Generation and application of o-Quinone methides bearing various substituents on the benzene ring

Article abstract of DOI:10.1002/adsc.200600508

o-Quinone methides (o-QMs) are highly reactive, short-lived intermediates, which have potential synthetic applicability. However, few studies on the generation of o-QMs bearing an electron-withdrawing group have been reported. Herein we present a general method for the generation of o-QMs, particularly those substituted with an 0lectrophilic substituent, from new precursors, 4H-1,2-benzoxazines 2. We have also studied systematically the Diels-Alder reactions of o-QMs with various dienophiles, such as vinyl ethers, enamines and imines. The reactions provide a versatile route to substituted chromans, phenols and 3,4-dihydro-2H-benzo[e]-[1,3]oxazines (3,4-dihydro-1,3-benzoxazines). Furthermore, we applied the new method to the derivatization of some natural products.

Full text of DOI:10.1002/adsc.200600508

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DOI: 10.1002/adsc.200600508
Generation and Application of o-Quinone Methides Bearing
Various Substituents on the Benzene Ring
Hiromichi Sugimoto,a Satoshi Nakamura,a and Tomohiko Ohwadaa,*
a
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax : (+81)-3-5841-4735; e-mail: ohwada@mol.f.u-tokyo.ac.jp
Received: October 5, 2006
This paper is dedicated to Professor Dr. Masakatsu Shibasaki, who has made enormous contributions to
chemistry, on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: o-Quinone methides (o-QMs) are highly philes, such as vinyl ethers, enamines and imines.
reactive, short-lived intermediates, which have po- The reactions provide a versatile route to substituted
tential synthetic applicability. However, few studies chromans, phenols and 3,4-dihydro-2H-benzo[e]-
on the generation of o-QMs bearing an electron-
A
withdrawing group have been reported. Herein we thermore, we applied the new method to the deriva-
present a general method for the generation of o- tization of some natural products.
QMs, particularly those substituted with an electro-
philic substituent, from new precursors, 4H-1,2-ben- Keywords: 4H-1,2-benzoxazines; chromans; inverse
zoxazines 2. We have also studied systematically the electron demand Diels-Alder reaction; phenols;
Diels–Alder reactions of o-QMs with various dieno- o-quinone methide
Introduction
Structurally novel chroman derivatives have been
isolated from nature,[9] and are of interest because
o-Quinone methides (o-QMs) are highly reactive, many display interesting biological properties, such as
short-lived intermediates, which have been used in the anti-malaria activity,[10] phytotoxicity,[11] and enhance-
synthesis of several natural products.[1,2] They undergo ment of erythropoietin gene expression.[12] Further-
1,4-conjugate addition with nucleophiles, and Diels– more, 3,4-dihydro-1,3-benzoxazines, which are akin to
Alder cycloadditions with various dienophiles.[3] Many chromans having a carbon atom replaced with nitro-
methods to generate o-QMs in situ from various pre- gen at the 3 position, show cytotoxic activity in vitro
cursors have been reported (Figure 1). However, they against some cancer cell lines.[13] Thus, both chromans
have various disadvantages, including inaccessibility of and 3,4-dihydro-1,3-benzoxazines are potential syn-
precursors,[2] undesirably high reaction temperatures,[2,4] thetic targets in the pursuit of compounds with inter-
long reaction time,[2–5] a need for additional cata- esting biological activities.
lysts,[2,6] and acidic[2,6] or basic[2,3m,7] conditions, and in
Unsubstituted 4H-1,2-benzoxazines have been re-
all cases side reactions can occur. In addition, there ported to afford the prototype o-QM by gentle heat-
have been few systematic studies of the generation and ing, through a retro-Diels–Alder reaction.[14a] This
applications of o-QMs with various substituents, partic- method has an advantage over the conventional
ularly electrophilic substituents, on the benzene ring. methods with respect to the mildness of the reaction
While some information is available on the generation conditions. Some derivatives of 4H-1,2-benzoxazine
of o-QMs with electron-donating groups, only a nitro were synthesized for the first time by means of a Frie-
group has been reported as an electron-withdrawing del–Crafts-type reaction of nitroalkenes with benzene
group.[8] o-QMs bearing a variety of electron-withdraw- in the presence of a strong Brønsted acid, such as tri-
ing groups have not been investigated. Very recently a fluoromethanesulfonic acid (TFSA),[14b–d] but this
reversible generation of some substituted o-QMs from method turned out to have limited applicability for
the conventional precursors and their reactivities in the synthesis of 4H-1,2-benzoxazine derivatives bear-
conjugate addition have been reported.[3p]
ing substituents on the benzene ring, because biaryl
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Figure 1. Conventional precursors for the thermal generation of o-QMs.
