Efficient generation of highly functionalized fused oxazepine frameworks based on a CAN-catalyzed four-component tetrahydropyridine synthesis/ring- closing metathesis sequence

Article abstract of DOI:10.1021/jo9021309

(Chemical Equation Presented) 1-Allyl(propargyl)-6-allyl(propargyl)oxy-1,4, 5,6-tetrahydropyridines, obtained through a CAN-catalyzed four-component reaction, were transformed into highly functionalized pyrido[2,1-b]-[1,3] oxazepines by ring-closing metat

Full text of DOI:10.1021/jo9021309

pubs.acs.org/joc
Efficient Generation of Highly Functionalized Fused Oxazepine
Frameworks Based on a CAN-Catalyzed Four-Component
Tetrahydropyridine Synthesis/Ring-Closing Metathesis Sequence
ꢀ
Vellaisamy Sridharan, Swarupananda Maiti, and J. Carlos Menendez*
´
ꢀ
Departamento de Quımica Organica y Farmaceutica,Facultad de Farmacia, Universidad Complutense,
ꢀ
28040 Madrid, Spain
josecm@farm.ucm.es
Received October 3, 2009
1-Allyl(propargyl)-6-allyl(propargyl)oxy-1,4,5,6-tetrahydropyridines, obtained through a CAN-
catalyzed four-component reaction, were transformed into highly functionalized pyrido[2,1-b]-
[1,3]oxazepines by ring-closing metathesis (RCM) and ring-closing enyne metathesis (RCEYM)
processes, which constitute the first examples of the preparation of 1,3-oxazepine systems using
metathesis reactions.
Introduction
Among these β-turn mimics, bicyclic oxazepines derived
from the pyrido[2,1-b][1,3]oxazepine ring system have
received much attention as frameworks for the construction
of peptidominetic compounds, specially conformationally
restricted dipeptide surrogates that are key structural frag-
ments of inhibitors of angiotensin-converting enzyme (ACE)
and neutral endopeptidase (NEP),2 among other relevant
targets.
The synthesis of pyrido[2,1-b][1,3]oxazepines has normally
been achieved by double cyclization of acyclic precursors
containing an ω-hydroxyalkyl chain and ω-formylalkyl2b or
ω-vinylalkyl3 substituents attached to a nitrogen atom. We
describe here an alternative procedure for the preparation of
densely functionalized derivatives of the pyrido[2,1-b]-
[1,3]oxazepine system, based on the use of our recently
described4 synthesis of 6-alkoxy-1,4,5,6-tetrahydropyridines
through a four-component reaction which is followed by
generation of the oxazepine moiety by ring-closing metathesis
strategies (Scheme 1).
Peptidomimetics are compounds that mimic the interac-
tion of bioactive peptides with their targets while having
improved pharmacokinetic properties such as increased
bioavailability and biostability. The use of peptidomimetics
has emerged as a powerful tool for overcoming the limita-
tions inherent in the physical characteristics of peptides, thus
improving their therapeutic potential, and for this reason
peptidomimetics are becoming increasingly important in
drug design.1 Azabicyclo[x.y.0]alkane frameworks are im-
portant building blocks for the construction of conforma-
tionally fixed mimics of β-turn (type II) secondary structures
of peptides. These unique heterocyclic frameworks can be
used to restrain the backbone geometry and side-chain
conformations of the native peptide to investigate structure-
-activity relationships and provide versatile templates for
generating combinatorial libraries and for the development
of compounds active at enzyme and receptor active sites.
(1) For selected reviews of the role of peptidomimetics in drug design, see:
(a) Giannis, A.; Rubsam, F. Adv. Drug. Res. 1997, 29, 1. (b) Leung, D.;
Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000, 43, 305. (c) Goodman, M.;
(2) (a) Robl, J. A. US Patent 5,508,272A (Apr 16, 1996). (b) Robl, J. A.; Sun,
C.-Q.; Stevenson, J.; Ryono, D. E.; Simpkins, L. M.; Cimarusti, M. P.; Dejneka, T.;
Slusarchyk, W. A.; Chao, S.;Stratton, L.; Misra, R. N.;Bednarz, M. S.;Asaad, M. M.;
Cheung, H. S.; Abboa-Offei, B. E.; Smith, P. L.; Mathers, P. D.; Fox, M.; Schaeffer,
T. R.; Seymour, A. A.; Trippodo, N. C. J. Med. Chem. 1997, 40, 1570.
ꢀ
Zapf, C.; Rew, Y. Pept. Sci 2001, 60, 229. (d) Perez, J. J.; Corcho, F.;
Llorens, O. Curr. Med. Chem. 2002, 9, 2209. (e) Estiarte, M. A.; Rich, D. H.
In Burger’s Medicinal Chemistry and Drug Discovery, 6th ed.; Abraham, D. J.,
~
Ed.;Wiley-Interscience: New York, 2003; Vol. 1, p 633. (f) Avendano, C.;
(3) Chiou, W.-H.; Mizutani, N.; Ojima, I. J. Org. Chem. 2007, 72, 1871.
ꢀ
ꢀ
Menendez, J. C. Clin. Transl. Oncol. 2007, 9, 563. (g) Clynen, E.; Baggerman,
G.; Husson, S. J.;Landuyt, B.; Schoofs, L. Expert Opin. DrugDiscov.2008, 3, 425.
(4) Sridharan, V.; Maiti, S.; Menendez, J. C. Chem.;Eur. J. 2009, 15,
4565.
DOI: 10.1021/jo9021309
r
Published on Web 11/18/2009
J. Org. Chem. 2009, 74, 9365–9371 9365
2009 American Chemical Society

Sridharan et al.
