Au(I)-Catalyzed Access to 1 H-Pyrrolo[1,2- a]indol-2(3- H)-ones via Oxidation of Terminal Alkynes

Article abstract of DOI:10.1021/acs.joc.8b02276

A facile gold-catalyzed oxidation of terminal alkynes for the construction of 1H-pyrrolo[1,2-a]indol-2(3-H)-ones is reported. Under relatively simple procedures, various 1H-pyrrolo[1,2-a]indol-2(3-H)-ones derivatives were obtained in good to excellent yie

Full text of DOI:10.1021/acs.joc.8b02276

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Note
Au(I)-Catalyzed Access to 1H-pyrrolo[1,2-a]indol-2(3-
H)-ones via Oxidation of Terminal Alkynes
Ting Li, and Ping Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02276 • Publication Date (Web): 16 Nov 2018
Downloaded from http://pubs.acs.org on November 16, 2018
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Au(I)-Catalyzed Access to 1H-pyrrolo[1,2-a]indol-2(3-H)-ones
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via Oxidation of
9
Terminal Alkynes
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,†
†
Ting Li,* and Ping Yang
†College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University,
Nanyang, Henan 473061, P. R. China.
E-mail：chemlt2015@nynu.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
Me4 BuXPhosAuCl/NaBArF
t
4
N
R
N
O
R
N-oxide (1.5 equiv.)
16 examples
up to 96% yield
ABSTRACT
A facile gold-catalyzed oxidation of terminal alkynes for the construction of
1H-pyrrolo[1,2-a]indol-2(3-H)-ones was reported. Under relatively simple
procedures, various 1H-pyrrolo[1,2-a]indol-2(3-H)-ones derivatives were
obtained in good to excellent yields, thus providing an efficient route for the
construction of 1H-pyrrolo[1,2-a]indol-2(3-H)-ones deritives.
Pyrrolo[1,2-a]indoles are structural motifs found in natural products,
pharmacologically active molecules, and molecular sensors, which possess potent
antibiotic and antitumor activities (Figure 1).1 Meanwhile, starting from this tricyclic
pyrrolo[1,2-a]indole skeleton, the total synthesis of several natural molecules could be
realized concisely.1 However, synthetic methods that provide selective access to this
nitrogen-containing heterocycle is much less developed. In 1983, Rapoport reported a
convenient one-flask synthesis of this pyrrolo[1,2-a]indole skeleton through
homoproline addition to dibromoquinone followed by irradiation during their study of
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the total synsthesis of Mitomycins (Scheme 1.1).2 Zhang also presented a platinum
-catalyzed cycloisomerization for the construction of the pyrrolo[1,2-a]indole
skeleton as the key step for the formal synthesis of 7-methoxymitosene (Scheme 1.2).3
Besides, other pathways for the synthesis of the pyrrolo[1,2-a]indole skeleton starting
from indoles has also been developed.4 However, these methods generally suffer from
drawbacks such as harsh reaction conditions, low efficiency and poor selectivity.
Therefore, the development of novel strategies for its expedient and flexible
construction is still of need, especially those based on assembling structures directly
from several readily available and easily diversified building blocks.5
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O
O
NH2
NHCOCH3
NH2
O
O
O
O
H3CO
X
H3CO
H3C
N
N
NH
N
H3C
O
O
O
Aziridinomitosene
X = OMe, NH2
Melatonin
7-Methoxymitosene
OH
NMe2
H
N
O
NH2
O
OH
O
O
O
OH
H2N
H3C
OMe
N
OH
N
N
NH
OH
OH
O
O
HO
OH
Mitosene C
Isatisine
HO
Yuremamine
Figure 1. Representative biologically active pyrrolo[1,2-a]indole derivatives.
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Scheme 1. Construction of pyrrolo[1,2-a]indole skeleton.
5
Previous work:
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O
O
OEt
Br
N
hv/dixoane
Et3N
OEt
(1)
R
R
N
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H
(R)
(R)
H
PtCl2, O2
O
(2)
(3)
O
R
R
N
N
O
Rh2(OAc)4
O
N2
R
R
N
R
O
N
H
N
H
This work:
[Au]/ N-oxide
(4)
R
N
N
R
O
Recently, gold(I)-catalyzed oxidation of alkynes using pyridine/quinoline N-oxides
as oxidants to synthesize various useful molecules was reported. The α-oxo gold (I)
carbene intermediates generated from alkynes can be trapped in situ by
internal/external nucleophiles, which circumvents the use of hazardous and potentially
explosive α-diazo ketone precursors.6-7 Very recently, the synthesis of
1H-pyrrolo[1,2-a]indol-2(3-H)-ones involving a rhodium-catalyzed intramolecular
aromatic carbenoid insertion was also reported (Scheme 1.3).8 Inspired by these
results,
we
envisioned
that
the
synthetically
useful
1H-pyrrolo[1,2-a]indol-2(3-H)-ones might be accessed directly through
a
gold-catalyzed9 intermolecular alkyne oxidation (Scheme 1.4).10 In this
communication, we describe herein the realization of such a gold catalyzed oxidative
protocol, providing a flexible and alternative way for the preparation of versatile
1H-pyrrolo[1,2-a]indol-2(3-H)-ones derivatives.
