Stereo-, Regio-, and Chemoselective [3 + 2]-Cycloaddition of (2E,4E)-Ethyl 5-(Phenylsulfonyl)penta-2,4-dienoate with Various Azomethine Ylides, Nitrones, and Nitrile Oxides: Synthesis of Pyrrolidine, Isoxazolidine, and Isoxazoline Derivatives and a Computational Study

Article abstract of DOI:10.1021/acs.joc.5b02845

One-pot chemo-, regio-, and stereoselective synthesis of series of heterocyclic and spiroheterocyclic compounds was accomplished through mono- and bis[3 + 2]-cycloaddition reactions of (2E,4E)-ethyl 5-(phenylsulfonyl)penta-2,4-dienoate as a dipolarophile with azomethine ylides, nitrones, and nitrile oxides in good yields. The structures of the products were established by spectroscopic techniques as well as by single-crystal XRD study, and DFT calculations were performed to further understand the mechanism of this [3 + 2]-cycloaddition reaction.

Full text of DOI:10.1021/acs.joc.5b02845

Subscriber access provided by - Access paid by the | UCSB Libraries
Article
Stereo, Regio and Chemoselective [3+2]-Cycloaddition of (2E,4E)-
Ethyl 5-(Phenylsulfonyl) Penta-2,4-Dienoate with Various Azomethine
Ylides, Nitrones and Nitrile Oxides - Synthesis of Pyrrolidine,
Isoxazolidine and Isoxazoline Derivatives and A Computational Study
Ulaganathan Sankar, Ch. Venkata Surya Kumar, Venkatesan
Subramanian, Kuppuswamy K. Balasubramanian, and Susrla Mahalakshimi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02845 • Publication Date (Web): 17 Feb 2016
Downloaded from http://pubs.acs.org on February 18, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Stereo, Regio and Chemoselective[3+2]ꢀCycloadditionof (2E,4E)ꢀ
Ethyl
5ꢀ(Phenylsulfonyl)Pentaꢀ2,4ꢀDienoatewith
Various
Azomethine Ylides, Nitrones and Nitrile Oxidesꢀ Synthesis of
Pyrrolidine,Isoxazolidine and IsoxazolineDerivatives and A
Computational Study
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
UlaganathanSankara,Ch. Venkata Surya Kumarb, V. Subramanianb*, K. K. Balasubramanianc*and S.
Mahalakshimia
aDepartment of Chemistry, Pachaiyappa’s College, University of Madras, Chennai 600030, India.
bChemical Laboratory, CSIRꢀCentral Leather Research Institute, Adyar, Chennai 600020, India.
cINSA Senior Scientist,Department of Chemistry, Indian Institute of Technology Madras, Chennai 600020,India.
Email: kkbalu@hotmail.com, subuchem@hotmail.com
ABSTRACT:One pot chemo, regio and stereoselective synthesis of series of heterocyclic and spiroheterocyclic
compounds were accomplished through mono and bis[3+2]ꢀcycloaddition reaction of (2E, 4E)ꢀethyl 5ꢀ(phenylsulfonyl)
pentaꢀ2, 4ꢀdienoate as a dipolarophile with azomethine ylides,nitrones and nitrile oxides in good yields. The structure of the
products were established by spectroscopic techniques as well as by single crystal XRD study and DFT calculation was
performed to further understand the mechanism ofthis[3+2]ꢀcycloaddition reaction.
O
O
O
S
O
O
O
O
O
O
S
O
O
O
O
O
S
O
N
R
2 examples
R
O
5 examples
O
O
N
N
2 examples
R
N
1,4-dioxane,
Reflux, 10 h
O
H
1,4-dioxane,
Reflux, 10-48 h
N
N
R
OH
DCM, rt,
16 h
R
Ninhydrin
O
R
O
H
O
O
O
S
N
H
O
N
O
S
R
OH
N
O
R
OH
O
O
S
Acenapthoquinone
Isatin
O
O
O
O
O
R
1,4-dioxane,
Reflux, 10-48 h
1,4-dioxane,
Reflux, 10-48 h
HN
N
R
O
5 examples
5 examples
TFA, Microwave,
DCM, 80 °C, 30 min
O
N
R
Si
O
R
O
R'
N
O
H
H
O
S
H
H
H
O
H
O
N
O
H
S
N
H
R
R'
6 examples
6:4 inseperable diastereomers
R
O
N
R
INTRODUCTION
The [3+2]ꢀcycloaddition, also known as the Huisgen cycloaddition,1a is a classical and fundamental reaction in organic
chemistry, involving the reaction of 1,3ꢀdipoles with olefinic or acetylenic dipolarophiles leading to production of various
heterocyclic scaffolds which are particularly useful for the creation of diverse chemical libraries of drugꢀlike molecules for
biological screening.1–5There has been tremendous activity in this area since the discovery of clickreaction.5fFunctionalized
pyrrolidines, isoxazolidines and pyrrolizidines with spirooxindoles ring systems are the central skeletons for numerous
alkaloids and pharmacologically important compounds.6Isoxazolidine unit constitutes an easily accessible nucleus that is
present in a number of natural and pharmacological compounds and displays a wide range of biological activity.
Isoxazolidines are masked γꢀamino alcohols. The NꢀO bond in isoxazolidines can be reductively cleaved to γꢀ amino
alcohols which are present in a wide range of biologically active compounds.7Spiroheterocyclic compounds represent an
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 21
1
2
3
4
5
6
7
8
9
important class of naturally occurring substances characterized by highly pronounced biological properties. Gelesmine,
pseudotabersonine, isoformosanine, and mitraphylline are some of the alkaloids containing spirooxindole ring
systems.8Of particular interest, spiropyrrolidinyloxindole ring systems are also found in a number of alkaloids such as
horsifiline, spirotryprostatine A and B, and elacomine etc.9Derivatives of spirooxindoles find very wide biological
applications as antiꢀmicrobial, antiꢀinflammatory, antiꢀtumourals, antiꢀbiotic agents and inhibitors of human NKꢀ1
receptors.10Hence, there has been renewed interest in the synthesis of spirooxindoles.11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RESULTS AND DISCUSSION
Sulfonyl dienes like 1ꢀarylsulphonyl 4ꢀsubstitutedꢀE,Eꢀ1,3ꢀdienes have attracted considerable attention as dipolarophiles and
in many cases they have been transformed into synthetically useful cycloadducts via chemoselective[3+2]ꢀcycloaddition.12aꢀ
cAmalrajet al13aand Rusilet al13b have reported the [3+2]ꢀcycloaddition of various azomethine ylides to dipolarophiles
containing exocyclic double bonds.Recently Tanmayaet al13creported the DFT calculations of regioselective [3+2]ꢀ
cycloaddition of vinyl sulfones with sugarazides. Houket al14 have reported the HOMOꢀLUMO calculation for a number of
electronegative alkenes. According to their FMO theory of calculation, the orbital coefficient of LUMO for ethyl acrylate is
larger than that of phenyl vinyl sulfone, and carboxylate is a more powerful electron withdrawing group compared to that of
phenyl sulphonyl group. Based on this, one can expect that in the case of the mono cycloaddition reaction of 1ꢀarylsulphonyl
4ꢀsubstitutedꢀE, Eꢀ1, 3ꢀdienes to azomethine ylides, might exhibit high chemoselectivity and that the reaction would occur at
the acrylate double bond rather than at the vinyl sulphone double bond. In fact we had observed this chemo selectivity in the
case of [3+2]ꢀcycloaddition of simple acyclic azomethine ylides15to 1ꢀarylsulphonyl 4ꢀsubstitutedꢀE, Eꢀ1, 3ꢀdienes. We have
recently observed that the chemo selectivity is dictated by the nature as well as by the steric bulk of the ylide (Scheme 1). In
the case of azomethine ylides, the chemoselectivity could be tuned in favour of the vinyl sulphonyl double bond by changing
its size which is also predicted by our DFT calculations.
Scheme 1.Synthesis of spiropyrrolidines (4aꢀe)a,b,c via [3+2]ꢀcycloaddition of diene 1and ninhydrin3 with various Nꢀ
substituted glycine2aꢀe.
O
H
N
O
6
R
OH
2a-e
O
O
7
OH
O
S
8
O
2
3
O
3
1
N
O
S
OH
4
O
O
O
5
O
O
S
O
24a-c
N
Si
O
1,4 dioxane, Reflux
10-48 h
R
4a-e
O
R'
N
R'
O
1
15
previous work15
O
O
O
R' = -Bn, t-But, Cp
O
S
2a, R = -Me; 2b, R = -Et; 2c, R = -Bn;
2d, R = -Ph; 2e, R = -Tr
O
O
S
O
O
S
O
O
O
O
O
(or)
O
O
O
(or)
N
N
R
N
R
R
O
O
O
6a-e
5a-e
7a-e
O
O
O
O
O
O
O
S
O
O
O
S
O
O
S
O
O
N
O
N
N
O
Me
O
Et
O
Bn
4a, 82% (10 h)
4c, 70% (10 h)
4b, 83% (10 h)
O
O
O
O
O
O
O
S
O
S
O
O
N
N
O
Ph
O
Tr
4d, 32% (48 h)d
4e, NR (48 h)e
aAll reactions were carried out with1(1 mmol), 3 (1 mmol) and 2aꢀe(1 mmol) in 1, 4ꢀdioxane (10 mL) at reflux for 10ꢀ48 h. bIsolated yield
of the pure product. cAll the compounds were fully characterized by their spectroscopic data (1H NMR, 13C NMR, and HRMS). dcrude LCꢀ
MS yield. eNoreaction.
2
ACS Paragon Plus Environment

Page 3 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
In this publication, we describe a stereo and regioselective route for the synthesis of highly functionalized pyrrolidines based
on chemoselective [3+2]ꢀcycloaddition of azomethine ylides generated from Nꢀalkylꢀαꢀamino acids and cyclic ketones to
(2E, 4E)ꢀethyl 5ꢀ(phenylsulphonyl)pentaꢀ2,4ꢀdienoate and present also the conclusions derived from the DFT calculations of
this cycloaddition reaction. Azomethine ylides can be generated a number of methods16among which the decarboxylation
route offers a convenient method for the synthesis of pyrrolidines. We first investigated the one pot [3+2]ꢀcycloaddition
reaction of (2E, 4E)ꢀethyl 5ꢀ(phenylsulfonyl) pentaꢀ2,4ꢀdienoate 115 with dipoles generated insitu from sarcosine 2 and
ninhydrin3 as outlined in Scheme 1. A clean reaction was observed when 1 was refluxed in 1,4 dioxane for 10 h with
sarcosine and ninhydrin without any catalyst, affording 4a as the only cycloaddition productin very good yield (Scheme 1).
LCꢀMS analysis of the crude product did not indicate the presence of any isomeric products like 5a, 6a and 7a(Scheme 1).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
The cycloadduct 4a was characterized by H NMR,13C NMR spectra, HRMS, and Xꢀray single crystal analysis.17 The
reaction of 1 with insitugenerated azomethine ylides from ninhydrin and ethylglycine orbenzylglycine orphenylglycine
ortritylglycine (2bꢀe) in refluxing 1,4 dioxane (10ꢀ48 h) afforded the corresponding cycloadduct, viz., of (E)ꢀethyl 3ꢀ(1'ꢀ
alkylꢀ1,3ꢀdioxoꢀ4'ꢀ(phenylsulfonyl)ꢀ1,3ꢀdihydro spiro [indeneꢀ2,2'ꢀpyrrolidine]ꢀ3'ꢀyl)acrylate 4bꢀe (Scheme 1) in good
yield.We couldnotdetect the presence of the other regioisomers5aꢀe, 6aꢀe and 7aꢀe, in any of the cases when the crude
1
products were analysed by LCꢀMS. While it was easy to rule out the alternative structures from H, 13C, DEPT, COSY
andHMBC spectral data, the relative stereochemistry at the spirocentreC2 in the cases of 4aꢀe could not be deduced from the
NMR data. However, it could be fixed from the single crystal Xꢀray data of 4a(Refer in supporting information (SI)).
