Retro-Diels-Alder reaction of 4H-1,2-benzoxazines to generate o-quinone methides: Involvement of highly polarized transition states

Article abstract of DOI:10.1021/jo702246w

(Chemical Equation Presented) Here, we describe mechanistic studies of the retro-Diels-Alder reaction of 4H-1,2-benzoxazines bearing various substituents on the benzene ring. 4H-1,2-Benzoxazines are very simple, but quite new, heterocyclic compounds that afford substituted o-quinone methides (o-QMs) through retro-Diels-Alder reaction under mild thermal conditions. The resultant o-QMs undergo Diels-Alder reaction in situ with dienophiles to give phenol and chroman derivatives. The mechanism of the generation of o-QMs has been little studied. Our experimental and density functional theory (DFT) studies have yielded the following results. (1) The generation of o-QMs, i.e., the retro-hetero-Diels-Alder reaction of 4H-1,2-benzoxazines, is rate determining, rather than the subsequent Diels-Alder reaction of the resultant o-QM with dienophiles. (2) The reaction rate is strongly influenced by the electronic features of substituents and the polarity of the solvent. The reaction proceeds faster in a polar solvent such as dimethyl sulfoxide, probably because of stabilization of the electronically polarized TS structure. (3) The reactions show characteristic positional effects of substitution on the benzene ring. While an electron-withdrawing group such as CF₃ at C₅, C₆, or C₇ positions decelerates the reaction, the same substituent at C₈ accelerates the reaction, compared with the reaction of unsubstituted 4H-1,2-benzoxazine. In particular, substitution at C₅ significantly decelerates the reaction as compared with the unsubstituted case. This is due to the difference in the inductive effect of CF₃ at the different positions. Similar positional effects occur with a halogen (Cl) and a nitro group. All these data support the involvement of polarized TS structures, in which the O-N bond cleavage precedes the C-C bond cleavage.

Full text of DOI:10.1021/jo702246w

Retro-Diels-Alder Reaction of 4H-1,2-Benzoxazines to Generate
o-Quinone Methides: Involvement of Highly Polarized
Transition States
Hiromichi Sugimoto, Satoshi Nakamura,† and Tomohiko Ohwada*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
ohwada@mol.f.u-tokyo.ac.jp
ReceiVed October 18, 2007
Here, we describe mechanistic studies of the retro-Diels-Alder reaction of 4H-1,2-benzoxazines bearing
various substituents on the benzene ring. 4H-1,2-Benzoxazines are very simple, but quite new, heterocyclic
compounds that afford substituted o-quinone methides (o-QMs) through retro-Diels-Alder reaction under
mild thermal conditions. The resultant o-QMs undergo Diels-Alder reaction in situ with dienophiles to
give phenol and chroman derivatives. The mechanism of the generation of o-QMs has been little studied.
Our experimental and density functional theory (DFT) studies have yielded the following results. (1)
The generation of o-QMs, i.e., the retro-hetero-Diels-Alder reaction of 4H-1,2-benzoxazines, is rate
determining, rather than the subsequent Diels-Alder reaction of the resultant o-QM with dienophiles.
(2) The reaction rate is strongly influenced by the electronic features of substituents and the polarity of
the solvent. The reaction proceeds faster in a polar solvent such as dimethyl sulfoxide, probably because
of stabilization of the electronically polarized TS structure. (3) The reactions show characteristic positional
effects of substitution on the benzene ring. While an electron-withdrawing group such as CF3 at C5, C6,
or C7 positions decelerates the reaction, the same substituent at C8 accelerates the reaction, compared
with the reaction of unsubstituted 4H-1,2-benzoxazine. In particular, substitution at C5 significantly
decelerates the reaction as compared with the unsubstituted case. This is due to the difference in the
inductive effect of CF3 at the different positions. Similar positional effects occur with a halogen (Cl) and
a nitro group. All these data support the involvement of polarized TS structures, in which the O-N bond
cleavage precedes the C-C bond cleavage.
Introduction
been reported,3 but in most cases, the substrates have been
confined to compounds containing bicyclo[2.2.1]heptane struc-
tures, which afford cyclopentadienes and olefins through the
cleavage of two C-C bonds. Recently, however, o-quinone
methides (o-QMs) bearing various substitutents on the benzene
In spite of its limited popularity, the retro-Diels-Alder
reaction has evolved as a useful protocol and remains the
preferred method for the preparation of several reactive olefins
or metastable molecular entities.1,2 A few experimental and
theoretical investigations of retro-Diels-Alder reactions have
(3) (a) Manka, J. T.; Douglass, A. G.; Kaszynski, P.; Friedli, A. C. J.
Org. Chem. 2000, 65, 5202-5206. (b) Wijnen, J. W.; Engberts, J. B. F. N.
J. Org. Chem. 1997, 62, 2039-2044. (c) Jenner, G.; Papadopoulos, M.;
Rimmelin, J. J. Org. Chem. 1983, 48, 748-749. (d) Desimoni, G.; Faita,
G.; Pasini, D.; Righetti, P. P. Tetrahedron 1992, 48, 1667-1674. (e) Patil,
M. P.; Sunoj, R. B. Org. Biomol. Chem. 2006, 4, 3923-3930. (f) Kotha,
S.; Banerjee, S.; Patil, M. P.; Sunoj, R. B. Org. Biomol. Chem. 2006, 4,
1854-1856. (g) Birney, D.; Lim, T. K.; Koh, J. H. P.; Pool, B. R.; White,
J. M. J. Am. Chem. Soc. 2002, 124, 5091-5099.
* Address correspondence to this author. Fax: +81-3-5841-4735.
† Current address: School of Chemistry, University of Edinburgh, The King’s
Buildings, West Mains Road, Edinburgh EH9 3JJ, United Kingdom.
(1) Klunder, A. J. H.; Zhu, J.; Zwanenburg, B. Chem. ReV. 1999, 99,
1163-1190.
(2) Ichihara, A. Synthesis 1987, 207-222.
10.1021/jo702246w CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/01/2007
10088
J. Org. Chem. 2007, 72, 10088-10095

Retro-Diels-Alder Reaction of 4H-1,2-Benzoxazines
SCHEME 1. Generation of o-QMs from
4H-1,2-Benzoxazines
can occur. In addition, there have been few studies of the
generation and applications of o-QMs containing a variety of
substituents attached at different positions. Recently, the
aromatic substituent effect on the reactivity of o-QMs for 1,4-
conjugate addition has been studied, and it turned out to be of
potential significance.6p Rokita et al. have reported substituent
effects on the rates of nucleophilic 1,4-conjugate addition of
some substituted o-QMs, particularly at the C6 and C7 positions,
and they showed that electronic perturbation of o-QMs by a
substituent greatly influenced their stability and reactivity.6p It
is possible that the electronic nature of substituents would
similarly have a great influence on the Diels-Alder reaction
of o-QMs.
