Continuous-flow preparation and use of β-chloro enals using the Vilsmeier reagent

Article abstract of DOI:10.1021/op300168z

The Vilsmeier reagent is used in the preparation of a wide variety of heterocycles, such as pyrazoles, via formation of β-chloroacrolein intermediates. However, use of this extremely reactive reagent on large scale requires special precautions to avoid potentially dangerous exotherms. This article describes the safe preparation at room temperature of the Vilsmeier reagent under flow conditions for the formation of β-chloroacroleins and 3-formylchromones, as well as the use of these in multistep, continuous flow processes for the syntheses of β-acrylonitriles and polysubstituted pyrazoles.

Full text of DOI:10.1021/op300168z

Communication
pubs.acs.org/OPRD
Continuous-Flow Preparation and Use of β‑Chloro Enals Using the
Vilsmeier Reagent
Laurent Pellegatti and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139,
United States
S
* Supporting Information
VR. We chose to employ DMF and phosphorus oxychloride as
precursors for the preparation of the VR (Scheme 1),11
a
ABSTRACT: The Vilsmeier reagent is used in the
preparation of a wide variety of heterocycles, such as
pyrazoles, via formation of β-chloroacrolein intermediates.
However, use of this extremely reactive reagent on large
scale requires special precautions to avoid potentially
dangerous exotherms. This article describes the safe
preparation at room temperature of the Vilsmeier reagent
under flow conditions for the formation of β-chloroacro-
leins and 3-formylchromones, as well as the use of these in
multistep, continuous flow processes for the syntheses of
β-acrylonitriles and polysubstituted pyrazoles.
Scheme 1. Preparation of β-chloroacroleins using POCl3 and
DMF as VR precursors
typical combination that also minimizes the formation of N,N-
dimethylcarbamoyl chloride (DMCC), a potential carcino-
gen.17 Upon subsequent introduction of acetophenone and
heating, the chloroiminium salt (2) is formed, which is
hydrolyzed to the corresponding β-chloroacrolein (3) upon
workup.
INTRODUCTION
■
Since Anton Vilsmeier and Albrecht Haack first reported it in
1927,1 the Vilsmeier reagent (VR) has been widely used for the
formylation of activated arene compounds. Beyond this initially
reported use, the VR has also been employed for the
preparation of β-chloroacroleins and β-chloroacrylonitriles
from acetophenones,2 which can in turn provide access to a
variety of heterocycles, such as pyrimidines,3,4 isothiazoles,5
oxazoles,6 isoxazoles,4 pyrazole,4 aminopyrazoles,7 furan,8
thiophenes,9 and pyrroles.10 Despite the fact that these
reactions have been extensively studied over the last century,11
the industrial use of the Vilsmeier reagent still requires careful
handling, due the extreme instability of the chloroiminium ion.
In the worst case, this instability can lead to an explosion,12
although this situation is typically avoided through careful
temperature control and/or dilute reaction conditions.
With this strategy in mind, we designed the continuous-flow
system depicted in Figure 1. Neat phosphorus oxychloride and
The development of chemical transformations under
continuous flow conditions has gained considerable attention
over the past decade.13 This is due, in part, to the benefits
associated with continuous processing, such as increased
reaction efficiency and waste minimization.13−15 The use of
flow systems can also allow for the safe handling of hazardous
and/or highly reactive starting materials and/or intermediates,
such as the Vilsmeier reagent. Recently, Rutjes reported the
controlled use of the VR for the formylation of electron-rich
arenes using microreactors under continuous flow conditions.16
Herein, we disclose the preparation of the Vilsmeier reagent
and its direct application to the synthesis of pyrazole derivatives
under flow conditions.
Figure 1. Setup for the preparation of β-chloroacroleins under flow
conditions.
