Esters and amides from activated alcohols using manganese(IV) dioxide: Tandem oxidation processes

Article abstract of DOI:10.1055/s-2003-39163

Manganese(IV) dioxide can be used in conjunction with sodium cyanide in THF-methanol or in methanol alone for the direct conversion of activated alcohols into methyl esters. Ethyl and isopropyl esters can also be prepared. Similarly, use of manganese(IV) dioxide and sodium cyanide in THF containing ammonia or primary amines can be used to convert alcohols into the corresponding amides. Several activated alcohols and one non-activated alcohol example are reported.

Full text of DOI:10.1055/s-2003-39163

PAPER
1055
Esters and Amides from Activated Alcohols using Manganese(IV) Dioxide:
Tandem Oxidation Processes
a
a
b
a
E
J
sters and
o
A
mides from
n
A
ctivate
d
A
a
lcohols us
t
ing Ma
h
nganese(IV)
a
D
ioxide n S. Foot, Hisashi Kanno, Gerard M. P. Giblin, Richard J. K. Taylor*
a
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
b
Department of Medicinal Chemistry, Neurology and GI CEDD, GlaxoSmithKline, The Frythe, Welwyn, Herts AL6 9AR, UK
Received 25 February 2003
directly into esters or amides in a one-pot, four-step se-
quence (Scheme 2).
Abstract: Manganese(IV) dioxide can be used in conjunction with
sodium cyanide in THF–methanol or in methanol alone for the di-
rect conversion of activated alcohols into methyl esters. Ethyl and
isopropyl esters can also be prepared. Similarly, use of manga-
nese(IV) dioxide and sodium cyanide in THF containing ammonia
or primary amines can be used to convert alcohols into the corre-
sponding amides. Several activated alcohols and one non-activated
alcohol example are reported.
MnO2
NaCN
OH
O
RCH2OH
RCHO
R
CN
R
CN
MeOH or
RNH2
Key words: alcohols, amides, esters, oxidations, tandem reactions
RCO2Me or RCONHR
Scheme 2 Esters and amides from alcohols
Introduction
Ester Synthesis
During our recent studies on manganese(IV) dioxide, we
have developed a number of synthetically useful tandem
oxidation processes. Amongst these, we have devised
5
Following on from the work by Corey et al., our initial
trial reactions centred on the use of readily available cin-
namyl alcohol. Extending the published route back a step
and using manganese dioxide (20 equiv), NaCN (5 equiv)
and acetic acid (1.5 equiv) afforded an excellent yield
routes from primary alcohols to alkenes, imines,2
1
2
3
4
amines, oximes, and nitriles. One of the main benefits
of this methodology is the in situ formation and consump-
tion of the intermediate aldehydes. In seeking to extend
this methodology, we were interested in a report by Co-
rey, Gilman and Ganem, concerning a one-pot conversion
of aromatic and unsaturated aldehydes into their corre-
sponding methyl esters using manganese dioxide, acetic
(
84%) of spectroscopically pure methyl trans-cinnamate
after a simple filtration and aqueous work-up (Scheme 3
and Table 1, entry i).
5
O
acid and sodium cyanide in methanol (Scheme 1). This
2
0 MnO2, 5 NaCN
OH
OMe
protocol was further expanded on in 1971 by Gilman to
prepare amides from aromatic aldehydes and cinnamalde-
MeOH, r.t.
With 1.5 AcOH, 2 d, 84%
No AcOH, 3 d, 78%
6
hyde (Scheme 1).
Scheme 3 Methyl trans-cinnamate from cinnamyl alcohol
1
5
0 MnO2
NaCN
10 MnO2
5 NaCN
5
PhCO2Me
PhCHO
PhCONH2
Acetic acid was used in the original procedure, but we
MeOH
.5 AcOH
95%
iPrOH
were concerned about the formation of hydrogen cyanide
in situ. To our delight, the reaction again went to comple-
tion in the absence of acetic acid, providing us with the de-
sired methyl ester, albeit in a slightly lower yield and
longer process (Scheme 3 and Table 1, entry ii, 78%, 3
days).
1
5
NH3
4%
>
6
Scheme 1 Esters and amides from aldehydes
We decided to investigate the extension of these methods
so that alcohols could be employed as starting materials.
Preliminary details of this study have been published. We
now report full details of the transformation of activated
alcohols (and a limited number of non-activated alcohols)
7
This procedure still had two major drawbacks. Firstly, the
length of time for the reaction: to allow the transformation
to be effected quickly and reproducibly, we needed to find
conditions that would allow a more rapid conversion. Sec-
ondly, the large amount of reagents: 5 equivalents of cya-
nide and 20 equivalents of manganese dioxide would not
be favourable for large-scale processes.
Synthesis 2003, No. 7, Print: 20 05 2003.
Art Id.1437-210X,E;2003,0,07,1055,1064,ftx,en;P01903SS.pdf.