compounds were obtained as major products when
The chemical nature of 4H-1,2-benzoxazine deriva-
substituted benzenes were used. This unexpected tives bearing various substituents on the benzene
result was due to an intermolecular reaction between moiety has not been well studied because of the lack
the substituted benzenes and nitroalkenes.[14d] While of suitable general synthetic methods. 4H-1,2-Benzox-
subsequent reports also described the synthesis of 4H- azines afford o-QMs with various substituents on the
1,2-benzoxazine derivatives,[14e–k] the yields were low benzene ring simply upon heating at low temperature
and the methods lacked generality, since only limited (Scheme 2).
starting materials could be employed, and the prod-
ucts were not amenable to further modification. Re-
cently, we have reported the synthesis of 4H-1,2-ben-
zoxazines bearing various substituents on the benzene
ring, from saturated nitroalkanes and methyl 3-aryl-2-
nitropropionates.[15] These starting materials are readi-
ly obtained by condensation of substituted benzalde-
hyde and methyl nitroacetate, followed by sodium
borohydride reduction of the olefin to give methyl 3-
aryl-2-nitropropionates. Methyl 3-aryl-2-nitropropio-
nates cyclized to give 4H-1,2-benzoxazine in the pres-
ence of TFSA (Scheme 1).
Scheme 2. Generation of o-QMs from 4H-1,2-benzoxazines.
Scheme 1. Reagents and conditions: a) TiCl4 (2 equivs.), N-methylmorpholine (4 equivs.), THF, 08C to room temperature,
18 h; b) NaBH4 (0.5 equivs.), CHCl3, room temperature, 3 h; c) trifluoromethanesulfonic acid (10 equivs.), CHCl3, 508C,
30 min.
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is an unstable orthoester compound.[17] Thus, after de-
silylation with tetrabutylammonium fluoride (TBAF),
the intermediate silyl acetal was converted to the cor-
responding o-substituted phenol in a good yield
(Table 1, entry 4). Imines also gave products, but the
yields varied from imine to imine. The imines of
formaldehyde 20e and f, which have only hydrogen
atoms on the carbon atom of the C=N bond, gave 3,4-
dihydro-1,3-benzoxazines in moderate yields (Table 1,
entries 6 and 7). The imines which bear OEt (20g)
and Ph (20h and i) on the carbon atom of the C=N
bond gave the unstable orthoester and aminoacetal
derivatives, respectively, which were difficult to iso-
Scheme 3.
The Diels–Alder reactions of o-QMs with some di- late. Subsequent acid-catalyzed hydrolysis without iso-
enophiles have been reported previously,[1-3] but the lation of the intermediates gave o-substituted phenol
combinatorial reactions of various o-QMs with vari- derivatives (Table 1, entries 8–10). In the case of the
ous dienophiles have not been fully reported yet. In imines 20h and i with a phenyl group on the carbon
addition, the reactivity of substituted o-QMs in terms atom of the C=N bond, the existence of the unstable
of the Diels–Alder diene has not been investigated. cyclized intermediate aminoacetal was observed by
In this paper, we have established a general method 1H NMR spectroscopy (Table 1, entries 9 and 10).
for the generation of o-QMs from the new precursors, When aliphatic ketimines were used as dienophiles,
4H-1,2-benzoxazines 2, and systematically studied the the expected products were not obtained (Scheme 4),
Diels–Alder reactions of o-QMs with various dieno-
philes.[16] Furthermore, we applied this method to de-
rivatize some natural products.
Scheme 4. Diels–Alder reaction of o-QM with an aliphatic
ketimine.
