Crucial dependence of chemiluminescence efficiency on the syn/anti conformation for intramolecular charge-transfer-induced decomposition of bicyclic dioxetanes bearing an oxidoaryl group

Article abstract of DOI:10.1021/jo2006945

Thermally stable rotamers of bicyclic dioxetanes bearing 6-hydroxynaphthalen-1-yl (anti-5a and syn-5a), 3-hydroxynaphthalen-1-yl (anti-5b and syn-5b), and 5-hydroxy-2-methylphenyl groups (anti-5c and syn-5c) were synthesized. These dioxetanes underwent TB

Full text of DOI:10.1021/jo2006945

ARTICLE
pubs.acs.org/joc
Crucial Dependence of Chemiluminescence Efficiency on the
Syn/Anti Conformation for Intramolecular Charge-Transfer-Induced
Decomposition of Bicyclic Dioxetanes Bearing an Oxidoaryl Group
Masakatsu Matsumoto,* Haruna Suzuki, Nobuko Watanabe, Hisako K. Ijuin, Jiro Tanaka, and
Chizuko Tanaka
Department of Chemistry, Kanagawa University, Tsuchiya, Hiratsuka, Kanagawa 259-1293, Japan
S Supporting Information
b
ABSTRACT: Thermally stable rotamers of bicyclic dioxetanes bearing
6-hydroxynaphthalen-1-yl (anti-5a and syn-5a), 3-hydroxynaphthalen-1-yl
(anti-5b and syn-5b), and 5-hydroxy-2-methylphenyl groups (anti-5c
and syn-5c) were synthesized. These dioxetanes underwent TBAF
(tetrabutylammonium fluoride)-induced decomposition accompanied by
the emission of light in DMSO and in acetonitrile at 25 °C. For all three
pairs of rotamers, the chemiluminescence efficiency ΦCL for anti-5 was 8ꢀ19
times higher than that for syn-5, and the rate of CTID (charge-transfer-
induced decomposition) for anti-5 was faster than that for syn-5. The chemiluminescence spectra of the rotamers for 5a and 5c,
respectively, were different. This discrepancy in the chemiluminescence spectra between rotamers can presumably be attributed to
the difference in the structures of de novo keto imide anti-14 and syn-14 in an excited state, which inherit the structures of the
corresponding intermediary anionic dioxetanes anti-13 and syn-13. The important difference in chemiluminescence efficiency
between anti-5 and syn-5 is discussed from the viewpoint of a chemiexcitation mechanism for CTID of oxidophenyl-substituted
dioxetane.
’ INTRODUCTION
finding suggested that the introduction of a substituent at the 2- or
6-position of a phenyl group in dioxetane such as 4 would make
rotation of the aromatic ring more difficult, so that the syn/anti
rotamers could become individually isolable. This idea was realized
in the form of three pairs of syn/anti rotamers of 2-Boc-5-tert-butyl-
4,4-dimethyl-2-aza-6,7-dioxabicyclo[3.2.0]heptane bearing a
6-hydroxynaphthalen-1-yl 5a, 3-hydroxynaphthalen-1-yl 5b, or
5-hydroxy-2-methylphenyl group 5c (Chart 1).16,17 We report
here that the chemiluminescence of these dioxetanes in CTID
changed with the stereochemistry of the rotamers, and the efficiencies
of chemiluminescence were decisively different between the rotamers.
Intramolecular charge-transfer-induced decomposition (CTID)
of a 1,2-dioxetane bearing an aromatic electron donor has
promising potential that could lead to highly efficient chemi-
luminescence1ꢀ5 and is now believed to play a key role in the
bioluminescence of various organisms.6 Thus, extensive research
has been conducted to elucidate the chemiexcitation process in
chemiluminescence and bioluminescence. CTID has further-
more stimulated the development of high-performance dioxetane-
based chemiluminescence systems that may be useful for modern
biological and clinical analysis.7ꢀ9 However, it is still unclear
how chemiluminescence is related to the structure and stereo-
chemistry of dioxetanes. For instance, it is unclear how the
conformation of an aryl group affects the chemiluminescence
efficiency for CTID-active dioxetane 1 bearing an oxidophenyl
group (Scheme 1). In addition, there have been few studies or
discussions of the efficiency of bioluminescence in the firefly
from the viewpoint of the stereochemistry of intermediary
dioxetanone 2 and/or excited oxyluciferin 3 (Scheme 1).10ꢀ13
Against this background, we found an unprecedented phenomen-
on that sheds light on the relationship between the stereochem-
istry of aryl-substituted dioxetanes and their chemiluminescence
efficiency.
’ RESULTS AND DISCUSSION
1. Synthesis of Thermally Stable Syn/Anti Rotamers of
N-(Boc)amino-Substituted Bicyclic Dioxetanes. First, we
synthesized dioxetane 5a to examine whether or not syn/anti
rotamers of aryl-substituted dioxetane could be isolated indivi-
dually in a stable form. The key precursor 6a was synthesized as
follows (Scheme 3). The first step of the synthetic sequence was
N-substitution of 1-(N-Boc)amino-2,2,4,4-tetramethylpentan-3-
one14 7 with 1-chloromethyl-6-methoxynaphthalene 8a to give
1-[N-Boc-N-(6-methoxynaphthalen-1-yl)methylamino]-2,2,4,4-
tetramethylpentan-3-one 9a, which was in turn subjected to
Dioxetanes 4 bearing a 3-hydroxyphenyl group have very
recently been found to show, at room temperature, syn/anti
rotational isomerism of an aromatic ring caused by steric hindrance
from adjacent N-acyl and tert-butyl groups (Scheme 2).14,15 This
Received: April 2, 2011
Published: May 16, 2011
r
2011 American Chemical Society
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LDA-mediated cyclization to give a stereoisomeric mixture of
hydroxypyrrolidine 10a. Dehydration of 10a gave dihydropyr-
role 11a, the methoxynaphthyl group of which was finally
demethylated with MeSNa in hot DMF to give 6a. When 6a
was irradiated in the presence of a catalytic amount of Rose
Bengal in ethyl acetate with a Na lamp under an oxygen atmo-
sphere at 0 °C, singlet oxygenation smoothly took place to
exclusively give dioxetane anti-5a (Scheme 4). This result shows
that singlet oxygen selectively attacked the less-crowded π-face
anti-5a did not change the syn/anti ratio and only resulted in
increased 12a. Fortunately, rotamer syn-5a could be isolated in
pure form by column chromatography (SiO2) and gave satisfac-
tory analytical data similar to the case of anti-5a. The stereo-
chemistry of syn-5a was determined by X-ray single crystallo-
graphic analysis (Figure 1). The isomerization of syn-5a similarly
occurred to give a 70:30 mixture of anti-5a and syn-5a together
with a small amount of 12a, when heated in refluxing toluene for
15 min. Such isomerization between anti-5a and syn-5a was
practically not observed at room temperature.
of 6a. The structure of anti-5a was determined by 1H NMR, 13
C
NMR, IR, Mass, HRMass spectral data and elemental analysis.
The stereochemistry of anti-5a was finally determined by X-ray
single crystallographic analysis,17 and the ORTEP view is shown
in Figure 1.
When anti-5a was heated in toluene at 110 °C for 15 min,
isomerization occurred to give a mixture of anti-5a and syn-5a
rotamers (70:30) along with a small amount of a decomposition
product, i.e., keto imide 12a (Scheme 4). Prolonged heating of
The results described above encouraged us to synthesize other
pairs of rotamers, anti-5b/syn-5b and anti-5c/syn-5c. Precursors
6b and 6c were similarly prepared as in the case of 6a, starting
from 1-chloromethyl-3-methoxynaphthalene 8b or 5-methoxy-
2-methylbenzyl chloride 8c in the place of 8a (Scheme 3). Singlet
oxygenation of 6b and 6c was carried out to exclusively give the
syn-form of the dioxetanes, syn-5b and syn-5c, respectively. This
result shows that 1O2 attacked with high π-face selectivity for 6b
and 6c as well as for 6a (Scheme 4). Thermal isomerization of
these dioxetanes was carried out as in the case of anti-5a to give a
mixture of syn/anti rotamers: anti/syn = 20:80 for 5b and 50:50
for 5c. Thus, we isolated anti-5b and anti-5c by column chro-
matography. Dioxetanes anti-5b, syn-5b, anti-5c, and syn-5c gave
satisfactory analytical data, and their stereochemistries were
determined by X-ray single crystallographic analysis (Figure S1
in the Supporting Information).
Scheme 1. Chemiluminescence of Oxidophenyl-Substituted
Dioxetane and Bioluminescence of the Firefly
2. Base-Induced Chemiluminescent Decomposition of
Syn/Anti Rotamers of Hydroxyaryl-Substituted Bicyclic Di-
oxetanes. When a solution of anti-5a in DMSO was added to a
solution containing a large excess of tetrabutylammonium fluor-
ide (TBAF) in DMSO at 25 °C, CTID of anti-5a took place
according to pseudo-first-order kinetics to give an orange light
(Figure 2) with maximum wavelength λmaxCL = 678 nm, chemi-
luminescence efficiency ΦCL = 2.8 ꢁ 10
,
ꢀ4 18,19 and rate of CTID
kCTID = 3.2 ꢁ 10ꢀ2
s
ꢀ1. These chemiluminescence properties
Scheme 2. Rotamers of Dioxetane 4
are summarized in Table 1. TBAF-induced chemiluminescent
decomposition of syn-5a also took place under the same condi-
tions. However, it showed unexpectedly weak chemilumines-
cence, the ΦCL of which was only 1/19 of that for anti-5a, and
both λmaxCL and kCTID were different from those for anti-5a, as
shown in Table 1 and Figure 2. Syn/anti isomerization did not
occur during TBAF-induced CTID: when the chemiluminescent
Chart 1. Rotamers of Dioxetanes 5aꢀc
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Scheme 3. Synthetic Pathway of Precursors 6aꢀc for the Synthesis of Dioxetanes 5aꢀc
Scheme 4. Singlet Oxygenation of Dihydropyrroles 6aꢀc, Isomerization of Dioxetanes 5aꢀc, and Their Thermal Decomposition
to Keto Imides 12aꢀc
could similarly be observed for a rather simple phenolic dioxetane.
Thus, TBAF-induced decomposition was examined for a pair of
isomers, i.e. anti-5b and syn-5b, in DMSO. The results summar-
ized in Table 1 show that ΦCL for anti-5b was 8 times higher than
that for syn-5b, and kCTID for anti-5b was considerably faster than
that for syn-5b, while both λmaxCL's were observed at 594 nm.