Scheme 2.Substrate scope forsynthesis of Spirooxindoles(9aꢀe)a,b,c
O
O
O
S
O
HN
N
O
9a-e
O
R
1,4 dioxne, Reflux
10-48 h
1
2a-e
O
O
N
S
8
H
O
N
O
O
R = -Me, -Et, -Bn, -Ph, -Tr
(or) other
isomers
10a-e
HN
R
O
O
O
O
O
O
O
O
S
O
S
O
S
O
O
O
HN
HN
HN
N
N
N
O
Bn
9a, 80% (10 h)
9c, 75%, (10 h)
O
O
9b, 82%, (10 h)
Me
Et
O
O
O
O
O
S
O
O
S
O
HN
HN
N
N
9d, 30%, (48 h)d
O
Ph
O
9e, NR (48 h)e
Tr
aAll reactions were carried out with1(1 mmol), 8 (1 mmol) and 2aꢀe(1 mmol) in 1, 4ꢀdioxane (10 mL) at reflux for 10ꢀ48 h.bIsolated yield of
the pure product. cAll the compounds were fully characterized by their spectroscopic data (1H NMR, 13C NMR, and HRMS). dcrude LCꢀMS
yield. eNoreaction.
Similarly the reaction of 1 with insitu generated azomethine ylides from isatin 8 and sarcosine orethylglycine or
benzylglycine or phenylglycine or tritylglycine (2aꢀe) in refluxing 1, 4 dioxane furnished respectively the cycloadducts9aꢀ
e,17 in good yield (Scheme 2). The reaction was highly chemo, stereo and regio selective in all cases, occurring only at the
vinylsulphone double bond.Similarly, azomethine ylides generated from acenaphthenequinone reacted smoothly and yielded
the spiropyrrolidine 12aꢀein good yields (Scheme 3). The chemo selectivity observed in the present case is in contrast to that
observed in the case of acyclic azomethine ylide generated through desilylative method.15
Scheme 3.Substrate scope for synthesis ofspiropyrrolidines(12aꢀe)a,b,c
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 21
1
2
3
4
5
6
7
8
9
O
O
S
N
O
O
O
12a-e
R
O
O
1,4 dioxne, Reflux
10-48 h
1
2a-e
O
O
O
S
OO
11
R = -Me, -Et, -Bn, -Ph, -Tr
(or) other isomers
N
R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
13a-e
O
O
O
O
S
O
S
N
O
S
N
O
O
O
O
O
O
O
O
O
N
Bn
Et
Me
12b, 70% (10 h)
12a, 78% (10 h)
12c, 75% (10 h)
O
O
O
S
N
O
S
N
O
O
O
O
O
O
Ph
Tr
12d, 24% (48h)d
12e, NR (48 h)e
aAll reactions were carried out with1 (1 mmol), 11 (1 mmol) and 2aꢀe (1 mmol) in 1, 4ꢀdioxane (10 mL) at reflux for 10ꢀ48 h.bIsolated yield
of the pure product. cAll the compounds were fully characterized by their spectroscopic data (1H NMR, 13C NMR, and HRMS). dcrude LCꢀ
MS yield. eNoreaction.
The chemo selectivity in the case of acyclic azomethine ylides generated by the desilylative method15was not altered when
the same ylide was generated by the decarboxylative method (Scheme 4), indicating that the chemo selectivity is not
influenced by the mode of generation of the ylide but is purely governed by the steric factors associated with the azomethine
ylides. This inference has been supported by DFT calculations also which clearly reveals that chemo selectivity of
cycloaddition is determined by the steric bulk of azomethine ylide.
Scheme 4.Synthesis of pyrrolidine15avia [3+2]ꢀcycloaddition of diene
paraformaldehyde
1 and Nꢀbenzyl glycine 2c with
O
O
S
O
O
15
N
78% yield
O
Paraformaldehyde
H
Bn
N
1
Bn
OH
1,4 dioxane, Reflux
10 h
2c
O
O
N
O
S
O
14
Bn
aA reaction was carried out on 1 (1 mmol), paraformaldehyde (2 mmol) and 2c (1 mmol) in 1,4ꢀdioxane (10 mL) atreflux for 10 h. The
b
product was fully characterized by its spectroscopic data (1H NMR, 13C NMR, and HRMS).
Scheme 5.Attempted Synthesis of spiropyrrolidines (17aꢀe, 19aꢀe)a via [3+2]ꢀcycloaddition of diene 1 and Nꢀalkyl
glycine2aꢀe with benzil 16 or cyclohexanone 18.
O
O
O
O
1,4 dioxne,
Reflux, 48 h
O
S
O
O
S
N
1
O
O
O
O
18
H
N
O
N
1,4 dioxne,
Reflux, 48 h
R
OH
2a-e
19a-e
R
R
17a-e
O 16
aAll the reactions were carried out with diene 1 (1 mmol), benzil16orcyclohexanone 18(1 mmol)and 2aꢀe(1 mmol)in 1,4ꢀdioxane (10 mL) at
reflux for 10ꢀ48 h.
4
ACS Paragon Plus Environment

Page 5 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
We studied the reaction of 1 with insitu generated azomethine ylides from ninhydrin3 and sarcosine 2ain various solvents
viz., toluene, methanol, 1, 4ꢀdioxane and acetonitrile. 1, 4ꢀdioxane was found to be the best in terms of yield, chemo, regio
and stereoselectivity. Strangely there was no reaction in the case of tritylglycine even after 48 h and in the case of
phenylglycine the yields of the cycloadduct 4d, 9d and 12d were rather low (20ꢀ24%). While isatin, ninhydrin and
acenaphthenequinone showed good reactivity, cyclohexanone and benzil, did not react under these conditions (Scheme 5).
An attempt to react the mono cycloadduct 4a with one more or excess equivalent of the azomethine ylide to get the
bisadduct was in vain even after prolonged heating (48 h).With a view to explore the scope of this [3+2]ꢀcycloaddition and
also to find out whether the same chemoselectivity will be encountered in the case of other kinds of 1,3ꢀdipoles, we
investigated the reactionof 1with nitrones20aꢀband nitrile oxides precursor 22aꢀb.18a In the event, we were surprised to note
that while the cycloaddition in the case of nitrones occurred at the vinyl sulphonyl double bond, in the case of nitrile oxides
it was the acrylate double bond that participated in the cycloaddition as outlined in Scheme 6.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6.Substrate scope for synthesis of Isoxazolidines21aꢀba,b and Isoxazolines23aꢀba,b
O
O
8
O
6
S
4
O
21a-b
5
7
O
3
N
1
2
N
O
R
O
S
R
20a-b
9
O
70 ºC, 1,4-dioxane
10 h
O
O
1
O
O
8
3
O
6
S
5
4
O
7
NCS, KHCO3
DCM, rt, 16 h
1O
2
N
21'a-b
R
9
R
N
OH
22a-b
21a (R= -H) = 56% isolated yield
21b (R= -F) = 65% isolated yield
O
5
O
O
4
O
O
O
7
8
7
S
8
S
4
5
O
6
O
6
3
1
2 O
N
R
3
1O
2
N
23a-b
23a'-b'
R
23a (R= -H) = 60% isolated yield
23b (R= -F) = 63% isolated yield
aReaction condition for nitrone cycloaddition:All the reactions were carried out on diene 1 (1 mmol) with nitrone 20aꢀb (1 mmol)in 1,4ꢀ
dioxane(10 mL) at 70 ºC for 10 h. bAll the compounds were fully characterized by their spectroscopic data (1H NMR, 13C NMR, and
HRMS).
aReaction condition for nitrile oxide cycloaddition:All the reactions were carried out diene 1 (1 mmol), Oxime 22aꢀb(1 mmol), NCS (1.1
mmol) and KHCO3(1.5 mmol) in DCM(10 mL) at rt for 16 h. bAll the compounds were fully characterized by their spectroscopic data (1H
NMR, 13C NMR, and HRMS).
Nitrones (20aꢀb) were prepared according to literature procedure.18bA smooth reaction was observed when 1 was refluxed
with nitrones 20ain 1,4 dioxane for 10 h without any catalyst, affording isoxazolidine derivative 21a in 56% yield (Scheme
6). LCꢀMS analysis of the crude productdid not indicate the presence of any isomeric products.Similarlytreatment of 1 with
nitrone 20bafforded the isoxazolidine21b.Structural elucidation of the isoxazolidine 21b was accomplished using 1D, 2D
NMRspectroscopy andHRMS. We have observed in our earlier work15 that the olefinic protons of the vinyl sulphonyl
moiety in the mono [3+2]ꢀcycloadducts resonate in the regionof δ 6.6 and 6.9 asdoubletand doublet of doublet respectively.
In the case of the adduct 21bthe signals of olefinic protons appeared at δ 5.9 and 6.8, indicating that the cycloaddition has
occurred on the vinylsulphonyl double bond. This was further evident from the HMBC spectrum which showed a correlation
between the olefinic protonH7 at δ 5.93 (1H, d, J = 15.5 Hz) and the ester carbonyl at 165.91(Ref Page S59–S63in SI).In the
1H NMR spectrum of 21bthe H4 and H3 proton of the isoxazolidine moiety resonated as doublet of doublet at δ 3.85 (J =
7.6, 4.4 Hz) and doublet at δ 3.95 (J = 7.2 Hz) respectively.The H5 proton of the ring appeared as triplet at δ 5.19 (J = 5.5
Hz). The H7 alkene proton appeared as doublet at δ 5.93 (J = 15.50 Hz) and the H8 alkene protonresonated atδ 6.86 as a
multiplet.The H,HꢀCOSY spectrum revealed a correlation between H4 proton at δ 3.85 ppm with H3 proton at δ 3.95 ppm
while there was no correlation between H5 proton at δ 5.19 ppm with H3proton at δ 3.95 ppmwhich is consistent with the
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 21
1
2
3
4
5
6
7
8
9
observed regioselectivity of cycloaddition. The NOESY NMR spectrum was also informative. It showed a correlation
between theH3and H5 proton indicating a cis relationship. A correlation between H4 with H8proton was also noticed in the
NOESY spectrum. Thus the relative stereochemistry between the three centres, viz. 3, 4 and 5 have been fixed. The
chemoselectivity observed in the case of nitrones was also predicted by DFT calculations. The regiochemistry observed in
the present study was similar to what has been reported in literature for nitrone [3+2]ꢀcycloaddition to electron deficient
olefins.18cꢀf
The reaction of 1 with nitrile oxides18g generatedinsitufrom benzaldoxime(22aꢀb), furnished respectively the 2ꢀisoxazolines
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
derivatives23aꢀb in good yield (Scheme 6). Interestingly the chemo selectivity observed in the caseof nitrile oxide
1
cycloaddition was opposite to that of the nitrone cycloaddition reaction.This was evident from a glance of the H NMR
spectrum, particularly that of the olefinic region (Ref Page S64ꢀS68in SI). One of the alkeneprotons, viz.,H6appeared as a
1
doublet at δ 6.76 (J = 14.9 Hz) and the otherproton H7 as a doublet of doublet at δ 6.96 (J = 14.9 Hz, J = 4.4 Hz).The H
NMR spectrum of 23aexhibited a doublet at δ 4.36 (J = 5.6 Hz) for H4proton of the 2ꢀisoxazoline moiety.While
theH5proton resonated as triplet at δ 5.62 (J = 5.8 Hz). The H,HꢀCOSY spectrum of 23a showed correlation between the
olefinic proton H7 at δ 6.96 ppm with the proton at H5 δ 5.62 ppm which in turn showed correlation with the proton H4at δ
4.36 ppm, establishing the regioselectivity,as well chemoselectivity. The correlation observed in the HMBC spectrum was in
accordance with the assigned structure.
BIS [3+2]ꢀCYCLOADDITION:
Next we explored the feasibility of synthesisofbis pyrrolidine by bis [3+2]ꢀcycloaddition of azomethine ylides (24aꢀc) to the
dienes(1aꢀb).
Scheme 7.Substrate scope for synthesis of bis pyrrolidines 25aꢀfa,b,c via[3+2]ꢀcycloaddition of dienes1withNꢀ
(methoxymethyl)ꢀNꢀ((trimethylsilyl)methyl) alkylamine24aꢀc.