DMF were merged using a Tee-mixer (0.04 in. ID) and
introduced into the first reactor (PFA tubing-0.04 in. ID) at
room temperature for 1.1−4.4 min to form the VR. A stream of
acetophenone in DMF was then mixed with the VR and this
combination is flowed into the second reactor (PFA tubing-
0.04 in. ID), which was submerged in an oil bath. The
temperature and the residence time were adjusted depending
on the stability and reactivity of the corresponding
RESULTS AND DISCUSSION
■
We set out to investigate the formation of β-chloroacroleins
starting from acetophenone derivatives and in situ generated
Received: June 27, 2012
Published: July 22, 2012
© 2012 American Chemical Society
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Table 1. Substrate scope for the preparation of β-chloroacroleins
a
b
Conditions: 4.4 equiv POCl3, 6.6 equiv DMF. Yields are of isolated products collected after equilibration of the system (average of two or more
runs).
chloroiminium ion (40−80 °C, 10−80 min). The crude
reaction mixture was then added to a flask containing aqueous
NaOAc solution (2 M), after which time the β-chloroacroleins
were isolated, in some cases as E/Z-mixtures.
Using the setup depicted in Figure 1, various substituted
acetophenones were efficiently converted to the corresponding
β-chloroacroleins or 3-formylchromones (Table 1). Notably,
the transformation was tolerant of a boronic acid moiety and
product 6 was obtained in 89% yield. Tetrasubstituted alkenes
7 and 8 could also be obtained in good yields (Table 1, entries
4−5), though in the case of compound 8 a residence time of 48
min was necessary in order for the reaction to reach full
conversion from 4′-methoxy-2-(4-methoxyphenyl)-
acetophenone. This methodology was then applied to several
acetyl heterocycles (Table 1, entries 6−8), and we found that β-
chloroacroleins 9−11 could be obtained, albeit in modest
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Scheme 2. Reaction sequence for the preparation of 3-formylchromones
Scheme 3. Continuous flow synthesis of β-chloroacrylonitriles and pyrazole derivatives
yields. The inefficiency of the reaction sequence with these
heterocyclic compounds as substrates is presumably a
consequence of the low stability of the corresponding iminium
salts, which decompose prior to aqueous workup. Additional
examples of reactions of heterocyclic substrates are provided in
the Supporting Information (SI). Finally, we found that
substituted 3-formylchromones could be obtained in excellent
yields from corresponding 2′-hydroxy acetophenones (Scheme
2).
Next, we sought to use the β-chloroacroleins generated in
this process for further transformations under flow conditions.
For example, β-chloroacrylonitriles can be formed from β-
chloroacroleins via treatment with hydroxylamine hydro-
chloride. As this transformation is also reported to be highly
exothermic, it is well-suited for application in a continuous-flow
process (Scheme 3, eq 1).18 Thus, a solution of hydroxylamine
hydrochloride in DMF (1 M) was mixed with the crude β-
chloroiminium salt, derived from acetophenone, under flow
conditions and introduced into a third reactor at 80 °C for 7.8
min. The reaction stream was subsequently collected in a flask
containing an aqueous solution of 2 M NaOAc to effect
hydrolysis. The desired product, 3-chloro-3-phenylacrylonitrile
(16), was isolated in 63% yield for the two-step process.
β-Chloroacroleins also serve as key intermediates in the
synthesis of a wide range of heterocycles. Thus, we decided to
demonstrate the utility of our procedure by preparing
functionalized pyrazoles from acetophenones in a multistep
process (Scheme 3, eqs 2, 3). Following β-chloroiminium salt
formation, the reaction stream was then mixed with a stream
containing one equivalent of the hydrochloride salt of an aryl
hydrazine hydrochloride and 1.2 equiv of trifluoroacetic acid
(TFA) as a THF/water or ethanol/water solution to provide
the desired pyrazole product. Starting from 4′-chloro-2′-
hydroxyacetophenone (17), compound 19 was synthesized in
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64% yield via the reaction of the corresponding iminium salt 18
at 60 °C for 7.8 min. Additionally, 1,5-diaryl-substituted
pyrazoles 22 and 1,4,5-triaryl-substituted pyrazole 23 were
also prepared in good yields from their corresponding ketones
(20), although in these instances the pyrazole formation
required higher temperatures to go to completion (70 and 80
°C, respectively). In both cases, EtOH/water (4:1) was used to
deliver the aryl hydrazine and TFA. In the case of 23, the use of
a 5 psi back-pressure regulator was also required.
snap column; eluting with the appropriate solvents as indicated
below). In some cases, the desired compounds could be
isolated without the need for purification by chromatography.
