Total synthesis of 4-azaeudistomin Y1 and analogues by inverse-electron demand diels-alder reactions of 3-aminoindoles with 1,3,5-triazines

Article abstract of DOI:10.1055/s-0032-1316857

A new inverse-electron-demand Diels-Alder (IDA) reaction of 3-aminoindoles as dienophiles was developed for the efficient preparation of 4-aza-β-carbolines in high yields. Because N¹-unprotected 3-aminoindoles show poor thermal stability, a one-pot protocol was developed that combines the removal of tert-butoxycarbonyl protecting groups with the IDA reaction. This protocol, using tert-butyl 1H-indol-3-ylcarbamates as reactants, gave the corresponding IDA products in excellent yields. The new IDA methodology was used in a total synthesis of 4-azaeudistomin Y₁, which was obtained in 57% overall yield in four steps. Moreover, the chemistry is suitable for the rapid preparation, through either Friedel-Crafts acylation or amide-formation reactions, of analogues that are useful for exploring structure-activity relationships at the C₁-position. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316857

PAPER
▌743
paper
Total Synthesis of 4-Azaeudistomin Y1 and Analogues by Inverse-Electron-
Demand Diels–Alder Reactions of 3-Aminoindoles with 1,3,5-Triazines
4-Azaeudistomin Y1 and Analogues
Guoxing Xu, Lianyou Zheng, Qun Dang,* Xu Bai*
The Center for Combinatorial Chemistry and Drug Discovery, The School of Pharmaceutical Sciences and The College of Chemistry,
Jilin University, Changchun, Jilin 130021, P. R. of China
Fax +86(431)85188955; E-mail: Qun_dang@merck.com; E-mail: xbai@jlu.edu.cn
Received: 02.01.2013; Accepted after revision: 24.01.2013
However, few methods for generating variations of the β-
Abstract: A new inverse-electron-demand Diels–Alder (IDA) re-
carboline core have appeared in the literature. Drug-dis-
action of 3-aminoindoles as dienophiles was developed for the effi-
cient preparation of 4-aza-β-carbolines in high yields. Because N1-
unprotected 3-aminoindoles show poor thermal stability, a one-pot
covery programs often begin with natural products as lead
substances that are subjected to optimization to produce
protocol was developed that combines the removal of tert-butoxy- drug candidates with the desired potency and physical
properties.10–12 One common strategy is to replace a ring
carbon atom with a nitrogen, which can increase aqueous
carbonyl protecting groups with the IDA reaction. This protocol, us-
ing tert-butyl 1H-indol-3-ylcarbamates as reactants, gave the
corresponding IDA products in excellent yields. The new IDA
solubility, modulate the octanol–water partition coeffi-
methodology was used in a total synthesis of 4-azaeudistomin Y1,
which was obtained in 57% overall yield in four steps. Moreover,
the chemistry is suitable for the rapid preparation, through either
Friedel–Crafts acylation or amide-formation reactions, of ana-
logues that are useful for exploring structure–activity relationships
at the C1-position.
cient log P, and increase selectivity toward a desired tar-
get. We envisioned a series of 4-aza-β-carboline
analogues of eudistomin Y1 as potential antibacterial
agents, but we needed to develop a new method for pre-
paring this new heterocyclic scaffold.
Key words: indoles, Diels–Alder reactions, heterocycles, total syn-
thesis
The inverse-electron-demand Diels–Alder (IDA) reaction
of nonaromatic electron-rich dienophiles is a proven tech-
nique for preparing various heterocycles.13,14 The use of
electron-rich aromatic heterocycles as dienophiles has
also been established as a productive method for synthe-
sizing fused heterocycles through IDA reactions.15–24
Both experimental and theoretical studies have shown that
the position of a strongly electron-donating group (e.g., an
amino group) dictates the regiochemical outcome of the
reaction.25,26 We recently reported that 2-aminoindoles
participate in IDA reactions with 1,3,5-triazines to give 3-
aza-α-carbolines regiospecifically.27 We therefore hy-
pothesized that IDA reactions of 3-aminoindoles with
1,3,5-triazines should produce 4-aza-β-carbolines
Eudistomins are a group of β-carboline natural products
with interesting biological activities.1 For example, eudis-
tomins D, G, H, I, K, N, and O exhibit antiviral activities2
and eudistomins Y1–Y7 show antibacterial activities.3
Consequently, a number of efforts to synthesize eudis-
tomins and their analogues have been reported,4–9 and
these have led to the synthesis of several eudistomins.4,5,7
We became interested in eudistomins and we planned to
investigate the structure–activity relationships of eudisto-
min analogues with modifications of the β-carboline core.
R2
NH2
N
N
R1 = H, Me, Bn
R2
R1
R
2 = CO2Et, CO2Bu, CF3, H
2
N
N
R1
3
R2
X
N
N
NH2
R2
N
R2
N
R2
N
N
H
N
R1
N
1
O
OH
N
R1
5
4
R2
X = CH, eudistomin Y1
X = N, 4-azaeudistomin Y1
Scheme 1 IDA reactions of aminoindoles with 1,3,5-triazines
SYNTHESIS 2013, 45, 0743–0752
Advanced online publication: 11.02.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316857; Art ID: SS-2012-H0003-OP
© Georg Thieme Verlag Stuttgart · New York

744
G. Xu et al.
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(Scheme 1). The 4-aza-β-carbolines obtained from IDA at the C1-position of 5b was functionalized by reduction
reactions of 3-aminoindoles and 1,3,5-triazines might be with sodium borohydride to give a high yield of the de-
used to prepare 4-azaeudistomin Y1 (Scheme 1). More- sired alcohol 8b. Oxidation of the primary alcohol group
over, such a new methodology might also allow the effi- to an aldehyde group with 1-hydroxy-1λ5,2-benziodoxol-
cient synthesis of analogues of 4-azaeudistomin Y1. Here, 1,3-dione (IBX)31,32 followed by a Grignard addition gave
we report the development of a new IDA reaction using 3- secondary alcohol 11b, which was subsequently oxidized
aminoindoles as dienophiles, and the application of this to give the dibenzyl-protected form of 4-azaeudistomin
new method in the total synthesis of 4-azaeudistomin Y1 Y1 12b. Unfortunately, all attempts to remove the two
and its analogues.
benzyl protecting groups [for example, by treatment with
hydrogen in the presence of palladium/carbon,33 with tri-
fluoroacetic acid,34 or with aluminum(III) chloride]35
failed to give the desired 4-azaeudistomin Y1.
3-Aminoindoles 4a and 4b were prepared from the corre-
sponding 3-indolecarboxylic acids by a two-step se-
quence involving a Curtius rearrangement and subsequent
removal of the tert-butoxycarbonyl (Boc) protecting
group (Scheme 2). Treatment of the resulting indolecar-
boxylic acids 6a and 6b with diphenylphosphoryl azide in
tert-butyl alcohol gave indoles 7a and 7b in moderate
yields.28,29 Subsequent removal of the Boc group by treat-
ment with hydrogen chloride in ethyl acetate gave the cor-
responding 3-aminoindoles 4a and 4b as their
hydrochloride salts, which could be used without purifica-
tion in subsequent reactions.