We initiated our study by choosing 1-(prop-2-yn-1-yl)-1H-indole 1a as the model
substrate, and some of the results are listed in Table 1. Initially, it was found that
reaction of 1a with pyridine oxide 2a in the presence of PPh3AuCl (5 mol%) and
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NaBArF (10 mol%) could afford the desired 1H-pyrrolo[1,2-a]indol-2(3-H)-one 3a,
4
5
6
7
8
albeit in only 48 %yield (Table 1, entry 1). Then, the influence of various gold
catalysts bearing different ligands was screened (Table 1, entries 2–6), and the
9
t
reaction worked in most cases and catalyst Me4 BuXPhosAuCl was found to be the
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best choice for this transformation. To our delight, further studies revealed that
when 2,6-dibromopyridine 1-oxide 2b was used as the oxidant11, the yield of 3a could
be increased to 86% yield (Table 1, entry 6). Different counteranions generated from
silver salts, like AgNTf2 and AgOTf, were both less efficient (Table 1, entries 10−11).
The effect of the solvents, like PhF and PhCF3, were also considered, but no better
results were observed (Table 1, entries 12−13).
Table 1. Optimization of the Reaction Conditionsa
[Au], N-oxide, DCE, 60 oC
N
N
O
1a
3a
OMe
Cy
tBu
tBu
Cy
Cy
tBu
P
MeO
iPr
P
Cy
P
iPr
iPr
iPr
P
tBu
iPr
iPr
iPr
iPr
iPr
t
JohnPhos
XPhos
Me4 BuXPhos
BrettPhos
N
Br
N
O
Br
N
O
N
O
Br
Cl
N
O
Cl
iPr
2e
O
2a
2c
2b
2d
Entry
1
N-oxide
Conditions
Ph3PAuCl (5 mol%),
Yieldb
48
2a
NaBArF (10 mol%), DCE, 60 oC, 2 h
4
2
3
4
5
2a
2a
2a
2a
JohnPhosAuCl (5 mol%),
52
47
71
75
NaBArF (10 mol%), DCE, 60 oC, 2 h
4
XPhosAuCl (5 mol%),
NaBArF (10 mol%), DCE, 60 oC, 2 h
4
BrettPhosAuCl (5 mol%),
NaBArF (10 mol%), DCE, 60 oC, 2 h
4
t
Me4 BuXPhosAuCl (5 mol%),
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NaBArF (10 mol%), DCE, 60 oC, 2 h
4
t
6
7
2b
2c
2d
2e
2b
2b
2b
2b
Me4 BuXPhosAuCl (5 mol%),
86
80
76
78
77
66
47
62
NaBArF (10 mol%), DCE, 60 oC, 2 h
4
t
Me4 BuXPhosAuCl (5 mol%),
NaBArF (10 mol%), DCE, 60 oC, 2 h
4
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t
8
Me4 BuXPhosAuCl (5 mol%),
NaBArF (10 mol%), DCE, 60 oC, 2 h
4
t
9
Me4 BuXPhosAuCl (5 mol%),
NaBArF (10 mol%), DCE, 60 oC, 2 h
4
t
10
11
12
13
Me4 BuXPhosAuCl (5 mol%),
AgOTf (10 mol%), DCE, 60 oC, 2 h
t
Me4 BuXPhosAuCl (5 mol%),
AgNTf2 (10 mol%), DCE, 60 oC, 2 h
t
Me4 BuXPhosAuCl (5 mol%),
NaBArF (10 mol%), PhF, 60 oC, 2 h
4
t
Me4 BuXPhosAuCl (5 mol%),
NaBArF (10 mol%), PhCF3, 60 oC, 2 h
4
aAll reactions were run in sealed vials with the initial [1a] = 0.1 M. DCE=
1,2-dichloroethane. b Yield of isolated product based on 1a.
