Pd(II)-catalyzed synthesis of carbolines by iminoannulation of internal alkynes via direct c-h bond cleavage using dioxygen as oxidant

Article abstract of DOI:10.1021/ol100272s

(Figure Presented) A palladium-catalyzed iminoannulation of internal alkynes via direct C-H bond cleavage was developed. Dioxygen was employed as a clean oxidant In this kind of catalysis. Carbolines were synthesized from tert-butylimines of N-substituted indole-2-carboxaldehydes or indole-3-carboxaldehydes.

Full text of DOI:10.1021/ol100272s

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1540-1543
Pd(II)-Catalyzed Synthesis of Carbolines
by Iminoannulation of Internal Alkynes
via Direct C-H Bond Cleavage Using
Dioxygen as Oxidant
Shengtao Ding,† Zhuangzhi Shi,† and Ning Jiao*,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking UniVersity, Xue Yuan Road 38, Beijing 100191, China, and
State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
jiaoning@bjmu.edu.cn
Received February 2, 2010
ABSTRACT
A palladium-catalyzed iminoannulation of internal alkynes via direct C-H bond cleavage was developed. Dioxygen was employed as a clean
oxidant in this kind of catalysis. Carbolines were synthesized from tert-butylimines of N-substituted indole-2-carboxaldehydes or
indole-3-carboxaldehydes.
Pyrido[3,4-b]indoles1 and pyrido[4,3-b]indoles,2 commonly
known as ꢀ- and γ-carbolines, are of great importance in
the areas of pharmaceuticals and are also versatile building
blocks for natural products, bioactive compounds, and drugs.3
Compounds containing the ꢀ-carboline units have been found
to exhibit a wide range of biological activities, such as
possessing potent and varied CNS and antitumor properties,
acting as inhibitors of IκB kinase and PDE5, etc.4 γ-Car-
bolines have also been investigated as antitumor agents.3g,5
Their importance has stimulated considerable attention from
† Peking University.
(3) (a) Wang, Y.-H.; Tang, J.-G.; Wang, R.-R.; Yang, L.-M.; Dong,
Z.-J.; Du, L.; Shen, X.; Liu, J.-K.; Zheng, Y.-T. Biochem. Biophys. Res.
Commun. 2007, 355, 1091–1095. (b) Liu, J.; Wu, G.; Cui, G.; Wang, W.-
X.; Zhao, M.; Wang, C.; Zhang, Z.; Peng, S. Bioorg. Med. Chem. 2007,
15, 5672–5693. (c) Wu, J.-P; Wang, J.; Abeywardane, A.; Andersen, D.;
Emmanuel, M.; Gautschi, E.; Goldberg, D. R.; Kashem, M. A.; Lukas, S.;
Wang, M.; Martin, L.; Morwick, T.; Moss, N; Pargellis, C.; Patel, U. R.;
Patnaude, L.; Peet, G. W.; Skow, D; Snow, R. J.; Ward, Y.; Werneburg,
B.; White, A. Bioorg. Med. Chem. Lett. 2007, 17, 4664–4669. (d) Moura,
D. J.; Richter, M. F.; Boeira, J. M.; Henriques, J. A. P.; Saffi, J. Mutagenesis
2007, 22, 293–302. (e) Herraiz, T. J. Agric. Food. Chem. 2007, 55, 8534–
8540. (f) Li, Y.; Liang, F.; Jiang, W.; Yu, F.; Cao, R.; Ma, Q.; Dai, X.;
Jiang, J.; Wang, Y.; Si, S. Cancer Biol. Ther. 2007, 6, 1193–1199. (g) Sako,
K.; Aoyama, H.; Sato, S.; Hashimoto, Y.; Baba, M. Bioorg. Med. Chem.
2008, 16, 3780–3790. (h) Deveau, A. M.; Costa, N. E.; Joshi, E. M.;
Macdonald, T. L. Bioorg. Med. Chem. Lett. 2008, 18, 3522–3525. (i) Cao,
R.; Yi, W.; Wu, Q.; Guan, X.; Feng, M.; Ma, C.; Chen, Z.; Song, H.; Peng,
W. Bioorg. Med. Chem. Lett. 2008, 18, 6558–6561.
‡ Chinese Academy of Sciences.
