A stable synthetic equivalent of 2,3-dihydropyridine

Article abstract of DOI:10.1055/s-2008-1078056

We introduce a synthetic procedure of 2,3-dihydropyridine derivative from its stable synthetic equivalent. The synthesis of a chiral 2,3-dihydropyridine derivative in a high yield and the unique mechanism of the unmasking step are described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078056

LETTER
2479
A Stable Synthetic Equivalent of 2,3-Dihydropyridine
M
asked 2,3-D
t
ihydrop
e
yridine phen Born, Yoshihisa Kobayashi*
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, Mail Code 0343,
La Jolla, CA 92093-0343, USA
E-mail: ykoba@ucsd.edu
Received 16 June 2008
product symbioimine (Figure 2).4 The intramolecular
Diels–Alder reaction of a chiral 2,3-dihydropyridine in-
termediate followed by isomerization is proposed for con-
struction of the tricyclic imine moiety as shown above. It
is an alternative route to the originally proposed biosyn-
thetic pathway via exo-Diels–Alder reaction from linear
trans-enone precursor followed by cyclic imine forma-
tion.5 In previously reported syntheses,4c,d the putative
chiral 2,3-dihydropyridine was formed in situ from a pre-
cursor, followed immediately by an intramolecular Diels–
Alder reaction. These Diels–Alder reactions suffered
from low yield due to the instability of the intermediate
under their respective reaction conditions.
Abstract: We introduce a synthetic procedure of 2,3-dihydropyri-
dine derivative from its stable synthetic equivalent. The synthesis of
a chiral 2,3-dihydropyridine derivative in a high yield and the
unique mechanism of the unmasking step are described.
Key words: dihydropyridine, synthetic equivalent, enamine, imine,
enone
2,3-Dihydropyridine has been implicated as a versatile in-
termediate in the proposed biosynthesis of alkaloids, high-
lighted by the biomimetic syntheses of a variety of natural
products such as keramaphidin B and manzamine A,1 as
well as intermediates in the reactions of pyridines
(Figure 1).2
Over the course of our own synthetic studies of symbio-
imine,6 we developed a remarkably mild and high-yield-
ing method to produce N-unprotected 2,3-
dihydropyridines from a masked synthetic equivalent, for
application in the total synthesis. Herein we report the
synthesis of a stable synthetic equivalent of 2,3-dihydro-
pyridine and the mechanism of its unique unmasking step.
Bn
+
N
N
X–
2,3-dihydropyridinium salt
2,3-dihydropyridine
Figure 1 Structures of 2,3-dihydropyridines
Our initial approach to 2,3-dihydropyridine necessitated a
preexisting cis-enone geometry to facilitate the intramo-
lecular imine formation, directly generating the dihydro-
pyridine. Unfortunately, under most N-deprotection
conditions, the cis-enone is highly susceptible to isomer-
izing to the more thermodynamically stable trans-enone.7
As a result, the imine formation by intramolecular cy-
clization was inhibited.
The stability of 2,3-dihydropyridine is assured so long as
an alkyl or electron-withdrawing group (e.g., acyl) is at-
tached to the nitrogen atom, effectively preventing facile
oxidation for aromatization. While N-alkyl 2,3-dihydro-
pyridinium salt is well documented, and even isol-
able,1b,c,g there is scant information on the synthesis and
physical properties of an N-unprotected 2,3-dihydropyri-
dine, other than that they are highly unstable.3 This is sur-
prising, given the potential number of chemical
transformations that such an intermediate can provide.
