A 'one pot' microwave-mediated synthesis of the basic canthine skeleton: Expedient access to unnatural β-carboline alkaloids

Article abstract of DOI:10.1016/S0040-4039(03)01019-0

In a 'one pot' microwave reaction, an acyl hydrazide-tethered indole underwent a 3-component condensation to form a triazine, followed by an inverse-electron demand Diels-Alder reaction and subsequent chelotropic expulsion of N₂ to deliver novel, unnatural β-carboline alkaloids in good isolated yields.

Full text of DOI:10.1016/S0040-4039(03)01019-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4495–4498
A ‘one pot’ microwave-mediated synthesis of the basic canthine
skeleton: expedient access to unnatural b-carboline alkaloids
Craig W. Lindsley,* David D. Wisnoski, Yi Wang, William H. Leister and Zhijian Zhao
Department of Medicinal Chemistry, Technology Enabled Synthesis Group, Merck Research Laboratories, PO Box 4,
West Point, PA 19486, USA
Received 24 March 2003; revised 16 April 2003; accepted 17 April 2003
Abstract—In a ‘one pot’ microwave reaction, an acyl hydrazide-tethered indole underwent a 3-component condensation to form
a triazine, followed by an inverse-electron demand Diels–Alder reaction and subsequent chelotropic expulsion of N to deliver
2
novel, unnatural b-carboline alkaloids in good isolated yields. © 2003 Elsevier Science Ltd. All rights reserved.
Canthines represent a tetracyclic subclass of b-carboline1
alkaloids that possess an additional D-ring (Fig. 1).
Since the isolation of the parent canthine in 1952 from
Pentaceras australis, over forty members of this class of
skeleton 4 in 45–56% overall yield. Despite this notable
synthetic advance, limited diversity exists at the C1/C2
positions of natural and unnatural canthine alkaloids
1–5
reported to date.
2
alkaloids have been isolated and characterized. More-
over, members of the canthine family have been shown
to exhibit a wide range of pharmacological activities
including –3antifungal, antiviral and antitumor
In a recent letter, our laboratory reported on a new
microwave-mediated protocol for the rapid synthesis of
diverse6 3,5,6-trisubstituted-1,2,4-triazines in high
yields. During the course of this work, readily avail-
able acyl hydrazide 1 was subjected to our standard
microwave conditions. In the event, heating a 1:1 ratio
of 1 and benzil 5 in the presence of 10 equiv. of
1
properties.
A number of synthetic approaches to access the can-
thine skeleton have been reported and typically employ
4
Pictet–Spengler or Bischler–Napieralski strategies. In
NH OAc in a single-mode microwave at 180°C for 5
4
1
992, Snyder disclosed an elegant strategy to access the
min delivered not only the desired triazine 6, but also
7
canthine skeleton utilizing indole as a dienophile in an
intramolecular inverse electron demand Diels–Alder
the 1,2-diphenyl canthine derivative 7 (Scheme 2).
LCMS and NMR analysis indicated a 9:1 ratio of 6:7
with isolated yields of 83% and 6%, respectively. Sig-
5
(
IEDDA) reaction (Scheme 1). Treatment of acyl
hydrazide-tethered indole 1 with a 1,2-diketone 2 and
excess of ammonium acetate in refluxing acetic acid for
several hours provided the triazine-tethered indole 3.
After purification, 3 was refluxed in triisopropylbenzene
(
232°C) for 1.5–20 h to provide the basic canthine
Figure 1. Canthine alkaloid tetracyclic skeleton.
*
Corresponding author. Tel.: +1-215-652-2265; fax: +1-215-652-6345;
e-mail: craig lindsley@merck.com
Scheme 1.
–
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01019-0

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496
C. W. Lindsley et al. / Tetrahedron Letters 44 (2003) 4495–4498
Scheme 3.
Scheme 2.
nificantly, in a single ‘pot’, 1 underwent a three compo-
nent condensation to generate triazine 6, followed by
an intramolecular IEDDA reaction and subsequent
chelotropic expulsion of N to generate the previously
2
unknown 1,2-diphenyl canthine 7.
Scheme 4.