(1) (a) Inman, W. D.; Brat, W. M.; Gassner, N. C.; Lokey, R. S.; Tenney,
K.; Suh, T.; Crews, P. J. Nat. Prod. 2010, 73, 255–257. (b) Till, M.; Prinsep,
M. R. J. Nat. Prod. 2009, 72, 796–798. (c) Takahashi, Y.; Kubota, T.;
Fromont, J.; Kobayashi, J. Org. Lett. 2009, 11, 21–24. (d) Wang, W.; Nam,
S.-J.; Lee, B.-C.; Kang, H. J. Nat. Prod. 2008, 71, 163–166. (e) Kearns,
P. S.; Rideout, J. A. J. Nat. Prod. 2008, 71, 1280–1282. (f) Teichert, A.;
Schmidt, J.; Porzel, A.; Arnold, N.; Wessjohann, L. J. Nat. Prod. 2007,
70, 1529–1531. (g) Costa, E. V.; Pinheiro, M. L. B. J. Nat. Prod. 2006, 69,
292–294. (h) Becher, P. G.; Beuchat, J.; Gademann, K.; Ju¨ttner, F. J. Nat.
Prod. 2005, 68, 1793–1795. (i) Iinuma, Y.; Kozawa, S.; Ishiyama, H.; Tsuda,
M.; Fkushi, E.; Kawabata, J.; Fromont, J.; Kobayashi, J. J. Nat. Prod. 2005,
68, 1109–1110. (j) Youssef, D. T. A. J. Nat. Prod. 2005, 68, 1416–1419.
(2) (a) Alekseyev, R. S.; Kurkin, A. V.; Yurovskaya, M. A. Chem.
Heterocycl. Compd. 2009, 45, 889–925. (b) Butin, A. V.; Pilipenko, A. S.;
Milich, A. A.; Finko, A. V. Chem. Heterocycl. Compd. 2009, 45, 613–
614.
10.1021/ol100272s  2010 American Chemical Society
Published on Web 03/08/2010

organic chemists and encouraged the development of new
synthetic strategies to construct carbolines.6 Recently, Larock
and co-workers developed a palladium-catalyzed annulation
between internal alkynes and tert-butylimines of N-substi-
tuted 3-iodoindole-2-carboxaldehydes or 2-haloindole-3-
carboxaldehydes (eq 1, Scheme 1).6a,d However, aryl halides
respectively, using O2 as the oxidant.10 On the basis of these
results, we envisioned a direct-dehydrogenative anulation
(DDA) of internal alkynes and tert-butylimines of N-
substituted indole-carboxaldehydes to generate carboline
derivatives (eq 2).
The initial iminoannulation of internal alkynes was
examined by the reaction of the tert-butylimine of 1-meth-
ylindole-2-carboxaldehyde (1a) with 4-octyne (2a) in DMF
in the presence of Pd(OAc)2 (10 mol %), K2CO3, and 4 Å
MS (150 mg) under O2 (1 atm). The expected product
ꢀ-carboline 3aa was successfully obtained in 48% yield
(entry 1, Table 1). The yield was slightly improved to 55%
Scheme 1. Pd-Catalyzed Approaches to Carbolines
Table 1. Optimization of Pd-Catalyzed Annulation Conditionsa
yield
entry
[Pd ]
base
K2CO3
K2CO3
Na2CO3
additive solvent (%)b
1
2
3
4
5
6
7
8
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd(OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
Pd (OAc)2
PdCl2
DMF
TBAB DMF
TBAB DMF
48
55
58
30
35
71
45
28
31
62
were required and halide byproducts were produced via these
methods. With the development of chemical science, C-H
functionalization has received substantial attention, because
of its sustainable and environmentally benign features.7
Herein, we describe a Pd(II)-catalyzed iminoannulation of
internal alkynes and tert-butylimines of N-substituted indole-
carboxaldehydes via direct C-H bond activation using
dioxygen as a clean oxidant (eq 2, Scheme 1).
