Inverse kinetic isotope effect in Magtrieve mediated oxidation or deoximation of benzaldoxime: Mechanistic implication

Article abstract of DOI:10.1016/j.tetlet.2012.01.111

Magtrieve (CrO₂) mediated reactions with benzaldoxime (1a) and its deuterium congener (d-1a) led to the observation of inverse deuterium kinetic isotope effect (i-DKIE) for the substrate's oxidation (Eq. 1a) as well as deoximation (Eq. 2a) proc

Full text of DOI:10.1016/j.tetlet.2012.01.111

Tetrahedron Letters 53 (2012) 1794–1797
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Inverse kinetic isotope effect in Magtrieve™ mediated oxidation
or deoximation of benzaldoxime: mechanistic implication
Sandeep Bhosale a, Dnyaneshwar P. Sonune a, Uppuleti Viplava Prasad b, Debnath Bhuniya a,
⇑
a Drug Discovery Facility, Advinus Therapeutics, Quantum Towers, Plot-9, Rajiv Gandhi Infotech Park, Phase-I, Hinjewadi, Pune 411057, India
b Department of Organic Chemistry, Andhra University, Visakhapatnam 530003, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Magtrieve™ (CrO2) mediated reactions with benzaldoxime (1a) and its deuterium congener (d-1a) led to
the observation of inverse deuterium kinetic isotope effect (i-DKIE) for the substrate’s oxidation (Eq. 1a)
as well as deoximation (Eq. 2a) process. Disappearance of the starting material 1a and formation of the
products—1,3-dipolar cycloaddition product (4a) as well as benzaldehyde (3a)—followed a typical 1st-
order kinetics. The observed kD/kH values, in the range of 2–4, suggest for a strong secondary isotope
effect which was further evidenced by the fact that d-labeling was retained in 3a. Therefore, the observed
i-SDKIE supports our original hypothesis that aldoxime (with sp2-C) interacts with CrO2 in a rate deter-
mining step to form a tetrahedral (now with sp3-C) structure, possibly like 6, which may act as a common
intermediate for both the pathways.
Received 16 December 2011
Revised 23 January 2012
Accepted 25 January 2012
Available online 6 February 2012
Keywords:
Magtrieve™
Aldoxime
Inverse secondary deuterium kinetic isotope
effect
Ó 2012 Elsevier Ltd. All rights reserved.
Recently, we have demonstrated that Magtrieve™ (CrO2) is an
effective oxidizing agent for the conversion of aldoxime (1) to nitrile
oxide (2), a versatile intermediate in organic synthesis.1a Often, min-
or amount of aldehyde (3) is also formed as a result of deoximation
of the aldoxime. Subsequently, we have reported that, such reaction
course is strongly perturbed in the presence of a stable radical like
TEMPO yielding the aldehyde as an exclusive product.1b From the
latter study, it is inferred that, a radical pathway might be involved
in the oxidation process, whereas, the deoximation reaction could
be explained by a kind of disproportion of a CrO2Áaldoxime adduct.
Results from our previous studies are summarized in Scheme 1. Sub-
sequently, we endeavored to investigate deuterium kinetic isotope
effect (DKIE)2,3 in these reactions (Eqs. 1 and 2).
In this Letter, we communicate our new observation of large
inverse secondary deuterium kinetic isotope effect (i-SDKIE)4 in
both the type of reactions: (i) oxidation to nitrile oxide (Eq. 1),
and (ii) deoximation to aldehyde (Eq. 2).
Benzaldoxime (1a) and its congener d-benzaldoxime (d-1a)
were chosen to study the kinetics (Scheme 2). Initial experiments
were carried out following our previously reported standard condi-
tion, that is, using 10 mol equiv of CrO2 as oxidizing agent, and
heating at 80 °C in MeCN solvent (0.2 M with respect to aldox-
ime).1 As benzonitrile oxide (2a) is not practical to isolate, forma-
tion of the corresponding 1,3-dipolar cycloaddition product 4a was
considered as a surrogate to monitor the progress of nitrileoxide
formation.
During the early trials, following two observations were made.
Firstly, the use of d-1a consistently led to faster reactions—both
for Eqs. 1a and 2a—indicative of i-DKIE (reactions monitored by
TLC as well as by HPLC). Secondly, aldehyde—the deoximation
product—retained the deuterium label, indicating for a SDKIE (con-
firmed by comparing Mass, and NMR spectra with an authentic
compound).