With the optimized reaction conditions in hand (Table 1, entry 6), we set out to
investigate the substrate scope of this transformation and the results are summarized
in Table 2. Indoles bearing a methyl group at different position on the indole ring
were firstly examined, and we found that substrates bearing a Me group at C−3, C−4,
C−5, C−6, or C−7 positions on the indole ring all worked well and good to excellent
yields (71−94%) of the corresponding 1H-pyrrolo[1,2-a]indol-2(3-H)-ones 3b−3f
were obtained (Table 1, entries 2−6). To our satisfaction, by utilization of this tandem
strategy, a range of functional groups could also be readily introduced, including the F
(Table 2, entry 7), Cl (Table 2, entry 8), Br (Table 2, entry 9), I (Table 2, entry 10),
OMe (Table 2, entry 11), OBn (Table 2, entry 12), and even NO2 (Table 2, entry 13).
It is worthy to note that the methodology could be further extended to ester containing
substrates 1n (Table 2, entry 14) and 1o (Table 2, entry 15) to provide 3n and 3o in
85% and 61% yield, respectively. Substrate 1p containing a Br at C3 position of
indole was also tested and no desired product was detected at all.
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Table 2. Reaction scope studya.
5
6
t
Me4 BuXPhosAuCl/ NaBArF4
N
7
8
N
R
R
O
N-oxide (1.5 equiv)
DCE, 60 oC, 2 h
9
entry
1
product
3
yield
entry
product
3
yield
77%
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Br
3a
86%
3i
9
N
N
O
O
O
O
Me
N
I
3j
10
11
71%
68%
3b
3c
2
3
82%
92%
N
O
Me
MeO
3k
N
N
N
O
O
Me
BnO
O2N
3d
3e
4
5
81%
94%
3l
12
13
89%
67%
N
O
3m
N
O
N
N
O
O
Me
3f
6
71%
3n
14
85%
N
O
MeOOC
Me
COOEt
F
3g
3h
7
8
81%
84%
15
16
3o
3p
61%
N
N
O
O
N
O
Br
Cl
trace
N
O
a Reactions run in vials; [1] = 0.1 M; isolated yields are reported.
Scheme 2. Transformations of 3a.
.
1) (CH2SH)2, BF3 Et2O
2) Raney Ni, MeOH, reflux
NaBH4, MeOH
RT, 0.5 h
N
N
N
OH
O
3a
4a
, 92%
5a
, 66%
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The synthetic utility of the 1H-pyrrolo[1,2-a]indol-2(3-H)-one products were also
examined by using 3a as an illustrative example. As shown in Scheme 2, we found
that reduction of 3a with NaBH4 in MeOH at room temperture would lead to 4a in
92% yield.12 Besides, routine deoxygenation of 3a was also tested to afford the
2,3-dihydro-1H-pyrrolo[1,2-a]indole product 5a smoothly in 66% yield in two steps
totally.8, 13
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Scheme 3. Construction of 4H-pyrido[3,2,1-jk]carbazol-5(6H)-one.
t
Me4 BuXPhosAuCl (5 % mol),
NaBArF4 (10 % mol),
(1.5 equiv.),
2b
DCE, 60 oC, 4 h
N
N
O
6
7
, 72%
Besides, we also found that this strategy could be applied to the construction of
4H-pyrido[3,2,1-jk]carbazol-5(6H)-one. As shown in Scheme 3, treatment of 6 under
similar
reaction
conditions
would
yield
the
compound
4H-pyrido[3,2,1-jk]carbazol-5(6H)-one 7 in 72% isolated yield, which provides a
effective method for the construction of this structure .14
I
n conclusion, we have presented a facile gold-catalyzed oxidation of
terminal alkynes for the construction of 1H-pyrrolo[1,2-a]indol-2(3-H)-ones.
Under relatively simple procedures, various
1H-pyrrolo[1,2-a]indol-2(3-H)-ones derivatives were obtained in good to
excellent yields, thus providing an efficient route for the construction of
1H-pyrrolo[1,2-a]indol-2(3-H)-ones deritives in organic synthesis. Further
investigation on detailed mechanism and synthetic applications for this
transformation is currently underway in our laboratory.
Experimental Section
General Information: Ethyl acetate (ACS grade), hexanes (ACS grade) and
anhydrous 1, 2-dichloroethane (ACS grade) were obtained commercially and used
without further purification. Methylene chloride, tetrahydrofuran, and diethyl ether
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were purified according to standard methods unless otherwise noted. Commercially
available reagents were used without further purification. High-resolution mass
spectra were obtained using electrospray ionization using an ICR analyzer (ESI-MS).
1H NMR spectra were recorded in chloroform-d3. Chemical shifts are reported in ppm
with the internal TMS signal at 0.0 ppm as a standard. The data are being reported as
(s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, brs = broad singlet,
coupling constant (s) in Hz, integration). 13C NMR spectra were recorded in
chloroform-d3. Chemical shifts are reported in ppm with the internal chloroform
signal at 77.0 ppm as a standard.
