Synthesis of 6 H-dibenzo[ b, d ]pyran-6-ones using the inverse electron demand Diels-Alder reaction

Article abstract of DOI:10.1021/jo201775e

A set of coumarin-fused electron-deficient 1,3-dienes was synthesized, which differ in the nature of the electron-withdrawing group (EWG) at the terminus of the diene unit and (when EWG = CO₂Me) the nature and position of substituents. These dienes reacted with the enamine derived from cyclopentanone and pyrrolidine to afford the corresponding cyclopenteno-fused 6H-dibenzo[b,d]pyran-6-ones, most likely via a domino inverse electron demand Diels-Alder (IEDDA)/elimination/transfer hydrogenation sequence. The parent diene (EWG = CO₂Me, no substituents) was reacted with a range of electron-rich dienophiles (mostly enamines) to afford the corresponding 6H-dibenzo[b,d]pyran-6-ones or their nondehydrogenated precursors, which were aromatized upon treatment with a suitable oxidant. The enamines could either be synthesized prior to the reaction or generated in situ. The syntheses of 30 dibenzopyranones are reported.

Full text of DOI:10.1021/jo201775e

Article
pubs.acs.org/joc
Synthesis of 6H-Dibenzo[b,d]pyran-6-ones Using the Inverse Electron
Demand Diels−Alder Reaction
Ian R. Pottie,†,§ Penchal Reddy Nandaluru,† Wendy L. Benoit,† David O. Miller,‡ Louise N. Dawe,†
and Graham J. Bodwell*,†
†Department of Chemistry, Memorial University, St. John’s, NL, Canada, A1B 3X7
‡CREAIT Network, Memorial University, St. John’s, NL, Canada, A1C 5S7
S
* Supporting Information
ABSTRACT: A set of coumarin-fused electron-deficient 1,3-
dienes was synthesized, which differ in the nature of the electron-
withdrawing group (EWG) at the terminus of the diene unit and
(when EWG = CO2Me) the nature and position of substituents.
These dienes reacted with the enamine derived from cyclo-
pentanone and pyrrolidine to afford the corresponding cyclo-
penteno-fused 6H-dibenzo[b,d]pyran-6-ones, most likely via a
domino inverse electron demand Diels−Alder (IEDDA)/elimi-
nation/transfer hydrogenation sequence. The parent diene (EWG
= CO2Me, no substituents) was reacted with a range of electron-rich dienophiles (mostly enamines) to afford the corresponding
6H-dibenzo[b,d]pyran-6-ones or their nondehydrogenated precursors, which were aromatized upon treatment with a suitable
oxidant. The enamines could either be synthesized prior to the reaction or generated in situ. The syntheses of 30
dibenzopyranones are reported.
diversity-oriented synthesis. An existing coumarin system can
be designed to function as either a diene or a dienophile in
either the normal or inverse electron demand version of the
reaction. For the normal Diels−Alder reaction, coumarin-based
dienophiles53−55 and a diene52 have been reported. Our group
communicated the only example of a coumarin-based diene
(13) to be used as a substrate in an inverse electron demand
Diels−Alder (IEDDA)-based synthesis of C-ring-functionalized
6H-dibenzo[b,d]pyran-6-ones56 14 (Scheme 1) and, more
recently, an application of this methodology in the total
synthesis of urolithin M7 (15).68 Reported herein are the
details of an exploration of the scope and limitations of this
methodology.
INTRODUCTION
■
A variety of natural products feature a 6H-dibenzo[b,d]pyran-6-
one (1) core, including fasciculiferol (2),1,2 alternariol (3),3
autumnariol (4),4 autumnariniol (5),4 altenuisol (6),5 and
ellagic acid (7)6,7 (Figure 1). A closely related structure, 6H-
benzo[d]naphtho[1,2-b]pyran-6-one (8), is common to several
bactericidal and antitumor natural products such as the
gilvocarcins (9),8−15 the ravidomycins (10),16−19 the chrys-
omycins (11),20,21 and arnottin I (12).22,23 Furthermore,
dibenzopyranones have served as intermediates in the synthesis
of cannabinoids24−27 and other pharmaceutically interesting
compounds, for example, progesterone, androgen, and
glucocorticoid receptor agonists,28−30 endothelial proliferation
inhibitors,31 and antidyslipidemic agents.32
Numerous approaches to the synthesis of 6H-dibenzo[b,d]-
pyran-6-ones have been reported. These can be broadly
classified according to the bonds formed during the key step(s)
as follows: approaches that involve (1) biaryl bond formation
followed by lactonization,33−40 (2) construction of an ester or
ether followed by intramolecular biaryl bond formation,41−43
(3) a cyclization to form the C ring (or B and C rings), with or
without a subsequent aromatization,27,44−57 (4) rearrangement
of spirocyclic compounds,58−60 (5) biomemitic syntheses of
alternarial derivatives,61−65 and (6) miscellaneous methods.66,67
In category 3, enediyne cycloaromatization,44−46 ruthenium-
catalyzed [2+2+2] cycloaromatization,27 6π electrocyclic ring
closure,47 condensations involving chromones48 and coumar-
ins49−51 bearing electron-withdrawing groups, and the Diels−
Alder reaction52−57 have been exploited. Of these methods, the
Diels−Alder reaction arguably offers the greatest potential for
RESULTS AND DISCUSSION
■
As reported earlier,56 coumarin-fused diene 13 was synthesized
in a single step from salicylaldehyde (16) and dimethyl
glutaconate (17) (Scheme 2). This involves a transesterification
and a vinylogous Knoevenagel condensation, although the
order of events is unclear. An important feature of diene 13 is
that the electron-withdrawing groups on the diene unit have a
1,3 relationship,69 as do the electron-donating groups on
Danishefsky’s diene.70 However, the synthesis of diene 13 is
not easily modified to allow for the incorporation of a variety of
other electron-withdrawing groups at the terminus of the diene
system. Accordingly, an alternative and more general approach
Received: August 25, 2011
Published: September 28, 2011
© 2011 American Chemical Society
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alkenes was identified as a promising route (Scheme 2). After
some optimization, good results were obtained using ethyl
acrylate. Diene 19 was obtained in 65% yield. However, the use
of these conditions with methyl vinyl ketone or acrylonitrile
afforded dienes 20 and 21 in very poor yield. Faced with the
prospect of reoptimizing the Heck reaction for each electron-
deficient alkene, another approach was investigated. This
involved the use of the Horner−Wadsworth−Emmons reaction
to generate the electron-deficient diene system, which had been
used successfully for other electron-deficient dienes (Scheme
Scheme 3
Figure 1. Structures of 6H-dibenzo[b,d]pyran-6-one (1), 6H-benzo-
[d]naphtho[1,2-b]pyran-6-one (8), and some natural products
possessing these core structures.
3).69,72−74 Thus, access to multigram quantities of 3-
formylcoumarin (22) was required, and this was achieved by
ozonolysis of diene 13. At 84%, the yield of this reaction is
somewhat better than that reported by Triggle et al. for the
oxidative cleavage of 19 using OsO4/NaIO4 (70%).75
Scheme 1
Aldehyde 22 was reacted with phosphonates 2376 and 2477
to afford dienes 21 and 25 in modest yield. In the case of
cyanodiene 21, an inseparable mixture of geometric isomers
favoring the E isomer (82:18 by 1H NMR analysis) was
obtained. On the other hand, only the E isomer of the
corresponding sulfone 25 was isolated. Methyl ketone 20 was
synthesized using a Wittig reaction between 3-formylcoumarin
(22) and ylide 26.78 Both geometric isomers were produced,
and the E isomer could be isolated in 82% yield using flash
chromatography. A 9:1 mixture of (Z)-20/(E)-20 (4%) was
also isolated. Finally, isomerically pure cyanodiene (E)-21 was
synthesized via decarboxylative Knoevenagel condensation of
22 with cyanoacetic acid (27). Attempts to generate the
corresponding nitrodiene using a Henry reaction of 22 with
nitromethane were unsuccessful.
Scheme 2
The investigation of the IEDDA chemistry of dienes 13, (E)-
20, (E)-21, and 25 commenced with the reaction of 13 with
ethyl vinyl ether. Although ethyl vinyl ether is a relatively weak
dienophile, it had been found to react with a related electron-
deficient diene at 80 °C.69 However, 13 was unreactive toward
ethyl vinyl ether (TLC analysis) after heating for 4 d at 120 °C
(sealed tube) or under catalysis by Yb(OTf)3,79 Eu(hfc)3,79 or
silica gel.80 Partial aromatic character (even a small amount) in
the pyranone ring would be expected to decrease the Diels−
Alder reactivity. In view of the lower reactivity of 13, a more
reactive dienophile was employed. Indeed, the enamine (28)
to the synthesis of a family of electron-deficient, coumarin-
fused dienes was sought.
The use of 3-bromocoumarin (18)71 as a common starting
material in the Heck reaction with various electron-deficient
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derived from cyclopentenone and pyrrolidine reacted smoothly
with diene 13 in dichloromethane at ambient temperature to
afford dibenzopyranone 38 in 43% yield (Scheme 4). Under
the same conditions, dienes (E)-20, (E)-21, and 25 provided
the corresponding dibenzopyranones 39−41 (25−38%).
Table 1. Results of IEDDA-Driven Domino Reactions of
Diene 13 with Enamines
Scheme 4
The products presumably arise from a formal IEDDA
reaction81 to afford adducts 29−32, followed by 1,2-elimination
to give cyclohexadienes 33−3682 and a dehydrogenation
(Scheme 4). Disproportionation products have been observed
in intramolecular IEDDA reactions of a related heterodiene,83
but none were observed in any of these reactions. Transfer
hydrogenation84 to enamine 28 (giving amine 37) is therefore a
more likely pathway for the dehydrogenation of 33−36 to
afford 38−41. Support for this notion is presented at the end of
this article. For dienes 13, (E)-20, and (E)-21, no intermediates
or byproducts were isolated or observed (TLC analysis) during
the course of these reactions. However, diene 25 gave rise to
the formation of dibenzopyranone 42 (49%), which lacks the
sulfonyl group, in addition to 41. Allylic sulfones are known to
undergo 1,4-elimination of benzenesulfinic acid;85 therefore, it
seems likely that 42 is formed by a 1,4-elimination of
benzenesulfinic acid from 32 followed by a 1,2-elimination of
pyrrolidine.86
Diene 13 was then reacted with a series of enamines,
whereby the outcome depended on the nature of the
dienophile (Table 1). The use of enamines 43, 45, 47, and
49,87 which are derived from acyclic carbonyl compounds or
cyclic ketones with a ring size of 5, led to the formation of
functionalized dibenzopyranones 44, 46, 48, and 50 in 43−64%
yield (Table 1, entries 1−4). As before, no intermediates or
byproducts were isolated or observed (TLC analysis) during
the course of these reactions.
crystal X-ray diffraction studies (Supporting Information).
Although neither product corresponds to diene 33 in the
proposed mechanism (Scheme 4), plausible pathways for their
formation based on this mechanism can be put forward
(Scheme 5). Following cycloaddition81 of 13 and 51 to afford
adduct 59, and subsequent elimination of pyrrolidine to give
60, diene 52a could arise from a double bond migration that
leads to the re-establishment of the coumarin system.88
A
subsequent double bond migration would afford diene 52b,
which was determined to have cis relative stereochemistry.
AM1 calculations predicted that 52b and its trans isomer are
within 1 kcal/mol of each other; therefore, it does not seem
likely that this process would give only the cis isomer. On the
other hand, diene 52b could be the product of a [1,5]-H shift89
of diene 60. If this is the case, then the cis relative
stereochemistry in 52b can be traced back to the precursor
diene 60 as well as cycloadduct 59. If the cycloaddition to
afford 59 is concerted, then it must have proceeded through a
Enamines 51 and 53, which are derived from cyclic ketones
with a ring size of ≥6, gave products that had not undergone
dehydrogenation (Table 1, entries 5,6). In the case of enamine
51, cyclohexadienes 52a (82%) and 52b (4%) were isolated.
The structures of both products were determined by single-
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the transfer hydrogenation. Enamine 57, which cannot give an
aromatized product according to the proposed mechanism,
reacted with diene 13 to give cyclohexadiene 58 (56%) (Table
1, entry 8). This compound is the product of a domino
IEDDA/1,2-elimination/[1,5]-H shift sequence. As for 52b,
successive double bond migrations could replace the [1,5]-H
shift.89
Scheme 5
In considering the further extension of the methodology, the
synthesis of the required enamines in reasonably pure form was
identified as a potential problem.90 As such, attention was
turned to the possibility of generating the enamines in situ.
Moreover, the proposed mechanism for dibenzopyranone
formation involves the elimination of the secondary amine
used to generate the enamine; therefore, the opportunity to
perform these reaction organocatalytically also presented itself.
A system consisting of diene 13, cyclopentanone, pyrrolidine,
and 4 Å molecular sieves was chosen for optimization (Table
transition state in which the NR2 group of the dienophile is exo
to the diene. If it is a stepwise reaction, then the first step
(conjugate addition) occurs with complete diastereoselectively.
Unfortunately, these considerations can only be applied to the
4% of the starting material that ended up as 52b. The lack of
any relative stereochemical relationships in 52a precludes
meaningful commentary about the nature of the cycloaddition.
Enamine 53 gave only the 1,4-cyclohexadiene 54, also in good
yield (80%).
Table 2. Optimization of the Synthesis of 38 Using In-Situ-
Generated Enamine 28
The failure of the reactions involving enamines 51 and 53 to
undergo dehydrogenation is likely a consequence of strain in
the dibenzopyranone products 61 and 62, which were
synthesized in high yield by the reactions of 52a and 54 with
DDQ (Scheme 6). AM1-calculated structures of 61 and 62
cyclopentanone
(equiv)
pyrrolidine
(equiv)
isolated
entry
1
conditions
yield (%)
1.5
0.2
rt, 45 min, 4 Å
MS
63
2
3
1.5
2.0
0.05
0.2
rt, 24 h, 4 Å MS
37
42
Scheme 6
rt, 20 min, 4 Å
MS
4
5
6
7
8
2.0
5.0
5.0
5.0
5.0
0.5
0.5
0.5
0.5
0.5
rt, 15 min, 4 Å
MS
56
66
59
15
74
rt, 15 min, 4 Å
MS
0 °C, 45 min, 4 Å
MS
40 °C, 45 min, 4
Å MS
rt, 15 min,
MgSO4
2). The initial experiment using 1.5 equiv of cyclopentanone
and 0.2 equiv of pyrrolidine afforded dibenzopyranone 38 in
63% yield after a 45 min reaction (Table 2, entry 1), which was
already significantly better than when preformed enamine 28
was employed (43%). Upon lowering the proportion of
pyrrolidine to 0.05 equiv (Table 2, entry 2), 38 was again
generated, but the reaction had not proceeded to completion
after 24 h. The use of 2.0 equiv of cyclopentanone (Table 2,
entries 3,4) resulted in the consumption of diene 13 within
15−20 min, but the yields were somewhat lower. A further
increase in the proportion of cyclopentanone to 5.0 equiv raised
the yield to 66% (Table 2, entry 5). Variation of the
temperature from 0 to 40 °C (Table 2, entries 5−7) had
only a small effect on the yield, the best yield being obtained at
room temperature. Finally, changing the drying agent from 4 Å
molecular sieves to MgSO4 improved the yield of 38 to 74%
(Table 2, entry 8).
have twisted structures (Supporting Information). The average
deviations from 0 or 180° of torsion angles around the biaryl
bond are ∼21°. By comparison, compounds 38, 44, and 46
were calculated to have essentially planar dibenzopyranone
systems. Dibenzopyranone 64, which was calculated to be
twisted to a similar extent as 52a and 54, also required a two-
step synthesis (Scheme 6). Enamine 63 reacted with diene 13
to afford a mixture of at least three unaromatized products (1H
NMR analysis), which could not be separated chromato-
graphically. Treatment of this mixture with DDQ afforded 64,
but the overall yield (28%) was low.