HCOONa·2H2O TBAB DMF
pyridine
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
TBAB DMF
TBAB DMF
TBAC DMF
TBAF DMF
TBAB DMA
TBAB DMSO
9
10
11
12
13
14
15
TBAB CH3CN 49
TBAB toluene 22
We recently developed direct-dehydrogenative anulation
(DDA) reactions of simple anilines8 or biaryls9 with internal
alkynes to generate indoles and carbazole derivatives,
TBAB THF
TBAB DMF
TBAB DMF
TBAB DMF
TBAB DMF
18
55
59
54
38
Pd (PhCN)2Cl2 NaHCO3
16c Pd (OAc)2
NaHCO3
NaHCO3
17d Pd (OAc)2
(4) (a) Wernike, C.; Schott, Y.; Enzensperger, C.; Schulze, G.; Lehmann,
J.; Rommelspacher, H. Biochem. Pharmacol. 2007, 74, 1065–1077. (b)
Hanson, S. M.; Czajkowski, C. J. Neurosci. 2008, 28, 3490–3499. (c)
Herraiz, T.; Guille´n, H.; Ara´n, V. J. Chem. Res. Toxicol. 2008, 21, 2172–
2180. (d) Mansoor, T. A.; Ramalho, R. M.; Mulhovo, S.; Rodrigues,
C. M. P.; Ferreira, M. J. U. Bioorg. Med. Chem. Lett. 2009, 19, 4255–
4258.
a 1a (0.20 mmol), 2a (0.40 mmol), [Pd] (10 mol %), base (0.40 mmol),
additive (0.20 mmol), 4 Å MS (150 mg), and solvent (2 mL) were heated
in a sealed tube under O2 (1 atm), 80 °C, 24 h. b Isolated yields. c 5 mol %
Pd(OAc)2 was employed. d The reaction was carried out under air.
(5) (a) Chen, J.; Dong, X.; Liu, T.; Lou, J.; Jiang, C.; Huang, W.; He,
Q.; Yang, B.; Hu, Y. Bioorg. Med. Chem. 2009, 17, 3324–3331. (b)
Ivachtchenko, A. V.; Frolv, E. B.; Mitkin, O. D.; Kysil, V. M.; Khvat,
A. V.; Okun, I. M.; Tkachenko, S. E. Bioorg. Med. Chem. Lett. 2009, 19,
3183–3187. (c) Bonjoch, J.; Diaba, F.; Pages, L.; Perez, D.; Soca, L.;
Miralpeix, M.; Vilella, D.; Anton, P.; Puig, C. Bioorg. Med. Chem. Lett.
2009, 19, 4299–4302.
when TBAB (1 equiv) was added (entry 2, Table 1). As other
bases such as Na2CO3, HCOONa·2H2O, pyridine, and
NaHCO3 (entries 3-6, Table 1) were tested in the reaction,
(6) (a) Zhang, H.; Larock, R. C. Org. Lett. 2001, 3, 3083–3086. (b)
Zhang, H.; Larock, R. C. Org. Lett. 2002, 4, 3035–3038. (c) Zhang, H.;
Larock, R. C. J. Org. Chem. 2002, 67, 7048–7056. (d) Zhang, H.; Larock,
R. C. J. Org. Chem. 2002, 67, 9318–9330. (e) Zhang, H.; Larock, R. C. J.
Org. Chem. 2003, 68, 5132–5138. (f) Lindsley, C. W.; Wisnoski, D. D.;
Wang, Y.; Leister, W. H.; Zhao, Z. Tetrahedron Lett. 2003, 44, 4495–
4498. (g) Batanova, O. V.; Dubovitskii, S. V. Tetrahedron Lett. 2004, 45,
1299–1300. (h) Golovko, T. V.; Soloveva, N. P.; Anisimova, O. S.;
Smirnova, O. B.; Evstratova, M. I.; Kiselev, S. S.; Granik, V. G. Russ.
Chem. Bull., Int. Ed. 2008, 57, 177–185. (i) Smirnova, O. B.; Golovko,
T. V.; Alekseeva, L. M.; Shashkov, A. S.; Granik, V. G. Russ. Chem. Bull.
2008, 57, 2410–2417. (j) Movassaghi, M.; Hill, M. D. Org. Lett. 2008, 10,
3485–3488. (k) Singh, V.; Hutait, S.; Batra, S. Eur. J. Org. Chem. 2009,
6211–6216. (l) Kulkarni, A.; Abid, M.; Huang, X. D. Tetrahedron Lett.