In the present retro-Diels-Alder reaction of 4H-1,2-benzox-
azine, a single C-C bond and a single O-N bond in the
asymmetrical six-membered ring are broken, in contrast to the
cleavage of two equivalent C-C bonds in the case of bicyclo-
[2.2.1]heptane derivatives. While this retro-Diels-Alder reac-
tion, which involves bond cleavage between heteroatoms, can
generate O-containing reactive intermediates (o-QMs), the
mechanism of this kind of asymmetric retro-hetero-Diels-Alder
reactions is not well understood.13 Herein, we show first that
this retro-Diels-Alder reaction process, rather than the Diels-
Alder reaction process of the resultant o-QMs with dienophiles,
is the rate-determining step in the overall reaction, and second
that there are significant impacts of the nature and position of
the substituent and the polarity of the solvent on the retro-hetero-
Diels-Alder reaction process of 4H-1,2-benzoxazines. We show
that these features can be attributed to the polarized nature of
the transition structures, on the basis of experimental kinetic
studies and DFT calculations.
ring have been generated through the thermal retro-Diels-Alder
reaction of 4H-1,2-benzoxazines (Scheme 1).4,5
o-QMs are highly reactive, short-lived intermediates. They
undergo 1,4-conjugate addition with nucleophiles6,7 and Diels-
Alder cycloaddition with various dienophiles,6,7 affording ortho-
functionalized phenol and chroman derivatives with high
chemo-, regio-, and stereoselectivities. This chemistry has been
utilized for the synthesis of chroman structures found in several
natural products.7,8 Many thermal methods to generate o-QMs
in situ from various precursors have been reported,7 but most
of them involve various disadvantages, including inaccessibility
of precursors,7 undesirably high reaction temperature,7,9 long
reaction time,7,9,10 a need for additional catalysts,7,11 and
acidic7,11 or basic conditions,6m,7,12 and in all cases, side reactions
(4) Sugimoto, H.; Nakamura, S.; Ohwada, T. AdV. Synth. Catal. 2007,
349, 669-679.
(5) For recent reports on 4H-1,2-benzoxazines, see: (a) Ohwada, T.; Ohta,
T.; Shudo, K. Tetrahedron 1987, 43, 297-305. (b) Ohwada, T.; Shudo, K.
Yakugaku Zasshi 1989, 109, 1-11. (c) Ohwada, T.; Okabe, K.; Ohta, T.;
Shudo, K. Tetrahedron 1990, 46, 7539-7555. (d) Hirotani, S.; Zen, S.
Yakugaku Zasshi 1994, 114, 272-276. (e) Hirotani, S.; Kaji, E. Tetrahedron
1999, 55, 4255-4270. (f) Supsana, P.; Tsoungas, P. G.; Vavounis, G.
Tetrahedron Lett. 2000, 41, 1845-1847. (g) Cotelle, P.; Vezin, H.
Tetrahedron Lett. 2001, 42, 3303-3305. (h) Supsana, P.; Tsoungas, P. G.;
Aubry, A.; Skoulika, S.; Varvounis, G. Tetrahedron 2001, 57, 3445-3453.
(i) Rousseau, B.; Rosazza, J. P. N. J. Agric. Food Chem. 1998, 46, 3314-
3317. (j) Napolitano, A.; d’Ischia, M. J. Org. Chem. 2002, 67, 803-810.
(k) Yato, M.; Ohwada, T.; Shudo, K. J. Am. Chem. Soc. 1990, 112, 5341-
5342. (l) Nakamura, S.; Uchiyama, M.; Ohwada, T. J. Am. Chem. Soc.
2003, 125, 5282-5283. (m) Nakamura, S.; Sugimoto, H.; Ohwada, T. J.
Am. Chem. Soc. 2007, 129, 1724-1732.
Results and Discussion
Generation of o-QMs from 4H-1,2-Benzoxazines. In gen-
eral, o-QMs are too unstable to be isolated and observed
spectroscopically, unless they are trapped with metals such as
Cp*Ir.6c,k,q In all reported thermal methods, o-QMs were
generated in situ, and underwent 1,4-conjugate addition with
nucleophiles or Diels-Alder cycloadditions with dienophiles.6,7
In this study, we used vinyloxycyclohexane as a Diels-Alder
dienophile, because of the reverse-electron demanding nature
of the Diels-Alder reaction of o-QMs (Scheme 2). That is,
o-QMs require a highly electron-rich dienophile, such as vinyl
ether.4 In addition, vinyloxycyclohexane has a high boiling point
among vinyl ethers, and its less volatile nature enabled us to
control the reaction conditions precisely.
(6) For recent reports on the use of o-quinone methides, see: (a) Adam,
W.; Hadjiarapoglou, L.; Peters, K.; Sauter, M. J. Am. Chem. Soc. 1993,
115, 8603-8608. (b) Van de Water, R. W.; Magdziak, D. J.; Chau, J. N.;
Pettus, T. R. R. J. Am. Chem. Soc. 2000, 122, 6502-6503. (c) Amouri, H.;
Vaissermann, J.; Rager, M. N.; Grotjahn, D. B. Organometallics 2000, 19,
1740-1748. (d) Jones, R. M.; Van de Water, R. W.; Lindsey, C. C.; Hoarau,
C.; Ung, T.; Pettus, T. R. R. J. Org. Chem. 2001, 66, 3435-3441. (e) Jones,
R. M.; Selenski, C.; Pettus, T. R. R. J. Org. Chem. 2002, 67, 6911-6915.
(f) Britt, P. F.; Buchanan, A. C.; Cooney, M. J.; Martineau, D. R. J. Org.
Chem. 2000, 65, 1376-1389. (g) Chiang, Y.; Kresge, A. J.; Zhu, Y. J. Am.
Chem. Soc. 2002, 124, 6349-6356. (h) Amouri, H.; Le Bras, J. Acc. Chem.
Res. 2002, 35, 501-510. (i) Paul, G. C.; Gajewski, J. J. J. Org. Chem.
1993, 58, 5060-5062. (j) Kasturi, T. R.; Jayaram, S. K.; Sattigeri, J. A.;
Pragnacharyulu, P. V. P.; Row, T. N. G.; Venkatesan, R. K. K.; Begum,
N. S.; Munirathinam, N. Tetrahedron 1993, 49, 7145-7158. (k) Lev, D.
A.; Grotjahn, D. B.; Amouri, H. Organometallics 2005, 24, 4232-4240.
(l) Wojciechowski, K.; Dolatowska, K. Tetrahedron 2005, 61, 8419-8422.