To address the reaction rate, we investigated the effect of
increasing the temperature. Initial trials in refluxing meth-
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1
056
J. S. Foot et al.
PAPER
anol gave only a 5% yield of methyl trans-cinnamate after served with as little as 0.2 molar equivalents of NaCN, al-
purification (see Table 1, entry iii), with 23% recovered though the yield was lower at only 52%.
cinnamyl alcohol. We deduced that this may be due to de-
The effect of varying the amount of manganese dioxide
was then evaluated using 1 molar equivalent of NaCN in
activation of the MnO at elevated temperatures in meth-
2
anol. Reduced yields were also witnessed when acetic
the THF–MeOH mixed solvent system. We found that in-
acid was used at raised temperatures.
creasing the amount from 20 to 30 molar equivalents did
We then proceeded to examine mixed solvent systems, us- not improve either the yield or the reaction time, whereas
ing methanol (5 mol equiv) in a range of solvents. The sol- reducing the quantities to less than 15 molar equivalents
vents investigated gave varied results (summarised in led to poorer yields and required a longer reaction time.
Table 1, entries iv–xv) and after extensive studies we This led us to select 15 molar equivalents as our optimum
found that THF containing MeOH (5 mol equiv) was most amount (i.e. ~7 molar equivalents per oxidation step), as
suitable, giving a reproducible 70% yield, after 5 hours at it was the minimum amount required to produce a 70%
reflux (entry xi).
yield after 5 hours at reflux in THF–MeOH. These condi-
tions also afforded us with identical yields upon scale up
Next we examined the quantities of reagents required for
the reaction. With the THF–MeOH mixed solvent system
at reflux and 20 molar equivalents of manganese dioxide,
we varied the amount of sodium cyanide: 0.05, 0.1, 0.2,
(
1 mmol to 10 mmol).
Alternatives to Sodium Cyanide
0
.5, 1 and 2 molar equivalents were tried, with 1 molar
equivalent retaining the same short reaction time and pro-
viding no loss in yield. This is a major advance, removing
the need for a large excess of NaCN. It is worth noting that
complete consumption of the starting material was ob-
We next investigated alternatives to NaCN (Table 2). As
expected, exchanging the cation of the salt still led to for-
mation of the desired methyl ester. Although in most cases
the reaction did go to completion (no starting alcohol
present by TLC) producing spectroscopically pure prod-
Table 1 Varying Solvent Conditions and Temperature for the Formation of Methyl trans-Cinnamate from Cinnamyl Alcohola
o
Entry
Solvent system
MeOH + 1.5 mol equiv HOAc
MeOH
Temperature ( C)
Time
2 d
Isolated yield (%)
i
r.t.
r.t.
65
r.t.
35
35
84
78
5b
ii
3 d
iii
iv
v
MeOH
2 d
Et O + 5 mol equiv MeOH
2 d
46
68
58b
2
Et O + 5 mol equiv MeOH
17 h
28 h
2
vi
Et O + 5 mol equiv MeOH
2
+
1.5 mol equiv HOAc
vii
viii
ix
CH Cl + 5 mol equiv MeOH
r.t.
40
40
3 d
17 h
2 d
62b
72
2
2
CH Cl + 5 mol equiv MeOH
2
2
CH Cl + 5 mol equiv MeOH
70
2
2
+
1.5 mol equiv HOAc
x
MeOAc + 5 mol equiv MeOH
THF + 5 mol equiv MeOH
57
66
16 h
5 h
51c
70
xi
xii
xiii
xiv
EtOAc + 5 mol equiv MeOH
MeCN + 5 mol equiv MeOH
ClCH CH Cl + 5 mol equiv MeOH
77
17 h
22 h
1 h
51c
42c
60
81
83
2
2
xv
DMF + 5 mol equiv MeOH
110
4 h
54b,c
a
All reactions performed with cinnamyl alcohol, using NaCN (5 mol equiv) and MnO (20 mol equiv), unless stated otherwise. Reactions were
2
followed by TLC, monitoring the time for the complete consumption of starting alcohol.
b
c
1
Crude product not spectroscopically pure; yield based on H NMR analysis or isolation after purification.
Reaction performed using NaCN (1 mol equiv) and MnO (15 mol equiv).
2
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PAPER
Esters and Amides from Activated Alcohols using Manganese(IV) Dioxide
1057
4
Table 2 Alternatives to NaCN for the MnO -Mediated Oxidation of
Cinnamyl Alcohol
lated studies ) would then occur. Attempts to prevent this
2
a
side reaction from occurring in the case of KOCN (e.g. by
use of molecular sieves or MgSO ) were unsuccessful.
4
Entry
Additive
2 mol equiv)
Yield of methyl
trans-cinnamate
(
(
or cinnamonitrile/
cinnamaldehyde) (%)
Substrate Range
i
Me SiCN
67
3
The optimised conditions for cinnamyl alcohol were then
applied to a variety of different alkenyl, alkynyl, benzylic,
heterocyclic and aliphatic alcohols (Table 3).
ii
KCN
64
iii
iv
v
CuCN
LiCN
(–/–)b
As can be seen from Table 3, only aromatic alkenyl and
alkynyl substrates were successful in this methodology
(entries vi–xiv). Non-aromatic alkenyl and alkynyl sys-
tems failed under both sets of conditions. Propargyl alco-
hol (1d) (entry iv), afforded a 19% yield of methyl cyano-
β-acrylate (2d) as a cis–trans mixture (7:1), presumably
from initial formation of methyl propargylate, followed
by Michael-type cyanide attack on the triple bond.
