Reaction pathway of POCl3-mediated Knoevenagel condensation of bisulfite adducts with 2,4-thiazolidinedione

Article abstract of DOI:10.1080/10426507.2015.1073277

We investigated the POCl₃-mediated transformation of aromatic bisulfite adducts to the corresponding 5- arylidenethiazolidine-2,4-diones. The in situ transformation of an aromatic bisulfite adduct to the parent aldehyde in a non-aqueous non-pol

Full text of DOI:10.1080/10426507.2015.1073277

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Reaction Pathway of POCl3-Mediated Knoevenagel
Condensation of Bisulfite Adducts with 2,4-
Thiazolidinedione
Sandeep Mohanty, Amrendra Kumar Roy, Sandeep Reddy, Vinay Kumar
Kuchipudi Pavithran & Arun Chandra Karmakar
To cite this article: Sandeep Mohanty, Amrendra Kumar Roy, Sandeep Reddy, Vinay Kumar
Kuchipudi Pavithran & Arun Chandra Karmakar (2015): Reaction Pathway of POCl3-Mediated
Knoevenagel Condensation of Bisulfite Adducts with 2,4-Thiazolidinedione, Phosphorus, Sulfur,
and Silicon and the Related Elements, DOI: 10.1080/10426507.2015.1073277
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1073277
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Sep 2015.
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Reaction Pathway of POCl3-Mediated Knoevenagel Condensation of Bisulfite Adducts with 2,4-
Thiazolidinedione
Sandeep Mohanty,a* Amrendra Kumar Roy,a Sandeep Reddy,a Kuchipudi Pavithran Vinay
Kumar,a Arun Chandra Karmakar.b
aDr. Reddy‟s Laboratories Limited, Process Research and Development, API Plant, Bollaram-III,
Plot No‟s 116, 126C, Survey No.157, S.V. Co-operative Industrial Estate, IDA Bollaram,
Jinnaram Mandal, Medak District, Hyderabad 502325, Andhra Pradesh, India.
bShasun Pharmaceuticals Limited, Shasun Road, Periya Kalapet, Pondicherry 605014, India.
*E-Mail ID: sandeepmohonty@drreddys.com, Tel. No.: +91 9989997191, Fax. No.: +91 8458
279619.
Abstract:
We investigated the POCl3-mediated transformation of aromatic bisulfite adducts to the
corresponding 5-arylidenethiazolidine-2,4-diones. The in situ transformation of an aromatic
bisulfite adduct to the parent aldehyde in a non-aqueous non-polar solvent (toluene) was
demonstrated using DoE (Design of experiment), off-line 1H NMR, on-line ReactIR, HPLC, LC-
MS, and GC-MS. By means of these analytical tools, we determined, for the first time, the
structure of the intermediate species (aldehyde) prior to the carbon–carbon double bond
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formation. The carbon–sulfur bond undergoes a fast cleavage, immediately after the addition of
POCl3, which finally affords the corresponding 5-arylidenethiazolidine-2,4-diones.
