Pd(II)-catalyzed aerobic oxidative intramolecular hydroamination and C-H functionalization of N-alkynyl anilines for the synthesis of indole derivatives

Article abstract of DOI:10.1016/j.tet.2013.01.031

A Pd(II)-catalyzed aerobic oxidative approach to 2,3-dihydro-1H-pyrrolo[1, 2-a]indoles from simple N-alkynyl anilines through tandem intramolecular hydroamination and aryl C-H activation process has been developed. Molecular oxygen was used as the sole oxidant to recycle the Pd-catalysis. This protocol is attractive due to the available starting materials and the valuable products.

Full text of DOI:10.1016/j.tet.2013.01.031

Tetrahedron 69 (2013) 4408e4414
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pd(II)-catalyzed aerobic oxidative intramolecular hydroamination
and CeH functionalization of N-alkynyl anilines for the synthesis
of indole derivatives
,b,
Long Ren a, Zhuangzhi Shi a, Ning Jiao a
*
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road 38, Beijing 100191, China
b State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A Pd(II)-catalyzed aerobic oxidative approach to 2,3-dihydro-1H-pyrrolo[1,2-a]indoles from simple N-
alkynyl anilines through tandem intramolecular hydroamination and aryl CeH activation process has
been developed. Molecular oxygen was used as the sole oxidant to recycle the Pd-catalysis. This protocol
is attractive due to the available starting materials and the valuable products.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 30 November 2012
Accepted 9 January 2013
Available online 26 January 2013
Keywords:
Indole derivatives synthesis
CeH bond activation
Pd catalyst
Molecular oxygen oxidant
2,3-Dihydro-1H-pyrrolo[1,2-a]indole
1. Introduction
containing this skeleton have also been discovered and synthesized,
ranging from antitumor antibiotic,1e4 enzyme inhibitors (III),5,6r-
2,3-Dihydro-1H-pyrrolo[1,2-a]indole (Fig.1, I) isa corestructureof
many bioactive molecules and pharmaceuticals. It was early found to
be naturally originated in microbial metabolites, mitomycin antibi-
otics (II).1,2 Afterward, large numbers of bioactive compounds
eceptorantagonists7,8 toantibacterialagents.3,9 Duetotheimportance
of these substituted dihydropyrrolo[1,2-a]indoles in biological ap-
plication, the corresponding synthesis methods have gathered much
interest of synthetic chemists. However, this special indole structure
with two five-membered rings fused together by a CeN bond as
a bridge make the synthesis more challenging than that of cyclano[b]
indoles and usually need multiple steps.10 Most of the strategies are
basedontheaccomplishmentofonecyclizationofeitherthetwo five-
membered rings, affording an indole or 1-phenylpyrrolidine, and
followed by another cyclization.11 In view of this limitation, a new
protocol design to directly synthesize the ternary fused ring in one-
step from easily available substrates is still attractive.
Considering indole is the core backbone of these structures,
a cascade reaction via indole construction may provide an alterna-
tive approach to 1H-pyrrolo[1,2-a]indoles. Recently, a variety of
well-established methods for indole synthesis have been signifi-
cantly developed. Based on the indole structures (Fig.1, IV), there are
several retrosynthetic disconnections, such as CaeN1,12 N1eC2,13
15,16
C2eC3,14 CbeC3
via intramolecular reactions and C2, C3-ex-
plant17 or a N1, C2, C3-explant18 via intermolecular reactions.19
Among them, the C2, C3-explant strategy by the reaction of ani-
lines with alkynes has been significantly studied. Since Larock and
co-workers reported the palladium-catalyzed heteroannulation of
internal alkynes with 2-iodoanilines,20 a great deal of attention has
been attracted to this intermolecular process due to the available
Fig. 1. 2,3-Dihydro-1H-pyrrolo[1,2-a]indole, and some bioactive compounds carrying
this ternary fused ring parent nucleus.
* Corresponding author. Tel./fax: þ86 10 8280 5297; e-mail address: jiaoning@
bjmu.edu.cn (N. Jiao).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.031

L. Ren et al. / Tetrahedron 69 (2013) 4408e4414
4409
substrates with high flexibility in substituents. As described by
Glorius et al.,15 indoles can be synthesized directly from enamines
catalyzed by Pd(OAc)2 by direct dual CeH bonds activation strategy.
The coupling of simple anilines with alkynes to indoles has also been
realized via Rh(II)-catalyzed oxidative cyclization by Fagnou and co-
workers.17b Despite the significances of these approaches, stoi-
chiometric amounts of Cu(OAc)2were required as oxidant in these
indole constructions. More recently, the Pd(II)-catalyzed synthesis
of multi-substituted indoles from the simple amines and internal
alkynes utilizing O2 as the oxidant has been developed by the groups
of Jiao21 and Yoshikai,16 respectively. However, it is noted that some
special indole frameworks are difficult to construct due to the lim-
ited substrate scope of these internal alkynes in this method. On the
basis of these results and our experience in this filed, we report here
a new protocol to directly synthesize the 1H-pyrrolo[1,2-a]indoles
by a cascade process from easily available substrates.
yield (entry 10). In a screening of the benzoate, PhCOOLi bearing
a better solubility in acetonitrile was tested to be the best additive in
this system at low temperature, and provided a more appealing
output at same time (entries 11 and 12). The reaction in sealed tube
exhibited best efficiency (entry 12, Table 1). It must also be noted that
a very small amount of b-H elimination byproduct 3a is conven-
tionally observed and hardly avoided in this reaction.
With these optimized conditions in hand, the scope of this
cascade transformation was investigated (Table 2). The unsub-
stituted aniline substrate 1b afforded the desired 1H-pyrrolo[1,2-a]
indoles product 2b in 55% yield. A series of electron-rich substrates
substituted with primary alkyl (1c), cyclic tertiary alkyl (1h), qua-
ternary alkyl, (1i) and even a phenyl group (1e) at para-position of
the benzene ring underwent well with moderate yields. It is
noteworthy that a hydroxyl group was also tolerated in this re-
action without protection giving 2g in 50% yield, which has been
reported to be a direct intermediate for the preparation of mito-
mycin.1 When the electron donating groups were changed to the
halides, the reaction produced the desired product with low yields
(2k 35%, 2l 31%). To our delight, other electron withdrawing sub-
stituents, such as trifluoromethyl, trifluoro methoxy, and acetyl,
presented satisfied results in this protocol (2n, 2o, 2p). ortho-
Substituted substrates, such as 1j only afforded the product in 29%
yield. If the substrate is substituted at the meta-position (1d,1f), the
regioselectivity could not be controlled, although the total yields
were higher than that of other substrate. The dimethyl substituted
1q achieved a high efficiency (77%). Meanwhile, the substrates with
a longer linker chain between nitrogen atom and alkynyl group
were also investigated, however, only trace amount of products
were observed.
