Coupling of activated esters to gramines in the presence of ethyl propiolate under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2006.12.016

The coupling of activated esters to gramine derivatives is described using ethyl propiolate. A series of substrates have been prepared using these mild conditions to provide a scope and limitations for this methodology.

Full text of DOI:10.1016/j.tetlet.2006.12.016

Tetrahedron Letters 48 (2007) 1291–1294
Coupling of activated esters to gramines in the presence
of ethyl propiolate under mild conditions
David T. Jones, Gerald D. Artman, III and Robert M. Williams*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
University of Colorado Cancer Center, Aurora, CO 80045, USA
Received 28 November 2006; accepted 6 December 2006
Abstract—The coupling of activated esters to gramine derivatives is described using ethyl propiolate. A series of substrates have
been prepared using these mild conditions to provide a scope and limitations for this methodology.
Ó 2007 Elsevier Ltd. All rights reserved.
During the course of the total syntheses of several
natural products and potential biomimetic precursor
substrates, we have needed to couple functionalized
activated esters to gramine derivatives of various indole
ring systems. Three literature methods can be used to
form the desired carbon–carbon bond. First, heating
of gramine 1 to temperatures greater than >120 °C leads
to spontaneous formation of 3-methylene-3H-indole (2)
via loss of the dimethyl amine (Scheme 1).1 Trapping of
2 with nucleophiles such as a malonate enolate or cya-
nide generates the desired 3-substituted indole 3. This
procedure can result in good yields of the coupled prod-
uct, but with the high temperatures employed may not
be suitable for sensitive substrates. Alternatively, Somei2
and Kametani3 independently reported that the temper-
ature can be reduced to ꢀ90 °C by the addition of
0.4 equiv of tri-n-butylphosphine. The precise role of
the phosphine catalyst is still unclear at this time. How-
ever, one mechanistic hypothesis is that it acts as a
nucleophilic catalyst forming a highly reactive phospho-
nium salt, which is more susceptible to the elimination
and formation of 2. As a milder alternative to the ther-
mal conditions, the indole nitrogen of gramine 1 can be
protected as the corresponding N-silyl gramine 4.4
Exposure of 4 to MeI or Me2SO4 generates a quaternary
ammonium salt, which is readily eliminated in the pres-
ence of TBAF to generate 2, which is trapped as before
Me
N
Me
Heat or
Bu3P, CH3CN
reflux
R
n
R
N
N
H
1
2
NaH
-Nuc
R3SiCl
Me
Nuc
N
Me
MeI or Me2SO4;
TBAF, -Nuc
R
R
N
H
N
SiR3
4
3
Nuc = malonates, cyanide, etc.
Scheme 1. Two methods for the coupling of gramines to activated
esters.
to yield 3. These reaction conditions are quite general
for a variety of substrates, but the use of a fluoride
source to generate intermediate 2 makes it incompatible
with substrates that require silyl protecting groups else-
where in the molecule.
Previously, our laboratory has successfully employed
the conditions developed by Somei and Kametani
for the preparation of substituted indole derivatives
utilized in the synthesis of brevianamides and
paraherquamides.5
Keywords: Indoles; Tryptophans; Gramines; Malonates; Indolines.
*
Corresponding author. Tel.: +1 970 491 6747; fax: +1 970 491
3944; e-mail: rmw@chem.colostate.edu
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.016

