Synthesis of Unsymmetrical α,α-Diarylacetates

Article abstract of DOI:10.1021/acs.joc.5b02383

Ethyl bromofluoroacetate has been developed as a precursor for the convenient synthesis of unsymmetrical α,α-diarylacetates featuring indoles, anilines, and other electron-rich aromatics. In conjunction with a mild Lewis acid catalyzed C-N → C-C exchange, intermediate arylglycines can be synthesized and transformed into α,α-diarylacetates in a one-pot protocol, resulting in a net diarylation reaction exhibiting a wide scope. In the context of diarylacetates, the synthetic equivalence of the fluorinated reagent with α-nitro-α-diazo carbonyls was established.

Full text of DOI:10.1021/acs.joc.5b02383

Article
pubs.acs.org/joc
Synthesis of Unsymmetrical α,α-Diarylacetates
Santosh D. Jadhav and Anand Singh*
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur-208016, India
S
* Supporting Information
ABSTRACT: Ethyl bromofluoroacetate has been developed as a
precursor for the convenient synthesis of unsymmetrical α,α-
diarylacetates featuring indoles, anilines, and other electron-rich
aromatics. In conjunction with a mild Lewis acid catalyzed C−N →
C−C exchange, intermediate arylglycines can be synthesized and
transformed into α,α-diarylacetates in a one-pot protocol, resulting
in a net diarylation reaction exhibiting a wide scope. In the context of
diarylacetates, the synthetic equivalence of the fluorinated reagent
with α-nitro-α-diazo carbonyls was established.
Scheme 1. Synthetic Approaches to Unsymmetrical
Diarylacetates
INTRODUCTION
■
The development of new methods to construct C−C bonds in
an efficient manner is a fundamental tenet of modern chemistry
research. Among the various kinds of reactions that can be
envisaged, arylation of sp3 carbon centers has attracted signifi-
cant attention from the synthetic community. While many
elegant processes are available for monoarylation,1 the
analogous bisarylation strategies are still in infancy, especially
relating to the construction of unsymmetrical geminal diaryl
motifs. Numerous biologically active compounds, including
marketed drugs such as Femara, Etoposide, and Zoloft, feature
the geminal diaryl moiety.2 While a few literature reports
provide innovative solutions to this problem, the reliance on
the use of diazo derivatives and the lack of generality highlight
the difficulties in this area.3 Given the challenges associated
with constructing this framework, we wanted to develop a
simple protocol that would also offer versatility in the selection
of the diaryl groups while maintaining simplicity such that no
prefunctionalization of substrates would be required.
Our hypothesis was to employ ethyl bromofluoroacetate
(1a) as a common progenitor for the convenient synthesis of
aryl glycines (18, 19), which would be viable precursors for
generating α,α-diarylacetates featuring indoles, anilines, and
other electron-rich aryls (Scheme 1b). The resulting approach
would involve the generation of aryl glycines using a three-
component reaction, which would preferably not require any
catalysts/promoters while being generally applicable (Scheme 1b).
This reaction would be a stepping stone toward our strategy
to synthesize α,α-diarylacetates, which would entail the trans-
formation of 4-fluoroanilinoyl-aryl glycines to bisarylated
products, including those featuring a free aniline group. Overall,
our plans attempt to address the synthesis of compounds
containing unsymmetrical bisarylated sp3 carbon centers.
Central to our hypothesis is the electrophilic nature of the
α-carbon in 1, the leaving group property of the bromine and
fluorine substituents, and the ability of 4-fluoroaniline to act as
a placeholder for the second arylation until subjected to Lewis
acid activation. We also envisaged that these reactions could be
performed in a one-pot operation, resulting in diarylation, and
offering access to a variety of unsymmetrical diarylacetates in
a convenient manner without the use of traditional coupling
reactions and explosive diazo precursors.
RESULTS AND DISCUSSION
■
Mindful of the potential limitations of any direct method to
synthesize unsymmetrical diarylacetates in high yield,4 our
studies began with attempts to evaluate the reactivity of ethyl
bromofluoroacetate with indoles and anilines to ascertain if
diarylacetate formation would be feasible, especially because
it involves the cleavage of a C−F bond. Additionally, geminal
dihaloacetates such as Br2CHCO2Et, BrFCHCO2Et, and
ClFCHCO2Et are not known to lend themselves to nucleophilic
attack by arene nucleophiles.5 We reasoned that, due to the
fluorine substituent, the α-carbon in 1a is more electrophilic
Received: October 14, 2015
© XXXX American Chemical Society
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than other geminal dihaloacetates (as reflected in radical
formations6) and, hence, may exhibit some reactivity. Indeed,
it was observed that a reaction involving indole, N-methylaniline,
and 1a resulted in the unsymmetrical diaryl product 7, albeit in
low yield. We investigated a few additional precursors and found
that, while N-methylaniline and indoline afforded diarylated
products in low yields (compounds 7, 8, and 9; Scheme 2a),
Scheme 3. Proposed Pathway for the Conversion of
Arylglycines to α,α-Diarylacetates
Scheme 2. Innate Reactivity of Indoles and Anilines with
Geminal Dihaloacetates
problem, but that method relies on the use of α-nitro-α-diazo
carbonyls whose explosive nature has been observed by synthetic
chemists in the past.3e,7 Our research efforts were aimed at
providing an efficient and convenient synthetic alternative while
maintaining a broad substrate scope.
The efficient assembly of the aryl glycines structure via a
three-component reaction involving ethyl bromofluoroacetate,
indole/anilines, and 4-fluoroaniline was critical for our
subsequent plan to generate unsymmetrical α,α-diarylacetates.
As shown in Scheme 4, the key indole-4-fluoroaniline adduct
Scheme 4. Synthesis of Intermediate Arylglycines 18 and 19
N-Bn, N-propargyl, and N-allyl anilines provided no product
(Scheme 2a). Employing pyrrole in place of indole also did
not lead to the desired product, indicating another limitation of
this protocol. Comparative reactions with ethyldibromoacetate
and ethylchlorofluoroacetate failed to elicit any reactivity,
thereby demonstrating that the fluorine substituent is necessary
(Scheme 2b). It was clear from these results that, even if the
direct reaction worked, its scope would be limited to synthesiz-
ing a few diarylacetates involving indoles and substituted
anilines and it would not be of significant practical value. Hence,
another strategy needed to be developed that could result in
all classes of unsymmetrical diarylacetates (viz. indole-indole,
indole-aniline, and aniline-aniline).
As per our hypothesis outlined in Scheme 1, we envisaged
that indolyl glycines could be valuable precursors for generating
a diverse selection of unsymmetrical α,α-diarylacetates if an
efficient method could be developed for the exchange of the
4-fluoroanilinoyl moiety with a different aryl group. A simple
strategy to realize this goal would be the development of a
Lewis acid catalyzed C−N → C−C exchange in arylated
4-fluoroanilinoyl amino esters (Scheme 3). The application of
the 4-fluoroaniline moiety as a leaving group (catalyzed by a
boronate urea) was recently demonstrated by Mattson et al.3e
in an elegant solution to the unsymmetrical diarylacetate synthesis
18 and the analogous N-methylaniline-4-fluoroanilne compound
19 were obtained in good yields. These reactions proceeded
without any catalyst and required only mild heating, which
increased the possibility of performing the subsequent step
in the same reaction vessel. We also determined that
4-methoxyaniline affords analogous product 18b in a lower
yield (59%), while 4-nitroaniline does not react at all under the
reaction conditions.
