Unexpected formation of highly functionalized dihydropyrans via addition-cyclization reactions between dimethyl oxoglutaconate and α,β-unsaturated hydrazones

Article abstract of DOI:10.1016/j.tetlet.2009.02.180

The condensation between dienophiles and α,β-unsaturated hydrazone azadienes was previously reported to afford piperidines. During an attempt to adapt this reaction to the preparation of piperidine-based conformationally restricted analogs of glutamate, i

Full text of DOI:10.1016/j.tetlet.2009.02.180

Tetrahedron Letters 50 (2009) 2298–2300
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Tetrahedron Letters
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Unexpected formation of highly functionalized dihydropyrans via
addition-cyclization reactions between dimethyl oxoglutaconate
and a,b-unsaturated hydrazones
Jason E. Mullins a, Jean-Louis G. Etoga a, Mariusz Gajewski b, Joseph I. DeGraw b, Charles M. Thompson a,b,
*
a The Department of Chemistry, The Center for Structural and Functional Neuroscience, The University of Montana, Missoula, MT 59812, United States
b The Department of Biomedical and Pharmaceutical Sciences, The Center for Structural and Functional Neuroscience, The University of Montana, Missoula, MT 59812, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The condensation between dienophiles and
a,b-unsaturated hydrazone azadienes was previously
Received 24 January 2009
Revised 20 February 2009
Accepted 23 February 2009
Available online 27 February 2009
reported to afford piperidines. During an attempt to adapt this reaction to the preparation of piperi-
dine-based conformationally restricted analogs of glutamate, it was discovered that the electrophile,
dimethyl oxoglutaconate (DOG) led to highly substituted dihydropyrans in 20–50% yield. The unexpected
pyran product likely results from an initial 1,4-addition of the hydrazone to the oxoglutaconate followed
by intramolecular cyclization of the resultant enolate oxygen to the
manipulations afford substituted tetrahydropyran 6-methamino-2,4-dicarboxylic acids.
Published by Elsevier Ltd.
a,b-unsaturated iminium ion. Further
The use of conformationally restricted amino acid analogs has
greatly advanced our understanding of glutamatergic receptor
and transporter pharmacology.1 By appropriately positioning or
locking key functional groups via ring systems, conformational bias
can yield useful information in the design of new pharmacologic
agents.1a,1b For example, conformationally restricted analogs of
glutamate including dihydrokainate (DHK), 2,4-pyrrolidine dicar-
(Scheme 1): formation/separation of the substituted tetrahydropi-
peridine regioisomers, reduction of the ketone, scission of the
N–N(Me)2 bond, and ester deprotection.
Nine unsymmetrical dimethyl hydrazones were prepared in
60–95% yield by the reaction of
a,b-unsaturated aldehydes with
N,N-dimethyl hydrazine in diethyl ether. The azadiene-based
hydrazones of acyloin, methacrolein, and cinnamaldehyde were
reacted with dimethyl oxoglutaconate (DOG) in 1.1:1.0 ratio in
CH3CN for 24–48 h to afford the presumed piperidine-[trans]-2,3-
diesters as oils in 20–50% yield after chromatography.7 Interest-
ingly, a single product was isolated and assigned as the piperidine
boxylate (
L L-trans-2,3-pyrrolidine dicarboxyl-
-trans-2,4-PDC),2 and
ate (
L
-trans-2,3-PDC)3 (Fig. 1) all show a high degree of selectivity
at excitatory amino acid transporters (EAATs).1a,4 In each of these
structures, the glutamate C2–C3 bond is restricted within the pyr-
rolidine ring. Given the subtle binding differences between the
EAAT subtypes and other glutamate transporters, the preparation
of the corresponding piperidine analogs would be of value (Fig. 1).
One possible synthetic approach to make piperidine dicarbox-
ylic acid analogs would employ the azadiene Diels Alder reaction
pioneered by Ghosez5 adapted for use with the dienophile di-
methyl oxoglutaconate (1; DOG). We showed previously that
DOG reacts with dienes in a Diels–Alder reaction or with anilines
in an addition cyclization to form quinolines in route to conform-
ationally restricted glutamate analogs.6 The reaction between
a
-oxoester 3a (Scheme 1) based on 1H NMR assignments with the
Me
CO2H
CO2H
Me
CO2H
N
H2N
L-glutamate
HO2C
CO2H
H
R
CH2CO2H
CO2H
dihydrokainic
acid (DHK)
N
H
DOG and the azadienes of
expected to afford either
a
,b-unsaturated hydrazones 2 is then
CO2H
a
-ketoester piperidine 3a or b-ketoester
piperidine analogs
of glutamate
piperidine dicarboxylates 3b that could be elaborated to the
desired targets (Scheme 1).