Cyclooctanone-derived enamine 55 was essentially unreac-
tive toward 13 at room temperature but reacted at reflux in
dichloromethane to afford dibenzopyranone 56 in just 15%
yield (Table 1, entry 7). The AM1-calculated structure of 56 is
also twisted. Presumably, the elevated temperature facilitated
Using the best conditions for the synthesis of 38, dienes (E)-
20, (E)-21, and 25 were converted into the corresponding
dibenzopyranones 39−41 in yields that matched or exceeded
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those obtained using preformed enamine 28 (Scheme 7). In the
case of sulfone-bearing diene 25, the byproduct 42 (45%) was
Table 3. Results of Reactions of Diene 13 with In-Situ-
Generated Enamines
Scheme 7
again produced along with 41 (14%). The product distribution
was similar to that obtained using preformed enamine 28.
Diene 13 was then reacted with a series of ketones under
conditions for the in situ generation of enamines (Table 3).
The use of 2-indanone (65) resulted in the formation of
dibenzopyranone 48 in substantially better yield than that when
preformed enamine 47 was employed (81 versus 55%) (Table
3, entry 1). The reaction with cyclohexanone (66) proceeded
slowly at room temperature (Table 3, entry 2), but the
outcome was similar to that obtained when using preformed
enamine 51. Upon moving to cycloheptanone (67),91 no
reaction occurred at room temperature. However, performing
the reaction in acetonitrile at reflux afforded dibenzopyranone
62 in 46% yield (Table 3, entry 3). In this case, the use of
preformed enamine 53 is the better option. Analogous behavior
was observed for acetophenone (68), which reacted in
acetonitrile at reflux to give dibenzopyranone 44 (74 versus
64% from 43) (Table 3, entry 4).
Owing to their expense or problems associated with the
synthesis of the corresponding enamines, the remaining
ketones were used only in the in situ method. Only 1.5 equiv
of expensive ketones (Table 3, entries 6−11) were employed.
Acetone (69) and cyclobutanone (71) reacted at room
temperature to afford dibenzopyranones 70 (66%) and 72
(26%) (Table 3, entries 5,6). The latter reaction was
considerably slower and lower yielding, but it provided a
novel entry to a benzocyclobutene system, which could serve as
a precursor to an electron-deficient ortho-xylylene. Like
cyclohexanone (66), tetrahydro-4H-thiapyan-4-one (73) and
N-methyl-4-piperidone (75) reacted at room temperature,
albeit significantly faster, to afford mixtures of nondehydro-
genated products (74a,b and 76a,b, respectively) in good yield
(Table 3, entries 7,8). Products 74a (78%) and 74b (11%)
could be separated by flash chromatography. However,
chromatographic separation of 76a and 76b (80% combined,
intramolecular hydride transfer in the resulting intermediate 87
(Scheme 8).92Alternatively, conjugate addition could occur to a
diene analogous to 33, which looks to be a much better Michael
acceptor, followed by a similar intramolecular hydride transfer.
Whatever the case, it is not obvious why this side reaction
occurs with ketone 77 and not with ketones 66, 73, and 75.
More hindered ketones 80 and 82 reacted at room
temperature, but they afforded the corresponding dibenzopyr-
anones 81 and 83 in just 15 and 17% yield, respectively. Finally,
methyl pyruvate (84) (10 equiv) was used, and despite the
electron-withdrawing ester group, it reacted relatively quickly at
room temperature to afford the nonaromatized product 85 in
59% yield. This compound and the other nonaromatized
products (74a,b, 76a,b, and 78a) were reacted with DDQ with
the intention of producing the corresponding aromatized
1
71:9 by H NMR analysis) was more difficult, and only 76a
(44%) could be obtained in pure form. The relative
stereochemistry in the minor products was not established
unambiguously, but by analogy to 52b, a cis relationship would
be expected.
The reaction involving tetrahydro-4H-pyan-4-one (77)
appeared to have stalled after 24 h and gave a chromato-
graphically separable mixture of diene 13 (18% recovery), 78a
(40%), and an unexpected byproduct 79 (32%) (Table 3, entry
9). A product analogous to 52b, 74b, and 76b was not isolated.
The structure of 79 was determined using a single-crystal X-ray
diffraction experiment (Supporting Information). Its formation
can be explained by a diastereoselective conjugate addition of
the enamine 86 to the convex face of 78a, followed by an
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for dehydrogenation must be available, such as transfer
hydrogenation to the ketone, which is present in excess.
To demonstrate that A-ring substituted dibenzopyranones
are also accessible using the IEDDA-based approach, a series of
salicylaldehydes was reacted with dimethyl glutaconate (17) to
afford the corresponding coumarin-fused dienes (Table 4).
Aldehydes 92, 94, 96, 98, and 101 were synthesized by
Skattebol formylation93 of the corresponding phenols, whereas
aldehydes 104 and 107 were synthesized by Duff formyla-
tion94,95 of the corresponding phenols. The methyl-substituted
salicylaldehydes 92, 94, and 96 reacted smoothly to afford
dienes 93, 95, and 97 in 72−80% yield (Table 4, entries 1−3).
Salicylaldehydes 98, 101, and 104 also afforded the desired
dienes 99, 102, and 105, but the yields were slightly lower
(65−71%) and the 2H-chromenes 100, 103, and 106 were also
formed in 15−25% yield (Table 4, entries 4−6). In the case of
5-nitrosalicylaldehyde (107), diene 108 was obtained in only
26% yield, and 2H-chromene 109 was the major product
(72%). In contrast to the diene products, which arise from a
combination of vinylogous Knoevenagel condensation and
transesterification, the 2H-chromene products arise from a
combination of vinylogous Knoevenagel condensation and
conjugate addition. The order of events and the factors
influencing the product distribution are, at this time, unclear.
The dienes were reacted with 28 using both the preformed
enamine and the method involving its generation in situ (Table
5). In the case of the parent diene 13, it had already been found
that the in situ method gave a much better yield of
dibenzopyranone 38 (Table 5, entry 1). This was also the
case for dienes 93, 95, 97, and 99, but the superiority of the in
situ method was less pronounced (Table 5, entries 2−5). For
dienes 102, 105, and 108, better yields were obtained using
preformed 28 (Table 5, entries 6−8). Overall, the yields using
preformed 28 were more consistent than when using the in situ
method. In both instances, nitro-substituted diene 108 stood
out as the poorest-yielding example.
Scheme 8
Scheme 9
products 88−91 (Scheme 9). Whereas dibenzopyranones 90
and 91 were isolated in reasonably good yield, the systems with
more oxidation-sensitive S and N atoms were obtained in 20
and 0% yield, respectively. An alternative aromatization using
MnO2 afforded dibenzopyranone 89 in 31% yield.
Some of the yields obtained using the in situ method were in
excess of 50%, which would be the theoretical limit if transfer
hydrogenation to the enamine were solely responsible for the
dehydrogenation step. Clearly, one or more other mechanisms
As a further example of the scope of the methodology,
salicylaldehyde (16) was reacted with dimethyl 3-methylglu-
taconate (117) to afford diene 118 (55%), which bears a
methyl group on the diene unit (see Scheme 10). Reaction of
118 with preformed enamine 28 gave dibenzopyranone 119
(67%), in which the newly formed aromatic ring is
hexasubstituted. Generation of the enamine in situ gave a
44% yield of 119.
Table 4. Results of Reactions of Dimethyl Glutaconate (17) with Salicylaldehydes
entry
aldehyde
92 R = 5-Me
diene (% yield)
2H-chromene (% yield)
1
2
3
4
5
6
7
93 R = 6-Me (78)
95 R = 7-Me (80)
97 R = 8-Me (72)
99 R = 6-OMe (71)
102 R = 6-Br (65)
105 R = 6-CO2Me (66)
108 R = 6-NO2 (26)
94 R = 4-Me
96 R = 3-Me
98 R = 5-OMe
101 R = 5-Br
100 R = 6-OMe (19)
103 R = 6-Br (25)
104 R = 5-CO2Me
107 R = 5-NO2
106 R = 6-CO2Me (15)
109 R = 6-NO2 (72)
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Table 5. Results of Reactions of Enamine 28 with Coumarin-Fused Electron Deficient Dienes
% yield (preformed
% yield in situ
entry
diene
13 R = H
dibenzopyranone
28)
(28)
1
2
3
4
5
6
7
8
38 R = H
43
47
51
48
51
51
41
24
74
50
57
54
64
35
34
22
93 R = 6-Me
110 R = 2-Me
111 R = 3-Me
112 R = 4-Me
113 R = 2-OMe
114 R = 2-Br
115 R = 2-CO2Me
116 R = 2-NO2
95 R = 7-Me
97 R = 8-Me
99 R = 6-OMe
102 R = 6-Br
105 R = 6-CO2Me
108 R = 6-NO2
follow-on products from 122. The relative stereochemistry in
122 was established using an X-ray crystal structure
determination (Supporting Information). While it is fully
consistent with a concerted cycloaddition, it does not rule out a
completely stereoselective stepwise mechanism. The much
slower rate of elimination in adduct 122 than that in the
corresponding enamine adducts (e.g., 29, Scheme 4) is likely
due to the absence of an organic base. In the reactions involving
enamines, pyrrolidine (a 2° amine), adducts such as 29 (a 3°
amine) and the enamines themselves (3° amines) are present.
In an attempt to use diene 124 as an IEDDA substrate, it was
reacted with enamine 28 at room temperature. However, no
products arising from cycloaddition were observed. Instead,
dibenzopyranone 123 was isolated in 75% yield after a 3 h
reaction. It thus appears that transfer hydrogenation is indeed a
facile process. The presence of 1-cyclopentylpyrrolidine (37) in
the reaction mixture was supported by GC-MS analysis (m/z =
139) of an extract of a (neutralized) acid wash of a reaction
between 124 and 28, for which independently synthesized 3798
was used as a standard.
Scheme 10
Scheme 11
CONCLUSIONS
■
Twelve coumarin-fused electron-deficient dienes were synthe-
sized, and they reacted with a variety of preformed and/or in-
situ-generated enamines. When the enamine was derived from
an acyclic carbonyl compound or a cyclic ketone with a ring
size of ≤5, 6H-dibenzo[b,d]pyran-6-ones were obtained from
room-temperature reactions. When the enamine was derived
from a cyclic ketone with a ring size of ≥6, dihydro-6H-
dibenzo[b,d]pyran-6-ones were obtained, unless a reaction
temperature of >40 °C was employed, in which case, the
aromatized products were generated. The dihydro-6H-dibenzo-
[b,d]pyran-6-one products could be dehydrogenated to afford
the corresponding 6H-dibenzo[b,d]pyran-6-ones. A total of 30
6H-dibenzo[b,d]pyran-6-ones were synthesized, including one
in which the newly formed six-membered ring was hexasub-
stituted. The reactions presumably commence with a formal
IEDDA reaction. The question of whether this step is
concerted or stepwise could not be addressed generally, but
the few pieces of evidence pertaining to the mechanism of the
cycloaddition step were fully consistent with a concerted
cycloaddition. Nevertheless, a stepwise mechanism cannot yet
be excluded.
Whereas ethyl vinyl ether was found to be unreactive toward
diene 13, ketene acetals 12096 and 12197 reacted slowly at
reflux in dichloromethane (see Scheme 11). In the case of 120,
IEDDA adduct 122 was isolated in 72% yield after 20 h of
reaction. Upon extending the reaction time to 48 h, 122 (60%)
was still the major product, but dibenzopyranone 123 (15%)
and cyclohexadiene 124 (9%) were also isolated. As for most of
the reactions with enamines described above, the formation of
dibenzopyranone 123 can be explained by a sequential
IEDDA/elimination/transfer hydrogenation process. Diene
124 appears simply to be the result of a sequential IEDDA/
elimination sequence. A 5 d reaction using ketene acetal 121
afforded only 123 (43%) and 124 (23%), both of which are
9021
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Article
1H), 7.33 (t, J = 8.1 Hz, 1H), 7.29 (d, J = 15.9 Hz, 1H), 2.40 (s, 3H);
13C NMR (CDCl3, 125 MHz) δ = 198.3 (0), 159.3 (0), 153.6 (0),
143.3 (1), 135.9 (1), 133.0 (1), 130.8 (1), 128.5 (1), 124.9 (1), 122.5
(0), 119.0 (0), 116.7 (1), 28.6 (3); GC-MS m/z (%) 214 (M+, 4), 171
(100); HRMS (EI) calcd for C13H10O3: 214.0629; found: 214.0607.
(E)-3-(2-Oxo-2H-chromen-3-yl)acrylonitrile (21). A mixture of
aldehyde 22 (264 mg, 1.51 mmol) and cyanoacetic acid (27) (141
mg, 1.66 mmol) was heated at 110 °C, and then, pyridine (4.0 mL)
was added dropwise over 30 s. The resulting mixture was stirred at 110
°C for 8 min and then cooled to room temperature. The reaction
mixture was dissolved in dichloromethane (20 mL), washed with
aqueous 1 M HCl solution, dried over MgSO4, and concentrated
under reduced pressure. The residue was subjected to flash
chromatography on silica gel (dichloromethane) to afford diene 21
(164 mg, 55%) as a light yellow solid: mp 170−172 °C; IR (nujol) ν =
2215 (m), 1724 (s), 1606 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ =
7.85 (s, 1H), 7.66−7.62 (m, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.39−7.35
(m, 2H), 7.20 (d, J = 16.4 Hz, 1H), 6.86 (d, J = 16.4 Hz, 1H); 13C
NMR (CDCl3, 125 MHz) δ = 158.6 (0), 153.5 (0), 144.8 (1), 143.9
(1), 133.7 (1), 128.8 (1), 125.1 (1), 121.0 (0), 118.5 (0), 118.0 (0),
116.7 (1), 102.8 (1); GC-MS m/z (%) 197 (M+, 100); HRMS (EI)
calcd for C12H7NO2: 197.0476; found: 197.0493.
EXPERIMENTAL SECTION
■
General Methods. General methods have been published else-
where.99
Methyl (E)-3-(2-Oxo-2H-chromen-3-yl)acrylate (13).56 To a mag-
netically stirred solution of salicylaldehyde (16) (0.44 mL, 4.1 mmol)
and dimethyl glutaconate (17) (0.57 mL, 4.1 mmol) in benzene (25
mL) was added piperidine (0.20 mL, 2.0 mmol) in one portion, and
the resulting mixture was heated at reflux with azeotropic removal of
water for 4 h. Upon cooling to room temperature, a white precipitate
formed, which was isolated by suction filtration. The filter cake was
washed with cool benzene (25 mL) to afford 17 (0.58 g, 62%) as a
white solid. The filtrate was concentrated under reduced pressure and
subjected to flash chromatography on silica gel (3% ethyl acetate/
dichloromethane) to afford a second batch of 17 (0.29 g, 30%, total =
0.87 g, 92%): mp 176−178 °C, IR (nujol) ν = 1727 (s) cm−1; UV−vis
(MeOH) λmax (log ε) = 315 (3.62), 290 (3.63) nm; 1H NMR (CDCl3,
500 MHz) δ = 7.88 (s, 1H), 7.59−7.55 (m, 3H), 7.35−7.30 (m, 2H),
7.10 (d, J = 15.3 Hz, 1H), 3.82 (s, 3H); 13C NMR (CDCl3, 75 MHz)
δ = 167.2 (0), 159.0 (0), 153.5 (0), 143.5 (1), 138.0 (1), 132.8 (1),
128.5 (1), 124.8 (1), 123.2 (1), 122.2 (0), 118.9 (0), 116.6 (1), 51.8
(3); EI-MS m/z (%) 230 (M+, 16), 171 (100); Anal. Calcd for
C13H10O4: C, 67.82; H, 4.38. Found: C, 67.71; H, 4.27.