R
N
Si
R
N
CO2Et
H
H
H
R'
O
S
O
S
O
24a-c
H
CO2Et
H
O
O
H
N
R
O
O
H
N
R
Microwave, DCM,
80 °C, 30 min
S
1a-b
H
O
R'
25a-f
R'
O
N
R
R' = H, -OMe
R = -Bn, t-But, Cp
6:4 inseperable diastereomers
Bn
N
CO2Et
H
CO2Et
H
H
N
H
CO2Et
H
H
H
O
S
N
O
S
H
H
H
H
H
H
O
S
CO2Et
CO2Et
OH
OH
H
H
CO2Et
N
OH
N
O
O
H
S
N
Bn
H
S
N
N
H
Bn
H
O
H
S
N
H
O
O
N
N
O
N
Bn
25c & 25c', 67% (30 mins)
25b & 25b', 76% (30 mins)
25a & 25a', 75%(30 mins)
Bn
CO2Et
H
CO2Et
H
MeO
N
MeO
H
CO2Et
H
H
N
H
H
MeO
N
O
S
H
H
H
O
H
H
O
S
CO2Et
H
H
O
CO2Et
S
OH
H
H
CO2Et
OH
N
N
Bn
O
H
O
N
S
N
H
MeO
S
N
Bn
O
H
H
H
S
MeO
N
H
MeO
O
N
O
N
O
N
Bn
25f & 25f', 62% (30mins)
25d & 25d, 72% (30 mins)
25e & 25e', 70% (30mins)
aAll reactions were carried out on 1aꢀb(1 mmol), 24aꢀc(3 mmol) and TFA (0.2 mmol) in DCM (5 mL), microwave at 80 °C for30 min.
bIsolated yield after flash column chromatography.cAll the compounds were fully characterized by their spectroscopic data (1H NMR, 13C
NMR, HRMS).
Literature survey19,20shows that [3+2]ꢀcycloaddition of azomethine ylides with conjugated dienes leads to a mixture of mono
and bis pyrrolidines. In the present work, bis[3+2]ꢀcycloaddition reaction of azomethine ylides generated insitu by
desilylation of synthons 24aꢀcwith 1ꢀarylsulfonylꢀ4ꢀethoxycarbonyl 1, 3ꢀdienes (1aꢀb) under microwave condition was
investigated. Initially Nꢀ(methoxymethyl)ꢀNꢀ((trimethylsilyl)methyl)benzylamine (24c) was selected as the dipole for the
bis[3+2]ꢀcycloaddition of diene1a as outlined in Schemeꢀ7.All the azomethine precursors(24aꢀc) were prepared by the
6
ACS Paragon Plus Environment

Page 7 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
known literature procedure21 and were characterized thoroughly by spectral means. When 1a reacted with 24aꢀcin the
absence of microwave irradiation, it led to a mixture of mono and bisadduct onlyeven under prolonged heating condition (24
h) in various solvents. However, under microwave condition, the bisadducts were obtained in good yield as a mixture of two
inseparable diastereomers in all the examples studied. In a typical experiment, microwave irradiation of a solution ofTFA
azomethine ylide precursor 24c and the dipolarophile 1a in dry dichloromethane in the presence of TFA at 80 °C in
microwave for 30 minled to clean reaction, affording the bis cycloadduct as an inseparable mixture of diasteromers 25cand
25c’in 67% yield. Under these conditions, the mono adduct was not observed. By adopting this method a number ofbis
pyrrolidine derivatives 25aꢀf (Schemeꢀ7) were synthesized in good yields.In all the cases the products appeared to be
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
homogeneous on TLC and the complexity could not be deciphered from H and 13CNMR spectra. HPLC analysis of the
bisadducts from reaction of 24aꢀb, showed only a single peak in several solvent systems studied. However in the case of the
bisadduct from the reaction of 24c,HPLC showed two peaks with retention times of 21.927 & 22.069 min in the ratio of
6:4(Page S85inSI) and revealed it to be a mixture of two products. LCꢀMS revealed them to be isomeric, suggesting that
they are diasteromers. When the mono pyrrolidine adduct 15, independently synthesized15, was reacted with
anotherequivalent of the same azomethine ylide24cunder microwave irradiation condition, it afforded the same
bisadduct25cas was obtained from the direct reaction.It was hoped that hydrolysis of the ester functionality in 25c would
furnish the diasteromeric acids which would show different TLC mobility and thus facilitate their separation by column
chromatography. With this intention, hydrolysis of the bisadduct 25c was carried outunder mild basic conditions to ensure
that in this process, the stereocentres at the sulphonyl end and ester end would not undergo epimerization. Exposure of the
mixture of diatstereomeic esters 25c and 25c’ to a 1N solution of LiOH at rt for 16 h, lead to a smooth saponification and
furnished a mixture of the diasteromeric acids 26c and 26c’ as depicted in Scheme 8.
Scheme 8.
Bn
N
Bn
N
CO2H
H
CO2Et
H
H
H
H
H
H
H
H
O
S
1N LiOH
CO2H
O
S
OH
CO2Et
H
O
H
H
S
N
H
S
N
H
O
H
O
N
N
Bn
Bn
Bn
O
N
O
N
Bn
26c'
25c'
26c
25c
Bn
Bn
6 : 4 inseperable diastereomers
6 : 4 inseperable diastereomers
The diasteromeric ratio of the carboxylic acids 26c and 26c’ was determined by reverse phase HPLC analysis, and found to
be nearly the same (6 : 4) (Page S86 in SI)as that of the starting esters 25c and 25c’. Esterification of these diasteromeric
mixture carboxylic acids 26c and 26c’ with ethanol and oxalylchloride furnished a product which exhibited the same
diasteromeric ratio and retention time in HPLC as that of the original ester 25c and 25c’ obtained in the direct bis
cycloaddition reaction, thus confirming that the in the course of the basic hydrolysis, the chiral centres were not epimerised
and were intact. Since the [3+2]ꢀcycloaddition is a concerted synprocess the stereochemistry at canters 2and 5as well as at 6
and 9 can be fixed as trans. Both the two cycloadditions can occur on the same phase of the 1, 3ꢀdiene π frame work or they
can occur on the opposite phases of 1,3ꢀdiene π frame work. Thus the two diasteromers should differ only in the
configuration at the 3,4 carbons of one of the pyrrolidines rings as visualized in Figure 1.
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 21
1
2
3
4
5
6
7
8
9
H
CO2Et
H
CO2Et
H
H
H
PhO2S
H
PhO2S
H
H
One attack from top
face and another from
bottom face
Both additions from
the bottom phase
Bn
N
H
CO2Et
1
H
8
7
CO2Et
1
H
H
6
9
5
2
3
9
6
2
5
4
H
PhO2S
4
H
3
H
8
7
PhO2S
H
N
2S,5R,6R,9S
N
N
Bn
2S,5R,6S,9R
Bn
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bn
25a
25a'
mirror
mirror
mirror image
mirror image
Bn
Bn
N
Bn
N
N
3
25a
4
4
25a'
3
2
CO2Et
7
H
H
H
8
9
CO2Et
1
5
2
H
5
1
H
6
6
9
8
H
PhO2S
H
PhO2S
H
7
2R,5S,6S,9R
2R,5S,6R,9S
N
One addition from the top
face and the other addition
from the bottom face
Both the additions
are from the top face
Bn
H
CO2Et
H
CO2Et
H
H
H
PhO2S
H
PhO2S
H
H
Figure 1. Mode of bis dipolar cycloaddition of dipole 24c with diene 1.
COMPUTATIONAL DETAILS
The geometries of reactants, products and all the transition states (TSs) were optimized using Density Functional Theory
(DFT) based Becke’s three parameter hybrid functional and LeeꢀYangꢀParr’s22 correlation functional (B3LYP) method
employing 6ꢀ31G(d)23basis set. All these calculations were performed using Gaussian 09 suite of programs.24All gasꢀphaseꢀ
optimized geometries were verified as minima or firstꢀorder saddle points by the frequency calculations. As in the standard
practise, the presence of one imaginary frequency criteria was used for the characterization of TSs. Further, the transition
states were also verified by the intrinsic reaction coordinate (IRC) calculations.25,26The fragment distortion and interaction
energies were computed at M06ꢀ2X/6ꢀ311G(d,p) level of theory by single point energy calculations on B3LYP/6ꢀ31G(d)
optimized geometries.
The global reactivity indices were estimated using the standard working equations proposed by Parr and Yang.27 The global
hardness (η) and electronic chemical potentials (ꢁ) were evaluated using the energies of highest occupied molecular orbital
(HOMO) and lowest unoccupied molecular orbital (LUMO). The Hirschfeld charges were calculated using B3LYP/dnd
method implemented in DMOL3 programme. These charges were used to calculate the local reactivity descriptors such as
condensed Fukui functions of reactants.
The aim of the computational calculation performed is to understand the mechanism of cycloaddition reaction. The nature of
the reactants and their feasibility to undergo reaction upon substitution on ylides with different groups was also investigated.
First of all, we examined the regioselectivity between 1 and the ylides. Overall reactivity and site selectivity of reactants and
their individual atoms can be explained using global and local reactivity indices. The global nucleophilicity (N)28was
calculated by using the equation (1)
N = EHOMO(nucleophile) ꢀ EHOMO(TCE)
(1)
Where tetracyanoethelene (TCE), is taken as a reference as it has lowest HOMO energy and large electrophilicity value (ω =
5.90 eV).
The local reactivity indices such as, local electrophilicity (ω+ )29 and the local nucleophilicity (Nk)30condensed to a particular
k
atom k were calculated from nucleophilic and electrophilic Fukui Functions31using equations (2) and (3).
ω+k = ω f+
(2) and
k
Nk = N fꢀk
(3) where f+k and fꢀk are Fukui functions.
8
ACS Paragon Plus Environment

Page 9 of 21
The Journal of Organic Chemistry
1
2
3
4
Reactants
5
6
7
8
The reactant (2E, 4E)ꢀethyl 5ꢀ(phenylsulfonyl) pentaꢀ2, 4ꢀdienoate (1) is an acyclic conjugated diene. The double bond
which is next to the ester group is denoted as C1ꢀC2 and double bond adjacent to phenyl sulphonyl group is referred to as
C3ꢀC4. 1 prefers to exist in the sꢀtrans conformation for steric reasons but during the [2+ 3] cycloaddtion reaction, it reacts
with its counter parts in the sꢀcis conformation. The sꢀcis conformation is less stable than sꢀtrans conformation only by 3.31
kcal/mol due to the steric interaction between hydrogens of C1 and C4 atoms. We have carried out the calculations for the
reaction of sꢀtrans diene with all the dipoles. However, we could locate the transition states only for the reaction outline in
Scheme 1. For the[2+3] cycloaddition reaction outline in the scheme 1, the calculated energy of activation in the case of
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
reaction involving the diene 1 in sꢀtrans confirmation is quite appreciably high when compared to that of sꢀcis diene (∆G‡
sꢀ
transꢀ∆G‡sꢀcis ~6.0 kcal/mol). Under the reaction conditions (reflux in dioxane) 1 is easily converted from sꢀtrans into the more
reactive sꢀcis conformation and tries to achieve a flat planar structure, before it reacts with the dienophile. The energy profile
for sꢀtrans to sꢀcis transformation is shown in Figure 2.
O
3
O
S
H
1
S
4
2
3
O
4
O
1
2
H
O
O
H
H
O
O
Figure 2.Structures of sꢀcis, sꢀtrans conformations and Sꢀtrans to Sꢀcis transformation of 1.