Results and Discussion
Diels–Alder Reactions of o-Quinone Methides with
Various Dienophiles
while the corresponding vinyl ether 20d gave the cy-
clized product in moderate yield (Table 1, entry 4). A
In the presence of a dienophile, heating of a solution possible reason for this result is that, when imines are
of unsubstituted 2a and nitro-substituted 4H-1,2-ben- used as dienophiles, this Diels–Alder reaction is influ-
zoxazine 2i in toluene afforded chroman derivatives enced by the bulk of the substituents on the carbon
in high yield (Scheme 3 and Table 1). This supports atom of C=N bond. The reactivity of the imine is not
the formation of unsubstituted o-QM 1a and nitro- high enough to allow o-QMs to react with bulky
substituted o-QM 1i upon the elimination of methyl imines such as ketimine. Because the length of the
cyanoformate in situ. In the presence of nitrile com- C=N bond of imines (1.27 Š) is shorter than that of
pounds such as acetonitrile and diethylcyanamide, no vinyl ethers (1.34 Š), steric congestion might have
cyclized product, such as 4H-1,2-benzoxazine deriva- more impact on the reactivity of the imine moiety.
tives, was formed, indicating the generation of o-QMs
The substituent effects on the reactants of the o-
from 2 was irreversible. Since Diels–Alder reactions QMs (1a and i) become clearer when the reactivities
of o-QMs are known to be of reverse electron- toward relatively electron-poor dienophiles 20n–p are
demand,[2] electron-rich dienophiles react more effi- compared. In the case of styrene 20n as a dienophile,
ciently. Indeed, as shown in Table 1, reactions with while unsubstituted o-QM 1a gave the product in
vinyl ethers 20a–d and enamines 20j–l gave products 69% yield (Table 1, entry 15), nitro-substituted o-QM
in good yields. Even in the cases of vinyl ethers and 1i gave the product in 80% yield (Table 1, entry 16)
enamines bearing a bulky substituent, such as vinyl under similar reaction conditions. When a trisubstitut-
ethers 20a–c and enamines 20j–l, the yields are high, ed or monosubstituted olefin (less electron-rich than
probably because the dienophiles are sufficiently elec- styrene) is used as a dienophile, unsubstituted o-QM
tron-rich to allow the reactions with o-QM (Table 1, 1a failed to react (Table 1, entries 17 and 19), but
entries 1–3 and 11–13). In most cases, reactions of nitro-substituted o-QM 1i gave the products, even
vinyl ethers and enamines gave the chroman struc- though in low yields (Table 1, entries 18 and 20). The
ture. In the case of vinyl silyl acetal 20c as a dieno- nitro group on the benzene ring of the o-QM 1i
phile, however, the cyclized compound could not be lowers the LUMOdiene energy, so that the LUMOdiene
–
isolated, probably because the cyclized intermediate HOMOdienophile energy gap becomes smaller and the
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Table 1. Diels–Alder reactions of o-QMs generated from 4H-1,2-benzoxazines with various dienophiles.[a]
[a]
A solution of 3-methoxycarbonyl-4H-1,2-benzoxazine (2a or 2i) and 2 equivs. of dienophile in 15 mL of dry toluene was
heated at 80–1208C with stirring for 2–12 h.
[b]
The products were obtained after acid-catalyzed hydrolysis or tetrabutylammonium fluoride deprotection of the cyclized
products obtained in footnote[a]
.
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orbital interaction between o-QM and the dienophile Application of o-Quinone Methides to Synthesis of
becomes stronger. These results clearly indicate that Euglobal G1 and G2 Analogues
the nitro group of o-QM accelerates the Diels–Alder
reaction.