These results showed that the marked syn/anti difference in
chemiluminescence properties could be attributed to the differ-
ence in the conformation of the entire hydroxynaphthalene ring.
Next, we examined the TBAF-induced decomposition of 5c,
Figure 1. ORTEP views of dioxetane anti-5a and syn-5a.
which bore a 3-hydroxyphenyl group substituted with a 6-methyl
group to prevent rotation of the aromatic ring. The results
reactions of anti-5a and syn-5a were individually quenched
midway, intact anti-5a and syn-5a were both confirmed to have
retained their stereochemistry.
summarized in Table 1 show that ΦCL for anti-5c was 10 times
higher than that for syn-5c, kCTID for the anti-rotamer was slightly
CL
faster than that for the syn-rotamer, and λmax for the syn-
The above results posed two questions. The first was whether
this phenomenonwas dueto the differencein theconformation of
the naphthalene ring itself20 or to a difference in the conformation
of the entire hydroxynaphthalene ring. The second was whether
this result was specific for naphthyl-substituted dioxetane 5a or
rotamer was longer than that for the anti-rotamer. Thus, the
rotamer-dependence of chemiluminescence properties was also
seen for a phenolic dioxetane.
As described above, by comparing the chemiluminescence
properties between anti- and syn-rotamers of 5aꢀc, we can see
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Figure 2. Chemiluminescence (CL) spectra of rotamers of dioxetanes 5aꢀc and fluorescence (FL) spectra of oxido anions 14aꢀc in DMSO: (A) CL of
anti-5a and syn-5a and FL of 14a; (B) CL of anti-5b and syn-5b, and FL of 14b; (C) CL of anti-5c and syn-5c, and FL of 14c.
Table 1. TBAF-Induced Chemiluminescent Decomposition of Rotamers of Dioxetanes 5aꢀc in DMSOa
kCTID
/
relative ΦCL
anti/syn
CL
λmax
/
nm
ΦCL b
Φfl
ΦS
sꢀ1
anti-5a
syn-5a
678
688
2.8 ꢁ 10ꢀ4
1.5 ꢁ 10ꢀ5
1.2 ꢁ 10ꢀ3
2.3 ꢁ 10ꢀ1
1.3 ꢁ 10ꢀ2
3.2 ꢁ 10ꢀ2
5.7 ꢁ 10ꢀ3
19
anti-5b
syn-5b
594
594
1.2 ꢁ 10ꢀ2
1.5 ꢁ 10ꢀ3
3.6 ꢁ 10ꢀ1
1.0 ꢁ 10ꢀ2
3.3 ꢁ 10ꢀ2
4.2 ꢁ 10ꢀ3
2.7 ꢁ 10ꢀ2
1.4 ꢁ 10ꢀ3
8
anti-5c
syn-5c
578
584
2.0 ꢁ 10ꢀ3
2.1 ꢁ 10ꢀ4
2.0 ꢁ 10ꢀ1
2.1 ꢁ 10ꢀ2
2.8 ꢁ 10ꢀ2
1.7 ꢁ 10ꢀ2
10
a All reactions were carried out at 25 °C. b Based on a value reported for the chemiluminescent decomposition of 3-adamantylidene-4-(3-tert-
butyldimethylsiloxy-phenyl)-4-methoxy-1,2-dioxetane in TBAF/DMSO.18,19
Table 2. TBAF-Induced Chemiluminescent Decomposition of Rotamers of Dioxetanes 5aꢀc in Acetonitrilea
kCTID
/
relative ΦCL
anti/syn
CL
λmax
/
nm
ΦCL b
Φfl
ΦS
sꢀ1
anti-5a
syn-5a
690
701
1.0 ꢁ 10ꢀ4
5.8 ꢁ 10ꢀ4
1.7 ꢁ 10ꢀ1
6.5 ꢁ 10ꢀ3
12
18
10
8.3 ꢁ 10ꢀ6
1.4 ꢁ 10ꢀ2
6.5 ꢁ 10ꢀ4
anti-5b
syn-5b
598
598
4.6 ꢁ 10ꢀ3
2.5 ꢁ 10ꢀ4
1.5 ꢁ 10ꢀ1
5.1 ꢁ 10ꢀ3
3.1 ꢁ 10ꢀ2
1.6 ꢁ 10ꢀ3
2.8 ꢁ 10ꢀ3
3.4 ꢁ 10ꢀ4
anti-5c
syn-5c
582
594
7.7 ꢁ 10ꢀ4
1.5 ꢁ 10ꢀ1
9.4 ꢁ 10ꢀ4
7.9 ꢁ 10ꢀ5
1.5 ꢁ 10ꢀ2
5.7 ꢁ 10ꢀ4
a All reactions were carried out at 25 °C. b Based on a value reported for the chemiluminescent decomposition of 3-adamantylidene-4-(3-tert-
butyldimethyl-siloxyphenyl)-4-methoxy-1,2-dioxetane in TBAF/DMSO.18,19
that (a) ΦCL values for anti-rotamers were an order of magni-
tude, or more, greater than those for the corresponding syn-
rotamers, and (b) anti-rotamers tended to decompose more
rapidly to give chemiluminescence with a shorter wavelength
compared to syn-rotamers.
TBAF-induced decomposition was carried out in acetonitrile
for these three pairs of stereoisomeric dioxetanes 5aꢀc, as in
DMSO. As summarized in Table 2, the results show that there
was a marked difference in ΦCL between anti- and syn-isomers,
though the ΦCL values in acetonitrile tended to be somewhat
smaller than those in DMSO. All of the chemiluminescence
spectra for 5aꢀc were observed in the region a little longer than
in DMSO, as shown in Figure 3. Rates of CTID in acetonitrile
were somewhat slower than those in DMSO.
The results described above raise important questions related
to the singlet-chemiexcitation mechanism for the CTID of
dioxetanes. It is not surprising that kCTID changed depending
on the conformation of the aromatic ring, since the structure of
dioxetanes has often been reported to affect kCTID.7 However,
before the present findings, we hardly expected the marked
difference in chemiluminescence efficiency between the anti-
5aꢀc and syn-5aꢀc rotamers. The difference in the chemilumi-
nescence spectra between anti- and syn-rotamers observed for 5a
and 5c was also rather unusual, since both rotamers, as expected,
gave the same decomposition product in CTID.
Thus, we attempted to investigate the fluorescence of emitters
produced from stereoisomeric 5aꢀc to understand chemiexcitation
for the present CTID. Freshly spent reaction mixtures from anti-5a
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Figure 3. Chemiluminescence (CL) spectra of rotamers of dioxetanes 5aꢀc and fluorescence (FL) spectra of oxido anions 14aꢀc in acetonitrile: (A)
CL of anti-5a and syn-5a and FL of 14a; (B) CL of anti-5b and syn-5b, and FL of 14b; (C) CL of anti-5c and syn-5c, and FL of 14c.
Scheme 5. Light Emission from de novo Keto Imide 14 for the Decomposition of Dioxetane 5 and Light Emission from Authentic
Keto Imide 14
fluorescence spectra of 14 was observed in acetonitrile (Figure 3).
Fluorescence efficiencies (Φfl 's) for 14aꢀc in DMSO and in
acetonitrile are shown in Tables 1 and 2. Based on these values,
singlet chemiexcitation efficiency, ΦS = ΦCL/Φfl, values were
estimated for syn-5a, anti- and syn-5b, and anti-5c. The results are
summarized in Tables 1 and 2.
Chart 2. Dioxetanes 15a and 15b Fused with a Tetrahydro-
furan Ring
On the other hand, ΦS's for anti-5a and syn-5c could not be
reliably estimated since the fluorescence spectra of authentic 14a
and 14c deviated to some extent from the corresponding
chemiluminescence spectra. Thus, we formally estimated ΦS's
for anti-5a and syn-5c as shown in Tables 1 and 2, by using the
Φfl 's of authentic 14a and 14c. The formal ΦS's for anti-5a and
anti-5b in DMSO were close to the values of ΦS reported for the
corresponding tetrahydrofuran analogs 15a and 15b: ΦS = 0.22
and 0.09 for 15a and 15b respectively (Chart 2).21 These
estimations suggest that the marked difference in ΦCL between
anti-5 and syn-5 can be attributed to a difference in singlet-
chemiexcitation efficiency (vide infra).
As noted above, the chemiluminescence spectra of anti-5a and
syn-5a did not coincide with each other, though both isomers of
5a exclusively produced the same keto ester 12a. This discrepancy
is likely due to the difference in stereochemistry between the two
de novo keto imides in an excited state; i.e. anti-14a(de novo)
formed from anti-5a and syn-14a(de novo) from syn-5a. Thus,
and syn-5a gave the same keto imide 12a in high yields after careful
neutralization. Similarly, 5b and 5c gave 12b and 12c in high yields.
These results strongly suggest that CTIDs of both anti-5 and syn-5
produced oxido anion 14 of keto imide 12 accompanied by the
emission of light through intermediary oxidoaryl-substituted dioxe-
tane anti-13 and syn-13, respectively (Scheme 5). Oxido anions
14aꢀc generated in situ from the corresponding authentic 12aꢀc
gave fluorescence in TBAF/DMSO, as shown in Figure 2. The
fluorescence spectrum of 14b practically coincided with the chemi-
luminescence spectra of both anti- and syn-5b, while those of 14a
and 14c coincided only with the chemiluminescence spectra of syn-
5a and anti-5c, respectively. A similar tendency in the relationship
between chemiluminescence spectra of 5 and the corresponding
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Scheme 6. Plausible Mechanism for the Intramolecular CT-Induced Decomposition of Oxidophenyl-Substituted Dioxetane
ARTICLE
Baader and his co-workers have very recently suggested that
path II, rather than path I, effectively leads to chemiexcitation.22
According to this mechanism, we attempted to explain the syn/
anti difference in chemiluminescence efficiency for the CTID of
oxidophenyl-substituted dioxetane A as a simple model. We
performed time-dependent DFT (TDDFT) calculations at the
B3LYP/6-31Gþ(d) level individually for the anti- and syn-forms
of 3-oxidophenyl-substituted dioxetane A and calculated the
charge distribution in C for each anti- and syn-series. The results
in Scheme 7 show that a negative charge is distributed more on
O1ꢀC4 (ꢀ0.78e) than on O2ꢀC3 (ꢀ0.51e) for species anti-C
before CꢀC bond cleavage into anti-E, whereas a negative charge
is distributed more on O2ꢀC3 (ꢀ0.64e) than on O1ꢀC4
(ꢀ0.56e) for syn-C. We can see from Scheme 7 that anti-C
favors path II more than syn-C. Therefore, chemiexcitation
presumably occurs more effectively for the anti-isomer of A than
for its syn-isomer. However, we cannot at present explain what
causes the difference in the distribution of the negative charge
between anti-C and syn-C, although an MO calculation suggested
that they had different dipole moments.