JOCArticle
SCHEME 1. Plan for the Synthesis of Pyrido[2,1-b]-
[1,3]oxazepines
TABLE 1. Scope and Yields of the Synthesis of 6-Alkoxy-1,4,5,6-
tetrahydropyridines
entry
compd
R1
R3
R6
yield, %
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
propargyl
propargyl
OEt
OEt
OEt
S-tBu
OEt
OMe
OEt
OMe
S-tBu
S-tBu
OEt
allyl
88
85
86
87
94
90
86
85
80
79
90
87
2-butenyl
prenyl
allyl
propargyl
propargyl
2-hexynyl
2-hexynyl
propargyl
2-hexynyl
allyl
10
11
12
5j
5k
5l
OEt
2-butenyl
SCHEME 3. Introduction of Substituents at the C2-CH3 Group
in 6-Alkoxy-1,4,5,6-tetrahydropyridines
SCHEME 2. Synthesis of Starting 6-Alkoxy-1,4,5,6-tetrahy-
dropyridines
TABLE 2. Scope and Yields of the Synthesis of 6-Alkoxy-1,4,5,6-
tetrahydropyridines Bearing Substituents at the C2-CH3 Group
entry
compd
R1
R2
R3
R6
yield, %
1
2
3
4
5
6
7
5m
5n
5o
5p
5q
5r
allyl
allyl
allyl
allyl
allyl
allyl
propargyl
Me
Me
Et
OEt
allyl
allyl
allyl
allyl
allyl
allyl
allyl
95
94
95
92
93
95
90
OMe
OMe
OMe
OEt
OMe
OEt
Results and Discussion
nBu
The preparation of the tetrahydropyridines 5 needed as
starting materials for our study is summarized in Scheme 2
and involved the four-component reaction between primary
amines 1, β-dicarbonyl compounds 2, R,β-unsaturated alde-
hydes 3, and alcohols 4 in acetonitrile, catalyzed by cerium-
(IV) ammonium nitrate (CAN).5,6 As shown in Table 1, this
reaction tolerated the use of both allyl/propargyl alcohols
and allyl/propargyl amines and afforded the corresponding
tetrahydropyridines 5a-l in excellent yields.
In order to increase structural variation in the starting
materials for our study, we planned to use the acidity of the
C2-methyl substituent, which is due to its conjugation with
the electron-withdrawing group at C-3.4 Indeed, treatment
of some of the tetrahydropyridines previously prepared with
LDA followed by alkyl bromides or iodides afforded com-
pounds 5m-s. The yields were excellent in all cases, and no
interference from the alkoxy group at C-6 was observed
(Scheme 3 and Table 2).
(CH2)2Ph
(CH2)2Ph
prenyl
5s
The next stage of our plan involved the generation of an
oxazepine ring by ring-closing metathesis.7 This may be con-
sidered as the most critical step in our synthetic scheme because
the preparation of medium-sized rings by RCM may be difficult
in some instances (specially from acyclic precursors) owing to
entropic factors and transannular repulsions that develop as the
ring is formed. Indeed, to our knowledge, the proposed trans-
formations are the first examples of the synthesis of 1,3-oxaze-
pines by ring-closing metathesis.8 Gratifyingly, and in spite of
these potential problems, in our case the reaction proceeded very
well, probably favored by the conformational constraints im-
posed by our semirigid substrate, and compounds 6a-h were
isolated in yields higher than 90%. As shown in Table 3, the
optimal reaction conditions for the most favorable reactions,
involving two allyl substituents, involved the use of 5-10% of
the Grubbs-1 catalyst at room temperature (entries 1 and 5-8).
The presence of a 2-butenyl substituent did not significantly
alter this reactivity (entry 2), while for the case of compound 5c,
bearing a prenyloxy substituent at C-6, reflux conditions were
(5) For some reviews of cerium ammonium nitrate-promoted synthetic
transformations, see: (a) Nair, V.; Matthew, J.; Prabhakaran, J. Chem. Soc.
Rev. 1997, 127. (b) Hwu, J. R.; King, K.-Y. Curr. Sci. 2001, 81, 1043. (c) Nair,
V.; Panicker, S. B.; Nair, L. G.; George, T. G.; Augustine, Z. Synlett 2003,
156. (d) Nair, V.; Balagopal, L.; Rajan, R.; Mathew, J. Acc. Chem. Res. 2004,
37, 21. (e) Nair, V.; Deepthi, A. Chem. Rev. 2007, 107, 1862.
(6) For representative recent examples of CAN-catalyzed reactions,
taken from the work of our group, see: (a) Sridharan, V.; Ribelles, P.;
ꢀ
Ramos, M. T.; Menendez, J. C. J. Org. Chem. 2009, 74, 5715. (b) Sridharan,
V.; Avendano, C.; Menendez, J. C. Tetrahedron 2009, 65, 2087. (c) Sridharan,
~
ꢀ
(7) For a review of the synthesis of oxygen and nitrogen heterocycles
using ring-closing metathesis reactions, see: Deiters, A.; Martin, S. F. Chem.
Rev. 2004, 104, 2199.
ꢀ
~
V.; Menendez, J. C. Org. Lett. 2008, 10, 4303. (d) Sridharan, V.; Avendano,
C.; Menendez, J. C. Synthesis 2008, 1039. (e) Sridharan, V.; Avendano, C.;
ꢀ
~
ꢀ
~
Menendez, J. C. Synlett 2007, 1079. (f) Sridharan, V.; Avendano, C.;
(8) For examples of the synthesis of 1,2-oxazepines by ring-closing
metathesis, see: (a) Koide, K.; Finkelstein, J. M.; Ball, Z.; Verdine, G. L.
J. Am. Chem. Soc. 2001, 123, 398. (b) Van der Jeught, S.; Stevens, C. V.;
Dieltiens, N. Synlett 2007, 3183.
ꢀ
~
Menendez, J. C. Synlett 2007, 881. (g) Sridharan, V.; Avendano, C.;
Menendez, J. C. Tetrahedron 2007, 63, 4407. (h) Sridharan, V.; Avendano,
ꢀ
~
ꢀ
C.; Menendez, J. C. Tetrahedron 2007, 63, 673. (i) See also ref 4.
9366 J. Org. Chem. Vol. 74, No. 24, 2009

Sridharan et al.
JOCArticle
TABLE 3. Synthesis of Pyrido[2,1-b][1,3]oxazepines by Ring-Closing Metathesis (RCM) Reactions
b
c
aAll reactions were carried out in dichloromethane. Together with 20% of the corresponding elimination product 7. Together with 23% of the
corresponding elimination product 7.
necessary (entry 3). For reactions involving reflux for several
hours, the desired compounds were accompanied by dihydro-
pyridines 7 (see below), arising from an elimination reaction
from the starting materials (entries 2 and 3).