2. Results and discussion
According to our previous study, para-methoxy substituted ani-
line 1a was selected as the model substrate for the conditions opti-
mization (Table 1). Fortunately, the desired 1H-pyrrolo[1,2-a]indole
product 2a was obtained in 7% yield (entry 1, Table 1). Based on this
result, a set of inorganic and organic oxidants in the presence of O2
had been screened. However, no better yield was given with the
serious decomposition of the starting material. When varying the
solvent under the mild oxidative atmosphere of O2 (1 atm), aceto-
nitrile doubled the yield to 16% with a recovery of 46% starting ma-
terial (entry 2). After the screening of different organic acids as well
as some Lewis acids, benzoic acid was turned out to be the preferable
choice with a yield of 38% (entries 3e7). In this regard, a PhCOOK in
the place of benzoic acid was tested under a higher catalyst loading of
20 mol %, which gave the desired productin 30%yield (entry 8). In the
presence of benzoic acid, PhCOOK reduced the reaction time mark-
edly with a better outcome, which indicates that benzoate ion may
play an important role in accelerating the reaction process (entry 9).
The reaction at 110 ꢀC consumed all substrate producing 2a in 46%
To study the substitutional flexibility on the alkynyl terminal,
we changed the ester group to phenyl group, but no product was
detected under the standard conditions. This observation helpfully
gave us an implicit on the mechanism that the Pd center may need
the C]O double bond for tautomerization to turn over itself to cis-
form after the trans-aminopalladation of alkynyl as a
p Lewis
acid.13g,22 Therefore, a variety of alkynyl ketones were designed to
Table 1
Optimization of catalytic conditionsa,b
O
O
N
O
O
O
Pd(OAc)2 (10 mol%),
acid (5 eq.)
O
+
MeO
additive (20 mol%)
O2 (1 atm), solvent (0.1 M),
MeO
N
MeO
NH
1a
2a
3a
Entry
Solvent
Acid
Additive
T (ꢀC)
Time (h)
Recovery of 1a (%)
Yield of 2a (%)
1c
2c
3
4
5
DMA
PivOH
PivOH
PivOH
AcOH
Phenol
PhCOOH
FeCl3
120
100
100
100
100
100
100
100
100
110
100
90
12
40
40
40
40
40
40
40
12
36
36
36
36
12
36
60
Massive
46
52
60
76
32
<5
36
<10
0
0
0
<5
32
60
Massive
7
16
25
8
6
38
0
30
37
46
45
52
45
36
20
<10
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CNe
CH3CNe
CH3CNe
CH3CNe
CH3CNe
CH3CNe
CH3CN
6
7
8d
9d
10
11
12
13
14
15
16
PhCOOK
PhCOOLi
PhCOOLi
PhCOOLi
PhCOOLi
PhCOOK
PhCOOLi
PhCOOLi
PhCOOK
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
PhCOOH
80
80
60
100
a
Reaction conditions: 1a (0.15 mmol), Pd(OAc)2 (0.015 mmol, 10 mol %), acid (0.75 mmol, 5 equiv), additive (0.03 mmol, 20 mol %), O2 (1 atm), solvent (1.5 mL, 0.1 M).
Isolated yields.
Solvent: PivOH (4:1).
20 mol % catalyst was employed in this reaction.
These reactions were carried out in sealed tube.
b
c
d
e

4410
L. Ren et al. / Tetrahedron 69 (2013) 4408e4414
Table 2
Pd(II) catalytic synthesis of 2,3-dihydro-1H-pyrrolo[1,2-a]indole ester derivatives by direct AreH bond activation utilizing O2 as oxidanta
O
O
O
O
Pd(OAc)2 (10 mol%),
PhCOOH (5 eq.)
PhCOOLi (20 mol%),
R
N
MeCN (0.1 M), O2,
NH
R
90 oC, 36 h.
2
1
b
b
yield of 2
yield of 2
substrate
substrate
product
O
product
O
O
O
NH
O
NH
42%
52%
O
N
N
2i
1i
1a
2a
O
O
O
O
O
HN
29%c
NH
55%
49%
N
2j
N
1b
2b
O
1j
O
O
O
O
F
NH
NH
NH
NH
Me
NH
35% (3k, 22%)
31% (3l, 18%)
43%d
Me
F
N
N
1k
1c
2c
2k
O
O
O
O
O
Cl
38%
33%
Cl
N
N
1l
O
2d
2l
71%
O
(3d, 27%)
O
O
O
O
N
O
O
H
1d
N
2m
N
2d'
O
1m
O
O
O
O
O
40%c
F3C
Ph
NH
50% (3e, 23%)
Ph
F3C
N
2e
N
1n
1e
2n
O
O
O
O
F3CO
O
NH
44%
50%
33%
F3CO
O
N
Me
N
1o
Me
2f
2o
50%
17%
NH
O
O
O
O
Me
1f
NH
N
2f'
O
N
2p
1p
O
O
O
Me
Me
Me
50%c
42%
HO
NH
77%
NH
HO
N
2q
N
2g
1g
1q
Me
O
O
NH
N
1h
2h
a Standard conditions (unless otherwise noted): 1 (0.15 mmol), Pd(OAc)2 (0.015 mmol, 10 mol%), PhCOOH (0.75 mmol, 5 eq.), PhCOOLi (0.03 mmol, 20 mol%), O2 (1
atm), MeCN (1.5 mL, 0.1 M), 90 oC (sealed) for 36 h.
b Isolated yields. The number in parentheses refers to isolated yield of byproduct 3.
c This reaction was carried out at 110 oC.
d This reaction was carried out at 130 oC.

L. Ren et al. / Tetrahedron 69 (2013) 4408e4414
4411
validate this speculation (Table 3). The reaction of 1r performed
3. Conclusion
well under the standard conditions and produced the desired
product 2r in 54% yield. Other alkynyl ketones were also examined.
Substrates with both aryl and alkyl acyl groups on the alkynyl
terminal reacted steadily under the optimal conditions, and pro-
vided 2r, 2s, and 2t in moderate yields, respectively. In addition, no
In summary, a methodology for the construction of 2,3-dihydro-
1H-pyrrolo[1,2-a]indole derivatives through a direct CeH bond
functionalization strategy has been developed.25 Molecular oxygen
was used as the sole oxidant to recycle the Pd-catalysis. This pro-
tocol is attractive due to the available starting materials and the
valuable products. A mechanism involving trans-aminopalladation,
ortho-carbopalladation, and reductive elimination was proposed.
However, the influence of electronic properties and a thermo-
instability of substrates were also presented in this methodology.
Research for a more efficient and stable catalytic system is un-
dergoing in our lab.
b
-H elimination byproducts 3 were observed for these alkynyl
ketone-type substrates.
Table 3
Pd(II) catalytic synthesis of 2,3-dihydro-1H-pyrrolo[1,2-a]indole ketone derivatives
by direct AreH bond activation utilizing O2 as oxidanta,b
O
R
R
O
Pd(OAc)2 (10 mol%),
PhCOOH (5 eq.)
O
PhCOOLi (20 mol%),
N
4. Experimental section
4.1. General information
MeCN (0.1 M), O2,
O
NH
90 oC, 36 h.
