Sustainable Radical Cascades to Synthesize Difluoroalkylated Pyrrolo[1,2-a]indoles

Article abstract of DOI:10.1021/acs.joc.7b03017

We disclose herein a photocatalytic difluoroalkylation and cyclization cascade reaction of N-(but-2-enoyl)indoles with broad substrate scopes in up to 90% isolated yield. This method provides sustainable and efficient access to synthesize difluoroalkylated pyrrolo[1,2-a]indoles with a quaternary carbon center under mild conditions.

Full text of DOI:10.1021/acs.joc.7b03017

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Note
Sustainable Radical Cascades to Synthesize
Difluoroalkylated Pyrrolo[1,2-a]indoles
Honggui Huang, Menglin Yu, Xiaolong Su, Peng Guo, Jia Zhao, Jiabing Zhou, and Yi Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03017 • Publication Date (Web): 22 Jan 2018
Downloaded from http://pubs.acs.org on January 22, 2018
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Page 1 of 39
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Sustainable Radical Cascades to Synthesize Difluoroalkylated
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Pyrrolo[1,2ꢀa]indoles
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Honggui Huanga, Menglin Yua, Xiaolong Sua, Peng Guoa, Jia Zhaoa, Jiabing
Zhoua and Yi Lia, b*
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aDepartment of Chemistry, Fuzhou University, Fuzhou 350116, China
bState Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou, 350116,
China
Email: liyiꢀchem@fzu.edu.cn
R2
R2
R3
R4
R3
R1
R1
visible light
CF2R
R4
CF R
Br
+
2
37 examples
up to 90% yield
R'
N
N
R5
R5
O
R'
O
R6
R6
Abstract. We disclosed herein a photocatalytic difluoroalkylation and cyclization cascade reaction of
Nꢀ(butꢀ2ꢀenoyl)indoles with broad substrate scopes in up to 90% isolated yield. This method provides
a sustainable and efficient access to synthesize difluoroalkylated pyrrolo[1,2ꢀa]indoles with a
quaternary carbon center under mild conditions.
Keywords: photoredox; difluoroalkylation; radical cascade; Nꢀ(butꢀ2ꢀenoyl)indole; polycycles
Figure 1 Representative biologically active compounds containing pyrrolo[1,2ꢀa]indole motifs.
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Pyrrolo[1,2ꢀa]indoles are important key structural components that are widely found in a number of
natural products and pharmacologically important agents (Figure 1).1 In this respect, great effort has
been devoted to the development of efficient methods toward these unique skeletons.2 For example,
Lu and coworkers reported in 2006 an intresting pallidiumꢀcatalyzed intramolecular alkyne insertion
protocol to rapidly establish pyrrolo[1,2ꢀa]indole skeletons (Scheme 1a).3 Remarkably, You group
accomplished an asymmetric version of pyrrolo[1,2ꢀa]indole formation through intramolecular
conjugated addition of C2ꢀsubstituted indoles in the presence of chiral phosphoric acids (Scheme 1b).4
Meanwhile, radical cascade cyclization has been recognized as an useful organic reaction to convert
simple starting materials to complex polycyclic molecules in a single synthetic operation. In 2010,
Stephenson et.al. disclosed visible light promoted intramolecular radical CꢀC bond formation of
substituted indoles for accessing a variety of biologically active molecules (Scheme 1c).5 Notably,
Tang group and Song group reported separately silverꢀmediated oxidative phosphinoylation of
substituted indoles to construct a variety of 2ꢀphosphinoylꢀpyrrolo[1,2ꢀa]indoles under mild conditions
(Scheme 1d).6 While a number of new synthetic methods for pyrroles have been developed in the last
decades, the demand for sustainable, simple and robust methods remains high, espacially in terms of
formation for multifunctional compounds with general diversity, applicability, and practicality.
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Scheme 1 Examples to construct pyrrolo[1,2ꢀa]indole motifs.
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Difluoroalkylation reaction is particularly of high significance, through which CF2 motif could be
introduced to molecules and improve molecules’ properties dramatically, such as electronegativity,
hydrophobicity, metabolic stability, and bioavailability.7 In addition, the alkyl groups (e.g. CF2CO2Et
moiety) offered further possibility of postfunctionalization. Recently, visible lightꢀinduced photoredox
alkylation turns out to be an efficient, sustainable method for introducing the difluoroacetyl
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functionality.8 Herein, we envisioned
a
photoredox difluoroalkylation/cyclization of
Nꢀ(butꢀ2ꢀenoyl)indoles to generate difluoroalkylated pyrrolo[1,2ꢀa]indoles notably with one
quaternary carbon center (Scheme 1e).
We began our studies by using Nꢀ(butꢀ2ꢀenoyl)indole 1a and BrCF2CO2Et as model substrates
(details for optimizations can be found in Supporting Information). At the beginning, the varies of
organophotocatalysts were tested; however all of them failed to launch this transformation (Table 1,
entries 1ꢀ4). To our great delight, careful optimizations with transtionꢀmetal photocatalysts revealed
that facꢀIr(ppy)3 was the best catalyst under irradiation of 3 W blue LEDs in the presence of Na2HPO4
for 12 hours (Table 1, entry 6). The expected product 3a was isolated in 71% yield. Other iridium
complexes were also tested; however, no better results were achieved (entries 7 and 8). The solvent
also affected this transformation significantly. Solvents, such as DMF, DMSO, dioxane or CH3CN,
were examined but did not lead to any improvement (entries 9ꢀ12). It is to our surprise that reaction in
toluene underwent smoothly with a yield of 33%, as toluene are generally considered to be inactive
solvent for photochemistry (entry 13). Gratefully, DCM turned out to be the best solvent for this
transformation with a full conversion and 85% isolated yield (entry 14). Therefore, the best reaction
conditions were revealed in entry 14 as follows: 1a, 2a (2.5 equiv.), facꢀIr(ppy)3 (0.01 equiv.) as
photocatalyst, Na2HPO4 (1.2 equiv.) as the base in DCM (0.1 M) irradiated by 3W blue LEDs for 12
hours.
Table 1 Screening of optimal reaction conditions.
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entrya
1
photocatalyst
solvent
3ab
9ꢀfluorenone
Mehtyl Blue
THF
THF
n.r.
n.r.
2
3
THF
THF
n.r.
n.r.
Eosin Y
Eosin B
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4
5
THF
n.r.
Ru(bpy)3Cl2
facꢀIr(ppy)3
6
THF
81% (71%)
25%
7
THF
Ir(dF(CF3)ppy)2(bpy)(PF6)
8
THF
n.r.
Ir(ppy)2(dtppy)
9
DMF
11%
facꢀIr(ppy)3
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14
48%
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
fac-Ir(ppy)3
DMSO
1,4ꢀdioxane
CH3CN
toluene
DCM
57%
n.r.
33%
99% (85%)
aReaction conditions: 1a (0.2 mmol), BrCF2CO2Et 2a (0.5 mmol), Na2HPO4 (0.24 mmol) and photocatalyst
b
(0.002 mmol) in solvent (2 mL) irradiated by 3 W blue LEDs at room temperature for 12 h. Determined by
crude 19F NMR with α,α,αꢀtrifluoromethyl benzene as the internal standard. Isolated yields were given in
parentheses.
With the optimized conditions in hand, we explore the scope and limitations to this cascade protocol
(Scheme 2). Firstly, the substitution patterns on the aromatic ring were studied. Either
electronꢀdonating or electronꢀwithdrawing groups were well tolerated on the different positions of the
aromatic ring and the desired products were generated in good yields (3bꢀ3q). Generally, substrates
with electronꢀdonating groups showed higher reactivity than those with electronꢀwithdrawing groups
(3b, 3c and 3d vs 3e and 3f; 3iꢀ3l vs 3g and 3h; 3nꢀ3p vs 3q). However, 3m with 5ꢀnitro substituent
was obtained in a yield of 7% probably because the substrate 1m was not stable when applied to the
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standard conditions. We then examine the substituents on the heteroꢀaromatic ring. To our delight,
phenyl substitute, methyl substitute, cyano substitute, ester substitute and formyl substitute on the
3ꢀposition of the heteroꢀaromatic ring were also compatible (3tꢀ3x, 49%ꢀ85% yields). The partially
decreased yield of 3r (49%) might be due to the steric hinder effect of the methyl group. Moreover,
our attempt to apply substrate with 7ꢀazoindole motif instead of indole was successes and the desired
product 3y was obtained in a yield of 65%. Our further attempts to modify the terminal olefin motif
were carried out. Applying hydrogen and phenyl group instead of methyl group on the olefin motif,
the corresponding products 3z and 3aa were also generated smoothly, albeit with decreased yields of
55% and 27%. We reasoned that the decreased yield of 3z might due to that hydrogen group are weak
substituent to stablize intermediate I (as proposed in Scheme 6). Phenyl group, on the other side, was
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too
steric
hinder
to
fulfil
the
step
from
intermediate
I
to
II.
1ꢀ(1HꢀIndolꢀ1ꢀyl)ꢀ2,3ꢀdimethylbutꢀ3ꢀenꢀ1ꢀone (1ab), with a methyl substituent attached on the
αꢀcarbon of the carbonyl unit, was conducted also and transformed to the desired product 3ab in a
good yield of 74% with a dr ratio of 5 to 1. Notably, when we conducted substrate 1ac with longer
chain
number
olefin, the
difluoroalkylated
product
3ac,
with
an
interesting
tetrahydropyrido[1,2ꢀa]indole skeleton, was generated in a reasonable yield of 64%.
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Scheme 2 Reaction conditions: 1 (0.2 mmol), BrCF2CO2Et 2a (0.5 mmol), Na2HPO4 (0.24 mmol) and
facꢀIr(ppy)3 (0.002 mmol) in DCM (2 mL) irradiated by 3 W blue LEDs at room temperature for 12 h. Isolated
yields were reported. aCHCl3 as the solvent.
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9
Subsequently, we evaluated the scope of difluoroalkyl bromides (Scheme 3). An array of
bromodifluoroacetates (3a, 3ad and 3ae), bromodifluoromethyl ketones (3af, 3ag and 3ah),
bromodifluoroacetamides (3ai and 3aj) and bromodifluoromethyl phosphonate (3ak) were found to be
compatible substrates, therefore yielding the corresponding products in moderate to good yields. As
3ag was provided in a yield of 41% when CH2Cl2 was used as the solvent, we then switched the
solvent to chloroform, which can afford almost equivalent result to CH2Cl2 during the optimizations
(details in SI). Gratefully, 3ag was generated in 60% yield with chloroform as solvent. Notably,
reaction of 1a with 2h gave 3aj in a relatively low yield of 23%, and we reasoned that the free
Nꢀhydrogen might quench the excited state photocatalyst.
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Scheme 3 Reaction conditions: 1a (0.2 mmol), 2 (0.5 mmol), Na2HPO4 (0.24 mmol) and facꢀIr(ppy)3 (0.002
mmol) in DCM (2 mL) irradiated by 3 W blue LEDs at room temperature for 12 h. Isolated yields were reported.
aCHCl3 as the solvent.
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In order to demonstrate the potential synthetic utility of this method, a gramꢀscale experiment with
1a was conducted which yielded 3a in a reasonable isolated yield of 71% (1.37 g, Scheme 4a). Further
transformations of the difluoroalkylation product 3a were explored to realize postfunctionalizations of
the CO2Et group (Scheme 4b). 3a can be easily reduced to the difluoroalkyl alcohol 4 in a quantitative
yield after simple reduction. Furthermore, the corresponding difluoroalkyl amide 5 could be obtained
in a suitable yield of 91%.
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Scheme 4 Synthetic utility of 3a.
Scheme 5 Mechanistic studies.
To gain insight into the mechanism of this cascade cyclization, control experiments were carried out.
Irradiated by visible light, the addition of both photocatalyst and base are crucial for this
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transformation (Scheme 5a). We then conducted radical trapping experiments to investigate the
possibility of a radical pathway. Experiments were performed with the addition of radical scavenger
(2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinoxyl (TEMPO, 2.5 equiv.) or 1,1ꢀdiphenylethylene (2.5 equiv)) to the
standard reaction of 1a (Scheme 5b and 5c). The formation of 3a was totally inhibited with the
observations of difluoroalkyl radical trapping compounds. These results confirmed the involvement of
a free radical pathway in this transformation. We also calculated the apparent quantum yield of the
model transformation with 1a (details found in the SI). A value of (1.53×10ꢀ3) unambiguously
indicates that this protocol proceeds via a photocatalytic pathway rather than radical propagation.
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[Ir3+
]
hv
Rf
Rf
[Ir3+]*
Me
Me
N
N
-H
III
Br Rf
Rf
3a
O
O
[Ir4+
]
Rf
Rf
Me
N
N
N
II
I
1a
O
Me
O
Me
O
Scheme 6 Proposed mechanism.
