Palladium-catalyzed double allylic alkylation of indole-2-hydroxamates: easy access to pyrazino[1,2-a]indole derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.11.031

The synthesis of pyrazino[1,2-a]indoles via a palladium-catalyzed double allylic alkylation of indole-2-hydroxamates is described. The reaction conditions are very mild and allow for a wide variety of substitutions on the indole core.

Full text of DOI:10.1016/j.tetlet.2009.11.031

Tetrahedron Letters 51 (2010) 363–366
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed double allylic alkylation of indole-2-hydroxamates:
easy access to pyrazino[1,2-a]indole derivatives
*
Sébastien Laliberté , Peter K. Dornan, Austin Chen
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Hwy, Kirkland, Qc, Canada H9H 3L1
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of pyrazino[1,2-a]indoles via a palladium-catalyzed double allylic alkylation of indole-2-
hydroxamates is described. The reaction conditions are very mild and allow for a wide variety of substi-
tutions on the indole core.
Received 7 October 2009
Revised 30 October 2009
Accepted 9 November 2009
Available online 13 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Over the years, pyrazino-indoles have been shown to be impor-
tant templates in medicinal chemistry. They have found various
applications such as antidepressant1, anti-inflammatory2 and
anti-obesity3 agents. Most methods described for their synthesis
are either lengthy or use conditions that are not compatible with
many functional groups. We report herein mild and versatile con-
ditions for the synthesis of pyrazino[1,2-a]indoles via palladium-
catalyzed double allylic alkylation of indole-2-hydroxamate.
In light of some recent work published by Trost4 and our group5
on the palladium-catalyzed allylic alkylation (Pd-AA) of 2-bromo-
pyrrole, we envisioned that a similar methodology might be appli-
cable to indole-2-hydroxamates, thus providing a quick access to
pyrazino-indoles (Scheme 1).
To assess the feasibility of this strategy, we first performed the
reaction using conditions that were developed by Trost’s group in
the synthesis of Agelastatin A.4 Unfortunately, treating 1 and 2 with
Pd2(dba)3ÁCHCl3, Trost’s ligand6 and HOAc in DCM gave no desired
product. However, when using conditions previously used in our
laboratory for the Pd-AA of 2-bromopyrrole (Table 1, entry 1), we
were pleased to observe, albeit in low yield, the desired product.
Interestingly, we also observed side product 4 arising from the
alkylation of a second hydroxamate rather than the desired intra-
molecular displacement by the indole. It is worth noting that no
alkylation at C-3 of the indole nor any of the possible eight-mem-
bered rings that could arise from the substitution on the terminal
carbon of the chain during the second alkylation were observed.
R
OBoc
R
O
O
HN OR'
Pd catalyst
+
N
H
N OR'
Ligand
N
H
OBoc
BocO
R
O
N
N OR'
Scheme 1. One-pot approach to pyrazino[1,2-a]indoles.
* Corresponding author.
E-mail address: sebastien_laliberte@merck.com (S. Laliberté).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.031