(m) Modica, E.; Zanaletti, R.; Freccero, M.; Mella, M. J. Org. Chem. 2001,
66, 41-52. (n) Marino, J. P.; Dax, S. L. J. Org. Chem. 1984, 49, 3671-
3672. (o) Barrero, A. F.; del Moral, J. F. Q.; Herrador, M. M.; Arteaga, P.;
Cortes, M.; Benites, J.; Rosellon, A. Tetrahedron 2006, 62, 6012-6017.
(p) Weinert, E. E.; Dondi, R.; Colloredo-Melz, S.; Frankenfield, K. N.;
Mitchell, C. H.; Freccero, M.; Rokita, S. E.; J. Am. Chem. Soc. 2006, 128,
11940-11947. (q) Amouri, H.; Besace, Y.; Le Bras, J.; Vaissermann, J. J.
Am. Chem. Soc. 1998, 120, 6171-6172.
(8) For example, see: (a) Rodriguez, R.; Adlington, R. M.; Moses, J.
E.; Cowley, A.; Baldwin, J. E. Org. Lett. 2004, 6, 3617-3619. (b) Baldwin,
J. E.; Mayweg, A. V. W.; Neumann, K.; Pritchard, G. J. Org. Lett. 1999,
1, 1933-1935. (c) Adlington, R. M.; Baldwin, J. E.; Pritchard, G. J.;
Williams, A. J.; Watkin, D. J. Org. Lett. 1999, 1, 1937-1939. (d) Adlington,
R. M.; Baldwin, J. E.; Mayweg, A. V. W.; Pritchard, G. J. Org. Lett. 2002,
4, 3009-3011. (e) Rodriguez, R.; Moses, J. E.; Adlington, R. M.; Baldwin,
J. E. Org. Biomol. Chem. 2005, 3, 3488-3495.
(9) Katada, T.; Eguchi, S.; Esaki, T.; Sasaki, T. J. Chem. Soc., Perkin
Trans. 1 1984, 2649-2653.
(10) Pettigrew, J. D.; Bexrud, J. A.; Freeman, R. P.; Wilson, P. D.
Heterocycles 2004, 62, 445-452.
(11) Chiba, K.; Hirano, T.; Kitano, Y.; Tada, M. Chem. Commun. 1999,
8, 691-692.
(12) Loubinoux, B.; Miazimbakana, J.; Gerardin, P. Tetrahedron Lett.
1989, 30, 1939-1942.
(7) For a recent review see: (a) Van de Water, R. W.; Pettus, T. R. R.
Tetrahedron 2002, 58, 5367-5405. (b) Pettus, T. R. R.; Selenski, C.;
Griesbeck, A. G. In Science of Synthesis; Griesbeck, A. G., Ed.; Houben-
Weyl: New York, 2006; Chapter 12, pp 831-899.
(13) Retro-Diels-Alder reaction of isomeric benzoxazine was reported:
Glover, S. A.; Jones, K. M.; McNee, I. R.; Rowbottom, C. A. J. Chem.
Soc., Perkin Trans. 2 1996, 1367-1376.
J. Org. Chem, Vol. 72, No. 26, 2007 10089

Sugimoto et al.
SCHEME 2
calculated activation energy and selected geometrical parameters
are shown in Table 2. The geometry of the transition structure
suggested that this retro-Diels-Alder reaction proceeds in a
concerted manner, but the bond cleavage occurs asynchronously
(Table 2 and Figure 1). The elongation of the O1-N2 bond of
the transition structure (2.458 Å, 177% elongation as compared
with the corresponding bond length in the reactant) was much
larger than that of the C3-C4 bond (1.887 Å, 125% elongation).
This is consistent with the notion that the O1-N2 bond of
4H-1,2-benzoxazine is weaker and more unstable than the
C3-C4 bond. The change of the lengths of the C3-C4 bond
and the O1-N2 bond along the reaction coordinate of the retro-
Diels-Alder reaction of unsubstituted 4H-1,2-benzoxazine (1a)
is shown in Figure 2. In the vicinity of the transition state, the
C3-C4 bond continues to elongate consistently, while the
elongation of the O1-N2 bond levels off. This is also consistent
with the foregoing idea that cleavage of the O1-N2 bond occurs
prior to that of the C3-C4 bond. In this case there is a possibility
of the system including a biradical character. However, the
process of the singlet biradical formation that involves homolytic
cleavage of the N-O bond of unsubstituted 4H-1,2-benzoxazine
(1a) demanded energy larger than the proposed asynchronous
concerted process did.14 This excludes the contribution of the
putative biradical process in the present case.
In addition, the frequency calculation of the transition state
showed the presence of a single imaginary frequency (387.4i
cm-1), which corresponds predominantly to stretching of the
C3-C4 bond. These results suggested that the degree of cleavage
of the C3-C4 bond has a greater influence on the reactivity in
this retro-Diels-Alder reaction.
Furthermore, a comparison of the natural population analysis
(NPA) charges between the reactant (1a) and the transition
structure (1a-TS) provides useful information about the redis-
tribution of electrons in the reaction. While the electron densities
of the O1, N2, and C3 atoms increased (-0.357 to -0.510,
-0.047 to -0.180, and +0.113 to +0.079, respectively), the
positive charge of the C4 atom increased (+0.040 to +0.139).
This coincides with the shift of the electron densities of the
O1-N2 bonding electrons to the O1 atom, and of the C3-C4
bonding electrons to the N2-C3 bond (Figure 3). As a result,
in this retro-Diels-Alder reaction, the C4 atom will be relatively
electron-deficient and the O1 atom will be electron-rich in the
transition structure (1a-TS) (Figure 3).
TABLE 1. Sequential Reactions Involving the Retro-Diels-Alder
Reaction of 4H-1,2-Benzoxazine and the Diels-Alder Reaction of
the Resultant o-QM with Vinyloxycyclohexane
R
solvent
toluene
T (°C)a
time (h)
yield (%)b
H (1a)
90
90
90
70
70
90
70
70
100
100
100
100
100
90
90
90
90
90
0.5
3
0.5
1
6
0.5
1
56
100
97
51
92
91
50
91
30
98
48
100
93
22
92
82
96
95
35
98
90
toluene
acetonitrile
acetonitrile
acetonitrile
dimethyl sulfoxide
dimethyl sulfoxide
dimethyl sulfoxide
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
6
1
5-CF3 (1j)
7-CF3 (1g)
12
1
12
0.5
1
12
1
3
0.5
1
12
1
8-CF3 (1l)
5-Cl (1m)
7-Cl (1d)
8-Cl (1o)
7-NO2 (1i)
100
100
90
8-NO2 (1p)
a Temperature was controlled within (0.1 °C. b Isolated yield.
