Regiospecific syntheses of 3-aza-α-carbolines via inverse electron-demand Diels-Alder reactions of 2-aminoindoles with 1,3,5-Triazines

Article abstract of DOI:10.1055/s-0029-1218345

The scope of 1,3,5-triazine inverse electron-demand Diels-Alder (IDA) reactions was expanded to include 2-aminoindoles as productive dienophiles leading to various 3-aza-α-carbolines in excellent yields. Furthermore, the two ester groups of the IDA produc

Full text of DOI:10.1055/s-0029-1218345

3206
LETTER
Regiospecific Syntheses of 3-Aza-a-carbolines via Inverse Electron-Demand
Diels–Alder Reactions of 2-Aminoindoles with 1,3,5-Triazines
S
ynthese
s
of 3-Az
u
a
-
a
-carboline
o
s
xing Xu, Lianyou Zheng, Shixue Wang, Qun Dang,* Xu Bai*
The Center for Combinatorial Chemistry and Drug Discovery, College of Chemistry and School of Pharmaceutical Sciences,
Jilin University, 75 Haiwai St., Changchun, Jilin 130012, P. R. of China
Fax +86(431)85188900; E-mail: qdang@jlu.edu.cn; E-mail: xbai@jlu.edu.cn
Received 10 August 2009
a-Carbolines are an interesting class of heterocycles with
Abstract: The scope of 1,3,5-triazine inverse electron-demand
intriguing biological activities.6–11 For example, mescen-
Diels–Alder (IDA) reactions was expanded to include 2-aminoin-
doles as productive dienophiles leading to various 3-aza-a-carbo-
lines in excellent yields. Furthermore, the two ester groups of the
grincin is an alkaloid natural product with neuroprotective
activities against L-glutamate toxicity.12,13 However, a-
IDA product were differentiated via reduction of the C4-ester to its carbolines are less frequently studied compared to b-car-
corresponding alcohol. This new IDA reaction could be potentially
bolines, possibly due to the relatively few available syn-
thetic methodologies to access a-carbolines.14 We
applied to the synthesis of various 3-aza-mescengrincin analogues
that may possess neuroprotective activities.
envision that an efficient entry to 3-aza-a-carbolines via
Key words: 2-aminoindoles, inverse electron-demand Diels–Alder
reactions, heterocycles, 3-aza-a-carbolines, regiospecific syntheses
IDA reactions of indoles with 1,3,5-triazines is feasible,
which should enable rapid exploration of biological activ-
ities of 3-aza-a-carboline analogues. Moreover, this IDA
strategy should be applicable to the synthesis of 3-aza-
mescengrincin analogues (Scheme 1), which could be ex-
plored for their potential neuroprotective activities.
Diels–Alder reactions have long been recognized as one
of the most efficient methods in organic synthesis since
multiple bonds are formed simultaneously. Subsequently,
hetero Diels–Alder reactions were developed to prepare
various heterocycles efficiently and have found wide ap-
plications in total synthesis of natural products1,2 and the
preparation of biologically active compounds.3 For in-
stance, the Boger group investigated the scope of inverse
electron-demand Diels–Alder (IDA) reactions between
1,3,5-triazines and various electron-rich dienophiles such
as enamines, ynamines, and amidines.4,5
Various examples of indoles as dienophiles in IDA reac-
tions were reported. For instance, the Seitz group reported
the IDA reactions of indoles with 1,2,4,5-tetrazines.15,16
The Haider group reported the IDA reactions of indoles
with pyridazines,17,18 and the Snyder group reported their
seminal work on IDA reactions of indoles with both
1,2,4,5-tetrazines and 1,2,4-triazines.19,20 For example,
Snyder et al. reported that indole reacted with 1,2,4-tria-
zine 3 to produce the IDA product 4 in 89% yield, along
with 6% of a rearrangement product 5 (Scheme 2).21
HO
EtO2C
OH
Herein we report our investigations of indoles as dieno-
philes for IDA reactions with 1,3,5-triazines and the de-
velopment of this new method to prepare various 3-aza-a-
carbolines.