Euglobal G1 and G2, derivatives of phloroglucinol,
isolated from Eucalyptus spp. have potent inhibitory
activity against Epstein-Barr virus activation.[18] These
compounds have a chroman structure fused with a
unique bicyclic structure (Figure 2). Biogenetically,
the euglobals have been proposed to be formed by
Diels–Alder Reactions of o-Quinone Methides with
Various Substituents on the Benzene Ring
4H-1,2-Benzoxazines with various substitutents on the Diels–Alder type cycloaddition of o-QMs derived
benzene ring can afford correspondingly substituted from oxidation of grandinol with a-pinene 20q, as de-
o-QMs. Formation of the chroman derivatives, the picted in Figure 2.[19] Some euglobal derivatives were
Diels–Alder products with n-butoxyethene 20a, sup- synthesized via o-QMs, and their antivirus activity
ports the formation of o-QMs substituted with various was examined by Singh et al.[19]
substituents on the aromatic ring (Scheme 5 and
To demonstrate the utility of our method of genera-
Table 2). Although the temperature had to be varied tion of o-QMs, we applied the present procedure to
in order to force the reaction to completion, the the synthesis of skeletal analogues of euglobals 19a–o
yields are generally high (Table 2). The reactions of (Scheme 7). Substituted o-QMs, derived from various
substituted o-QMs with the imines, such as N-methyli- substituted 4H-1,2-benzoxazines, were reacted with a-
denebenzylamine 20e and benzylidenephenylamine pinene 20q to give the basic skeleton of euglobals in
20h (Scheme 6), are shown in Table 3.
moderate yield (Table 4, entries 3–16). However, un-
Depending on the substituents of the imines, the substituted o-QM 1a did not react with a-pinene 20q
3,4-dihydro-1,3-benzoxazines or open-chain phenol (Table 4, entry 1). This is a similar situation to that of
derivatives (after hydrolysis) were obtained in moder- 1a, which did not react with the trisubstituted olefin
ate to high yields (Table 3). The electron-withdrawing 20o at 1208C (Table 1, entry 17) because of the
ability of the substituent on the benzene ring of the higher-lying LUMOdiene of 1a. At a higher tempera-
4H-1,2-benzoxazines 2 affected the reaction rate. The ture (1508C), however, 1a reacted with a-pinene 20q
stronger the electron-withdrawing ability of the sub- to give the product in 28% yield (Table 4, entry 2).
stituent, the more slowly the reaction proceeded When the o-QM 1b, which has a methyl group on the
(Tables 2 and 3). For example, when the nitro-substi- benzene ring, is used as the diene, it did not give the
tuted 4H-1,2-benzoxazine 2i was used as a precursor, product even at 1508C, probably because of its
it slowly reacted with the dienophiles at below 1008C. higher-lying LUMOdiene (Table 4, entry 3). When o-
4H-1,2-Benzoxazines with a strongly electron-with- QMs with an electron-withdrawing group on the ben-
drawing substituent, such as CF3 (2g), CN (2h), or zene ring were used, they gave the expected products
NO2 (2i), on the benzene ring reacted with the dieno- in moderate yield (Table 4, entries 4–16). These re-
philes at a higher reaction temperature, 1208C.
sults support the idea that the reactivity of o-QM
These results showed that the generation of o-QMs with an electron-withdrawing group on the benzene
from 4H-1,2-benzoxazines bearing various substitu- ring is higher than that of o-QM with an electron-do-
tents on the benzene ring is general with the present nating group. In addition, there is no significant effect
method, which should be widely applicable in the syn- of the substituent of o-QMs on the regioselectivity
thesis of chromans, 3,4-dihydro-1,3-benzoxazines and (Table 4, entries 3/4, 5/6, 7/8, 9/10, 11/12, and 14/15).
o-substituted phenols having various substituents on The stereochemistry of the products was confirmed
1
the benzene ring.
by means of NOE experiments in H NMR spectros-
Scheme 5.
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Table 2. Diels–Alder reactions of various substituted o-QMs generated from substi-
tuted 4H-1,2-benzoxaizines with butoxyethene 20a.[a]
[a]
A solution of substituted 3-methoxycarbonyl-4H-1,2-benzoxazine and 2 equivs. of
n-butoxyethene 20a in 15 mL of dry toluene was heated at 80–1208C with stirring
for 3–8 h. The solvent was evaporated under reduced pressure to give the product.
copy. Generally, the stronger the electron-withdraw- method o-QMs substituted with various substituents
ing ability, the higher is the yield of the cycloaddition. can be generated and trapped with dienophiles. The
method requires heating, but to a much lower temper-
ature than in the cases of the conventional precursors,
Conclusions
and no additional acid or base catalysts are required
for the formation of the Diels–Alder adducts. This
We have developed a new and efficient method for method can allow the generation of various substitut-
the generation of various substituted o-QMs from the ed o-QMs simply by moderate heating. The Diels–
versatile precursors 4H-1,2-benzoxazines. In this Alder reaction proceeds efficiently with a variety of
Scheme 6.