Keywords:
Knoevenagel condensation, Statistical design of experiment, 1H NMR, ReactIR, LC-MS
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Introduction
5-Benzylidenes with a thiazolidine-2,4-dione ring system, form the core chemical structures of
many pharmacologically1 and biologically active compounds in medicinal chemistry.2 These
compounds are synthesized via the Doebner modification of the Knoevenagel condensation
reaction. 3 In general, Knoevenagel reactions4 are carried out in the presence of weak bases; acid-
catalyzed Knoevenagel reactions are rare. Recently, significant progress has been made in the
heterogeneous Knoevenagel condensation using various modified catalysts.5 Most studies use
aldehydes as the starting materials. However, aldehydes are sensitive to oxygen, light, and
moisture, and are known to readily polymerize and decompose during storage. 6 The conversion
of aldehydes to the corresponding crystalline bisulfite adducts provides significant stability to the
parent aldehyde,7,8 and facilitates their use in the purification of aldehydes.9 In contrast to the
numerous coupling reactions between aldehydes and active methylene groups, the bisulfite
adducts of aldehydes have rarely been used for direct carbon–carbon bond formation
reactions.10,11 Recently, Khosropour et al., 12 reported the direct coupling of bisulfite adducts to
azlactones using POCl3 to facilitate carbon–carbon bond formation in polar solvents such as
acetonitrile. After screening various reagents, they found that reactions with POCl3 (2.0 mmol)
afforded the best result (86% yield), but the authors also reported that bisulfite adducts are stable
in POCl3. Encouraged by this work we further explored this concept for the synthesis of a small
library of 5-arylidenethiazolidine-2,4-diones from bisulfite adducts of different aromatic
aldehydes (with EWG and EDG) as shown in Scheme 1.13 Our results showed that conversions
in aprotic solvents are low, and that POCl3 worked more efficiently in non-polar solvents such as
toluene. We suggested that the reaction of aromatic bisulfite adducts with thiazolidine-2,4-dione
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3 would first involve the activation of the hydroxyl group of compound 2 by POCl3 to afford
intermediate 4, followed by the coupling of thiazolidine-2,4-dione 3 to give intermediate 5 and,
finally, to afford 5-arylidene-2,4-thiazolidinedione 6 (Scheme 1). In the aforementioned
publication14 we also proposed a plausible pathway for the formation of 6 from the bisulfite
adduct 2 of an aromatic aldehyde 1 with two labile intermediates (Scheme 1; 4 and 5). To the
best of our knowledge, this type of transformation from 2 to 6 with POCl3 ours was the first
report. The mechanism was not well understood and therefore in order to provide a deeper
understanding of the reaction pathway, we again re-examined the reaction and the intermediates.
Herein, we report our preliminary results on this subject.
Results and Discussion:
In order to provide a deeper understanding of the reaction pathway, we re-examined the reaction
and the intermediates with HPLC (High-performance liquid chromatography). A model
condensation reaction between a bisulfite adduct 2 and 2,4-thiazolidinedione 3 was selected for
this investigation (Scheme 1). We first monitored the reaction mass with HPLC at regular time
intervals. Relative retention time (RRT) of bisulfite adduct 2, thiazolidine-2,4-dione 3, and of
product 6 was determined by HPLC co-injection. Notably, an intermediate X (plot c, Figure 1)
was found in the HPLC profile, following a parabolic pattern (plot a: bisulfite adduct 2, plot b:
thiazolidine-2,4-dione 3, plot d: product 6, plot c: unknown). At temperatures lower than 60 °C,
we observed an accumulation of this intermediate X; as the temperature was increased, the
intermediate (plot c, Figure 1) converted into the desired product 6 (Scheme 2).
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According to our earlier proposed mechanism,14 we expected to observe two plots for
intermediates 4 and 5; therefore, we reasoned that the intermediate X might be assigned to
intermediates 4 or 5 or to some other unknown species. However observing only one peak in
HPLC, we hypothesised that as the analysis of the reaction mass by HPLC was done offline; any
intermediate with a very short lifetime would not be observed in the HPLC reaction profile.
Furthermore, this reaction (Scheme 1) has multicomponent intermediates; hence, we thought of
utilizing the unique capabilities of ReactIR technology to visualize the progress of the reaction
online, so that information on the various transient species formed in the reaction can be
obtained. As a model reaction, the coupling of bisulfite adduct 2 with thiazolidine-2,4-dione 3
was performed in toluene using 2.0 equivalents of POCl3 with ReactIR probe dipped into the
reaction mass. The IR spectrum of the reaction mass was recorded after every 45 s, and the
obtained reaction profile is shown in Figure 2 capturing the various reaction components.
