Temperature-gradient-directed NMR monitoring of a [3 + 3]-cyclocondensation reaction between alkynone and ethyl 2-amino-1 H-indole-3-carboxylate toward the synthesis of pyrimido[1,2-a]indole catalyzed by Cs2CO3

Article abstract of DOI:10.1080/00397911.2012.687423

We describe a NMR strategy to resolve temperature-gradient-monitored real-time chemical reaction involving a [3 + 3]-cyclocondensation reaction between alkynone and ethyl 2-amino-1H-indole-3-carboxylate toward the synthesis of pyrimido[1,2-a]indole cataly

Full text of DOI:10.1080/00397911.2012.687423

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Temperature-Gradient-Directed
NMR Monitoring of a [3 + 3]-
Cyclocondensation Reaction Between
Alkynone and Ethyl 2-Amino-1H-
indole-3-carboxylate Toward the
Synthesis of Pyrimido[1,2-a]indole
Catalyzed by Cs2CO3
Harsh M. Gauniyal a , Sahaj Gupta b , Sudhir K. Sharma b & Usha
Bajpai c
a Sopisticated Analytical Instrument Facility, Central Drug Research
Institute, CSIR, Lucknow, India
b Medicinal and Process Chemistry Division, Central Drug Research
Institute, CSIR, Lucknow, India
c Department of Physics, University of Lucknow, Lucknow, India
Accepted author version posted online: 22 Jan 2013.Published
online: 28 Apr 2013.
To cite this article: Harsh M. Gauniyal , Sahaj Gupta , Sudhir K. Sharma & Usha Bajpai (2013):
Temperature-Gradient-Directed NMR Monitoring of a [3 + 3]-Cyclocondensation Reaction Between
Alkynone and Ethyl 2-Amino-1H-indole-3-carboxylate Toward the Synthesis of Pyrimido[1,2-a]indole
Catalyzed by Cs2CO3 , Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 43:15, 2090-2099
To link to this article: http://dx.doi.org/10.1080/00397911.2012.687423
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Synthetic Communications1, 43: 2090–2099, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.687423
TEMPERATURE-GRADIENT-DIRECTED NMR
MONITORING OF A [3 þ 3]-CYCLOCONDENSATION
REACTION BETWEEN ALKYNONE AND ETHYL
2-AMINO-1H-INDOLE-3-CARBOXYLATE TOWARD THE
SYNTHESIS OF PYRIMIDO[1,2-a]INDOLE CATALYZED
BY Cs2CO3
Harsh M. Gauniyal,1 Sahaj Gupta,2 Sudhir K. Sharma,2 and
Usha Bajpai3
1Sopisticated Analytical Instrument Facility, Central Drug Research
Institute, CSIR, Lucknow, India
2Medicinal and Process Chemistry Division, Central Drug Research Institute,
CSIR, Lucknow, India
3Department of Physics, University of Lucknow, Lucknow, India
GRAPHICAL ABSTRACT
Abstract We describe a NMR strategy to resolve temperature-gradient-monitored real-time
chemical reaction involving a [3 þ 3]-cyclocondensation reaction between alkynone and
ethyl 2-amino-1H-indole-3-carboxylate toward the synthesis of pyrimido[1,2-a]indole cat-
alyzed by Cs2CO3. The in situ NMR study clearly indicates that the reactant undergoes
[3 þ 3]-cyclocondensation reaction through a concerted mechanism, resulting in the pro-
duct formation. The detailed NMR spectroscopic data led to the optimization of the reac-
tion conditions and quantitative analysis of the product accurately and efficiently.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Alkynone; cyclocondensation; heterogenous catalyst; 1H NMR; HR-MAS;
magic angle; nucleophile
Received March 2, 2012.
CDRI Communication No. 8227.
Address correspondence to Harsh M. Gauniyal, Sophisticated Analytical Instrument Facility,
Central Drug Research Institute, CSIR, Chattar Manzil Palace, Lucknow 226001, India. E-mail:
hmgnmr@gmail.com
2090