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General Procedures for the Synthesis of N-Propargyl Substituted Indoles: 12 Sodium
hydride (6 mmol) was added to a solution of the appropriate indole (5 mmol) in DMF
(10 mL) at 0 °C. After 1 h of stirring at room temperture the solution was cooled at
0 °C and propargyl bromide (6 mmol) was added. The reaction was stirred at room
temperture until disappearance of the starting material (TLC). Then water was added,
before being extracted with dichloromethane. The combined organic extracts were
dried (MgSO4) and concentrated under reduced pressure. Chromatography of the
residue using ethyl acetate/hexanes mixtures gave analytically pure unsubstituted
-(prop-2-yn-1-yl)-1H-indole. Compounds 1a,15 1b,16 1c, 16 1d, 16 1e,16 1f,16 and 1o16
are known compounds.
5-fluoro-1-(prop-2-yn-1-yl)-1H-indole (1g): Isolated as a white solid (657 mg, 76%
1
yield): mp 84−86 °C. H NMR (400 MHz, CDCl3) δ 7.32 (dd, J = 8.9, 4.3 Hz, 1H),
7.30 – 7.27 (m, 1H), 7.24 (d, J = 3.2 Hz, 1H), 7.01 (td, J = 9.1, 2.5 Hz, 1H), 4.86 (d, J
= 2.5 Hz, 2H), 2.42 (t, J = 2.5 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.1 (d,
J = 234.7 Hz), 132.4, 129.2 (d, J = 11.3 Hz), 128.9, 110.3 (d, J = 26.4 Hz), 110.0 (d, J
= 9.8 Hz), 105.9 (d, J = 23.5 Hz), 102.1 (d, J = 4.7 Hz), 77.4, 73.8, 36.1.
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H8FNa: 196.0533, found 196.0534.
5-chloro-1-(prop-2-yn-1-yl)-1H-indole (1h): Isolated as a white solid (813 mg, 86%
yield): mp 110−112 °C. 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 1.6 Hz, 1H), 7.33
(d, J = 8.7 Hz, 1H), 7.24 – 7.15 (m, 2H), 6.48 (d, J = 3.2 Hz, 1H), 4.86 (d, J = 2.5 Hz,
2H), 2.42 (t, J = 2.5 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 134.2, 129.9, 128.6,
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125.7, 122.2, 120.5, 110.3, 101.7, 76.7, 73.8, 36.0. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C11H8ClNa: 212.0237, found 212.0234.
7
8
9
5-bromo-1-(prop-2-yn-1-yl)-1H-indole (1i): Isolated as a white solid (897 mg, 77%
yield): mp 121−123 °C. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 1.4 Hz, 1H), 7.34
(dd, J = 8.7, 1.4 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 3.1 Hz, 1H), 6.48 (d, J
= 3.1 Hz, 1H), 4.84 (d, J = 2.1 Hz, 2H), 2.43 (t, J = 2.3 Hz, 1H). 13C{1H} NMR (101
MHz, CDCl3) δ 134.4, 130.6, 128.5, 124.7, 123.6, 113.2, 110.8, 101.7, 76.7, 73.9,
36.0. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H8BrNa: 255.9732, found
255.9738.
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5-iodo-1-(prop-2-yn-1-yl)-1H-indole (1j): Isolated as a white solid (1068 mg, 76%
yield): mp 141−143 °C. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 1.5 Hz, 1H), 7.49
(dd, J = 8.6, 1.6 Hz, 1H), 7.18 (dd, J = 12.4, 5.9 Hz, 2H), 6.46 (dd, J = 3.2, 0.6 Hz,
13
1H), 4.84 (d, J = 2.5 Hz, 2H), 2.42 (t, J = 2.5 Hz, 1H). C{1H} NMR (101 MHz,
CDCl3) δ 134.9, 131.4, 130.2, 129.9, 128.1, 111.4, 101.4, 83.5, 76.8, 73.9, 36.0.
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H8INa: 303.9594, found 303.9591.
5-methoxy-1-(prop-2-yn-1-yl)-1H-indole (1k): Isolated as a white solid (666 mg, 72%
yield): mp 151−153 °C. 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.9 Hz, 1H), 7.18
(d, J = 3.1 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.98 – 6.68 (m, 1H), 6.47 (d, J = 3.1 Hz,
13
1H), 4.84 (d, J = 2.5 Hz, 2H), 3.87 (s, 3H), 2.40 (t, J = 2.5 Hz,1H). C{1H} NMR
(101 MHz, CDCl3) δ 154.3, 131.1, 129.3, 127.8, 112.1, 110.0, 102.8, 101.6, 77.8,
73.4, 55.9, 36.0. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H11NONa:
208.0733, found 208.0736.
