Regioselective electrophilic formylation - 3-substituted thiophenes as a case study

Article abstract of DOI:10.1016/S0040-4039(00)00254-9

A variety of methods for regioselective formylation have been examined and exemplified with 3-methylthiophene. Optimal yields and regioselectivity for 2-formylation were obtained with N-formylpyrrolidine (11:1) although up to a 46:1 ratio could be obtained with MeOCHCl₂:TiCl₄, albeit in lower yield. Optimal 5-formylation (1:1.5) was obtained when using N- formylindoline:(COCl)₂. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00254-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2749–2752
Regioselective electrophilic formylation — 3-substituted
thiophenes as a case study
∗
Otto Meth-Cohn and Mark Ashton
Chemistry Department, University of Sunderland, Sunderland SR1 3SD, UK
Received 21 December 1999; accepted 9 February 2000
Abstract
A variety of methods for regioselective formylation have been examined and exemplified with 3-
methylthiophene. Optimal yields and regioselectivity for 2-formylation were obtained with N-formylpyrrolidine
(11:1) although up to a 46:1 ratio could be obtained with MeOCHCl2:TiCl4, albeit in lower yield. Optimal
5-formylation (1:1.5) was obtained when using N-formylindoline:(COCl)2. © 2000 Elsevier Science Ltd. All
rights reserved.
Formylation is a key process in organic synthesis, with the resulting aldehyde function being
a ‘crossroads’ intermediate. Not surprisingly, a large number of methods have been developed for
1
+
this reaction. Reagents for electrophilic formylation are mostly of the form Y–CH_X . Thus, the
+
+
reactions attributed to Vilsmeier (ClCH_NR ), Rieche (e.g. MeOCHCl →MeO_CHCl ), Gatter-
2
2
2
+
+
man (Zn[CN] /HCl→HC_NH ), Gatterman–Koch (CO/HCl/Lewis acid→HC_O ) and even Duff
2
2
+
(
CH _NH — followed by dehydrogenation of initially formed RCH NH ) all fit this pattern. The
2 2 2 2
difference between these reagents lies primarily in: (i) their reactivity; O-based reagents more reactive
than N-based ones; and (ii) their steric bulk. From a regioselectivity viewpoint the more reactive systems
would be expected to be less selective while a sterically bulky reagent should favour the least hindered
site of reaction (and vice versa).
Some limited work has been published on the regioselectivity of electrophilic formylation. Thus,
Vilsmeier formylation of anisole gives 89:11 (58%) of 4- to 2-isomers with DMF/POCl but 94:6
3
(
75%) when the bulkier pyrophosphoryl chloride is used, with this rising to >98:2 (72%) when N-
2
3
methylformanilide replaces the DMF. Some work has been reported by Detty and Hays on the
DMF/POCl formylation of 3-alkylthiophenes (a ratio of 2:5 substitution using 3-Me, Et, n-Pr, i-Pr and
3
n-Bu derivatives were 6.1, 2.85, 3.55, 1.1, and 2.7 to 1, respectively) while using N-methylformanilide
(NMFA) gave ratios of 3.0, 2.0, 1.8, 1.8 and 0.7 to 1, respectively. The effect of the increasing size of
the Vilsmeier amide is clearly evident, with the bulkier NMFA giving up to a two-fold improvement in
regioselection.
∗
Corresponding author. E-mail: otto.meth-cohn@sunderland.ac.uk (O. Meth-Cohn)
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00254-9
tetl 16534

2
750
We herein examine the role of the bulk of the formylating agent in the formylation of 3-
methylthiophene by examining the ratio of the product 2- to 5-formyl isomers (2 and 3) (Scheme
1).
Scheme 1.
1. Formylation of 3-MT utilizing Vilsmeier reagents
4
Using Vilsmeier reagents the bulk of the amide in particular and of the reagent in general is
examined, using 3-methylthiophene (3-MT) 1 as the substrate. There is much demand for regioselectively
formylated 3-MT as a veterinary drug intermediate.
Table 1 shows the effect of decreasing (N-formylpyrrolidine) and increasing the size of Vilsmeier
aliphatic amides compared to DMF, the most commonly employed reagent. A 4.5-fold change in
regioselection is observed. Globular systems (adamantyl) seem to convey little extra benefit. Clearly, for
optimal 2-formylation N-formylpyrrolidine is the best Vilsmeier amide, while dicyclohexylformamide
confers maximum 5-selectivity.
Table 1
2 3
Vilsmeier formylation of 3-MT (1) using aliphatic amides R NCHO/POCl
Aromatic Vilsmeier amides prove much more effective in ensuring optimal 5-formylation, the steric
bulk conferred by one benzene ring being almost equivalent to that of two cyclohexyl rings (Table
2
). Unfortunately, N-formyldiphenylamine is not effective as a Vilsmeier amide. Surprisingly, loading
the phenyl ring with extra ortho-substituents decreases the regioselectivity slightly, no doubt due to
the enforced orthogonality of the aromatic ring. When planarity of the ring was fixed by use of N-
formylindoline, optimal 5-selectivity was observed. However, this is a rather sensitive amide to the
usual POCl , and we utilized the milder acid halide, oxalyl chloride. Unfortunately, bulkier planar
3
formamides such as N-formylcarbazole, -tetrahydrocarbazole, -hexahydrocarbazole or -2-methylindoline

