Esterification of carboxylic acids and etherification of phenols with amide acetals

Article abstract of DOI:10.1055/s-2008-1077882

The esterification and etherification of unhindered, as well as severely hindered, carboxylic acids and phenols with basic amide acetals, such as N,N-dimethylformamide dimethyl acetal, and their side reactions are discussed. Modified procedures are descri

Full text of DOI:10.1055/s-2008-1077882

ACCOUNT
1603
Esterification of Carboxylic Acids and Etherification of Phenols with Amide
Acetals
Esterification of
C
e
arboxylic
A
l
cids an
m
d
Etherification of
P
u
henols with
t
A
mide
A
ceta
V
ls orbrüggen*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany
E-mail: helvor@chemie.fu-berlin.de
Received 19 February 2008
Dedicated with gratitude to Professor Carl Djerassi, who not only tolerated, but encouraged and supported my work on amide acetals
during 1962–1963 in his group at Stanford University, USA.
+
H
H
Abstract: The esterification and etherification of unhindered, as
well as severely hindered, carboxylic acids and phenols with basic
amide acetals, such as N,N-dimethylformamide dimethyl acetal,
and their side reactions are discussed. Modified procedures are de-
scribed in which these side reactions are avoided to achieve high or
near quantitative yields of the desired corresponding methyl esters
or phenol methyl ethers. On the addition of N,N-dimethylform-
amide dimethyl acetal, solutions of 4-nitrobenzoic acid in basic sol-
vents, such as tetrahydrofuran or 1,4-dioxane, form precipitates of
the corresponding iminium carboxylates, which give near quantita-
tive yields of the desired methyl 4-nitrobenzoate, as well as N,N-
dimethylformamide and methanol.
O
H+
4
RCO2R'
R
O R'
RCO2H 1 + R'OH 2
– H3O+
3
O
H
Scheme 1
In addition to acidic catalysts, molecular sieves, or other
special catalysts,3–8 condensation agents, such as trialkyl
ortho esters7,8 in the presence of Lewis acids or N,N¢-dicy-
clohexylcarbodiimide (DCC)9 in the presence of 4-(di-
methylamino)pyridine (DMAP),10 are frequently used to
achieve the elimination of water in esterifications. Yet, on
employing DCC, the resulting N,N¢-dicyclohexylurea
(DC-urea) as well as any added catalysts, such as DMAP,
have to be removed on workup.
1
2
3
Introduction
Preparation and Properties of Amide Acetals
Esterification of Carboxylic Acids and Etherification of
Phenols with Amide Acetals
4
Side Reactions during the Esterifications and Etherifica-
tions
Thus, in small-scale esterifications of carboxylic acids or
etherifications of phenols, the use of diazomethane or
trimethylsilyldiazomethane11,12 to give the corresponding
methyl esters or aryl methyl ethers is still a standard pro-
cedure because only nitrogen is usually evolved during
the reaction.11,12 Because of the pronounced toxicity of di-
azomethane and the explosion hazard, as well as the rela-
tively high cost connected with preparative amounts of
diazomethane and, in particular, trimethylsilyldiazo-
methane, their general preparative use for the esterifica-
tion of carboxylic acids and the etherification of phenols
has been problematic for many years. Furthermore, the
ready addition of diazomethane to aldehydes and ketones
to form insertion products or epoxides, as well as the ad-
dition of diazomethane to the olefinic bonds of a,b-unsat-
urated carbonyl compounds or to acetylenic bonds, have
always to be considered.13
4.1
4.2
Suppression of the Formation of Quaternary Salts and Other
Side Reactions
Tetrahydrofuran or 1,4-Dioxane as Optimal Reaction Sol-
vents
Attempted Suppression of Condensation Reactions
Concluding Remarks
4.3
5
Key words: phenols, esterification, ethers, amide acetals, carboxy-
lic acids
1
Introduction
The esterification of carboxylic acids is a very important
reaction in preparative organic chemistry.1,2 Thus, even in
relatively recent years, new procedures have been de-
scribed for the dehydration of equimolar mixtures of car-
boxylic acids 1 and alcohols 2,3–7 e.g. by heating them in
the presence of a variety of acidic catalysts. The desired
esters 4 are formed via the rather bulky tetrahedral ortho
ester intermediates 3 and the subsequent elimination of
water (Scheme 1). As a consequence, sterically hindered
carboxylic acids, such as 2,4,6-trimethylbenzoic acid, do
not react in this way under standard esterification condi-
tions with alcohols.
Thus, there is a definite need for other general esterifica-
tion or etherification reagents, such as the hitherto rather
neglected basic N,N-dialkylformamide acetals, which do
not react with isolated olefinic bonds. On workup, besides
the desired esters or ethers, these amide acetals give only
N,N-dialkylformamides and the employed alcohol as side
products instead of those products, such as the aforemen-
tioned DC-urea, which have to be removed by chromatog-
raphy.
SYNLETT 2008, No. 11, pp 1603–1617
x
x
.x
x
.2
0
0
8
Advanced online publication: 23.06.2008
DOI: 10.1055/s-2008-1077882; Art ID: A48208ST
© Georg Thieme Verlag Stuttgart · New York

1604
2
H. Vorbrüggen
ACCOUNT
Preparation and Properties of Amide Acetals
Me
Me
OEt
OEt
Me
Me
H
+
NaOEt
EtOH
Et3OBF4
–
N
N
BF4
In a seminal publication in 1961,14 Meerwein and co-
workers described the reaction of N,N-dimethylform-
amide (DMF) (5) with triethyloxonium tetrafluoroborate,
to give iminium tetrafluoroborate 6b, followed by treat-
ment of 6b with sodium ethoxide to afford the hitherto un-
known DMF diethyl acetal 7b (bp 135–136 °C).14,15 The
corresponding dimethyl acetal 7a (bp 102–104 °C) was
subsequently prepared by the alkylation of DMF (5) with
dimethyl sulfate to give the corresponding iminium meth-
yl sulfate 6a,15 followed by treatment with sodium meth-
oxide in methanol (Scheme 2).15,16 Dimethyl acetal 7a is
nowadays produced on a large technical scale, e.g. by
BASF. Amide acetal 7a and diethyl acetal 7b are readily
transacetalized14,16,17 on heating with higher boiling pri-
mary or secondary alcohols 2 while distilling off methanol
or ethanol, respectively, to provide acetals 7b–g (e.g.,
Scheme 2).
OEt
Me
Me
7b
6b
5
N
CHO
Me
Me
OMe
OMe
Me
–
H
+
NaOMe
MeOH
Me2SO4
N
N
MeOSO3
Me
OMe
6a
7a
Me
Me
OR'
OR'
Me
Me
OMe
OMe
2 R'OH 2, Δ
N
7b–g
N
– 2 MeOH
7a
a R' = Me; b R' = Et; c R' = CH2Ph; d R' = CH2CMe3
e R' = CMe3; f R' = CH(Me)Et; g R',R' = (CH2)2
Scheme 2
HN(CH2CH2OH)2
8
N
9
benzene, Δ, 90%
– Me2NH, – MeOH
O
N
O
Di-tert-butyl acetal 7e is synthesized by treatment of tet-
ramethylformamidinium chloride with potassium tert-bu-
toxide,17 by transacetalization of 7a with absolute tert-
butyl alcohol in the presence of 2,4,6-tri-tert-butylphe-
nol,18 or in situ from DMF dineopentyl acetal 7d and tert-
butyl alcohol in the conversion of a proline analogue into
the corresponding tert-butyl ester.19
N
Me
Me
OMe
OMe
N
N
N
N
H
Δ
N
CHOMe
10
7a
2
17%
11
OMe
OMe
OR'
OR'
1. Me2SO4
2 R'OH 2
N
CHO
N
N
Δ
2. NaOMe,
MeOH
Transamination of DMF dialkyl acetal 7a or 7b with pip-
eridine and morpholine affords, with the evolution of di-
methylamine, the corresponding amide acetals in up to
64% yield.14,17 The combined transamination–transacetal-
ization of 7a with N,N-bis(2-hydroxyethyl)amine (8)
gives bicyclic amide acetal 9 in 90% yield, as well as di-
methylamine and methanol or ethanol, respectively (e.g.,
Scheme 3).17 Unfortunately, the transamination of 7a with
pyrrolidine affords only about 17% of the desired N,N-tet-
13a
– 2 MeOH
12
13b,c
a R' = Me; b R' = Et; c R' = CH2Ph
Scheme 3
ramethyleneformamide dimethyl acetal 13a; the main
product is the corresponding basic aminal methoxy(dipyr-
rolidino)methane (10), which is transformed on further
heating, with elimination of methanol, into tetrapyrrolidi-
noethene (11).20 Dimethyl acetal 13a is, therefore, pre-
Biographical Sketch
Helmut Vorbrüggen was joined the pharmaceutical ods
for
the
fluoro-
born in 1930 in Duisburg- research of Schering AG in dehydroxylation of alco-
Homberg, Germany. He Berlin in 1966. During stud- hols. In addition to his in-
studied chemistry in Göttin- ies on the synthesis and dustrial work, he obtained in
gen, where he received his modification of nucleosides, 1972 his Habilitation at the
Ph.D. under the supervision he introduced trimethylsilyl Institute of Technology in
of Professor H. Brockmann triflate, as a new gentle Berlin, where he taught
in 1958. After postdoctoral Lewis acid, into preparative courses in preparative or-
studies on the synthesis and organic chemistry. He and ganic chemistry as adjunct
structure of natural products his group subsequently syn- professor up until 1993.
with Professor H. Erdtman thesized new, highly potent Since his retirement from
in Stockholm in 1958–1959, prostaglandin and prostacy- Schering AG in 1995, he has
with Professor C. Djerassi at clin analogues. In addition continued part of his work
Stanford from 1959 to 1963 to developing synthetic as guest professor at the In-
and with Professor R. B. methods such as aminations stitut für Chemie and Bio-
Woodward at the Wood- in heterocyclic chemistry, chemie
of
the
Free
ward Research Institute in he has recently been investi- University in Berlin.
Basel from 1963 to 1966, he gating new efficient meth-
Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York

