A facile microwave assisted synthesis of spiro-1,3-oxazines from N-(2-(cyclohex-1-en-1-yl)ethyl)amides

Article abstract of DOI:10.1016/j.tetlet.2014.06.042

A mild and efficient methodology has been developed for the synthesis of spiro-1,3-oxazine derivatives by the microwave assisted cyclization of N-2-(1′-cyclohexenyl)ethyl-acetamides/benzamides. The reaction was catalyzed by in situ generated trimethylsilyl iodide and featured by its very short reaction time. The starting materials were easily obtained by the condensation of substituted acetic/benzoic acids with 2-(1′-cyclohexenyl) ethyl amine.

Full text of DOI:10.1016/j.tetlet.2014.06.042

Accepted Manuscript
A facile microwave assisted synthesis of spiro-1,3-oxazines from N-(2-(cyclo-
hex-1-en-1-yl)ethyl)amides
Ujwal Pratim Saikia, Diganta Baruah, Pallab Pahari, Manash Jyoti Borah, Amrit
Goswami, Dilip Konwar
PII:
S0040-4039(14)01033-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.06.042
TETL 44766
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 April 2014
5 June 2014
6 June 2014
Please cite this article as: Saikia, U.P., Baruah, D., Pahari, P., Borah, M.J., Goswami, A., Konwar, D., A facile
microwave assisted synthesis of spiro-1,3-oxazines from N-(2-(cyclohex-1-en-1-yl)ethyl)amides, Tetrahedron
Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.06.042
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A facile microwave assisted synthesis of spiro-1,3-oxazines from N-(2-(cyclohex-
1-en-1-yl)ethyl)amides
Ujwal Pratim Saikia, Diganta Baruah, Pallab Pahari,* Manash Jyoti Borah, Amrit Goswami,
and Dilip Konwar*
Synthetic Organic Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat-785006, Assam,
India.
Email: ppahari@gmail.com; Tel: +913762372142; Fax: +913762370011
Keywords: Spiroxazine / Microwave assisted synthesis / Trimethylsilyl iodide
______________________________________________________________________________
Abstract: A mild and efficient methodology has been developed for the synthesis of spiro-1,3-oxazine
derivatives by the microwave assisted cyclization of N-2-(1′-cyclohexenyl)ethyl-acetamides/benzamides.
The reaction was catalyzed by in situ generated trimethylsilyl iodide and featured by its very short
reaction time. The starting materials were easily obtained by the condensation of substituted
acetic/benzoic acids with 2-(1′-cyclohexenyl)ethyl amine.
______________________________________________________________________________
1,3-Oxazine nucleus is one of the privileged heterocyclic motifs of remarkable
pharmacological importance.1 Both natural and synthetic compounds containing 1,3-oxazine
show a wide range of biological activities like analgesics,2 antibacterial,3,4 antifungal,3 anti-
malarial,5 anti-anginal,6 antihypertensive,7 acetylcholine esterase inhibition,8 anti-arthritis,9
anti-tubercular,10,11 antitumor,12 antiviral13 etc. Efavirenz (1),14 the anti-HIV drug and PA-824
(2),15 an experimental anti-tuberculosis drug contains substituted 1,3-oxazine framework in
their backbone. Recently, 1,3-oxazine derivatives were used in molecular switches,16 cyanide
detectors,17 stimulus responsive quantum dots18 etc. Besides, those compounds are also used
as intermediates in the synthesis of a broad range of heretocyclic compounds19 and polymers.20
On the other hand, spirocyclic frameworks are found in a number of different biological as well
as industrially important compounds.21 Spiro-1,3-oxazines are also well known for their
photochromic properties.22