5-(benzyloxy)-1-(prop-2-yn-1-yl)-1H-indole (1l): Isolated as a white solid (809 mg,
62% yield): mp 182−184 °C. 1H NMR (400 MHz, CDCl3) δ 7.48 (dd, J = 7.9, 0.9 Hz,
2H), 7.39 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 8.0 Hz, 2H), 7.20 – 7.16 (m, 2H), 7.00 (dd, J
= 8.8, 2.4 Hz, 1H), 6.44 (dd, J = 3.1, 0.7 Hz, 1H), 5.11 (s, 2H), 4.84 (d, J = 2.5 Hz,
2H), 2.39 (t, J = 2.5 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 153.5, 137.7, 131.3,
129.3, 128.5, 127.9, 127.7, 127.5, 112.9, 110.0, 104.5, 101.7, 77.7, 73.5, 70.9, 36.0.
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C18H15NONa: 284.1046, found
284.1043.
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5-nitro-1-(prop-2-yn-1-yl)-1H-indole (1m): Isolated as a yellow solid (560 mg, 56%
yield): mp 200−202 °C. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 2.2 Hz, 1H), 8.16
(dd, J = 9.1, 2.2 Hz, 1H), 7.44 (d, J = 9.1 Hz, 1H), 7.37 (d, J = 3.3 Hz, 1H), 6.72 (dd,
J = 3.3, 0.7 Hz, 1H), 4.93 (d, J = 2.6 Hz, 2H), 2.48 (t, J = 2.6 Hz, 1H). 13C{1H} NMR
(101 MHz, CDCl3) δ 138.5, 130.5, 128.2, 118.3, 117.6, 109.4, 104.7, 76.5, 74.6, 36.4.
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H8N2O2Na: 223.0478, found
223.0471.
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methyl 1-(prop-2-yn-1-yl)-1H-indole-5-carboxylate (1n): Isolated as a white solid
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(896 mg, 84% yield): mp 202−204 °C. H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H),
7.83 (dd, J = 8.3, 1.4 Hz, 1H), 7.68 – 7.62 (m, 1H), 7.39 (d, J = 3.2 Hz, 1H), 6.58 (dd,
J = 3.2, 0.8 Hz, 1H), 4.94 (d, J = 2.5 Hz, 2H), 3.95 (s, 3H), 2.44 (t, J = 2.5 Hz, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 168.1, 135.2, 132.5, 130.4, 123.6, 121.0, 120.7,
111.6, 102.5, 77.2, 74.1, 52.0, 36.0. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C13H11NO2Na: 236.0682, found 236.0687.
General Procedures for the Synthesis of 1H-pyrrolo[1,2-a]indol-2(3-H)-one: To a
vial containing 2 mL of DCE was added sequentially the alkyne 1 (0.2 mmol),
t
6-dibromopyridine 1-oxide 2b (0.3 mmol, 1.5 equiv), Me4 BuXPhosAuCl (0.01
mmol), and NaBArF (0.02 mmol). The resulting mixture was stirred at 60 °C, and the
4
progress of the reaction was monitored by TLC. Upon completion, the reaction
mixture was concentrated under vacuum. The residue was purified by
chromatography on silica gel (eluent: hexanes/ethyl acetate) to afford the desired
1H-pyrrolo[1,2-a]indol-2(3-H)-one 3.
1H-pyrrolo[1,2-a]indol-2(3H)-one (3a): Isolated as a white solid (29 mg, 86% yield):
mp 190−192 °C. This compound is known and the spectroscopic data match those
reported.8 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.6 Hz, 1H), 7.25 – 7.13 (m,
13
3H), 6.38 (s, 1H), 4.48 (s, 2H), 3.73 (s, 2H). C{1H} NMR (101 MHz, CDCl3) δ
208.7, 136.5, 133.5, 130.5, 121.5, 120.8, 120.3, 109.7, 95.7, 52.3, 37.6.
3-methyl-1H-pyrrolo[1,2-a]indol-2(3H)-one (3b): Isolated as a white solid (30 mg,
82% yield): mp 209−211 °C. 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.7 Hz, 1H),
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7.18 (ddd, J = 9.9, 6.7, 1.6 Hz, 3H), 4.45 (s, 2H), 3.64 (s, 2H), 2.30 (s, 3H). C{1H}
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NMR (101 MHz, CDCl3) δ 208.9, 133.8, 133.3, 130.8, 121.5, 119.6, 118.9, 109.5,
104.3, 52.5, 36.4, 9.0. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H11NONa:
208.0733, found 208.0731.