General Procedure B for the Continuous Flow Synthesis of
β-Chloroacrylonitriles. Using the reaction setup as depicted in
Scheme 3 and the General procedure A for the preparation of
the β-chloroiminium salt, an oven-dried screw-top volumetric
flask (100 mL), fitted with a Teflon screw-cap, was charged
with hydroxylamine hydrochloride (100 mmol). The vessel was
evacuated and backfilled with argon (this process was repeated
a total of three times), and DMF was added via syringe to make
the solution volume 100 mL. The flask was then sonicated to
solubilize the reagent, after which the solution was loaded into a
plastic syringe and fitted to the system using a fourth Harvard
Apparatus PHD2000 syringe pump (f4) and mixed with the
stream exiting the second reactor (R2, t2, T2). The resulting
stream was then introduced into a third reactor (653 cm of
PFA capillary tubing (1/16 in. OD × 0.04 in. ID), 5.3 mL, R3,
t3, T3). The reaction proceeded at the indicated flow rate for
each stream. Reactors R2 and R3 were submerged in an oil bath
set at the appropriate reaction temperature. The products were
collected and isolated in the same manner described in General
procedure A.
CONCLUSIONS
■
We have demonstrated the preparation of a variety of β-
chloroacrolein derivatives using the Vilsmeier reagent generated
in a continuous-flow process. These transformations can be
efficiently performed in a safe manner by this continuous
process in the generation and reaction of the thermally sensitive
Vilsmeier reagent. We have further demonstrated the direct use
of the generated β-chloroacroleins, for the synthesis of a β-
chloroacrylonitrile and of 1,4-disubstituted, 1,5-diaryl, and
1,4,5-triarylsubstituted pyrazoles under flow conditions. We
expect that this technique should be readily adaptable for large-
scale work.
General Procedure C for the Continuous Flow Synthesis of
Pyrazole Derivatives. Using the reaction setup as depicted in
Scheme 3 and the General procedure A for the preparation of
the β-chloroiminium salt, an oven-dried screw-top volumetric
flask (25 mL), fitted with a Teflon screw-cap, was charged with
the acetophenone substrates (6.25−25 mmol). The vessel was
evacuated and backfilled with argon (this process was repeated
a total of three times), and DMF was added via syringe to make
the solution volume 25 mL. This acetophenone solution ([C])
was then loaded into a 30 mL plastic syringe and fitted to a
third Harvard Apparatus PHD2000 syringe pump (f 3), and
mixed with the stream exiting the first reactor. The resulting
stream was then introduced into a second reactor (R2, t2, T2). A
second oven-dried screw-top volumetric flask (50 mL), fitted
with a Teflon screw-cap, was charged with the arylhydrazine
hydrochloride (12.5 mmol) and TFA (15 mmol). A mixture of
Solvent (THF/water (4:1) or EtOH/water (4:1)) was then
added to bring the solution volume to 50 mL. The flask was
then sonicated to solubilize the mixture, after which it was
loaded into a 50 mL plastic syringe and fitted to the system
using a fourth Harvard Apparatus PHD2000 syringe pump (f4)
and mixed with the stream exiting the second reactor. The
resulting stream was then introduced into a third reactor (R3, t3,
T3). The reaction proceeded at the indicated flow rate for each
stream. Reactors were submerged in an oil bath set at the
appropriate reaction temperature. The products were collected
and isolated in the same manner as that described in General
procedure A.
Flow Parameters and Analytical Data. (E/Z)-3-Chloro-3-
phenylacrylaldehyde (4). Flow parameters: [C] = 1 M, f1 = 40
μL/min, f 2 = 50 μL/min, f3 = 195 μL/min, t1 = 1.1 min, t2 = 20
min, T2 = 80 °C, R1 = 12.3 cm of PFA capillary tubing (1/16 in.