Heating of a solution of 4H-1,2-benzoxazines (1) bearing
various substituents on the benzene ring in the presence of
vinyloxycyclohexane afforded the chroman derivatives (3) in
high yields under optimal reaction conditions (temperature and
time) (Table 1). The high-yield formation of the chroman
derivatives is indicative of quantitative in situ generation of
o-QMs (2) from the corresponding 4H-1,2-benzoxazines. The
overall reaction includes two steps (the retro-Diels-Alder
reaction of the 4H-1,2-benzoxazine to generate the o-QM, and
the Diels-Alder reaction of the resultant o-QM with the vinyl
ether) (see Scheme 2). Our kinetic studies of unsubstituted 4H-
1,2-benzoxazine (1a) revealed that the former step, i.e., the retro-
Diels-Alder reaction, is rate-determining (Figure S1, Supporting
Information). That is, the orders of the reagent concentration
dependency of the rate of appearance of the chroman product
were 1.06 and 0.02 for 1a and the vinyl ether, respectively.
Therefore, the overall reaction rate is independent of the
concentration of the vinyl ether, and represents the rate of the
retro-Diels-Alder reaction of 4H-1,2-benzoxazines (1), not that
of the Diels-Alder reaction of o-QMs (2).
Solvent Effect on the Retro-Diels-Alder Reaction of
Unsubstituted 4H-1,2-Benzoxazines. The present retro-Diels-
Alder reaction of 1a proceeded efficiently in various solvents,
including toluene (ꢀ ) 2.4), acetonitrile (ꢀ ) 37.5), and dimethyl
sulfoxide (ꢀ ) 46.7) (Table 1). Judging from the yields under
similar conditions (90 °C, 0.5 h) (Table 1), the reaction rate
seems to depend on the polarity of the solvents: as the polarity
of the solvent increases, the yield is increased. The experimental
reaction rates in the individual solvents and the thermodynamic
(14) While probably due to the shallow potential energy surface, it was
difficult to find the transition structure for the homolytic cleavage of the
N-O bond of 1a; we obtained the biradical structure of 1a in UB3LYP/
6-31+G(d,p) calculations, which involved homolytic cleavage of the N-O
bond. Formation of the biradical intermediate was endothermic, and the
energy difference from 1a is 39.6 kcal/mol (UB3LYP/6-311+G(d,p)//
UB3LYP/6-31+G(d,p)). This result suggests that the activation energy for
the putative biradical formation process, the rate-determining step in the
singlet biradical pathway, will be highly energetic as compared with the
asynchronous concerted process (30.0 kcal/mol, B3LYP/6-311+G(d,p)//
B3LYP/6-31+G(d,p)) (see Figure S4, Supporting Information).
To gain insight into the reaction mechanism of the rate-
determining retro-Diels-Alder reaction, we have carried out a
detailed investigation of the reaction profile by means of
experimental kinetic studies and theoretical DFT calculations.
Theoretical Mechanistic Insight into Retro-Diels-Alder
Reaction of Unsubstituted 4H-1,2-Benzoxazine. First, the
retro-Diels-Alder reaction of unsubstituted 4H-1,2-benzoxazine
(1a) was studied in detail by means of DFT calculations. The
(15) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165-195.
10090 J. Org. Chem., Vol. 72, No. 26, 2007

Retro-Diels-Alder Reaction of 4H-1,2-Benzoxazines
TABLE 2. Calculated Thermodynamic and Selected Geometric Parameters, and NPA Atomic Charges in the Retro-Diels-Alder Reaction of
Unsubstituted 4H-1,2-Benzoxazine (1a)a
∆E0,calcd
O1-N2
(Å)
C3-C4
(Å)
C8aO1N2
(deg)
C4aC4C3
(deg)
P(O1-N2)
P(C3-C4)
species
(kcal/mol)b
q(O1)
q(N2)
q(C3)
q(C4)c
(%)d
(%)d
7-H reactant (1a)
7-H TS (1a-TS)
1.389
2.458
1.507
1.887
120.2
101.2
110.1
105.1
-0.357
-0.510
-0.047
-0.180
0.113
0.079
0.040
0.139
-
30.0
76.9
25.2
a All structures were obtained at the B3LYP/6-31+G(d,p) level. b ∆E0,calcd was calculated at the B3LYP/6-311+G(d,p)//B3LYP/6-31+G(d,p) level with
inclusion of ZPE correction. c Total charge of the CH2 group at C4, i.e., summation of charges of C4 and the two bearing hydrogen atoms. d Also given is
the relative lengthening of the bonds on going from the stable conformer of the reactant to the transition state (expressed in percent): P(l) ) (lTS - lreactant)/
(lreactant) × 100 (%).
TABLE 3. Experimental and Calculated Thermodynamic
Parameters for the Retro-Diels-Alder Reaction of
4H-1,2-Benzoxazine 1a in Several Solvents
104k (s-1
at T (°C)
)
Ea,exp
∆Ecalcd
solvent
toluene
ꢀ
T (°C)a
(kcal/mol)b (kcal/mol)c
2.4
80.0
90.0
1.47 ( 0.02
4.72 ( 0.14
28.8 ( 0.4
31.6
30.0
29.9
100.0 14.1 ( 0.25
110.0 36.2 ( 1.02
60.0
70.0
80.0
acetonitrile 37.5
0.533 ( 0.05 27.9 ( 1.0
2.01 ( 0.02
5.40 ( 0.35
FIGURE 1. Calculated structures of reactant and transition state in
the retro-Diels-Alder reaction of unsubstituted 4H-1,2-benzoxazine
(1a).
90.0 18.5 ( 1.55
dimethyl
sulfoxide
46.7
60.0
70.0
80.0
0.483 ( 0.06 27.3 ( 0.7
1.94 ( 0.07
5.46 ( 0.27
90.0 14.5 ( 0.78
b
a Temperature was controlled within (0.1 °C. Ea,exp is the experimental
activation energy and k is the reaction rate constant of the retro-Diels-
Alder reaction in each solvent at each temperature. c ∆Ecalcd is the calculated
activation energy in the presence of dielectric medium, using the SCIPCM
model at the B3LYP/6-311+G(d,p)//B3LYP/6-31+G(d,p) level.
∆Ecalcd in dimethyl sulfoxide was also 1.7 kcal/mol lower than
that in toluene, this value being very close to the experimental
difference (1.5 kcal/mol). The acceleration of the reactions in
polar solvents was assumed to be due to the polar nature of the
transition structure, arising from the N-O bond cleavage. In
fact, unsubstituted 4H-1,2-benzoxazine (1a) generated o-QM
(2a) in dimethyl sulfoxide upon quite mild heating (at 50 °C,
though the reaction was slow) without any additional catalyst.
This is one of the mildest conditions known for the generation
of o-QMs. In the cases of the bicyclo[2.2.1]heptane derivatives,
solvent effects have also been reported.3b-d This is consistent
with the involvement of a slightly polarized TS, which is more
stabilized than the initial state in a polar solvent.
