Regioselectivity of a 1,3-dipolar cycloaddition to phenyl vinyl sulfoxide

Article abstract of DOI:10.1002/jhet.286

(Chemical Equation Presented) The regioselectivity of the 1,3-dipolar cycloaddition of benzonitrile N-oxide to phenyl vinyl sulfoxide is established by isotopic labeling and ¹³C NMR analysis, and by DFT calculations.

Full text of DOI:10.1002/jhet.286

1318
Regioselectivity of a 1,3-Dipolar Cycloaddition to Phenyl Vinyl
Sulfoxide
Vol 46
Tyler C. Gray,a Faraj Hasanayn,b David P. Richardson,a*
and J. Hodge Markgrafay
aDepartment of Chemistry, Williams College, Williamstown, Massachusetts 01267
bDepartment of Chemistry, American University of Beirut, Beirut, Lebanon
*E-mail: david.p.richardson@williams.edu
yIn memoriam; deceased January 11, 2007.
Received December 12, 2008
DOI 10.1002/jhet.286
Published online 10 November 2009 in Wiley InterScience (www.interscience.wiley.com).
The regioselectivity of the 1,3-dipolar cycloaddition of benzonitrile N-oxide to phenyl vinyl sulfoxide
is established by isotopic labeling and 13C NMR analysis, and by DFT calculations.
J. Heterocyclic Chem., 46, 1318 (2009).
INTRODUCTION
ratio is dramatically altered (90:10 to 10:90) depending
on R [7b]. Clearly, direct analysis of the product ratio
cannot be used to determine the regioselectivity when R
¼ H, as the two intermediates (3a/3b) yield the same
product (2a/2b), although this case may easily be the
most relevant to understanding the influence of the
S(O)Ph group. Herein, we report the results for a simple
isotope labeling experiment that solve this problem.
Our approach, summarized in Scheme 2, was to ana-
lyze product 2 by 13C NMR spectroscopy following
reaction of 1 with a sample of 4 selectively enriched
with 13C in the 1-position (C1). The results show that
the 13C label is incorporated largely at the 5-position of
the isoxazole ring. We estimate a regioselectivity of
110:1 based on the integrated 13C peak areas in the final
product. These conclusions were then supported with
DFT calculations.
The synthesis of 3-phenylisoxazoles is an active area
because that structural unit is the core of many com-
pounds with biological or agricultural activity [1]. One
of the prominent routes to these molecules is the reac-
tion of a benzonitrile N-oxide 1 with a substituted
alkyne or alkene, a pathway first recognized as a 1,3-
dipolar cycloaddition by Huisgen [2]. Several hundred
examples of this process have been documented [3].
The parent compound 2 can be prepared by this pro-
cedure with acetylene as the dipolarophile [4], but more
often a two-step sequence is used whereby a monosub-
stituted alkene serves as the dipolarophile, followed by
an elimination process on the intermediate isoxazoline 3
(Scheme 1). In the latter case, two distinct isomeric
intermediates are possible depending on whether the ox-
ygen terminal of 1 adds to the substituted or the unsub-
stituted carbon of the alkene (paths a and b, respectively
in Scheme 1). This reaction is known to be generally
regioselective for the 5-substituted cycloadduct 3a [5].
However, yields for the process are not quantitative, and
rigorous analyses for the isomeric 4-substituted cycload-
duct are seldom reported [6].
RESULTS AND DISCUSSION
Synthesis. Standard procedures were used to convert
1-13C-ethyl iodide to phenyl 1-13C-vinyl sulfoxide 4*
(see Experimental Section). A mixture consisting of
ꢀ80% unlabeled 4 and 20 % labeled 4 (i.e. 4*) was
then reacted with benzonitrile N-oxide 1 under condi-
tions [7] that directly produced 3-phenyl-5-isoxazole 2
(Scheme 2). The crude product of this reaction was con-
taminated only with by-products resulting from the phe-
nylsulfenous acid elimination (i.e. Ph2S2); purification
by flash column chromatography produced pure 2.