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D. T. Jones et al. / Tetrahedron Letters 48 (2007) 1291–1294
Table 1. Alkylation of gramine (5) with diethylmalonate (11) in the
presence of commercially available activated actetylenes
Unfortunately, as our malonate and indole substrates
have become more complex the yields for this condensa-
tion reaction can be quite variable and range from good
(ꢀ70%) to poor (ꢀ30%). As a result, we have examined
alternative conditions for this key bond-forming
reaction and were drawn to a report by Sainsbury,
who demonstrated the facile coupling of gramine and
an activated ester at room temperature using activated
acetylenes.6 The activation of gramine 5 occurs via con-
jugate addition on dimethyl acetylenedicarboxylate
(DMAD, 6) generating zwitterion 7 (Scheme 2). The loss
of ammonium species via elimination leads to the forma-
tion of enamine 8 and reactive 3-methylene-3H-indole
(2). Trapping of the anion of N-formyl diethylamino-
malonate (9) generates the desired product 10 in 90%
yield after only 15 min. With only two examples of this
reaction reported by Sainsbury, we have performed a
series of experiments to explore the scope and limita-
tions of these conditions in effort to better understand
how this mild coupling method can be applied to natural
product synthesis.7
O
NMe2
CO2Et
CO2Et
R2
O
N
H
5
R1
solvent, rt, 15 min
O
O
N
12
H
EtO
OEt
11
Entry
R1
R2
Solvent
Yield of 12 (%)
a
b
c
d
e
f
g
h
i
H
H
H
Et
THF
THF
THF
THF
THF
THF
THF
THF
CH3CN
CH2Cl2
MeOH
Et2O
78
77
47
0
0
0
0
0
85
86
60
90
Me
tert-Bu
Me
Et
Et
Et
Me
Et
Et
Et
Et
n-Propyl
Me
Et
Ph
Ph
H
H
H
H
j
k
l
In the original report by Sainsbury, the only activated
acetylene employed was DMAD. As such, we com-
menced our experiments by screening a panel of com-
mercially available activated acetylenes (Table 1).8,9
Due to the speed of the reaction, two important details
were quickly ascertained from the coupling of gramine
(5) to diethylmalonate (11) in THF at rt. First, acetyl-
enes possessing a single carboxylate group (entries a–c)
generated 12 in moderate to good yields (47–78%).
Second, once the acetylene was di-substituted with a
carboxylate group at one terminus and an alkyl or aryl
group at the other, no reaction was observed between
the malonate and the gramine (entries e–h). It is postu-
lated that these results are observed due to the acetylene
becoming: (1) more electron-rich and therefore less sus-
ceptible to conjugate addition (entries d–f); and (2) more
sterically encumbered (entries g and h). This initial
screening of reagents revealed that commercially avail-
able ethyl propiolate readily affords the alkylated mal-
onate 12 in a good yield (entries i–l).
With the reagent screen completed, we began to explore
the influence of different solvents on this reaction. Our
initial reagent screen was conducted in THF, the same
solvent employed by Sainsbury. We have found that
performing the coupling in different solvents can signif-
icantly influence the yield of this reaction. Switching
from THF to CH3CN (entry i) or CH2Cl2 (entry j)
increased the yield from 78% to 85% and 86%, respec-
tively. Interestingly, a protic solvent like MeOH (entry
k) also generates the desired product, albeit in a de-
pressed 60% yield. However, Et2O (entry l) proved to
be the best solvent for this reaction resulting in 90%
yield of the alkylated product 12 after 15 min at room
temperature.
Based on these preliminary results, we alkylated a series
of malonate derivatives 13 with gramine (5) in the pres-
ence of ethyl propiolate in less than 20 min (Table 2).10
Me
Me
CO2Me
CO2Me
O
N
Me
Me
N
Table 2. Coupling of gramine (5) with different activated esters 13 in
the presence of ethyl propiolate
THF
rt
N
H
CO2Me
CO2Et
R2
MeO
O
R1
N
H
6
5
O
7
5,
OEt
R2
EtO
Et2O, rt, 15 min
R1
N
O
O
Me2N
CO2Me
H
14
13
-
OHCHN CO2Et
CO2Et
EtO
OEt
NHCHO
8
Entry
Ester derivatives
Yield of 14 (%)
MeO2C
9
90%
a
b
c
d
e
f
R1 = CN, R2 = H
R1 = CO2Et, R2 = NHBoc
R1 = Ac, R2 = H
R1 = NO2, R2 = H
R1 = N = CPh2, R2 = H
R1 = NHBoc, R2 = H
R1 = N3, R2 = H
67
65
83
65a
41
0
N
H
10
N
2
g
0
Scheme 2. DMAD mediated coupling of gramine to N-formyl
diethylaminomalonate.
a Due to solubility problems, this coupling was conducted in CH2Cl2.