We next examined the preparation of fused oxazepine
systems by use of a ring-closing enyne metathesis (RCEYM)
protocol, which again was unprecedented.9 These reactions
proved more challenging than the standard RCM processes
previously studied and required extensive optimization work,
which was carried out on the reactionstarting from compound
5e. As shown in Scheme 4 and Table 4, the desired product 6i
was accompanied by variable amounts of the known10 dihy-
dropyridine 7, from elimination of a molecule of propargyl
(9) For a review of enyne metathesis, see: Diver, S. T.; Giessert, A. J.
Chem. Rev. 2004, 104, 1317–1382.
ꢀ
(10) Maiti, S.; Menendez, J. C. Synlett 2009, 2249.
J. Org. Chem. Vol. 74, No. 24, 2009 9367

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SCHEME 4. Optimization Study of the Ring-Closing Enyne
Metathesis Reaction Starting from Compound 5e
TABLE 5. Synthesis of Pyrido[2,1-b][1,3]oxazepines through Ring-
Closing Enyne Metathesis (RCEYM) Reactionsa
TABLE 4. Yields Obtained in the RCM Optimization Study Starting
from Compound 5e
ethylene
atmosphere
yield
time, h 6i/7, %
entry
catalyst
temp, °C
1
2
3
4
5
6
7
Grubbs-1 (5%) no
Grubbs-1 (10%) no
Grubbs-2 (5%) no
Grubbs-1 (5%) yes
Grubbs-1 (5%) yes
Grubbs-2 (5%) yes
Grubbs-1 (10%) yes
refluxing CH2Cl2 24 32/48
refluxing CH2Cl2 45/46
refluxing CH2Cl2 24 0/80
rt 24 51/9
refluxing CH2Cl2 17 57/33
5
rt
rt
24 0/37
24 90/0
alcohol from the starting material. Since preliminary experi-
ments showed that the desired RCM reaction in the presence of
5 mol % of the Grubbs-1 catalyst did not take place at room
temperature, we carried it out in refluxing dichloromethane, but
a long reaction time (24 h) was required. Under these condi-
tions, and not wholly unexpectedly, the major product was
dihydropyridine 7 (entry 1). Use of 10 mol % of the Grubbs-1
catalyst allowed a substantial reduction in the reaction time,
leading to equimolecular amounts of both products (entry 2).
An attempt to use the Grubbs-2 catalyst was disappointing, as
the reaction times were similar to those needed for the Grubbs-1
catalyzed reactions, and furthermore, it seemed to favor the
undesired elimination (entry 3). At this stage, we decided to
study the effect of carrying out the reaction under an ethylene
atmosphere.11 Under these conditions, the use of 5 mol % of
Grubbs-1 catalyst allowed us to carry out the reaction at room
temperature with very little competing elimination, although the
yield of compound 6i was only 51% (entry 4). Reflux conditions
increased conversion, but at the cost of favoring elimination,
and the yield of 6i remained essentially unchanged (entry 5).
Grubbs-2 catalyst, as in the previous case, gave only elimination
product (entry 6). Finally, we found that the use of 10 mol % of
Grubbs-1 catalyst at room temperature for 24 h led to the
desired compound 6i in an excellent 90% yield, without any
noticeable competing elimination (entry 7).
aConditions: Grubbs-1, ethylene, rt, 24 h.
the final products, namely vinyl substituents at the C-3 or C-4
positions. On the basis of the previously mentioned difference in
reactivity for vinyl and prenyl side chains, it was possible to
control the outcome of the metathesis reaction in substrates
possessing three potentially reactive substituents with a central
alkynyl chain. Thus, compound 5s, bearing propargyl, allyl, and
4-methyl-3-pentenyl substituents on nitrogen, oxygen, and car-
bon, respectively, afforded an excellent yield of the pyrido[2,1-b]-
[1,3]oxazepine 6p as the only observed product, without any
competing or additional metathesis reactions being observed.
The fact that compound 5l gave vinyl derivative 6o, instead of
the expected 2-propenyl derivative, must be due to a cross-
metathesis reaction between the initial product (bearing a
2-propenyl chain) and ethylene. There are some examples of
related domino enyne-cross-metathesis processes,12 although
The optimal conditions thus established for the enyne me-
tathesis were then applied to a range of additional substrates,
again in excellent yields. As shown in Table 5, the “yne”
component of the reaction can be placed either on nitrogen or
on oxygen, allowing us to achieve two types of substitution on
(11) For the acceleration of RCEYM reactions in the presence of
ethylene, see: (a) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem.
1998, 63, 6082. For representative examples of the synthetic application of
this protocol, see ref 4 and: (b) Saito, N.; Sato, Y.; Mori, M. Org. Lett. 2002,
(12) (a) Royer, F.; Vilain, C.; Elkaım, L.; Grimaud, L. Org. Lett. 2003, 5,
¨
2007. (b) Lee, H.-Y.; Kim, H. Y.; Tae, H.; Kim, B. G.; Lee, J. Org. Lett. 2003,
5, 3439.
ꢀ
ꢀ~
3, 803. (c) Nunez, A.; Cuadro, A. M.; Alvarez-Builla, J.; Vaquero, J. J. Chem.
Commun. 2006, 2690.
9368 J. Org. Chem. Vol. 74, No. 24, 2009

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SCHEME 5. Postcyclization Transformations: Use of Com-
pounds 6k and 6m as Diels-Alder Dienes
SCHEME 6. CAN-Catalyzed Three-Component Synthesis of
Pyrido[2,1-b]oxazoles and Pyrido[2,1-b][1,3]oxazines 10
TABLE 7. Results Obtained in the Synthesis of Compounds 10
TABLE 6. Results Obtained in the Synthesis of Compounds 8
R1
R2
n
yield, %
entry
R1
R2
starting material
product
yield, %
entry
compd
1
2
3
4
5
6
10a
10b
10c
10d
10e
10f
H
n-Bu (R)
H
H
H
H
OEt
OEt
OEt
OMe
OtBu
StBu
1
1
2
2
2
2
79
86a
90
82
89
88
1
2
OEt
St-Bu
n-Pr
H
6k
6m
8a
8b
96
92
we have not found literature precedent for the behavior observed
by us in RCEYM reactions carried out under an ethylene
atmosphere. Our result is relevant in that it shows that some
caution may be needed in the future in the use of ethylene
atmospheres in ring-closing enyne metathesis reactions. When
the 1-butyl analogue of compound 5l was submitted to our
metathesis conditions in an ethylene atmosphere, we observed
about 30% of the corresponding cross-metathesis product in the
crude reaction product, which shows that the cross-metathesis
reaction between ethylene and the 2-propenyl analogue of 6o
must have been aided by the presence of the conjugated double
bond on the adjacent oxazepine ring.