2009, 50, 1791–1794. (m) Chiba, S.; Xu, Y.-J.; Wang, Y.-F. J. Am. Chem.
Soc. 2009, 131, 12886–12887.
(7) For recent reviews on C-H activation, see: (a) Giri, R.; Shi, B.-F.;
Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. ReV. 2009, 38, 3242–
3272. (b) Collet, F.; Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061–
5074. (c) Whited, M. T.; Grubbs, R. H. Acc. Chem. Res. 2009, 42, 1607–
1616. (d) McGlacken, G. P.; Bateman, L. M. Chem. Soc. ReV. 2009, 38,
2447–2464. (e) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094–5115. (f) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074–1086. (g) Joucla, L.;
Djakovitch, L. AdV. Synth. Catal. 2009, 351, 673–714. (h) Catellani, M.;
Motti, E.; Della Ca, N. Acc. Chem. Res. 2008, 41, 1512–1522. (i) Li, B.-J.;
Yang, S.-D.; Shi, Z.-J. Synlett 2008, 7, 949–957.
(8) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N. Angew.
Chem., Int. Ed. 2009, 48, 4572–4576.
(9) Shi, Z.; Ding, S.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48,
7895–7898.
Org. Lett., Vol. 12, No. 7, 2010
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it was revealed that NaHCO3 is the most effective base for
this transformation (71% yield, entry 6, Table 1). Under these
conditions, different phase-transfer catalysts (entries 7 and
8, Table 1), solvents (entry 9-13, Table 1), and Pd catalysts
(entries 14 and 15, Table 1) were investigated but gave lower
efficiencies. ꢀ-Carboline 3aa was produced in 38% yield
when this reaction was carried out under air (entry 17, Table
1).
Table 3. Pd(OAc)2-Catalyzed DDA Reaction of 1a with Internal
Alkynes 2a
Under the optimal conditions, we then investigated the
scope of this transformation by different N-substituted tert-
butylimines of indole-carboxaldehydes (Table 2). Using
Table 2. Pd(OAc)2-Catalyzed DDA Reaction of 1 with 2aa
a Conditions: 1a (0.40 mmol), 2 (0.80 mmol), Pd(OAc)2 (10 mol %),
TBAB (0.40 mmol), NaHCO3 (0.80 mmol), and 4 Å MS (300 mg) in 4 mL
of DMF under O2 (1 atm), 80 °C, 36 h. b Isolated yield. c The ratio was
1
determined by HNMR.
The scope of the direct-dehydrogenative annulation (DDA)
reaction was further expanded to a variety of internal alkynes
(Table 3). The results in Table 3 demonstrate that this
transformation has a high degree of functional group toler-
ance in the internal alkyne partners. Alkyl groups, aryl
a Conditions: 1 (0.40 mmol), 2a (0.80 mmol), Pd(OAc)2 (10 mol %),
TBAB (0.40 mmol), NaHCO3 (0.80 mmol), and 4 Å MS (300 mg) in 4 mL
of DMF under O2 (1 atm), 80 °C, 36 h. b Isolated yield.
(10) For some reviews, see: (a) Stahl, S. S. Angew. Chem., Int. Ed. 2004,
43, 3400–3420. (b) Punniyamurthy, T.; Velusamy, S.; Iqbal, J. Chem. ReV.
2005, 105, 2329–2364. For some Pd-catalyzed examples, see: (c) Stahl,
S. S. Science 2005, 309, 1824–1826. (d) Nielsen, R. J.; Goddard, W. A.,
III J. Am. Chem. Soc. 2006, 128, 9651–9660. (e) Steinhoff, B. A.; Stahl,
S. S. J. Am. Chem. Soc. 2006, 128, 4348–4355. (f) Li, B.; Tian, S.; Fang,
Z.; Shi, Z. Angew. Chem., Int. Ed. 2008, 47, 1115–1118. (g) Liu, G.; Yin,
G.; Wu, L. Angew. Chem., Int. Ed. 2008, 47, 4733–4736. (h) Wang, D.-H.;
Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190–7191. (i)
Konnick, M. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 5753–5762.
For some our recent works, see: (j) Chen, A; Lin, R.; Liu, Q; Jiao, N. Chem.