OD × 0.04 in. ID), 100 μL, R2 = (703 cm of PFA capillary
tubing (1/16 in. OD × 0.04 in. ID), 5.7 mL). The spectral data
is in accord with that previously reported.19
(Z)-3-Chloro-3-(3-fluoro-4-methoxyphenyl)acrylaldehyde
(5). Flow parameters: [C] = 1 M, f1 = 40 μL/min, f2 = 50 μL/
min, f 3 = 195 μL/min, t1 = 1.1 min, t2 = 20 min, T2 = 80 °C, R1
= 12.3 cm of PFA capillary tubing (1/16 in. OD × 0.04 in. ),
100 μL, R2 = (703 cm of PFA capillary tubing (1/16 in. OD ×
EXPERIMENTAL SECTION
■
General Remarks. Flash chromatography, if needed, was
performed using a Biotage Isolera 4 instrument with cartridges
packed with Silicycle SilicaFlashP60 (230−400 mesh).
Continuous flow studies were carried out using Harvard
Apparatus syringe pumps PHD-2000 and/or PHD Ultra.
Copies of the 1H and 13C spectra can be found at the end of
the SI. All GC analyses were performed on an Agilent 6890 gas
chromatograph with an FID detector using a J&W DB-1
column (10 m, 0.1 mm I.D.).
General Procedure A for the Continuous Flow Synthesis of
β-Chloroacroleins and 3-Formyl Chromones. Using the
reaction setup as depicted in Figure 1, DMF and POCl3 were
loaded into 10 mL plastic syringes and introduced into the first
reactor (R1, t1) via two separate Harvard Apparatus PHD2000
syringe pumps at two different flow rates, f1 and f2. An oven-
dried screw-top volumetric flask (25 mL), fitted with a Teflon
screw-cap, was charged with the acetophenone substrates
(6.25−25 mmol). The vessel was evacuated and backfilled with
argon (this process was repeated a total of three times), and
DMF was added via syringe to make the solution volume 25
mL. This acetophenone solution was then loaded into a 30 mL
plastic syringe and fitted to a third Harvard Apparatus
PHD2000 syringe pump (f3). The stream from this pump
was then mixed with the stream exiting the first reactor and
introduced into the second reactor (R2, t2). The reaction
proceeded at the indicated flow rate for each stream. R2 was
submerged in an oil bath set at the appropriate reaction
temperature (T2). After reaching steady state (2−3 reactor
volumes), a sample was collected for 30 min into a beaker
containing aqueous NaOAc (2M). In the event that the desired
product precipitated from the solution, it was isolated by
filtration of the reaction mixture and was washed with water
before drying. Otherwise, the reaction mixture was then
extracted with ethyl acetate (3 × 50 mL). The combined
organic phases were then washed with water (3 × 50 mL) and
then brine (30 mL), dried over Na2SO4, and concentrated in
vacuo. The crude mixture was then purified by column
chromatography via the Biotage Isolera 4 (silica-packed 25 g
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0.04 in. ), 5.7 mL). Analysis: mp 94−95 °C; IR (ATR, cm−1):
3045, 1661, 1589, 1510, 1426, 1124, 1017, 800; 1H NMR (400
MHz, CDCl3) δ 10.15 (d, 1H, J = 6.8 Hz), 7.57−7.44 (m, 2H),
7.00 (t, 1H, J = 8.5 Hz), 6.58 (d, 1H, J = 6.8 Hz), 3.94 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 191.4, 152.1 (d, J = 238.6 Hz),
150.8, 150.7 (d, J = 2.6 Hz), 128.1 (d, J = 6.6 Hz), 123.9 (d, J =
3.4 Hz), 123.3, 115.1 (d, J = 20.8 Hz), 113.0 (d, J = 2.2 Hz),
56.4; Anal. Calcd for C10H8ClFO2: C, 55.96; H, 3.76. Found:
C, 55.90; H, 3.78.
