxane (58%). Starting from indole, the overall
yield of 1 was calculated to be 14%.
Table 3
The effect of varying solvents on the formation of 10 and 11.
Reaction conditions
% Yield
DMFa
Time
Temperature (ꢀC)
Solvent
Method
10 and 11b
Ratio of 10 and 11c
a
Entry
POCl3
1
2
3
5
2 equiv
2 equiv
2 equiv
2 equiv
1 equiv
6 h
2 h
6 h
6 h
87.5
153
153
131
TCE
DMF
DMF
B
D
B
B
0
35
68
53
–
–
–
1.00:0.23
1.00:0.20
1.00:0.36
1 equiv
C6H5Cl
Reaction conditions: See Experimental. B, heat under reflux for 6 h; D, heat to 70ꢀC for 2 h.
a Equivalents of DMF and POCl3 are relative to 1 equiv of starting material 1,4,9-trimethylcarbazole 9.
b The ‘‘combined yield’’ of 10 and 11 refers to an isolated yield of 3-formyl-1,4,9-trimethylcarbazole and 6-formyl-1,4,9-trimethylcarbazole after
column chromatography.
c Determined from NMR analysis from the singlet peaks corresponding to the formyl proton at 10.10–10.50 ppm.
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F. M. Deane, C. M. Miller, A. R. Maguire, and F. O. McCarthy
Vol 48
Scheme 3
formylation of 6-methoxy-1,4-dimethylcarbazole 12 fol-
lowing newly our newly developed chlorobenzene pro-
tocol led to new formylated intermediates 14 and 15,
which have clear synthetic potential while use of the
Dalton method proved most effective for the synthesis
of the 3-formyl derivative 13 [12]. Overall, it is clear
that as formylations of the carbazole nucleus are com-
plex, selective formylation to the desired C3 formyl de-
rivative can be achieved by careful optimization of
reaction conditions.
Synthesis of 6-methylellipticine 3. Similar to the
synthesis of ellipticine 1, the isomeric mixture of 3-
formyl- and 6-formyl-1,4,9-trimethylcarbazole, 10 and
11, was carried through a modified Cranwell–Saxton
route where purification by recrystallization was
achieved at the N-tosyl derivative 26 (Scheme 4).
Regarding the synthesis of amines, 24 and 25, and the
N-tosyl amide 26, reaction conditions differed from
those described for ellipticine 1.
Through use of sodium borohydride in methanol,
reduction of imines 22 and 23 to the corresponding
amines 24 and 25 was found to be more efficient and
higher yielding than the hydrogenation reaction described
for 22 and 23. Dalton reported the formation of 23,
whereas compound 25 or 26 has not been reported previ-
ously [12]. The tosylation reaction was found to proceed
with greater efficiency through use of potassium carbon-
ate, tosyl chloride in a solvent mixture of THF and water,
although the yield was slightly lower than that observed
for the formation of 21. Cyclization to 6-methylellipticine
3 was achieved in similar conditions to those quoted for
ellipticine 1 with good yields (55%). The overall yield of
6-methylellipticine 3, starting from 1,4-dimethylcarbazole
5, was calculated to be 15%.
EXPERIMENTAL
General procedures. Melting points were measured on a
Uni-Melt Thomas Hoover Capillary Melting Point apparatus
and are uncorrected. Low-resolution mass spectra were
recorded on a Waters Micromass Quattro Micro mass spec-
trometer (Instrument number QAA1202) in electrospray ioni-
zation (ESI) positive and negative modes and a Waters Micro-
mass LCT Premier (Instrument number KD160) was used for
high-resolution acquisitions. Infrared (IR) spectra were
recorded as potassium bromide (KBr) disks on a Perkin-Elmer
FT-IR Paragon 1000 or a Spectrum One FT-IR spectrophotom-
eter. 1H (300 MHz) and 13C-NMR (75 MHz) NMR were
recorded on a Bruker Avance 300 NMR spectrometer. All
spectra were recorded at 20ꢀC in deuterated chloroform
(CDCl3) with tetramethylsilane (TMS) as an internal standard
unless otherwise stated. Chemical shifts (dH and dC) are
reported in parts per million (ppm), relative to TMS and cou-
pling constants are expressed in Hertz (Hz). Splitting patterns
in 1H-NMR spectra are designated as s (singlet), br s (broad
singlet), d (doublet), dd (doublet of doublets), ddd (doublet of
doublet of doublets), dt (doublet of triplets), t (triplet), q (quar-
tet), and m (multiplet). Thin-layer chromatography (TLC) was
carried out on precoated silica gel plates (Merck 60 PF254).
Visualization was achieved by UV light (254 nm), vanillin or
potassium permanganate staining. Column chromatography
was carried out using Kieselgel 60, 0.040–0.063 nm (Merck).