Commun. 2009, 6842–6844. (k) Zhang, C.; Jiao, N. J. Am. Chem. Soc. 2010,
132, 28–29.
N-substituted tert-butylimines of indole-2-carboxaldehydes
led to good yields of the corresponding ꢀ-carbolines (entries
1, 3, and 4, Table 2). Moreover, when the N-substituted tert-
butylimines of indole-3-carboxaldehydes were allowed to
react with 4-octyne, the C-H bond at C-2 could also be
cleaved, generating the corresponding γ-carbolines with
moderate yields (entries 5 and 6, Table 2). However, the
tert-butylimine of indole-2-carboxaldehyde 1b did not work
under these conditions (entry 2, Table 2).
1542
Org. Lett., Vol. 12, No. 7, 2010

groups, and esters are well tolerated, generating the corre-
sponding carbolines in moderate yields. But-2-yne-1,4-diyl
diacetate (2c) smoothly underwent cyclization with 1a,
leading to 3ac in 42% yield (entry 2, Table 3). It is
particularly noteworthy that with unsymmetrical alkynes with
an ester group and an aryl group, such as 3-phenylpropiolates,
a single carboline isomer was obtained with high regiose-
lectivity (entries 6 and 7, Table 3). However, other unsym-
metrical alkynes, such as 1-phenylpropyne, 1-phenylhexyne,
phenylcyclopropylacteylene, and but-2-ynyl acetate, pro-
duced two regioisomers.
D as well as a Pd0 complex, which can be reoxidized to a
PdII species for a new catalytic cycle by O2 (1 atm). As
previously suggested by Heck12 and Larock,6a,d the tert-butyl
group of the tert-butylcarbolinium salt D apparently frag-
ments to produce carbolines 3 (Scheme 2).
In summary, we have demonstrated a novel Pd(II)-
catalyzed direct-dehydrogenative annulation (DDA) of in-
ternal alkynes and tert-butylimines of N-substituted indole-
carboxaldehydes via direct C-H bond activation leading to
carboline derivatives. Use of dioxygen (1 atm) as the oxidant
and the absence of ligands make this approach very easy to
handle. Further efforts to expand the scope of this transfor-
mation and the synthetic applications are ongoing in our
laboratory.
A plausible mechanism for the DDA reaction of 1 with
alkyne 2 is illustrated in Scheme 2. The initiated electrophilic
Acknowledgment. Financial support from Peking Uni-
versity, National Science Foundation of China (Nos. 20702002,
20872003), and National Basic Research Program of China
(973 Program) (Grant No. 2009CB825300) are greatly
appreciated. We thank Wei Jia and Riyuan Lin in this group
for reproducing the results of 3da, 3ad, and 3ag.
Scheme 2. Plausible Mechanism for the DDA Reaction
Supporting Information Available: Experimental details
and NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL100272S
(11) (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172–1175. (b)
Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130,
8172–8174. (c) Beck, E. M.; Hatley, B. R.; Gaunt, M. J. J. Am. Chem. Soc.
2006, 128, 2528–2529. (d) Grimster, N. P.; Gauntlett, C.; Godfrey, C. M. R.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44, 3125–3129. (e) Ferrira, E. M.;
Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578–9579. (f) Dwight, T. A.;
Rue, N. R.; Charyk, D.; Josselyn, R.; Deboef, B. Org. Lett. 2007, 9, 3137–
3139. (g) Kong, A.; Han, X.; Lu, X. Org. Lett. 2006, 8, 1339–1342.
(12) (a) Wu, G.; Rheingold, A. L.; Geib, S. J.; Heck, R. F. Organome-
tallics 1987, 6, 1941–1946. (b) Wu, G.; Geib, S. J.; Rheingold, A. L.; Heck,
R. F. J. Org. Chem. 1988, 53, 3238–3241.
aromatic palladation11 affords a PdII intermediate A. The
resulting intermediate A subsequently inserts into 2 to
produce a vinylic palladium(II) intermediate B, followed by
reaction with the neighboring imine substituent to form a
seven-membered palladacyclic immonium salt C. Subsequent
reductive elimination generates a tert-butylcarbolinium salt
Org. Lett., Vol. 12, No. 7, 2010
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