Based on these preliminary studies, we proposed a reaction mechanisum as following (Scheme 6,
take the formation of 3a for example). Irradiated by visible light, the photocatalyst [Ir3+] transfer to an
excited state which is subsequently oxidized by RfBr to give [Ir4+] complex and Rf radical. The
addition of Rf radical to 1a produce intermediate I. Intromelacular radical cyclizition on C2 of the
indole ring deliver intermediate II which is subsequently oxidized by [Ir4+] complex to form the
intermediate III and regenerate the [Ir3+] catalyst. Finally, deprotonation of this cationic intermediate
III by base eventually yields the terminal product 3a.
In conclusion, we have developed an efficient procedure to generate a wide range of
difluoroalkylated pyrrolo[1,2ꢀa]indoles with one quaternary carbon center through
visibleꢀlightꢀmediated radical difluoroalkylation/cyclization. This sustainable strategy has attracted
special attention due to its commendable functional group tolerance, operational simplicity, and good
to high yields under mild conditions. Moreover, these products, difluoroalkylated
pyrrolo[1,2ꢀa]indoles, could be of importance in medicinal and synthetic chemistry.
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Experimental Section
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General Information: Unless otherwise stated, all reactions utilizing airꢀsensitive reagents were
carried out in flameꢀdried glassware under nitrogen. All solvents were purified and dried according to
standard methods prior to use. 1H NMR, 13C NMR and 19F NMR spectra were recorded on a BRUKER
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1
400 MHz spectrometer in deuterated solvent. H NMR chemical shifts are reported in ppm with
internal TMS signal at 0.0 ppm as a standard. The data is reported as (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet or unresolved, brs = broad singlet, coupling constant(s) in Hz,
integration). 13C NMR spectra were recorded in deuterated solvent. Chemical shifts are reported in
ppm with internal solvent signal as standard. 19F NMR chemical shifts were determined relative to
CFCl3 as the external standard. 31P NMR chemical shifts were determined relative to H3PO4 (85%) as
the external standard. HRMS were obtained on Bruker Compact QꢀTOF and Waters GCTꢀTOF. IR
measurements were conducted on Nicolet is 50 KBr pelleting method. Known substrates 2b-2e[9], 2f[10]
2g-2h[11] were prepared according to literature procedures.
,
General Procedure A for the Synthesis of 1a-1k, 1n-1u, 1y-1ac: To a solution of indole (2 mmol) in
AcOH (5 mL) at room temperature was added NaBH3CN (6 mmol, 377 mg). The reaction was stirred
at the room temperature for 2ꢀ4 h until the disappearance of indole confirmed by TLC, then H2O was
added to reaction mixture and pH value of the reaction was adjusted to 9ꢀ10 by adding saturated
aqueous NaOH. Then reaction mixture was diluted with EtOAc, washed with brine and H2O; and dried
over anhydrous Na2SO4. Removal of the solvent provided intermediate indoline, which was used
without further purification. 3ꢀMethylbutꢀ3ꢀenoyl chloride (4 mmol, 474 mg) was added to a stirred
suspension of K2CO3 (4 mmol, 553 mg) in distilled water (5 mL) and acetone (20 mL) at 0 °C, and
intermediate indoline was added dropwise into the mixture. The suspension was stirred at 0 °C, until
the disappearance of intermediate indoline confirmed by TLC. The mixture was concentrated under
reduced pressure and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4,
concentrated under reduced pressure to give intermediate 1ꢀ(indolinꢀ1ꢀyl)ꢀ3ꢀmethylbutꢀ3ꢀenꢀ1ꢀone.
Then 1ꢀ(indolinꢀ1ꢀyl)ꢀ3ꢀmethylbutꢀ3ꢀenꢀ1ꢀone was dissolved in dry toluene (15 mL) in a round
bottomed flask equipped with a reflux condenser and DDQ (5 mmol, 1.13 g) was added. The reaction
mixture was refluxed for 12 hours. The reaction was then cooled to room temperature, diluted with
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EtOAc, washed with water and brine, dried over anhydrous Mg2SO4. The solvent was removed in
vacuo and the crude reaction mixture was purified by flash column chromatography on silica gel to
give 1a-1k, 1n-1u, 1y-1ac (three steps).
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General Procedure B for the Synthesis of 1l, 1m, 1w-1x: 3ꢀMethylbutꢀ3ꢀenoyl chloride (4 mmol,
474 mg) was added to a stirred suspension of K2CO3 (4 mmol, 553 mg) in distilled water (5 mL) and
acetone (20 mL) at 0 °C, and indole (2 mmol) was added dropwise into the mixture. The suspension
was stirred at 0 °C, until the disappearance of indole confirmed by TLC. The mixture was concentrated
under reduced pressure and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4,
The solvent was removed in vacuo and the crude reaction mixture was purified by flash column
chromatography on silica gel to give 1l, 1m, 1w-1x.
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Characterization of New Substrates. 1-(Indol-1-yl)-3-methylbut-3-en-1-one (1a). According to
general procedure A with indole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1a was obtained in 72% yield (287
mg, colorless oil, three steps). 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 8.3 Hz, 1H, ArꢀH), 7.61 (d, J
= 7.7 Hz, 1H, ArꢀH), 7.48 (t, J = 2.9 Hz, 1H, ArꢀH), 7.41 (t, J = 7.9 Hz, 1H, ArꢀH), 7.33 (td, J = 7.5,
1.9 Hz, 1H, ArꢀH), 6.66 (t, J = 2.9 Hz, 1H, ArꢀH), 5.09 (s, 1H, C=CHH), 4.96 (s, 1H, C=CHH), 3.66 (s,
2H, COCH2), 1.94 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 169.2, 138.6, 135.7, 130.4, 125.2,
125.1, 123.8, 120.8, 116.8, 115.4, 109.2, 45.4, 22.7; HRMS (ESI) exact mass calculated for C13H14NO+
[M+H+]: 200.1070, found: 200.1071; IR (neat): νmax (cmꢀ1) = 1701, 1654, 1554, 1449, 1362, 1122, 924,
754; Rf = 0.3 (petroleum ether/EtOAc 30:1).
1-(4-Bromo-indol-1-yl)-3-methylbut-3-en-1-one (1b). According to general procedure A with
4ꢀbromoꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1b was obtained in 30% yield (138 mg, white solid,
1
three steps). H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.3 Hz, 1H, ArꢀH), 7.55 (d, J = 3.9 Hz, 1H,
ArꢀH), 7.47 (d, J = 7.8 Hz, 1H, ArꢀH), 7.25 (t, J = 8.1 Hz, 1H, ArꢀH), 6.74 (d, J = 3.8 Hz, 1H, ArꢀH),
5.09 (s, 1H, C=CHH), 4.95 (s, 1H, C=CHH), 3.67 (s, 2H, COCH2), 1.92 (s, 3H, CH3); 13C NMR (101
MHz, CDCl3) δ 169.2, 138.3, 136.0, 131.0, 126.7, 126.2, 125.6, 115.8, 115.6, 114.6, 109.0, 45.4, 22.6;
HRMS (ESI) exact mass calculated for C13H13BrNO+ [M+H+]: 278.0175, found: 278.0178; IR (neat):
o
νmax (cmꢀ1) = 1709, 1623, 1533, 1470, 1420, 1246, 822, 750; m.p. = 50ꢀ52 C; Rf = 0.3 (petroleum
ether/EtOAc 30:1).
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1-(4-Chloro-indol-1-yl)-3-methylbut-3-en-1-one (1c). According to general procedure A with
4ꢀchloroꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1c was obtained in 49% yield (343 mg, white solid,
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three steps). H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H, ArꢀH), 7.49 (d, J = 3.9 Hz, 1H, ArꢀH),
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7.33ꢀ7.25 (m, 2H, 2(ArꢀH)), 6.75 (d, J = 3.8 Hz, 1H, ArꢀH), 5.08 (s, 1H, C=CHH), 4.95 (s, 1H,
C=CHH), 3.64 (s, 2H, COCH2), 1.92 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 169.2, 138.3, 136.3,
129.1, 126.0, 125.9, 125.6, 123.6, 115.6, 115.2, 107.1, 45.3, 22.6; HRMS (ESI) exact mass calculated
for C13H13ClNO+ [M+H+]: 234.0680, found: 234.0683; IR (neat): νmax (cmꢀ1) = 1712, 1611, 1550, 1423,
1340, 1246, 895, 750; m.p. = 60ꢀ61 oC; Rf = 0.3 (petroleum ether/EtOAc 30:1).
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1-(4-Fluoro-indol-1-yl)-3-methylbut-3-en-1-one (1d). According to general procedure A with
4ꢀfluoroꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1d was obtained in 35% yield (153 mg, colorless oil,
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three steps). H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 8.3 Hz, 1H, ArꢀH), 7.46 (d, J = 3.8 Hz, 1H,
ArꢀH), 7.31 (td, J = 8.2, 5.5 Hz, 1H, ArꢀH), 6.99 (dd, J = 9.6, 8.1 Hz, 1H, ArꢀH), 6.75 (d, J = 3.8 Hz,
1H, ArꢀH), 5.09 (s, 1H, C=CHH), 4.95 (s, 1H, C=CHH), 3.66 (s, 2H, COCH2), 1.92 (s, 3H, CH3); 13
C
NMR (101 MHz, CDCl3) δ 169.2, 155.6 (d, J = 248.0 Hz), 138.3, 137.7 (d, J = 9.2 Hz), 126.0 (d, J =
7.3 Hz), 125.0, 119.1 (d, J = 21.9 Hz), 115.5, 112.8 (d, J = 3.9 Hz), 109.1 (d, J = 18.4 Hz), 104.6, 45.4,
22.6; 19F NMR (376 MHz, CDCl3) δ ꢀ(121.94ꢀ121.98) (m); HRMS (ESI) exact mass calculated for
C13H13FNO+ [M+H+]: 218.0976, found: 218.0978; IR (neat): νmax (cmꢀ1) = 1708, 1599, 1543, 1485,
1432, 1214, 789, 744; Rf = 0.3 (petroleum ether/EtOAc 30:1).
3-Methyl-1-(4-methyl-indol-1-yl)but-3-en-1-one (1e). According to general procedure A with
4ꢀmethylꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1e was obtained in 58% yield (245 mg, colorless oil,
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three steps). H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.2 Hz, 1H, ArꢀH), 7.49 (d, J = 3.8 Hz, 1H,
ArꢀH), 7.35ꢀ7.23 (m, 1H, ArꢀH), 7.12 (d, J = 7.3 Hz, 1H, ArꢀH), 6.70 (d, J = 3.7 Hz, 1H, ArꢀH),
5.20ꢀ5.04 (m, 1H, C=CHH), 4.96 (s, 1H, C=CHH), 3.67 (s, 2H, COCH2), 2.56 (s, 3H, ArꢀCH3), 1.93 (s,
3H, CH2=CCH3); 13C NMR (101 MHz, CDCl3) δ 169.2, 138.7, 135.5, 130.2, 130.0, 125.3, 124.6, 124.3,
115.3, 114.3, 107.5, 45.3, 22.7, 18.5; HRMS (ESI) exact mass calculated for C14H16NO+ [M+H+]:
214.1226, found: 214.1228; IR (neat): νmax (cmꢀ1) = 1703, 1643, 1540, 1486, 1420, 1264, 735, 704; Rf =
0.3 (petroleum ether/EtOAc 30:1).
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1-(4-(Benzyloxy)-indol-1-yl)-3-methylbut-3-en-1-one (1f). According to general procedure A with
4ꢀbenzyloxyꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1f was obtained in 37% yield (282 mg, white
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solid, three steps). H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.3 Hz, 1H, ArꢀH), 7.52 (d, J = 6.9 Hz,
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2H, 2(ArꢀH)), 7.47ꢀ7.35 (m, 4H, 4(ArꢀH)), 7.31 (t, J = 8.1 Hz, 1H, ArꢀH), 6.89ꢀ6.79 (m, 2H, 2(ArꢀH)),
5.24 (s, 2H, ArꢀCH2), 5.15ꢀ5.04 (m, 1H, C=CHH), 4.96 (s, 1H, C=CHH), 3.66 (s, 2H, COCH2), 1.93 (s,
3H, CH3); 13C NMR (101 MHz, CDCl3) δ 169.3, 151.9, 138.5, 137.1, 137.0, 128.6, 127.9, 127.4, 126.1,
123.5, 120.9, 115.4, 110.1, 106.4, 105.8, 70.1, 45.5, 31.0, 22.6; HRMS (ESI) exact mass calculated for
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C20H20NO2 [M+H+]: 306.1489, found: 306.1491; IR (neat): νmax (cmꢀ1) = 1706, 1629, 1554, 1488,
1432, 1242, 744, 695; m.p. = 38ꢀ40 oC; Rf = 0.3 (petroleum ether/EtOAc 20:1).