(E)-1-(Phenylsulfonyl)-2-(2-oxo-2H-chromen-3-yl)ethene (25).
To a stirred 0 °C slurry of 60% sodium hydride (0.449 g, 11.2
mmol) in anhydrous THF (50 mL) was added dropwise a solution of
phosphonate 2477 (3.11 g, 11.2 mmol) in anhydrous THF (10 mL),
and the resulting clear solution was stirred for 15 min at 0 °C. A
solution of aldehyde 22 (1.63 g, 9.35 mmol) in anhydrous THF (50
mL) was then added dropwise. The reaction mixture was stirred at 0
°C for 30 min and then at room temperature for 24 h. The solvent was
removed under reduced pressure, and the residue was subjected to
column chromatography on silica gel (dichloromethane) to afford 25
Ethyl (E)-3-(2-Oxo-2H-chromen-3-yl)acrylate (19). A mixture of
3-bromocoumarin (1.00 g, 5.18 mmol), ethyl acrylate (0.84 mL, 7.70
mmol), Pd(OAc)2 (46 mg, 0.20 mmol), tri-o-tolylphosphine (94 mg,
0.31 mmol), CuI (35 mg, 0.18 mmol), and triethylamine (3.58 mL,
25.8 mmol) in benzene (10 mL) was heated at reflux for 4 h under a
nitrogen atmosphere. The reaction mixture was cooled to room
temperature, and aqueous 1 M HCl solution (20 mL) was added. The
resulting mixture was extracted with chloroform, and the combined
organic extracts were dried over Na2SO4. The solvent was removed
under reduced pressure, and the residue was subjected to flash
chromatography on silica gel (chloroform). The product was triturated
with ether (2 × 5 mL) to afford 19 as a cream-colored solid (0.82 g,
65%): mp 120−121 °C; IR (powder) ν = 2978 (w), 1708 (s), 1604
1
(1.20 g, 41%) as a white solid: mp 205−206 °C; H NMR (CDCl3,
500 MHz) δ = 7.96−7.94 (m, 3H), 7.79 (d, J = 15.1 Hz, 1H), 7.65−
7.56 (m, 5H), 7.51 (d, J = 14.7 Hz, 1H), 7.36−7.33 (m, 2H); 13C
NMR (CDCl3, 125 MHz) δ = 158.6 (0), 153.7 (0), 146.5 (1), 140.2
(0), 135.4 (1), 133.7 (1), 133.5 (1), 133.0 (1), 129.4 (1), 128.8 (1),
127.8 (1), 125.1 (1), 120.4 (0), 118.7 (0), 116.7 (1); EI-MS m/z (%)
312 (M+, 2), 171 (100). HRMS (EI) calcd for C17H12O4S: 312.0456;
found: 312.0434.
1
(m), 1165 (s) cm−1; H NMR (CDCl3, 500 MHz) δ = 7.88 (s, 1H),
7.60−7.54 (m, 2H), 7.57 (d, J = 16.1 Hz, 1H), 7.36 (d, J = 8.3 Hz,
1H), 7.33−7.30 (m, 1H), 7.10 (d, J = 15.9 Hz, 1H), 4.27 (q, J = 7.1
Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (500 MHz) δ 166.9,
159.1, 153.5, 143.4, 137.8, 132.9, 128.5, 124.8, 123.8, 122.4, 119.0,
116.7, 60.8, 14.3; APCI-(+)-MS m/z (%) 245 ([M + 1]+, 12), 200
(14), 199 (100); HRMS (APCI-(+)) calcd for C14H13O4: 245.0814;
found: 245.0815.
Standard Procedure A (for IEDDA Reactions Using Preformed
Enamines). To a magnetically stirred, room-temperature solution of
the diene (4.34 mmol) in dichloromethane (25 mL) was added neat
enamine (6.51 mmol) dropwise, and the resulting solution was stirred
at room temperature for the amount of time indicated. The
disappearance of the starting material was monitored by TLC. The
solvent was then removed under reduced pressure, and the residue was
subjected to flash chromatography on silica gel (4% ethyl acetate/
dichloromethane, unless otherwise stated) to afford the product(s).
Standard Procedure B (for IEDDA Reactions Using in Situ-
Generated Enamines). To a magnetically stirred, room-temperature
solution of the diene (4.34 mmol), the ketone (21.7 mmol for
inexpensive ketones or 6.5 mmol for expensive ketones), and MgSO4
(1.00 g, 8.31 mmol) in dichloromethane (25 mL) was added
pyrrolidine (0.18 mL, 2.2 mmol). The mixture was stirred at room
temperature, and the disappearance of the diene was monitored by
TLC. When the diene had been consumed, the MgSO4 was removed
by gravity filtration. The filtrate was washed with aqueous 1 M HCl
solution, dried over MgSO4, and concentrated under reduced pressure.
The residue was subjected to flash chromatography on silica gel to
afford the product(s).
3-Formyl-2-oxo-2H-chromene (22). Ozone was bubbled through a
−55 °C (dry ice/acetone bath) solution of diene 13 (3.00 g, 13.0
mmol) for 50 min, at which time the solution had become dark blue.
Nitrogen gas was then bubbled through the solution for 30 min, and
the temperature was allowed to rise to −30 °C. Dimethyl sulfide (3.5
mL, 48 mmol) was added in one portion, and the temperature was
allowed to rise slowly to room temperature. The resulting mixture was
stirred at room temperature for 16 h and concentrated under reduced
pressure. The residue was subjected to flash chromatography on silica
gel (2.5% ethyl acetate/dichloromethane) to afford aldehyde 22 (1.90
g, 84%) as a white solid: mp 132−134 °C (lit.100 mp: 131−132 °C);
1
IR (nujol) ν = 1737 (s), 1692 (s), 1609 (s) cm−1; H NMR (CDCl3,
500 MHz) δ = 10.27 (s, 1H), 8.43 (s, 1H), 7.72−7.68 (m, 2H), 7.42−
7.37 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ = 187.7, 160.1, 155.5,
145.6, 135.0, 130.8, 125.3, 121.8, 118.2, 117.1; EI-MS m/z (%) 174
(M+, 21), 146 (100).
(E)-4-(2-Oxo-2H-chromen-3-yl)but-3-en-2-one (20). To a mag-
netically stirred solution of aldehyde 22 (2.59 g, 14.9 mmol) in THF
(75 mL) was added ylid 2678 (4.73 g, 14.9 mmol) in one portion, and
the resulting mixture was heated at reflux for 2 h. The reaction was
cooled to room temperature and then concentrated under reduced
pressure. The residue was subjected to flash chromatography on silica
gel (3% ethyl acetate/dichloromethane) to afford diene 20 (2.61 g,
82%) as a white solid: mp 157−158 °C; IR (nujol) ν = 1704 (s), 1661
Standard Procedure for the Synthesis of Enamines. A magneti-
cally stirred solution of the ketone (0.10 mol), pyrrolidine (0.15 mol
for most ketones; 1.5 mol for aryl ketones), and benzene (200 mL)
was heated at reflux with azeotropic removal of water until the
appropriate volume of water had been removed from the reaction
mixture. The reaction mixture was cooled to room temperature and
then concentrated under reduced pressure. The residue was subjected
to vacuum distillation to afford the enamine.
1
(s), 1603 (m) cm−1; H NMR (CDCl3, 500 MHz) δ = 7.94 (s, 1H),
7.61−7.57 (m, 2H), 7.47 (d, J = 15.9 Hz, 1H), 7.36 (d, J = 8.3 Hz,
9022
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The Journal of Organic Chemistry
Article
Benzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-pyran-6-one-8-car-
boxylic Acid Methyl Ester (38). Using standard procedure A (3 h), 38
(0.65 g, 43%) was obtained as a white solid: mp 231−232 °C; IR
(nujol) ν = 1721 (s), 1600 (m) cm−1; UV−vis (MeOH) λmax (log ε) =
(2), 33.0 (2), 25.1 (2); EI-MS m/z (%) 236 (M+, 100); HRMS (EI)
calcd for C16H12O2: 236.0837; found: 236.0835. Using standard
procedure B (4 h, scaled down by a factor 3.1, dichloromethane used
for chromatography), 41 (0.05 g, 14%) was obtained as a white solid,
and 42 (0.10 g, 45%) was obtained as a white solid.
1
335 (3.85), 322 (3.84), 303 (3.92), 285 (4.14), 276 (4.08) nm; H
NMR (CDCl3, 500 MHz) δ = 8.91 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H),
7.52−7.49 (m, 1H), 7.37−7.32 (m, 2H), 3.94 (s, 3H), 3.48−3.43 (m,
4H), 2.28 (quint, J = 7.7 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ =
166.0 (0), 160.9 (0), 155.3 (0), 151.9 (0), 141.8 (0), 134.4 (0), 132.0
(1), 130.7 (1), 126.8 (1), 126.6 (0), 124.3 (1), 120.4 (0), 118.8 (0),
117.9 (1), 52.1 (3), 35.3 (2), 33.6 (2), 24.9 (2); EI-MS m/z (%) 294
(M+, 100); Anal. Calcd for C18H14O4: C, 73.46; H, 4.79. Found: C,
73.19; H, 4.67. Using standard procedure B (15 min), 38 (0.95 g,
74%) was obtained as a white solid.
9-Phenyl-6H-dibenzo[b,d]pyran-6-one-8-carboxylic Acid Methyl
Ester (44).56 Using standard procedure A (3 h), 44 (0.90 g, 64%) was
obtained as a white solid: mp 195−196 °C; IR (nujol) ν = 1738 (s),
1719 (s) cm−1; 1H NMR (CDCl3, 300 MHz) δ = 8.81 (s, 1H), 8.03−
8.01 (m, 2H), 7.56−7.31 (m, 8H), 3.74 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ = 166.9 (0), 160.0 (0), 151.8 (0), 148.7 (0), 139.8 (0), 136.5
(0), 132.7 (1), 131.4 (1), 131.1 (0), 128.2 (1), 128.1 (1), 124.7 (1),
124.2 (1), 123.2 (1), 119.6 (0), 117.8 (1), 117.1 (0), 52.3 (3); GC-MS
m/z (%) 330 (M+, 81), 299 (100); Anal. Calcd for C21H14O4: C,
76.36; H, 4.27. Found: C, 76.20; H, 4.10. For the in situ method, a
modification of standard procedure B was used. To a solution of diene
13 (1.00 g, 4.34 mmol), acetophenone (2.53 mL, 21.7 mmol), and
MgSO4 (1.00 g, 83 mmol) in CH3CN (25 mL) was added pyrrolidine
(0.18 mL, 2.17 mmol) dropwise, and the mixture was heated at reflux
for 12 h. The mixture was cooled to room temperature, and MgSO4
was removed by gravity filtration. The filtrate was washed with
aqueous 1 M HCl solution, dried over MgSO4, and concentrated
under reduced pressure to leave an oily solid. Hexanes (2 mL) was
added to this material, and after manual agitation for 5 min, the
hexanes solution was decanted into another flask. The solid residue
that remained was subjected to flash chromatography on silica gel (4%
ethyl acetate/dichloromethane) to afford 44 (1.06, 74%) as a white
solid.
Benzo[b]-9H-fluoreno[2,1-d]-6H-pyran-6-one-8-carboxylic Acid
Methyl Ester (46). Using standard procedure A (3 h), 46 (635 mg,
43%) was obtained as a white solid: mp 256−257 °C; IR (nujol) ν =
1741 (s), 1720 (s), 1599 (m) cm−1; 1H NMR (CDCl3, 500 MHz) δ =
8.89 (s, 1H), 8.42 (d, J = 7.3 Hz, 1H), 8.32 (d, J = 7.0 Hz, 1H), 7.70
(d, J = 7.7 Hz, 1H), 7.60−7.59 (m, 1H), 7.49−7.43 (m, 4H), 4.39 (s,
2H), 4.08 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ = 167.6 (0), 160.9
(0), 152.0 (0), 147.3 (0), 144.8 (0), 140.0 (0), 137.8 (0), 133.5 (0),
132.4 (1), 130.9 (1), 129.3 (1), 127.4 (1), 127.1 (0), 126.6 (1), 125.4
(1), 124.7 (1), 124.5 (1), 119.5 (0), 118.6 (0), 118.3 (1), 52.8 (3),
39.8 (2); EI-MS m/z (%) 342 (M+, 98), 283 (100); HRMS (EI) calcd
for C22H14O4: 342.0891; found: 342.0903.
8-Acetylbenzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-pyran-6-one
(39).56 Using standard procedure A (12 h, scaled down by a factor of
3.1, chloroform used for chromatography), 39 (0.13 g, 34%) was
obtained as a white solid: mp 220−223 °C; IR (powder) ν = 1720 (s),
1
1603 (m), 1184 (s) cm−1; H NMR (CDCl3, 500 MHz) δ = 8.83 (s,
1H), 8.26 (d, J = 8.1 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H), 7.44 (d, J = 8.2
Hz, 1H), 7.39 (t, J = 7.7 Hz, 1H), 3.49 (t, J = 7.5 Hz, 2H), 3.44 (t, J =
7.8 Hz, 2H), 2.73 (s, 3H), 2.28 (quint, J = 7.7 Hz, 2H); 13C NMR
(500 MHz) δ = 198.6, 161.2, 154.4, 152.0, 142.3, 134.6, 133.5, 131.3,
130.9, 126.9, 124.5, 120.3, 118.9, 118.0, 35.1, 33.9, 28.3, 25.2; ESI-
(+)-MS m/z (%) 279 ([M + 1]+, 100), 171 (15); HRMS (EI) calcd
for C18H14O3: 278.0943; found: 278.0947. Using standard procedure B
(5 h, scaled down by a factor of 3.1, chloroform used for
chromatography), 39 (0.18 g, 46%) was obtained as a white solid.
8-Cyanobenzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-pyran-6-one
(40). Using standard procedure A (3 h, scaled down by a factor 2.8,
chloroform used for chromatography), 40 (0.15 g, 38%) was obtained
as a white solid: mp 301−304 °C; IR (powder) ν = 2220 (w), 1724
1
(s), 1594 (m) cm−1; H NMR (CDCl3, 500 MHz) δ = 8.62 (s, 1H),
8.21 (d, J = 8.0 Hz, 1H), 7.60 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 8.2 Hz,
1H), 7.41 (t, J = 7.6 Hz, 1H), 3.59 (t, J = 7.3 Hz, 2H), 3.31 (t, J = 7.6
Hz, 2H), 2.40 (quint, J = 7.5 Hz, 2H); 13C NMR (500 MHz) δ =
160.0, 155.9, 152.0, 141.4, 135.3, 133.7, 131.6, 126.8, 124.7, 121.2,
118.3, 118.2, 116.7, 109.3, 36.0, 32.8, 24.7; ESI-(+)-MS m/z (%) 262
([M + 1]+, 100), 263 (15), 284 (20); HRMS (EI) calcd for
C17H11NO2: 261.0790; found: 261.0793. Using standard procedure B
(3 h, scaled down by a factor 2.8, chloroform used for
chromatography), 40 (0.15 g, 38%) was obtained as a white solid.