Synthesis of ellipticine 1. 1,4-Dimethylcarbazole 5. Indole
(30.002 g, 0.256 mol), hexane-2,5-dione (66 mL, 0.530 mol)
CONCLUSIONS
We have successfully devised a route to the key in-
termediate 3-formyl-1,4-dimethylcarbazole 6 with a sig-
nificant improvement in yields compared with previ-
ously published procedures through use of chloroben-
zene as solvent. Applying this method to the modified
Cranwell–Saxton route, the overall yield of ellipticine 1
(from starting material indole) increased from 3% to
14%. In contrast, treatment of 1,4,9-trimethylcarbazole
9 under the same conditions did not lead to an
improvement relative to reaction in DMF. Interestingly,
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Modifications to the Vilsmeier-Haack Formylation of 1,4-Dimethylcarbazole and Its
Application to the Synthesis of Ellipticines
819
Scheme 4. Reagents and conditions: (i) hexane-2,5-dione, p-TsOH, EtOH, reflux for 2 h, 5 ¼ 57%; (ii) NaH, MeI DMF, r.t. overnight, 9 ¼ 94%;
(iii) POCl3, DMF, chlorobenzene, reflux for 6.5 h, 6 and 8 ¼ 64%; (iv) POCl3, DMF, reflux for 6 h, 10 and 11 ¼ 68% (v) aminoacetaldehyde
diethylacetal, 110ꢀC for 2 h, 17 and 18 ¼ 100%, 22 and 23 ¼ 95%; (vi) PtO2, H2, EtOH, r.t. at 50 psi for 3 d, 19 and 20 ¼ 98%, or NaBH4,
MeOH, r.t. for 2 h, 24 and 25 ¼ 92%; (vii) p-TsCl, pyridine, r.t. for 3 d, 21 ¼ 68% or p-TsCl, K2CO3, THF, H2O (1:2), r.t. for 1.5 h, 26 ¼ 55%;
and (viii) HCl, dioxane, reflux for 6 h, 1 ¼ 58%, 3 ¼ 55%.*Attempts to isolate 7-formyl-6-methoxy-1,4-dimethylcarbazole 14 from the mixture
were unsuccessful.
and a catalytic amount of p-toluenesulfonic acid were dissolved
in ethanol (300 mL) and heated under reflux for 2 h. After this
time, the reaction mixture was cooled to room temperature,
evaporated under reduced pressure, and the resulting purple
solid was purified by flash chromatography eluting with hexane-
ethyl acetate (9:1) to afford an off-white solid. Subsequent
recrystallization from ethyl acetate and hexane produced 1,4-
dimethylcarbazole 5 (28.425 g, 57%) as white crystals: m.p.
94–95ꢀC (ref. 12, 92–93ꢀC); mmax (cmꢁ1) (KBr) 3417, 2919,
1455, 728; dH (300 MHz) 2.52 [3H, s, C(1)CH3], 2.85 [3H, s,
C(4)CH3], 6.93 [1H, d, J ¼ 7.3, C(3)H], 7.12 [1H, d, J ¼ 7.3,
C(2)H], 7.24 [1H, overlapping ddd, J ¼ 8.0, 6.8, 1.2, C(6)H],
7.40 [1H, overlapping ddd, J ¼ 8.0, 6.9, 0.9, C(7)H], 7.46 [1H,
d, J ¼ 7.8, C(8)H], 7.97 (1H, br s, NH), 8.17 [1H, d, J ¼ 7.9,
C(5)H]; m/z (ESþ) 196 [M þ H]þ (20%), 119 (7), 84 (5).
Formylation of 1,4-dimethylcarbazole 5.
sure to afford a brown solid, which was diluted with ethyl ace-
tate (50 mL), washed with water (4 ꢂ 20 mL), brine (10 mL),
dried, and evaporated under reduced pressure. The resulting
brown solid was purified by column chromatography (hexane-
ethyl acetate, 100:0 to 90:10).
Method B. Method B is initially the same as method A. Af-
ter dropwise addition of POCl3, the reaction was heated under
reflux for 6 h. Workup of the reaction mixture proceeded via
the same reaction conditions as method A.
Method C. Method C is initially the same as method A. Af-
ter dropwise addition of POCl3, the reaction was heated under
vigorous reflux for 3.5 h. After this time, further equivalents
of POCl3 and DMF (see Tables 1–3) were added and the reac-
tion mixture was heated under reflux for a further 3 h. Workup
of the reaction mixture proceeded via the same reaction condi-
tions as method A.
Method A. POCl3 was added, dropwise, to an ice-cold solu-
tion of 1,4-dimethylcarbazole 5 (3.515 g, 0.018 mol) and DMF
(1.4 mL, 0.018 mol) in solvent (50 mL) (see Tables 1–3) over
the course of 10 min. The reaction mixture was heated under
reflux for 3.5 h, cooled, poured into a solution of sodium ace-
tate (20 mL, 25% w/w), and evaporated under reduced pres-
Method D. Method D is initially the same as method A. Af-
ter dropwise addition of POCl3, the reaction was heated to
70ꢀC for 2 h after which time workup of the reaction mixture
proceeded via the same reaction conditions as method A.