3-Methyl-1-(5-methyl-indol-1-yl)but-3-en-1-one (1g). According to general procedure A with
5ꢀmethylꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1g was obtained in 37% yield (156 mg, colorless
oil, three steps). 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.4 Hz, 1H, ArꢀH), 7.44 (d, J = 3.8 Hz, 1H,
ArꢀH), 7.39 (s, 1H, ArꢀH), 7.22 (dd, J = 8.4, 1.7 Hz, 1H, ArꢀH), 6.59 (d, J = 3.8 Hz, 1H, ArꢀH), 5.08 (s,
1H, C=CHH), 4.95 (s, 1H, C=CHH), 3.64 (s, 2H, COCH2), 2.49 (s, 3H, ArꢀCH3), 1.93 (s, 3H,
CH2=CCH3); 13C NMR (101 MHz, CDCl3) δ 169.0, 138.7, 133.9, 133.4, 130.6, 126.5, 125.1, 120.8,
116.3, 115.2, 109.0, 45.3, 22.6, 21.4; HRMS (ESI) exact mass calculated for C14H16NO+ [M+H+]:
214.1226, found: 214.1228; IR (neat): νmax (cmꢀ1) = 1697, 1552, 1497, 1466, 1372, 1203, 809, 716; Rf =
0.3 (petroleum ether/EtOAc 30:1).
1-(5-Methoxy-indol-1-yl)-3-methylbut-3-en-1-one (1h). According to general procedure A with
5ꢀmethoxyꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1h was obtained in 52% yield (237 mg, colorless
oil, three steps). 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 9.0 Hz, 1H, ArꢀH), 7.44 (d, J = 3.8 Hz, 1H,
ArꢀH), 7.05 (d, J = 2.6 Hz, 1H, ArꢀH), 6.99 (dd, J = 9.0, 2.5 Hz, 1H, ArꢀH), 6.57 (d, J = 3.8 Hz, 1H,
ArꢀH), 5.06 (s, 1H, C=CHH), 4.99ꢀ4.81 (m, 1H, C=CHH), 3.87 (s, 3H, ArꢀOCH3), 3.61 (s, 2H,
COCH2), 1.88 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 168.8, 156.6, 138.7, 131.4, 130.4, 125.7,
+
117.5, 115.2, 113.5, 109.0, 103.6, 55.6, 45.1, 22.6; HRMS (ESI) exact mass calculated for C14H16NO2
[M+H+]: 230.1176, found: 230.1178; IR (neat): νmax (cmꢀ1) = 1698, 1611, 1559, 1473, 1339, 1147, 811,
715; Rf = 0.3 (petroleum ether/EtOAc 25:1).
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1-(5-Bromo-indol-1-yl)-3-methylbut-3-en-1-one (1i). According to general procedure A with 5ꢀ bromo
ꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1i was obtained in 65% yield (261 mg, white solid, three
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steps). H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 8.7 Hz, 1H, ArꢀH), 7.69 (d, J = 2.0 Hz, 1H, ArꢀH),
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7.53ꢀ7.38 (m, 2H, 2(ArꢀH)), 6.57 (d, J = 3.8 Hz, 1H, ArꢀH), 5.08 (s, 1H, C=CHH), 4.94 (s, 1H,
C=CHH), 3.63 (s, 2H, COCH2), 1.91 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 169.0, 138.3, 134.3,
132.0, 128.0, 126.1, 123.5, 118.1, 117.1, 115.5, 108.3, 45.3, 22.6; HRMS (ESI) exact mass calculated
for C13H13BrNO+ [M+H+]: 278.0175, found: 278.0177; IR (neat): νmax (cmꢀ1) = 1705, 1623, 1559, 1433,
1336, 1197, 794, 715; m.p. = 44ꢀ45 oC; Rf = 0.3 (petroleum ether/EtOAc 30:1).
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1-(5-Chloro-indol-1-yl)-3-methylbut-3-en-1-one (1j). According to general procedure A with
5ꢀchloroꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1j was obtained in 75% yield (440 mg, colorless oil,
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three steps). H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 8.9 Hz, 1H, ArꢀH), 7.55 (d, J = 2.1 Hz, 1H,
ArꢀH), 7.51 (d, J = 3.7 Hz, 1H, ArꢀH), 7.33 (dd, J = 8.9, 2.1 Hz, 1H, ArꢀH), 6.60 (d, J = 3.7 Hz, 1H,
ArꢀH), 5.08 (d, J = 2.3 Hz, 1H, C=CHH), 5.01ꢀ4.87 (m, 1H, C=CHH), 3.65 (s, 2H, COCH2), 1.92 (s,
3H, CH3); 13C NMR (101 MHz, CDCl3) δ 169.0, 138.3, 134.0, 131.5, 129.4, 126.3, 125.3, 120.4, 117.7,
115.5, 108.5, 45.3, 22.6; HRMS (ESI) exact mass calculated for C13H13ClNO+ [M+H+]: 234.0680,
found: 234.0682; IR (neat): νmax (cmꢀ1) = 1702, 1624, 1557, 1445, 1370, 1182, 797, 715; Rf = 0.3
(petroleum ether/EtOAc 30:1).
1-(5-Fluoro-indol-1-yl)-3-methylbut-3-en-1-one (1k). According to general procedure A with
5ꢀfluoroꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1k was obtained in 32% yield (138 mg, colorless oil,
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three steps). H NMR (400 MHz, CDCl3) δ 8.47 (dd, J = 9.0, 4.8 Hz, 1H, ArꢀH), 7.53 (d, J = 3.8 Hz,
1H, ArꢀH), 7.24 (dd, J = 8.7, 2.6 Hz, 1H, ArꢀH), 7.17ꢀ7.05 (m, 1H, ArꢀH), 6.62 (d, J = 3.8 Hz, 1H,
ArꢀH), 5.08 (s, 1H, C=CHH), 5.00ꢀ4.89 (m, 1H, C=CHH), 3.66 (s, 2H, COCH2), 1.91 (s, 3H, CH3); 13C
NMR (101 MHz, CDCl3) δ 168.9, 159.7 (d, J = 240.2 Hz), 138.5, 132.1, 131.3 (d, J = 10.0 Hz), 126.6,
117.7 (d, J = 9.0 Hz), 115.4, 112.8 (d, J = 24.7 Hz), 108.8 (d, J = 4.0 Hz), 106.4 (d, J = 23.8 Hz), 45.2,
22.6; 19F NMR (376 MHz, CDCl3) δ ꢀ(115.51ꢀ116.58) (d, J = 5.9 Hz); HRMS (ESI) exact mass
calculated for C13H13FNO+ [M+H+]: 218.0976, found: 218.0980; IR (neat): νmax (cmꢀ1) = 1701, 1465,
1445, 1378, 1346, 1243, 814, 718; Rf = 0.3 (petroleum ether/EtOAc 30:1).
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Methyl 1-(3-methylbut-3-enoyl)-indole-5-carboxylate (1l). According to general procedure B with
methyl indolꢀ5ꢀcarboxylate and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1l was obtained in 19% yield (103 mg,
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white solid). H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.8 Hz, 1H, ArꢀH), 8.30 (t, J = 1.7 Hz, 1H,
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ArꢀH), 8.06 (dd, J = 8.8, 1.5 Hz, 1H, ArꢀH), 7.54 (dd, J = 3.8, 1.7 Hz, 1H, ArꢀH), 6.70 (dd, J = 4.0, 2.1
Hz, 1H, ArꢀH), 5.08 (s, 1H, C=CHH), 4.95 (s, 1H, C=CHH), 3.96 (s, 3H, CO2CH3), 3.66 (s, 2H,
COCH2), 1.91 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 169.2, 167.3, 138.2, 130.1, 126.5, 126.3,
125.7, 123.0, 116.3, 115.6, 109.5, 100.0, 52.1, 45.4, 22.6; HRMS (EI) exact mass calculated for
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C15H15NO3 [M +]: 257.1046, found: 257.1046; IR (neat): νmax (cmꢀ1) = 1710, 1612, 1540, 1436, 1374,
1204, 777, 756; m.p. = 68ꢀ70 oC; Rf = 0.3 (petroleum ether/EtOAc 15:1).
3-Methyl-1-(5-nitro-indol-1-yl)but-3-en-1-one (1m). According to general procedure B with
5-nitroꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1m was obtained in 65% yield (318 mg, yellow solid).
1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 9.1 Hz, 1H, ArꢀH), 8.51 (d, J = 2.2 Hz, 1H, ArꢀH), 8.27 (dd,
J = 9.1, 2.3 Hz, 1H, ArꢀH), 7.67 (d, J = 3.8 Hz, 1H, ArꢀH), 6.81 (d, J = 3.8 Hz, 1H, ArꢀH), 5.12 (s, 1H,
C=CHH), 4.97 (s, 1H, C=CHH), 3.70 (s, 2H, COCH2), 1.94 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3)
δ 169.3, 144.4, 138.6, 137.9, 130.2, 127.9, 120.4, 117.0, 116.9, 115.9, 109.5, 45.4, 22.6; HRMS (EI)
exact mass calculated for C13H12N2O3+ [M +]: 244.0845, found: 244.0845; IR (neat): νmax (cmꢀ1) = 1718,
1515, 1443, 1333, 1308, 1192, 790, 743; m.p. = 39ꢀ40 oC; Rf = 0.3 (petroleum ether/EtOAc 15:1).
1-(6-Bromo-indol-1-yl)-3-methylbut-3-en-1-one (1n). According to general procedure with
6ꢀbromoꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1n was obtained in 50% yield (414 mg, colorless oil,
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three steps) H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 1.3 Hz, 1H, ArꢀH), 7.42 (d, J = 3.9 Hz, 1H,
ArꢀH), 7.39 (d, J = 1.5 Hz, 2H, 2(ArꢀH)), 6.58 (dd, J = 3.8, 0.8 Hz, 1H, ArꢀH), 5.12ꢀ5.02 (m, 1H,
C=CHH), 4.93 (t, J = 1.2 Hz, 1H, C=CHH), 3.61 (s, 2H, COCH2), 1.90 (s, 3H, CH3); 13C NMR (101
MHz, CDCl3) δ 169.1, 138.3, 136.2, 129.1, 127.0, 125.6, 121.8, 120.0, 118.8, 115.5, 108.9, 45.2, 22.6;
HRMS (ESI) exact mass calculated for C13H13BrNO+ [M+H+]: 278.0175, found: 278.0179; IR (neat):
νmax (cmꢀ1) = 1705, 1612, 1578, 1448, 1424, 1339, 885, 809; Rf = 0.3 (petroleum ether/EtOAc 30:1).
1-(6-Chloro-1-indol-yl)-3-methylbut-3-en-1-one (1o). According to general procedure A with
6ꢀchloroꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1o was obtained in 73% yield (344 mg, colorless oil,
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three steps). H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H, ArꢀH), 7.49 (d, J = 8.0 Hz, 2H, 2(ArꢀH)),
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7.42ꢀ7.18 (m, 1H, ArꢀH), 6.62 (d, J = 3.8 Hz, 1H, ArꢀH), 5.08 (s, 1H, C=CHH), 4.95 (s, 1H, C=CHH),
3.65 (s, 2H, COCH2), 1.92 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 169.1, 138.3, 135.9, 131.1,
128.7, 125.6, 124.4, 121.4, 117.0, 115.5, 108.9, 45.3, 22.6; HRMS (ESI) exact mass calculated for
C13H13ClNO+ [M+H+]: 234.0680, found: 234.0683; IR (neat): νmax (cmꢀ1) = 1707, 1621, 1567, 1427,
1343, 895, 812, 782; Rf = 0.3 (petroleum ether/EtOAc 30:1).
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1-(6-Fluoro-indol-1-yl)-3-methylbut-3-en-1-one (1p). According to general procedure A with
6ꢀfluoroꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1p was obtained in 63% yield (407 mg, colorless oil,
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three steps). H NMR (400 MHz, CDCl3) δ 8.27 (dd, J = 10.3, 2.4 Hz, 1H, ArꢀH), 7.54ꢀ7.39 (m, 2H,
2(ArꢀH)), 7.04 (td, J = 8.9, 2.4 Hz, 1H, ArꢀH), 6.60 (d, J = 3.8 Hz, 1H, ArꢀH), 5.07 (t, J = 1.5 Hz, 1H,
C=CHH), 5.00ꢀ4.85 (m, 1H, C=CHH), 3.62 (s, 2H, COCH2), 1.91 (s, 3H, CH3); 13C NMR (101 MHz,
CDCl3) δ 169.2, 161.3 (d, J = 240.6 Hz), 138.3, 135.7 (d, J = 13.0 Hz), 126.6 (d, J = 1.7 Hz), 125.4 (d,
J = 4.0 Hz), 121.3 (d, J = 9.9 Hz), 115.5, 111.9 (d, J = 24.2 Hz), 108.9, 104.1 (d, J = 28.6 Hz), 45.2,
22.6; 19F NMR (376 MHz, CDCl3) δ ꢀ(116.47ꢀ116.60) (m); HRMS (ESI) exact mass calculated for
C13H13FNO+ [M+H+]: 218.0976, found: 218.0979; IR (neat): νmax (cmꢀ1) = 1702, 1612, 1579, 1476,
1436, 1344, 918, 811; Rf = 0.3 (petroleum ether/EtOAc 30:1).