8-(Phenylsulfonyl)benzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-
pyran-6-one (41) and benzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-
pyran-6-one (42). To a magnetically stirred solution of diene 25 (312
mg, 1.00 mmol) in dichloromethane (5.75 mL) was added enamine 28
(206 mg, 1.50 mmol) dropwise, and the resulting mixture was stirred
for 5 min at room temperature. The mixture was diluted with
dichloromethane (20 mL), washed with aqueous 1 M HCl solution
(20 mL), dried over MgSO4, and concentrated under reduced
pressure. The residue was subjected to flash chromatography
(dichloromethane) to afford 42 (116 mg, 49%, Rf (30% ethyl
acetate/hexanes) = 0.80) as a white solid and then 41 (92.3 mg, 25%,
Rf (30% ethyl acetate/hexanes) = 0.40) as a white solid. 41: mp 285−
Benzo[b]-9H-fluoreno[3,4-d]-6H-pyran-6-one-8-carboxylic Acid
Methyl Ester (48). Using standard procedure A (24 h), 48 (0.82 g,
55%) was obtained as a white solid: mp 206−208 °C; IR (nujol) ν =
1745 (s), 1720 (s), 1607 (m) cm−1; 1H NMR (CDCl3, 500 MHz) δ =
8.87 (s, 1H), 8.51−8.49 (m, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.60 (d, J =
7.4 Hz, 1H), 7.54−7.50 (m, 1H), 7.40−7.35 (m, 2H), 7.28−7.23 (m,
2H), 4.34 (s, 2H), 3.99 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ =
165.5 (0), 160.8 (0), 153.4 (0), 151.2 (0), 144.7 (0), 139.2 (0), 138.8
(0), 134.1 (0), 131.5 (1), 130.5 (1), 128.2 (1), 127.2 (1), 126.3 (0),
126.0 (1), 125.1 (1), 123.3 (1), 121.9 (0), 117.7 (1), 117.6 (0), 52.2
(3), 39.2 (2); EI-MS m/z (%) 342 (M+, 100); HRMS (EI) calcd for
C22H14O4: 342.0891; found: 342.0902. Using standard procedure B (3
h), 48 (1.21 g, 81%) was obtained as a white solid.
9-(−1-Piperidinyl)-6H-dibenzo[b,d]pyran-6-one-8-carboxylic Acid
Methyl Ester (50).56 Using standard procedure A (18 h), 50 (0.71 g,
48%) was obtained as a white solid: mp 130−131 °C; IR (nujol) ν =
1
286 °C; H NMR (CDCl3, 500 MHz) δ = 9.04 (s, 1H), 8.18 (d, J =
8.7 Hz, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.57−
7.53 (m, 3H), 7.42 (d, J = 8.6 Hz, 1H), 7.36 (t, J = 7.5 Hz, 1H), 3.46
(t, J = 7.5 Hz, 2H), 3.28 (t, J = 7.8 Hz, 2H), 2.26 (quint, J = 7.8 Hz,
2H); 13C NMR (CDCl3, 125 MHz) δ = 160.3 (0), 152.1 (0), 151.4
(0), 143.3 (0), 140.4 (0), 137.5 (0), 135.7 (0), 133.6 (1), 131.4 (1),
130.4 (1), 129.3 (1), 128.1 (1), 126.9 (1), 124.5 (1), 121.2 (0), 118.3
(0), 118.1 (1), 35.4 (2), 32.2 (2), 25.0 (2); APCI-(+)-MS m/z (%)
377 ([M + 1]+, 100); HRMS (EI) calcd for C22H16O4S: 376.0769;
found: 376.0767. 42: mp 165−166 °C; IR (nujol) ν = 1723 (s), 1712
(s), 1598 (m) cm−1; 1H NMR (CDCl3, 500 MHz) δ = 8.30 (d, J = 7.3
Hz, 1H), 8.17 (d, J = 7.1 Hz, 1H), 7.48−7.45 (m, 2H), 7.38 (d, J = 7.4
Hz, 1H), 7.34−7.30 (m, 1H), 3.46 (t, J = 7.4 Hz, 2H), 3.08 (t, J = 7.8
Hz, 2H), 2.36−2.24 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ = 161.8
(0), 153.7 (0), 151.4 (0), 139.5 (0), 131.7 (0), 129.7 (1), 129.6 (1),
126.4 (1), 125.1 (1), 124.1 (1), 120.2 (0), 119.6 (0), 117.7 (1), 35.4
1
1718 (s) cm−1; H NMR (CDCl3, 500 MHz) δ = 8.68 (s, 1H), 7.99
(d, J = 6.9 Hz, 1H), 7.48 (t, J = 8.5 Hz, 1H), 7.47 (s, 1H), 7.30−7.34
(m, 2H), 3.93 (s, 3H), 3.26−3.28 (m, 4H), 1.76−1.81 (m, 4H), 1.66−
1.71 (m, 2H); 13C NMR (CDCl3, 125 MHz) δ = 167.3 (0), 160.6 (0),
156.6 (0), 152.1 (0), 138.1 (0), 135.6 (1), 131.1 (1), 124.3 (1), 122.9
(1), 122.7 (0), 117.9 (1), 117.7 (0), 111.7 (0), 108.6 (1), 52.8 (2),
52.3 (3), 25.6 (2), 24.0 (2); EI-MS m/z (%) 337 (M+, 44), 322 (100);
HRMS (EI) calcd for C20H19NO4: 337.1313; found: 337.1314.
Benzo[b]-3,5,6,7,8,8a-hexahydronaphthaleno[2,1-d]-6H-pyran-
6-one-8-carboxylic Acid Methyl Ester (52a) and (8aS*,12aR*)-
Benzo[b]-4a,5,6,7,8,8a-hexahydronaphthaleno[2,1-d]-6H-pyran-6-
one-8-carboxylic Acid Methyl Ester (52a). Using standard procedure
A (3 h), 52a (1.09 g, 82%, Rf (4% ethyl acetate/dichloromethane) =
0.45) was obtained as a white solid, and 52b (0.05 g, 4%, Rf (4% ethyl
acetate/dichloromethane) = 0.55) was obtained as a white solid. 52a:
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1
mp 168.5−170 °C; IR (nujol) ν = 1711 (s) cm−1; H NMR (CDCl3,
300 MHz) δ = 7.55 (d, J = 7.6 Hz, 1H), 7.49−7.44 (m, 1H), 7.35−
7.25 (m, 2H), 3.79 (s, 3H), 3.79−3.75 (m, 1H), 3.59−3.48 (m, 2H),
3.32 (dd, J = 23.4, 5.3 Hz, 1H), 2.40−2.35 (m, 1H), 2.08−1.79 (m,
4H), 1.59−1.40 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ = 167.4 (0),
160.3 (0), 152.5 (0), 148.6 (0), 145.0 (0), 130.3 (1), 123.9 (1), 123.4
(1), 119.5 (0), 117.9 (0), 117.4 (0), 116.9 (1), 51.2 (3), 42.1 (1), 36.4
(2), 31.7 (2), 29.0 (2), 26.7 (2), 26.5 (2); EI-MS m/z (%) 310 (M+,
59), 251 (100); Anal. Calcd for C19H18O4: C, 73.53; H, 5.85. Found:
chromatography on silica gel (2% ethyl acetate/dichloromethane) to
afford 61 (0.59 g, 96%) as a white solid: mp 163−164 °C; IR (nujol) ν
= 1721 (s) cm−1; UV−vis (MeOH) λmax (log ε) = 334 (3.36), 322
(3.42), 283 (3.85) nm; 1H NMR (CDCl3, 300 MHz) δ = 8.71 (s, 1H),
8.27 (d, J = 8.2 Hz, 1H), 7.52−7.46 (m, 1H), 7.39−7.28 (m, 2H), 3.93
(s, 3H), 3.31−3.27 (m, 4H), 1.92−1.66 (m, 4H); 13C NMR (CDCl3,
75 MHz) δ = 167.0 (0), 160.9 (0), 151.6 (0), 145.9 (0), 136.9 (0),
136.3 (0), 130.7 (0), 130.2 (1), 129.9 (1), 128.3 (1), 123.6 (1), 119.6
(0), 118.5 (0), 117.8 (1), 52.2 (3), 32.6 (2), 28.5 (2), 22.6 (2), 21.7
(2); EI-MS m/z (%) 308 (M+, 100); Anal. Calcd for C19H16O4: C,
74.01; H, 5.23. Found: C, 73.98; H, 5.08.
1
C, 73.36; H, 6.04. 52b: mp 209.5−211 °C; H NMR (CDCl3, 300
MHz) δ = 7.70 (dd, J = 8.7, 2.7 Hz, 1H), 7.63 (d, J = 3.1 Hz, 1H),
7.58−7.52 (m, 1H), 7.37−7.31 (m, 2H), 3.83 (s, 3H), 3.24−3.18 (m,
1H), 3.08−3.05 (m, 1H), 2.29−2.86 (m, 1H), 1.78−1.70 (m, 2H),
1.60−1.37 (m, 4H), 1.28−1.19 (m, 1H); 13C NMR (CDCl3, 75 MHz)
δ = 167.4 (0), 159.5 (0), 153.9 (0), 152.8 (0), 132.6 (0), 132.1 (1),
130.0 (1), 124.6 (1), 124.2 (1), 120.3 (0), 117.8 (0), 117.5 (1), 51.8
(3), 37.1 (1), 34.4 (1), 25.6 (2), 24.9 (2), 22.4 (2); EI-MS m/z (%)
310 (M+, 54), 251 (100); Anal. Calcd for C19H18O4: C, 73.53; H, 5.85.
Found: C, 73.47; H, 5.76. Using standard procedure B (5 d), 52a
(0.99 g, 74%) was obtained as a white solid, and 52b (0.11 g, 8%) was
obtained as a white solid.
Compound 62. To a magnetically stirred solution of 54 (0.50 g,
1.5 mmol) in benzene (25 mL) was added DDQ (0.35 g, 1.5 mmol) in
one portion, and the resulting mixture was heated at reflux for 72 h.
The reaction mixture was cooled to room temperature, and the tan
precipitate was removed by suction filtration. The filtrate was
concentrated under reduced pressure, and the residue was subjected
to flash chromatography on silica gel (3% ethyl acetate/dichloro-
methane) to afford 62 (0.48 g, 97%) as a white solid: mp 151−152 °C,
IR (nujol) ν = 1720 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ = 8.61
(s, 1H), 7.96 (dd, J = 7.7, 1.3 Hz, 1H), 7.50−7.47 (m, 1H), 7.39 (dd, J
= 8.4, 1.2 Hz, 1H), 7.32−7.29 (m, 1H), 3.94 (s, 3H), 3.36−3.34 (m,
Compound 54. Using standard procedure A (3 h), 54 (1.13 g,
80%) was obtained as a white solid: mp 135−136 °C; IR (nujol) ν =
1703 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ = 7.58 (dd, J = 8.4, 1.2
Hz, 1H), 7.52−7.49 (m, 1H), 7.35 (dd, J = 8.2, 1.3 Hz, 1H), 7.34−
7.30 (m, 1H), 3.86−3.81 (m, 2H), 3.79 (s, 3H), 3.58−3.52 (m, 1H),
3.21−3.26 (m, 1H), 2.34−2.37 (m, 1H), 2.07−2.11 (m, 1H), 1.95−
1.99 (m, 1H), 1.79−1.88 (m, 3H), 1.66−1.69 (m, 1H), 1.36−1.42 (m,
2H); 13C NMR (CDCl3, 125 MHz) δ = 167.3 (0), 160.7 (0), 153.1
(0), 150.7 (0), 148.8 (0), 130.7 (1), 124.2 (1), 123.1 (1), 122.2 (0),
120.2 (0), 117.8 (0), 117.3 (1), 51.5 (3), 42.4 (1), 35.4 (2), 33.5 (2),
28.3 (2), 27.2 (2), 26.7 (2), 25.5 (2); EI-MS m/z (%) 324 (M+, 84),
293 (100); Anal. Calcd for C20H20O4: C, 74.06; H, 6.21. Found: C,
73.80; H, 6.27.
Compound 56. To a magnetically stirred solution of diene 13 (500
mg, 2.17 mmol) in dichloromethane (25 mL) was added 1-(1-
pyrrolidinyl)cyclooctene (1.12 g, 6.51 mmol) dropwise, and the
resulting solution was heated at reflux for 48 h. The reaction mixture
was cooled to room temperature, and the solvent was removed under
reduced pressure. The residue was subjected to flash chromatography
on silica gel (dichloromethane) to afford 56 (108 mg, 15%) as a white
solid: mp 153−155 °C; IR (nujol) ν = 1733 (s), 1719 (s), 1606 (m)
cm−1; 1H NMR (CDCl3, 500 MHz, 333 K) δ = 8.76 (s, 1H), 8.27 (dd,
J = 8.4, 1.1 Hz, 1H), 7.51−7.47 (m, 1H), 7.38 (dd, J = 8.5, 1.2 Hz,
1H), 7.34−7.31 (m, 1H), 3.94 (s, 3H), 3.39−3.34 (m, 2H), 3.29−3.24
(m, 2H), 2.07−2.02 (m, 2H), 1.98−1.93 (m, 2H), 1.70−1.65 (m, 2H),
1.47−1.40 (m, 2H); 13C NMR (CDCl3, 125.8 MHz, 333 K) δ = 167.8,
161.0, 152.0, 149.5, 140.3, 135.6, 132.2, 130.7, 130.3, 127.8, 124.0,
121.1, 118.9, 118.4, 52.2, 31.4, 31.1, 29.4, 28.9, 27.2, 26.0; EI-MS m/z
(%) 336 (M+, 100); HRMS (EI) calcd for C21H20O4: 336.1360; found:
336.1368.
2H), 3.28−3.26 (m, 2H), 1.98−1.97 (m, 4H), 1.86−1.84 (m, 2H); 13
C
NMR (CDCl3, 125 MHz) δ = 168.0 (0), 161.1 (0), 151.8 (0), 151.6
(0), 141.8 (0), 135.5 (0), 131.3 (1), 130.3 (0), 129.6 (0), 127.6 (1),
123.9 (1), 120.2 (0), 118.8 (0), 118.0 (1), 52.4 (3), 31.5 (2), 31.0 (2),
26.7 (2), 26.3 (2); EI-MS m/z (%) 322 (M+, 100); Anal. Calcd for
C20H18O4: C, 74.52; H, 5.63. Found: C, 74.37; H, 5.60. Using standard
procedure B, 62 (0.65 g, 46%) was obtained as a white solid.