With a high yielding synthesis of the precursor 18 in hand,
we explored the scope of the Lewis acid catalyzed installation of
a second aryl group.8 Under the reaction conditions outlined
in Table 1, a test reaction employing 18a and 2-methylindole
revealed that many Lewis acid catalysts (10 mol %) afforded
the product 24 efficiently (BF3−OEt2 (94%); Cu(OTf) (87%);
Cu(OTf)2 (93%); Ag(OTf) (96%); Zn(OTf)2 (92%);
Sc(OTf)3 (98%)), and we selected Sc(OTf)3 for further studies
because it provided the highest yield. Using the same test
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In order to access unsymmetrical aniline-aniline and other
aniline-aryl derivatives, the 4-fluoroaniline derivative 19 was
subjected to Sc(OTf)3 under similar conditions outlined for the
indole precursor 18.9 It was found that free anilines reacted via
the para position to afford the unsymmetrical diarylacetates in
generally high yields (52−86%).10 Gratifyingly, N-benzylaniline
provided the product in good yield, thereby overcoming the
limitation of the direct protocol in Scheme 2. Various N-
substituted anilines, including N-methylaniline, N-propargylaniline,
and indoline, provided the corresponding products in high
yields. 1,3,5-Trimethoxybenzene and pyrrole also exhibited
good reactivity, as shown in Table 2. During our studies, it was
Table 1. Synthesis of Unsymmetrical Indole-Indole, Indole-
Aniline, and Indole-Aryl Derivatives
Table 2. Synthesis of Unsymmetrical Bisaniline and Aniline-
Aryl Diarylacetates
discovered that para-substituted anilines did not participate
(as Ar2) in this reaction. It was observed that, while the reactions
with indole derivative 18 were complete in 3−4 h, the reactions
with N-methylaniline derivative 19 took longer (12 h) for
completion. This difference can be attributed either to a possible
competitive binding of Sc(OTf)3 to 19 or to the greater
electronic assistance provided by the indole ring in cleaving the
C−N(aniline) bond compared to N-methylaniline.
With the development of efficient protocols for accessing
various unsymmetrical α,α-diarylacetates, we proceeded to test
whether the steps involved could be performed in a one-pot
operation. Employing the above optimized conditions sequen-
tially in the same reaction vessel smoothly afforded a variety
of diarylacetates, as depicted in Table 3. While any indole or
N-substituted aniline can be used in the first step, free anilines
can only be employed as the second aryl group (Ar2) because, if
employed along with 4-F-aniline, they compete for C−N bond
formation with 1a and result in very low yields of the desired
intermediate. The bisindole, indole-aniline, and the bisaniline
products were synthesized efficiently (Table 3). Employing
1,3,5-trimethoxybenzene as the second nucleophile, the
diaryl derivative 29 could also be accessed. Attempts to use
1,3,5-trimethoxybenzene as the first nucleophile in this one-pot
protocol did not provide any product. Under these optimized
reaction to evaluate arylglycines 18a and 18b, the 4-methoxy
derivative was found to afford the product 24 in only 46% yield,
while the 4-fluoro derivative resulted in 98% yield, and hence,
18a was selected for further studies. As shown in Table 1,
various substituted indoles (as Ar2) were tolerated well, and
indoline also provided the product (8) in 94% yield. Free anilines
as well as N-substituted anilines reacted smoothly to afford the
indole-aniline diarylacetates in high yields, as depicted in Table 1.
Among other aryl moieties, 1,3,5-trimethoxybenzene provided
the product (29) in high yield, while 1,3-dimethoxybenzene
afforded regioisomers out of which compound 30 was the major
product (49% yield). Pyrrole also resulted in the indole-pyrrole
product 31 in 67% yield. 1-Naphthol provided the diaryl product
in 71% yield, and 2-naphthol underwent an arylation−cyclization
to afford the lactone 33 in 56% yield. Other heterocycles such as
furan, thiophene, anisole, benzofuran, and benzothiophene did
not react under these conditions. Key advantages of this protocol
over the method in Scheme 2a includes the applicability of
non-aniline electron-rich aryl moieties, the applicability of free
anilines, improved scope with N-substituted anilines, and the
high yields, particularly in the case of compound 8, wherein an
increase of 51% was observed compared to the direct method.
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the leaving group property of the 4-fluoroaniline moiety under
Lewis acidic conditions. The synthetic method developed has
a wide scope and is also amenable to be performed in a one-pot
variant, effectively accomplishing a diarylation reaction that has
been a challenging problem in the literature. The results also
demonstrate the synthetic equivalence of ethyl bromofluor-
oacetate with α-nitro-α-diazo carbonyls with respect to the
synthesis of diarylacetates. Further application of this reagent in
the development of new reactions is currently being explored in
our laboratory.
Table 3. One-Pot Synthesis of Unsymmetrical Diarylacetates
EXPERIMENTAL SECTION
■
General Information. All reactions were carried out under an
argon atmosphere with dry solvents under anhydrous conditions.
Reagents were purchased at the highest commercial quality and used
without further purification, unless otherwise stated. Yields refer to
chromatographically pure material. Reaction were monitored by
thin-layer chromatography (TLC) carried out on 0.25 mm Merck
silica gel plates (60F-254) using UV light as a visualizing agent and
p-anisaldehyde or KMnO4 stain, and heat as developing agents. Merck
silica gel (particle size 100−200 and 230−400 mesh) was used for flash
column chromatography.
NMR spectra were recorded on 500 (1H: 500 MHz, 13C: 125 MHz)
or 400 (1H: 400 MHz, 13C: 100 MHz) NMR spectrometers in CDCl3
having TMS 0.03% as internal standard. Mass spectrometric data were
obtained using Q-TOF ESI-MS.
The following abbreviations were used to explain the multiplicities:
s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of
doublet, ddd = doublet of a doublet of doublet.
General Procedure (I) for the Direct Synthesis of Unsym-
metrical Indole-N-Substituted Aniline Diarylacetates 7−12.
A dried vial equipped with a magnetic bar was charged with indole
(1 equiv), aniline (2 equiv), ethyl bromofluoroacetate (2 equiv), and
diisopropylethylamine (2 equiv). The reaction was performed in a
nitrogen atmosphere at 60 °C using DCE (2.3 mL per mmol of
indole) as solvent. After completion of reaction (checked by TLC),
the reaction mixture was poured into a separating funnel containing
50 mL of ethyl acetate/water (1:1). The layers were separated, and
the aqueous layer was extracted with ethyl acetate (2 × 20 mL). All
organic layers were combined, dried over sodium sulfate, and con-
centrated in vacuo. The residue was purified by column chromatog-
raphy using ethyl acetate/petroleum ether as eluting solvent.
General Procedure (II) for the Preparation of Diarylacetates
8, 21−32 from Ethyl 2-(4-Fluorophenylamino)-2-(1H-indol-3-
yl)acetate (18).
conditions, we again evaluated a series of dihaloacetates and
found that only ethyl bromofluoroacetate and ethyl iodo-
fluoroacetate reacted to provide the product (Table 3b). Since
iodo-derivative 1d has to be synthesized from the commercially
available bromofluoroacetate 1a, it offers no advantage over
1a.11 A comparison with the two-step methods outlined above
revealed that the yields were slightly diminished (by 5−10%).
A major advantage in terms of efficiency is that the inter-
mediates analogous to 18 and 19 do not have to be isolated for
every combination of Ar1 and Ar2. Additionally, the mild con-
ditions, operational simplicity, and general applicability render
this method very useful for populating the α,α-diarylacetate
chemical space.
A dried vial equipped with a magnetic bar was charged with ethyl
2-(4-fluorophenylamino)-2-(1H-indol-3-yl) acetate 18 (1 equiv), aryl
nucleophile (Ar1) (1.5 equiv), scandium triflate (0.1 equiv), and 1,2
dichloroethane (DCE; 6.0 mL per mmol of 18). The reaction was
heated at 60 °C under a nitrogen atmosphere. After 3−4 h (monitored
by TLC), the reaction mixture was poured into a separating funnel
containing 50 mL of ethyl acetate/water (1:1). The layers were
separated, and the aqueous layer was extracted with ethyl acetate
(2 × 20 mL). All organic layers were combined, dried over sodium
sulfate, and concentrated in vacuo. The residue was purified by
column chromatography using ethyl acetate/petroleum ether as eluting
solvent.
CONCLUSION
■
In summary, we have shown the application of ethyl bromo-
fluoroacetate as a reagent for the convenient synthesis of
unsymmetrical α,α-diarylacetates. The reactions developed rely
on the propensity of a suitably placed C−F bond to cleave and
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General Procedure (III) for the Synthesis of Diarylacetates
34−42 from Methyl 2-(4-Fluorophenylamino)-2-(4-(methylamino)-
phenyl)acetate (19).