ACCOUNT
Esterification of Carboxylic Acids and Etherification of Phenols with Amide Acetals
1605
Me
H
RCO2H 1
+
–OCOR
RCO2R' 4
N
– R'OH 2
– DMF 5
Me
O-R'
15
Me
Me
OR'
Me
+ N
Me
H
6
_OR'
N
+
OR'
OR' 14
7
6
Me
H
ArOH 16
– R'OH 2
a. R' = Me; b. R' = Et
+ N
Me
–OAr 17
O-R'
ArOR' 18
– DMF 5
6
Scheme 4
pared by the O-methylation of N,N-tetramethyl- The rate of the subsequent nucleophilic reactions of the
eneformamide (12) with dimethyl sulfate, followed by carboxylate 15 or phenolate anions 17 is dependent on the
treatment with sodium methoxide in absolute methanol to acidity of the corresponding carboxylic acids 1 and phe-
afford 13a (bp 160–161 °C) in 5616 or 69%21 yield. This nols 16 generating iminium cations 6, as well as in partic-
product can then be transacetalized, e.g. with ethanol or ular on the nucleophilicity of anions 15 and 17. Yet, the
benzyl alcohol, to give amide acetals 13b or 13c, respec- nucleophilicity of the carboxylate 15 or phenolate anions
tively (Scheme 3). As subsequently described, 13a can 17 decreases with the increasing acidity of carboxylic
also be prepared and reacted in situ on adding pyrrolidine acids 1 or phenols 16!
to mixtures of carboxylic acids and DMF dimethyl acetal
7a (see Scheme 11).
The dissociation of amide acetals 7 to give iminium cat-
ions 6 and alkoxide anions 14 explains the above dis-
Amide acetals such as 7 and 13 are thermally quite stable, cussed ready transacetalization of amide acetals 7a and 7b
yet hydrolyze instantly in an exothermic reaction on addi- or 13a with higher boiling alcohols 2 to give amide acetals
tion of water or aqueous alcohols to give DMF (5)11 and 7b–g or 13b and 13c, after distilling off methanol or eth-
N,N-tetramethyleneformamide (12), respectively, and the anol (e.g., Schemes 2 and 3). Likewise, it explains the
corresponding alcohols 2. Thus, any excess of amide ace- transamination of 7a or 7b with secondary amines, such as
tals will efficiently remove any traces of humidity in the piperidine, morpholine, or pyrrolidine, to give the corre-
reagents or solvent.
sponding amide acetals, such as 13a (Scheme 3), while
evolving dimethylamine.14,16,17
The electrical conductivity as well as the basicity of solu-
tions of amide acetals, such as 7 or 13, is due to their par- The ready exothermic condensation of amide acetals 7 or
tial dissociation into their corresponding iminium cations, 13 with active methyl or methylene groups proceeds, like-
e.g. 6 or 91 (see Scheme 21) and alkoxide anions 14 wise, via iminium cations 6 or 91, respectively, and alk-
(Scheme 4).14 On addition of carboxylic acids 1 or phe- oxides 14 to result in the formation of b-(dimethyl-
nols 16 to amide acetals, e.g. 7, these equilibria are shift- amino)enones or b-(dimethylamino)ene-containing es-
ed, depending on the acidity of 1 and 16, leading in situ to ters.
dramatically increased amounts of the reactive iminium
cations, e.g. 6, carboxylate 15 or phenolate anions 17,
Thus, methyl cyanoacetate (19) with 7a instantly gives
crystalline product 20,14,22–26 whereas the acidic CH moi-
respectively, and the free alcohols 2 (Scheme 4). Iminium
eties in ethyl cyano(phenyl)acetate26 or compound 2127
cations 6 react, as subsequently discussed, with carboxy-
are C-alkylated on heating with amide acetals, such as 7a,
late 15 or phenolate anions 17 to give the corresponding
to give ethyl cyano(methyl)phenylacetate or 22, respec-
esters 4 or phenyl ethers 18 (Scheme 4) without involving
tively (e.g., Scheme 5) (cf. also the concomitant conden-
any sterically demanding intermediates, such as 3
(Scheme 1).
Me2N
CN
Me2NCH(OMe)2 7a
NC
CO2Me
neat, 24 °C
>90%
CO2Me
19
20
CN
CN
H
Me
Me2NCH(OMe)2 7a
CO2Et
CO2Et
THF, 15 h, Δ
22
MeO
H
21
MeO
89%
H
C
NMe2
H
N
H
N
N
N
Me2NCH(OMe)2 7a
concd NH4OH soln
N
N
O
24 h, 90 °C
99%
17 h, 22 °C
98%
O
N
N
H
O
N
24
23
25
Me
Me
Scheme 5
Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York

