The Diels-Alder reactions of quinone imine ketals

Article abstract of DOI:10.1139/v03-188

N-Benzoyl- and N-arylsulfonyl-p-benzoquinone-mono-imine ketals (QIKs) undergo smooth Diels-Alder cycloadditions with typical 1,3-butadienes to yield the expected endo adducts. Treatment with catalytic acid rapidly converts the adducts to dihydronaphthalen

Full text of DOI:10.1139/v03-188

131
The Diels–Alder reactions of quinone imine ketals1
Scott C. Banfield and Michael A. Kerr
Abstract: N-Benzoyl- and N-arylsulfonyl-p-benzoquinone-mono-imine ketals (QIKs) undergo smooth Diels–Alder
cycloadditions with typical 1,3-butadienes to yield the expected endo adducts. Treatment with catalytic acid rapidly
converts the adducts to dihydronaphthalenes. The N-benzoyl derivatives require high pressures for cycloadditions while
the N-tosyl and N-nosyl derivatives proceed under thermal (ambient pressure) conditions. In all cases the cycloadditions
are completely regioselective.
Key words: Diels–Alder, quinone imine ketal, hyperbaric chemistry.
Résumé : Les cétals des N-benzoyl- et N-arylsulfonyl-p-benzoquinonemonoimines donnent facilement des réactions de
cycloaddition de Diels–Alder avec les buta-1,3-diènes typiques et ils conduisent à la formation des adduits endo atten-
dus. Le traitement avec une quantité catalytique d’acide provoque une transposition des adduits en dihydronaphtalènes.
Les dérivés N-benzoylés nécessitent de hautes pressions pour donner les réactions de cycloaddition alors que les déri-
vés N-tosyl- et N-nosyl- se produisent à des conditions de température et de pression ambiantes. Dans tous les cas, les
réactions de cycloadditions sont complètement diastéréosélectives.
Mots clés : Diels–Alder, cétal de la quinoneimine, chimie hyperbarique.
Banfield and Kerr 138
Scheme 1.
Introduction
The synthetic utility of the Diels–Alder reaction is ques-
tioned by no one. Its versatile ability to form a cyclohexene
ring (with up to four new stereocenters) with exquisite con-
trol is well documented (1). So much work has been done to
expand our understanding of this process over the years that
one may now plan a complex synthesis involving a Diels–
Alder reaction with a high degree of confidence for success.
Even though the Diels–Alder reaction is a “mature reaction”
in terms of its development, many opportunities exist to ex-
pand its utility. These include new dienophiles, dienes, and
catalysts. Such developments allow the synthetic chemist the
opportunity to tackle new and exciting challenges. Several
years ago, we reported the participation of a benzoylated
quinone imine ketal 1 in [4+2]-cycloadditions at ultra-high
pressures (Scheme 1) (2). Prior to that work, the only report
of such reactivity was made by Coutts et al. (3), in which
several examples of sulphonylated quinone imine ketals as
dienophiles were reported, although Swenton and co-
workers (4) have explored the otherwise rich chemistry of
benzoylated quinone imine ketals. The stable cycloadducts 2
could be isolated and purified or treated with acid to yield a
dihydronaphthalene 3. Subsequent to our initial report, we
disclosed the synthesis of the tricyclic ergot skeleton using
this reaction (5). This in turn inspired us to explore a general
strategy for the synthesis of 5-methoxy indoles, which we
recently reported in preliminary form (6). In the present pa-
per we report the full details and an expanded scope of the
hyperbaric Diels–Alder reactions of N-benzoyl quinone
imine ketals, as well as a more generally usable and scalable
thermal variant involving the N-arylsulphonyl counterparts.
Results and discussion
Synthesis of quinone imine ketals
The N-benzoyl quinone imine ketals 5a–d were prepared
by a simplification of the anodic oxidation method reported
by Swenton et al. (4a) (Table 1). The oxidation is technically
simple and is carried out in an open beaker on a stir plate
with a platinum mesh electrode at a constant current of 0.3
A. Although other N-acyl derivatives (pivaloyl, acetyl, tert-
butoxycarbonyl) were considered, the low reactivity of these
compounds in a Diels–Alder sense, compared with the N-
arylsulphonyl compounds (vide infra), led us to pursue the
N-tosyl and N-nosyl derivatives instead.
Received 8 July 2003. Published on the NRC Research Press
Web site at http://canjchem.nrc.ca on 9 January 2004.
This paper is dedicated to Ed Piers who continues to be an
inspirational role model to so many.
S.C. Banfield and M.A. Kerr.2 Department of Chemistry,
The University of Western Ontario, London, ON N6A 5B7,
Canada.
While anodic oxidation yielded the desired products in the
preparation of the N-arylsulphonyl QIKs, the yields were
less than optimal and the reactions somewhat messy. We
turned to oxidation with phenyliodo bis acetate (PIBA) (7).
The preparation of QIKs by oxidation with this reagent has
1This article is part of a Special Issue dedicated to Professor
Ed Piers.
2Corresponding author (e-mail: makerr@uwo.ca).
Can. J. Chem. 82: 131–138 (2004)
doi: 10.1139/V03-188
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Can. J. Chem. Vol. 82, 2004
Table 2. The synthesis of arylsulfonyl QIKs.
Table 1. Synthesis of N-benzoyl quinone imine ketals (QIK).
not been reported. Table 2 shows the results for the prepara-
tion of a series of N-arylsulphonyl QIKs 7a–f by chemical
oxidation of arylsulfonanilides 6a–f.