Table 1 IDA Reactions of 3-Aminoindoles with 1,3,5-Triazines
R2
R2
NH2⋅HCl
N
IDA
N
N
N
+
N
R1
N
R1
R2
R2
N
R2
1
4
5
Entrya Indole R1 Triazine R2
Time Product Yield
(h)
(%)
CO2H
NHBoc
NH2
1
2
3
4
5
6
7
4a
4a
4a
4a
4a
4a
4b
Bn 1a
Bn 1a
Bn 1b
Bn 1c
Bn 1d
Bn 1e
COSEt
COSEt
CO2Et
CO2Bn
12b
5a
92
80
85
92
0d
1) DPPA
2) tBuOH
HCl
7b,c 5a
EtOAc
N
N
N
R
R
R
13
5b
5c
5d
5e
5f
6a R = Bn
6b R = H
7a R = Bn, 60%
7b R = H, 57%
4a R = Bn, 86%
4b R = H, 95%
8
4-BrC6H4 48
Scheme 2 Synthesis of 3-aminoindoles 4a and 4b
OMe
48
0d
To test the concept of using 3-aminoindoles 4a and 4b as
dienophiles in IDA reactions, we selected the S2,S4,S6-tri-
ethyl 1,3,5-triazine-2,4,6-tricarbothioate (1a; Table 1)30
H
1b
CO2Et
14e
44
a All reactions were conducted using the indole (1 equiv) and triazine
as a reactant for our initial investigations because this (2 equiv) in DMF at 50 °C.
b Indole (2 equiv) and triazine (1 equiv) were used.
compound has better solubility than the commonly used
triethyl 1,3,5-triazine-2,4,6-tricarboxylate (1b). The reac-
tion of indole 4a with triazine 1a in N,N-dimethylform-
amide under mild thermal conditions gave an excellent
yield of the desired IDA product 5a (Table 1, entry 1). In-
creasing the temperature shortened the reaction time but
gave a lower yield (entry 2), probably as a result of partial
decomposition of the highly electron-rich 3-aminoindole
4a at the higher temperature. We therefore explored the
scope of the IDA reaction of 3-aminoindoles with other
1,3,5-triazines (entries 3–7). Electron-deficient triazines
1b and 1c were also good substrates for this reaction, giv-
ing good-to-high yields of the corresponding IDA prod-
ucts, whereas triazines 1d and 1e did not give the expected
products, probably because they are insufficiently elec-
tron-deficient to function as dienes in the IDA reaction.
Finally, the N1-unprotected 3-aminoindole 4b was also
shown to act as a dienophile, although it gave only a mod-
erate yield of the IDA product, probably as a result of its
poor thermal stability.
c The reaction was conducted at 80 °C.
d Only traces of the products were detected by LC/MS.
e The reaction was conducted in DMSO.
Because the N1-benzyl group proved to be unexpectedly
stable toward various deprotection strategies, we decided
to investigate the conversion of the N1-unprotected β-car-
boline 5f into 4-azaeudistomin Y1. However, the initial
IDA reaction of 1H-indol-3-amine (4b) gave only a mod-
erate yield of compound 5f (Table 1, entry 7). We there-
fore attempted to optimize this reaction to generate larger
amounts of the N1-unprotected β-carboline with a greater
efficiency. We hypothesized that the lower yield of the
IDA reaction of 1H-indol-3-amine (4b) was probably due
to its poor stability (highly electron-rich nature) under the
thermal reaction conditions. One approach to solving this
problem might be to generate the reactive species in situ,
a technique that has already been successfully applied in
several IDA reactions.18,36 Previously, we demonstrated
that 2-aminofurans generated in situ from their Boc-pro-
tected analogues participate in IDA reactions with 1,3,5-
triazines and give the desired IDA products in high
Having developed a robust method for preparing the de-
sired 4-aza-β-carboline 5b, we next examined its conver-
sion into 4-azaeudistomin Y1 (Scheme 3). The ester group
Synthesis 2013, 45, 743–752
© Georg Thieme Verlag Stuttgart · New York

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4-Azaeudistomin Y1 and Analogues
745
CO2Et
CO2Et
N
N
N
NaBH4
HCl (concd)
77%
IBX
N
N
N
EtOH
THF
82%
EtOAc
N
N
N
CO2Et
72%
OH
Bn
OH
Bn
Bn
9b
5b
8b
Br
N
IBX
N
N
OBn
N
EtOAc
86%
N
N
Mg
N
N
N
THF
71%
Bn
CHO
Bn
OBn
HO
12b
Bn
OBn
HO
10b
11b
Scheme 3 Initial attempt at a total synthesis of 4-azaeudistomin Y1
yields.24 We therefore decided to investigate the IDA re- (entries 2 and 3) and, under otherwise identical condi-
actions of Boc-protected aminoindoles under conditions tions, the IDA product 5f was obtained in lower yields.
suitable for in situ removal of Boc groups that were re- This result suggests that the rate-limiting step is the IDA
ported previously,24 and our results are summarized in reaction step rather than the Boc deprotection step, and
Table 2.
that some degree of decomposition of the 1H-indol-3-
amine probably occurred. To investigate whether an ex-
cess of the Lewis acid is required, we conducted the reac-
tion in the presence of either a catalytic amount of boron
trifluoride etherate (entry 4) or in the absence of the Lewis
acid (entry 5). A catalytic amount of Lewis acid gave only
a trace of the IDA product, whereas none was formed in
the absence of the Lewis acid; unreacted indole 7b re-
mained under both sets of conditions. These results show
that the Boc-protected 3-aminoindole is not sufficiently
electron rich to participate in IDA reactions with 1,3,5-tri-
azines and that the in situ removal of the Boc group re-
quires the presence of an excess of boron trifluoride
etherate. Therefore, the optimal conditions for the one-pot
Boc-removal–IDA reaction of tert-butyl 3-amino-1H-
indole-1-carboxylate (7b) are those shown in entry 1 of
Table 2.
Table 2 IDA Reactions of tert-Butyl 3-Amino-1H-indole-1-carbox-
ylate (7b) with 1,3,5-Triazine 1b
Entrya
Ratio 7b/1b
(equiv)
Lewis Acid
(equiv)
Time
Yieldb
(%)
1
2
3
4
5
1:2
2:1
1:1
1:2
1:2
BF3·OEt2, (6)
BF3·OEt2, (6)
BF3·OEt2, (6)
BF3·OEt2, (0.1)
none
1 h
1 h
1 h
4 d
4 d
95
71
69
tracec
0c
a All reactions were conducted on 0.5 mmol scale of the limiting
reagent in 3:1 CHCl3–AcOH (4 mL) under N2 at 20 °C.
b Yield of isolated product.
c Unreacted indole 7b remained.