Subsequently, for all kinetic experiments, reactions were set as
per our reported procedure1 with the changes that 0.1 M aldoxime
concn, and 1.0 equiv TEMPO were used (Scheme 2).11,12 Progress of
the reactions was monitored by taking aliquots at different time
points, and quantifying the starting materials and products by
HPLC. Representative chromatographic profile for the reactions as
depicted in Eqs. 1a and 2a is presented in Figure 1a and b. Detailed
-
CrO2 (10 equiv), 80 oC,
~2h
O
N
O
H
+
+
R
Eq. 1 (Ref. 1a)
R
2
OH
N
3
(major)
R
1
Eq. 2 (Ref. 1b)
O
H
(0.2 M
in MeCN)
3 (exclusive)
R
CrO2 (10 equiv), TEMPO
(1 equiv), 80 oC, ~15 mins
⇑
Corresponding author. Tel.: +91 20 66539600; fax: +91 20 66539620.
E-mail address: debnath.b@advinus.com (D. Bhuniya).
Scheme 1. Effect of TEMPO in CrO2 mediated oxidation of aldoximes.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.111

S. Bhosale et al. / Tetrahedron Letters 53 (2012) 1794–1797
1795
CrO2 (10 equiv),
H
CrO2 (10 equiv),
MeCN (0.1 M),
80 oC
TEMPO (1.0 equiv),
MeCN (0.1 M),
80 oC
Ph
-
O
OH
N
CO2Et
N
O
H(D)
O
H(D)
+
N
H(D)
O
+
Ph
Ph
Ph
1a
Eq 2a
Eq 1a
Ph
CO2Et
3a
3a
4a
2a
Scheme 2. Reactions chosen for studying kinetic isotope effect.
(b) For the conversion of d-1a into d-3a as shown in Eq 2a.
(a) For the conversion of d-1a into 4a and d-3a as shown in Eq 1a.
4a (RT: 2.67 min)
d-1a (RT: 1.79 min)
d-3a (RT: 1.51 min)
d-3a (RT: 1.32 min)
TEMPO
(RT: 2.49 min)
d-1a (RT: 1.67 min)
100 min
60 min
40 min
30 min
20 min
10 min
20 min
5 min
10 min
5 min
1 min
RT (min)
RT (min)
Figure 1. Representative chromatograghic profile to monitor progress of the reactions as depicted in Scheme 2. Corresponding HPLC signals for the starting material 1a (d-1a)
and for the products 3a (d-3a) and 4a were characterized by HPLC-Mass as well as by matching with the authentic compounds.13,14 At each time point, 100
L of aliquot was
withdrawn from the reaction mixture (0.1 M with respect to starting concn of 1a; initial solvent content of 8.2 mL), which was then diluted by 10 times, before injecting
2.0
L of latter stock solution into HPLC for analysis using UV detector (kmax set at 260 and 245 nm for Eqs. 1a and 2a, respectively).11,12 Detailed HPLC conditions and
protocols are given as Supplementary data.
l
l
(b) Formation of 3a (Eq 1a)
(c) Formation of 4a (Eq 1a)
4ad-1a (r2=0.97)
4a1a (r2=0.99)
(a) Consumption of 1a (Eq 1a)
25
20
15
10
5
100
80
60
40
20
0
d-3a (r2=0.98)
d-1a (r2=0.99)
1a (r2=0.98)
100
80
60
40
20
0
3a (r2=0.95)
i-SDKIE=2.35
i-SDKIE=1.73
i-SDKIE=2.82
0
0
20
40
60
80
100
120
0
20
40
60
80
100
120
0
20
40
60
80
100
120
Time (min)
Time (min)
Time (min)
(d) Consumption of 1a (Eq 2a)
(e) Formation of 3a (Eq 2a)
100
80
60
40
20
0
d-1a (r2=0.96)
1a (r2=0.97)
100
80
60
40
20
0
i-SDKIE=3.75
d-3a (r2=0.99)
3a (r2=0.98)
i-SDKIE=3.89
0
10
20
30
40
0
10
20
30
40
Time (min)
Time (min)
Figure 2. Kinetic plots for Eqs. 1a and 2a. Real time concentration of starting materials 1a (d-1a) and products 3a (d-3a) and 4a were derived from the observed area under
the HPLC signals as exemplified in Figure 1 followed by quantification based on HPLC comparison with the authentic compounds. For detailed HPLC analysis, Supplementary
data is referred. Plots were generated using PRISM (GraphPad Software). Best fit non-linear curves were obtained using one phase decay equation: Y = (Y0ÀPla-
teau)Ãexp(ÀkÃt) + Plateau; Y is [C]rxn in mM; t is time in min; Y0 is Y at 0 min; k is the rate constant. For Eq. 1a, graph parameters: (i) Y0 = 100 mM and Plateau = 0 mM for 1a
(based on 100% consumption); (ii) Y0 = 0 mM and Plateau = 82 mM for 4a (based on a max of 82% yield); (iii) Y0 = 0 mM and Plateau = 18 mM for 3a (based on a max of 18%
yield). For Eq. 2, graph parameters: (i) Y0 = 100 mM & Plateau = 0 mM for 1a (based on 100% consumption); (ii) Y0 = 0 mM & Plateau = 100 mM for 3a (based on a max of 100%
yield).

