Microwave-induced solid-supported Fischer indolization, a key step in the total synthesis of the sempervirine type methoxy analogues

Article abstract of DOI:10.1016/j.tetlet.2004.10.008

Fischer indole synthesis on solid-support under microwave irradiation towards 5-methoxy-2-(2-pyridyl)indoles has been developed, as the key step in the total synthesis of new 9-methoxyindolo[2,3-a]quinolizine alkaloids. A general protocol for the synthesi

Full text of DOI:10.1016/j.tetlet.2004.10.008

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8831–8834
Microwave-induced solid-supported Fischer indolization, a key
step in the total synthesis of the sempervirine type
methoxy analogues
q
Teodozja Lipi n´ ska*
Department of Chemistry, University of Podlasie, 3 Maja 54, 08-110 Siedlce, Poland
Received 12 January 2004; revised 24 September 2004; accepted 1 October 2004
Abstract—A general protocol for the synthesis of 2-heteroaryl-5-methoxyindoles has been developed utilizing a microwave-induced
solid-supported Fischer indolization under controlled conditions This route uses 2-acetylpyridine as a model and 3-acetyl derivatives
of cycloalkeno[c]fused pyridines as the synthetic building blocks towards new 9-methoxyindolo[2,3-a]quinolizine alkaloids.
ꢀ
2004 Elsevier Ltd. All rights reserved.
The indolo[2,3-a]quinolizine ring system is the main
structural moiety of sempervirine 1a and some related
alkaloids, which exhibit cytostatic, anti-HIV, immuno-
uable intermediates in the synthesis of sempervirine 1a
5
a
5b
(R = H, n = 2) and related systems 1b–d via the route
outlined in Scheme 1.
1
stimulant and sedative activities. This type of alkaloid
can exist as either cations or inner salts (zwitterions),
The present paper describes microwave-induced solid-
supported Fischer indolization as the key step in the
preparation of the model compound 9-methoxyin-
2
depending on pH. This balance is of great importance
for biological systems where it is responsible for trans-
3
port into cells as well as for interactions with DNA.
These unique structural and biological characteristics
have promoted interest in the synthesis of semperv-
dolo[2,3-a]quinolizine 9b from 2-acetylpyridine
6
(Scheme 2), and in the total synthesis of new semperv-
irine methoxy analogues 2a–d from ketones 5a–d (see
Schemes 1 and 3).
2
,4,5a
5b
irine
and its analogues. However, no synthetic ap-
proach to derivatives bearing a methoxy group on the
phenyl ring has as yet been reported. Some methoxy-
substituted indole alkaloids exhibit strong effects on
The methods reported for Fischer synthesis of 2-(2-
pyridinyl)indoles 7a involve heating phenylhydrazones
6
7
the nervous system.
in polyphosphoric acid at 180ꢁC, or in zinc chloride–
8
methylnaphthalene at over 200ꢁC. These drastic condi-
We have recently reported the preparation of 3-acetyl
derivatives of cycloalkeno[c]fused pyridines 5a–d as val-
tions are not suitable for obtaining 5-methoxyindoles,
which can be synthesized only in a weak acid medium
R
R
A
B
N(-)
C
+
( )n
A
B
N
H
N
N
D
SCH3
D
Ac
N
SCH3
n=1-4
E
E
(
)n
( )n
3
4
a-d; R=H,
5a-d
1
2
a-d; R=H, (n=2, sempervirine)
a-d; R=OCH3
a-d; R=OCH
3
Scheme 1.
Keywords: Fischer indole synthesis; Microwaves; Solid support; 2-Heteroaryl-5-methoxyindoles; Sempervirine type methoxy analogues.
q
This is Part 27 in a series ꢀ1,2,4-Triazines in Organic Synthesisꢁ for Part 26 see: Ref. 19.
Tel.: +48 25 6431013; fax: +48 25 6442045; e-mail: tlip@ap.siedlce.pl
*
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.008

8832
T. Lipi n´ ska / Tetrahedron Letters 45 (2004) 8831–8834
R
R
R
A
B
N
C
+
N
N
N
i, ii
iii
iv-viii
N
H
N
Ac
N
(-)
D
SO Ph
2
6
7a, R=H
8a, R=H
8b, R=OCH3
9a, R=H
9b, R=OCH3
7
b, R=OCH3
Scheme 2. Reagents and conditions: (i) PhNHNH
THF, PhSO
Cl, 0ꢁC to rt; (iv) THF, n-BuLi, À70ꢁC, BrCH
0% NaOH, D; (viii) 10% NaOH/CHCl
2
ÆHCl for 7a or p-CH
3
OC
6
H
4
NHNH
2
ÆHCl for 7b, reflux EtOH; (ii) MK10/ZnCl
2
, MW; (iii) NaH,
, rt 2h; (vii) MeOH,
2
2
CHO; (v) AcOH, À78ꢁC to 0ꢁC, NH
4
Cl (aq), AcOEt; (vi) CHCl
3
1
3
.