2
1
O
O
4.1.1. Analytical. Flash Column Chromatography was applied to
obtain all reaction yields and performed on silica gel
300e400 mesh. NMR spectra were recorded on a Bruker AVIII-400
spectrometer. All 1H NMR chemical shifts were reported in units
parts per million referencing to the residual H-solvent signals by
assigning CHCl3 resonance as 7.26 ppm in CDCl3 or DMSO reso-
O
O
N
N
2r 54%
2s 45% c
O
O
nance as 2.49 ppm in DMSO-d6. All 13C NMR chemical shifts (
d)
O
O
were reported in units ppm by assigning CHCl3 resonance as
77.0 ppm in CDCl3 or DMSO resonance as 39.7 ppm in DMSO-d6. All
coupling constants (J) were reported in Hertz (Hz). High Resolution
Mass Spectra were measured by APEX IV Fourier Transform Ion
Cyclotron Resonance Mass Spectrometer in ESI Positive (showed
a systematic error of about 0.0005). Melting points were recorded
on Accurate Micro-Melting Point Measuring Instrument X-5B and
are reported uncorrected. Infrared spectra were recorded on
a Nicolet FTIR Spectrophotometer NEXUS-470. The wavenumbers
N
N
2t 45%
2u 28%
a Standard conditions (unless otherwise noted): 1 (0.15 mmol), Pd(OAc)2 (0.015
mmol, 10 mol%), PhCOOH (0.75 mmol, 5 eq.), PhCOOLi (0.03 mmol, 20 mol%),
O2 (1 atm), MeCN (1.5 mL, 0.1 M), 90 oC (sealed) for 36 h.
b Isolated yields.
c This reaction was carried out at 110 oC.
Based on these above results, a proposed mechanism is outlined
in Fig. 2. First, Pd(OAc)2 plays as a Lewis acid to active the alkyne
group, subsequent intramolecular hydroamination generated
trans-nitropalladation intermediates A.13g,22 Then intermediates B
as the tautomer of A undergo rotation to generate the cis-form
Pd(II) species C, followed by electrophilic aromatic palladation to
form intermediates D.23 Finally, reductive elimination of D yield
2with the formation of Pd(0), which can be reoxidized to Pd(II)
species by molecular oxygen to complete the catalytic cycle.24
During this process, intermediates E could be generated from B
(n .
) of recorded IR signals are quoted in cmꢁ1
4.1.2. Chemical. All substrates were directly synthesized according
the reported methods and isolated through recrystallization and
Flash Column Chromatography, The purities were confirmed by
NMR. Pd(OAc)2 was purchased from Strem Chemical. Unless oth-
erwise noted, all commercially obtained reagents were used as
received. MeCN was distilled in small scale with CaH2 and stored
under Argon. Reactions were carried in Schlenk tube or in sealed
tube with a magnetic stirrer and all isolated yields were calculated
based on the starting material 1.
under these acetic conditions and subsequently undergo
b-H
elimination25 and aromatization to generate the byproducts 3.
4.2. General experimental procedure for syntheses of
2,3-dihydro-1H-pyrrolo[1,2-a]indoles (2)
N
O
To a 40 mL seal tube, 1(0.15 mmol), Pd(OAc)2 (3.4 mg,
0.015 mmol, 10 mol %), PhCOOH (91.5 mg, 0.75 mmol, 5 equiv) and
PhCOOLi (3.8 mg, 0.03 mmol, 20 mol %) were added under O2, the
tube was added with MeCN (1.5 mL) via syringe and sealed up. The
formed mixture was stirred at 90 ꢀC under O2 for 36 h as monitored
by TLC. The solution was then cooled to room temperature, diluted
with ethyl acetate (10 mL) and stirred with saturated Na2CO3
aqueous solution (10 mL) for 5 min. After separating, the aqueous
portion was extracted with ethyl acetate (5 mLꢂ3). The organic
portions were combined, dried over MgSO4, filtered, and evapo-
rated under vacuum. The residue was purified through Flash Col-
umn Chromatography on silica gel to afford 2.
N
XPd
O
O
C
PdII
D
O
2
1
O2
N
N
Pd0
PdX
PdX
O
O
B
A
3
O
O
H
N
N
O
F
PdX
O
O
4.2.1. Methyl 7-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate (2a, Table 2). Yellow solid, 52% yield; mp 109e110 ꢀC;
FTIR (neat, cmꢁ1): 3440, 2946, 2834, 1694, 1615, 1544, 1476, 1456,
E
O
Fig. 2. Proposed mechanism for syntheses of 2,3-dihydro-1H-pyrrolo[1,2-a]indole
derivatives.
1160, 811, 778; 1H NMR (400 MHz, CDCl3):
d 7.61 (s, 1H), 7.08 (d,

4412
L. Ren et al. / Tetrahedron 69 (2013) 4408e4414
J¼8.7 Hz, 1H), 6.81 (d, J¼8.6 Hz, 1H), 4.01 (t, J¼7.1 Hz, 2H), 3.88
(overlap, 6H), 3.21 (t, J¼7.4 Hz, 2H), 2.64e2.51 (m, 2H); 13C NMR
(100 MHz, CDCl3): d 165.98, 152.33, 133.04, 131.53, 128.66, 123.19,
121.03, 109.89, 98.94, 50.64, 44.30, 26.62, 26.03, 21.63; HRMS (ESI,
positive): m/z calculated for C14H15NO2 (Hþ) 230.1181, found:
230.1176.
(100 MHz, CDCl3):
d 165.93, 155.71, 152.93, 131.87, 127.79, 111.54,
110.49, 103.53, 98.77, 55.82, 50.61, 44.64, 26.49, 26.36; HRMS (ESI,
positive): m/z calculated for C14H15NO3 (Hþ) 246.1130; C14H15NO3
(Naþ) 268.0950, found: 246.1125, 268.0944.
4.2.8. Methyl 8-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate (2f0, Table 2). Light yellow solid, 17% yield; mp
137e138 ꢀC; FTIR (neat, cmꢁ1): 2957, 2921, 2851, 1698, 1527, 1490,
4.2.2. Methyl 2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-carboxylate
(2b, Table 2). Yellow solid, 55% yield; mp 92e94 ꢀC; FTIR (neat,
cmꢁ1): 3466, 2946, 2888, 2851, 1739, 1684, 1612, 1545, 1480, 1455,
1438, 1187, 1091, 759; 1H NMR (400 MHz, CDCl3):
d 7.13e7.04 (m,
2H), 6.98 (d, J¼6.8 Hz,1H), 4.09 (t, J¼7.1 Hz, 2H), 3.84 (s, 3H), 3.28 (t,
1206, 1105, 753; 1H NMR (400 MHz, CDCl3):
d
8.10 (dd, J¼6.5, 1.6 Hz,
J¼7.5 Hz, 2H), 2.85 (s, 3H), 2.61 (p, J¼7.3 Hz, 2H); 13C NMR (100 MHz,
1H), 7.30e7.16 (m, 4H), 4.12 (t, J¼7.6 Hz, 2H), 3.90 (s, 3H), 3.30 (t,
CDCl3): d 165.56, 153.13, 133.38, 132.40, 129.36, 123.92, 121.94,
J¼7.6 Hz, 2H), 2.71e2.61 (m, 2H); 13C NMR (100 MHz, CDCl3):
107.50,100.24, 50.66, 44.67, 27.31, 26.13, 22.51; HRMS (ESI, positive):
d
165.93, 152.87, 132.71, 130.94, 121.71, 121.61, 121.42, 109.80, 99.14,
m/z calculated for C14H15NO2 (Hþ) 230.1181, found: 230.1176.