Global and Local Properties
In order to rationalize the chemoselectivity and regioselectivity, we calculated conceptual density functional theory based
global and local reactive descriptors. The calculated reactivity descriptors are listed in supporting information (SI) (Table S1
and S2 respectively). The analysis of global reactive indices suggests that, electronic chemical potential of dipoles
(azomethine ylides, nitrones and nitrile oxides) (ꢀ0.110 to ꢀ0.135 a.u.) is higher than that of dipolarophile (1) (ꢀ0.173 a.u.)
indicating that, the charge transfer will take place from the dipole towards dipolarophile. 1 has strong electrophilic character
with large global electrophilicity (ω) value of 2.35 eV. The chosen dipoles are nucleophilic in nature due to their low ω
values (0.4 to 2.1 eV) and high global nucleophilicity values (N). The dipoles of 18 (18aꢀe) have large ω values compared to
other dipoles. Thus, the dipoles of 18 may react slowly with 1. It can be seen from the results for Schemes 1ꢀ5, the
nucleophilic nature of ylides increases graduallywith substitution of alkyl groups on nitrogen which is due to the electron
releasing nature of alkyl group. On the other hand, for Scheme 6, the nucleophilic nature of dipole decreases due to the
substitution of electronegative fluorine atom. On the whole, diene 1 will act as electrophile and dipoles will act as
nucleophile.
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 21
1
2
3
4
5
6
7
8
9
The diene 1 has highest electrophilic activation (ωk+ =0.25 eV) at C4 in contrast to other three active carbons C1, C2 and C3.
The C1 has more nucleophilic character (Nk = 0.26 eV) when compared to C4 (Nk =0.21 eV). In other words, even though,
the electrophilic nature of C1 is nearly as same as C4, nucleophilic character of C1 atom dominates its electrophilic
character, making C4 atom, a preferable electrophilic site in diene 1 for nucleophilic attack. The electrophilicity at C4 can be
attributed due to the presence of strong electron withdrawing phenyl sulphonyl group at C4. On the other hand at C1, the
ester group which is also an electron withdrawing but not as strong as phenyl sulphonyl. It is clear from the results that C3ꢀ
C4 is more favourable double bond for 1, 3ꢀdipolar cycloaddition reaction than C1ꢀC2 double bond, and C4 be the preferable
electrophilic site for nucleophilic attack. The dipoles have the largest nucleophilic activation at C7 (O7 for nitrone and nitrile
oxide). Thus, C7 and O7 are the nucleophilic sites in dipoles. These findings reveal that C4 of 1 is preferred electrophilic site
for nucleophilic attack (C7/O7) of dipoles which confirms the regioselectivity of 1,3ꢀdipolar cycloaddition reactions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Geometries of TSs
The geometries of TSs and the respective energy profile for the Schemes 1ꢀ6are depicted in Figure 3ꢀ10 respectively. The
TS structures are named according to their corresponding ylide/nitrone labelling (numbering). The careful examination of
geometrical parameters of various TSs reveals that, for the Scheme 1, the newly forming CꢀC bonds for TS1 are longer than
the forming CꢀC bonds of TS2, TS3 and TS4. The longer forming CꢀC bonds of TS1 implying lesser steric repulsion
between reacting groups. The geometrical parameters of this transition state (TS1) resemble reactants indicating early
transition state nature. On the other hand, the shorter forming CꢀC bonds of TS2, TS3 and TS4, reveal that there is a
considerable increase in the steric repulsion between the reacting groups which leads to the destabilization of the
corresponding transition states. The similar reactivity trend as of Scheme 1 is also observed in the case of Schemes 2 and
3.It is interesting to note different trend in the reactivity for Scheme 4. The newly forming CꢀC bonds in TS1 are shorter
than that of corresponding CꢀC bonds in TS2. In all the transition states of all the Schemes, the incoming bonds (CꢀC bonds
in Schemes 1ꢀ5 and CꢀO and CꢀC bonds in Scheme 6) form with unequal bond lengths showing the asynchronous nature of
transition states. The degree of synchronicity can be measured by the difference between the ratios of the forming bond
lengths in the TS and the corresponding bond lengths in the product (∆dTS/P).32The bond lengths of newly forming bonds and
∆dTS/P values are listed in SI (Table S3). For Schemes 1ꢀ6, ∆dTS/P values indicate TSs areasynchronous nature. However,
Scheme 5, ∆dTS/Pfor TSs in Scheme 5 is higher (> 0.70) which indicates that, the reactions are strongly asynchronous.
Figure 3 Optimized geometries of TSs and energy profile for the reaction of 1 with ylide of 3a (Scheme 1), computed using B3LYP/6ꢀ
31g(d) level (greyꢀ carbon, white– hydrogen, yellow– sulfur, redꢀ oxygen and blueꢀ nitrogen)
10
ACS Paragon Plus Environment

Page 11 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4 Optimized geometries of TSs and energy profile for the reaction of 1 with ylide of 8a (Scheme 2), computed using B3LYP/6ꢀ
31g(d) level (greyꢀ carbon, white– hydrogen, yellow– sulfur, redꢀ oxygen and blueꢀ nitrogen).
Figure 5 Optimized geometries of TSs and energy profile for the reaction of 1 with ylide of 11a (Scheme 3), computed using B3LYP/6ꢀ
31g(d) level (greyꢀ carbon, white– hydrogen, yellow– sulfur, redꢀ oxygen and blueꢀ nitrogen).
Figure 6 Optimized geometries of TSs and energy profile for the reaction of 1 with ylide of 2a (Scheme 4), computed using B3LYP/6ꢀ
31g(d) level (greyꢀ carbon, white– hydrogen, yellow– sulfur, redꢀ oxygen and blueꢀ nitrogen).
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 21
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 7 Optimized geometries of TSs and energy profile for the reaction of 1 with ylide of 16a (Scheme 5), computed using B3LYP/6ꢀ
31g(d) level (greyꢀ carbon, white– hydrogen, yellow– sulfur, redꢀ oxygen and blueꢀ nitrogen).
Figure 8 Optimized geometries of TSs and energy profile for the reaction of 1 with ylide of 18a (Scheme 5), computed using B3LYP/6ꢀ
31g(d) level (greyꢀ carbon, white– hydrogen, yellow– sulfur, redꢀ oxygen and blueꢀ nitrogen).
Figure 9 Optimized geometries of TSs and energy profile for the reaction of 1 with ylide of 20a(Scheme 6), computed using B3LYP/6ꢀ
31g(d) level (greyꢀ carbon, white– hydrogen, yellow– sulfur, redꢀ oxygen and blueꢀ nitrogen).
12
ACS Paragon Plus Environment

Page 13 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 10 Optimized geometries of TSs and energy profile for the reaction of 1 with ylide of 22a (Scheme 6), computed using B3LYP/6ꢀ
31g(d) level (greyꢀ carbon, white– hydrogen, yellow– sulfur, redꢀ oxygen and blueꢀ nitrogen).
Distortion/Interaction Analysis:
The distortion/interaction transition state model developed by Ess and Houk is a highly insightful method for
understanding reactivity and activation barriers in cycloadditions33. The energy of activation (∆E‡) is divided into two major
components called distortion energy (∆E‡dist) and interaction energy (∆E‡int). Distortion energy is calculated as the difference
in energy of the reactants between distorted geometry and the fully optimized ground state geometry. The interaction energy
is the energy difference between the energy of the geometry on the reaction coordinate and the energy of the corresponding
distorted diene and dienophile parts. The ∆E‡ is the energy utilized for distorting reactant geometry to form product.
dist
Higher value of ∆E‡distsignifies requirement of considerable activation barrier.
The calculated distortion and interaction energies are tabulated in SI (Table S4 and S5). It is evident from the
results that the TS which has low distortion energy and high interaction energy, has low activation barrier. In the case of
Schemes 1, 2 and 3, TS1 and TS3 have low and comparable distortion energies. Thus, the reactivity is governed by
interaction energy. ∆E‡ is highest for TS1 which confirms the requirement of low activation barrier. For Scheme 4, TS2
int
has less distortion and more interaction energies and hence lowest activation barrier.
In the case of Scheme 5, the reaction is completely controlled by the distortion energy of reactants. It can be seen
that there is no appreciable contribution from the ∆E‡int. Since ∆E‡ is high, the activation barriers are also high. On the
dist
other hand, for Scheme 6, in the case of nitrones, TS2 exhibits less activation energy, which is controlled by ∆E‡ as
int
distortion energy is similar for all the TSs. As compared with nitrones in Scheme 6, nitrile oxide dipoles have high ∆E‡
.
dist
This is may be due to the presence of triple bond in nitrile oxide which requires more energy for distortion. As a
consequence, the activation barriers are high.
The distortion/interaction analysis also suggest the stereo selectivity of 1,3 dipolar cycloaddition reaction. For all
the schemes, Exo TSs exhibit low ∆E‡distwhich is responsible for low activation barrier than endo TS. The ∆E‡intvalues also
suggest that, the reaction pathway involving TSex is feasible.
Energies of TSs
The reaction energies and activation barriers associated with TSs of all schemes are compiled in SI (Table S6). In the case of
Schemes 1ꢀ3, the reaction pathway associated with TS1 is more favourable as the activation barriers are low. Accordingly, it
can be predicted that the product associated with TS1 of these schemes will be dominating, in agreement with the
experimental observations. In the case of Scheme 4, TS2 has lowest activation barrier compared to TS1. Hence, the reaction
at C1ꢀC2 is favourable for Scheme 4. In the case of Scheme 5, the activation barriers are very high (30ꢀ50 kcal/mol). This
may be due to the steric repulsions exerted by bulky groups. It requires more energy to cross the activation barrier. Thus, the
reaction may not undergo further in normal reaction conditions. In the case of Scheme 6, for dipoles of nitrone20b, the
activation barrier for TS2 is low, which means nitrone (20b) reacts with C3ꢀC4 double bond by bonding the most
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 21
1
2
3
4
nucleophilic O7 with C3 whereas for nitrileoxide the reaction happens at C1ꢀC2 double bond through TS4. In this case, most
nucleophilic O7 bonded with C1.
5
6
7
8
The stereoselectivity of [3+2]ꢀcycloaddition reactions can be explained by reaction energies of exoꢀendo isomers. The
reaction involved TSex is the most favourable reaction pathway due to its low activation barrier and formation of stable
product. The TSs of exo and endo pathways for [3+2]ꢀcycloaddition reaction of 1 with dipole 3a (Schemeꢀ1) and their
corresponding energy profileare shown in Figure 11 (geometries and energy profiles of all other schemes are given in SI as
Figure S3ꢀ S12). The activation energies of endo and exo attacks for all the schemes are tabulated in SI (Table S7).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 11 Optimized geometries and energy profile of exo and endo TSs for the reaction of 1 with ylide of 3a (Scheme 1).
Scheme 7 illustrates theaddition of dipole at free double bond to form a bisproduct. The two possible reaction path ways for
bisaddition of dipole were investigated. The TSs and corresponding energy profiles for bisaddition are shown in Figure 12.
The reaction energies are given in SI (Table S8). The TSs associated with the two pathways have high activation barriers
(34ꢀ35 kcal/mol) which elucidate that, the reaction may be possible on heating. The TSs and products of both pathways are
separated by 1.0 kcal/mol each. Thus, the reaction is possible via both the pathways which may lead to the formation of
racemic mixture of products (25c and 25c’).
Figure 12 Optimized geometries and energy profile for TSs of bis reaction (Scheme 7).
CONCLUSIONS
In conclusion, we have demonstrated that the chemoselectivity of the cycloaddition of azomethine ylides to (2E, 4E)ꢀethyl 5ꢀ
(phenylsulfonyl) pentaꢀ2, 4ꢀdienoate is dependent upon the nature of the dipole as well as by its steric bulk. While simple
azomethine ylides underwent the [3+2]ꢀcycloaddition preferentially at the acrylate double bond, sterically bulky azomethine
ylides exhibited opposite chemoselectivity, reacting at the vinylsulphonyl double bond. In the case of nitrones the
cycloaddition occurred at the vinyl sulphonyl double bond, whereas in the case of nitrile oxides it took place at the acrylate
double bond. The analysis of activation barriers, global and local reactive indices has been studied in order to rationalize the
regioselectivity. The nucleophilic and electrophilic sites involved in the reaction and the effect of substitution on ylides are
14
ACS Paragon Plus Environment

Page 15 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
explained using global and local reactive descriptors. The regioselectivity is also revealed by the reaction energies.