9-Formyl-1,4-dimethylcarbazole 7. M.p. 145-146ꢀC; mmax
(cmꢁ1) (KBr) 3017, 2918, 1679, 1589; dH (300 MHz) 2.64 [3H, s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

820
F. M. Deane, C. M. Miller, A. R. Maguire, and F. O. McCarthy
Vol 48
C(1)CH3], 2.73 [3H, s, C(4)CH3], 7.02 [1H, d, J ¼ 7.6, C(3)H],
7.11 [1H, d, J ¼ 7.6, C(2)H], 7.36 [1H, overlapping ddd, J ¼ 7.7,
7.5, 1.3, C(6)H], 7.44 [1H, overlapping ddd, J ¼ 8.0, 7.4, 1.5,
C(7)H], 8.02 [1H, d, J ¼ 8.1, C(8)H], 8.64 [1H, d, J ¼ 7.8,
C(5)H], 9.90 (1H, s, NACHO); dC (75 MHz) 20.6 [CH3,
C(1)CH3], 22.5 [CH3, C(4)CH3], 110.4 (C, aromatic C), 117.3
(CH, aromatic CH), 119.5 (C, aromatic C), 122.1 (CH, aromatic
CH), 124.5 (CH, aromatic CH), 125.9 (CH, aromatic CH), 126.9
(CH, aromatic CH), 127.2 (C, aromatic C), 130.4 (CH, aromatic
CH), 131.5 (C, aromatic C), 136.5 (C, aromatic C), 137.7 (C, aro-
matic C), 160.2 (C, C¼¼O); m/z (ESþ) 224 [M þ H]þ (6%), 151
(2), 101 (100). HRMS Found: [M þ H]þ, 224.1077. Calc. for
C15H14NO: [M þ H]þ, 224.1075; Found C, 80.51; H, 5.90; N,
6.42. C15H13NO requires C, 80.69; H, 5.87; N, 6.27.
ArCHN of 17), 9.18 (1H, br s, NH of 17), 9.23 (0.08H, br s, NH
of 18); m/z (ESþ) 339 [M þ H]þ (100%), 250 (4), 175 (4).
3-(2,2-Diethoxyethylaminomethyl)-1,4-dimethylcarbazole 19
and 6-(2,2-diethoxyethylaminomethyl)-1,4-dimethylcarbazole
20. A mixture of 3- and 6-(2,2-diethoxyethyliminomethyl)-1,4-
dimethylcarbazole, 17 and 18 (1.00:0.08) (14.215 g, 0.042 mol)
was dissolved in absolute ethanol (50 mL) and transferred to a
hydrogenation vessel. Platinum oxide (0.142 g, 0.63 mmol) was
added, and the reaction mixture was shaken under an atmos-
phere of hydrogen at 50 psi for 3 days after which time the solu-
tion was filtered over celite and concentrated under reduced
pressure to produce a mixture of 3- and 6-(2,2-diethoxyethyla-
minomethyl)-1,4-dimethylcarbazole, 19 and 20, (1.00:0.07) as
green/brown oil (14.071 g, 98%), which was used without fur-
ther purification: mmax (cmꢁ1) (film) 3525, 3316, 3153, 2975,
2921, 1598, 1457, 1116, 1053, 753; dH (300 MHz) (for the
minor isomer, 6-(2,2–diethoxyethylaminomethyl)-1,4-dimethyl-
carbazole 20 one proton equates to 0.07H) 1.17–1.24 (6.42H, m,
2ꢂ OCH2CH3 of 19, 2ꢂ OCH2CH3 of 20) 1.94 (1.07H, br s,
ArCH2NH of 19, ArCH2NH of 20), 2.45 [3H, s, C(1)CH3 of 19],
2.50 [0.21H, s, C(1)CH3 of 20], 2.84 [3H, s, C(4)CH3 of 19],
2.86 [0.21H, s, C(4)CH3 of 20], 3.47–3.73 (6.42H, m, 2ꢂ
OCH2CH3 of 19, 2ꢂ OCH2CH3 of 20, NHCH2CH of 19,
NHCH2CH of 20), 3.96 (2H, s, ArCH2NH of 19), 3.98 (0.14H,
s, ArCH2NH of 20), 4.41 [0.07H, t, J ¼ 5.1, CH(OEt)2 of 20],
4.66 [1H, t, J ¼ 5.6, CH(OEt)2 of 19], 6.91 [0.07H, d, J ¼ 7.5,
C(3)H of 20], 7.10 [0.07H, d, J ¼ 7.5, C(2)H of 20], 7.14 [1H, s,
C(2)H of 19], 7.19–7.25 {1.07H, m, including 7.22 [1H, ddd, J
¼ 8.1, 7.0, 1.3, C(6)H of 19], C(7)H of 20}, 7.35–7.41 {1.07H,
m, including 7.38 [1H, overlapping ddd, J ¼ 8.1, 7.0, 1.1, C(7)H
of 19], C(8)H of 20}, 7.44 [1H, d, J ¼ 7.6, C(8)H of 19], 8.07
[0.07H, br s, C(5)H of 20], 8.21 [1H, d, J ¼ 7.9, C(5)H of 19],
8.36 (1.07H, s, NH of 19, NH of 20); m/z (ESþ) 341 [M þ H]þ
(100%), 244 (12), 208 (8).