50.68, 44.45, 26.61, 26.11; HRMS (ESI, positive): m/z calculated for
C13H13NO2 (Hþ) 216.1024, found: 216.1019.
4.2.9. Methyl 7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate (2g, Table 2). White solid, 50% yield (under 110 ꢀC);
mp 269e270 ꢀC; FTIR (neat, cmꢁ1): 3735, 3266, 2893, 1723, 1660,
1626, 1532, 1490, 1459, 1238, 1195, 1116, 869, 780; 1H NMR
4.2.3. Methyl 7-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate (2c, Table 2). Yellow solid, 49% yield; mp 151e152 ꢀC;
FTIR (neat, cmꢁ1): 3451, 2946, 2854, 1690, 1616, 1547, 1454, 1424,
(400 MHz, DMSO-d6):
d
8.96 (s, AreOH, 1H), 7.31 (d, J¼2.3 Hz, 1H),
1112, 810; 1H NMR (400 MHz, CDCl3):
d
7.90 (s,1H), 7.13 (d, J¼8.2 Hz,
7.17 (d, J¼8.6 Hz, 1H), 6.62 (dd, J¼8.6, 2.4 Hz, 1H), 4.05 (d, J¼14.3 Hz,
2H), 3.74 (s, 3H), 3.12 (t, J¼7.5 Hz, 2H), 2.54 (dd, J¼14.5, 7.4 Hz, 2H);
1H), 7.02 (d, J¼8.2 Hz, 1H), 4.08 (t, J¼7.1 Hz, 2H), 3.89 (s, 3H), 3.27 (t,
J¼7.5 Hz, 2H), 2.63 (p, J¼7.3 Hz, 2H), 2.48 (s, 3H); 13C NMR (100 MHz,
13C NMR (100 MHz, DMSO-d6):
d 164.97, 153.02, 152.89, 131.73,
CDCl3):
d
166.03,152.88,131.19,131.12,131.05,123.14,121.24,109.45,
126.96, 111.21, 111.19, 105.48, 97.25, 50.52, 44.71, 26.39, 26.26;
HRMS (ESI, positive): m/z calculated for C13H13NO3 (Hþ) 232.0974;
C13H13NO3 (Naþ) 254.0793, found: 232.0968, 254.0788.
98.63, 50.65, 44.50, 26.60, 26.20, 21.64; HRMS (ESI, positive): m/z
calculated for C14H15NO2 (Hþ) 230.1181, found: 230.1176.
4.2.4. Methyl 6-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate (2d, Table 2). Light yellow solid, 38% yield; mp
134e135 ꢀC; FTIR (neat, cmꢁ1): 3448, 2925, 1670, 1622, 1547, 1469,
4.2.10. Methyl 7-cyclohexyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate (2h, Table 2). Yellow solid, 42% yield; mp 147e148 ꢀC;
FTIR (neat, cmꢁ1): 3423, 2921, 2839, 1692, 1618, 1545, 1457, 1110,
1443, 1232, 1106, 818, 776; 1H NMR (400 MHz, CDCl3):
d
7.95 (d,
783; 1H NMR (400 MHz, CDCl3):
d
7.95 (s, 1H), 7.17 (d, J¼8.3 Hz, 1H),
J¼8.7 Hz,1H), 6.87 (dd, J¼8.7, 2.1 Hz, 1H), 6.72 (d, J¼1.8 Hz,1H), 4.04
7.08 (dd, J¼8.3,1.0 Hz,1H), 4.07 (t, J¼7.1 Hz, 2H), 3.90 (s, 3H), 3.26 (t,
J¼7.5 Hz, 2H), 2.69e2.57 (m, 3H), 1.99e1.72 (m, 5H), 1.58e1.22 (m,
(t, J¼7.1 Hz, 2H), 3.81e3.96 (overlap, 6H), 3.25 (t, J¼7.5 Hz, 2H),
2.72e2.56 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
165.92, 156.12,
5H); 13C NMR (100 MHz, CDCl3):
d 166.04, 152.88, 141.89, 131.32,
151.89, 133.33, 124.94, 122.03, 110.69, 99.02, 93.94, 55.73, 50.66,
44.31, 26.68, 26.01; HRMS (ESI, positive): m/z calculated for
C14H15NO3 (Hþ) 246.1130, found: 246.1125.
131.15, 121.14, 119.08, 109.52, 98.84, 50.65, 45.02, 44.48, 35.14, 27.14,
26.63, 26.29, 26.20; HRMS (ESI, positive): m/z calculated for
C19H23NO2 (Hþ) 298.1807, found: 298.1802.
4.2.5. Methyl 8-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate (2d0, Table 2). Light yellow solid, 33% yield; mp
179e180 ꢀC; FTIR (neat, cmꢁ1): 3434, 2954, 2852, 1706, 1608, 1573,
4.2.11. Methyl 7-tert-butyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate (2i, Table 2). Yellow solid, 42% yield; mp 158e160 ꢀC;
FTIR (neat, cmꢁ1): 3445, 2958, 2866, 1686, 1542, 1475, 1452, 1193,
1442, 1091, 765; 1H NMR (400 MHz, CDCl3):
d
7.14 (t, J¼8.0 Hz, 1H),
1107, 784; 1H NMR (400 MHz, CDCl3):
d
8.16 (d, J¼1.7 Hz, 1H), 7.29
6.87 (d, J¼8.0 Hz, 1H), 6.68 (d, J¼7.9 Hz, 1H), 4.09 (t, J¼7.2 Hz, 2H),
(dd, J¼8.5, 1.9 Hz, 1H), 7.18 (d, J¼8.5 Hz, 1H), 4.06 (t, J¼7.2 Hz, 2H),
3.98 (s, 3H), 3.86 (s, 3H), 3.28 (t, J¼7.5 Hz, 2H), 2.68e2.56 (m, 2H);
3.90 (s, 3H), 3.26 (t, J¼7.5 Hz, 2H), 2.67e2.57 (m, 2H), 1.42 (s, 9H);
13C NMR (100 MHz, CDCl3):
d
165.22, 153.85, 152.49, 134.60, 122.86,
13C NMR (100 MHz, CDCl3):
d 166.04, 152.89, 144.79, 130.94, 130.91,
119.51, 103.36, 102.88, 99.36, 56.04, 51.21, 44.87, 27.26, 26.29; HRMS
(ESI, positive): m/z calculated for C14H15NO3 (Hþ) 246.1130, found:
246.1125.
119.81, 117.51, 109.25, 98.96, 50.65, 44.48, 34.82, 31.94, 26.65, 26.23;
HRMS (ESI, positive): m/z calculated for C17H21NO2 (Hþ) 272.1650,
found: 272.1645.