With this result in hand, our efforts centered on the
optimization of this ‘one pot’ reaction to deliver 7
exclusively. Reaction parameters were quickly evalu-
ated in an automated fashion on a single-mode
microwave (Table 1). By simply increasing the reac-
tion time from 5 to 60 min at 180°C, the ratio of 6:7
could be increased from 9:1 to 1:2, as determined by
analytical LCMS. Further increasing the temperature
to 220°C, 100°C above the boiling point of HOAc, for
In order to probe the reaction’s generality, large quanti-
ties of 1 were required. Following literature prepara-
tions, 1 could be made on multigram scales; however, 1
was found to decompose upon storage at room temper-
ature. Therefore, a microwave-accelerated variant of
Laasko’s thermal protocol was developed whereby 1
was prepared only as needed, and used immediately
7a
5,9
4
0 min altered the selectivity to 0.5:9.5, in favor of 7.
(
Scheme 4). In this instance, microwave heating of
Under these optimal reaction conditions, the pressure
inside the microwave vessel reached 12 PSI, well within
the safety limits of the instrument.
commercially available ester 8 with hydrazine at 150°C
in THF for only 2 min afforded 1 in quantitative
10
yield. Isolation simply involved evaporation of the
solvent, and subsequent reactions could be conducted
in the same microwave reaction vessel.
Application of these optimal conditions on a 0.5 mmol
scale reaction that employed a 1:1 ratio of 1 to 5 with
an excess of NH OAc for 40 min at 220°C delivered 7
Treatment of a variety of 1,2-diketones and 1 under our
standard ‘one pot’ procedure delivered unnatural can-
thine alkaloids in moderate to excellent isolated yields
4
8
in 80% isolated yield. Analysis of the crude reaction by
LCMS and NMR failed to detect any trace of triazine
(
Fig. 2). Functionalized aryl analogs such as 9 and 10
6
(Scheme 3). With a ‘one pot’ protocol for the expedi-
provided the best yields (>80%), while heteroaryl con-
geners, exemplified by 11 and 12 afforded reasonable
yields (ꢀ60%). In general, dialkyl derivatives afforded
lower overall yields (ꢀ30%) under this protocol, as
illustrated by 13 and the novel pentacyclic congener 14.
However, replacement of one alkyl group with a phenyl
subtituent increased the yield to 62%, though a 1:1
mixture 15a:15b of regioisomers resulted. Preparative
mass-guided HPLC on a custom Agilent 1100 instru-
ent synthesis of the basic canthine skeleton in hand,
attention was now directed at probing the generality of
this reaction with respect to other 1,2-diketones.
Table 1. Optimization of ‘one pot’ synthesis of 7
11
ment smoothly separated the regioisomers.
All attempts to modify reaction parameters to increase
the ‘one pot’ yields of C1/C2 dialkyl analogs failed.
Ultimately, improved yields were achieved by a ‘two
pot’ microwave-accelerated procedure that required
only 35 min total reaction time (Scheme 5). In the
event, our standard triazine protocol was employed to
a
Entry
Time (min)
Temp. (°C)
6:7
1
2
3
4
5
6
7
5
10
20
40
60
40
40
180
180
180
180
180
200
220
9:1
6
deliver 17 in 5 min at 180°C. After isolation, 17 was
7:3
2:1
1:1
1:2
dissolved in 1.8 mL of dry DMF and heated at 250°C,
almost 100°C above the boiling point of DMF, for 30
min in a single-mode microwave to provide 18 in 55%
7a
overall yield from 1. Caution, this reaction generated
5 PSI of pressure, just below the safety threshold of
1:5
1
0.5:9.5
the microwave. A number of solvents (dichloroethane,
dioxane, toluene and ethanol) were examined for the
a
Ratios determined by analytical LCMS.

C. W. Lindsley et al. / Tetrahedron Letters 44 (2003) 4495–4498
4497
Figure 2. Representative unnatural canthine alkaloids.
Scheme 6.
Scheme 5.
Figure 3. Generic unnatural canthine alkaloid library.
conversion of 17 to 18 at a variety of temperatures, but
only DMF provided the desired canthine core.
biological activities. For these reasons, in addition to a
simple ‘one pot’ protocol for 3-position diversity, the
preparation of a library of unnatural canthine alkaloids
coupled with biological screening is in progress (Fig. 3).