3- and 6-Formyl-1,4-dimethylcarbazole,
6 and 8. mmax
(cmꢁ1) (KBr) 3238, 2920, 2850, 1646, 1585, 734; dH (300
MHz) (for the minor isomer 6-formyl-1,4-dimethylcarbazole 8
one proton equates to 0.08H) 2.57 [0.24H, s, C(1)CH3 of 8],
2.58 [3H, s, C(1)CH3 of 6], 2.9 [0.24H, s, C(4)CH3 of 8], 3.2
[3H, s, C(4)CH3 of 6], 7.03 [0.08H, d, J ¼ 7.4, C(3)H of 8],
7.21 [0.08H, d, J ¼ 7.6, C(2)H of 8], 7.33 [1H, ddd, J ¼ 8.1,
7.0, 1.4, C(6)H of 6], 7.48 [1H, overlapping ddd, J ¼ 8.1, 7.0,
1.1, C(7)H of 6], 7.54 [1.08H, d, J ¼ 7.9, C(8)H of 6, C(8)H
of 8], 7.77 [1H, s, C(2)H of 6], 7.98 [0.08H, dd, J ¼ 8.4, 1.5,
C(7)H of 8], 8.28 [1H, d, J ¼ 8.0, C(5)H of 6], 8.36 (1H, br s,
NH of 6), 8.41 (0.8H, br s, NH of 8), 8.66 [0.08H, br s, C(5)H
of 8], 10.11 (0.08H, s, CHO of 8), 10.46 (1H, s, CHO of 6);
m/z (ESþ) 224 [M þ H]þ (34%), 146 (2), 118 (6).
Typical procedure for hydrolysis of 9-formyl-1,4-dimethyl-
carbazole 7. A solution of 7 (4.870 g, 21.8 mmol) in dichloro-
methane (250 mL) was stirred with silica (25 g) and 1M sulphu-
ric acid (2 drops) for 5 days. The reaction mixture was filtered,
dried (magnesium sulfate), and evaporated under reduced pres-
sure to afford 1,4-dimethylcarbazole 5 (4.254 g, 100%) as a
white solid with identical characteristics to those above.
N-tosyl-3-(2,2-diethoxyethylaminomethyl)-1,4-dimethyl-carba-
zole 21. To a solution of 3- and 6-(2,2-diethoxyethylamino-
methyl)-1,4-dimethylcarbazole, 19 and 20, (1:0.07) (14.071 g,
0.041 mol) in pyridine (200 mL) was added p-toluenesulfonyl
chloride (11.820 g, 0.062 mol) and the reaction mixture was
stirred at room temperature for 3 days. After this time, the reac-
tion mixture was poured into water (200 mL) and extracted with
ether (3 ꢂ 100 mL). The organic layer was subsequently washed
with hydrochloric acid (1M, 3 ꢂ 100 mL), brine (100 mL), water
(100 mL), dried, and evaporated under reduced pressure to yield
a brown solid, which was purified by recrystallization (dichloro-
methane-hexane) to afford the single isomer of N-tosyl-3-(2,2-
diethoxyethylaminomethyl)-1,4-dimethyl-carbazole 21 as an
off-white solid (13.771 g, 68%): m.p. 177–179ꢀC (ref. 18,
183.5–185ꢀC); mmax (cmꢁ1) (KBr) 3370, 2975, 2914, 2869,
1596, 1455, 1349, 1172, 1167, 1113, 736; dH (300 MHz) 1.07
(6H, t, J ¼ 7.0, 2ꢂ OCH2CH3), 2.39 [3H, s, C(1)CH3], 2.42
[3H, s, C(40)CH3], 2.81 [3H, s, C(4)CH3], 3.19 (2H, d, J ¼ 5.5,
NCH2CH), 3.25–3.57 (4H, m, 2ꢂ OCH2CH3), 4.13 [1H, t, J ¼
5.4, CH(OEt)2], 4.66 (2H, s, ArCH2N), 6.96 [1H, s, C(2)H],
7.21–7.28 [3H, m, C(30)H, C(50)H, C(6)H], 7.41 [1H, overlap-
ping ddd, J ¼ 8.1, 7.0, 1.0, C(7)H], 7.47 [1H, d, J ¼ 7.6,
C(8)H], 7.73 [2H, d, J ¼ 8.3, C(20)H, C(60)H], 7.99 (1H, br s,
NH), 8.20 [1H, d, J ¼ 7.8, C(5)H]; m/z (ESþ) 403 [M þ H—
C6H4CH3]þ (34%), 341 [M—SO2C6H4CH3]þ (20).