4.2.6. Methyl 7-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate (2e, Table 2). Yellow solid, 50% yield; mp 158e159 ꢀC;
FTIR (neat, cmꢁ1): 3434, 2993, 2946, 2858, 1687, 1545, 1465, 1443,
4.2.12. Methyl 5-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate (2j, Table 2). White solid, 29% yield (under 110 ꢀC);
mp 150e152 ꢀC; FTIR (neat, cmꢁ1): 3452, 2985, 2957, 2924, 2852,
1688, 1618, 1548, 1498, 1452, 1264, 792, 733; 1H NMR (400 MHz,
1107, 766; 1H NMR (400 MHz, CDCl3):
d 8.33 (s, 1H), 7.68 (d,
J¼7.5 Hz, 2H), 7.43 (t, J¼7.0 Hz, 3H), 7.31 (t, J¼7.3 Hz, 1H), 7.25 (d,
CDCl3):
d
7.68 (d, J¼8.1 Hz, 1H), 7.10 (t, J¼8.0 Hz, 1H), 6.62 (d,
J¼8.5 Hz, 1H), 4.06 (t, J¼7.2 Hz, 2H), 3.90 (s, 3H), 3.25 (t, J¼7.5 Hz,
J¼7.8 Hz, 1H), 4.37 (t, J¼7.2 Hz, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.22 (t,
2H), 2.68e2.55 (m, 2H); 13C NMR (100 MHz, CDCl3):
d 165.84,
J¼7.6 Hz, 2H), 2.64e2.53 (m, 2H); 13C NMR (100 MHz, CDCl3):
153.46, 142.38, 135.13, 132.22, 131.47, 128.63, 127.52, 126.52, 121.44,
120.01, 110.03, 99.46, 50.72, 44.54, 26.62, 26.19; HRMS (ESI, posi-
tive): m/z calculated for C19H17NO2 (Hþ) 292.1338, found: 292.1332.
d 166.01, 152.54, 146.71, 132.61, 123.08, 122.09, 114.11, 102.44, 99.26,
55.42, 50.62, 47.69, 26.86, 25.84; HRMS (ESI, positive): m/z calcu-
lated for C14H15NO3 (Hþ) 246.1130; C14H15NO3 (Naþ) 268.0950,
found: 246.1125, 268.0944.
4.2.7. Methyl 6-methyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate (2f, Table 2). Yellow solid, 33% yield; mp 155e156 ꢀC;
FTIR (neat, cmꢁ1): 2953, 2924, 2853, 1690, 1547, 1440, 1206, 1104,
4.2.13. Methyl 7-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate (2k, Table 2). Yellow solid, 35% yield; mp 112e113 ꢀC;
FTIR (neat, cmꢁ1): 3435, 2985, 2954, 2924, 2856, 1687, 1628, 1546,
810, 747; 1H NMR (400 MHz, CDCl3):
d
7.96 (d, J¼8.1 Hz, 1H),
7.09e7.01 (m, 2H), 4.04 (t, J¼6.9 Hz, 2H), 3.89 (s, 3H), 3.25 (t,
1454, 1118, 777; 1H NMR (400 MHz, CDCl3):
d
7.75 (dd, J¼10.0,
J¼7.5 Hz, 2H), 2.62 (p, J¼7.4 Hz, 2H), 2.47 (s, 3H); 13C NMR
2.5 Hz, 1H), 7.12 (dd, J¼8.8, 4.4 Hz, 1H), 6.91 (td, J¼9.0, 2.5 Hz, 1H),

L. Ren et al. / Tetrahedron 69 (2013) 4408e4414
4413
4.08 (t, J¼7.2 Hz, 2H), 3.88 (s, 3H), 3.27 (t, J¼7.6 Hz, 2H), 2.71e2.59
(m, 2H); 13C NMR (100 MHz, CDCl3):
165.58, 159.20 (d,
139e141 ꢀC; FTIR (neat, cmꢁ1): 3433, 2922, 1702, 1622, 1533, 1437,
1095, 828, 778; 1H NMR (400 MHz, CDCl3):
6.87 (s, 1H), 6.82 (s,
d
d
JCF¼236.2 Hz), 154.14, 131.61 (d, JCF¼11.0 Hz), 129.26, 110.38 (d,
JCF¼10.0 Hz), 109.80 (d, JCF¼26.4 Hz), 106.95 (d, JCF¼25.1 Hz), 99.44
(d, JCF¼4.3 Hz), 50.75, 44.74, 26.60, 26.33; 19F NMR (376 MHz,
1H), 4.05 (t, J¼7.2 Hz, 2H), 3.83 (s, 3H), 3.27 (t, J¼7.6 Hz, 2H), 2.81 (s,
3H), 2.65e2.54 (m, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
165.63, 152.73, 133.77, 131.95, 131.73, 127.10, 125.62, 107.59, 99.98,
CDCl3):
d
ꢁ121.94; HRMS (ESI, positive): m/z calculated for
50.64, 44.52, 27.25, 26.12, 22.44, 21.31; HRMS (ESI, positive): m/z
calculated for C15H17NO2 (Hþ) 244.1338; C15H17NO2 (Naþ) 266.1157,
found: 244.1332, 266.1152.
C13H12FNO2 (Hþ) 234.0930, found: 234.0925.
4.2.14. Methyl 7-chloro-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate (2l, Table 2). Brown solid, 31% yield; mp 132e134 ꢀC;
FTIR (neat, cmꢁ1): 3456, 2953, 2924, 2852, 1681, 1615, 1542, 1488,
4.2.20. 1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)
hexan-1-one(2r, Table 3). White solid, 54% yield; mp 137e138 ꢀC;
FTIR (neat, cmꢁ1): 3420, 2959, 2927, 2855, 1628, 1575, 1530, 1484,
1455, 1206, 1108, 780; 1H NMR (400 MHz, CDCl3):
d 8.05 (s, 1H),
7.17e7.09 (m, 2H), 4.08 (t, J¼7.2 Hz, 2H), 3.89 (s, 3H), 3.27 (t,
1450, 1260, 795; 1H NMR (400 MHz, CDCl3):
d
7.88 (d, J¼1.9 Hz, 1H),
J¼7.5 Hz, 2H), 2.65 (p, J¼7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
7.11 (d, J¼8.7 Hz, 1H), 6.85 (dd, J¼8.7, 2.2 Hz, 1H), 4.09 (t, J¼7.2 Hz,
2H), 3.89 (s, 3H), 3.30 (t, J¼7.4 Hz, 2H), 2.76 (t, J¼7.4 Hz, 2H),
2.73e2.60 (m, 2H), 1.83e1.70 (m, 2H), 1.46e1.32 (m, 4H), 0.92 (t,
d
165.46, 153.97, 131.83, 131.05, 127.51, 121.98, 121.00, 110.72, 99.05,
50.83, 44.67, 26.60, 26.19; HRMS (ESI, positive): m/z calculated for
C13H12ClNO2 (Hþ) 250.0635, found: 250.0629.
J¼6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 195.63, 156.22, 151.60,
131.75, 127.84, 112.16, 110.30, 109.87, 104.39, 55.80, 44.39, 41.03,
31.88, 27.62, 26.52, 24.36, 22.70, 14.02; HRMS (ESI, positive): m/z
calculated for C18H23NO2 (Hþ) 286.1807; C18H23NO2 (Naþ)
308.1626, found: 286.1802, 308.1621.