1606
H. Vorbrüggen
ACCOUNT
sations of active methyl or methylene groups with 7a formation of tetramethylammonium salts of the employed
during esterifications, e.g., Scheme 11). carboxylic acids 1 or phenols 16.
Likewise, the condensation of primary aliphatic, aromat- The reaction of benzoic acid (26) with excess dimethyl ac-
ic, or heterocyclic amines28,29 with 7a gives rise to the cor- etal 7a in benzene for 1 hour at 80 °C gives only 78% yield
responding N,N-dimethylamidines (cf. formation of 24, of methyl benzoate (27a) (Scheme 6). Yet, with excess di-
Scheme 5),14,17,18 whereas amides react on short heating30 ethyl acetal 7b or dibenzyl acetal 7c the same reaction
or at room temperature31 with 7a. The condensation of conditions give 83% yield of ethyl benzoate (27b) or 79%
amides, such as acetamide or benzamide, with three yield of benzyl benzoate (27c), respectively.39–41 Benzoic
equivalents of 7a in methanol for 3 hours at room temper- acid (26) with optically active DMF di-sec-butyl acetal 7f
ature results in nearly quantitative yields of methyl acetate after 2 hours in benzene at 80 °C affords the inverted sec-
or methyl benzoate, respectively.31
butyl benzoate (27f) in 73% yield, proving thus the SN2
mechanism of these esterification reactions which was
also supported by kinetic studies.40 The esterification of
phenols proceeds via an analogous SN2 mechanism (cf.
Scheme 18). Strongly hindered 2,4,6-trimethylbenzoic
acid (28), which is not converted into the corresponding
ester under standard esterification conditions (see
Scheme 1) with methanol,40 gives with amide acetals 7a–
c at 80 °C only 71% yield of methyl 2,4,6-trimethylben-
zoate (29a), yet 84% yield of ethyl 2,4,6-trimethylben-
zoate (29b) and 75% yield of benzyl 2,4,6-
trimethylbenzoate (29c) (Scheme 6).40 Treatment of nico-
tinic acid (30) for 16 hours at 22 °C with a slight excess of
7b in dichloromethane provides ethyl nicotinate (31),
whose preparation by acid-catalyzed esterification is not
feasible, in 81% yield (Scheme 6).39,41
The acidic heterocyclic NH moiety in cytosine (23) is N-
alkylated while the amino group is transformed into an
amidine functionality on reaction with excess amide ace-
tal 7a to give the intermediate N4-[(dimethylamino)meth-
ylene]-1-methylcytosine (24), which is readily cleaved
using concentrated ammonium hydroxide to give 1-meth-
ylcytosine (25) (Scheme 5).32–34
Different amide acetals condense with reactive methylene
groups with widely varying rates. Thus, the rates of the
condensation of amide acetals 7 with deoxybenzoin in-
crease in the order 7a < 7b < di-tert-butyl acetal 7e, which
gives the highest condensation rate because tert-butoxy
anion 14e is the strongest base in this series.17,24 These
condensation reactions have found many synthetic appli-
cations. Nowadays, however, the Bredereck aminal
(Me2N)2CHOt-Bu, which on dissociation generates the
amidinium cation Me2N+=CHNMe2 and the tert-butoxy
anion, has become the preferred reagent for condensations
with weakly activated methyl or methylene groups.23–25
1.5 equiv Me2NCH(OR')2
benzene, 1–2 h, 80 °C
7
CO2H
26
CO2R'
27
a R' = Me (78%); b R' = Et (83%); c R' = CH2Ph (79%);
f R' = CH(Me)Et (73%)
The chemistry of amide acetals has been reviewed, for ex-
ample, in 1969,35 1977,36 and 1979.37
Me
Me
1.5 equiv Me2NCH(OR')2
benzene, 1 h, 80 °C
7
Me
CO2H
28
Me
Me
CO2R'
29
Me
3
Esterification of Carboxylic Acids and Ether-
ification of Phenols with Amide Acetals
a. R' = Me (71%); b. R' = Et (84%) ; c. R' = CH2Ph (75%)
The esterification of carboxylic acids 1 with DMF diethyl
acetal 7b to give the corresponding ethyl esters 4b,38–41
and the etherification of phenols 16, e.g. with 7b or 7c to
give the corresponding ethyl or benzyl aryl ethers 18b and
18c, respectively, were discovered in 1963.39,41 In these
reactions with amide acetals 7 or 13, only DMF (5) or
N,N-tetramethyleneformamide (12) and alcohols, such as
methanol, ethanol, or benzyl alcohol, are formed as side
products, which can usually be readily separated on aque-
ous workup from the more lipophilic esters 4 or aryl ethers
18 (e.g., Scheme 4). As emphasized in Section 2, any ex-
cess of the employed amide acetals 7 or 13 will remove
any humidity in the solvents or in the employed carboxy-
lic acids 1 or phenols 16, which sometimes might only be
available as their corresponding hydrates. Any unreacted
amide acetals 7 or 13 will then be instantly hydrolyzed
during workup on addition of water or aqueous alcohol to
DMF (5) or N,N-tetramethyleneformamide (12) and alco-
hols 2. Yet, as subsequently discussed in Section 4.1, an
excess of amide acetal 7a, in particular, will also favor the
1.1 equiv Me2NCH(OEt)2 7b
CO2H
CO2Et
31
CH2Cl2, 16 h, 22 °C
N
N
30
81%
Scheme 6
The reaction of phenol (32) with DMF dibenzyl acetal 7c
for 46 hours in boiling 1,2-dichloroethane affords benzyl
phenyl ether (33) in 64% yield, whereas the much more
acidic 2,4,6-trichlorophenol (34) is converted by amide
acetal 7c after 37 hours at 24 °C in dichloromethane into
the corresponding benzyl ether 35 in 87% yield
(Scheme 7).39,41
On heating benzoic acid (26) with DMF ethylene acetal
7g for 4 hours in boiling benzene, a 74% yield of 2-hy-
droxyethyl benzoate (36) is obtained.42 Carboxylic acids 1
also react with bicyclic amide acetals, such as 1-aza-4,6-
dioxabicyclo[3.3.0]octane (9) and its analogues, to give
esters 37 (Scheme 8).43
Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York

ACCOUNT
Esterification of Carboxylic Acids and Etherification of Phenols with Amide Acetals
1607
Me2NCH(OCH2Ph)2 7c
OH
32
O
DCE, 46 h, Δ
33
64%
Cl
Cl
Cl
Me2NCH(OCH2Ph)2 7c
Cl
OH
34
Cl
O
CH2Cl2, 37 h, 24 °C
87%
35
Cl
Scheme 7
Me
Me
O
O
7a
N
7g
CO2H
CO2Me
45
N
N
O
44
H
OH
CO2H
CHO
benzene, 4 h, 80 °C
74%
O
26
36
O
O
CO2Me
N
7a
N
CO2H
R"
N
H
H
O
O
RO2C
4 h, Δ, toluene
NMe2
OH
N
R'
46
47
72%
RCO2H
Δ
R"
R'
1
O
37
Scheme 10
R' = H, Et; R" = H, Ph
Scheme 8
Heating 3-methyl-4-nitrobenzoic acid (48) in boiling
DMF as solvent with three equivalents of dimethyl acetal
7a in the presence of equivalent amounts of pyrrolidine,52
which transforms 7a at least partially in situ into the more
reactive amide acetal 13a (cf. Scheme 3), effects with
evolution of dimethylamine both condensation with the
activated methyl group and the formation of the methyl
ester to give the crude and rather unstable enamine-con-
taining compound 49a in 85% yield (Scheme 11).52 The
ester product 49a might, however, contain some of the
pyrrolidino derivative 49b derived from the intermediate
formation of 13a. Enamines, such as 49, are readily re-
duced in a Leimgruber–Batcho reaction sequence to give
the corresponding indoles, such as 50. A number of con-
densations of o-nitro-substituted alkylbenzenes with
amide acetals to give analogues of 49, and their subse-
quent conversion into indoles, such as 50, have been de-
scribed and reviewed.53
Amino acids with excess DMF dimethyl acetal 7a give the
corresponding N-[(dimethylamino)methylene]amino
methyl esters in often very high yields.44–49 Thus, the re-
action of alanine (38) with 7a affords amidine-containing
methyl ester 3943,45,47 in 6546 or 92% yield (e.g.,
Scheme 9).48 Tyrosine (40) also reacts with amide acetal
7a in a fivefold excess without any solvent to give, after 3
hours at ca 110 °C, the corresponding amidine-containing
methyl ester 41, in which the phenolic hydroxy group is
also methylated, in only 29% yield.48 In addition, anthra-
nilic acid (42) on heating with 7a in DMF (5) with con-
comitant removal of methanol affords amidine-containing
ester 43 in 95% yield (Scheme 9).47 Yet, amino acids such
as optically active phenylglycine are racemized on heat-
ing with 7a to give the corresponding amidine-containing
esters in toluene!50
In contrast to the above, the reaction of proline (44) with
dimethyl acetal 7a affords the methyl ester of N-formyl-
proline 45,51 and N-benzoylglycine (46) with 7a gives
72% yield of methyl 2-(benzoylamino)-3-(dimethylami-
no)prop-2-enoate (47) (Scheme 10).49
NR2
MeO2C
HO2C
Me
Me2NCH(OMe)2 7a
pyrrolidine, DMF, 4 h, Δ
NO2
NO2
85%
49
48
a R = Me; b R,R = (CH2)4
Me2NCH(OMe)2 7a
Me
CO2Me
NMe2
MeO2C
Me
CO2H
H2, Pd/C
39
3 h, Δ
92%
38
N
NH2
N
H
50
Scheme 11
7a
MeO
HO
CO2Me
NMe2
CO2H
3 h, Δ
N
29%
41
H2N
40
In contrast to the previously discussed SN2 reactions of
iminium cations 6 (and 91) with anions of carboxylic
acids 15 and phenols 17, carboxylic acids and phenols re-
act with DMF di-tert-butyl acetal 7e via the nascent tert-
butyl cation (51). Thus, benzoic acid (26) on heating in
benzene or toluene with a fourfold excess of di-tert-butyl
acetal 7e gives tert-butyl benzoate 52 in 77% yield,54 as
well as tert-butanol, DMF (5), and 2-methylpropene (53)
7a
DMF 5, Δ
CO2H
NH2
CO2Me
– MeOH
95%
Me
N
N
42
43
Me
Scheme 9
Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York