Geometrical parameters and bond lengths of newly forming bonds indicate that the cycloaddition reactions follow a
concerted mechanism with asynchronous transition states. The failure of the diene 1 to undergo the [2+3]ꢀcycloaddtion with
the 1,3ꢀdipoles generated from benzil 16/ cyclohexanone 18 and Nꢀalkylglycines 2aꢀe, outlined in Scheme 5 is also
explained by the high activation barriers of the transition states.
9
EXPERIMENTAL SECTION
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General considerations: All reactions were carried out under an atmosphere of dry nitrogen. All reagents were purchased
from commercial sources and used without further purification. Solvents were distilled prior to use. Column chromatography
was performed on flash silica gel (230ꢀ400 mesh).1H NMR (300 MHz or 400 MHz) and 13C NMR (75 MHz or 100 MHz)
were recorded using CDCl3 or DMSO as solvent and TMS as an internal standard (Chemical shift in (δ) ppm). High
resolution mass spectrometry (HRMS) data were obtained using Electron ionization (EI) and the quadruple double focusing
mass analyser was used. Melting points were determined on a melting point apparatus and are uncorrected. Thin layer
chromatography (TLC) was performed using commercially available silica gel coated aluminium plate were visualized using
iodine vapour and short wave UV lamp. All microwave reactions were performed on Biotage® Initiator+microwave
reactor. Operating high frequency microwave 2.45 GHz with continuous irradiation power from 0 to 300 W with utilization
of the standard absorbance level of 300W maximum power.
General procedure for synthesis of spiropyrrolidnes 4aꢀe, 9aꢀe, 12aꢀe:
A mixture of (2E, 4E)ꢀethyl 5ꢀ(phenylsulfonyl) pentaꢀ2,4ꢀdienoate 1(1 mmol),ninhydrin3 orisatin 8oracenaphthenequinone
11 (1 mmol) and sarcosine or ethylglycine or benzylglycine or phenylglycine or tritylglycine 2aꢀe (1 mmol) was refluxed in
1,4ꢀdioxane (10 mL) for 10ꢀ48 h. The progress of the reaction wasmonitored by TLC. After completion of reaction,the
solvent was evaporated underreduced pressure. Purification of the residue on
a
silica gel (230ꢀ400
mesh)columnchromatography using 30ꢀ40% of ethyl acetate in petroleum ether as eluent furnishedanalytically pure (E)ꢀethyl
3ꢀ(1'ꢀalkylꢀ1,3ꢀdioxoꢀ4'ꢀ(phenylsulfonyl)ꢀ1,3ꢀdihydrospiro[indeneꢀ2,2'ꢀpyrrolidine]ꢀ3'ꢀyl)acrylate (4aꢀe), (E)ꢀethyl 3ꢀ(1'ꢀ
alkylꢀ2ꢀoxoꢀ4'ꢀ(phenylsulfonyl)spiro[indolineꢀ3,2'ꢀpyrrolidine]ꢀ3'ꢀyl)acrylate (9aꢀe) and (E)ꢀethyl 3ꢀ(1'ꢀalkylꢀ2ꢀoxoꢀ4'ꢀ
(phenylsulfonyl)ꢀ2Hꢀspiro[acenapthyleneꢀ1,2'ꢀpyrrolidine]ꢀ3'ꢀyl)acrylate (12aꢀe).
(E)ꢀethyl 3ꢀ(1'ꢀmethylꢀ1,3ꢀdioxoꢀ4'ꢀ(phenylsulfonyl)ꢀ1,3ꢀdihydrospiro[indeneꢀ2,2'ꢀpyrrolidine ]ꢀ3'ꢀyl)acrylate (4a).
Colorless solid (377 mg, 82%); mp 158.1–159 °C; 1H NMR (400 MHz, CDCl3) δ 7.97ꢀ7.86 (m, 6H), 7.60ꢀ7.53(m, 3H),
6.20 (dd, J=15.5,5.7 Hz, 1H), 5.50 (d, J=15.5 Hz, 1H), 4.18 (m, 1H), 3.95 (q, J=7.1 Hz, 2H), 3.80 (dd, J=10.4, 4.8 Hz, 1H),
3.70 (t, J=9.5 Hz, 1H), 3.51 (t, J=10.0 Hz 1H), 2.20 (s, 3H), 1.13 (t, J=7.1 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ
202.5, 198.3, 164.4, 141.6, 140.5, 139.4, 137.9, 136.9, 136.8, 134.1, 129.4, 128.7, 126.1, 123.5, 122.9, 76.7, 65.6, 60.3, 54.0,
49.8, 35.9, 14.0 ppm. HRMS(EI) m/z calculated for C24H23NO6S (M)+: 453.1246, found: 453.1245.
(
E
)ꢀethyl 3ꢀ(1'ꢀethylꢀ1,3ꢀdioxoꢀ4'ꢀ(phenylsulfonyl)ꢀ1,3ꢀdihydrospiro[indeneꢀ2,2'ꢀpyrrolidine] ꢀ3'ꢀyl)acrylate (4b).
1
Pale yellow solid(393 mg, 83%); mp 148.8–150 °C; H NMR (400 MHz, CDCl3) δ7.86ꢀ7.79 (m, 6H), 7.53ꢀ7.45 (m, 3H)
6.07 (dd, J=15.5, 5.7 Hz, 1H), 5.41 (d, J=15.5 Hz, 1H), δ 4.16 (m, 1H), 3.86 (q, J=7.0 Hz, 2H), 3.80 (dd,J=5.0, 5.3 Hz, 1H),
3.59 (t,J=9.6 Hz, 1H), 3.41 (t, J=10.0 Hz, 1H), 2.32 (m, 2H), 1.04 (t, J=7.0 Hz, 3H), 0.85 (t, J=7.1 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 202.7, 198.7, 164.3, 141.6, 140.3, 139.2, 137.8, 136.8, 136.7, 134.0, 129.3, 128.7, 126.2, 123.3, 122.8,
65.3, 60.2, 51.2, 50.0, 44.4, 14.4, 13.9 ppm; HRMS(EI) m/z calculated for C25H25NO6S (M)+: 467.1402, found : 467.1401.
(E)ꢀethyl 3ꢀ(1'ꢀbenzylꢀ1,3ꢀdioxoꢀ4'ꢀ(phenylsulfonyl)ꢀ1,3ꢀdihydrospiro[indeneꢀ2,2'ꢀpyrrolidine ]ꢀ3'ꢀyl)acrylate (4c).
Pale yellow solid (419 mg, 78%); mp 179.5–179.6 °C; 1H NMR (400 MHz, CDCl3) δ 7.87ꢀ7.79 (m, 6H), 7.60 (m, 1H), 7.53
(m, 2H), 7.14 (m, 3H), 7.06 (m, 2H), 6.21 (dd, J=15.5, 5.8 Hz, 1H), 5.54 (d, J=15.5 Hz, 1H), 4.23 (m, 1H), 3.94 (q, J=7.1
Hz, 2H ), 3.67 (m, 2H), 3.49 (m, 3H), 1.12 (t, J=7.1 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 200.6, 196.6, 162.8,
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 21
1
2
3
4
140.1, 138.6, 137.7, 135.9, 135.1, 135.06, 134.8, 132.5, 127.7, 127.3, 127.1, 126.6, 126.0, 124.7, 121.6, 121.3, 63.9, 58.7,
52.7, 50.4, 48.4, 12.4 ppm; HRMS(EI) m/z calculated for C30H27NO6S(M)+: 529.1559, found : 529.1558.
5
6
7
8
9
(E)ꢀethyl 3ꢀ(1'ꢀmethylꢀ2ꢀoxoꢀ4'ꢀ(phenylsulfonyl)spiro[indolineꢀ3,2'ꢀpyrrolidine]ꢀ3'ꢀyl)acrylate (9a).
Colorless solid (357 mg, 80%); mp177.4 – 178.5 °C; 1H NMR (300 MHz, CDCl3) δ 7.91 (m, 2H), 7.76 (m, 1H), 7.64ꢀ7.52
(m, 3H), 7.29 (m, 2H), 7.09 (m, 1H), 6.78 (d,J= 7.5 Hz, 1H), 6.41 (dd, J=15.6, 6.9 Hz, 1H), 5.38 (d, J= 15.6 Hz, 1H), 4.25
(m, 1H), 4.01 (q, J=7.2 Hz, 2H), 3.73 (m, 1H), 3.58 (m, 2H), 2.1 (s, 3H), 1.16 (t, J=7.2 Hz, 3H) ppm; 13C NMR (75 MHz,
CDCl3) δ 176.7, 165.0, 141.2, 140.5, 138.2, 133.9, 130.0, 129.3, 128.6, 125.8, 125.6, 124.4, 123.4, 109.9, 64.7, 60.3, 52.5,
51.6, 34.9, 14.0 ppm; HRMS(EI) m/z calculated for C23H24N2O5S (M)+: 440.1405, found : 440.1404.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
E
)ꢀethyl 3ꢀ(1'ꢀethylꢀ2ꢀoxoꢀ4'ꢀ(phenylsulfonyl)spiro[indolineꢀ3,2'ꢀpyrrolidine]ꢀ3'ꢀyl)acrylate (9b).
1
Colorless solid (378 mg, 82%); mp 141.7–142.5 °C; H NMR (400 MHz, CDCl3) δ 7.91 (d, J=2.8 Hz, 2H), 7.60ꢀ7.52 (m,
3H), 7.52 (b, 1H), 7.20ꢀ7.26 (m, 2H), 7.07 (m, 1H), 6.73 (d, J=7.6 Hz, 1H), 6.33 (dd, J = 15.6,6.8 Hz,1H), 5.32 (d, J=15.6
Hz,1H), 4.22 (m, 1H), 4.00 (q, J=7.2 Hz, 2H), 3.85 (m, 1H), 3.51 (m, 2H), 2.29 (m, 2H), 1.16 (t, J=7.2 Hz, 3H), δ 0.94 (t,
J=7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.0, 164.9, 141.1, 140.2, 138.1, 133.9, 129.8, 129.3, 128.7, 126.4,
125.6, 124.3, 123.4, 109.8, 64.4, 60.3, 51.8, 49.7, 43.2, 14.0, 13.7 ppm; HRMS(EI) m/z calculated for C24H26N2O5S (M)+:
454.1562, found : 454.1560.
(
E
)ꢀethyl 3ꢀ(1'ꢀbenzylꢀ2ꢀoxoꢀ4'ꢀ(phenylsulfonyl)spiro[indolineꢀ3,2'ꢀpyrrolidine]ꢀ3'ꢀyl)acrylate (9c).
1
Colorless solid (393 mg, 75%); mp 206.6–207.7 °C; H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H, ꢀNH), 7.85 (d, J=7.9 Hz,
2H), 7.62 (m, 1H), 7.52 (m, 2H), 7.30ꢀ7.07 (m, 8H), 6.80 (d, 1H, J=7.7 Hz), 6.47 (dd, J=15.6, 6.7 Hz, 1H), 5.45 (d, J=15.6
Hz, 1H), 4.31 (m, 1H), 4.01 (q, J=7.1 Hz, 2H), 3.57 (m, 3H), 3.47 (d, J=13.2 Hz, 1H), 3.31 (d, J=13.1 Hz, 1H), 1.16 (t, J=7.1
Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 177.1, 165.0, 141.5, 140.4, 137.6, 137.5, 133.9, 130.1, 129.3, 128.9, 128.3,
128.0, 127.2, 126.1, 125.7, 124.2, 123.6, 110.2, 64.7, 60.4, 52.8, 51.8, 50.0, 14.1 ppm; HRMS(EI) m/z calculated for
C29H28N2O5S (M)+: 516.1718, found : 516.1715.
((
E)ꢀethyl 3ꢀ(1'ꢀmethylꢀ2ꢀoxoꢀ4'ꢀ(phenylsulfonyl)ꢀ2Hꢀspiro[acenapthyleneꢀ1,2'ꢀpyrrolidine]ꢀ3'ꢀyl) acrylate (12a).
