Observations on the DDQ oxidation of 1-acyldihydropyridines - A synthetic application

Article abstract of DOI:10.1055/s-2001-17509

A synthetic application of the rate difference in oxidation of regioisomerically substituted N-acyldihydropyridines is reported. This has allowed for isolation of pure 4-substituted pyridine isomers without the need for chromatography. Diels-Alder adducts between a dihydropyridine and DDQ were isolated and formation of novel hydroquinone ethers was also observed during some reactions.

Full text of DOI:10.1055/s-2001-17509

1784
PAPER
Observations on the DDQ Oxidation of 1-Acyldihydropyridines – A Synthetic
Application
O
bservations on th
e
e
DDQ of
b
r
opyridin
a
e
s
-
A Synthetic
A
J
pplicatio
.
n
Wallace,* Andrew D. Gibb,* Ian F. Cottrell, Derek J. Kennedy, Karel M. J. Brands, Ulf H. Dolling
Department of Process Research, Merck Sharp & Dohme Research Laboratories, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU,
UK
Fax +44(1992)452581; E-mail: debra_wallace@merck.com
Received 8 May 2001; revised 22 June 2001
Abstract: A synthetic application of the rate difference in oxidation
of regioisomerically substituted N-acyldihydropyridines is report-
ed. This has allowed for isolation of pure 4-substituted pyridine iso-
mers without the need for chromatography. Diels–Alder adducts
between a dihydropyridine and DDQ were isolated and formation of
novel hydroquinone ethers was also observed during some reac-
tions.
R1
N
O
R1
N
O
O
Me
Me
R2
N
N
OMe
OMe
N
3
1
2
Scheme 1
Key words: N-acyldihydropyridine, DDQ oxidation, Diels–Alder,
hydroquinone ether
Table 1 Addition of Ethyl Grignard Reagent to Weinreb Amide 3
O
O
We recently required an efficient and scaleable synthesis
of 4-substituted-3-acyl pyridines 1 (Scheme 1). For this
purpose the Weinreb amides of 4-substituted nicotinic ac-
ids 2 were regarded as suitable intermediates, which
would allow for rapid access to either aldehydes or ke-
tones from a common intermediate. Various methods
have been developed for the addition of organometallic
reagents to activated pyridines, with the selectivity of the
reaction depending on the nature of the organometallic,
the structure of the pyridine and the activating reagent
used.1,2 In particular, the operationally straightforward
copper-catalyzed addition of Grignard reagents to 3-sub-
stituted 1-acylpyridinium salts, followed by oxidation of
the resulting dihydropyridine, has been developed into a
powerful synthetic method for the synthesis of the corre-
sponding 4-substituted compounds.3 This procedure
avoids the necessity of preparing complex organometallic
reagents and we envisaged that this strategy would be ap-
plicable in our case. However, unless the addition reaction
occurred with complete regioselectivity, a potentially
Et
O
Me
+
Me
N
Me
N
+
Et
N
OMe
OMe
3
N
OMe
N
Et
N
PhO
O
PhO
O
PhO
O
4
5
6
Entry
Additive
none
4
5
6
1
2
3
4
5
6
7
34
50
76
82
77
64
70
53
40
23
17
22
35
27
13
10
1
10% Cul
10% CuBr◊DMS
10% CuBr◊DMS1
20% CuBr◊DMS
1
1
10% Cul, 3 equiv DMS
10% Cul, 3 equiv DMS1
1
3
Reagents and Conditions: PhOCOCl, additive, THF, –78 °C, 30 min,
cumbersome purification of the isomeric dihydropy- EtMgBr (1EtMgCl), –78 °C, 1h.
ridines would be required. In this paper we describe our
observations on the selective oxidation of regioisomeric
N-acyldihydropyridines with 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) which can provide pure 4-sub- of reactions were carried out to determine the optimum
stituted pyridine derivatives without the need for com- conditions for addition of simple Grignard reagents to the
plete regioselectivity in the addition step.
1-acylpyridinium salt of the Weinreb amide. Despite liter-
ature precedent for related transformations,3 we were dis-
appointed to obtain only modest selectivities for the
desired 4-isomer and always obtained a mixture of N-
acyldihydropyridines 4-6 (Table 1). The optimum condi-
tions were, formation of the acylpyridinium salt with phe-
nyl chloroformate at –78 °C in the presence of 10 mol%
copper bromide-dimethyl sulfide complex, followed by
slow addition of the Grignard reagent at the same temper-
ature (Entries 3 and 4). Interestingly, the Grignard reagent
The desired Weinreb amide 3 was synthesized in 95%
yield from nicotinic acid by reaction with N,O-dimethyl-
hydroxylamine hydrochloride in the presence of 1-(3-di-
emthylamionopropyl)-3-ethylcarbodiimide hydrochlor-
ide (EDC) and 1-hydroxybenzotriazole (HOBt). A series
Synthesis 2001, No. 12, 25 09 2001. Article Identifier:
1437-210X,E;2001,0,12,1784,1789,ftx,en;E03401SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Observations on the DDQ Oxidation of 1-Acyldihydropyridines
1785
Table 2 Synthesis of 4-Substituted Pyridines
Following a simple acid-base extractive work-up the de-
sired 4-substituted pyridine was obtained as a pure prod-
uct (>99% by HPLC) without the need for further
purification.