1608
H. Vorbrüggen
ACCOUNT
O
Me
Me
H
O
Me
4
OCMe3
OCMe3
–
PhCO2H 26
+
PhCO2
N
N
– DMF 5
benzene, 80 °C
– Me3COH
6e
OCMe3
CMe3
Me
7e
–
PhCO2
52 (77%)
Me3C+
Me
51
– H+
PhO–
53
Me
Me
H
7e
+
N
PhO–
OH
OCMe3
5 h, 100–110 °C
– Me3COH
– DMF
5
Me 6e O CMe3
32
54
(39%)
Scheme 12
(e.g., Scheme 12). The nascent tert-butyl cation (51) de- moser introduced DMF dineopentyl acetal 7d, which on
rived from 6e either combines with the adjacent carboxy- the addition of free carboxylic acids 1 and free alcohols 2
late anion to give the desired tert-butyl ester 52 and DMF gives an equilibrium between iminium cations 6d and 6
(5), or loses a proton to give 2-methylpropene (53). Anal- resulting nearly exclusively in the formation of the desired
ogously, phenol (32) combines via its corresponding phe- corresponding esters 4, DMF (5), and free neopentyl alco-
nolate anion with the nascent tert-butyl cation (51) on hol (55) (Scheme 13).39 Phenolate anions 17 of more acid-
heating with excess 7e at 100–110 °C to give the corre- ic phenols 16 react analogously with the iminium cation 6
sponding tert-butyl phenyl ether (54) in 39% yield,55,56 as to give the corresponding phenyl ethers 18 [cf. the subse-
well as DMF (5) and 2-methylpropene (53) (Scheme 12). quently described alkylation of 4-nitrophenol (81) with
Further applications of 7e in the conversion of carboxylic 3a-hydroxy steroid 78, Scheme 18].
acids 1 into tert-butyl esters can be found in the litera-
N-Benzyloxycarbonylglycine (56) reacts with acid-labile
4-methoxybenzyl alcohol (57) in the presence of DMF di-
ture.57–68
Di-tert-butyl acetal 7e can also be prepared in situ from neopentyl acetal 7d to give the corresponding 4-methoxy-
tert-butyl alcohol in the presence of dineopentyl deriva- benzyl ester 58 in 74% yield, as well as small amounts of
tive 7d in boiling benzene in the conversion of L-trans-N- bis(4-methoxybenzyl) ether (59) and 4-methoxybenzyl
benzoyl-4-hydroxyproline into its tert-butyl ester in 82% neopentyl ether (60).39 Likewise, hindered 2,6-dichlo-
yield.19
robenzoic acid (61) and allylic alcohol 62 react in the
presence of 7d to give ester 63 (Scheme 14).74
As a preparative alternative to di-tert-butyl acetal 7e, so-
lutions of carboxylic acids 1, such as benzoic acid in On slow addition of DMF dineopentyl acetal 7d employ-
dichloromethane, have been reacted with a cyclohexane ing high dilution techniques, solutions of hydroxy acids,
solution
of
tert-butyl
trichloroacetimidate such as 64 in boiling toluene, are converted via the corre-
[Me3COC(=NH)CCl3], which is obtained on the addition sponding iminium salt intermediates, e.g. 65, in which the
of potassium tert-butoxide in tert-butyl alcohol–diethyl iminium cation moiety is attracted to the carboxylate an-
ether to trichloroacetonitrile.69–71 In this manner, after 14 ion, into medium-sized lactones with Walden inversion of
hours and only in the presence of boron trifluoride–diethyl the chiral center. In this manner, lactone 66 was formed in
ether complex, tert-butyl benzoate was formed in 92% 48% yield along with its corresponding dimers, trimers,
yield.69 Likewise, carboxylic acids 1, as well as phenols and tetramers, as well as neopentyl alcohol (55) and DMF
16, can be reacted with O-tert-butyl-N,N¢-diisopropyl- (5) (Scheme 15).75 This new lactonization procedure has
isourea [Me3COC(=Ni-Pr)NHi-Pr] to provide the corre- subsequently found a number of applications76–84 giving
sponding tert-butyl esters or ethers, respectively, in high lactones in yields of up to 90%.
yields.72
The reaction of unsaturated hydroxy acid 67 with amide
Because the methylene group in derivatives of neopentyl acetal 7d in 1-methylnaphthalene for 10 minutes at 22 °C,
alcohol (55), such as in the iminium cation 6d, reacts very however, results in the fragmentation of 67 to afford, via
slowly73 with nucleophilic carboxylate anions 14, Eschen- intermediate 68, cyclohexadiene 69 in >84% yield.85 The
(–OAr 17)
RCO2H 1
Me
+N
H
Me
Me
OCH2CMe3
OCH2CMe3
–OCOR 15 + Me3CCH2OH 55
(ArOH 16)
N
Me 6d OCH2CMe3
R'OH 2
7d
H
Me
+ N
Me
RCO2R' 4
(ArOR' 18)
–OCOR 15
(–OAr 17)
+
Me3CCH2OH 55
– DMF 5
OR'
6
Scheme 13
Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York

ACCOUNT
Esterification of Carboxylic Acids and Etherification of Phenols with Amide Acetals
1609
OMe
Cbz
O
N
H
C
O
58
+
Me2NCH(OCH2CMe3)2 7d
4-MeOC6H4CH2OH 57
Cbz
N
H
CO2H
CHCl3, 47 h, 24 °C
– Me3CCH2OH 55, – DMF 5
74%
MeO
56
O
2
59
+
MeO
O
CMe3
60
Me2NCH(OCH2CMe3)2 7d
Cl
Cl
Cl
Me
OH
O
O
62
CO2H
Me
– Me3CCH2OH 55, – DMF 5
61
63
Cl
Scheme 14
HO2C
(CH2)10
Me2N
(H2C)10
CO
(CH2)10
Me
N
OCH2CMe3
PhMe
O
O
HO
+
–O
130 °C, 19 h
– Me3CCH2OH 55
– DMF 5
n-C6H13 Me
OCH2CMe3
n-C6H13
n-C6H13
H
7d
66
+ oligomers
64
O
48%
65
Scheme 15
analogous fragmentation of compound 70 with 7d in di- olefins 78 and 79 exclusively (Scheme 17).87,88 Further
ethyl phthalate at 0 °C affords nearly pure product 71 in examples of such fragmentations can be found in the liter-
ca. 92% yield (Scheme 16).86
ature.89,90
Whereas the reactions of b-hydroxy carboxylic acids 72 Analogously, ether formation from the reaction of phenols
with DMF dimethyl acetal 7a afford preponderantly esters 16 with chiral alcohols 2 in the presence of DMF dineo-
73, some quantities of tetramethylammonium salts 74 (cf. pentyl acetal 7d affords, via phenolate anions 17, the cor-
Section 4.1), and only 5% of olefins 75 and 76, the reac- responding inverted phenyl ethers 18.41 Thus, 4-
tions of 72 with DMF dineopentyl acetal 7d give, via 77, nitrophenol (81) and 3a-hydroxy-5a-androstan-17-one
(80), containing an axial 3-hydroxy group, on heating
with dineopentyl acetal 7d for 24 hours at 80 °C in abso-
lute benzene are converted into 3b-(4-nitrophenoxy)-5a-
androstan-17-one (82), with an equatorial 3-(4-nitro-
O
H
O
Me
Me
H
H
CO2H
Me2NCH(OCH2CMe3)2 7d
Me
+
Me
Me
phenoxy) substituent, in 68% yield; the reaction also gives
24% yield of 5a-androst-2-en-17-one and free neopentyl
alcohol (55) (Scheme 18).41,91 The yield of product 82 can
probably be raised by adding dineopentyl acetal 7d dis-
solved in absolute toluene slowly over ca. 24 hours to a
solution of steroid alcohol 80 and 4-nitrophenol (81) in
absolute toluene at 80 °C. The detailed procedure for the
preparation of 82 is described in an English translation.91
1-methylnaphthalene
10 min, 22 °C
Me
H
68
O
OH
69
+
N
Me
67
– 2 Me3CCH2OH 55
90%
Me
Me
HO
H
Me
H
Me2NCH(OCH2CMe3)2 7d
In addition to the examples discussed above, a number of
aliphatic,68,92–102 aromatic, and heterocyclic103–106 carbox-
ylic acids 1, as well as some phenols 16,107 have been con-
verted by amide acetals, such as 7a–c, into the
corresponding esters 4 and phenyl ethers 18.
diethyl phthalate, 0°C
– 2 Me3CCH2OH 55
– CO2, – DMF 5
CO2H
71
Me
70
Me
92% (96% E,E; 4% E,Z)
Scheme 16
Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York