Due to its inherent instability and predisposition to
isomerization and oxidation, a mild condition is required
to generate 2-alkyl-2,3-dihydropyridine A from a precur-
sor (Scheme 1). We designed masked compound B as the
stable synthetic equivalent. The aza-1,3-diene moiety of
A is masked by formal 1,4-addition of nucleophile X. The
The significance of a 2,3-dihydropyridine intermediate
has been proposed in biosynthesis of the marine natural
–
–
OR
OSO3
OSO3
intramolecular
endo-Diels–Alder
Me
Me
Me
isomerization
reaction
N
HN
HN
H
H
H
H
OR
OH
OH
H
H
cycloaddition
Precursor
symbioimine
Figure 2 Proposed biosynthetic pathway of symbioimine
SYNLETT 2008, No. 16, pp 2479–2482
x
x
.x
x
.2
0
0
8
Advanced online publication: 12.09.2008
DOI: 10.1055/s-2008-1078056; Art ID: S05508ST
© Georg Thieme Verlag Stuttgart · New York

2480
S. Born, Y. Kobayashi
LETTER
O
O
O
R2O
NH
N
R2O
R1
N
R1
R1
X
X
A
C
R2 = allyl
X = SEt
B
O
O
OR2
HN
OR2
O
O
P
O
HN
R1
R1
OHC
+
OMe
OMe
F
D
E
Scheme 1 Design of masked 2,3-dyhydropyridine
OR
deprotection of carbamate B will induce a facile elimina-
tion of X– to regenerate the aza-1,3-diene moiety. An ap-
propriate scavenger must trap the resulting X–
immediately, otherwise A will react with X– to form a 1,4-
adduct.
N
N
OR
1
Ph
We anticipated an alloc group (R2 = allyl) could be the
best candidate for the carbamate B, because the eliminat-
ed X– will be scavenged by highly electrophilic Pd–p-allyl
complex, concomitantly regenerating Pd(0) for the cata-
lytic cycle. Compound B will be formed readily by dehy-
dration of acyclic aminoketone C. Ketone C will be
obtained by 1,4-addition of thiolate (X = SEt) to trans-
enone D, which will be readily formed by condensation of
phosphonate E and amino aldehyde F. It should be noted
that a preparation of a chiral 2,3-dihydropyridine would
be possible by using chiral aldehyde F. For the application
to the synthesis of symbiomime, we planned a synthesis of
masked compound 2 as a synthetic equivalent of 2,3-dihy-
dropyridine 1 as shown in Figure 3.
O
O
N
SEt
2
Ph
Figure 3 Design of model 2,3-dihydropyridine 1
good yield. Next, treatment of enone 5 with ethanethiol in
the presence of a catalytic amount of DBU under solvent-
free conditions gave the conjugate adduct 6 as a 1:1 mix-
ture of diastereomers. Taking the material directly on to
the subsequent cyclodehydration step without purifica-
tion, treatment with 10 mol% of PPTS under dilute reflux-
ing benzene yielded the masked 2,3-dihydropyrdine 2 as
a single regioisomer for an enanine moiety in excellent
yield.8
The masked 2,3-dihydropyridine 2 was prepared in three
steps in good yields as shown in Scheme 2. Beginning
from commercially available b-ketophosphonate 3, a
Horner–Wadsworth–Emmons olefination with racemic
aldehyde 4 yielded the exclusive trans-isomer 5 in very
The inherent reactivity of the 2,3-dihydropyridine sug-
gests that of the many protecting groups for amine com-
O
O
O
NaH (1.1 equiv)
THF, r.t., 1 h
P(OMe)2
NHAlloc
OHC
NHAlloc
5
Ph
(1 equiv)
Ph
4
3
EtSH (1.1 equiv)
DBU (1 mol%)
neat, r.t., 30 min
99% (1:1 dr)
THF, r.t, 1 h
86%
O
NHAlloc
SEt
PPTS (10 mol%)
O
N
O
PhH, reflux, 1 h
95% (1:1 dr)
SEt
Ph
Ph
2
6