Because of the electronic and steric differences between
2-aminoindoles and 3-aminoindoles, a comparison of the
two systems under the same reaction conditions might
provide insights into their IDA reactions. We therefore
treated indole 2a with triazine 1b under the optimal con-
ditions for the protected 3-aminoindole 7b. The reaction
took 46 hours to complete and gave a 63% yield of the de-
sired IDA product 13 (Scheme 4). These results suggest
that 1H-indole-2-amine is less reactive than 1H-indole-3-
amine toward the IDA reaction with triazine 1b. The lon-
The reaction of indole 7b with an excess of triazine 1b un-
der our previously reported conditions24 (Table 2, entry 1)
gave an excellent yield of the desired IDA product 5f. It is
likely that the presence of an excess of the triazine 1b
ensured speedy capture of the reactive and less-stable
3-aminoindole generated in situ, thereby resulting in an
excellent yield of the IDA product. To confirm this hy-
pothesis, we used the triazine 1b as the limiting reagent
EtO2C
CO2Et
BF3-OEt2, 20 °C
N
CHCl3–AcOH
+
NHBoc
N
N
CO2Et
N
63%
N
H
N
H
EtO2C
N
CO2Et
2a
1b
13
Scheme 4 Comparative reactivity of a 2-aminoindole derivative
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 743–752

746
G. Xu et al.
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CO2Et
CO2Et
N
N
N
NaBH4
72%
N
N
N
X
N
N
N
H
CO2Et
H
H
OH
OH
5f
14a
14
KMnO4 80%
CO2Et
CO2Et
N
N
1) (COCl)2
N
N
N
2) AlCl3, PhOMe
58%
H
N
H
CO2H
O
OMe
15
16
Scheme 5 Elaboration of compound 5f to 4-azaeudistomin Y1
ger reaction time probably contributed to the lower yield Oxidation of alcohol 14 with potassium permanganate
of the IDA product 13.
gave the carboxylic acid 15, which is already in the de-
sired oxidation state for 4-azaeudistomin Y1. To introduce
the aroyl group at the C1-position, we chose to use a
Friedel–Crafts acylation reaction40,41 instead of the previ-
ous two-step sequence (Grignard addition followed by ox-
idation; Scheme 3). Conversion of carboxylic acid 15 into
the corresponding acyl chloride by treatment with oxalyl
chloride in the presence of catalytic amount of N,N-di-
methylformamide, followed by a Friedel–Crafts reaction
with anisole in the presence of aluminum(III) chloride
gave keto ester 16 in 58% yield (Scheme 5). All attempts
to couple compound 15 with phenol directly failed to give
the desired Friedel–Crafts product, and only the phenyl
ester product was obtained.
Having established that the key intermediate 5f could be
efficiently prepared by our newly developed method, we
examined its conversion into 4-azaeudistomin Y1 by the
synthetic sequence shown in Scheme 5. Selective reduc-
tion of 5f with sodium borohydride gave the alcohol 14 as
the major product in good yield. To establish the regio-
chemistry of product 14 unambiguously, we performed an
X-ray crystal structure determination (Figure 1), which
confirmed that the hydroxymethyl group is attached at the
C1-position.37
To prepare 4-azaeudistomin Y1 from compound 16, it was
necessary to remove the C3-ester group and the methyl
group from the phenyl ether. Application of the Von
Strandtmann conditions38 produced compound 17 in 40%
yield (Scheme 6). We also attempted a two-step procedure
involving hydrolysis followed by decarboxylation with
acetic anhydride–acetic acid,18 but decarboxylation was
not achieved. To prevent escape of hydrogen chloride
from the reaction system under the Von Strandtmann con-
ditions, we conducted the reaction in a sealed steel bomb
reactor. To our delight, the ester and methyl groups were
both removed, and 4-azaeudistomin Y1 was obtained in
90% yield (Scheme 6). This completed a total synthesis of
4-azaeudistomin Y1 in five steps and 28% overall yield.
Figure 1 X-ray crystal structure of IDA product 1437
However, removal of the C3-ester group by using the con-
ditions shown in Scheme 3 (concentrated hydrochloric
acid)38 failed to give the desired product 14a. Attempts to
perform a two-step decarboxylation through hydrolysis of
compound 14 to the carboxylic acid followed by decar-
boxylation by treatment with acetic anhydride and acetic
acid18 or with copper(II) oxide, quinoline, and acetic
acid39 were also unsuccessful (Scheme 5). We therefore
hypothesized that installation of the desired moiety at the
C1-position, followed by global deprotection under
strongly acidic conditions might result in the desired re-
moval of the C3-ester group.
Given that compound 5f has a similar electronic configu-
ration to compound 16, it was possible that one of the two
ester groups might be eliminated selectively. Treatment of
compound 5f with concentrated hydrochloric acid indeed
led to a clean removal of the C3-ester group. Moreover,
the C1-ester group was also hydrolyzed under the reaction
conditions, leading to the desired carboxylic acid 18 in ex-
cellent yield (Scheme 7).
We had therefore developed an efficient two-step se-
quence involving an IDA reaction and subsequent
Synthesis 2013, 45, 743–752
© Georg Thieme Verlag Stuttgart · New York

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4-Azaeudistomin Y1 and Analogues
747
N
HCl (concd)
N
N
H
120 °C
40%
CO2Et
N
O
OMe
17
N
N
H
N
HCl (concd)
O
OMe
N
16
N
H
120 °C
sealed tube
90%
O
OH
4-azaeudistomin Y1
Scheme 6 Synthesis of 4-azaeudistomin Y1 and an O-methoxy analogue
CO2Et
Table 3 Friedel–Crafts Reactions of Compound 18
N
N
HCl (concd)
N
N
Entry ArH
Product
Yield
(%)
reflux, 8 h
89%
N
N
H
H
CO2Et
CO2H
5f
18
N
N
Scheme 7 Synthesis of 5H-pyrimido[5,4-b]indole-4-carboxylic acid
N
H
1
PhOMe
73
O
deesterification for converting triazine 1b into the acid 18,
an excellent intermediate for the total synthesis of 4-
azaeudistomin Y1 and its analogues. Conversion of com-
pound 18 into the corresponding acyl chloride, followed
by Friedel–Crafts reaction with anisole gave the ketone 17
in good yield (Table 3, entry 1). We then examined the ex-
pansion of the scope of the Friedel–Crafts acylation to
give the 4-azaeudistomin Y1 analogues 19a–c in a single
step (entries 2–4).
OMe
17
N
N
N
N
N
H
2
3
4
1-methoxynaphthalene
78
65
79
O
OMe
19a
19b
19c
N
As evident in Table 3, both electron-rich aromatic (entries
1 and 2) and heteroaromatic (entries 3 and 4) compounds
are good substrates for the Friedel–Crafts reaction with
compound 18. A library of C1-analogues of 4-azaeudisto-
min Y1 could therefore be readily prepared. The availabil-
ity of compound 17 should also enable us to improve our
total synthesis of 4-azaeudistomin Y1. Treatment of com-
pound 17 with concentrated hydrochloric acid38 at 120 °C
gave 4-azaeudistomin Y1 in 93% yield (Scheme 8). Thus,
4-azaeudistomin Y1 was synthesized in 57% overall yield
in four steps starting from the commercially available tri-
azine 1b.