Unnatural canthin-6-one alkaloid congeners could also
be obtained by selective oxidation following the proce-
12
dure prescribed by Snyder. In this instance, treatment
of canthine 7 with BTAP (triethylbenzylammonium
permanganate) in CH Cl /HOAc delivers previously
In summary, a microwave-mediated protocol for the
2
2
‘
one pot’ synthesis of the basic canthine alkaloid skele-
unknown 1,2-diphenyl canthin-6-one 19 in 60% isolated
yield (Scheme 6). All attempts to oxidize 11 to the
analogous canthin-6-one under this protocol were
unsuccessful. In this case, oxidation at the C1/C2
pyridyl ring nitrogens occurred quickly and led to
complex mixtures.
ton has been developed on a single-mode microwave
7a
synthesizer. This new ‘one pot’ procedure was found
to be general for the synthesis of C1/C2 diaryl canthi-
nes. A complimentary ‘two pot’ microwave-accelerated
procedure was also developed to productively deliver
C1/C2 dialkyl canthine congeners. In addition to
providing high yielding access to a number of previ-
ously unknown canthine and canthin-6-one alkaloids,
reaction times have been reduced 10- to 700-fold over
conventional thermal methods. Applications of this
‘one pot’ procedure for diversity-oriented organic syn-
Recently, diversity-oriented synthesis has garnered a
great deal of attention as unnatural analogs of natural
products have been shown to possess novel biological
1
3
activity. Relatively few canthine alkaloids have been
discovered or synthesized, yet possess a wide range of

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C. W. Lindsley et al. / Tetrahedron Letters 44 (2003) 4495–4498
thesis of unnatural canthine alkaloids coupled with
biological screening is in progress and will be reported
in due course.
the Emrys Liberator™ reactor cavity for 5 min at 180°C.
After 5 min, the vessel was rapidly cooled to 40°C by the
unit. Upon removal from the reactor cavity, the homoge-
neous solution was concentrated on a nitrogen evapora-
tor and analyzed by LCMS. Two peaks in a 9:1 ratio
were detected corresponding to 6 (3.84 min.) and 7 (2.71
min.), respectively. The sample was purified by prepara-
tive mass guided HPLC to deliver 162 mg (83%) of pure
6 and 10.8 mg (6.3%) of pure 7.
Acknowledgements
The authors would like to thank Dr. Charles W. Ross
III for obtaining HRMS data (accurate mass
measurements).
Analytical data for 6: Analytical LCMS indicated a single
peak (3.843 min, CH CN/H O/0.1%TFA, 4 min gradient)
3
2
>
(
98% pure by UV (214 nm) and 100% pure by ELSD.
1
H NMR, 300 mHz, CDCl ): l 7.49 (m, 3H), 7.39 (m,
3
References
5H), 7.29 (s, 2H), 7.27 (d, J=3 Hz, 1H), 7.19 (m, 2H),
.08 (m, 2H), 6.32 (dd, J=0.9, 3.2 Hz, 1H), 4.36 (t,
J=6.3 Hz, 2H), 3.32 (t, J=6.9 Hz, 2H), 2.61 (quint.
7
1
2
3
. For an excellent review on the canthine and canthin-6-
one alkaloids, see: Ohmoto, T.; Koike, K. In The Alka-
loids; Brossi, A., Ed.; Academic Press: New York, 1989;
Vol. 36, pp. 135–170.
. (a) Haynes, H. F.; Nelson, E. R.; Price, J. R. Aust. J. Sci.
Res. Ser. A 1952, 5, 387; (b) Nelson, E. R.; Price, J. R.
Aust. J. Sci. Res. Ser. A 1952, 5, 563; (c) Nelson, E. R.;
Price, J. R. Aust. J. Sci. Res. Ser. A 1952, 5, 68.
. (a) Anderson, L. A.; Harris, A.; Phillipson, J. D. J. Nat.
Prod. 1983, 46, 374; (b) Arisawa, M.; Kinghorn, A. D.;
Cordell, G. A.; Farnsworth, N. R. J. Nat. Prod. 1983, 46,
J=6.9 Hz, 2H); HRMS calcd for C26
391.1917; found 391.1915 (M+H).