56
25c
Bu NCN
4
vi
vii
viii
ix
x
KOCN
NaSMe
NaN3
6 (49/11)c
(–/–)b
(–/–)b
(–/55)d
However, the benzylic and heterocyclic systems (entries
vii–xiv) gave clean conversion into the corresponding me-
thyl esters in good yields (40–64%), using the conditions
optimised for cinnamyl alcohol.
NaClO2
KSCOMe
NaI
(–/64)d
(–/80) d
xi
xii
xiii
Attempts to produce esters from unactivated alcohols
were unsuccessful: with tetrahydrofurfuryl alcohol a low
yield of what appeared to be the dimeric ester 2o (entry
KSCN
(4/62) e
4c
Ph
N+
1
9
xv, identified by MS and H NMR spectroscopy ) was
formed, whilst decanol (1p) (entry xvi) proved to be com-
pletely unreactive under these conditions.
Cl-
HO
H
S
a
All reactions carried out on a 1 mmol scale, using MnO (20 mol
2
Having shown that the methodology worked on a range of
substrates, we then focused on improving the yields of
those benzylic and heterocyclic systems from Table 2
(Procedure A). We exposed a selection of alcohols to the
room temperature conditions (B) that gave an 84% yield
of methyl trans-cinnamate in the initial studies. As pre-
dicted, in most cases this greatly improved the yields (see
entries viii–x, xiii, xiv), although longer reaction times
were required.
equiv), MeOH (5 mol equiv) and the relevant salt (2 mol equiv) in
THF at reflux. Reactions were followed by TLC until complete con-
sumption of starting alcohol was observed. Yield based on product re-
covered after simple filtration and aqueous work-up unless otherwise
stated.
b
Cinnamaldehyde only observed product by TLC, reaction not
worked up.
c
Isolated yield after purification by column chromatography.
d
e
Cinnamaldehyde was the only product isolated.
1
Yield calculated from H NMR analysis.
Formation of Ethyl and Isopropyl Esters
uct, we were unable to improve upon the 70% yield af-
forded by NaCN (see Table 2, entries i–v). To try and
address the toxicity issues presented by the use of cyanide,
we then studied various related replacements (see entries
vi–xiii). Only two of the eight compounds provided us
with methyl trans-cinnamate, namely potassium cyanate
To expand the scope of the methodology, we then looked
at the use of alternative alcohols to methanol. To achieve
this, we replaced the 5 equivalents of methanol with etha-
nol, isopropanol and tert-butanol in the optimised condi-
tions for cinnamyl alcohol. Only ethanol showed some
(
entry vi) and 3-benzyl-5-(2-hydroxyethyl)-4-methylthia-
1
product formation (by H NMR spectroscopy). Assuming
8
zolium chloride (entry xiii), both in low yields. With the
remaining compounds, only the intermediate cinnamalde-
hyde was obtained. An interesting side reaction was also
observed with potassium cyanate and potassium thiocyan-
ate, as both afforded an isolable amount of cinnamonitrile
that both isopropanol and tert-butanol were not sufficient-
ly reactive in refluxing THF, we attempted the same reac-
tion in a higher boiling solvent (acetonitrile). Once again,
1
no product was observed in the H NMR spectrum.
Switching to the room temperature conditions, we then
tried again, using the appropriate alcohol as solvent.
These conditions afforded a 49% isolated yield of ethyl
trans-cinnamate (2p) and only a 10% yield of isopropyl
trans-cinnamate (2q) (Scheme 4). From these results we
concluded that although it may be possible to form high
–
in the case of the cyanate, this was the major product
(
49%, entry vi). This outcome is thought to be due to an in
situ attack of the protonated anion by water, releasing am-
monia (also CO and H S), which could then condense
2
2
with the aldehyde present to give the imine. Further oxi-
dation of the imine by MnO to the nitrile (as seen in re-
2
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J. S. Foot et al.
PAPER
yields of ethyl and isopropyl esters via this method, the provided the same product in a similar yield (29%), sug-
timescale would be too long to make the route viable.
gesting that this reaction can also proceed via a hemi-ace-
tal intermediate, rather than an acyl cyanide (see
Scheme 5).