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
indoline (46 mg, 0.48 mmol) provided 8 after flash chromatography
(15−25% ethyl acetate in petroleum ether) as a brown paste (96 mg,
94%). Rf = 0.3 (30% ethyl acetate in petroleum ether). IR (neat):
1
νmax/cm−1 3403, 2978, 2902, 2857, 1723, 1616. H NMR (400 MHz,
Chloroform-d) δ 8.12 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.33 (d, J =
8.1 Hz, 1H), 7.17 (dd, J = 12.9, 7.3 Hz, 3H), 7.07 (q, J = 7.7 Hz, 2H),
6.62 (d, J = 7.9 Hz, 1H), 5.14 (s, 1H), 4.28−4.15 (m, 2H), 3.54 (t, J =
8.4 Hz, 2H), 2.98 (t, J = 7.9 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H), (NH
proton not observed). 13C{1H}NMR (100 MHz, Chloroform-d)
δ 173.8, 150.9, 136.4, 129.9, 129.1, 127.5, 126.8, 124.8, 123.2, 122.2,
119.6, 119.2, 114.5, 111.3, 109.3, 61.1, 48.6, 47.6, 29.9, 14.3. Exact mass
A dried vial equipped with a magnetic bar was charged with methyl
2-(4-fluorophenylamino)-2-(4-(methylamino)phenyl)acetate 19
(1 equiv), aryl nucleophiles (Ar2) (1.5 equiv), scandium triflate
(0.1 equiv), and DCE (6.0 mL per mmol of 19) as solvent. The
reaction was heated at 60 °C under a nitrogen atmosphere. After 12 h
(monitored by TLC), the reaction mixture was poured into a separating
funnel containing 50 mL of ethyl acetate/water (1:1). The layers
were separated, and the aqueous layer was extracted with ethyl acetate
(2 × 20 mL). All organic layers were combined, dried over sodium
sulfate, and concentrated in vacuo. The residue was purified by column
chromatography using ethyl acetate/pet ether as eluting solvent.
General Procedure (IV) for the One-Pot Synthesis of
Unsymmetrical Diarylacetates.
+
calculated for C20H21N2O2 [M + H]+: 321.1598; found: 321.1602.
Ethy-2-(2-methyl-1H-indol-3-yl)-2-(4-(methylamino)phenyl)-
acetate (9).
According to the general procedure IV, 2-methylindole (100 mg,
0.762 mmol) and N-methylaniline (164 mg, 1.52 mmol) provided 9
after flash chromatography (15−25% ethyl acetate in petroleum ether)
as a dark yellow solid (192 mg, 78%). Rf = 0.4 (30% ethyl acetate in
petroleum ether). IR (neat): νmax/cm−1 3400, 2662, 2929, 2905, 1719.
mp = 97−99 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.89 (s, 1H),
7.53−7.46 (m, 1H), 7.28−7.24 (m, 2H), 7.14−7.06 (m, 3H), 7.01
(ddd, J = 8.0, 7.1, 1.1 Hz, 1H), 6.62 (d, J = 8.7 Hz, 2H), 5.17 (s, 1H),
4.24−4.14 (m, 2H), 2.81 (s, 3H), 2.34 (s, 3H), 1.22 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz Chloroform-d) δ 173.7, 146.2, 135.3, 132.9,
129.4(C-2), 128.0, 121.2, 119.7, 119.6, 114.0, 110.3, 109.1, 61.1, 47.6,
A dried vial equipped with a magnetic bar was charged with Ar1
(indole/aniline) (1.0 equiv), 4-fluoroaniline (2.0/3.0 equiv), ethyl
bromofluoroacetate (1.5 equiv), and diisopropylethylamine (1.5 equiv).
The reaction was performed in a nitrogen atmosphere at 60 °C using
DCE (2.3 mL per mmol of Ar1) as solvent. After consumption of
indole/aniline (as determined by TLC analysis), the reaction was
cooled to room temperature and then aryl nucleophile Ar2 (indoles/
anilines; 2.0 equiv) was added, followed by scandium triflate (0.1 equiv),
and DCE (1 mL). The reaction was again heated at 60 °C under a
nitrogen atmosphere. After completion of reaction (monitored by
TLC), the reaction mixture was poured into a separating funnel
containing ethyl acetate/water (1:1). The layers were separated, and the
aqueous layer was extracted with ethyl acetate (2 × 25 mL). All organic
layers were combined, dried over sodium sulfate, and concentrated in
vacuo. The residue was purified by column chromatography using ethyl
acetate/petroleum ether as eluting solvent.
+
2.0, 14.4, 12.4. Exact mass calculated for C20H23N2O2 [M + H]+:
323.1754; found: 323.1763.
Ethyl 2-(4-(Benzylamino)phenyl)-2-(1H-indol-3-yl)acetate (10).4
According to the general procedure II, 18 (100 mg, 0.33 mmol) and
N-benzylaniline (91 mg, 0.5 mmol) provided 10 after flash chromato-
graphy (15−25% ethyl acetate in petroleum ether) as a yellowish paste
(107 mg, 86%). Rf = 0.3 (30% ethyl acetate in petroleum ether).
1
IR (neat): νmax/cm−1 3407, 3057, 2981, 2926, 1719, 1621. H NMR
(400 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H),
7.37−7.29 (m, 5H), 7.27 (dd, J = 6.0, 2.8 Hz, 1H), 7.23 (s, 2H), 7.18−
7.11 (m, 2H), 7.05 (t, J = 7.5 Hz, 1H), 6.61−6.54 (m, 2H), 5.12 (s,
1H), 4.31−4.26 (m, 2H), 4.24−4.14 (m, 2H), 4.02 (s, 1H), 1.25 (t, J =
7.1 Hz, 3H). 13C{1H}NMR (100 MHz Chloroform-d) δ 173.6, 147.4,
139.5, 136.4, 129.4, 128.8, 127.7, 127.7, 127.4, 126.8, 123.2, 122.3,
119.7, 119.3, 114.6, 113.0, 111.2, 61.1, 48.6, 48.3, 14.4. Exact mass
Ethyl 2-(1H-Indol-3-yl)-2-(4-(methylamino)phenyl)acetate (7).
+
calculated for C25H24N2O2 [M].+: 384.1832; found: 384.1834.
According to the general procedure I, indole (100 mg, 0.854 mmol)
and N-methylaniline (183 mg, 1.71 mmol) provided 7 after flash
chromatography (15−25% ethyl acetate in petroleum ether) as a
cream colored solid (103 mg, 39%). Rf = 0.3 (20% ethyl acetate in
petroleum ether). IR (neat): νmax/cm−1 3411, 2979, 2926, 2813, 1720,
1601. mp = 140−142 °C. 1H NMR (400 MHz, Chloroform-d) δ 8.11
(s, 1H), 7.51−7.44 (m, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.26 (s, 2H),
7.19−7.13 (m, 2H), 7.06 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 6.56 (d, J =
8.5 Hz, 2H), 5.14 (s, 1H), 4.28−4.13 (m, 2H), 3.73 (s, 1H), 2.81 (s,
3H), 1.26 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (125 MHz, Chloroform-
d) δ 173.6, 148.5, 136.4, 129.3, 127.4, 126.8, 123.2, 122.2, 119.7, 119.3,
114.6, 112.6, 111.2, 61.1, 48.3, 30.9, 14.4. Exact mass calculated for
Ethyl 2-(1H-Indol-3-yl)-2-(4-(prop-2-ynylamino)phenyl)acetate (11).4
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
N-propargylaniline (63 mg, 0.48 mmol) provided 11 after flash
chromatography (15−25% ethyl acetate in petroleum ether) as a
brown solid (98 mg, 92%). Rf = 0.3 (30% ethyl acetate in petroleum
ether). IR (neat): νmax/cm−1 3410, 3286, 2980, 2925, 2853, 1721.
1
mp = 109−111 °C. H NMR (400 MHz, Chloroform-d) δ 8.08 (s,
+
C19H21N2O2 [M + H]+: 309.1598; found: 309.1600.