3-(2,2-Diethoxyethyliminomethyl)-1,4-dimethylcarbazole 17
and 6-(2,2-diethoxyethyliminomethyl)-1,4-dimethylcarbazole
18. A mixture of 3- and 6-formyl-1,4-dimethylcarbazole, 6 and
8, (1.00:0.08) (20.013 g, 0.089 mol) and amino-acetaldehyde
diethyl acetal (12.9 mL, 0.089 mol) was heated at 110ꢀC as stir-
ring for 4 h. After this time, the reaction mixture was allowed to
cool, diluted with toluene (50 mL), and evaporated under
reduced pressure to produce a mixture of 3- and 6-(2,2-diethox-
yethyliminomethyl)-1,4-dimethylcarbazole,
17
and
18,
(1.00:0.08) as a yellow/orange oil, which was used without fur-
ther purification (30.325 g, 100%): mmax (cmꢁ1) (film) 3159,
2974, 2890, 1636, 1588, 1500, 1116, 1066, 746; dH (300 MHz)
(for the minor isomer, 6-(2,2-diethoxyethyliminomethyl)-1,4-
dimethylcarbazole 18 one proton equates to 0.08H) 1.18–1.27
(6.48H, m, 2ꢂ OCH2CH3 of 17, 2ꢂ OCH2CH3 of 18), 2.43 [3H,
s, C(1)CH3 of 17], 2.48 [0.24H, s, C(1)CH3 of 18], 2.80 [3H, s,
C(4)CH3 of 17], 2.82 [0.24H, s, C(4)CH3 of 18], 3.46–3.81
[4.32H, m, 2ꢂ OCH2CH3 of 17, 2ꢂ OCH2CH3 of 18], 3.85
[2.16H, d, J ¼ 4.8, NCH2CH of 17, NCH2CH of 18], 4.89
[1.08H, t, J ¼ 5.4, CH(OEt)2 of 17, CH(OEt)2 of 18], 6.88
[0.08H, d, J ¼ 7.7, C(3)H of 18], 7.08 [0.08H, d, J ¼ 7.7, C(2)H
of 18], 7.22 [1H, ddd, J ¼ 8.1, 7.2, 1.1, C(6)H of 17], 7.33–7.42
{1.08H, m, including 7.37 [1H, ddd, J ¼ 8.1, 7.1, 1.0, C(7)H of
17], C(8)H of 18}, 7.47 [1H, d, J ¼ 7.9, C(8)H of 17], 7.79–7.85
{1.08H, m, including 7.81 [1H, s, C(2)H of 17], C(7)H of 18},
8.14 [1H, d, J ¼ 7.9, C(5)H of 17], 8.36 [0.08H, d, J ¼ 1.1,
C(5)H of 18], 8.41 (0.08H, s, ArCHN of 18), 8.74 (1H, s,
Ellipticine (5,11-dimethyl-6H-pyrido[4,3-b]carbazole) 1. To
stirring solution of N-tosyl-3-(2,2-diethoxyethylamino-
a
methyl)-1,4-dimethylcarbazole 21 (13.778 g, 0.028 mol) in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Modifications to the Vilsmeier-Haack Formylation of 1,4-Dimethylcarbazole and Its
Application to the Synthesis of Ellipticines
821
1,4-dioxane (150 mL), hydrochloric acid (6M, 30 mL) was
added and the reaction mixture was heated under reflux for 6
h. After this time, the solution was cooled, poured into water
(200 mL), made alkaline with potassium carbonate solution
(10% v/v), and extracted with chloroform (3 ꢂ 100 mL). The
organic layer was washed with brine (100 mL), water (100
mL), dried, and evaporated under reduced pressure to produce
a green solid, which was further purified by chromatography
(dichloromethane–methanol, 100:0 to 80:20) to afford ellipti-
cine 2 as an orange solid (3.983 g, 58%): m.p. 315–316ꢀC
(ref. 12, 315–317ꢀC): mmax (cmꢁ1) (KBr) 3369, 3138, 2860,
1617, 1589, 1413, 737; dH (300 MHz, d6-DMSO) 2.72 [3H, s,
C(5)CH3], 3.19 [3H, s, C(11)CH3], 7.18 [1H, ddd, J ¼ 8.0,
6.7, 1.5, C(9)H], 7.45 [1H, overlapping ddd, J ¼ 8.1, 6.7, 1.0,
C(8)H], 7.49 [1H, dd, J ¼ 8.1, 1.0, C(7)H], 7.86 [1H, d, J ¼
6.1, C(4)H], 8.31 [1H, d, J ¼ 7.9, C(10)H], 8.35 [1H, d, J ¼
6.1, C(3)H], 9.62 [1H, s, C(1)H], 11.33 (1H, s, NH); m/z
(ESþ) 247 [M þ H]þ (84%), 169 (100), 148 (12).
2.87 [3H, s, C(1)CH3 of 10], 2.88 [0.6H, s, C(4)CH3 of 11],
3.17 [3H, s, C(4)CH3 of 10], 4.14 [3H, s, N(9)CH3 of 10],
4.16 [0.6H, s, N(9)CH3 of 11], 6.98 [0.2H, d, J ¼ 7.4, C(3)H
of 11], 7.15 [0.2H, d, J ¼ 7.4, C(2)H of 11], 7.32 [1H, ddd, J
¼ 8.1, 7.1, 1.1, C(6)H of 10], 7.45 [1.2H, d, J ¼ 8.1, C(8)H of
10, C(8)H of 11] 7.54 [1H, ddd, J ¼ 8.2, 7.1, 1.1, C(7)H of
10], 7.69 [1H, s, C(2)H of 10], 8.00 [0.2H, dd, J ¼ 8.6, 1.5,
C(7)H of 11], 8.28 [1H, d, J ¼ 8.0, C(5)H of 10], 8.63 [0.2H,
d, J ¼ 1.4, C(5)H of 11], 10.09 (0.2H, s, CHO of 11), 10.43
(1H, s, CHO of 10); m/z (ESþ) 238 [M þ H]þ (88%), 142
(4), 119 (10).