Phenyl vinyl sulfoxide 4 and its 2-substituted analogs
(RACH¼¼CHAS(O)APh) are among the useful dipolaro-
philes in the synthesis of isoxazoles via 1,3-dipolar cyclo-
addition, particularly, because subsequent elimination of
phenylsulfenous acid occurs spontaneously [7]. Maiorana
and coworkers investigated the regioselectivity of the
addition step in the 2-substituted systems based on the
distribution of the final isomeric oxazole products using
1H NMR spectroscopy and found that the regioselectivity
13C NMR analysis. Initial chemical shift assignment
of the isoxazole carbons in the 13C NMR spectrum of 2
was straightforward (see Experimental Section). In
C
V
2009 HeteroCorporation

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Regioselectivity of a 1,3-Dipolar Cycloaddition to Phenyl Vinyl Sulfoxide
1319
Scheme 1
earlier work, we definitively assigned the signal at d
161.48 to C3 by preparing 2 selectively 13C-lableled at
this position [8]. This was accomplished by using the
synthetic approach summarized in Scheme 2 beginning
with benzaldehyde oxime 13C-labeled at the oxime car-
bon. C4 and C5 (d 102.42 and 158.85, respectively)
were assigned by comparison with data from the NMR
literature [9].
The first row in Table 1 gives the integrated peak
areas observed in a natural abundance sample of 2. In
this case, the areas of C4 and C5 are roughly equal (C5/
C4 ¼ 1.12), and each is about three times the C3 peak
area. The second row gives 13C data observed when 2 is
prepared from a mixture that was ꢀ20% 13C1-enriched
phenyl 1-vinyl sulfoxide (4*) and 80% natural abun-
dance 4. As expected, the enrichment causes significant
Scheme 2
Journal of Heterocyclic Chemistry
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T. C. Gray, F. Hasanayn, D. P. Richardson, and J. H. Markgraf
Vol 46
1
Table 1
Data from 13C NMR analysis of 2.
mon integration practice in H NMR spectroscopy). In
this study, however, as we are comparing relative peak
areas for the same carbon atoms in isotopically-distinct
isomers, this limitation does not apply.
Integrated peak area ratio
C5/C3 C4/C3 C5/C4
DFT calculations and analysis. 1,3-Dipolar addition
reactions have been the subject of numerous electronic
structure investigations [10]. Among the earlier studies in
this area is work by Houk [11], which analyzed the fron-
tier MO interactions in cycloaddition reactions. Subse-
quent studies used increasingly more sophisticated theo-
retical tools to obtain more accurate activation and reac-
tions energies. However, elucidation and interpretation of
the factors that control reactivity and regioselectivity in
1,3-dipolar addition reactions remains debatable and an
active topic of research. For instance, Although Schleyer
searched for a role for the in plane aromaticity in the
cyclic transition states of 1,3-dipolar addition reactions
[12], Ponti and Molteni advocated a possible role for the
reactivity indices of the separate reactants in driving the
reactions in the context of hard-soft acid-base theory
[13]. More recently, Ess and Houk showed that the reac-
tivities of different 1,3-dipoles correlate with the energy
needed to distort the dipole and the dipolarophile to the
transition state geometries (Ezd) [14]. Because none of the
prior theoretical studies had considered any dipolar reac-
tions of a vinyl sulfoxide, we became interested in inves-
tigating the reaction we studied experimentally (1 þ 4)
using density functional theory. For this purpose, we used
the B3LYP and B3P86/6-31þG(d,p) levels of theory to
study the transition states (TS), and products of the actual
molecules used in the experiments. To present the results
in perspective, we also calculated the reactions between 1
and each of ethylene and propene. Relevant geometrical
parameters and energies of the reaction of 4 are presented
in Figure 1, and Table 2 compares the results for the three
alkenes considered.
Natural abundance
3.53
53.59
50.66
50.66
50.66
3.15
3.56
0.95
0.41
0.46
1.12
15.05
13C-Enricheda
13C 1st adjustmentb
13C 2nd adjustmentc
13C Final adjustmentd
a Observed areas when 2 is prepared from 4* with 17% 13C label at
the 1-position.
b Adjusted peak areas in the 13C-enriched experiment; obtained by sub-
tracting the contribution from natural abundance component (83% of
the area in row 1) from the observed area (row 2).
c Estimated distribution of the 13C label originating from 4* onto C5
and C4 before scaling (see Discussion).
d Scaled for C5/C4 relative sensitivity (1.12).
increase in the C5 and C4 peak areas relative to C3.