R2
N
O
O
1. CuBr DMS, PhOCOCl
R1
R1
R2MgCl, THF
A difference in oxidation rates between 1,2- and 1,4- di-
hydropyridines has been noted before,5 but the synthetic
potential does not appear to have been exploited. To sur-
vey the scope of this reaction a range of dihydropyridines
were synthesized by addition of Grignard reagents to the
1-acylpyridinium salts of both Weinreb amide 3 and ethyl
nicotinate 7 using the copper bromide-dimethyl sulfide
protocol. In most cases the 4-substituted regioisomer was
obtained as the major product (Table 2). However, lower
selectivities were observed when employing bulkier Grig-
nard reagents (Entries 10 and 11) or when using bromide
counter ions (Entries 1 and 5). No direct addition of the
Grignard moiety to the ester or Weinreb amide function-
alities was observed. In all cases oxidation of these crude
mixtures with DDQ (0.6 – 0.9 equiv)6 in isopropyl acetate
(IPAc) led to rapid conversion of the 4-substituted deriv-
ative and, as found for the ethyl case, a simple aqueous
work-up provided the 4-substituted pyridines 2 and 8 as
pure compounds. Notably, the yields for this two step pro-
cess are comparable to those typically obtained for related
transformations,3c despite the lower selectivity obtained in
our first step.
N
2. DDQ, IPAc
3: R1 = N(OMe)Me
7: R1 = OEt
2: R1 = N(OMe)Me
8: R1 = OEt
Entry
SM
R2
Selectivity
Product
Yield (%)
for 4-isomer
1a
2
7
7
7
7
3
3
3
3
3
3
3
Et
58
90
84
85
76
87
83
86
77
59
41
8a
8b
8c
8d
2a
2b
2c
2d
2e
2f
44
62
56
47
49
62
57
65
60
48
16
Me
Ph
3
4
Bn
5a
6
Et
Me
Ph
7
8
Bn
9
c-Hex
i-Pr
t-Bu
10
11
2g
While carrying out these reactions we observed that al-
though the 1,4-dihydropyridines were consumed in pref-
erence to the other isomers, the use of a full equivalent of
reagent did lead to consumption of these compounds, al-
though pure 4-substituted pyridines were surprisingly still
obtained after work-up. This led us to propose that reac-
tion of the 1,2-dihydropyridines (e.g. 5) with DDQ did not
afford the expected aromatised product. In an attempt to
explain this finding the N-acyldihydropyridines 4-6 were
separated by chromatography and subjected individually
to the oxidation conditions. As expected, compound 4 re-
acted quickly to give the 4-ethylpyridine 2a in an isolated
yield of 81% (Scheme 2). The 2-isomer 6 did not react un-
a EtMgBr used.
counterion also affected the isomeric ratio, with higher se-
lectivities for the desired 4-isomer obtained from the reac-
tion with ethylmagnesium chloride rather than the
corresponding bromide (Entries 4 and 7 verses 3 and 6).4
In a bid to avoid tedious chromatography to separate the
mixture of N-acyldihydropyridines 4–6, the crude reac-
tion mixture was subjected to DDQ oxidation. We were
surprised to observe that the 1,4-dihydropyridine 4 was
aromatised significantly faster than compounds 5 and 6.
Et
N
O
O
O
Me
Me
Me
N
N
N
OMe
OMe
OMe
DDQ, IPAc
60 oC, 24 h
N
Et
Et
PhO
N
O
PhO
O
PhO
O
O
4
6
5
Me
N
DDQ,
IPAc,
RT
DDQ,
IPAc,
RT
DDQ,
IPAc,
RT
DMSO
60 o
OMe
81%
9
C
Et
N
OH
Et
NC
Cl
Cl
PhO
O
CN
O
No reaction
CD2Cl2,
RT, 7 days
Et
N
O
N
Me
NC
CN
Cl
N
(via 5)
OH
Me(OMe)N
OMe
O
O
10a,10b
Cl
2a
Scheme 2
Synthesis 2001, No. 12, 1784–1789 ISSN 0039-7881 © Thieme Stuttgart · New York

1786
D. J. Wallace et al.
PAPER
der standard conditions, even after a prolonged reaction dimerization of enols12 and during the oxidation of silyl
time (24 h). On the other hand, when compound 5 was enol ethers to enones.13 In addition, the oxidation of
treated with DDQ the starting material was consumed styrene mainly affords the hydroquinone 2-phenylethyl
within one hour, but none of the expected 6-ethyl pyridine ether.14 The favored mechanism for these transformations
derivative 9 was seen in the acid extract following stan- is considered to be a single electron transfer from the
dard work-up. Monitoring the reaction by NMR (d8-tolu- charge transfer complex, rather than hydride transfer.
ene) confirmed the disappearance of starting material and While DDQ hydride abstraction from benzylic positions
clean conversion to two new products was observed. Di- is clearly a known transformation, significant activation is
rect concentration of the reaction mixture and purification usually required in the aromatic ring (e.g. p-methoxyben-
by column chromatography then afforded the Diels–Alder zyl ethers are cleaved at r.t. by DDQ, while benzyl ethers
adducts 10a and 10b as a 2:1 mixture.7
are relatively stable). In our case, it seems unlikely that
sufficient stabilization of a carbocation at the benzylic po-
sition would exist to support a hydride transfer mecha-
nism. Therefore, mechanistically we also favor an initial
single electron transfer followed by a recombination of
the resulting radicals to yield the observed products. This
process appears limited to the ester series, for example,
treatment of 2a with DDQ afforded <1% of the corre-
sponding dihydroquinone ether.