N
O
O
HO
CO2Et
O
N
X
N
H
O
HO
N
Given the structural similarity between 1,2,4-triazine 3
and 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine (6a), we de-
cided to explore the IDA reactions of indole with 1,3,5-tri-
azine 6a using the Snyder conditions. Treatment of 1,3,5-
triazine 6a with four equivalents of indole in diglyme at
N
H
HO
mescengricin (1) X = CH
3-aza-mescengrincin (2) X = N
Scheme 1 Retrosynthetic strategy to 3-aza-mescengrincin
EtO2C
CO2Me
CO2Me
CO2Et
N
N
N
N
N
H
CO2Me
CO2Me
+
N
diglyme
120 °C
16 h
N
CO2Me
HN
H
O
CO2Me
3
4
5
Scheme 2 IDA reaction of indole and a 1,2,4-triazine21
SYNLETT 2009, No. 19, pp 3206–3210
x
x
.x
x
.2
0
0
9
Advanced online publication: 03.11.2009
DOI: 10.1055/s-0029-1218345; Art ID: W12609ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Aza-a-carbolines
Table 2 IDA Reactions of 8a–c with 6a–ea
3207
120 °C did not produce any IDA product after 48 hours,
and only starting materials were recovered (entry 2,
Table 1). Other solvents and conditions were also ex-
plored (entries 3–6, Table 1), but none produced any IDA
product, and only starting materials remained after pro-
longed heating. This observation indicated that there are
significant differences in reactivity between 1,2,4-triazine
3 and 1,3,5-triazine 6a, thus caution should be used when
generalizations of results obtained with one azadiene are
made to another azadiene.
X
X
N
N
N
+
NH2⋅HCl
X
N
N
R
N
X
X
N
R
6a–e
8a R = H
8b R = Me
8c R = Bn
7 R = H
9 R = Me
10 R = Bn
Entry
6
X
8
Conditions
Product Yield
(%)
Table 1 Attempted IDA Reactions of Indole with 1,3,5-Triazine 6aa
1
2
6a
6a
6a
6a
6b
6b
6b
6b
6c
6d
6e
CO2Et 8a
CO2Et 8a
CO2Et 8b
CO2Et 8c
25 °C, 4.5 hb
50 °C, 11 hd,c
50°C, 18 hd
50 °C, 18 h
50 °C, 7.5 h
50 °C, 17 h
50 °C, 18 hc
50 °C, 18 h
50 °C, 4 he
50 °C, 19 h
50 °C, 84 hd
7a
7a
99
82
94
97
94
97
79
93
94
78
0
EtO2C
CO2Et
N
indole
N
N
CO2Et
3
9a
N
N
CO2Et
EtO2C
N
H
4
10a
7b
9b
9b
10b
7c
6a
7a
5
CF3
CF3
CF3
CF3
8a
8b
8b
8c
Entry
Dienes Conditions
Product Yield (%)
1
2
3
4
5
6
3
diglyme, 120 °C, 16 h
4
89b
0c
6
7
6a
6a
6a
6a
6a
diglyme, 120 °C, 48 h
diglyme, 50 °C, 48 h
MeOH, reflux, 48 h
CH2Cl2, reflux, 48 h
DMSO, 100 °C, 33 h
7a
7a
7a
7a
7a
0c
8
0c
9
CO2Bu 8a
0c
10
11
H
8a
8a
7d
0d
Ph
7e
a All reactions were conducted using 1 equiv of indoles and 2 equiv of
1,3,5-triazines in MeOH unless noted.
b DMSO as the solvent.
a All reactions were conducted using 4 equiv of indole under nitrogen,
and monitored by LC-MS, checked after 12, 24, and 48 h.
b A yield of 6% of 5 was also obtained (Scheme 2, ref. 21).
c Both starting materials remained.
c Et3N (2 equiv) was added.
d DMSO–MeOH (1:1) as the solvent.
e i-PrOH as the solvent.
d Mostly 6a remained, trace indole left, reaction was messy.
To address the lack of reactivity for indole toward 1,3,5-
triazine 6a, we envisioned that 2-aminoindoles could
serve as productive dienophiles. The amino group should
increase the HOMO energy for 2-aminoindoles due to the
strong electron-donating capability of the amino group,22
which should enhance their reactivity as dienophiles in
IDA reactions.