FIGURE 2. Increases of C3-C4 and O1-N2 bond lengths in the
vicinity of the transition state (B3LYP/6-31+G(d,p) level).
Kinetic Studies of Retro-Diels-Alder Reaction of 4H-1,2-
Benzoxazines Bearing Various Substituents at C7: Substitu-
ent Effect. The yield of the chroman product also seemed to
be dependent on the nature of the substituent, for example, at
the C7 position, judging from the yields obtained under similar
conditions (Table 1 and Scheme 1). For example, the reactions
of 4H-1,2-benzoxazines bearing an electron-withdrawing group,
such as CF3 (1g) and NO2 (1i), at C7 were apparently slower
than that of unsubstituted 4H-1,2-benzoxazine (1a).
To get more quantitative information about the substituent
effect, we carried out kinetic measurements of the reactions of
7-substituted 4H-1,2-benzoxazines (1a-i, Scheme 1) in a
nonpolar solvent, toluene, where the retro-Diels-Alder reaction
is slow. When the reaction was carried out in a polar solvent,
such as dimethyl sulfoxide, it was difficult to obtain accurate
kinetic data, because the reaction was too rapid at high
temperature. The 4H-1,2-benzoxazines (1b-i) bearing various
substituents at C7 were prepared and the reaction rates were
measured. All the substrates showed first-order kinetics with
FIGURE 3. Electron shifts in the retro-Diels-Alder reaction of 4H-
1,2-benzoxazine (1a).
parameters of the retro-Diels-Alder reaction of unsubstituted
4H-1,2-benzoxazine (1a) are shown in Table 3, together with
the DFT calculated activation energies. While the calculated
activation energies ∆Ecalcd are consistently overestimated as
compared with the experimental activation energies Ea,exp, the
relative magnitudes of the Ea,exp and ∆Ecalcd values agree well.
It is apparent that the reactions are more rapid in polar solvents,
such as acetonitrile or dimethyl sulfoxide. The experimental
activation energies Ea,exp were 27.3 ( 0.7 kcal/mol in dimethyl
sulfoxide and 28.8 ( 0.4 kcal/mol in toluene, the difference
being 1.5 kcal/mol. The SCIPCM calculated activation energy
J. Org. Chem, Vol. 72, No. 26, 2007 10091

Sugimoto et al.
TABLE 4. Experimental Thermodynamic Parameters of the Retro-Diels-Alder Reaction
T
104k (s-1
at T (°C)
)
Ea,exp
T
104k (s-1
at T (°C)
)
Ea,exp
substituent
σp
(°C)a
(kcal/mol)b
substituent
σp
(°C)a
(kcal/mol)b
7-H (1a)
0
80.0
90.0
100.0
110.0
80.0
1.47 ( 0.02
4.72 ( 0.14
14.1 ( 0.25
36.2 ( 1.02
4.38 ( 0.11
12.7 ( 0.38
37.0 ( 1.01
68.2 ( 0.67
9.01 ( 0.24
24.3 ( 0.87
66.5 ( 0.44
1.60 ( 0.04
5.17 ( 0.09
14.1 ( 0.06
33.8 ( 1.61
1.58 ( 0.52
4.49 ( 0.12
13.9 ( 0.23
34.7 ( 0.98
28.8 ( 0.4
7-CO2Me (1f)
0.45
100.0
110.0
120.0
100.0
110.0
120.0
100.0
110.0
120.0
100.0
110.0
120.0
3.08 ( 0.02
9.24 ( 0.29
24.5 ( 0.29
2.03 ( 0.01
6.20 ( 0.20
16.7 ( 0.21
1.55 ( 0.02
4.62 ( 0.17
12.7 ( 0.17
1.16 ( 0.04
3.77 ( 0.16
9.68 ( 0.92
30.2 ( 0.6
30.6 ( 0.6
30.7 ( 0.2
31.0 ( 1.5
7-CF3 (1g)
7-CN (1h)
7-NO2 (1i)
0.54
0.66
0.78
7-Me (1b)
-0.17
27.9 ( 0.5
90.0
100.0
110.0
90.0
100.0
110.0
80.0
7-F (1c)
0.06
0.22
27.6 ( 0.5
28.5 ( 0.8
7-Cl (1d)
90.0
100.0
110.0
80.0
90.0
100.0
110.0
7-Br (1e)
0.23
28.4 ( 0.6
b
a Temperature was controlled within (0.1 °C. Ea,exp is the experimental activation energy and k is the reaction rate constant of the retro-Diels-Alder
reaction in toluene at each temperature.
TABLE 5. Experimental Thermodynamic Parameters for the Retro-Diels-Alder Reaction of 4H-1,2-Benzoxazine Bearing CF3 or Cl at C5-C8
and NO2 at C7-C8
T
104k (s-1
at T (°C)
)
Ea,exp
104k (s-1
at T (°C)
)
Ea,exp
substituent
(°C)a
(kcal/mol)b
substituent
T (°C)a
(kcal/mol)b
5-CF3 (1j)
100.0
110.0
120.0
100.0
110.0
120.0
100.0
110.0
120.0
80.0
1.08 ( 0.02
3.03 ( 0.06
8.86 ( 0.24
1.42 ( 0.02
4.04 ( 0.04
11.5 ( 0.25
2.03 ( 0.01
6.20 ( 0.20
16.7 ( 0.21
1.87 ( 0.93
5.07 ( 0.08
35.8 ( 1.07
30.6 ( 0.8
30.4 ( 0.4
30.6 ( 0.6
27.7 ( 1.4
5-Cl (1m)
90.0
100.0
110.0
80.0
0.786 ( 0.02
2.39 ( 0.10
6.98 ( 0.05
2.54 ( 0.02
8.00 ( 0.10
23.1 ( 0.60
57.7 ( 3.88
1.60 ( 0.04
5.17 ( 0.09
14.1 ( 0.06
33.8 ( 1.61
0.734 ( 0.01
2.52 ( 0.01
7.52 ( 0.09
1.16 ( 0.04
3.77 ( 0.16
9.68 ( 0.92
5.87 ( 0.23
15.5 ( 0.53
41.9 ( 1.40
30.2 ( 0.2
28.0 ( 0.5
6-CF3 (1k)
7-CF3 (1g)
8-CF3 (1l)
6-Cl (1n)
7-Cl (1d)
90.0
100.0
110.0
80.0
28.5 ( 0.8
90.0
100.0
110.0
60.0
70.0
80.0
100.0
110.0
120.0
90.0
100.0
110.0
90.0
100.0
8-Cl (1o)
27.2 ( 0.5
31.0 ( 1.5
27.1 ( 0.6
7-NO2 (1i)
8- NO2 (1p)
b
a Temperature was controlled within (0.1 °C. Ea,exp stands for the activation energy and k for the reaction rate constant of the retro-Diels-Alder
reaction in toluene at each temperature.
respect to the substrate concentration. The experimental and
calculated thermodynamic parameters of the retro-Diels-Alder
reactions of 4H-1,2-benzoxazines (1b-i) bearing various sub-
stituents at C7 are shown in Tables 4 and 5, respectively.
The 4H-1,2-benzoxazines (1f-i) bearing a strong electron-
withdrawing substituent (in terms of σp) on the benzene ring
had larger Ea,exp values than that of the unsubstituted substrate
(1a) (Table 4). The electron-donating methyl group (1b) reduced
the activation energy as compared with that of 1a. For example,
the magnitudes of the DFT-calculated activation energies,
corrected for the zero-point energies (ZPE) (Table S1, Sup-
porting Information). The calculated activation energy ∆E0,calcd
of 1i (R ) 7-NO2, 31.3 kcal/mol) was 2.2 kcal/mol higher than
that of 1b (R ) 7-Me, 29.1 kcal/mol).
A Hammett plot of the experimental relative reaction rates
at 110 °C, log(k110,R/k110,H), against σp values is shown in Figure
4. A plot of the relative rates (logarithmic) against σp rather
than σm showed a better linear correlation (regression coefficient
r ) 0.993, excluding halogen atoms (see below); see also Figure
S3 in the Supporting Information). This is consistent with the
calculated TS structures, in which the electronic nature of the
C3-C4 bond located at the para position with respect to the
7-substituent seemed to have a great influence on the reactivity.
The negative slope of the relationship (F) -1.33, excluding
halogen atoms, see below) is indicative of the creation of the
electron-deficient reaction center, which might be assigned to
Ea,exp of 4H-1,2-benzoxazine (1i, R ) NO2) bearing a NO2 group
at C7 was 31.0 kcal/mol, and that of 4H-1,2-benzoxazine (1b,
R ) CH3) bearing a methyl group at C7 was 27.9 kcal/mol,
while that of the unsubstituted compound (1a, R ) H) was 28.8
kcal/mol. In fact, the rate constant k100 at 100 °C of 1b (37.0 ×
104) was approximately 30 times that of 1i (1.16 × 104). This
indicates that the electron-withdrawing substituent at the C7
position retarded the reaction. This tendency is consistent with
10092 J. Org. Chem., Vol. 72, No. 26, 2007

Retro-Diels-Alder Reaction of 4H-1,2-Benzoxazines
inductive effects. The results, however, suggested that the
stabilization of transition state was dominant over the destabiliz-
ing inductive effect.
Such a substituent effect on the retro-Diels-Alder reactions
is also consistent with the changes in the NPA charges from
the reactants to the TSs (Table S1, Supporting Information). In
the cases of truly electron-withdrawing substituents (1f-i), such
as CF3, CN, and NO2, the positive charge of the CH2 group at
C4 increased along the reaction path, the increase being larger
than that of the unsubstituted compound (1a), probably because
of the electron-withdrawing inductive/resonance effect of the
substituent. The NPA charge of the CH2 group at C4 of 4H-
1,2-benzoxazine bearing an NO2 group changed from the
comparable positive value (reactant: +0.047) to the most
positive value (TS: +0.163) along the reaction path. The
inductive/resonance effect of an electron-withdrawing substituent
reduced the availability of the bonding electrons of the C3-C4
bond, resulting in retardation of the reaction (Figure 5). In the
case of the electron-donating substituent (1b: Me), the increase
of the charge of the CH2 group at C4 in the transition from the
reactant to the TS (+0.093) is smaller than that in the
unsubstituted compound (1a: +0.099).
FIGURE 4. Correlation between the relative reaction rate constants
(k110, the reaction rate constant of the retro-Diels-Alder reaction in
toluene at 110 °C) and Hammett σp.15
Positional Effect of Substitution in Retro-Diels-Alder
Reactions of 4H-1,2-Benzoxazines. Positional effects of sub-
stitution on the reactivities of 4H-1,2-benzoxazines were also
examined. 4H-1,2-Benzoxazines with a CF3 group at C5 (1j),
C6 (1k), C7 (1g), or C8 (1l), a Cl group at C5 (1m), C6 (1n), C7
(1d), or C8 (1o), or a NO2 group at C7 (1i) or C8 (1p) were
prepared.17 The experimental and calculated thermodynamic
parameters for the retro-Diels-Alder reactions of 4H-1,2-
benzoxazines bearing CF3 (1j,1k, 1g and 1l) or Cl at C5-C8
(1m, 1n, 1d, and 1o) are shown in Table 5. The magnitude of
the experimental activation energies (Ea,exp) varied significantly,
depending upon the position of the given substituent, i.e., CF3,
Cl, or NO2 (Table 5).
To our surprise, while the reactions of 4H-1,2-benzoxazines
bearing CF3 or Cl at C5 (1j/1m), C6 (1k/1n), or C7 (1g/1d) were
much slower than that of unsubstituted 4H-1,2-benzoxazine (1a),
those of 4H-1,2-benzoxazines bearing the substituent at C8
(1l/1o) were much faster than in the case of 1a. Thus, it is not
appropriate to generalize that an electron-withdrawing group
or halogen atom on the benzene ring of 4H-1,2-benzoxazines
decelerates the retro-Diels-Alder reaction. Acceleration or
deceleration of the reaction depends significantly on the position
of the substitution.
The activation energy (Ea,exp) of 4H-1,2-benzoxazine bearing
CF3 at C8 (1l) (27.7 kcal/mol) was found to be smaller than
those of 4H-1,2-benzoxazines bearing CF3 at C5 (1j), C6 (1k),
and C7 (1g) (30.6, 30.4, and 30.6 kcal/mol, respectively).
Correspondingly, the reaction rate (k), for example at 100 °C,
of 4H-1,2-benzoxazine bearing CF3 at C8 (1l) was larger than
those of the compounds with CF3 at C5 (1j), C6 (1k), and C7
(1g). A similar acceleration owing to substitution at C8 was also
observed in the case of a Cl substituent. That is, the activation
energy (Ea,exp) of 4H-1,2-benzoxazine bearing Cl at C8 1o was
the smallest (27.2 kcal/mol), while that of 4H-1,2-benzoxazine
bearing Cl at C5 1m was the largest (30.2 kcal/mol) among the
regioisomers 1m, 1n, 1d, and 1o. The Ea,exp values of 4H-1,2-
benzoxazines bearing Cl at C6 (1n) and C7 (1d) were similar in
FIGURE 5. Resonance destabilization (left)/stabilization (right) of the
transition state arising from the substituent at C7.
C4, in the transition structure. This is consistent with the
calculated charge distribution shown in Figure 3.
In this Hammett plot (Figure 4), halogen substituents are
located slightly above the line. This indicates that halogen atoms
accelerated the reaction, probably because the electron defi-
ciency of the reaction center in the transition state could be
stabilized by the lone pair electrons of halogen atoms (Figure
5).16
In all cases of calculated TS (1b-TS to 1i-TS), the reactions
appeared to proceed in an asynchronous and concerted manner,
as in the case of unsubstituted 4H-1,2-benzoxazine (1a).
Irrespective of the substituents of the 4H-1,2-benzoxazines, the
elongation of the O1-N2 bond was more significant than that
of the C3-C4 bond in the transition structures (see Table S1,
Supporting Information). This suggested that the electron flow
in the retro-Diels-Alder reactions of 4H-1,2-benzoxazines
(1c-i) that bear any substituent at the C7 position is essentially
as shown in Figure 3.
The destabilization of C4 by the inductive/resonance effect
of the electron-withdrawing substituents would decelerate this
retro-Diels-Alder reaction, and the stabilization of C4 owing
to the resonance effect of the lone-pair electrons would
accelerate the reaction. In fact, as compared with the calculated
charges of the CH2 group at C4 in the transition structures, the
CH2 group at C4 of the compounds with electron-withdrawing
groups (1g: CF3, 1h: CN and 1i: NO2) was more positively
charged (+0.154, +0.159, and +0.163, respectively) than in
the halogen compounds (1c: F, +0.144; 1d: Cl, +0.146; and
1e: Br, +0.146) (Table S1, Supporting Information). The
halogen atoms might also block the reaction through their
(17) CF3 and Cl groups were selected because they could be introduced
at any position on the benzene ring. In fact, for example, 4H-1,2-benzoxazine
bearing an NO2 group at C5 was not able to be prepared.
(16) Brown, H. C.; Okamoto, Y.; Ham, G. J. Am. Chem. Soc. 1957, 79,
1906-1909.
J. Org. Chem, Vol. 72, No. 26, 2007 10093

Sugimoto et al.
magnitude (28.0 and 28.5 kcal/mol, respectively). The retarding
effect of the substituent at C5 was more apparent in the case of
Cl (1m) than CF3 (1j). These tendencies are consistent with
the relative magnitude of the DFT-calculated activation energies,
corrected for the zero-point energies (ZPE) (see Table S2,
Supporting Information). The calculated activation energy
∆E0,calcd of 1l (R ) 8-CF3, 29.0 kcal/mol) was smaller than
those of 1j, 1k, and 1g (30.4, 30.3, and 30.5 kcal/mol,
respectively). A similar trend was found in the Cl substituent
(Table S2, Supporting Information). The retro-Diels-Alder
reactions of 4H-1,2-benzoxazine bearing CF3 or Cl at any
position appeared to proceed asynchronously and concertedly,
judging from the vibration mode of a single imaginary frequency
and the elongation of the O1-N2 bond in the calculated
transition states. The bond angles of C8aO1N2 and C4aC4C3
in the transition state structures of the 4H-1,2-benzoxazines were
comparable in magnitude among all the positional isomers of
substitution (C5-C8) in both CF3 and Cl substituted compounds
(Table S2 and Scheme 1). The geometrical similarity of these
TS structures indicated that the differences in the reaction rates
among the 4H-1,2-benzoxazines (for CF3, 1g and 1j-l; for Cl,
1d and 1m-o) bearing the same substituent at different positions
are not due to steric factors, but rather are mainly due to
electronic effects arising from the subtituent at the individual
position. The length of the C3-C4 bond in the transition structure
(1l-TS) of 4H-1,2-benzoxazine bearing CF3 at C8 was the
shortest (1.887 Å) and 1l gave the smallest ∆E0,elec. That of the
isomer bearing CF3 at C5 (1j), which gave higher ∆E0,elec, was
the longest (1.911 Å). This result indicates that the earlier the
transition state with respect to the C3-C4 bond cleavage (i.e.,
the less the bond cleavage proceeds), the lower the reaction
barrier. In this context, the C3-C4 bond length can be considered
as an indicator of the reaction progress. A similar trend was
observed in the case of the Cl group. The transition state
structure (1m-TS) of 4H-1,2-benzoxazine bearing Cl at C5
suggested the involvement of a later transition state (i.e., the
bond cleavage proceeded to greater extent) with respect to the
C3-C4 bond (1.899 Å), as compared with that of 4H-1,2-
benzoxazine bearing Cl at C7 (1d-TS, 1.875 Å). On the other
hand, the C3-C4 bond length in the transition state structure
(1o-TS) of 4H-1,2-benzoxazine bearing Cl at C8 is exceptional.
The C3-C4 bond length of 1o-TS was 1.884 Å, which is longer
than that of 1d-TS (Cl at C7), while 1o-TS was more stabilized
than 1d-TS. The reason for this is not clear, but an alternative
stabilization effect may be involved.18
FIGURE 6. Deceleration (left) and acceleration (right) of C3-C4 bond
cleavage.
that of 4H-1,2-benzoxazine bearing NO2 at C7 (1i, 31.0 kcal/
mol). This apparent positional acceleration/deceleration effect
is consistent with the highly polarized transition structure of
the retro-Diels-Alder reaction.
Conclusion
In this paper we present a mechanistic study of the retro-
Diels-Alder reaction of 4H-1,2-benzoxazines with various
substituents on the benzene ring. This reaction provides
substituted o-QMs under mild thermal conditions, and is useful
in synthetic chemistry. The results of DFT calculations are
consistent with the experimental kinetic and thermodynamic
data. The reaction proceeded in an asynchronous and concerted
manner. As a result, the reaction rates were greatly affected by
the electronic nature and positions of substituents, and by the
polarity of the solvent. The reaction proceeded faster in a polar
solvent, such as dimethyl sulfoxide, because the transition state
is significantly polarized by asymmetrical bond cleavage.
Comparison of the bond lengths and frequency analysis of the
transition state showed that the O1-N2 bond is cleaved
significantly, and the bonding nature of the remaining C3-C4
bond has a great influence on the reaction rate. The effect of
substituent position was found to be significant. The reaction
of 4H-1,2-benzoxazine bearing an electron-withdrawing group
such as CF3 at C5 (1j), C6 (1k), or C7 (1g) was slower than that
of unsubstituted 4H-1,2-benzoxazine (1a), while that of 4H-
1,2-benzoxazine bearing CF3 at C8 (1l) was faster than that of
1a. This tendency was also seen in the case of Cl and NO2
groups. The present detailed study has uncovered characteristic
effects of substitution position and solvent polarity on the retro-
hetero-Diels-Alder reactions to generate o-QMs.
Experimental Section
Diels-Alder Reactions of o-Quinone Methides Generated
from 4H-1,2-Benzoxazines with Vinyloxycyclohexane (3a-p):
Typical Procedure for 2-Cyclohexyloxychroman (3a). A solution
of 1a (180 mg, 0.940 mmol) and vinyloxycyclohexane (252 mg,
2.00 mmol, 2.1 equiv) in dry toluene (15 mL) was heated at 90 °C
with stirring for 3 h. Then the solvent was evaporated under reduced
pressure to give a residue, which was column-chromatographed on
These positional effects of the substituents can be explained
by postulating that an electron-withdrawing substituent at C5
predominantly has an inductive effect on the C3-C4 bond, and
the same substituent at C8 has an inductive effect on the
O1-N2 bond; this view is supported by the results of NPA
analysis (Figure 6).19
The effect of a nitro group at C8 was also studied in the retro-
Diels-Alder reaction of 4H-1,2-benzoxazine. The experimental
thermodynamic parameters for the retro-Diels-Alder reaction
of 4H-1,2-benzoxazine bearing NO2 at C8 (1p) are shown in
Table 5. As expected, Ea,exp of 4H-1,2-benzoxazine bearing NO2
at C8 (1p) (27.1 kcal/mol) was smaller than that of unsubstituted
4H-1,2-benzoxazine (1a, 28.8 kcal/mol) and also smaller than
(19) Acceleration of the retro-Diels-Alder reaction of 4H-1,2-benzox-
azine bearing CF3 at C8 (1l) might be related to the fact that the negative
charge of N2 in the reactant 1l (-0.043) is the smallest among the isomers
(1g and 1j-l) (see Table S2, Supporting Information). This small negative
charge of N2 of 1l can be interpreted in terms of the inductive effect of
CF3 at C8, which polarizes the electron density of the O1-N2 bond toward
the O1 atom. Consequently, the electron-deficient N2 promotes redistribution
of the electrons of the C3-C4 bond into the N2-C3 bond (Figure 6). The
NPA charge also showed the negative charge of C4 was the highest in 1j
among the isomers bearing CF3 at C5 (1j), C6 (1k), C7 (1g), or C8 (1l).
This might mean that the inductive effect of the 5-CF3 group on the
C3-C4 bond is the strongest in the case of 1j. This effect retarded the
cleavage of the C3-C4 bond, as depicted in Figure 6, and thus the substrate
bearing CF3 at C5 (1j) showed the smallest reaction rate among the isomers
(1g and 1j-l) (Table 5).
(18) The geometrical distortion, i.e., bending of the Cl atom toward the
O-N bond moiety of the heterocycle in the TS structure (1o-TS), suggested
involvement of a different stabilization arising from orbital interaction
between the non-bonding orbital of the 8-Cl atom and the O1-N2 σ*-orbital
(see Table S3 and Figure S5 in the Supporting Information).
10094 J. Org. Chem., Vol. 72, No. 26, 2007

Retro-Diels-Alder Reaction of 4H-1,2-Benzoxazines
silica gel (eluent: n-hexane-ethyl acetate (10:1)) to afford 2-cyclo-
hexyloxychroman 3a as a colorless oil (216 mg, 0.874 mmol, 100%
yield).
corrections at the B3LYP/6-31+G(d,p) level, which was scaled by
the factor of 0.9614.21 Natural charge analysis with NBOs22 was
performed at the B3LYP/6-31+G(d,p) level. Effects of dielectric
solvent were simulated by using the SCIPCM model23 as imple-
mented in Gaussian 03. SCIPCM calculations were single-point
calculations; i.e., geometry was taken from the gas-phase calcula-
tions and was not reoptimized using the dielectric model. The
performance of the B3LYP method with the 6-31+G(d,p) basis
set is known as a reliable method to calculate the Diels-Alder
reaction of o-QMs.24
Kinetic Studies: Order Dependencies on 4H-1,2-Benzoxazine
(1a) and Vinyl Ether. Initial kinetics was measured in toluene-d8
at 90 °C by 1H NMR, with various concentrations of 4H-1,2-
benzoxazine (1a) and vinyl ether. Magnetic field locking and
external standard peaks were obtained by using a capillary tube
filled with acetic acid/toluene-d8. The order dependency on each
component was determined by the slope of ln k-ln [component]
relationships (Figure S1, Supporting Information). The order
dependencies on 4H-1,2-benzoxazine (1a) and vinyl ether were
found to be 1.06 and 0.02, respectively.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Priority Areas “Advanced
Molecular Transformations of Carbon Resources” from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan.
Determination of Activation Energy Ea of Retro-Diels-Alder
Reactions: Typical Procedure. The substrate 4H-1,2-benzoxazine
(1a-p) (0.075 mmol) and vinyloxycyclohexane (0.15 mmol, 2
equiv to 1a-p) were dissolved in 1.5 mL of toluene-d8. The mixture
was transferred into a NMR tube under an Ar atmosphere. The
tube was placed in a temperature-controlled oil bath preheated to
the desired temperature ((0.1 °C). At different time intervals the
tubes were removed from the bath and cooled to 0 °C, and the
Supporting Information Available: Spectroscopic and analyti-
cal data, experimental procedures, Cartesian coordinates, and
energetic and geometrical values of calculated species. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
progress of the reaction in each case was followed by H NMR
JO702246W
spectroscopy. Magnetic field locking and external standard peaks
were obtained by using a capillary tube filled with acetic acid/
toluene-d8. The concentration of the substrate in the mixture was
obtained by comparing the integration values of the substrate and
external standard. The ratios of disappearance of the starting
substrate against time were plotted to give first-order kinetics
(regression coefficient r > 0.99). Activation energies Ea,exp were
calculated by Arrhenius equation. Arrhenius plots were shown in
Figure S2 in the Supporting Information.
Computational Methods. Ab initio calculations were performed
with the Gaussian 03 suite of programs.20 Geometry optimizations
were performed by using the B3LYP/6-31+G(d,p) method. Single-
point energies were calculated at the B3LYP/6-311+G(d,p) level.
For compounds that have multiple conformations, the conformation
with the lowest energy was chosen for the present study. Frequency
calculations were carried out at the B3LYP/6-31+G(d,p) level and
performed on all of the species to confirm convergence to appro-
priate local minima or saddle points on the energy surface. In all
instances, transition state structures gave one significant imaginary
frequency, while no imaginary frequencies were observed for the
minimum-energy species. Corrections of the energies were made
from the frequency calculations, including zero-point energy
(20) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; 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.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03; Gaussian, Inc.; Pittsburgh, PA, 2003.
(21) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502-16513.
(22) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. ReV. 1988, 88,
899-926.
(23) Foresman, J. B.; Keith, T. A.; Wiberg, K. B.; Snoonian, J.; Frisch,
M. J. J. Phys. Chem. 1996, 100, 16098-16104.
(24) Wang, H.; Wang, Y.; Han, K.-L.; Peng, X.-J. J. Org. Chem. 2005,
70, 4910-4917.
J. Org. Chem, Vol. 72, No. 26, 2007 10095