10-Phenyl-6H-dibenzo[b,d]pyran-6-one-8-carboxylic Acid Methyl
Ester (64). To a magnetically stirred solution of diene 13 (1.00 g, 4.34
mmol) in dichloromethane (25 mL) was added 2-phenyl-1-(1-
pyrrolidinyl)ethene (63) (1.62 g, 8.68 mmol) dropwise, and the
resulting mixture was stirred at room temperature for 15 min. The
reaction mixture was washed with aqueous 1 M HCl solution, dried
over MgSO4, and concentrated under reduced pressure. To the residue
was added benzene (50 mL) and DDQ (536 mg, 2.36 mmol). The
resulting mixture was heated at reflux for 48 h. After cooling to room
temperature, the reaction mixture was concentrated under reduced
pressure, and the residue was subjected to flash chromatography on
silica gel (5% ethyl acetate/dichloromethane) to afford 64 (408 mg,
28%) as a white solid: mp 188−189 °C; IR (nujol) ν = 1740 (s), 1728
(s), 1603 (m) cm−1; 1H NMR (CDCl3, 500 MHz) δ = 9.12 (d, J = 2.1
Hz, 1H), 8.27 (d, J = 2.1 Hz, 1H), 7.53−7.50 (m, 3H), 7.39−7.33 (m,
4H), 7.13−7.11 (m, 1H), 6.87−6.84 (m, 1H), 3.98 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ = 165.4 (0), 160.8 (0), 151.9 (0), 141.2 (0),
140.3 (0), 138.4 (1), 136.1 (0), 131.5 (1), 131.0 (1), 129.6 (0), 129.4
(1), 128.7 (1), 128.4 (1), 128.1, (1), 123.6 (1), 123.0 (0), 117.9 (1),
117.7 (0), 52.6 (3); EI-MS m/z (%) 330 (M+, 100); Anal. Calcd for
C21H14O4: C, 76.36; H, 4.27. Found: C, 76.01; H, 4.20.
9-Methyl-6H-dibenzo[b,d]pyran-6-one-8-carboxylic Acid Methyl
Ester (70). Using standard procedure B (inexpensive ketone, 1 h),101
70 (0.769 g, 66%) was obtained as a white solid: mp 216−217 °C; IR
10,10-Dimethyl-9,10-dihydro-6H-dibenzo[b,d]pyran-6-one
(58).56 Using standard procedure A (3 h), 58 (0.69 g, 56%) was
obtained as a white solid: mp 139−141 °C; IR (nujol) ν = 1717 (s)
(neat) ν = 1715 (s), 1608 (m), 1310 (m), 1240 (m), 1186 (m) cm−1
;
cm−1; UV−vis λmax (log ε) (MeOH) 308 (3.29), 288 (3.35) nm; H
1
1H NMR (CDCl3, 300 MHz) δ = 8.09 (s, 1H), 8.05 (dd, J = 6.3, 2.4
Hz, 1H), 7.93 (s, 1H), 7.54−7.49 (m, 1H), 7.37−7.33 (m, 2H), 3.95
(s, 3H), 2.78 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ = 166.2 (0),
160.4 (0), 151.9 (0), 147.5 (0), 137.0 (0), 133.5 (1), 131.4 (1), 130.0
(0), 124.7 (1), 124.6 (1), 123.2 (1), 118.9 (0), 117.9 (1), 117.0 (0),
52.2 (3), 22.5 (3); EI-MS m/z (%) 268 (M+, 71), 237 (100); Anal.
Calcd for C16H12O4: C, 71.64; H, 4.51. Found: C, 71.58; H, 4.40.
Compound (72). Using standard procedure B (expensive ketone,
48 h, scaled down by a factor of 2), 72 (0.16 g, 26%) was obtained as a
white solid: mp 245−246 °C; IR (nujol) ν = 1723 (s), 1611 (m) cm−1;
1H NMR (CDCl3, 500 MHz) δ = 8.84 (s, 1H), 7.84 (d, J = 7.5 Hz,
1H), 7.52−7.49 (m, 1H), 7.35−7.31 (m, 2H), 3.94 (s, 3H), 3.60 (s,
4H); 13C NMR (CDCl3, 125 MHz) δ = 165.0 (0), 161.0 (0), 155.3
(0), 151.9 (0), 140.8 (0), 133.0 (0), 131.6 (1), 131.3 (1), 125.8 (1),
125.3 (0), 124.6 (1), 119.9 (0), 117.5 (1), 117.3 (0), 52.1 (3), 32.1
NMR (CDCl3, 300 MHz) δ = 8.04 (d, J = 8.3 Hz, 1H), 7.48−7.45 (m,
1H), 7.37 (dd, J = 8.2, 1.1 Hz, 1H), 7.31−7.26 (m, 1H), 6.72 (t, J = 1.7
Hz, 1H), 3.82 (s, 3H), 3.47 (d, J = 1.6 Hz, 2H), 1.73 (s, 6H); 13C
NMR (CDCl3, 75 MHz) δ = 166.7 (0), 160.7 (0), 152.7 (0), 149.5
(0), 145.3 (1), 130.2 (1), 126.7 (1), 123.4 (1), 122.0 (0), 120.7 (0),
117.8 (1), 117.6 (0), 51.8 (3), 37.8 (0), 28.26 (3), 25.5 (2); EI-MS m/
z (%) 284 (M+, 6), 269 (100); Anal. Calcd for C17H16O4: C, 71.82; H,
5.67. Found: C, 71.82; H, 5.74.
Benzo[b]-5,6,7,8-tetrahydronaphthaleno[2,1-d]-6H-pyran-6-one-
8-carboxylic Acid Methyl Ester (61). To a magnetically stirred
solution of 52a (0.62 g, 2.0 mmol) in benzene (100 mL) was added
DDQ (0.50 g, 2.2 mmol) in one portion, and the resulting mixture was
heated at reflux for 24 h. The reaction mixture was cooled to room
temperature and gravity filtered, and the filtrate was concentrated
under reduced pressure. The residue was subjected to flash
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(2), 31.0 (2); EI-MS m/z (%) 280 (100, M+); HRMS (EI) calcd for
C17H12O4: 280.0735; found: 280.0736.
62.0 (2), 53.9 (2), 53.6 (2), 52.7 (3), 42.3 (0), 40.7 (1), 38.6 (1), 28.7
(2), 26.4 (2), 23.4 (2), 23.3 (2); EI-MS m/z (%) 465 (M+, 5), 464
(6), 347 (2), 252 (3), 223 (3), 154 (46), 153 (47), 110 (44), 97 (100).
Compound 81. Using standard procedure B (expensive ketone, 24
h, reflux, scaled down by a factor of 2), 81 (107 mg, 15%) was
obtained as a white solid: mp 230−231 °C; IR (nujol) ν = 1727 (s),
Benzo[b]-6,8a-dihydroisothiochromano[7,8-d]-6H-pyran-6-one-
carboxylic Acid Methyl Ester (74a) and Benzo[b]-4a,8a-
dihydroisothiochromano[7,8-d]-6H-pyran-6-one-carboxylic Acid
Methyl Ester (74b). Using standard procedure B (expensive ketone,
24 h), 74a (1.13 g, 79%) was obtained as a white solid, and 74b (0.16
g, 11%) was obtained as a white solid. 74a: mp 212−214.5 °C; IR
(nujol) ν = 1706 (s), 1605 (m) cm−1; 1H NMR (CDCl3, 500 MHz) δ
= 7.63 (d, J = 7.2 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 9.0 Hz,
1H), 7.35 (t, J = 8.1 Hz, 1H), 4.10−4.04 (m, 2H), 3.81 (s, 3H), 3.72−
3.67 (m, 1H), 3.39−3.33 (m, 1H), 3.08−3.01 (m, 2H), 2.90−2.87 (m,
1H), 2.80−2.75 (m, 1H), 2.40−2.35 (m, 1H); 13C NMR (CDCl3, 125
MHz) δ = 167.3 (0), 160.4 (0), 153.0 (0), 145.5 (0), 143.3 (0), 131.0
(1), 124.6 (1), 123.4 (1), 121.2 (0), 120.2 (0), 117.5 (1), 117.3 (0),
51.8 (3), 44.5 (1), 37.2 (2), 34.4 (2), 32.0 (2), 27.0 (2); EI-MS m/z
(%) 328 (M+, 26), 269 (93), 61 (100); HRMS (EI) calcd for
C18H16O4S: 328.0768; found: 328.0750. 74b: mp 199−200 °C; IR
(nujol) ν = 1719 (s), 1708 (s), 1608 (m) cm−1; 1H NMR (CDCl3, 500
MHz) δ = 7.74 (dd, J = 8.2, 1.1 Hz, 1H), 7.70 (d, J = 2.6 Hz, 1H),
7.60−7.57 (m, 1H), 7.39−7.36 (m, 2H), 3.84 (s, 3H), 3.59−3.54 (m,
1H), 3.31−3.27 (m, 1H), 3.22−3.20 (m, 1H), 2.89 (t, J = 12.7 Hz,
1H), 2.68 (td, J = 13.4, 2.3 Hz, 1H), 2.49−2.46 (m, 1H), 2.25−2.22
(m, 1H), 2.07−2.01 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ = 166.8
(0), 159.1 (0), 154.0 (0), 150.4 (0), 132.6 (1), 131.4 (0), 131.1 (1),
124.9 (1), 124.1 (1), 117.8 (0), 117.6 (1), 117.2 (0), 52.0 (3), 38.1
(1), 34.1 (1), 26.4 (2), 25.0 (2), 24.3 (2); EI-MS m/z (%) 328 (M+,
68), 223 (85), 61 (100); HRMS (EI) calcd for C18H16O4S: 328.0768;
found: 328.0767.
1
1715 (s), 1598 (m) cm−1; H NMR (CDCl3, 500 MHz) δ = 8.87 (s,
1H), 8.30 (d, J = 7.9 Hz, 1H), 7.53−7.50 (m, 1H), 7.40−7.36 (m,
2H), 4.43 (m, 1H), 4.27 (m, 1H), 3.97 (s, 3H), 2.25−2.17 (m, 2H),
1.78−1.75 (m, 1H), 1.68−1.66 (m, 1H), 1.48−1.44 (m, 1H), 1.38−
1.34 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ = 166.1 (0), 161.1 (0),
158.4 (0), 151.7 (0), 144.6 (0), 131.5 (0), 131.0 (1), 130.7 (1), 126.4
(1), 124.5 (1), 123.9 (0), 119.4 (0), 118.6 (0), 118.0 (1), 52.1 (3),
48.6 (2), 43.9 (1), 42.9 (1), 25.8 (2), 25.0 (2); EI-MS m/z (%) 320
(M+, 51), 292 (100); HRMS (EI) calcd for C20H16O4: 320.1048;
found: 320.1063.
9-Methylbenzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-pyran-6-
one-8-carboxylic Acid Methyl Ester (83). Using standard procedure
B (3 d, scaled down by a factor of 2), 83 (114 mg, 17%) was obtained
as a white solid: mp 206−207 °C; IR (nujol) ν = 1726 (s), 1716 (s),
1
1606 (m) cm−1; H NMR (CDCl3, 500 MHz) δ = 8.99 (s, 1H), 8.26
(d, J = 8.3 Hz, 1H), 7.55−7.52 (m, 1H), 7.41 (dd, J = 8.3, 1.1 Hz, 1H),
7.37 (t, J = 7.7 Hz, 1H), 4.14−4.11 (m, 1H), 3.96 (s, 3H), 3.58−3.40
(m, 2H), 2.35−2.30 (m, 1H), 2.11−2.07 (m, 1H), 1.29 (d, J = 7.1 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ = 165.8 (0), 161.0 (0), 160.3
(0), 152.0 (0), 140.8 (0), 134.8 (0), 132.6 (1), 130.8 (1), 127.0 (1),
125.3 (0), 124.3 (1), 120.6 (0), 118.9 (0), 118.0 (1), 52.1 (3), 39.0
(1), 33.4 (2), 33.1 (2), 20.3 (3); EI-MS m/z (%) 308 (M+, 100);
HRMS (EI) calcd for C19H16O4: 308.1049; found: 308.1049.
9,10-Dihydro-6H-dibenzo[b,d]pyran-6-one-8,9-dicarboxylic Acid
Dimethyl Ester (85). To a magnetically stirred solution of diene 13
(502 mg, 2.18 mmol), methyl pyruvate (2.00 mL, 22.1 mmol), and
MgSO4 (500 mg, 4.15 mmol) in dichloromethane (12.5 mL) was
added pyrrolidine (1.63 mL, 19.5 mmol) dropwise, and the resulting
mixture was stirred at room temperature for 1.5 h. The reaction
mixture was diluted with dichloromethane (25 mL), washed with
aqueous 1 M HCl solution, dried over MgSO4, and concentrated
under reduced pressure. The crude yellow oil was then subjected to
flash chromatography on silica gel (5% ethyl acetate/dichloro-
methane) to afford 85 (400 mg, 59%) as a yellow solid: mp 130−
134 °C; IR (nujol) ν = 1728 (s), 1712 (s), 1605 (m) cm−1; 1H NMR
(CDCl3, 500 MHz) δ = 7.87 (s, 1H), 7.78−7.76 (m, 1H), 7.60−7.56
(m, 1H), 7.38−7.33 (m, 2H), 4.08 (dd, J = 10.1, 2.6 Hz, 1H), 3.89−
3.83 (m, 4H), 3.65 (s, 3H), 3.05 (dd, J = 18.0, 7.7 Hz, 1H); 13C NMR
(CDCl3, 125 MHz) δ = 171.9 (0), 166.0 (0), 158.8 (0), 153.4 (0),
147.7 (0), 132.7 (1), 130.4 (1), 126.9 (0), 124.7 (1), 124.7 (1), 118.6
(0), 118.3 (0), 117.2 (1), 52.6 (3), 52.2 (3), 36.3 (1), 26.0 (2); EI-MS
m/z (%) 314 (M+, 8), 255 (100); HRMS (EI) calcd for C17H14O6:
314.0789; found: 314.0801.
11-Methylbenzo[b]-1,2,3,4,6,8a-hexahydroisoquinolinono[7,8-
d]-6H-pyran-6-one-carboxylic Acid Methyl Ester (76a) and 11-
Methylbenzo[b]-1,2,3,4,4a,8a-hexahydroisoquinolino[7,8-d]-6H-
pyran-6-one-carboxylic Acid Methyl Ester (76b). Using standard
procedure B (expensive ketone, 5 h, chromatography using 5%
MeOH/dichloromethane), 76a (0.63 g, 44%) and a mixture of 76a
and 76b (0.50 g, 36%, 27: 9) were obtained (combined yield =1.13 g,
80%, 71: 9) as white solids. Compound 76a: mp 122−123 °C, IR
1
(nujol) ν = 1713 (s), 1668 (m), 1607 (m) cm−1; H NMR (CDCl3,
500 MHz) δ = 7.71 (dd, J = 7.5, 1.3 Hz, 1H), 7.52−7.49 (m, 1H), 7.36
(d, J = 7.7 Hz, 1H), 7.33 (t, J = 7.7 Hz, 1H), 3.99 (m, 1H), 3.81 (s,
3H), 3.79−3.75 (m, 1H), 3.61−3.48 (m, 2H), 3.44−3.41 (m, 1H),
3.17−3.14 (m, 1H), 2.35 (s, 3H), 2.34−2.31 (m, 1H), 2.23−2.18 (m,
1H), 2.06 (t, J = 11.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ =
167.4 (0), 160.4 (0), 152.8 (0), 145.7 (0), 142.4 (0), 130.8 (1), 124.3
(1), 123.7 (1), 121.0 (0), 119.3 (0), 117.6 (0), 117.4 (1), 62.7 (2),
57.9 (2), 51.7 (3), 45.2 (3), 41.3 (1), 31.0 (2), 27.1 (2); EI-MS m/z
(%) 325 (M+, 52), 281 (100); HRMS (EI) calcd for C19H19O4N
325.1313; found: 325.1315.
