Improved pinner reaction with CPME as a solvent

Article abstract of DOI:10.1080/00397910802632548

The classical Pinner reaction has been improved by the utilization of 4N-HCl solution in cyclopentyl methyl ether (CPME) as a solvent, wherein direct isolation of the product was possible by a simple filtration.

Full text of DOI:10.1080/00397910802632548

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Improved Pinner Reaction with
CPME as a Solvent
Kiyoshi Watanabe a , Naoto Kogoshi a , Hideaki Miki a
& Yasuhiro Torisawa b
a Specialty Chemicals Division, Zeon Corporation,
Tokyo, Japan
b Faculty of Pharmacy, Takasaki University of Health
and Welfare, Takasaki, Japan
Published online: 27 Apr 2009.
To cite this article: Kiyoshi Watanabe , Naoto Kogoshi , Hideaki Miki & Yasuhiro
Torisawa (2009) Improved Pinner Reaction with CPME as a Solvent, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:11, 2008-2013, DOI: 10.1080/00397910802632548
To link to this article: http://dx.doi.org/10.1080/00397910802632548
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Synthetic Communications1, 39: 2008–2013, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802632548
Improved Pinner Reaction with CPME
as a Solvent
Kiyoshi Watanabe,1 Naoto Kogoshi,1 Hideaki Miki,1 and
Yasuhiro Torisawa2
1Specialty Chemicals Division, Zeon Corporation, Tokyo, Japan
2Faculty of Pharmacy, Takasaki University of Health and Welfare,
Takasaki, Japan
Abstract: The classical Pinner reaction has been improved by the utilization of
4N-HCl solution in cyclopentyl methyl ether (CPME) as a solvent, wherein direct
isolation of the product was possible by a simple filtration.
Keywords: CPME, HCl, Pinner reaction, solvent
INTRODUCTION
Operationally simple synthetic procedures are always in demand for
modern process research. Particularly, improvement of classical transfor-
mations by replacing hazardous reagents with safer ones that are environ-
mentally benign is an immediate task. The Pinner reaction is a standard
process that can combine nitriles with a variety of nucleophiles under
anhydrous acidic conditions, affording a useful key intermediate salt
for agrochemical and medicinal research. For example, imino ether
hydrochlorides (imidates) are useful precursors for the synthesis of
heterocyclic ring systems such as oxazoles, imidazoles, and their benzo
derivatives. They are also useful in the conversion of nitriles into esters
Received August 13, 2008.
Address correspondence to Yasuhiro Torisawa, Faculty of Pharmacy,
Takasaki University of Health and Welfare, 60 Naka Orui, Takasaki, Gunma
370-0033, Japan. E-mail: torisawa@takasaki-u.ac.jp
2008

Improved Pinner Reaction
2009
and for the preparation of amidines, another versatile heterocyclic build-
ing block found in various chemicals and pharmaceutics.[1]
Imino ethers are synthesized via the Pinner process in which a nitrile and
an alcohol in anhydrous solvent are treated with a large excess of anhydrous
hydrogen chloride (HCl) gas. As noted elsewhere, if the reaction is con-
ducted at temperatures warmer than 0ꢀC, the product imino ether salt
may decompose to give an amide and an alkyl halide, or in some cases,
use of solvent tends to lower the yields of the product. When the nitrile is
sterically hindered, the reaction may not take place.[1] Furthermore, the
operational drawback associated with this protocol was the use of a large
excess of toxic, corrosive, and hard-to-handle HCl gas. It may be difficult
to determine exactly how much gas was involved in the reaction mixture,
and consequently, a large excess of this hazardous reagent is invariably used,
as noted in the patent.[2]
A straightforward improvement might be achieved, however, by the
use of HCl solution in a proper solvent. One such improvement has been
filed in the recent patent,[2] which now prompted us to disclose our
procedure for the improvement of the Pinner process with a new HCl
solution, attaining an operationally simple isolation of the resulting
imino derivatives in excellent yields.
4N-HCl IN CPME
Our recent review mentioned the invention of the new ethereal solvent,
cyclopentyl methyl ether (CPME), as an alternative process solvent, which
has show some applicability in modern organic synthesis.[3] Particularly its
stability toward HCl and other protic acids including H2SO4 is note-
worthy. Taking advantage of this nature, a 4N-HCl solution in CPME
has been developed and is now available as a commercial product. This
stock solution is usually kept in a refrigerator for a long period of time.[3]
We examined the utility of this 4N-HCl solution, first with an appli-
cation in the workup stage of the conventional Grignard addition to the
nitrile 1. The workup stage of the Grignard reaction needed acidic treat-
ment, and in the case of imine hydrolysis, it often required a long stirring
period with aq. citric acid, for example. When 4N-HCl in CPME solution
was applied to this hydrolysis, a more convenient and quick workup was
attained as shown in Scheme 1.
In particular, in the case of the nitriles without pyridine rings,
this workup became more convenient without neutralization of the
acidic mixture. CPME was a quite useful ether solvent in the extractive
isolation from aqueous acidic mixtures. Such operations are usually
small matters in laboratory synthesis, but they are still important in