1H), 7.46 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.26 (d, J =
8.7 Hz, 2H), 7.18−7.13 (m, 2H), 7.05 (t, J = 7.9 Hz, 1H), 6.62 (d, J =
8.6 Hz, 2H), 5.14 (s, 1H), 4.27−4.13 (m, 2H), 3.89 (d, J = 2.5 Hz,
2H), 2.20 (t, J = 2.4 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H). 13C{1H}NMR
(100 MHz, Chloroform-d) δ 173.5, 146.1, 136.4, 129.4, 128.7, 126.8,
123.2, 122.2, 119.7, 119.2, 114.4, 113.6, 111.3, 81.1, 71.4, 61.1, 48.3,
Ethyl 2-(1H-Indol-3-yl)-2-(indolin-5-yl)acetate (8).
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+
33.8, 14.3. Exact mass calculated for C21H20N2O2 [M]+: 332.1519;
found: 332.1520.
pure 19 after flash chromatography (15−25% ethyl acetate in petroleum
ether) as a brown solid (226 mg, 80%). Rf = 0.4 (20% ethyl acetate in
petroleum ether). IR (neat): νmax/cm−1 3414, 2982, 2901, 2816, 1731,
Ethyl 2-(4-Fluorophenylamino)-2-(1H-indol-3-yl)acetate (18a).12
1
1614, 1512. mp = 74−76 °C. H NMR (400 MHz, Chloroform-d) δ
7.28 (d, J = 8.6 Hz, 2H), 6.84 (t, J = 8.7 Hz, 2H), 6.58 (d, J = 8.6 Hz,
2H), 6.51 (dd, J = 9.0, 4.4 Hz, 2H), 4.90 (s, 1H), 4.72 (s, 1H), 4.23 (dq,
J = 10.8, 7.1 Hz, 1H), 4.13 (dq, J = 10.8, 7.1 Hz, 1H), 3.78 (s, 1H), 2.82
(s, 3H), 1.22 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (100 MHz,
Chloroform-d) δ 172.5, 156.11 (d, J = 235.5 Hz), 149.4, 142.80 (d, J =
1.7 Hz), 128.3, 125.7, 115.71 (d, J = 22.5 Hz), 114.37 (d, J = 7.2 Hz),
112.6, 61.6, 61.0, 30.7, 14.2. Exact mass calculated for C17H19FN2O2+
[M]+: 302.1425; found: 302.1444.
A dried vial equipped with a magnetic bar was charged with indole
(100 mg, 0.854 mmol), 4-fluoroaniline (285 mg, 2.56 mmol), ethyl
bromofluoroacetate (316 mg, 1.71 mmol), and diisopropylethylamine
(221 mg, 1.71 mmol). The reaction was performed in a nitrogen
atmosphere at 60 °C using DCE as solvent. After 18 h (reaction
completion checked by TLC), the reaction mixture was poured into a
separating funnel containing 50 mL of ethyl acetate/water (1:1). The
layers were separated, and the aqueous layer was extracted with ethyl
acetate (2 × 20 mL). All organic layers were combined, dried over
sodium sulfate, and concentrated in vacuo. The residue provided pure
18 after flash chromatography (15−25% ethyl acetate in petroleum
ether) as a pale yellow solid (232 mg, 87%). Rf = 0.4 (20% ethyl
acetate in petroleum ether). IR (neat): νmax/cm−1 3408, 3058, 2982,
2846, 1729, 1614. mp = 128−130 °C. 1H NMR (500 MHz,
Chloroform-d) δ 8.19 (s, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.19 (d,
J = 8.1 Hz, 1H), 7.14−7.08 (m, 1H), 7.08−7.02 (m, 1H), 7.00 (d, J =
2.6 Hz, 1H), 6.78−6.70 (m, 2H), 6.48−6.41 (m, 2H), 5.22 (s, 1H),
4.55 (s, 1H), 4.14 (dq, J = 10.9, 7.1 Hz, 1H), 4.01 (dq, J = 10.8,
7.1 Hz, 1H), 1.09 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (100 MHz,
Chloroform-d) δ 172.8, 156.23 (d, J = 235.8 Hz), 143.0, 136.5, 125.8,
123.3, 122.6, 120.1, 119.5, 115.77 (d, J = 22.4 Hz), 114.44 (d, J =
7.2 Hz), 112.2, 111.6, 61.8, 55.0, 14.2. Exact mass calculated for
Ethyl 2-(1H-Indol-3-yl)-2-(1-methyl-1H-indol-3-yl)acetate (20).3e
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
N-methylindole (63 mg, 0.48 mmol) provided 21 after flash
chromatography (15−25% ethyl acetate in petroleum ether) as a red
paste (97 mg, 91%). Rf = 0.3 (30% ethyl acetate in petroleum ether).
IR (neat): νmax/cm−1 3426, 3051, 2924, 2874, 1726. 1H NMR (400 MHz,
Chloroform-d) δ 8.02 (s, 1H), 7.63 (dq, J = 7.8, 1.1 Hz, 2H), 7.30−7.25
(m, 2H), 7.24−7.19 (m, 1H), 7.16 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.08
(ddd, J = 8.1, 6.9, 1.3 Hz, 2H), 7.06−7.02 (m, 1H), 6.96 (s, 1H), 5.52−
5.46 (m, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.65 (s, 3H), 1.25 (t, J = 7.1 Hz,
3H). 13C{1H}NMR (100 MHz, Chloroform-d) δ 173.7, 137.3, 136.5,
128.1, 127.2, 126.8, 123.4, 122.2, 121.8, 119.6, 119.6, 119.4, 119.2, 113.9,
112.2, 111.4, 109.5, 61.2, 40.7, 32.9, 14.4. Exact mass calculated for
C21H21N2O2+ [M + H]+: 333.1598; found: 333.1608.
−
C18H16FN2O2 [M − H]−: 311.1201; found: 311.1197.
Ethyl 2-(1H-Indol-3-yl)-2-(4-methoxyphenylamino)acetate (18b).
Ethyl 2-(5-Bromo-1H-indol-3-yl)-2-(1H-indol-3-yl)acetate (21).3e
Employing the procedure outlined for 18a, indole (100 mg,
0.854 mmol) and 4-methoxyaniline (474 mg, 2.56 mmol) provided
18b after flash chromatography (15−25% ethyl acetate in petroleum
ether) as a yellow paste (164 mg, 59%). Rf = 0.3 (20% ethyl acetate in
petroleum ether). IR (neat): νmax/cm−1 3404, 3057, 2983, 2935, 2833,
1730. 1H NMR (400 MHz, Chloroform-d) δ 8.27 (s, 1H), 7.84 (d, J =
7.8 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.25−7.13 (m, 3H), 6.76 (d, J =
8.9 Hz, 2H), 6.63 (d, J = 9.0 Hz, 2H), 5.34 (s, 1H), 4.26 (dq, J = 10.7,
7.1 Hz, 1H), 4.14 (dq, J = 10.8, 7.1 Hz, 1H), 3.73 (s, 3H), 1.22 (t, J =
7.1 Hz, 3H). 13C{H}NMR (100 MHz, Chloroform-d) δ 173.0, 152.7,
140.9, 136.6, 126.0, 123.2, 122.6, 120.1, 119.7, 116.6, 115.0, 112.8,
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
5-bromoindole (94 mg, 0.48 mmol) provided 22 after flash chromato-
graphy (15−25% ethyl acetate in petroleum ether) as a violet paste
(146 mg, 97%). Rf = 0.2 (30% ethyl acetate in petroleum ether). IR
(neat): νmax/cm−1 3409, 3054, 2978, 2927, 1718. 1H NMR (396 MHz,
Chloroform-d) δ = 8.10 (s, 1H), 8.05 (s, 1H), 7.78 (d, J = 1.4, 1H),
7.60 (d, J = 7.9, 1H), 7.31 (d, J = 8.1, 1H), 7.24 (dd, J = 8.6, 1.8, 1H),
7.20 (t, J = 7.5, 1H), 7.11 (d, J = 8.6, 2H), 7.00 (d, J = 2.3, 1H), 6.93
(d, J = 2.3, 1H), 5.43 (s, 1H), 4.23 (q, J = 7.1, 2H), 1.28 (t, J = 7.1,
4H). 13C{1H}NMR (100 MHz, Chloroform-d) δ 173.5, 136.5, 135.0,
128.4, 126.6, 125.0, 124.8, 123.4, 122.3, 122.0, 119.7, 119.3, 113.3,
113.2, 112.9(C-2), 111.4, 61.5, 40.7, 14.3. Exact mass calculated for
−
111.5, 61.6, 55.8, 55.3, 14.3. Exact mass calculated for C19H19N2O3
[M − H]−: 323.1401; found: 323.1391.