O
20 MnO2, 5 NaCN
OH
OR
O
ROH, rt, 7 days
2p, R = Et, 49%
1a
i
2
q, R = Pr, 10%
15 MnO , THF, reflux
OH
OH
2
O
Scheme 4 Ethyl and isopropyl trans-cinnamate from cinnamyl al-
3
4
cohol
O
OH
MnO2
These results led us to propose that the manganese dioxide
oxidation–trapping sequence might be applicable to lac-
tonisation routes. To test this we prepared the diol 3.10
This was then used under the optimised conditions and al-
lowed to stir at reflux for 4 hours. Upon standard work-up,
MnO2
H
O
With NaCN, 35%
No NaCN, 29%
OH
Scheme 5 Hemi-acetal mechanism
1
1
isochroman-1-one (4) was obtained in a 35% isolated
yield. Repetition of this experiment without cyanide also
a
b
Table 3 Alcohol Examples at Both Reflux (Procedure A) and Room Temperature (Procedure B)
Entry
i
Alcohol
Product
Procedure A
Procedure B
time (h), isolated yield (%) time (day), isolated yield (%)
O
4, 70
2, 84
OH
OMe
OMe
1
a
2a
O
ii
18, trace
18, trace
OH
1
b
2b
iii
OH
O
OMe
1
c
2c
iv
v
CN
O
18, 19
(E:Z, 1:7)
OH
OMe
1
d
2d
O
24, trace
18, 66
OH
OMe
1
e
2e
vi
O
OH
OMe
1
f
2f
vii
O
18, 53
15, 57
OH
OMe
O
1
g
2g
2h
viii
5, 48c
OH
OMe
MeO
MeO
1
h
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PAPER
Esters and Amides from Activated Alcohols using Manganese(IV) Dioxide
1059
a
b
Table 3 Alcohol Examples at Both Reflux (Procedure A) and Room Temperature (Procedure B) (continued)
Entry
ix
Alcohol
Product
Procedure A
Procedure B
time (h), isolated yield (%) time (day), isolated yield (%)
15, 46
22, 41
3, 80c
O
OH
OMe
OMe
Br
Br
1
i
2
i
x
O
2, 68
OH
O2N
O2N
1
j
2j
xi
O
2, 57
2, 64
18, 41
N
N
OH
OMe
1
k
2k
xii
xiii
O
N
OH
OH
N
OMe
OMe
1
l
2l
O
3, 55
N
N
1
m
2m
xiv
xv
O
O
O
20, 41
7, 77d
OH
OMe
1
n
2n
22, trace
O
OH
O
O
O
O
1
o
2o
xvi
CH (CH ) CH OH
99% reclaimed starting material 16 h
3
2 8
2
1
p
a
Reactions carried out on a 1 mmol scale, using MnO (15 mol equiv), MeOH (5 mol equiv) and NaCN (1 mol equiv) in THF at reflux. Reactions
2
were followed by TLC until complete consumption of starting alcohol was observed. Yield based on product recovered after simple filtration
and aqueous work-up unless otherwise stated.
b
Reactions carried out on a 1 mmol scale, using MnO (20 mol equiv), HOAc (1.5 mol equiv) and NaCN (5 mol equiv) in MeOH at r.t.. Reac-
2
tions were followed by TLC until complete consumption of starting alcohol was observed. Yield based on product recovered after simple fil-
tration and aqueous work-up unless otherwise stated.
c
1
Trace of starting material; yield calculated from H NMR analysis.
d
Isolated yield after purification by column chromatography.
Amide Synthesis
perature than at reflux (at higher temperatures the corre-
sponding imine tended to predominate2 ). A large excess
,12
The conversion of benzyl alcohol into N-isobutylbenza- of isobutylamine was also found to be required for good
mide was investigated next. Efficient conversion was yields, as shown in Scheme 6. Dichloromethane can also
achieved in THF, with higher yields obtained at room tem- be used as a solvent.
Scheme 6 N-Isobutylbenzamide from benzyl alcohol
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1
060
J. S. Foot et al.
PAPER
Table 4 Amine Variationsa
tries ii–vii), secondary (entries viii–x) and allyl (entry vii)
amines. When using cyclohexylamine (entry v) and tert-
butylamine (entry vi) lower yields of the corresponding
amide were observed. This was thought to be due to the
increased steric hindrance of the amine alkyl group.
Entry
i
Amine
mol equiv used)
Product
Time (h),
isolated yield (%)
(
O
NH (4)
24, 53
3
NH2
Substrate Range
5
b
ii
i-BuNH (5)
O
24, 86
2
The optimum conditions were then applied to a range of
alcohols using 5 molar equivalents of isobutylamine
N
H
(
Table 5). The aromatic and heterocyclic examples tested
5
a
all afforded the corresponding amides in good yield (en-
tries i–viii). With cinnamyl alcohol, the yield was less sat-
isfactory. However, by lowering the reaction temperature
to 0 ºC, a yield of 52% could be achieved (entry ix). When
using trans- and cis-hex-2-en-1-ol (entries x and xi), in-
creased yields were observed by carrying out the reaction
in hexane. In more polar solvents, we believe that cyanide
addition occurs to the carbon–carbon and carbon–nitro-
gen double bonds leading to by-product formation. An at-
tempt on a propargylic system gave only a low yield of the
expected product (entry xii), whilst using the unactivated
alcohol, furfuryl alcohol, gave a 45% yield of the corres-
ponding amide (entry xiii).
iii
iv
v
MeNH (2)
O
24, 69
24, 67
21, 42
2
N
H
5
O
c
i-PrNH (5)
2
N
H
5
d
NH2
O
N
H
(
1.5)
5
e
O
vi
t-BuNH (1.5)
22, 3b
24, 45
24, 73
24, 62
24, 25
Table 5 Alcohol Variationsa
2
N
H
Entry
i
Alcohol
Product
Time (h),
isolated
yield (%)
5
O
f
vii
viii
ix
H2N
23, 81b
O
(
5)
N
OH
OH
H
N
H
MeO
O2N
MeO
5
g
O
1
h
6a
O
Me NH (5)
2
ii
17, 77
N
N
H
2
O N
5
h
O
1i
6b
NH
iii
iv
O
24, 60
24, 61
N
N
N
(
1.6)
OH
OH
N
H
5
O
i
x
Et NH (5)
1k
1l
6c
O
2
N
N
H
5
j
N
N
a
6d
All reactions carried out on benzyl alcohol (1 mmol), using MnO2
20–40 mol equiv) and NaCN (1 mol equiv) in THF at r.t. Reactions
were followed by TLC until complete consumption of starting alcohol
was observed.
v
O
26, 65
23, 64
(
OH
N
H
N
N
b
Main product was benzyl benzoate (25%).