CO2H
CO2H
N
H
N
H
Therefore, an azadiene Diels–Alder sequence was envisioned as
a rapid approach to making a new panel of glutamate analogs
L-trans-2,4 PDC
L-trans-2,3 PDC
* Corresponding author. Tel.: +1 406 243 4643; fax: +1 406 243 5228.
E-mail address: chuck.thompson@mso.umt.edu (C.M. Thompson).
Figure 1. Structures of glutamate and conformationally restricted piperidine
analog of glutamate.
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.02.180

J. E. Mullins et al. / Tetrahedron Letters 50 (2009) 2298–2300
2299
R2
R
O
R3 2 H
R3
H
H
O
R1
CO2Me
CO2Me
R1
CO2Me
CO2Me
+
MeO2C
CO2Me
N
H
N
N
N
1: dimethyl oxoglutaconate
(DOG)
O
Me
Me
Me
Me
+
3a: α-ketoester
3b: β-ketoester
Me
N
R2
R3
CO2Me
R3
R2
R1
Me
N
R1
2: azadiene
O
CO2Me
N
Me
4: pyran
N
Me
Scheme 1. Proposed synthesis of piperidines via an azadiene-DOG reaction.
CO2Me
CO2Me
corresponding piperidine formed from dimethyl fumarate.5 The
modest yield for this reaction was perplexing because the starting
material was consumed in each instance resulting only in product
and baseline material by tlc. Combustion analysis, high resolution
mass analysis, and the 1H NMR spectra were largely consistent
with piperidine 3a although the 13C NMR spectra showed only
two carbonyl signals between 165 and 170 ppm curiously lacking
the ketone. We preliminarily ascribed this anomaly as possible for-
mation of an enol owing to a singlet at 6.4 ppm and the suscepti-
R3
R3
R2
R1
R2
R1
Me
N
R2
b
CO2Me
a
Me
N
R3
O
CO2Me
O
R1
NH2
Me
N
5a-i
2
4a-i
N
Me
e
CO2H
CO2Me
R3
R3
R1
R2
R1
O2N
R2
d
c
H
bility of
a-amino ketoesters to racemize. However, deuterium
N
O
CO2H
O
CO2Me
exchange experiments (acid or base promoted) indicated no
evidence of keto-enol equilibrium. Attempts to isolate the enol as
silyl, methyl or acetyl enol ether also failed. Mild reduction (NaBH4,
etc.) to convert the ketone to alcohol in the presence of the esters
was unsuccessful and strong reduction (LAH) typically led to a
mixture of over-reduced molecules. Use of Zn/HCl reported for
the bis-reduction of both enamine and N–N moiety in the reported
tetrahydropiperidine adducts5 failed to provide the saturated
piperidine. The inconsistent and failed outcomes in these experi-
ments, formation of a single regioisomers, and lack of a 13C NMR
absorbance for a ketone suggested that the reaction between
DOG and an azadiene does not afford the desired piperidines and
a more thorough spectral examination was undertaken.
A 2D NMR study revealed a structure more consistent with a
dihydropyran (Scheme 1) although the azomethine N@CH appears
well upfield (6.4–6.5 ppm) of the usual position (7.0–7.5 ppm) due
to the electron-donating –N(CH3)2 group.8 In order to identify and
confirm pyrans as the products, a DEPT experiment was conducted
on the putative 6-methyl pyran product 4c isolated from the reac-
tion between DOG and methacrolein azadiene. The DEPT shows
three methine CH carbons and two quaternary carbons. The corre-
sponding piperidine product (3a or 3b) would also show three
methines but only one quaternary carbon. Dihydropyran 4c also
shows a CH carbon at 135.5 ppm consistent with the exocyclic
hydrazino –CH carbon and a –CH at 108.5 ppm consistent with
an alkene –CH carbon in the pyran ring. Carbon 4 at 36.0 ppm
matches well with a CH adjacent to a methyl ester. The two quater-
nary carbons (carbon 2 and 6) show shifts of 143.0 and 78.5 ppm
and are consistent with a cyclic enol ether and quaternary ether,
respectively. Like analysis of the other dihydropyrans 4 showed
complete agreement of the carbon connectivity.