Scheme 7. Charge Distribution on Biradical Anion anti-C
and syn-C for the Intramolecular CT-Induced Decomposition
of Oxidophenyl-Substituted Dioxetane
anti-14a(de novo) and syn-14a(de novo) may more or less inherit
the corresponding conformations from intermediary dioxetanes
anti-13a and syn-13a, as illustrated in Scheme 5. If we consider
that the fluorescence spectra of authentic 14a coincided with the
chemiluminescence spectra of syn-5a in both solvent systems
(DMSO and acetonitrile), syn-14a(de novo) had a structure
similar to that of authentic 14a. This was also the case for 5c.
These results suggest that the features of chemiexcitation for
anti-5 should not be the same as those for syn-5. Thus, we finally
attempted to elucidate how the chemiexcitation process was
affected by the syn/anti conformational isomerism of a dioxetane
bearing an oxidoaryl group. A plausible mechanism of chemiex-
citation proposed for the CTID of oxidophenyl-substituted
dioxetane A is illustrated in Scheme 6, where the reaction
proceeds as follows:7
(i) Intramolecular CT takes place from an oxidoaryl anion to
OꢀO for dioxetane A to form B in the transition state.
(ii) The OꢀO bond of B cleaves to give two types of biradical
anion, CI and/or CII, as a canonical structure.
(iii) Cleavage of the CꢀC bond in biradical anion CI gives a
radical ion pair DI, which is annihilated by intermolecular
backward electron transfer (BET) to form excited oxido-
phenyl carbonyl E (path I). On the other hand, cleavage
of biradical anion CII gives excited oxidophenyl carbonyl
E directly or through intramolecular BET of DII (path II).
’ CONCLUSION
We successfully synthesized three pairs of thermally stable
isomeric bicyclic dioxetanes bearing 6-hydroxynaphthalen-1-yl
(anti-5a and syn-5a), 3-hydroxynaphthalen-1-yl (anti-5b and syn-
5b), and 5-hydroxy-2-methylphenyl groups (anti-5c and syn-5c).
TBAF-induced decomposition of these dioxetanes showed che-
miluminescence, the properties of which were different between
anti-5 and syn-5. Among these differences, the most prominent
was a marked discrepancy in chemiluminescence efficiency
between the rotamers: anti-5aꢀc emitted 8ꢀ19 times more
light than the corresponding syn-5aꢀc. Thus, if such a phenom-
enon occurs in general for a nonisolable syn/anti mixture of
oxidoaryl-substituted dioxetanes, chemiluminescence would ap-
pear to practically arise only from the anti-rotamer. The chemi-
luminescence spectra of the anti- and syn-rotamers of 5a and 5c
were also different to some extent. This phenomenon can
presumably be attributed to the difference in structure between
de novo keto imide anti-14 and syn-14 in an excited state, which
inherit the structures of the corresponding intermediary anionic
dioxetanes anti-13 and syn-13.
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The present findings should stimulate further studies of the
mechanism of the singlet-chemiexcitation process for dioxetane-
based chemiluminescence as well as bioluminescence and should
provide new insight into the design of high-performance chemi-
luminescent compounds.
(Mþ, 6), 200 (15), 199 (13), 172 (15), 171 (100), 149 (14), 141 (11),
128 (16), 69 (17), 57 (69), 56 (19), 55 (20). HRMS (ESI):450.2638,
calcd for C26H37NO4Na [M þ Naþ] 450.2620. Anal. Calcd for
C26H37NO4: C, 73.03; H, 8.72; N, 3.28. Found: C, 72.94; H, 8.97;
N, 3.24.
1
9c: Colorless oil (mixture of stereoisomers). H NMR (500 MHz,
CDCl3): δH 1.20ꢀ1.58 (m, 24H), 2.15 (s, 3H), 3.43ꢀ3.58 (m, 2H),
3.76 (s, 3H), 4.25ꢀ4.40 (m, 2H), 6.56 (broad s, 1H), 6.68 (dd, J = 8.2
and 2.8 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H) ppm. 13C NMR (125 MHz,
CDCl3): δC 17.9 (CH3), 25.1 (CH3 ꢁ 2), 27.9 (CH3 ꢁ 3), 28.1 (broad
CH3 ꢁ 3), 46.0 (C), 49.0 and 50.0 (broad CH2), 51.1 (C), 54.8 and 55.7
(broad CH2), 55.0 (CH3), 79.5 and 80.0 (broad C), 111.3 and 111.6
(CH), 111.4 (CH), 126.8 and 127.3 (C), 130.9 (CH), 136.6 and 137.7
(C), 156.5 (C), 158.0 (C), 217.5 (C) ppm. IR (liquid film): ν 2974,
2935, 1697, 1682, 1612, 1581 cmꢀ1. Mass (m/z, %): 391 (Mþ, 1), 208
(13), 164 (42), 136 (11), 135 (100), 134 (28), 57 (57). HRMS (ESI):
414.2645, calcd for C23H37NO4Na [M þ Naþ] 414.2620.
’ EXPERIMENTAL SECTION
General. Melting points were uncorrected. IR spectra were taken on
an FT/IR infrared spectrometer. 1H and 13C NMR spectra were
recorded on a 400 and 500 MHz spectrometers. Mass spectra were
obtained by using double-focusing mass spectrometers and an ESI-TOF
mass spectrometer. Column chromatography was carried out using silica
gel or NH-silica gel.
Synthesis of 1-[N-Boc-N-(6-methoxynaphthalen-1-yl)methyl]-
amino-2,2,4,4-tetramethylpentan-3-one (9a). Typical Proce-
dure. A solution of 1-(N-Boc)amino-2,2,4,4-tetramethylpentan-3-one
(7) (10.3 g, 40.0 mmol) in dry DMF (25 mL) was added dropwise over
5 min to a suspension of sodium hydride (60% in oil, 1.71 g, 42.8 mmol)
in dry DMF (80 mL) under a nitrogen atmosphere at 0 °C and stirred at
room temperature for 1 h. To the solution, 1-chloromethyl-6-methox-
ynaphthalene (8a) (8.88 g, 43.0 mmol) was added at 0 °C and stirred at
room temperature for 16 h. The reaction mixture was poured into sat. aq.
NH4Cl and then extracted with AcOEt. The organic layer was washed
with sat. aq. NaCl, dried over anhydrous MgSO4, and concentrated in
vacuo. The residue was chromatographed on silica gel and eluted with
hexaneꢀAcOEt (9:1) to give 1-[N-Boc-N-(6-methoxynaphthalen-
1-yl)methyl]amino-2,2,4,4-tetramethylpentan-3-one (9a) as a color-
less solid (14.6 g, 86% yield). According to the procedure described
above, 1-[N-Boc-N-(3-methoxynaphthalen-1-yl)methyl]amino-2,2,4,4-
tetramethylpentan-3-one (9b) and 1-[N-Boc-N-(5-methoxy-2-methyl-
benzyl)]amino-2,2,4,4-tetramethylpentan-3-one (9c) were synthesized
by using 1-chloromethyl-3-methoxynaphtalene (8b) and 5-methoxy-2-
methylbenzyl chloride (8c) instead of 8a in 84% and 90% yield,
respectively. 9aꢀ9c were observed as a mixture of stereoisomers by
1H and 13C NMR.
Synthesis of 1-Boc-3-tert-butyl-3-hydroxy-2-(6-methoxy-
naphthalen-1-yl)-4,4-dimethyl-pyrrolidine (cis-10a and trans-
10a). Typical Procedure. BuLi (1.65 M in hexane, 12.0 mL, 19.8 mmol)
was added to a solution of diisopropylamine (3.0 mL, 21 mmol) in dry THF
(35 mL) under a nitrogen atmosphere at 0 °C and was stirred at room
temperature for 30 min. To the solution, 1-[N-Boc-N-(6-methoxynaph-
thalen-1-yl)methylamino]-2,2,4,4-tetramethylpentan-3-one (9a) (4.27 g,
10.0 mmol) in dry THF (15 mL) was added dropwise over 3 min at
40 °C and stirred for 15 min. The reaction mixture was quenched with H2O,
poured into sat. aq. NH4Cl, and then extracted with AcOEt. The organic
layer was washed with sat. aq. NaCl, dried over anhydrous MgSO4, and
concentrated in vacuo. The residue was chromatographed on silica gel and
eluted with hexaneꢀAcOEt (5:1) to give 1-Boc-3-tert-butyl-c-3-hydroxy-r-
2-(6-methoxynaphthalen-1-yl)-4,4-dimethylpyrrolidine (cis-10a) as a pale
yellow solid (2.30 g, 54% yield) and 1-Boc-3-tert-butyl-t-3-hydroxy-r-2-
(6-methoxynaphthalen-1-yl)-4,4-dimethylpyrrolidine (trans-10a) as a pale
yellow solid (1.73 g, 41% yield).
According to the procedure described above, 1-Boc-3-tert-butyl-3-
hydroxy-2-(3-methoxynaphthalen-1-yl)-4,4-dimethylpyrrolidine, cis-10b
and trans-10b, were synthesized from 9b in 54% and 40% yield, res-
pectively. 1-Boc-3-tert-butyl-3-hydroxy-2-(5-methoxy-2-methylphenyl)-4,
4-dimethylpyrrolidine, cis-10c and trans-10c, were also synthesized from
9c in 79% and 16% yield, respectively. cis-10aꢀcis-10c were observed by
1H and 13C NMR as a mixture of rotamers, and only the main isomers were
assigned by 1H and 13C NMR.