Scheme 2 Synthesis of the masked 2,3-dihydropyridine 2
Synlett 2008, No. 16, 2479–2482 © Thieme Stuttgart · New York

LETTER
Masked 2,3-Dihydropyridine
2481
monly in use today, not all deprotection conditions are In this letter, we have shown that synthesis of a stable syn-
created equal. A brief survey of the more common pro- thetic equivalent of 2,3-dihydropyridine and a unique
tecting groups found that the deprotection conditions of mechanism in the unmasking step. The masked 2,3-dihy-
allyloxy carbonyl (alloc) group of 2 were sufficiently mild dropyridine 2 was obtained via a high yielding three-step
to produce the desired product, and depending on the con- process from a trans-enone. In the unmasking step, the
centration (0.5 M), allowed the palladium loading to be thiol served to regenerate the catalyst by intercepting the
dropped to an effective 2.5 mol% (Scheme 3) to yield the Pd-p-allyl intermediate. The 2,3-dihydropyridine 1 gener-
stable (>48 h at 25 °C in CDCl3) 2,3-dihydropyrdine 1.9 It ated by this strategy has direct applications as a biomimet-
was found that dihydropyridine 1 decomposes upon puri- ic intermediate in the synthesis of several classes of
fication with silica, but that catalyst removal via Celite fil- alkaloid natural products. Utilization of this methodology
tration and subsequent high-vacuum drying to remove in the total synthesis of symbioimine will be reported in
allyl ethyl sulfide yielded the desired product essentially due course.
free of impurities as shown in Scheme 2.
Acknowledgment
O
We greatly acknowledge the University of California for financial
support. We also thank Dr. Yongxuan Su for Mass Spectroscopy
and Dr. Anthony Mrse for help with NOESY experiments
Pd2dba3 (5 mol%)
dppb (10 mol%)
O
N
N
THF, r.t., 2 h
quant
SEt
2
1
Ph
Ph
References and Notes
Scheme 3 Unmasking the 2,3-dihydropyridine equivalent 2
(1) (a) Baldwin, J. E.; Whitehead, R. C. Tetrahedron Lett. 1992,
33, 2059. (b) Yu, L.-B.; Chen, D.; Li, J.; Ramirez, J.; Wang,
P. G.; Bott, S. G. J. Org. Chem. 1997, 62, 208. (c)Baldwin,
J. E.; Spring, D. R.; Whitehead, R. C. Tetrahedron Lett.
1998, 39, 5417. (d) Ruggeri, R. B.; Hansen, M. M.;
Heathcock, C. H. J. Am. Chem. Soc. 1988, 110, 8734.
(e) Kaiser, A.; Billot, X.; Gateau-Olesker, A.; Marazano, C.;
Das, B. C. J. Am. Chem. Soc. 1998, 120, 8026. (f) Baldwin,
J. E.; Claridge, T. D. W.; Culshaw, A. J.; Heupel, F. A.; Lee,
V.; Spring, D. R.; Whitehead, R. C. Chem. Eur. J. 1999, 5,
3154. (g) Jakubowicz, K.; Abdeljelil, K. B.; Herdemann, M.;
Martin, M.-T.; Gateau-Olesker, A.; Al-Mourabit, A.;
Marazano, C.; Das, B. C. J. Org. Chem. 1999, 64, 7381.
(h) Gomez, J.-M.; Gil, L.; Ferroud, C.; Gateau-Olesker, A.;
Martin, M.-T.; Marazano, C. J. Org. Chem. 2001, 66, 4898.
(i) Herdemann, M.; Al-Mourabit, A.; Martin, M.-T.;
Marazano, C. J. Org. Chem. 2002, 67, 1890. (j) Wypych,
J.-C.; Nguyen, T. M.; Nuhant, P.; Bénéchie, M.; Marazano,
C. Angew. Chem. Int. Ed. 2008, 47, 5418.
(2) Jones, G. In Comprehensive Heterocyclic Chemistry II, Vol.
5; Katritzky, A.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996, 167.
(3) (a) Hasan, I.; Fowler, F. W. J. Am. Chem. Soc. 1978, 100,
6696. (b) Lasne, M.; Ripoll, J.; Guillemin, J.; Denis, J.