1610
H. Vorbrüggen
ACCOUNT
–
+NMe4
+
CO2
CO2H
CO2Me
Me2NCH(OMe)2 7a
H
H
H
H
R
H
H
+
–
+
Ph
75
Ph
74
Ph
R
Ph
R
Ph
R
CHCl3, 20 h, 22 °C
– MeOH
76
73
R
OH
OH
OH
72
R = Me 65%
R = Et 80%
30%
15%
5%
5%
O
O
CO2H
H
O
H
N
Me2NCH(OCH2CMe3)2 7d
Ph
H
H
R
Ph
R
R
Ph
+
Ph
CHCl3, 20 h, 22 °C
– Me3CCH2OH 55
OH
78
79
R
72
77
R = Ph
1
:
8.5
Me
Me
Scheme 17
O
O
Me2NCH(OCH2CMe3)2 7d
NO2
OH
O2N
81
HO
O
C6H6, 24 h, 80 °C
82 68%
H 80
H
+ DMF 5 + Me3CCH2OH 55
Scheme 18
These lower yields of, in particular, methyl esters are due
to the gradual methylation of the relatively unhindered
DMF dimethyl acetal 7a by the reactive intermediate imi-
nium cation 6a to give, via 83, trimethyl orthoformate
(84) and trimethylamine (85). Trimethylamine (85) is
again methylated by 6a to result finally in tetramethylam-
monium salts 86 of the employed carboxylic acids 1,108,109
as well as DMF (5) and trimethyl orthoformate (84), thus,
diminishing the yields of the desired methyl esters 4a
(Scheme 19). Phenols, such as 2,4,6-trichlorophenol (34)
or picric acid, react analogously with 7a to afford methyl
ethers and the corresponding tetramethylammonium phe-
nolate, such as 103 (see Scheme 23).109
4
Side Reactions during the Esterifications and
Etherifications
4.1
Suppression of the Formation of Quaternary
Salts and Other Side Reactions
Although DMF dimethyl acetal 7a and DMF diethyl ace-
tal 7b have been used in a number of esterifications of al-
iphatic and aromatic or heteroaromatic carboxylic
acids68,92–106 and etherifications of phenols,107 they have,
nevertheless, not yet become standard reagents for the
conversion of carboxylic acids 1 into their methyl or ethyl
esters 4, respectively, or for the conversion of phenols 16
into their corresponding methyl or ethyl ethers 18, to re-
place diazomethane or other reagents. This is apparently
because of the product yields achieved from their reac-
tions. For example, benzoic acid (26) and 2,4,6-trimethyl-
benzoic acid (28) with DMF dimethyl acetal 7a gave only
78% yield of methyl benzoate (27a) and 71% yield of
methyl 2,4,6-trimethylbenzoate (29a), respectively
(Scheme 6; see also Scheme 17),12–14 whereas near quan-
titative yield of the two products would have been desir-
able.
Compared with benzoic acid (26) (pKa = 4.20), the rather
strongly acidic 4-nitrobenzoic acid (87) (pKa = 3.42),
whose anion is consequently a much weaker nucleophile
than the benzoate anion, reacts much slower with DMF
dimethyl acetal 7a via 6a and gives, therefore, with a
threefold excess of 7a in the absence of solvents after 24
hours at 22 °C only 32% yield of the desired methyl ester
88, yet 45% yield of the crystalline tetramethylammonium
4-nitrobenzoate 89 (Scheme 20).108,109
Me
Me
Me
OMe
OMe
OMe
–OMe
OMe
Me
Me
OMe
OMe
Me
RCO2
H
+
–
RCO2H 1
N
7a
+
Me
N
N
7a
N
15
6a
– MeOH
Me
OMe
83
Me
RCO2H 1
Me
Me
H
HC(OMe)3 84
–
–
+NMe4
N
+
RCO2Me 4a
RCO2
RCO2
15
– DMF 5
NMe3
85
86
OMe
6a
Scheme 19
Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York

ACCOUNT
Esterification of Carboxylic Acids and Etherification of Phenols with Amide Acetals
1611
7a over a period of 5 hours increased the yield of 88 to
90% (Scheme 21).41,110 The competing formation of tet-
ramethylammonium 4-nitrobenzoate (89) can, thus, be
dramatically reduced, if not avoided altogether, on the
slow addition of amide acetals, such as 7a.
O2N
CO2Me
88 32%
Me2NCH(OMe)2 7a
24 h, 22 °C
neat
+
+
O2N
CO2H
–
+NMe4
O2N
CO2
The addition of even more reactive N,N-tetramethylene-
formamide dimethyl acetal 13a, which forms the corre-
sponding reactive iminium cation 91 most readily
analogous to the reactivity of related pyrrolidine enamines
or other derivatives,111–114 to a suspension of 4-nitroben-
zoic acid (87) in 1,2-dichloroethane gives methyl ester 88,
via the corresponding iminium salt of 91 and 4-nitroben-
zoate anion (90), in 92% yield after a period of 4 hours and
in quantitative yield after 25 hours (Scheme 21).41,110 The
N-alkylation of 13a by the iminium cation 91 is, therefore,
apparently much less favored!
87
89 45%
Scheme 20
Iminium cations 6b and 6c derived from DMF diethyl ac-
etal 7b and DMF dibenzyl acetal 7c, respectively, will re-
act, for steric reasons, much slower with their amide
acetals 7b and 7c to give the corresponding diethyldi-
methylammonium or dibenzyldimethylammonium car-
boxylates. Thus, this explains the generally higher yield of
ethyl benzoate (27b) or benzyl benzoate (27c) achieved
on reaction of benzoic acid (26) with amide acetals 7b or
7c (Scheme 6; see also Scheme 17). Likewise, the more
hindered nitrogen in amide acetal 13a is methylated much
slower by its corresponding iminium cation 91 than 7a is
by 6a (Scheme 21).
Because these crucial experiments on the favorable effect
of adding amide acetal 7a slowly to a suspension of 4-ni-
trobenzoic acid (87) to obtain high yields of methyl 4-ni-
trobenzoate (88) were originally published in German41
and, thus, were unfortunately overlooked,37 these proce-
dures have been reproduced in English.110 For the esterifi-
cation or etherification of carboxylic acids 1 or phenols
16, respectively, with alcohols 2 in the presence of DMF
dineopentyl acetal 7d (see Scheme 13), which reacts very
slowly with carboxylic acids or phenols to give the corre-
sponding neopentyl esters or ethers,40 amide acetal 7d
should also be added slowly to a solution of the substrates,
whereupon the reactive intermediate iminium cation 6 of
the employed alcohol 2 is formed in equilibrium with free
neopentyl alcohol (55)40 to afford the corresponding es-
ters 4 or phenyl ethers 18 in high yields.
Furthermore, as emphasized above, the stronger carboxy-
lic acids 1 are, the weaker the nucleophilic strength of
their corresponding carboxylate anions 15 and, thus, the
lower the rate of their reaction with iminium cations 6 to
give the desired esters 4. Yet, on reaction of carboxylic ac-
ids 1 with amide acetals 7, the ion pairs or salts of iminium
cations 6 and carboxylate anions 15 will form readily even
in diluted solutions using rather nonpolar solvents, such as
1,2-dichloroethane or toluene, to react to give the corre-
sponding esters 4. In contrast, the undesired alkylation of
the dimethylamino group in amide acetals 7a, 7b, or 7c by
iminium cations 6a, 6b, or 6c, respectively, is dependent
on the concentration of the free amide acetals 7a, 7b, or 7c
and, thus, can readily occur in the absence of solvents!
4.2
Tetrahydrofuran or 1,4-Dioxane as Optimal
Reaction Solvents
As we recently discovered, 4-nitrobenzoic acid (87),
which is only partially soluble in dichloromethane, 1,2-
dichloroethane, ethyl acetate, or toluene, dissolves readily
at room temperature in the more ‘basic’ solvents tetrahy-
drofuran (THF) or 1,4-dioxane, whereas other ethereal
solvents, such as 1,2-dimethoxyethane or tert-butyl meth-
yl ether, are much less effective. The slow addition of a
solution of DMF dimethyl acetal 7a in THF to a boiling
solution of 87 in THF over a period of 0.5–2 hours with
Thus, it is obvious that to keep the stationary concentra-
tion of the amide acetals, and in particular of 7a, as low as
possible, the solutions of the amide acetals should be add-
ed slowly to the stirred solutions of carboxylic acids 1.41
On the addition of a solution of dimethyl acetal 7a in 1,2-
dichloroethane to a stirred suspension of 4-nitrobenzoic
acid (87) in 1,2-dichloroethane over a period of 3 hours at
24 °C, methyl 4-nitrobenzoate (88) was obtained in 70%
yield. However, performing the addition of the solution of
DCE
3 h, 24 °C, 70%
5 h, 24 °C, 90%
Me
Me
OMe
OMe
Me
Me
H
MeOH
N
7a
N
6a
– DMF
or
5
OMe
THF, 2 h, 65 °C
+
+
>90%
–
O2N
CO2
O2N
CO2H
87
O2N
CO2Me
90
MeOH
+
88
+
OMe
H
DCE
– 12
N
13a
N
4 h, 30 °C, 92%
25 h, 100%
OMe
OMe
91
Scheme 21
Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York