9a: Coloress granules, mp 79.0ꢀ80.0 °C (from AcOEtꢀhexane)
1
(mixture of stereoisomers). H NMR (400 MHz, CDCl3): δH 1.15ꢀ
1.60 (m, 24H), 3.34ꢀ3.63 (m, 2H), 3.92 (s, 3H), 4.85 (broad s, 2H),
7.00ꢀ7.20 (m, 3H), 7.39 (dd, J = 8.1 and 7.3 Hz, 1H), 7.65 (d, J = 8.1
Hz), 7.73ꢀ7.97 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3): δC 25.2
(CH3 ꢁ 2), 28.0 (CH3 ꢁ 3), 28.2 (CH3 ꢁ 3), 46.1 (C), 49.0 and 49.8
(broad CH2), 51.4 (C), 53.8 and 55.6 (broad CH2), 55.2 (CH3), 79.8
(broad C), 106.7 (CH), 118.5 (CH), 120.8 and 122.7 (broad CH),
124.1 and 124.9 (broad CH), 125.9 (CH), 126.3 (broad C), 126.2 and
126.6 (broad CH), 133.2 and 133.7 (broad C), 135.1 (C), 156.7 (C),
157.3 (C), 217.7 (C) ppm. IR (KBr): ν 2978, 2965, 2934, 1699, 1675,
1626 cmꢀ1. Mass (m/z, %): 427 (Mþ, 4), 200 (26), 172 (17), 171 (100),
128 (10), 57 (11). HRMS (ESI): 450.2607, calcd for C26H37NO4Na [M
þ Naþ] 450.2620. Anal. Calcd for C26H37NO4: C, 73.03; H, 8.72; N,
3.28; Found: C, 72.98; H, 9.05; N, 3.29.
cis-10a: Colorless plates, mp 178.5ꢀ179.0 °C (from CH2Cl2ꢀ
1
hexane). H NMR (400 MHz, CDCl3): δH 0.72 (s, 9H), 0.90 (broad
s, 9H), 1.27 (s, 3H), 1.39 (s, 3H), 1.86 (s, 1H), 3.37 (d, J = 10.3 Hz, 1H),
3.75 (d, J = 10.3 Hz, 1H), 3.94 (s, 3H), 5.96 (s, 1H), 7.15 (d, J = 2.7 Hz,
1H), 7.20 (dd, J = 9.3 and 2.7 Hz, 1H), 7.38ꢀ7.45 (m, 2H), 7.67 (d with
fine coupling, J = 6.8 Hz, 1H), 8.20 (d, J = 9.3 Hz, 1H) ppm. 13C NMR
(125 MHz, CDCl3): δC 21.4 (CH3), 26.3 (CH3), 27.8 (CH3 ꢁ 3), 28.1
(CH3 ꢁ 3), 39.3 (C), 46.5 (C), 55.2 (CH3), 59.4 (CH), 61.1 (CH2),
79.1 (C), 85.8 (C), 106.6, (CH), 118.5 (CH), 124.1 (CH), 125.8 (CH),
125.8 (CH), 126.9 (CH), 128.1 (C), 135.0 (C), 138.5 (C), 154.3 (C),
157.0 (C) ppm. IR (KBr): ν 3581, 3446, 2977, 2884, 1685, 1626,
1601 cmꢀ1. Mass (m/z, %): 427 (Mþ, 17), 371 (29), 327 (29), 326
(100), 314 (21), 244 (11), 213 (20), 200 (20), 199 (32), 198 (55), 186
(20), 171 (57), 57 (39). HRMS (ESI): 450.2612, calcd for C26H37NO4-
Na [M þ Naþ] 450.2620. Anal. Calcd for C26H37NO4: C, 73.03; H,
8.72; N, 3.28. Found: C, 73.04; H, 9.05; N, 3.25.
9b: Colorless plates, mp 91.0ꢀ91.5 °C (from AcOEtꢀhexane)
(mixture of stereoisomers). 1H NMR (400 MHz, CDCl3): δH
1.20ꢀ1.60 (m, 24H), 3.47ꢀ3.61 (m, 2H), 3.91 (s, 3H), 4.84 (broad s,
2H), 6.87 (d, J = 2.2 Hz, 1H), 7.03 (d, J = 2.2 Hz, 1H), 7.35 (dd, J = 8.1
and 6.8 Hz, 1H), 7.44 (dd, J = 8.1 and 6.8 Hz, 1H), 7.75 (d, J = 8.1 Hz,
1H), 7.69ꢀ7.89 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3): δC 25.2
(CH3 ꢁ 2), 28.0 (CH3 ꢁ 3), 28.2 (CH3 ꢁ 3), 46.0 (C), 48.7 and 49.6
(broad CH2), 51.3 (C), 54.5 and 55.7 (broad CH2), 55.1 (CH3), 79.8
and 80.2 (broad C), 104.7 and 105.0 (broad CH), 115.9 and 116.9
(broad CH), 122.4 and 122.9 (broad CH), 123.6 (CH), 126.1 (CH),
126.6 and 126.9 (broad C), 127.5 (CH), 134.8 and 135.6 (broad C),
135.2 (C), 156.5 (C), 157.2 (C), 217.5 (C) ppm. IR (KBr): ν 3006,
2979, 2965, 2938, 1703, 1670, 1631, 1605 cmꢀ1. Mass (m/z, %): 427
trans-10a: Colorless granules, mp 182.5ꢀ183.0 °C (from AcOEtꢀ
1
hexane). H NMR (400 MHz, CDCl3): δH 076 (broad s, 9H), 0.79
(broad s, 9H), 1.34 (s, 3H), 1.58 (s, 3H), 2.14 (broad s, 1H), 3.69
(s, 2H), 3.93 (s, 3H), 5.67 (broad, 1H), 7.13 (d, J = 2.7 Hz, 1H), 7.16
(dd, J = 9.3 and 2.7 Hz, 1H), 7.36 (dd, J = 8.1 and 7.1 Hz, 1H), 7.60 (d,
J = 7.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 8.20ꢀ8.30 (m, 1H) ppm.
5012
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The Journal of Organic Chemistry
ARTICLE
13C NMR (125 MHz, CDCl3): δC 26.7 (CH3), 27.8 (CH3), 27.8
(CH3 ꢁ 3), 28.3 (broad CH3 ꢁ 3), 39.3 (C), 46.6 (broad C), 55.1
(CH3), 61.9 (CH2), 70.0 (CH), 79.2 (C), 90.5 (broad C), 106.3 (CH),
118.0 (CH), 123.9 (CH), 125.5 (CH), 126.3 (CH), 126.6 (CH), 127.7
(C), 135.1 (C), 139.7 (C), 154.6 (C), 156.8 (C) ppm. IR (KBr): ν 3389,
2978, 2959, 2933, 1669, 1627, 1603 cmꢀ1; Mass (m/z, %): 427 (Mþ,
12), 371 (30), 327 (31), 326 (100), 314 (21), 244 (13), 243 (13), 240
(13), 213 (23), 200 (26), 199 (51), 198 (93), 186 (30), 183 (10), 172
(12), 171 (72), 57 (43). HRMS (ESI): 450.2610, calcd for C26H37NO4-
Na [M þ Naþ] 450.2620. Anal. Calcd for C26H37NO4 þ 1/10hexane:
C, 73.24; H, 8.87; N, 3.21. Found: C, 73.00; H, 9.15; N, 3.30.
cis-10b: Colorless granules, mp 138.5ꢀ139.0 °C (from CH2Cl2ꢀ
hexane). 1H NMR (500 MHz, CDCl3): δH 0.72 (s, 9H), 0.91 (broad s,
9H), 1.27 (s, 3H), 1.38 (s, 3H), 1.88 (s, 1H), 3.38 (d, J = 10.5 Hz, 1H),
3.74 (d, J = 10.5 Hz, 1H), 3.88 (s, 3H), 5.97 (s, 1H), 7.08 (broad s, 1H),
7.30 (d, J = 2.8 Hz, 1H), 7.37 (dd, J = 8.2 and 6.9 Hz, 1H), 7.42 (dd, J =
8.2 and 6.9 Hz, 1H), 7.74 (d, J = 8.2 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H)
ppm. 13C NMR (125 MHz, CDCl3): δC 21.4 (CH3), 26.3 (CH3), 27.8
(CH3 ꢁ 3), 28.0 (CH3 ꢁ 3), 39.2 (C), 46.5 (C), 55.1 (CH3), 59.0 (CH),
61.0 (CH2), 79.1 (C), 85.9 (C), 105.9 (CH), 119.2 (CH), 123.4 (CH),
124.1 (CH), 125.9 (CH), 127.8 (CH), 128.2 (C), 135.0 (C), 140.4 (C),
154.2 (C), 156.8 (C) ppm. IR (KBr): ν 3500, 2977, 2964, 2928, 2889,
1689, 1664, 1626, 1604 cmꢀ1. Mass (m/z, %): 427 (Mþ, 14), 371 (25),
327 (26), 326 (100), 314 (13), 213 (15), 200 (13), 199 (22), 198 (55),
186 (13), 184 (10), 171 (46), 58 (12), 57 (65), 56 (25), 55 (19). HRMS
(ESI): 450.2642, calcd for C26H37NO4Na [M þ Naþ] 450.2620. Anal.
Calcd for C26H37NO4: C, 73.03; H, 8.72; N, 3.28. Found: C, 73.02; H,
8.97; N, 3.29.
trans-10b: Colorless granules, mp 187.0ꢀ188.0 °C (from AcOEtꢀ
hexane). 1H NMR (400 MHz, CDCl3): δH 0.80 (broad s, 18H), 1.34 (s,
3H), 1.61 (s, 3H), 2.15 (s, 1H), 3.68 (s, 2H), 3.90 (s, 3H), 5.67 (s, 1H),
7.06 (s with fine coupling, 1H), 7.33ꢀ7.48 (m, 3H), 7.73 (d, J = 7.8 Hz,
1H), 8.25 (broad d, J = 7.8 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3):
δC 26.6 (CH3), 27.8 (CH3 ꢁ 4), 28.4 (broad CH3 ꢁ 3), 39.3 (C), 46.7
(C), 55.2 (CH3), 61.7 (CH2), 69.6 (C), 79.3 (C), 90.5 (C), 105.7 (CH),
118.9 (CH), 123.1 (CH), 124.6 (CH), 125.8 (CH), 127.6 (CH), 127.9
(C), 135.1 (C), 141.7 (C), 154.5 (C), 156.7 (C) ppm. IR (KBr): ν 3443,
3006, 2978, 2932, 2881, 1683, 1627, 1606 cmꢀ1. Mass (m/z, %): 427
(Mþ, 2), 326 (29), 252 (11), 240 (30), 213 (10), 200 (12), 199 (34),
198 (100), 197 (17), 186 (18), 185 (11), 184 (21), 183 (16), 171 (49),
154 (18), 141 (11), 128 (16), 127 (15), 115 (12), 57 (93), 56 (15), 55
(18). HRMS (ESI): 450.2632, calcd for C26H37NO4Na [M þ Naþ]
450.2620. Anal. Calcd for C26H37NO4: C, 73.03; H, 8.72; N, 3.28.
Found: C, 73.06; H, 9.03; N, 3.27.
cis-10c: Colorless granules, mp 100.5ꢀ101.0 °C (from hexaneꢀ
AcOEt). 1H NMR (500 MHz, CDCl3): δH 0.98 (broad s, 9H), 1.08 (s,
9H), 1.23 (s, 3H), 1.29 (s, 3H), 1.72 (s, 1H), 2.42 (s, 3H), 3.30 (d, J =
10.1 Hz, 1H), 3.65 (d, J = 10.1 Hz, 1H), 3.75 (s, 3H), 5.26 (s, 1H), 6.74
(dd, J = 8.3 and 2.7 Hz, 1H), 6.88 (d, J = 2.7 Hz, 1H), 7.02 (d, J = 8.3 Hz,
1H) ppm. 13C NMR (125 MHz, CDCl3): δC 20.6 (CH3), 21.2 (CH3),
26.2 (CH3), 27.9 (CH3 ꢁ 3), 28.0 (CH3 ꢁ 3), 39.2 (C), 46.1 (C), 55.2
(CH3), 60.6 (CH), 61.1 (CH2), 79.3 (C), 86.0 (C), 113.0 (CH), 113.6
(CH), 129.1 (C), 131.5 (CH), 141.6 (C), 154.1 (C), 157.8 (C) ppm.