2010
K. Watanabe et al.
Scheme 1. Workup with 4N-HCl in CPME.
plant work (reduction of workup operations and amounts of solvents
employed).
In our second application, further simplification in the workup was
demonstrated wherein a simple deprotection of an N-Boc group was
attempted in a routine amino acid synthesis as illustrated Scheme 2.
Thus, cold 4N-HCl in CPME (4 equiv.) was slowly added to a stirred
solution of ethyl (ꢁ)-erythro-N-(t-butoxycarbonyl)-2-amino-3-hydroxy-
3-phenylpropionate (3) in CPME under a nitrogen atmosphere at 0ꢀC.
Stirring for 6 h at room temperature completed the deprotection, and
the precipitate was collected by filtration, washed with CPME, and dried
under vacuum to afford the corresponding 3-phenylserine ethyl ester
hydrochloride (4)[4] as a white solid (97%). In this way, the deprotection
reaction can be carried out by stirring the substrates in 4N-HCl solution
followed by simple isolation by filtration to obtain the pure isolated
product.
This also indicated that amine hydrochloride salts are usually insolu-
ble in CPME and thus can be easily purified by simple filtration from the
reaction mixtures.[3] These applications and other literature precedents[3]
indicated we should carry out an improvement of the Pinner process by
the use of 4N-HCl in CPME as a key reagent.[3,5]
Scheme 2. Deprotection with 4N-HCl in CPME.

Improved Pinner Reaction
2011
PINNER REACTION IN CPME
Improvement of the Pinner process by 4N-HCl in CPME was carried out,
focusing on the safe and effective preparation of some imino ethers from
nitrites. Our protocol highlights the fewest operational steps involved for
the direct isolation of the pure product. Thus, our protocol for the Pinner
reaction in CPME can be exemplified in the following reaction shown in
Scheme 2.
Typically, cold 4N-HCl in CPME (4 equiv.) was added to a solution
of nitrile and anhydrous methanol (3 equiv.) in CPME (ꢂ 4 V) with stir-
ring under a nitrogen atmosphere at 0ꢀC. The resulting reaction mixture
was stirred at 0ꢀC for an additional hour before it was placed in a refrig-
erator (0–5ꢀC) for 48 h (during this time, white crystalline material preci-
pitated). The precipitate was immediately collected by filtration at room
temperature, washed with CPME, and dried under vacuum to afford the
crystalline imidate hydrochloride as a white solid (86–91%), which was
identical with the authentic material.[2] Our process is very simple and
effective with the fewest operational steps when compared with the pre-
vious protocol. Extractive workup was tedious and less effective because
it took large amounts of extraction solvent, which was evaporated for the
isolation of products as shown in the following example with dioxane as a
solvent (Scheme 3).
In the previous patent, in which a 4M-HCl solution in dioxane was
employed as a solvent for the same transformation, anhydrous ether
was required as a cosolvent and tedious workup for the evaporation of
dioxane was inevitable before the precipitation of the product with the
addition of ether.[2] This protocol thus required ether as an initial solvent,
which was evaporated during workup, and further addition of ether for
precipitation. Obviously, this is not recommended for scalable prepara-
tion of the Pinner products, which are oftentimes sensitive to moisture
and very prone to decomposition, as mentioned earlier. The quick
workup sequence with CPME solution is thus very valuable in handling
such sensitive intermediates. Some other examples are shown in Table 1,
demonstrating the ample generality of this protocol.[5]
In conclusion, we have demonstrated a very simple Pinner reaction
using CPME as the key solvent. In this way, telescoping the lengthy steps
Scheme 3. Pinner reaction with 4N-HCl in CPME.