3-(2,2-Diethoxyethyliminomethyl)-1,4,9-trimethylcarbazole 22
and 6-(2,2-diethoxyethyliminomethyl)-1,4,9-trimethyl-carbazole
23. Using the same procedure as described for the synthesis of
17 and 18, and starting from 10 and 11 (8.830 g, 0.037 mol),
3- and 6-(2,2-diethoxyethyliminomethyl)-1,4,9-trimethylcarba-
zole, 22 and 23 (1.00:0.20) was afforded as an orange solid,
which was used without further purification (12.457 g, 95%):
mmax (cmꢁ1) (KBr) 2976, 2914, 2870, 1665, 1596, 1455, 1168,
1090, 737; dH (300 MHz) (for the minor isomer, 6-(2,2-dieth-
oxyethyliminomethyl)-1,4-dimethylcarbazole 23 one proton
equates to 0.20H) 1.21 (7.2H, t, J ¼ 7.0, 2ꢂ OCH2CH3 of 22,
2ꢂ OCH2CH3 of 23), 2.82 [0.6H, s, C(1)CH3 of 23], 2.83
[3H, s, C(1)CH3 of 22], 2.86 [0.6H, s, C(4)CH3 of 23], 2.97
[3H, s, C(4)CH3 of 22], 3.57–3.82 (4.8H, m, 2ꢂ OCH2CH3 of
22, 2ꢂ OCH2CH3 of 23), 3.83–3.86 (2.4H, m, NCH2CH of 22,
NCH2CH of 23), 4.09 [3H, s, N(9)CH3 of 22], 4.10 [0.6H, s,
N(9)CH3 of 23], 4.85 [1.2H, t, J ¼ 5.4, CH(OEt)2 of 22,
CH(OEt)2 of 23], 6.91 [0.2H, d, J ¼ 7.4, C(3)H of 23], 7.08
[0.2H, d, J ¼ 7.4, C(2)H of 23], 7.26 [1H, ddd, J ¼ 8.0, 7.0,
1.2, C(6)H of 22], 7.38 [0.2H, d, J ¼ 8.6, C(8)H of 23], 7.40
[1H, d, J ¼ 8.0, C(8)H of 22], 7.48 [1H, ddd, J ¼ 8.1, 7.1,
1.1, C(7)H of 22], 7.82 [1H, s, C(2)H of 22], 7.95 [0.2H, dd, J
¼ 8.6, 1.5, C(7)H of 23], 8.24 [1H, d, J ¼ 7.9, C(5)H of 22],
8.43 [0.2H, d, J ¼ 1.3, C(5)H of 23], 8.45 (0.2H, s, ArCHN of
23), 8.83 (1H, s, ArCHN of 22); m/z (ESþ) 353 [M þ H]þ
(100%), 247 (2), 175 (4).
3-(2,2-Diethoxyethylaminomethyl)-1,4,9-trimethylcarbazole 24
and 6-(2,2-diethoxyethylaminomethyl)-1,4,9-trimethy-lcarbazole
25. To a stirring mixture of 3- and 6-(2,2-diethoxyimino-
methyl)-1,4,9-trimethylcarbazole, 22 and 23, (1.00:0.20)
(12.457 g, 0.035 mol) in methanol (300 mL) at 0ꢀC was added
sodium borohydride (13.392 g, 0.354 mol) in portions over a
period of 30 min. Once addition was complete, the mixture
was stirred at room temperature for a further 2 h. After this
time, the reaction mixture was evaporated under reduced pres-
sure to afford a white residue, which was acidified to pH 1
using hydrochloric acid (1M), basified using sodium hydroxide
(30%), and extracted with toluene (3 ꢂ 100 mL). The organic
layer was washed with brine (2ꢂ 50 mL), dried, and evapo-
rated under reduced pressure to afford a mixture of 6- and 3-
(2,2-diethoxyethylaminomethyl)-1,4,9-trimethylcarbazole, 24
and 25, (1.00:0.18) as brown oil, which was used without fur-
ther purification (11.529 g, 92%): mmax (cmꢁ1) (film) 3334,
2973, 2926, 1467, 1129, 1061, 748; dH (300 MHz) (for the
minor isomer, 6-(2,2-diethoxyethylaminomethyl)-1,4-dimethyl-
carbazole 25 one proton equates to 0.18H) 1.20 (7.08H, t, J ¼
7.0, 2ꢂ OCH2CH3 of 24, 2ꢂ OCH2CH3 of 25), 1.52 (1.18H,
br s, NH of 24, NH of 25), 2.81 [0.54H, s, C(1)CH3 of 25],
2.82 [3H, s, C(1)CH3 of 24], 2.84 [3.54H, s, C(4)CH3 of 25,
C(4)CH3 of 24], 3.45–3.73 (7.08H, m, 2ꢂ OCH2CH3 of 24,
Synthesis of 6-methylellipticine 3. 1,4,9-Trimethylcarba-
zole 9. 1,4-Dimethylcarbazole 5 (35.555 g, 0.182 mol) was
dissolved in anhydrous DMF (150 mL) and stirred at 0ꢀC
under nitrogen for 10 min. Sodium hydride (60% dispersion in
mineral oil, 8.750 g, 0.365 mol) was added portion wise to the
reaction mixture over a period of 5 min and the mixture was
stirred for a further 10 min. Methyl iodide (23 mL, 0.365 mol)
was added in one portion, and the reaction mixture was
allowed to warm to room temperature and stirred overnight.
Water (100 mL) was added resulting in the formation of a
white precipitate and the whole mixture was extracted with
ethyl acetate (3 ꢂ 50 mL). The combined organic layers were
washed with water (2ꢂ 50 mL), brine (2ꢂ 50 mL), dried, and
concentrated under reduced pressure to afford 1,4,9-trimethyl-
carbazole 9 as an off-white solid (35.756 g, 94%): m.p. 128–
129ꢀC (ref. 12, 131–132ꢀC); mmax (cmꢁ1) (KBr) 3038, 3010,
2922, 1469, 744; dH (300 MHz) 2.84 [6H, s, C(1)CH3,
C(4)CH3], 4.11 [3H, s, N(9)CH3], 6.88 [1H, d, J ¼ 7.3,
C(3)H], 7.07 [1H, d, J ¼ 7.2, C(2)H], 7.23 [1H, ddd, J ¼ 8.0,
7.0, 1.1, C(6)H], 7.39 [1H, d, J ¼ 8.0, C(8)H], 7.47 [1H, ddd,
J ¼ 8.1, 7.0, 1.1, C(7)H], 8.18 [1H, d, J ¼ 7.9, C(5)H]; m/z
(ESþ) 210 [M þ H]þ (24%), 147 (10), 115 (100).
