(PhO)3P·Cl2-promoted bischler-napieralski-type cyclization: A mild access to β-carbolines

Article abstract of DOI:10.1055/s-2005-862394

A novel mild access to the β-carboline skeleton is described. The reaction is a Bischler-Napieralski-type cyclocondensation, promoted by (PhO)₃P·Cl₂, which is performed in dichloromethane at -30 °C. The products are easily obtained i

Full text of DOI:10.1055/s-2005-862394

LETTER
661
(PhO)3P·Cl2-Promoted Bischler–Napieralski-Type Cyclization: a Mild Access
to b-Carbolines
M
ildBischler–Na
p
l
ieralsk
b
i-Type Cycl
e
a
Università di Modena e Reggio Emilia, Dipartimento di Chimica, via Campi 183, 41100 Modena, Italy
Fax +39(059)373543; E-mail: prati.fabio@unimore.it
b
Discovery Chemistry Research and Technologies, Eli Lilly & Co., Lilly Corporate Center, Indianapolis, Indiana, 46285, USA
Received 17 December 2004
can be employed to prime cyclization, the more often em-
ployed being exposure to dehydrating agents, like P2O5,11
polyphosphoric acid12 or esters thereof.13 Two remarkable
exceptions exist, namely the recent and intriguing Tf2O/
Abstract: A novel mild access to the b-carboline skeleton is de-
scribed. The reaction is a Bischler–Napieralski-type cycloconden-
sation, promoted by (PhO)3P·Cl2, which is performed in
dichloromethane at –30 °C. The products are easily obtained in
good yields and do not require further chromatographic purifica- DMAP protocol developed in Banwell’s group,14 and the
tion.
(COCl)2/FeCl3-promoted procedure by Larsen and co-
workers.15 Although both these high-yielding methods
Key words: triphenyl phosphite, chlorine, indoles, alkaloids,
Bischler–Napieralski cyclizations
have well demonstrated their usefulness in promoting
Bischler–Napieralski-type reactions, either on urethanes14
or b-arylethylamines,15 respectively, it is worth noting
that they exhibit limitations towards cyclization of in-
doles. Most recently, for instance, Li and colleagues failed
in applying them satisfactorily to indole urethanes16 and
were forced to move back to the classical Bischler–
Napieralski reaction, which still represents, as yet, the
only straightforward route to 3,4-dihydro-b-carbolines
from indoles, whereas the perhaps most exploited Pictet–
Spengler reaction leads to 1,2,3,4-tetrahydro-b-carbo-
lines.6 Awkward reagents and harsh conditions, however,
may preclude successful application of Bischler–
Napieralski cyclization when sensitive functional groups
are present.6 Hence, with the aim to bridge this gap and
encouraged by preliminary results in our hands,1 we were
prompted to apply our (PhO)3P·Cl2 methodology for the
cyclocondensation of a variety of indolamides.
The demand for milder methods to carry on reactions,
which are generally performed under severe conditions,
has become an attractive challenge when new modifica-
tions of existing procedures are proposed. In this respect,
our recent efforts in providing a new, mild and simple
method for deacylation of amides have been oriented ac-
cordingly.1 In the course of that study, we also disclosed a
preliminary report of the first and mildest example of a
Bischler–Napieralski-type cyclization at low temperature
promoted by the triphenyl phosphite–chlorine complex,
(PhO)3P·Cl2.1–3
Along this line, we wish herein to follow up this kind of
chemistry and report its natural extension to indolamides
for the synthesis of b-carboline derivatives, a fascinating
class of naturally occurring alkaloids endowed with a va-
riety of biological and psychotropic properties.4 Classical-
ly, cyclization of N-b-arylethylamides through Bischler–
Napieralski reaction5,6 proceeds via formation of an imi-
nochloride intermediate, which is formed by exposure of
the substrate to a suitable halogenating reagent.7 Subse-
quently, the iminochloride undergoes an intramolecular
electrophilic substitution, thus affording the cyclic prod-
uct.7 It is likely, as already suggested, that, once formed,
the iminochloride rearranges into a nitrilium intermedi-
ate,7,8 which is more willing to be trapped by the electron-
rich aromatic ring.
For our purposes, commercially available tryptamine was
envisaged as a convenient starting material for the con-
struction of the b-carboline skeleton. Firstly, conversion
into variously substituted tryptamides was achieved, on
multigram scale, by classical acylation with the appro-
priate acyl chloride in dichloromethane, affording the cor-
responding amides 1a–d in 70–92% yield.17 In contrast,
1e was prepared from commercially available L-tryp-
tophan according to standard procedures. When trypt-
amides 1a–e were treated with a slight excess of
(PhO)3P·Cl2 at –30 °C in dichloromethane in the presence
of triethylamine,18 the expected cyclic products 2a–e were
obtained in good to excellent yields, as depicted in
Scheme 1.
