A highly efficient transacetalization of 2-formylpyrrole acetals in alkaline media

Article abstract of DOI:10.1016/j.cclet.2011.10.004

The reaction of 2-formylpyrrole acetals with sodium alkoxide in alcohols at reflux temperature smoothly proceeded to generate corresponding transacetalization products in nearly quantitative yields. A plausible mechanism involving the formation of a highl

Full text of DOI:10.1016/j.cclet.2011.10.004

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 33–36
www.elsevier.com/locate/cclet
A highly efficient transacetalization of 2-formylpyrrole acetals in
alkaline media
*
Zhao Hua Yan , Run Hua Kang, Yong Jie Liu, Sen Lin
**
Department of Chemistry, Nanchang University, Nanchang 330031, China
Received 9 June 2011
Available online 9 November 2011
Abstract
The reaction of 2-formylpyrrole acetals with sodium alkoxide in alcohols at reflux temperature smoothly proceeded to generate
corresponding transacetalization products in nearly quantitative yields. A plausible mechanism involving the formation of a highly
reactive intermediate azafulvene species was proposed to explain the observed transformation.
# 2011 Zhao Hua Yan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: 2-Formylpyrrole acetal; Transacetalization; Sodium alkoxide
Acetal is one of the most widely used and versatile protecting group of carbonyl, hydroxyl, and diol groups in
organic synthesis. They are usually prepared through the reaction of carbonyl compound with alcohol, diol, or trialkyl
orthoformate in the presence of a protic or lewis acid [1]. Transacetalization has become increasingly useful in organic
synthesis. For example, transacetalization is often needed to switch one protecting group to another, and a variety of
interesting compounds of 1,3-dioxanes, 1,3-oxazolidines and bioactive products were synthesized by transaceta-
cetalization [2–4]. Traditionally, protic or lewis acid is usually employed to catalyze transacetalization. Recently,
2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) [5] and ruthenium, rhodium and iridium complexes [6] have been
employed to catalyze transacetalization. However, transacetalization in alkaline media was only sporadically reported
in the case of the specific b-keto acetals substrates [7].
2-Formylpyrrole compounds have been widely used in the synthesis of oligopyrrolic compounds, porphyrins and
many bioactive natural and non-natural products [8,9]. In our ongoing program on acid-catalyzed trimerization of 2-
formylpyrrole acetals directed towards the synthesis of a new type of ring system heterocyclic compound, we required
various 2-formylpyrrole acetal as substrates.
First, we prepared 2-formylpyrrole acetal via reaction of 2-formylpyrrole compound with alcohol in the presence of
para-toluenesulfonic acid [10]. However in most cases, 2-formylpyrrole acetals were obtained in low or moderate
yields with the formation of considerable amount of other unidentified product as by-product requiring cumbersome
separation, and only in few cases, desired 2-formylpyrrole acetal was prepared in high yield.
* Corresponding author.
** Corresponding author.
E-mail address: yanzh@ncu.edu.cn (Z.H. Yan).
1001-8417/$ – see front matter # 2011 Zhao Hua Yan. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.10.004

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Z.H. Yan et al. / Chinese Chemical Letters 23 (2012) 33–36
- RO-
_
Base
OR
OR
OR
OR
OR
N
H
N
N
_
N
OR
OR
I
II
1
III
+ R1O-
_
OR1
OR1
OR1
OR
OR1
N
N
_
N
- RO-
H+
+ R1O-
N
H
OR1
OR1
IV
V
2
VI
Fig. 1. Hypothesized process for transacetalization of 2-formylpyrrole acetal.
Me
Me
NaOEt
EtOH
O
OEt
OEt
N
H
N
H
EtOOC
EtOOC
rt, 8 h
98%
O
1a
2a
Scheme 1. Transacetalization of 1a with sodium ethoxide.
In order to develop a general and robust protocol for the preparation of 2-formylpyrrole acetals, we turned our
attention to transacetalization method. However, the use of reported conditions involving lewis acid still gives the
unidentified by-products. It has been reported that nitrogen-unprotected pyrrole is prone to forming highly reactive
azafulvene species [11,12] which can be attacked by a nucleophile to form a substituted pyrrole. Based on this specific
reactivity of pyrrole compounds, we hypothesized that the reaction of 2-formylpyrrole acetal with a strong base (for
example, sodium alkoxide) will lead to species I (Fig. 1), followed by subsequent attack of a nucleophile (for example,
alkoxide anion) on 2-methylene carbon would give a transacetalization product 2.
To test hypothesis, we treated 1a with various bases in alcohols. We were pleased to find that the reaction with
sodium ethoxide in EtOH at room temperature proceeded to give the corresponding transacetalization product 2a in
98% isolated yield (Scheme 1). Reaction time can be reduced to 2 h under reflux temperature.
This preliminary result encouraged us. To the best of our knowledge, this kind of transacetalization of 2-
formylpyrrole acetal through reaction with sodium alkoxide has not yet been reported. In order to investigate the scope
and generality of transacetalization of 2-formylpyrrole acetal with sodium alkoxide, we screened a variety of 2-
formylpyrrole acetal substrates. Herein we want to report our results.
It is important to note that 2-formylpyrrole acetals without electron-withdrawing group on pyrrole ring are usually
unstable, so we here selected some stable 2-formylpyrrole acetals with electron-withdrawing group on pyrrole ring as
substrates to investigate the scope and generality of transacetalization.
Acetals derived from a number of 2-formylpyrrole can undergo efficient transacetalization under these newly
developed conditions. It is worth noting that methanol, ethanol, propanol and butanol are all compatible. In these
reactions, sodium alkoxides were made in situ by reaction of metallic sodium with alcohol prior to the addition of a
substrate, and functioned as both a base and a nucleophilic anion. Not surprisingly, the transesterification of ester
groups in the substrates also took place with the concurrent transacetalization of the acetal group (entries 2, 7, 8, 9, and
10 in Table 1).
Considering the relatively slow formation of sodium alkoxides resulting from the reactions of metallic sodium and
secondary alcohols and tertiary alcohols, at this stage, sodium alkoxides of secondary alcohols and tertiary alcohols
were not yet tested for the transacetalization.
Electron-rich 2-pyrrolecarbaldehyde ethylene diol acetal and 4-bromo-2-pyrrolecarbaldehyde ethylene diol
acetal (both substrates are all very unstable. In the presence of traces of moisture or protic solvent, they quickly
decomposed and were converted to their parent compounds 2-pyrrolecarbaldehyde and 4-bromo-2-pyrrolecarbal-
dehyde) were also used as substrates for the reaction with sodium methoxide in methanol. From TLC, we observed
the similar phenomina indicating that the transacetalization also went well. Likewise, due to the unstability of the