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Table 3. Diels–Alder reactions of various substituted o-QMs generated from substituted 4H-1,2-benzoxazines with benzylme-
thyleneamine 20e and benzylidenephenylamine 20h.[a,b]
[a]
A solution of substituted 3-methoxycarbonyl-4H-1,2-benzoxazine and 2 equivs. of N-methylidene benzylamine 20e in
15 mL of dry toluene was heated at 80–1208C with stirring for 6–8 h. Then the solvent was evaporated under reduced
pressure to give the product.
[b]
A solution of substituted 3-methoxycarbonyl-4H-1,2-benzoxazine and 2 equiv of benzylidene phenylamine 20h in 15 mL
of dry toluene was heated at 90-1208C with stirring for 8-10 h. After acid-catalyzed hydrolysis of the cyclized intermedi-
ate, the solvent was evaporated under reduced pressure to give the product.
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Figure 2. Grandinol and euglobals G1 and G2.
Scheme 7.
reference in CDCl3 as the solvent, unless otherwise speci-
fied. Chemical shifts are shown in ppm. Coupling constants
are given in Hertz. Electron spray ionization time-of-flight
mass spectra (ESI-MS) and high-resolution ESI mass spec-
tra (HR-MS) were recorded on a Bruker Daltonics (micro-
TOF-05). Low-resolution FAB mass spectra (MS, FAB+)
and high-resolution FAB mass spectra (HR-MS, FAB+)
were recorded on JEOL MStaton JMS-700 and JEOL JMS-
SX 102A spectrometers. The combustion analyses were car-
ried out in the microanalytical laboratory of this faculty.
electron-rich dienophiles to give chromans, 3,4-dihy-
dro-1,3-benzoxazines and o-substituted phenols in
good yields with high regio-, chemo- and stereoselec-
tivities. The generation of various substituted o-QMs
allowed us to investigate the reactivity of these o-
QMs. This novel method has been applied to the
rapid synthesis of complex natural product deriva-
tives. The present findings greatly enhance the applic-
ability of o-QMs in synthetic chemistry.
Synthesis of 3-Methoxycarbonyl-4H-1,2-benzoxazine
(2a)
Experimental Section
To ice-cooled dry THF (25 mL) a solution of TiCl4 (2.3 mL,
22.6 mmol, 2.4 equivs.) in CCl4 (10 mL) was added at 08C.
Then, to this solution a solution of benzaldehyde (1.00 g,
9.44 mmol) and methyl nitroacetate (1.14 g, 9.53 mmol,
1.0 equiv.) in dry THF (10 mL) was added, and the whole
was stirred for 2 h at 08C. A solution of N-methylmorpho-
line (3.81 g, 37.8 mmol, 4.0 equivs.) in dry THF (20 mL) was
slowly added over 2 h, and the whole was stirred vigorously
for 20 h at 188C. Then, water (100 mL) was added, and the
whole was extracted with ether. The organic phase was
washed with brine, dried over Na2SO4, and the solvent was
General Methods
All moisture-sensitive reactions were carried out under an
argon atmosphere unless otherwise noted. All other re-
agents were commercially available and used without fur-
ther purification. Thin-layer chromatography was carried
out on precoated glass plates (E. Merck Brinkman, Kiesel-
gel 60 F254, 0.25 mm thickness). Column chromatography
was carried out on silica gel [silica gel 60 N (100–210 mm),
Merck]. All the melting points were measured with a
Yanaco Micro Melting Point Apparatus and are uncorrect-
ed. Proton (400 MHz) NMR spectra were measured on a
Bruker AV400 NMR spectrometer with TMS as an internal
evaporated under reduced pressure to give
a residue
(2.24 g), which was column-chromatographed on silica gel
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Table 4. Diels–Alder reactions of various substituted o-QMs generated from substituted 4H-1,2-benzoxazines with a-pinene
20q.[a]
[a]
To a solution of 10 equivs. of a-pinene 20q in toluene, a solution of substituted 3-methoxycarbonyl-4H-1,2-benzoxazine in
toluene was slowly added at 1508C. Then the whole was stirred for 6 h at 1508C, and the solvent was evaporated under
reduced pressure to give the product.