3-Formyl-1,4,9-trimethylcarbazole 10 and 6-formyl-1,4,9-
trimethylcarbazole 11. Starting materials used were 1,4,9-tri-
methylcarbazole 9 (11.510 g, 0.055 mol), POCl3 (10.1 mL,
0.0110 mol) and DMF (200 mL).The reaction was initiated
using the same procedure as described for the formylation of
1,4-dimethylcarbazole 5. Workup for this reaction differed
from that of 3-formyl-1,4-dimethylcarbazole 6. After the initial
reaction (via conditions B or D, see Table 3), the reaction mix-
ture was cooled to room temperature and poured into water.
Using potassium carbonate solution (10% w/v), the reaction
mixture was basified and then extracted with chloroform. The
organic layer was washed successively with saturated aqueous
sodium bicarbonate, brine, dried over magnesium sulfate, and
evaporated under reduced pressure to afford a brown oil. This
was purified using column chromatography eluting with hex-
ane-ethyl acetate (100:0 to 80:20) to give a single band con-
sisting of a mixture (which could not be separated) of 3-
formyl- and 6-formyl-1,4,9-trimethylcarbazole, 10 and 11,
(1.00:0.20) (8.830 g, 68%) as an off-white solid: mmax (cmꢁ1
)
(KBr) 2926, 2694, 1678, 1588, 1560, 744, 727; dH (300 MHz)
(for the minor isomer, 6-formyl-1,4,9-trimethylcarbazole 11
one proton equates to 0.2H) 2.85 [0.6H, s, C(1)CH3 of 11],
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

822
F. M. Deane, C. M. Miller, A. R. Maguire, and F. O. McCarthy
Vol 48
2ꢂ OCH2CH3 of 25, NCH2CH of 24, NCH2CH of 25), 3.94
(2H, s, ArCH2NH of 24), 3.99 (0.36H, s, ArCH2NH of 25),
4.08 [3H, s, N(9)CH3 of 24], 4.09 [0.54H, s, N(9)CH3 of 25],
4.65 [1H, t, J ¼ 5.6, CH(OEt)2 of 24], 4.67 [0.18H, t, J ¼ 5.5,
CH(OEt)2 of 25], 6.86 [0.18H, d, J ¼ 7.3, C(3)H of 25], 7.05
[0.18H, d, J ¼ 7.3, C(2)H of 25], 7.12 [1H, s, C(2)H of 24],
7.16–7.26 {1.18H, m, including 7.21 [1H, ddd, J ¼ 8.0, 6.9,
1.1, C(6)H of 24], C(8)H of 25}, 7.37 [1H, d, J ¼ 8.1, C(8)H
of 24], 7.40–7.49 {1.18H, m, including 7.45 [1H, ddd, J ¼
8.1, 7.1, 1.0, C(7)H of 24], C(7)H of 25}, 8.09 [0.18H, br s,
C(5)H of 25], 8.24 [1H, d, J ¼ 7.9, C(5)H of 24]; m/z (ESþ)
355 [M þ H]þ (100%), 251 (16), 222 (45).
[1H, ddd, J ¼ 8.3, 7.3, 1.1, C(8)H], 7.90 [1H, d, J ¼ 6.2,
C(4)H], 8.36 [1H, d, J ¼ 7.9, C(10)H], 8.50 [1H, d, J ¼ 6.2,
C(3)H], 9.70 [1H, s, C(1)H]; m/z (ESþ) 261 [M þ H]þ
(100%), 115 (40), 74 (18).
Formylation of 6-methoxy-1,4-dimethylcarbazole 12. Under
general conditions method C above, a solution of 6-methoxy-
1,4-dimethylcarbazole 12 (7.292 g, 0.0324 mol), DMF and
phosphorous oxychloride in chlorobenzene (200 mL) was
reacted. After workup, this resulted in a brown solid, which
was purified by column chromatography eluting with hexane-
ethyl acetate (100:0 to 80:20) to afford three bands; a yellow
solid consisting of 8-formyl-6-methoxy-1,4-dimethylcarbazole
15 (0.487 g, 6%), a yellow solid consisting of a mixture of 7-
formyl-6-methoxy-1,4-dimethylcarbazole 14 and 8-formyl-6-
methoxy-1,4-dimethylcarbazole 15 (0.023 g)* (0.7:1), and a
cream solid containing 3-formyl-6-methoxy-1,4-dimethylcarba-
zole 13 (2.62 g, 22%).