All electron-deficient 1,3,5-triazines 6a–c reacted with 2-
aminoindoles 8a–c productively leading to desired pyrim-
ido[4,5-b]indoles 7a–c, 9a,b, and 10a,b in excellent
yields (>90%). On the other hand, the reactions in the
presence of triethylamine (entries 2 and 6) produced the
same products without base (entries 1 and 5), but with
lower yields. One likely cause for the lower yield under
basic conditions was the poor stability of the 2-aminoin-
dole free bases. The other was that acids were beneficial
for the second step of the cascade reactions by promoting
the elimination of ammonia as the ammonium salt. As ex-
pected the unsubstituted 1,3,5-triazine 6d was much less
reactive but still gave the desired product in good yield,
albeit at a much slower reaction rate (entry 10). The 2,4,6-
triphenyl-1,3,5-triazine 6e was not reactive enough to par-
ticipate in the IDA reaction, and when reaction tempera-
ture was raised to >120 °C the 2-aminoindole 8a
decomposed before any desired IDA product could be de-
tected. The experimentally observed reactivity of 1,3,5-
triazines 6a–e was consistent with previous reports, but
the large differences in reaction rates for indoles 8a–c
were somewhat unexpected. The N1-unsubstituted 2-ami-
noindole 8a was much more reactive compared to 2-ami-
noindoles 8b,c, even though the calculated HOMO
The 2-aminoindoles 8a–c were prepared and used as
hydrogen chloride salts using reported procedures with
minor modifications.23 Initially, 2-aminoindole 8a was
tested with 1,3,5-triazine 6a in DMSO at room tempera-
ture, which gave the desired 9H-pyrimido[4,5-b]indole 7a
in excellent yield (entry 1, Table 2). This observation in-
dicated that 2-aminoindole 8a was indeed capable of func-
tioning as a productive dienophile in the IDA reaction. In
contrary to most IDA reactions, which often require ther-
mal conditions (medium to elevated temperatures), the
IDA reactions with compound 8a proceeded rapidly at
room temperature, which indicated that compound 8a had
a higher propensity as a dienophile in IDA reactions.
Encouraged by the initial success, the scope of this new
IDA reaction was then explored with 2-aminoindoles 8a–
c and various 1,3,5-triazines 6a–e. Results from this study
are summarized in Table 2.
Synlett 2009, No. 19, 3206–3210 © Thieme Stuttgart · New York

3208
G. Xu et al.
LETTER
energies were very similar among the three compounds.24
One possible explanation is that the steric hindrance of the
N1-substituents slowed down the [4+2] cycloaddition re-
action.
X
X
N
N
IDA
N
N
NH2⋅HCl
+
X
N
N
X
X
N
R
R
8a–c
6a–d
7,9,10
The regiochemical outcome of IDA reactions were rela-
tively predictable, and recent theoretical studies further
delineated that the electronic effect of both 1,3,5-triazines
and dienophiles controlled the regiochemical selectivity
of IDA reactions.25,26 Theoretical calculations suggested
that the strong electron-donating amino group of five-
membered aromatic dienophiles dictated the regiochemis-
try of IDA products. Analogously, 2-aminoindoles should
react with 1,3,5-triazines in a similar fashion as 2-ami-
nopyrroles and produce IDA products 7, 9, and 10. How-
ever, to unambiguously determine the regiochemistry of
these new IDA products, an X-ray structure of compound
9b was obtained (Figure 1), which confirmed the predict-
ed regiochemistry.27
– NCX
X
N
X
N
X
N
X
N
N
N
N
– NH4Cl
X
X
N
NH2⋅HCl
R
R
A
B
Scheme 3 Proposed mechanism of the IDA reaction
explore the selective reduction of diester 10a, and results
from this investigation are summarized in Table 3.
The reduction of 10a using the Boger conditions preferen-
tially produced one major isomer but the selectivity was
moderate (entries 1–3, Table 3). The major isomer was
isolated, and unexpectedly all spectral data indicated that
it was the C4-reduced product 11b. The initial structural
1
assignment of 11b was based on the comparison of H
NMR spectra between 10a and 11b. One of the aromatic
peaks in 10a (d = 8.88 ppm) was significantly shifted in
11b (to d = 8.2 ppm), which was consistent with reduction
of the C4 ester since reduction of the C2 ester (compound
11a) should have minimal effect on the aromatic peaks.
Preliminary optimization led to a condition (entry 7,
Table 3) that gave compound 11b in 62% yield. Thus, the
two ester groups in compound 10a could be differentiated
with 95% selectivity for the reduction of the C4 ester vs.
the C2 ester.