Benzo[b]-6,8a-dihydroisochromano[7,8-d]-6H-pyran-6-one-car-
boxylic Acid Methyl Ester (78a) and Compound 79. Using standard
procedure B (expensive ketone, 24 h), 78a (0.43 g, 40%) was obtained
as a white solid, and 79 (0.65 g, 32%) was obtained as a white solid.
Benzo[b]isothiochromano[7,8-d]-6H-pyran-6-one-carboxylic
Acid Methyl Ester (88). To a magnetically stirred solution of 74a (200
mg, 0.61 mmol) in benzene (10 mL) was added DDQ (140 mg, 0.61
mmol) in one portion, and the resulting mixture was heated at reflux
for 48 h. The reaction was cooled to room temperature, and the
solvent was removed under reduced pressure. The residue was
subjected to flash chromatography on silica gel (5% ethyl acetate/
dichloromethane) to afford 88 (39 mg, 20%) as a white solid: mp
1
78a: mp 188−189.5 °C; IR (nujol) ν = 1712 (s), 1608 (m) cm−1, H
NMR (CDCl3, 500 MHz) δ = 7.72 (dd, J = 7.3, 1.3 Hz, 1H), 7.53−
7.50 (m, 1H), 7.36 (dd, J = 8.3, 1.3 Hz, 1H), 7.35−7.32 (m, 1H), 4.52
(dd, J = 10.8, 3.9 Hz, 1H), 4.27−4.24 (m, 1H), 3.98−3.95 (m, 1H),
3.84−3.81 (m, 1H), 3.81 (s, 3H), 3.64−3.48 (m, 3H), 3.34 (t, J = 10.2
Hz, 1H), 2.42−2.39 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ = 167.2
(0), 160.3 (0), 152.7 (0), 144.7 (0), 140.3 (0), 131.0 (1), 124.4 (1),
123.6 (1), 121.5 (0), 119.3 (0), 117.5 (0), 117.4 (1), 73.9 (2), 70.9
(2), 51.7 (3), 43.1 (1), 33.0 (2), 27.1 (2); EI-MS m/z (%) 312 (M+,
33), 253 (100); HRMS (EI) calcd for C18H16O5: 312.0997; found:
312.1006. 79: mp 286−287 °C; 1H NMR (CDCl3, 500 MHz) δ = 7.85
(s, 1H), 7.77 (d, J = 7.4 Hz, 1H), 7.71−7.67 (m, 1H), 7.46−7.67 (m,
2H), 4.51 (dd, J = 14.2, 3.8 Hz, 1H), 4.29 (t, J = 12.2 Hz, 1H), 4.01−
3.95 (m, 2H), 3.87 (s, 3H), 3.85−3.76 (m, 4H), 3.53−3.47 (m, 2H),
3.36 (t, J = 10.9 Hz, 1H), 3.29 (t, J = 11.9 Hz, 1H), 2.77−2.73 (m,
1H), 2.68 (d, J = 14.1 Hz, 1H), 2.48−2.23 (m, 5H), 2.02−1.84 (m,
4H); 13C NMR (CDCl3, 125.8 MHz) δ = 167.9 (0), 158.3 (0), 154.3
(0), 149.1 (0), 134.2 (1), 132.8 (0), 132.6 (1), 125.8 (1), 124.1 (1),
118.1 (1), 117.7 (0), 117.4 (0), 65.4 (2), 65.3 (2), 62.8 (1), 62.3 (2),
1
150−152 °C; IR (nujol) ν = 1721 (s), 1607 (m) cm−1; H NMR
(CDCl3, 500 MHz) δ = 8.85 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.55−
7.52 (m, 1H), 7.44 (dd, J = 8.2, 1.4, 1H), 7.37−7.34 (m, 1H), 4.26 (s,
2H), 3.97 (s, 3H), 3.60 (t, J = 6.2 Hz, 2H), 3.01 (t, J = 6.7 Hz, 2H);
13C NMR (CDCl3, 125 MHz) δ = 166.8 (0), 160.8 (0), 151.8 (0),
147.4 (0), 136.9 (0), 134.6 (0), 131.0 (1), 130.9 (1), 129.9 (0), 128.0
(1), 124.3 (1), 120.3 (0), 118.3 (1), 117.8 (0), 52.6 (3), 27.5 (2), 26.6
(2), 25.8 (2); EI-MS m/z (%) 326 (M+, 74), 311 (100); HRMS (EI)
calcd for C18H14SO2: 326.0613; found: 326.0620.
11-Methylbenzo[b]-1,2,3,4,6,8a-hexahydroisoquinolinono[7,8-
d]-6H-pyran-6-one-carboxylic Acid Methyl Ester (89). To a magneti-
cally stirred solution of 76a and 76b (220 mg, 0.68 mmol) in toluene
(25 mL) was added manganese dioxide (62.3 mg, 0.72 mmol) in one
9025
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Article
portion, and the resulting mixture was heated at reflux for 12 h. The
reaction mixture was cooled to room temperature and filtered through
a plug of Celite. The filtrate was concentrated under reduced pressure,
and the residue was subjected to flash chromatography on silica gel
(5% methanol/dichloromethane) to afford 89 (68.3 mg, 31%) as a
yellow solid: mp 165−168 °C, IR (nujol) ν = 1720 (s) cm−1; 1H NMR
(CDCl3, 500 MHz) δ = 8.89 (s, 1H), 8.02 (d, J = 8.3 Hz, 1H), 7.55−
7.52 (m, 1H), 7.43 (dd, J = 6.7, 1.2 Hz, 1H), 7.38−7.35 (m, 1H), 4.07
(s, 2H), 3.93 (s, 3H), 3.50 (t, J = 6.3 Hz, 2H), 2.81 (t, J = 6.4 Hz, 2H),
2.58 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ = 166.5 (0), 160.9 (0),
151.9 (0), 143.7 (0), 135.6 (0), 134.4 (0), 131.3 (1), 130.7 (1), 130.0
(0), 128.2 (1), 124.1 (1), 120.0 (0), 118.3 (1), 118.2 (0), 60.6 (2),
52.3 (3), 51.8 (2), 46.3 (3), 29.3 (2); EI-MS m/z (%) 323 (M+, 18),
293 (96), 222 (100); Anal. Calcd for C19H17NO4: C, 70.58; H, 5.30;
N, 4.33. Found: C, 70.39; H, 5.62; N, 4.38.
122.0 (0), 118.7 (0), 116.3 (1), 51.8 (3), 20.7 (3); EI-MS m/z (%)
244 (M+, 21), 185 (100); Anal. Calcd for C14H12O4: C, 68.85; H, 4.95.
Found: C, 68.67; H, 4.83.
Methyl (E)-3-(7-Methyl-2-oxo-2H-chromen-3-yl)acrylate (95). To
a magnetically stirred solution of 4-methylsalicylaldehyde (94)93 (1.29
g, 10.8 mmol) and dimethyl glutaconate (17) (1.51 mL, 10.8 mmol) in
benzene (16 mL) was added piperidine (0.53 mL, 5.4 mmol)
dropwise, and the resulting mixture was heated at reflux with
azeotropic removal of water for 1 h. The reaction was cooled to
room temperature, whereupon a white precipitate formed. Suction
filtration afforded 95 (1.86 g, 71%). The filtrate was concentrated
under reduced pressure. The residue was taken up in dichloromethane
(100 mL), washed with aqueous 1 M HCl solution, and washed with
water (50 mL). The organic layer was dried over MgSO4 and then
concentrated under reduced pressure. The residue was subjected to
flash chromatography on silica gel (4% ethyl acetate/dichloro-
methane) to afford a second batch of 95 (0.23 g, 9%) (total yield:
2.09 g, 80%): mp 222−223 °C; IR (nujol) ν = 1713 (s), 1616 (m)
cm−1; 1H NMR (CDCl3, 500 MHz) δ = 7.84 (s, 1H), 7.56 (d, J = 16.3
Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.16−7.12 (m, 2H), 7.08 (d, J =
15.7 Hz, 1H), 3.81 (s, 3H), 2.48 (s, 3H); 13C NMR (CDCl3, 125
MHz) δ = 167.5 (0), 159.3 (0), 153.7 (0), 144.6 (0), 143.6 (1), 138.3
(1), 128.2 (1), 126.1 (1), 122.6 (1), 121.1 (0), 116.8 (1), 116.6 (0),
51.8 (3), 22.0 (3); GC-MS m/z (%) 244 (M+, 20), 185 (100); HRMS
(EI) calcd for C14H12O4: 244.0735; Found: 244.0735.
Benzo[b]isochromano[7,8-d]-6H-pyran-6-one-carboxylic Acid
Methyl Ester (90). To a magnetically stirred solution of 78a (151
mg, 0.48 mmol) in benzene (50 mL) was added DDQ (109 mg, 0.48
mmol) in one portion, and the resulting mixture was heated at reflux
for 24 h. The reaction mixture was then cooled to room temperature,
diluted with benzene (25 mL), and gravity filtered to remove the light
brown precipitate. The filtrate was concentrated under reduced
pressure. The residue was subjected to flash chromatography on silica
gel (5% ethyl acetate/dichloromethane) to afford 90 (101 mg, 67%) as
a white solid: mp 216−217 °C, IR (nujol) ν = 1723 (s), 1705 (s),
1
1598 (m) cm−1; H NMR (CDCl3, 500 MHz) δ = 8.94 (s, 1H), 7.78
Methyl (E)-3-(8-Methyl-2-oxo-2H-chromen-3-yl)acrylate (97). To
a magnetically stirred solution of 3-methylsalicylaldehyde (96)93 (2.71
g, 19.8 mmol) and dimethyl glutaconate (17) (3.5 mL, 20 mmol) in
benzene (30 mL) was added piperidine (1.0 mL, 9.9 mmol) dropwise,
and the resulting mixture was heated at reflux with azeotropic removal
of water for 1 h. The reaction mixture was cooled to room
temperature, whereupon a white precipitate formed. Suction filtration
afforded 97 (0.54 g, 11%) as a white solid. The filtrate was
concentrated under reduced pressure. The residue was taken up in
dichloromethane (50 mL), washed with aqueous 1 M HCl solution,
and washed with water. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was subjected to
flash chromatography on silica gel (dichloromethane) to afford a
second batch of 97 (2.95 g, 61%) (total yield: 3.49 g, 72%): mp 131−
132 °C; IR (nujol) ν = 1725 (s), 1712 (s), 1600 (m) cm−1; 1H NMR
(CDCl3, 500 MHz) δ = 7.85 (s, 1H), 7.55 (d, J = 16.0 Hz, 1H), 7.41
(d, J = 6.9 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.9 Hz, 1H),
7.08 (d, J = 15.5 Hz, 1H), 3.81 (s, 3H), 2.44 (s, 3H); 13C NMR
(CDCl3, 125 MHz) δ = 167.2 (0), 159.0 (0), 151.8 (0), 143.9 (1),
138.1 (1), 134.1 (1), 126.2 (1), 126.0 (0), 124.3 (1), 122.8 (1), 121.7
(0), 118.5 (0), 51.7 (3), 15.2 (3); EI-MS m/z (%) 244 (M+, 16), 185
(100); Anal. Calcd for C14H12O4: C, 68.85; H, 4.95. Found: C, 68.39;
H, 4.91.
(d, J = 7.7 Hz, 1H), 7.57−7.53 (m, 1H), 7.44 (d, J = 7.9 Hz, 1H),
7.38−7.35 (m, 1H), 5.28 (s, 2H), 4.08 (t, J = 6.1 Hz, 2H), 3.95 (s,
3H), 3.47 (t, J = 6.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ = 166.2
(0), 160.7 (0), 151.9 (0), 142.8 (0), 135.1 (0), 134.8 (0), 131.6 (1),
131.0 (1), 129.9 (0), 128.0 (1), 124.4 (1), 120.1 (0), 118.4 (1), 117.9
(0), 70.0 (2), 64.5 (2), 52.3 (3), 28.3 (2); EI-MS m/z (%) 310 (M+,
84), 251 (100); Anal. Calcd for C18H14O5: C, 69.67; H, 4.55. Found:
C, 69.54; H, 4.75.
6H-Dibenzo[b,d]pyran-6-one-8,9-dicarboxylic Acid Dimethyl
Ester (91). To a magnetically stirred solution of 85 (60 mg, 0.19
mmol) in benzene (5.0 mL) was added DDQ (44 mg, 0.19 mmol) in
one portion, and the resulting mixture was heated at reflux for 48 h.
The reaction mixture was cooled to room temperature, filtered
through a plug of Celite, and concentrated under reduced pressure.
The residue was then subjected to flash chromatography on silica gel
(5% ethyl acetate/dichloromethane) to afford 91 (40 mg, 67%) as a
white solid: mp 151−152 °C; IR (nujol) ν = 1728 (s), 1714 (s), 1612
1
(m) cm−1; H NMR (CDCl3, 500 MHz) δ = 8.83 (s, 1H), 8.33 (s,
1H), 8.08 (d, J = 7.5 Hz, 1H), 7.59−7.55 (m, 1H), 7.40−7.37 (m,
2H), 4.00 (s, 3H), 3.97 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ =
167.5 (0), 165.7 (0), 159.6 (0), 151.9 (0), 138.6 (0), 137.4 (0), 132.2
(1), 132.1 (1), 130.4 (0), 125.0 (1), 123.4 (1), 122.4 (1), 122.3 (0),
118.0 (1), 116.6 (0), 53.2 (3), 52.9 (3); EI-MS m/z (%) 312 (M+, 80),
281 (100); Anal. Calcd for C17H12O6: C, 65.39; H, 3.87. Found: C,
65.13; H, 3.93.
Methyl (E)-3-(6-Methoxy-2-oxo-2H-chromen-3-yl)acrylate (99)
and Methyl (6-Methoxy-3-(methoxycarbonyl)-2H-chromen-2-yl)-
acetate (100). To a magnetically stirred solution of 5-methoxysali-
cylaldehyde (98)93 (4.00 g, 26.3 mmol) and dimethyl glutaconate (17)
(3.7 mL, 26 mmol) in benzene (75 mL) was added piperidine (1.3
mL, 13 mmol) dropwise, and the resulting mixture was heated at reflux
with azeotropic removal of water for 2 h. The reaction mixture was
cooled to room temperature, whereupon a yellow precipitate formed.