364
S. Laliberté et al. / Tetrahedron Letters 51 (2010) 363–366
Table 1
Optimisation of solvent and additives
O
N
N
OBoc
OMe
O
Pd2(dba)3CHCl3 (5 mol%)
P(Oi-Pr)3 (30 mol%)
H
O
N
N OMe
+
+
N
H
HN OMe
solvent, rt
H
N OMe
O
N
OBoc
3
4
2
1
Entry
Solvent
Equiv of 2
Additive
Yield 3a (%)
Yield 4a (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Toluene
DMF
EtOH
THF
MeCN
DCE
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.3
1.8
1.5
1.5
1.5
1.5
None
None
None
None
None
None
None
None
None
None
HOAcb
DIPEAc
28
21
28
7
20
8
18
19
10
11
9
27
13
10
16
14
16
0
27
64
69
37
57
60
57
62
16
0
c
Cs2CO3
LiClc
a
b
c
Yields determined by HPLC.
10 mol %.
1.0 equiv.
A rapid screen of solvents (Table 1, entries 1–7) showed that
DCE and DCM were the preferred solvents for this reaction, giving
the desired product in 64% and 69% yield, respectively.
such as HOAc (which had previously proven beneficial),4 but none
showed any improvement to the reaction (entries 11–14).
When examining the palladium source, we observed that both
Pd2(dba)3 and Pd(dba)2 gave good yields of the desired product.
However Pd/C, Pd(OAc)2, Pd(P(tBu)3)2 and [Pd(C3H5)Cl]2 gave no
conversion. Among the various ligands tested, P(O-iPr)3 gave the
best results while alkyl phosphines displayed no conversion to
product (Table 2, entries 1–7). By modifying the amount of ligand,
it was found that an increasing ratio of ligand/Pd up to 2.7 gave in-
creased conversion with no significant further increase at higher
ratios. (Table 2, entries 8–12).
With DCM as the solvent, the amount of dicarbonate 2 used was
examined (Table 1, entries 7–10). Increasing the amount of electro-
phile 2 from 1 to 1.5 equiv diminished the amount of side product 4
and increased the amount of the desired product. However, further
increases to 1.8 equiv and higher did not result in any improvement
in yield and the reaction became much slower. This behaviour may
be explained by the excess electrophile sequestering the catalyst,
thus slowing down the reaction. Several additives were also tested,
Table 2
Optimisation of reaction conditions
O
N
OBoc
O
OMe
N
O
H
"Pd" (5 mol%), Ligand
DCM, rt
N
N OMe
+
+
N
H
HN OMe
H
N OMe
O
N
OBoc
3
4
2
1
Entry
Catalyst
Ligand
Ratio Ligand/Pd
Yield 3a (%)
Yield 4a (%)
1
2
3
4
5
6
7
8
9
Pd2(dba)3ÁCHCl3
Pd(dba)2
P(Oi-Pr)3
P(Oi-Pr)3
P(OPh)3
PPh3
P(t-Bu)3
P(n-Bu)3
dppp
P(Oi-Pr)3
P(Oi-Pr)3
P(Oi-Pr)3
P(Oi-Pr)3
P(Oi-Pr)3
2.7
2.7
2.7
2.7
2.7
2.7
2.7
1.5
2.0
2.5
3.0
4.0
69
65
26
45
0
9
9
16
10
0
0
0
0
11
11
10
9
Pd2(dba)3ÁCHCl3
Pd2(dba)3ÁCHCl3
Pd2(dba)3ÁCHCl3
Pd2(dba)3ÁCHCl3
Pd2(dba)3ÁCHCl3
Pd2(dba)3ÁCHCl3
Pd2(dba)3ÁCHCl3
Pd2(dba)3ÁCHCl3
Pd2(dba)3ÁCHCl3
Pd2(dba)3ÁCHCl3
0
0
Trace
56
66
68
70
10
11
12
a
Yields determined by HPLC

