Intramolecular Diels-Alder synthesis of 7-aza-α-carboline compounds

Article abstract of DOI:10.1016/j.tetlet.2010.01.095

An efficient, versatile, and scalable route for the synthesis of 7-aza-α-carboline compounds is described. The tricyclic system has been prepared from modified pyrazinones using a key intramolecular [4+2] Diels-Alder transformation.

Full text of DOI:10.1016/j.tetlet.2010.01.095

Tetrahedron Letters 51 (2010) 1739–1741
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular Diels–Alder synthesis of 7-aza-a-carboline compounds
*
Michael B. Wallace , Nicholas Scorah, Phong H. Vu, Jason W. Brown, Jeffrey A. Stafford, Qing Dong
Department of Medicinal Chemistry, Takeda San Diego, 10410 Science Center Drive, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, versatile, and scalable route for the synthesis of 7-aza-a-carboline compounds is described.
The tricyclic system has been prepared from modified pyrazinones using a key intramolecular [4+2]
Diels–Alder transformation.
Received 5 January 2010
Revised 22 January 2010
Accepted 25 January 2010
Available online 1 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
a
-Carboline compounds have shown potential in numerous
dride followed by hydrogenation in the presence of palladium
hydroxide gave the benzyl-deprotected product 8a in 24% yield,
along with starting material and a complex mixture of over-re-
duced by-products. The electron-withdrawing effect provided by
the indole acyl group seemed to be necessary for successful de-
benzylation. In addition, acylation facilitated the reaction by
improving the solubility of intermediate 7a. De-acylation occurred
slowly during the hydrogenation process. Chlorination of the pyri-
done 8a with POCl3 gave compound 9a in high yield.
The use of a p-methoxybenzyl-(PMB)-protecting group pro-
vided a more facile and high-yielding conversion of 7 into 9. The
PMB deprotection and pyridone chlorination was accomplished
in a single high-yielding step with POCl3 in the presence of tetra-
methylammonium chloride. With the successful synthesis of our
target 8-chloro compounds (9a and 9c), we had versatile interme-
diates which could be used for 8-position SAR development via dis-
placement reactions and palladium-coupling chemistry.
drug discovery applications, such as antiviral agents and inhibitors
for oncology targets and metabolic diseases.1 In the course of our
recent medicinal chemistry efforts, we designed and pursued a no-
vel series of compounds built upon a 7-aza-a-carboline scaffold
(Fig. 1). For SAR purposes, we required a synthetic scheme that
would be amenable to substitution at the 3-, 5-, and 8-positions
of the core. Syntheses of modified
widely reported.2 However, convenient approaches to the synthe-
sis of a functionalized 7-aza-
-carboline core are severely limited.3
The intramolecular Diels–Alder reaction has proven to be a
powerful transformation utilized in the synthesis of complex het-
erocyclic systems.4 Hoornaert and co-workers described an elegant
a-carboline systems have been
a
route to the synthesis of a- and b-carbolines from pyrazinones via
a key intramolecular Diels–Alder reaction step (Fig. 2).5 We sought
to adopt a modification of this methodology in order to access the
7-aza-
a-carboline core.
The synthesis of the functionalized 7-aza-
a
-carboline scaffold is
The inverse demand Diels–Alder reaction required a sufficiently
electron-rich dienophile for compatibility with the electron defi-
outlined in Scheme 1. The known dichloropyrazinone compounds
1a and 1b were synthesized from the reaction of an N-benzylic
cyanomethylamine with oxalyl chloride.6 Selective 2-chloro dis-
placement with the substituted 2-aminopyridine 2a and 2b under
basic conditions produced compounds 3a–c in moderate yields.
The subsequent reaction with ethynyltrimethylsilane using Sono-
gashira coupling conditions provided the acetylene-containing
pyrazinone intermediates 4a–c.
6
5
4
7
3
N
8
2
N
N
1
H
The Diels–Alder reaction of compounds 4a–c by thermolysis in
toluene proceeded with the loss of ClCN (Fig. 3) to give compounds
5a–c in high yields. The TMS group of 5a–c was converted to an
iodo group using Lewis acid catalyzed iodination conditions7 to
yield compounds 6a–c. The Suzuki coupling reaction of 6a–c with
3-(ethylsulfonyl)-phenylboronic acid afforded compounds 7a–c.
Deprotection of the benzyl analogue 7a proved to be an ineffi-
cient process. Acylation of the indole nitrogen with acetic anhy-
Figure 1. 7-Aza-
a
-carboline core.
R
R6
N
R
H
N
tetrahydronaphthalene
reflux
N
Cl
R1
O
R6
O
N
N
H
R1
* Corresponding author. Tel.: +1 858 731 3598; fax: +1 858 550 0526.
E-mail address: michael.wallace@takedasd.com (M.B. Wallace).
Figure 2. Key b-carboline synthesis step.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.095