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(eluent: n-hexane-ethyl acetate=6:1) to afford the inter-
mediate nitroolefin; yield: 1.70 g.
2H), 1.31–1.26 (m, total 2H), 0.91–0.83 (m, total 3H);
13C NMR (CDCl3): d=152.6, 129.2, 127.2, 122.7, 120.5,
116.9, 97.1, 68.0, 31.7, 26.6, 20.6, 19.3, 13.8; anal. calcd. for
C13H18O2: C 75.69, H 8.80, N, 0.00; found: C 75.64, H 8.65,
N 0.00.
This crude intermediate was dissolved in a mixture of
CHCl3 (70 mL) and i-PrOH (20 mL). To this solution, SiO2
(6.00 g) and NaBH4 (0.309 g, 4.72 mmol) were added, and
the reaction mixture was stirred at room temperature for 4
h. Then, aqueous 12 N HCl (5 mL) was carefully added, and
the whole was filtered to remove silica gel. The solution was
evaporated under reduced pressure to give a residue, which
was column-chromatographed on silica gel (eluent: n-
hexane-ethyl acetate=10:1) to afford methyl 2-nitro-3-phe-
nylpropionate as a white solid; yield: 0.953 g, 4.56 mmol,
overall 48%, based on benzaldehyde).
Methyl 3-(2-Hydroxyphenyl)propionate (5)
A solution of 2a (180 mg, 0.940 mmol) and tert-butyl(1-me-
thoxyvinyloxy)dimethylsilane
(377 mg,
2.00 mmol,
2.1 equivs.) in dry toluene (15 mL) was heated at 1008C
with stirring for 2 h. Then the solvent was evaporated under
reduced pressure to give an intermediate. 1.0M TBAF solu-
tion in THF (1.0 mL) was added to the intermediate at 08C.
The solvent was stirred for 5 min. Then the solvent was
evaporated under reduced pressure to give a residue, which
was column-chromatographed on silica gel (eluent: n-
hexane-ethyl acetate=3:1) to afford methyl 3-(2-hydroxy-
To
a solution of methyl 2-nitro-3-phenylpropionate
(204 mg, 0.98 mmol) in ice-cooled dry CHCl3 (20 mL),
TFSA (0.90 mL, 10.0 mmol, 10 equivs.) was added slowly.
The mixture was stirred at 508C for 30 min, then the whole
was poured into ice-water (100 mL), and extracted with
CHCl3. The organic phase was washed with brine, dried
over Na2SO4, and the solvent was evaporated under reduced
pressure to give a residue (196 mg), which was column-chro-
matographed on silica-gel (eluent: n-hexane-ethyl acetate=
6 :1) to afford 3-methoxycarbonyl-4H-1,2-benzoxazine 2a as
white powder; yield: 155 mg (0.81 mmol, 83%); mp 64–
668C (colorless plates, recrystallized from n-hexane/CHCl3).
1H NMR (CDCl3/TMS): d=7.26–7.23 (m, total 1H), 7.11–
7.04 (m, total 3H), 3.94 (s, 3H), 3.66 (s, 2H); 13C NMR
(CDCl3): d=163.2, 151.4, 149.3, 128.6, 128.1, 125.0, 114.8,
114.3, 53.2, 22.3; anal. calcd. for C10H9NO3: C 62.82, H 4.74,
N 7.33; found: C 62.74, H 4.86, N 7.32.
phenyl)propionate
5 as a white solid; yield: 144 mg
(0.800 mmol, 85%); mp 40–418C (white powder, recrystal-
lized from n-hexane/ether). 1H NMR (DMSO-d6): d=9.37
(s, 1H), 7.06–6.99 (m, total, 2H), 6.78 (d, J=8.0 Hz, 1H),
6.80 (dd, J=7.4, 7.4 Hz, 1H), 3.58 (s, 3H), 3.34 (s, 2H), 2.77
(t, J=7.4 Hz, 2H), 2.56 (t, J=8.1 Hz, 2H); 13C NMR
(CDCl3): d=176.0, 154.2, 130.5, 128.0, 127.3, 120.9, 117.1,
52.3, 34.9, 24.7; anal. calcd. for C10H12O3: C 66.65, H 6.71, N
0.00; found: C 66.52, H, 6.71, N, 0.00.