1796
S. Bhosale et al. / Tetrahedron Letters 53 (2012) 1794–1797
HPLC methods and protocols for the estimation of real time concn
of the starting materials and products are given in the Supplemen-
tary data (Table S1–S12). The data of time versus the estimated
concentrations of 1a (d-1a), 3a (d-3a) and 4a, thus obtained, were
subsequently used to derive kinetic plots as shown in Figure 2a–e.
Whereas, oxidation (Eq. 1a) of benzaldoxime (1a) took almost
200 min to reach a near completion stage, the corresponding deu-
terium congener (d-1a) required about 100 min (Fig. 2a). Similarly,
the deoximation reaction (Eq. 2a) was essentially over by 20 min
for d-1a, however, it required 55 min for 1a to reach a near comple-
tion status (Fig. 2d). These reactions appear to follow pseudo 1st
order kinetics, as the best fit curves were achieved with r2 values
very close to 1 by applying a single phase decay equation (a Stan-
dard PRISM GraphPad Software used). It is reasonable to assume
that the reactions progressed on heterogenous surface of CrO2,
explain the observed 1st order kinetics. Values of inverse kinetic
isotope effects (i-KIE) were derived from ratio of the decay con-
stants that is kD/kH (k values obtained using the PRISM file). These
are presented in Table 1.
The observed i-SDKIE values, in the range of about 2–4 (Table 1)
for both the reactions (Scheme 2), provide a strong evidence for con-
version of sp2-C center into sp3-C one in the rate determining step.15
Therefore, the present data fit well to our originally proposed1b reac-
tion mechanism, that, aldoxime (with sp2-C) initially forms an ad-
duct (like structure 5) on CrO2 surface which subsequently
undergoes a rearrangement process to form a tetrahedral (now with
sp3-C) structure (like 6) in the rate determining step (Fig. 3).
Intermediate 6 could be a common intermediate for both the
pathways—nitrile oxide formation as well as deoximation. It is
important mentioning here that the conversion of structures like
5 to 6 was also proposed by Shinada and Yoshihara16 while pre-
dicting mechanism of MnO2 mediated deoximation of carbonyl
compounds.
In summary, a strong and inverse secondary deuterium kinetic
isotope effect was observed in CrO2 mediated oxidation as well as
deoximation of benzaldoxime (1a). These results provide further
evidence to the previously proposed mechanism of Magtreive™
and possibly for MnO2 mediated conversion of aldoximes to nitrile
oxides (Eq. 1) as well as aldehydes (Eq. 2). Certainly, the present
research outcome provides a new scope in physical organic chem-
istry to completely unveil the mechanism of the general reactions
described in Eqs. 1 and 2 by conducting more systematic kinetic
studies with appropriately substituted benzaldoximes.
Acknowledgments
Authors are grateful to Drs. Rashmi Barbhaiya and Kasim A.
Mookhtiar for their support and encouragement. Dr. Mahesh Mone
is being specifically acknowledged for analytical support. Advinus
Publication No. ADV-A-017.
Supplementary data
Supplementary data (HPLC method, protocol and measurement
of real-time concentrations of 1a (d-1a), 3a (d-3a) and 4a) associ-
ated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2012.01.111.
References and notes
Table 1
1. (a) Bhosale, S.; Kurhade, S.; Prasad, U. V.; Palle, V. P.; Bhuniya, D. Tetrahedron
Lett. 2009, 50, 3948–3951. and the references cited herein; (b) Bhosale, S.;
Kurhade, S.; Vyas, S.; Palle, V. P.; Bhuniya, D. Tetrahedron 2010, 66, 9582–9588.