+
C20H21BrN3O2 [M + NH4]+: 414.0812; found: 414.0813.
Ethyl 2-(4-(Methylamino)phenyl)-2-(phenylamino)acetate (19).12
Ethyl 2-(1H-Indol-3-yl)-2-(3-methyl-1H-indol-2-yl)acetate (22).4
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
3-methylindole (63 mg, 0.48 mmol) provided 23 after flash chromato-
graphy (15−25% ethyl acetate in petroleum ether) as a brown solid
(103 mg, 91%). Rf = 0.2 (30% ethyl acetate in petroleum ether).
IR (neat): νmax/cm−1 3408, 3056, 2922, 2855, 1721. mp = 107−109 °C.
1H NMR (400 MHz, Chloroform-d) δ 8.49 (s, 1H), 7.96 (s, 1H), 7.52−
7.43 (m, 2H), 7.25 (d, J = 8.1 Hz, 1H), 7.21−7.05 (m, 3H), 7.05−6.96
(m, 3H), 5.43 (s, 1H), 4.24−4.09 (m, 2H), 2.28 (s, 3H), 1.22 (t, J =
7.1 Hz, 3H). 13C{1H}NMR (100 MHz, Chloroform-d)δ 171.4, 135.2,
134.3, 129.1, 127.9, 125.2, 122.1, 121.5, 120.7, 119.0, 118.0, 117.8, 117.5,
111.6, 110.3, 109.8, 107.4, 60.6, 39.4, 13.2, 7.5. Exact mass calculated for
C21H21N2O2+ [M + H]+: 333.1598; found: 333.1609.
A dried vial equipped with a magnetic bar was charged with
N-methylaniline (100 mg, 0.933 mmol), 4-fluoroaniline (415 mg,
3.73 mmol), ethyl bromofluoroacetate (345 mg, 1.87 mmol), and
diisopropylethylamine (241 mg, 1.87 mmol). The reaction was performed
in a nitrogen atmosphere at 60 °C using DCE as solvent. After 18 h
(reaction completion checked by TLC), the reaction mixture was
poured into a separating funnel containing 50 mL of ethyl acetate/water
(1:1). The layers were separated, and the aqueous layer was extracted
with ethyl acetate (2 × 20 mL). All organic layers were combined, dried
over sodium sulfate, and concentrated in vacuo. The residue provided
F
DOI: 10.1021/acs.joc.5b02383
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Ethyl 2-(1H-Indol-3-yl)-2-(5-methoxy-1H-indol-3-yl)acetate
6.94 (s, 2H), 6.48 (s, 1H), 5.22 (s, 1H), 4.19−4.06 (m, 2H), 3.57
(br s, 2 H), 2.24 (s, 3H), 1.97 (s, 3H), 1.18 (t, J = 7.0 Hz, 3H).
13C{1H}NMR (100 MHz, Chloroform-d) δ 172.6, 141.6, 135.3, 133.7,
129.2, 126.4, 125.8, 122.5, 121.1, 119.5, 118.5, 117.9, 116.4, 113.3,
110.1, 59.9, 43.5, 18.3, 16.0, 13.2. Exact mass calculated for
(23).3e
+
C20H23N2O2 [M + H]+: 323.1754; found: 323.1765.
Ethyl 2-(4-Amino-3-fluorophenyl)-2-(1H-indol-3-yl)acetate (27).
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
5-methoxyindole (71 mg, 0.48 mmol) provided 24 after flash
chromatography (15−25% ethyl acetate in petroleum ether) as a
violet solid (109 mg, 98%). Rf = 0.2 (30% ethyl acetate in petroleum
ether). IR (neat): νmax/cm−1 3408, 3057, 2982, 2937, 2831, 1721.
mp = 54−57 °C. 1H NMR (400 MHz, Chloroform-d) δ 8.05 (s, 1H),
7.94 (s, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.20−
7.13 (m, 2H), 7.12−7.06 (m, 2H), 6.94 (dd, J = 14.5, 2.4 Hz, 2H),
6.84 (dd, J = 8.8, 2.4 Hz, 1H), 5.44 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H),
3.79 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (100 MHz,
Chloroform-d) δ 173.8, 154.1, 136.5, 131.6, 127.1, 126.8, 124.3, 123.6,
122.2, 119.6, 119.3, 113.5, 113.3, 112.4, 112.1, 111.4, 101.3, 61.3,
According to the general procedure II, 18 (100 mg, 0.33 mmol) and
2-fluoroaniline (53 mg, 0.5 mmol) provided 28 after flash chromatog-
raphy (15−25% ethyl acetate in petroleum ether) as a pink paste
(84 mg, 84%). Rf = 0.3 (30% ethyl acetate in petroleum ether). IR
(neat): νmax/cm−1 3384, 3057, 2981, 2926, 1721, 1636. 1H NMR
(400 MHz, Chloroform-d) δ 8.15 (s, 1H), 7.45 (d, J = 8.0 Hz, 1H),
7.34 (d, J = 8.2 Hz, 1H), 7.22−7.16 (m, 2H), 7.11−7.03 (m, 2H), 7.00
(dd, J = 8.1, 1.6 Hz, 1H), 6.73−6.66 (m, 1H), 5.13 (s, 1H), 4.22 (qd,
J = 7.2, 3.1 Hz, 2H), 3.67 (s, 2H), 1.27 (t, J = 7.1 Hz, 3H). 13C
{1H}NMR (100 MHz, Chloroform-d) δ 173.2, 151.65 (d, J = 239.0
Hz), 136.4,133.62 (d, J = 13.2 Hz), 129.50 (d, J = 6.2 Hz), 126.6,
124.5, 123.2, 122.4, 119.8, 119.1, 116.84 (d, J = 3.9 Hz), 115.47 (d, J =
19.6 Hz), 113.8, 111.4, 61.3, 48.1, 14.3. Exact mass calculated for
+
56.0, 40.8, 14.4. Exact mass calculated for C21H21N2O3 [M + H]+:
349.1547; found: 349.1550.
Ethyl 2,2-Di(1H-indol-3-yl)acetate (24).
+
C18H18FN2O2 [M + H]+:313.1347; found: 313.1350.
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
2-methylindole (63 mg, 0.48 mmol) provided 25 after flash chromato-
graphy (15−25% ethyl acetate in petroleum ether) as a red paste
(104 mg, 98%). Rf = 0.2 (30% ethyl acetate in petroleum ether). IR
(neat): νmax/cm−1 3402, 3056, 2981, 2933, 1720. 1H NMR (400 MHz,
Chloroform-d) δ 7.92 (s, 1H), 7.78 (s, 1H), 7.67 (d, J = 7.8 Hz, 1H),
7.42 (d, J = 7.7 Hz, 1H), 7.25−6.96 (m, 6H), 6.90 (d, J = 1.4 Hz, 1H),
5.40 (d, J = 1.3 Hz, 1H), 4.28−4.05 (m, 2H), 2.25 (s, 3H), 1.19 (t, J =
7.1 Hz, 3H). 13C{1H}NMR (100 MHz, Chloroform-d)δ 173.1, 136.1,
134.9, 132.6, 127.7, 126.7, 123.2, 121.7, 120.7, 119.5, 119.2, 119.1,
118.6, 113.2, 111.0, 110.1, 108.1, 60.8, 40.0, 14.0, 11.8.). Exact mass
Ethyl 2-(4-Amino-3-bromophenyl)-2-(1H-indol-3-yl)acetate (28).
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
2-bromoaniline (83 mg, 0.48 mmol) provided 29 after flash chromatog-
raphy (15−25% ethyl acetate in petroleum ether) as a red paste (83 mg,
50%). Rf = 0.3 (30% ethyl acetate in petroleum ether). IR (neat):
1
νmax/cm−1 3377, 3056, 2980, 2927, 1721, 1619. H NMR (400 MHz,
+
calculated for C21H21N2O2 [M + H]+: 333.1598; found: 333.1607.