CH O
3
CH O
CH O
3
3
CH O
CH O
3
3
N
SCH3
A
C
A
B
N
C
+
N
H
N
N
_
B
N
N
D
N
H
iv
N
i, ii
v-ix
N
iii
(-)
D
5
a- 5d
SO Ph
2
(
)n
E
E
4a, n=2
4b, n=1
4c, n=3
4d, n=4
( )n
( )n
( )
n
( )n
10a, n=2
10c, n=3
1
1a, n=2
1c, n=3
2
a, n=2
c, n=3
1
2
Scheme 3. Reagents and conditions: (i) p-CH
THF, PhSO
Cl, 0ꢁC to rt; (v) THF, n-BuLi, À70ꢁC, BrCH
0% NaOH, D; (ix) 10% NaOH/CHCl
3
OC
6
H
4
NHNH
2
ÆHCl, reflux EtOH, 20min; (ii) MK10/ZnCl
2
, MW; (iii) Ni-R, EtOH, 0–5ꢁC; (iv) NaH,
, rt 2h; (viii) MeOH,
2
2
CHO; (vi) AcOH, À78ꢁC to 0ꢁC, NH
4
Cl (aq), AcOEt; (vii) CHCl
3
1
3
.
9
due to cleavage of the methoxy group. Until now only
simple Fischer indole syntheses have been performed on
due to the initiation of the microwave-induced Fischer
reaction. We found that over a short period of time,
the transformation of the substrate was not complete,
1
0
solid support under microwave irradiation. To dev-
elop conditions for obtaining 2-heteroaryl-5-methoxy-
indoles 4a–d, first we investigated the synthesis of
5-methoxy-2-(2-pyridyl)indole 7b (Scheme 2) as a
model by using the Fischer indole synthesis on an
1
4a
while over longer periods the yield of product 7b de-
creased, because degradation processes set in. Next, the
following steps were undertaken: the reaction leading
to N-protected methoxyindole 8b (60%) and a one-pot
procedure for C ring construction, were performed
1
1
acidic solid support under microwave irradiation.
5
b,15
under the conditions developed previously.
1
product 9b was obtained as an inner salt.
The final
6a
We used a single-mode microwave reactor, with feed-
back temperature control (IR detector). Firstly, the
activity of the fresh solid support, montmorillonite
Our preliminary investigations thus suggested that the
syntheses of 2a–d, that is, the new methoxy analogues
of sempervirine could be successfully conducted.
K10 modified with zinc chloride (MK10/ZnCl ) was
2
1
2
examined by performing the synthesis of 7a (Scheme
). Then, we developed the conditions (temperature
and time) for the Fischer synthesis of 5-methoxy-2-(2-
pyridinyl)indole (7b) from 2-acetylpyridine and p-meth-
oxyphenylhydrazine with (MK10/ZnCl ), but without
solvent. The temperature diagram of the ongoing
Fischer reaction towards 7b is shown in Figure 1a. We
arrived at a reasonable yield of 40–45% when we
stopped irradiation after 2.5min from the moment the
temperature started to increase rapidly (about 100ꢁC)
2
The starting compounds were the acetyl derivatives of
condensed pyridines 5a–d which were obtained from 3-
1
7
(methylthio)-1,2,4-triazine via a three-step synthesis,
which included an aza-Diels–Alder reaction with cyclic
2
1
3
5
,18
enamines.
appropriate p-methoxyphenylhydrazones (see Scheme
These ketones were transformed into the
3), mixed with the support (MK10/ZnCl ) and irradi-
2
ated (after evaporation of ethanol) in a microwave reac-
Temp (ºC)
(a)
(b)
Power (%)
Temp (ºC)
Power (%)
1
1
1
1
60
40
20
00
100
160
100
9
8
7
6
0
0
0
0
90
140
120
100
80
80
7
6
0
0
8
6
4
2
0
0
0
0
0
50
50
40
30
4
3
2
1
0
0
0
0
0
60
40
20
20
10
0
0
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Time (min)
Time (min)
Temp. adjusted
Temp
Temp. adjusted
Temp
Power
Power
Figure 1. Temperature and power of the ongoing microwave-induced Fischer reactions on the solid support MK10/ZnCl
reactor Synthewave 402, 300W, Prolabo). (a) Synthesis of 7b (b) synthesis of 4c.