2
751
proved ineffective Vilsmeier amides and the non-planar but buckled 5-methyl-5,6-dihydrophenanthridine
conferred no extra selection.
Table 2
2 3
Vilsmeier formylation of 3-MT (1) using aromatic amides R NCHO/POCl
+
Varying the bulk of the Vilsmeier leaving group X in R N_CHX (X=Cl, OPOCl , CF SO ) by use
2
2
3
3
of (COCl) , O(POCl ) , or (CF SO ) as the Vilsmeier acylating agent had only a very small effect on
2
2 2
3
2 2
the regioselection (6.3, 6.1, 5.8), suggesting quite reasonably that the Vilsmeier leaving group is trans to
the largest N-substituent.
2. Formylation of 3-MT utilizing Rieche reagents
It is evident from the above results that Vilsmeier reagents are sterically bulky formylating agents.
In order to improve 2-formylation selectivity further we therefore examined the more reactive but
+
sterically less demanding Rieche reagents (e.g. MeOCHCl →MeO_CHCl ). A Lewis acid such as TiCl
2
4
is required to convert the covalent equivalent of the Vilsmeier reagent into the active ionic agent. Table 3
records some of our results. In brief, the regioselectivity was excellent but the overly vigorous reagent
5
tended to destroy some of the 3-methylthiophene, making reproducibility a problem. Yields and product
ratios were thus variable and are unreliable. No product was observed using BF , ZnCl , Hf(OTf) ,
3
2
4
Yb(OTf) or FeCl as Lewis acid.
3
3
Rieche’s reagent should prove optimally regioselective in the formylation of more stable substrates.
Thus, using 3-bromothiophene, formylation at −12°C using TiCl gave the formyl-3-bromothiophene in
4
83% yield and with a 94:1 ratio of 2- to 5-isomers.
Finally, we have also investigated other bulkier but perhaps milder analogues of MeOCHCl as
2
formylating agents. The bromo-analogue (MeOCHBr ) and thio-analogue (MeSCHCl ) both gave only
2
2
tarry products with 3-MT.
In conclusion, we have shown that regioselective formylation of 3-substituted thiophenes may be
optimized by either: (i) utilizing small (→2-isomer) or large planar, aromatic Vilsmeier reagents (→5-
isomer); or (ii) by utilizing the much smaller but more reactive Rieche reagents (→2-isomer). This
methodology is now being applied to other regioselection problems.

2
752
Table 3
2 2 2
Rieche formylation of 3-MT (1) using MeOCHCl /Lewis acid/CH Cl
Acknowledgements
We thank Laporte Fine Chemicals (formerly Inspec Fine Chemicals) and the EPSRC for a CASE
Award to MA.
References
1
. For a useful overview and leading references, see: March, J. Advanced Organic Chemistry, 4th edn; Wiley-Interscience: New
York, 1992; 542.
2
3
4
. Downie, I. M.; Earle, M. J.; Heaney, H.; Shuhaibar, K. F. Tetrahedron 1993, 49, 4015–4034.
. Detty, M. R.; Hays, D. S. Heterocycles 1995, 40, 925–937.
. Typical conditions for Vilsmeier formylation: To N-methylformanilide (1.49 g, 0.011 M) was added POCl
with ice-bath cooling and stirring. After 5 min heating at 80°C, 3-methylthiophene (0.98 g, 0.96 mL, 0.010 M) was added
and the solution heated for 2 h at 80°C. The mixture was poured onto ice–water, basified (sat. aqueous K CO solution)
and extracted with CH Cl ) and evaporated, and the residue distilled on a Kugelrohr at
(4×30 mL) washed, dried (MgSO
135°C/10 mm.
. Typical conditions for Rieche formylation: To a mixture of 3-methylthiophene (2.36 g, 2.32 mL, 0.024 M) and methyl
dichloromethyl ether (2.98 g, 2.35 mL, 0.026 M) in dry CH Cl (7.59 g, 4.39 mL, 0.04
(15 mL) at −12°C was added TiCl
M) dropwise over 40–50 min with stirring. After an additional 1 h at this temperature, water (30mL) was carefully added
3
(5.0 mL) dropwise
2
3
2
2
4
∼
5
2
2
4
dropwise over 15 min and stirring continued for 30 min. Extraction of the aqueous phase with more CH
drying of the combined organic phase, afforded a product which was further worked up as above.
2
Cl
2
(3×30 mL) and