The Diels–Alder reactivity of QIKs
As expected, the removal of one carbonyl from conjuga-
tion with the dienophilic double bond greatly attenuates the
dienophilicity of QIKs with respect to the parent p-
benzoquinones. In fact, when QIKs 5 were subjected to reac-
tion with a variety of 1,3-butadienes at elevated temperatures
(150 °C), only decomposition was observed after 3 days. At
this stage, high pressures were examined for several reasons,
as follows: (i) The thermal activation (∆H‡) can be replaced
by entropic activation (∆V‡) without the problem of thermal
decomposition, and (ii) it is suspected that much of the low
reactivity of these systems stems from the steric encum-
brance imposed by the quaternary center adjacent to the re-
acting π-system, an encumbrance that can be overcome by
the use of high pressures (8). In the case of the arylsulfonyl
QIKs 7, the increased electron-withdrawing ability of the
tosyl or nosyl groups may overcome the inherent lack of re-
activity, and a thermal process may be viable.
reacting π-systems, all but precludes the transition state A′
leading to the pseudo-meta regioisomer B′ (Fig. 1).
High pressure Diels–Alder reactions
The N-benzoyl QIK 5a was subjected to reaction with a
series of 5 dienes at 13 kbar (1 bar = 105 Pa) at ambient tem-
perature3 (Table 3). Typically, the reactions took about
7 days to proceed to completion and generally led to clean
conversion to the endo cycloadducts.4 These adducts are sur-
prisingly stable to isolation and chromatography, although
prolonged exposure to silica gel leads to small conversions
to the aromatized species (vide infra). A consideration when
using 2,3-dimethylbutadiene (entry d) is competitive poly-
merization of the diene. Use of a large excess of the diene
often resulted in the solidification of the entire reaction mix-
ture. This result is typical of our experiences using dienes
that are unsubstituted at both termini of the diene moiety at
elevated pressures. The fact that 1-tert-butyldimethylsilyl-
oxy-1,3-butadiene (entry e) underwent reaction in higher
A key positive attribute of QIKs as dienophiles resides in
the very properties that cause problems with reactivity. The
presence of only one LUMO – lowering group on the react-
ing dienophilic π-bond imparts a degree of regioselectivity
often missing in the parent quinones. In addition, the ketal
moiety, which is restricted to be essentially orthogonal to the
3 This excludes the heating of the sample, which undoubtedly occurs upon compression of the high-pressure apparatus.
4 The fact that these are endo adducts has been confirmed by NOESY experiments and has been published (ref. 2).
© 2004 NRC Canada

Banfield and Kerr
133
Fig. 1. Possible regiochemical outcomes for Diels–Alder reac-
Table 4. Hyperbaric Diels–Alder–aromatization results.
tions.
Table 3. Isolation of the initial adducts.
yield and in less time is not surprising, since it is highly acti-
vated by the electron-donating silyloxy substituent.
Of interest to us for the synthesis of alkaloids was the fact
that treatment of the adducts with a trace of acid effected the
smooth aromatization to a dihydronaphthalene (i.e., 2→3 in
Scheme 1). Table 4 shows the results of a series of reactions
in which the initially formed adduct was isolated and the
crude material treated with a drop of concentrated HCl in
THF to effect the formation of the dihydronaphthalene. It is
important to note that for some cases in this series of reac-
tions the temperature of the high-pressure reactor was raised
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Can. J. Chem. Vol. 82, 2004
Table 5. Thermal Diels–Alder reactions of QIKs.
to 50 °C. This relatively minor increase in temperature re-
duced the reaction times from 7 days to 12 h.
The method of aromatization was also investigated. Mild
acid sources such as silica gel were ineffective in promoting
the transformation, while a mild Lewis acid such as ytter-
bium triflate resulted in decomposition. Use of p-toluene-
sulfonic acid resulted in the formation of desired product but
also produced the free phenol, possibly because of hydroly-
sis by the water of hydration in the tosic acid.
Ambient pressure Diels–Alder reactions
In an attempt to make this reaction more widely applica-
ble, we examined the Diels–Alder cycloadditions of N-tosyl
and N-nosyl QIKs in the cycloadditions process. Replace-
ment of the benzoyl moiety with the more electron-
withdrawing aryl sulfonyl group should serve to enhance the
dienophilicity of the QIK. To this end, 7a–c and 7f were
heated in toluene with a series of 1,3-butadienes (Table 5).
The N-tosyl QIKs underwent cycloadditions smoothly at
140 °C (sealed tube), while the more reactive nosyl deriva-
tives required 100 °C as the reaction temperature. In most
cases, a substantial amount of conversion to the dihydrona-
phthalene was observed. The aromatization was driven to
completion by treatment with acid, as before, to yield the
dihydronaphthalenes 10 in excellent yields. Other than the
milder reaction temperatures, an advantage of using a nosyl
group is the ease of removal of such a group from the adduct
(9). On a larger scale, the reaction was performed in
refluxing xylenes, using a standard reflux apparatus, and the
aromatization was performed by addition of HCl directly to
the xylenes solution. The dihydronaphthalene precipitated
from the reaction mixture upon cooling with no significant
reduction in chemical yield.
The cycloadducts themselves are suitable substrates for
further oxidation and cycloadditions (Scheme 2). Adduct
10c was hydrogenated to yield 11, which could be oxidized
as before in excellent yield to the QIK 12. Cycloaddition of
12 with 3-methyl-1,3-pentadiene proceeded to give, after
aromatization with catalytic HCl, the linear tricycle 13.