While 1,2-dihydropyridines have been previously used as
dienes in Diels–Alder reactions,8 and DDQ has been
shown to be a reactive dienophile under some conditions,9
we believe this is the first example of the isolation of a Di-
els–Alder adduct between a 1,2-dihydropyridine and
DDQ. On heating 10a and 10b in DMSO (60 ºC) an essen-
tially quantitative conversion to the starting dihydropyri-
dine 5 and DDQ was seen. Moreover, a sample of the
adducts, in CD2Cl2 slowly produced the 6-substituted py- In summary, we have developed a synthetic application of
ridine 9 after standing for several days at RT. Apparently, an unexpected difference in the rate of DDQ oxidation of
the kinetically formed cycloaddition products can under- various 1-acyldihydropyridines, allowing convenient ac-
go a relatively facile retro Diels–Alder reaction, after cess to 4-substituted pyridines as pure isomers without the
which the N-acyldihydropyridine 5 is oxidized by the re- need for chromatographic purification. The kinetic prod-
generated DDQ to give the thermodynamically more sta- uct of the reaction of 6-substituted dihydropyridines with
ble pyridine and dihydroquinone products. Accordingly, DDQ is a mixture of Diels–Alder adducts, which convert
when the DDQ oxidation of 5 is heated to 60 ºC for several to the expected pyridines at a much slower rate. We have
hours, the pyridine derivative 9 can be isolated in modest also shown that certain 4-substituted pyridines can react
yield (45%).10
with DDQ to give hydroquinone ether addition com-
pounds.
During the course of these studies we noticed that pro-
longed reaction times could also lead to decomposition of
the 4-substituted pyridine product thus lowering isolated
yields. In several control reactions a range of 4-substituted
esters 8 and Weinreb amides 2 were treated with 0.5 equiv
of DDQ at r.t. In most cases a gradual erosion of the start-
ing material was seen over several hours, with up to 30%
of the starting pyridine lost after 24 hours. However, in
some cases product loss was more rapid than in others. In
particular, ethyl 4-ethylnicotinate 8a and the correspond-
ing 4-benzyl analogue 8d both showed fairly rapid con-
version to new products. These new products were
identified as the hydroquinone ethers 11 and 12 formed in
14% and 47% yields respectively, after treating 8a and 8d
with 1 equiv of DDQ (Scheme 3).
Infra-red spectra were recorded on a Perkin-Elmer 781 spectropho-
tometer. NMR spectra were recorded on Bruker DRX400 or
DPX250 instruments using an internal deuterium lock at ambient
probe temperature. High resolution mass spectra were recorded on
a Micromass LCT TOFMS fitted with a Z-Spray ion source operat-
ing in electrospray mode with positive ion detection. Chemicals and
solvents were obtained from commercial sources and were used as
received.
N-Methoxy-N-methyl-3-pyridylcarboxamide 315
NEt3 (47.0 mL, 338 mmol) was added dropwise to a suspension of
nicotinic acid (40.0 g, 325 mmol), N,O-dimethylhydroxylamine hy-
drochloride (33.3 g, 341 mmol), 1-hydroxybenzotriazole hydrate
(15.0 g, 98 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodi-
imide hydrochloride (75.0 g, 391 mmol) in CH3CN (400 mL) at r.t.,
under a nitrogen atmosphere. After 2 h H2O (400 mL) was added
and the CH3CN removed under vacuum. The aqueous layer was ex-
tracted with EtOAc (3 ¥ 400 mL). The combined organic layers
were dried (Na2SO4) and concentrated in vacuo to afford the Wein-
reb amide 3 as a colourless oil.
NC
CN
R
O
DDQ,
IPAc, RT
HO
O
R
O
OEt
Yield: 51.1 g, 95%.
Cl
Cl
OEt
N
1H NMR (250 MHz, CD2Cl2): d = 8.78 (dd, 1 H, J = 2.1, 0.8 Hz,
1H), 8.54 (dd, 1 H, J = 4.8, 2.1 Hz), 7.88 (dt, 1 H, J = 7.9, 2.1 Hz),
7.24 (ddd, 1 H, J = 7.9, 4.8, 0.8 Hz), 3.43 (s, 3 H), 3.23 (s, 3 H).
N
11: R = Me, 14%
12 : R = Ph, 47%
8a : R = Me
8d : R = Ph
Ethyl 4-Ethylpyridine-3-carboxylate 8a; Standard Procedure
To a solution of ethyl nicotinate 7 (1.41 g, 9.34 mmol) in anhyd
THF (20 mL) under a nitrogen atmosphere was added copper bro-
mide dimethylsulphide complex (193 mg, 0.937 mmol) and the re-
sulting mixture was cooled to –78 °C. Phenyl chloroformate (1.29
Scheme 3
Hydroquinone ethers have been observed previously
during the oxidation of sterically hindered phenols,11 the
Synthesis 2001, No. 12, 1784–1789 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Observations on the DDQ Oxidation of 1-Acyldihydropyridines
1787
mL, 10.4 mmol) was added and the resulting suspension was stirred
at the same temperature for 20 min. Ethylmagnesium bromide (10.4
mL, 1.0 M in THF, 10.4 mmol) was added dropwise over 10 min,
the reaction was stirred for a further hour, quenched with a sat.