1
m
6e
O
vi
OH
N
H
Amine Variations
S
S
1
q
6f
These conditions were next applied to a range of amines
with benzyl alcohol (Table 4). This methodology was uti-
lised successfully with ammonia (entry i), primary (en-
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Esters and Amides from Activated Alcohols using Manganese(IV) Dioxide
1061
a
Table 5 Alcohol Variations (continued)
available 2,4-dodecadien-1-ol (7) in one step, using the
tandem oxidation process shown in Scheme 7.16
Entry
Alcohol
Product
Time (h),
isolated
yield (%)
Conclusions
vii
24, 60
O
OH
OH
N
H
In conclusion, we have successfully developed one-pot
procedures for the conversion of activated primary alco-
hols into methyl esters and amides. The procedures are
practically straightforward, using mild conditions and wa-
ter-insensitive environments, and afford good to excellent
yields of the products by a simple filtration and solvent
evaporation work-up (occasionally with need for chro-
matographic purification). We have applied our method-
ology to the synthesis of a simple natural product, forming
N-isobutyl-2E,4E-dodecadienamide in 51% yield from
commercially available 2,4-dodecadien-1-ol.
S
S
1
r
s
6
O
g
viii
ix
26, 59
N
H
O
O
1
6h
O
24, 36
(
10, 52)c
OH
N
H
1
1
a
6i
O
x
18, 18
All reagents were purchased from commercial sources and used
without further purification unless specified. Manganese(IV) diox-
ide used was purchased from Aldrich, cat. no. 21,764-6 (<5 micron,
activated, 85%). THF was distilled from sodium–benzophenone
ketyl immediately before use. Petroleum ether is the fraction with
bp 40–60 °C. Flash chromatography was performed on Matrix sili-
ca gel 60 (70–200 microns) using the eluent specified. NMR spectra
were recorded on a Jeol 270 MHz spectrometer. Mps were deter-
mined using a Gallenkamp platform mp apparatus and are uncor-
rected. Mass spectra were recorded on a Fisons analytical autospec
instrument in chemical ionisation mode. IR spectra were recorded
on a ThermoNicolet IR100 spectrometer between 600 and 4000
d
(
22, 55)
N
H
OH
b
6j
xi
(21, 32)d
6, 31e
O
N
H
OH
1
c
6k
xii
O
N
OH
–
1
cm using NaCl discs. 2-(2-Hydroxymethylphenyl)ethanol (3) was
1
0
prepared using an adaptation of the literature procedure. The
structures of known compounds were confirmed by comparison of
NMR data with those published (and by mp comparison for solids).
1
f
6l
xiii
O
48, 45
OH
N
H
Methyl Ester Formation; Representative Procedures
Procedure A; Reflux in THF with MeOH (5 Mol Equiv)
Methyl trans-Cinnamate (2a)
O
O
1
o
6m
1
7
a
All reactions carried out on corresponding alcohol (1 mmol), using
To a mixture of cinnamyl alcohol (0.134 g, 1 mmol), sodium cya-
nide (0.049 g, 1 mmol) and manganese(IV) dioxide (1.31 g, 15
mmol) stirring in THF (10 mL) at r.t., was added MeOH (0.21 mL,
5 mmol). The reaction was heated to reflux and left to stir for 5 h.
The resulting mixture was then filtered through a pad of Celite and
the solvent removed in vacuo. Extraction with CH Cl (50 mL) was
MnO (20–40 mol equiv), isobutylamine (5 mol equiv) and NaCN (1
2
mol equiv) in THF at r.t.. Reactions were followed by TLC until com-
plete consumption of starting alcohol was observed.
b
Reaction also carried out with benzylamine (5 mol equiv), giving N-
benzyl-4-methoxybenzamide (6n) in a 51% yield after 24 h.
2
2
c
Reaction carried out at 0 ºC.
Reaction carried out using hexane as the solvent.
Diethylamine used in place of isobutylamine.
followed by washing with water (2 × 10 mL) and then sat. aq NaCl
d
(10 mL), before drying the organic layer (MgSO ). Filtration and re-
4
e
moval of solvent in vacuo afforded the title compound 2a.
Yield: 0.113 g (70%); light yellow crystals; mp 35 °C (lit.18 mp 35–
3
6 °C).