3-Methyl-1-(6-methyl-indol-1-yl)but-3-en-1-one (1q). According to general procedure A with
6ꢀmethylꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1q was obtained in 36% yield (198 mg, colorless
oil, three steps). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H, ArꢀH), 7.47 (d, J = 7.9 Hz, 1H, ArꢀH), 7.41
(d, J = 3.8 Hz, 1H, ArꢀH), 7.15 (d, J = 8.0 Hz, 1H, ArꢀH), 6.61 (d, J = 3.7 Hz, 1H, ArꢀH), 5.08 (s, 1H,
C=CHH), 4.95 (s, 1H, C=CHH), 3.65 (s, 2H, COCH2), 2.53 (s, 3H, ArꢀCH3), 1.93 (s, 3H, CH2=CCH3);
13C NMR (101 MHz, CDCl3) δ 169.2, 138.7, 136.1, 135.3, 128.0, 125.2, 124.5, 120.3, 117.0, 115.2,
109.1, 45.4, 22.6, 22.0; HRMS (ESI) exact mass calculated for C14H16NO+ [M+H+]: 214.1226, found:
214.1229; IR (neat): νmax (cmꢀ1) = 1702, 1613, 1580, 1429, 1383, 810, 783, 715; Rf = 0.3 (petroleum
ether/EtOAc 30:1).
1-(7-Chloro-indol-1-yl)-3-methylbut-3-en-1-one (1r). According to general procedure A with
7ꢀchloroꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1r was obtained in 49% yield (343 mg, colorless oil,
three steps). 1H NMR (400 MHz, CDCl3) δ 7.56ꢀ7.47 (m, 2H, 2(ArꢀH)), 7.38 (d, J = 7.8 Hz, 1H, ArꢀH),
7.24 (t, J = 7.8 Hz, 1H, ArꢀH), 6.64 (dd, J = 3.7, 1.2 Hz, 1H, ArꢀH), 5.06 (s, 1H, C=CHH), 5.00 (s, 1H,
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C=CHH), 3.69 (s, 2H, COCH2), 1.93 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 167.9, 138.5, 134.2,
132.7, 127.3, 126.9, 124.6, 121.5, 119.6, 115.8, 108.2, 46.3, 22.4; HRMS (ESI) exact mass calculated
for C13H13ClNO+ [M+H+]: 234.0680, found: 234.0683; IR (neat): νmax (cmꢀ1) = 1712, 1611, 1579, 1454,
1363, 899, 754, 705; Rf = 0.3 (petroleum ether/EtOAc 30:1).
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3-Methyl-1-(7-methyl-indol-1-yl)but-3-en-1-one (1s). According to general procedure A with
7ꢀmethylꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1s was obtained in 62% yield (520 mg, light yellow
oil, three steps). 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 9.0, 5.6 Hz, 2H, 2(ArꢀH)), 7.33ꢀ7.09 (m,
2H, 2(ArꢀH)), 6.65 (d, J = 3.8 Hz, 1H, ArꢀH), 5.10 (s, 1H, C=CHH), 5.01 (s, 1H, C=CHH), 3.69 (s, 2H,
COCH2), 2.62 (s, 3H, ArꢀCH3), 1.95 (s, 3H, CH2=CCH3). 13C NMR (101 MHz, CDCl3) δ 168.5, 138.9,
135.3, 132.1, 128.3, 126.7, 126.5, 124.3, 118.7, 115.6, 109.0, 45.9, 22.9, 22.6; HRMS (ESI) exact mass
calculated for C14H16NO+ [M+H+]: 214.1226, found: 214.1229; IR (neat): νmax (cmꢀ1) = 1712, 1613,
1576, 1456, 1336, 899, 786, 753; Rf = 0.3 (petroleum ether/EtOAc 30:1).
3-Methyl-1-(3-methyl-indol-1-yl)but-3-en-1-one (1t). According to general procedure A with
3ꢀmethylꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1t was obtained in 23% yield (124 mg, yellow oil,
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three steps). H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 8.2 Hz, 1H, ArꢀH), 7.59ꢀ7.47 (m, 1H, ArꢀH),
7.46ꢀ7.38 (m, 1H, ArꢀH), 7.35 (dd, J = 7.5, 1.2 Hz, 1H, ArꢀH), 7.24 (s, 1H, ArꢀH), 5.08 (s, 1H,
C=CHH), 4.96 (s, 1H, C=CHH), 3.62 (s, 2H, COCH2), 2.32 (s, 3H, ArꢀCH3), 1.94 (s, 3H, CH2=CCH3);
13C NMR (101 MHz, CDCl3) δ 168.8, 138.8, 136.0, 131.4, 125.2, 123.5, 122.0, 118.8, 118.5, 116.8,
115.1, 45.4, 22.7, 10.0; HRMS (ESI) exact mass calculated for C14H16NO+ [M+H+]: 214.1226, found:
214.1229; IR (neat): νmax (cmꢀ1) = 1756, 1701, 1669, 1524, 1450, 1351, 1132, 752; Rf = 0.3 (petroleum
ether/EtOAc 30:1).
3-Methyl-1-(3-phenyl-indol-1-yl)but-3-en-1-one (1u). According to general procedure A with
3ꢀphenylꢀindole and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1u was obtained in 47% yield (324 mg, white solid,
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three steps). H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.2 Hz, 1H, ArꢀH), 7.85 (d, J = 7.8 Hz, 1H,
ArꢀH), 7.72ꢀ7.64 (m, 2H, 2(ArꢀH)), 7.60 (s, 1H, ArꢀH), 7.53 (t, J = 7.5 Hz, 2H, 2(ArꢀH)), 7.50ꢀ7.35 (m,
3H, 3(ArꢀH)), 5.11 (s, 1H, C=CHH), 5.00 (s, 1H, C=CHH), 3.72 (s, 2H, COCH2), 1.96 (s, 3H, CH3);
13C NMR (101 MHz, CDCl3) δ 169.0, 138.5, 136.4, 133.3, 128.9, 127.9, 127.5, 125.5, 124.0, 123.8,
121.8, 120.0, 116.9, 115.3, 45.2, 22.6; HRMS (ESI) exact mass calculated for C19H18NO+ [M+H+]:
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276.1383, found: 276.1384; IR (neat): νmax (cmꢀ1) = 1705, 1634, 1587, 1451, 1372, 1206, 1190, 1144
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747, 699; m.p. = 45ꢀ47 oC; Rf = 0.3 (petroleum ether/EtOAc 25:1).
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1-(3-Methylbut-3-enoyl)-indole-3-carbonitrile (1v). According to general procedure
B with
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indolꢀ3ꢀcarbonitrile and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1v was obtained in 71% yield (320 mg, white
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solid). H NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 8.2, 3.1 Hz, 1H, ArꢀH), 8.05 (d, J = 3.3 Hz, 1H,
ArꢀH), 7.84ꢀ7.60 (m, 1H, ArꢀH), 7.55ꢀ7.36 (m, 2H, 2(ArꢀH)), 5.12 (s, 1H, C=CHH), 4.98 (s, 1H,
C=CHH), 3.69 (s, 2H, COCH2), 1.92 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 168.8, 137.7, 134.7,
132.5, 127.7, 127.1, 125.3, 119.6, 117.0, 116.2, 113.9, 93.9, 45.2, 22.5; HRMS (EI) exact mass
calculated for C14H12N2O+ [M +]: 224.0944, found: 224.0951; IR (neat): νmax (cmꢀ1) = 2225, 1720, 1549,
1454, 1363, 1198, 902, 748; m.p. = 54ꢀ55 oC; Rf = 0.3 (petroleum ether/EtOAc 15:1).
Methyl 1-(3-methylbut-3-enoyl) -indole-3-carboxylate (1w). According to general procedure B with
methyl indolꢀ3ꢀcarboxylate and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1w was obtained in 39% yield (199 mg,
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white solid). H NMR (400 MHz, CDCl3) δ 8.52ꢀ8.43 (m, 1H, ArꢀH), 8.18ꢀ8.09 (m, 2H, 2(ArꢀH)),
7.48ꢀ7.33 (m, 2H, 2(ArꢀH)), 5.09 (s, 1H, C=CHH), 4.96 (s, 1H, C=CHH), 3.95 (s, 3H, CO2CH3), 3.68
(s, 2H, COCH2), 1.92 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 169.3, 164.3, 138.0, 136.0, 131.0,
127.2, 126.0, 124.9, 121.5, 116.6, 115.9, 113.7, 51.6, 45.1, 22.6; HRMS (EI) exact mass calculated for
C15H15NO3 [M]: 257.1052, found: 257.1056; IR (neat): νmax (cmꢀ1) = 1710, 1559, 1449, 1366, 1198,
1150, 773, 753; m.p. = 50ꢀ51 oC; Rf = 0.3 (petroleum ether/EtOAc 15:1).
1-(3-Methylbut-3-enoyl)-indole-3-carbaldehyde (1x). According to general procedure B with
indolꢀ3ꢀcarbaldehyde and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1x was obtained in 42% yield (190 mg, white
solid). 1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H, CHO), 8.48 (d, J = 8.0 Hz, 1H, ArꢀH), 8.42ꢀ8.21 (m,
1H, ArꢀH), 8.13 (s, 1H, ArꢀH), 7.61ꢀ7.34 (m, 2H, 2(ArꢀH)), 5.14 (s, 1H, C=CHH), 5.00 (s, 1H,
C=CHH), 3.75 (s, 2H, COCH2), 1.95 (s, 3H, CH3). 13C NMR (101 MHz, CDCl3) δ 185.6, 169.3, 137.9,
136.4, 135.2, 126.9, 125.9, 125.5, 122.6, 121.8 116.5, 116.0, 45.2, 22.6; HRMS (EI) exact mass
calculated for C14H13NO2 [M]: 227.0946, found: 227.0955; IR (neat): νmax (cmꢀ1) = 1722, 1673, 1551,
1448, 1350, 1185, 782, 574; m.p. = 56ꢀ58 oC; Rf = 0.3 (petroleum ether/EtOAc 15:1).
3-Methyl-1-(1-pyrrolo[2,3-b]pyridin-1-yl)but-3-en-1-one (1y). According to general procedure with
1ꢀpyrrolo[2,3ꢀb]pyridine and 3ꢀmethylbutꢀ3ꢀenoyl chloride, 1y was obtained in 36% yield (217 mg,
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yellow oil, three steps). 1H NMR (400 MHz, CDCl3) δ 8.39 (dd, J = 4.8, 1.7 Hz, 1H, ArꢀH), 8.03 (d, J
= 4.2 Hz, 1H, ArꢀH), 7.89 (dd, J = 7.8, 1.7 Hz, 1H, ArꢀH), 7.21 (dd, J = 7.8, 4.8 Hz, 1H, ArꢀH), 6.62 (d,
J = 4.1 Hz, 1H, ArꢀH), 5.00 (t, J = 1.6 Hz, 1H, C=CHH), 4.95 (s, 1H, C=CHH), 4.36 (d, J = 1.0 Hz, 2H,
COCH2), 1.95 (d, J = 1.1 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 169.8, 147.6, 143.7, 139.2,
129.3, 125.6, 123.8, 118.7, 114.6, 105.9, 45.9, 23.0; HRMS (ESI) exact mass calculated for
C12H13N2O+ [M+H+]: 201.1022, found: 201.1024; IR (neat): νmax (cmꢀ1) = 1765, 1654, 1584, 1503,
1422, 799, 772, 730; Rf = 0.3 (petroleum ether/EtOAc 20:1).
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1-(Indol-1-yl)but-3-en-1-one (1z). According to general procedure with indole and butꢀ3ꢀenoyl chloride,
1z was obtained in 55% yield (205 mg, yellow oil, three steps). 1H NMR (400 MHz, CDCl3) δ 8.50 (d,
J = 8.3 Hz, 1H, ArꢀH), 7.60 (d, J = 7.7 Hz, 1H, ArꢀH), 7.48 (d, J = 3.8 Hz, 1H, ArꢀH), 7.39 (t, J = 7.7
Hz, 1H, ArꢀH), 7.35ꢀ7.25 (m, 1H, ArꢀH), 6.68 (d, J = 3.8 Hz, 1H, ArꢀH), 6.28ꢀ6.03 (m, 1H, CH=CH2),
5.36ꢀ5.18 (m, 2H, CH=CH2), 3.74 (d, J = 6.6 Hz, 2H, COCH2); 13C NMR (101 MHz, CDCl3) δ 169.3,
135.7, 130.3, 129.8, 125.2, 124.6, 123.8, 120.8, 119.5, 116.7, 109.4, 40.8; HRMS (ESI) exact mass
calculated for C12H12NO+ [M+H+]: 186.0913, found: 186.0915; IR (neat): νmax (cmꢀ1) = 1742, 1625,
1581, 1454, 1389, 1157, 1094, 753; Rf = 0.3 (petroleum ether/EtOAc 30:1).
