Regioselective Formylation of Pyrrole-2-Carboxylate: Crystalline Vilsmeier Reagent vs Dichloromethyl Alkyl Ether

Article abstract of DOI:10.1021/acs.oprd.8b00233

New preparations of crystalline Vilsmeier reagent (VR) and dichloromethyl propyl or butyl ether were developed. The methods are environmentally benign and applicable to large-scale synthesis. Formylations of 1H-pyrrole-2-carboxylates were achieved with th

Full text of DOI:10.1021/acs.oprd.8b00233

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Communication
Regioselective formylation of pyrrole-2-carboxylate:
Crystalline Vilsmeier reagent vs dichloromethyl alkyl ether
Takuya Warashina, Daisuke Matsuura, Tetsuya Sengoku,
Masaki Takahashi, Hidemi Yoda, and Yoshikazu Kimura
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00233 • Publication Date (Web): 28 Sep 2018
Downloaded from http://pubs.acs.org on September 28, 2018
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Regioselective Formylation of Pyrrole-2-Carboxylate:
Crystalline Vilsmeier Reagent vs Dichloromethyl Alkyl Ether
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†
†
‡
○
iD
‡
iD
○
Hidemi
Takuya Warashina, Daisuke Matsuura, Tetsuya Sengoku,
Masaki Takahashi,
‡
○
iD
,†,
iD
○
Yoshikazu Kimura*
Yoda,
†
Research and Development Department, Iharanikkei Chemical Industry Co. Ltd. Kambara,
Shimizuꢀku, Shizuoka 421ꢀ3203, Japan
‡
Department of Applied Chemistry, Faculty of Engineering, Shizuoka University, 3ꢀ5ꢀ1 Johoku,
Nakaꢀku, Hamamatsu 432ꢀ8561, Japan
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ABSTRACT: New preparations of crystalline Vilsmeier reagent (VR) and dichloromethyl propyl or
butyl ether were developed. The methods are environmentally benign and applicable to largeꢀscale
synthesis. Formylations of 1Hꢀpyrroleꢀ2ꢀcarboxylates were achieved with these reagents,
regioselectively affording the 4ꢀformyl and 5ꢀformyl derivatives in nearly quantitative yields.
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Keywords: Vilsmeier–Haack formylation, dichloromethyl propyl ether, dichloromethyl butyl ether
1
Hꢀpyrroleꢀ2ꢀcarboxylate, regioselectivity, aldehyde
1
. INTRODUCTION
Direct introduction of the formyl group into desired position of the aromatic nucleus is important
synthetic method, because the aromatic aldehydes can be transformed to various functional groups in
organic molecules. In this communication, we describe the regioselective preparations of ethyl
1
2
4
ꢀformylꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (2a) and ethyl 5ꢀformylꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (3a). Both
of these pyrrole derivatives are useful intermediates in the synthesis of pharmaceuticals and
1
,2
industrial materials.
POCl
3
ꢀDMF/ EDC (Ref. 1a)
(This work)
2a: 42 %
2a: <1 %
3a: 46 %
3a: >99 %
solid VR / CHCl
3
Scheme 1 Formylation of 1a with Vilsmeier reagent
Formylation of aromatic compounds is routinely accomplished by use of the VilsmeierꢀHaack
3
reagent (VR). However, this reagent often gives a mixture of differentlyꢀsubstituted formylation
products. For example, reaction of ethyl 1Hꢀpyrroleꢀ2ꢀcarboxylate (1a) with VR prepared from
1
a,2d,2e,2f)
DMF and POCl
3
has been reported to give a mixture of 2a and 3a (Scheme 1).
Moreover,
it is unsuitable for largeꢀscale synthesis due to the hazardous nature of the reagents and/or
byꢀproducts, which include phosphorus.
