A lewis acid-promoted pinner reaction

Article abstract of DOI:10.3762/bjoc.9.179

Carbonitriles and alcohols react in a Lewis acid-promoted Pinner reaction to carboxylic esters. Best results are obtained with two equivalents of trimethylsilyl triflate as Lewis acid. Good yields are achieved with primary alcohols and aliphatic or benzylic carbonitriles, but the straightforward synthesis of acrylates and benzoates starting with acrylonitrile and benzonitrile, respectively, is similarly possible. Phenols are not acylated under these reaction conditions. The method has been used for the first total synthesis of the natural product monaspilosin. In the reaction of benzyl alcohols variable amounts of amides are formed in a Ritter-type side reaction.

Full text of DOI:10.3762/bjoc.9.179

A Lewis acid-promoted Pinner reaction
Dominik Pfaff, Gregor Nemecek and Joachim Podlech*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1572–1577.
Institut für Organische Chemie, Karlsruher Institut für Technologie
(KIT), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
doi:10.3762/bjoc.9.179
Received: 23 May 2013
Accepted: 11 July 2013
Published: 02 August 2013
Email:
Joachim Podlech* - joachim.podlech@kit.edu
* Corresponding author
Associate Editor: T. J. J. Müller
Keywords:
© 2013 Pfaff et al; licensee Beilstein-Institut.
License and terms: see end of document.
carbonitriles; carboxylic esters; Lewis acids; Pinner reaction; Ritter
reaction
Abstract
Carbonitriles and alcohols react in a Lewis acid-promoted Pinner reaction to carboxylic esters. Best results are obtained with two
equivalents of trimethylsilyl triflate as Lewis acid. Good yields are achieved with primary alcohols and aliphatic or benzylic
carbonitriles, but the straightforward synthesis of acrylates and benzoates starting with acrylonitrile and benzonitrile, respectively,
is similarly possible. Phenols are not acylated under these reaction conditions. The method has been used for the first total syn-
thesis of the natural product monaspilosin. In the reaction of benzyl alcohols variable amounts of amides are formed in a Ritter-type
side reaction.
Introduction
In 1877 Pinner and Klein discovered the proton-induced imidate
syntheses [1,2]. They passed anhydrous gaseous hydrogen chlo-
ride through a mixture of isobutyl alcohol and benzonitrile. A
crystalline product precipitated, which they identified as an
imidate hydrochloride (Scheme 1). Best results in the Pinner
reaction are obtained with primary or secondary alcohols and
Scheme 1: Imidate hydrochloride synthesis discovered by Pinner and
Klein [1,2].
aliphatic or aromatic nitriles.
A plausible mechanism (Scheme 2) starts with a protonation of
the nitrile by the strong acid hydrogen chloride leading to a Various transformations are possible with the imidate
highly activated nitrilium cation, which can be attacked by the hydrochlorides: Hydrolysis at low pH leads to carboxylic esters,
alcohol component. Proton transfer (P.T.) yields the imidate where basic hydrolysis yields imidates. Reaction with amines
hydrochloride [3].
furnishes amidinium compounds and the reaction with alcohols
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While developing a total synthesis of altenuic acid II [11], we
observed the reaction of an aliphatic hydroxy group with aceto-
nitrile in the presence of two equivalents of hafnium triflate
[Hf(OTf)4] yielding the respective acetate. A detailed investi-
gation on this reaction is reported in this article [12].
Results and Discussion
The Lewis acid-mediated Pinner reaction of aliphatic alcohols
with nitriles was first observed by us, when hafnium triflate was
present in the reaction mixture. We first aimed to replace this
rather expensive Lewis acid with a more favorable substitute.
Scheme 2: Mechanism of the Pinner reaction.
gives rise to ortho esters. A less frequently used pyrolysis leads As a test reaction for optimization we used the acylation of
to carboxamides (Scheme 3) [3-5].