IR (KBr): ν 3585, 3435, 2976, 2954, 2871, 1687, 1606 cmꢀ1. Mass (m/z,
%): 391 (Mþ, 5), 291 (21), 290 (100), 278 (14), 204 (11), 177 (11), 164
(17), 163 (22), 162 (25), 150 (15), 148 (13), 135 (33), 134 (15), 57
(59). HRMS (ESI): 414.2639, calcd for C23H37NO4Na [M þ Naþ]
414.2620. Anal. Calcd for C23H37NO4: C, 70.55; H, 9.52; N, 3.58.
Found: C, 70.49; H, 9.91; N, 3.57.
NMR (125 MHz, CDCl3): δC 20.1 (CH3), 26.5 (CH3), 27.5 (CH3),
28.0 (broad CH3 ꢁ 3), 28.4 (broad CH3 ꢁ 3), 39.3 (C), 46.2 (broad C),
55.3 (CH3), 61.8 (broad CH2), 71.2 (CH), 79.3 (C), 90.6 (broad C),
112.6 (CH), 114.0 (CH), 128.9 (C), 131.5 (CH), 142.4 (broad C),
154.6 (C), 157.4 (C) ppm. IR (KBr): ν 3477, 2974, 2931, 2881, 1691,
1608 cmꢀ1. Mass (m/z, %): 391 (Mþ, 3), 291 (21), 290 (100), 278 (13),
204 (25), 164 (14), 163 (19), 162 (29), 150 (12), 148 (13), 135 (30),
134 (13), 57 (57), 56 (12), 55 (11). HRMS (ESI): 414.2628, calcd for
C23H37NO4Na [M þ Naþ] 414.2620. Anal. Calcd for C23H37NO4: C,
70.55; H, 9.52; N, 3.58. Found: C, 70.52; H, 9.89; N, 3.56.
Synthesis of 1-Boc-4-tert-butyl-5-(6-methoxynaphthalen-
1-yl)-3,3-dimethyl-2,3-dihydropyrrole (11a). Typical Proce-
dure. Thionyl chloride (1.38 mL, 18.9 mmol) was added to a solution
of 1-Boc-3-tert-butyl-t-3-hydroxy-r-2-(6-methoxynaphthalen-1-yl)-4,4-
dimethylpyrrolidine (trans-10a) (6.24 g, 14.6 mmol) and pyridine
(12 mL, 150 mmol) in dry THF (60 mL) under a nitrogen atmo-
sphere at 0 °C and was stirred at room temperature for 1 h. The reaction
mixture was poured into sat. aq. NaHCO3 and extracted with AcOEt.
The organic layer was washed with sat. aq. NaCl, dried over anhydrous
MgSO4, and concentrated in vacuo. The residue was chromatographed
on silica gel and eluted with hexaneꢀAcOEt (4:1) to give 1-Boc-4-tert-
butyl-5-(6-methoxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydropyrrole (11a)
as a colorless solid (5.58 g, 94% yield).
Dehydration of trans-10b and trans-10c were similarly carried out to
give 1-Boc-4-tert-butyl-5-(3-methoxynaphthalen-1-yl)-3,3-dimethyl-2,3-
dihydropyrrole (11b) and 1-Boc-4-tert-butyl-5-(5-methoxy-2-methyl-
phenyl)-3,3-dimethyl-2,3-dihydropyrrole (11c) in 98% and 95% yield,
respectively.
1
11a: Colorless granules, mp 100.0ꢀ101.5 °C (from hexane). H
NMR (400 MHz, CDCl3): δH 0.67 (s, 9H), 0.87 (s, 9H), 1.41 (s, 3H),
1.45 (s, 3H), 3.60 (qAB, J = 10.7 Hz, 2H), 3.92 (s, 3H), 7.08 (d, J =
2.4 Hz, 1H), 7.11 (dd, J = 9.0 and 2.4 Hz, 1H), 7.17 (dd, J = 7.1 and 1.2
Hz, 1H), 7.35 (dd, J = 8.3 and 7.1 Hz, 1H), 7.64ꢀ7.70 (m, 2H) ppm. 13C
NMR (125 MHz, CDCl3): δC 27.4 (CH3 ꢁ 3), 28.1 (CH3), 28.7
(CH3), 32.0 (CH3 ꢁ 3), 34.4 (C), 43.8 (C), 55.2 (CH3), 63.6 (CH2),
79.0 (C), 105.6 (CH), 118.4 (CH), 125.3 (CH), 126.1 (CH), 126.6
(CH), 127.8 (CH), 129.5 (C), 133.6 (C), 134.3 (C), 134.9 (C), 136.5
(C), 152.4 (C), 157.2(C) ppm. IR (KBr): ν 2976, 2958, 1678,
1626 cmꢀ1. Mass (m/z, %): 409 (Mþ, 29), 354 (15), 353 (55), 339
(19), 338 (74), 309 (32), 308 (11), 296 (18), 295 (25), 294 (100), 282
(14), 253 (10), 252 (45), 238 (46), 197 (19), 183 (19). HRMS (ESI):
432.2504, calcd for C26H35NO3Na [M þ Naþ] 432.2515. Anal. Calcd
for C26H35NO3: C, 76.25; H, 8.61; N, 3.42. Found: C, 76.20; H, 8.88;
N, 3.43.
1
11b: Colorless columns, mp 148.0ꢀ148.5 °C (from AcOEt). H
NMR (400 MHz, CDCl3): δH 0.67 (s, 9H), 0.90 (s, 9H), 1.41 (s, 3H),
1.45 (s, 3H), 3.61 (qAB, J = 10.7 Hz, 2H), 3.92 (s, 3H), 7.01 (d, J =
2.6 Hz, 1H), 7.08 (d, J = 2.6 Hz, 1H), 7.29 (ddd, J = 8.5, 6.8, and 1.2 Hz,
1H), 7.38 (ddd, J = 8.3, 6.8, and 1.2 Hz, 1H), 7.68 (d with fine coupling,
J = 8.3 Hz, 1H), 7.69 (d with fine coupling, J = 8.5 Hz, 1H) ppm. 13C
NMR (125 MHz, CDCl3): δC 27.4 (CH3 ꢁ 3), 28.1 (CH3), 28.6
(CH3), 32.0 (CH3 ꢁ 3), 34.4 (C), 43.8 (C), 55.3 (CH3), 63.6 (CH2),
79.0 (C), 105.7 (CH), 120.9 (CH), 123.5 (CH), 126.0 (CH), 126.0
(CH), 126.7 (CH), 129.7 (C), 132.9 (C), 134.2 (C), 136.5 (C), 136.7
(C), 152.3 (C), 156.6 (C) ppm. IR (KBr): ν 2958, 2929, 2870, 1680,
1628, 1597 cmꢀ1. Mass (m/z, %): 409 (Mþ, 18), 353 (31), 339 (11),
338 (46), 309 (25), 307 (17), 295 (23), 294 (100), 292 (26), 277 (10),
262 (13), 252 (34), 239 (10), 238 (58), 236 (11), 197 (15), 183 (17), 69
(20), 57 (48), 56 (20), 55 (24). HRMS (ESI): 432.2526, calcd for
C26H35NO3Na [M þ Naþ] 432.2515. Anal. Calcd for C26H35NO3: C,
76.25; H, 8.61; N, 3.42. Found: C, 76.14; H, 8.83; N, 3.41.
trans-10c: Coloress granules, mp 134.5ꢀ135.5 °C (from hexaneꢀ
AcOEt). 1H NMR (500 MHz, CDCl3): δH 0.90 (s, 9H), 1.08 (broad s,
9H), 1.29 (s, 3H), 1.54 (s, 3H), 2.09 (broad s, 1H), 2.42 (broad s, 3H),
3.59 (broad s, 2H), 3.74 (s, 3H), 4.97 (broad s, 1H), 6.70 (dd, J = 8.3 and
2.8 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H) ppm. 13C
1
11c: Coloress needles mp 83.5ꢀ84.5 °C (from hexane). H NMR
(500 MHz, CDCl3): δH 0.96 (s, 9H), 1.06 (s, 9H), 1.33 (s, 3H), 1.35
(s, 3H), 2.14 (s, 3H), 3.48 (qAB, J = 10.7 Hz, 2H), 3.77 (s, 2H), 6.68 (d,
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The Journal of Organic Chemistry
ARTICLE
J = 2.7 Hz, 1H), 6.74 (dd, J = 8.2 and 2.7 Hz, 1H), 6.98 (d, J = 8.2 Hz,
1H) ppm. 13C NMR (125 MHz, CDCl3): δC 18.7 (CH3), 27.8 (CH3),
27.9 (CH3 ꢁ 3), 28.4 (CH3), 31.9 (CH3 ꢁ 3), 34.2 (C), 43.5 (C), 55.3
(CH3), 63.4 (CH2), 79.2 (C), 113.2 (CH), 116.6 (CH), 129.7 (CH),
129.9 (C), 134.3 (C), 134.5 (C), 137.5 (C), 152.3 (C), 156.8 (C) ppm.
IR (KBr): ν 2976, 2958, 2927, 2870, 1672, 1618, 1601, 1576 cmꢀ1. Mass
(m/z, %): 373 (Mþ, 12), 317 (25), 302 (44), 259 (17), 258 (100), 202
(44), 57 (36), 55 (10). HRMS (ESI): 396.2519, calcd for C23H35NO3-
Na [M þ Naþ] 396.2515. Anal. Calcd for C23H35NO3: C, 73.96; H,
9.44; N, 3.75. Found: C, 73.78; H, 9.82; N, 3.72.