1
Yellow solid (376 mg, 78%); mp 133.1ꢀ134.3 °C; H NMR (400 MHz, CDCl3) δ8.10(d,J=8.0 Hz, 1H), 7.96 (d, J=6.8 Hz,
2H),7.90 (d, J=8.4 Hz, 1H), 7.80 (d, J=6.8 Hz, 1H), 7.73ꢀ7.2 (m, 6H), 6.19 (dd, J=15.6,6.4 Hz, 1H), 5.24 (d, J=15.6 Hz, 1H),
4.37 (m, 1H), 3.89–3.67 (m, 5H), 2.00 (s, 3H), 1.06 (t, J=7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 207.7, 164.8,
143.1, 140.7, 138.4, 136.2, 134.1, 132.4, 131.6, 130.6, 129.5, 129.0, 128.8, 128.4, 125.9, 125.3, 120.9, 120.9, 80.1, 65.3,
60.2, 53.3, 52.2, 35.1, 14.1 ppm; HRMS(EI) m/z calculated for C27H25NO5S (M)+: 475.1453, found : 475.1450.
((E)ꢀethyl 3ꢀ(1'ꢀethylꢀ2ꢀoxoꢀ4'ꢀ(phenylsulfonyl)ꢀ2Hꢀspiro[acenapthyleneꢀ1,2'ꢀpyrrolidine]ꢀ3'ꢀyl) acrylate (12b).
Yellow solid (347 mg, 70%); mp 155.9 – 156.4 °C;1H NMR (400 MHz, CDCl3) δ8.08(d,J=8.0 Hz, 1H), 7.95 (d, J=5.6 Hz,
2H),7.88 (d, J=8.4 Hz, 1H), 7.78 (d, J=6.4 Hz, 1H), 7.71ꢀ7.26 (m, 6H), 6.16 (dd, J=15.6 , 6.4 Hz, 1H), 5.16 (d, J=15.6 Hz,
1H), 4.41 (m, 1H), 3.95 (d, J=10.6 Hz, 1H), 3.84 (q, J=7.2 Hz, 2H), 3.72 (m, 1H), 3.63 (t, J=10.4 Hz, 1H), 2.21 (m, 1H),
2.10 (m, 1H), 1.05 (t, J=7.2 Hz, 3H), 0.88 (t, J=7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 207.8, 164.6, 142.8,
140.3, 138.1, 136.5, 133.9, 132.2, 131.3, 130.3, 129.3, 129.2, 128.9, 128.8, 128.3, 125.6, 125.7, 120.8, 120.6, 80.0, 64.9,
60.1, 52.2, 50.3, 43.0, 14.0, 13.9 ppm; HRMS(EI) m/z calculated for C28H27NO5S(M)+: 489.1609, found : 489.1605.
((
E)ꢀethyl 3ꢀ(1'ꢀbenzylꢀ2ꢀoxoꢀ4'ꢀ(phenylsulfonyl)ꢀ2Hꢀspiro[acenapthyleneꢀ1,2'ꢀpyrrolidine]ꢀ3'ꢀyl) acrylate (12c).
1
Yellow solid (420 mg, 75%); mp207.3 – 207.4 °C; H NMR (400 MHz, CDCl3) δ 8.12 (d, J=8.0 Hz, 1H), 7.88 (m, 4H),
7.74ꢀ7.52 (m, 6H), 7.23 (m, 3H), 7.13 (d, J=6.6 Hz, 2H), 6.27 (dd, J= 15.6, 6.5 Hz, 1H), 5.28 (d, J=15.6 Hz, 1H), 4.23 (m,
1H), 3.90 (q, J=7.1 Hz, 2H), 3.82 (m, 1H), 3.68 (m, 2H), 3.29 (d, 1H), 3.23 (d, 1H), 1.09 (t, J=7.1 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3) δ 207.1, 164.7, 143.04, 140.3, 137.7, 136.3, 133.9, 132.3, 131.3, 130.4, 129.3, 129.0, 128.9, 128.4, 128.3,
128.2, 127.8, 127.8, 127.2, 125.8, 125.3, 121.1, 120.6, 79.8, 65.2, 60.2, 52.7, 52.2, 50.7, 14.0 ppm; HRMS(EI) m/z
calculated forC33H29NO5S (M)+: 551.1766, found : 551.1765.
Synthesis of 1,3,4tri substituted pyrrolidine 15:
16
ACS Paragon Plus Environment

Page 17 of 21
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
A mixture of (2E, 4E)ꢀethyl 5ꢀ(phenylsulfonyl) pentaꢀ2,4ꢀdienoate 1(1 mmol), paraformaldehyde (2 mmol) and
benzylglycine 2c(1 mmol) was refluxed in 1,4ꢀdioxane (10 mL) for 10 h. The progress of the reaction wasmonitored by
TLC. After completion of reaction,the solvent was evaporated under reduced pressure. Purification of the residue on a silica
gel (230ꢀ400 mesh) column chromatography using 30ꢀ40% of ethyl acetate in petroleum ether as eluent furnished
analytically pure(E)ꢀethyl 1ꢀbenzylꢀ4ꢀ(2ꢀ(phenylsulfonyl)vinyl)pyrrolidineꢀ3ꢀcarboxylate 15.
9
(
E
)ꢀethyl 1ꢀbenzylꢀ4ꢀ(2ꢀ(phenylsulfonyl)vinyl)pyrrolidineꢀ3ꢀcarboxylate (15).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Colorless syrup (271 mg, 67%); H NMR (300 MHz,CDCl3) δ 7.86 (m, 2H), 7.62ꢀ7.51 (m, 3H), 7.31ꢀ7.24 (m, 5H), 7.01
(dd,J=15.2, 8.2 Hz,1H), 6.39 (d, J=15.2 Hz, 1H), 4.11 (q,J= 7.2 Hz, 2H), 3.61 (s, 2H), 3.27 (m, 1H), 2.84 (m, 4H), 2.50 (m,
1H), 1.18 (t, J= 7.2Hz,3H) ppm;13CNMR (75 MHz, CDCl3) δ 172.8, 147.0, 140.3, 138.1, 133.2, 130.7, 129.3, 128.7, 128.4,
127.1, 126.9, 60.9, 59.3, 58.2, 56.1, 48.3, 42.9, 14.1 ppm; HRMS(EI) m/z calculated for C22H25NO4S (M)+: 399.1504,
found: 399.1503.
General procedure for isoxazolidines 21aꢀb:
A mixture of (2E, 4E)ꢀethyl 5ꢀ(phenylsulfonyl) pentaꢀ2,4ꢀdienoate 1(1 mmol) and nitrones 20aꢀb (1 mmol) was heated at 70
ºC in 1,4ꢀdioxane (10 mL) for 10 h. The progress of the reaction wasmonitored by TLC. After completion of reaction,the
solvent was evaporated under reduced pressure. Purification of the residue on
a
silica gel (230ꢀ400
mesh)columnchromatography using 40ꢀ50% of ethyl acetate in petroleum ether as eluent furnishedanalytically pure (E)ꢀethyl
3ꢀ(2ꢀmethylꢀ3ꢀphenylꢀ5ꢀ(phenylsulfonyl)isoxazolidinꢀ4ꢀyl)acrylate 21a and (E)ꢀethyl 3ꢀ(3ꢀ(4ꢀfluorophenyl)ꢀ2ꢀmethylꢀ5ꢀ
(phenylsulfonyl)isoxazolidinꢀ4ꢀyl)acrylate 21b.
(E)ꢀethyl 3ꢀ(2ꢀmethylꢀ3ꢀphenylꢀ5ꢀ(phenylsulfonyl)isoxazolidinꢀ4ꢀyl)acrylate (21a).
Pale yellow solid (228 mg, 56%);mp132.5–133 °C;1H NMR (400 MHz, CDCl3) δ 7.75 (m, 2H), 7.56 (m,1H), 7.43 (m, 2H),
7.21 (m, 3H), 7.08 (m, 2H), 6.93 (dd, J=15.6, 5.6 Hz, 1H), 5.99 (d, J=15.6 Hz, 1H), 5.18 (t, J=4.0 Hz, 1H), 4.19 (q, J=7.2
Hz, 2H), 3.91 (m,2H), 2.56 (s, 3H), 1.27 (t, J=7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 166.0, 145.0, 137.8, 135.8,
134.3, 129.5, 128.8, 128.6,128.5, 128.0, 122.5, 80.0, 75.9, 74.3, 60.8, 42.6, 14.3 ppm. HRMS(EI) m/z calculated for
C21H23NO5S (M)+: 401.1296,found: 401.1308.
(E)ꢀethyl 3ꢀ(3ꢀ(4ꢀfluorophenyl)ꢀ2ꢀmethylꢀ5ꢀ(phenylsulfonyl)isoxazolidinꢀ4ꢀyl)acrylate (21b).
Pale yellow solid (276 mg, 65%);mp110–111 °C;1H NMR (500 MHz, CDCl3) δ 7.75 (d, J=7.5 Hz, 2H), 7.58 (t,J=7.5
Hz,1H), 7.44 (t, J=7.5 Hz, 2H), 7.10 (m, 2H), 6.86 (m, 3H), 5.96 (d, J=15.5 Hz, 1H), 5.17 (t, J=5.5 Hz, 1H), 4.20 (q, J=7.0
Hz, 2H), 3.95 (b, 1H), 3.86 (dd,J=4.5, 5.0 Hz, 1H), 2.59 (s, 3H), 1.29 (t, J=7.0 Hz, 3H) ppm; 13C NMR (125 MHz, CDCl3)
δ165.9, 163.8, 161.8, 144.7, 137.7, 134.5, 131.3, 129.8, 129.8, 129.6, 128.5, 122.7, 115.9, 115.7, 79.7, 76.1, 73.5, 60.8, 42.5,
14.3 ppm.HRMS(EI) m/z calculated for C21H22FNO5S (M)+: 419.1202, found: 419.1201.
General procedure for isoxazolidines 23aꢀb:
A mixture of (2E, 4E)ꢀethyl 5ꢀ(phenylsulfonyl) pentaꢀ2,4ꢀdienoate 1(1 mmol), Oxime 22aꢀb (1 mmol), NCS (1.1 mmol) and
KHCO3 (1.5 mmol)was stirred in dichloromethane(10 mL) at rt for 16 h. The progress of the reaction wasmonitored by TLC.
After completion of reaction, water wasadded and the reaction mixture was extracted with DCM(3 X 15 mL). The combined
organic layer was dried over Na2SO4andevaporated under reduced pressure. Purification of the residue on a silica gel (230ꢀ
400 mesh)columnchromatography using 40ꢀ50% of ethyl acetate in petroleum ether as eluent furnished analytically pure
((E)ꢀethyl 3ꢀ(3ꢀphenylꢀ5ꢀ(phenylsulfonyl)ꢀ4,5ꢀdihydroisoxazolꢀ4ꢀyl)acrylate 23a and (E)ꢀethyl 3ꢀ(3ꢀ(4ꢀfluorophenyl)ꢀ5ꢀ
(phenylsulfonyl)ꢀ4,5ꢀdihydroisoxazolꢀ4ꢀyl)acrylate 23b.
(E)ꢀethyl 3ꢀ(3ꢀphenylꢀ5ꢀ(phenylsulfonyl)ꢀ4,5ꢀdihydroisoxazolꢀ4ꢀyl)acrylate (23a).
Colorless solid(234 mg, 60%); mp144.5–145 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J=2.40 Hz, 2H), 7.71 (m, 3H), 7.59
(m, 2H), 7.44 (m, 3H), 7.00 (dd, J=14.8, 4.0 Hz, 1H), 6.79 (d, J=14.8 Hz, 1H), 5.63 (t, J=4.4 Hz, 1H), 4.36 (d,J=6.0 Hz, 1H),
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 21
1
2
3
4
5
4.21 (q, J=6.9Hz, 2H), 1.20 (t, J=6.9 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.7, 153.9, 140.2, 139.4, 133.8, 133.0,
130.8, 129.4, 128.7, 127.9, 127.5, 127.2, 82.1, 62.6, 58.6, 13.8 ppm.HRMS(EI) m/z calculated for C20H19NO5S (M)+:
385.0983, found: 385.0982.
6
7
8
9
(
E
)ꢀethyl 3ꢀ(3ꢀ(4ꢀfluorophenyl)ꢀ5ꢀ(phenylsulfonyl)ꢀ4,5ꢀdihydroisoxazolꢀ4ꢀyl)acrylate (23b).