Surprisingly, the bisulfite adduct 2 disappeared immediately after completion of POCl3 addition
to the reaction mass at RT with simultaneous formation of a curve g in Figure 2. It appears that
bisulfite adduct was not stable in POCl3 even at RT, this observation was in contradiction with
Khosropour report. An increase in the reaction temperature from 35 °C to 110 °C resulted in
reduction of curve „g‟ with simultaneous increase in the concentration of product 6 represented
by “curve b” as shown in Figure 2.
From the visual comparison of HPLC plot (Figure 1) and ReactIR plot (Figure 2), it appeared
that the intermediate X in Figure 1 (plot „c‟) and Figure 2 (curve „g‟) are representing the same
component. This assumption was validated by the fact that the IR spectra of the component
represented by curve „g‟ matched with that of the standard reference IR spectra of 4-
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ethoxybenzaldehyde (1). Hence, at first sight it can be assumed that the reaction was proceeding
through the insitu formation of aldehyde 1 as shown in Scheme 2. Additionally ReactIR also
helped in identifying the other POCl3 related by-products of the reaction as shown in Figure 2.14
The outcome of the HPLC and ReactIR analysis was further substantiated by monitoring the
1
reaction progress by H NMR. Due to the poor solubility of 2 and 3 in toluene, the reaction
progress was investigated by off-line 1H NMR. The stacked plots of 1H NMR spectrum (Figures
4) taken at different temperatures showed that the bisulfite adduct 2 was instantaneously de-
protected to aldehyde 1 upon addition of POCl3 at room temperature (35 C). This was
confirmed by the disappearance of the characteristic -CH proton ( 5.59) and OH ( 4.87) of
bisulfite adduct 2 (Figure 3 and 4) with a simultaneous appearance of the characteristic aldehydic
proton at  9.86 (Figure 4) immediately after the completion of POCl3 addition. Notably, major
conversion of aldehyde 1 to the final product 6 started at 75 C and by the time the reaction
temperature reached 110 C almost all of the insitu generated aldehyde 1 converted to the desired
product 6. This was confirmed by the disappearance of the aldehydic proton at  9.86 with
simultaneous appearance of the characteristic =CH proton (Figure 4) of the product 6 at  7.74.
These findings are in agreement with those obtained from ReactIR confirming once again that
the condensation proceeds through the insitu regeneration of aldehyde rather than earlier
proposed intermediates for the same type of reactions (Scheme 1; intermediate 4 and 5).
1
To further support our results (HPLC, ReactIR and H NMR), we investigated the formation of
the intermediate species for the reaction of 2 with 3 using offline LC-MS to check for the
possible trace level intermediates in the reaction mass. We performed our study using an AB
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SCIEX TripleTOF 4600 mass spectrometer coupled with an Agilent 1290 series LC system; the
reaction mass isolated at different intervals was monitored using negative-ion mode mass
spectra. The reaction produced clean spectra, which displayed cationic species at [2a + H]+ m/z
151.0 (absolute mass 150.07) and [1a + H]+ m/z 250 (absolute mass 249.05) for product 6
(Figure 5).
1
The observation of 1 in both H NMR and LC-MS provides strong evidence for the in situ
regeneration of 1, thus confirming our observations from HPLC and ReactIR. We reasoned that
POCl3 facilitates the cleavage of bisulfite adduct 2 to 1 releasing POCl2(OH) and SO2 (g)
(Scheme 3). As a result, based on our observations from the analytical tools, the modified
plausible mechanism was shown in Scheme 4. We used GC-MS to confirm the evolution of SO2
during the course of the reaction. GC-MC results clearly indicated that the m/z value of the gas
evolved during the reaction of 2 with POCl3 in consistent with that of SO2 released from the
reaction mass (Scheme 4).
In order to ascertain the effect of POCl3, one-control condensation reaction of 3 was performed
using free aldehyde 1. Formation of product 6 in presence of POCl3 further confirm the essential
role of POCl3 in the transformation of 2 to 1 and subsequently to product 6 (Scheme 5).