3
VR is usually prepared from N,Nꢀdimethylformamide (DMF) and phosphoryl trichloride (POCl ),
and used in situ without isolation. We recently developed new preparations of VR (Scheme 2) using
5
phthaloyl dichloride. This method avoids the production of wasteꢀwater containing phosphorus. As
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phthalic anhydride is soluble in many solvents, VR is easily isolated in solid form, which later can
be deployed in a preferred synthesis solvent.
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Scheme 2 Preparation of VR
2
. SELECTIVE PREPARATION OF 5-FORMYL-2-CAROXYLATES USING SOLID VR
First, reactions of 1a with solid VR were examined in several solvents. As shown in Table 1, 3a was
produced regioselectively in CH Cl or CHCl . This selectivity was seen not only with solid VR, but
also with VR prepared in situ from oxalyl chloride and DMF (Table 1, entry 3). This method
accompanies generation of CO + CO . We believe use of solid VR prepared from DMF and
phthaloyl dichloride in advance is favorable in large scale. Solid VR did not dissolve in any of the
solvents except CHCl and this caused the heterogeneous reaction to proceed slowly. Slow reactions
2
2
3
2
3
were observed in DMF and acetonitrile at 45 ºC, but the selectivity for 3a was high. Reaction of 1a
with solid VR in POCl3, even though it did not dissolve completely, gave the best result (Table 1,
entry 9), but a solvent containing phosphorous is not suitable for large scale synthesis. This
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indicates that the reactivity of the Vilsmeier reagent seems to be due to the structure of VR.
Table 1 Smallꢀscale formylation of 1a with solid VR in several solvents
a
b
entry
solvent temp.(°C) time(h) conv.(%)
2a/3a
1
2
CH
CHCl
CHCl
CHCl
CH CN
2
Cl
2
rt
15
5
100
100
98
95
79
62
5
<0.1/ >99.9
<0.1/ >99.9
<0.1/ >99.9
<0.1/ >99.9
<0.1/ >99.9
<0.1/ >99.9
<0.1/ >99.9
3
rt
c
3
3
rt
4
4
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7
8
3
45
45
45
45
45
2
3
6
DMF
6
AcOEt
toluene
6
6
0
0 / 0
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POCl
3
45
2
100
<0.1/>99.9
a
1
a (417 mg, 3 mmol), solid VR (576 mg, 4.5 mmol), solvent (10mL)
b
Conversion and ratio of 2a/3a were determined by GC and
the structures were confirmed by GCMS.
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c
VR prepared in situ from oxalyl chloride and DMF in CHCl3.
As the reactivity of solid VR toward the formylation of aromatic compounds is expected to be lower
than that of a VR reagent prepared from POCl and DMF, we believe this reveals the cause of the
3
selective formylation. As shown in Scheme 3, form A is believed to be the active species in the case
3
b
of VR prepared from POCl and DMF, which might show higher reactivity than form C derived
3
from DMF and oxalyl chloride or phthaloyl dichloride. This feature is consistent with Brown’s
postulate for the reactivityꢀselectivity relationship that, in a given reaction, a highly reactive species
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gives low selectivity, whereas a less reactive species gives high selectivity.
Scheme 3 Structures of Vilsmeier reagents derived from POCl vs (COCl) or phthaloyl dichloride
3
2
The analogous reaction (Scheme 4) of methyl 1Hꢀpyrroleꢀ2ꢀcarboxylate (1b) with solid VR gave
4
methyl 5ꢀformylꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate (3b) in excellent yield.