In order to demonstrate the synthetic value of the products
arising from the enyne metathesis, we decided to briefly
study a protocol combining the ring-closing metathesis
reaction with cycloaddition chemistry. Thus, in order to
examine the role of some compounds 6 as Diels-Alder
dienes,13 we carried out the reaction between compounds
6k and 6m and N-methylmaleimide. As shown in Scheme 5
and Table 6, this reaction afforded the tetracyclic com-
pounds 8 at room temperature, in excellent yields and in a
completely diastereoselective fashion. The stereochemistry
proposed for compounds 8 was based on a literature report
for a related case, which was confirmed by X-ray diffrac-
tion,14 and is in agreement with the expected anomeric and
endo effects. The very brief construction of this hitherto
unknown polyheterocyclic framework proves the power of
our strategy to efficiently generate structural diversity and
complexity in few steps from very simple starting materials.
Finally, we also explored the possibility of carrying out a
variation of our tetrahydropyridine synthesis that included an
intramolecular last step and which would lead to bicyclic
systems related to compounds 6 in one operation. Although
some examples of this type of reaction are known in the
literature for the generation of pyrido[2,1-b]oxazole deriva-
tives (Scheme 6, n = 1), it is normally performed as a two-
component protocol,15 and the only three-component version
aAs a 7:3 diastereomer mixture.
that we are aware of proceeds in rather low yield (47%
average).16 As shown in Scheme 6 and Table 7, CAN was an
excellent catalyst for the generation of this type of frame-
work (compounds 10a,b, entries 1 and 2) from β-dicarbonyl
compounds 2, acrolein 3, and amino alcohols 9 (n = 1). The
same conditions could also be applied to the synthesis of
pyrido[2,1-b][1,3]oxazines 10c-f by using amino alcohols 9
where n = 2 (entries 3-6). However, the reactions involving
the use of 4-aminobutanol and 5-aminopentanol, which
would have afforded pyrido[2,1-b][1,3]oxazepine and pyrido-
[2,1-b][1,3]oxazocine derivatives, respectively, gave a complex
mixture. This result proved that the three-component reaction
is not suitable for the generation of medium-sized rings and
is therefore complementary to the RCM-based protocol
described in this paper.
In conclusion, we have extended and generalized the CAN-
catalyzed four-component synthesis of 1,4,5,6-tetrahydropyri-
dines to include the preparation of 1-allyl(propargyl)-6-allyl-
(propargyl)oxy-1,4,5,6-tetrahydropyridines, some of which
were further functionalized through a regioselective γ-deproto-
nation-allylation process. These starting materials were trans-
formed into highly functionalized pyrido[2,1-b][1,3]oxazepine
frameworks related to bioactive peptidomimetic compounds
using ring-closing metathesis (RCM) and ring-closing enyne
metathesis (RCEYM) processes, which constitute the first
examples of the preparation of 1,3-oxazepine systems using
metathesis chemistry. A modified version of the CAN-catalyzed
tetrahydropyridine synthesis involving an intramolecular final
step was also developed, which was complementary to the
metathesis-based method in that it allowed very efficient access
to pyrido[2,1-b]oxazoles and pyrido[2,1-b][1,3]oxazines.
Experimental Section
General Procedure for the Four-Component 6-Alkoxy-1,4,5,6-
tetrahydropyridine Synthesis: Preparation of Compounds 5a-l.
To a stirred solution of amine 1 (3.9 mmol, 1.3 equiv) and β-keto
ester 2 (3 mmol, 1 equiv) in acetonitrile (5 mL) was added CAN
(5 mol %). Stirring was continued for 30 min at room tempera-
ture. Acrolein 3 (3.3 mmol, 1.1 equiv) and alcohol 4 (6 mmol,
2 equiv) were then added, and stirring was continued for another
1 h. After completion of the reaction, the mixture was diluted
with CH2Cl2 (60 mL), washed with water followed by brine, and
dried (anhydrous Na2SO4). The solvent was evaporated under
(13) Ma, S.; Ni, B.; Liang, Z. J. Org. Chem. 2004, 69, 6305.
(14) For a review of the synthetic applications of the RCEYM/
Diels-Alder sequence, see: Kotha, S.; Meshram, M.; Tiwari, A. Chem.
Soc. Rev. 2009, 38, 2065.
(15) (a) De Kok, P. M. T.; Bastiaansen, L. A. M.; Van Lier, P. M.;
Vekemans, J. A. J. M.; Buck, H. M. J. Org. Chem. 1989, 54, 1313.
(b) Caballero, E.; Puebla, P.; Medarde, M.; San Feliciano, A. Tetrahedron
€
1993, 49, 10079–10088. (c) Noel, R.; Vanucci-Bacque, C.; Fargeau-Bellassoued,
M.-C.; Lhommet, G. J. Org. Chem. 2005, 70, 9044.
ꢀ
€
ꢀ
(16) Noel, R.; Fargeau-Bellassoued, M.-C.; Vanucci-Bacque, C.; Lhommet,
G. Synthesis 2008, 1948.
J. Org. Chem. Vol. 74, No. 24, 2009 9369

Sridharan et al.
JOCArticle
reduced pressure, and the residue was purified by rapid column
chromatography on activated neutral alumina (grade II-III),
eluting with a petroleum ether-ethyl acetate mixture (95:5, v/v)
to give pure compounds 5. Data for representative compounds
(5a, 5d, and 5k) follow. Characterization data for all compounds
5a-l can be found in the Supporting Information.
(()-Methyl 1-allyl-6-allyloxy-2-propyl-1,4,5,6-tetrahydropyr-
idine-3-carboxylate (5o): colorless viscous liquid; IR (neat)
2959.3, 1684.3, 1570.4, 1264.0, 1174.4, 1120.4, 1054.2, 919.6
cm-1; 1H NMR (250 MHz, CDCl3) δ 1.01 (t, J = 7.4 Hz, 3H),
1.41-1.66 (m, 3H), 1.99-2.09 (m, 1H), 2.26-2.59 (m, 3H),
3.11-3.23 (m, 1H), 3.67 (s, 3H), 3.75-3.85 (m, 1H), 4.00-4.03
(m, 2H), 4.08-4.17 (m, 1H), 4.47 (br s, 1H), 5.09-5.34 (m, 4H),
5.75-5.97 (m, 2H); 13C NMR (62.9 MHz, CDCl3) δ 14.7, 18.5,
23.1, 25.8, 31.3, 50.9, 52.1, 68.1, 85.7, 96.9, 116.5, 117.4, 135.2,
135.3, 156.5, 169.2. Anal. Calcd for C16H25NO3: C, 68.79; H,
9.02; N, 5.01. Found: C, 68.69; H, 8.86; N, 5.12.