In summary, we have shown that quinone imine ketals
bearing an electron-withdrawing group on the nitrogen atom
are willing participants in hyperbaric or thermal Diels–Alder
reactions. The adducts are readily aromatized with loss of
methanol to produce dihydronaphthalenes in excellent
yields. The synthetic utility of this process, including the
conversion to 5-methoxyindoles, will be the subject of up-
coming reports from our lab.
Experimental section
General considerations
Infrared spectra were obtained as thin films on NaCl
plates. NMR spectra were obtained at 600 or 400 MHz (1H)
and 150 or 100 MHz (13C). Spectra were obtained in CDCl3
1
(referenced at 7.26 ppm for H and 77.0 ppm for 13C) or
1
DMSO-d6 (referenced at 2.49 ppm for H and 39.5 ppm for
13C). Coupling values (J) are in Hz. EI Mass spectra were
obtained at an ionizing voltage of 70 eV. Hyperbaric condi-
tions were achieved using a LECOTM Tempres high-pressure
chemical reactor. Dichloromethane, toluene, and THF were
distilled prior to use, according to the standard procedures
© 2004 NRC Canada

Banfield and Kerr
135
Scheme 2.
General procedure for the high-pressure Diels–Alder
reactions of N-benzoyl quinone imine ketals
Preparation of 8a and 9a
The quinone imine ketal 5a (0.257 g, 1 mmol) was placed
in a length (7′′ (1′′ = 25.4 mm)) of heat-shrinkable Teflon
tubing. Dry CH2Cl2 (2 mL) was added, followed by an ex-
cess (0.5 mL) of technical grade piperylene. The tube was
closed with a brass clamp and placed in the LECOTM
Tempres high-pressure chemical reactor. The pressure was
raised to 13 kbar for a period of 7 days. The reaction mix-
ture was poured directly onto a flash column of silica gel
and eluted with 20% EtOAc in hexanes to produce 290 mg
1
(90% yield) of a pure product, 8a. H NMR (250 MHz,
CDCl3) δ: 7.89 (d, J = 7.5 Hz, 2H), 7.52 (t, J = 7.5 Hz, 1H),
7.40 (t, J = 7.5, Hz, 2H), 6.09 (dd, J = 10.2, 2.1 Hz, 1H),
6.01 (d, J = 10.4 Hz, 1H), 5.71–5.68 (m, 2H), 3.28 (s, 3H),
3.25 (s, 3H), 3.27–3.22 (m, 1H), 2.72–2.64 (m, 2H), 2.20–
1.88 (m, 2H), 1.48 (d, J = 7.6 Hz, 3H). 13C NMR (63 MHz,
CDCl3) δ: 179.5, 164.7, 138.8, 133.4, 133.0, 132.9, 129.4,
128.5, 125.0, 123.8, 99.5, 49.7, 47.7, 43.7 (two signals),
35.0, 24.3, 18.7. IR (thin film) (cm–1) ν: 3050, 3010, 2950,
2920, 2815, 1655, 1640, 1440, 1255. MS m/z (relative inten-
sity): 326 (12, [M + 1]), 325 (48, [M]+), 294 (15), 293 (21),
258 (43), 237 (20), 105 (100). HR-MS (EI 70 eV) calcd. for
C20H23NO3: 325.1678; found: 325.1687.
(10). All other reagents were used as purchased from
Aldrich or Lancaster and without purification. Reactions
were checked for completion by TLC (EM Science, silica
1
gel 60 F254) and (or) H NMR. Flash chromatography was
performed using silica gel purchased from Silicycle Chemi-
cal Division Inc. (230–400 mesh). The synthesis of the N-
benzoyl quinone imine ketals was carried out in the manner
described by Swenton et al. (4a) with the only change being
that the reaction was performed in an open beaker using a
simple power source capable of producing a constant current
of 0.3 A. The anode was a 2.5 cm × 5 cm Pt mesh cylinder,
and the cathode was a 1 cm diameter Pt wire hoop. A simple
laboratory power source was employed in the anodic oxida-
tions. The Diels–Alder chemistry of the N-benzoyl quinone
imine ketals has been described by us (2, 5, 6); however, a
representative example for the preparation and Diels–Alder
reaction of 5a is given below.
Preparation of 9a
The reaction performed, as for the preparation of 8a, us-
ing 5a (0.776 g, 3.0 mmol) and piperylene (0.613 g,
9.0 mmol) resulted in the formation of crude 8a, which was
taken up in 20 mL THF. Concentrated HCl (1 drop) was
added, and the mixture was stirred for 30 min, after which
time solid NaHCO3 was added. The mixture was then stirred
for an additional 10 min, and anhyd MgSO4 was then added;
stirring continued for 10 min further. The mixture was fil-
tered, washed with THF, and concentrated. The crude resi-
due was purified via trituration with cold hexanes; the solid
General procedure for the preparation of N-benzoyl
quinone imine ketals via anodic oxidation
1
was filtered and dried. The yield was 0.857 g (97%). H
NMR (400 MHz, DMSO) δ: 9.79 (s, 1H), 7.97 (app d, J =
6.8 Hz, 2H), 7.59–7.49 (m, 3H), 7.12 (d, J = 8.6 Hz, 1H),
6.85 (d, J = 8.6 Hz, 1Hz), 5.91–5.84 (m, 2H), 3.80 (s, 3H),
3.63–3.56 (m, 1H), 3.28–3.24 (m, 1H), 3.09–3.02 (m, 1H),
1.05 (d, J = 7.0 Hz, 3H). 13C NMR (100 MHz, DMSO) δ:
165.9, 154.8, 137.7, 134.6, 131.4, 130.6, 128.4, 127.7,
127.5, 127.0, 122.8, 122.7, 107.5, 55.4, 29.9, 24.0, 22.4. IR
(thin films) ν: 3276, 1643. MS m/z (relative intensity): 294
(14, [M + 1]), 293 (66, [M]+), 188 (21), 105 (100), 77 (43).