The synthesis of a simple natural product, N-isobutyl-
2
E,4E-dodecadienamide (8), was then attempted. This
Procedure B; Room Temperature in MeOH
Methyl trans-Cinnamate (2a)
To a mixture of cinnamyl alcohol (0.134 g, 1 mmol), sodium cya-
nide (0.245 g, 5 mmol) and manganese(IV) dioxide (1.74 g, 20
mmol) stirring in MeOH (10 mL) at r.t., was added glacial HOAc
compound has been isolated from Echinacea angustifo-
lia, Echinacea atrorubens and Piper sarmentosum,
and was successfully synthesised from the commercially
1
3
14
15
Scheme 7 Natural product synthesis: N-Isobutyl-2E,4E-dodecadienamide from 2,4-dodecadien-1-ol
Synthesis 2003, No. 7, 1055–1064 ISSN 0039-7881 © Thieme Stuttgart · New York

1
062
J. S. Foot et al.
PAPER
(
81 µL, 1.5 mmol). The reaction was left to stir at r.t. for 2 days. The
(1.31 g, 15 mmol) was added and the reaction allowed to stir for 24
h. The resulting mixture was then fitered through a pad of Celite and
the solvent removed in vacuo. Extraction with CH Cl (100 mL)
resulting mixture was then filtered through a pad of Celite and the
solvent removed in vacuo. Extraction with CH Cl (50 mL) was fol-
2
2
2
2
lowed by washing with water (2 × 10 mL) and then sat. aq NaCl (10
was followed by washing with H O (40 mL) and then sat. aq NaCl
2
mL), before drying the organic layer (MgSO ). Filtration and re-
(40 mL), before drying the organic layer (MgSO ). Filtration and re-
4
4
moval of solvent in vacuo afforded the title compound 2a.
moval of the solvent in vacuo gave a clear oil, which was purified
by flash chromatography (petroleum ether–EtOAc, 5:1) to afford
the title compound 5a.
Yield: 0.136 g (84%); light yellow crystals.
Phenylpropynoic Acid Methyl Ester (2f)19
Yield: 0.152 g (86%); light yellow solid; mp 55–56 °C (lit. mp 54–
32
Procedure A.
56 °C).
Yellow oil.
Benzamide (5b)33
3
4
Methyl Benzoate (2g)20
Procedure A.
White solid; mp 127–128 °C (lit. mp 127–128 °C).
N-Methylbenzamide (5c)35
Yellow oil.
35
White solid; mp 76–77 °C (lit. mp 71–72 °C).
Methyl 4-Methoxybenzoate (2h)17
Procedure A.
White solid; mp 46–47 °C (lit.21 mp 46 °C).
N-Isopropylbenzamide (5d)32
White solid; mp 97–98 °C (lit. mp 98–99.5 °C).
36
N-Cyclohexylbenzamide (5e)37
White solid; mp 147–148 °C (lit. mp 152–154 °C).
3
7
Methyl 4-Bromobenzoate (2i)22
Procedure B.
White solid; mp 75–77 °C (lit.23 mp 74–77 °C).
N-tert-Butylbenzamide (5f)38
White solid; mp 123–124 °C (lit. mp 124–126 °C).
38
Methyl 4-Nitrobenzoate (2j)24
Procedure B.
Yellow solid; mp 92–94 °C (lit.25 mp 93–95 °C).
N-Allylbenzamide (5g)39
Colourless oil.
N,N-Dimethylbenzamide (5h)40
Colourless oil.
Methyl Pyridine-2-carboxylate (2k)26
Procedure A.
1
-Benzoylpyrrolidine (5i)41
Colourless oil.
Yellow oil.
Methyl Pyridine-3-carboxylate (2l)27
Procedure A.
White solid; mp 37–39 °C (lit.28 mp 36–38 °C).
N,N-Diethylbenzamide (5j)42
Colourless oil.
4
3
N-Isobutyl-4-methoxybenzamide (6a)
Methyl Pyridine-4-carboxylate (2m)20
43
Yellow solid; mp 99–100 °C (lit. mp 100–102 °C).
Procedure B.
4
3
Colourless oil.
N-Isobutyl-4-nitrobenzamide (6b)
4
4
Yellow solid; mp 117–118 °C (lit. mp 121.5–122 °C).
Methyl 2-Furoate (2n)29
Procedure B.
4
5
N-Isobutyl-(E)-cinnamamide (6i)
4
5
White solid; mp 109-110 °C (lit. mp 110–112 °C).
Colourless oil.
N,N-Diethyl-3-phenylprop-2-ynamide (6l)46
Yellow oil.
Ethyl trans-Cinnamate (2p)30
Procedure A.
4
7
Colourless oil.
N-Benzyl-4-methoxybenzamide (6n)
4
7
White solid; mp 127–128 °C (lit. mp 128–129 °C).
Isopropyl trans-Cinnamate (2q)31
Procedure A.
1
5
N-Isobutyl-(2E,4E)-dodecadienamide (8)
Yellow solid; mp 86–87 °C (lit. mp 88 °C).
4
8
Colourless oil.
The following compounds prepared by the representative procedure
are novel, and have therefore been fully characterised.
Isochromanone (4)11
Procedure B.
N-Isobutyl-2-pyridinecarboxamide (6c)
Yield: 0.108 g (60%); white solid; mp 54.5–55.5 °C; R 0.30
Colourless oil.
f
(
EtOAc–petroleum ether, 1:2).
Amide Formation; Representative Procedure
3
2
IR (Nujol): 3332, 1667 cm–1.
N-Isobutylbenzamide (5a)
To a mixture of benzyl alcohol (0.108 g, 1 mmol), isobutylamine
0.365 g, 5 mmol) and sodium cyanide (0.049 g, 1 mmol) stirring in
1
H NMR (270 MHz, CDCl ): δ = 0.97 (6 H, d, J = 6.8 Hz), 1.85 (1
3
(
H, nonet, J = 6.8 Hz), 3.20–3.40 (2 H, m), 7.39 (1 H, ddd, J = 7.9,
4
H, dt, J = 7.9, 1.2 Hz), 8.45–8.60 (1 H, m).