Synthesis of 1-Boc-4-tert-butyl-5-(6-hydroxynaphthalen-
1-yl)-3,3-dimethyl-2,3-dihydropyrrole (6a). Typical Proce-
dure. A solution of 1-Boc-4-tert-butyl-5-(6-methoxynaphthalen-1-yl)-
3,3-dimethyl-2,3-dihydropyrrole (11a) (2.37 g, 5.79 mmol) and sodium
thiomethoxide (5.12 g, 69.5 mmo) in dry DMF (80 mL) was stirred
under a nitrogen atmosphere at 150 °C for 40 min. The reaction mixture
was poured into sat. aq. NH4Cl and extracted with AcOEt. The organic
layer was washed with sat. aq. NaCl, dried over anhydrous MgSO4, and
concentrated in vacuo. The residue was chromatographed on silica gel
and eluted with hexaneꢀAcOEt (3:1 to 2:1) to give of 1-Boc-4-tert-
butyl-5-(6-hydroxynaphthalen-1-yl)-3,3-dimethyl-2,3-dihydropyrrole
(6a) as a colorless solid (2.05 g, 90% yield).
(C), 114.5 (CH), 117.8 (CH), 129.6 (C), 129.9 (CH), 134.2 (C), 134.8
(C), 137.4 (C), 152.6 (C), 153.2 (C) ppm. IR (KBr): ν 3288, 2989,
2970, 2927,2871, 1645, 1601 cmꢀ1. Mass (m/z, %): 359 (Mþ, 10), 303
(25), 289 (11), 288 (54), 245 (17), 244 (100), 228 (11), 188 (48), 186
(11), 57 (69), 56 (11), 55 (13). HRMS (ESI): 382.2361, calcd for
C22H33NO3Na [M þ Naþ] 382.2358. Anal. Calcd for C22H33NO3: C,
73.50; H, 9.25; N, 3.90. Found: C, 73.28; H, 9.59; N, 3.87.
Singlet Oxygenation of 1-Boc-4-tert-butyl-5-(6-hydroxy-
naphthalen-1-yl)-3,3-dimethyl-2,3-dihydropyrrole (6a): Ty-
pical Procedure. A solution of 1-Boc-4-tert-butyl-5-(6-hydroxynaphthalen-
1-yl)-3,3-dimethyl-2,3-dihydropyrrole (6a) (150 mg, 0.379 mmol) and Rose
Bengal (1.8 mg) in AcOEt (25 mL) was irradiated externally with a 940 W Na
lamp under an oxygen atmosphere at 0 °C for 3 h. After the photolysate was
concentrated in vacuo, the residue was chromatographed on silica gel and
eluted with hexaneꢀAcOEt (2:1) at low temperature to give 2-Boc-5-tert-
butyl-1-(6-hydroxynaphthalen-1-yl)-4,4-dimethyl-2-aza-6,7-dioxabicyclo-
[3.2.0]heptane (anti-5a) as a colorless solid (155 mg, 96% yield).
According to the procedure described above, dihydropyrroles 6b and
6c were transformed to the corresponding dioxetanes 2-Boc-5-tert-
butyl-1-(3-hydroxy-naphthalen-1-yl)-4,4-dimethyl-2-aza-6,7-
dioxabicyclo[3.2.0]heptane (syn-5b) and 2-Boc-5-tert-butyl-1-(5-hydro-
xy-2-methylphenyl)-4,4-dimethyl-2-aza-6,7-dioxabicyclo[3.2.0]heptane
(syn-5c) in respective yields of 92% and 88%.
Demethylation of 11b and 11c were similarly carried out to give
1-Boc-4-tert-butyl-5-(3-hydroxynaphthaeln-1-yl)-3,3-dimethyl-2,3-dihy-
dropyrrole (6b) and 1-Boc-4-tert-butyl-5-(5-hydroxy-2-methylphenyl)-
3,3-dimethyl-2,3-dihydropyrrole (6c) in 81% and 69% yield, respectively.
6a: Colorless granules mp, 200.0ꢀ200.5 °C (from 1,2-dichloro-
ethaneꢀhexane). 1H NMR (400 MHz, CDCl3): δH 0.69 (s, 9H), 0.88
(s, 9H) 1.41 (s, 3H), 1.45 (s, 3H), 3.62 (qAB, J = 10.5 Hz, 2H), 5.32
(broad s, 1H), 7.04 (dd, J = 9.0 and 2.4 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H),
7.17 (dd, J = 7.1 and 1.2 Hz, 1H), 7.34 (dd, J = 8.1 and 7.1 Hz, 1H), 7.59
(d, J = 8.1 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H) ppm. 13C NMR (125 MHz,
acetone-d6): δC 28.1 (CH3 ꢁ 3), 28.7 (CH3), 29.2 (CH3), 32.8 (CH3 ꢁ
3), 35.3 (C), 44.8 (C), 64.9 (CH2), 79.3 (C), 110.2 (CH), 119.4 (CH),
126.3 (CH), 126.8 (CH), 127.4 (CH), 129.1 (CH), 130.2 (C), 135.5
(C), 136.1 (C), 136.1 (C), 136.8 (C), 153.0 (C), 156.2 (C) ppm. IR
(KBr): ν 3278, 2971, 1682, 1633, 1577 cmꢀ1. Mass (m/z, %): 395 (Mþ,
17), 339 (33), 325 (12), 324 (48), 296 (12), 295 (47), 281 (24), 280
(100), 238 (27), 224 (52), 183 (25), 169 (23), 57 (13). HRMS (ESI):
418.2348, calcd for C25H33NO3Na [M þ Naþ] 418.2358. Anal. Calcd
for C25H33NO3 þ 1/15CH2ClCH2Cl: C, 75.07; H, 8.34; N, 3.48.
Found: C, 75.26; H, 8.54; N, 3.51.
anti-5a: Pale yellow granules, mp 181.5ꢀ184.0 °C (dec.) (from
AcOEt). 1H NMR (400 MHz, CDCl3): δH 0.69 (s, 9H), 0.88 (s, 9H),
1.26 (s, 3H), 1.60 (s, 3H), 3.95 (d, J = 10.5 Hz, 1H), 4.20 (d, J = 10.5 Hz,
1H), 5.27 (s, 1H), 7.07 (dd, J = 9.3 and 2.7 Hz, 1H), 7.19 (d, J = 2.7, 1H),
7.45 (dd, J = 8.3 and 7.6 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.97 (dd, J =
7.6 and 1.2 Hz, 1H), 8.42 (d, J = 9.3 Hz, 1H) ppm. 13C NMR (125 MHz,
CDCl3): δC 22.0, 26.8, 26.9, 27.2, 37.9, 43.1, 63.1, 81.3, 104.3, 107.5,
111.1, 117.5, 125.3, 126.0, 126.3, 127.5, 128.5, 132.7, 135.5, 153.3, 154.3
ppm. IR (KBr): ν 3321, 3006, 2979, 2930, 2891, 1703, 1664, 1637,
1604 cmꢀ1. Mass (m/z, %): 427 (Mþ, 10), 395 (Mþ-O2, 4), 327 (21),
271 (32), 270 (94), 243 (11), 242 (19), 214 (10), 213 (16), 187 (20),
172 (14), 171 (100). HRMS (ESI): 450.2258, calcd for C25H33NO5Na
[M þ Naþ] 450.2256. Anal. Calcd for C25H33NO5 þ 1/5AcOEt: C,
69.61; H, 7.83; N, 3.15. Found: C, 69.61; H, 7.74; N, 3.22.
syn-5b: Colorless needles, mp 170.0ꢀ171.5 °C (dec.) (from
1
AcOEtꢀCH2Cl2). H NMR (400 MHz, CDCl3): δH 0.74 (s, 9H),
0.91 (s, 9H), 1.27 (s, 3H), 1.63 (s, 3H), 3.96 (d, J = 10.5 Hz, 1H), 4.21
(d, J = 10.5 Hz, 1H), 5.46 (broad s, 1H), 7.17 (d, J = 2.6 Hz, 1H), 7.30
(ddd, J = 8.5, 7.0, and 1.3 Hz, 1H), 7.39 (ddd, J = 8.1, 7.0, and 1.0 Hz,
1H), 7.68 (d, J = 8.1 Hz, 1H), 7.80 (d, J = 2.6 Hz, 1H), 8.37 (d, J = 8.5 Hz,
1H) ppm. 13C NMR (125 MHz, CDCl3): δC 22.2, 26.9, 27.0, 27.3, 38.0,
43.2, 63.1, 80.9, 103.9, 107.8, 111.2, 122.1, 123.6, 124.4, 125.9, 126.8,
127.7, 135.0, 135.2, 152.6, 153.7 ppm. IR (KBr): ν 3383, 2979,1671,
1635 cmꢀ1. Mass (m/z, %): 427 (Mþ, 6), 271 (13), 270 (37), 242 (12),
213 (13), 187 (10), 172 (12), 171 (100), 115 (33), 57 (45), 56 (30), 55
(14). HRMS (ESI): 450.2266, calcd for C25H33NO5Na [M þ Naþ]
450.2256. Anal. Calcd for C25H33NO5: C, 70.23; H, 7.78; N, 3.28.
Found: C, 70.06; H, 7.91; N, 3.33.