From the total amount of this increase, we can, in fact,
determine that a total of 17% of the product obtained in
the enriched experiment comes from labeled 4*. The
distribution of 13C from C1 of this component onto the
C5 and C4 positions in 2 (2a*/2b* in Scheme 2) pro-
vides the measure of regioselectivity in our reaction.
When the natural abundance 13C contributions from the
C1 and C2 carbons of the 4(83%)/4*(17%) mixture are
subtracted from the areas in row 2, the resulting data
(third row in Table 1) clearly show that in the reaction
of 4* with 1, the 13C label at C1 has been deposited
largely at the 5-position of the isoxazole ring. This
implies that C4 in 2 originates mostly from the C2 car-
bon of 4*, which is not labeled. If the reaction were
100% regioselective, the natural 13C abundance at C2 in
4* (1.108%) should produce a net peak area of 0.54 for
C4 in row 3 (i.e. 17% of the respective C4 value in row
1). As the observed area, 0.95, is larger by 0.41, this
excess area must have come from a small fraction of the
13C label at C1 in 4*, and this can now be used to make
a quantitative estimate of the regioselectivity. To do
this, we first scale the excess area by 1.12 to account
for the inherently greater sensitivity of C5 toward inte-
gration (i.e. C5/C4 ¼ 1.12 in row 1). Thus, our analysis,
based on the final, adjusted integrated 13C data (row 5),
affords an overall regioselectivity of 50.66:0.46, or
110:1, for the reaction between 1 and 4 (in dichloro-
ethane at 50ꢁC).
Figure 1 shows that the TS in which the oxygen atom
adds to the substituted carbon of 4 (TS3a) is 2.8 kcal/
mol lower in energy than the alternative TS where oxy-
z
gen adds to the terminal carbon (TS3b) z(DDGꢁ , at 298
K and 1 atm). A nearly identical DDGꢁ is obtained at
the B3P86 level, and this value remains largely
unchanged when the energies are calculated in a
dichloroethane solvent continuum. The computed regio-
selectivity agrees well with the estimated experimental
regioselectivity of 110:1, which affords and experimen-
tal DDGz ¼ 2.6 kcal/mol at 323 K. The calculations
reveal that the kinetic product (3a) is also the thermody-
namic product in the given reaction, with DDGꢁ ¼ 5.5
kcal/mol in favor of the isomer in which the S(O)Ph
substituent is attached at the 5-position before loss of
phenylsulfenous acid to give the isoxazole ring (Fig. 1).
In light of the recent studies by Ess and Houk [14],
we analyzed the calculated regioselectivity in reactions
It should be noted that, because of differences in
relaxation times (T1) and NOE effects between proto-
nated (i.e. C4, C5) and non-protonated carbons (i.e. C3),
integrated peak areas from Fourier-Transform 13C NMR
spectra acquired with standard pulse sequences cannot
be used to obtain accurate values for relative numbers
of carbons in the same molecule (in contrast to the com-
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Regioselectivity of a 1,3-Dipolar Cycloaddition to Phenyl Vinyl Sulfoxide
1321
˚
Figure 1. Selected B3LYP geometric parameters and energies of the transition states and products in the reaction between 4 and 1 (in A and
kcal/mol).
of 4 using the activation strain model. This model is
built on a thermodynamic cycle that gives the activation
energy (DEz) as the sum of a distortion energy (DEzd;
defined as the energy needed to distort the equilibrium
geometry of the reactants to the respective geozmetries in
the TS) and an electronic interaction term (DEint, for the
energy change that takes place when the distorted reac-
tants are brought to the TS). In our system, DEzd has a
term from the dipole (DEdz1) and another from the alkene
(DEzd2, Table 2). Each of these terms is larger for the
higher energy TS (TS3b). The net difference between
the total DEzd in the two TSs (DDEzd ¼ 2.9 kcal/mol) is
very close to the difference between the actual activa-
tion energies (DDEz ¼ 2.4 kcal/mol). This behavior is in
line with the general conclusions reached by Ess and
Houk [14] on the reactivities of 1,3-dipole addition
reactions.