2
(monomode microwave

T. Lipi n´ ska / Tetrahedron Letters 45 (2004) 8831–8834
Table 1. Yields and properties of indole 7b and 4a–d obtained from
8833
References and notes
13
the solid-supported Fischer synthesis under microwave irradiation
a
f
b
1
. (a) Beljanski, M.; Beljanski, M. S. Oncology 1986, 43, 198–
Entry Substrate
n
Product
R
Yield (%) Mp (ꢁC)
203; (b) Beljanski, M.; Crochet, S. Int. J. Oncol. 1996, 8,
1143–1148, and references cited therein; For activity of
1
4a
1
2
3
4
5
6
7b
4a
4b
0.33 43
0.65 35
0.62 45
0.68 40
0.70 38
128–129
177–178
193–194
182–183
141–142
5a
5b
5c
5d
2
1
3
4
homeopathic drugs containing sempervirine see: (c)
www.ansci.cornell.edu/plants/medicinal/gels.html.
. For a review on the structure and synthesis of the
indolo[2,3-a]quinolizine alkaloids see: Gribble, G. W. In
Stereoselective Synthesis, Part A, Studies in Natural
Products; Atta ur-Rahman, Ed.; Elsevier, 1988; Vol. 1,
pp 123–162.
14b
4c
4d
2
a
TLC plates (silica gel 60 F254 on aluminium roll, Merck) were
developed in chloroform-acetone 50:1 system.
Product isolated by column chromatography.
b
3
4
5
. Aihara, J. I.; Ichikawa, H.; Tokiwa, H.; Okumura, Y.
Bull. Chem. Soc. Jpn. 1990, 63, 2498–2503.
. Chaterjee, A.; Sahu, A.; Saha, M.; Banerji, J. Monatsh.
Chem. 1996, 127, 1259–1262.
. (a) Rykowski, A.; Lipi n´ ska, T. Synth. Commun. 1996, 26,
1
3
tor at the programmed temperature up to 150ꢁC. The
temperature diagram observed in the course of the
microwave-assisted Fischer synthesis of 4c
1
4b
is shown
in Figure 1b. A similar temperature increase was ob-
served during the synthesis of indoles 4a, 4b and 4d.
The yields and the physical properties of the products
4
9
409–4414; (b) Lipi n´ ska, T. Tetrahedron Lett. 2002, 43,
565–9567.
6. Szanty, C.; Honty, K. Monoterpenoid Indole Alkaloids
suppl. to vol 25 part 4. In The Chemistry of Heterocyclic
Compounds; Saxton, J. E., Ed.; John Wiley and Sons: New
York, 1994; pp 161–217.
4
a–d and 7b are reported in Table 1. We performed pilot
rearrangements of 4a and 4c into the new sempervirine
methoxy analogues 2a and 2c as shown in Scheme 3.
The desulfurization of 4a and 4c resulted in compounds
10a and 10c (45–55%). After N-protection, intermedi-
ates 11a and 11c were isolated by preparative thin layer
7
8
9
. Sugasawa, S.; Terashima, M.; Kanaoka, Y. Chem. Pharm.
Bull. 1956, 4, 16–19.
. Bently, R.; Stevens, T. S.; Thompson, M. J. Chem. Soc.
C) 1970, 791–795.
. For a review on Fischer indole synthesis: Hughes, D. L.
(
chromatography (silica gel plates) in 35–45% yields. We
1
5
used the Gribble method for the final construction of
6b
Org. Prep. Proced. Int. 1993, 25, 609–647.
1
the C ring. The final sempervirine analogues 2a
1
and
were obtained as neutral (inner) compounds (zwit-
1
0. (a) Abramovitch, R. C.; Bulman, A. Synlett 1992, 795–
797; (b) Villemin, D.; Labiad, A.; Ouhilal, Y. Chem. Ind.
1989, 607–609; (c) Sridar, V. Indian J. Chem. 1997, 36D,
86–88.
6c
2
c
terions are not the sole forms, see Scheme 1) by extrac-
tion with chloroform from a strong alkaline medium.