NH3 Cl
7a-d,f,g
O
6a-d
a. DOG 1, CH3CN b. PtO2, H2 @ 50 psi or RaNi/EtOH
c. p-nitrobenzoyl chloride, TEA d. 3M HCl, e. 6M HCl
Scheme 2. Formation and functionalization of pyrans formed via DOG-azadiene
condensation.
Table 1
Pyran intermediates and products (Scheme 2)a
Entry
R1
R2
R3
4 (%)
5 (%)
6 (%)
7 (%)
a
b
c
d
e
f
H
H
H
nPr
H
H
Et
Ph
Me
Me
Ph
H
H
H
H
H
H
H
Me
H
32
26
40
54
20
40
28
25
41
70
92
82
92
42
40
52
51
—
—
—
—
—
96
72
62
97
n/a
52c
50c
n/a
n/a
Me
iPr
H
61b
35b
20b
48b
50b
H
H
H
g
h
i
Me
a
All structures showed satisfactory combustion analysis and/or HRMS in addi-
tion to spectral identification.
b
RaNi, MeOH.
c
6N HCl from 5 directly. n/a = not obtained.
hydrazones were found to result in the corresponding pyrans 4
all of which are summarized in Table 1. The stereochemical
arrangement of substituents could not be ascertained from the
product mixture.
To further confirm this reaction sequence, the structure of the
novel pyran products, and the potential for this addition-cycliza-
tion reaction deprotection of the pyrans were undertaken. The first
objective was to remove the exocyclic hydrazone group from pyr-
ans 4a–i. We discovered that H2/PtO2 (10% by weight) and
CF3CO2H (4 equiv) reduce the C@N bond and cleave the N–N bond
and also reduce the enol ether unsaturation to afford primary
amines 5. Likewise, Ra–Ni (6%) in methanol at room temperature
converted the pyrans to primary amine 5.9 Although the yields
Based on this evidence, we have identified a new reaction
between DOG and azadienes to afford tri- or tetrasubstituted pyr-
ans (Scheme 2). Thus, the panel of azadienes originally planned for
piperidine synthesis clearly affords the corresponding pyrans 4
(Scheme 2). This conclusion is also consistent with our failure to
reduce the ketone, to functionalize the mistaken enol and the
upfield shift in the azomethine. The formation of pyrans also
explains the single regioisomer question. Six additional azadiene

2300
J. E. Mullins et al. / Tetrahedron Letters 50 (2009) 2298–2300
R
R
CO2Me
CO2Me
"A"
R
O
N
N
N
N
Me
N
N
O
O
CO2Me
CO2Me
Me
Me
Me
Me
Me
+
R
O
R
O
CO2Me
CO2Me
OMe
CO2Me
CO2Me
Me
MeO
"B"
O
N
N
N
N
O
Me
Me
Me
Scheme 3. Pathway leading to pyran and piperidine from azadiene and DOG.
for the RaNi process (entries 4e–i) were lower, isolation and work-
up were superior to PtO2.
P30-NS055022), the Center for Structural and Functional Neurosci-
ence (NIH P20-RR015583) and scientific advice from Prof. C. Sean
Esslinger and Dr. Travis T. Denton.
Pyrans 5f and g were amenable to direct conversion to the fully
deprotected pyran dicarboxylic acids 7f and g using 6 M HCl
(ꢀ50% yield). However, pyrans 5a–e, h, and i were challenging to
isolate and separate from impurities by this reaction and therefore,
were not amenable to direct deprotection. As a result, the primary
amines were reacted with 1.5 equiv p-nitrobenzoyl chloride
(1.5 equiv) in CH2Cl2 with TEA (2.0 equiv) to afford amides 6a–d
as tan foams in 40–45% yield. We were unable to convert pyrans
5e, h, and i to the amides 6 or directly to product 7 presumably
due to their sensitivity to acid (decomposition noted by tlc). High
resolution mass spectrometry, 1H NMR, 13C NMR and IR supported
the structures of amides 6a–d. The analysis was consistent with
assignment as tetrahydopyrans.