N
H
pyrrole
O
HN
N
N
H
1-methyl-1H-indole
O
NMe
In summary, 3-aminoindoles were used as productive di-
enophiles in IDA reactions with 1,3,5-triazines to give the
corresponding 4-aza-β-carbolines. One problem with us-
ing 3-aminoindoles as a dienophiles is their poor stability,
which contributed to the moderate yields initially ob-
served for the IDA reactions. To alleviate this problem,
we developed a one-pot protocol involving Boc-removal
N
N
N
HCl (concd)
N
N
N
H
sealed tube
120 °C, 5 h
H
O
OH
O
OMe
93%
4-azaeudistomin Y1
17
Scheme 8 Improved total synthesis of 4-azaeudistomin Y1
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 743–752

748
G. Xu et al.
PAPER
Anal. Calcd for C13H16N2O2 (232): C, 67.22; H, 6.94; N, 12.06.
Found: C, 67.49; H, 6.97; N, 12.06.
from tert-butyl 3-amino-1H-indole-1-carboxylate as a re-
actant with a subsequent IDA reaction to give the corre-
sponding IDA products in excellent yields. The new IDA
method was applied to the total synthesis of 4-azaeudisto-
min Y1, which was obtained in 57% overall yield in four
steps. Moreover, the chemistry that we have established is
suitable for the rapid generation of analogues (either
through Friedel–Crafts acylation or amide-formation
reactions) that are useful for exploring structure–activity
relationships pertaining to the C1-position.
5-Benzylpyrimido[5,4-b]indoles 5a–c; General Procedure
The 3-aminoindole hydrochloride (0.25 mmol) was added to a
stirred soln of the appropriate 1,3,5-triazine 1 (0.50 mmol) in DMF
(1 mL) under N2 at 50 °C. When the reaction was complete, the
mixture was added to H2O (10 mL). The aqueous phase was extract-
ed with CH2Cl2 (3 × 5 mL), and the organic extracts were combined,
washed with brine, dried (Na2SO4), and evaporated to dryness. The
residue was purified by column chromatography (silica gel).
S2,S4-Diethyl 5-Benzyl-5H-pyrimido[5,4-b]indole-2,4-dicarbo-
thioate (5a)
Purification by column chromatography [silica gel, PE–
EtOAc (100:7)] gave a yellow solid; yield: 100 mg (92%); mp 126–
128 °C.
1H NMR (300 MHz, CDCl3): δ = 8.62 (d, J = 7.5 Hz, 1 H), 7.76–
7.71 (m, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.51–7.46 (m, 1 H), 7.22–
7.20 (m, 3 H), 6.96–6.93 (m, 3 H), 6.06 (s, 2 H), 3.15 (q, J = 7.5 Hz,
2 H), 3.01 (q, J = 7.5 Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H), 1.31 (q,
J = 7.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 194.1, 190.7, 152.5, 148.9, 144.90,
139.7, 136.5, 132.3, 128.7, 127.5, 127.2, 126.0, 123.0, 122.4, 120.5,
111.1, 49.8, 23.9, 23.7, 14.7, 14.0.
MS (ESI): m/z = 436 [M + H]+.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C23H22N3O2S2:
Triazines 1b, 1d, and 1e were purchased (Aldrich) and used without
further purification. Triazines 1a and 1c were synthesized as de-
scribed in the literature.21 THF was distilled from sodium/benzo-
phenone. Et3N and t-BuOH were distilled from CaH2. CH2Cl2 and
EtOH were dried with MgSO4 and Na2SO4. Other commercial re-
agents were used as received without additional purification. Melt-
ing points were measured with a SGW X-4 apparatus. Mass spectra
and HPLC (ELSD) data was recorded on an Agilent 1100 LC/MS
system using a 4.6 × 50 mm column (C-18 AQ+, 5 μm) with elution
by a 5–95% (v/v) linear gradient of MeCN in H2O containing
0.035% TFA over 5 min at a flow rate of 3.5 mL/min. Anal. TLC
was performed on 2.5 × 5 cm plates coated with a 0.25-mm thick-
ness of silica gel GF254. Column chromatography was performed on
silica gel G (200–300 mesh). NMR spectra were recorded on a
Varian 300 MHz spectrometer. 1H NMR spectra (300 MHz) shifts
are referenced to TMS as internal standard. 13C NMR spectra (75
MHz) were determined with complete proton decoupling. High-res-
olution mass spectrometric analyses and elemental analyses were
carried out at Jilin University.
436.1148; found: 436.1147.
Diethyl 5-Benzyl-5H-pyrimido[5,4-b]indole-2,4-dicarboxylate
(5b)
Purification by column chromatography [silica gel, PE–CH2Cl2–
EtOAc (5:5:1)] gave a yellow solid; yield: 86 mg (85%); mp 112–
115 °C.
tert-Butyl (1-Benzyl-1H-indol-3-yl)carbamate (7a)
Et3N (1.7 mL, 11.90 mmol) and DPPA (3.275 g, 11.90 mmol) were
added to a soln of 1-benzyl-1H-indole-3-carboxylic acid42 (2.990 g,
11.90 mmol) in THF (40 mL) under N2 at r.t. After 48 h, the solvent
was removed under reduced pressure, t-BuOH (40 mL) was added,
and the mixture was refluxed for 5 h under N2. The solvent was re-
moved under reduced pressure, and the residue was purified by
chromatography [silica gel, PE–EtOAc (10:1)] to give a white sol-
id; yield: 2.302 g (60%); mp 165–167 °C.
1H NMR (300 MHz, CDCl3): δ = 8.64 (d, J = 8.1 Hz, 1 H), 7.77–
7.72 (m, 1 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.48–7.47 (m, 1 H), 7.26–
7.20 (m, 3 H), 6.93–6.90 (m, 2 H), 5.86 (s, 2 H), 4.59 (q, J = 7.2 Hz,
2 H), 4.31 (q, J = 7.2 Hz, 2 H), 1.51 (t, J = 7.2 Hz, 3 H), 1.20 (q,
J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 165.0, 164.0, 151.3, 147.0, 144.8,
138.9, 136.0, 132.2, 129.0, 128.4, 127.9, 126.0, 123.2, 122.3, 120.5,
110.7, 63.0, 62.7, 48.5, 14.4, 13.8.
1H NMR (300 MHz, CDCl3): δ = 7.47–7.45 (m, 2 H), 7.29–7.21 (m,
4 H), 7.19–7.04 (m, 4 H), 6.44 (s, 1 H), 6.24 (s, 2 H), 1.51 (s, 9 H).
MS (ESI): m/z = 404 [M + H]+.