HR-MS (EI 70 eV) calcd. for C19H19NO2: 293.1416; found:
293.1409.
Preparation of 5a
N-(4-Methoxyphenyl)benzamide (3.00 g, 13.2 mmol) was
dissolved in 300 mL of a 2% solution of LiClO4–CH3OH.
The mixture was cooled to 0 °C, and NaHCO3 (6.00 g) was
added. The mixture was rapidly stirred and anodically oxi-
dized at a constant current (0.3 A) until consumption of the
starting material was complete by TLC (approximately
140 min). The oxidation was stopped, and additional benza-
mide (2.62 g, 11.5 mmol) was added and allowed to dis-
solve, and the oxidation resumed until complete by TLC,
approximately 140 min. The mixture was then poured into
water and extracted several times with CH2Cl2. The com-
bined organic layers were then washed with brine, dried
(Na2SO4), filtered, and concentrated. The crude dienophile
was then purified via flash chromatography (30%EtOAc–
hexane) to yield 5.79 g (22.5 mmol, 91% yield) of the de-
sired quinone imine ketal 5a. 1H NMR (400 MHz, CDCl3) δ:
7.91 (d, J = 8.2 Hz, 2H), 7.60–7.56 (m, 1H), 7.48–7.44 (m,
2H), 6.57 (d, J = 9.0 Hz, 2H), 6.46 (d, J = 8.6 Hz, 2H), 3.34
(s, 6H). 13C NMR (100 MHz, CDCl3) δ: 180.3, 155.3, 139.6,
133.8, 132.9, 129.7, 128.9, 127.1, 93.2, 50.4. HR-MS (EI
70 eV) calcd. for C15H15NO3: 257.1052; found: 257.1047.
Typical procedure for the synthesis of N-arylsulfonyl
quinone imine ketals
Preparation of 7a
In a 250 mL round-bottom flask, containing 125 mL of
methanol, was dissolved 10.00 g (36 mmol) of 6a. The solu-
tion was cooled to 0 °C; then 11.70 g (36 mmol) of diace-
toxyiodobenzene was added portion-wise over 5 min. The
flask was purged with argon and stirred until complete by
TLC (approximately 30 min). The reaction mixture was then
poured into water and extracted with EtOAc, then washed
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Can. J. Chem. Vol. 82, 2004
successively with water, saturated NaHCO3 (aq), and brine;
then it was dried with MgSO4, filtered, and concentrated.
The crude product was then purified via recrystalization
from CH2Cl2 to yield 9.87 g (32 mmol, 89% yield) of the
product 7a as a white solid. mp 109–111 °C. 1H NMR
(600 MHz, DMSO-d6) δ: 7.81 (d, J = 8.2 Hz, 2H), 7.45 (d,
J = 8.2 Hz, 2H), 7.36 (dd, J = 10.5, 2.2 Hz, 1H), 7.12 (dd,
J = 10.5, 2.9 Hz, 1H), 7.01 (dd, J = 10.2, 2.9 Hz, 1H), 6.36
(dd, J = 10.2, 2.2 Hz, 1H), 3.28 (s, 6H), 2.40 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ: 162.8, 143.9, 143.2, 141.9,
137.4, 130.4, 129.4, 127.1, 123.0, 91.9, 50.3, 21.7. IR (thin
film) (cm–1) ν: 2835, 1555, 1321, 1156. MS m/z (relative in-
tensity): 308 (3, [M + 1]), 307 (19, [M]+), 276 (27), 152
(100), 139 (13), 121 (14), 91 (33). HR-MS (EI 70 eV) calcd.
for C15H17NO4S: 307.0878; found: 307.0879.
DMSO-d6, trans-isomer) δ: 7.79 (d, J = 8.3 Hz, 2H), 7.42 (d,
J = 8.3 Hz, 2H), 6.79 (d, J = 10.2 Hz, 1H), 6.62 (d, J =
1.6 Hz, 1H), 6.36 (dd, J = 10.2, 1.6 Hz, 1H), 3.85 (s, 3H),
1
3.20 (s, 6H), 2.39 (s, 3H). H NMR (400 MHz, DMSO-d6,
cis-isomer) δ: 7.79 (obscured by aryl sulfonyl, 2H), 7.42 (d,
J = 8.3 Hz, 2H), 7.42 (obscured by aryl sulfonyl, 1H), 6.89
(d, J = 10.2 Hz, 1H), 5.77 (m, 1H), 3.79 (s, 3H), 3.20 (s,
6H), 2.39 (s, 3H). 13C NMR (100 MHz, DMSO-d6, both iso-
mers) δ: 170.7, 169.4, 166.3, 165.5, 143.7, 143.6, 142.8,
141.1, 138.4, 138.1, 130.7, 129.7 (two overlapping signals),
126.7, 126.6, 122.8, 102.7, 96.4, 92.7, 92.6, 56.6, 56.5, 50.8
(two overlapping signals), 21.0 (two overlapping signals). IR
(thin film) (cm–1) ν: 2835, 1596, 1302, 1146. MS m/z (rela-
tive intensity): 338 (2, [M + 1]), 337 (9, [M]+), 306 (36),
182 (100), 151 (8), 91 (24). HR-MS (EI 70 eV) calcd. for
C16H19NO5S: 337.0984; found: 337.0989.