NH4Cl solution (30 mL) and extracted with isopropyl acetate (IP-
Ac) (2 ¥ 20 mL). The combined organic layers were washed with aq
HCl (30 mL, 1.0 M) and then concentrated in vacuo to give a yellow
oil. This oil was dissolved in IPAc (20 mL) and DDQ (1.49 g, 6.56
mmol) was added. After stirring for 10 min at r.t. the mixture was
washed with aqueous HCl (2 ¥ 20 mL, 1.0 M) and the pH of the
combined aq wash was adjusted to 10 (K2CO3 or NaOH). The aq
layer was then extracted with CH2Cl2 (2 ¥ 30 mL), the combined or-
ganic layers dried (Na2SO4) and concentrated in vacuo to afford 8a
as a pale yellow oil.
HRMS (m/z): [M + H]+ calcd for C9H13N2O2, 181.0977; found,
181.0980.
N-Methoxy-N-methyl[4-phenyl(3-pyridyl)]carboxamide 2c
Yield: 955 mg, 57%; a white solid; mp (hexanes) 47–48 °C.
IR (nujol): 1610, 1570, 1540cm-1.
1H NMR (400 MHz, d6DMSO): d = 8.68 (d, 1 H, J = 5.2 Hz), 8.60
(s, 1 H), 7.49–7.47 (m, 6 H), 3.40 (s, 3 H), 3.06 (s, 3 H).
13C NMR (100.6 MHz, d6DMSO): d = 151.1, 148.2, 147.0, 138.4,
131.5, 129.5, 129.4, 128.9, 124.4, 61.5, 34.1.
HRMS (m/z): [M + H]+ calcd for C14H15N2O2, 243.1134; found,
243.1137.
Yield: 737 mg, 44%.
IR (film): 1705, 1570, 1540cm-1.
N-Methoxy-N-methyl[4-benzyl(3-pyridyl)]carboxamide 2d
Yield: 1.19 g, 65%;pale yellow oil.
1H NMR (250 MHz, CD2Cl2): d = 8.89 (s, 1 H), 8.46 (d, 1 H, J = 5.0
Hz), 7.11 (d, 1 H, J = 5.0 Hz), 4.26 (q, 2 H, J = 7.2 Hz), 2.88 (q,
2 H, J = 7.5 Hz), 1.28 (t, 3 H, J = 7.2 Hz), 1.13 (t, 3 H, J = 7.5 Hz).
13C NMR (62.5 MHz, CD2Cl2): d = 165.5, 154.9, 152.6, 151.8,
126.3, 124.9, 61.6, 27.2, 14.9, 14.4.
HRMS (m/z): [M + H]+ calcd for C10H14NO2, 180.1025; found,
180.1027.
IR (film): 1630, 1570, 1540cm-1.
1H NMR (400 MHz, d6DMSO): d = 8.51 (d, 1 H, J = 5.2 Hz), 8.49
(s, 1 H), 7.31–7.29 (m, 2 H), 7.22–7.19 (m, 4 H), 4.01 (s, 2 H), 3.45
(s, 3 H), 3.32 (s, 3 H).
13C NMR (100.6 MHz, d6DMSO): d = 167.0, 151.8, 151.7, 149.0,
140.5, 133.2, 130.9, 130.2, 128.2, 126.3, 62.6, 39.5, 34.9.
HRMS (m/z): [M + H]+ calcd for C15H17N2O2, 257.1290; found,
257.1302.
Ethyl 4-Methylpyridine-3-carboxylate 8b16
Yield: 1.67g, 62%; pale yellow oil.
N-Methoxy-N-methyl[4-cyclohexyl(3-pyridyl)]carboxamide 2e
Yield: 1.05g, 60%; pale yellow oil.
IR (film): 1640, 1570, 1545cm-1.
1H NMR (400 MHz, d6DMSO): d = 8.52 (d, 1 H, J = 5.3 Hz), 8.40
(s, 1 H), 7.35 (d, 1 H, J = 5.3 Hz), 3.52 (s, 3 H), 3.28 (s, 3 H), 2.60
(tt, 1 H, J = 11.7, 3.2 Hz), 1.84–1.70 (m, 5 H), 1.49–1.25 (m, 5 H).
1H NMR (250 MHz, CD2Cl2): d = 8.89 (s, 1 H), 8.48 (d, 1 H, J = 5.3
Hz), 7.13 (d, 1 H, J = 5.3 Hz), 4.33 (q, 2 H, J = 7.0 Hz), 2.55 (s,
3 H), 1.35 (t, 3 H, J = 7.0 Hz).
Ethyl 4-Phenylpyridine-3-carboxylate 8c17
Yield: 1.303 g, 56%; a pale yellow oil.
