Efficient nazarov cyclization/Wagner-Meerwein rearrangement terminated by a CuII-promoted oxidation: Synthesis of 4-alkylidene cyclopentenones

Article abstract of DOI:10.1002/chem.201203396

The discovery and elucidation of a new Nazarov cyclization/Wagner-Meerwein rearrangement/oxidation sequence is described that constitutes an efficient strategy for the synthesis of 4-alkylidene cyclopentenones. DFT computations and EPR experiments were conducted to gain further mechanistic insight into the reaction pathways. The ultimate sequence: A series of 1,4-dien-3-ones were subjected to copper(II) complexes (1 equiv) under an air atmosphere to provide access to 4-alkylidene cyclopentenones through an original Nazarov cyclization/Wagner-Meerwein rearrangement/oxidation/elimination sequence (see scheme). Copyright

Full text of DOI:10.1002/chem.201203396

DOI: 10.1002/chem.201203396
Efficient Nazarov Cyclization/Wagner–Meerwein Rearrangement
Terminated by a CuII-Promoted Oxidation: Synthesis of 4-Alkylidene
Cyclopentenones
David Lebœuf,[a] Eric Theiste,[a] Vincent Gandon,[b] Stephanie L. Daifuku,[a]
Michael L. Neidig,[a] and Alison J. Frontier*[a]
Abstract: The discovery and elucidation of a new Nazarov cyclization/Wagner–
Keywords: copper
· cyclization ·
Meerwein rearrangement/oxidation sequence is described that constitutes an effi-
cient strategy for the synthesis of 4-alkylidene cyclopentenones. DFT computations
and EPR experiments were conducted to gain further mechanistic insight into the
reaction pathways.
density functional calculations · ho-
mogeneous catalysis · oxidation ·
rearrangement
Introduction
Functionalized cyclopentenone derivatives are useful build-
ing blocks for the preparation of biologically active mole-
cules. The Nazarov cyclization and its variations are becom-
ing a highly versatile set of strategies for the efficient, ster-
eoselective synthesis of these compounds.[1] Specifically, the
recent development of several methods involving capture of
the oxyallyl cation intermediate by either a nucleophile[2] or
through Wagner–Meerwein rearrangement[3,4] has broad-
ened the array of cyclopentenone compounds that can be
prepared by using the Nazarov cyclization.
Scheme 1. Copper(II)-mediated cyclization of 1,4-dien-3-one 1.
In recent studies, we have synthesized 2,4,5-trisubstituted
cyclopentenones with adjacent quaternary carbon centers in
high chemo- and stereospecificity by using the Nazarov cyc-
lization/Wagner–Meerwein rearrangement.[3c–d] For example,
cyclopentenone 2 was obtained in 80% yield from 1 after
4p-electrocyclization followed by two consecutive [1,2]-
phenyl shifts (Scheme 1). The cyclization of mixtures of E
and Z isomers of alkylidene b-ketoesters is stereoconver-
gent: E/Z isomerization occurs readily, and only the Z
isomer cyclizes.[5] We demonstrated that the chemoselectivi-
ty of the [1,2]-suprafacial migration was dependent upon not
only migratory aptitude, but also on the steric profile of
both the migrating group of the substrate and the promo-
ter.[3b–d] Furthermore, we found that migratory aptitudes
could be assessed with a high level of accuracy using DFT
calculations.[3d]
Herein, we report the discovery and elucidation of a one-
pot Nazarov cyclization/Wagner–Meerwein rearrangement/
oxidation sequence that provides access to 4-alkylidene
cyclopentenones.
Results and Discussion
We have shown that Nazarov cyclization substrates bearing
electron-donating groups (EDG) at C5 (e.g., 1 in Scheme 1)
undergo cyclization/rearrangement sequences with high effi-
ciency and selectivity. However, Nazarov cyclization of sub-
strates bearing electron-withdrawing groups (EWG) at C5
have never proceeded as smoothly as their electron-rich
counterparts.[5] Therefore, extending the cyclization/rear-
rangement sequence to a substrate like 6 (C5=4-nitrophen-
yl; see Scheme 2) was expected to be a challenge. An assess-
ment of the cyclization/rearrangement reaction pathways
available to substrate 6 was conducted using DFT calcula-
tions, with Cu2+ as promoter.[6–8] In our previous experimen-
tal and computational work on related cyclizations, we
[a] Dr. D. Lebœuf, E. Theiste, S. L. Daifuku, Prof. M. L. Neidig,
Prof. A. J. Frontier
Department of Chemistry, University of Rochester
Rochester, NY 14627 (USA)
E-mail: frontier@chem.rochester.edu
[b] Prof. V. Gandon
Universitꢀ Paris-Sud, UMR CNRS 8182
Orsay, 91405 (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203396.
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Chem. Eur. J. 2013, 19, 4842 – 4848