Finally, to examine if S(O)Ph imparts any special
substituent effects on the dipolarophilicity of ethylene,
we calculated the reactions of ethylene and propene
with 1. The results are included in Table 2. In spite of
the large electronic difference among the given three
alkenes when the lower energy TS3a is considered, zthe
activation energy appears to be rather invariant: DGꢁ
¼
26.8, 27.2, and 25.8 kcal/mol, for Y ¼ H, CH3 or
S(O)Ph, respectively. The same holds for the reaction
energies: DGꢁrxn ¼ ꢂ23.3 (H), ꢂ22.7 (CH3), and ꢂ24.0
(S(O)Ph). Similarly, the calculated regioselectivity is
z
comparable for Y ¼ CH3 (DDGꢁ ¼ 3.3 kcal/mol) and
z
S(O)Ph (DDGꢁ ¼ 2.8 kcal/mol). Noticeably, the small
variations in the activation energies among the three
substituents correlate with the variation in the respective
distortion energies.
Table 2
B3LYP activation and reaction energies of addition of PhCNO (1) to substituted ethylene (CH2¼CHY).a
DEzd1
DEzd2
DGꢁrxn
z
Y
O adds to
DEz
DGꢁ
S(O)Ph
S(O)Ph
CH3
CH3
H
C1
C2
14.4
17.5
14.9
17.9
14.1
26.8
29.6
27.2
30.5
25.8
17.6
18.7
17.6
19.3
17.1
4.3
5.6
3.7
4.9
3.0
ꢂ24.0
ꢂ18.9
ꢂ22.7
ꢂ18.3
ꢂ23.3
C1
C2
C1 ¼ C2
z
DEz is the raw electronic activation energy without ZPE correction. DGꢁ and DGꢁrxn are the standard state activation and reaction free energies,
respectively, obtained at 298 K and 1 atm using unscaled harmonic vibrational frequencies. DEzd1 and DEdz2 are the energies needed to distort the
geometries of 1 and the alkene, respectively, to their corresponding parameters in the transition state. When Y ¼ S(O)Ph, the results are for the
lowest energy conformer.
a Units are in kcal/mol, relative to the separated reactants.
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T. C. Gray, F. Hasanayn, D. P. Richardson, and J. H. Markgraf
Vol 46
with saturated NH4Cl solution (3 mL), and extracted with
CH2Cl2. The extract was washed with water (2 ꢃ 10 mL),
dried (anhydrous Na2SO4), and evaporated to give 0.092 g of
crude product 2. Purification by flash liquid chromatography
(4:1 hexane:ethyl acetate on flash silica gel) removed the
Ph2S2 by-product and afforded 2 as a pale yellow oil in ca.
94% purity by GC-MS analysis. 13C NMR (deuteriochloro-
form) d 102.42 (C4), 126.86 (C20/30; assignments may be
interchanged), 128.76 (C10), 128.91 (C20/30; assignments may
be interchanged), 130.00 (C40), 158.85 (C5), 161.48 (C3).
Computational methods. All computations were carried
out using Gaussian 03. [19]. The B3LYP [20] and B3P89 [21]
levels of theory and the standard 6-31þG(d,p) basis set [22]
were used to optimize the reactants, transition states, and prod-
ucts for normal mode vibrational analysis. Several conformers
defined by rotation of the S(O)Ph group were considered for
the transition state and products, but we report only the results
for the lowest energy conformer. Solvent effects were calcu-
lated via single point calculations on the gas phase optimized
geometries using the polarizable continuum model (PCM)
[23].
Overall, the DFT calculations support the experimen-
tal quantification of the regioselectivity in the reaction
between 1 and 4 made from the integrated 13C areas of
the final product (2). The calculations confirm that the
observed regioselectivity is not the result of any special
effects provided by the S(O)Ph group.