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4-methyl-1H-pyrrolo[1,2-a]indol-2(3H)-one (3c): Isolated as a white solid (34 mg,
92% yield): mp 200−202 °C. white solid (92% yield). 1H NMR (400 MHz, cdcl3) δ
7.17 – 7.04 (m, 2H), 6.96 (dd, J = 6.5, 0.5 Hz, 1H), 6.39 (d, J = 0.6 Hz, 1H), 4.46 (s,
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2H), 3.72 (s, 2H), 2.56 (s, 3H). C{1H} NMR (101 MHz, cdcl3) δ 208.7, 135.9,
133.2, 130.3, 121.6, 120.6, 107.3, 94.2, 52.3, 37.5, 18.7. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C12H11NONa: 208.0733, found 208.0734.
5-methyl-1H-pyrrolo[1,2-a]indol-2(3H)-one (3d): Isolated as a white solid (30 mg,
82% yield): mp 212−214 °C. 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.14 (d, J =
8.2 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 6.29 (s, 1H), 4.47 (s, 2H), 3.71 (s, 2H), 2.46 (s,
13
3H). C{1H} NMR (101 MHz, CDCl3) δ 208.8, 136.5, 132.0, 130.8, 129.6, 123.0,
120.6, 109.3, 95.2, 52.3, 37.6, 21.5. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C12H11NONa: 208.0733, found 208.0737.
6-methyl-1H-pyrrolo[1,2-a]indol-2(3H)-one (3e): Isolated as a white solid (35 mg,
94% yield): mp 210−212 °C. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.1 Hz, 1H),
7.06 (s, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.32 (s, 1H), 4.46 (s, 2H), 3.71 (s, 2H), 2.48 (s,
13
3H). C{1H} NMR (101 MHz, CDCl3) δ 208.9, 135.7, 133.9, 131.4, 128.3, 122.0,
120.4, 109.7, 95.5, 52.2, 37.5, 21.7. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C12H11NONa: 208.0733, found 208.0729.
7-methyl-1H-pyrrolo[1,2-a]indol-2(3H)-one (3f): Isolated as a white solid (30 mg,
82% yield): mp 207−209 °C. 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 7.9 Hz, 1H),
7.01 (t, J = 7.5 Hz, 1H), 6.92 (d, J = 7.1 Hz, 1H), 6.35 (s, 1H), 4.78 (s, 2H), 3.68 (s,
13
2H), 2.63 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ 209.1, 136.7, 133.2, 130.6,
123.0, 120.5, 120.4, 118.6, 96.1, 55.1, 36.9, 17.6. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C12H11NONa: 208.0733, found 208.0739.
7-fluoro-1H-pyrrolo[1,2-a]indol-2(3H)-one (3g): Isolated as a white solid (31 mg,
1
81% yield): mp 197−199 °C. H NMR (400 MHz, CDCl3) δ 7.32 – 7.22 (m, 1H),
7.14 (dt, J = 28.0, 14.0 Hz, 1H), 6.95 (td, J = 9.1, 2.4 Hz, 1H), 6.35 (s, 1H), 4.48 (s,
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2H), 3.71 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 208.0, 158.3 (d, J = 235.0 Hz),
138.3, 130.5 (d, J = 54.0 Hz), 128.1 (d, J = 60.0 Hz), 110.1 (d, J = 9.9 Hz), 109.8 (d, J
= 26.4 Hz), 95.9 (d, J = 4.6 Hz), 52.4, 37.7. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C11H8NOFNa: 212.0482, found 212.0483.
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7-chloro-1H-pyrrolo[1,2-a]indol-2(3H)-one (3h): Isolated as a white solid (34 mg,
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84% yield): mp 220−222 °C. H NMR (400 MHz, CDCl3) δ 7.60 – 7.56 (m, 2H),
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7.15 (s, 2H), 6.33 (s, 1H), 4.48 (s, 2H), 3.72 (s, 2H). C{1H} NMR (101 MHz,
CDCl3) δ 207.7, 138.0, 132.0, 131.5, 126.1, 121.8, 120.3, 110.5, 95.6, 52.3, 37.6.
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H8NOClNa: 228.0187, found
228.0183.
7-bromo-1H-pyrrolo[1,2-a]indol-2(3H)-one (3i): Isolated as a white solid (39 mg,
77% yield): mp 215−217 °C. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 1.8 Hz, 1H),
7.26 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.32 (d, J = 0.8 Hz, 1H), 4.45 (s,
13
2H), 3.72 (s, 2H). C{1H} NMR (101 MHz, CDCl3) δ 207.7, 137.9, 132.3, 132.1,
124.4, 123.4, 113.6, 111.0, 95.5, 52.3, 37.6. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C11H8NOBrNa: 271.9681, found 271.9678.