THF (10 mL) at r.t., was added manganese(IV) dioxide (1.31 g, 15
mmol). After 30 min, a further portion of manganese(IV) dioxide
.9, 1.2 Hz), 7.82 (1 H, td, J = 7.9, 1.5 Hz), 8.15 (1 H, br s), 8.18 (1
Synthesis 2003, No. 7, 1055–1064 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Esters and Amides from Activated Alcohols using Manganese(IV) Dioxide
1063
1
3
C NMR (67.9 MHz, CDCl ): δ = 20.3, 28.8, 47.9, 122.3, 126.1,
HRMS (CI): m/z calcd for C H NOS: 184.0796; found: 184.0798
3
9
14
1
37.4, 148.1, 150.2, 164.4.
(0.8 ppm error).
+
MS (CI): m/z = 179 (MH , 100%).
N-Isobutyl-3-furancarboxamide (6h)
Yield: 0.099 g (59%); white solid; mp 91–92 °C; R 0.20 (EtOAc–
petroleum ether, 1:2).
HRMS (CI): m/z calcd for C H N O: 179.1184; found: 179.1188
1
0
15
2
f
(
1.9 ppm error).
–
1
IR (Nujol): 3257, 1627 cm .
N-Isobutyl-3-pyridinecarboxamide (6d)
Yield: 0.109 g (61%); white solid; mp 50.5–51.5 °C; R 0.18
1
H NMR (270 MHz, CDCl ): δ = 0.90 (6 H, d, J = 6.7 Hz), 1.82 (1
f
3
(EtOAc).
H, nonet, J = 6.7 Hz), 3.10–3.25 (2 H, m), 6.48 (1 H, br s), 6.60–
–
1
6.75 (1 H, m), 7.30–7.45 (1 H, m), 7.94 (1 H, s).
IR (Nujol): 3267, 1643 cm .
1
13C NMR (67.9 MHz, CDCl
43.9, 144.7, 162.9.
): δ = 20.2, 28.7, 46.9, 108.5, 122.9,
3
H NMR (270 MHz, CDCl ): δ = 0.94 (6 H, d, J = 6.8 Hz), 1.88 (1
3
1
H, nonet, J = 6.8 Hz), 3.25 (2 H, dd, J = 6.8, 6.0 Hz), 6.74 (1 H, br
s), 7.33 (1 H, dd, J = 8.0, 4.9 Hz), 8.08 (1 H, dt, J = 8.0, 1.7 Hz),
+
MS (CI): m/z = 168 (MH , 100%).
8
.65 (1 H, dd, J = 4.9, 1.7 Hz), 8.94 (1 H, d, J = 1.7 Hz).
HRMS (CI): m/z calcd for C H NO : 168.1025; found: 168.1023
(0.9 ppm error).
9
14
2
1
3
C NMR (67.9 MHz, CDCl ): δ = 20.3, 28.7, 47.5, 123.6, 130.7,
3
1
35.2, 147.9 152.1, 165.9.
+
N-Isopropyl-2E-hexenamide (6j)
Yield: 0.093 g (55%); white solid; mp 43–44 °C; R 0.29 (EtOAc–
petroleum ether, 1:2).
MS (CI): m/z = 179 (MH , 100%).
f
HRMS (CI): m/z calcd for C H N O: 179.1184; found: 179.1188
1
0
15
2
(
2.0 ppm error).
–
1
IR (Nujol): 3303, 1667, 1627, 1551 cm .
1
N-Isobutyl-4-pyridinecarboxamide (6e)
H NMR (270 MHz, CDCl ): δ = 0.89 (3 H, t, J = 7.3 Hz), 0.90 (6
3
Yield: 0.115 g (65%); pale yellow solid; mp 64–65 °C; R 0.33
H, d, J = 6.8 Hz), 1.45 (2 H, sext, J = 7.3 Hz), 1.78 (1 H, nonet, J =
6.8 Hz), 2.00–2.22 (2 H, m), 3.08–3.22 (2 H, m), 5.72 (1 H, br s),
5.78 (1 H, dt, J = 15.5, 1.5 Hz), 5.78 (1 H, dt, J = 15.5, 7.0 Hz).
f
(EtOAc–MeOH, 10:1).
–
1
IR (Nujol): 3306, 1638 cm .
13C NMR (67.9 MHz, CDCl
24.4, 144.5, 173.1.
): δ = 14.3, 20.8, 22.2, 29.2, 34.7, 47.5,
1
3
H NMR (270 MHz, CDCl ): δ = 0.91 (6 H, d, J = 6.8 Hz), 1.85 (1
3
1
H, nonet, J = 6.8 Hz), 3.15–3.35 (2 H, m), 7.01 (1 H, br s), 7.58 (2
H, dd, J = 4.3, 1.7 Hz), 8.62 (2 H, dd, J = 4.3, 1.7 Hz).
+
MS (CI): m/z = 170 (MH , 100%).
1
3
C NMR (67.9 MHz, CDCl ): δ = 20.2, 28.6, 47.6, 121.1, 142.1,
HRMS (CI): m/z calcd for C H NO: 170.1545; found: 170.1544
3
10 20
1
50.4, 165.9.