Figure 1: Representative example of 1,3-oxazine containing bioactive compounds.
A number of different methodologies have been developed for the synthesis of 1,3-
oxazines.23,24 While classical methods of condensation of 3-aminopropanol with aldehydes or
ketones are widely used,23b-e several others like acid or base catalyzed cyclization of N-(3-
oxopropyl)amides or N-(3-hydroxypropyl)amides,23f-j insertion of carbon monoxide into N-O
bond of isoxazolidines,23k reaction of active methylenes with chloroalkyl isocyanates,23l
cycloaddition of heterocumulenes with vinyl oxetanes,23m amidoalkylation of the terminal
olefins,23n Pd(0)-catalyzed cyclization of γ-allylbenzamides24 etc. are also known. Although there
are many methods for the synthesis of 1,3-oxazines, only a few examples of preparation of
spiroxazines are reported.25 So, development of a versatile, mild and efficient method of the
synthesis of 1,3-oxazines, especially spiro-1,3-oxazines, is still important. In this context, we
report herein the synthesis of spiro-1,3-oxazines by cyclization of N-2-(1′-cyclohexenyl)ethyl-
acetamides in the presence of in situ generated TMSI under microwave irradiation.
Trimethylsilyl iodide (TMSI) is well known for its potential as an effective reagent in various
organic reactions.26

In continuation of our research work in the synthesis of isoquinoline alkaloids,27 we
were interested to prepare 1-benzylisoquinoline by cyclization of N-(2-(cyclohex-1-en-1-
yl)ethyl)-2-phenylacetamide (9). For this purpose, compound 9 was prepared by the
condensation of 2-cyclohexynylethyl amine (7) with phenylacetic acid (8) (Scheme 1). Generally
the formation of amide from acid and amine requires drastic conditions or presence of a
catalyst. But in this example the compound 9 could easily be prepared by refluxing a mixture of
7 and 8 in toluene while using a Dean-Stark apparatus to remove the water formed during the
reaction. Now, it was known that a phosphorous oxychloride (POCl3)-mediated Bischler–
Napieralski type cyclization of 9 provided 3,4,5,6,7,8-hexahydro-1-benzylisoquinoline. For a
milder alternative trimethylsilyl chloride (TMSCl) was selected as a catalyst. When a mixture of
9 and TMSCl was refluxed in CH3CN for 6 h (Entry 1, Table 1), the reaction produced a colourless
solid compound after purification. A detailed spectroscopic analysis of the compound showed
that spiro-1,3-oxazine 10 was produced instead of isoquinoline. The structure of the compound
1
13
13
was confirmed by H and C NMR analysis. In the C spectra there was a quaternary carbon
peak at 74.7 ppm which suggested the existence of an oxygenated carbon centre of spiro-oxa
skeleton. The mass spectral data also corroborated the deduced structure. To improve the yield
the reaction was carried out using TMSBr and TMSI, prepared in situ from TMSCl by the
addition of KBr and KI, respectively (Entries 2-3, Table 1). It was observed that the best yield of
the product (62%) was obtained when TMSI was used. The best solvent was found to be
acetonitrile26a and other solvents like chloroform, dichloromethane, toluene, or water gave
very low yield of the product (Entry 4-7, Table 1). In the absence of TMSCl the reaction failed to
produce any products. For further improvement the reaction was carried out under microwave
heating condition (Entries 8-9, Table 1). In this context, it is to be noted that the microwave
irradiation often leads to the dramatic acceleration of the rate of the reaction along with the
increased products yields due to the direct absorption of microwave energy by the reactive
species.28 In the studied example, the reaction was complete within 1 minute with very good
yield (83%) under microwave irradiation (Entry 9, Table 1).

Scheme 1. Synthesis of N-2-(1′-cyclohexenyl)ethyl-2-phenylacetamide (9) and it’s cyclization
Table 1. Optimization of the spirocyclization reaction condition.
Entry
Reagentsa
TMSCl
Solvents
CH3CN
CH3CN
CH3CN
CHCl3
Conditions
100 °C
Time
6 h
Yield (%)b
1
2
3
4
5
6
7
8
9
40
43
62
35
30
33
30
83
83
TMSCl-KBr
TMSCl-KI
TMSCl-KI
TMSCl-KI
TMSCl-KI
TMSCl-KI
TMSCl-KI
TMSCl-KI
100 °C
12 h
6 h
100 °C
100 °C
6 h
CH2Cl2
Toluene
H2O
100 °C
8 h
100 °C
8 h
100 °C
8 h
CH3CN
CH3CN
µW, 100 °C
µW, 80 °C
10 min
1 min
a1.5 equivalents of each of the TMSCl and potassium salts were used.
bYields refer to isolated yield of the products.