Having recognized the role of POCl3, it was decided to optimize the reaction with the help of
DoE approach utilizing bisulfite adduct 2 and thiazolidine-2,4-dione 3 as a substrate for the
model reaction. Three reaction parameters that were selected for DoE are captured in Table 1
along with their experimental range. A 23 full factorial design (= 8 experiments) was planned to
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study the effect of the three variables on the formation of aldehyde 1 and the desired product 6.
Results of this full factorial design are presented in Table 2.
The first step of DoE data analysis was the identification of few significant reaction variables
(Table 1) that were affecting the formation of aldehyde 1 from bisulfite adduct 2. Based on Half-
Normal plot (Figure 5) and Pareto analysis (Figure 6), it was clear that the formation of aldehyde
1 was only affected by POCl3 equivalents while other two variables (Table 1) were having
insignificant effect. This fact was also confirmed from the ANOVA analysis (Table 3) and was
further augmented by the regression analysis where only POCl3 appeared in the regression
equation-1 and same has been depicted in 3D plot given in Figure-6. Observed and calculated
values of the unknown intermediate are close enough (see residuals in Table 4) to conclude that
Equation-1 explains the relationship very well. Another important observation is that the
formation of 1 from 2 was facilitated by low equivalents of POCl3 whereas high POCl3
equivalents favored product formation (Table 2).
√
Similarly, the statistical analysis of DoE data was performed for the product 6. Based on Half
normal curve (Figure 8) and Pareto chart (Figure 9), it was once again found that the product 6
formation was only influenced by the POCl3 equivalents but in this case excess of POCl3 was
required (Compare with quantity of POCl3 required for aldehyde 1 formation). This was also
indicated by ANOVA (Table 5), regression analysis (equation-2) and is presented graphically in
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Figure 9. Observed and calculated values of the product were close enough (Table 6) to conclude
that equation-2 explains the relationship very well.
.
The main observation from the DoE approach was that the formation of aldehyde 1 and product
6 was influenced by the equivalent of POCl3 used. Formation of aldehyde 1 from bisulfite adduct
2 is favored by low equivalents of POCl3 (Equation 1) whereas the product 6 formation was
favored by the high equivalents of POCl3 (Equation 2), which is also evident from equation 1
and 2. Another point from the DoE data that needs to be stressed here is that the reaction with
high equivalents of POCl3 was not having aldehyde 1 as the high equivalents of POCl3 as the
high equivalents of POCl3 was driving the reaction immediately to product 6. A possible
explanation for this observation might be the conversion of bisulfite adduct 2 to aldehyde 1
which in turn converting to the product 6. Therefore studies with DoE approach was confirms
aldehyde as an intermediate in this reaction. This is further augmented by the fact that aldehyde 1
was the major product wherein catalytic quantity of POCl3 was used whereas in case of excess
POCl3, desired product 6 was the major component (Table 2).
Hence a refined methodology of one pot direct condensation of bisulfite adduct with
thiazolidine-2,4-dione 3 was developed which enabled us to use bisulfite directly for the
reaction. It was evident that it involved two chemical step, first step involves insitu deprotection
of bisulfite adduct to parent aldehyde at room temperature and this deprotection was found to
be instantaneous and catalyzed by POCl3. While the second step of condensation of insitu
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generated aldehyde 1 with thiazolidine-2,4-dione 3 will excess POCl3 and higher temperature.