13C NMR (75 MHz, CDCl3): δ = 137.3, 134.2, 128.6, 128.5, 128.4,
127.4, 126.7, 126.6, 122.1, 118.7, 118.0, 116.7, 114.5, 109.6, 49.9,
28.3.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C23H22N3O4: 404.1605;
found: 404.1606.
Dibenzyl 5-Benzylpyrimido[5,4-b]indole-2,4-dicarboxylate (5c)
Purification by column chromatography [silica gel, PE–CH2Cl2–
EtOAc (5:5:1)] gave a white solid; yield: 121 mg (92%); mp 156–
158 °C.
MS (ESI): m/z = 345 [M + Na]+.
Anal. Calcd for C20H22N2O2 (322): C, 74.51; H, 6.88; N, 8.69.
Found: C, 74.60; H, 6.92; N, 8.70.
1H NMR (300 MHz, CDCl3): δ = 8.63 (d, J = 8.1 Hz, 1 H), 7.74–
7.71 (m, 1 H), 7.57–7.52 (m, 2 H), 7.50–7.45 (m, 2 H), 7.40–7.33
(m, 3 H), 7.30 (s, 5 H), 7.20–7.17 (m, 3 H), 6.88–6.85 (m, 2 H), 5.78
(s, 2 H), 5.57 (s, 2 H), 5.30 (s, 2 H).
13C NMR (75 MHz, CDCl3): δ = 164.7, 163.7, 151.2, 144.6, 138.2,
135.7, 135.6, 134.5, 132.1, 128.8, 128.7, 128.6, 128.6, 128.5, 128.5,
128.4, 128.2, 127.7, 126.0, 125.9, 123.1, 122.2, 120.4, 110.6, 68.3,
67.8, 48.4.
tert-Butyl 1H-Indol-3-ylcarbamate (7b)
Et3N (0.9 mL, 6.21 mmol) and DPPA (1.707 g, 6.21 mmol) were
added to a soln of 1H-indole-3-carboxylic acid (1.000 g, 6.21
mmol) in THF (20 mL) under N2 at r.t. After 48 h, the solvent was
removed under reduced pressure, t-BuOH (20 mL) was added, and
the mixture was refluxed for 5 h under N2. The solvent was removed
under reduced pressure, and the residue was purified by chromatog-
raphy [silica gel, PE–CH2Cl2–EtOAc (200:100:30)] to give a white
solid; yield: 793 mg (57%); mp 177–179 °C.
MS (ESI): m/z = 528 [M + H]+.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C33H26N3O4: 528.1918;
1H NMR (300 MHz, CDCl3): δ = 9.90 (s, 1 H), 7.45–7.42 (m, 1 H),
7.29–7.26 (m, 1 H), 7.10–7.06 (m, 2 H), 6.95 (s, 1 H), 5.78 (s, 1 H),
1.52 (s, 9 H).
found: 528.1920.
13C NMR (75 MHz, DMSO-d6): δ = 153.5, 133.9, 121.2, 121.0,
118.2, 117.9, 115.3, 114.4, 111.2, 78.3, 28.3.
MS (ESI): m/z = 255 [M + Na]+.
Diethyl 5H-Pyrimido[5,4-b]indole-2,4-dicarboxylate (5f)
Triazine 1b (297 mg, 0.5 mmol) and indole 7b (116 mg, 0.25 mmol)
were dissolved in a mixture of CHCl3 (3 mL) and AcOH (1 mL) un-
der N2 at r.t. BF3·Et2O (0.4 mL) was added. After 0.5 h, the reaction
Synthesis 2013, 45, 743–752
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4-Azaeudistomin Y1 and Analogues
749
was quenched with sat. aq NaHCO3 and the pH was adjusted to 6–
7. The organic phase was separated and the aqueous phase was ex-
tracted with CH2Cl2 (3 × 10 mL). The organic extracts were com-
bined, washed with brine, dried (Na2SO4), and evaporated to
dryness. The residue was purified by chromatography [silica gel,
PE–CH2Cl2–EtOAc (10:5:3)] to give a gray solid; yield: 149 mg
(95%); mp 174–176 °C.
1H NMR (300 MHz, CDCl3): δ = 9.94 (s, 1 H), 8.56 (d, J = 7.8 Hz,
1 H), 7.77–7.72 (m, 1 H), 7.64 (t, J = 7.8 Hz, 1 H), 7.48–7.43 (m, 1
H), 4.61 (q, J = 6.9 Hz, 4 H), 1.55–1.48 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 165.7, 164.2, 151.8, 147.6, 143.2,
134.3, 132.5, 130.9, 123.4, 122.4, 120.4, 112.9, 63.1, 63.0, 14.5,
14.4.
MS (ESI): m/z = 314 [M + H]+.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H16N3O4: 314.1135;
the organic extracts were combined, washed with brine, dried
(Na2SO4), and evaporated to dryness. The residue was purified by
chromatography [silica gel, CH2Cl2–EtOAc (1:1)] to give a yellow
oil; yield: 295 mg (72%). This was used without further purification
in the next reaction.
[4-(Benzyloxy)phenyl](5-benzyl-5H-pyrimido[5,4-b]indol-4-
yl)methanone (12b)
Alcohol 11b (265 mg, 0.56 mmol) and IBX31 (315 mg, 1.12 mmol)
were dissolved in EtOAc (5 mL) and the soln was refluxed for 2 h.
The mixture was then cooled to r.t. and the precipitate was separated
by filtration. The residue was washed with EtOAc (3 × 5 mL) and
the organic phases were combined, evaporated to dryness, and pu-
rified by chromatography [silica gel, PE–EtOAc (4:1)] to give a yel-
low solid; yield: 227 mg (86%); mp 140–142 °C.
1H NMR (300 MHz, CDCl3): δ = 9.18 (s, 1 H), 8.54 (d, J = 8.1 Hz,
1 H), 7.77–7.72 (m, 1 H), 7.62–7.57 (m, 3 H), 7.48–7.36 (m, 6 H),
6.55 (s, 5 H), 6.71–6.70 (m, 2 H), 5.57 (s, 2 H), 5.12 (s, 2 H).
found: 314.1138.
Ethyl 5-Benzyl-4-(hydroxymethyl)-5H-pyrimido[5,4-b]indole-
2-carboxylate (8b)
13C NMR (75 MHz, CDCl3): δ = 186.1, 157.9, 144.6, 143.1, 140.3,
138.7, 130.8, 130.3, 127.8, 126.1, 123.4, 123.3, 123.2, 123.0, 122.3,
122.1, 121.4, 121.3, 117.0, 116.1, 115.1, 109.2, 104.9, 64.8, 42.7.
Diester 5b (2.632 g, 6.52 mmol) was dissolved in a mixture of EtOH
(20 mL) and THF (20 mL) under N2 in an ice bath. NaBH4 (247 mg,
6.52 mmol) was added in a portionwise manner. After 4 h, the reac-
tion was quenched with H2O (100 mL) and the pH of the mixture
was adjusted to 5–6 with 5 M aq HCl. The aqueous phase was ex-
tracted with CH2Cl2 (3 × 30 mL) and the organic extracts were com-
bined, washed with brine, dried (Na2SO4), and evaporated to
dryness. The residue was purified by chromatography [silica gel,
CH2Cl2–EtOAc–MeOH (50:10:1)] to give a light-yellow solid;
yield: 1.927 g (82%); mp 187–189 °C.
