A Merged Aldol Condensation, Alkene Isomerization, Cycloaddition/Cycloreversion Sequence Employing Oxazinone Intermediates for the Synthesis of Substituted Pyridines

Article abstract of DOI:10.1055/s-0036-1588729

A domino reaction sequence has been evaluated that begins with union of novel dihydrooxazinone precursors with 2-alkynyl-substituted benzaldehyde components through aldol condensation. Ensuing operations, including alkene isomerization, Diels-Alder, and retrograde Diels-Alder with loss of CO ₂ occurs in the same reaction vessel to provide polysubstituted tricyclic pyridine products.

Full text of DOI:10.1055/s-0036-1588729

SYNLETT
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9
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6
-
5
2
1
4
1
4
3
7
-
2
0
9
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©
Georg Thieme Verlag Stuttgart · New York
2017, 28, A–C
A
letter
Synlett
J. B. Williamson et al.
Letter
A Merged Aldol Condensation, Alkene Isomerization, Cycloaddi-
tion/Cycloreversion Sequence Employing Oxazinone Intermedi-
ates for the Synthesis of Substituted Pyridines
Jill B. Williamson1
O
CHO
N
OMe
Emily R. Smith
O
DBU
Jonathan R. Scheerer*
R2
N
R2
PhMe
110 °C
R1
O
R1
9
examples
MeO
Department of Chemistry, The College of William & Mary,
P.O. Box 8795, Williamsburg, VA 23187, USA
jrscheerer@wm.edu
aldol
condensation
retro-
[4+2]
up to 77% yield
O
O
O
MeO
N
R2
R1
O
O
N
N
R2
R2
OMe
OMe
alkene
isomerization
[4+2]
R1
R1
Received: 05.01.2017
Accepted after revision: 01.02.2017
Published online: 23.02.2017
for conversion of [2.2.2]diazabicycloalkene adducts such as
into pyridone products resembling 4 was general, we de-
2
DOI: 10.1055/s-0036-1588729; Art ID: st-2017-r0010-l
sired a more expedient overall sequence. We anticipated
that an analogous domino reaction process initiated with a
dihydrooxazinone precursor 5 might also undergo aldol
condensation and isomerization and intercept oxazinone 7
Abstract A domino reaction sequence has been evaluated that begins
with union of novel dihydrooxazinone precursors with 2-alkynyl-substi-
tuted benzaldehyde components through aldol condensation. Ensuing
operations, including alkene isomerization, Diels–Alder, and retrograde
(Scheme 1, eq. 2). Following cycloaddition of 7, the result-
Diels–Alder with loss of CO occurs in the same reaction vessel to pro-
vide polysubstituted tricyclic pyridine products.
ing intermediate cycloadduct 8, which bears a lactone-
2
bridging function, would extrude CO possibly at the tem-
2
peratures necessary for the preceding cycloaddition and
thereby deliver the tricyclic pyridine product 9. In this way,
we anticipated that the cycloaddition and cycloreversion
steps could be merged into a single operation. Although not
widely explored, oxazinone cycloaddition/cycloreversion
Key words cycloaddition, cycloreversion, pyridine synthesis, domino
reactions, Diels–Alder, oxazinone
The value of domino reactions, which consist of two or
more chemical events that occur in a single flask, has been
6
reactions are known from the work Hoornaert, however,
2
most clearly elucidated by Tietze, and is also apparent to
our desire to incorporate these pericyclic processes into
more elaborate domino reaction pathways was not estab-
lished. We reasoned that successful execution of the desired
plan would advance new chemistry and provide comple-
mentary methods for the rapid assembly of polycyclic sub-
stituted pyridines, a widespread and privileged scaffold
that is shared among many molecules that find application
the practicing chemist: fewer time-consuming purification
processes and mitigation of solvent waste is advantageous
as compared to stepwise synthesis and is more aligned with
3
the principles of the ideal synthesis.
Previous efforts from our lab have employed a domino
reaction process involving an aldol condensation of diketo-
piperazine precursors, alkene isomerization to an interme-
7
in medicine, agriculture, and material science. Given the
diate pyrazinone, and cycloaddition to construct the
many valuable properties of pyridines, continued efforts di-
rected toward the construction of pyridines are warranted
and remain an active research area. Metal-free domino re-
4
[
2.2.2]diazabicyclic functionality (Scheme 1, eq. 1). If the
8
cycloaddition event intercepts an alkyne dienophile, the re-
sulting diazabicycloalkene adduct (e.g., 2) can undergo fur-
ther reaction: cycloreversion and extrusion of one bridging
lactam function (as an isocyanate or cyanogen derivative)
action processes, such as the one described in this letter, of-
fer the potential for direct synthesis of substituted pyri-
dines with minimal environmental impact.9
In order to begin our study of the domino reaction se-
quence, we first needed to prepare the requisite dihydroo-
xazinone precursors (e.g., 5), which were apparently un-
known. We determined that the glycine-glycolate derived
dihydrooxazinone precursor 5a could be prepared in three
steps starting from chloroacetic acid (Scheme 2).10 The lac-
tim ether functionality in 5a was established by Staudinger
5
to afford 2-pyridone or pyridine structures. We deter-
mined that intermediate [2.2.2]diazabicyclic structures re-
sembling 2 could be reliably converted into the derived pyr-
idone 4 through a three-step process that involved activa-
tion of one lactam bridge as the derived acetylated
intermediate 3 prior to thermal extrusion (microwave, 300
W, 1 h, max. temp ca. 200 °C). While the three-step process
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–C