EXPERIMENTAL
Melting points were determined on a MelTemp apparatus.
Extracts were dried over Na2SO4, and solvents were removed
by rotary evaporation at reduced pressure. Product purities
were determined by gas chromatography-mass spectrometry
analysis on a Hewlett Packard HP 6890 system equipped with
a HP-5MS crosslinked diphenyl (5%) dimethyl (95%) polysi-
loxane capillary column (30 m ꢃ 0.25 mm ꢃ 0.25 lm film), a
5973 mass selective detector, and a HP Kayak XA computer.
NMR spectra were measured at 298 K with a Bru¨ker Avance
DRX 500 MHz NMR spectrometer operating at frequencies of
500.630 (1H) and 125.884 (13C) using a standard 5 mm broad-
1
band multinuclear (PABBO) probehead (90ꢁ pulse widths: H,
Acknowledgment. This work was supported by a Senior Scien-
tist Mentor Initiative Award from The Camille and Henry Drey-
fus Foundation, Inc. (Award SI-00-031 to J. Hodge Markgraf).
Computer resources provided by NCSA grant CHE060011N are
gratefully acknowledged. Additional support was provided by the
Williams College Faculty Research Fund. The authors thank
Deborah Morandi for assistance with preparation of the
manuscript.
11.5 ls; 13C, 6.0 ls). Chemical shifts (ppm) were measured
relative to internal Me4Si (1H) or internal CDCl3 (13C). 13C
chemical shifts were measured using a standard power gated
decoupling pulse sequence (zgpg30) from the Bru¨ker pulse
sequence library. Spectral windows for 13C acquisitions were
set at 240 ppm, and a total of ca. 300 scans of 32 k data points
were collected and then zero-filled to 64 k points before Fou-
rier transformation. The recycle delay (D1) was set at 2 s.
Phenyl 1-13C-vinyl sulfoxide (4). The synthesis of phenyl
vinyl sulfoxide selectively 13C-labeled in the 1-position began
with a sample of ca. 20% 13C-enriched 1-13C-ethyl iodide that
was prepared by mixing 4 volumes of unlabeled ethyl iodide
(Sigma–Aldrich, 17780) with 1 volume of 99% atom purity
1-13C-ethyl iodide (Cambridge Isotope Laboratories, CLM-
1025). As shown in Scheme 2, preparation of phenyl 1-13C-
vinyl sulfoxide 4 proceeded from labeled ethyl iodide via the
sequence: 1-13C-ethyl phenyl sulfide 5 [15] to 1-13C-chlor-
oethyl phenyl sulfide 6 [16] to phenyl 1-13C-vinyl sulfide 7
[17] to 4 [18], following methods that have been reported pre-
viously. The crude product was used for the subsequent syn-
thesis of 2; GC-MS analysis of crude 4 showed that it was at
least 94% pure.
3-Phenyl-5-13C isoxazole (2). We have reported a general
synthesis of unlabeled 3-phenyl-5-isoxazole beginning from
benzaldehyde oxime previously [7a]. Adaptation of this
method using phenyl 1-13C-vinyl sulfoxide 4 afforded 3-phe-
nyl-5-13C isoxazole 2, as follows. To a solution of N-chloro-
succinimide (0.119 g, 0.8913 mmol) and pyridine (4 lL, 0.124
mmol) in 1,1,2-trichloroethane (TCE) (1.0 mL) was added
benzaldehyde oxime (0.098 g, 0.809 mmol; Aldrich 245674)
and the solution was stirred at 50ꢁC for 30 min. A solution of
phenyl 1-13C-vinyl sulfoxide 4 (0.138 g, 0.905 mmol) and trie-
thylamine (0.12 mL, 0.86 mmol) in TCE (98 lL) was added
dropwise via Pasteur pipet over 3 min. The solution was
stirred at 50ꢁC for 20 min and then heated to reflux for an
additional 60 min. The reaction mixture was cooled to room
temperature and evaporated to dryness, and the residue was
treated with 2M NaOH (5 mL). The mixture was heated at
reflux for 35 min, cooled to room temperature, neutralized
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet