A new approach to 1,4-oxazines and 1,4-oxazepines via base-promoted exo mode cyclization of alkynyl alcohols: Mechanism and DFT studies

Article abstract of DOI:10.1021/ol301219c

A new approach was developed to synthesize 1,4-oxazine and 1,4-oxazepine derivatives without solvent and metal. Regioselective cyclization occurred to afford exclusively the exo-dig product, and stereochemistry was studied by circular dichroism and specif

Full text of DOI:10.1021/ol301219c

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3134–3137
A New Approach to 1,4-Oxazines and
1,4-Oxazepines via Base-Promoted Exo
Mode Cyclization of Alkynyl Alcohols:
Mechanism and DFT Studies
Jaya Kishore Vandavasi,† Wan-Ping Hu,‡ Hsing-Yin Chen,† Gopal Chandru Senadi,†
Chung-Yu Chen,§ and Jeh-Jeng Wang*,†
Departments of Medicinal and Applied Chemistry, Biotechnology, and Pharmacy,
Kaohsiung Medical University, Kaohsiung, Taiwan
jjwang@kmu.edu.tw
Received May 4, 2012
ABSTRACT
A new approach was developed to synthesize 1,4-oxazine and 1,4-oxazepine derivatives without solvent and metal. Regioselective cyclization
occurred to afford exclusively the exo-dig product, and stereochemistry was studied by circular dichroism and specific optical rotation
techniques. The Grignard reaction is a key synthetic step to produce high diastereomeric compounds via Cram’s rule and was well supported by
DFT calculations. A hydroalkoxylation mechanism was proposed and supported by DFT calculations.
The design andsynthesisofappropriately desired, quick,
and tolerable methods to attain the architectural complex
molecules from simple starting materials is challenging
work in modern synthetic and medicinal chemistry. The
method for the synthesis of compounds containing nitro-
gen and oxygen in a cyclic ring is of growing importance by
virtue of such molecules being present in numerous biolo-
gically important compounds.1 In particular, much work
has been dedicated to design the most effective routes to
cyclic compounds. The addition of various OꢀH nucleophiles
to carbonꢀcarbon (CꢀC) multiple bonds represents one
of the great methods for preparing such oxygen-containing
heterocycles.2ꢀ4 However, due to somany factors including
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† Department of Medicinal and Applied Chemistry.
‡ Department of Biotechnology.
§ Department of Pharmacy.
ꢀ
Ballesteros, A.; Gonzalez, J. M. J. Am. Chem. Soc. 2003, 125, 9028–
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r
10.1021/ol301219c
Published on Web 06/04/2012
2012 American Chemical Society