MS (ESI): m/z = 470 [M + H]+.
Anal. Calcd for C31H23N3O2 (469): C, 79.30; H, 4.94; N, 8.95.
Found: C, 79.12; H, 4.93; N, 8.92.
tert-Butyl 1H-Indol-2-ylcarbamate (2a)
Et3N (0.9 mL, 6.21 mmol) and DPPA (1.707 g, 6.21 mmol) were
added to a soln of 1H-indole-2-carboxylic acid (1.000 g, 6.21
mmol) in THF (20 mL) under N2 at r.t. After 48 h, the solvent was
removed under reduced pressure, t-BuOH (20 mL) was added, and
the mixture was refluxed for 5 h under N2. The solvent was removed
under reduced pressure, and the residue was purified by chromatog-
raphy [silica gel, PE–CH2Cl2–EtOAc (100:50:2)] to give a white
solid; yield: 756 mg (52%); mp 156–157 °C.
1H NMR (300 MHz, CDCl3): δ = 8.60 (dd, J = 2.5, 8.1 Hz, 1 H),
7.69–7.65 (m, 1 H), 7.48–7.42 (m, 2 H), 7.28–7.26 (m, 3 H), 6.95–
6.92 (m, 2 H), 5.75 (s, 2 H), 5.08 (s, 2 H), 4.59 (q, J = 6.3 Hz, 2 H),
1.52 (t, J = 6.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 164.1, 149.0, 147.2, 145.7, 143.3,
136.9, 131.2, 129.4, 129.3, 128.0, 125.3, 122.8, 121.6, 120.5, 110.2,
62.8, 62.5, 48.4, 14.4.
1H NMR (300 MHz, CDCl3): δ = 9.88 (s, 1 H), 7.43–7.03 (m, 4 H),
6.92 (s, 1 H), 6.74 (s, 1 H), 1.55 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 147.7, 129.7, 127.3, 122.2, 114.9,
114.8, 113.6, 105.3, 79.3, 76.6, 23.1.
MS (ESI): m/z = 362 [M + H]+.
MS (ESI): m/z = 255 [M + Na]+.
Anal. Calcd for C21H19N3O3 (361): C, 69.79; H, 5.30; N, 11.63.
Found: C, 70.02; H, 11.77; N, 5.28.
Anal. Calcd for C13H16N2O2 (232): C, 67.22; H, 6.94; N, 12.06.
Found: C, 67.61; H, 6.99; N, 12.24.
(5-Benzyl-5H-pyrimido[5,4-b]indol-4-yl)methanol (9b)
Ester 8b (602 mg, 1.67 mmol) was dissolved in concd aq HCl (10
mL) and the mixture was refluxed for 2 h. The mixture was then
cooled to r.t. and the precipitate that formed was collected by filtra-
tion and dried to give a yellow solid; yield: 372 mg (77%). This was
used without purification in the next reaction.
Diethyl 5H-Pyrimido[5,4-b]indole-2,4-dicarboxylate (13)
BF3·Et2O (0.4 mL) was added to a soln of triazine 1b (297 mg, 0.5
mmol) and indole 2a (116 mg, 0.25 mmol) in a mixture of CHCl3 (3
mL) and AcOH (1 mL) under N2 at r.t. After 0.5 h, the reaction was
quenched with sat. aq NaHCO3 and the pH was adjusted to 6–7. The
organic phase was separated and the aqueous phase was extracted
with CH2Cl2 (3 × 10 mL). The organic extracts were combined,
washed with brine, dried (Na2SO4), and evaporated to dryness. The
residue was purified by chromatography [silica gel, PE–CH2Cl2–
EtOAc (20:10:3)] to give a yellow solid; yield: 149 mg (95%); mp
201–202 °C.
5-Benzyl-5H-pyrimido[5,4-b]indole-4-carbaldehyde (10b)
Alcohol 9b (372 mg, 1.29 mmol) and IBX11 (720 mg, 2.57 mmol)
were dissolved in EtOAc (10 mL), and the mixture was refluxed for
5 h, then cooled to r.t. The precipitate that formed was removed by
filtration and washed with EtOAc (2 × 5 mL). The filtrate was evap-
orated to dryness and purified by column chromatography [silica
gel, CH2Cl2–EtOAc (10:1)] to give a yellow viscous solid; yield:
265 mg (72%). This was used without further purification in the
next reaction.
1H NMR (300 MHz, CDCl3): δ = 12.11 (s, 1 H), 8.87 (d, J = 8.4 Hz,
1 H), 8.07 (d, J = 8.1 Hz, 1 H), 7.72 (t, J = 7.5 Hz, 1 H), 7.46 (t,
J = 7.5 Hz, 1 H), 4.76–4.65 (m, 4 H), 1.63–1.56 (m, 6 H).
[4-(Benzyloxy)phenyl](5-benzyl-5H-pyrimido[5,4-b]indol-4-
yl)methanol (11b)
13C NMR (75 MHz, CDCl3): δ = 165.3, 165.0, 158.1, 150.5, 147.1,
141.5, 130.4, 126.6, 122.3, 117.9, 115.5, 113.3, 63.3, 62.8, 14.3,
14.2.
MS (ESI): m/z = 314 [M + H]+.
The data were consistent with those reported in the literature.27
1-(Benzyloxy)-4-bromobenzene43 (346 mg, 1.31 mmol) was dis-
solved in THF (5 mL) under N2, and Mg (38 mg, 1.58 mmol) and a
piece of I2 (5 mg) were added. When the reaction started, the soln
was heated and refluxed for 2 h. The mixture was then was then
cooled to r.t. and a soln of aldehyde 10b (252 mg, 0.88 mmol) in
THF (2 mL) was added in a dropwise manner. After 30 min, the re-
action was quenched with 1 M aq HCl and the pH was adjusted to
5. The aqueous phase was extracted with CH2Cl2 (3 × 10 mL) and
Ethyl 4-(Hydroxymethyl)-5H-pyrimido[5,4-b]indole-2-carbox-
ylate (14)
Diester 13 (555 mg, 1.77 mmol) was dissolved in a mixture of EtOH
(10 mL) and THF (10 mL) cooled in an ice bath under N2. NaBH4
© Georg Thieme Verlag Stuttgart · New York
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G. Xu et al.