9H-fluoren-9-ylmethanol (1) with acetonitrile as the nitrile
component and solvent (Scheme 4). This substrate and the
respective ester 2 are simply detected by thin-layer chromato-
graphy (TLC) and their molecular weights prevent losses during
evaporation procedures.
Scheme 4: Reaction used for optimizations.
A 72% yield was achieved, when two equivalents of
hafnium(IV) triflate were used and when the nitrile was used as
the solvent (Table 1, entry 1). Catalytic amounts of this Lewis
acid led to unsatisfactory yields, when the reaction was
performed in acetonitrile or in mixtures of acetonitrile with
water (Table 1, entries 2 and 3). The 3% yield in acetonitrile/
water (10:1) suggests that water is detrimental in the Pinner
Scheme 3: Transformations of imidate hydrochlorides.
The harsh reaction conditions preclude a broad application of reaction. Among various tested Lewis acids, the best results
the Pinner reaction. The high toxicity and the laborious were obtained with aluminium tribromide at 50 °C (65%,
handling of gaseous hydrogen chloride are further drawbacks of Table 1, entry 5) and with trimethylsilyl triflate at room
this reaction. Nevertheless, milder protocols have developed temperature (83%, Table 1, entry 7). The less expensive
over the decades: Luo and Jeevanandam used trimethylsilyl trimethylsilyl chloride turned out to be an unsuitable alternative
chloride (TMSCl) and ethanol for an in situ generation of (Table 1, entry 8). The yield could not be improved, when two
hydrogen chloride [6]. Watanabe et al. reported on a Pinner equivalents of aluminium bromide were used together with
reaction with a 4 N hydrogen chloride solution in cyclopentyl catalytic amounts of hafnium triflate (Table 1, entry 6).
methyl ether (CPME) [7]. An ionic liquid based on a sulfonic
acid was used by Jiang et al. [8], where this method has only Since two equivalents of a Lewis acid are necessary for
been applied to aliphatic nitriles. A transition metal-catalyzed optimum results, we presume activation of both the alcohol and
Pinner reaction using dihydridotetrakis(triphenylphos- the nitrile. A plausible mechanism includes formation of a silyl
phano)ruthenium ([RuH2(PPh3)4]) as catalyst has been applied ether and an N-nitrilium cation. The former should be more
to aliphatic nitriles and alcohols and was similarly used for nucleophilic than an alcohol and the latter should be an effi-
intramolecular reactions [9]. Schaefer et al. reported a base- cient electrophile (Scheme 5). Reaction of silyl ether and
catalyzed Pinner reaction, which gave only poor yields because nitrilium cation leads to a cationic N,O-bis(trimethylsilyl)imino
of the setting of an equilibrium [10].
ester, which is hydrolyzed to a carboxylic ester. Formation of
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Beilstein J. Org. Chem. 2013, 9, 1572–1577.
Table 1: Selection of optimization experiments.
#
Lewis acid (equiv)
Conditions
Yield (s. m.)a [%]
1
2
3
4
5
6
7
8
9
Hf(OTf)4 (2.0)
Hf(OTf)4 (0.2)
Hf(OTf)4 (0.2)
AlBr3 (2.0)
MeCN, rt, 48 h
72 (15)
25 (69)
3 (81)
MeCN, rt, 65 h
MeCN/H2O 10:1, rt, 65 h
MeCN, rt, 65 h
50 (39)
65 (20)
64 (24)
83 (9)
AlBr3 (2.0)
MeCN, 50 °C, 90 h
MeCN, rt, 65 h
AlBr3 (2.0), Hf(OTf)4 (0.1)
TMSOTf (2.0)
TMSCl (2.0)
MeCN, rt, 65 h
MeCN, rt, 65 h
33 (59)
80 (10)
TMSOTf (2.0)
MeCN, Et3Nb, rt, 65 h
aYields of recovered starting material (s. m.) given in parentheses. bEt3N (1 equiv) was added.
herein reported Lewis acid promoted Pinner reaction furnished
52% of this substrate, where a less-sensitive substrate could be
applied without the necessity of an inert atmosphere. The com-
paratively low yields in the reactions with benzonitrile are most
probably caused by the lower electrophilicity of the benzoni-
trilium ion. The positive charge is significantly stabilized by the
+M effect of the π system.
The high yields observed in the reactions of para-nitrobenzyl
alcohol (21) and especially in its reaction with acrylonitrile
brought us to the speculation that the nitro group has a special
beneficial effect on this reaction, possibly as radical scavenger.
It turned out that the addition of nitrobenzene [16] in the reac-
tions with acrylonitrile led to increased yields in some cases.
Scheme 5: Plausible mechanism of the Lewis acid-promoted Pinner
reaction.
the Brønsted acid trifluoromethanesulfonic acid is to be Other radical scavengers like hydroquinone had a similar effect.
expected under these reaction conditions, but seems to have no
influence on the reaction outcome. A similar reaction with the Reaction of hexane-1,6-diol (31) gives moderate yields of the
addition of one equivalent of triethylamine led to a virtually diacylated products, where significant amounts of the
identical yield (Table 1, entry 9).
monoesters were isolated (Table 2, entry 7). Alcohols with
further functional groups were similarly tested, but poor yields
With the optimized reaction conditions we tested a selection of were observed, when ester or carbamate groups were present in
nitriles and alcohols. All reactions required the application of the substrates (Table 2, entries 8 and 9). The Lewis acid
the nitrile as solvent. Low yields were observed, when trimethylsilyl triflate possibly cleaves the benzyloxycarbonyl
equimolar amounts of the nitrile and the alcohol were used in (Z) group, since the similar trimethylsilyl iodide (TMSI) is
methylene chloride as inert solvent. The tested nitriles are known to cleave Z protecting groups [17]. Poor yields are
acetonitrile, benzyl cyanide, benzonitrile, and acrylonitrile obtained in the Lewis acid mediated reaction of nitriles with
(Table 2).
secondary alcohols such as cyclohexanol (Table 2, entry 10).
No product at all was obtained, when the tertiary alcohol
Best yields were obtained in the reactions of primary alcohols 1-methylcyclohexanol (48) was exposed to these conditions
with acetonitrile and benzyl cyanide (Table 2, entries 1–4). (Table 2, entry 11).
Somewhat lower yields were observed with acrylonitrile; never-
theless, reported methods for the preparation of acrylate 5 lead The Lewis acid promoted Pinner reaction is highly chemo-
to similar, and in some cases even lower yields [13,14]. A stan- selective; phenols were not acylated by these conditions and
dard protocol for the synthesis of 9H-fluoren-9-ylmethyl acry- were re-isolated with high yields (Table 2, entries 12–14). In
late starting with the moisture-sensitive acryloyl chloride under this context we tested 4-(2-hydroxyethyl)phenol (53) containing
an inert atmosphere was reported to yield only 33% [15]. The an aliphatic and a phenolic hydroxy function in the reaction
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Beilstein J. Org. Chem. 2013, 9, 1572–1577.