4.2.15. Methyl 6,8-dimethoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indole-
9-carboxylate (2m, Table 2). Yellow solid, 43% yield (under 130 ꢀC);
mp 148e149 ꢀC; FTIR (neat, cmꢁ1): 3434, 2992, 2937, 2840, 1708,
1623, 1579, 1504, 1450, 1210, 1098, 802; 1H NMR (400 MHz, CDCl3):
d
6.32 (d, J¼9.1 Hz, 2H), 4.01 (t, J¼7.0 Hz, 2H), 3.94 (s, 3H), 3.83 (s,
4.2.21. (7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-
yl)(phenyl)methanone (2s, Table 3). Brown solid, 45% yield (under
110 ꢀC); mp 151e152 ꢀC; FTIR (neat, cmꢁ1): 3489, 3056, 2929, 2835,
1720, 1612,1513,1474, 1452, 1268, 801, 726, 702; 1H NMR (400 MHz,
6H), 3.23 (t, J¼7.5 Hz, 2H), 2.64e2.53 (m, 2H); 13C NMR (100 MHz,
CDCl3):
d 165.10, 157.17, 154.44, 151.12, 134.73, 113.97, 99.44, 93.93,
86.04, 55.98, 55.61, 50.91, 44.60, 26.93, 26.31; HRMS (ESI, positive):
m/z calculated for C15H17NO4 (Hþ) 276.1236; C15H17NO4 (Naþ)
298.1055, found: 276.1230, 298.1050.
CDCl3):
d
7.71 (d, J¼2.4 Hz, 1H), 7.69e7.61 (m, 2H), 7.55e7.41 (m,
3H), 7.16 (d, J¼8.7 Hz, 1H), 6.87 (dd, J¼8.7, 2.5 Hz, 1H), 4.08 (t,
J¼7.1 Hz, 2H), 3.86 (s, 3H), 2.74 (t, J¼7.4 Hz, 2H), 2.56e2.44 (m, 2H);
4.2.16. Methyl 7-(trifluoromethyl)-2,3-dihydro-1H-pyrrolo[1,2-a]in-
dole-9-carboxylate (2n, Table 2). Yellow solid, 40% yield (under
110 ꢀC); mp 135e136 ꢀC; FTIR (neat, cmꢁ1): 3434, 2989, 2951, 2898,
2850, 1670, 1624, 1548, 1492, 1463, 1111, 826; 1H NMR (400 MHz,
13C NMR (100 MHz, CDCl3):
d 192.08, 156.16, 153.72, 141.83, 132.14,
130.65, 128.28, 128.04, 127.87, 112.49, 110.64, 109.26, 103.86, 55.77,
44.82, 27.45, 26.80; HRMS (ESI, positive): m/z calculated for
C19H17NO2 (Hþ) 292.1338, found: 292.1332.
CDCl3):
4.12 (t, J¼7.2 Hz, 2H), 3.91 (s, 3H), 3.29 (t, J¼7.6 Hz, 2H), 2.73e2.62
(m, 2H); 13C NMR (100 MHz, CDCl3):
165.31, 154.45, 133.98,
d
8.38 (s, 1H), 7.41 (d, J¼8.4 Hz, 1H), 7.27 (d, J¼8.5 Hz, 1H),
4.2.22. (7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-
yl)(naphthalen-2-yl)methanone (2t, Table 3). Light yellow solid,
45% yield; mp 187e189 ꢀC; FTIR (neat, cmꢁ1): 3445, 2961, 2936,
2836, 1606, 1500, 1440, 1421, 1045, 779; 1H NMR (400 MHz,
d
130.30, 126.58 (m), 123.88 (quint, JCF¼37.1 Hz), 119.06 (q,
JCF¼4.2 Hz), 118.58 (q, JCF¼3.6 Hz), 109.99, 100.11, 50.91, 44.62,
26.62, 26.08; 19F NMR (376 MHz, CDCl3):
d
ꢁ60.40; HRMS (ESI,
CDCl3):
d
8.16 (s, 1H), 7.92 (t, J¼9.0 Hz, 3H), 7.80 (d, J¼8.1 Hz, 1H),
positive): m/z calculated for C14H12F3NO2 (Hþ) 284.0898;
7.73 (d, J¼2.0 Hz, 1H), 7.64e7.50 (m, 2H), 7.17 (d, J¼8.7 Hz, 1H),
6.89 (dd, J¼8.7, 2.0 Hz, 1H), 4.10 (t, J¼7.0 Hz, 2H), 3.83 (s, 3H), 2.77
(t, J¼7.3 Hz, 2H), 2.58e2.42 (m, 2H); 13C NMR (100 MHz, CDCl3):
C14H12F3NO2 (Naþ) 306.0718, found: 284.0893, 306.0712.
4.2.17. Methyl 7-(trifluoromethoxy)-2,3-dihydro-1H-pyrrolo[1,2-a]
indole-9-carboxylate (2o, Table 2). Yellow solid, 44% yield; mp
113e114 ꢀC; FTIR (neat, cmꢁ1): 3434, 2983, 2856, 1670, 1628, 1546,
d 191.56, 156.32, 153.44, 139.12, 134.46, 132.65, 132.31, 128.77,
128.34, 128.18, 128.09, 127.87, 127.24, 126.53, 125.09, 112.54,
110.48, 109.61, 104.31, 55.78, 44.74, 27.46, 26.78; HRMS (ESI,
positive): m/z calculated for C23H19NO2 (Hþ) 342.1494, found:
342.1489.
1460, 1285, 1257, 777; 1H NMR (400 MHz, CDCl3):
d 7.95 (s, 1H), 7.21
(d, J¼8.7 Hz, 1H), 7.07 (d, J¼8.7, 1H), 4.12 (t, J¼7.2 Hz, 2H), 3.90 (s,
3H), 3.31 (t, J¼7.5 Hz, 2H), 2.68 (p, J¼7.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3):
d
165.42, 154.42, 144.55, 131.15, 120.79 (q,
4.2.23. 1-(7-Methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-9-yl)-2,2-
dimethylpropan-1-one (2u, Table 3). Light yellow solid, 28% yield;
mp 148e150 ꢀC; FTIR (neat, cmꢁ1): 3446, 2978, 2952, 2932, 2832,
1617, 1497, 1476, 1453, 1060, 858, 793; 1H NMR (400 MHz, CDCl3):
JCF¼255.6 Hz), 115.56, 114.20, 110.35, 99.78, 50.86, 44.75, 26.68,
26.28; 19F NMR (376 MHz, CDCl3):
d
ꢁ57.96; HRMS (ESI, positive):
m/z calculated for C14H12F3NO3 (Hþ) 300.0848, found: 300.0842.
d
7.80 (d, J¼2.4 Hz, 1H), 7.13 (d, J¼8.7 Hz, 1H), 6.85 (dd, J¼8.7,
4.2.18. Methyl 7-acetyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate(2p, Table 2). Yellow solid, 50% yield; mp 134e136 ꢀC;
2.3 Hz, 1H), 4.08 (t, J¼7.1 Hz, 2H), 3.89 (s, 3H), 3.37 (t, J¼7.3 Hz,
2H), 2.69e2.59 (m, 2H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3):
FTIR (neat, cmꢁ1): 3451, 2949, 2851, 1693, 1671, 1608, 1546, 1455,
d 202.53, 155.69, 150.82, 132.03, 127.87, 111.50, 110.26, 108.38,
1
1112, 816, 784, 609; H NMR (400 MHz, CDCl3):
d
8.74 (s, 1H), 7.91
105.82, 55.87, 44.31, 42.82, 30.02, 27.20, 26.72; HRMS (ESI, posi-
tive): m/z calculated for C17H21NO2 (Hþ) 272.1650, found:
272.1645.