PAPER
(134 mg, 3.54 mmol) was added in a portionwise manner. After 2 h,
the reaction was quenched with H2O (50 mL) and the pH was ad-
justed to 4–5 with 5 M aq HCl. The aqueous phase was extracted
with EtOAc (3 × 20 mL), and the organic extracts were combined,
washed with brine, dried (Na2SO4), and evaporated to dryness. The
residue was purified by chromatography [silica gel, CH2Cl2–
EtOAc–MeOH (50:20:1)] to give a gray solid; yield: 347 mg (72%),
mp >200 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.91 (s, 1 H), 8.30 (d, J = 6.9
Hz, 1 H), 7.81–7.68 (m, 2 H), 7.40–7.35 (m, 1 H), 5.04 (s, 2 H), 4.42
(q, J = 7.2 Hz, 2 H), 1.38 (t, J = 7.2 Hz, 3 H).
The precipitate was collected by filtration, dried, and purified by
chromatography [silica gel, CH2Cl2–EtOAc–MeOH (20:20:1)] to
give a light-green solid; yield: 44 mg (90%); mp >316 °C dec.
1H NMR (300 MHz, DMSO-d6): δ = 12.16 (s, 1 H), 10.60 (s, 1 H),
9.21 (s, 1 H), 8.33 (d, J = 8.1 Hz, 1 H), 8.29 (d, J = 9.0 Hz, 2 H),
7.81–7.78 (m, 1 H), 7.75–7.73 (m, 1 H), 7.42–7.37 (m, 1 H), 6.97
(d, J = 9.0 Hz, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 190.6, 162.8, 149.8, 147.6,
143.0, 141.6, 133.8, 130.9, 128.7, 127.1, 121.3, 120.8, 119.3, 115.2,
113.3.
MS (ESI): m/z = 290 [M + H]+.
13C NMR (75 MHz, DMSO-d6): δ = 164.0, 151.9, 145.5, 145.0,
142.2, 130.3, 128.5, 121.3, 120.7, 119.4, 113.2, 63.3, 61.1, 14.2.
MS (ESI): m/z = 272 [M + H]+.
Anal. Calcd for C17H11N3O2 (289): C, 70.58; H, 3.83; N, 14.53.
Found: C, 70.48; H, 3.82; N, 14.49.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H14N3O3: 272.1030;
5H-Pyrimido[5,4-b]indole-4-carboxylic Acid (18)
Diester 5f (620 mg, 1.98 mmol) was dissolved in concd HCl (25
mL) and the soln was reflux for 8 h. The mixture was then cooled to
r.t. and precipitate that separated was collected by filtration and dis-
solved in H2O (20 mL). The pH of the soln was adjusted to 6–7 with
aq NH3. The resulting precipitate was separated by filtration. The
pH of the filtrate was then adjusted to 3 with 4 M aq HCl. The re-
sulting precipitate was collected by filtration and dried to give a yel-
low solid; yield: 44 mg (89%); mp 264–267 °C.
1H NMR (300 MHz, DMSO-d6): δ = 12.27 (s, 1 H), 11.91 (s, 1 H),
9.17 (s, 1 H), 8.39–8.30 (m, 1 H), 7.89–7.78 (m, 1 H), 7.76–7.70 (m,
1 H), 7.48–7.33 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 171.5, 154.8, 153.3, 147.9, 136.0,
134.4, 126.3, 125.7, 124.1, 118.4, 118.3.
MS (ESI): m/z = 214 [M + H]+.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H8N3O2: 214.0611;
found: 272.1023.
2-(Ethoxycarbonyl)-5H-pyrimido[5,4-b]indole-4-carboxylic
Acid (15)
Ester 14 (460 mg, 1.7 mmol) was dissolved in H2O (20 mL) and the
soln was heated to 50 °C. KMnO4 (405 mg, 2.6 mmol) was added,
and the mixture was kept at 50 °C for 2 h. The mixture was then
cooled to r.t. and filtered through a pad of Celite. The pH of the fil-
trate was adjusted to 2–3 with 5 M aq HCl, and the precipitate that
separated was collected by filtration and dried to give a light-yellow
solid; yield: 389 mg (80%), mp 196–198 °C.
1H NMR (300 MHz, DMSO-d6): δ = 12.23 (s, 1 H), 8.36 (d, J = 1.8
Hz, 1 H), 7.88 (d, J = 8.1 Hz, 1 H), 7.81–7.78 (m, 1 H), 7.47–7.44
(m, 1 H), 4.46 (q, J = 6.9 Hz, 2 H), 1.40 (t, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 166.8, 163.6, 150.2, 146.3,
143.5, 136.7, 131.5, 129.7, 121.6, 121.4, 119.2, 113.7, 61.4, 14.2.
found: 214.0602.
MS (ESI): m/z = 286 [M + H]+.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H12N3O4: 286.0822;
found: 286.0814.
Aryl 5H-Pyrimido[4,5-b]indol-4-yl Ketones; General Proce-
dure
Acid 18 (70 mg, 0.33 mmol) was dissolved in SOCl2 (5 mL) under
N2, and the soln was refluxed for 5 h. The mixture was then evapo-
rated to dryness and the residue was dissolved in CH2Cl2 (5 mL) in
an ice bath. Anhyd AlCl3 (350 mg, 2.62 mmol) and the appropriate
coupling agent (1.64 mmol) were slowly added. The soln was
stirred and allowed to warm to r.t. When the reaction was complete,
it was quenched by addition of H2O (15 mL) in an ice bath, and the
aqueous phase was extracted with EtOAc (3 × 10 mL). The organic
extracts were combined, washed with brine, dried (Na2SO4), and
evaporated to dryness. The residue was purified by column chroma-
tography (silica gel, PE–CH2Cl2–EtOAc).
Ethyl 4-(4-Methoxybenzoyl)-5H-pyrimido[5,4-b]indole-2-car-
boxylate (16)
Acid 15 (389 mg, 1.36 mmol) was dissolved in CH2Cl2 (5 mL) un-
der N2 in an ice bath, and a drop of DMF was added, followed by
oxalyl chloride (346 mg, 2.73 mmol). After 2 h, the mixture was
evaporated to dryness. The residue was dissolved in PhOMe (10
mL) under N2 in an ice bath and anhyd AlCl3 was slowly added. The
soln was stirred and allowed to warm to r.t. over 15 h and then the
reaction was quenched by addition of H2O (15 mL) in an ice bath.
The aqueous phase was extracted with EtOAc (3 × 10 mL). The or-
ganic extracts were combined, washed with brine, dried (Na2SO4),
and evaporated to dryness. The residue was purified by chromatog-
raphy [silica gel, CH2Cl2–EtOAc (20:1)] to give a yellow solid;
yield: 294 mg (58%); mp 190–192 °C.
(4-Methoxyphenyl)(5H-pyrimido[5,4-b]indol-4-yl)methanone
(17)
Purification by column chromatography [silica gel, CH2Cl2–
EtOAc (10:1)] gave a yellow solid; yield: 73 mg (73%); mp 224–
226 °C.
1H NMR (300 MHz, CDCl3): δ = 10.10 (s, 1 H), 9.32 (s, 1 H), 8.62–
8.58 (m, 2 H), 8.44 (d, J = 7.5 Hz, 1 H), 7.73–7.68 (m, 1 H), 7.61–
7.58 (m, 1 H), 7.44–7.39 (m, 1 H), 7.07–7.03 (m, 2 H), 3.93 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 190.9, 163.5, 150.0, 147.5,
143.1, 141.0, 133.4, 130.9, 128.7, 128.5, 121.3, 120.8, 119.2, 113.7,
113.3, 56.6.