7-iodo-1H-pyrrolo[1,2-a]indol-2(3H)-one (3j): Isolated as a white solid (42 mg, 71%
yield): mp 211−213 °C. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 1.3 Hz, 1H), 7.45
(dd, J = 8.5, 1.6 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.31 (d, J = 0.8 Hz, 1H), 4.48 (s,
13
2H), 3.73 (s, 2H), 1.57 (s, 2H). C{1H} NMR (101 MHz, CDCl3) δ 207.7, 137.4,
132.9, 132.7, 129.8, 129.6, 111.5, 95.2, 83.9, 52.2, 37.5. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C11H8NOINa: 319.9543, found 319.9544.
7-methoxy-1H-pyrrolo[1,2-a]indol-2(3H)-one (3k): Isolated as a white solid (27 mg,
68% yield): mp 201−203 °C.. 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J = 8.8 Hz, 1H),
7.10 (d, J = 2.2 Hz, 1H), 6.86 (dd, J = 8.8, 2.3 Hz, 1H), 6.30 (s, 1H), 4.45 (s, 2H),
13
3.86 (s, 3H), 3.70 (s, 2H). C{1H} NMR (101 MHz, CDCl3) δ 208.7, 154.7, 137.2,
131.0, 128.9, 111.5, 110.3, 102.9, 95.5, 55.8, 52.4, 37.7. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C12H11NO2Na: 224.0682, found 224.0685.
7-(benzyloxy)-1H-pyrrolo[1,2-a]indol-2(3H)-one (3l): Isolated as a white solid (49
mg, 89% yield): mp 190−192 °C. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 7.4 Hz,
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2H), 7.40 (t, J = 7.4 Hz, 2H), 7.34 (d, J = 7.3 Hz, 1H), 7.16 (dd, J = 10.8, 5.5 Hz, 2H),
6.94 (dd, J = 8.7, 2.3 Hz, 1H), 6.30 (s, 1H), 5.11 (s, 2H), 4.46 (s, 2H), 3.71 (s, 2H).
13C{1H} NMR (101 MHz, CDCl3) δ 208.7, 153.8, 137.5, 137.3, 130.9, 129.0, 128.5,
127.8, 127.5, 112.2, 110.30, 104.5, 95.5, 70.8, 52.4, 37.7. HRMS (ESI-TOF) m/z:
[M + Na]+ Calcd for C18H15NO2Na: 300.0995, found 300.0991.
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7-nitro-1H-pyrrolo[1,2-a]indol-2(3H)-one (3m): Isolated as a white solid (29 mg,
67% yield): mp 218−220 °C. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 2.0 Hz, 1H),
8.13 (dd, J = 9.0, 2.1 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 6.59 (s, 1H), 4.59 (s, 2H),
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3.80 (s, 2H). C{1H} NMR (101 MHz, CDCl3) δ 206.5, 141.7, 139.8, 136.3, 129.7,
118.0, 117.4, 110.0, 109.5, 98.5, 52.3, 37.5. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C11H8N2O3Na: 239.0427, found 239.0423.
methyl 2-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indole-6-carboxylate (3n): Isolated as a
white solid (39 mg, 85% yield): mp 195−197 °C. 1H NMR (400 MHz, CDCl3) δ 7.99
(s, 1H), 7.83 (dd, J = 8.4, 1.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 6.43 (d, J = 0.8 Hz,
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1H), 4.53 (s, 2H), 3.94 (s, 3H), 3.75 (s, 2H). C{1H} NMR (101 MHz, CDCl3) δ
207.5, 167.9, 140.2, 134.1, 132.9, 123.2, 121.4, 120.3, 111.9, 96.4, 52.4, 52.0, 37.7.
HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C13H11NO3Na: 252.0631, found
252.0632.
ethyl 2-(2-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)acetate (3o): Isolated as a
white solid (30 mg, 61% yield): mp 200−202 °C. 1H NMR (400 MHz, CDCl3) δ 7.61
(d, J = 7.8 Hz, 1H), 7.22 (ddd, J = 7.8, 7.0, 3.8 Hz, 2H), 7.18 (ddd, J = 8.1, 7.3, 1.3
Hz, 1H), 4.49 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.73 (s, 4H), 1.27 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 208.2, 171.6, 135.0, 133.6, 129.8, 121.7, 120.2,
118.9, 109.7, 101.4, 60.9, 52.5, 36.9, 30.7, 14.2. HRMS (ESI-TOF) m/z: [M + Na]+
Calcd for C14H13NO3Na: 266.0788, found 266.0782.