13C NMR (100.6 MHz, d6DMSO): d = 168.6, 153.7, 150.9, 147.5,
1H NMR (250 MHz, CDCl3): d = 9.01 (s, 1 H), 8.70 (d, 1 H, J = 5.1
Hz), 7.25–7.10 (m, 6 H), 4.13 (q, J = 7.1 Hz, 2 H), 1.04 (t, J = 7.1
Hz, 3 H).
132.0, 122.1, 61.7, 41.7, 34.1, 33.6, 27.0, 26.3cm-1.
HRMS (m/z): [M + H]+ calcd for C14H21N2O2, 249.1603; found,
249.1599.
Ethyl 4-Benzylpyridine-3-carboxylate 8d18
Yield: 1.25 g, 47% (after flash chromatography); colourless oil.
N-Methoxy-N-methyl[4-isopropyl(3-pyridyl)]carboxamide 2f
Yield: 718 mg, 48%; pale yellow oil.
IR (film): 1640, 1575, 1540 cm-1.
1H NMR (400 MHz, d6DMSO): d = 8.52 (d, 1H, J = 5.3 Hz), 8.40
(s, 1 H), 7.39 (d, J = 5.3 Hz, 1 H), 3.53 (s, 3 H), 3.27 (s, 3 H), 2.99
(qn, 1 H, J = 6.8 Hz), 1.22 (d, 6 H, J = 6.8 Hz).
13C NMR (100.6 MHz, d6DMSO): d = 168.5, 155.0, 151.0, 147.5,
131.8, 121.5, 61.7, 33.9, 31.1, 23.5.
1H NMR (250 MHz, CD2Cl2): d = 8.97 (s, 1 H), 8.47 (d, 1 H, J = 5.1
Hz), 7.25–7.10 (m, 5 H), 7.01 (d, 1 H, J = 5.1 Hz), 4.30 (s, 2 H), 4.25
(q, 2 H, J = 7.1 Hz), 1.26 (t, 3 H, J = 7.1 Hz).
N-Methoxy-N-methyl[4-ethyl(3-pyridyl)]carboxamide 2a
Yield: 578 mg, 49%; a pale yellow oil.
IR (film): 1640, 1570, 1540 cm-1.
1H NMR (400 MHz, d6DMSO): d = 8.51 (d, 1 H J = 5.1 Hz), 8.43
(s, 1 H), 7.31 (d, 1 H, J = 5.2 Hz), 3.50 (s, 3 H), 3.38 (s, 3 H), 2.65
(q, 2 H, J = 7.5 Hz), 1.32 (t, 3H, J = 7.5 Hz).
HRMS (m/z): [M + H]+ calcd for C11H17N2O2, 209.1290; found,
209.1298.
13C NMR (100.6 MHz,): d = 168.4, 150.8, 150.5, 147.5, 132.2,
N-Methoxy-N-methyl[4-tert-butyl(3-pyridyl)]carboxamide 2g
Yield: 216 mg, 16%; white solid; mp (hexanes) 67–68 °C.
IR (nujol): 1630, 1560, 1540 cm-1.
1H NMR (400 MHz, d6DMSO): d = 8.51 (d, 1 H, J = 5.5 Hz), 8.32
(d, 1 H, J = 0.6 Hz), 7.45 (dd, 1 H, J = 5.5, 0.6 Hz), 3.54 (s, 3 H),
3.24 (s, 3 H), 1.38 (s, 9 H).
13C NMR (100.6 MHz, d6DMSO): d = 168.0, 156.4, 150.6, 148.4,
131.2, 122.8, 61.3, 36.7, 34.4, 31.3.
HRMS (m/z): [M + H]+ calcd for C12H19N2O2, 223.1447; found,
223.1453.
124.1, 61.7, 33.9, 25.8, 14.5.
HRMS (m/z): [M + H]+ calcd for C10H15N2O2, 195.1134; found,
195.1143.
N-Methoxy-N-methyl[4-methyl(3-pyridyl)]carboxamide 2b
Yield: 985 mg, 62%; pale yellow oil.
IR (film): 1640, 1578, 1545 cm-1.
1H NMR (400 MHz, d6DMSO): d = 8.47 (d, 1 H, J = 5.1 Hz), 8.45
(s, 1 H), 7.30 (d, 1 H, J = 5.1 Hz), 3.49 (s, 3 H), 3.27 (s, 3 H), 2.27
(s, 3 H).
13C NMR (100.6 MHz, d6DMSO): d = 169.1, 151.4, 148.3, 145.6,
133.7, 126.7, 62.7, 34.6, 19.9.
Isolation of Dihydropyridine Isomers
To a cooled (–78 °C) solution of Weinreb amide 3 (2.00 g, 12.0
mmol) in anhyd THF (25 mL) under a nitrogen atmosphere was
Synthesis 2001, No. 12, 1784–1789 ISSN 0039-7881 © Thieme Stuttgart · New York

1788
D. J. Wallace et al.
PAPER
added phenyl chloroformate (1.66 mL, 13.2 mmol) and the resulting
suspension was stirred at the same temperature for 20 min. Ethyl-
magnesium bromide (13.2 mL, 1.0 M in THF, 13.2 mmol) was add-
ed dropwise over ten min, the reaction was stirred for an additional
hour, quenched with a sat. NH4Cl solution (40 mL) and extracted
with IPAc (2 x 30 mL). The combined organic layers were washed
with aq HCl (30 mL, 1.0 M) and then concd in vacuo to give a yel-
low oil; a portion of this crude mixture containing the 2-, 4-, and 6-
dihydropyridine isomers in a 13:34:53 ratio (by HPLC). This was
separated by preparative HPLC to give the pure isomers, 4 as a
white solid, 5 and 6 respectively as oils.