SYNTHESIS OF PYRIMIDO[1,2-a]INDOLE
2091
INTRODUCTION
Nuclear magnetic resonance (NMR) has evolved into a nondestructive and
enlightening technique in different fields of natural sciences[1] such as biochemistry,[2]
biology,[3] medicine,[4] and all branches of chemistry.[5] The beauty of NMR over
other spectroscopic techniques is its noninvasive=nonoptical sampling and the wide
variety of experiments made possible by an almost unlimited choice of radio-
frequency pulse sequences that may be used for observing nuclear spin.[6] NMR spec-
troscopy, being noninvasive in nature, is one of the best techniques for monitoring
chemical and enzymatic reactions.[7] At high magnetic fields, there is usually enough
frequency resolution to follow the fate of each molecular species, even if they have
closely related or isomeric structures.[8] Moreover, the linear correlation between res-
onance intensity and molar quantity of each component of the reaction makes mea-
suring the time course of enzyme-catalyzed conversions relatively simple.[9] The
major problem associated with the use of solution-phase NMR technique for
real-time heterogeneous reactions is the peak broadening. The chemical shift ani-
sotropy is created during the experiment by the presence of solid catalytic material.
In nuclear magnetic resonance, magic angle spinning (MAS) is a technique
often used to perform experiments in solid-state NMR spectroscopy.[10] High-resolu-
tion–magic angle spinning nuclear magnetic resonance (HR-MAS NMR) allows the
application of solution-state NMR experiments to samples that are not fully soluble
and contain solids.[11] It allows the analysis of materials that swell, become partially
soluble, or form true solutions in a solvent even when some solids are still present.[12]
In an HR-MAS experiment, a heterogeneous or multiphase sample is spun at a high
speed (typically 3–5 kHz) around an axis oriented at an angle of 54.7ꢀ magic angle
with respect to the direction of the static magnetic field. Because of the presence
of solid heterogeneous catalyst Cs2CO3, this reaction optimization is also carried
out by HR-MAS NMR.
Keeping this in our mind, and because of continuation of our interest in the
synthesis of indole-based polycycles of biological interest,[13] we herein report mon-
itoring=synthesis of a [3 þ 3]-cyclocondensation reaction by temperature gradient
NMR measurements in an NMR probe in solution state as well as in HR-MAS
mode. To the best of our knowledge, such a study has not been performed. For this
purpose, bifunctional nucleophile (NaH and NbH2), 2-amino-1H-indole-3-carboxyl-
ate 1, and bifuctional 3-carbon building block alkynones 2 catalyzed by solid
Cs2CO3 were selected to furnish a pyrimidine ring annulated to the indole, a privilege
class molecule. In this study, solid heterogeneous catalyst Cs2CO3 does not hamper
the analysis in liquid-phase NMR even with temperature and spinning. The material
does not swell and the catalyst remains below the RF coil. NMR of liquid is easier
because an internal molecular motion already eliminates effects of the chemical shift
anisotropy and magnetic dipole–dipole interactions.
RESULTS AND DISCUSSION
The reaction was initially standardized by refluxing the ethyl 2-amino-1H-
indole-3-carboxylates 1 (100 mg, 0.423 mmol) and 1-(4-methoxyphenyl)-3-phenyl-
prop-2-yn-1-one 2 (86 mg, 0.423 mmol) in the presence of Cs2CO3 as the base