1
Colorless solid (257 mg, 63%); mp133–134 °C; H NMR (300 MHz, CDCl3) δ 7.87 (m, 2H), 7.69 (m, 3H), 7.57 (m, 2H),
7.12 (m, 2H), 6.97 (dd, J=14.7, 4.2 Hz, 1H), 6.77 (d, J=14.7 Hz, 1H), 5.63 (t, J=4.5 Hz, 1H), 4.35 (d, J=5.4 Hz, 1H), 4.19 (q,
J = 7.2 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 167.5, 165.7, 162.4, 152.8, 140.0, 139.4, 133.8,
133.0, 129.4, 129.3, 127.8, 123.8, 123.8, 116.1, 115.8, 82.1, 62.6, 58.5, 13.8 ppm. HRMS(EI) m/z calculated for
C20H18FNO5S (M)+: 403.0889, found: 403.0888.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the synthesis of Nꢀ(methoxymethyl)ꢀNꢀ((trimethylsilyl)methyl) alkylamines (24aꢀc).
(Chloromethyl)trimethylsilylamine (5 mmol)was added to a solution of benzylamine orcyclopentylamine ortertꢀbutylamine
(10 mmol) in acetonitrile (150 mL) and the reaction mixture was refluxed for 16 h.The progress of the reaction
wasmonitored by TLC. After completion of reaction, acetonitrile was removed under reduced pressure, water was added and
the reaction mixture was extracted with diethyl ether (3×100 mL). The combined organic layers were dried over Na2SO4,
evaporated
under
reduced
pressure
to
furnished
analytically
pure
product
Nꢀ
((trimethylsilyl)methyl)(phenyl)methanamineorNꢀ((trimethylsilyl)methyl)
cyclopentanamineorNꢀ
((trimethylsilyl)methyl)(phenyl) methanamine , which was used as such for the next step without any purification.To a
stirred solution of methanol (12 mmol) and 37% aqueous formaldehyde (12 mmol) at 0 °C was added 2ꢀmethylꢀNꢀ
((trimethylsilyl)methyl)propanꢀ2ꢀamine
orNꢀ((trimethylsilyl)methyl)cyclopentanamine
orNꢀ
((trimethylsilyl)methyl)(phenyl)methanamine (10 mmol) drop wise over a period of 10 min. The resulting mixture was
stirred for 2 h, anhydrous K2CO3 (2.5 mmol) was added toa mixture and stirred at 0 °C for 30 mins. After completion of the
reaction was monitored by TLC,water was added and the reaction mixture was extracted with diethyl ether (3×100 mL). The
combined organic layers were dried over Na2SO4, evaporated under reduced pressure to furnished crude product. The pure
compound was isolated by fractional distillation to get Nꢀ(methoxymethyl)ꢀNꢀ((trimethylsilyl)methyl)tertꢀbutylamine or Nꢀ
(methoxymethyl)ꢀNꢀ((trimethylsilyl)methyl)cyclopentanamineorNꢀ(methoxymethyl)ꢀNꢀ((trimethylsilyl) methyl)benzylamine
(24aꢀc). All the compounds are liquid.
N
ꢀ(methoxymethyl)ꢀ
Colorless oil (87%),1H NMR (300 MHz, CDCl3)δ 4.15 (s, 2H), 3.16 (s, 3H), 1.97 (s, 2H), 1.05 (s, 9H), 0.04 (s, 9H) ppm.
ꢀ(methoxymethyl)ꢀ ꢀ((trimethylsilyl)methyl) cyclopentanamine (24b).
Nꢀ((trimethyl silyl)methyl)tertꢀbutylamine (24a).
N
N
Pale yellow oil (78%),1H NMR (300 MHz, CDCl3)δ 4.10 (s, 2H), 3.21 (s, 3H), 3.15 (m, 1H), 2.22 (s, 2H), 1.32 – 1.83 (m,
8H), 0.04 (s, 9H) ppm.
N
ꢀ(methoxymethyl)ꢀNꢀ((trimethylsilyl)methyl) benzylamine (24c).
Pale yellow oil (90%),1H NMR (300 MHz, CDCl3)δ 7.14 – 7.06 (m, 5H), 4.44 (s, 2H), 3.62 (s, 3H), 3.24 (s, 2H), 1.69 (s,
2H), 0.04 (s, 9H) ppm.
General procedure for the synthesis of 3, 3’ꢀ bis pyrrolidine (25aꢀf)
TFA (0.1 mmol) was added to a solution of diene1aor 1b (1 mmol) and 24aor 24b or 24c (3 mmol) in DCM (5 mL). The
reaction mixture was stirred at 80 °C in microwave for 30 min. The progress of the reaction wasmonitored by TLC. After
completion of reaction,water (30 ml) was added to the mixture and then extracted with DCM (2x30 mL), combined organic
layer was washed with 10% NaHCO3 (30 mL), water (30 mL) and saturated brine (30 mL), organic layer was dried over
18
ACS Paragon Plus Environment

Page 19 of 21
The Journal of Organic Chemistry
1
2
3
Na2SO4 andevaporated under reduced pressure. Purification of the residue on
a
silica gel (230ꢀ400
4
mesh)columnchromatography using 30ꢀ60% of ethyl acetate in petroleum ether as eluent furnishedanalytically pure
5
6
7
8
inseparable mixture of diastereomers 25aꢀf (6:4).
Ethylꢀ1ꢀtertꢀbutylꢀ4ꢀ(1ꢀtertꢀbutylꢀ4ꢀ(phenylsulfonyl)pyrrolidinꢀ3ꢀyl)pyrrolidineꢀ3ꢀcarboxylate (25a and 25a’).
1
Colourless syrup (350 mg, 75%); H NMR (400 MHz,CDCl3) δ7.91 (m, 2H), 7.65ꢀ7.53 (m, 3H), 4.14 (q, J=7.1 Hz, 2H),
3.82 (m, 1H), 2.42ꢀ2.92 (m, 11H), 1.25 (t, J=7.1 Hz, 3H), 1.05 (s, 9H), δ 0.93 (s, 9H) ppm.13C NMR (100 MHz, CDCl3) δ
174.9, 174.8, 138.6, 138.5, 133.4, 133.4, 128.9,128.8, 128.7, 66.0, 65.9, 60.6, 60.5, 55.2, 53.7, 52.0, 51.9, 51.7, 50.3, 50.2,
50.0,49.7, 49.5, 49.3, 47.3, 47.1, 46.2, 45.9, 44.2, 44.0, 43.7, 42.6, 42.3, 28.2, 26.9, 25.9, 15.4 ppm. HRMS(EI) m/z
calculated for C25H40N2O4S (M)+: 464.2708, found: 464.2705.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethylꢀ1ꢀcyclopentylꢀ4ꢀ(1ꢀcyclopentylꢀ4ꢀ(phenylsulfonyl)pyrrolidinꢀ3ꢀyl)pyrrolidineꢀ3ꢀcarboxylate (25band 25b’).
Colourless syrup (376 mg, 76%),1H NMR (300 MHz, CDCl3)δ 7.93 (m, 2H), 7.64ꢀ7.53 (m, 3H), 4.14 (q, 2H), δ 3.76 (m,
1H), 2.32ꢀ2.94 (m, 13H), 1.49ꢀ1.66 (m, 14H), 1.23 (m, 5H) ppm. 13CNMR (75 MHz, CDCl3) δ 174.5, 138.4, 133.6, 129.1,
128.8, 66.4, 66.2, 65.8, 60.8, 57.5, 56.9, 56.7, 54.1, 46.0, 44.4, 42.5, 31.7, 31.7, 24.0, 24.0, 23.8, 14.2 ppm.HRMS(EI) m/z
calculated for C27H40N2O4S (M)+: 488.2708, found:488.2708.
Ethylꢀ1ꢀbenzylꢀ4ꢀ(1ꢀbenzylꢀ4ꢀ(phenylsulfonyl)pyrrolidinꢀ3ꢀyl)pyrrolidineꢀ3ꢀcarboxylate (25c and 25c’).
1
Colourless syrup (361 mg, 67%); H NMR (300 MHz, CDCl3)δ7.89 (m, 2H),δ 7.83 (m, 1H), δ 7.53 (m, 2H) 7.30ꢀ7.14 (m,
10H), 4.11 (q, 2H), 3.89 (m, 1H), 3.47 (m, 4H, ꢀCH2Ph), 3.04 (m, 1H), 2.84ꢀ2.52 (m, 10H), 1.249(t, 3H) ppm. 13C NMR (75
MHz, CDCl3) δ 174.8, 174.5, 138.9, 138.7, 138.6, 138.5, 138.4, 133.7, 133.6, 129.3, 129.2, 128.8, 128.7, 128.6, 128.4,
128.3, 127.6, 127.1, 66.3, 66.1, 60.8, 60.8, 60.8, 59.7, 59.7, 59.4, 59.4, 59.2, 58.5, 58.3, 58.0, 57.7, 57.0, 54.9, 54.7, 46.5,
46.0, 45.0, 44.5, 43.5, 42.9, 14.2 ppm.HRMS(EI) m/z calculated for C31H36N2O4S (M)+: 532.2395, found: 532.2394.
Ethylꢀ4ꢀ(4ꢀ(4ꢀmethoxyphenylsulfonyl)ꢀ1ꢀtertꢀbutylpyrrolidinꢀ3ꢀyl)ꢀ1ꢀtertꢀbutyl pyrrolidineꢀ3ꢀcarboxylate (25d and
25d’).
1
Colourless syrup (360 mg, 72%); H NMR (400 MHz, CDCl3)δ 7.79 (d, 2H), 6.98 (d, 2H), 4.12 (q, 2H), 3.85 (s, 3H, ꢀ
OCH3), 3.72 (m, 1H), 2.44ꢀ2.92 (m, 11H), 1.25 (t, 3H), 1.03 (s, 9H), 0.92 (s, 9H) ppm.13C NMR (100 MHz, CDCl3) δ 174.7,
163.5, 130.9, 130.8, 129.9, 129.7, 114.1, 66.0, 60.6, 55.5, 51.7, 50.1, 49.5, 47.4, 47.2, 45.9, 44.30, 44.0, 42.3, 25.5, 13.2
ppm.HRMS(EI) m/z calculated for C26H42N2O5S (M)+: 494.2814, found: 494.2814.
Ethylꢀ4ꢀ(4ꢀ(4ꢀmethoxyphenylsulfonyl)ꢀ1ꢀcyclopentylpyrrolidinꢀ3ꢀyl)ꢀ1ꢀcyclopentyl pyrrolidineꢀ3ꢀcarboxylate (25e and
25e’).
1
Colourless syrup (367 mg, 70%); H NMR (400 MHz, CDCl3)δ 7.77 (d, 2H), 6.96 (d, 2H), 4.11 (q, 2H), 3.87 (s, 3H, ꢀ
OCH3), 3.74 (m, 1H), 2.49ꢀ3.09 (m, 13H), 1.46ꢀ1.77 (m, 14H), 1.23 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ174.6,
163.6, 131.0, 130.8, 114.2, 65.9, 65.8, 60.8, 57.5, 55.6, 54.3, 46.1, 44.4, 31.6, 31.5, 24.0, 23.9, 14.1 ppm. HRMS(EI) m/z
calculated for C28H42N2O5S (M)+: 518.2814, found: 518.2812.
Ethylꢀ4ꢀ(4ꢀ(4ꢀmethoxyphenylsulfonyl)ꢀ1ꢀbenzylpyrrolidinꢀ3ꢀyl)ꢀ1ꢀbenzylpyrrolidineꢀ3ꢀcarboxylate (25f and 25f’).