Although the stepwise deprotection reactions of amide and
esters were examined, we preferred to identify a one-step process.
Dual hydrolysis of the methyl esters and amide bond under basic
conditions failed leading to a complex mixture of products. How-
ever, reacting 6a–d in 3 M HCl for 24 h at reflux cleanly hydrolyzed
both ester and amide protecting groups with the p-nitrobenzoic
acid by-product precipitating during the course of the reaction.
Standard workup afforded the 6-methanaminopyran 2,4-diacids
7a–d in 50–60% yield without further purification.
The mechanism of the reaction is deserving of note. The pyran
products 4 likely result from initial addition of the azadiene onto
the DOG backbone followed by an intramolecular conjugate addi-
tion by the enolate oxygen. (Scheme 3, path ‘A’). The planned
azadiene-DOG synthesis of piperidines could occur either by a
Diels–Alder or via the same initial addition but cyclization via
the enolate carbon (Scheme 3, path ‘B’). In an effort to alter the
reaction outcome and favor C-alkylation, solvents other than
CH3CN were explored including polar, protic solvents (water, iso-
propanol, etc.), and non-polar solvents (ether, pentane) but the
reaction led to the same pyran product (lower yields) regardless
of the azadiene employed.
Because certain transannular amino acid analogs show activity
as inhibitors of glutamate receptors, the pyrans 7a–d, f, and g
prepared in this study were tested at the AMPA,10 NMDA,11 and
kainate12 glutamate receptors using radioligand binding assays
(MDS Pharma Services; Taipei, Taiwan). The results indicated that
the pyrans were inactive except the 6-methyl analog 7c that
showed 17% inhibition of the AMPA receptor at 100 nM. We are
currently exploring variants of this structure as selective inhibitors.
References and notes
1. (a) Bridges, R. J.; Esslinger, C. S. Pharmacol. Ther. 2005, 107, 271–285; (b)
Bridges, R.L. The Ins and Outs of Glutamate Transporter Pharmacology, Tocris
Reviews No. 17; 2001.; (c) Acher, F.C. Metabotropic Glutamate Receptors Tocris
Bioscience Scientific Review Series; 2006.
2. Bridges, R. J.; Stanley, M. S.; Anderson, M. W.; Cotman, C. W.; Chamberlin, A. R.
J. Med. Chem. 1991, 34, 717–725.
3. Willis, C. L.; Humphrey, J. M.; Koch, H. P.; Hart, J. A.; Blakely, T.; Ralston, L.;
Baker, C. A.; Shim, S.; Kadri, M.; Chamberlin, A. R.; Bridges, R. J.
Neuropharmacology 1996, 35, 531–539.
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Amara, S. G. J. Neurosci. 1994, 14, 5559–5569.
5. Serckx-Poncin, B.; Hesbain-Frisque, A. M.; Ghosez, L. Tetrahedron Lett. 1982, 23,
3261–3264.
6. (a) Carrigan, C. N.; Bartlett, R. D.; Esslinger, C. S.; Cybulski, K. A.;
Tongcharoensirikul, P.; Bridges, R. J.; Thompson, C. M. J. Med. Chem. 2002, 45,
2260–2276; (b) Denton, T. T.; Seib, T.; Bridges, R. J.; Thompson, C. M. Bioorg.
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7. Representative synthesis. Dimethyl 2-[(E)-(dimethylhydrazino)methyl]-2-methyl-
3,4-dihydro-2H-pyran-4,6-dicarboxylate (4c). To
a solution of methacrolein
azadiene (0.36 g, 3.2 mmol) in CH3CN (5 mL) was added 1 (0.5 g, 2.9 mmol)
and was stirred for 24 h. The CH3CN was removed and the red oil was
chromatographed (SiO2,1:4 EtOAc:hex) to afford 4c as a light yellow oil (40%).