PFA capillary tubing (1/16 in. OD × 0.04 in. ID), 100 μL, R2 =
436 cm of PFA capillary tubing (1/16 in. OD × 0.04 in. ID),
8.5 mL. Analysis: mp 78−79 °C; IR (ATR, cm−1): 3024, 1671,
1
1592, 1412, 1216, 1123, 709; H NMR (400 MHz, CDCl3) δ
10.22 (dd, 1H, J = 6.7, 0.5 Hz), 8.73 (ddd, 2H, J = 4.4, 1.7, 0.5
Hz), 7.58 (ddd, 2H, J = 4.4, 1.7, 0.5 Hz), 6.75 (dd, 1H, J = 6.7,
0.5 Hz); 13C NMR (101 MHz, CDCl3) δ 190.8, 150.8, 148.9,
142.8, 126.5, 120.6; Anal. Calcd for C8H6ClNO: C, 57.33; H,
3.61. Found: C, 56.58; H, 3.79.
(Z)-(4-(1-Chloro-3-oxoprop-1-en-1-yl)phenyl)boronic acid
(6). Flow parameters: [C] = 1 M, f1 = 40 μL/min, f 2 = 50 μL/
min, f3 = 97.5 μL/min, t1 = 1.1 min, t2 = 30 min, T2 = 80 °C, R1
= 12.3 cm of PFA capillary tubing (1/16 in. OD × 0.04 in. ID),
100 μL, R2 = (703 cm of PFA capillary tubing (1/16 in. OD ×
0.04 in. ID), 5.7 mL). Analysis: mp 190 °C; IR (ATR, cm−1):
3330, 2882, 1648, 1577, 1412, 1341, 1143, 1075, 621; 1H NMR
(400 MHz, d6-DMSO) δ 10.14 (d, 1H, J = 6.7 Hz), 8.29 (s,
2H), 7.96−7.77 (m, 4H), 7.01 (d, 1H, J = 6.7 Hz); 13C NMR
(101 MHz, d6-DMSO) δ 191.5, 150.8, 135.9, 134.5, 126.1,
124.5; Anal. Calcd for C9H8BClO3: C, 51.37; H, 3.83. Found:
C, 51.12; H, 3.75.
(E/Z)-3-Chloro-3-(pyridin-3-yl)acrylaldehyde (11). Flow
parameters: [C] = 1 M, f1 = 10 μL/min, f 2 = 12.5 μL/min,
f 3 = 48.75 μL/min, t1 = 4.4 min, t2 = 80 min, T2 = 60 °C, R1 =
12.3 cm of PFA capillary tubing (1/16 in. OD × 0.04 in. ID),
100 μL, R2 = (703 cm of PFA capillary tubing (1/16 in. OD ×
0.04 in. ID), 5.7 mL. Analysis: mp 45−46 °C; IR (ATR, cm−1):
3014, 2853, 1665, 1603, 1581, 1413, 1236, 1120, 1021, 696; 1H
NMR (400 MHz, CDCl3) δ 10.21 (d, 1H, J = 6.7 Hz), 8.97 (d,
1H, J = 2.4 Hz), 8.71 (dd, 1H, J = 4.8, 1.5 Hz), 8.05 (dt, 1H, J =
8.1, 2.0 Hz), 7.42 (dd, 1H, J = 8.1, 4.8 Hz), 6.70 (d, 1H, J = 6.7
Hz); 13C NMR (101 MHz, CDCl3) δ 190.8, 152.2, 148.9,
147.8, 134.8, 131.8, 125.6, 123.7; Anal. Calcd for C8H6ClNO:
C, 57.33; H, 3.61. Found: C, 57.07; H, 3.61.