Quinone imine ketal (7b)
Quinone imine ketal (7f)
Oxidation of 11.10 g (36 mmol) of the nosylated p-
anisidine 6b with 11.62 g (36 mmol) of diacetoxyiodoben-
zene in 125 mL of methanol was performed in a similar
manner to the preparation of compound 7a, method A. The
crude product was purified via a mixed recrystalization from
EtOAc–MeOH to yield 9.00 g (26.6 mmol, 74% yield) of
Oxidation of 2.00 g (6.4 mmol) of the tosylated p-
anisidine 6f with 2.07 g (6.4 mmol) of diacetoxyiodoben-
zene in 20 mL of methanol was performed in a similar
manner to the preparation of compound 7a, method B. Fil-
tration and washing with hexanes yielded 1.78 g (5.2 mmol,
81% yield) of the product 7f as a yellow solid and as a
(1.1:1) mixture of cis- and trans-isomers, respectively. No
1
the product 7b as an off-white solid. mp 132–135 °C. H
NMR (400 MHz, CDCl3) δ: 8.39 and 8.18 (AA′BB′ system,
4H), 7.52 (dd, J = 10.5, 2.0 Hz, 1H), 6.87 (dd, J = 10.5,
2.7 Hz, 1H), 6.80 (dd, J = 10.2, 2.7 Hz, 1H), 6.34 (dd, J =
10.2, 2.0 Hz, 1H), 3.38 (s, 6H). 13C NMR (100 MHz,
CDCl3) δ: 164.3, 150.2, 146.1, 144.7, 143.4, 129.9, 128.5,
124.1, 123.1, 91.7, 50.3. IR (thin film) (cm–1) ν: 1532, 1326,
1154. MS m/z (relative intensity): 338 (5, [M]+), 307 (46),
170 (14), 152 (100), 121 (28), 106 (17). HR-MS (EI 70 eV)
calcd. for C14H14N2O6S: 338.0573; found: 338.0568.
1
further purification was required. mp 100–102 °C. H NMR
(400 MHz, DMSO-d6, trans-isomer) δ: 7.82 (d, J = 8.4 Hz,
2H), 7.57 (dd, J = 10.4, 2.0 Hz, 1H), 7.47–7.45 (m, 2H),
7.18 (d, J = 10.4 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 3.20 (s,
1
6H), 2.41 (s, 3H). H NMR (400 MHz, DMSO-d6, cis-iso-
mer) δ: 7.83 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 2.1 Hz, 1H),
7.47–7.45 (m, 2H), 7.10 (d, J = 10.3 Hz, 1H), 6.60 (dd, J =
10.3, 2.1 Hz, 1H), 3.20 (s, 6H), 2.41 (s, 3H). 13C NMR
(100 MHz, DMSO-d6, both isomers) δ: 161.8, 160.9, 152.8,
149.7, 144.2, 144.1, 143.5, 142.2, 137.1, 137.0, 132.6,
131.6, 129.5 (two overlapping signals), 127.2, 127.1, 125.1,
124.7, 94.34, 94.31, 51.61, 51.58, 21.7 (two overlapping sig-
nals). IR (thin film) (cm–1) ν: 2924, 2837, 1320, 1156. MS
m/z (relative intensity): 343 (9, [M + 2]), 342 (6, [M + 1]),
341 (23, [M]+), 310 (45), 306 (32), 186 (100), 139 (23), 91
(92). HR-MS (EI 70 eV) calcd. for C15H16ClNO4S:
341.0489; found: 341.0494.
Quinone imine ketal (7c)
Oxidation of 3.85 g (12.5 mmol) of the tosylated p-
anisidine 6c with 4.03 g (12.5 mmol) of diacetoxyiodoben-
zene in 50 mL of methanol was performed in a similar man-
ner to the preparation of compound 7a, method A. The crude
product was purified via a recrystalization from CH2Cl2 to
yield 3.05 g (9.0 mmol, 72% yield) of the product 7c as a
1
yellow solid. mp 137–140 °C. H NMR (400 MHz, DMSO-
d6) δ: 7.80 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.30
(d, J = 10.5 Hz, 1H), 7.05 (dd, J = 10.5, 2.5 Hz, 1H), 5.98
(d, J = 2.5 Hz, 1H), 3.60 (s, 3H), 3.27 (s, 6H), 2.41 (s, 3H).
13C NMR (100 MHz, DMSO-d6) δ: 159.1, 150.2, 144.7,
144.0, 137.3, 129.7, 126.7, 120.9, 111.6, 94.3, 55.3, 49.9,
21.1. IR (thin film) (cm–1) ν: 2938, 1313, 1147. MS m/z (rel-
ative intensity): 338 (2, [M + 1]), 337 (10, [M]+), 306 (100),
182 (51), 151 (43), 91 (35). HR-MS (EI 70 eV) calcd. for
C16H19NO5S: 337.0984; found: 337.0992.
Typical procedure for the thermal Diels–Alder–
aromatization reactions of quinone imine ketals
Preparation of dihydronaphthalene (10a)
The quinone imine ketal 7a (0.503 g, 1.6 mmol) and
piperylene (0.393 g, 5.8 mmol) were taken up in dry toluene
(2.3 mL) in an oven-dried sealed tube. One crystal of the
radical inhibitor BHT was added, and the tube was flushed
with argon before sealing. The reaction mixture was heated
at 140 °C for a period of 24 h, after which time the reaction
mixture was concentrated and taken up in dry THF (20 mL).