Suction filtration (filter cake was washed with cold benzene (2 × 40
mL)) afforded 99 (4.89 g, 71%) as a white solid. The filtrate was
concentrated under reduced pressure, and the residue was subjected to
flash chromatography on silica gel (5% ethyl acetate/dichloro-
methane) to afford 100 (1.32 g, 19%) as a yellow solid. 99: mp
Methyl (E)-3-(6-Methyl-2-oxo-2H-chromen-3-yl)acrylate (93). To
a magnetically stirred solution of 5-methylsalicylaldehyde (92)93 (5.40
g, 40.0 mmol) and dimethyl glutaconate (17) (5.58 mL, 40.0 mmol) in
benzene (50 mL) was added piperidine (1.96 mL, 20.0 mmol)
dropwise, and the resulting mixture was heated at reflux with
azeotropic removal of water for 1 h. The mixture was cooled to
room temperature, whereupon a white precipitate formed. Suction
filtration afforded 93 (6.78 g, 70%) as a white solid. The filtrate was
concentrated under reduced pressure, and the residue was taken up in
dichloromethane (100 mL), washed with aqueous 1 M HCl solution,
and washed with water. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The residue was recrystallized
from 95% ethanol to afford another batch of 93 (0.78 g, 8%) (total
yield: 7.56 g, 78%): mp 176−177 °C; IR (nujol) ν = 1723 (s), 1710
1
202−203 °C; IR (nujol) ν = 1729 (s), 1713 (s), 1634 (m) cm−1; H
NMR (CDCl3, 500 MHz) δ = 7.82 (s, 1H), 7.57 (d, J = 15.7 Hz, 1H),
7.28 (d, J = 8.8 Hz, 1H), 7.17−7.09 (m, 2H), 6.95 (d, J = 2.8 Hz, 1H),
3.87 (s, 3H), 3.82 (s, 3H); 13C NMR (CDCl3, 125.8 MHz) δ = 167.4
(0), 159.2 (0), 156.3 (0), 148.1 (0), 143.3 (1), 138.1 (1), 123.3 (1),
122.6 (0), 121.0 (1), 119.3 (0), 117.7 (1), 110.0 (1), 55.9 (3), 51.9
(3); EI-MS m/z (%) 260 (M+, 39), 201 (100); HRMS (EI) m/z calcd
for C14H12O5: 260.0684; found: 260.0709. 100: mp 66−67 °C; IR
(nujol) ν = 1745 (s), 1699 (s), 1640 (m) cm−1; 1H NMR (CDCl3, 500
1
(s), 1603 (m) cm−1; H NMR (CDCl3, 500 MHz) δ = 7.81 (s, 1H),
7.55 (d, J = 16.3 Hz, 1H), 7.38 (dd, J = 8.4, 1.9 Hz, 1H), 7.32 (s, 1H),
7.23 (d, J = 9.0 Hz, 1H), 7.09 (d, J = 15.7 Hz, 1H), 3.81 (s, 3H), 2.42
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ = 167.3 (0), 159.2 (0), 151.7
(0), 143.5 (1), 138.2 (1), 134.5 (0), 134.0 (1), 128.2 (1), 123.0 (1),
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MHz) δ = 7.46 (s, 1H), 6.84 (dd, J = 9.0, 3.0 Hz, 1H), 6.80 (d, J = 8.8
Hz, 1H), 6.70 (d, J = 3.1 Hz, 1H), 5.67 (dd, J = 10.5, 3.4 Hz, 1H), 3.82
(s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 2.78 (dd, J = 15.1, 9.9 Hz), 2.54
(dd, J = 14.9, 3.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ = 170.2
(0), 164.7 (0), 154.4 (0), 146.3 (0), 133.5 (1), 124.8 (0), 120.4 (0),
118.3 (1), 117.9 (1), 112.8 (1), 70.5 (1), 55.7 (3), 52.0 (3), 51.8 (3),
38.1 (2); EI-MS m/z (%) 292 (M+, 9), 219 (100); HRMS (EI) m/z
calcd for C15H16O6: 292.0946; found: 292.0975.
(3), 39.1 (2); GC-MS m/z (%) 320 (M+, 5), 247 (100). HRMS (EI)
calcd for C16H16O7: 320.0896; found: 320.0903.
Methyl (E)-3-(6-Nitro-2-oxo-2H-chromen-3-yl)acrylate (108)
methyl (3-(Methoxycarbonyl)-6-nitro-2H-chromen-2-yl)acetate
(109). To a magnetically stirred solution of 5-nitrosalicyladlehyde
(108)94,95 (2.85 g, 17.0 mmol) and dimethyl glutaconate (17) (2.40
mL, 17.0 mmol) in benzene (60 mL) was added piperidine (0.84 mL,
8.5 mmol) dropwise, and the resulting mixture was heated at reflux
with azeotropic removal of water for 30 min. During this time, a white
solid formed in the reaction mixture. The reaction mixture was cooled
to room temperature and suction filtered, and the filter cake was
washed with cold benzene (2 × 25 mL) to afford 108 (1.22 g, 26%) as
a white solid. The filtrate was concentrated under reduced pressure,
and then, the residue was subjected to flash chromatography on silica
gel (5% ethyl acetate/dichloromethane) to give 109 (3.83 g, 72%) as a
white solid. 108: mp 210−211 °C; IR (nujol) ν = 1768 (s), 1697 (s),
Methyl (E)-3-(6-Bromo-2-oxo-2H-chromen-3-yl)acrylate (102)
Methyl (6-Bromo-3-(methoxycarbonyl)-2H-chromen-2-yl)acetate
(103). To a magnetically stirred solution of 4-bromosalicylaldehyde
(101)93 (2.50 g, 12.4 mmol) and dimethyl glutaconate (17) (1.75 mL,
12.4 mmol) in benzene (20 mL) was added piperidine (0.61 mL, 6.2
mmol) dropwise, and the resulting mixture was heated at reflux with
azeotropic removal of water for 1 h. The reaction mixture was cooled
to room temperature, whereupon a white precipitate formed. Suction
filtration (filter cake washed with cold benzene (2 × 25 mL)) afforded
102 (2.12 g, 55%). The filtrate was concentrated under reduced
pressure, and the residue was subjected to flash chromatography on
silica gel (5% ethyl acetate/dichloromethane) to afford a second batch
of 102 (0.38 g, 10%) (total yield: 2.50 g, 65%) and 103 (1.32 g, 25%)
as a white solid. 102: mp 210−211 °C; IR (nujol) ν = 1740 (s), 1707
1
1611 (m), 1208 (m) cm−1; H NMR (CDCl3, 500 MHz) δ = 8.68−
8.67 (m, 2H), 8.47 (dd, J = 9.5, 3.1 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H),
7.54 (d, J = 15.9 Hz, 1H), 6.97 (d, J = 16.0 Hz, 1H), 3.76 (s, 3H); 13
C
NMR (CDCl3, 125 MHz) δ = 166.2 (0), 158.0 (0), 156.6 (0), 143.7
(0), 143.2 (1), 137.6 (1), 127.4 (1), 124.8 (1), 123.0 (0), 122.7 (1),
119.2 (0), 117.8 (1), 51.9 (3); EI-MS m/z (%) 275 (M+, 14), 216
(100); HRMS (EI) calcd for C13H9NO6: 275.0430; found: 275.0435.
109: mp 143−144 °C; IR (nujol) ν = 1729 (s), 1697 (s), 1612 (m)
cm−1; 1H NMR (CDCl3, 500 MHz) δ = 8.16 (dd, J = 9.0, 2.5 Hz, 1H),
8.09 (d, J = 2.5 Hz, 1H), 7.52 (s, 1H), 6.96 (d, J = 9.0 Hz, 1H), 5.85
(dd, J = 9.6, 3.2 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 2.80 (dd, J = 15.4,
10.0 Hz, 1H), 2.71 (dd, J = 15.4, 3.8 Hz, 1H); 13C NMR (CDCl3, 125
MHz) δ = 169.5 (0), 163.9 (0), 158.0 (0), 142.3 (0), 131.6 (1), 127.8
(1), 126.0 (0), 124.3 (1), 119.7 (0), 117.5 (1), 72.2 (1), 52.4 (3), 52.0
(3), 39.3 (2); EI-MS m/z (%) 307 (M+, 5), 247 (100); HRMS (EI)
calcd for C14H13NO7: 307.0691; found: 307.0677.
1
(s), 1630 (m) cm−1; H NMR (CDCl3, 500 MHz) δ = 7.78 (s, 1H),
7.68 (d, J = 1.4 Hz, 1H), 7.66 (dd, J = 8.7, 2.5 Hz, 1H), 7.55 (d, J =
15.9 Hz, 1H), 7.24 (d, J = 9.4 Hz, 1H), 7.12 (d, J = 15.8 Hz, 1H), 3.82
(s, 3H); 13C NMR (CDCl3, 125 MHz) δ = 167.1 (0), 158.3 (0), 152.3
(0), 141.9 (1), 137.5 (1), 135.5 (1), 130.6 (1), 124.2 (1), 123.5 (0),
120.4 (0), 118.4 (1), 117.4 (0), 51.9 (3); GC-MS m/z (%) 310
(M+ 81Br, 16), 308 (M+ 79Br, 16), 249 (100); HRMS (EI) calcd for
C13H9O479Br: 307.9683; found: 307.9671. 103: mp 77−79 °C; IR
(nujol) ν = 1727 (s), 1693 (s), 1632 (m) cm−1; 1H NMR (CDCl3, 500
MHz) δ = 7.40 (s, 1H), 7.34 (dd, J = 8.5, 2.3 Hz, 1H), 7.28 (d, J = 3.0
Hz, 1H), 6.76 (d, J = 8.9 Hz, 1H), 5.72 (dd, J = 9.7, 3.2 Hz, 1H), 3.83
(s, 3H), 3.71 (s, 3H), 2.77 (dd, J = 15.6, 9.6 Hz, 1H), 2.59 (dd, J =
15.5, 3.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ = 169.9 (0), 164.3
(0), 151.7 (0), 134.9 (1), 132.1 (1), 131.0 (1), 125.3 (0), 121.7 (0),
118.9 (1), 113.9 (0), 70.9 (1), 52.1 (3), 51.9 (3), 38.5 (2); EI-MS m/z
(%) 342 (M+ 81Br, 6), 340 (M+ 79Br, 6), 267 (100); HRMS (EI) calcd
for C14H13O579Br: 339.9945; found: 339.9916.
Methyl (E)-3-(6-(Methoxycarbonyl)-2-oxo-2H-chromen-3-yl)-
acrylate (105) and Methyl (3,6-bis(methoxycarbonyl)-2H-chro-
men-2-yl)acetate (106). To a magnetically stirred solution of methyl
3-formyl-hydroxybenzoate (104)94,95 (508 mg, 2.8 mmol) and
dimethyl glutaconate (17) (0.39 mL, 2.8 mmol) in benzene (10
mL) was added piperidine (0.14 mL, 1.4 mmol) dropwise, and the
resulting mixture was heated at reflux with azeotropic removal of water
for 2 h. The reaction mixture was cooled to room temperature,
whereupon a white precipitate formed. Suction filtration (filter cake
washed with cold benzene (2 × 10 mL)) afforded 105 (0.22 g, 28%)
as a white solid. The filtrate was concentrated under reduced pressure,
and the residue was subjected to flash chromatography on silica gel
(5% ethyl acetate/dichloromethane) to afford a second batch of 105
(0.31 g, 38%) (total yield: 0.53 g, 66%) and 106 (0.13 g, 15%) as a
white solid. 105: mp 233−234 °C; IR (nujol) ν = 1748 (s), 1720 (s)
cm−1; 1H NMR (CDCl3, 500 MHz) δ = 8.27 (d, J = 2.0 Hz, 1H), 8.23
(dd, J = 9.4, 2.0 Hz, 1H), 7.90 (s, 1H), 7.57 (d, J = 15.6 Hz, 1H), 7.40
(d, J = 9.3 Hz, 1H), 7.13 (d, J = 15.7 Hz, 1H), 3.97 (s, 3H), 3.83 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ = 167.1 (0), 165.4 (0), 158.3
(0), 156.2 (0), 142.9 (1), 137.5 (1), 133.6 (1), 130.5 (1), 127.0 (0),
124.1 (1), 123.2 (0), 118.7 (0), 116.9 (1), 52.6 (3), 52.0 (3); EI-MS
m/z (%) 288 (M+, 14), 229 (100); HRMS (EI) calcd for C15H12O6:
288.0633; found: 288.0616. 106: mp 126−127 °C; IR (nujol) ν =
1737 (s), 1692 (s), 1609 (s) cm−1; 1H NMR (CDCl3, 500 MHz) δ =
7.95 (dd, J = 8.3, 2.0 Hz, 1H), 7.91 (s, 1H), 7.87 (d, J = 2.0 Hz, 1H),
6.90 (d, J = 8.8 Hz, 1H), 5.79 (dd, = 9.6, 3.3 Hz, 1H), 3.90 (s, 3H),
3.84 (s, 3H), 3.71 (s, 3H), 2.79 (dd, J = 15.5, 9.6 Hz, 1H), 2.65 (dd, J
= 14.7, 3.7 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ = 169.9 (0),
166.1 (0), 164.4 (0), 156.6 (0), 133.9 (1), 132.8 (1), 130.6 (1), 124.6
(0), 124.0 (0), 119.5 (0), 117.1 (1), 71.5 (1), 52.2 (3), 52.1 (3), 51.9
2-Methylbenzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-pyran-6-
one-8-carboxylic Acid Methyl Ester (110). Using standard procedure
A (3 h), 110 (0.63 g, 47%) was obtained as a white solid: mp 258−260
1
°C; IR (nujol) ν = 1724 (s), 1715 (s), cm−1; H NMR (CDCl3, 500
MHz) δ = 8.94 (s, 1H), 7.99 (s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.27 (d,
J = 7.6 Hz, 1H), 3.95 (s, 3H), 3.49−3.43 (m, 4H), 2.47 (s, 3H), 2.28
(quint, J = 7.6 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ = 166.1 (0),
161.2 (0), 155.2 (0), 150.0 (0), 141.7 (0), 134.6 (0), 133.8 (0), 132.1
(1), 131.6 (1), 126.9 (1), 126.5 (0), 120.5 (0), 118.5 (0), 117.6 (1),
52.1 (3), 35.4 (2), 33.6 (2), 25.0 (2), 21.4 (3); EI-MS m/z (%) 308
(M+, 100); HRMS (EI) calcd. for C19H16O4: 308.1048; found:
308.1034. Using standard procedure B (2 h, scaled down by a factor of
2.1, chloroform used for chromatography), 110 (0.32 g, 50%) was
obtained as a white solid.
3-Methylbenzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-pyran-6-
one-8-carboxylic Acid Methyl Ester (111). Using standard procedure
A (3 h), 111 (0.68 g, 51%) was obtained as a white solid: mp 268−269
1
°C; IR (nujol) ν = 1720 (s), 1623 (m) cm−1; H NMR (CDCl3, 500
MHz) δ = 8.90 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.16−7.13 (m, 2H),
3.94 (s, 3H), 3.43 (t, J = 7.7 Hz, 4H), 2.45 (s, 3H), 2.27 (quint, J = 7.7
Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ = 166.1 (0), 161.2 (0),
155.1 (0), 151.9 (0), 141.7 (0), 141.3 (0), 134.6 (0), 132.0 (1), 126.6
(1), 126.2 (0), 125.4 (1), 120.0 (0), 118.0 (1), 116.2 (0), 52.0 (3),
35.2 (2), 33.6 (2), 24.9 (2), 21.3 (3); GC-MS m/z (%) 308 (M+,
100); HRMS (EI) m/z calcd for C19H16O4: 308.1048; found:
308.1064. Using standard procedure B (2 h, scaled down by a factor
of 4.3, chloroform used for chromatography), 111 (0.18 g, 57%) was
obtained as a white solid.