2. For the basis of kinetic isotope effects, please see: (a) Melander, L. C. S.;
Saunders, W. In Reaction Rates of Isotopic Molecules; Krieger: Malabar, FL, 1987;
(b) Anslyn, E. V.; Dougherty, D. A. In Modern Physical Organic Chemistry;
University Science Books: Sausalito, California, 2005. Chapter 8: Experiments
Related to Thermodynamics and Kinetics.
3. For review articles on kinetic isotope effects in organic and organometallic
reactions, please see: (a) Scheppele, S. E. Chem. Rev. 1972, 72, 511–532; (b)
Matsson, O.; Westaway, K. C. Adv. Phys. Org. Chem. 1999, 31, 143–248; (c)
Westaway, K. C. Adv. Phys. Org. Chem. 2006, 41, 217–273; (d) Gómez-Gallego,
M.; Sierra, M. A. Chem. Rev. 2011, 111, 4857–4963.
Kinetic parameters in Eqs. 1 and 2a
Eq.
Decay constant, k (10À3 minÀ1
)
i-SDKIE
(kD/kH)
Expression
H-congener
D-congener
Eq. 1a
Eq. 2a
À(d[1a]/dt)/[1a]
(d[3a]/dt)/[1a]
(d[4a]/dt)/[1a]
À(d[1a]/dt)/[1a]
(d[3a]/dt)/[1a]
15.91
11.66
16.45
73.06
61.59
37.49
32.86
28.51
273.8
240.0
2.35
2.82
1.73
3.75
3.89
a
Values obtained form PRISM plot.
4. For examples of inverse deuterium kinetic isotope effect (i-DKIE) reported in
various organic reactions, which are relevant for the present work, please see:
Refs. 5–10. In most of the cases, modest secondary DKIEs (1.0 < kD/kH < 2.0)
have been reported. For examples of large i-DKIE (kD/kH > 2.0), see Refs. 9a,10.
5. Unusual case in SN2 reaction: Gronert, S.; Fagin, A. E.; Wong, L. J. Am. Chem. Soc.
2007, 129, 5330–5331.
6. Addition or substitution reactions to carbonyl or ester functionalities: (a)
Amaral, L. Do; Bull, H. G.; Cordes, E. H. J. Am. Chem. Soc. 1972, 94, 7579–7580;
(b) Wigfield, D. C.; Gowland, F. W. Tetrahedron Lett. 1979, 24, 2205–2208; (c)
Gajewski, J. J.; Bocian, W.; Brichford, N. L.; Henderson, J. L. J. Org. Chem. 2002,
67, 4236–4240. and the references cited herein; (d) Rogers, C. J.; Dickerson, T. J.;
Janda, K. D. Tetrahedron 2006, 62, 352–356; (e) Dam, J. H.; Fristrup, P.; Madsen,
R. J. Org. Chem. 2008, 73, 3228–3235; (f) Tormos, J. R.; Wiley, K. L.; Wang, Y.;
Fournier, D.; Masson, P.; Nachon, F.; Quinn, D. M. J. Am. Chem. Soc. 2010, 132,
17751–17759.
OH
O
Cr
(d-
TS
)
TS
N
O
Ph
H(D)
TS
d-
TS
7. Cycloaddition reactions (a) Mataka, S.; Ma, J.; Tsuzuki, H.; Nishiyama, K.;
Thiemann, T.; Tashiro, M. Rep. Inst. Adv. Mat. Study 1996, 10, 93–94; (b)
Singleton, D. A.; Hang, C. J. Am. Chem. Soc. 1999, 121, 11885–11893.
8. Electrophilic aromatic substitution: Tunge, J. A.; Foresee, L. N. Organometallics
2005, 24, 6440–6444.
9. Electrophilic bromination of olefin: (a) Nagorski, R. W.; Slebocka-Tilk, H.;
Brown, R. S. J. Am. Chem. Soc. 1994, 116, 419–420; (b) Sleboeka-Tilk, H.;
Neverov, A.; Motallebi, S.; Brown, R. S.; Donini, O.; Gainsforth, J. L.;
Klobukowski, M. J. Am. Chem. Soc. 1998, 120, 2578–2585.
10. Metal-hydride transfer: (a) Janak, K. E.; Churchill, D. G.; Parkin, G. Chem.
Commun. 2003, 1, 22–23; (b) Churchill, D. G.; Janak, K. E.; Wittenberg, J. S.;
Parkin, G. J. Am. Chem. Soc. 2003, 125, 1403–1420.