General Procedure for the RCM and RCEYM Reactions of
Compounds 5. Synthesis of Fused Oxazepines 6. To a solution of
the suitable 6-alkoxy-1,4,5,6-tetrahydropyridine derivative 5
(1 mmol) in dry dichloromethane (10 mL) was added Grubbs
first-generation catalyst (5 or 10 mol %, as specified in Tables 3
and 4), and the reaction mixture was stirred or refluxed in the
presence or absence of ethylene gas under the conditions men-
tioned in Tables 3 and 4. After the completion of the reaction
was verified by TLC, the reaction mixture was concentrated to
dryness and the crude residue was purified by chromatography
on neutral Al2O3 (activity IV) column, eluting with a 90:10
petroleum ether-ethyl acetate mixture. Data for representative
examples (compounds 6a, 6d, 6g, and 6l) follow. Characteriza-
tion data for all compounds 6 can be found in the Supporting
Information.
(()-Ethyl 7-methyl-5,9,10,10a-tetrahydro-2H-pyrido[2,1-b]-
[1,3]oxazepine-8-carboxylate (6a): colorless viscous liquid; IR
(neat) 2973.1, 2932.5, 1679.7, 1579.0, 1431.0, 1272.9, 1096.5
cm-1; 1H NMR (CDCl3, 250 MHz) δ 1.28 (t, J = 7.1 Hz, 3H),
1.77-1.83 (m, 1H), 1.92-2.01 (m, 1H), 2.44 (s, 3H), 2.44-2.51
(m, 2H), 3.73-3.82 (m, 1H), 4.09-4.39 (m, 5H), 4.87 (dd, J =
4.4, 3.6 Hz, 1H), 5.78-5.97 (m, 2H); 13C NMR (CDCl3,
62.9 MHz) δ 15.0, 16.8, 19.4, 27.4, 49.3, 59.5, 65.3, 87.9, 97.6,
130.3, 131.2, 152.4, 169.6. Anal. Calcd for C13H19NO3: C, 65.80;
H, 8.07; N, 5.90. Found: C, 65.45; H, 7.92; N, 5.85.
(()-Methyl 7-ethyl-5,9,10,10a-tetrahydro-2H-pyrido[2,1-b]-
[1,3]oxazepine-8-carboxylate (6d): colorless viscous liquid; IR
(neat) 2944.7, 1683.8, 1569.6, 1270.2, 1176.0, 1125.6, 1100.5
cm-1; 1H NMR (250 MHz, CDCl3) δ 1.17 (t, J = 7.3 Hz, 3H),
1.67-1.81 (m, 1H), 1.92-2.03 (m, 1H), 2.45-2.62 (m, 3H),
3.15-3.29 (m, 1H), 3.68 (s, 3H), 3.71-3.83 (m, 1H), 4.20-4.41
(m, 3H), 4.85 (t, J = 3.6 Hz, 1H), 5.79-5.89 (m, 2H); 13C NMR
(62.9 MHz, CDCl3) δ 13.8, 19.2, 22.9, 27.2, 49.2, 50.9, 65.4, 87.6,
96.0, 130.4, 130.6, 157.9, 169.2. Anal. Calcd for C13H19NO3: C,
65.80; H, 8.07; N, 5.90. Found: C, 65.61; H, 7.93; N, 5.80.
(()-Ethyl 7-(3-phenylpropyl)-5,9,10,10a-tetrahydro-2H-pyrido-
[2,1-b][1,3]oxazepine-8-carboxylate (6g): colorless viscous liquid;
IR (neat) 3025.8, 2933.8, 2857.3, 1681.5, 1573.9, 1453.4, 1361.5,
1269.3, 1144.9, 1096.0 cm-1; 1H NMR (250 MHz, CDCl3) δ 1.29
(t, J = 7.1 Hz, 3H), 1.63-1.84 (m, 2H), 1.85-2.04 (m, 2H),
2.44-2.55 (m, 3H), 2.63-2.86 (m, 2H), 3.13-3.25 (m, 1H),
3.54-3.63 (m, 1H), 3.91 (dd, J = 4.9 and 17.8 Hz, 1H), 4.14 (q,
J = 7.1 Hz, 2H), 4.20-4.25 (m, 1H), 4.28-4.36 (m, 1H), 4.76 (t,
J = 3.5 Hz, 1H), 5.59-5.66 (m, 1H), 5.72-5.81 (m, 1H),
7.17-7.29 (m, 5H); 13C NMR (62.9 MHz, CDCl3) δ 15.0, 19.4,
27.3, 28.9, 31.0, 36.2, 49.1, 59.4, 65.4, 87.8, 97.0, 126.2, 128.7 (2C),
129.0 (2C), 130.5, 130.6, 142.5, 155.9, 168.9. Anal. Calcd for
C21H27NO3: C, 73.87; H, 7.97. N, 4.10; Found: C, 73.65; H, 7.63;
N, 3.97.
(()-Ethyl 1-allyl-6-allyloxy-2-methyl-1,4,5,6-tetrahydropyri-
dine-3-carboxylate (5a): colorless viscous liquid; IR (neat)
2979.5, 2931.3, 1681.7, 1579.9, 1381.2, 1273.9, 1119.8, 1055.1
cm-1; 1H NMR (CDCl3, 250 MHz) δ 1.27 (t, J = 7.1 Hz, 3H),
1.45-1.58 (m, 1H), 2.01-2.11 (m, 1H), 2.26-2.35 (m, 1H), 2.42
(s, 3H), 2.52-2.60 (m, 1H), 3.79-3.89 (m, 1H), 3.99-4.19 (m,
5H), 4.47 (bs, 1H), 5.09-5.34 (m, 4H), 5.75-6.02 (m, 2H); 13
C
NMR (CDCl3, 62.9 MHz) δ 15.0, 16.6, 18.4, 25.4, 52.2, 59.3,
68.3, 86.0, 97.4, 116.2, 117.5, 135.0, 135.2, 152.3, 169.4. Anal.