2092
H. M. GAUNIYAL ET AL.
(210 mg, 0.635 mmol) in 5 ml of acetonitrile. It showed complete conversion of the
starting material on thin-layer chromatography (TLC) after 6 h (Scheme 1). The
crude reaction mixture was extracted with ethyl acetate (3 ꢁ 10 mL). The combined
organic extracts were washed with brine, dried over anhydrous sodium sulfate, and
evaporated under reduced pressure in vacuo. The crude reaction mixture was puri-
fied by column chromatography on 60 to 120-mesh silica using EtOAc=hexane
(1:19) as eluent to afford ethyl 2-(4-methoxyphenyl)-4-phenyl-pyrimido[1, 2-a]-
indole-10-carboxylate 3 in 80% quantitative isolated yield and 93% purity based
on high-performance liquid chromatography (HPLC). No traces of the starting
material or any other by products were detected. The isolated compound was
characterized by using NMR spectroscopy in CDCl3 and details are given in the
Supplemental material, available online.
The reaction was carried out in CH3CN at reflux in the conventional method,
so in the NMR tube CD3CN was used as reaction medium. On the basis of NMR
spectra in CD3CN of two starting materials and the final product obtained after
purification, we conclude that the disappearance of signals NaH and NbH2 at 8.92
and 6.03 ppm in 2-amino-1H-indole-3-carboxylates 1, the slight shifting of two
doublets of p-methoxy substituted aryl ring of 1-(4-methoxyphenyl)-3-phenylprop-2-
yn-1-one 2 towards downfield from 7.08, 8.18 to 7.10, 8.36 respectively, and the
appearance of signal at 7.29 singlet of the pyrimidine ring clearly indicate the forma-
tion of 2-(4-methoxyphenyl)-4-phenyl-pyrimido[1,2-a]indole-10-carboxylate 3.[14]
To get an insight into the mechanism of this pyrimido[1,2-a]indole formation,
the reaction was monitored by real-time NMR measurements in an NMR probe
using 600 ml of the total reaction mixture under stoichiometric conditions
(0.021 mmol of 1, 0.021 mmol 2, and 0.0318 mmol of base) in deuterated acetonitrile
(CD3CN). The recording of the NMR spectra were carried out as soon as the
shimming and temperature of the mixture were maintained. From NMR studies it
was found that no reaction occurred when where 1 and 2 mixed together in the
absence of a base. The starting materials were retained as such even after increasing
the temperature from 303 to 328 K (Fig. 1). Then, in a NMR tube, Cs2CO3 was
added to a solution of 1 and 2 in deuterated acetonitrile, and the reaction started
slowly as the NMR peaks of starting materials were diminished while the new peaks
started to form in trace amounts at 303 K. The NaH and NbH2 of 1 disappeared
immediately and appearance of product 3 started slowly without the formation of
other intermediates at different temperature ranges. Monitoring of the reaction con-
tinued and we observed the complete conversion of starting materials 1 and 2 into
Scheme 1. Synthesis of 2-(4-methoxyphenyl)-4-phenyl-pyrimido[1,2-a]indole-10-carboxylate (3) from
2-amino-1H-indole-3-carboxylates (1) and 1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-one (2). Reaction
conditions: (I) Cs2CO3=CH3CN, reflux, 6 h, or Cs2CO3=CD3CN in NMR probe at 348 K.

SYNTHESIS OF PYRIMIDO[1,2-a]INDOLE
2093
Figure 1. Stack plot of NMR resonances with different temperatures in the reaction mixture prior to the
addition of the catalyst.
the product 3 within 45 min. Further we extended the reaction time up to 1 h 10 min
as shown in Fig. 2.
The absence of the formation of other intermediates during the completion
of reaction in NMR studies clearly indicated that the [3 þ 3]-cyclocondensation
reaction undergoes a concerted mechanism (Scheme 2).
The mechanism was further supported by monitoring the reaction with
HR-MAS probe real-time NMR measurements using 50 ml of the total reaction
mixture in deuterated acetonitrile (CD3CN) under the same stoichiometric
conditions in a 5-mm NMR tube, and the recording of the HR-MAS NMR
spectra was carried out as soon as the spinning speed was achieved (4.0 kHz) with
slight shimming in the z axis. Temperature range for monitoring the reaction

2094
H. M. GAUNIYAL ET AL.
Figure 2. Stack plot of NMR resonances with different temperatures in the reaction mixture after addition
of the catalyst.
was kept from 300 to 350 K. At 338 K, the time elasped is 45 min and this is the
point for major product formation. After this point, product formation remains
constant (Fig. 3).
Scheme 2. Concerted mechanism for the synthesis of 2-(4-methoxyphenyl)-4-phenyl-pyrimido[1,2-a]indole-
10-carboxylate (3) via [3þ 3]-cyclocondensation reaction.