1-(Indol-1-yl)-3-phenylbut-3-en-1-one (1aa). According to general procedure with indole and
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3ꢀphenylbutꢀ3ꢀenoyl chloride, 1aa was obtained in in 28% yield (146 mg, yellow oil, three steps). H
NMR (400 MHz, CDCl3) δ 8.52 (d, J = 8.2 Hz, 1H, ArꢀH), 7.61 (d, J = 7.7 Hz, 1H, ArꢀH), 7.57ꢀ7.50
(m, 3H, 3(ArꢀH)), 7.45ꢀ7.27 (m, 5H, 5(ArꢀH)), 6.68 (d, J = 3.8 Hz, 1H, ArꢀH), 5.70 (s, 1H, C=CHH),
5.31 (s, 1H, C=CHH), 4.15 (s, 2H, COCH2); 13C NMR (101 MHz, CDCl3) δ 169.0, 140.9, 139.7, 135.7,
130.4, 128.7, 128.2, 125.8, 125.3, 125.0, 123.9, 120.9, 116.8, 116.7, 109.5, 42.9; HRMS (ESI) exact
mass calculated for C18H16NO+ [M+H+]: 262.1226, found: 262.1228; IR (neat): νmax (cmꢀ1) = 1736,
1641, 1554, 1489, 1357, 1101, 753, 689; Rf = 0.3 (petroleum ether/EtOAc 30:1).
1-(Indol-1-yl)-2,3-dimethylbut-3-en-1-one (1ab). According to general procedure with indole and
2,3ꢀdimethylbutꢀ3ꢀenoyl chloride, 1ab was obtained in 39% yield (168 mg, colorless oil, three steps).
1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.3 Hz, 1H, ArꢀH), 7.61 (d, J = 7.7 Hz, 1H, ArꢀH), 7.56 (d,
J = 3.8 Hz, 1H, ArꢀH), 7.47ꢀ7.38 (m, 1H, ArꢀH), 7.33 (t, J = 7.5 Hz, 1H, ArꢀH), 6.65 (d, J = 3.9 Hz, 1H,
ArꢀH), δ 5.02 (s, 2H, C=CH2), 3.92 (q, J = 6.8 Hz, 1H, CHCH3), 1.86 (s, 3H, CCH3), 1.52 (d, J = 6.7
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Hz, 3H, CHCH3). 13C NMR (101 MHz, CDCl3) δ 172.3, 144.6, 135.9, 130.3, 125.1, 125.1, 123.8, 120.8,
116.9, 113.7, 108.9, 47.6, 20.1, 16.7; HRMS (EI) exact mass calculated for C14H15NO [M]: 213.1154,
found: 213.1157; IR (neat): νmax (cmꢀ1) = 1702, 1538, 1450, 1348, 1299, 907, 750, 715; Rf = 0.4
(petroleum ether/EtOAc 30:1).
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1-(Indol-1-yl)-4-methylpent-4-en-1-one (1ac). According to general procedure with indole and
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4ꢀmethylpentꢀ4ꢀenoyl chloride, 1ac was obtained in 48% yield (204 mg, yellow oil, three steps). H
NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.3 Hz, 1H, ArꢀH), 7.61 (d, J = 7.7 Hz, 1H, ArꢀH), 7.49 (d, J =
3.8 Hz, 1H, ArꢀH), 7.44ꢀ7.35 (m, 1H, ArꢀH), 7.32 (t, J = 7.4 Hz, 1H, ArꢀH), 6.67 (d, J = 3.8 Hz, 1H,
ArꢀH), 4.87 (s, 1H, C=CHH), 4.81 (s, 1H, C=CHH), 3.08 (t, 2H, J = 7.2 Hz, COCH2CH2), 2.58 (t, 2H,
J = 7.4 Hz, COCH2CH2), 1.87 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3) δ 171.0, 144.0, 135.7, 130.4,
125.1, 124.5, 123.6, 120.8, 116.6, 110.7, 109.2, 34.2, 32.1, 22.8; HRMS (ESI) exact mass calculated
for C15H18NO+ [M+H+]: 228.1383, found: 228.1388; IR (neat): νmax (cmꢀ1) = 1702, 1635, 1559, 1450,
1323, 765, 745, 715; Rf = 0.3 (petroleum ether/EtOAc 30:1).
General Procedure for the Synthesis of 3a-3ak: To a 10 mL sealed tube equipped with a rubber
septum and magnetic stir bar, 1 (0.2 mmol), facꢀIr(ppy)3 (0.002 mmol, 1.3 mg) and Na2HPO4 (0.24
mmol, 32.4 mg) were added. The tube was evacuated and backfilled with nitrogen for 3 times. 2 (0.5
mmol) and DCM (2.0 mL) were added; then the mixture was stirred and irradiated by 3 W blue LEDs
for 12 hours at room temperature. After the reaction was completed (detected by TLC), the crude
mixture was purified directly by flash column chromatography on silica gel to give 3.
Ethyl
2,2-difluoro-3-(1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)propanoate
(3a).
According to general procedure with 1a and 2a, 3a was obtained in 85% yield (55 mg, colorless oil).
1H NMR (400 MHz, CDCl3) δ 8.18ꢀ7.99 (m, 1H, ArꢀH), 7.69ꢀ7.45 (m, 1H, ArꢀH), 7.31 (td, J = 7.1, 1.6
Hz, 2H, 2(ArꢀH)), 6.32 (s, 1H, ArꢀH), 4.16ꢀ4.08 (m, 1H, CF2CHH), 3.96 (dd, J = 10.8, 7.1 Hz, 1H,
CF2CHH), 3.36 (d, J = 18.2 Hz, 1H, COCHH), 3.11ꢀ2.80 (m, 1H, COCHH), 2.67 (dd, J = 17.6, 15.9
Hz, 2H, CO2CH2), 1.61 (s, 3H, CCH3), 1.18 (t, J = 7.2 Hz, 3H, CH2CH3); 13C NMR (101 MHz, CDCl3)
δ 169.5, 163.8 (t, J = 32.0 Hz), 149.5, 134.7, 130.1, 124.3, 124.0, 120.9, 115.5 (dd, J = 253.7, 251.2
Hz), 114.0, 99.9, 63.3, 49.0 (d, J = 3.5 Hz), 44.0 (t, J = 22.3 Hz), 35.5 (dd, J = 3.7, 1.4 Hz), 28.8 (d, J =
2.0 Hz), 13.6; 19F NMR (376 MHz, CDCl3) δ ꢀ99.47 (dt, J = 266.4, 15.9 Hz), ꢀ104.54 (dt, J = 266.4,
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17.5 Hz); HRMS (ESI) exact mass calculated for C17H18F2NO3 [M+H+]: 322.1249, found: 322.1251;
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15:1).
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Ethyl
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(3b). According to general procedure with 1b and 2a, 3b were obtained in 76% yield (61 mg, colorless
oil). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.1 Hz, 1H, ArꢀH), 7.46 (d, J = 7.8 Hz, 1H, ArꢀH), 7.19
(t, J = 7.9 Hz, 1H, ArꢀH), 6.41 (s, 1H, ArꢀH), 4.19ꢀ4.10 (m, 1H, CF2CHH), 4.09ꢀ4.00 (m, 1H,
CF2CHH), 3.39 (d, J = 18.4 Hz, 1H, COCHH), 2.97 (d, J = 18.4 Hz, 1H, COCHH), 2.69 (t, J = 16.5
Hz, 2H, CO2CH2), 1.63 (s, 3H, CCH3), 1.22 (t, J = 7.1 Hz, 3H, CH2CH3); 13C NMR (101 MHz, CDCl3)
δ 169.6, 163.6 (t, J = 32.0 Hz), 150.0, 135.2, 130.4, 127.1, 125.1, 115.4 (dd, J = 253.3, 251.7 Hz),
114.2, 113.0, 99.8, 63.4, 48.8 (d, J = 3.7 Hz), 43.9 (t, J = 22.4 Hz), 35.6 (d, J = 3.4 Hz), 28.9 (d, J = 1.9
Hz), 13.7; 19F NMR (376 MHz, CDCl3) δ ꢀ99.33 (dt, J = 267.1, 15.7 Hz), ꢀ104.85 (dt, J = 267.1, 17.4
+
Hz); HRMS (ESI) exact mass calculated for C17H17BrF2NO3 [M+H+]: 400.0354, found: 400.0357;
IR (neat): νmax (cmꢀ1) = 1749, 1645, 1594, 1420, 1265, 1177, 732, 703; Rf = 0.3 (petroleum ether/EtOAc
15:1).
Ethyl
3-(8-chloro-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-2,2-difluoropropanoate
(3c). According to general procedure with 1c and 2a, 3c were obtained in 90% yield (64 mg, yellow
oil). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.8 Hz, 1H, ArꢀH), 7.38ꢀ7.13 (m, 2H, 2(ArꢀH)), 6.45 (s,
1H, ArꢀH), 4.19ꢀ4.09 (m, 1H, CF2CHH), 4.09ꢀ3.99 (m, 1H, CF2CHH), 3.39 (d, J = 18.4 Hz, 1H,
COCHH), 2.97 (d, J = 18.4 Hz, 1H, COCHH), 2.69 (t, J = 16.6 Hz, 2H, CO2CH2), 1.63 (s, 3H, CCH3),
1.22 (t, J = 7.1 Hz, 3H, CH2CH3); 13C NMR (101 MHz, CDCl3) δ 169.5, 163.6 (t, J = 32.0 Hz), 150.0,
133.3, 130.7, 125.7, 124.8, 124.0, 115.4 (dd, J = 253.4, 251.6 Hz), 112.4, 98.1, 63.3, 48.8 (d, J = 3.6
Hz), 43.9 (t, J = 22.5 Hz), 35.6 (d, J = 3.6 Hz), 28.9 (d, J = 1.8 Hz), 13.6; 19F NMR (376 MHz, CDCl3)
δ ꢀ99.46 (dt, J = 267.1, 15.8 Hz), ꢀ104.82 (dt, J = 267.1, 17.4 Hz); HRMS (ESI) exact mass calculated
+
for C17H17ClF2NO3 [M+H+]: 356.0680, found: 356.0683; IR (neat): νmax (cmꢀ1) = 1721, 1645, 1589,
1425, 1381, 1383, 1063, 776; Rf = 0.3 (petroleum ether/EtOAc 15:1).
Ethyl
2,2-difluoro-3-(8-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)propanoate
(3d). According to general procedure with 1d and 2a, 3d was obtained in 79% yield (54 mg, yellow
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oil). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.0 Hz, 1H, ArꢀH), 7.44ꢀ7.20 (m, 1H, ArꢀH), 7.00 (dd,
J = 10.0, 8.1 Hz, 1H, ArꢀH), 6.43 (s, 1H, ArꢀH), 4.20ꢀ4.12 (m, 1H, CF2CHH), 4.10ꢀ4.02 (m, 1H,
CF2CHH), 3.39 (d, J = 18.4 Hz, 1H, COCHH), 2.99 (d, J = 18.3 Hz, 1H, COCHH), 2.77ꢀ2.53 (m, 2H,
CO2CH2), 1.63 (s, 3H, CCH3), 1.23 (t, J = 7.1 Hz, 3H, CH2CH3); 13C NMR (101 MHz, CDCl3) δ 169.5,
163.7 (t, J = 32.0 Hz), 155.3 (d, J = 248.5 Hz), 149.6, 132.0 (d, J = 9.9 Hz), 125.0 (d, J = 7.3 Hz),
123.1 (d, J = 21.2 Hz), 115..4 (dd, J = 254.4, 252.7 Hz), 110.1 (d, J = 3.9 Hz), 109.7 (d, J = 18.7 Hz),
95.7, 63.3, 49.0 (d, J = 3.5 Hz), 43.9 (t, J = 22.3 Hz), 35.5 (d, J = 3.5 Hz), 28.8 (d, J = 1.8 Hz), 13.6;
19F NMR (376 MHz, CDCl3) δ ꢀ99.78 (dt, J = 266.9, 16.1 Hz), ꢀ104.64 (dt, J = 266.9, 17.4 Hz),
ꢀ(121.43ꢀ121.47) (m); HRMS (ESI) exact mass calculated for C17H17F3NO3+ [M+H+]: 340.1155, found:
340.1158; IR (neat): νmax (cmꢀ1) = 1715, 1644, 1588, 1492, 1437, 1383, 903, 779; Rf = 0.3 (petroleum
ether/EtOAc 15:1).
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Ethyl 3-(1,8-dimethyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-2,2-difluoropropanoate (3e).