Calcd for C15H23NO3: C, 67.90; H, 8.74; N, 5.28. Found: C,
67.62; H, 8.51; N, 5.20.
(()-S-tert-Butyl 1-allyl-6-allyloxy-2-methyl-1,4,5,6-tetrahy-
dropyridine-3-carbothioate (5d): colorless viscous liquid; IR
1
(neat) 2958.4, 2922.9, 1628.4, 1544.2, 1253.5, 1058.1 cm-1; H
NMR (CDCl3, 250 MHz) δ 1.50 (s, 9H), 1.52-1.64 (m, 1H),
2.04-2.14 (s, 1H), 2.38 (s, 3H), 2.42-2.55 (m, 1H), 2.57-2.67
(m, 1H), 3.81-4.19 (m, 4H), 4.44 (bs, 1H), 5.08-5.35 (m, 4H),
5.75-6.10 (m, 2H); 13C NMR (CDCl3, 62.9 MHz) δ 17.2, 18.9,
25.5, 30.7, 46.9, 52.1, 68.4, 85.5, 106.2, 116.4, 117.7, 134.6, 134.9,
150.6, 191.5. Anal. Calcd for C17H27NO2S: C, 65.98; H, 8.79; N,
4.53. Found: C, 65.63; H, 8.53; N, 4.50.
(()-Ethyl 6-allyloxy-2-methyl-1-(prop-2-ynyl)-1,4,5,6-tetra-
hydropyridine-3-carboxylate (5k): colorless viscous liquid; IR
(neat) 3253.1, 2978.6, 2936.4, 2115.5, 1681.9, 1584.6, 1433.2,
1274.4, 1120.0, 1058.8 cm-1; 1H NMR (CDCl3, 250 MHz) δ 1.28
(t, J = 7.1 Hz, 3H), 1.49-1.63 (m, 1H), 2.00-2.10 (m, 1H), 2.29
(t, J = 2.4 Hz, 1H), 2.32-2.40 (m, 1H), 2.48-2.56 (m, 1H), 2.51
(s, 3H), 4.00-4.19 (m, 6H), 4.62 (t, J = 2.2 Hz, 1H), 5.15-5.37
(m, 2H), 5.88-6.15 (m, 1H); 13C NMR (CDCl3, 62.9 MHz) δ
14.9, 16.8, 18.6, 25.7, 39.6, 59.6, 68.3, 72.6, 80.2, 86.5, 100.3,
117.6, 135.1, 150.8, 169.3. Anal. Calcd for C15H21NO3: C, 68.42;
H, 8.04; N, 5.32. Found: C, 68.10; H, 7.90; N, 5.20.
General Procedure for the γ-Alkylation Reactions: Prepara-
tion of Compounds 5m-t. To a solution of the suitable 1,4,5,6-
tetrahydropyridine derivative 5 (1 mmol) in dry tetrahydrofuran
(10 mL) was added LDA [prepared from diisopropylamine
(2 equiv) and n-BuLi (1.6 M hexane solution, 2.05 equiv),
30 min, 0 °C]. The reaction mixture was stirred at -5 to 0 °C
for 30 min, and then allyl iodide or propargyl bromide
(1.1 equiv) was added. The resulting solution was stirred at
0 °C for the 2 h, and, after the completion of the reaction was
verified by TLC, a few drops of cold saturated aqueous NH4Cl
solution were added and the organic layer was concentrated to
dryness. The residue was dissolved in dichloromethane and
washed with water. The organic layer was dried over Na2SO4
and concentrated to dryness. The crude residue was chromato-
graphed on neutral Al2O3 (activity grade IV), eluting with a 98:2
petroleum ether-ethyl acetate mixture containing 0.25% Et3N.
Data for representative examples (compounds 5m and 5o)
follow. Characterization data for all compounds 5m-t can be
found in the Supporting Information.
(()-Ethyl 1-allyl-6-allyloxy-2-ethyl-1,4,5,6-tetrahydropyri-
dine-3-carboxylate (5m): colorless viscous liquid; IR (neat)
1
2979.9, 1682.3, 1574.1, 1267.6, 1175.3, 1120.7, 1050.3 cm-1; H
NMR (250 MHz, CDCl3) δ 1.17 (t, J = 7.3 Hz, 3H), 1.30 (t, J =
7.0 Hz, 3H), 1.44-1.56 (m, 1H), 2.00-2.09 (m, 1H), 2.33-2.61
(m, 3H), 3.16-3.28 (m, 1H), 3.76-3.88 (m, 1H), 4.01-4.04 (m,
2H), 4.09-4.22 (m, 3H), 4.48 (br s, 1H), 5.09-5.35 (m, 4H),
5.65-5.94 (m, 2H); 13C NMR (62.9 MHz, CDCl3) δ 13.9, 14.9,
18.6, 22.6, 25.7, 51.9, 59.3, 68.1, 85.8, 96.9, 116.4, 117.4, 135.3
(2C), 157.4, 168.8. Anal. Calcd for C16H25NO3: C, 68.79; H, 9.02;
N, 5.01. Found: C, 68.48; H, 8.95; N, 5.16.
(()-Methyl 7-Methyl-3-(1-butylvinyl)-5,9,10,10a-tetrahydro-
2H-pyrido[2,1-b][1,3]oxazepine-8-carboxylate (6l): colorless vis-
cous liquid; IR (neat) 2957.4, 2930.9, 1683.7, 1577.7, 1426.9,
1275.0, 1178.9, 1108.5 cm-1; 1H NMR (CDCl3, 250 MHz) δ 0.91
(t, J = 7.3 Hz, 3H), 1.38-1.53 (m, 2H), 1.84-1.98 (m, 2H), 2.19
(t, J = 7.4 Hz, 2H), 2.31-2.60 (m, 2H), 2.43 (s, 3H), 3.66 (s, 3H),
3.91 (d, J = 18.0 Hz, 1H), 4.24 (dd, J = 17.4, 5.9 Hz, 1H), 4.39
(d, J = 15.3 Hz, 1H), 4.48 (d, J = 15.3 Hz, 1H), 4.89-4.96 (m,
9370 J. Org. Chem. Vol. 74, No. 24, 2009

Sridharan et al.