This reaction proceeded through an Aldol type intermediate 7 which was captured by XIC mass
spectra of the reaction mass (Figure 11). This intermediate 7 was not captured by HPLC/ReactIR
or by 1H NMR, probably because of very low concentration. Based on the above information, a
probable reaction mechanism is shown in Scheme 3. Examining the course of the reaction with
1
different analytical and spectroscopic tools (HPLC, ReactIR, H NMR, LC-MS and GC-MS)
confirmed that the reaction proceeds via in situ generation of aromatic aldehyde (resulting from
the dissociation of bisulphite adduct in presence POCl3), not the intermediates proposed earlier
phosphorodichloridate 4 and sulphonate moiety 5. Significant improvement in yield was
demonstrated with a single reaction. Interestingly, our investigation on POCl3 mediated synthesis
of 6 unfolds three important synthetic aspects of the reaction: (a) the regeneration of an aromatic
aldehyde 1 from aromatic bisulphite adduct 2 in a non-polar solvent like toluene using catalytic
POCl3, (b) initiation of reaction at low temperature, and (c) in-situ generation of a second
intermediate 7 which in turn facilitates carbon-carbon bond formation to give product 6. Based
on our findings we optimized and modified version of the synthesis of POCl3 mediated synthesis
of 5-benzylidene at lower temperature resulting in good yield. To the best of our knowledge, this
is the first report where in situ regeneration of intermediate aldehyde in synthesis of 5-
benzylidenes was confirmed using analytical and spectroscopic tools.
Based on this new one pot methodology for the direct Knoevenagel condensation of bisulfite
adducts of aldehydes with thiazolidine-2,4-dione, a small library of four compounds (8-11) were
synthesized as shown in Figure 11.
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The present methodology gave excellent yield of the desired product (6, 8, 9, 10 and 11) as
captured in the experimental section (>77%). Inspired by these results, we carried out a reaction
between pioglitazone-adduct, isolated from a pharmaceutically important aryl aldehyde
o
intermediate of pioglitazone, and 1.33 equiv of POCl3 in toluene at 90-100 C to afford 5-
arylidene 11 in good yield (Figure 12). In addition to the present methodology, other advantages
include rapid product isolation (6, 8-11), a cleaner reaction, and better operational efficiency.
Experimental:
General Experimental Procedure:
Synthesis of (Z)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione (6)
A slurry of bisulfite adduct 2 (10 g, 39.40 mmol) with thiazolidine-2,4-dione 3 (4.6 g, 39.30
mmol) was prepared in toluene (10 mL) in a 100 mL reaction vessel. POCl3 (8.0 g, 52.40 mmol)
was added in one portion at 25 C. The reaction temperature was gradually raised to 90-100 C,
and the reaction mass temperature was maintained at 90 C for 6 h. After the visual absence of
aldehyde on TLC, the reaction mass was slowly quenched by adding ice-cold water at 10 C, and
the biphasic slurry was stirred below 20 C for 10 min. The resulting bright yellow crystalline
material was filtered. The wet cake obtained was washed with toluene (2  10 mL) at 25 C and
dried in vacuum at 50 C to afford product 6 in 81% yield.
Procedure for monitoring the reaction mass by 1H NMR
The 1H NMR spectra was recorded offline in DMSO-d6 at 400 MHz on Bruker Avance 400MHz
spectrometer. The chemical shift values were reported on ppm scale with respect to
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tetramethylsilane (TMS) (0.00 ppm) as the internal standard. The reaction was performed as per
optimized conditions described above. Samples for NMR were drawn via a pipette under N2
atmosphere and the reaction mixture was concentrated by evaporation (with N2 pressure) below
30 oC. 50 mg of dry sample under N2 atmosphere was transferred to a micro-sample NMR tube
for recording the spectra. Samples were drawn after the addition of POCl3 at different
temperatures between 35 oC to 110 oC.
Procedure for monitoring the reaction mass by ReactIR
Reaction monitoring by on-line ReactIR: ReactIR 45m (Mettler Toledo) was used for monitoring
on-line reactions in our initial study. The ReactIR probe was immersed in the reaction mixture to
obtain samples for the instrument. During the reaction, IR spectra were recorded in 45 s intervals
for 2 h and then compared to standard reference spectra. Prior to the reaction, the IR spectra of
the starting materials were recorded in DMSO. Distinct characteristic peaks in the range 1900–
800 cm1 were recorded in the IR spectra by eliminating the overlapped DMSO peaks.