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Scheme 4 Result for selective formylation of 1b with solid VR
Gramꢀscale experiments with 1a or 1b also afforded 3a or 3b in more than 99% selectivity (see
Experimental)
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. SELECTIVE PREPARATION OF 4-FORMYL-2-CARBOXYLATES USING
DICHLOROMETYL ALKYL ETHERS HAVING LONG CARBON CHAINS
Dichloromethyl methyl ether (5a) is known to be a robust reagent for the formylation of aromatics in
8
the presence of Lewis acids. The only known preparations of 5a have been performed using highly
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10
toxic PCl
5
or triphenylphosphine oxideꢀphosgene from methyl formate (4a). As 4a is a very
volatile liquid (boiling point 32 ºC, flash point ꢀ 20 ºC), it is also difficult to handle in an industrial
setting. We recently reported an alternative method for the production of 5a using oxalyl chloride
1
1
(
Scheme 5). The method avoids the use of toxic reagents, but the volatile liquid handling problem
remains.
a: R = Me b: R = Et
70 – 83 % isolated yields at 1 mol scale
c: R = Pr
d: R = Bu
Scheme 5 Preparations of dichloromethyl alkyl ethers
The new methods could be applied to alkyl formates having C1ꢀC4 carbon chains to give the
corresponding dichloromethyl alkyl ethers derived from alkyl formates having higher boiling points.
With large amounts of dichloromethyl alkyl ethers (5aꢀ5d) having C1ꢀC4 carbon chains at our
disposal, the reactivities of these reagents were our next focus.
The formylation of 1a with 5c or 5d in the presence of a Lewis acid was examined first. In the
3 3 4
presence of AlCl , the reaction afforded exclusively 2a. Other Lewis acids, such as FeCl or TiCl ,
1
2
showed somewhat lower selectivities. The role of nitromethane is not clarified, but we used in
1b
accordance with the previous paper. Though we fell to get somewhat better solubility of AlCl
3
,
actually do not know what is true. These results are summarized in Table 2. Although reaction of 1a
1b,1c,1e
with the methyl ether 5a in the presence of AlCl
3
has been reported to give exclusively 2a,
it is
noteworthy that 5c and 5d, whose raw materials 4c and 4d have higher boiling points than that of 4a,
are also useful for selective formylation. Similar selectivity was shown in methyl ester 1b, which
afforded 2b exclusively. (Table 2, entry 7)
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Table 2 Smallꢀscale formylations of 1a or 1b with 5c or 5d in the presence of Lewis acid
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1
1
1
1
1
1
1
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0
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a
b
entry
5
Lewis acid
FeCl
solvent
temp (°C)
0ꢀrt
time (h) conv (%)
2a/3a
1
2
3
4
5
6
5d
5d
5d
5d
5d
5c
3
CH
CH
2
Cl
Cl
2
2
2
2
5
2
1
72
100
100
72
80/20
85/15
TiCl
TiCl
4
4
2
2
ꢀ15
CH
2
Cl
2
3
/CH NO
2
= 1/1
ꢀ15
85/15
AlCl
AlCl
AlCl
3
3
3
CH
Cl
2 2
0
>99.9/<0.1
>99.9/<0.1
>99.9/<0.1
CH
2
Cl
2
2
/CH
/CH
3
NO
NO
2
2
= 1/1
= 1/1
ꢀ15
95
CH
2
Cl
3
ꢀ15
100
2
b/3b
7
5c
AlCl
3
CH Cl
2 2
/CH
3
NO
2
= 1/1
ꢀ15
2
95
>99.9/<0.1
a
1a or 1b (3 mmol), 5 (3.6 mol), Lewis acid (6 mmol), solvent (10 mL)
b
Conversion and ratio of 2a/3a or 2b/3b were determined by GC and the structures were confirmed
by GCMS.
4
. CONCLUSIONS
In conclusion, the ready availability of solid Vilsmeier reagent and dichloromethyl propyl and butyl
ethers for the regioselective formylation of pyrrole derivatives should make this a very attractive
method for laboratory and industrial use. Although this paper showed only one example, the
information seems to provide useful synthetic tools on selective synthesis of other heteroaromatics.
5. EXPERIMENTAL
Preparation of dichloromethyl alkyl ethers (5c and 5d).