(d, J¼8.5 Hz, 1H), 7.28 (d, J¼8.2 Hz, 1H), 4.16 (t, J¼7.1 Hz, 2H), 3.94 (s,
3H), 3.32 (t, J¼7.5 Hz, 2H), 2.79e2.64 (m, 5H); 13C NMR (100 MHz,
CDCl3):
d 198.53, 165.45, 154.25, 135.16, 131.36, 130.41, 123.45,
122.00, 109.84, 100.56, 50.97, 44.63, 26.72, 26.68, 26.14; HRMS (ESI,
positive): m/z calculated for C15H15NO3 (Hþ) 258.1130; C15H15NO3
(Naþ) 280.0950, found: 258.1125, 280.0944.
Acknowledgements
Financial support from National Basic Research Program of
China (973 Program) (Grant No. 2009CB825300), National Science
Foundation of China (No. 21172006), and Peking University are
greatly appreciated.
4.2.19. Methyl 6,8-dimethyl-2,3-dihydro-1H-pyrrolo[1,2-a]indole-9-
carboxylate(2q, Table 2). Light yellow solid, 77% yield; mp

4414
L. Ren et al. / Tetrahedron 69 (2013) 4408e4414
Perboni, A.; Sferrazza, A.; Stabile, P. Org. Lett. 2010, 12, 3279e3281; (g) Lu, X.-Y.;
Supplementary data
Han, X.-L. Org. Lett. 2010, 12, 3336e3339; (h) Wetzel, A.; Gagosz, F. Angew.
Chem., Int. Ed. 2011, 50, 7354e7358; (i) Wu, C.-Y.; Hu, M.; Liu, Y.; Song, R.-J.; Lei,
Y.; Tang, B.-X.; Li, R.-J.; Li, J.-H. Chem. Commun. 2012, 3197e3199; (j) Gabriele,
B.; Veltri, L.; Mancuso, R.; Salerno, G.; Costa, M. Eur. J. Org. Chem. 2012,
2549e2559.
Supplementary data (starting material syntheses, characteriza-
tion of byproduct representative 3a, and copies of NMR spectra)
associated with this article can be found in the online version.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.01.031.
14. Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc. 2000, 122, 5662e5663.
€
€
15. Wurtz, S.; Rakshit, S.; Neumann, J. J.; Droge, T.; Glorius, F. Angew. Chem., Int. Ed.
2008, 47, 7230e7233.
16. Wei, Y.; Deb, I.; Yoshikai, N. J. Am. Chem. Soc. 2012, 134, 9098e9101.
17. (a) Shen, M.; Li, G.-S.; Lu, B. Z.; Hossain, A.; Roschangar, F.; Farina, V.; Sen-
anayake, C. H. Org. Lett. 2004, 6, 4129e4132; (b) Stuart, D. R.; Bertrand-La-
perle, M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc. 2008, 130,
16474e16475; (c) Varma, P. P.; Sherigara, B. S.; Mahadevan, K. M.; Hulikal, V.
Synth. Commun. 2009, 39, 158e165; (d) Yao, C.-S.; Wang, D.-L.; Lu, J.; Qin, B.-
B.; Zhang, H.-H.; Li, T.-J.; Yu, C.-X. Tetrahedron Lett. 2011, 52, 6162e6165; (e)
References and notes
1. Yamada, Y.; Matsui, M. Agric. Biol. Chem. 1971, 35, 282e284.
2. Remers, W. A.; Roth, R. H.; Weiss, M. J. J. Am. Chem. Soc. 1964, 86, 4612e4617.
3. Luly, J. R.; Rapoport, H. J. Org. Chem. 1984, 49, 1672e1674.
4. (a) Lim, H.-J.; Sulikowski, G. A. Tetrahedron Lett. 1996, 37, 5243e5246; (b) Beall,
H. D.; Winski, S.; Swann, E.; Hudnott, A. R.; Cotterill, A. S.; O’Sullivan, N.; Green,
S. J.; Bien, R.; Siegel, D.; Ross, D.; Moody, C. J. J. Med. Chem. 1998, 41, 4755e4766.
5. Kleinwӓchter, P.; Schlegel, B.; Groth, I.; Hӓrtl, A.; Grӓfe, U. J. Antibiot. 2001, 54,
510e512.
ꢀ
Cabrera, A.; Ayala, P. S. M.; Rubio-Perez, L.; Amezquita-Valencia, M. Tetrahe-
dron Lett. 2011, 52, 6758e6762; (f) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou,
K. J. Am. Chem. Soc. 2010, 132, 18326e18339; (g) Zhou, F.; Han, X.-L.; Lu, X.-Y.
Tetrahedron Lett. 2011, 52, 4681e4685; (h) Maizuru, N.; Inami, T.; Kurahashi,
T.; Matsubara, S. Org. Lett. 2011, 13, 1206e1209; (i) Huestis, M. P.; Chan, L.;
Stuart, D. R.; Fagnou, K. Angew. Chem., Int. Ed. 2011, 50, 1338e1341; (j) Murru,
S.; Gallo, A. A.; Srivastava, R. S. Eur. J. Org. Chem. 2011, 2035e2038; (k) Gui-
6. Bach, N. J.; Sall, D. J. PCT Int. Appl. WO 00/37472, 2000.
7. (a) Wang, Z. -Y.; Dufresne, C.; Guay, D.; Leblanc, Y. PCT Int. Appl. WO 02/094830
A2, 2004; (b) Beaulieu, C.; Guay, D.; Wang, Z.-Y.; Leblanc, Y.; Roy, P.; Dufresne,
C.; Zamboni, R.; Berthelette, C.; Day, S.; Tsou, N.; Denis, D.; Greig, G.; Mathieu,
M.-C.; O’Neill, G. Bioorg. Med. Chem. Lett. 2008, 18, 2696e2700.
8. Jones, R. M.; Buzard, D. J.; Han, S.; Lehmann, J.; Lopez, L. A.; Ullman, B.; Ka-
wasaki, A. M.; Thoresen, L.; Zhu, X. -W. PCT Int. Appl. WO 2011/005290 A1, 2011.
9. Fotso, S.; Mahmud, T.; Zabriskie, T. M.; Santosa, D. A.; Sulastri; Proteau, P. J. J.
Antibiot. 2008, 61, 449e456.
ꢀ
larte, V.; Castroviejo, M. P.; García-García, P.; Fernandez-Rodríguez, M. A.;
Sanz, R. J. Org. Chem. 2011, 76, 3416e3437; (l) Ackermann, L.; Lygin, A. V. Org.
Lett. 2012, 14, 764e767.