B
Synlett
J. B. Williamson et al.
Letter
Previous
work
O
O
O
i. LiHMDS, –78 °C
ii. Ac2O
–78 to 23 °C
1. KI
AcOH
100 °C
MW
300 W
1 h
NDMB
NDMB
H
O
R
CHO
MeO
N
AcO
N
H
NDMB
R
R
NDMB
N
iii. DBU, 100 °C
2. Ac O
retro-
[4+2]
(1)
2
py
1
aldol condensation
alkene isomerization
2
3
4
R
MeO
DMB = 2,4-dimethoxybenzyl
[4+2]
This work
O
O
O
O
O
O
N
R
OMe
CHO
MeO
aldol
O
R
O
R
N
N
N
N
R
R
R
R
(2)
OMe alkene
OMe
R
MeO
retro-
[4+2]
[4+2]
5
6
R
7
R
8
9
isomerization
Scheme 1 Comparison of domino reactions using diketopiperazine or oxazinone precursor in the synthesis of pyridone and pyridine products
reduction of the derived azide and cyclization of the inter-
mediate aza-Wittig intermediate on the pendant methyl es-
ter at 90 °C. The desired product 5a was separated from the
stoichiometric phosphine oxide byproduct most conve-
niently by distillation using a Kugelrohr apparatus.
dine product 13a (ca. 10–20%). Slow addition of the alde-
hyde via syringe pump improved the yield of product 13a to
77%.11 No intermediate products resulting from aldol addi-
tion, condensation, isomerization, or cycloaddition were
evident, and the unpurified reaction mixture appeared to
contain only 13a and unreacted aldehyde component (in
some cases). It was remarkable to us that DBU is sufficiently
basic to promote enolization and aldol condensation of di-
hydrooxazinone substrates, which contrasts with our previ-
ous work using diketopiperazine starting materials (e.g., 1),
which required a stronger base (NaOMe or LiHMDS) to pro-
O
O
1
2
. NaN3, H2O
N3
PPh3
O
Cl
CO2H
O
. BrCH2CO2Me
K2CO3, 40 °C
PhMe
90 °C
N
MeO2C
5a
MeO
1
2
. chloroacetyl chloride
py, CH2Cl2, 0 °C
. NaN3
O
22% yield (3 steps)
3,4
mote enolization and aldol addition (see Scheme 1, eq. 1).
OH
O
butanone, 80 °C
N
MeO2C
R
3. PPh , PhMe
R
O
3
CHO
9
0 or 110 °C
a
DBU
(1.5 equiv)
N
OMe
R = Me
R = Ph
MeO R = Me 5b (31% yield)
b
O
R = Ph 5c (48% yield)
N
PhMe
110 °C, 16 h
R2
R2
Scheme 2 Synthesis of dihydrooxazinone precursors. a Step 3: 90 °C.
Step 3: 110 °C.
R1
(
1.5 equiv)
R1
b
MeO
5a R2 = H
5b R = Me
5c R = Ph
1
1
1
1
0 R = H
1
2
1 R = n-Bu
1
2
2 R = Ph
Although dihydrooxazinone 5a was somewhat prone to
degradation (by putative polymerization to insoluble prod-
ucts with unresolved spectroscopic characteristics), materi-
al purified by Kugelrohr distillation was stable in the freez-
er on the duration of weeks. The C-5 methyl- and phenyl
substituted dihydrooxazinones 5b and 5c were prepared
using a modified sequence starting from lactate and man-
delate precursors (Scheme 2). The synthesis of C-5 phenyl-
dihydrooxazinone 5c required more elevated temperatures
N
OMe
N
OMe
N
OMe
n-Bu
13b 10% yield
Ph
1
3a 77% yield
13c 13% yield
N
OMe
N
OMe
Me
N
OMe
Me
Me
n-Bu
14b 54% yield
Ph
1
4a 58% yield
14c 61% yield
N
OMe
N
OMe
Ph
N
OMe
Ph
(110 °C) and longer duration (24 h) in order to promote
complete cyclization of the aza-Wittig intermediate on the
methyl ester and deliver the lactim O-methyl ether func-
tionality. The more robust stability of 5b and 5c was a fa-
vorable attribute that enabled purification on silica gel and
improved the efficiency of the reaction sequence (31 and
Ph
n-Bu
15b 22% yield
Ph
15a 32% yield
15c 50% yield
Scheme 3 Domino reaction sequence leading to tricyclic pyridine
products
48% yield over three steps).