Oxalyl chloride 82.5 g (0.65 mol) was slowly added dropwise to a mixture of propyl formate 44.1 g (0.5
mol) and Nꢀmethylformanilide 6.76 g (0.05 mol) at 60 ºC during 3 h. After the addition, the mixture was
stirred for further 14 h at the same temperature until generation of the gas was blown out. The mixture
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was distilled equipped with 300 mm vigreux column to give 52.8 g of 5c (74% yield) having bp 71ꢀ72 ºC/
9
b
9
0 torr (lit 129 ºC/ 760 torr).
1
H NMR (300 MHz, CDCl
3
): δ = 0.90 (t, J = 6.6 Hz, 3H), 1.66ꢀ2.73 (m, 2H), 3.93 (t, J = 6.6 Hz, 2H),
13
7
.33 (s, 1H) ppm. C NMR (75 MHz, CDCl ): δ = 10.3, 21.9, 68.0, 98.0 ppm.
3
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Oxalyl chloride 82.5 g (0.65 mol) was slowly added dropwise to a mixture of butyl formate 51.1 g (0.50
mol) and Nꢀmethylformanilide 6.76 g (0.05 mol) at 60 ºC during 3 h. After the addition, the mixture was
stirred for further 14 h at the same temperature until generation of the gas was blown out. The mixture
was distilled equipped with 300 mm vigreux column to give 67.1 g of 5d (83% yield) having bp 62ꢀ63
8
ºC/ 21 torr (lit bp 48ꢀ49 ºC/ 15 torr).
1
H NMR (300 MHz, CDCl
3
): δ = 0.95 (t, J = 7.2 Hz, 3H), 1.35ꢀ1.52 (m, 2H), 1.63ꢀ1.69 (m, 2H), 3.98 (t, J
1
3
=
6.3 Hz, 2H), 7.32 (s, 1H) ppm. C NMR (75 MHz, CDCl ): δ = 13.6, 19.0, 30.5, 66.3, 97.2 ppm.
3
Synthesis of 3a
Representative example for small-scale 5-formylation of 1a with VR (Table 1)
5
VR (colorless solid, 725.8 mg, 5.67 mmol) was added to a stirred solution of ethyl
1
3
Hꢀpyrroleꢀ2ꢀcarboxylate 1a (526.9 mg, 3.78 mmol) in dry CHCl (13 mL) at 0 ºC, and the resulting
mixture was stirred at room temperature for 5h. GC analysis showed that 1a was completely
consumed and that the 2a/3a ratio was <0.1 / >99.9.
Gram-scale formylation of 1a with VR
5
VR (colorless solid, 3.01 g, 23.5 mmol) was added to a stirred solution of ethyl
1
3
Hꢀpyrroleꢀ2ꢀcarboxylate 1a (2.00 g, 14.6 mmol) in dry CHCl (49 mL) at 0 ºC, and the resulting
mixture was stirred at room temperature for 5h. GC analysis showed that 1a was completely
consumed and that the 2a/3a ratio was 1/99. The reaction mixture was neutralized with satd. aq.
NaHCO
3
(30 mL) at pH 7 in an ice bath, then extracted with CH
2 2
Cl (2 x 30 mL). The combined
organic layers were washed with brine (30 mL), dried over Na
2
SO , and concentrated under vacuum.
4
The residue was purified via column chromatography on silica gel (cyclohexane/AcOEt, 8:1) to
afford pure ethyl 5ꢀformylꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate 3a (2.16 g, 89 % yield).
1
3
H NMR (300 MHz, CDCl ): δ = 9.90 (br s, 1H), 9.67 (s, 1H), 6.94 (d, J = 2.4 Hz, 2H), 4.38 (q, J =
13
7
.2 Hz, 2H), 1.39 ppm (t, J = 7.2 Hz, 3H). C NMR (75 MHz, CDCl
3
): δ = 180.4, 160.4, 134.3,
+
128.6, 119.7, 115.6, 61.4, 14.3 ppm. GCMS: m/z = 167 (M , relative intensity 48%), 166 (0.7%), 139
2g
(
42%), 138 (6%), 122 (89%), 120 (48%), 93 (base peak). mp 72.6ꢀ72.7 ºC (lit. 72ꢀ74 ºC).