1H NMR (300 MHz, CDCl3): δ = 10.38 (s, 1 H), 8.84 (d, J = 9.3 Hz,
2 H), 8.59 (d, J = 8.1 Hz, 1 H), 7.74–7.71 (m, 1 H), 7.64 (d, J = 8.1
Hz, 1 H), 7.48–7.43 (m, 1 H), 7.04 (d, J = 9.3 Hz, 2 H), 4.62 (q,
J = 7.5 Hz, 2 H), 3.93 (s, 3 H), 1.56 (t, J = 7.5 Hz, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 189.7, 163.7, 163.5, 150.5,
145.1, 143.8, 140.5, 133.7, 131.5, 129.0, 128.4, 121.7, 121.6, 119.4,
113.7, 113.6, 61.4, 55.6, 14.2.
MS (ESI): m/z = 376 [M + H]+.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H18N3O4: 376.1292;
MS (ESI): m/z = 304 [M + H]+.
Anal. Calcd for C18H13N3O2 (303): C, 71.28; H, 4.32; N, 13.85.
Found: C, 71.17; H, 4.31; N, 13.80.
found: 376.1285.
4-Azaeudistomin Y1 {(4-Hydroxyphenyl)(5H-pyrimido[5,4-
b]indol-4-yl)methanone}
Ester 16 (64 mg, 0.17 mmol) was dissolved in concd aq HCl (8 mL)
in a steel bomb reactor and the soln was heated at 120 °C for 5 h.
The mixture was then cooled to r.t. and poured into H2O (10 mL).
(4-Methoxy-1-naphthyl)(5H-pyrimido[5,4-b]indol-4-yl)meth-
anone (19a)
Purification by column chromatography [silica gel, CH2Cl2–
EtOAc (5:1)] gave a yellow solid; yield: 97 mg (78%); mp 248–
250 °C.
Synthesis 2013, 45, 743–752
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4-Azaeudistomin Y1 and Analogues
751
1H NMR (300 MHz, DMSO-d6): δ = 12.38 (s, 1 H), 9.23 (s, 1 H),
8.56 (d, J = 8.4 Hz, 1 H), 8.44–8.38 (m, 2 H), 8.18 (d, J = 8.1 Hz,
1 H), 7.91–7.70 (m, 4 H), 7.51–7.46 (m, 1 H), 7.20 (d, J = 8.1 Hz,
1 H), 4.17 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 194.9, 158.5, 150.1, 147.8,
143.2, 141.8, 135.1, 132.2, 131.0, 128.8, 128.3, 125.9, 125.1, 125.0,
124.9, 121.9, 121.4, 120.9, 119.3, 113.3, 103.1, 56.1.
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J. P.; Wennberg, T.; Vuorela, H. Curr. Med. Chem. 2004, 11,
1375.
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Diego, 1987.
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1976, 309, 679.
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61, 5204.
MS (ESI): m/z = 354 [M + H]+.
Anal. Calcd for C22H15N3O2 (353): C, 74.78; H, 4.28; N, 11.89.
Found: C, 74.98; H, 4.29; N, 11.93.
5H-Pyrimido[5,4-b]indol-4-yl(1H-pyrrol-2-yl)methanone (19b)
Purification by column chromatography [silica gel, CH2Cl2–EtOAc
(5:1)] gave a yellow solid; yield: 56 mg (65%); mp 270–272 °C.
1H NMR (300 MHz, DMSO-d6): δ = 12.29 (s, 1 H), 12.11 (s, 1 H),
9.23 (s, 1 H), 8.32 (d, J = 8.1 Hz, 1 H), 7.74–7.70 (m, 1 H), 7.41–
7.34 (m, 2 H), 6.38–6.36 (m, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 179.5, 150.0, 147.7, 143.2,
141.0, 130.9, 130.6, 128.4, 127.4, 121.3, 121.2, 120.8, 119.2, 113.4,
110.8.
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5833.
(19) Lee, L.; Snyder, J. K. In Advances in Cycloadditions; Vol. 6;
Harmata, M., Ed.; JAI Press: Stamford, 1999, 119.
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8419.
MS (ESI): m/z = 263 [M + H]+.
Anal. Calcd for C15H10N4O (262): C, 68.69; H, 3.84; N, 21.36.
Found: C, 68.85; H, 3.83; N, 21.42.
(21) Dang, Q.; Gomez-Galeno, J. E. J. Org. Chem. 2002, 67,
8703.
(22) Lahue, B. R.; Wan, Z.-K.; Snyder, J. K. J. Org. Chem. 2003,
68, 4345.
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W. Y.; Bai, H. C.; Chung, M.; Hecker, S. J. Tetrahedron
Lett. 2009, 50, 2874.
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S. Synthesis 2008, 136.
(1-Methyl-1H-indol-3-yl)(5H-pyrimido[5,4-b]indol-4-yl)meth-
anone (19c)
Purification by column chromatography [silica gel, CH2Cl2–
EtOAc (5:1)] gave a brown solid; yield: 85 mg (79%); mp 221–
224 °C.
1H NMR (300 MHz, DMSO-d6): δ = 12.20 (s, 1 H), 9.31 (s, 1 H),
9.25 (d, J = 0.9 Hz, 1 H), 8.56–8.52 (m, 1 H), 8.54 (d, J = 8.4 Hz,
1 H), 7.74–7.53 (m, 2 H), 7.40–7.36 (m, 3 H), 3.99 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 185.7, 149.9, 147.7, 143.1,
142.0, 141.6, 136.7, 128.2, 130.7, 127.3, 123.3, 122.8, 121.6, 121.2,
120.6, 119.2, 113.4, 112.9, 110.8, 33.4.
MS (ESI): m/z = 327 [M + H]+.
Anal. Calcd for C20H14N4O (326): C, 73.61; H, 4.32; N, 17.17.
Found: C, 73.39; H, 4.33; N, 17.23.
(30) The solubilities of 1a and 1b in DMF were 1.53 and 0.06
mmol/mL, respectively; see: Xu, G.; Zheng, L.; Wang, S.;
Dang, Q.; Bai, X. Synth. Commun. 2010, 40, 361.
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437.
Acknowledgment
This work was supported by grants (20802024 and 81072526) from
the National Natural Science Foundation of China and Changchun
Discovery Sciences, Ltd.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
(34) Fletcher, S.; Gunning, P. T. Tetrahedron Lett. 2008, 49,
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nnfomartit
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(37) Crystallographic data for compound 14 have been deposited
with the accession number CCDC 907559 and can be
obtained free of charge from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: +44(1223)336033; E-mail:
deposit@ccdc.cam.ac.uk; Web site:
www.ccdc.cam.ac.uk/conts/retrieving.html.
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