Procedure monitoring the reaction by HPLC
Offline HPLC analysis was performed using Waters 2690 HPLC system. Reaction mass
sampling for HPLC was drawn via a pipette under N2 atmosphere and transferred to a 50 mL
round bottom flask (RBF), and the reaction mass was concentrated by evaporation (with N2
pressure). 20 mg of dry sample was removed and transferred to a 10.0 mL volumetric flask. The
freshly prepared diluted sample was then transferred to the injection loop for analysis (sample in
5 mL of diluent). HPLC conditions required for reactions to progress include Column: Kromasil,
Altima C18, 150 x 4.6, 3m, λmax 245 nm, Flow: 1.0 mL/min, Run time: 30min, and diluent
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DMSO. Chromatograms were recorded for samples at different intervals over the course of the
reaction.
1
(Z)-5-(4-ethoxybenzylidene)thiazolidine-2,4-dione (6): 80%, Yellow solid, 98.6%. H NMR
(400 MHz, CDCl3): δ 12.50 (s, 1H), 7.74 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.8 Hz,
13
2H), 4.10 (q, J = 6.8 Hz, 2H), 1.3–1.36 (t, J = 6.8 Hz, 3H) ppm; C NMR (100 MHz, CDCl3):
167.9, 167.3, 160.0, 132.1, 131.8, 125.2, 120.0, 129.5, 115.2, 63.4, 14.4 ppm; ESI-MS: m/z
248.3 (M-1).
1
(Z)-5-(4-methoxybenzylidene)thiazolidine-2,4-dione (8): 77%, Yellow solid, 99.0%. H NMR
(400 MHz, CDCl3): δ 12.50 (s, 1H), 7.75 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz,
13
2H), 3.83 (s, 3H) ppm; C NMR (100 MHz, CDCl3): 167.9, 167.4, 160.9, 132.0, 131.8, 131.7,
125.5, 120.3, 114.8, 55.5 ppm; ESI-MS: m/z 234.0 (M-1).
1
(Z)-5-(4-chlorobenzylidene)thiazolidine-2,4-dione (9): 80.8%, Light brown solid, 99.2% H
13
NMR (400 MHz, DMSO-d6): δ 12.66 (s, 1H), 7.78 (s, 1H), 7.63–7.58 (m, 4H) ppm; C NMR
(400 MHz, DMSO-d6): 172.1, 170.1, 134.1, 132.8, 131.2 (2C), 129.1, 128.2, 127.5, 127.4 ppm;
ESI-MS: m/z 238.4 (M-1).
1
(Z)-5-(4-nitrobenzylidene)thiazolidine-2,4-dione (10): 81.7%, Yellow solid, 97.1%. H NMR
(400 MHz, CDCl3): δ 12.82 (s, 1H), 7.86 (s, 1H), 8.30–8.40 (d, J = 8.6 Hz, 2H), 7.60–7.80 (d, J
= 8.6 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): 167.3, 167.0, 147.4, 139.3, 130.9, 129.1,
124.2, 116.2 ppm; ESI-MS: m/z 249.0 (M-1).
1
(Z)-5-(4-(2-(5-ethylpyridin-2-yl)ethoxy)benzylidene)thiazolidine-2,4-dione (11): H NMR (400
MHz, DMSO-d6): 12.5 (s, 1H), 8.3–7.0 (m, 7H), 4.40 (t, J = 6.8 Hz, 2H), 3.20 (t, J = 6.8 Hz, 2H),
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13
2.60 (q, J = 7.4 Hz, 2H), 1.20 (d, J = 7.5 Hz, 3H) ppm; C NMR (100 MHz, DMSO d6): 167.9,
167.4, 160.1, 155.1, 148.5, 136.7, 135.7, 132, 131, 125, 123, 120, 115.3, 67, 36.5, 24.9, 15.3
ppm; ESI-MS: m/z 355.1 (M+1).