Tetrahedron Lett. 1984, 35, 3847.
(4) (a) Kita, M.; Kondo, M.; Koyama, T.; Yamada, K.;
Matsumoto, T.; Lee, K.; Woo, J.; Uemura, D. J. Am. Chem.
Soc. 2004, 126, 4794. (b) Kita, M.; Ohishi, N.; Washida, K.;
Kondo, M.; Koyama, T.; Yamada, K.; Uemura, D. Bioorg.
Med. Chem. 2005, 13, 5253. (c) Zou, Y.; Che, Q.; Snider,
B. B. Org. Lett. 2006, 24, 5605. (d) Kim, J.; Thomson, R. J.
Angew. Chem. Int. Ed. 2007, 46, 3104.
The unmasking step of 2 to obtain 1 is quite unique, be-
cause of the reaction mechanism (Scheme 4). The alloc
deprotection begins by the nucleophilic attack of Pd(0) on
the allyl carbamate of the masked 2,3-dihydropyridine 2,
generating the Pd–p-allyl complex and carbamic acid 7,
which spontaneously undergoes decarboxylation. The re-
sulting enamine induces an elimination of ethanethiolate
to form 1. There is no need for the addition of an external
nucleophile (such as diethylamine, pyrrolidine, or dime-
done) to intercept the Pd–p-allyl system and regenerate
Pd(0) for the catalytic cycle. Instead, the extruded
ethanethiolate can serve in this capacity as well as help
avoiding an unwanted formation of conjugate adducts of
1. Dihydropyridine 1 is a racemic mixture, but the
enantiomerically pure form will be obtained by this proce-
dure starting from a single enantiomer of 4.
O
O
Pd
O
N
O
N
Pd0
SEt
SEt
Ph
Ph
2
SEt
PdII
(5) Kita, M.; Uemura, D. Chem. Lett. 2005, 454.
O
–SEt
(6) Born, S.; Olson, E. E.; Kobayashi, Y. Synthetic Studies
towards (+)-Symbioimine, In Abstracts of Papers; 232nd
National Meeting of the American Chemical Society: San
Francisco CA, Sept 10–14, 2006, American Chemical
Society: Washington D. C., 2006; ORGN-748.
(7) Under thermal (>100 °C), Brønsted/Lewis acid (TfOH,
TFA, CSA–TsOH, BF3·OEt, MeAlCl2, Et2AlCl, EtAlCl2,
etc.), basic (NaOEt, NaOH, LDA, etc.), or nucleophilic
conditions (dimedone, piperidine, NaSEt, etc.).
N
–O
Ph
N
SEt
Ph
1
7
Scheme 4 Mechanism of Pd(0)-catalyzed unmasking step to gene-
rate 2,3-dihydropyridine
Synlett 2008, No. 16, 2479–2482 © Thieme Stuttgart · New York

2482
S. Born, Y. Kobayashi
LETTER
(8) Experimental Procedure for Preparation of Compound 2
To a 50 mL round-bottom flask at 25 °C was added 6
(1.23 g, 3.38 mmol) and benzene (34 mL). Pyridinium
p-toluenesulfonate (PPTS, 85 mg, 0.34 mmol, 10 mol%) was
then added and the solution allowed stirring under reflux
while monitoring by TLC. After 1 h, the reaction was
quenched by the addition of sat. NaHCO3, and separated.