2-Phenylaminomethylphenol (10a)
A solution of 2a (190 mg, 0.990 mmol) and benzylidenephe-
nylamine (363 mg, 2.00 mmol, 2.0 equivs.) in dry toluene
(15 mL) was heated at 1008C with stirring for 8 h. Then the
solvent was evaporated under reduced pressure to give an
intermediate. Aqueous 2 N HCl (5 mL) and THF (5 mL)
were added to the intermediate. The solvent was stirred for
2 h. The whole was extracted with water. The aqueous
phase was neutralized by aqueous 2 N NaOH. The whole
was extracted with AcOEt. The organic phase was washed
with brine, dried over Na2SO4. Then the solvent was evapo-
rated under reduced pressure to give a residue, which was
column-chromatographed on silica gel (eluent: n-hexane-
ethyl acetate=1:1) to afford 2-phenylaminomethylphenol
10a as a white solid; yield: 182 mg (0.910 mmol, 92%); mp
131–1328C (white powder, recrystallized from n-hexane/
ether). 1H NMR (CDCl3/TMS): d=8.18 (s, 1H), 7.30–7.18
(m, total 5H), 6.97–6.87 (m, total 4H), 4.45 (s, 2H), 4.00 (s,
1H); 13C NMR (CDCl3): d=155.4, 149.3, 129.3, 128.6, 127.9,
126.2, 119.2, 116.0, 115.3, 112.6; anal. calcd. for C13H13NO:
C 78.36, H 6.58, N 7.03; found: C 78.23, H 6.77, N 7.24.
Preparation of Imines 20e and 20f; Typical Procedure
for Benzylmethyleneamine (20e)
To a solution of benzylamine (524 mg, 4.89 mmol) and par-
aformaldehyde (149 mg, 4.95 mmol) in dry CHCl3, MgSO4
(1.10 g) was added. The solution was stirred at room temper-
ature for 6 h. Then, the whole was filtered to remove
MgSO4. The solvent was evaporated under reduced pressure
to give a solid, which was recrystallized from n-hexane/ether
to afford benzylmethyleneamine 20e as a white powder;
yield: 361 mg (3.03 mmol, 62%); mp 46–478C (white
powder, recrystallized from n-hexane/ether). 1H NMR
(CDCl3/TMS): d=7.35–7.22 (m, total 5H), 3.97 (s, 2H), 3.45
(s, 2H); 13C NMR (CDCl3): d=138.4, 128.9, 128.2, 127.0,
73.8, 57.1; anal. calcd. for C8H9N: C 80.63, H 7.61, N 11.75;
found: C 80.35, H 7.77, N, 11.66.
Cyclization Reaction of o-Quinone Methides
Generated from 4H-1,2-Benzoxazines; Typical
Procedure for 2-Butoxychroman (3a)
Supporting Information
Characterization data for all compounds made are given in
the electronic Supporting Information.
A solution of 2a (180 mg, 0.940 mmol) and n-butoxyethene
(200 mg, 2.00 mmol, 2.1 equivs.) in dry toluene (15 mL) was
heated at 908C with stirring for 3 h. Then the solvent was
evaporated under reduced pressure to give a residue, which
was column-chromatographed on silica gel (eluent: n-
hexane-ethyl acetate=10:1) to afford 2-butoxychroman 3a
Acknowledgements
as
a colorless oil; yield: 176 mg, 0.860 mmol, 91%).
1H NMR (CDCl3/TMS): d=7.05 (dd, J=7.9, 7.3 Hz, 2H),
6.86–6.79 (m, total 2H), 5.21 (t, J=2.8 Hz, 1H), 3.83–3.80
(m, total 1H), 3.58–3.54 (m, total 1H), 1.54–1.49 (m, total
This work was supported by a Grant-in-Aid for Scientific Re-
search on Priority Areas “Advanced Molecular Transforma-
tions of Carbon Resources” from the Ministry of Education,
678
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 669 – 679

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www.asc.wiley-vch.de
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