To the best of our knowledge, literature reports formation
of the iminochloride usually by means of harsh reagents
and often by heating the reaction mixture to high temper-
atures. In particular, the most widespread conditions in-
volve POCl3,9 or SnCl4/POCl310 in high boiling solvents,
such as toluene or xylene; alternatively, other approaches
According to a typical experimental procedure, chlorine is
bubbled through a glass septum in a solution of (PhO)3P
in anhydrous dichloromethane at –30 °C under Ar atmo-
sphere, until the solution appears intensely yellow. The
color is discharged by addition of a few further drops of
(PhO)3P, thus obtaining an almost colorless and clear
mixture. Substrate and base are added and the mixture is
SYNLETT 2005, No. 4, pp 0661–0663
Advanced online publication: 22.02.2005
DOI: 10.1055/s-2005-862394; Art ID: G46904ST
© Georg Thieme Verlag Stuttgart · New York
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4.
0
3.
2
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0
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662
A. Spaggiari et al.
LETTER
left to stir at the same temperature over two hours. The
cold bath is then removed and the mixture stirred for an
additional 12 hours. Meanwhile, precipitation of b-carbo-
line as hydrochloride may occur, thus facilitating recovery
by simple filtration (as for 2a).19 Should this not be the
case, a final extraction step is performed, and the desired
product is recovered as free base.20 Nonetheless, no addi-
tional chromatographic purification is strictly required,
since major by-products are completely removed during
acid–base extraction. The results are summarized in
Table 1.
Acknowledgment
We thank MIUR (COFIN 2003) for financial support, as well as
Fondazione Cassa di Risparmio di Modena for the generous purcha-
se of a Bruker Avance 400 NMR spectrometer. We are grateful to
Alessandro Borghi for preliminary experiments. Thanks are due to
Maria Cecilia Rossi and Cinzia Restani (Centro Interdipartimentale
Grandi Strumenti at Università di Modena) for valuable assistance
during advanced NMR experiments and to Prof. Franco Ghelfi
(Università di Modena) for kindly providing chlorine delivery
facilities.
References
R'
R'
N
(1) Spaggiari, A.; Blaszczak, L. C.; Prati, F. Org. Lett. 2004, 6,
3885.
NH
R
(2) (a) Hatfield, L. D.; Blaszczak, L. C.; Fisher, J. W. US Patent
4,230,644, 1980; Chem. Abstr. 1981, 94, 156523.
(b) Hatfield, L. D.; Blaszczak, L. C.; Fisher, J. W. US Patent
4,226,986, 1980; Chem. Abstr. 1981, 94, 103348.
(3) (a) Coe, D. G.; Landauer, S. R.; Rydon, H. N. J. Chem. Soc.
1954, 2281. (b) Rydon, H. N.; Tonge, B. L. J. Chem. Soc.
1956, 3043. (c) Tseng, C. K. J. Org. Chem. 1979, 44, 2793.
(4) (a) Schultes, R. E.; Hofmann, A. The Botany and Chemistry
of Hallucinogens; Charles C. Thomas Publisher:
Springfield, 1980. (b) Freedland, C. S.; Mansbach, R. S.
Drug and Alcohol Dependence 1999, 54, 183. (c) Ott, J. J.
Psychoact. Drugs 1999, 31, 171. (d) Airaksinen, M. M.;
Kari, I. Med. Biol. 1981, 59, 21. (e) Airaksinen, M. M.;
Kari, I. Med. Biol. 1981, 59, 190.
(5) Bischler, A.; Napieralski, B. Ber. 1893, 26, 1903.
(6) For an excellent review, see: Love, B. Org. Prep. Proced.
Int. 1996, 28, 1.
(7) Fodor, G.; Gal, J.; Phillips, B. A. Angew. Chem., Int. Ed.
Engl. 1972, 11, 919.
(8) (a) Nicoletti, M.; O’Hagan, D.; Slawin, A. M. Z. J. Chem.
Soc., Perkin Trans. 1 2002, 116. (b) Doi, S.; Shirai, N.;
Sato, Y. J. Chem. Soc., Perkin Trans. 1 1997, 2217.
(9) (a) Huang, W. J.; Singh, O. V.; Chen, C. H.; Lee, S. S. Helv.
Chim. Acta 2004, 87, 167. (b) Wang, Y. C.; Georghiou, P.