H N (M+H),
22 4
8. Experimental procedure for ‘one pot’ synthesis of 7: To a
5 mL Emrys Liberator™ reaction vial (Part c 351521)
with a stir bar was placed benzil, 5, (105 mg, 0.5 mol) the
indole-tethered acyl hydrazide, 1, (109 mg, 0.5 mmol),
ammonium acetate (385 mg, 5.0 mmol) and 2 mL of
glacial HOAc. The reaction vessel was heated in the
Emrys Liberator™ reactor cavity for 40 min at 220°C.
Quickly, ꢀ12 PSI of pressure was generated in the
reaction vessel and detected by the instrument. After 40
min, the vessel was rapidly cooled to 40°C by the unit.
Upon removal from the reactor cavity, the homogeneous
solution was concentrated on a nitrogen evaporator and
analyzed by LCMS. A major peak corresponding to 7
(2.708 min.) was observed—no peak (3.84 min.) corre-
sponding to 6 was detected. The crude LCMS purity for
7 was 77% (214 nm and ELSD). The sample was purified
by preparative mass guided HPLC to deliver 144 mg
(80%) of pure 7. Analytical LCMS indicated a single peak
2
22; (c) Ohmoto, T.; Nikaido, T.; Koide, K.; Kohda, K.;
Sankawa, U. Chem. Pharm. Bull. 1988, 36, 4588; (d)
Ouyang, Y.; Koide, K.; Ohmoto, T. Phytochemistry 1994,
3
6, 1543–1546.
4
. (a) Mitscher, L. A.; Shipchandler, M.; Showalter, H. D.
H.; Bathla, M. S. Heterocycles 1975, 3, 7; (b) Hagen, T.
J.; Cook, J. M. Tetrahedron Lett. 1988, 29, 2421; (c)
Hagen, T. J.; Narayanan, K.; Names, J.; Cook, J. M. J.
Org. Chem. 1989, 54, 2170; (d) Markgraf, J. H.; Finkel-
stein, M.; Cort, J. R. Tertahedron 1996, 52, 461 and
references cited therein.
(2.711 min, CH
CN/H O/0.1%TFA, 4 min gradient)
3
2
5
. Benson, S. C.; Li, J.-H.; Snyder, J. K. J. Org. Chem.
>98% pure by UV (214 nm) and 100% pure by ELSD.
( H NMR, 300 mHz, CDCl ): l 7.69 (m, 1H), 7.59 (m,
3
1H), 7.44 (m, 2H), 7.31 (m, 9H), 7.16 (m, 1H), 4.42 (t,
1
1
992, 57, 5285–5287.
6. Zhao, Z.; Leister, W. H.; Strauss, K. A.; Wisnoski, D.
D.; Lindsley, C. W. Tetrahedron Lett. 2003, 44, 1123–
J=5.7 Hz, 2H), 3.71 (t, J=5.7 Hz, 2H), 2.61 (t, J=5.7
1
127.
Hz, 2H); HRMS calcd for C26H N (M+H), 361.1699;
20 2
7
. (a) The single-mode microwave synthesizer empoyed for
this work was a Smithsynthesizer™, a unit now refered to
and sold under the name Emrys Liberator™ by Personal
Chemistry. For information on Personal Chemistry’s
microwave technology for organic synthesis, in-
found 361.1705 (M+H).
9. Laasko, P. V.; Robinson, R.; Vanderwala, H. P. Tetra-
hedron 1957, 1, 103.
10. Methyl carboxypropyl indole, 8: commercially avaialable
form Aldrich. Cat.c S54,041-2, $220/g.
cluding
the
Emrys
Liberator™,
see:
http://
11. Leister, W.; Strauss, K.; Wisnoski, D.; Zhao, Z.; Linds-
ley, C. J. Comb. Chem. 2003, in press.
www.personalchemistry.com; (b) Experimental procedure
for 6/7: To a 5 mL Emrys Liberator™ reaction vial (Part
c 351521) with a stir bar was placed benzil, 5, (105 mg,
12. Li, J.-H.; Snyder, J. K. Tetrahderon Lett. 1994, 35, 1485–
1488.
13. Pelish, H. E.; Westwood, N. J.; Feng, Y.; Kirchhausen,
T.; Shair, M. D. J. Am. Chem. Soc. 2001, 123, 6740–6741
and references cited therein.
0
0
.5 mol) the indole-tethered acyl hydrazide, 1, (109 mg,
.5 mmol), ammonium acetate (385 mg, 5.0 mmol) and 2
mL of glacial HOAc. The reaction vessel was heated in