JOCArticle
diastereoisomers A and B (7:3); IR (neat) 2956.8, 2932.8,
3H), 5.91 (dd, J = 5.1, 4.4 Hz, 1H); 13C NMR (CDCl3, 62.9
MHz) δ 14.3, 17.0, 19.8, 21.9, 27.0, 36.9, 47.8, 51.0, 65.3, 88.1,
96.9, 111.9, 125.3, 142.3, 147.0, 153.6, 169.8. Anal. Calcd for
C17H25NO3: C, 70.07; H, 8.65; N, 4.81. Found: C, 69.88; H, 8.55;
N, 4.71.
General Procedure for the Diels-Alder Reaction between
Compounds 6k,m and N-Methylmaleimide. A solution of com-
pounds 6k or 6m (1 mmol) and N-methylmaleimide (1 mmol) in
benzene (10 mL) was stirred at room temperature for 24 h. The
reaction mixture was evaporated to dryness, and the residue was
purified by II-III activity alumina chromatography, eluting
with a 75:25 petroleum ether-ethyl acetate mixture.
1679.0, 1567.4, 1416.0, 1274.7, 1097.4 cm-1
;
1H NMR
(CDCl3, 250 MHz) δ 0.87-0.99 (m, 3H, A þ B), 1.19-1.73
(m, 10H, A þ B), 2.08-2.28 (m, 2H, A þ B), 2.44 (s, 3H, A þ B),
2.61-2.70 (m, 1H, A þ B), 3.70-3.82 (m, 1H, A þ B), 3.89-3.97
(m, 1H, A þ B), 4.04-4.17 (m, 3H, A þ B), 4.60 (dd, J = 9.8, 2.3
Hz, 0.3H, B), 4.77 (dd, J = 9.6, 3.8 Hz, 0.7H, A); 13C NMR
(CDCl3, 62.9 MHz) δ 14.4, 15.0, 17.9, 18.6, 21.0, 22.6, 22.9, 23.1,
26.9, 27.9, 28.1, 29.0, 34.2, 34.4, 57.3, 57.5, 59.1, 59.2, 70.2, 70.6,
87.3, 88.3, 94.1, 95.3, 150.8, 151.8, 169.3. Anal. Calcd for
C15H25NO3: C, 67.38; H, 9.42; N, 5.24. Found: C, 67.01; H,
9.22; N, 5.13.
(()-(3aR*,7aS*,13aS*,13bR*)-Ethyl 2,11-dimethyl-1,3-dioxo-
5-propyl-2,3a,4,6,7a,8,9,13,13a,13b-decahydroisoindolo[5,6-e]pyrido-
[20,10-b][1,3]oxazepine-10-carboxylate (8a): white solid; mp 179-
180 °C; IR (neat) 2959.5, 2935.3, 1697.9, 1574.7, 1433.7, 1277.8,
1114.3, 1017.8 cm-1; 1H NMR (CDCl3, 250 MHz) δ 0.75 (t, J =
7.3 Hz, 3H), 0.98-1.12 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 1.29-1.43
(m,1H),1.57-1.70 (m, 1H), 1.91-2.01(m,2H),2.13-2.34(m,3H),
2.46-2.61 (m, 3H), 2.50 (s, 3H), 2.90 (s, 3H), 3.07 (dd, J = 8.7, 4.6
Hz, 1H), 3.18 (t, J = 7.6 Hz, 1H), 4.05-4.20 (m, 5H), 4.58 (bs, 1H),
4.74 (d, J = 14.0 Hz, 1H); 13C NMR (CDCl3, 62.9 MHz) δ 13.9,
14.9, 15.9, 18.5, 21.5, 25.2, 27.2, 30.6, 35.1, 41.3, 41.6, 44.1, 51.2, 59.5,
67.9, 90.8, 99.2, 132.9, 137.6, 150.5, 169.5, 178.6, 179.8. Anal. Calcd
for C23H32N2O5: C, 66.32; H, 7.74; N, 6.73. Found: C, 66.11; H,
7.65; N, 6.60.
Ethyl 6-methyl-3,4,9,9a-tetrahydro-2H,8H-pyrido[2,1-b][1,3]-
oxazine-7-carboxylate (10c): colorless viscous liquid; IR (neat)
2956.6, 2854.9, 1682.0, 1582.2, 1434.0, 1272.8, 1111.6, 1046.6
cm-1; 1H NMR (CDCl3, 250 MHz) δ 1.28 (t, J = 7.1 Hz, 3H),
1.43-1.50 (m, 1H), 1.69-1.98 (m, 3H), 2.36-2.47 (m, 2H), 2.38
(s, 3H), 3.15 (td, J = 13.6, 2.7 Hz, 1H), 3.86 (td, J = 11.6, 2.6 Hz,
1H), 3.98-4.09 (m, 1H), 4.12-4.17 (m, 3H), 4.54 (t, J = 3.6 Hz,
1H); 13C NMR (CDCl3, 62.9 MHz) δ 14.9, 16.7, 19.2, 26.8, 27.2,
47.0, 59.4, 68.2, 85.3, 99.6, 152.0, 169.4. Anal. Calcd for
C12H19NO3: C, 63.98; H, 8.50; N, 6.22. Found: C, 63.80; H,
8.41; N, 6.18.
Methyl 6-methyl-3,4,9,9a-tetrahydro-2H,8H-pyrido[2,1-b]-
[1,3]oxazine-7-carboxylate (10d): white solid; mp 69-70 °C; IR
(neat) 2949.0, 2853.7, 1684.0, 1581.4, 1430.5, 1274.9, 1115.5,
1047.5 cm-1; 1H NMR (CDCl3, 250 MHz) δ 1.44-1.50 (m, 1H),
1.71-1.97 (m, 3H), 2.28-2.50 (m, 2H), 2.38 (s, 3H), 3.16 (td,
J = 13.6, 2.7 Hz, 1H), 3.67 (s, 3H), 3.86 (td, J = 11.9, 2.6 Hz,
1H), 3.98-4.17 (m, 2H), 4.54 (t, J = 3.6 Hz, 1H); 13C NMR
(CDCl3, 62.9 MHz) δ 16.7, 19.2, 26.8, 27.2, 47.1, 51.1, 68.2, 85.3,
99.3, 152.4, 169.8. Anal. Calcd for C11H17NO3: C, 62.54; H,
8.11; N, 6.63. Found: C, 62.34; H, 8.00; N, 6.61.