General Procedures for the Synthesis of 4a: To a MeOH solution of 3a (0.2 mmol)
was added NaBH4 (0.3 mmol, 1.5 equiv) at 0 °C, and then the resulting mixture was
stirred at room temperture for 0.5 h. Upon completion, the reaction mixture was
concentrated under vacuum. The residue was purified by chromatography on silica gel
(eluent:
hexanes/ethyl
acetate)
to
afford
the
desired
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1H-pyrrolo[1,2-a]indol-2(3-H)-one 4a in 92% yield.
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2,3-dihydro-1H-pyrrolo[1,2-a]indol-2-ol (4a): Isolated as a white solid (32 mg, 92 %
yield): mp 184−186 °C. 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.7 Hz, 1H), 7.24
(d, J = 8.1 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H), 6.23 (s, 1H),
5.05 (d, J = 2.5 Hz, 1H), 4.24 (dd, J = 10.9, 5.4 Hz, 1H), 3.98 (dd, J = 10.9, 2.4 Hz,
1H), 3.34 (dd, J = 16.6, 6.1 Hz, 1H), 2.97 (dd, J = 16.6, 2.2 Hz, 1H), 2.07 (br, 1H).
13C{1H} NMR (101 MHz, CDCl3) δ 141.2, 132.7, 120.6, 120.5, 119.3, 110.0, 109.4,
93.8, 75.0, 52.6, 35.1. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C11H11NONa:
196.0733, found 196.0732.
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General Procedures for the Synthesis of 5a: To a solution of 3a (0.2 mmol) in dry
CH2Cl2 (3 mL) was added 1,2-ethanedithiol (10 equiv) and boron trifluoride etherate
(2.5 equiv). The mixture was stirred for 2 h at room temperature and then cooled to 0
ºC before the addition of 1 N NaOH (3 mL). The aqueous phase was extracted with
CH2Cl2. The organic layers were washed with 1 N NaOH (3 mL) and H2O (3 mL),
dried over Na2SO4 and concentrated. The reaction mixture was disloved in methanol
(4 mL) and to this solution was added Raney nickel under hydrogen atmosphere and
heated to reflux for 2 h. The reaction mixture was filtered through Celite and washed
with diethyl ether. The residue was purified by chromatography on silica gel (eluent:
hexanes/ethyl acetate) to afford the desired compound 5a in 66% yield. Spectral data
of 5a was consistent with that reported in the literature.17
General Procedures for the Synthesis of 7: To a vial containing 2 mL of DCE was
added sequentially the alkyne 6 (0.2 mmol), 6-dibromopyridine 1-oxide 2b (0.3
t
mmol, 1.5 equiv), Me4 BuXPhosAuCl (0.01 mmol), and NaBArF (0.02 mmol). The
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resulting mixture was stirred at 60 °C for 4 h. Upon completion, the reaction mixture
was concentrated under vacuum. The residue was purified by chromatography on
silica gel (eluent: hexanes/ethyl acetate) to afford the desired compound 7.
4H-pyrido[3,2,1-jk]carbazol-5(6H)-one (7): Isolated as a white solid (32 mg, 72%
yield): mp 211−213 °C. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.2 Hz, 1H), 7.50
(t, J = 7.6 Hz, 1H), 7.33 – 7.29 (m, 2H), 7.22 (dt, J = 8.9, 4.6 Hz, 3H), 4.74 (s, 2H),
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3.98 (s, 2H). C{1H} NMR (101 MHz, CDCl3) δ 201.7, 126.1, 125.8, 123.5, 121.1,
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120.3, 120.1, 120.0, 119.4, 118.9, 114.9, 110.5, 108.7, 52.1, 40.0. HRMS (ESI-TOF)
m/z: [M + Na]+ Calcd for C15H11NONa: 244.0733, found 244.0736.
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Supporting Information Available: Copies of H and 13C NMR spectra for the
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products and substrates. This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We are grateful for the financial support from the Natural Science
Foundation of China (21602120), and Special Fund of Nanyang Normal University
(QN2018002).
References
(1) (a) Siuta, G. P.; Franck, R. W.; Kempton, R. P. Mitomycin synthesis. J. Org.
Chem. 1974, 39, 3739-3744. (b) Galm, U.; Hager, M. H.; Van Lanen, S. G.; Ju, J.;
Thorson, J. S.; Shen, B. Antitumor antibiotics: bleomycin, enediynes, and mitomycin.
Chem. Rev. 2005, 105, 739-758. (c) Guillaumel, J.; Léonce, S.; Pierré, A.; Renard, P.;
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