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According to general procedure with 1e and 2a, 3e was obtained 78% yield (52 mg, yellow oil). H
NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 1H, ArꢀH), 7.24 (t, J = 7.7 Hz, 1H, ArꢀH), 7.11 (d, J =
7.4 Hz, 1H, ArꢀH), 6.36 (s, 1H, ArꢀH), 4.17ꢀ4.19 (m, 1H, CF2CHH), 4.02ꢀ4.39 (m, 1H, CF2CHH), 3.36
(d, J = 18.2 Hz, 1H, COCHH), 2.96 (d, J = 18.2 Hz, 1H, COCHH), 2.68 (t, J = 16.6 Hz, 2H, CO2CH2),
2.52 (s, 3H, ArꢀCH3), 1.62 (s, 3H, CCH3), 1.19 (t, J = 7.1 Hz, 3H, CH2CH3); 13C NMR (101 MHz,
CDCl3) δ 169.6, 163.8 (t, J = 32.0 Hz), 148.9, 134.3, 130.3, 129.8, 124.7, 124.1, 115.5 (dd, J = 253.6,
251.0 Hz), 111.5, 98.4, 63.3, 49.1(d, J = 3.7 Hz), 44.1 (t, J = 22.3 Hz), 35.5 (d, J = 3.7 Hz), 28.8 (d, J =
2.0 Hz), 18.5, 13.6; 19F NMR (376 MHz, CDCl3) δ ꢀ99.57 (dt, J = 266.4, 15.9 Hz), ꢀ104.52 (dt, J =
+
266.6, 17.5 Hz); HRMS (ESI) exact mass calculated for C18H20F2NO3 [M+H+]: 336.1406, found:
336.1409; IR (neat): νmax (cmꢀ1) = 1710, 1653, 1589, 1470, 1380, 1202, 777, 736; Rf = 0.3 (petroleum
ether/EtOAc 15:1).
Ethyl 3-(8-(benzyloxy)-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-2,2-difluoropropano
ate (3f). According to general procedure with 1f and 2a, 3f was obtained in 76% yield (65 mg, yellow
oil). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 1H, ArꢀH), 7.50 (d, J = 7.1 Hz, 2H, 2(ArꢀH)),
7.43 (t, J = 7.2 Hz, 2H, 2(ArꢀH)), 7.41ꢀ7.34 (m, 1H, ArꢀH), 7.25 (t, J = 8.1 Hz, 1H, ArꢀH), 6.82 (d, J =
8.0 Hz, 1H, ArꢀH), 6.50 (s, 1H, ArꢀH), 5.22 (s, 2H, ArꢀCH2), 4.18ꢀ4.10 (m, 1H, CF2CHH), 4.06ꢀ4.98
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(m, 1H, CF2CHH), 3.38 (d, J = 18.3 Hz, 1H, COCHH), 2.96 (d, J = 18.3 Hz, 1H, COCHH), 2.67 (t, J =
16.7 Hz, 2H, CO2CH2), 1.61 (s, 3H, CCH3), 1.19 (t, J = 7.1 Hz, 3H, CH2CH3); 13C NMR (101 MHz,
CDCl3) δ 169.7, 163.8 (t, J = 29.7 Hz), 151.8, 148.0, 137.0, 131.2, 128.6, 128.0, 127.4, 125.1, 125.0,
115.5 (t, J = 250.8 Hz), 107.3, 106.1, 97.3, 70.1, 63.3, 49.1 (d, J = 3.6 Hz), 44.1 (t, J = 22.4 Hz), 35.4,
28.9, 13.6; 19F NMR (376 MHz, CDCl3) δ ꢀ99.55 (dt, J = 266.3, 16.0 Hz), ꢀ104.70 (dt, J = 266.3, 17.5
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Hz); HRMS (ESI) exact mass calculated for C24H24F2NO4 [M+H+]: 428.1668, found: 428.1670; IR
(neat): νmax (cmꢀ1) = 1744, 1661, 1567, 1495, 1434, 1382, 972, 774; Rf = 0.3 (petroleum ether/EtOAc
10:1).
Ethyl (1,7-dimethyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-2,2-difluoropropanoate (3g).
According to general procedure with 1g and 2a, 3g was obtained in 62% yield (42 mg, yellow oil). 1H
NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.2 Hz, 1H, ArꢀH), 7.31 (s, 1H, ArꢀH), 7.14 (d, J = 8.2 Hz, 1H,
ArꢀH), 6.24 (s, 1H, ArꢀH), 4.18ꢀ4.07 (m, 1H, CF2CHH), 4.06ꢀ3.91 (m, 1H, CF2CHH), 3.34 (d, J = 18.2
Hz, 1H, COCHH), 2.94 (d, J = 18.2 Hz, 1H, COCHH), 2.65 (t, J = 16.7 Hz, 2H, CO2CH2), 2.46 (s, 3H,
ArꢀCH3), 1.60 (s, 3H, CCH3), 1.19 (t, J = 7.1 Hz, 3H, CH2CH3); 13C NMR (101 MHz, CDCl3) δ 169.3,
163.8 (t, J = 32.0 Hz), 149.6, 135.0, 134.0, 128.3, 125.3, 120.8, 115.5 (dd, J = 252.2, 254.5 Hz), 113.5,
99.7, 63.3, 49.0 (d, J = 3.4 Hz), 44.0 (t, J = 22.3 Hz), 35.4 (dd, J = 3.5, 1.5 Hz), 28.8 (d, J = 2.0 Hz),
21.6, 13.6; 19F NMR (376 MHz, CDCl3) δ ꢀ99.57 (dt, J = 266.3, 16.0 Hz), ꢀ104.43 (dt, J = 266.2, 17.5
Hz); HRMS (ESI) exact mass calculated for C18H20F2NO3 [M+H+]: 336.1406, found: 336.1410; IR
+
(neat): νmax (cmꢀ1) = 1698, 1638, 1423, 1392, 1264, 1194, 731, 703; Rf = 0.3 (petroleum ether/EtOAc
15:1).
Ethyl 2,2-difluoro-3-(7-methoxy-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)propanoate
(3h). According to general procedure with 1h and 2a, 3h was obtained in 68% yield (48 mg, colorless
oil). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.8 Hz, 1H, ArꢀH), 6.99 (d, J = 2.4 Hz, 1H, ArꢀH), 6.93
(dd, J = 8.8, 2.4 Hz, 1H, ArꢀH), 6.26 (s, 1H, ArꢀH), 4.18ꢀ4.10 (m, 1H, CF2CHH), 4.03ꢀ3.95 (m, 1H,
CF2CHH), 3.87 (s, 3H, ArꢀOCH3), 3.34 (d, J = 18.2 Hz, 1H, COCHH), 2.94 (d, J = 18.3 Hz, 1H,
COCHH), 2.65 (t, J = 16.4 Hz, 2H, CO2CH2), 1.60 (s, 3H, CCH3), 1.20 (t, J = 7.1 Hz, 3H, CH2CH3);
13C NMR (101 MHz, CDCl3) δ 169.1, 163.8 (t, J = 28.2 Hz), 157.0, 150.4, 135.8, 124.9, 115.5 (dd, J =
252.8,247.2 Hz), 114.6, 112.4, 103.9, 99.9, 63.4, 55.7, 48.9 (d, J = 3.4 Hz), 44.0 (t, J = 22.3 Hz), 35.5
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(d, J = 3.7 Hz), 28.8, 13.6; 19F NMR (376 MHz, CDCl3) δ ꢀ99.59 (dt, J = 266.3, 16.0 Hz), ꢀ104.44 (dt,
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J = 266.4, 17.5 Hz); HRMS (ESI) exact mass calculated for C18H20F2NO4 [M+H+]: 352.1355, found:
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352.1358; IR (neat): νmax (cmꢀ1) = 1717, 1590, 1511, 1444, 1477, 1199, 862, 737; Rf = 0.3 (petroleum
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ether/EtOAc 15:1).
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Ethyl
3-(7-bromo-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-2,2-difluoropropanote
(3i). According to general procedure with 1i and 2a, 3i was obtained in 76% yield (61 mg, yellow oil).
1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.5 Hz, 1H, ArꢀH), 7.66 (s, 1H, ArꢀH), 7.42 (d, J = 8.3 Hz,
1H, ArꢀH), 6.27 (s, 1H, ArꢀH), 4.15 (dt, J = 14.3, 7.2 Hz, 1H, CF2CHH), 4.09ꢀ3.96 (m, 1H, CF2CHH),
3.36 (d, J = 18.3 Hz, 1H, COCHH), 2.95 (d, J = 18.3 Hz, 1H, COCHH), 2.66 (t, J = 16.8 Hz, 2H,
CO2CH2), 1.61 (s, 3H, CCH3), 1.22 (t, J = 7.1 Hz, 3H, CH2CH3); 13C NMR (101 MHz, CDCl3) δ 169.3,
163.7 (t, J = 32.0 Hz), 150.8, 136.4, 128.7, 126.9, 123.6, 117.5, 115.4 (dd, J = 252.6, 254.5 Hz), 115.2,
99.2, 63.3, 48.8 (d, J = 3.4 Hz), 43.8 (t, J = 22.3 Hz), 35.6 (d, J = 3.3 Hz), 28.8 (d, J = 1.9 Hz), 13.7;
19F NMR (376 MHz, CDCl3) δ ꢀ99.88 (dt, J = 266.7, 16.3 Hz), ꢀ104.47 (dt, J = 266.9, 17.5 Hz); HRMS
(ESI) exact mass calculated for C17H17BrF2NO3 [M+H+]: 400.0354, found: 400.0357; IR (neat): νmax
+
(cmꢀ1) = 1720, 1665, 1583, 1447, 1360, 1193, 807, 751; Rf = 0.3 (petroleum ether/EtOAc 15:1).
Ethyl
3-(7-chloro-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-2,2-difluoropropanote
(3j). According to general procedure with 1j and 2a, 3j was obtained in 89% yield (63 mg, colorless
oil). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.7 Hz, 1H, ArꢀH), 7.49 (s, 1H, ArꢀH), 7.28 (d, J = 8.8
Hz, 1H, ArꢀH), 6.27 (s, 1H, ArꢀH), 4.19ꢀ4.11 (m, 1H, CF2CHH), 4.01 (d, J = 10.6 Hz, 1H, CF2CHH),
3.36 (d, J = 18.3 Hz, 1H, COCHH), 2.95 (d, J = 18.3 Hz, 1H, COCHH), 2.66 (t, J = 16.8 Hz, 2H,
CO2CH2), 1.61 (s, 3H, CCH3), 1.21 (t, J = 7.3 Hz, 3H, CH2CH3); 13C NMR (101 MHz, CDCl3) δ 169.3,
163.7 (t, J = 32.1 Hz), 151.0, 135.9, 129.8, 128.4, 124.2, 120.6, 115.4 (dd, J = 253.4, 251.7 Hz), 114.8,
99.3, 63.3, 48.8 (d, J = 3.5 Hz), 43.8 (t, J = 22.3 Hz), 35.6 (dd, J = 3.3, 1.4 Hz), 28.7 (d, J = 2.1 Hz),
13.7; 19F NMR (376 MHz, CDCl3) δ ꢀ99.83 (dt, J = 266.6, 16.2 Hz), ꢀ104.49 (dt, J = 266.6, 17.4 Hz);
HRMS (ESI) exact mass calculated for C17H17ClF2NO3 [M+H+]: 356.0860, found: 356.0864; IR
+
(neat): νmax (cmꢀ1) = 1721, 1652, 1585, 1450, 1265, 1065, 808, 740.; Rf = 0.3 (petroleum ether/EtOAc
15:1).
Ethyl
2,2-difluoro-3-(7-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)propanoate
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According to general procedure with 1k and 2a, 3k was obtained in 76% yield (51 mg, yellow oil). 1H
NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 8.7, 4.7 Hz, 1H, ArꢀH), 7.30ꢀ7.13 (m, 1H, ArꢀH), 7.05 (t, J =
9.1 Hz, 1H, ArꢀH), 6.30 (s, 1H, ArꢀH), 4.15 (t, J = 8.9 Hz, 1H, CF2CHH), 4.06ꢀ3.98 (m, 1H, CF2CHH),
3.36 (d, J = 18.3 Hz, 1H, COCHH), 2.96 (d, J = 18.2 Hz, 1H, COCHH), 2.66 (t, J = 16.8 Hz, 2H,
CO2CH2), 1.62 (s, 3H, CCH3), 1.22 (t, J = 7.2 Hz, 3H, CH2CH3); 13C NMR (101 MHz, CDCl3) δ 169.1,
163.7 (t, J = 31.9 Hz), 160.1 (d, J = 240.6 Hz), 151.3, 135.7 (d, J = 10.3 Hz), 126.5 (d, J = 1.4 Hz),
115.4 (t, J = 268.4 Hz), 114.8 (d, J = 9.8 Hz), 111.9 (d, J = 25.6 Hz), 106.7 (d, J = 24.2 Hz), 99.8 (d, J
= 4.0 Hz), 63.3, 48.8 (dd, J = 3.5, 1.0 Hz), 43.9 (dd, J = 22.9, 21.8 Hz), 35.5 (dd, J = 3.3, 1.5 Hz), 28.7
(d, J = 2.0 Hz), 13.6; 19F NMR (376 MHz, CDCl3) δ ꢀ99.78 (dt, J = 267.0, 16.3 Hz), ꢀ104.52 (dt, J =
266.6, 17.5 Hz), ꢀ(117.60ꢀ117.79) (m); HRMS (ESI) exact mass calculated for C17H17F3NO3+ [M+H+]:
340.1155, found: 340.1157; IR (neat): νmax (cmꢀ1) = 1716, 1612, 1590, 1472, 1444, 1365, 1065, 737; Rf
= 0.3 (petroleum ether/EtOAc 15:1).