Chloroform-d) δ 8.03 (s, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.37 (d, J =
7.9 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.18 (s, 1H), 7.12−7.06 (m, 2H),
7.00 (t, J = 7.5 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 5.02 (s, 1H),
4.13 (qd, J = 7.1, 4.1 Hz, 2H), 3.96 (s, 2H), 1.19 (t, J = 7.1 Hz, 3H).
13C{1H}NMR (100 MHz, Chloroform-d) δ 171.9, 142.1, 135.2,
131.2, 128.8, 127.4, 125.5, 122.0, 121.3, 118.7, 118.0, 114.6, 112.7,
Ethyl 2-(4-Aminophenyl)-2-(1H-indol-3-yl)acetate (25).3e
+
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
aniline (45 mg, 0.48 mmol) provided 26 after flash chromatography
(15−25% ethyl acetate in petroleum ether) as a brown solid (88 mg,
93%). Rf = 0.3 (30% ethyl acetate in petroleum ether). IR (neat):
νmax/cm−1 3410, 3062, 2980, 2924, 1720. mp = 147−149 °C. 1H NMR
(400 MHz, Chloroform-d) δ 8.15 (s, 1H), 7.44 (dq, J = 7.9, 1.0 Hz,
1H), 7.24 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.15−7.10 (m,
1H), 7.06−7.02 (m, 2H), 6.57 (d, J = 8.5 Hz, 2H), 5.14−5.08 (m,
1H), 4.25−4.10 (m, 2H), 3.56 (s, 2H), 1.23 (t, J = 7.1 Hz, 3H). 13C
{1H}NMR (100 MHz, Chloroform-d) δ 173.5, 145.4, 136.3, 129.3,
128.6, 126.6, 123.1, 122.1, 119.5, 119.1, 115.2, 114.2, 111.2, 61.0, 48.2,
110.2, 108.2, 60.1, 46.7, 13.2. Exact mass calculated for C18H18BrN2O2
[M + H]+: 373.0546; found: 373.0554.
Ethyl 2-(1H-Indol-3-yl)-2-(2,4,6-trimethoxyphenyl)acetate (29).
According to the general procedure II, 18 (100 mg, 0.33 mmol) and
1,3,5-trimethoxybenzene (81 mg, 0.5 mmol) provided 30 after flash
chromatography (15−25% ethyl acetate in petroleum ether) as a light
brown solid (110 mg, 93%). Rf = 0.3 (30% ethyl acetate in petroleum
ether). IR (neat): νmax/cm−1 3402, 2938, 2840, 1730, 1609, 1595.
+
14.2. Exact mass calculated for C18H19N2O2 [M + H]+: 295.1441;
found: 295.1448.
1
mp = 119−122 °C. H NMR (500 MHz, Chloroform-d) δ = 8.01 (s,
Ethyl 2-(4-Amino-2,5-dimethylphenyl)-2-(1H-indol-3-yl)acetate
(26).
1H), 7.72−7.67 (m, 1H), 7.29−7.24 (m, 1H), 7.14−7.08 (m, 2H),
7.00 (d, J = 2.0, 1H), 6.16 (s, 2H), 5.67 (s, 1H), 4.27 (dq, J = 10.8, 7.1,
1H), 4.14 (dq, J = 10.7, 7.1, 1H), 3.81−3.80 (m, 3H), 3.79 (s, 6H),
1.21 (t, J = 7.1, 3H). 13C{1H}NMR (100 MHz, Chloroform-d) δ
173.9, 160.2, 158.3, 136.0, 127.8, 123.7, 121.5, 119.5, 119.2, 113.8,
111.1, 110.6, 91.0, 60.7, 55.8, 55.4, 37.1, 14.5. Exact mass calculated for
+
C21H23NO5 [M]+: 369.1571; found: 369.1574.
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
2,5-dimethylaniline (58 mg, 0.48 mmol) provided 27 after flash
chromatography (15−25% ethyl acetate in petroleum ether) as a gray
paste (96 mg, 97%). Rf = 0.2 (30% ethyl acetate in petroleum ether).
Ethyl 2-(2,4-Dimethoxyphenyl)-2-(1H-indol-3-yl)acetate (30).
1
IR (neat): νmax/cm−1 3386, 2978, 2925, 1722, 1627, 1574. H NMR
(400 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.34 (d, J = 7.9 Hz, 1H),
7.25 (s, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H),
G
DOI: 10.1021/acs.joc.5b02383
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
1,3-dimethoxybenzne (66 mg, 0.48 mmol) provided 31 after flash
chromatography (15−25% ethyl acetate in petroleum ether) as a
yellowish paste (53 mg, 49%). Rf = 0.2 (30% ethyl acetate in
petroleum ether). IR (neat): νmax/cm−1 3407, 3058, 2927, 2824, 1720.
1H NMR (400 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.52 (d, J =
7.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.21−7.16 (m, 1H), 7.15 (s,
1H), 7.08 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.49 (d, J =
2.4 Hz, 1H), 6.35 (dd, J = 8.5, 2.4 Hz, 1H), 5.48 (s, 1H), 4.26−4.14
(m, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 1.24 (t, J = 7.1, 3H).
13C{1H}NMR (100 MHz, Chloroform-d) δ 173.7, 160.0, 157.9, 136.4,
129.8, 127.0, 123.3, 122.3, 120.2, 119.7, 119.6, 113.3, 111.2, 104.1,
122.9, 120.4, 119.8, 119.1, 111.6, 111.6, 109.6, 42.1. Exact mass
+
calculated for C20H13NaNO2 [M + Na]+:322.0838; found: 322.0845.
Ethyl 2-(4-Aminophenyl)-2-(4-(methylamino)phenyl)acetate
(34).3e
According to the general procedure III, 19 (100 mg, 0.33 mmol) and
aniline (46 mg, 0.5 mmol) provided 34 after flash chromatography
(15−25% ethyl acetate in petroleum ether) as a brown paste (80 mg,
85%). Rf = 0.3 (30% ethyl acetate in petroleum ether). IR (neat):
+
1
νmax/cm−1 3413, 3375, 2980, 2927, 2813, 1723. H NMR (400 MHz,
98.5, 60.9, 55.6, 55.4, 42.0, 14.4. Exact mass calculated for C20H22NO4
[M + H]+: 340.1543; found: 340.1544.
Chloroform-d) δ 7.09 (d, J = 19.9 Hz, 4H), 6.58 (dd, J = 25.1, 8.3 Hz,
4H), 4.79 (s, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.62 (s, 1H), 2.80 (s, 3H),
1.23 (t, J = 7.1 Hz, 3H) (NH protons not observed). 13C{1H}NMR
(100 MHz, Chloroform-d) δ 173.6, 148.4, 145.4, 129.6, 129.5, 129.4,
128.0, 115.2, 112.5, 60.9, 55.6, 30.9, 14.3. Exact mass calculated for
Ethyl 2-(1H-Indol-3-yl)-2-(1H-pyrrol-2-yl)acetate (31).
+
C17H21N2O2 [M + H]+: 285.1598; found: 285.1602.
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
pyrrole (32 mg, 0.48 mmol) provided 32 after flash chromatography
(15−25% ethyl acetate in petroleum ether) as a dark red paste (57 mg,
67%). Rf = 0.3 (30% ethyl acetate in petroleum ether). IR (neat):
νmax/cm−1 3405, 3057, 2980, 2923, 1721. 1H NMR (400 MHz,
Chloroform-d) δ 8.67 (s, 1H), 8.09 (s, 1H), 7.56 (d, J = 7.9 Hz, 1H),
7.36 (d, J = 8.1 Hz, 1H), 7.22−7.17 (m, 1H), 7.13−7.07 (m, 2H),
6.75−6.69 (m, 1H), 6.16 (t, J = 2.6 Hz, 2H), 5.32 (s, 1H), 4.22 (qd,
J = 7.1, 0.9 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13C{1H}NMR (100 MHz,
Chloroform-d) δ 171.6, 135.2, 126.7, 125.3, 121.8, 121.4, 118.9, 118.1,
116.4, 112.4, 110.2, 107.2, 106.0, 60.4, 41.2, 13.1. Exact mass calculated
for C16H17N2O2+ [M + H]+: 269.1285; found: 269.1298.