4-Methylbenzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-pyran-6-
one-8-carboxylic Acid Methyl Ester (112). Using standard procedure
A (3 h), 112 (0.65 g, 48%) was obtained as a white solid: mp 228−229
1
°C; IR (nujol) ν = 1718 (s), 1193 (m) cm−1; H NMR (CDCl3, 500
MHz) δ = 8.82 (s, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.6 Hz,
1H), 7.19 (t, J = 7.8 Hz, 1H), 3.93 (s, 3H), 3.39 (t, J = 7.6 Hz, 4H),
2.44 (s, 3H), 2.24 (quint, J = 7.7 Hz, 2H); 13C NMR (CDCl3, 125
MHz) δ = 165.9 (0), 160.8 (0), 155.0 (0), 150.0 (0), 141.7 (0), 134.7
(0), 132.1 (1), 131.8 (1), 126.9 (0), 126.3 (0), 124.5 (1), 123.6 (1),
120.1 (0), 118.3 (0), 52.0 (3), 35.4 (2), 33.5(2), 24.8 (2), 16.2 (3);
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The Journal of Organic Chemistry
Article
GC-MS m/z (%) 308 (M+, 100); HRMS (EI) calcd for C19H16O4:
308.1049; found: 308.1045. Using standard procedure B (2 h, scaled
down by a factor of 3.5, chloroform used for chromatography), 112
(0.20 g, 54%) was obtained as a white solid.
and the filter cake was washed with cold 95% ethanol (25 mL) to
afford 118 (1.55, 55%) as a white solid: mp 163−164.5 °C; IR (nujol)
ν = 1699 (s), 1609 (m) cm−1; 1H NMR (CDCl3, 500 MHz) δ = 7.74
(s, 1H), 7.57−7.52 (m, 2H), 7.35−7.29 (m, 2H), 6.44 (d, J = 1.2 Hz,
1H), 3.77 (s, 3H), 2.53 (d, J = 1.5 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ = 166.7 (0), 159.1 (0), 153.6 (0), 150.1 (0), 140.1 (1), 132.2
(1), 129.8 (0), 128.2 (1), 124.6 (1), 120.8 (1), 118.8 (0), 116.5 (1),
51.3 (3), 17.7 (3); GC-MS m/z (%) 244 (M+, 23), 185 (100); HRMS
(EI) calcd for C14H12O4: 244.0735; found: 244.0750.
2-Methoxybenzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-pyran-6-
one-8-carboxylic Acid Methyl Ester (113). Using standard procedure
A (3 h), 113 (0.72 g, 51%) was obtained as a light orange solid: mp
1
244−245 °C; IR (nujol) ν = 1719 (s), 1703 (s), 1600 (m) cm−1; H
NMR (CDCl3, 500 MHz) δ = 8.86 (s, 1H), 7.71 (d, J = 2.9 Hz, 1H),
7.34 (d, J = 9.0 Hz, 1H), 7.09 (dd, J = 9.0, 2.0 Hz, 1H), 3.95 (s, 3H),
3.90 (s, 3H), 3.51−3.44 (m, 4H), 2.29 (quint, J = 7.5 Hz, 2H); 13C
NMR (CDCl3, 125 MHz) δ = 166.1 (0), 161.2 (0), 155.9 (0), 155.2
(0), 146.2 (0), 141.7 (0), 134.4 (0), 132.2 (1), 126.8 (0), 120.6 (0),
119.3 (0), 118.6 (1), 116.8 (1), 111.3 (1), 55.8 (3), 52.1 (3), 35.2 (2),
33.6 (2), 25.0 (2); GC-MS m/z (%) 324 (M+, 100); HRMS (EI) calcd
for C19H16O5: 324.0997; found: 324.1024. Using standard procedure B
(3 h, scaled down by a factor of 2.3), 113 (0.40 g, 64%) was obtained
as a white solid.
7-Methylbenzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-pyran-6-
one-8-carboxylic Acid Methyl Ester (119). Using standard procedure
A (3 h, scaled by a factor of 2.0), 119 (0.45 g, 67%) was obtained as a
1
white solid: mp 174−175 °C; H NMR (CDCl3, 500 MHz) δ = 8.15
(d, J = 8.2 Hz, 1H), 7.48−7.45 (m, 1H), 7.34 (dd, J = 8.3, 1.3 Hz, 1H),
7.29 (t, J = 7.4 Hz, 1H), 3.97 (s, 3H), 3.47 (t, J = 7.1, 2H), 3.03 (t, J =
7.7 Hz, 2H), 2.81 (s, 3H), 2.22 (quint, J = 7.6 Hz, 2H); 13C NMR
(CDCl3, 125 MHz) δ = 169.3 (0), 160.3 (0), 151.5 (0), 149.8 (0),
140.1 (0), 138.0 (0), 134.3 (0), 132.8 (0), 130.1 (1), 126.7 (1), 123.8
(1), 119.3 (0), 119.2 (0), 117.2 (1), 52.4 (3), 36.1 (2), 32.3 (2), 25.1
(2), 20.7 (3); GC-MS m/z (%) 308 (M+, 100); HRMS (EI) calcd for
C19H16O4: 308.1048; found: 308.1039. Using standard procedure B (8
h, scaled down by a factor of 2.1) 119 (0.28 g, 44%) was obtained as a
white solid.
2-Bromobenzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-pyran-6-
one-8-carboxylic Acid Methyl Ester (114). Using standard procedure
A (3 h, scaled down by a factor of 2.0), 114 (0.41 g, 51%) was
obtained as a white solid: mp 262−263 °C; IR (nujol) ν = 1731 (s),
1
1716 (s) cm−1; H NMR (CDCl3, 500 MHz) δ = 8.95 (s, 1H), 8.33
9,9-Diethoxy-8,9,10,10a-tetrahydro-6H-dibenzo[b,d]pyran-6-
one-8-carboxylic Acid Methyl Ester (122), 9-Ethoxy-6H-dibenzo-
[b,d]pyran-6-one-8-carboxylic Acid Methyl Ester (123), and 9-
Ethoxy-10,10a-dihydro-6H-dibenzo[b,d]pyran-6-one-8-carboxylic
Acid Methyl Ester (124). To a solution of diene 13 (0.40 g, 1.74
mmol) in dichloromethane (8 mL) was added 1,1-diethoxyethene
(1.15 g, 9.91 mmol), and the resulting mixture was heated at reflux 20
h. The reaction mixture was cooled to room temperature, the solvent
was removed under reduced pressure, and the residue was subjected to
flash chromatography on silica gel (dichloromethane) to give 122
(0.43 g, 72%) as a pale yellow solid: mp 151−154 °C; IR (powder) ν
= 1738 (s), 1649 (w), 1201 (s) cm−1; 1H NMR (CD2Cl2, 500 MHz) δ
= 7.32−7.27 (m, 2H), 7.20−7.17 (m, 1H), 7.01−7.05 (m, 1H), 6.89
(dd, J = 5.3, 3.2 Hz, 1H), 3.89 (m, 1H), 3.80−3.78 (m, 1H), 3.67−
3.61 (m, 2H), 3.66 (s, 3H), 3.59−3.53 (m, 2H), 2.77 (ddd, J = 13.0,
5.7, 1.8 Hz, 1H), 2.34 (dd, J = 13.0, 11.1 Hz, 1H), 1.18 (t, J = 7.0 Hz,
3H), 1.17 (t, J = 7.0 Hz, 3H); 13C NMR (300 MHz, CD2Cl2) δ =
169.5, 163.0, 150.7, 136.3, 130.0, 128.6, 125.4, 125.0, 124.4, 117.3,
99.2, 56.6, 56.1, 52.7, 50.2, 33.2, 30.7, 15.4, 15.3; APCI-(−)-MS m/z
(%) 346 (M+, 5), 345 (40), 300 (15), 299 (100); HRMS (APCI-(+))
calcd for C19H23O6: 347.1495; found: 347.1497. Upon extending the
reaction time to 2 d, compounds 122 (0.36 g, 60%) 123 (0.078 g,
15%), and 124 (0.047 g, 9%) were obtained. 123: mp 218−220 °C; IR
(d, J = 1.5 Hz, 1H), 7.61 (dd, J = 8.6, 2.2 Hz, 1H), 7.29 (d, J = 8.6 Hz,
1H), 3.96 (s, 3H), 3.47 (t, J = 7.7 Hz, 4H), 2.31 (quint, J = 7.8 Hz,
2H); 13C NMR (CDCl3, 125 MHz) δ = 166.3 (0), 160.8 (0), 156.1
(0), 151.3 (0), 142.4 (0), 133.9 (1), 133.6 (0), 132.6 (1), 129.9 (1),
127.8 (0), 121.0 (0), 120.8 (0), 120.0 (1), 117.6 (0), 52.7 (3), 35.6
(2), 34.0 (2), 25.4 (2); EI-MS m/z (%) 374 (M+ 81Br, 97), 372
(M+ 79Br, 100); Anal. Calcd for C18H13O4Br: C, 57.53; H, 3.50. Found:
C, 57.93; H, 3.51; HRMS (EI) calcd for C18H13O4Br: 371.9996;
found: 371.9991. Using standard procedure B (2 h, scaled down by a
factor of 2), 114 (0.22 g, 35%) was obtained as a white solid.
Benzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-pyran-6-one-2,8-di-
carboxylic Acid Dimethyl Ester (115). Using standard procedure A (3
h), 115 (0.62 g, 41%) was obtained as a white solid: mp > 300 °C; IR
1
(nujol) ν = 1731 (s), 1706 (s), 1666 (s), 1586 (m) cm−1; H NMR
(CDCl3, 500 MHz) δ = 9.00−8.99 (m, 2H), 8.19 (dd, J = 8.2, 2.2 Hz,
1H), 7.46 (d, J = 7.9 Hz, 1H), 4.00 (s, 3H), 3.97 (s, 3H), 3.59 (t, J =
7.4 Hz, 2H), 3.49 (t, J = 7.9 Hz, 2H), 2.33 (quint, J = 7.3 Hz, 2H); 13
C
NMR (CDCl3, 125 MHz) δ = 166.1 (0), 166.0 (0), 160.4 (0), 155.8
(0), 154.9 (0), 142.2 (0), 133.7 (0), 132.2 (1), 131.7 (1), 129.1 (1),
127.3 (0), 126.4 (0), 120.3 (0), 118.8 (0), 118.1 (1), 52.5 (3), 52.2
(3), 35.2 (2), 33.7 (2), 25.0 (2); GC-MS m/z (%) 352 (M+, 100);
HRMS (EI) calcd for C20H16O6: 352.0947; found: 352.0946. Using
standard procedure B (2 h, scaled down by a factor of 3.1, chloroform
used for chromatography), 115 (0.17 g, 34%) was obtained as a white
solid.
2-Nitrobenzo[b]-2,3-dihydro-1H-indeno[5,4-d]-6H-pyran-6-one-
8-carboxylic Acid Methyl Ester (116). Using standard procedure A
(1.5 h), 116 (0.19 g, 24%) was obtained as a white solid: mp 272−273
°C; IR (nujol) ν = 1753 (s), 1729 (s), 1599 (m), 1529 (s), 1354 (s)
cm−1; 1H NMR (CDCl3, 500 MHz) δ = 9.22 (d, J = 2.8 Hz, 1H), 9.00
(s, 1H), 8.41 (dd, J = 8.9, 2.7 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 3.98
(s, 3H), 3.60 (t, J = 7.3 Hz), 3.52 (t, J = 8.2 Hz), 2.37 (quint, J = 7.7
Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ = 165.7 (0), 159.6 (0),
156.4 (0), 155.7 (0), 144.1 (0), 142.5 (0), 132.5 (0), 132.3 (1), 128.2
(0), 125.6 (1), 122.9 (1), 120.3 (0), 119.3 (0), 119.0 (1), 52.4 (3),
35.1 (2), 33.7 (2), 25.0 (2); EI-MS m/z (%) 339 (M+, 100); Anal.
Calcd for C18H13NO6: C, 63.72; H, 3.86; N, 4.13. Found: C, 63.37; H,
3.72; N, 4.05. Using standard procedure B (2 h, scaled down by a
factor of 4.8, 1:49 methanol/chloroform used for chromatography),
116 (0.070 g, 22%) was obtained as a pale yellow solid.
1
(powder) ν = 1711 (s), 1608 (m) cm−1; H NMR (CD2Cl2, 500
MHz) δ = 8.70 (s, 1H), 8.06 (dd, J = 7.9, 1.6 Hz, 1H), 7.57−7.54 (m,
2H), 7.39−7.33 (m, 2H), 4.34 (q, J = 7.0 Hz, 2H), 3.91 (s, 3H), 1.55
(t, J = 6.9 Hz, 3H); 13C NMR (500 MHz) δ 165.3, 163.3, 160.4, 152.6,
139.7, 135.1, 131.9, 124.9, 123.6, 122.6, 118.2, 117.8, 113.9, 104.7,
65.7, 52.5, 14.7; EI-MS m/z (%) 299 ([M + 1]+, 100), 267 (60);
HRMS (APCI-(+)) calcd for C17H15O5: 299.0919; found: 299.0917.
124: mp 177−180 °C; IR (powder) ν = 1703 (s), 1618 (m), 1520 (s)
1
cm−1; H NMR (CD2Cl2, 500 MHz) δ = 7.91 (d, J = 3.4 Hz, 1H),
7.32−7.26 (m, 2H), 7.18−7.15 (m, 1H), 7.07−7.05 (m, 1H), 4.41−
4.35 (m, 1H), 4.27−4.21 (m, 1H), 4.16 (ddd, J = 18.8, 7.6, 3.3 Hz,
1H), 3.75 (s, 3H), 3.35 (dd, J = 17.2, 7.6 Hz, 1H), 2.63 (dd, J = 18.8,
16.9 Hz, 1H), 1.44 (t, J = 7.0 Hz, 3H); 13C NMR (300 MHz, CD2Cl2)
δ = 171.4, 164.0, 161.3, 150.8, 141.1, 129.0, 125.9, 124.5, 121.8, 117.7,
111.8, 106.7, 63.3, 51.5, 32.2, 31.2, 15.1; EI-MS m/z (%) 301 ([M +
1]+, 100), 241 (55), 323, (50), 269 (40); HRMS (EI) calcd for
C17H16O5: 300.0998; found: 300.1006.
Methyl (E)-3-(2-Oxo-2H-chromen-3-yl)but-2-enoate (118). To a
magnetically stirred solution of salicylaldehyde 16 (1.24 mL, 11.6
mmol) and dimethyl 3-methylglutaconate (117) (1.83 mL, 11.6
mmol) in benzene (43 mL) was added piperidine (0.57 mL, 5.8
mmol) dropwise, and the resulting mixture was heated at reflux for 45
h. The mixture was cooled to room temperature, whereupon a white
precipitate formed. This precipitate was isolated by suction filtration,
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra for compounds 13, 19−22, 25,
38−42, 44, 46, 48, 50, 52a,b, 54, 56, 58, 61, 62, 64, 70, 72,
74a,b, 76a, 78a, 79, 81, 83, 85, 88−91, 93, 95, 97, 99, 100,
9028
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The Journal of Organic Chemistry
Article
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2867.
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Gottardis, M.; Jones, T. K. J. Med. Chem. 1998, 41, 303.
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102, 103, 105, 106, 108, 109, 110−116, 118, 119, and 122−
124. CIFs for compounds 52a, 52b, 79, and 122. Experimental
details for X-ray crystallography and views of compounds 52a,
52b, 79, and 122 in the crystal. Calculated torsion angles in
compounds 38, 44, 46, 48, 56, 61, 62, and 64. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: (+1) 709-864-8406. Fax: (+1) 709-864-3702. E-mail:
gbodwell@mun.ca
Present Address
§Department of Chemistry, Mount St. Vincent University,
Halifax, NS, Canada, B3M 2J6.
(32) Sashidhara, K. V.; Kumar, A.; Kumar, M.; Sonkar, R.; Bhatia, G.;
Khanna, A. K. Biorg. Med. Chem. Lett. 2010, 20, 4248.
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J.; Siddiqui, M. A.; Snieckus, V. J. Org. Chem. 1991, 56, 3763.
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Goor, D.; Roeters, T.; Bergweff, J.; Van der Eem, R.; Basten, J. Eur. J.
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6255.
ACKNOWLEDGMENTS
■
Financial support of this work from the Natural Sciences and
Engineering Research Council (NSERC) of Canada is
gratefully acknowledged.
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