Conclusion
Analysis of the data obtained from various PAT tools and DoE helped in understanding the
reaction pathway of POCl3 mediated of one pot direct condensation of bisulfite adduct with
thiazolidine-2,4-dione. Based on the experimental evidence, the above reaction could be
exploited in two different ways. If the desired output is only the de-protections of bisulfite adduct
to aldehyde then catalytic quantity of POCl3 is to be used at room temperature. On the other hand
if condensation product is desired than excess POCl3 is to be used and reaction is to be
performed at high temperature. The yield obtained from the current methodology was much
higher than the yield obtained from the direct condensation of free aldehyde.
Acknowledgments
We are grateful to the management of Dr. Reddy‟s Laboratories Limited for giving support to
carry out this work.
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Table 1. Reaction variables (factors) considered for the optimization of product 6.
Factor
Name
POCl3
Unit
Equiv.
h
Min. (-1)
0.33
2.0
Max. (+1)
2.0
A
B
C
Reaction time
Reaction temperature
8.0
oC
60
110
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Table 2. Results of 23 full factorial design
Std. run
POCl3 equiv.
0.33
2.0
Time (h)
Temperature (oC)
Aldehyde (1)
59.30
0.29
Product (6)
0.32
1
2
3
4
5
6
7
8
2
2
8
8
2
2
8
8
60
60
83.70
3.70
0.33
2.0
60
78.57
0.23
60
82.07
2.29
0.33
2.0
110
110
110
110
83.04
3.74
80.58
2.71
0.33
2.0
49.93
4.10
82.17
POCl3 equivalents favored product formation (Table 2).
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Table 3. ANOVA Table for Unknown intermediate ( ).
√
Source
Sum of Squares
93.35
Df
Mean Square
93.35
F Value
91.81
p-value Prob >F
< 0.0001
Model
1.00
1.00
6.00
7.00
POCl3
93.35
93.35
91.81
< 0.0001
Residual
Cor Total
6.10
1.02
99.46
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Table 4: Observed and predicted values of aldehyde 1
Residual
Observed
Predicted
Observed
√
√
√
(1o)
√
59.3
0.29
78.57
0.23
83.04
3.74
43.93
4.1
7.70
0.54
8.86
0.48
9.11
1.93
6.63
2.02
8.08
1.24
8.08
1.24
8.08
1.24
8.08
1.24
-0.38
-0.71
0.79
-0.76
1.04
0.69
-1.45
0.78
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Table 5. ANOVA table for product 6 formation.
Sum of
Mean
square
p-value
Prob >F
< 0.0001
< 0.0001
Source
Df
F Value
squares
12760.03
12760.03
10.91
Model
POCl3 Equiv.
Residual
1.00
1.00
6.00
7.00
12760.03
12760.03
1.82
7015.44
7015.44
Cor Total
12770.94
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Table 6: Observed and predicted values of Product (6)
Observed Predicted
Residual
product
Product
0.32
83.70
3.70
82.07
2.29
80.58
2.71
2.255
82.13
2.255
82.13
2.255
82.13
2.255
82.13
-1.935
1.57
1.445
-0.06
0.035
-1.55
0.455
0.04
82.17
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Figure 1. Conversion of 2 to 6 by HPLC (area %).
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Figure 2. On-line ReactIR plot for POCl3-mediated coupling of 2 with 3: (a) By-product of
POCl3 (b) product 6 (c) POCl3 (d) toluene (e) By-product of POCl3 (f) thiazolidine-2,4-dione (3)
(g) intermediate X
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Figure 3. 1H NMR of bisulfite adduct before POCl3 addition
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1
Figure 4. H NMR plots for the reaction of (2) with (3) in the presence of 2.0 equivalents of
POCl3.
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Figure 5: (a)LC-MS chromatogram for aldehyde 1 during the transformation of 2 to 6.
(b)Relative effect of various reaction variables on Unknown intermediate ( ).
√
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Figure 6. Pareto Chart for identification of important reaction variables affecting aldehyde
( ).
√
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