Concentrated HCl (2 drops) was added, and the mixture was
stirred under argon for 30 min, after which time solid
NaHCO3 was added. The mixture was then stirred for an ad-
ditional 10 min, and anhyd MgSO4 was then added; stirring
continued for 10 min further. The mixture was filtered,
washed with THF, and concentrated. The crude residue was
purified via trituration with cold hexane; the solid was fil-
Quinone imine ketal (7d)
Oxidation of 5.00 g (16.3 mmol) of the tosylated p-
anisidine 6d with 5.25 g (16.3 mmol) of diacetoxyiodoben-
zene in 50 mL of methanol was performed in a similar
manner to the preparation of compound 7a, method A. The
crude product was purified via recrystalization from CH2Cl2
to yield 4.74 g (14.1 mmol, 87% yield) of the product 7d as
a yellow solid and as a (1.8:1) mixture of trans- and cis-iso-
1
mers, respectively. mp 110–112 °C. H NMR (400 MHz,
© 2004 NRC Canada

Banfield and Kerr
137
tered and dried to yield 0.509 g (1.48 mmol, 90% yield) of
the product 10a as a white solid. mp 152–156 °C. H NMR
as a white solid. mp 160–162 °C. 1H NMR (400 MHz,
DMSO) δ: 9.24 (s, 1H), 7.55 (app d, J = 8.3 Hz, 2H), 7.35
(app d, J = 8.3 Hz, 2H), 6.62 (d, J = 8.7 Hz, 1H), 6.50 (d,
J = 8.7 Hz, 1H), 5.51–5.50 (m, 1H), 3.70 (s, 3H), 3.45–3.41
(m, 1H), 3.24 (dd, J = 21.6, 5.4 Hz, 1H), 2.89 (dd, J = 21.6,
2.3 Hz, 1H), 2.37 (s, 3H), 1.67 (s, 3H), 1.00 (d, J = 6.8 Hz,
3H). 13C NMR (100 MHz, DMSO) δ: 154.7, 142.5, 140.3,
137.9, 137.1, 129.3, 126.5, 126.0, 125.3, 123.3, 117.8,
107.1, 55.3, 34.1, 24.3, 21.2, 21.0, 20.4. IR (thin film) (cm–1)
ν: 3279, 1486, 1161. MS m/z (relative intensity): 358 (15,
[M + 1]), 357 (62, [M]+), 202 (100), 187 (45), 172 (18), 91
(12). HR-MS (EI 70 eV) calcd. for C20H23NO3S: 357.1399;
found: 357.1402.
1
(400 MHz, DMSO-d6) δ: 9.23 (s, 1H), 7.58 (d, J = 8.3 Hz,
2H), 7.37 (d, J = 8.3 Hz, 2H), 6.60 (d, J = 8.7 Hz, 1H), 6.36
(d, J = 8.7 Hz, 1H), 5.90–5.79 (m, 2H), 3.81–3.71 (m, 1H),
3.69 (s, 3H), 3.27–3.20 (m, 1H), 2.99–2.93 (m, 1H), 2.38 (s,
3H), 1.06 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ: 155.4, 143.5, 137.7, 136.7, 130.2, 129.5, 127.2, 125.4,
124.9, 124.3, 123.0, 107.2, 55.3, 29.7, 24.2, 22.5, 21.5. IR
(thin film) (cm–1) ν: 3244, 1484, 1160. MS m/z (relative in-
tensity): 344 (17, [M + 1]), 343 (73, [M]+), 277 (7), 188
(100), 92 (6), 91 (24). HR-MS (EI 70 eV) calcd. for
C19H21NO3S: 343.1242; found: 343.1245.
Dihydronaphthalene (10b)
Dihydronaphthalene (10e)
The reaction between quinone imine ketal 7a (0.504 g,
1.6 mmol) and 2,3-dimethyl-1,3-butadiene (0.509 g,
5.7 mmol) was performed in a similar manner to the prepa-
ration of compound 10a. The crude residue was purified via
trituration with cold hexane; the solid was filtered and dried
to yield 0.506 g (1.41 mmol, 88% yield) of the product 10b
as a white solid. mp 172–175 °C. 1H NMR (400 MHz,
DMSO-d6) δ: 9.21 (s, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.34 (d,
J = 8.3 Hz, 2H), 6.67–6.61 (m, 2H), 3.71 (s, 3H), 3.02–2.97
(m, 4H), 2.36 (s, 3H), 1.66 (s, 3H), 1.57 (s, 3H). 13C NMR
(100 MHz, DMSO-d6) δ: 154.7, 142.7, 138.1, 133.3, 129.5,
126.7, 126.0, 125.5, 123.4, 122.0, 121.8, 107.2, 55.2, 32.1,
30.8, 20.9, 18.2 (two overlapping signals). IR (thin film)
(cm–1) ν: 3274, 1486, 1161. MS m/z (relative intensity): 358
(16, [M + 1]), 357 (66, [M]+), 202 (3), 186 (100), 171 (23),
91 (18). HR-MS (EI 70 eV) calcd. for C20H23NO3S:
357.1399; found: 357.1406.
The reaction between quinone imine ketal 7a (0.304 g,
0.99 mmol) and methyl (E)-3,5-hexadienoate (0.442 g,
3.5 mmol) was performed in a similar manner to the prepa-
ration of compound 10a. The crude residue was purified via
flash chromatography (40% EtOAc–hexane) to yield 0.303 g
(0.75 mmol, 76% yield) of the product 10e as a white solid.