6b: Colorless needles mp 204.0ꢀ206.0 °C (from 1,2-dichloro-
ethaneꢀhexane). 1H NMR (400 MHz, CDCl3): δH 0.71 (s, 9H), 0.89
(s, 9H) 1.40 (s, 3H), 1.46 (s, 3H), 3.62 (qAB, J = 10.5 Hz, 2H),
5.71ꢀ5.77 (m, 1H), 6.97 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H),
7.28 (ddd, J = 8.3, 6.8, and 1.3 Hz, 1H), 7.37 (ddd, J = 8.1, 6.8, and 1.3
Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.3 Hz, 1H) ppm. 13
C
NMR (125 MHz, CDCl3): δC 27.6 (CH3 ꢁ 3), 27.9 (CH3), 28.6
(CH3), 31.9 (CH3 ꢁ 3), 34.5 (C), 44.0 (C), 63.7 (CH2), 79.7 (C), 109.5
(CH), 120.1 (CH), 123.3 (CH), 126.0 (CH), 126.1 (CH), 126.5 (CH),
129.5 (C), 132.7 (C), 134.5 (C), 136.5 (C), 137.4 (C), 152.7 (C), 153.1
(C) ppm. IR (KBr): ν 3234, 2989, 2966, 2927, 2862, 1649, 1618,
1595 cmꢀ1. Mass (m/z, %): 395 (Mþ, 18), 339 (35), 325 (13), 324 (63),
295 (11), 281 (22), 280 (100), 278 (21), 238 (13), 224 (51), 222 (19),
69 (11), 57 (88), 55 (14). HRMS (ESI): 418.2377 calcd for
C25H33NO3Na [M þ Naþ] 418.2358. Anal. Calcd for C25H33NO3:
C, 75.91; H, 8.41; N, 3.54. Found: C, 75.95; H, 8.81; N, 3.54.
syn-5c: Coloress needles, mp 177.0ꢀ178.0 °C (dec.) (from hexaneꢀ
CH2Cl2). 1H NMR (500 MHz, CDCl3): δH 1.02 (s, 9H), 1.07 (s, 9H),
1.19 (s, 3H), 1.49 (s, 3H), 2.34 (s, 3H), 3.71 (d, J = 10.3 Hz, 1H), 4.05
(d, J = 10.3 Hz, 1H), 5.08 (s, 1H), 6.74 (dd, J = 8.1 and 2.9 Hz, 1H), 6.97
(d, J = 8.1 Hz, 1H), 7.39 (d, J = 2.9 Hz, 1H) ppm. 13C NMR (125 MHz,
CDCl3): δC 20.9, 22.2, 26.4, 26.5, 27.6, 38.0, 43.0, 63.1, 80.7, 103.9,
107.3, 115.3, 117.9, 127.7, 132.6, 136.8, 153.5, 153.9 ppm. IR (KBr): ν
3408, 2979, 2933, 1676, 1612 cmꢀ1. Mass (m/z, %): 391 (Mþ, 2), 359
(Mþ-O2,14), 334 (14), 303 (27), 288 (18), 278 (15), 244 (15), 234
(46), 149 (11), 135 (100), 134 (18), 107 (18), 57 (87), 56 (26), 55 (17).
HRMS (ESI): 414.2270, calcd for C22H33NO5Na [M þ Naþ]
414.2256. Anal. Calcd for C22H33NO5: C, 67.49; H, 8.50; N, 3.58.
Found: C, 67.48; H, 8.75; N, 3.52.
6c: Coloress granules mp 176.5ꢀ177.5 °C (from AcOEt). 1H NMR
(400 MHz, CDCl3): δH 0.96 (s, 9H), 1.09 (s, 9H), 1.32 (s, 3H), 1.33 (s,
3H), 2.13 (s, 3H), 3.47 (s, 2H), 4.88 (s, 1H), 6.62 (d, J = 2.8 Hz, 1H),
6.67 (dd, J = 8.1 and 2.8 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H) ppm. 13C
NMR (125 MHz, CDCl3): δC 18.8 (CH3), 27.7 (CH3), 28.0 (CH3 ꢁ
3), 28.4 (CH3), 31.9 (CH3 ꢁ 3), 34.3 (C), 43.6 (C), 63.5 (CH2), 79.7
5014
dx.doi.org/10.1021/jo2006945 |J. Org. Chem. 2011, 76, 5006–5017

The Journal of Organic Chemistry
ARTICLE
Thermal Isomerization of 2-Boc-5-tert-butyl-1-(6-hydroxy-
naphthalen-1-yl)-4,4-dimethyl-2-aza-6,7-dioxabicyclo[3.2.0]-
heptane (anti-5a) to syn-5a Isomer. Typical Procedure. A
solution of 2-Boc-5-tert-butyl-1-(6-hydroxynaphthalen-1-yl)-4,4-dimethyl-
2-aza-6,7-dioxabicyclo[3.2.0]heptane (anti-5a) (92.5 mg, 0.216 mmol) in
toluene (5 mL) was stirred at 110 °C for 15 min. The reaction mixture was
concentrated in vacuo, and the residue was chromatographed on silica gel
and eluted with benzeneꢀAcOEt (10:1) to give syn-5a as a colorless solid
(18.9 mg, 20% yield).
Dioxetanes syn-5a, anti- and syn-5b, and anti- and syn-5c were similarly
decomposed thermally to give the corresponding keto imides N-Boc-
N-(2,2,4,4-tetramethyl-3-oxopentyl)-6-hydroxynaphthalene-1-carboxa-
mide (12a) (89% yield), N-Boc-N-(2,2,4,4-tetramethyl-3-oxopentyl)-3-
hydroxynaphthalene-1-carboxamide (12b) (87% yield from anti-5b, 99%
yield from syn-5b) and N-Boc-N-(2,2,4,4-tetramethyl-3-oxopentyl)-5-
hydroxy-2-methylbenzamide (12c) (92% yield from anti-5c, 87% yield
from syn-5c).
12a: Colorless granules, mp 104.0ꢀ105.0 °C (from AcOEtꢀ
hexane). 1H NMR (400 MHz, CDCl3): δH 0.75 (s, 9H), 1.35 (s, 9H),
1.42 (s, 6H), 4.19 (broad s, 2H), 5.29 (broad s, 1H), 7.12 (dd, J = 9.0 and
2.4 Hz, 1H), 7.15 (d, J = 2.4 Hz), 7.32 (dd, J = 7.1 and 1.0 Hz, 1H), 7.38
(dd, J = 8.3 and 7.1 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 9.0 Hz,
1H) ppm. 13C NMR (125 MHz, CDCl3): δC 25.1, 26.8, 28.3, 46.3, 50.7,
52.1, 83.4, 109.9, 119.1, 120.9, 125.1, 125.2, 126.9, 128.2, 134.9, 136.4,
153.7, 154.1, 172.8, 217.1 ppm. IR (KBr): ν 3460, 2984, 2934, 1738,
1716, 1677, 1669, 1626 cmꢀ1. Mass (m/z, %): 427 (Mþ, 6), 327 (10),
271 (15), 270 (46), 242 (12), 213 (14), 187 (13), 172 (15), 171 (100),
143 (20), 57 (19). HRMS (ESI): 450.2246, calcd for C25H33NO5Na
[M þ Naþ] 450.2256. Anal. Calcd for C25H33NO5: C, 70.23; H, 7.78;
N, 3.28. Found: C, 70.28; H, 7.99; N, 3.33.
12b: Colorless needles, mp 151.5ꢀ152.0 °C (from AcOEtꢀhexane).
1H NMR (400 MHz, CDCl3): δH 0.75 (s, 9H), 1.36 (s, 9H), 1.43 (s,
6H), 4.20 (broad s, 2H), 5.77ꢀ5.87 (m, 1H), 7.18 (d, J = 2.6 Hz, 1H),
7.20 (d, J = 2.6 Hz, 1H), 7.35 (ddd, J = 8.3, 7.0, and 1.3 Hz), 7.41 (ddd,
J = 8.1, 7.0, and 1.1 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 8.3 Hz,
1H) ppm. 13C NMR (125 MHz, CDCl3): δC 25.0, 26.7, 28.2, 46.3, 50.7,
52.0, 83.7, 111.3, 115.8, 124.3, 124.6, 125.1, 126.6, 126.7, 134.9, 137.6,
152.9, 153.4, 172.2, 217.8 ppm. IR (KBr): ν 3328, 2994, 2982, 2971,
1736, 1672, 1642, 1627, 1606, 1578 cmꢀ1. Mass (m/z, %): 427 (Mþ, 5),
271 (13), 270 (35), 242 (11), 213 (15), 172 (13), 171 (100), 115 (40),
57 (57), 56 (21), 55 (15). HRMS (ESI): 450.2265, calcd for
C25H33NO5Na [M þ Naþ] 450.2256. Anal. Calcd for C25H33NO5:
C, 70.23; H, 7.78; N, 3.28. Found: C, 70.08; H, 8.10; N, 3.26.
12c: Coloress granules, mp 135.5ꢀ136.0 °C (from hexane). 1H
NMR (500 MHz, CDCl3): δH 1.08 (s, 9H), 1.33 (s, 9H), 1.35 (s, 6H),
2.24 (s, 3H), 4.07 (broad s, 2H), 6.18 (s, 1H), 6.75ꢀ6.88 (m, 2H), 7.02
(d, J = 7.8 Hz, 1H) ppm. 13C NMR (125 MHz, CDCl3): δC 18.2, 25.0,
27.1, 28.2, 46.3, 50.7, 51.8, 83.5, 112.8, 116.4, 126.6, 131.7, 139.0, 153.6,
153.7, 172.7, 217.5 ppm. IR (KBr): ν 3275, 2974, 2933, 1734, 1678,
1645, 1618, 1581 cmꢀ1. Mass (m/z, %): 391 (Mþ, 1), 234 (37), 149
(17), 135 (100), 134 (14), 107 (16), 57 (66), 56 (34), 55 (20). HRMS
(ESI): 414.2278, calcd for C22H33NO5Na [M þ Naþ] 414.2256. Anal.
Calcd for C22H33NO5: C, 67.49; H, 8.50; N, 3.58. Found: C, 67.11; H,
8.89; N, 3.54.
Similarly, dioxetanes syn-5b and syn-5c were individually isomerized
thermally to the corresponding dioxetanes anti-5b and anti-5c in
respective isolated yields of 13% and 48%.
syn-5a: Pale yellow plates, mp 148.0ꢀ148.5 °C (from benzeneꢀ
CH2Cl2). 1H NMR (500 MHz, CDCl3): δH 0.81 (broad s, 9H), 0.92 (s,
9H), 1.15 (s, 3H), 1.53 (s, 3H), 3.77 (d, J = 10.0 Hz, 1H), 4.18 (d, J =
10.0 Hz, 1H), 6.35ꢀ6.60 (m, 1H), 6.85ꢀ7.20 (m, 2H), 7.27ꢀ7.37 (m,
2H), 7.62 (d, J = 7.8 Hz, 1H), 8.79 (d, J = 9.6 Hz, 1H) ppm. 13C NMR
(125 MHz, CDCl3): δC 21.3, 26.4, 27.4, 27.6, 38.0, 43.5, 63.1, 81.3,
108.0, 108.9, 109.9, 118.4, 124.1, 124.4, 127.8, 128.2, 129.5, 134.6, 135.8,
153.3, 154.7 ppm. IR (KBr): ν 3369, 2979, 2930, 1703, 1667, 1626,
1602 cmꢀ1. Mass (m/z, %): 427 (Mþ, 2), 395 (Mþ-O2, 1), 327 (11),
271 (15), 270 (45), 242 (11), 187 (17), 172 (13), 171 (100), 143 (21),
57 (19). HRMS (ESI): 450.2257, calcd for C25H33NO5Na [M þ Naþ]
450.2256. Anal. Calcd for C25H33NO5 þ 2/3benzene: C, 72.62; H, 7.78;
N, 2.92. Found: C, 72.86; H, 7.86; N, 2.81.