With three dihydrooxazinone precursors (5a–c) in
hand, we selected the most simple 2-alkynyl benzaldehyde
derivative 10 with which to initiate our studies of the dom-
ino reaction sequence (Scheme 3). When 10 and 5a were
heated in toluene at 110 °C with DBU (1.5 equiv) we ob-
served a small amount the desired tricyclic 2-methoxypyr-
Two additional benzaldehyde derivatives 11 and 12 (ex-
tending either n-butyl or phenyl residues from the alkyne
terminus) were prepared in order to explore this domino
sequence in more detail. Using the unsubstituted dihydroo-
xazinone precursor 5a with either 11 or 12, the resulting 2-
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–C

C
Synlett
J. B. Williamson et al.
Letter
methoxypyridine products 13b and 13c were obtained,
however, the isolated yield for these products was low (10%
and 13%). Attempts to improve the reaction yield efficiency
by varying temperature, stoichiometry, or base were met
without success.
Reactions performed with the methyl-substituted dihy-
drooxazinone precursor 5b gave more consistent results
with each of the three benzaldehyde reaction components
(5) (a) Margrey, K. M.; Hazzard, A. D.; Scheerer, J. R. Org. Lett. 2014,
16, 904. (b) Leibowitz, M. K.; Winter, E. S.; Scheerer, J. R. Tetra-
hedron Lett. 2015, 56, 6069.
(
6) (a) Rogiers, J.; Wu, X. J.; Toppet, S.; Compernolle, F.; Hoornaert,
G. J. Tetrahedron 2001, 57, 8971. (b) De Borggraeve, W.;
Rombouts, F.; Van der Eycken, E.; Hoornaert, G. J. Synlett 2000,
713. (c) Wu, X. J.; Dubois, K.; Rogiers, J.; Toppet, S.;
Compernolle, F.; Hoornaert, G. J. Tetrahedron 2000, 56, 3043.
(d) Van der Eycken, E.; Deroover, G.; Toppet, S. M.; Hoornaert, G.
J. Tetrahedron Lett. 1999, 40, 9147. (e) Medaer, B. P.; Hoornaert,
G. J. Tetrahedron 1999, 55, 3987. (f) Medaer, B. P.; Vanaken, K. J.;
Hoornaert, G. J. Tetrahedron 1996, 52, 8813. (g) Medaer, B.;
Vanaken, K.; Hoornaert, G. Tetrahedron Lett. 1994, 35, 9767.
(
10–12), and the desired products 14a, 14b, and 14c were
obtained in 58, 54, and 61% yield. Use of 5-phenyl dihydro-
oxazinone 5c was also successful in the reaction sequence
with the alkynyl benzaldehyde derivatives 10–12 and af-
forded the respective tricyclic products 15a, 15b, and 15c in
(h) Vanaken, K. J.; Lux, G. M.; Deroover, G. G.; Meerpoel, L.;
Hoornaert, G. J. Tetrahedron 1994, 50, 5211. (i) Fannes, C.;
Meerpoel, L.; Toppet, S.; Hoornaert, G. Synthesis 1992, 705.
(j) Fannes, C. C.; Hoornaert, G. J. Tetrahedron Lett. 1992, 33,
32%, 22%, and 50% yield. Overall, reactions with the 5-alkyl
dihydrooxazinones 5b or 5c did not benefit from slow addi-
tion of aldehyde; as such these reactions did not require the
syringe pump and were thus more convenient to execute. In
all reactions performed, the unpurified reaction products
were uncomplicated and contained desired products and
unreacted starting materials and only trace impurities. Ac-
cordingly, we attribute the modest yields in several cases to
poor mass recovery, a feature consistent with the observed
propensity of the dihydrooxazinone precursors to degrade
and polymerize.
The reaction sequence described in this letter demon-
strates the proof of principle of a domino reaction sequence
that features several base-promoted and pericyclic bond-
forming and bond-cleaving processes. The sequence is initi-
ated by condensation of novel dihydrooxazinone starting
materials with aromatic aldehyde precursors. The ensuing
alkene isomerization to the intermediate oxazinone pre-
cedes merged cycloaddition and cycloreversion sequence
2049. (k) Tutonda, M. G.; Vandenberghe, S. M.; Vanaken, K. J.;
Hoornaert, G. J. J. Org. Chem. 1992, 57, 2935. (l) Vanaken, K. J.;
Meerpoel, L.; Hoornaert, G. J. Tetrahedron Lett. 1992, 33, 2713.