1
mp 124–127 °C. H NMR (400 MHz, DMSO-d6) δ: 9.31 (s,
1H), 7.57 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 6.65
(d, J = 8.7 Hz, 1H), 6.42 (d, J = 8.7 Hz, 1H), 5.95–5.87 (m,
2H), 4.18–4.14 (m, 1H), 3.70 (s, 3H), 3.59 (s, 3H), 3.29–
3.22 (m, 1H), 3.00–2.94 (m, 1H), 2.65 (dd, J = 15.4, 3.8 Hz,
1H), 2.38 (s, 3H), 2.14 (dd, J = 15.4, 10.5 Hz, 1H). 13C
NMR (100 MHz, DMSO-d6) δ: 171.5, 155.1, 142.8, 137.9,
137.2, 129.6, 127.8, 126.8, 126.3, 125.8, 125.4, 124.5,
107.8, 55.4, 51.3, 40.5, 31.2, 24.1, 21.0. IR (thin film) (cm–1)
ν: 3255, 1735, 1485, 1161. MS m/z (relative intensity): 402
(8, [M + 1]), 401 (30, [M]+), 327 (31), 246 (18), 186 (84),
172 (100), 91 (28). HR-MS (EI 70 eV) calcd. for
C21H23NO5S: 401.1297; found: 401.1292.
Dihydronaphthalene (10c)
The reaction between quinone imine ketal 7a (1.00 g,
3.25 mmol) and cyclopentadiene (0.98 mL, 11.8 mmol) was
performed in a similar manner to the preparation of com-
pound 10a. The crude residue was purified via trituration
with cold hexane; the solid was filtered and dried to yield
1.082 g (3.17 mmol, 98% yield) of the product 10c as an
off-white solid. mp 137–140 °C. 1H NMR (400 MHz,
DMSO-d6) δ: 9.51 (s, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.31 (d,
J = 8.1 Hz, 2H), 6.65 (dd, J = 5.2, 3.0 Hz, 1H), 6.58 (d, J =
8.8 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 6.26 (dd, J = 5.2,
3.0 Hz, 1H), 3.94 (br s, 1H), 3.76 (br s, 1H), 3.68 (s, 3H),
2.33 (s, 3H), 1.90 (d, J = 7.0 Hz, 1H), 1.67 (d, J = 7.0 Hz,
1H). 13C NMR (150 MHz, DMSO-d6) δ: 151.6, 149.4, 142.8,
142.7, 142.2, 138.1, 137.1, 129.4, 126.8, 124.1, 123.8,
109.3, 68.8, 55.3, 48.0, 46.2, 20.9. IR (thin film) (cm–1) ν:
3260, 1490, 1161. MS m/z (relative intensity): 342 (11, [M +
1]), 341 (43, [M]+), 186 (100), 160 (13), 91 (25). HR-MS
(EI 70 eV) calcd. for C19H19NO3S: 341.1086; found:
341.1081.
Dihydronaphthalene (10f)
The reaction between quinone imine ketal 7c (0.501 g,
1.49 mmol) and piperylene (0.357 g, 5.2 mmol) was per-
formed in a similar manner to the preparation of compound
10a. The crude residue was purified via trituration with cold
hexane; the solid was filtered and dried to yield 0.472 g
(1.26 mmol, 85% yield) of the product 10f as an off-white
1
solid. mp 210–213 °C. H NMR (400 MHz, DMSO-d6) δ:
8.90 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz,
2H), 6.30 (s, 3H), 5.89–5.80 (m, 2H), 3.96–3.95 (m, 1H),
3.75 (s, 3H), 3.23–3.10 (m, 1H), 3.05 (s, 3H), 2.96–2.93 (m,
1H), 2.37 (s, 3H), 1.07 (d, J = 7.0 Hz, 3H). 13C NMR
(100 MHz, DMSO-d6) δ: 156.1, 155.2, 141.9, 141.8, 139.4,
130.8, 128.7, 126.7, 122.6, 114.1, 113.7, 92.9, 55.4, 54.5,
29.8, 23.7, 22.5, 20.9. IR (thin film) (cm–1) ν: 3239, 1591,
1160. MS m/z (relative intensity): 374 (6, [M + 1]), 373 (15,
[M]+), 218 (100), 186 (18), 91 (16). HR-MS (EI 70 eV)
calcd. for C20H23NO4S: 373.1348; found: 373.1352.
Dihydronaphthalene (10d)
Dihydronaphthalene (10g)
The reaction between quinone imine ketal 7a (0.508 g,
1.65 mmol) and 3-methyl-1,3-pentadiene (0.471 g, 5.7 mmol)
was performed in a similar manner to the preparation of
compound 10a. The crude residue was purified via
trituration with cold hexane; the solid was filtered and dried
to yield 0.563 g (1.58 mmol, 96% yield) of the product 10d
The reaction between quinone imine ketal 7f (0.500 g,
1.46 mmol) and 1-phenyl-1,3-butadiene (0.686 g, 5.27 mmol)
was performed in a similar manner to the preparation of
compound 10a. The crude residue was purified via
trituration with cold hexane; the solid was filtered and dried
to yield 0.631 g (1.43 mmol, 98% yield) of the product 10g
© 2004 NRC Canada

138
Can. J. Chem. Vol. 82, 2004
as a white solid. mp 152–155 °C. 1H NMR (400 MHz,
DMSO-d6) δ: 9.17 (s, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.31 (d,
J = 8.1 Hz, 2H), 7.23 (dd, J = 7.4, 7.2 Hz, 2H), 7.15 (t, J =
7.4 Hz, 1H), 7.06 (d, J = 7.2 Hz, 2H), 6.37 (s, 1H), 5.96–
5.88 (m, 2H), 5.19–5.18 (m, 1H), 3.77 (s, 3H), 3.45–3.44
(m, 2H), 2.36 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ:
151.4, 144.5, 143.2, 136.5, 135.9, 131.5, 131.1, 129.5,
129.3, 128.4, 127.9, 127.0, 126.0, 124.9, 123.7, 121.8, 60.0,
40.9, 24.9, 21.0. IR (thin film) (cm–1) ν: 3329, 1161. MS m/z
(relative intensity): 440 (12, [M + 1]), 439 (40, [M]+), 311
(16), 284 (100), 249 (45), 234 (30), 130 (42), 91 (78). HR-
MS (EI 70 eV) calcd. for C24H22ClNO3S: 439.1009; found:
439.1005.