3-Formyl-6-methoxy-1,4-dimethylcarbazole 13. M.p. 206-
207ꢀC (ref. 12, 206ꢀC); mmax (cmꢁ1) (KBr) 3305, 2832, 1656,
1579, 1222; dH (300 MHz) 2.55 [3H, s, C(1)CH3], 3.17 [3H, s,
C(4)CH3], 3.95 (3H, s, OCH3), 7.12 [1H, dd, J ¼ 8.8, 2.4,
C(7)H], 7.43 [1H, d, J ¼ 8.8, C(8)H], 7.74 [1H, s, C(2)H],
7.76 [1H, d, J ¼ 2.4, C(5)H], 8.25 (1H, br s, NH), 10.44 (1H,
s, CHO); m/z (ESþ) 254 [M þ H]þ (32%), 119 (2), 105 (6).
7-Formyl-6-methoxy-1,4-dimethylcarbazole 14. dH (300
MHz) 2.52 [3H, s, C(1)CH3], 2.85 [3H, s, C(4)CH3], 4.04 (1H,
s, OCH3), 6.92 [1H, d, J ¼ 7.2, C(3)H], 7.18 [1H, d, J ¼ 7.3,
C(2)H], 7.66 [1H, s, C(8)H], 8.06 [1H, s, C(5)H], 8.06 (1H, br
s, NH), 10.59 (1H, s, CHO).
N-tosyl-3-(2,2-diethoxyethylaminomethyl)-1,4,9-trimethyl-car-
bazole 26. Potassium carbonate (6.754 g, 0.049 mol) was
added to a solution containing a mixture of 3- and 6-(2,2-
diethoxyethylaminomethyl)-1,4-dimethylcarbazole, 24 and 25,
(1:0.18) (11.529 g, 0.033 mol) and p-toluenesulfonyl chloride
(9.323 g, 0.049 mol) in THF and water (1:2, 150 mL) and the
mixture was stirred for 1.5 h. After this time, the reaction was
poured into water (100 mL), and extracted with chloroform
(2ꢂ 100mL). The organic layer was washed with brine (2 ꢂ
50 mL), dried, and evaporated under reduced pressure result-
ing in a brown solid, which was recrystallized (dichlorome-
thane-hexane) to afford the single isomer N-tosyl-3-(2,2-dieth-
oxyethylaminomethyl)-1,4-trimethylcarbazole 26 as an off-
white solid (9.222 g, 55%): 156–157ꢀC; mmax (cmꢁ1) (KBr)
2975, 2928, 1470, 1340, 1156, 1119, 1094, 746; dH (300
MHz) 1.07 (6H, t, J ¼ 7.0, 2ꢂ OCH2CH3), 2.39 [3H, s,
C(40)CH3], 2.71 [3H, s, C(1)CH3], 2.80 [3H, s, C(4)CH3],
3.18 (2H, d, J ¼ 5.5, NCH2CH), 3.28–3.55 (4H, m, 2ꢂ
OCH2CH3), 4.08 [3H, s, N(9)CH3], 4.19 [1H, t, J ¼ 5.4,
CH(OEt)2], 4.65 (2H, s, ArCH2N), 6.88 [1H, s, C(2)H], 7.23
[1H, ddd, J ¼ 8.1, 7.0, 1.2, C(6)H] 7.28 [2H, d, J ¼ 8.4,
C(30)H, C(50)H], 7.38 [1H, d, J ¼ 8.0, C(8)H], 7.47 [1H, ddd,
J ¼ 8.1, 7.0, 1.0, C(7)H], 7.74 [2H, d, J ¼ 8.3, C(20)H,
C(60)H], 8.21 [1H, d, J ¼ 7.9, C(5)H]; dC 15.7 (2ꢂ CH3),
16.5 (CH3), 20.6 (CH3), 21.8 (CH3), 32.6 (CH3), 49.8 (CH2),
51.0 (CH2), 63.4 (CH2), 102.4 (CH2), 108.7 (CH), 117.6
(quat.), 119.3 (2ꢂ CH), 123.1 (quat.), 123.2 (quat.), 124.0
(CH), 124.2 (quat.), 125.3 (CH), 127.8 (2ꢂ CH), 129.9 (2ꢂ
CH), 131.4 (quat.), 131.8 (CH), 138.0 (quat.), 139.9 (quat.),
142.5 (quat.), 143.4 (quat.); m/z (ESþ) 531 [M þ Na]þ (2%),
417 [M—C6H4CH3]þ (90), 354 [M þ H—SO2C6H4CH3]þ
8-Formyl-6-methoxy-1,4-dimethylcarbazole 15. M.p. 154–
156ꢀC (ref. 19, 161ꢀC); mmax (cmꢁ1) (KBr) 3350, 2956, 1672,
1479, 1230, 802; dH (300 MHz) 2.56 [3H, s, C(1)CH3], 2.81
[3H, s, C(4)CH3], 3.98 (1H, s, OCH3), 6.97 [1H, d, J ¼ 7.3,
C(3)H], 7.19 [1H, d, J ¼ 7.3, C(2)H], 7.43 [1H, d, J ¼ 2.4,
C(7)H], 8.00 [1H, d, J ¼ 2.4, C(5)H], 9.96 (1H, br s, NH),
10.17 (1H, s, CHO); m/z (ESþ) 254 [M þ H]þ (50%), 105
(4), 101 (100).
Acknowledgments. We are grateful to Waters, Enterprise Ire-
land, Cancer Research Ireland and Cork County council higher
education grant for their financial support.
(30); HRMS Found: [M
þ
Na]þ, 531.2291. Calc. for
REFERENCES AND NOTES
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