1
1. For a review on microwave-assisted synthesis on solid-
supports see, for example: (a) Perreux, L.; Loupy, A.
Tetrahedron 2001, 57, 9199–9223; (b) Varma, R. S.
Tetrahedron 2002, 58, 1235–1255.
1
4a
The structures of all the new intermediates: 7b,
1
8b,
4d, 10a,c and 11a,c and the final synthetic
4b
4
a,b, 4c,
alkaloids: 9b,
1
6a
16b
16c
2a
and 2c
were determined by
1
1
2. Lipi n´ ska, T.; Guibe-Jampel, E.; Petit, A.; Loupy, A.
Synth. Commun. 1999, 29, 1349–1354.
1
13
spectroscopic methods: IR, H NMR, C NMR, MS,
HRMS-ESI(+). The presence of the methoxy group
was verified by the H NMR spectra of these com-
3. General experimental procedure for Fischer synthesis on
solid-support under microwave irradiation: To a refluxing
mixture of p-methoxyphenylhydrazine hydrochloride
(3.3mmol) in ethanol (15mL) was added a solution of
acetyl pyridine 6 or 5a–d (3mmol) in ethanol (10mL).
After 25min of refluxing, the reaction was complete
(TLC). The reaction mixture was concentrated under
reduced pressure to half the original volume (for removal
1
pounds, appearing as a singlet at ꢀ3.95ppm and by a
simplification of the aromatic proton signals in compar-
ison to the spectra of the corresponding analogues
5
not possessing the CH Ogroup, as obtained earlier.
3
In the C NMR spectra the MeOsignals appeared at
56ppm.
1
3
ꢀ
5
2
b
of water) and the solid support, MK10/ZnCl
0
(1g,
.36mmol ZnCl ) was added. After mixing manually, the
2
In conclusion, we have determined conditions for the
microwave-induced solid-supported Fischer synthesis
of 5-methoxy-2-(2-pyridyl)indole (7b) and four new 5-
methoxy-2-(cycloalka[c]pyridin-3-yl)indoles (4a–d) as
the key intermediates in the preparation of 9-methoxy-
indolo[2,3-a]quinolizine alkaloids. After testing the syn-
thesis of tetracyclic molecule 9b, we performed two pilot
syntheses towards the methoxy analogues of semperv-
irine with six- and seven-membered E rings (2a and
solvent was evaporated under reduced pressure. The
resulting supported substrate was placed into four iden-
tical Pyrex vials, which were fitted in turn into a Pyrex
cylindrical vessel and irradiated in a Synthewave 402
microwave reactor (Prolabo, 300W, open system). The
temperature setpoint was programmed at 140ꢁC or 150ꢁC
(
Fig. 1: temp adjusted). Irradiation was stopped after 2–
2
.5min from the moment the temperature began rapidly
increasing. The solids from the vials were cooled and
extracted several times with diethyl ether (100mL) and
diethylamine (2mL). The residue obtained after evapora-
tion of the solvent was purified by column chromatogra-
phy on silica gel (Merck, 100–200 mesh) to afford the
pure products: 7b (eluted with chloroform) or 4a–d
2
c). Currently, research is being carried out to expand
the scope of this synthesis and to investigate the phys-
ico-chemical and pharmacological properties of these
compounds.
(
eluted with chloroform–hexane 2:1). The yields and
physical properties of products 7b and 4a–d are shown
in Table 1.
4. Selected data for compounds 7b and 4c. (a) 5-Methoxy-2-
Acknowledgements
1
À1
The author thanks Professor Andrzej Rykowski from
the University of Podlasie for fruitful discussions.