Figure 1 X-ray structure of IDA product 9b
EtO2C
HOH2C
N
N
NaBH4 (5 equiv)
The IDA reactions of 2-aminoindoles 8a–c with 1,3,5-tri-
azines should also proceed as a cascade reaction in a sim-
ilar manner as the previously reported 2-aminopyrrole
IDA reactions (Scheme 3).28 The [4+2] cycloaddition of
1,3,5-triazines with 2-aminoindoles produces a bicyclic
intermediate A, which is likely going through a zwitteri-
onic transition state as revealed by theoretical studies.25
Compound A undergoes elimination of ammonium chlo-
ride to give intermediate B, and a final retro Diels–Alder
reaction with the loss of NC–X to produce pyrimido[4,5-
b]indoles 7, 9, and 10.
CO2Et
CH2OH
EtOH,
25 °C, 94%
N
N
N
N
Bn
Bn
10a
12
Scheme 4
To determine the structure of 11b unambiguously, both
esters in compound 10a were reduced to give the diol 12
in excellent yield (Scheme 4). 1D ROESY NMR studies
were performed on both compounds 11b and 12. Both
HOCH2 groups in compound 12 were irradiated in sepa-
rate 1D ROESY experiments, but only one of them pro-
duced a NOE with an aromatic proton (C5–H) and this
HOCH2 group was assigned as C4 CH2OH group. The
HOCH2 group in compound 11b has the same chemical
shift as the C4 CH2OH group in 12, and it also produced a
NOE with an aromatic proton in a 1D ROESY experi-
ment. These results further confirmed the structural as-
signment for 11b.
To synthesize 3-aza-mescengrincin and its analogues, the
two ester groups in compounds 10a have to be differenti-
ated, preferably leaving the C4 ester group intact since
mescengrincin has an ester group at the C4-position. Bo-
ger et al. reported selective reduction of pyrimidine-2,4-
diesters as part of their seminal work on the application of
1,3,5-triazine IDA reactions to the synthesis of bleomycin
and related natural products.29,30 Therefore, we set out to
Synlett 2009, No. 19, 3206–3210 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Aza-a-carbolines
3209
Table 3 Selective Reduction of Diester 10aa
EtO2C
EtO2C
HOH2C
N
N
N
+
CO2Et
CH2OH
CO2Et
N
N
N
N
N
N
Bn
Bn
Bn
11b
10a
11a
Entry
Conditions
11a/11bb
1:4.4
Yield of 11b (%)
1
2
3
4
5
6
7
EtOH, –10 °C, 1 h
THF, –10 °C, 1 h
i-PrOH, –10 °C, 4 h
NIc
NIc
9
1:2.9
1:6.8
EtOH–THF, –10 °C, 2 h
EtOH–THF, –30 °C, 4 h
EtOH–THF, –20 °C, 3.5 h
EtOH–THF, –20 °C, 24 hd
1:10.0
1:7.3
33
NIc
55
62
1:9.5
1:18.7
a All reactions were conducted under anhyd conditions using 2 equiv of NaBH4 except entry 7.
b The ratio of compounds 11a and 11b was determined by LC-MS analysis;
c NI denotes no isolation was performed.
d Conditions: 1 equiv of NaBH4 was used.
(3) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
In summary, 2-aminoindoles 8a–c were introduced as
productive dienophiles in IDA reactions with various
1,3,5-triazines, which produced highly substituted 3-aza-
a-carbolines in excellent yields. Unlike most IDA reac-
tions that often require thermal conditions (moderate to el-
evated temperatures), the 2-aminoindoles 8a–c are highly
reactive, and its IDA reactions proceeded smoothly at
room temperature. This methodology represents a new en-
try to 3-aza-a-carboline synthesis and should complement
existing methods to readily access the 3-aza-a-carboline
scaffold. Furthermore, the two ester groups of the IDA
product 10a were differentially reduced with 95% selec-
tivity toward the C4 ester group. The application of this
new IDA reaction to the synthesis of various 3-aza-
mescengrincin analogues and exploration of their neuro-
protective activities are in progress and will be reported in
due course.
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Acknowledgment
We thank Professor Zhixiang Yu (College of Chemistry, Peking
University) who encouraged us to explore these IDA reactions in
the presence of base (Et3N). This work was supported by grants
(2009ZX09501-010) from the National Sci-Tech Major Special
Item and (90713008 and 20802024) from the National Natural Sci-
ence Foundation of China and Changchun Discovery Sciences, Ltd.
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(22) HOMO energies for indole and 8a are –124.5 kcal/mol and
–114.1 kcal/mol, respectively (calculated using Spartan with
the B3LYP/6-31G* method).
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LETTER
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B3LYP/6-31G* method).
6029.
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Synlett 2009, No. 19, 3206–3210 © Thieme Stuttgart · New York