SYNTHESIS OF PYRIMIDO[1,2-a]INDOLE
2095
Figure 3. Stack plot of NMR resonances in HR-MAS probe with different temperatures in the reaction
mixture after addition of the catalyst.
Figure 4. Complete reaction chart of integration vs. temperature. (Figure is provided in color online.)

2096
H. M. GAUNIYAL ET AL.
The product formation started at 338 K as indicated by the variation in the
integral area (Fig. 4). After increasing to 348 K, there was no variation in the integral
area, which indicates that the reaction was completed at 338 K (optimum tempera-
ture) as shown in integration vs. temp chart (Fig. 4).
CONCLUSION
In summary, we have shown that the completion of the reaction using hetero-
geneous catalysis could be monitored using temperature-gradient real-time NMR
spectroscopy. The reaction completion time and volume used are much shorter.
Also, as no intermediate formation is observed in the 1H NMR, we believe that reac-
tion is achieved through concerted [3 þ 3]-cyclocondensation mechanism.
EXPERIMENTAL
All the products were characterized by 1H, 13C, DEPT90, DEPT135, two-
dimensional heteronuclear single quantum coherence (HSQC), and heteronuclear
multiple bond correlation (HMBC) spectroscopy. All the chemicals used in the study
were purchased from Sigma Aldrich. The NMR spectra were recorded at room tem-
perature as well as in different temperature ranges required for the completion of
the reaction using Bruker Avance 400-MHz and Avance 300-MHz FT-NMR spectro-
meters equipped with a 5-mm multinuclear inverse, HRMAS probe, and QNP probe
head with z-shielded gradient. Chemical shifts are given on the parts per million (ppm)
scale and are referenced to tetramethylsilane (TMS) at 0.00 ppm for protons and for
13C NMR spectra. Spectra recorded in CD3CN solvent peak at 1.94, was taken as,
a reference. In the one-dimensional measurements (1H, 13C, and DEPT) 32 K data
points were used for the flame ionization detector (FID). The pulse programs of the
following 2D experiments were taken from the Bruker software library and the para-
meters were as follows: 300=75 MHz gradient HSQC spectra: relaxation delay d1 ¼ 2s;
1
evolution delay d2 ¼ 3.44 ms; 90ꢀ pulse, 6.85 ms for H, 10 ms for 13C hard pulses at
ꢂ3.0 dB and 60 ms for 13C globally optimized alternating phases of rectangular pulses
(GARP) decoupling with gradient ratio GPZ1–GPZ2–GPZ3 ¼ 50:30:40.1; 1024 data
points in t2; spectral width 9.0 ppm in F2 and 160 ppm in F1; number of scans 32;
256 experiments in t1; linear prediction to 512; zero filling up to 1 K and apodization
with sine bell in both dimensions prior to double Fourier transformation; 300=75 MHz
gradient HMBC spectra: relaxation delay d1 ¼ 2 s; delay of the low-pass J-filter
d2 ¼ 3.44 ms; delay for evolution of long-range coupling d6 ¼ 71 ms with gradient ratio
same as HSQC; 2048 data points in t2; spectral width 11.0 ppm in F2 and 240 ppm in
F1; number of scans 52; 256 experiments in t1; linear prediction to 512; zero filling up
to 2 K and apodization with 90ꢀ shifted square sine bell in F1 dimension and sine bell
in F2 dimension prior to double Fourier transformation.
Procedure for the Synthesis of 2-(4-Methoxyphenyl)-
4-phenyl-pyrimido[1,2-a]indole-10-carboxylate 3
Ethyl 2-amino-1H-indole-3-carboxylate (1.0 equiv, 1), 1-(4-methoxyphenyl)-
3-phenylprop-2-yn-1-one (1.0 equiv, 2), and Cs2CO3 (1.5 equiv) were mixed in