S. Laliberté et al. / Tetrahedron Letters 51 (2010) 363–366
365
With a suitable set of reaction conditions developed, we next
sought to determine the effect of the hydroxamate substituent.
To our knowledge, since it was first reported by Trost4, methyl
and benzyl hydroxamates are the only hydroxamates that have
been successfully used in Pd-AA. It was envisaged that increasing
the bulkiness of the O-substituent would disfavour the formation
of by-product 4. Indeed, as shown in Table 3, when the size of
the substituent was increased from Me to i-Pr to t-Bu the yield of
the product improved from 58% to 78% to 81%.
tion proceeded smoothly for a wide variety of substituents on the
indole (Table 4). More specifically, electron-donating, electron-
withdrawing as well as conjugating groups were all tolerated at
various positions. It is of special interest that a bromine atom (Ta-
ble 4, entry 9) does not react under the reaction conditions and
thus offers a good handle for subsequent elaboration of this sub-
strate under transition-metal-catalyzed coupling conditions. Fur-
thermore, every position of the indole could be substituted
without affecting the outcome of the reaction.
When an alkyl amide was used (Table 3, entry 5), no reaction
occurred, demonstrating that the enhanced nucleophilicity pro-
vided by the neighbouring oxygen atom (
for the reaction to proceed.
Finally, the corresponding primary amide and secondary amine
are easily accessible via cleavage of the N–O bond using samarium
iodide8 followed by reduction of the carbonyl group with LiAlH4 in
ethyl ether (Scheme 2).
a
-effect)7 is mandatory
The scope of the methodology was then extended to substituted
indole-2-hydroxamates. We were pleased to observe that the reac-
In conclusion, a general method 9 for the synthesis of pyrazi-
no[1,2-a]indole derivatives has been developed. The reaction
Table 3
Optimisation of hydroxamate substituent
OBoc
O
Pd2(dba)3CHCl3 (5 mol%)
O
P(Oi-Pr)3 (30 mol%)
+
N
N R
N
H
HN R
DCM, rt
OBoc
1
3
2
Entry
R
Yielda (%)
1
2
3
4
5
OMe
OBn
Oi-Pr
Ot-Bu
DMBb
58
72
78
81
0
a
Isolated yield.
DMB = 2,4-dimethoxybenzyl.
b
Table 4
Indole substrate scope
R2
R5
R1
R2
R5
R1
OBoc
R3
R4
Pd2(dba)3CHCl3 (5 mol%)
P(Oi-Pr)3 (30 mol%)
O
R3
R4
O
+
N
N Ot-Bu
N
H
HN Ot-Bu
DCE, rt
OBoc
1
2
3
Entry
R1
R2
R3
R4
R5
Isolated yield (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
Br
H
OMe
Cl
H
H
H
H
H
H
CN
H
H
H
H
H
H
H
H
H
Me
H
81
70
72
75
55
65
70
88
60
F
CO2Et
OMe
H
Me
Cl
F
F
F
O
O
b
a
N
N
N
NH
N
NH
Ot-Bu
Scheme 2. Reagents and conditions: (a) SmI2, THF, 0 °C, 20 min, 91%; (b) LAH, Et2O, reflux, 90%.

366
S. Laliberté et al. / Tetrahedron Letters 51 (2010) 363–366
8. Keck, G. E.; McHardy, S. F.; Wager, T. T. Tetrahedron Lett. 1995, 36, 7419.
9. General procedure for the palladium-catalyzed allylic alkylation: To a stirred
solution of indole-2-hydroxamate10 (1.0 equiv) and 2-butene-1,4-di-tert-
butyldicarbonate (1.5 equiv) in DCM or DCE (0.1 M) was added a pre-stirred
solution of Pd2(dba)3CHCl3 (0.05 equiv) and P(OiPr)3 (0.3 equiv) in DCM or DCE.
The reaction was stirred at room temperature until completion as determined
by HPLC. The crude reaction mixture was then concentrated and purified by
silica gel chromatography.
conditions are very mild, taking place at room temperature under
catalytic conditions and allow for a wide variety of substitutions on
the indole core.
Work is currently underway in our laboratory to develop an
asymmetric version of this reaction.
10. The indole-2-hydroxamates were prepared according to a modified version of
Gissot, A.; Volonterio, A.; Zanda, M. J. Org. Chem. 2005, 70, 6925. To a stirred
mixture of ethyl-5-chloroindole-2-carboxylate (1.0 equiv) and O-t-
butylhydroxylamine hydrochloride (1.2 equiv) in THF (0.2 M) at À78 °C was
added dropwise LiHMDS 1 M THF solution (5 equiv). The solution was stirred
at À20 °C for 1 h. Work-up followed by trituration in 10% ether/hexanes
afforded the product in 95% yield. In some cases the hydroxamates were
synthesised using indole-2-carboxylic acid and hydroxlamines via standard
peptidic coupling.
References and notes
1. Bös, M.; Jenck, F.; Moreau, J. L.; Mutel, V.; Sleight, A. J.; Widmer, U. Bioorg. Med.
Chem. Lett. 1997, 32, 253.
2. Goldberg, D. R. et al Bioorg. Med. Chem. Lett. 2008, 18, 938.
3. Rover, S. et al Bioorg. Med. Chem. Lett. 2005, 15, 3604.
4. Trost, B. M.; Dong, G. J. Am. Chem. Soc. 2006, 128, 6054.
5. Chen, A.; Sun, X. T. Tetrahedron Lett. 2007, 48, 3459.
6. Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992, 114, 9327.
7. Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry; KA/PP: NewYork, 2000.
Part A, p 293.