2012
K. Watanabe et al.
Table 1. Pinner reaction with 4 N-HCl in CPME
R
HCl solution
Solvent
Yield (%)
1,4-Dioxane
CPME
Et2O
CPME
86a
90
CPME
CPME
CPME
CPME
86
91
aU.S. Patent 6,806,380 B2.[2]
into an operationally simple process is very desirable in modern process
research because it reduces the cost of labor and the amount of waste.
One of the general strategies for the minimization of the workup stage
is a careful selection of the solvent employed, and the present protocol
indicates the usefulness of CPME in both the reaction and workup
stages. Further application of CPME in process research as well as labo-
ratory synthesis is now in progress. We have surveyed some conventional
oxidations, such as Swern oxidation and 2,2,6,6-tetramethylpiperidine
1-oxyl (TEMPO) (radical) oxidation, and these were effectively carried
out in CPME as a solvent. Direct chlorination of primary alcohol was
possible by stirring 4N-HCl in CPME at ambient temperature. These
findings will be reported as subsequent reports in due course.
EXPERIMENTAL
Synthesis of 1,3-Dimethoxypropanimine as a General Procedure
To an ice-cooled and stirred solution of 3-methoxypropionitrile (3, 2.5 g,
29.4 mmol) in anhydrous methanol (3.6 mL, 88.9 mmol) and CPME
(10 mL), 4N-HCl solution in CPME (30 mL) was added, and the resulting
mixture was kept stirring for 2 h before it was refrigerated for 48 h until

Improved Pinner Reaction
2013
enough white precipitates had formed. The precipitate was immediately
collected by filtration at room temperature, washed with CPME (ca.
10 mL), and dried under vacuum to afford the crystalline imidate hydro-
chloride as a white solid (4, 4.1 g, 91%), identical with the authentic
material.[2] 1H NMR (CDCl3): d 12.72 (br s, 1H), 11.80 (br s, 1H), 4.30
(s, 3H), 3.80 (t, J ¼ 5.65 Hz, 2H), 3.25 (s, 3H), 2.95 (t, J ¼ 5.54 Hz, 2H).
13C NMR (CDCl3): d 178.9, 67.7, 61.3, 59.2, 34.0.
The same reaction with 4N-HCl in dioxane was carried out for
comparison according to the literature.[2] To an ice-cooled mixture of 3
(29.4 mmol) in anhydrous methanol (88.9 mmol) and ether (10 mL),
4N-HCl solution in dioxane was added, and the resulting mixture was
kept stirring for 2 h before it was kept in a refrigerator for 48 h to form
a precipitate (during this time, a small amount of white crystalline
material precipitated). The reaction mixture was removed from the refrig-
erator and warmed to approximately 40ꢀC with a warm water bath.
Nitrogen gas was then bubbled through the warm reaction mixture to
remove excess HCl chloride. The volume of the solvent was further
reduced in vacuo, and anhydrous ether (10 mL) was added to effect pre-
cipitation. The precipitate was collected by filtration, washed with ether
(10 mL), and dried under vacuum to afford 3.9 g (86%) of the authentic
crystalline imidate hydrochloride salt (4).
ACKNOWLEDGMENT
We thank Drs. Y. Suto and N. Yamagiwa of Takasaki University of
Health & Welfare for their helpful assistance in manuscript preparation.
REFERENCES
ꢀ
1. Kurti, L.; Czako, B. In Strategic Applications of Named Reactions in Organic
¨
Synthesis: Background and Detailed Mechanisms; Academic Press: San Diego,
CA, 2005.
2. Kolb, H. C.; Kanamarlapudi, R. C.; Richardson, P. F.; Khan, G. Modified
safe and efficient process for the environmentally friendly synthesis of imido-
esters. US Patent 6,806,380 B2, 2004.
3. Watanabe, K.; Yamagiwa, N.; Torisawa, Y. CMPE as an alternative process
solvent. Org. Process Res. Dev. 2007, 11, 251.
4. Hoenig, H.; Seufer-Wasserthal, P.; Weber, H. Chemo-enzymatic synthesis of
all isomeric phenylserines and -isoserines. Tetrahedron 1990, 46, 3841.
5. Kogoshi, N.; Miki, H. Process for producing imidoesters hydrochlorides.
JP 2007-320854, 2007.