1612
H. Vorbrüggen
ACCOUNT
vigorous stirring leads immediately to a salt precipitate and then evaporating the solvent from the reaction mix-
comprising 4-nitrobenzoate anion (90) and iminium cat- ture in vacuo. Furthermore, dimethyl maleate (100) is
ion 6a which reacts, apparently in situ, to give the desired isomerized after 4.5 days at 25 °C to dimethyl fumarate
methyl 4-nitrobenzoate (88), DMF (5), and methanol. (94) by a methoxide anion, which is formed in situ from
When the turbid boiling reaction mixture becomes sud- added excess DMF dimethyl acetal 7a.116 Consequently, 2
denly clear (after ca. 1 h), the reaction is complete and the equivalents of reagent 7a should be added slowly to a so-
addition of any further amounts of amide acetal 7a should lution of maleic acid (95), e.g. in boiling THF, to prevent
be stopped. The evaporation of the reaction mixture gives any intermediate formation of the methoxide anion. Cool-
the crude crystalline methyl ester 88, which is dissolved in ing the crude reaction mixture with ice and quenching any
tert-butyl methyl ether and filtered over a layer of silica excess of 7a with a slight excess of acetic acid gives crude
gel to afford the pure crystalline product 88 in practically oily dimethyl maleate (100) in near quantitative yield
quantitative yield (see Scheme 21).110 The initial forma- (Scheme 22). Crude dimethyl maleate (100), which does
tion of such insoluble salts of iminium cation 6a and the not contain dimethyl fumarate (94) according to thin-layer
corresponding carboxylate 15 or phenolate anions 17 in chromatography, already partially isomerizes to 94 on fil-
benzene or toluene has been observed before.39–41
tration of the crude brownish reaction product over silica
gel, previously deactivated as a stirred suspension in ethyl
acetate overnight.
The analogous reaction of fumaric acid (92) (pKa = 3.03,
4.47) with DMF dimethyl acetal 7a in boiling THF af-
fords, via its corresponding insoluble iminium salt 93 Likewise, rather lipophilic 2,4,6-trichlorophenol (34)
comprising a fumarate dianion and two iminium cations (pKa = 6.21) on slow addition of a solution of DMF di-
6a, dimethyl fumarate (94) in near quantitative yield methyl acetal 7a in boiling THF does not give any precip-
(Scheme 22).115
itate of the corresponding iminium phenolate 101, but
results anyhow in crystalline methyl ether 102 in 83%
yield and very probably in some tetramethylammonium
phenolate 103, which has previously been observed
(Scheme 23).109 This reaction has not as yet been opti-
mized.
Yet the reaction of maleic acid (95) (pKa = 2.00, 6.26),
which is a much stronger acid than fumaric acid (92) and,
therefore, behaves quite differently, in boiling THF with
1 equivalent of 7a afforded no precipitate of the corre-
sponding iminium salt 96, but only the monomethyl ester
97 after workup which is probably in equilibrium with 98 Phenols, such as 34, should be reacted with amide acetals
and 99. The monoester 97–99 can also, however, be readi- under argon to prevent darkening of the reaction mixture
ly prepared by keeping a solution of maleic anhydride in and loss of material because of apparent phenol oxidation
excess methanol for about 3 days at ambient temperature of the intermediate phenolate anion in 101.
CO2Me
CO2H
Me2NCH(OMe)2 7a
92
THF, 2 h, 65 °C
93%
94
MeO2C
HO2C
–
CO2
Me2N
C
H
OMe
–O2C
MeO
C
H
NMe2
6a
7a
(
)
(6a)
93
MeO
MeO
CO2H
CO2Me
OH
CO2Me
Me2NCH(OMe)2 7a
O
O
H
THF, 2–3 h, 65 °C
95%
CO2H
CO2H
CO2Me
O
O
–
99
100
97
98
95
CO2
O
Me2N
C
H
OMe
(6a)
CO2H
96
Scheme 22
Cl
Cl
Cl
Cl
Cl
Me2NCH(OMe)2 7a
Cl
OH
O–
+NMe4
Cl
OMe
+
Cl
THF, 2–3 h, 65 °C
83%
102
103
34
Cl
Cl
–O
Cl
Me2N
C
H
OMe
101
Cl
Scheme 23
Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York

ACCOUNT
Esterification of Carboxylic Acids and Etherification of Phenols with Amide Acetals
1613
NC
H
Phenols 16 react analogously with alcohols 2 in the pres-
ence of DMF dineopentyl acetal 7d to give phenyl ethers
18, as demonstrated by the synthesis of phenyl ether 82
(see Scheme 18). The slow addition of amide acetal 7d,
e.g. in THF, to solutions of alcohols 2 and phenols 16 in
THF or 1,4-dioxane under argon should raise the yields of
the resulting phenyl ethers, such as 82, considerably by
avoiding any formation of quaternary salts, such as tet-
ramethylammonium phenolates (see also the suspected
formation of 103, Scheme 23),109 which diminish the
yields of the desired phenyl ethers 18!
Me2N
CN
CN
106
CO2Me
Me
Me
CO2Me
6a
7a
N
OMe
– MeOH
CO2Me
H
20
107
CN
A
CN
Me
Me
O-Me
– DMF 5
–OCOCH2CN
Me2NCH(OMe)2 7a
CO2Me
N+
6a
80 °C, benzene
– MeOH
19
CO2H
H
105
B
104
B
–OMe
H
H
Me
N
OCOCHCN
Me
The question as to whether the readily available N,N-di-
methylamidines shown in Schemes 5 and 9 can also be N-
alkylated by DMF dimethyl acetal 7a has apparently not
yet been addressed.
CN
H
OMe
108
Me
N
CN
CN
Me2N
Me2N
O
O
Me
Me
Me
109
111
+
N
O
– CO2
50%
O
In summary, even stronger carboxylic acids, such as 4-ni-
trobenzoic acid (87), or acidic phenols, such as 2,4,6-
trichlorophenol (34), afford the corresponding methyl es-
ters, such as 88, in near quantitative yields or phenyl
ethers, such as 102, in high yields if amide acetals, e.g. 7a,
are added slowly in the basic solvents THF or 1,4-diox-
ane.
110
CN
112
Scheme 24
Yet, even with the slow addition of a solution of equiva-
lent amounts of amide acetal 7a in dry ethyl acetate over
a period of 20 hours at 24 °C to a solution of cyanoacetic
acid (104) in ethyl acetate we obtained, according to gas
chromatography–mass spectrometry, a 5:1 mixture of 111
and 112 in nearly quantitative yield. The repetition of this
experiment using 1,4-dioxane as basic solvent as men-
tioned above afforded, likewise, a practically quantitative
yield of the mixture of 111 and 112 with 111 being in
large excess.
4.3
Attempted Suppression of Condensation
Reactions
As already discussed in Sections 2 and 3, reactive methyl
or methylene groups, such as in methyl cyanoacetate (19)
(Scheme 5) or in N-benzoylglycine (46) (Scheme 10),
condense instantly with DMF dimethyl acetal 7a with
evolution of heat to give the corresponding crystalline
enamine-containing esters, such as 20,16,17 whose struc-
ture and E/Z-equilibria have been investigated,117,118 and
47.
As briefly mentioned by Eschenmoser et al.,40 the rather
strong cyanoacetic acid (104) with DMF dimethyl acetal
7a in boiling benzene affords, probably via route B, ca.
50% yield of b-(dimethylamino)-substituted acrylonitrile
as a mixture of isomers 111 and 112 (Scheme 24). The
repetition of this experiment in 1,4-dioxane as solvent af-
forded quantitative yield of the mixture of 111 and 112.119
The combination of a carboxylic acid moiety and an adja-
cent active methylene group in one molecule, as in cy-
anoacetic acid (104), obviously makes it an unsuitable
model for selective esterification. Therefore, we added a
solution of 1 equivalent of DMF dimethyl acetal 7a in
THF to a solution of equimolar amounts of methyl cy-
anoacetate (19) and 4-nitrobenzoic acid (87) in THF over
a period of 1 hour, whereupon the undesired crystalline
enamine-containing ester 20 was obtained as one of the
main products in 40% yield, whereas the desired crystal-
line methyl 4-nitrobenzoate (88) could only be isolated in
2.2% yield after chromatography (Scheme 25).
Thus, we wondered whether cyanoacetic acid (104) could
be converted selectively by amide acetal 7a via route A
into the desired methyl cyanoacetate (19) without the si-
multaneous or subsequent condensation of its active
methylene group with 7a to give the above-mentioned
enamine-containing ester 20, via carbanion 106 and inter-
mediate 107 (Scheme 24, cf. Scheme 5). We hoped that
on the dissociation of 7a to 6a in the presence of equiva-
lent or slightly excess amounts of cyanoacetic acid (104)
only methanol would be formed and not the methoxide
anion, which would remove a proton from the reactive
methylene group in 19 to give either enamine-containing
ester 20, via route A and 106 and 107, or a mixture of (E)-
and (Z)-3-(dimethylamino)acrylonitrile (111) and (112),
respectively, via route B and intermediates 109 and 110,
followed by decarboxylation.
Therefore, selective esterifications of carboxylic acids 1
(or etherifications of phenols 16) with amide acetals, such
as 7a, do not seem to be possible in the presence of active
CH2, CH, NH2, or NH groups!
O2N
CO2H
87
O2N
CO2Me
88 2.2%
Me2NCH(OMe)2 7a
+
+
THF, 1 h, 80 °C
Me2N
20 40%
CN
CO2Me
NC
CO2Me
19
Scheme 25
Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York