the relatively high bond enthalpies of most OꢀH σ-bonds
and the modest reactivity of electron-rich olefins with
nucleophiles, an efficient intramolecular hydrofunctiona-
lization reaction remains a challenge. For intramolecular
alkynyl alcohol hydroalkoxylations, their exist two possi-
ble compounds elucidated by the exo and endo-enol ethers,
as shown in Figure 1, where either exo-dig or endo-dig
cyclization affords six- or seven-membered rings according
to the Baldwin rules.2a Metal catalysis represents a new
frontier in this regard, and there exists plenty of methods to
achieve such conversions. Yamamoto and co-workers
reported the coinage metal-assisted synthesis of hetero-
cycles from various substrates via CꢀO bond formation.3
However, unlike addition of other nucleophiles, analogue
addition of OH functionality across CꢀC triple bonds is
supposed to be difficult due to their poor nucleophilicity of
the hydroxyl group. Unfortunately, the formation of
seven-membered rings by metal catalysts is not common
compared to five- and six-membered rings. In addition,
very expensive catalysts are known to catalyze such pro-
cesses. Considering these aspects, we sought to develop a
new method which overcomes these issues. Herein, we
report a metal as well as a solvent-free protocol for the
hydroalkoxylation of alkynyl alcohols with NaH under
very mild conditions.
Table 1. Optimization Reaction Conditions for Cyclizationa
SN
base
solvent
time
4 h
temp (°C)
yield (%)
1
2
K2CO3
Na2CO3
Cs2CO3
t-BuOK
NaH
DMF
DMF
DMF
DMF
DMF
130
130
130
130
110
80
32
12 h
6 h
traces
26
3
4
4 h
traces
41
5
4 h
6
DBU
4 h
0
7
DABCO
NaH
4 h
80
0
8
THF
4 h
reflux
reflux
reflux
110
110
110
110
70
traces
34
9
NaH
toluene
CH3CN
DMF
4 h
10
11b
12
13b
14
15
16
NaH
4 h
37
NaH
4 h
55
NaH
1 h
75
NaH
1 h
76
NaH
30 min
40 min
4 h
57
NaH
94
NaNH2
70
41
a Reactions were performed with 1 equiv of base unless otherwise
noted. b Reactions were performed with 2 equiv of base.
the exo mode cyclization with compound A1 from alkynyl
alcohols with metals such as Au,11 Ru,12 Pd,13 Ga,14 Pt,15
and base16,17 such as sodium amide was reported; the
reaction involves more steps to convert into the exocylic
product with high temperature and prolonged reaction
times, and the reaction was not explored well with various
substrates, even though we performed our reaction with
sodium amide. Unfortunately, the reaction was not con-
trolled at that temperature, and it was decomposed.
Endo mode cyclization with alkynyl alcohols was reported
with metals such as Os,18 W,19 Ru,20 Rh,21 Mo,22 and
others.
Figure 1. Three possible cyclized intermediates.
Earlier reports explored the synthesis of exocylic as well
as endocyclic ring formation from various starting materi-
als in the presence of metal or Lewis acids or bases,6
whereas in most cases, the exo mode cyclization has given
the A2 compound from alkynyl alcohols with lanthanide
catalysts,5 W,6 Au,7 Ag,8 Cu,9 and base.10 In a similar way,
We designed our route starting from amino acids to
synthesize the oxazine and oxazepine derivatives. To the
best of our knowledge, such a route has not been docu-
mented, and to date, NaH has not been exploited as a
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Org. Lett., Vol. 14, No. 12, 2012
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Table 2. One Chiral Center of 1,4-Oxazines
Figure 2. Grignard reagent attack on carbonyl group of D and L
forms of alanine derivatives. For clarity, the tosyl group sub-
stituent is represented in wireframe.
a The L form. b Racemic. c The D form.
reagent without solvent for the synthesis of 1,4-oxazine
and 1,4-oxazepine derivatives2bꢀf with high regioselectiv-
ity at moderate temperature with less reaction time from
N-tosyl amide derivatives.
Herein, we report the stereospecific synthesis of oxazines
with one chiral center (Table 2) as well as with two chiral
carbon centers (Figure 3). The investigation of this reac-
tion started with amino acid derivative N-(2 hydroxy-1-
methylethyl)-4-methylbenzenesulfonamide 9 to obtain
compound 4. The reaction was optimized with various
bases, whereas the best condition was observed in the
presence of NaH without solvent at 70 °C for 40 min as
itproducedthedesiredcompound withexcellent94% yield
(Table 1, entry 15). With this optimized condition in hand,
we explored the scope of the reaction with different amino
acid derivatives. In Table 2 with various substituents, the
cyclization was successful with high yields. The D and L
forms of alanine derivatives were afforded in excellent
yields, 94 and 91% (entries 1 and 8). An isobutyl chain
on an adjacent carbon of nitrogen resulted in high yields,
78 and 86%, with D and L forms (entries 2 and 9). By
replacing the isobutyl with isopropyl, entry 5 produced a
satisfactory yield of 72%. The benzyl group also produced
the desired compound in a high yield of 85% (entry 3), and
substitutedalkynes gavemoderate yields, 59ꢀ64% (entries
4, 6, 7, and 10). All of the reactions were well tolerated to
afford the desired compound 4 in moderate to excellent
yields.
Figure 3. Two chiral centered 1,4-oxazines. aL form. bD form.
The desired diastereomeric alcohols were obtained from
the aldehydes via the Grignard reaction (see the Support-
ing Information). Herethe stereoselectivity wasinduced by
the adjacent carbon stereochemistry which was studied in
detail by the Cram’s rule23 application (see the Supporting
Information), and density functional theory (DFT)
calculations24 (Figure 2) were employed to rationalize the
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Org. Lett., Vol. 14, No. 12, 2012