Ethyl 2-(4-Amino-2,5-dimethylphenyl)-2-(4-(methylamino)-
phenyl)acetate (35).
According to the general procedure III, 19 (100 mg, 0.33 mmol) and
2,5-diethylaniline (60 mg, 0.5 mmol) provided 35 after flash
chromatography (15−25% ethyl acetate in petroleum ether) as an
orange solid (89 mg, 86%). Rf = 0.3 (30% ethyl acetate in petroleum
ether). IR (neat): νmax/cm−1 3412, 3380, 2981, 2924, 1725. mp =
1
157−159 °C. H NMR (400 MHz, Chloroform-d) δ 7.04 (d, J =
Ethyl 2-(4-Hydroxynaphthalen-1-yl)-2-(1H-indol-3-yl)acetate
(32).
8.4 Hz, 2H), 6.91 (s, 1H), 6.54 (d, J = 8.6 Hz, 2H), 6.48 (s, 1H), 4.95
(s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.51 (s, 2H), 2.80 (s, 3H), 2.16 (s,
3H), 2.08 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H), (NH proton not
observed). 13C{1H}NMR (100 MHz, Chloroform-d) δ 174.0, 148.3,
143.4, 134.9, 130.2, 129.7, 127.9, 127.5, 120.0, 117.3, 112.5, 60.9,
+
52.4, 30.9, 19.5, 17.2, 14.3. Exact mass calculated for C19H25N2O2
[M + H]+: 313.1911; found: 313.1916.
Ethyl 2-(4-Amino-3-fluorophenyl)-2-(4-(methylamino)phenyl)-
acetate (36).
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
1-naphthol (70 mg, 480 μmol) provided 32 after flash chromatography
(15−25% ethyl acetate in petroleum ether) as a red paste (78 mg,
71%). Rf = 0.3 (30% ethyl acetate in petroleum ether). IR (neat):
νmax/cm−1 3414, 3059, 2980, 2843, 1711. 1H NMR (400 MHz,
Chloroform-d) δ 8.28−8.20 (m, 1H), 8.13 (dd, J = 7.9 Hz, 1.0, 1H),
8.10 (s, 1H), 7.57−7.38 (m, 3H), 7.36−7.29 (m, 1H), 7.22−7.11 (m,
2H), 7.09−6.99 (m, 2H), 6.48 (d, J = 7.9 Hz, 1H), 5.92 (s, 1H), 4.25
(qd, J = 7.1, 1.0 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H). 13C{1H}NMR
(100 MHz, Chloroform-d) δ 174.1, 151.3, 136.5, 132.8, 127.0, 126.9,
126.5, 126.5, 125.0, 125.0, 124.1, 123.3, 122.7, 122.4, 119.8, 119.2,
113.5, 111.4, 108.3, 61.5, 45.0, 14.3. Exact mass calculated for
According to the general procedure III, 19 (100 mg, 0.33 mmol) and
2-fluoroaniline (55 mg, 0.5 mmol) provided 36 after flash chromatog-
raphy (15−25% ethyl acetate in petroleum ether) as a yellow paste
(84 mg, 84%). Rf = 0.3 (30% ethyl acetate in petroleum ether). IR
(neat): νmax/cm−1 3379, 2981, 2922, 2851, 1726, 1636. 1H NMR
(400 MHz, Chloroform-d) δ 7.14−7.10 (m, 2H), 6.96 (dd, J = 12.2,
2.0 Hz, 1H), 6.89−6.83 (m, 1H), 6.69 (dd, J = 9.2, 8.1 Hz, 1H), 6.58
(d, J = 8.6 Hz, 2H), 4.78 (s, 1H), 4.18 (qd, J = 7.1, 0.8 Hz, 2H), 2.82
(s, 3H), 1.25 (t, J = 7.1 Hz, 3H), (NH protons not observed).
13C{1H}NMR (100 MHz, Chloroform-d) δ 173.2, 151.61 (d, J =
239.0 Hz), 148.3, 133.42 (d, J = 13.0 Hz), 130.40 (d, J = 6.2 Hz),
129.4, 127.8, 124.55 (d, J = 3.0 Hz), 116.81 (d, J = 3.8 Hz), 115.60 (d,
J = 19.7 Hz), 112.8, 61.1, 55.5, 31.0, 14.3. Exact mass calculated for
+
C22H20NO3 [M + H]+:346.1438; found: 346.1432.
1-(1H-Indol-3-yl)naphtho[2,1-b]furan-2(1H)-one (33).
+
C17H19FN2O2 [M]+: 302.1425; found: 302.1435.
According to the general procedure II, 18 (100 mg, 0.32 mmol) and
2-naphthol (70 mg, 480 μmol) provided 33 after flash chromatography
(15−25% ethyl acetate in petroleum ether) as a yellowish paste
(54 mg, 56%). Rf = 0.3 (30% ethyl acetate in petroleum ether). IR
(neat): νmax/cm−1 3410, 2956, 2924, 2854, 1798. 1H NMR (400 MHz,
Chloroform-d) δ = 8.19 (s, 1H), 7.91 (dd, J = 18.2, 8.4 Hz, 2H), 7.54
(d, J = 8.2 Hz, 1H), 7.46 (t, J = 8.5 Hz, 2H), 7.41−7.30 (m, 3H), 7.18
(t, J = 7.8 Hz, 1H), 7.06 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H),
5.49 (s, 1H). 13C{1H}NMR (100 MHz, Chloroform-d) δ 176.2, 151.8,
136.6, 131.1, 130.5, 129.7, 129.3, 127.5, 126.1, 124.9, 123.7, 123.4,
Ethyl 2-(4-Amino-3-bromophenyl)-2-(4-(methylamino)phenyl)-
acetate (37).
According to the general procedure III, 19 (100 mg, 0.33 mmol) and
2-bromoaniline (85 mg, 0.5 mmol) provided 37 after flash
H
DOI: 10.1021/acs.joc.5b02383
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The Journal of Organic Chemistry
Article
chromatography (15−25% ethyl acetate in petroleum ether) as a
brown paste (63 mg, 52%). Rf = 0.3 (30% ethyl acetate in petroleum
ether). IR (neat): νmax/cm−1 3376, 3413, 2980, 2928, 2901, 2813,
1725, 1615. 1H NMR (400 MHz, Chloroform-d) δ 7.34 (d, J = 2.0 Hz,
1H), 7.09 (d, J = 8.4 Hz, 2H), 7.04 (dd, J = 8.2, 2.0 Hz, 1H), 6.68
(d, J = 8.3 Hz, 1H), 6.55 (d, J = 8.6 Hz, 2H), 4.74 (s, 1H), 4.17 (q, J =
7.1 Hz, 2H), 4.01 (s, 2H), 2.80 (s, 4H), 1.23 (t, J = 6.8 Hz, 3H).
13C{1H}NMR (100 MHz, Chloroform-d) δ 173.2, 148.6, 143.1, 132.5,
130.9, 129.4, 128.7, 127.4, 115.8, 112.6, 109.3, 61.2, 55.2, 30.9, 14.3.
Ethyl 2-(4-(Methylamino)phenyl)-2-(2,4,6-trimethoxyphenyl)-
acetate (41).
According to the general procedure III, 19 (100 mg, 0.33 mmol) and
N-methylaniline (83 mg, 0.5 mmol) provided 41 after flash chromatog-
raphy (15−25% ethyl acetate in petroleum ether) as an orange solid
(96 mg, 81%). Rf = 0.3 (30% ethyl acetate in petroleum ether). IR
+
Exact mass calculated for C17H19BrN2O2 [M]+: 362.0624; found:
362.0634.
1
(neat): νmax/cm−1 3406, 2935, 2839, 1735. mp = 163−165 °C. H
Ethyl 2-(Indolin-5-yl)-2-(4-(methylamino)phenyl)acetate (38).