1614
5
H. Vorbrüggen
ACCOUNT
dioxane ought to be added dropwise over a period of 2–5
hours at 24 °C or 65 °C, depending on the acidity of the
Concluding Remarks
Although DMF dimethyl acetal 7a is readily and rather acid or phenol, to a stirred solution of the particular car-
cheaply available in any amount and, furthermore, gives boxylic acid 1 or phenol 16 in THF or 1,4-dioxane to ob-
on esterification or etherification in THF only DMF (5) tain, after aqueous workup or filtration over silica gel or
and methanol as hydrophilic side products, it might some- alumina, the desired esters 4 or phenyl ethers 18, usually
times be advisable to employ the even faster and more se- in high or near quantitative yields.
lectively
reacting
N,N-tetramethyleneformamide
We hope, therefore, that DMF dimethyl acetal 7a, which
is stable in the absence of humidity and, furthermore, can
be readily redistilled (bp 102–104 °C), as well as other
amide acetals, such as 7b–e or 13a–c, will be used more
generally in the future for esterifications of carboxylic
acids 1 to give esters 4 and etherifications of phenols 16
to give phenyl ethers 18, replacing the use of, in particu-
lar, toxic and dangerous diazomethane or diazoethane.
Furthermore, DMF dibenzyl acetal 7c, which can also be
generated in situ by the addition of slightly more than 2
equivalents of benzyl alcohol to DMF dimethyl acetal 7a
and subsequent removal of the methanol formed by warm-
ing the mixture to about 40 °C at reduced pressure, as well
as DMF bis(4-methoxybenzyl) acetal, which can be
generated in situ from 4-methoxybenzyl alcohol (57) and
DMF dineopentyl acetal 7d (cf. Scheme 14), ought to
replace benzyldiazomethane and perhaps also the imino
dimethyl acetal 13a. This latter reagent is rather expensive
and only commercially available from some minor suppli-
ers; however, 13a can also be generated in situ by adding
pyrrolidine to esterifications with 7a (see Scheme 11).52
Yet, following esterification or etherification with amide
acetals 13a and workup, the more lipophilic N,N-tetra-
methyleneformamide (12) is formed as a side product,
which is not as readily separated from the solution of the
resulting esters 4 or ethers 18 by simple extraction with
water as DMF (5). Filtration, however, of the crude esters,
e.g. in tert-butyl methyl ether or toluene, over a small lay-
er of silica gel or deactivated neutral alumina (activity II)
efficiently removes methanol, DMF (5), or N,N-tetrame-
thyleneformamide (12), whereas crude phenyl ethers,
such as 102, in tert-butyl methyl ether are readily purified
on filtration over a layer of neutral or basic alumina!
In hindsight, it was unfortunate that the publications de- ether benzyl trichloroacetimidate [PhCH2OC(=NH)CCl3],70
scribing the formation of quaternary salts,41,108,109 such as prepared by the addition of benzyl alcohol to trichloroac-
74, 89 and 103 during ester formation and their etonitrile! Such imino ethers [ROC(=NH)CCl3] are also
avoidance41 by adding amide acetals 7a or 13a in DCE commercially available, yet only react with carboxylic ac-
slowly over a period of 4–6 hours to obtain high or nearly ids in the presence of Lewis acids, e.g. boron trifluoride–
quantitative yields of the desired esters, e.g. methyl 4-ni- diethyl ether complex.
trobenzoate (88) (see Schemes 19– 21), were all pub-
lished in German. Consequently, the problem of the for-
mation of tetramethylammonium salts was overlooked Note Added in Proof
and, thus, was not discussed in a subsequent review on
amide acetals.37
Finally, it should be noted that the triethylammonium salt
of uridine 5′-O-phosphate 113 reacts in DMF at 100 °C
with DMF ethylene acetal 7g to give 24% of uridine 5′-O-
hydroxyethyl phosphate ester 114 as well as 25% of the
N3-hydroxyethyl uridine 5′-O-hydroxyethyl phosphate
ester 115 (Scheme 26).42
Instead of reacting carboxylic acids 1 or phenols 16 with
a solution of diazomethane in diethyl ether, which has to
be prepared anew each time, one can employ DMF di-
methyl acetal 7a or N,N-tetramethyleneformamide di-
methyl acetal 13a as dilute solutions, e.g. in THF or 1,4-
dioxane. These solutions of amide acetals in THF or 1,4-
O
H
N
N
O
O
P
O
O
(CH2)2
O
O
HO
114 24%
H
N
_
O
O
O
Me
HO
OH
N
O
N
O
P
O
O
_
Me
O
O
HO
N
O
DMF, 12 h, 100 °C
OH
+
HO
OH
113
N
O
O
P
Et3NH
(CH )
2 2-O
HO
O
115 26%
_
O
HO
OH
Scheme 26
Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York