SYNTHESIS OF PYRIMIDO[1,2-a]INDOLE
2097
acetonitrile and refluxed for 6 h. The progress of reaction was monitored by TLC
and HPLC. After completion, the crude reaction mixture was extracted with ethyl
acetate (3 ꢁ 10 mL). The combined organic extracts were washed with brine, dried
over anhydrous sodium sulfate, and evaporated under reduced pressure in vacuo.
The crude reaction mixture was purified by column chromatography on 60 to
120-mesh silica using EtOAc=hexane (1:19) as eluent to afford 3.
2-(4-Methoxyphenyl)-4-phenyl-pyrimido[1,2-a]indole-10-carboxylate (3)
Yield ¼ 0.102 g (70%), orange solid, mp 138–140 ꢀC, Rf ¼ 0.43 (1:10 EtOAc–
hexane); IR (KBr) nmax, 3350, 2906, 2357, 1725, 1617, 1010 cmꢂ1 1H NMR
;
(300 MHz, CD3CN) d ¼ 8.46 (1H, d, J ¼ 8.1 Hz, ArH), 8.36 (2H, d, J ¼ 8.7 Hz,
ArH), 7.76–7.59 (5H, m, ArH), 7.40 (1H, t, J ¼ 7.8 Hz, ArH), 7.30 (1H, s, ArH),
7.10 (2H, d, J ¼ 8.7 Hz, ArH), 6.95 (1H, t, J ¼ 7.8 Hz, ArH), 6.48 (1H, d, J ¼ 8.7 Hz,
Hz, ArH), 4.47 (2H, q, J ¼ 6.9 Hz, OCH2), 3.90 (3H, s, OCH3), 1.53 (3H, t,
J ¼ 6.9 Hz, CH3); 13C NMR (75 MHz, CD3CN) d ¼ 162.5, 148.9, 133.9, 130.7,
130.5, 129.4, 129.2, 128.5, 128.2, 124.9, 121.2, 120.9, 114.9, 114.4, 105.2, 59.1,
55.3, 14.1 ppm; mass (ESþ) m=z 422.9 (Mþ þ 1). Anal. calcd. for C27H22N2O3: C,
76.76; H, 5.25; N, 6.63. Found: C, 76.75; H, 5.24; N, 6.65.
1
General Procedure for the H NMR Analysis
To a solution of 2-amino-1H-indole-3-carboxylates (0.021 mmol) and 1-(4-
methoxyphenyl)-3-phenylprop-2-yn-1-one (0.021 mmol) in 0.6 ml acetonitrile-d3,
Cs2CO3 (0.0318 mmol) was added in a 5-mm NMR tube spinning the sample at
20 Hz throughout the experiment, and after each temperature increment shimming
of the compound was carried out.
1
General Procedure for the H HR-MAS NMR Analysis
Cs2CO3 (0.0318 mmol) was added to a solution of 2-amino-1H-indole-3-
carboxylates (0.021 mmol) and 1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-one
(0.021 mmol) in deuterated acetonitrile (40 ml) in a 50-ml 4-mm HR-MAS rotor,
and the rotor was sealed by spacer and screw cap. The HR-MAS rotor was then
1
directly inserted in the shimmed and tuned 4-mm H=13C HR-MAS dual probe.
As soon as the spinning speed (4.0 kHz) was achieved, recording of the NMR data
was carried out in a temperature range from 300 to 348 K.
ACKNOWLEDGMENT
S. G. and S. K. S. are thankful to the Council for Scientific and Industrial
Research, New Delhi, for providing a fellowship.
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