NMR (400 MHz, Chloroform-d) δ 7.14 (d, J = 8.5 Hz, 2H), 6.56−6.48
(m, 2H), 6.14 (d, J = 0.7 Hz, 2H), 5.19 (s, 1H), 4.27−4.07 (m, 2H),
3.80 (s, 3H), 3.77 (s, 6H), 2.78 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H) (NH
proton not observed). 13C {1H}NMR (100 MHz, Chloroform-d) δ
174.4, 160.2, 158.2, 148.1, 130.1, 128.1, 112.3, 110.5, 91.0, 60.6, 55.8,
55.4, 45.2, 14.5. Exact mass calculated for C20H25NO5+ [M]+: 359.1727;
found: 359.1736.
According to the general procedure III, 19 (100 mg, 0.33 mmol) and
indoline (59 mg, 0.5 mmol) provided 38 after flash chromatography
(15−25% ethyl acetate in petroleum ether) as a red paste (82 mg,
80%). Rf = 0.3 (30% ethyl acetate in petroleum ether). IR (neat):
Ethyl 2-(4-(Methylamino)phenyl)-2-(1H-pyrrol-2-yl)acetate (42).
1
νmax/cm−1 3409, 3384, 2978, 2925, 2853, 1727. H NMR (400 MHz,
Chloroform-d) δ 7.12 (d, J = 8.5 Hz, 2H), 7.05 (s, 1H), 6.93 (d, J =
8.0 Hz, 1H), 6.55 (dd, J = 8.3, 1.8 Hz, 3H), 4.79 (s, 1H), 4.17 (q, J =
7.1 Hz, 2H), 3.51 (t, J = 8.3 Hz, 2H), 2.97 (t, J = 8.3 Hz, 2H),
2.80 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H) (NH proton not observed).
13C{1H}NMR (100 MHz, Chloroform-d) δ 173.8, 150.7, 148.4,
130.0, 129.9, 129.4, 128.3, 127.5, 124.9, 112.5, 109.3, 60.9, 55.9, 47.6,
According to the general procedure III, 19 (100 mg, 0.33 mmol) and
pyrrole (33 mg, 0.5 mmol) provided 42 after flash chromatography
(15−25% ethyl acetate in petroleum ether) as a dark red paste (56 mg,
66%). Rf = 0.3 (30% ethyl acetate in petroleum ether). IR (neat):
νmax/cm−1 3408, 2981, 2923, 2896, 1723. 1H NMR (500 MHz,
Chloroform-d) δ 8.77 (s, 1H), 7.08 (d, J = 8.5 Hz, 2H), 6.74 (q, J =
2.6 Hz, 1H), 6.55 (d, J = 8.6 Hz, 2H), 6.15 (q, J = 2.8 Hz, 1H),
6.03 (d, J = 3.5 Hz, 1H), 4.94 (s, 1H), 4.19 (qd, J = 7.1, 2.5 Hz, 2H),
2.81 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H) (NH proton not observed).
13C{1H}NMR (100 MHz, Chloroform-d) δ 173.1, 148.7, 128.8, 128.5,
127.1, 117.6, 112.6, 108.4, 107.3, 61.4, 49.4, 30.9, 14.3. Exact mass
+
30.9, 30.0, 14.3. Exact mass calculated for C19H23N2O2 [M + H]+:
311.1754; found: 311.1764.
Ethyl 2-(4-(Benzylamino)phenyl)-2-(4-(methylamino)phenyl)-
acetate (39).
+
calculated for C15H18N2O2 [M]+: 258.1363; found: 258.1355.
Ethyl 2-(1-Methyl-1H-indol-3-yl)-2-(4-(prop-2-ynylamino)-
phenyl)acetate (43).
According to the general procedure III, 19 (100 mg, 0.33 mmol) and
N-benzylaniline (60 mg, 0.5 mmol) provided 39 after flash chromatog-
raphy (15−25% ethyl acetate in petroleum ether) as a brown paste
(94 mg, 76%). Rf = 0.3 (30% ethyl acetate in petroleum ether). IR
(neat): νmax/cm−1 3414, 3025, 2980, 2926, 2900, 2813, 1725, 1614,
1519. 1H NMR (400 MHz, Chloroform-d) δ 7.37−7.27 (m, 5H), 7.12
(dd, J = 8.6, 7.0 Hz, 4H), 6.60−6.54 (m, 4H), 4.80 (s, 1H), 4.30 (s,
2H), 4.18 (q, J = 7.1 Hz, 2H), 2.81 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H)
(NH protons not observed). 13C{1H}NMR (100 MHz, Chloroform-d)
δ 173.7, 148.4, 147.2, 139.6, 129.5, 129.4, 128.7, 128.6, 128.2, 127.6,
127.3, 112.9, 112.5, 60.9, 55.6, 48.5, 30.9, 14.3. Exact mass calculated
According to the general procedure IV, N-methylindole (100 mg,
0.762 mmol) and N-propargylaniline (150 mg, 1.14 mmol) provided
43 after flash chromatography (15−25% ethyl acetate in petroleum
ether) as a yellow paste (194 mg, 73%). Rf = 0.3 (20% ethyl acetate in
petroleum ether). IR (neat): νmax/cm−1 3394, 3283, 3052, 2980, 2934,
1728, 1614. 1H NMR (400 MHz, Chloroform-d) δ 7.52 (d, J = 8.0 Hz,
1H), 7.35−7.28 (m, 3H), 7.25 (d, J = 5.5 Hz, 1H), 7.15−7.05 (m,
2H), 6.66 (d, J = 8.5 Hz, 2H), 5.19 (s, 1H), 4.31−4.17 (m, 2H), 3.91
(d, J = 2.2 Hz, 2H), 3.74 (s, 3H), 2.24 (t, J = 1.78 Hz, 1H), 1.30 (t, J =
7.1 Hz, 3H) (NH proton not observed). 13C{1H}NMR (125 MHz,
Chloroform-d) δ 173.5, 146.0, 137.1, 129.3, 128.8, 127.9, 127.2, 121.8,
119.2, 119.1, 113.5, 112.8, 109.3, 81.1, 71.4, 61.0, 48.2, 33.7, 32.7,
+
for C24H26N2O2 [M]+: 374.1989; found: 374.1985.
Ethyl 2-(4-(Methylamino)phenyl)-2-(4-(prop-2-ynylamino)-
phenyl)acetate (40).
+
14.3. Exact mass calculated for C22H22N2O2 [M]+: 346.1676; found:
346.1681.
According to the general procedure III, 19 (100 mg, 0.33 mmol)
and N-propargylaniline (65 mg, 0.5 mmol) provided 40 after flash
chromatography (15−25% ethyl acetate in petroleum ether) as a
yellow paste (92 mg, 86%). Rf = 0.3 (30% ethyl acetate in petroleum
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02383.
■
S
1
ether). IR (neat): νmax/cm−1 3409, 3283, 2923, 1725, 1614, 1519. H
NMR (400 MHz, Chloroform-d) δ 7.17−7.11 (m, 4H), 6.63 (d, J =
8.5 Hz, 2H), 6.56 (d, J = 8.6 Hz, 2H), 4.81 (s, 1H), 4.18 (q, J = 7.1 Hz,
2H), 3.91 (d, J = 2.4 Hz, 2H), 2.81 (s, 3H), 2.21 (t, J = 2.3 Hz, 1H),
1.24 (t, J = 7.1 Hz, 3H) (NH proton not observed. 13C{1H}NMR
(100 MHz, Chloroform-d) δ 173.6, 148.4, 145.9, 129.7, 129.5, 129.4,
128.1, 113.6, 112.5, 81.2, 71.4, 61.0, 55.7, 33.8, 30.9, 14.3. Exact mass
1H and 13C spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: anands@iitk.ac.in.
■
+
calculated for C20H22N2O2 [M]+: 322.1676; found: 322.1685.
I
DOI: 10.1021/acs.joc.5b02383
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The Journal of Organic Chemistry
Article
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.S. gratefully acknowledges funding from IIT Kanpur (IITK/
CHM/20130024) and BRNS (BRNS/CHM/2014118). S.D.J.
thanks CSIR, India, for a research fellowship. A.S. thanks Prof.
Vinod K. Singh for the use of his laboratory during the
execution of this work.
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DOI: 10.1021/acs.joc.5b02383
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