Z.H. Yan et al. / Chinese Chemical Letters 23 (2012) 33–36
35
Table 1
Transacetalization of 2-formylpyrrole acetals with sodium alkoxide in alcohol at reflux.a
Entry
1
Substrate
Sodium alkoxide
NaOEt
Product
Yieldb (%)
98
Me
Me
O
OEt
OEt
EtOOC
EtOOC
N
H
N
H
O
1a
2a
Me
2
3
4
1a
NaOMe
NaOEt
99
96
98
OMe
OMe
MeOOC
N
H
2b
O2N
O2N
O
OEt
OEt
N
N
H
H
O
1b
2c
O2N
1b
1b
NaOMe
OMe
N
H
OMe
2d
NaOBun
NaOMe
NaOEt
97
99
99
97
O2N
5
6
7
8
OBun
OBun
N
H
2e
Ph
O
Ph
O
OMe
OMe
MeOOC
MeOOC
EtOOC
PrnOOC
N
H
N
H
1c
2f
Ph
1c
OEt
N
H
OEt
2g
NaOPrn
Ph
1c
OPrn
OPrn
N
H
2h
9
2g
2h
NaOMe
NaOMe
2f
2f
99
99
10
a
General conditions: a solution of 1 (0.5 mmol) and NaOR (3.0 mmol, was made in situ by addition of 3.0 mmol of sodium metal in ROH till it
disappeared) in 10 mL of ROH was heated at refluxed for 2 h.
b
Isolated yield.
products 2-pyrrolecarbaldehyde methanol acetal and 4-bromo-2-pyrrolecarbaldehyde methanol acetal, we cannot
1
obtain their H and 13C NMR spectra.
A number of mechanistic information has also been obtained. First, an intermediate 2c0 was isolated by quenching
the reaction at early stage. Monitoring by 1H NMR, 2c0 was also shown to be converted to the product 2f under the
standard conditions (Scheme 2). Second, nitrogen-methylated products of 1a–1c and acetal derived from
benzaldehyde did not undergo transacetalization. These combined observations are consistent with the proposed
mechanism (see Fig. 1).
In conclusion, nitrogen-unprotected 2-formylpyrrole acetals can react with sodium alkoxide in alcohol at
reflux temperature smoothly to give the corresponding transacetalization products in nearly quantitative yields.
This mild and highly efficient procedure will find usefulness for the preparation of acid sensitive 2-formylpyrrole
acetals.

36
Z.H. Yan et al. / Chinese Chemical Letters 23 (2012) 33–36
Ph
Ph
NaOMe
MeOH
O
O
N
H
N
H
OH
MeOOC
MeOOC
rt, 2 h
30%
O
OMe
1c
2c'
Scheme 2. The preparation of 2c0.
Acknowledgments
We thank The Ministry of Education of The People’s Republic of China, Department of education of Jiangxi
Province and Jiangxi Provincial Natural Science Foundation for financial support. We also appreciate The Analysis
Center of Nanchang University for physical characterization of all the compounds. Special thanks to Dr. Yu Jin-Quan
in Scripps Institute in the United States of America for his highly valuable assistance.
References
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