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Methyl 1-(3-ethoxy-2,2-difluoro-3-oxopropyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indole-7-
carboxylate (3l). According to general procedure with 1l and 2a, 3l was obtained in 65% yield (50 mg,
white solid). 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 1.6 Hz, 1H, ArꢀH), 8.13ꢀ7.94 (m, 2H, 2(ArꢀH)),
6.39 (s, 1H, ArꢀH), 4.17ꢀ4.09 (m, 1H, CF2CHH), 4.03ꢀ3.96 (m, 4H, CF2CHH and CO2CH3), 3.38 (d, J
= 18.4 Hz, 1H, COCHH), 2.98 (d, J = 18.4 Hz, 1H, COCHH), 2.68 (t, J = 16.7 Hz, 2H, CO2CH2), 1.63
(s, 3H, CCH3), 1.19 (t, J = 7.2 Hz, 3H, CH2CH3); 13C NMR (101 MHz, CDCl3) δ 169.5, 167.2, 163.7 (t,
J = 32.0 Hz), 150.6, 134.5, 132.6, 126.1, 125.4, 123.1, 115.4 (dd, J = 254.2, 252.6 Hz), 113.5, 100.3,
63.3, 52.2, 48.9 (d, J = 3.4 Hz), 43.9 (t, J = 22.3 Hz), 35.6 (d, J = 3.9 Hz), 28.8 (d, J = 2.0 Hz), 13.6;
19F NMR (376 MHz, CDCl3) δ ꢀ99.73 (dt, J = 266.8, 16.0 Hz), ꢀ104.52 (dt, J = 266.9, 17.5 Hz); HRMS
(EI) exact mass calculated for C19H19F2NO5 [M]: 379.1231, found: 379.1232; IR (neat): νmax (cmꢀ1) =
1749, 1712, 1437, 1388, 1299, 1191, 1086, 769; m.p. = 61ꢀ63oC; Rf = 0.3 (petroleum ether/EtOAc
10:1).
Ethyl
2,2-difluoro-3-(1-methyl-7-nitro-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)propanoate
(3m). According to general procedure with 1m and 2a, 3m was obtained in 7% yield (5 mg, colorless
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oil); H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 2.1 Hz, 1H, ArꢀH), 8.25 (dd, J = 9.0, 2.1 Hz, 1H,
ArꢀH), 8.17 (d, J = 8.9 Hz, 1H, ArꢀH), 6.50 (s, 1H, ArꢀH), 4.26ꢀ4.13 (m, 1H, CF2CHH), 4.17ꢀ4.04 (m,
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1H, CF2CHH), 3.43 (d, J = 18.5 Hz, 1H, COCHH), 3.03 (d, J = 18.5 Hz, 1H, COCHH), 2.70 (t, J =
17.6 Hz, 2H, CH2CH3), 1.59 (s, 3H, CCH3), 1.26 (t, J = 6.8 Hz, 3H, CH2CH3); 13C NMR (101 MHz,
CDCl3) δ 169.4, 163.6 (t, J =28.8 Hz), 152.5, 144.8, 134.6, 115.3 (t, J = 263.2 Hz), 128.9, 119.5, 117.3,
114.0, 100.4, 63.4, 52.7, 48.7, 43.7 (t, J = 22.3 Hz), 35.9, 13.8;19F NMR (376 MHz, CDCl3) δ ꢀ100.46
(dt, J = 267.1, 16.0 Hz), ꢀ104.46 (dt, J = 267.4, 17.5 Hz); HRMS (EI) exact mass calculated for
C17H16F2N2O5 [M]: 366.1027, found: 366.1031; IR (neat): νmax (cmꢀ1) = 1753, 1523, 1460, 1341, 1191,
1066, 817, 733; m.p. = 56ꢀ59 oC; Rf = 0.3 (petroleum ether/EtOAc 8:1).
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Ethyl
3-(6-bromo-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-2,2-difluoropropanoate
(3n). According to general procedure with 1n and 2a, 3n was obtained in 82% yield (65 mg, yellow
oil). 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H, ArꢀH), 7.39 (d, J = 3.1 Hz, 2H, 2(ArꢀH)), 6.29 (s, 1H,
ArꢀH), 4.22ꢀ4.09 (m, 1H, CF2CHH), 4.03 (d, J = 7.1 Hz, 1H, CF2CHH), 3.36 (d, J = 18.4 Hz, 1H,
COCHH), 2.96 (d, J = 18.3 Hz, 1H, COCHH), 2.66 (t, J = 16.8 Hz, 2H, CO2CH2), 1.61 (s, 3H, CCH3),
1.22 (t, J = 7.2, Hz, 3H, CH2CH3); 13C NMR (101 MHz, CDCl3) δ 169.3, 163.7 (t, J = 32.0 Hz), 149.9,
133.5, 130.6, 127.5, 122.0, 117.4, 117.0, 115.4 (dd, J = 252.5, 254.5 Hz), 99.7, 63.3, 48.9 (d, J = 3.2
Hz), 43.9 (t, J = 22.3 Hz), 35.6 , 28.7 (d, J = 1.9 Hz), 13.7; 19F NMR (376 MHz, CDCl3) δ ꢀ99.85 (dt, J
= 266.9, 16.2 Hz), ꢀ104.47 (dt, J = 266.8, 17.4 Hz); HRMS (ESI) exact mass calculated for
C17H17BrF2NO3 [M+H+]: 400.0354, found: 400.0357; IR (neat): νmax (cmꢀ1) = 1719, 1615, 1583,
+
1440, 1357, 823, 737, 592; Rf = 0.3 (petroleum ether/EtOAc 15:1).
Ethyl
3-(6-chloro-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-2,2-difluoropropanoate
(3o). According to general procedure with 1o and 2a, 3o was obtained in 81% yield (65 mg, colorless
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oil). H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H, ArꢀH), 7.43 (d, J = 8.4 Hz, 1H, ArꢀH), 7.34ꢀ7.16 (m,
1H, ArꢀH), 6.30 (s, 1H, ArꢀH), 4.14 (dt, J = 14.1, 7.2 Hz, 1H, CF2CHH), 4.02 (dt,J = 14.5, 7.2 Hz, 1H,
CF2CHH), 3.36 (d, J = 18.3 Hz, 1H, COCHH), 2.96 (d, J = 18.3 Hz, 1H, COCHH), 2.66 (t, J = 16.8
Hz, 2H, CO2CH2), 1.62 (s, 3H, CCH3), 1.22 (t, J = 7.2 Hz, 3H, CH2CH3); 13C NMR (101 MHz, CDCl3)
δ 169.4, 163.7 (t, J= 32.0 Hz), 150.0, 133.1, 130.3, 129.9, 124.9, 121.6, 115.4 (dd, J = 253.5, 251.6
Hz), 114.2, 99.7, 63.3, 48.9 (d, J = 3.5 Hz), 43.9 (t, J = 22.3 Hz), 35.6 (d, J = 3.3 Hz), 28.8 (d, J = 1.8
Hz), 13.7; 19F NMR (376 MHz, CDCl3) δ ꢀ99.84 (dt, J = 266.7, 16.1 Hz), ꢀ104.47 (dt, J = 266.9, 17.5
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Hz); HRMS (ESI) exact mass calculated for C17H17ClF2NO3 [M+H+]: 356.0860, found: 356.0865; IR
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(neat): νmax (cmꢀ1) = 1717, 1654, 1597, 1444, 1370, 825, 736; Rf = 0.3 (petroleum ether/EtOAc 15:1).
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Ethyl
2,2-difluoro-3-(6-fluoro-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)propanoate
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(3p). According to general procedure with 1p and 2a, 3p was obtained in 88% yield (60 mg, colorless
oil). 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 8.8, 2.4 Hz, 1H, ArꢀH), 7.44 (dd, J = 8.7, 5.0 Hz, 1H,
ArꢀH), 7.04 (td, J = 9.1, 2.4 Hz, 1H, ArꢀH), 6.29 (s, 1H, ArꢀH), 4.17ꢀ4.09 (m, 1H, CF2CHH), 4.04ꢀ3.96
(m, 1H, CF2CHH), 3.35 (d, J = 18.3 Hz, 1H, COCHH), 2.96 (d, J = 18.3 Hz, 1H, COCHH), 2.66 (dd, J
= 17.5, 16.0 Hz, 2H, CO2CH2), 1.61 (s, 3H, CCH3), 1.20 (t, J = 7.1 Hz, 3H, CH2CH3); 13C NMR (101
MHz, CDCl3) δ 169.4, 163.7 (t, J = 32.0 Hz), 160.4 (d, J = 241.8 Hz), 149.6 (d, J = 4.0 Hz), 130.9 (d, J
= 1.8 Hz), 129.9 (d, J = 12.8 Hz), 121.5 (d, J = 9.6 Hz), 115.4 (dd, J = 253.5, 251.3 Hz), 112.5 (d, J =
24.2 Hz), 101.4, 101.1, 99.6, 63.3, 48.9 (dd, J = 3.5, 1.2 Hz), 44.0 (dd, J = 22.9, 21.7 Hz), 35.5 (dd, J =
3.6, 1.4 Hz), 28.8 (d, J = 2.5 Hz), 13.6; 19F NMR (376 MHz, CDCl3) δ ꢀ99.72 (dt, J = 266.9, 16.1 Hz),
ꢀ104.52 (dt, J = 266.9, 17.5 Hz), ꢀ(117.31ꢀ117.37) (m); HRMS (ESI) exact mass calculated for
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C17H17F3NO3 [M+H+]: 340.1155, found: 340.1159; IR (neat): νmax (cmꢀ1) = 1713, 1607, 1578, 1447,
1375, 865, 822; Rf = 0.3 (petroleum ether/EtOAc 15:1).
Ethyl 3-(1,6-dimethyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-2,2-difluoropropanoate (3q).
According to general procedure with 1q and 2a, 3q was obtained in 72% yield (48 mg, colorless oil).
1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H, ArꢀH), 8.01 (dd, J = 8.4, 1.7 Hz, 1H, ArꢀH), 7.56 (dd, J =
8.3, 1.4 Hz, 1H, ArꢀH), 6.38 (s, 1H, ArꢀH), 4.18ꢀ4.09 (m, 1H, CF2CHH), 4.08ꢀ3.99 (m, 1H, CF2CHH),
3.97 (s, 3H, ArꢀCH3), 3.40 (d, J = 18.3 Hz, 1H, COCHH), 3.00 (d, J = 18.3 Hz, 1H, COCHH), 2.69 (t,
J = 16.8 Hz, 2H, CO2CH2), 1.64 (s, 3H, CCH3), 1.21 (t, J = 7.2 Hz, 3H, CH2CH3); 13C NMR (101
MHz, CDCl3) δ 169.2, 167.2, 163.7 (t, J = 32.0 Hz), 152.8, 138.4, 129.6, 125.9, 125.6, 120.5, 115.6,
99.9, 63.3, 52.1, 48.8 (d, J = 3.3 Hz), 43.8 (t, J = 22.3 Hz), 35.7 (d, J = 3.2 Hz), 28.7, 13.7; 19F NMR
(376 MHz, CDCl3) δ ꢀ99.88 (dt, J = 267.0, 16.3 Hz), ꢀ104.45 (dt, J = 267.0, 17.4 Hz); HRMS (ESI)
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exact mass calculated for C18H20F2NO3 [M+H+]: 336.1406, found: 336.1408; IR (neat): νmax (cmꢀ1) =
1698, 1567, 1445, 1312, 1211, 1104, 801, 754; Rf = 0.3 (petroleum ether/EtOAc 15:1).
Ethyl
3-(5-chloro-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-2,2-difluoropropanoate
(3r). According to general procedure with 1r and 2a, 3r was obtained in 68% yield (48 mg, yellow oil).
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1H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 7.7 Hz, 1H, ArꢀH), 7.30 (t, J = 6.5 Hz, 1H, ArꢀH), 7.20 (t, J
= 7.8 Hz, 1H, ArꢀH), 6.37 (s, 1H, ArꢀH), 4.17 (dd, J = 10.7, 7.2 Hz, 1H, CF2CHH), 4.03 (dd, J = 10.8,
7.2 Hz, 1H, CF2CHH), 3.37 (d, J = 18.1 Hz, 1H, COCHH), 2.98 (d, J = 18.1 Hz, 1H, COCHH),
2.72ꢀ2.57 (m, 2H, CO2CH2), 1.61 (s, 3H, CCH3), 1.23 (t, J = 7.1 Hz, 3H, CH2CH3); 13C NMR (101
MHz, CDCl3) δ 167.7, 163.7 (t, J = 32.0 Hz), 152.1, 137.6, 128.9, 126.0, 125.1, 120.1, 119.2, 115.4
(dd, J = 253.4, 251.8 Hz), 100.1, 63.3, 48.9 (dd, J = 3.4, 1.2 Hz), 43.9 (t, J = 22.4 Hz), 34.5 (dd, J =
3.1, 1.7 Hz), 28.7 (d, J = 2.1 Hz), 13.7; 19F NMR (376 MHz, CDCl3) δ ꢀ100.16 (ddd, J = 266.6, 18.6,
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14.7 Hz), ꢀ104.10 (dt, J = 266.7, 17.2 Hz); HRMS (ESI) exact mass calculated for C17H17ClF2NO3
[M+H+]: 356.0860, found: 356.0864; IR (neat): νmax (cmꢀ1) = 1756, 1603, 1557, 1412, 1321, 1267,
1189, 865, 733; Rf = 0.3 (petroleum ether/EtOAc 15:1).