1740
M. B. Wallace et al. / Tetrahedron Letters 51 (2010) 1739–1741
Br
H
N
Cl
N
Cl
N
NH2
Br
N
Cl
a
b
c
R
N
N
+
N
O
N
R
H
R1
R1
3a
3b
3c
O
N
R
.
HCl
2a
: R1 = Me
2b: R1 = Cl
1a: R = Bn
1b: R = PMB
: R1 = Me, R = Bn
: R1 = Me, R = PMB
: R1 = Cl, R = PMB
TMS
I
TMS
H
e
f
d
R
N
R
N
R1
N
N
Cl
R1
N
O
O
N
H
N
H
N
R1
O
N
R
N
6a-c
5a-c
4a-c
S
O O
S
O O
S
For 7a:
O
O
g
h
NH
R
N
N
R1
R1
O
N
N
Cl
O
N
N
H
N
H
N
H
For 7b and 7c:
8a
7a-c
9a: R1 = Me
9c: R1 = Cl
i
Scheme 1. Synthesis of the functionalized 7-aza-
a-carboline compounds 9a and 9c. Reagents, conditions, and yields: (a) (COCl)2, Et3NÁHCl, chlorobenzene (85%); (b) NaH,
THF (40–72%); (c) TMS–acetylene, (Ph3P)2PdCl2, Et3N, Ph3P, CuI, THF (81–96%); (d) toluene, 110 °C, 4 days (82–89%); (e) I2, AgBF4, dichloromethane (>85%); (f) 3-EtSO2Ph-
B(OH)2, (Ph3P)4Pd, aq K2CO3, dioxane (68–85%); (g) 1—Ac2O, 2—H2, Pd(OH)2, HOAc (24%); (h) POCl3 (92%); (i) POCl3, Me4N+ClÀ (79–85%).
cient diene in order for the reaction to occur. When the TMS group
of 4a was replaced with an electron deficient 3-(ethylsulfonyl)-
phenyl group, the Diels–Alder reaction failed to proceed.
The conditions for the Diels–Alder reaction were optimized as
the scale of the reaction was increased from milligram to multi-
gram quantities (Table 1). Initially, the reactions were carried out
by heating the mixture for two hours in tetrahydronaphthalene
at 200 °C. Yields were improved by running the reaction at lower
reaction temperature (110 °C), which required longer reaction
times (4 days) to push the reaction to nearly complete consump-
tion of starting material. The solvent was changed with decreasing
reaction temperature in order to facilitate its removal. The use of
different non-polar solvents had no noticeable effect on the
reaction.9
The desilylation products 10a–c were significant side-products
of the Diels–Alder reactions. Lowering the reaction temperature
decreased the amount of the side-product, and the addition of
diisopropylethylamine (DIEA) to the reaction eliminated it com-
pletely. The DIEA prevented the possibility of acidic desilylation
caused by derivatives of the cyanogen chloride leaving group (cya-
nic acid, hydrochloric acid). The dilute solutions (0.01 M) favorable
for the intramolecular reaction soon became impractical upon scal-
ing the reaction to multi-gram quantities. However, at 110 °C we
were also able to increase the concentration (0.04) without a de-
crease in product yield. Both methyl and chloro group R1 substitu-
ents were well tolerated.
We have demonstrated an efficient, scalable route for the syn-
thesis of functionalized 7-aza-a-carboline compounds. This meth-
Table 1
Optimization of the Diels–Alder reaction conditions
TMS
TMS
H
N
R
R1
N
O
N
Cl
R1
N R
+
N
O
N
O
N
R1
N
R
N
H
N
H
10a-c
5a-c
4a: R1 = Me, R = Bn
4b: R1 = Me, R = PMB
4c: R1 = Cl, R = PMB
Reactant
Scale (g of 4)
Concentration (M)
Solvent
Temperature (°C)
Time (h)
% Yield 4a
% Yield 5b
% Yield 10a
4a
4a
4a
4b
4b
4b
4c
0.12
2.0
3.5
11.0
8.8
35.2
5.8
0.01
0.02
0.02
0.04
0.01
0.04
0.02
Tetrahydronaphthalene
1,2-Dichlorobenzene
Bromobenzene
Bromobenzene
Bromobenzene
200
160
140
140
115
110
110
2
3.5
16
6
48
94
96
0
5
6
40
6
1
51
42
61
12
73
89
88
12
26
9
42
15
2
Toluene
Toluene, DIEA (1.5 equiv)
2
0
a
Analytical HPLC ratio analysis.8
Isolated yield.
b