Colourless syrup (353 mg, 62%);1H NMR (400 MHz, CDCl3)δ 7.77 (dd, 2H), 7.05ꢀ7.30 (m, 12H), 4.11 (q, 2H), 3.85 (s,
3H), 3.80 (m, 1H), 3.29ꢀ3.56 (m, 4H), 2.53ꢀ3.04 (m, 11H), 1.17 (t, 3H) ppm. 13C NMR (100 MHz, CDCl3) δ 175.5, 165.5,
139.4, 138.8, 132.0, 130.0, 129.96, 129.3, 129.2, 128.1, 128.0, 115.6, 67.7, 67.3, 61.9, 60.5, 60.0, 58.5, 57.2, 56.3, 55.4,
47.1, 45.6, 44.5, 43.9 14.4 ppm. HRMS(EI) m/z calculated for C32H38N2O5S (M)+: 562.2501, found: 562.2500.
ACKNOWLEDGMENTS
US is thanks to a Principal Pachaiyappa’s College (affiliated to University of Madras) for providing the facilities for the
work and SAIF IITM for HRMS.
ASSOCIATED CONTENT
* Supporting Information
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 21
1
2
3
4
5
6
7
1
Copies of H NMR and 13C NMR spectra for all compounds, COESY, HMBC and NOESY spectra for 21b&23a. Xꢀray
structures and data of compounds 4a & 9a (CIF). Additional details on computations, including total energies and Cartesian
Coordinates for computed structures and TS structures. The Supporting Information is available free of charge on the ACS
Publications website at DOI:
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
1) (a) 1,3ꢀDipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vols. 1 and 2. (b) Huisgen, "Kinetics
and Mechanism of 1,3ꢀDipolar Cycloaddition". Angew. Chem. Int. 1963, 2, 633.
2) Tsuge, O.; Kanemasa, S.; In Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic Press: San Diego,
1989; Vol. 45, p 231.
3) Grigg, R.; Sridharan, V.; Advances in Cycloaddition; Curran, D. P., Ed.; Jai Press: London, 1993; Vol. 3, p 161.
4) (a) Pellissier, H. Tetrahedron. 2007, 63, 3235. (b) Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2006, 2873. (c) Pandey,
G.; Banerjee, P.; Gadre, S. R.Chem. Rev. 2006, 106, 4484. (d) RuckꢀBraun, K.; Freysoldt, T. H. E.; Wierschem, F.Chem.
Soc. Rev. 2005, 34, 507. (e) Kanemasa, S. Synlett. 2002, 9, 1371.
5) (a) Najera, C.; Sansano, J. M.Curr. Org. Chem. 2003, 7, 1105. (b) Harwood, L. M.; Vickers, R. J. in Synthetic
Applications of 1,3ꢀDipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products (Eds.: A. Padwa, W. H.
Pearson), John Wiley & Sons, New York, 2002, p. 169. (c) Gothelf, K. V. in Cycloaddition Reactions in Organic
Synthesis (Eds.: S. Kobayashi, K. A. Jorgensen), WileyꢀVCH, Wenham, 2002, ch. 6, p. 211. (d) Karlsson, S.; Hogberg,
H. E.Org. Prep. Proced. Int. 2001, 33, 103. (e) Gothelf, K. V.; Jorgensen, K, A.Chem. Rev. 1998, 98, 863.(f) Coldham, I.;
Hufton, R.Chem. Rev. 2005, 105, 2765.
6) (a) Daly, J. W.; Spande, T. W.; Whittaker, N.; Highet, R. J.; Feigl, D.; Noshimori, N.; Tokuyama, T.; Meyers, C. W. J.
Nat. Prod. 1986, 46, 210. (b) Molineux, R. J.; In Alkaloids: Chemical and Biological Perspective; Pelletier, S. W.; Ed.;
Wiley: New York, 1987, Chapter 1; (c) Fujimori, S. Jap. Pat. Appl. 88ꢀ2912; Chem. Abstr. 1990, 112, 98409. (d)
Waldmann, H. Synlett. 1995, 2, 133. (e) Mukherjee, S.; Raunak.;Dhawan, A.; Prasad, A, K.; Carl E Olsen.; Cholli, A, S.;
Errington, W.; Watterson, A, C.; Parmer, V, S.Ind. J. Org. Chem. 2004, 43B, 2670.
7) Andersen, B, B.; Ahmadian, H, L, S, M.; Stensbol, T, B.; Madsen, U.; Bges, K, P.; Krogsgaard, L, P. J. Med. Chem.
2000, 43, 4910.
8) (a) Carroll, W. A.; Grieco, P. J. Am. Chem. Soc. 1993, 115, 1164. (b) Early, W. G.; Oh, T.; Overman, L.
Tetrahedron.1988, 44, 3785. (c) Ban, Y.; Taga, N.; Oishi, T. Chem. pharm. Bull. 1976, 24, 736.
9) Hilton, S. T.; Ho, T. C.; Pljevaljcic, G.; Jones, K. Org. Lett. 2000, 2, 2639.
10) (a) Okita, T.; Isobe, M. Tetrahedron. 1994, 50, 11143. (b) Rosenmond, P.; HosseiniꢀMerescht, M.; Bub. Leibigs. Ann.
Chem. 1994, 2, 151. (c) Kornet, M. J.; Thio, A. P. J. Med. Chem. 1976, 19, 892.
11) (a) Poornachandran, M.; Raghunathan, R. Synth Commun. 2007, 37, 2507. (b) Augustine, T.; Kanakam, C, C.; Mary
Vithiya, S.; Ramkumar, V. Tetrahedron Lett. 2009, 50, 5906. (c) Suresh Babu, A. R.; Raghunathan, R.; Satiskumar, B, K.
Tetrahedron Lett. 2009, 50, 2818. (d) Dandia, A.; Jain, A, K.; Laxkar, A, K.; Bhati, D, S. Tetrahedron Lett. 2013, 54,
3180. (e) Arumugam, N.; Periyasami, G.; Raghunathan, R.; Kamalraj, S.; Muthumary. J. Eur. J. Med. Chem. 2011, 46,
600. (f) Lanka, S.; Thennarasu, S.; Perumal, P, T. RSC Adv.2014, 4, 2263. (g) Lanka, S.; Thennarasu, S.; Perumal, P, T.
Tetrahedron Lett. 2012, 53, 7052. (h) Ahmad, A, N.; Arulananda, B, S.; Vadia, R.; Chennakesava, R. Synlett. 2012, 4,
5549.
12) For review of sulfonyl diene in organic synthesis.; (a) Backvall, J, E.; Chinchilla, R.; Najera, C.; Yus, M. Chem. Rev.
1998, 98, 2291. (b) Nigel, S.; Simpkins. Tetrahedron. 1990, 46, 6984. (c) Blumberg, L, C.; Costa, B.; Goldstein,
R.Tetrahedron Lett.2011, 52, 872. (d) Beugemans, R.; Benadjila, I, L.; Chastanet, J.; Negron, G.; Roussi, G. Can. J.
Chem. 1958, 63, 725.
13) (a) Amal Raj, A.; Raghunathan , R.; SrideviKumari. M. R.; Raman, N. Bioorg. Med. Chem. 2003, 11, 407. (b) Rusil, I.;
Ashraf, A, M.; Choon, T, S.; Shahida, A, N.; Yoon, Y, K.; Raju, S, K.; Hasnah, O. WO2012/99452; (2012). (c) Sahu, D.;
Pathak, T.; Ganguly, B.Org. Lett. 2014, 16, 2100.
20
ACS Paragon Plus Environment

Page 21 of 21
The Journal of Organic Chemistry
1
2
3
4
14) (a) Houk, K, N. in Pericyclic Reactions, Vol. II, Marchand, A, P.; Lehr, R, E. (Eds.), Academic Press, New York, 1977,
p. 203. (b) Houk, K, N.; Sims, J.; Watts, C, R.; Luskus, L, J. J. Am. Chem. Soc. 1973, 95, 7301.
5
6
15) Sankar, U.; Mahalakshmi, S.; Balasubramanian, K, K. Synlett. 2013, 24, 1533.
7
8
9
16) (a) Belyk. K. M.; Beguin, C. D.; Palucki, M.; Grinberg. N.; DaSilva, J.; Askina, D.; Yasuda, N.Tetrahedron Lett.2004,
45, 3265. (b) Blumberg, L.C.; Costa, B.; Goldstein, R.Tetrahedron Lett. 2011, 52, 872 (Reference cited there in for cyclo
addition chemistry). (c) Suresh Babu, A. R.; Raghunathan, R.Tetrahedron Lett. 2008, 49, 4618.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
17) The Xꢀray crystal structure data of 4aand 9ahave been deposited at the Cambridge crystallographic Data Centre and
allocated the deposited numbers as follow CCDC#865207 (4a) andCCDC# 898323 (9a). The data can be obtained free
of charge from the Cambridge crystallographic data center via www.ccdc.cam.ac.uk/data_request/cif
.
18) (a) Nitrile oxides, nitrones and nitronates in organic synthesis; Novalstrategiesc in synthesis 2nd edition; Henry Feuer,
Ed.; Wiley Sons: New Jersey, 2008.(b) Patrick, T, B.; Shadmehr, M.; Khan, A, H.; Singh, R, K.; Asmelash, B. J.
Fluorine. Chemistry. 2012, 143, 109.(c) Andrade, M, M.; Barros, M, T.; Pinto, R, C. Tetrahedron, 2008, 64, 10521. (d)
Hang, X, C.; Chen, Q, Y.; Xiao, J, C. Synlett. 2008, 13, 1989.(e) Lavanya, G.; L. Mallikarjuna, R, L.; Padmavathi,
V.;Padmaja, A. E. J. Med. Chem. 2014,73, 187. (f) Blas, D, J.; Carretero, C, J.; Dominguez, E. Tetrahedron Asymmerty.
1995, 6, 1035.(g)Romanski, J.; Nowak, P.; Maksymiuk, A.; Chapuis, C.; Jurczak, J. RSC. Adv. 2013, 3, 23105.
19) (a) Gregory, L, H.; Bradley, J, B. Tetrahedron Lett. 2006, 47, 2229. (b) Qun, L.; Weibo, W.; Kristine, B, B.; Akiyo, C.;
Lisa, H. Bioorg. Med. Chem. Lett. 1998, 8, 1953. (c) Mark, G.; Andrew, C, M.; Jonathan, F, M. Tetrahedron Lett.2010,
51, 1026. (d) Pabbaraja, S.; Rao, Y, S.; Debjit, B.; Srivari, C. Synthesis. 2006, 16, 2646.
20) (a) Rodriguez, S, R, M.; Beat, W.; Hans, I. Tetrahedron Asymmerty. 2003, 14, 1547.
21) Takeuchi, H.; Fuijimoto, T.; Hoshino, K.; Motoyoshiya, J.; Kakehi, A.; Yamamoto, I. J. Org. Chem. 1998, 63, 7172.
22) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
23) Hehre, W. J.; Radom, L.; Schleyer, P. R.; Pople, J. A. Ab initio molecular orbital theory. Ed.; Wiley: New York, 1986.
24) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.; Peralta, Jr., J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers,
E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J. ; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar,
S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O. ; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A.
D. Farkas, J.; Foresman, B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.02; Gaussian, Inc.:
Wallingford, CT, 2009.
25) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154.
26) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523.
27) Parr, R. G.; Yang, W. Density Functional Theory of Atoms and Molecules; Oxford University Press: New York, 1989.
28) (a) Domingo, L. R.; Chamorro, E.; and Perez, P. J. Org. Chem. 2008, 73, 4615.(b) Domingo, L. R.; Picher, M. T.
Tetrahedron. 2004, 60, 5053.
29) Padmanabhan, J.; Parthasarathy, R.; Elango, M.; Subramanian, V.; Krishnamoorthy, B. S.; GuitierrezꢀOliva, S.; Toroꢀ
labbe, A.; Roy, D. R.; Chattaraj, P. K. J. Phys. Chem. A. 2007, 111, 9130.
30) Perez, P.; Domingo, L. R.; DuqueꢀNorena, M.; Chamorro, E. J.Mol. Struct. (THEOCHEM) 2009, 895, 86.
31) Geerlings, P.; De Proft, F.; Langenaeker, W. Chem.Rev. 2003, 103, 1793.
32) Contini, A.; Leone, S.; Menichetti, S.; Viglianisi, C.; Trimarco, P. J. Org. Chem.2006, 71, 5507.
33) Ess,D. H.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 10646−10647.
21
ACS Paragon Plus Environment