3.94 (dd, 1 H, J = 6.8, 2.3 Hz), 3.68 (s, 3 H), 3.27 (s, 3 H), 2.19 (m,
1 H), 1.27 (m, 1 H), 1.00 (t, 3 H, J = 7.6 Hz).
13C NMR (100.6 MHz, CD2Cl2): d = 178.5, 176.1, 162.4, 152.2,
150.8, 147.5, 146.1, 138.6, 135.4, 130.1, 126.7, 122.3, 115.0, 114.7,
62.6, 57.2, 56.7, 56.6, 53.5, 45.6, 32.9, 25.0, 10.5.
35
HRMS (m/z): [M + H]+ calcd for C25H 21Cl2 N4O6, 543.0838;
found, 543.0845.
Minor Isomer 10b
1H NMR (400 MHz, CD2Cl2): d = 7.49–7.18 (m, 5 H), 6.91 (d, 1 H,
J = 6.3 Hz), 5.91 (d, 1 H, J = 1.4 Hz), 4.50 (dt, 1 H, J = 9.9, 2.6 Hz),
3.97 (dd, 1 H, = 6.7, 2.2 Hz), 3.66 (s, 3 H), 3.24 (s, 3 H), 2.22 (m, 1
H), 1.38 (m, 1 H), 1.04 (t, 3 H, J = 7.6 Hz).
Phenyl 2-Ethyl-3-(N-methoxy-N-methylcarbamoyl)-1,2-
dihydropyridinecarboxylate 6
IR (film): 1790, 1730, 1640, 1655, 1590, 1540 cm-1.
13C NMR (100.6 MHz, CD2Cl2): d = 178.4, 176.0, 162.5, 154.1,
151.0, 147.6, 146.0, 138.8, 135.3, 130.2, 126.7, 122.1, 114.9, 114.8,
62.5, 57.0, 56.5, 56.3, 54.7, 46.0, 32.8, 26.5, 10.6.
1H NMR (400 MHz, d6DMSO): d = 7.35 (m, 2 H), 7.19 (m, 1 H),
7.13 (m, 2 H), 6.98 (d, 1 H, J = 7.5 Hz), 6.62, (d, 1 H, J = 5.8 Hz),
5.57 (dd, 1 H, J = 7.5, 5.8 Hz), 5.22 (t, 1 H J = 6.3 Hz), 3.59 (s, 3
H), 3.11 (s, 3 H), 1.56 (m, 2 H), 0.82 (t, 3 H, J = 7.5 Hz).
Synthesis of the Hydroquinone Ethers
To a solution of 8a (368 mg, 2.05 mmol) in IPAc (6.0 mL) under a
nitrogen atmosphere was added DDQ (467 mg, 2.05 mmol) and the
resulting mixture was stirred at r.t. for 24 h. The organic layer was
then diluted with IPAc (10 mL), washed with aq HCl (10 mL, 1.0
M), K2CO3 solution (10 mL, 10% aq), dried (Na2SO4) and then con-
centrated in vacuo. The crude oil was purified by chromatography
(MeOH–EtOAc, 10:90) to give the addition compound 11 as a dark
oil. Yield: 120 mg, 14%.
13C NMR (100.6 MHz, d6DMSO): d = 167.8, 151.7, 151.2, 129.7,
127.8, 126.9, 126.5, 126.1, 121.7, 107.1, 61.1, 53.5, 34.3, 26.1, 9.6.
HRMS (m/z): [M + H]+ calcd for C17H21N2O4, 317.1501; found,
317.1508.
Phenyl 4-Ethyl-3-(N-methoxy-N-methylcarbamoyl)-1,4-
dihydropyridinecarboxylate 4
Mp 43–44 °C.
IR (nujol): 1740, 1725, 1685, 1655, 1615, 1585 cm-1.
IR (film): 3400, 2220, 1720, 1600, 1570, 1510 cm-1.
1H NMR (400 MHz, CD3CN): d = 9.08 (s, 1 H), 8.74 (d, 1 H, J =
5.4 Hz), 7.94 (d, 1 H, J = 5.4 Hz), 6.37 (q, 1 H, J = 6.3 Hz), 4.30 (q,
2 H, J = 7.2 Hz), 1.61 (d, 3 H, J = 6.3 Hz), 1.31 (t, 3 H, J = 7.1 Hz).
13C NMR (100.6 MHz, CD2Cl2): d = 166.2, 155.4, 154.5, 153.5,
151.9, 151.4, 135.8, 130.2, 124.8, 123.0, 114.4, 114.0, 110.7, 103.1,
81.3, 63.4, 24.0, 15.5.