M. B. Wallace et al. / Tetrahedron Letters 51 (2010) 1739–1741
1741
R
N
References and notes
R
O
N
1. (a) Blackburn, T. P.; Bolton, D.; Forbes, I. T.; Johnson, C. N.; Marin, R. T.; Thomas,
D. R.; Thompson, M.; Upton, N. Bioorg. Med. Chem. Lett. 1994, 4, 279; (b)
Sennbenn, P.; Mantoulidis, A.; Treu, M.; Tontsch-Grunt, U.; Spevak, W.;
McConnel, D.; Schoop, A.; Brueckner, R.; Jacobi, A.; Guertler, U.; Schnapp, G.;
Klein, C.; Himmelsbach, F.; Pautsch, A.; Betzmeier, B.; Herfurth, L.; Mack, J.;
Wiedenmayer, D.; Bader, G.; Reiser, U. U.S. Patent Appl. US 07/0004684.; (c)
Kubota, H.; Miura, M.; Sasuga, D.; Moritani, H. Eur. Patent Appl. EP1367058.
2. For recent approaches, see: (a) Schmittel, M.; Steffen, J.-P.; Rodriguez, D.;
Engelen, B.; Neumann, E.; Cinar, M. E. J. Org. Chem. 2008, 73, 3005; (b) Mehta, L.
K.; Parrick, J.; Payne, F. J. Chem. Soc., Perkin Trans. 1 1993, 11, 1261; (c) Molina, P.;
Alajarin, M.; Vidal, A.; Sanchez-Andrada, P. J. Org. Chem. 1992, 57, 929; (d)
Schneider, C.; Gueyrard, D.; Popowycz, F.; Joseph, B.; Goekjian, P. G. Synlett 2007,
14, 2237; (e) Malapel-Andrieu, B.; Mérour, J.-Y. Tetrahedron 1998, 54, 11095.
3. (a) Bahekar, R. H.; Jain, M. R.; Jadav, P. A.; Goel, A.; Patel, D. N.; Prajapati, V. M.;
Gupta, A. A.; Modi, H.; Patel, P. R. Bioorg. Med. Chem. 2007, 15, 5950; (b) Bhatti, I.
A.; Busby, R. E.; Mohamed, M.; Parrick, J.; Shaw, C. J. G. J. Chem. Soc., Perkin Trans.
1 1997, 24, 3581.
O
TMS
Cl
Cl
N
NH
TMS
N
N
HN
R1
N
R1
4a-c
- ClCN
R
O
TMS
N
4. (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. Angew.
Chem., Int. Ed. 2002, 41, 1668; (b) Roush, W. R.. In Comprehensive Organic
Synthesis; Pergamon Press: Oxford, 1991; Vol. 5. p 513.
HN
R1
N
5. Thari, A.; Buysens, K. J.; Van der Eycken, E. V.; Vandenberghe, D. M.; Hoornaert,
G. J. Tetrahedron 1998, 54, 13211.
6. (a) Vekemans, J.; Pollers-Wieërs, C.; Hoornaert, G. J. Heterocycl. Chem. 1983, 20,
919; (b) Rombouts, F. J. R.; De Borggraeve, W.; Toppet, S. M.; Compernolle, R.;
Hoornaert, G. J. Tetrahedron Lett. 2001, 42, 7397.
5a-c
Figure 3. Proposed Diels–Alder reaction mechanism.
7. Wilson, S. R.; Jacob, L. A. J. Org. Chem. 1986, 51, 4833.
8. HPLC/MS compound purity data were acquired on an Agilent LC/MS single
quadrupole system equipped with electrospray ionization (ESI) source, UV
detector (220 and 254 nm), and evaporative light-scattering detector (ELSD).
Data are reported for HPLC product peak integration ratios at 254 nm.
9. Sauer, J.; Sustmann, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 779.
od allows for a high degree of diversity at the 5- and 8-positions of
the tricyclic core. These results provide new possibilities for utiliz-
ing the 7-aza-a-carboline system in drug discovery.
Supplementary data
Supplementary data (chemistry experimental procedures and
compound characterization) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.01.095.