1H NMR (CDCl3): d 6.39 (br s, 1H), 6.18 (br s, 1H), 3.80 (s, 3H), 3.73 (s, 3H), 3.55 (m,
1H), 2.74 (s, 6H), 2.55 (dd, J = 6.7, 13.5 Hz, 1H), 1.91 (br t, J = 12.3 Hz, 1H), 1.50 (s,
3H); 13C NMR (CDCl3): d 172.8, 163.2, 143.1, 135.5, 108.4, 78.4, 52.2, 52.1, 42.6,
36.3, 31.5, 27.3; Anal. Calcd for C13H20N2O5: C, 54.92; H, 7.09; N, 9.85. Found C,
55.04; H, 7.02; N, 9.69. Dimethyl 6-methyl-6-{[(4-nitrobenzoyl)amino]
-
methyl}tetrahydro-2H-pyran-2,4-dicarboxylate (6c). To 4c (0.29 g, 1.0 mmol) in
MeOH (10 mL) were added 10% PtO2 (0.29 g) and TFA (0.46 g, 4.0 mmol) in a Parr
flask. The reaction with H2 (50 psi) was conducted for 18 h, filtered through Celite
and concentrated. The resulting clear oil was extracted from CH2Cl2 to afford the
primary amine 5c (0.20 g, 82%) as a pale yellow oil. Amine 5c (0.2 g, 0.83 mmol)
was dissolved in CH3OH (10 mL) and reacted with TEA (0.13 g, 1.25 mmol) and p-
nitrobenzoyl chloride (0.15 g, 0.83 mmol) at rt for 24 h. Workup and purification
(40% EtOAc:hex) afforded the amide 6c (0.17 g, 52%) as a tan foam. 1H NMR
(CDCl3): d 8.28 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 6.52 (br s, 1H), 4.20 (dd,
J = 2.2, 12.1 Hz 1H) 3.75 (s, 3H), 3.72 (m, 1H), 3.71 (s, 3H), 3.52 (dd, J = 7.0, 14.3 Hz
1H), 2.86 (m, 1H), 2.27 (m, 1H), 1.95 (m, 1H), 1.68 (m, 2H), 1.35 (s, 3H); 13C NMR
(CDCl3): d 173.7, 170.7, 165.9, 149.6, 139.7, 128.2, 123.8, 74.0, 69.8, 52.4, 52.2,
41.85, 36.5, 35.2, 29.7, 27.0; Anal. Calcd for C18H22N2O8: C, 54.82; H, 5.62; N, 7.1.
Found C, 54.68; H, 5.63; N, 6.85. 6-(Aminomethyl)-6-methyltetrahydro-2H-pyran-
2,4-dicarboxylic acid (7c). Compound 6c (0.05 g, 0.13 mmol) was dissolved in 3 M
HCl (5 mL) and brought to reflux for 24 h, cooled, filtered, and extracted with
EtOAc (3 Â 25 mL). The resulting H2O layer was concentrated to a solid in vacuo,
and triturated with water to afford the diacid hydrochloride product 7c (0.017 g,
62%) as a tan solid. 1H NMR (D2O): d 4.12 (d, J = 12.1 Hz, 1H), 3.41 (d, J = 13.9 Hz,
1H), 2.72 (m, 2H), 2.12 (d, J = 13.9 Hz, 1H), 1.83 (d J = 14.2 Hz, 1H), 1.49–1.39 (br
m, 2H) 1.16 (s, 3H); 13C NMR (D2O): d 177.8, 174.8, 72.9, 69.4, 40.9, 35.9, 34.8,
29.7, 25.3. HRMS Calcd for C9H16NO5: 218.1036. Found: 218.1028. (M+H)+.
8. (a) Remuzon, P.; Dussy, C.; Jacquet, J.-P.; Roty, P.; Bouzard, D. Tetrahedron:
Asymmetry 1996, 7, 1181–1188; (b) Solladie-Cavallo, A.; Bonne, F. Tetrahedron:
Asymmetry 1996, 7, 171–180.
Acknowledgments
9. Alexakis, A.; Lensen, N.; Mangeney, P. Tetrahedron Lett. 1991, 32, 1171–1173.
10. Honore, T.; Lauridsen, J.; Krogsgaard-Larsen, P. J. Neurochem. 1982, 38, 173–
178.
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The authors acknowledge financial support of the NIH to CMT
(RO1 NS38248). The authors are also grateful for the support of
the Core Laboratory for Neuromolecular Production (NIH