1H NMR (400 MHz, d6DMSO): d = 7.52 (d, 1 H, J = 1.4 Hz), 745
(m, 2 H), 7.31 (m, 1 H), 7.28 (m, 2 H), 6.98 (dt, 1 H, J = 8.3, 1.4
Hz), 5.22, (dd, 1 H, J = 8.3, 4.4 Hz), 3.70 (s, 3 H), 3.44 (q, 1 H, J =
4.5 Hz), 3.20 (s, 3 H), 1.48 (m, 2 H), 0.90 (t, 3 H, J = 7.4 Hz).
13C NMR (100.6 MHz, d6DMSO): d = 169.1, 151.4, 150.2, 130.3,
127.7, 126.9, 122.8, 122.3, 116.9, 112.6, 61.7, 35.0, 3406, 29.3,
10.2.
HRMS (m/z): [M + H]+ calcd for C18H14Cl235N3O4, 406.0361;
found, 406.0371.
HRMS (m/z): [M + H]+ calcd for C17H21N2O4, 317.1501; found,
317.1510.
Adduct 12
Yield: 402 mg, 47%; brown solid; mp 143–145 °C.
Phenyl 6-Ethyl-3-(N-methoxy-N-methylcarbamoyl)-1,2-
dihydropyridinecarboxylate 5
IR (CHCl3): 3500, 2120, 1730, 1630, 1590, 1560 cm-1.
1H NMR (400 MHz, CD2Cl2): d = 8.91 (br s, 1 H), 8.75 (br s, 1 H),
8.05 (d, 1 H, J = 5.1 Hz), 7.32–7.10 (m, 5 H), 7.05 (s, 1 H), 4.01 (m,
2 H), 1.10 (t, 3 H, J = 7.1 Hz).
13C NMR (100.6 MHz, d6DMSO): d = 165.8, 161.1, 154.6, 153.2,
149.4, 137.5, 133.8, 131.8, 130.5, 129.9, 129.7, 129.3, 124.8, 122.6,
116.7, 114.4, 109.0, 99.4, 83.3, 62.3, 14.3.
1H NMR (400 MHz, d6DMSO): d = 7.64 (q, 1 H, J = 1.1 Hz), 7.44
(m, 2 H), 7.29 (m, 1 H), 7.25 (m, 2 H), 6.35 (ddd, 1 H, J = 9.9, 1.2,
1.0 Hz), 5.77, (ddd, 1 H, J = 9.9, 4.6, 1.0 Hz), 4.87 (br q, 1 H, J =
6.5Hz), 3.68 (s, 3 H), 3.20 (s, 3 H), 1.78 (m, 1 H), 1.60 (m, 1 H),
0.96 (t, 1 H, J = 7.5 Hz, 3 H).
13C NMR (100.6 MHz, d6DMSO): d = 166.8, 152.0, 151.1, 131.2,
129.8, 126.4, 121.9, 121.7, 121.3, 113.4, 60.9, 54.2, 33.9, 27.6, 8.6.
HRMS (m/z): [M + H]+ calcd for C23H16Cl235N3O4, 468.0518;
found, 468.0529.
Synthesis of the Diels–Alder Adducts 10a and 10b
To a solution of dihydropyridines 4, 5 and 6, (estimated to contain
153 mg of 6-isomer 5, 0.48 mmol), in IPAc (5.0 mL) under a nitro-
gen atmosphere at r.t. was added DDQ (184 mg, 0.810 mmol). The
resulting black solution was stirred at the same temperature for 30
min, concd in vacuo and purified by chromatography to give an in-
separable mixture of the Diels–Alder adducts 10a and 10b, in a
60:40 ratio of epimers. Yield: 151 mg, approx 57% yield based on
starting 6-isomer; mp decomposed above 200 ºC.
Hydroquinone Ether Derived from 2a
Yield: 6.0 mg, <1%.
1H NMR (250 MHz, CD3OD): d = 8.59 (br s, 1 H), 8.44 (br s, 1 H),
7.85 (d, 1 H, J = 5.0 Hz), 5.36 (q, 1 H, J = 6.5 Hz), 3.38 (br s, 3 H),
3.32 (br s, 3 H), 1.54 (d, 3 H, J = 6.5 Hz).
LCMS: 421.1 ([M + H]+, Cl35Cl35, 100%), 423.1 ([M + H]+,
Cl35Cl37, 66%).
IR (nujol, mixture): 2320, 1790, 1740, 1700, 1640, 1565 cm-1.
Acknowledgement
Major Isomer 10a
1H NMR (400 MHz, CD2Cl2): d = 7.49–7.18 (m, 5 H), 6.95 (d, 1 H,
J = 6.8 Hz), 5.98 (d, 1 H, J = 1.2 Hz), 4.37 (dt, 1 H, J = 9.8, 2.3 Hz),
We thank Paul Byway for the mass spectral analysis.
Synthesis 2001, No. 12, 1784–1789 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Observations on the DDQ Oxidation of 1-Acyldihydropyridines
(6) Based on selectivity for the addition reaction.
1789
References
(7) The two isomers could not be unambiguously assigned.
(8) For example see, inter alia (a) Comins, D. L.; Brooks, C. A.;
Al-Awa, R. S.; Goehring, R. R. Org. Lett. 1999, 1, 229.
(b) Campbell, M. M.; Sainsbury, M.; Searle, P. A.; Davies,
G. M. Tetrahedron Lett. 1992, 33, 3181. (c) Comins, D. L.;
Al-Awar, R. S. J. Org. Chem. 1992, 57, 4098.