E. Org. Lett. 2002, 4, 2675. (c) Fujii, T.; Ohba, M.; Ohashi,
T. Tetrahedron 1993, 49, 1879. (d) Hino, T.; Lai, Z.; Seki,
H.; Hara, R.; Kuramochi, T.; Nakagawa, M. Chem. Pharm.
Bull. 1989, 37, 2596. (e) Whaley, W. M.; Govindachari, T.
R. Org. React. 1951, 6, 74.
(PhO)3P·Cl2
O
CH2Cl2, –30 °C
R
N
N
H
H
2
1
Scheme 1 General scheme for Bischler–Napieralski reaction
promoted by (PhO)3P·Cl2 reagent
Noteworthily, 2a (harmalane)21a is a pharmacologically
active compound,21b whilst b-carboline 2d is closely relat-
ed to the fungal alkaloid infractin, originally isolated from
Cortinarius infractus.22 In addition, derivative 2e bears
structural resemblance to a metabolite present in the
entheogenic mushroom Amanita muscaria.4a,23
Table 1 Cyclization Results
Substrate
R
R¢
Product
2a
Yield (%)
1a
1b
1c
1d
1e
Me
H
98
51
65
50
62
Ph
H
2b
CH2Ph
H
2c
CH2CH2COOMe
Me
H
2d
COOMe
2e
(10) Tsuda, Y.; Kimiaki, I.; Toda, J.; Taga, J. Heterocycles 1976,
5, 157.
(11) Itoh, N.; Sugasawa, S. Tetrahedron 1957, 1, 45.
(12) Snyder, H. R.; Werber, F. X. J. Am. Chem. Soc. 1950, 72,
2962.
(13) (a) Kanaoka, Y.; Sato, E.; Yonemitsu, O.; Ban, Y.
Tetrahedron Lett. 1964, 35, 2419. (b) Kanaoka, Y.; Sato, E.;
Ban, Y. Chem. Pharm. Bull. 1967, 15, 101. (c) Kende, A.
S.; Ebetino, F. H.; Battista, R.; Boatman, R. J.; Lorah, D. P.;
Lodge, E. Heterocycles 1984, 21, 91.
When compared to available methodologies24 for the syn-
thesis of b-carbolines, our (PhO)3P·Cl2-primed protocol
offers an alternative route to perform similar cyclocon-
densations and is well tolerated by the sensitive indole
skeleton. Most interestingly, this method represents the
mildest procedure ever described in the literature for
Bischler–Napieralski-type cyclizations.
Furthermore, preliminary attempts to assess whether this
approach can be extended to the synthesis of 3,4-dihy-
droisoquinolines, yet another important class of bioactive
alkaloids, would suggest that this chemistry can be suc-
cessfully applied also to a variety of substituted b-phenyl-
ethylamides, albeit with less satisfactory yields. A
painstaking investigation along this direction and applica-
tion of this methodology to the total synthesis of natural
alkaloids are currently representing a central issue in our
laboratory and further developments will be reported in
due course.
(14) Banwell, M. G.; Bissett, B. D.; Busato, S.; Cowden, C. J.;
Hockless, D. C. R.; Holman, J. W.; Read, R. W.; Wu, A. W.
J. Chem. Soc., Chem. Commun. 1995, 2551.
(15) Larsen, R. D.; Reamer, R. A.; Corley, E. G.; Davis, P.;
Grabowski, E. J. J.; Reider, P. J.; Shinkai, I. J. Org. Chem.
1991, 56, 6034.
(16) Chern, M. S.; Shih, Y. K.; Dewang, P. M.; Li, W. R. J.
Comb. Chem. 2004, 6, 855.
(17) Synthesis of Tryptamine Amides (1a–d); General
Procedure.
Tryptamine (4500 mg, 28 mmol) was dissolved in dry
CH2Cl2 (20 mL) in a two-necked 100 mL flask, and Et3N
Synlett 2005, No. 4, 661–663 © Thieme Stuttgart · New York

LETTER
(4.3 mL, 30.8 mmol) was added. The appropriate acyl
Mild Bischler–Napieralski-Type Cyclizations
663
(20) Synthesis of 1-Phenyl-4,9-dihydro-3H-b-carboline (2b).