Multi-gram scale formylation of 1a with VR
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Ethyl 1Hꢀpyrroleꢀ2ꢀcarboxylate 1a (6.4 g, 46 mmol) was added to a stirred solution of VR (8.9 g,
7
0 mmol) in dry CHCl
temperature for 4 h. GCꢀMS analysis showed that 1a was completely consumed and that the 2a was
produced as a sole product. The reaction mixture was neutralized with satd. NaHCO solution at pH
, then extracted with CH Cl (2 x 50 mL). The combined organic layers were washed with brine
100 mL), dried over Na SO , filtrated through a silicaꢀgel pad, and concentrated under vacuum to
3
(70 mL) at one portion, and the resulting mixture was stirred at room
3
1
1
1
1
1
1
1
1
1
1
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2
2
2
2
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7
8
9
0
7
2
2
(
2
4
give 7.00 g of 3a (90% yield) which was almost pure and identified with the above product by
GCꢀMS. mp 72.0ꢀ72.4 ºC.
Synthesis of 3b
Small-scale 5-formylation of 1b with VR (Scheme 4)
5
VR (colorless solid, 660.0 mg, 5.15 mmol) was added to a stirred solution of methyl
1
3
Hꢀpyrroleꢀ2ꢀcarboxylate 1b (401.8 mg, 3.21 mmol) in dry CHCl (11 mL) at 0 ºC, and the resulting
mixture was stirred at room temperature for 5.5 h. GC analysis showed that 1b was completely
consumed and that the 2b/3b ratio was <0.1 / >99.9. The mixture was neutralized with satd. aq.
NaHCO
3
(30 mL) in an ice bath, and extracted with AcOEt (2 × 30 mL). The combined organic
SO , and concentrated under vacuum. The
layers were washed with brine (30 mL), dried over Na
2
4
residue was purified via column chromatography on silica gel (cyclohexane/AcOEt, 8:1) to afford
pure methyl 5ꢀformylꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate 3b (489.0 mg, 99 % yield).
1
H NMR (300 MHz, CDCl
3
): δ = 9.92 (br s, 1H), 9.68 (s, 1H), 6.94 (d, J = 2.4 Hz, 2H), 3.92 (s, 3H)
): δ = 180.4, 160.9, 134.5, 128.2, 119.7, 115.7, 52.2 ppm. GCMS:
m/z = 153 (M , relative intensity 74%), 152 (4%), 122 (base peak), 120 (51%), 93 (50%). mp
13
ppm. C NMR (75 MHz, CDCl
3
+
2
h
1
00ꢀ101 ºC (lit. 96 ºC).
Gram-scale 5-formylation of 1b with VR
Methyl 1Hꢀpyrroleꢀ2ꢀcarboxylate 1b (2.00 g, 16.0 mmol) was added to a stirred solution of VR
(
3.07 g, 24.0 mmol) in dry CHCl
room temperature for 5.5 h. GCꢀMS analysis showed that 1b was completely consumed and that the
b was produced as a sole product. The reaction mixture was neutralized with satd. aq. NaHCO at
pH 7, then extracted with CH Cl (2 x 30 mL). The combined organic layers were washed with brine
50 mL), dried over Na SO , and concentrated under vacuum. The residue was filtered through a
3
(53 mL) at one portion, and the resulting mixture was stirred at
3
3
2
2
(
2
4
silicaꢀgel pad to afford almost pure 3b (2.14 g, 87 % yield). mp 98.8ꢀ99.2 ºC.