Figure 4. 1,4-Oxazepines.
chiral properties of the products. To examine the origin of
the observed stereospecificity, we calculate the D and
L form amino acid derivatives attacked by the nucleophile.
The DFT results show that if the starting amino acid
derivative is in the D form, the resultant (R,S) intermediate
will be more stable than the (R,R) by ca. 8 kcal/mol, and
vice versa (Figure 2), consistent with the experimental
observation. Inspection of the optimized structures clearly
reveals that the stereospecificity arises from the steric
hindrance given by the alkyne group adjacent to the
nitrogen atom.
With various functional groups, the two chiral centered
molecules were also afforded in moderate to high yields
(Figure 3) with the same reaction conditions, whereas with
fluoro and methyl groups, the yields were low compared
to the other functional groups (compounds 3j, 3n, 3o, 3s,
and 3t). The stereochemistry of compounds with one chiral
center and two chiral center molecules was studied by
circular dichroism and specfic optical rotation (see the
Supporting Information).
The 7-exo-dig cyclization also proceeded smoothly to
give 1,4-oxazepine derivatives with the same method
(Table 1, entry 15) from β-amino acid derivatives. Mod-
erate to high yields were obtained withvarious substituents
(Figure 4). 1,4-Oxazine and 1,4-oxazepine derivatives were
screened against various cancer cell lines, and promising
results were observed with compound 4c against MCF-7
cell lines (see the Supporting Information).
Figure 5. Mechanism and M06-2X/6-31þG* free energy profile.
9.4 kcal/mol, while the analogous process along path B is
endergonic (6.0 kcal/mol) with a relatively high energetic
barrier of 18.2 kcal/mol. All these computational results,
in terms of both thermodynamic and kinetic points of
view, support mechanism A as the dominant reaction
pathway.
The exo-dig cyclization was proposed in two possible
pathways, which are sketched in Figure 5: route A pro-
ceeds via the formation of the allene intermediate, 1Db,
followed by nucleophilic attack, whereas in route B, direct
attack of nucleophile takes place on the acetylene inter-
mediate, 1Dd. On the basis of DFT calculations (Figure 5),
the allene intermediate was found to be 0.9 kcal/mol lower
than the acetylene intermediate, indicating that the equili-
brium is shifted in the former. The DFT results further
point out that the cyclization reaction along path A is
an exergonic process (ꢀ12.0 kcal/mol) with a barrier of
In summary, we have developed a highly efficient and
convenient method to synthesize the regio- and stereo-
selective 1,4-oxazine and 1,4-oxazepine derivatives with-
out metal and solvent and exo-dig cyclization supported by
DFT calculations.
Acknowledgment. We thank the National Science Coun-
cil of the Republic of China for financial support. This work
was also supported by a grant from the Kaohsiung Medical
University Research Foundation.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds
and biological data provided. This material is available
free of charge via the Internet at http://pubs.acs.org.
(23) (a) Chen, X.; Hortelano, E. R.; Eliel, E. L. J . Am. Chem. Soc.
1990, 112, 6130–6131. (b) Chen, X.; Hortelano, E. R.; Eliel, E. L.; Frye,
S. V. J. Am. Chem. Soc. 1992, 114, 1778–1784.
(24) Density functional theory of M06-2X/6-31þG* level was used
for geometry optimizations and frequency analyses in this work. The
free energy corrections were made at the condition of 1 atm, and all
calculations were performed using Gaussian 09 package.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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