11. Typical procedure for monitoring the reaction under Eq. 1a. To a solution of
benzaldoxime 1a (100 mg, 0.82 mmol, 1.0 equiv) and ethyl acrylate (248 mg,
2.48 mmol, 3.0 equiv.) in 8.2 mL acetonitrile (0.1 M with respect to 1a),
Magtrieve™ (693 mg, 8.25 mmol, 10 equiv) was added in one portion and
the reaction mixture was stirred at 80 °C (preheated oil bath). To monitor
>
AEH AHD
AEH
6
d-
AED
6
OH
sp3-C
O
Cr
O
OH
O
N
Cr
O
N
Ph
sp2-C
H(D)
Ph
H(D)
(d
5
d
-5
(d- )
6
6
)
-5
5
Figure 3. Structures of 5 and 6 to fit the theory of inverse SDKIE.

S. Bhosale et al. / Tetrahedron Letters 53 (2012) 1794–1797
1797
progress of the reaction, aliquots were collected at 5, 10, 20, 40, 60, 80, 100,
140, and 200 min for analysis using HPLC. For d-1a, additional aliquots were
collected at 15, 30 and 50 mins as the reaction was faster compared to the
13. Benzaldoximes 1a and d-1a were prepared in-house from 3a and d-3a (Alfa
Aesar, CAS 3592-47-0, Stock H51103), and the analytical data were
#
compared with the authentic compounds used in our previous study (Ref.
1b). Characteristic signals: (i) in 1H NMR (400 MHz; CDCl3): d 8.15 (s, oximino-
CH) for 1a which is missing for d-1a; (ii) in 13C NMR (100 MHz; CDCl3): d
150.57 (s, oximino-C) for 1a and 150.29 (t, J = 25 Hz, oximino-C) for d-1a; (iii)
Mass (m/z): 122.2 [M+1] for 1a which is 123.2 [M+1] for d-1a.
H-congener. At each time point, 100 lL of aliquot was withdrawn and was
immediately diluted by 10 times with cold MeCN to obtain a stock solution
suitable for HPLC analysis. Separately, a stock solution of 10 mM 1a in MeCN
was used as equivalent to 0 min aliquot. All the stock solutions were stored at
0 °C, and 2.0
(UV detection done at kmax = 260 nm).
l
L of the stock solutions were injected to the HPLC for analyses
14. Authentic 4a was obtained in pure form after column chromatography
(67.2 mg, 75%) starting from 50.0 mg of 1a in a separate reaction. 1H NMR
(400 MHz; DMSO-d6): d 1.23 (t, J = 7.1 Hz, 3H), 3.62 (dd, J = 17.4, 6.6 Hz, 1H),
3.78 (dd, J = 17.4, 12.0 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 5.27 (dd, J = 12.0, 6.6 Hz,
1H), 7.42–7.52 (aromatics, 3H), 7.66–7.74 (aromatics, 2H). 13C NMR (100 MHz;
CDCl3): d 14.03, 38.75, 61.87, 78.01, 126.84(2C), 128.51, 128.69(2C), 130.39,
155.97, 170.11. MS (m/z): 220.3 [M+1] base peak.
12. Typical procedure for monitoring the reaction under Eq. 2a. To a solution of
benzaldoxime 1a (100 mg, 0.82 mmol, 1.0 equiv) and TEMPO (128 mg,
0.82 mmol, 1.0 equiv), in 8.2 mL acetonitrile (0.1 M with respect to 1a),
Magtrieve™ (693 mg, 8.25 mmol, 10 equiv) was added in one portion, and
the reaction mixture was stirred at 80 °C (preheated oil bath). To monitor
progress of the reaction, aliquots were collected at 1, 5, 10, 15, 20, 25, 30, 40,
and 55 min for analysis using HPLC. For d-1a, additional aliquots were
15. For theory behind the observation of inverse SDKIE upon
a
change in
hybridization from sp2-C to sp3-C in
examples, see: (a) Refs. 2,3d,6c,d,9b.
a rate determining step, and some
collected at
2 and 7 min as the reaction was faster compared to the
H-congener. Aliquot processing protocol and HPLC analysis method were
16. Shinada, T.; Yoshihara, K. Tetrahedron Lett. 1995, 36, 6701–6704.
same as for Eq. 1a except that UV detector was set at kmax = 245 nm.