6-Fluoro-4-oxo-4H-chromene-3-carbaldehyde (12). Flow
parameters: [C] = 0.5 M, f1 = 40 μL/min, f 2 = 50 μL/min, f 3 =
195 μL/min, t1 = 1.1 min, t2 = 20 min, T2 = 80 °C, R1 = 12.3
cm of PFA capillary tubing (1/16 in. OD × 0.04 in. ID), 100
μL, R2 = (703 cm of PFA capillary tubing (1/16 in. OD × 0.04
in. ID), 5.7 mL. Analysis: mp 151−152 °C; IR (ATR, cm−1):
3069, 1694, 1638, 1564, 1473, 1315, 1133, 720; 1H NMR (400
MHz, CDCl3) δ 10.36 (d, 1H, J = 0.5 Hz), 8.54 (d, 1H, J = 0.5
Hz), 7.92 (dd, 1H, J = 8.0, 3.1 Hz), 7.57 (ddt, 1H, J = 9.2, 4.2,
0.5 Hz), 7.47 (dddd, 1H, J = 9.2, 7.4, 3.1, 0.5 Hz); 13C NMR
(101 MHz, CDCl3) δ 188.4, 175.3, 160.8, 160.4 (d, J = 249.8
Hz), 152.5 (d, J = 2.1 Hz), 126.8 (d, J = 7.6 Hz), 123.1 (d, J =
25.4 Hz), 120.9 (d, J = 8.3 Hz), 119.7, 111.4 (d, J = 24.0 Hz);
Anal. Calcd for C10H5FO3: C, 62.51; H, 2.62. Found: C, 62.30;
H, 2.44.
(E/Z)-3-Chloro-3-(4-chlorophenyl)-2-methylacrylaldehyde
(7). Flow parameters: [C] = 1 M, f1 = 20 μL/min, f 2 = 25 μL/
min, f3 = 97.5 μL/min, t1 = 2.2 min, t2 = 40 min, T2 = 80 °C, R1
= 12.3 cm of PFA capillary tubing (1/16 in. OD × 0.04 in. ID),
100 μL, R2 = (703 cm of PFA capillary tubing (1/16 in. OD ×
0.04 in. ID), 5.7 mL). Analysis: E/Z: 80/20, IR (ATR, cm−1):
1
3071, 2895, 1668, 1590, 1487, 1398, 1279, 1093, 835, 682; H
NMR (400 MHz, CDCl3) δ 9.40 (s, 1H), 7.49−6.93 (m, 5H),
2.00 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 191.6, 189.6,
152.8, 146.1, 136.8, 136.6, 136.1, 135.8, 134.1, 132.9, 131.3,
129.9, 129.4, 128.8, 14.1, 13.4; Anal. Calcd for C10H8Cl2O: C,
55.84; H, 3.75. Found: C, 55.82; H, 3.69.
(E/Z)-3-Chloro-2,3-bis(4-methoxyphenyl)acrylaldehyde
(8). Flow parameters: [C] = 0.5 M, f1 = 10 μL/min, f2 = 12.5
μL/min, f 3 = 97.5 μL/min, t1 = 4.4 min, t2 = 48 min, T2 = 80
°C, R1 = 12.3 cm of PFA capillary tubing (1/16 in. OD × 0.04
in. ID), 100 μL, R2 = 703 cm of PFA capillary tubing (1/16 in.
OD × 0.04 in. ID), 5.7 mL. Analysis: E/Z: 80/20, IR (ATR,
7-Chloro-4-oxo-4H-chromene-3-carbaldehyde (13). Flow
parameters: [C] = 0.5 M, f1 = 40 μL/min, f 2 = 50 μL/min, f 3 =
195 μL/min, t1 = 1.1 min, t2 = 20 min, T2 = 80 °C, R1 = 12.3
cm of PFA capillary tubing (1/16 in. OD × 0.04 in. ID), 100
μL, R2 = (703 cm of PFA capillary tubing (1/16 in. OD × 0.04
in. ID), 5.7 mL. Analysis: mp >250 °C; IR (ATR, cm−1): 3067,
1
cm−1): 2869, 1678, 1606, 1511, 1245, 1172, 1023, 770; H
NMR (400 MHz, CDCl3) δ 9.62 (s, 1H), 7.57−7.36 (m, 2H),
7.30−7.15 (m, 3H), 7.07−6.92 (m, 4H), 3.85 (s, 3H), 3.81 (s,
3H); 13C NMR (101 MHz, CDCl3) δ 191.9, 190.4, 161.8,
160.8, 159.5, 155.0, 139.5, 132.2, 131.9, 131.7, 131.3, 128.1,
126.4, 114.0, 113.9, 113.7, 113.4, 55.6, 55.3, 55.3, 55.2; ; Anal.