The aqueous layer was extracted twice with EtOAc, the
combined organics washed with brine, and dried over
Na2SO4. Concentration in vacuo yielded crude material
which was then purified on SiO2 (hexane–EtOAc, 5:1) to
yield compound 2 (1:1 mixture of diastereomers 2 and 2¢,
1.07 g, 95%) as a clear oil. 1H NMR (400 MHz, CDCl3):
d = 7.28–7.20 (m, 2 H and 2 H¢), 7.18–7.08 (m, 3 H and 3
H¢), 6.00–5.90 (m, 1 H and 1 H¢), 5.32 (d, J = 17.2 Hz, 1 H
and 1 H¢), 5.23 (d, J = 10.0 Hz, 1 H and 1 H¢), 4.95 (d, J =
4.4 Hz, 1 H), 4.90 (d, J = 3.6 Hz, 1 H¢), 4.63 (d, J = 5.6 Hz,
2 H and 2 H¢), 3.73 (dd, J = 2.4, 12.8 Hz, 1 H), 3.67 (dd,
J = 2.8, 12.8 Hz, 1 H¢), 3.34 (dd, J = 7.2, 12.8 Hz, 1 H¢), 3.31
(app. t, J = 4.8 Hz, 1 H¢), 3.14 (dd, J = 9.2, 12.4 Hz, 1 H),
2.99 (m, 1 H), 2.89–2.65 (m, 4 H and 4 H¢), 2.45 (q, J = 7.6
Hz, 2 H), 2.43 (q, J = 7.2 Hz, 2 H¢), 2.14–2.10 (m, 1 H),
1.95–1.90 (m, 1 H¢), 1.20 (t, J = 7.2 Hz, 3 H¢), 1.18 (t, J = 7.2
Hz, 3 H), 1.06 (d, J = 6.8 Hz, 3 H), 0.99 (d, J = 6.8 Hz, 3 H¢).
3C NMR (100 MHz, CDCl3): d = 154.0 (C and C′), 141.5
(C′), 141.5, 139.9, 138.8 (C′), 132.5 (C and C′), 128.5 (2C′),
128.5 (2C), 128.2 (2 C and 2 C′), 125.8 (C and C′), 118.1 (C
and C′), 112.7 (C and C′), 66.42 (C′), 66.38, 49.0, 48.5 (C′),
45.7, 45.1 (C′), 37.0 (C′), 36.8, 34.7 (C′), 34.4, 33.5 (C′),
26.5 (C′), 24.0, 16.9, 15.2 (C′), 14.89 (C′), 14.85. HRMS: m/
z calcd for C20H27NO2S: 345.1757; found: 345.1755.
(9) Experimental Procedure for Preparation of Compound 1
To a 10 mL round-bottom flask at 25 °C was added 2 (70
mg, 0.20 mmol) in THF (0.4 mL), and placed under a blanket
of nitrogen. Then, Pd2dba3·CHCl3 (5.2 mg, 0.005 mmol,
5 mol%) and 1,4-bis(diphenylphosphino)butane (dppb,
8.6 mg, 0.020 mmol, 10 mol%) were added and the solution
allowed stirring while monitoring by TLC. Upon completion
after 2 h, the solution was diluted with THF, filtered over
Celite, and concentrated in vacuo to yield compound 1 as a
viscous oil. 1H NMR (400 MHz, CDCl3): d = 7.28–7.23 (m,
2 H), 7.20–7.14 (m, 3 H), 6.21 (dd, J = 3.5, 9.5 Hz, 1 H), 5.86
(dd, J = 2.5, 10.0 Hz, 1 H), 3.66 (dd, J = 7.0, 15.5 Hz, 1 H),
3.16 (dd, J = 12.0, 16.0 Hz, 1 H), 2.86 (t, J = 7.5 Hz, 2 H),
2.56 (t, J = 8.5 Hz, 2 H), 2.27 (m, 1 H), 0.98 (d, J = 7.5 Hz,
3 H). 13C NMR (100 MHz, CDCl3): δ = 165.3, 142.7, 141.5,
128.6 (2 C), 128.3 (2 C), 125.9, 121.7, 53.4, 35.7, 32.6, 30.4,
17.3. HRMS: m/z calcd for C14H19N: 199.1356; found:
199.1357.
Synlett 2008, No. 16, 2479–2482 © Thieme Stuttgart · New York