ACCOUNT
Esterification of Carboxylic Acids and Etherification of Phenols with Amide Acetals
1615
(25) Bredereck, H.; Simchen, G.; Funke, B. Chem. Ber. 1971,
104, 2709.
(26) Bredereck, H.; Simchen, G.; Horn, P. Chem. Ber. 1970, 103,
210.
(27) JP 55118452, ???; Chem. Abstr. ???, 95, 6861.
(28) Zemlicka, J. Collect. Czech. Chem. Commun. 1963, 28,
1060.
(29) Zemlicka, J. Collect. Czech. Chem. Commun. 1970, 35,
3575.
(30) Wrobel, J.; Millen, J.; Sredy, J.; Dietrich, A.; Kelly, J. M.
J. Med. Chem. 1989, 32, 2493.
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Tetrahedron Lett. 1997, 38, 2367.
(32) Holtwick, J. B.; Golankiewicz, B.; Holmes, B. N.; Leonard,
N. J. J. Org. Chem. 1979, 44, 3835.
(33) Helfer, D. L.; Hosmane, R. S.; Leonard, N. L. J. Org. Chem.
Thus, salts of phosphate esters and probably salts of other
moderately acidic inorganic acids such as monoesters of
sulfuric acid or mono- or diesters of boric acid can also be
esterified by amide acetals.
Acknowledgment
The author is very much indebted to his former and present acade-
mic colleagues at the Institut für Chemie und Biochemie, Freie Uni-
versität Berlin, Professors R. Haag, H.-H. Limbach, J. Mulzer,
H.-U. Reissig, and A. D. Schlüter for their generous hospitality in
providing him with a laboratory and an office, and in particular to
Professor H.-U. Reissig for material support of his research. The do-
nation of a substantial amount of DMF dimethyl acetal by BASF is
furthermore gratefully acknowledged.
1981, 46, 4803.
(34) Hosmane, R. S.; Leonard, N. J. Synthesis 1981, 118.
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heat was evolved. To test whether 7g might be an interesting
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groups, I prepared DMF diethyl acetal 7b and converted it
with ethylene glycol into DMF ethylene acetal 7g. Yet,
cholestan-3-one only reacted with 7g in boiling CH2Cl2 after
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83% yield, see: Vorbrüggen, H. Steroids 1963, 1, 45. On
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2,4,6-trichlorophenol, with diethyl acetal 7b and dibenzyl
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phenyl ethers. While wondering about the possible scope of
these new esterifications, I contacted Dr. John G. Moffatt at
the neighboring Syntex Laboratories in Palo Alto and asked
him whether he might be interested in trying to synthesize
esters from nucleotides using diethyl acetal 7b. A few days
later, John called and told me that a new postdoc of his, who
had just completed his Ph.D. with A. Eschenmoser at ETH
in Zürich, had informed him that A. Eschenmoser was also
working on the esterifications of carboxylic acids with
amide acetals. When I discussed this work with C. Djerassi,
who had generously supported my little additional research
project, he only commented, ‘Write him!’. This I did
although with some trepidation as a completely unknown
scientist, but I received an immediate reply in which A.
Eschenmoser suggested that we should publish our results in
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Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York

1616
H. Vorbrüggen
ACCOUNT
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afforded homogeneous 5a-androst-2-en-17-one, which was
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0.056 g (24%); mp 106.5–107 °C. Further elution (toluene,
1 L) gave additional pure 82 (0.051 g). Combined yield:
0.239 g (68%).
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Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York

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yellowish solution resulted, indicating the completion of the
reaction. Evaporation of the mixture afforded the crude
crystalline product (1.33 g), which was dissolved in tert-
butyl methyl ether (20 mL) and filtered over a layer of silica
gel (18 g) to give crystalline methyl 4-nitrobenzoate (88).
Yield: 0.94 g (100%); mp 94–96 °C. Recrystallization
(boiling hexane, 40 mL) resulted in the first crop of pure 88
(0.69 g); mp 96 °C. Concentration of the mother liquor
afforded another crop of pure 88 (0.16 g). Combined yield:
0.85 g (90%). The remaining hexane mother liquor still
contained, according to TLC (hexane–EtOAc, 4:1), methyl
4-nitrobenzoate (88).
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To a stirred boiling solution of fumaric acid (92) (1.16 g, 10
mmol) in abs THF (30 mL) in a 100-mL three-necked round-
bottom flask, connected to a reflux condenser and an
addition funnel and in an oil bath at 80 °C, was added
dropwise a solution of DMF dimethyl acetal 7a (4 mL, 30
mmol) in abs THF (20 mL) over a period of 1 h, whereupon
salt 93 formed as a colorless precipitate. Because the
solution was still somewhat turbid, additional 7a (1.3 mL, 10
mmol) in abs THF (10 mL) was added over a period of 0.5
h, and the mixture was heated for another 0.5 h and stirred
overnight at r.t. for 16 h. The resulting yellowish solution
was decanted from a small amount of colorless precipitate
(0.03 g), which was washed with tert-butyl methyl ether and
the extracts were filtered. On evaporation, the filtrate gave a
crude yellowish crystalline substance (1.63 g) that was
dissolved in tert-butyl methyl ether (125 mL) and filtered
over a layer of silica gel (16 g). The slightly yellowish
solution gave, on evaporation, spontaneously crystallizing
homogeneous dimethyl fumarate (94). Yield: 1.3 g (93%);
mp 99–103 °C; Rf = 0.35 (hexane–EtOAc, 9:1).
Using 7a and DCE: To a suspension of 4-nitrobenzoic acid
(87) (3.342 g, 20 mmol) in DCE (25 mL) was added a
solution of DMF dimethyl acetal 7a (8.2 mL, 62 mmol) in
DCE (25 mL) over a period of 5 h at 24 °C with stirring.
Stirring was continued for a further 66 h, whereupon a clear
yellowish solution resulted. After evaporation at 35 °C/0.5
Torr, the crystalline residue was extracted with boiling Et2O
(3 × 70 mL) resulting in, after further evaporation, crude
methyl 4-nitrobenzoate (88). Yield: 3.265 g (90%); mp 92–
94 °C. Recrystallization from boiling hexane resulted in pure
88; mp 95–96 °C (Lit. mp 96 °C; see also ref. 108). The
crystalline yellowish residue (0.480 g) that remained after
the extraction with Et2O was recrystallized (abs EtOH, 5
mL) to give acidic tetramethylammonium salt 89 (0.063 g);
mp 278–281 °C. On acidification of the mother liquor with
1 M H2SO4 and extraction with CH2Cl2, pure 4-nitrobenzoic
acid (87) was recovered; mp 242 °C (see also ref. 20).
Using 13a and DCE: To a suspension of 4-nitrobenzoic acid
(87) (2.507 g, 15 mmol) in DCE (40 mL) was added N,N-
tetramethylene-formamide dimethyl acetal 13a (4.656 mL,
30 mmol) with stirring at 30 °C. After 4 h at 30 °C, the
mixture was stirred with sat. NaHCO3 soln (20 mL) and then
was extracted with Et2O (3 × 20 mL). After evaporation of
the ethereal extract, pure, homogeneous, crystalline methyl
4-nitrobenzoate (88) was obtained. Yield: 2.496 g (92%).
The repetition of this experiment over a period of 25 h at 30
°C and workup with NaHCO3 gave crystalline 88; Yield:
2.712 g (100%) (see also ref. 20)
(116) Lau, C. M.; Boyer, J. H. J. Chem. Res., Synop. 1990, 34.
(117) Shvo, Y.; Shanan-Atidi, H. J. Am. Chem. Soc. 1969, 91,
6689.
(118) Wawer, I.; Osek, J. J. Chem. Soc., Perkin Trans. 2 1985,
1669.
(119) (E)- and (Z)-3-(Dimethylamino)acrylonitrile (111) and
(112)
In a 100-mL three-necked round-bottom flask, connected to
a reflux condenser and an addition funnel and in an oil bath
at 80 °C, was stirred a solution of cyanoacetic acid (104)
(1.70 g, 20 mmol) in 1,4-dioxane (30 mL, previously dried
over 4 Å MS). To this solution was added DMF dimethyl
acetal 7a (4 mL, 30 mmol) in 1,4-dioxane (20 mL) with
vigorous stirring over a period of 1 h. Heating was continued
for a further 1 h. After cooling the mixture and evaporating
off the solvent, the crude dark oily product (3.16 g) was
extracted with tert-butyl methyl ether and the extracts were
filtered over a layer of silica gel (ca. 16 g). On evaporation
of the yellow filtrate, homogeneous 3-
Using 7a and THF: To a stirred boiling solution of 4-nitro-
benzoic acid (87) (0.84 g, 5 mmol) in abs THF (30 mL) in a
100-mL three-necked round-bottom flask, connected to a
reflux condenser and an addition funnel and in an oil bath at
80 °C, was added dropwise a solution of DMF dimethyl
acetal 7a (1.8 mL, 15 mmol) in abs THF (20 mL), where-
upon a colorless precipitate formed. After the addition of
about 10 mL (7.5 mmol) of the THF solution of 7a, a clear
(dimethylamino)acrylonitrile (111/112) was obtained.
Yield: 1.92 g (100%); Rf = 0.72 (tert-butyl methyl ether).
Synlett 2008, No. 11, 1603–1617 © Thieme Stuttgart · New York