Synthesis of 2a
Typical example for small-scale 4-formylation of 1a with 5c or 5d (Table 2)
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Powdered AlCl
3
(1.05 g, 7.90 mmol) was added portion wise to a stirred solution of 1a (535.9 mg,
3
2 2 3 2
.85 mmol) in dry CH Cl /CH NO (13 mL, 1/1), and then 5c (680.0 mg, 4.76 mmol) was added
dropwise at ꢀ15 ºC over a period of 10 min. The whole mixture was stirred for 1 h at the same
temperature. Upon complete conversion of the starting material, as confirmed by GC (2a/3a =
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
>
99.9 : <0.1).
Gram-scale formylation of 1a with 5c
Powdered AlCl (5.78 g, 43.5 mmol) was added portion wise to a stirred solution of 1a (3.01 g, 21.7
mmol) in dry CH Cl /CH NO (72 mL, 1:1), and then 5c (3.80 g, 26.5 mmol) was added dropwise at
3
2
2
3
2
ꢀ15 ºC over a period of 10 min. The whole mixture was stirred for 2 h at the same temperature. Upon
complete conversion of the starting material, as confirmed by GC (2a/3a = 99: 1), the mixture was
quenched with H
2
O (30 mL) and extracted with EtOAc (2 × 30 mL). The organic layer was
successively washed with satd. aq. NaHCO
3
(30 mL) and brine (30 mL), dried over Na SO , and
2
4
concentrated in vacuo. The residue was purified via column chromatography on silica gel
(cyclohexane/AcOEt, 8:1 to 2:1) to afford pure ethyl 4ꢀformylꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate 2a (3.41 g,
9
4 % yield).
1
3
H NMR (300 MHz, CDCl ): δ = 9.86 (s, 1H), 9.74 (br s, 1H), 7.57 (dd, J = 3.3, 1.5 Hz, 1H),
13
7
.33ꢀ7.32 (m, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H) ppm. C NMR (75 MHz,
+
CDCl
3
): δ = 185.7, 161.0, 128.5, 127.5, 125.1, 114.1, 61.2, 14.3 ppm. GCMS: m/z = 167 (M ,
relative intensity 34%), 166 (7%), 139 (18%), 138 (18%), 122 (53%), 120 (base peak). mp 101ꢀ102
1b
ºC (lit. 101ꢀ102 ºC).
Synthesis of 2b (Table 2, entry 7)
Powdered AlCl
3
(1.09 g, 8.18 mmol) was added portion wise to a stirred solution of 1b (511.6 mg,
Cl /CH NO (14 mL, 1:1), and then 5c (870 mg, 6.08 mmol) was added
4.09 mmol) in dry CH
2
2
3
2
dropwise at ꢀ15 ºC over a period of 10 min. The whole mixture was stirred for 2 h at the same
temperature. Upon complete conversion of the starting material, as confirmed by GC (2b/3b =
>
99.9 : <0.1), the mixture was quenched with H
The organic layer was successively washed with satd. aq. NaHCO
over Na SO , and concentrated in vacuo. The residue was purified via column chromatography on
2
O (30 mL) and extracted with CH
2 2
Cl (2 × 30 mL).
3
(30 mL) and brine (30 mL), dried
2
4
silica gel (cyclohexane/AcOEt, 8:1 to 2:1) to afford pure methyl 4ꢀformylꢀ1Hꢀpyrroleꢀ2ꢀcarboxylate
2b (520.0 mg, 83 % yield).
1
3
H NMR (300 MHz, CDCl ): δ = 9.86 (s, 1H), 9.73 (br s, 1H), 7.58 (d, J = 3.3, 1.5 Hz, 1H),
1
3
7
1
.33ꢀ7.32 (m, 1H), 3.91 (s, 3H) ppm. C NMR (75 MHz, CDCl
3
): δ = 185.7, 161.4, 128.7, 127.5,
+
24.7, 114.3, 52.1 ppm. GCMS: m/z = 153 (M , relative intensity 43%), 152 (20%), 122 (38%), 120
2
h
(
base peak). mp125ꢀ126 (lit. 104 ºC).