(0.3 ppm error).
+
MS (CI): m/z = 179 (MH , 100%).
N-Isopropyl-2Z-hexenamide (6k)
Yield: 0.055 g (32%); colourless oil; R 0.29 (EtOAc–petroleum
ether, 1:2).
HRMS (CI): m/z calcd for C H N O: 179.1184; found: 179.1184
1
0
15
2
f
(
0.0 ppm error).
–
1
IR (Nujol): 3293, 2959, 2932, 2871, 1658, 1632, 1548 cm .
N-Isobutyl-2-thiophenecarboxamide (6f)
Yield: 0.116 g (64%); white solid; mp 86–87 °C; R 0.31 (EtOAc–
1
H NMR (270 MHz, CDCl ): δ = 0.89 (6 H, d, J = 6.8 Hz), 0.90 (3
f
3
petroleum ether, 1:2).
H, t, J = 7.4 Hz), 1.45 (2 H, sext, J = 7.4 Hz), 1.76 (1 H, nonet, J =
6.8 Hz), 2.59 (2 H, qd, J = 7.4, 1.5 Hz), 3.03–3.16 (2 H, m), 5.69 (1
H, dt, J = 11.5, 1.5 Hz), 5.76 (1 H, br s), 5.93 (1 H, dt, J = 11.5, 7.4
Hz).
–
1
IR (Nujol): 3238, 1618 cm .
1
H NMR (270 MHz, CDCl ): δ = 0.91 (6 H, d, J = 6.8 Hz), 1.85 (1
3
H, nonet, J = 6.8 Hz), 3.22 (2 H, dd, J = 6.8, 6.0 Hz), 6.45 (1 H, br
s), 7.04 (1 H, dd, J = 4.7, 3.6 Hz), 7.43 (1 H, dd, J = 4.7, 1.2 Hz),
1
3
C NMR (67.9 MHz, CDCl ): δ = 13.9, 20.2, 22.6, 28.6, 30.8, 46.7,
3
1
22.6, 145.1, 166.8.
7
.54 (1 H, dd, J = 3.6, 1.2 Hz).
+
1
3
MS (CI): m/z = 170 (MH , 100%).
C NMR (67.9 MHz, CDCl ): δ = 20.2, 28.7, 47.4, 127.6, 127.9,
3
1
29.7, 139.4, 162.2.
HRMS (CI): m/z calcd for C H NO: 170.1545; found:
1
0
20
+
170.1545 (–0.3 ppm error).
MS (CI): m/z = 184 (MH , 100%).
HRMS (CI): m/z calcd for C H NOS: 184.0796; found: 184.0795
9
14
N-Isobutyl-2-tetrahydrofurancarboxamide (6m)
(
0.5 ppm error).
Yield: 0.077 g (45%); colourless oil; R 0.27 (EtOAc–petroleum
f
ether, 2:1).
N-Isobutyl-3-thiophenecarboxamide (6g)
Yield: 0.110 g (60%); white solid; mp 86.5–87.5 °C; R 0.11
–
1
IR (Nujol): 3329, 2959, 2930, 2872, 1659 cm .
f
1
(
EtOAc–petroleum ether, 1:2).
H NMR (270 MHz, CDCl ): δ = 0.84 (6 H, d, J = 6.8 Hz), 1.60–
3
–
1
1.92 (3 H, m), 1.92–2.10 (1 H, m), 2.10–2.35 (1 H, m), 2.90–3.15 (2
H, m), 3.75–4.00 (2 H, m), 4.28 (1 H, dd, J = 8.2, 5.6 Hz), 6.70 (1
H, br s).
IR (Nujol): 3248, 1623 cm .
1
H NMR (270 MHz, CDCl ): δ = 0.91 (6 H, d, J = 6.8 Hz), 1.84 (1
3
H, nonet, J = 6.8 Hz), 3.14–3.24 (2 H, m), 6.65 (1 H, br s), 7.27 (1
H, dd, J = 5.1, 3.0 Hz), 7.41 (1 H, dd, J = 5.1, 1.2 Hz), 7.54 (1 H,
dd, J = 3.0, 1.2 Hz).
1
3
C NMR (67.9 MHz, CDCl ): δ = 20.0, 25.6, 28.6, 30.2, 46.0, 69.4,
3
7
8.5, 173.1.
+
1
3
MS (CI): m/z = 172 (MH , 100%).
C NMR (67.9 MHz, CDCl ): δ = 20.2, 28.7, 47.2, 126.3, 128.0,
3
1
37.9, 163.4.
HRMS (CI): m/z calcd for C H NO : 172.1338; found: 172.1336
9
18
2
+
(1.2 ppm error).
MS (CI): m/z = 184 (MH , 100%).
Synthesis 2003, No. 7, 1055–1064 ISSN 0039-7881 © Thieme Stuttgart · New York

1
064
J. S. Foot et al.
PAPER
Acknowledgements
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1
We are grateful to the EPSRC and GlaxoSmithKline for CASE stu-
dentship support (J S F) and to the Kureha Chemical Industry for in-
dustrial studentship support (H K).
(
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(
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(
(
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1
(
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1
Synthesis 2003, No. 7, 1055–1064 ISSN 0039-7881 © Thieme Stuttgart · New York