Regioselective Formylation of Pyrrole-2-Carboxylate: Crystalline

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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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Organic Process Research & Development

Regioselective Formylation of Pyrrole-2-Carboxylate: Crystalline Vilsmeier Reagent vs Dichloromethyl Alkyl Ether iD iD Hidemi Takuya Warashina,† Daisuke Matsuura,† Tetsuya Sengoku,‡○ Masaki Takahashi,‡○

iD Yoshikazu Kimura*,†,○ iD Yoda,‡○

†

Research and Development Department, Iharanikkei Chemical Industry Co. Ltd. Kambara, Shimizu-ku, Shizuoka 421-3203, Japan

‡

Department of Applied Chemistry, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Naka-ku, Hamamatsu 432-8561, Japan

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Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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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 large-scale synthesis. Formylations of 1H-pyrrole-2-carboxylates were achieved with these reagents, regioselectively affording the 4-formyl and 5-formyl derivatives in nearly quantitative yields.

Keywords: Vilsmeier–Haack formylation, dichloromethyl propyl ether, dichloromethyl butyl ether 1H-pyrrole-2-carboxylate, 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 4-formyl-1H-pyrrole-2-carboxylate (2a)1 and ethyl 5-formyl-1H-pyrrole-2-carboxylate (3a).2 Both of these pyrrole derivatives are useful intermediates in the synthesis of pharmaceuticals and industrial materials.1,2

POCl3-DMF/ EDC (Ref. 1a)

2a:

42 %

3a: 46 %

solid VR / CHCl3 (This work)

2a:

99 %

Scheme 1 Formylation of 1a with Vilsmeier reagent Formylation of aromatic compounds is routinely accomplished by use of the Vilsmeier-Haack reagent (VR).3 However, this reagent often gives a mixture of differently-substituted formylation products. For example, reaction of ethyl 1H-pyrrole-2-carboxylate (1a) with VR prepared from DMF and POCl3 has been reported to give a mixture of 2a and 3a (Scheme 1). 1a,2d,2e,2f) Moreover, it is unsuitable for large-scale synthesis due to the hazardous nature of the reagents and/or by-products, which include phosphorus. VR is usually prepared from N,N-dimethylformamide (DMF) and phosphoryl trichloride (POCl3), and used in situ without isolation. We recently developed new preparations of VR (Scheme 2) using phthaloyl dichloride.5 This method avoids the production of waste-water containing phosphorus. As



phthalic anhydride is soluble in many solvents, VR is easily isolated in solid form, which later can be deployed in a preferred synthesis solvent.

Scheme 2 Preparation of VR5

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 CH2Cl2 or CHCl3. 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 + CO2. 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 CHCl3 and this caused the heterogeneous reaction to proceed slowly. Slow reactions 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 indicates that the reactivity of the Vilsmeier reagent seems to be due to the structure of VR.6

Table 1 Small-scale formylation of 1a with solid VR in several solvents

entrya

solvent

1

CH2Cl2

2a/3ab

time(h)

conv.(%)

rt

15

100

99.9

CHCl3

rt

5

100

99.9

CHCl3

rt

4

98

99.9

4

CHCl3

45

2

95

99.9

5

CH3CN

45

6

79

99.9

6

DMF

45

6

62

99.9

7

AcOEt

45

6

5

99.9

8

toluene

45

6

0

0/ 0

2 3

c

temp.(°C)


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9

POCl3

45

2

100

99.9

a

1a (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.

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 POCl3 and DMF, we believe this reveals the cause of the selective formylation. As shown in Scheme 3, form A is believed to be the active species in the case of VR prepared from POCl3 and DMF,3b which might show higher reactivity than form C derived from DMF and oxalyl chloride or phthaloyl dichloride. This feature is consistent with Brown’s postulate for the reactivity-selectivity relationship that, in a given reaction, a highly reactive species gives low selectivity, whereas a less reactive species gives high selectivity.7

Scheme 3 Structures of Vilsmeier reagents derived from POCl3 vs (COCl)2 or phthaloyl dichloride The analogous reaction (Scheme 4) of methyl 1H-pyrrole-2-carboxylate (1b) with solid VR gave methyl 5-formyl-1H-pyrrole-2-carboxylate (3b) in excellent yield.4



Scheme 4 Result for selective formylation of 1b with solid VR

Gram-scale experiments with 1a or 1b also afforded 3a or 3b in more than 99% selectivity (see Experimental)

3. 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 the presence of Lewis acids.8 The only known preparations of 5a have been performed using highly toxic PCl59 or triphenylphosphine oxide-phosgene from methyl formate (4a).10 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 (Scheme 5).11 The method avoids the use of toxic reagents, but the volatile liquid handling problem remains.

a: R = Me b: R = Et c: R = Pr

70 – 83 % isolated yields at 1 mol scale

d: R = Bu

Scheme 5 Preparations of dichloromethyl alkyl ethers The new methods could be applied to alkyl formates having C1-C4 carbon chains to give the corresponding dichloromethyl alkyl ethers derived from alkyl formates having higher boiling points. With large amounts of dichloromethyl alkyl ethers (5a-5d) having C1-C4 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 presence of AlCl3, the reaction afforded exclusively 2a. Other Lewis acids, such as FeCl3 or TiCl4, showed somewhat lower selectivities.12 The role of nitromethane is not clarified, but we used in accordance with the previous paper.1b Though we fell to get somewhat better solubility of AlCl3, actually do not know what is true. These results are summarized in Table 2. Although reaction of 1a with the methyl ether 5a in the presence of AlCl3 has been reported to give exclusively 2a,1b,1c,1e 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 Small-scale formylations of 1a or 1b with 5c or 5d in the presence of Lewis acid

entrya 5

Lewis acid

solvent

temp (°C)

time (h)

conv (%)

2a/3ab

1

5d

FeCl3

CH2Cl2

0-rt

2

72

80/20

2

5d

TiCl4

CH2Cl2

-15

2

100

85/15

3

5d

TiCl4

CH2Cl2/CH3NO2= 1/1

-15

2

100

85/15

4

5d

AlCl3

CH2Cl2

0

5

72

>99.9/99.9/99.9/99.9/99.9 : 99.9 :

Regioselective Formylation of Pyrrole-2-Carboxylate: Crystalline

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