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■
ASSOCIATED CONTENT
s Supporting Information
○
NMR spectra of the products
1
1
1
1
1
1
1
1
1
1
2
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2
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■
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail (Yoshikazu Kimura): kimura.yoshikazu@iharanikkei.co.jp
ORCID
Tetsuya Sengoku: 0000ꢀ0002ꢀ5208ꢀ9460
Masayuki Takahashi: 0000ꢀ0001ꢀ6613ꢀ4173
Hidemi Yoda: 0000ꢀ0001ꢀ8843ꢀ6850
Yoshikazu Kimura: 0000ꢀ0003ꢀ1586ꢀ842x
Notes
The authors declare no competing financial interest.
■
REFERENCES AND NOTES
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0
1
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3
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2
3
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5
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0
(
(
(
3) (a) Vilsmeier, A.; Haack, A. Action of phosphorus halides on alkylformanilides. A new method
for the preparation of secondary and tertiary pꢀalkylaminonobenzaldehydes, Ber. Dtsch. Chem.
Ges. 1927, 60B, 119ꢀ122. (b) Marson, C.M. Reactions of carbonyl compounds with (monohalo)
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Reactions Vol. 49 pp 1ꢀ330 (1997) ed. by Paquette, A. John Wiley & Sons. Inc.
4) Similar poor selective formylations of methyl ester (1b) were reported in several literatures; (a)
Chakraborty, T. K.; Udawant, S. P.; Roy, S.; Mohan, B. K.; Rao, K. S.; Dutta, S. K.; Kunwar, A. C.
Synthesis and characterization of Bocꢀprotected 4ꢀaminoꢀ and 5ꢀaminopyrroleꢀ2ꢀcarboxylic acid
methyl esters, Tetrahedron Lett. 2006, 47, 4631ꢀ4634. (b) Schmuck, C. Selfꢀassembly of 2ꢀ
(
guanidiniocarbonyl)ꢀpyrroleꢀ4ꢀcarboxylate in dimethyl sulfoxide: an entropy driven
oligomerization, Tetrahedron 2001, 57, 3063ꢀ3067, and Reference 2h.
5) (a) Kimura, Y.; Matsuura, D.; Hanawa, T.; Kobayashi, Y. New preparation method for Vilsmeier
reagent and related imidoyl chlorides, Tetrahedron Lett. 2012, 53, 1116ꢀ1118. (b) Kimura, Y.;
Matsuura, D. Novel synthetic methods for the VilsmeierꢀHaack reagent and green routes to acid
chlorides, alkyl formates, and alkyl chlorides, Inter. J. Org. Chem. 2013, 3(3A), 1ꢀ7.
3
(6) Although reactions of anisole or 1,2ꢀdimethoxybenzene with VR prepared in situ from POCl and
DMF reportedly gave the corresponding aldehyde products (Reference 3c), use of solid VR or
VR prepared in situ from oxalyl chloride and DMF did not give the aldehyde products at all in
CHCl
3
at reflux temperature by our hands. Also see, Downie, I.; Earle, M.J.; Heaney, H.;
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Shuhaibar, K.F. Vilsmeier formylation and glyoxalation reactions of nucleophilic aromatic
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1
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1
2
2
2
2
2
2
2
2
2
2
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3
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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2
3
4
5
6
7
8
9
0
1
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4
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0
1
242ꢀ1248.
(
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dichloromethyl ethers, Ann. Univ. Turku 1961, 49 , 42; Chem. Abstr. 1961, 55, 98919.
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(
(
(
11) Kimura, Y.; Warashina, T. Convenient preparation of dichloromethyl alkyl ethers, Tetrahedron
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3
12) To produce high regioselectivity, use of 2 equiv of AlCl was necessary.
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