(9) (a) Asato, A. E.; Kieffer, E. F. J. Chem. Soc., Chem.
Commun. 1968, 1684. (b) Pointer, D. J.; Wilford, J. B.;
Hodder, O. J. R. J. Chem. Soc. B 1971, 2009. (c) Nishida,
S.; Murakami, M.; Oda, H.; Tsuji, T.; Mizuno, T.;
Matsubara, M.; Kikai, N. J. Org. Chem. 1989, 54, 3859.
(10) The high temperature and long reaction time may lead to
some decomposition, lowering the final yield compared to
the oxidations of the 4-substituted compounds.
(11) Becker, H.-D. J. Org. Chem. 1965, 30, 982.
(12) Becker, H.-D. J. Org. Chem. 1965, 30, 989.
(13) (a) Williams, J. M.; Marchesine, G.; Reamer, R. A.; Dolling,
U.-H.; Grabowski, E. J. J. J. Org. Chem. 1995, 60, 5337.
(b) Bhattacharya, A.; DiMichele, L. M.; Dolling, U.-H.;
Douglas, A. W.; Grabowski, E. J. J. J. Am. Chem. Soc. 1988,
110, 3318. (c) Bhattacharya, A.; DiMichele, L. M.; Dolling,
U.-H.; Grabowski, E. J. J.; Grenda, V. J. J. Org. Chem.
1989, 54, 6118.
(1) For reviews see: (a) Comins, D. L.; O’Connor, S. Adv.
Heterocyclic Chem. 1988, 44, 199. (b) Stout, D. M.;
Meyers, A. I. Chem. Rev. 1982, 82, 233.
(2) (a) Piers, E.; Soucy, M. Can. J. Chem. 1974, 52, 3563.
(b) Akiba, K.; Iseki, Y.; Wada, M. Tetrahedron Lett. 1982,
23, 429. (c) Akiba, K.; Iseki, Y.; Wada, M. Bull. Chem. Soc.
Jpn. 1984, 57, 1994. (d) Akiba, K. Bull. Chem. Soc. Jpn.
1992, 101, 339. (e) Mangeney, P.; Gosmini, R.; Raussou, S.;
Commercon, M.; Alexakis, A. J. Org. Chem. 1994, 59,
1877. (f) Mangeney, P.; Gosmini, R.; Raussou, S.;
Commercon, M.; Alexakis, A. Tetrahedron Lett. 1993, 34,
6399. (g) Shiao, M.-J.; Tarng, K.-Y. Heterocycles 1990, 31,
637. (h) Shiao, M.-J.; Chia, W.-L. Synth. Commun. 1991, 21,
401. (i) Chia, W.-L.; Shiao, M.-J. Tetrahedron Lett. 1991,
32, 2033. (j) Shing, T.-L.; Chia, W.-L.; Shiao, M.-J.; Chau,
T.-Y. Synthesis 1991, 849. (k) Shiao, M.-J.; Liu, K.-L.; Lin,
L.-G. Synlett 1992, 655. (l) Shiao, M.-J.; Chia, W.-L.;
Shing, T.-L.; Chow, T. J. J. Chem. Research (S) 1992, 247.
(m) Shiao, M.-J.; Chia, W.-L.; Peng, C.-J.; Shen, C.-C. J.
Org. Chem. 1993, 58, 3162.
(3) (a) Comins, D. L.; Abdullah, A. H. J. Org. Chem. 1982, 47,
4315. (b) Comins, D. L.; Mantlo, N. B. J. Heterocyclic
Chem. 1983, 20, 1239. (c) Comins, D. L.; Stroud, E. D.;
Herrick, J. L. Heterocycles 1984, 22, 151. (d) Comins, D.
L.; Smith, R. K.; Stroud, E. D. Heterocycles 1984, 22, 339.
(e) Comins, D. L.; Stroud, E. D. J. Heterocycl. Chem. 1985,
22, 1419. (f) Comins, D. L.; Stroud, E. D. Heterocycles
1986, 24, 3199.
(14) Simandi, T. L.; Simandi, L. I. React. Kinet. Catal. Lett. 1997,
62, 257.
(15) Raghuram, T.; Vijaysaradhi, S.; Singh, I.; Singh, J. Synth.
Commun. 1999, 29, 3215.
(16) Bobbit, J. M.; Scola, D. A. J. Org. Chem. 1960, 25, 560.
(17) Palacios, F.; Rubiales, G. Tetrahedron Lett. 1996, 37, 6379.
(18) McCullough, K. J.; MacTavish, J.; Proctor, G. R.; Redpath,
J. J. Chem. Soc., Perkin Trans. 1 1996, 2553.
(4) To the best of our knowledge the effect of the counterion has
not been studied in detail.
(5) (a) Eisner, U.; Kuthan, J. Chem. Rev. 1972, 72, 1.
(b) Wallenfels, K.; Gellrich, M. Justus Liebigs Ann. Chem.
1959, 621, 149. (c) Bodor, N.; Kaminski, J. J. Theochem
1988, 163, 315. (d) Eisner, U.; Sadeghi, M. M.; Hambright,
W. P. Tetrahedron Lett. 1978, 3, 303.
Synthesis 2001, No. 12, 1784–1789 ISSN 0039-7881 © Thieme Stuttgart · New York