D. T. Jones et al. / Tetrahedron Letters 48 (2007) 1291–1294
1293
As a result, several trends were observed. First, activated
esters 13 needed to have a pKa lower than 16 in DMSO
for good to excellent yields of the alkylated product (en-
tries a–d). Second, alkylations of activated esters with
low pKa’s like ethyl cyanomalonte (entry a) and ethyl
nitroacetate (entry d) were often accompanied by small
amounts of dialkylated products (<20%), thereby
depressing the yield of monoalkylated product 14. Mal-
onates that contain bulky substituents like N-Boc dieth-
ylaminomalonate (entry b) also gave lower yields (65%)
presumably due to increased steric interactions. Interest-
ingly, coupling of the benzophenone imine of glycine
(entry e) did afford product, but in a disappointing
41% yield. We believe this example represents the upper
limit of the pKa range required for this methodology
(pKa = 19.5). This is further confirmed by the failed
alkylation of N-Boc ethyl glycine (entry f) and ethyl azido-
acetate (entry g), both of which have pKa’s greater
than 20.
In addition to the scope of the activated ester, we
explored the influence of indole ring system of the
gramine and its ability to couple to the activated ester
in the presence of ethyl propiolate. Commercially
available indoles were converted to their respective
gramines 15 using the known literature procedures
(CH2O, Me2NH, AcOH, rt) in good to excellent yields.
Exposure of gramine 15 to N-Boc diethylaminomalo-
nate (13b) in the presence of ethyl propiolate in Et2O
readily generated the desired tryptophan derivatives 16
(Table 3). Both electron-poor and electron-rich indole
ring systems couple under these conditions in good
yields. In addition, sterically demanding C2-substituted
gramines (Table 3, entry g) readily afford the tryptophan
derivative 16g in 62% yield. The coupled products 16
can readily be converted to the racemic tryptophan
derivatives using the known literature methods.11
In conclusion, we have studied the scope and limitations
on the mild coupling of activated esters to gramines
using the inexpensive reagent ethyl propiolate. In com-
parison to similar reactions, this carbon–carbon bond-
forming event takes place at room temperature in
moderate to good yields in several common organic
solvents using many different activated esters and
gramines. Finally, we are attempting to develop an
asymmetric variant of this coupling reaction for the
enantioselective synthesis of tryptophans analogues
readily derived from various gramines.
Table 3. Coupling of N-Boc diethylaminomalonate (13b) with various
indole derivatives of gramine 15 in the presence of ethyl propiolate
CO2Et
O
EtO2C
NMe2
13b,
OEt
NHBoc
R
R
Et2O, rt, 15 min
15
N
H
16
N
H
Entry
a
Gramine
Yield of 16 (%)
Acknowledgments
NMe2
Cl
54
The authors acknowledge financial support from the
National Institutes of Health (CA70375) and the NSRA
Postdoctoral Fellowship for G.D.A. (GM72296). Mass
spectra were obtained on instruments supported by the
NIH Shared Instrumentation Grant GM49631.
N
H
NMe2
b
c
44
65
N
H
Cl
Supplementary data
NMe2
Supplementary data (experimental procedures and
NMR spectral data) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.12.016.
N
H
BnO
MeO
NMe2
NMe2
d
e
42
53
References and notes
N
H
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61
62
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N
H
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NMe2
Ph
g
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H

1294
D. T. Jones et al. / Tetrahedron Letters 48 (2007) 1291–1294
5. For representative examples using N-silyl indoles to
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´
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´
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single portion followed by ethyl propiolate (1.1 equiv) via
syringe. The reaction mixture is stirred until no more
starting material is visible by TLC (ꢀ20 min). The reaction
mixture is poured into a separatory funnel containing
EtOAc. The organic solution is washed with 1 N HCl,
water and brine. The organic layer is dried over Na2SO4
and the volatile organics removed under reduced pressure.
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