ꢀ
ꢀ
18. (a) Barluenga, J.; Jimenez-Aquino, A.; Aznar, F.; Valdes, C. J. Am. Chem. Soc. 2009,
131, 4031e4041; (b) Hong, D.; Chen, Z.; Lin, X.; Wang, Y. Org. Lett. 2010, 12,
4608e4611.
19. For some reviews on indole synthesis, see: (a) Gribble, G. W. J. Chem. Soc., Perkin
Trans. 1 2000, 1045e1075; (b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev.
2004, 104, 3079e3159; (c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105,
2873e2920 For other examples, see: (d) Iida, H.; Yuasa, Y.; Kibayashi, C. J. Org.
Chem. 1980, 45, 2938e2942; (e) Chen, C.-Y.; Lieberman, D. R.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676e2677; (f) Larock, R. C.;
Yum, E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652e7662; (g) Yamazaki, K.;
10. (a) Banwell, M. G.; Kelly, B. D.; Kokas, O. J.; Lupton, D. W. Org. Lett. 2003, 5,
2497e2500; (b) Xu, D.-Q.; Yang, W.-L.; Luo, S.-P.; Wang, B.-T.; Wu, J.; Xu, Z.-Y.
Eur. J. Org. Chem. 2007, 1007e1012; (c) Xu, D.-Q.; Wu, J.; Luo, S.-P.; Zhang, J.-X.;
Wu, J.-Y.; Du, X.-H.; Xu, Z.-Y. Green Chem. 2009, 11, 1239e1246; (d) Wahab, B.;
Ellames, G.; Passey, S.; Watts, P. Tetrahedron 2010, 66, 3861e3865; (e) Sun, K.;
Liu, S.; Bec, P. M.; Driver, T. G. Angew. Chem., Int. Ed. 2011, 50, 1702e1706; (f)
Sturino, C. F.; O’Neill, G.; Lachance, N.; Boyd, M.; Berthelette, C.; Labelle, M.; Li,
L.; Roy, B.; Scheigetz, J.; Tsou, N.; Aubin, Y.; Bateman, K. P.; Chauret, N.; Day, S.
ꢀ
Nakamura, Y.; Kondo, Y. J. Org. Chem. 2003, 68, 6011e6019; (h) Nazare, M.;
Schneider, C.; Lindenschmidt, A.; Will, D. W. Angew. Chem., Int. Ed. 2004, 43,
4526e4528; (i) Jia, Y.-X.; Zhu, J.-P. J. Org. Chem. 2006, 71, 7826e7834; (j)
Crawley, M. L.; Goljer, I.; Jenkins, D. J.; Mehlmann, J. F.; Nogle, L.; Dooley, R.;
Mahaney, P. E. Org. Lett. 2006, 8, 5837e5840; (k) Leogane, O.; Lebel, H. Angew.
Chem., Int. Ed. 2008, 47, 350e352; (l) Pei, T.; Chen, C.-Y.; Dormer, P. G.; Davies, I.
W. Angew. Chem., Int. Ed. 2008, 47, 4231e4233; (m) Alex, K.; Tillack, A.; Schwarz,
N.; Beller, M. Angew. Chem., Int. Ed. 2008, 47, 2304e2307; (n) Shen, M.; Leslie, B.
E.; Driver, T. G. Angew. Chem., Int. Ed. 2008, 47, 5056e5059.
ꢀ
H.; Levesque, J.-F.; Seto, C.; Silva, J. H.; Trimble, L. A.; Carriere, M.-C.; Denis, D.;
Greig, G.; Kargman, S.; Lamontagne, S.; Mathieu, M.-C.; Sawyer, N.; Slipetz, D.;
Abranham, W. M.; Jones, T.; McAuliffe, M.; Piechuta, H.; Nicoll-Griffith, D. A.;
Wang, Z.; Zamboni, R.; Young, R. N.; Metters, K. M. J. Med. Chem. 2007, 50,
794e806.
11. (a) Artis, D. R.; Cho, I.-S.; Jaime-Figueroa, S.; Muchowski, J. M. J. Org. Chem. 1994,
59, 2456e2466; (b) Komoda, T.; Shinoda, Y.; Nakatsuka, S.-I. Biosci. Biotechnol.
Biochem. 2003, 67, 659e662; (c) Kraus, G. A.; Wu, T. Tetrahedron 2005, 61,
9502e9505; (d) Scopton, A.; Kelly, T. R. J. Org. Chem. 2005, 70, 10004e10012; (e)
Thalji, R. K.; Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2005, 70,
6775e6781.
12. (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
14560e14561; (b) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.;
Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184e16186; (c) Jana, S.; Clements, M.
D.; Sharp, B. K.; Zheng, N. Org. Lett. 2010, 12, 3736e3739; (d) Cho, S. H.; Yoon, J.;
Chang, S. J. Am. Chem. Soc. 2011, 133, 5996e6005; (e) Yan, Q.; Luo, J.; Zhang-
Negrerie, D.; Li, H.; Qi, X.-X.; Zhao, K. J. Org. Chem. 2011, 76, 8690e8697.
13. (a) Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126,
10546e10547; (b) Kothandaraman, P.; Rao, W.; Foo, S. J.; Chan, P. W. H. Angew.
Chem., Int. Ed. 2010, 49, 4619e4623; (c) Kusama, H.; Miyashita, Y.; Takaya, J.;
Iwasawa, N. Org. Lett. 2006, 8, 289e292; (d) Isono, N.; Lautens, M. Org. Lett.
2009, 11, 1329e1331; (e) Oh, C. H.; Karmakar, S.; Park, H.; Ahn, Y.; Kim, J. W. J.
Am. Chem. Soc. 2010, 132, 1792e1793; (f) Cacchi, S.; Fabrizi, G.; Goggiamani, A.;
20. (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689e6690 For his re-
views, see: (b) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285e2309; (c) Zeni,
G.; Larock, R. C. Chem. Rev. 2006, 106, 4644e4680.
21. Shi, Z.-Z.; Zhang, C.; Li, S.; Pan, D.-L.; Ding, S.-T.; Cui, Y.-X.; Jiao, N. Angew. Chem.,
Int. Ed. 2009, 48, 4572e4576.
~
22. (a) Minatti, A.; Munis, K. Chem. Soc. Rev. 2007, 36, 1142e1152; (b) Lei, A.-W.; Lu,
X.-Y. Org. Lett. 2000, 2, 2699e2702; (c) Shen, Z.-M.; Lu, X.-Y. Tetrahedron 2006,
62, 10896e10899.
23. Lafrance, M.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496e16497.
24. Hajra, A.; Wei, Y.; Yoshikai, N. Org. Lett. 2012, 14, 5488e5491.
25. (a) Larini, P.; kefalidis, C. E.; jazzar, R.; Renaudat, A.; Clot, E.; Baudoin, O. Chem.
dEur. J 2012, 18, 1932e1944; (b) Ryan, C.; Lewis, A. K. de K.; Caddick, S.;
Kaltsoyannis, N. Theor. Chem. Acc. 2011, 129, 303e312; (c) Lloyd-Jones, G. C.;
Slatford, P. A. J. Am. Chem. Soc. 2004, 126, 2690e2691; (d) Ng, S. M.; Zhao, C.-Y.;
Lin, Z.-Y. J. Organomet. Chem. 2002, 662, 120e129.