(2-pyridyl)indole 7b: IR (KBr, cm ) 3190, 3050, 2990,
2950, 2830, 1620, 1595, 1545, 1450, 1260, 1220, 1150, 1120,

8834
T. Lipi n´ ska / Tetrahedron Letters 45 (2004) 8831–8834
1
030; H NMR (500MHz, CDCl
1
6
7
3
) d 3.86 (s, 3H, H
3
CO),
.89 (dd, J = 8.8, 2.4Hz, 1H), 6.95 (d, J = 1.8Hz, 1H),
16. Crude final products were purified by PTLC on silica
gel (eluent: chloroform–methanol) to give the pure alka-
loid 9b, 2a or 2c, which were pale-yellow amorphous
unstable substances. The UV measurements were made for
.10 (d, J = 2.4Hz, 1H), 7.14–7.17 (m, 1H), 7.26, (d,
J = 8.8Hz, 1H), 7.68–7.72 (m, 1H), 7.77 (d, J = 8.0Hz,
1
1
H), 8.57 (d, J = 4.8Hz, 1H), 9.84 (s, 1H); C NMR
3
À4
3
c = 5 · 10 mol/dm solutions in methanol. (a) 9-Meth-
oxyindolo[2,3-a]quinolizin-6-ium 9b: yield 55% (from 8b);
(
125MHz, CDCl ) d 55.78 (OCH ), 100.34, 102.35,
3
3
1
1
1
7
1
12.13, 113.83, 119.77, 121.83, 129.45, 131.96, 136.59,
R = 0.25 (chloroform–methanol 4:1); UV: kmax, nm (log
f
+
37.27, 149.04, 150.44, 154.39; MS-EI m/z (%): 224 (M ,
e): 223.5 (4.27), 243.0 (4.02), 307.5 (3.35), 351.5 (3.60), 386
(3.30); HRMS-ESI(+): found 249.1035 [M + H]; calcd
+
00), 209 (75), 181 (68); Anal. Calcd for C14
H
12
2
N O : C,
4.98; H, 5.39; N, 12.49%; Found: C, 74.81; H, 5.33; N,
2.39%; (b) 6,7,8,9-Tetrahydro-3-(5-methoxyindol-2-yl)-1-
for C H N O: 249.1022; (b) 2,3,4,13-Tetrahydro-
2
1
6
13
10-methoxy-1H-benz[g]indolo[2,3-a]quinolizin-6-ium 2a:
yield 42% (from 11a); R = 0.22 (chloroform–methanol
(methylsulfanyl)-5H-cyclohepta[c]pyridine 4c: IR (KBr,
cm ): 3405, 3100, 3060, 2995, 2925, 2850, 1620, 1580,
f
À1
10:1); UV: kmax, nm (log e): 232.5 (4.15), 249.5 (4.40),
263.5 (4.55), 351.5 (3.77), 385.0 (3.25); HRMS ESI(+):
1
540, 1490, 1435, 1410, 1345, 1295, 1215, 1190, 1155, 1030;
1
+
found 303.1503 [M + H], calcd for
H NMR (400MHz, CDCl
m, 2H), 2.67 (s, 3H), 2.78–2.81 (m, 2H), 2.87–2.81 (m, 2H),
.87 (s, 3H, H CO), 6.87 (d, J = 2.0Hz, 1H), 6.89 (dd,
J = 8.8, 2.4Hz, 1H), 7.09 (d, J = 2.4Hz, 1H), 7.26 (s, 1H),
3
) d 1.60–1.66 (m, 4H), 1.82–1.86
20 19 2
C H N O:
(
3
303.1492; (c) 1,2,3,4,5,14-hexahydro-11-methoxycyclo-
hept[g]indolo[2,3-a]quinolizin-7-ium 2c: yield 46% (from
3
11c); R = 0.24 (chloroform–methanol 10:1); UV: kmax, nm
f
13
7.33 (d, J = 8.8Hz, 1H), 9.20 (s, 1H); C NMR (100Hz,
(log e): 230.0 (4.35), 244.5 (4.08), 303.0 (3.42), 356.5 (3.88),
386.5 (3.45); HRMS-ESI(+): found: 317.1651 [M + H],
+
CDCl ) d 14.31, 26.91, 27.54, 30.02, 32.84, 36.24, 55.95
3
(
OCH ), 99.64, 102.47, 12.18, 113.51, 116.45, 129.87, 131.60,
calcd for C H N O: 317.1648.
21 21
3
2
134.72, 137.98, 147.34, 152.51, 154.54, 156.33; MS-EI
m/z (%): 338 (M , 100), 323 (46), 305 (58), 295 (15); HRMS
17. Paudler, W. W.; Chen, T.-K. J. Heterocycl. Chem. 1970, 7,
767–771.
+
EI: found 338.1466, calcd for C20
5. Gribble, G. W.; Barden, T. C.; Johnson, D. A. Tetrahe-
dron 1988, 44, 3195–3202.
H
22ON
2
S: 338.1453.
18. Rykowski, A.; Lipi n´ ska, T. Pol. J. Chem. 1997, 71, 83–90.
19. Mojzych., M.; Karczmarzyk, Z.; Rykowski, A. J. Chem.
Crystallogr. 2004, in press.
1