(()-(3aR*,7aS*,13aS*,13bR*)-S-tert-Butyl 2,11-dimethyl-1,3-
dioxo-2,3a,4,6,7a,8,9,13,13a,13b-decahydroisoindolo[5,6-e]pyrido-
[20,10-b][1,3]oxazepine-10-carbothioate (8b): white solid; mp 205-
206 °C; IR (neat) 2956.1, 2920.3, 1697.7, 1537.0, 1433.0, 1313.3,
1019.7 cm-1; 1H NMR (CDCl3, 250 MHz) δ 1.17-1.30 (m, 2H),
1.50 (s, 9H), 1.55-1.75 (m, 1H), 1.98-2.06 (m, 1H), 2.14-2.59
(m, 2H), 2.45 (s, 3H), 2.73 (dd, J = 15.5, 7.2 Hz, 1H), 2.93 (s, 3H),
3.11-3.24 (m, 2H), 4.01-4.38 (m, 4H), 4.53 (s, 1H), 5.84-5.87
(m, 1H); 13C NMR (CDCl3, 62.9 MHz) δ 16.4, 19.3, 25.1, 25.4,
27.2, 30.6, 40.7, 41.0, 43.6, 47.1, 51.0, 74.1, 90.6, 108.0, 125.9,
141.2, 148.3, 178.3, 179.7, 192.2. Anal. Calcd for C22H30N2O4S:
C, 63.13; H, 7.22; N, 6.69. Found: C, 62.98; H, 7.12; N, 6.62.
General Procedure for the Three-Component Synthesis of
Compounds 10. To a stirred solution of the suitable amino
alcohol 9 (3.9 mmol, 1.3 equiv) and β-keto ester, 2 (3 mmol,
1 equiv) in acetonitrile (5 mL) was added CAN (5 mol %).
Stirring was continued for 30 min at room temperature, acrolein
(3.3 mmol, 1.1 equiv) was then added, and stirring was con-
tinued for another 1 h. After completion of the reaction, as
indicated by TLC, the mixture was diluted with CH2Cl2 (60 mL),
washed with water and brine, and dried (anhydrous Na2SO4),
and the solvent was evaporated under reduced pressure. Com-
pounds 10 were purified by rapid alumina column chromatog-
raphy on activated, neutral alumina, eluting with a petroleum
ether-ethyl acetate mixture (95:5, v/v).
tert-Butyl 6-methyl-3,4,9,9a-tetrahydro-2H,8H-pyrido[2,1-b]-
[1,3]oxazine-7-carboxylate (10e): colorless viscous liquid; IR
(neat) 2962.8, 2927.1, 1681.6, 1584.5, 1364.8, 1278.2, 1116.2,
1043.9 cm-1; 1H NMR (CDCl3, 250 MHz) δ 1.41-1.52 (m, 1H),
1.50 (s, 9H), 1.67-1.96 (m, 3H), 2.28-2.42 (m, 2H), 2.32 (s, 3H),
3.12 (td, J = 13.6, 2.7 Hz, 1H), 3.86 (td, J = 12.1, 2.6 Hz, 1H),
3.95-4.02 (m, 1H), 4.11-4.18 (m, 1H), 4.53 (t, J = 3.6 Hz, 1H);
13C NMR (CDCl3, 62.9 MHz) δ 16.8, 19.7, 26.7, 27.2, 28.9, 47.0,
68.2, 78.9, 85.4, 101.6, 150.7, 169.2. Anal. Calcd for C14H23NO3:
C, 66.37; H, 9.15; N, 5.53. Found: C, 66.11; H, 9.01; N, 5.41.
S-tert-Butyl 6-methyl-3,4,9,9a-2H,8H-pyrido[2,1-b][1,3]oxazine-
7-carbothioate (10f): viscous liquid; IR (neat) 2959.0, 2919.7,
1
1629.2, 1547.5, 1430.3, 1273.7, 1072.6 cm-1; H NMR (CDCl3,
250 MHz) δ 1.43-1.53 (m, 1H), 1.51 (s, 9H), 1.72-2.00 (m, 3H),
2.33 (s, 3H), 2.44-2.52 (m, 2H), 3.17 (td, J = 13.6, 2.7 Hz, 1H),
3.85 (td, J = 12.0, 2.6 Hz, 1H), 3.99-4.17 (m, 2H), 4.51 (t, J =
3.6 Hz, 1H); 13C NMR (CDCl3, 62.9 MHz) δ 17.2, 19.9, 27.0, 27.4,
30.6, 46.9, 47.0, 68.2, 84.9, 108.2, 149.9, 192.1. Anal. Calcd for
C14H23NO2S: C, 62.42; H, 8.61; N, 5.20. Found: C, 62.13; H, 8.41;
N, 5.03.
Ethyl 5-methyl-2,3,8,8a-tetrahydro-7H-oxazolo[3,2-a]pyridine-
6-carboxylate (10a): colorless viscous liquid; IR (neat) 2954.8,
1
2932.5, 1677.2, 1560.4, 1415.3, 1277.2, 1095.4 cm-1; H NMR
(CDCl3, 250 MHz) δ 1.27 (t, J = 7.1 Hz, 3H), 1.35-1.48 (m, 1H),
2.18-2.32 (m, 2H), 2.44 (s, 3H), 2.66-2.74 (m, 1H), 3.48-3.58
(m, 2H), 3.88-3.98 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.17-4.25
(m, 1H), 4.64 (dd, J = 9.9, 3.4 Hz, 1H); 13C NMR (CDCl3, 62.9
MHz) δ 15.0, 18.2, 21.7, 26.9, 46.2, 59.2, 66.0, 87.7, 93.9, 151.8,
169.3. Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63.
Found: C, 62.31; H, 7.99; N, 6.48.
Acknowledgment. Financial support from MCYNN (Grant
Nos. CTQ2006-10930-BQU and CTQ2009-12320-BQU) and
ꢀ
UCM (Grupos de Investigacion, Grant No. 920234) is grate-
fully acknowledged
Supporting Information Available: Copies of 1H NMR and
13C NMR spectra for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Ethyl 3-butyl-5-methyl-2,3,8,8a-tetrahydro-7H-oxazolo[3,2-
a]pyridine-6-carboxylate (10b): colorless viscous liquid, two
J. Org. Chem. Vol. 74, No. 24, 2009 9371