By close analogy to the procedure described above, triphenyl
phosphite (1.16 mL, 4.3 mmol) was dissolved in anhyd
CH2Cl2 (14 mL) at –30 °C under argon atmosphere. Then,
Cl2 was bubbled in, until the solution turned intensely
yellow. The color was discharged by addition of a few
further drops of triphenyl phosphite and tryptamine
benzamide 1b (1000 mg, 3.9 mmol) was added, quickly
followed by Et3N (637 mL, 4.58 mmol), and the system was
maintained under vigorous stirring over 2 h at –30 °C before
removing the cold bath. After an additional 12 h period at
r.t., the dark mixture was treated with 10% HCl and
extracted with CH2Cl2 (4 × 10 mL). The aqueous phase was
then basified to pH 10 with 20% NaOH and repeatedly
extracted with CH2Cl2 (4 × 15 mL). The organic phases were
pooled, dried and rotary evaporated, to afford 2b (505 mg,
51%) as a yellow fine powder (mp 196–198 °C). 1H NMR
(200 MHz, CDCl3): d = 2.99 (2 H, t, J = 8.5 Hz, CH2CH2N),
4.06 (2 H, t, J = 8.5 Hz, CH2CH2N), 7.10–7.85 (9 H, m,
arom.), 8.24 (1 H, br, NH). 13C NMR (50 MHz, CDCl3): d =
19.2, 48.8, 111.9, 117.9, 119.9, 120.4, 124.6, 127.8, 128.8,
129.9, 136.5, 137.6, 159.4. Anal. Calcd for C17H14N2: C,
82.90; H, 5.73; N, 11.37. Found: C, 82.85; H, 5.64; N, 11.49.
(21) (a) Späth, E.; Lederer, E. Ber. 1930, 63, 120.
(b) Rommelspacher, H.; Brüning, G.; Susilo, R.; Nick, M.;
Hill, R. Eur. J. Pharmacol. 1985, 109, 363.
(22) Steglich, W.; Kopanski, L.; Wolf, M.; Moser, M.;
Tegtmeyer, G. Tetrahedron Lett. 1984, 25, 2341.
(23) (a) Wasson, R. G. Soma, Divine Mushroom of Immortality;
Harcourt, Brace and Jovanovich: New York, 1968.
(b) Wasson, R. G.; Kramrisch, S.; Ott, J.; Ruck, C. A. P.
Persephone’s Quest – Entheogens and the Origins of
Religion; Yale University Press: New Haven, 1986.
(24) Application of Banwell’s method14 to substrate 1b failed to
give the expected b-carboline 2b.
chloride (1.1 equiv) dissolved in CH2Cl2 (10 mL) was then
cautiously dropped in, under vigorous stirring. The reaction
mixture was heated to reflux for 90 min, until TLC showed
disappearance of starting tryptamine. Thereafter, the mixture
was washed with 10% HCl, sat. NaCl and finally with H2O,
each time extracting with CH2Cl2. The organic phases were
pooled, dried over MgSO4 and evaporated in vacuo, to
provide a thick foam which was triturated with light
petroleum, thus affording the desired amide as a reddish-
brown fine powder (70–92% yield).
(18) The role of the base is to shield (PhO)3P·Cl2 from the action
of adventitious HCl, which is reported to enhance its
degradation into an inactive form. For more detailed
mechanistic insights, see Ref. 1,2a.
(19) Synthesis of Harmalane Hydrochloride (2a).
In a three-necked 50 mL round bottom flask, anhyd CH2Cl2
(15 mL) was cooled to –30 °C under argon atmosphere.
Triphenyl phosphite (1.2 mL, 4.6 mmol) was added and Cl2
was bubbled in, until the solution became bright yellow. The
color was discharged by addition of a few drops of triphenyl
phosphite, and tryptamine acetamide 1a (850 mg, 4.2 mmol)
was then added, quickly followed by Et3N (671 mL, 4.83
mmol). The reaction was stirred over a 2-hour period, then
the cold bath was removed and the mixture left to stir at r.t.
After 12 h, a conspicuous yellow solid had precipitated and
was recovered by centrifugation, thus affording 909 mg
(98%) of harmalane (2a) as hydrochloride. 1H NMR (200
MHz, DMSO-d6): d = 2.79 (3 H, s, Me), 3.19 (2 H, t, J = 8.1
Hz, CH2CH2N), 3.88 (2 H, t, J = 8.1 Hz, CH2CH2N), 7.78–
8.14 (4 H, m, arom.), 12.87 (1 H, br, NH), 13.07 (1 H, br,
HCl). 13C NMR (50 MHz, DMSO-d6): d = 19.0, 19.1, 42.1
113.7, 121.6, 122.2, 123.0, 124.3, 126.8, 128.5, 140.9,
167.2. MS: m/z = 221 (M+), 207, 182, 154, 128, 91, 77, 63,
44. Anal. Calcd for C12H13ClN2: C, 65.31; H, 5.94; N, 12.69.
Found: C, 65.42; H, 6.05; N, 12.73.
Synlett 2005, No. 4, 661–663 © Thieme Stuttgart · New York