trated, and the crude residue was purified via trituration with
cold hexane to yield 0.487 g (1.25 mmol, 85% yield) of the
product 10i as a yellow solid. mp 166–169 °C. H NMR
1
(400 MHz, DMSO-d6) δ: 9.75 (s, 1H), 8.41 (d, J = 8.9 Hz,
2H), 7.92 (d, J = 8.9 Hz, 2H), 6.63 (d, J = 8.8 Hz, 1H), 6.46
(d, J = 8.8 Hz, 1H), 5.53–5.52 (m, 1H), 3.70 (s, 3H), 3.44–
3.43 (m, 1H), 3.28–3.21 (m, 1H), 2.94–2.88 (m, 1H), 1.67
(s, 3H), 1.02 (d, J = 6.8 Hz, 3H).13C NMR (100 MHz,
DMSO-d6) δ: 155.3, 149.6, 146.4, 140.7, 137.1, 128.4,
126.4, 124.7, 124.6, 123.8, 118.1, 107.5, 55.3, 34.2, 24.8,
21.1, 20.3. IR (thin film) (cm–1) ν: 3283, 1532, 1349, 1165.
MS m/z (relative intensity): 389 (10), 388 (45), 202 (100),
172 (32), 122 (16), 76 (9). HR-MS (EI 70 eV) calcd. for
C19H20N2O5S: 388.1093; found: 388.1091.
Dihydronaphthalene (10h)
The quinone imine ketal 7b (0.511 g, 1.51 mmol) and
piperylene were taken up in dry toluene (2.3 mL) in an
oven-dried sealed tube. One crystal of the radical inhibitor
BHT was added, and the tube was flushed with argon before
sealing. The reaction mixture was heated at 100 °C for a pe-
riod of 7 h, after which time the reaction mixture was con-
centrated and taken up in dry THF (20 mL). Concentrated
HCl (2 drops) was added, and the mixture was stirred under
argon for 30 min, after which time solid NaHCO3 was
added. The mixture was then stirred for an additional
10 min, and anhyd MgSO4 was then added, stirring for
10 min further. The mixture was then filtered, washed with
reagent grade THF, and concentrated. The crude residue was
purified via trituration with cold hexane; the solid was fil-
tered and dried to yield 0.564 g (1.50 mmol, 99% yield) of
Acknowledgement
We are grateful to the Natural Sciences and Engineering
Research Council of Canada (NSERC), The Ontario Minis-
try of Science and Technology, and MedMira Laboratories
for funding. S.C.B. is an NSERC PGSB scholar.
References
1. For an excellent review with many leading references see:
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7. A. Pelter and S. Elgendy. Tetrahedron Lett. 677 (1988).
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Chap 7.
1
the product 10h as a white solid. mp 193–195 °C. H NMR
(400 MHz, DMSO-d6) δ: 9.74 (s, 1H), 8.41 (d, J = 8.8 Hz,
2H), 7.94 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 8.7 Hz, 1H), 6.35
(d, J = 8.7 Hz, 1H), 5.90–5.75 (m, 2H), 3.78–3.76 (m, 1H),
3.70 (s, 3H), 3.27–3.22 (m, 1H), 3.00–2.94 (m, 1H), 1.07 (d,
J = 7.0 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ: 155.5,
149.6, 146.4, 140.1, 130.7, 128.4, 126.3, 125.2, 124.6,
123.8, 122.8, 107.4, 55.3, 29.6, 24.0, 22.4. IR (thin film)
(cm–1) ν: 3275, 1588, 1532, 1349, 1167. MS m/z (relative in-
tensity): 375 (11, [M + 1]), 374 (49, [M]+), 188 (100), 173
(32), 122 (10). HR-MS (EI 70 eV) calcd. for C18H18N2O5S:
374.0936; found: 374.0940.
Dihydronaphthalene (10i)
The quinone imine ketal 7b (0.500 g, 1.48 mmol) and 3-
methyl-1,3-pentadiene (0.447 g, 5.44 mmol) were taken up
in dry toluene (2.3 mL) in an oven-dried sealed tube. One
crystal of the radical inhibitor BHT was added, and the tube
was flushed with argon before sealing. The reaction mixture
was heated at 100 °C for a period of 8 h, at which point
NMR analysis revealed 100% conversion to the desired
dihydronaphthalene 10i. The reaction mixture was concen-
9. R.E. Heckert and H.R. Snyder. J. Am. Chem. Soc. 74, 2006
(1952).
10. D.D. Perrin and W.L.F. Armarego. In Purification of labora-
tory chemicals. 3rd ed. Pergamon, New York. 1988.
© 2004 NRC Canada