Calcd for C17H15ClO3: C, 67.44; H, 4.99. Found: C, 67.17; H,
5.15.
(E/Z)-3-Chloro-3-(1H-indol-3-yl)acrylaldehyde (9). Flow
parameters: [C] = 1 M, f1 = 80 μL/min, f 2 = 100 μL/min, f 3
= 390 μL/min, t1 = 2.8 min, t2 = 10 min, T2 = 40 °C, R1 = 61.7
cm of PFA capillary tubing (1/16 in. OD × 0.04 in. ID), 500
μL, R2 = 703 cm of PFA capillary tubing (1/16 in. OD × 0.04
in. ID), 5.7 mL. Analysis: E/Z: 6/94, IR (ATR, cm−1): 3169,
2988, 1632, 1564, 1426, 1388, 1232, 1133, 1084, 720; 1H NMR
(400 MHz, d6-DMSO) δ 12.30 (s, 1H), 10.11 (d, 1H, J = 7.0
Hz), 8.24 (d, 1H, J = 3.2 Hz), 7.96−7.82 (m, 1H), 7.54 (dt, 1H,
J = 8.2, 0.9 Hz), 7.34−7.13 (m, 2H), 6.73 (d, 1H, J = 7.0 Hz);
13C NMR (101 MHz, d6-DMSO) δ 190.6, 146.8, 137.8, 132.6,
123.6, 123.2, 122.0, 120.1, 118.7, 113.1, 112.4; Anal. Calcd for
C11H8ClNO: C, 64.25; H, 3.92. Found: C, 64.39; H, 3.95.
(Z)-3-Chloro-3-(pyridin-4-yl)acrylaldehyde (10). Flow pa-
rameters: [C] = 1 M, f1 = 20 μL/min, f 2 = 25 μL/min, f 3 = 97.5
μL/min, t1 = 2.2 min, t2 = 60 min, T2 = 60 °C, R1 = 12.3 cm of
1
1707, 1695, 1648, 1606, 1594, 1339, 1166, 889, 764; H NMR
(400 MHz, CDCl3) δ 10.35 (s, 1H), 8.51 (s, 1H), 8.22 (d, 1H, J
= 8.5 Hz), 7.56 (d, 1H, J = 1.9 Hz), 7.46 (dd, 1H, J = 8.5, 1.9
Hz); 13C NMR (101 MHz, CDCl3) δ 188.3, 175.3, 160.7,
156.3, 145.9, 141.2, 127.6, 123.9, 120.6, 118.9; Anal. Calcd for
C10H5ClO3: C, 57.58; H, 2.42. Found: C, 57.31; H, 2.30.
(Z)-3-Chloro-3-phenylacrylonitrile (16). Flow parameters:
[C] = 1 M, f1 = 40 μL/min, f 2 = 50 μL/min, f3 = 195 μL/min,
f4 = 390 μL/min, t1 = 1.1 min, t2 = 20 min, t3 = 7.8 min, T2 = 80
°C, T3 = 80 °C, R1 = 12.3 cm of PFA capillary tubing (1/16 in.
OD × 0.04 in. ID), 100 μL, R2 = 703 cm of PFA capillary
tubing (1/16 in. OD × 0.04 in. ID), 5.7 mL, R3 = 653 cm of
PFA capillary tubing (1/16 in. OD × 0.04 in. ID), 5.3 mL.
Analysis: mp 34−35 °C; IR (ATR, cm−1): 3060, 2220, 1597,
1
1575, 1489, 1445, 1229, 676; H NMR (400 MHz, CDCl3) δ
7.66−7.61 (m, 2H), 7.53−7.47 (m, 1H), 7.46−7.39 (m, 2H),
6.02 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 152.9, 133.8,
131.9, 128.8, 126.7, 115.5, 96.1; Anal. Calcd for C9H6ClN: C,
66.07; H, 3.70. Found: C, 65.79; H, 3.94.