Table 2: Variation of nitriles and alcohols.a
#
R1 = Me
R1 = Bn
R1 = Ph
R1 = Vinyl
R2−OH
Product, Yield [%]
1
2
3
4
5
6
7
8
9
10
Fluorenylmethanol (1)
Me(CH2)9OH (6)
2, 83
3, 86
4, 44
9, 23
14, 27
19, 26
24, 39
29, 31
—
5, 52 (67b)
10, 29 (40b)
15, 38 (16b)
20, 23 (19b)
25, 85
7, 80
8, 85
Cl(CH2)6OH (11)
12, 84
13, 90
Et[O(CH2)2]2OH (16)
p-NO2C6H4CH2OH (21)
p-HO2CC6H4CH2OH (26)
HO(CH2)6OH (31)
17, 75
18, 85
22, 90
23, 78
27, 88
28, 87
30, 64
32, 32 (33, 19c)
37, 21
34, 46 (35, 37c)
38, 16
—
EtO2C(CH2)5OH (36)
Z-NH(CH2)4OH (41)
cyHexOH (45)
39, 10
0
40, 7
42, 13
43, 13
44, 14
46, 15
47, 25
—
—
11
0
0
—
—
(48)
12
13
14
15
PhOH (49)
0
0
0
0
—
—
—
0
—
—
—
0
—
—
—
0
p-NO2C6H4OH (50)
3,4,5-Trimethoxyphenol (51)
p-MeOC6H4CH2OH (52)
aAlcohol (1 equiv), TMSOTf (2 equiv) dissolved in the nitrile (4 mL/mmol alcohol), rt, 65 h. bTMSOTf (2 equiv) and nitrobenzene (1 equiv) were added.
cTMSOTf (4 equiv) was added. Yield of the monoacylated by-products 33 and 35, respectively, in parentheses.
with acetonitrile and benzyl cyanide, respectively (Scheme 6).
The respective esters 54 and 55 were obtained with good yields:
no esterification of the phenolic hydroxy group was observed.
The reaction of 4-(2-hydroxyethyl)phenol (53) with benzyl
cyanide yielded monaspilosin (55), an aromatic ester isolated
from the mould fungus Monascus pilosus by Cheng et al. [18].
This compound was reported to have radical scavenger prop-
erties. The first total synthesis of this natural product was here-
with achieved with 73% yield in only one step.
Good yields were observed, when benzyl alcohols with elec-
tron withdrawing (−M) substituents such as 4-nitrobenzyl
alcohol (21, Table 2, entry 5) and 4-hydroxymethylbenzoic acid
(26, Table 2, entry 6) were reacted with benzyl cyanide or
acetonitrile and even with acrylonitrile. A protection of the
Scheme 6: Synthesis of monaspilosin.
carboxylic acid turned out to be not necessary. In contrast, a
4-methoxy-substituted benzyl alcohol 52, i.e., an electron-rich
benzyl alcohol, furnished no carboxylic ester at all (Table 2, cant positive partial charge) reacts at the nitrogen atom of a
entry 15). Rather poor yields of the respective carboxylic esters nitrile. This transformation is a competition to the Pinner reac-
were achieved, when unsubstituted benzyl alcohol (56) or tion, when benzyl alcohols are used. A possible mechanism of
4-fluorobenzyl alcohol (64) were reacted with one of the this reaction is given in Scheme 7. Double silylation leads to the
carbonitriles (Table 3). Instead we isolated significant amounts formation of a good leaving group and the highly electrophilic
of carboxamides. These amides result from a Ritter-type reac- benzylic carbon is attacked by the nitrile yielding a nitrilium
tion [19-21], where a carbenium ion (or a substrate with signifi- cation. The reaction is finalized by hydrolysis furnishing the
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Beilstein J. Org. Chem. 2013, 9, 1572–1577.
Table 3: Carboxamide formation in a Pinner-type reaction.a
#
R1
R2
Yield [%] (Product)
Ester
Amide
1
2
3
4
5
6
7
8
Me
Bn
Bn (56)
41 (57)
18 (58)
59 (60)
66 (61)
90 (63)
63 (66)
79 (67)
70 (68)
89 (69)
Bn (56)
18 (59)
Ph
Bn (56)
0
Vinyl
Me
Bn
Bn (56)
4 (62)
p-FC6H4CH2 (64)
p-FC6H4CH2 (64)
p-FC6H4CH2 (64)
p-FC6H4CH2 (64)
29 (65)
0
0
0
Ph
Vinyl
aAlcohol (1 equiv), TMSOTf (2 equiv) dissolved in the nitrile (4 mL/mmol alcohol), rt, 65 h.
Acknowledgements
This work was supported by the Landesgraduiertenförderung
Baden-Württemberg (grant for G. N.).
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