Ethyl 3-(1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-2,2-difluoropropanoate (3s).
According to general procedure with 1s and 2a, 3s was obtained in 68% yield (45 mg, yellow oil). 1H
NMR (400 MHz, CDCl3) δ 7.31 (d, J = 7.7 Hz, 1H, ArꢀH), 7.18 (t, J = 7.6 Hz, 1H, ArꢀH), 7.08 (d, J =
7.3 Hz, 1H, ArꢀH), 6.32 (s, 1H, ArꢀH), 4.13 (dd, J = 10.7, 7.2 Hz, 1H, CF2CHH), 3.98 (dd, J = 10.8,
7.2 Hz, 1H, CF2CHH), 3.35 (d, J = 18.1 Hz, 1H, COCHH), 2.95 (d, J = 18.2 Hz, 1H, COCHH), 2.90 (s,
3H, ArꢀCH3), 2.75ꢀ2.51 (m, 2H, CO2CH2), 1.60 (s, 3H, CCH3), 1.20 (t, J = 7.2 Hz, 3H, CH2CH3); 13C
NMR (101 MHz, CDCl3) δ 179.9, 174.6, 169.1 (d, J = 1.1 Hz), 163.8, 151.0, 138.6, 136.3, 135.6, 130.9,
130.3, 129.4, 126.7, 125.7, 124.6, 118.1, 115.1 (dd, J = 252.5, 254.6 Hz), 100.4, 49.0 (d, J = 2.6 Hz),
44.1 (dd, J = 21.9, 22.6 Hz), 34.5 (dd, J = 3.5, 1.7 Hz), 28.8, 21.6, 13.6; 19F NMR (376 MHz, CDCl3) δ
ꢀ99.71 (dt, J = 266.3, 16.1 Hz), ꢀ104.35 (dt, J = 266.4, 17.4 Hz); HRMS (ESI) exact mass calculated
for C18H20F2NO3+ [M+H+]: 336.1406, found: 336.1408; IR (neat): νmax (cmꢀ1) = 1709, 1605, 1589, 1403,
1367, 1271, 1190, 769, 745; Rf = 0.3 (petroleum ether/EtOAc 15:1).
Ethyl 3-(1,9-dimethyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-2,2-difluoropropanoate (3t).
According to general procedure with 1t and 2a, 3t were obtained in 49% yield (35 mg, yellow oil). 1H
NMR (400 MHz, CDCl3) δ 8.21ꢀ7.96 (m, 1H, ArꢀH), 7.46 (dd, J = 7.3, 1.9 Hz, 1H, ArꢀH), 7.40ꢀ7.22
(m, 2H, 2(ArꢀH)), 4.00 (dd, J = 10.8, 7.1 Hz, 1H, CF2CHH), 3.71 (dd, J = 10.8, 7.1 Hz, 1H, CF2CHH),
3.40 (d, J = 18.3 Hz, 1H, COCHH), 2.93 (dd, J = 18.2, 1.7 Hz, 1H, COCHH), 2.87ꢀ2.52 (m, 2H,
CO2CH2), 2.27 (s, 3H, ArꢀCH3), 1.64 (s, 3H, CCH3), 1.07 (t, J = 7.1 Hz, 3H, CH2CH3); 13C NMR (101
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MHz, CDCl3) δ 169.2, 163.6 (t, J = 31.9 Hz), 142.7, 135.9, 129.7, 124.1, 124.0, 118.9, 115.6 (dd, J =
255.4, 249.8 Hz), 113.8, 109.3, 63.3, 49.1 (d, J = 4.4 Hz), 43.3 (dd, J = 23.1, 21.6 Hz), 35.4 (d, J = 4.9
Hz), 27.6 (d, J = 1.5 Hz), 13.4, 8.53; 19F NMR (376 MHz, CDCl3) δ ꢀ97.80 (dt, J = 265.7, 14.7 Hz),
ꢀ105.61 (ddd, J = 265.7, 19.5, 16.5 Hz); HRMS (ESI) exact mass calculated for C18H20F2NO3+ [M+H+]:
336.1406, found: 336.1409; IR (neat): νmax (cmꢀ1) = 1736, 1597, 1551, 1457, 1376, 1363, 779, 758; Rf =
0.3 (petroleum ether/EtOAc 15:1).
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Ethyl
2,2-difluoro-3-(1-methyl-3-oxo-9-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)propanoate
(3u). According to general procedure with 1u and 2a, 3u was obtained in 78% yield (62 mg, yellow
oil). 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.9 Hz, 1H, ArꢀH), 7.48 (td, J = 10.2, 9.6, 6.8 Hz, 5H,
5(ArꢀH)), 7.54ꢀ7.47 (m, 2H, 2(ArꢀH)), 7.34ꢀ7.26 (m, 1H, ArꢀH), 4.18ꢀ4.11 (m, 1H, CF2CHH),
4.05ꢀ3.97 (m, 1H, CF2CHH), 3.46 (d, J = 18.2 Hz, 1H, COCHH), 2.99 (d, J = 18.2 Hz, 1H, COCHH),
2.57 (t, J = 17.3 Hz, 2H, CO2CH2), 1.60 (s, 3H, CCH3), 1.22 (t, J = 7.2, Hz, 3H, CH2CH3); 13C NMR
(101 MHz, CDCl3) δ 169.6, 163.7 (t, J = 32.2 Hz), 144.2, 135.4, 132.4, 129.9, 129.6, 128.7, 127.8,
124.5, 124.4, 119.8, 116.2, 115.5 (dd, J = 3.0, 1.4 Hz), 113.8, 63.3, 49.1 (d, J = 3.0 Hz), 43.2 (t, J =
22.0 Hz), 36.4, 28.7, 13.7; 19F NMR (376 MHz, CDCl3) δ ꢀ100.32 (dt, J = 264.8, 17.2 Hz), ꢀ103.87 (dt,
J = 264.6, 17.1 Hz); HRMS (ESI) exact mass calculated for C23H22F2NO3 [M+H+]: 398.1562, found:
+
398.1565; IR (neat): νmax (cmꢀ1) = 1740, 1633, 1598, 1451, 1380, 1264, 735, 702; Rf = 0.3 (petroleum
ether/EtOAc 15:1).
Ethyl
3-(9-cyano-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)-2,2-difluoropropanoate
(3v). According to general procedure with 1v and 2a, 3v was obtained in 85% yield (59 mg, white
solid). 1H NMR (400 MHz, CDCl3) δ 8.18ꢀ8.03 (m, 1H, ArꢀH), 7.77ꢀ7.62 (m, 1H, ArꢀH), 7.54ꢀ7.36 (m,
2H, ArꢀH), 4.32ꢀ3.99 (m, 2H, CF2CH2), 3.51 (d, J = 18.6 Hz, 1H, COCHH), 3.02 (d, J = 18.7 Hz, 1H,
COCHH), 2.94ꢀ2.68 (m, 2H, CO2CH2), 1.76 (s, 3H, CCH3), 1.30 (t, J = 7.2 Hz, 3H, CH2CH3); 13C
NMR (101 MHz, CDCl3) δ 169.0, 163.1 (t, J = 32.0 Hz), 157.6, 132.1, 129.1, 126.0, 125.8, 119.8,
115.1 (t, J = 253.9 Hz), 114.3, 113.2, 84.8, 63.6, 47.5 (t, J = 3.0 Hz), 42.3 (t, J = 22.1 Hz), 36.6 (t, J =
1.8 Hz), 27.6 (d, J = 1.7 Hz), 13.7. 19F NMR (376 MHz, CDCl3) δ ꢀ(100.16ꢀ101.13) (m),
ꢀ(103.90ꢀ105.41) (m); HRMS (EI) exact mass calculated for C18H16F2N2O3 [M +]: 346.1124, found:
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0.3 (petroleum ether/EtOAc 15:1).
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carboxylate (3w). According to general procedure with 1w and 2a, 3w was obtained in 57% yield (43
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mg, colorless oil). H NMR (400 MHz, CDCl3) δ 8.21ꢀ8.05 (m, 2H, 2(ArꢀH)), 7.48ꢀ7.36 (m, 2H,
2(ArꢀH)), 4.13ꢀ4.04 (m, 1H, CF2CHH), 4.02ꢀ3.94 (m, 4H, CF2CHH and CO2CH3), 3.55 (d, J = 18.8 Hz,
1H, COCHH), 3.74ꢀ3.14 (m, 1H, CO2CHH), 3.04ꢀ2.85 (m, 2H, COCHH and CO2CHH), 1.76 (s, 3H,
CCH3), 1.18 (t, J = 7.1 Hz, 3H, CH2CH3). 13C NMR (101 MHz, CDCl3) δ 170.3, 164.3, 163.7 (t, J =
32.1 Hz), 155.6, 131.7, 129.6, 125.4, 125.0, 122.2, 115.7 (dd, J = 254.6, 252.3 Hz), 113.8, 106.4, 63.3,
51.6, 47.8 (t, J = 2.4 Hz), 40.8 (dd, J = 22.7, 20.9 Hz), 37.2 (d, J = 3.5 Hz), 26.8, 13.6; 19F NMR (376
MHz, CDCl3) δ ꢀ99.29 (ddd, J = 263.0, 20.7, 12.0 Hz), ꢀ104.50 (ddd, J = 263.1, 20.2, 16.3 Hz); HRMS
(EI) exact mass calculated for C19H19F2NO5 [M]: 379.1231, found: 379.1236; IR (neat): νmax (cmꢀ1) =
1756, 1706, 1564, 1454, 1179, 1147, 795, 756; Rf = 0.3 (petroleum ether/EtOAc 15:1).
Ethyl
2,2-difluoro-3-(9-formyl-1-methyl-3-oxo-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)propanoate
(3x). According to general procedure with 1x and 2a, 3x was obtained in 76% yield (53 mg, colorless
oil). 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H, CHO), 8.22ꢀ8.02 (m, 2H, 2(ArꢀH)), 7.53ꢀ7.35 (m, 2H,
2(ArꢀH)), 4.18ꢀ3.96 (m, 2H, CO2CH2), 3.56 (d, J = 18.7 Hz, 1H, COCHH), 3.14ꢀ2.98 (m, 2H, CF2CHH
and COCHH), 2.97ꢀ2.79 (m, 1H, CF2CHH), 1.77 (s, 3H, CCH3), 1.21 (t, J = 7.1 Hz, 3H, CH2CH3); 13C
NMR (101 MHz, CDCl3) δ 184.1, 170.3, 163.4 (t, J = 32.0 Hz), 156.8, 131.6, 129.8, 125.9, 125.5,
120.4, 115.4 (dd, J = 255.4, 252.9 Hz), 114.0, 113.9, 63.4, 47.6 (t, J = 2.9 Hz), 42.4 (dd, J = 22.7, 21.2
Hz), 37.2 (d, J = 2.9 Hz), 28.0 (d, J = 1.5 Hz), 13.6. 19F NMR (376 MHz, CDCl3) δ ꢀ99.83 (ddd, J =
264.7, 21.2, 11.9 Hz), ꢀ104.72 (ddd, J = 264.5, 20.2, 14.7 Hz); HRMS (EI) exact mass calculated for
C18H17F2NO4 [M]: 349.1126, found: 349.1132; IR (neat): νmax (cmꢀ1) = 1758, 1668, 1552, 1455, 1338,
1178, 1062, 759; Rf = 0.3 (petroleum ether/EtOAc 15:1).
Ethyl 2,2-difluoro-3-(6-methyl-8-oxo-7,8-dihydro-6H-pyrido[3,2-b]pyrrolizin-6-yl)propanoate (3y).
According to general procedure with 1y and 2a, 3y was obtained in 65% yield (42 mg, yellow oil). 1H
NMR (400 MHz, CDCl3) δ 8.49 (s, 1H, ArꢀH), 7.86 (d, J = 7.9 Hz, 1H, ArꢀH), 7.26 (s, 1H, ArꢀH), 6.32
(s, 1H, ArꢀH), 4.19 (s, 1H, CF2CHH), 4.08 (s, 1H, CF2CHH), 3.41 (d, J = 18.4 Hz, 1H, COCHH), 3.03
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