(m) Meerpoel, L.; Hoornaert, G. Tetrahedron Lett. 1989, 30, 3183.
(
7) (a) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
(b) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627. (c) Henry, G. D.
Tetrahedron 2004, 60, 6043. (d) Joule, J. A.; Mills, K. Heterocyclic
Chemistry; Blackwell Publishing: Oxford, 2000, 4th ed. 63.
(8) Selected reviews: (a) Varela, J. A.; Saá, C. Chem. Rev. 2003, 103,
3
787. (b) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan,
V. Chem. Rev. 2013, 113, 3084. (c) Hill, M. D. Chem. Eur. J. 2010,
6, 12052. (d) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A.
1
B. Chem. Rev. 2012, 112, 2642. (e) Nakao, Y. Synthesis 2011,
3209.
(9) (a) Allais, C.; Grassot, J. M.; Rodriguez, J.; Constantieux, T. Chem.
Rev. 2014, 114, 10829. (b) Kral, K.; Hapke, M. Angew. Chem. Int.
Ed. 2011, 50, 2434.
10) See Supporting Information for procedures that accompany
Scheme 2 and the spectra and corresponding characterization
data for all new compounds (including 5a–c, 13b,c, 14a–c, 15a–c).
(
(
evolving CO ) to give 2-methoxypyridine products. The
2
(11) Representative Procedure for the Domino Reaction Leading
to Tricyclic Pyridine Product 13a
overall multicomponent domino reaction process is pro-
moted with mild organic base (DBU) and occurs at conve-
niently accessible temperatures (110 °C).
Dihydrooxazinone 5a (50 mg, 0.38 mmol) was dissolved in
toluene (3.0 mL, 0.12 M) and DBU (85 μL, 0.57 mmol, 1.5 equiv)
was added. The reaction vessel was heated in an oil bath to a
gentle reflux (110 °C) and 2-alkynyl benzaldehyde 10 (74 mg,
Acknowledgment
1
.5 equiv) in toluene (1.0 mL) was introduced slowly to the reac-
tion over 2 h (using a syringe pump). After stirring for 18 h at
10 °C, the reaction was cooled to r.t., transferred to a separa-
The authors acknowledge support from the National Institutes of
Health (R15 GM107702 to J.R.S.).
1
tory funnel, and partitioned between sat. aq NH Cl (10 mL) and
4
EtOAc (10 mL). The organic layer was removed, and the aqueous
portion was extracted with EtOAc (3 × 10 mL). The combined
Supporting Information
organic layers were washed with brine (10 mL), dried (Na SO ),
filtered through Celite, and concentrated in vacuo. The resulting
residue (82 mg) was purified by flash column chromatography
Supporting information for this article is available online at
2
4
http://dx.doi.org/10.1055/s-0036-1588729.
S
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ortioIgnfrm oaitn
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References and Notes
on silica gel (gradient elution: 20% → 80% of CHCl in hexane) to
3
afford compound 13a (57 mg, 77% yield) as a light yellow oil;
R = 0.20 (50% CHCl –Hex). IR (film): 1586, 1463, 1307, 1029,
(1) Present address: J. B. Williamson, Department of Chemistry,
f
3
–1 1
The University of North Carolina, Chapel Hill, NC 27599, USA.
2) (a) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006. (b) Tietze, L. F.;
Modi, A. Med. Res. Rev. 2000, 20, 304. (c) Tietze, L. F. Chem. Rev.
772 cm . H NMR (400 MHz, CDCl ): δ = 7.88 (d, J = 8.6 Hz, 1 H),
3
(
7.62 (d, J = 7.8 Hz, 1 H), 7.52 (d, J = 7.4 Hz, 1 H), 7.34 (t, J = 7.4 Hz,
1 H), 7.26 (t, J = 7.4 Hz, 1 H), 4.00 (s, 3 H), 3.87 (s, 2 H). 13C NMR
(100 MHz, CDCl ): δ = 163.9, 162.5, 140.4, 139.8, 130.0, 128.4,
3
1
996, 96, 115.
126.9, 126.0, 125.0, 119.2, 108.7, 53.7, 38.6. HRMS: m/z calcd for
+
(
(
3) Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657.
4) (a) Margrey, K. A.; Chinn, A. J.; Laws, S. W.; Pike, R. D.; Scheerer,
J. R. Org. Lett. 2012, 43, 2458. (b) Laws, S. W.; Scheerer, J. R.
J. Org. Chem. 2013, 78, 2422.
C13H NONa [M + Na] : 198.0913; found: 198.0913.
9
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–C