anti-5b: Pale yellow granules, mp 154.5ꢀ155.5 °C (from AcOEtꢀ
hexane). 1H NMR (400 MHz, CDCl3): δH 0.76 (broad s, 9H), 0.96 (s,
9H), 1.16 (s, 3H), 1.55 (s, 3H), 3.74 (d, J = 10.0 Hz, 1H), 4.16 (d, J = 10.0
Hz, 1H), 5.13 (s, 1H), 7.14 (d, J = 2.6 Hz, 1H), 7.17 (d,
J = 2.6 Hz, 1H), 7.32 (ddd, J = 8.6, 6.8, and 1.7 Hz, 1H), 7.38 (dd with
fine coupling, J = 8.0 and 6.8 Hz, 1H), 7.64 (d with fine coupling, J=8.0Hz,
1H), 8.81(d, J= 8.6 Hz, 1H) ppm. 13CNMR(125 MHz,CDCl3):δC 21.3,
26.5, 27.5, 38.0, 43.4, 63.1, 81.7, 108.1, 108.5, 111.3, 118.9, 123.8, 126.0,
127.1, 127.5, 128.0, 135.5, 136.5, 152.0, 154.8 ppm. IR (KBr): ν 3340,
2979, 2933, 2888, 1696, 1671, 1633, 1623, 1604, 1578 cmꢀ1. Mass (m/z,
%): 427 (Mþ, 0.8), 395 (Mþ-O2, 0.3), 270 (19), 187 (17), 172 (13), 171
(100), 115 (44), 57 (36), 56 (20), 55 (11). HRMS (ESI): 450.2266, calcd
for C25H33NO5Na [M þ Naþ] 450.2256. Anal. Calcd for C25H33NO5: C,
70.23; H, 7.78; N, 3.28. Found: C, 70.30; H, 8.09; N, 3.27.
anti-5c: Coloress granules, mp 156.0ꢀ157.0 °C (from hexaneꢀ
1
CH2Cl2). H NMR (500 MHz, CDCl3): δH 1.03 (s, 9H), 1.10 (s,
3H), 1.12 (s, 9H), 1.46 (s, 3H), 2.42 (s, 3H), 3.64 (d, J = 10.1 Hz, 1H),
4.04 (d, J = 10.1 Hz, 1H), 5.60 (broad s, 1H), 6.68 (dd, J = 8.2 and 2.7 Hz,
1H), 6.73 (d, J = 2.7 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H) ppm. 13C NMR
(125 MHz, CDCl3): δC 21.1, 22.2, 26.5, 27.1, 27.8, 37.8, 43.1, 63.0, 81.3,
107.2, 107.8, 115.2, 115.2, 129.9, 133.4, 137.5, 152.7, 154.4 ppm. IR
(KBr): ν 3396, 2976, 2933, 1674, 1612 cmꢀ1. Mass (m/z, %): 391 (Mþ,
1), 359 (Mþ-O2,10), 334 (11), 303 (20), 288 (15), 278 (12), 244 (12),
234 (43), 135 (100), 134 (16), 107 (18), 57 (69), 56 (18), 55 (11).
HRMS (ESI): 414.2266, calcd for C22H33NO5Na [M þ Naþ]
414.2256. Anal. Calcd for C22H33NO5: C, 67.49; H, 8.50; N, 3.58.
Found: C, 67.23; H, 8.79; N, 3.53.
Thermal Decomposition of 2-Boc-5-tert-butyl-1-(6-hydro-
xynaphthalen-1-yl)-4,4-dimethyl-2-aza-6,7-dioxabicyclo-
[3.2.0]heptane (anti-5a) to N-Boc-N-(2,2,4,4-tetramethyl-3-
oxopentyl)-6-hydroxynaphthalene-1-carboxamide (12a). Typi-
cal Procedure. A solution of 2-Boc-5-tert-butyl-1-(6-hydroxynaphthalen-
1-yl)-4,4-dimethyl-2-aza-6,7-dioxabicyclo[3.2.0]heptane (anti-5a) (32.7 mg,
0.0765 mmol) in p-xylene (1 mL) was refluxed under a nitrogen atmosphere
for 1 h. After being allowed to cool, the reaction mixture was concentrated in
vacuo. The residue was chromatographed on silica gel and eluted with
hexaneꢀAcOEt (3:1) to give N-Boc-N-(2,2,4,4-tetramethyl-3-oxopentyl)-
6-hydroxynaphthalene-1-carboxamide (12a) as a colorless solid (27.3 mg,
83% yield).
Base-Induced Decomposition of 2-Boc-5-tert-butyl-1-(6-hy-
droxynaphthalen-1-yl)-4,4-dimethyl-2-aza-6,7-dioxabicyclo-
[3.2.0]heptane (anti-5a) to N-Boc-N-(2,2,4,4-tetramethyl-3-
oxopentyl)-6-hydroxynaphthalene-1-carboxamide (12a). Ty-
pical Procedure. TBAF(1MinTHF, 0.50mL, 0.50mmol, 5.0equiv) in
DMSO (1.5 mL) was added dropwise over 50 s to a solution of 2-Boc-5-
tert-butyl-1-(6-hydroxynaphthalen-1-yl)-4,4-dimethyl-2-aza-6,7-
dioxabicyclo[3.2.0]heptane (anti-5a) (10.0 mg, 0.0234 mmol) in DMSO
(1.0 mL) and stirred for 4 min. The reaction mixture was poured into sat.
aq. NH4Cl and extracted with AcOEt. The organic layer was washed with
sat. aq. NaCl, dried over anhydrous MgSO4, and concentrated in vacuo.
The residue was chromatographed on silica gel and eluted with benze-
neꢀAcOEt (4:1) to give 10.0 mg of N-Boc-N-(2,2,4,4-tetramethyl-3-
oxopentyl)-6-hydroxynaphthalene-1-carboxamide (12a) as a pale yellow
solid in a quantitative yield.
Dioxetanes syn-5a, anti- and syn-5b, and anti- and syn-5c were
similarly decomposed to give the corresponding keto imides 12a
(48% yield, conversion yield 97%), 12b (94% yield from anti-5b; 48%
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yield, conversion yield 97%, from syn-5b), and 12c (86% yield from anti-
5c, 89% yield from syn-5c).
(3) (a) Schaap, A. P.; Handley, R. S.; Giri, B. P. Tetrahedron Lett.
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(4) The chemiluminescent (CL) decomposition of hydroxyphenyl-
substituted dioxetanes has been proposed to proceed by the CIEEL5
(chemically initiated electron exchange luminescence) mechanism,
where an initially formed radical ion pair is annihilated by back electron
transfer (BET) to give an excited aromatic carbonyl compound. How-
ever, the question of whether such a CL reaction includes BET as a
fundamental process is still being argued. Therefore, we have recently
been using the term CTID, which includes CIEEL and other CT-
induced mechanisms.
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Chemiluminescence Measurement and Time Course for
the Charge-Transfer-Induced Decomposition of Dioxe-
tanes. General Procedure. Chemiluminescence was measured
using a spectrophotometer and/or a multichannel detector.
A freshly prepared solution (2.0 mL) of TBAF (1.0 ꢁ 10ꢀ1 or 1.0 ꢁ
10ꢀ2 mol/L) in DMSO or acetonitrile was transferred to a quartz cell
(10 ꢁ 10 ꢁ 50 mm), and the latter was placed in the spectrometer,
which was thermostatted with stirring at 25 °C. After ca. 1 min, a solution
of the dioxetane anti-5aꢀc or syn-5aꢀc in DMSO or acetonitrile (1.0 ꢁ
10ꢀ3 or 1.0 ꢁ 10ꢀ5 mol/L, 1.0 mL) was added by a syringe, and
measurement was started immediately. The time course of the intensity
of light emission was recorded and processed according to first-order
kinetics. The total light emission was estimated by comparing it to that of
an adamantylidene-dioxetane, the chemiluminescence efficiency ΦCL of
which has been reported to be 0.29 and which was used here as a
standard.18,19
Fluorescence Measurement of Authentic Emitters 13aꢀd.
A freshly prepared solution of 2.0 ꢁ 10ꢀ5ꢀ3.0 ꢁ 10ꢀ4 mol dmꢀ3 of
12aꢀd and 1.0 ꢁ 10ꢀ3 mol dmꢀ3 of TBAF in DMSO or acetonitrile was
transferred to a quartz cell (10 ꢁ 10 ꢁ 50 mm3), and the latter was
placed in the spectrometer, which was thermostatted with stirring at
25 °C. Thus, the fluorescence spectra of 13aꢀd were measured, and
their fluorescence efficiencies (Φfl 's) were estimated using fluorescein
as a standard.
’ ASSOCIATED CONTENT
Supporting Information. 1H/13C NMR spectra of
S
b
5aꢀc, 6aꢀc, 9aꢀc, 10aꢀc, 11aꢀc, 12aꢀc, and ORTEP views
and crystallographic information files for anti-5bꢀc and syn-
5bꢀc. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: matsumo-chem@kanagawa-u.ac.jp.
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’ ACKNOWLEDGMENT
We gratefully acknowledge financial assistance provided by
Grants-in-aid (Nos. 22550046 and 21550052) for Scientific
Research from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
’ REFERENCES
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(15) For convenience sake, we call a rotamer an anti-form when the
dioxetane OꢀO and a hydroxyl group on an aromatic ring are on
opposite sides of the pyrrolidine ring, while in the syn-form the dioxetane
OꢀO and a hydroxyl group on an aromatic ring are on the same side of
the pyrrolidine ring.
(16) Part of this work has been reported as a preliminary communi-
cation.17
(17) Matsumoto, M.; Suzuki, H.; Sano, Y.; Watanabe, N.; Ijuin, H. K.
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(18) ΦCL was estimated based on the value 0.29 for the chemilumines-
cent decomposition of 3-adamantylidene-4-methoxy-4-(3-siloxyphenyl)-
1,2-dioxetane in a TBAF/DMSO system.19
(19) Trofimov, A. V.; Mielke, K.; Vasil’ev, R. F.; Adam, W. Photo-
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(20) The B-ring of a naphthalene-1-yl group and dioxetane OꢀO are
on opposite sides of the pyrrolidine ring for anti-5a, and the B-ring and
dioxetane OꢀO are on the same side of the pyrrolidine ring for syn-5a.
(21) Hoshiya, N.; Fukuda, N.; Watanabe, N.; Matsumoto, M.
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5017
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