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Organic Process Research & Development
Communication
(4-Chloro-2-hydroxyphenyl)(1-(4-chlorophenyl)-1H-pyra-
zol-4-yl)methanone (19). Flow parameters: [C] = 0.5 M,
Solvent = THF/water (4:1), f1 = 40 μL/min, f 2 = 50 μL/min,
f3 = 195 μL/min, f4 = 390 μL/min, t1 = 1.1 min, t2 = 20 min, t3
= 7.8 min, T2 = 80 °C, T3 = 60 °C, R1 = 12.3 cm of PFA
capillary tubing (1/16 in. OD × 0.04 in. ID), 100 μL, R2 = 703
cm of PFA capillary tubing (1/16 in. OD × 0.04 in. ID), 5.7
mL, R3 = 653 cm of PFA capillary tubing (1/16 in. OD × 0.04
in. ID), 5.3 mL. Analysis: mp 213-214 °C; IR (ATR, cm−1):
ACKNOWLEDGMENTS
■
L.P. and S.L.B. thank the Novartis International AG for
funding. The Bruker 400 MHz NMR spectrometer used in this
work was supported by grants from the National Institutes of
Health (1S10RR13886-01). We thank Dr. N. Chernyak, Dr. A.
DeAngelis, Dr. M. McGowan, and Dr. W. Shu for help in the
preparation of this manuscript.
REFERENCES
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1
3265, 1635, 1595, 1487, 1431, 1261, 850, 770; H NMR (400
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128.8, 128.2, 127.0, 126.2, 122.2, 122.1, 119.8, 118.6, 113.5;
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1-(4-Methoxyphenyl)-5-phenyl-1H-pyrazole (22). Flow
parameters: [C] = 1 M, Solvent = EtOH/water (4:1), f1 = 40
μL/min, f 2 = 50 μL/min, f 3 = 195 μL/min, f4 = 780 μL/min, t1
= 1.1 min, t2 = 20 min, t3 = 5.0 min, T2 = 80 °C, T3 = 70 °C, R1
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0.04 in. ID), 5.7 mL, R3 = 653 cm of PFA capillary tubing (1/16
in. OD × 0.04 in. ID), 5.3 mL. Analysis: mp 93−94 °C; IR
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MHz, CDCl3) δ 7.85 (d, 1H, J = 8.8 Hz), 7.70 (d, 2H, J = 7.0
Hz), 7.45−7.32 (m, 3H), 7.08−7.00 (m, 3H), 6.89 (dd, 2H, J =
9.1, 0.6 Hz), 3.79 (s, 3H); 13C NMR (101 MHz, CDCl3) δ
154.2, 137.9, 137.2, 135.7, 132.8, 128.8, 128.5, 126.1, 122.8,
114.9, 114.1, 55.7.
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1-(4-Chlorophenyl)-4,5-bis(4-methoxyphenyl)-1H-pyrazole
(23). Flow parameters: [C] = 0.5 M, Solvent = EtOH/water
(4:1), f1 = 10 μL/min, f 2 = 12.5 μL/min, f 3 = 97.5 μL/min, f4 =
195 μL/min, t1 = 4.4 min, t2 = 48 min, t3 = 17 min, T2 = 80 °C,
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× 0.04 in. ID), 100 μL, R2 = 703 cm of PFA capillary tubing (1/
16 in. OD × 0.04 in. ID), 5.7 mL, R3 = 653 cm of PFA capillary
tubing (1/16 in. OD × 0.04 in. ID), 5.3 mL, 5 psi back pressure
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1611, 1493, 1377, 1243, 1030, 951, 798; H NMR (400 MHz,
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= 8.8 Hz), 7.11 (d, 2H, J = 8.8 Hz), 7.03 (d, 2H, J = 8.8 Hz),
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C, 70.68; H, 4.90. Found: C, 70.38; H, 5.01.
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ASSOCIATED CONTENT
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* Supporting Information
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AUTHOR INFORMATION
■
Corresponding Author
̈
*sbuchwal@mit.edu.
Notes
(18) (a) Cao, J.; Gao, H; Green, J.; Marhefka, C. WO/2004/041813,
The authors declare no competing financial interest.
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