After optimization of the conditions,29 the applicability of the reaction towards different
substrates was studied. N-2-(1′-cyclohexenyl)ethyl-2-(4-methoxyphenyl) acetamide (11) was
prepared by the condensation of 7 and 4-methoxyphenylacetic acid. A cyclization of 11 under
microwave heating condition produced the corresponding spiroxazine derivative 12 in 86%
yield. It has to be noted that the reaction was selective and no demethylation product was
observed. Similarly, dimethoxy benzyl derivative 13 produced the corresponding spiroxazine 14.
In order to evaluate the effect of an electron withdrawing group in the substrate, two nitro
containing amides 15 and 17 were subjected to cyclization reaction. In both the cases
spirocyclic compounds 16 and 18 were formed in 80% and 78% yield, respectively. The styrene
substituted spiroxazine 20 was prepared using a similar cyclization of cinnamyl amide 19. To
widen the scope of the reaction, the benzamide derivatives 21, 23, and 25 was prepared by the
condensation of corresponding acid chlorides with amine 7. In these examples the benzamides
could not be prepared by the direct dehydrative condensation of acid and amine. The
spirocyclization of benzamides produced benzene, p-bromobenzene, and pyridine substituted
spiroxazines 22, 24, and 26, respectively. All compounds were well characterized by their 1H, 13C
NMR as well as mass spectroscopic data.
Table 2. Synthesis of spiro-1,3-oxazine derivatives
Entry
Substrates
Products
Time
(min)
1
Yield (%)a
83
1
2
1
86

3
4
1
5
89
80
HN
O
13
OMe
OMe
5
6
5
2
78
75
7
8
2
2
85
83

9
5
70
aYields refer to isolated yield of the products.
Regarding the mechanism of the reaction, TMSI is proposed to react with amide to form
HI which protonates the double bond of cyclohexene. The iodide promoted N-desilylation leads
to the spirocyclization via carboximidic acid tautomer of amide 30 (Scheme 2).
Scheme 2. Plausible mechanism of spirocyclization
In conclusion, a mild and efficient methodology has been developed for the synthesis of
spiro-1,3-oxazine derivatives using a TMSI mediated cyclization of N-2-(1′-cyclohexenyl)ethyl-
acetamides/benzamides. While TMSI is known to cleave the C-O bond of ethers and esters to
the corresponding alcohols or halides, in this report it is used in C-O bond forming reaction. A
very short reaction time, clean reaction profile, and mild conditions constitute the significant
features of the synthesis. Application of the methodology in the synthesis of different
biologically and industrially important compounds is underway.

Acknowledgments
The work is financially supported by CSIR, New Delhi through the grant HCP0001, CSC0125, and
MLP3000/03. The authors thank analytical facility CSIR-NEIST for recording the spectral data.
The authors are also thankful to Ms. Sampurna Bordoloi for carrying out some initial
experiments.
Supplementary data
Supplementary information containing the detailed experimental procedure and the
characterization data of all the synthesized compounds can be found in the online version.
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29. General Procedure for the preparation of 3,4,5,6,7,8-hexahydroisoquinolines : TMSCl (1.5
mmol) and KI (1.5 mmol) was dissolved in CH3CN (3 mL) in a 10 mL microwave reaction vial. The
mixture was allowed to stir for 15 min when a deep yellow color generated. The amide (1
mmol) dissolved in CH3CN (3 mL) was added. Sealed with a Teflon septum, the mixture was

heated under microwave at 80 °C for 1 minute. After cooling, excess ammonia was added to
neutralize the solution and the CH3CN was removed in vacuum. The mixture was extracted with
ethyl acetate (2 × 20 mL) and the combined organic layer was washed with water, sodium
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Graphical Abstract
A facile microwave assisted synthesis of spiro-1,3-oxazines from N-(2-(cyclohex-
1-en-1-yl)ethyl)amides
Ujwal Pratim Saikia, Diganta Baruah, Pallab Pahari,* Manash Jyoti Borah, Amrit Goswami,
and Dilip Konwar*