FULL PAPER
than a methyl group, the rearrangement of a4 to a6 is ex-
pected. From a6, the PNP shift to a7 was found to require a
higher free energy of activation than the H-shift to a8.
Overall, a8 should be favored both kinetically and thermo-
dynamically. Dissociation of Cu2+ from this intermediate
should then lead to 7. This projected outcome is interesting
when compared with the experimental result in Scheme 1.
However, when the cyclization/rearrangement of 6 was
performed, an unexpected result was obtained. By subject-
ing 6 to the usual reaction conditions (one equivalent of
[(MeCN)5CuACHTUNTRGNEUNG(SbF6)2] in dichloromethane heated at reflux in
ꢀ
an open vessel), a complete inversion of the C1 C2 bond
was observed, but no cyclization occurred. When compound
6’ was subjected to the same promoter, in 1,2-dichloroethane
instead of dichloromethane, cyclization provided 4-methyli-
dene cyclopentenone 8 (87%). This reaction behavior was
ꢀ
consistent with the DFT calculations, in that the C1 C2
bond isomerized and the 4-nitrophenyl group did not mi-
grate, but compound 6 also exhibits new reactivity leading
to a different type of product (8 rather than 7), through
some kind of oxidative process [Eq. (1)].
When we conducted further studies to test whether the
oxidation pathway could be generalized, we found that
cyclopentenones with exocyclic double bonds could be ob-
tained in good yields from several other substrates with
electron-withdrawing aromatic substituents (62–92% yield;
ꢀ
Table 1). The isomerization of the C1 C2 olefin of 9 was
also observed by H NMR spectroscopy during its conver-
1
Scheme 2. Computed intermediates for the Cu2+-mediated cyclization of
1,4-dien-3-one 6 (UB3LYP/6-31G**//PCM correction, kcalmolꢀ1). PNP=
4-nitrophenyl.
sion to 10 (Table 1, entry 1). Interestingly, substrates 13 and
15 were transformed into products 14 and 16 exclusively
(Table 1, entries 3 and 4). The stereochemistry of compound
14 was assigned by NOE analysis. The result obtained with
substrate 17 was initially surprising (Table 1, Entry 5). We
did not observe a second [1,2]-phenyl shift, as might be ex-
pected based on the result shown in Scheme 1. The result
may be understood by comparing intermediates 4 and 4’
(Scheme 3). The C5 to C1 phenyl shift is probably hindered
by the C2 phenyl in 4’, whereas in 4, the C2 phenyl is not in
a position to impede the second [1,2]-phenyl shift. Lastly,
when substrate 19 was heated at reflux with one equivalent
found that the barrier heights corresponding to the diaster-
ꢀ
eomutation of the C1 C2 double bond ranged from 12 to
25 kcalmolꢀ1, and we found that substrates with stronger
electron-donating groups at C5 isomerized more slowly.[3d]
ꢀ
This trend was attributed to an increase in the C1 C2 bond
order as a function of the greater electron-releasing ability
of the substituent at C5. If this hypothesis is correct, the bar-
ꢀ
rier for diastereomutation at C1 C2 should decrease if C5=
4-nitrophenyl. This supposition is corroborated by DFT
computations, which predict a free energy of activation of
8.3 kcalmolꢀ1 for the formation of a2 from a1 (Scheme 2).
Then, complex a2 is expected to isomerize into the Naza-
rov-ready conformer a3 though the low-lying transition
state TSa2ꢀa3. As in our previous studies, the barrier for 4p-
electrocyclization leading to a4 should be about 19 kcal
molꢀ1, and the cyclization should be endergonic. Not surpris-
ingly, since the phenyl group has a higher migratory aptitude
of [tBuBox-Cu
product cyclopentenone 20 was obtained (Table 1, entry 6).
In this case, the use of [(MeCN)5Cu(SbF6)2] as promoter led
ACHTUNGTRNE(NUNG SbF6)2] in an open vessel, the oxidation
AHCTUNGTRENNUNG
to the exclusive formation of the classical Nazarov cycload-
duct.
Unfortunately, subjection of substrate 21 (bearing an iso-
propyl group at C1) led to a complex mixture with no trace
of 22 detected [Eq. (2)]. It is possible that the steric bulk of
the isopropyl group prevents oxidation, or that the increased
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A. J. Frontier et al.
Table 1. CuII-promoted Nazarov cyclization/Wagner–Meerwein rear-
rangement/oxidation sequence.
Entry Substrate
T
t
Product
Yield
[%]
[8C] [h]
1
85
85
85
4
2
3
69[a]
92[a]
79[a]
2
3
Scheme 3.
[Eq. (3)]. Elevated reaction temperatures were required for
this reaction. For example, in dichloromethane heated at
reflux, the formation of compound 24 was not observed and
compound 25 was obtained as the major product
[Eq. (4)].
4
5
6
85
85
85
2
4
4
80[a]
85[a]
62[b]
[a] Reaction conditions: substrate in (CH2Cl)2 (0.03m) in the presence of
one equivalent of [(MeCN)5Cu(SbF6)2] at the indicated temperature in
an open vessel. [b] Reaction conditions: substrate in (CH2Cl)2 (0.03m) in
the presence of one equivalent of [tBuBox-Cu(SbF6)2] at the indicated
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
temperature in an open vessel. PNP=4-nitrophenyl.
The cyclization of compound 26, initially expected to pro-
duce a spirocyclic product,[3a–b] also terminated with an oxi-
dation. Ring contraction is probably blocked by the large
gem-dimethyl group. Cyclization/oxidation was complete in
8 h, providing 27 in 95% yield (Scheme 4). The structure of
27 was confirmed by X-ray crystallography (Figure 1). When
the reaction was run under rigorously anaerobic conditions,
and an aliquot was removed and quenched after a reaction
time of 18 h, compound 28 was the only product detected.[9]
However, when dry O2 (g) was added to this reaction mix-
ture, formation of the oxidized product 27 was observed.
This result indicates that oxygen is essential for the conver-
sion of 26 to 27, and is responsible for the oxidation of a re-
active intermediate. The putative intermediate structure is
branching allows alternative rearrangement pathways to
compete with the oxidation.
Further experimentation revealed that this reaction path-
way is not limited to acyclic substrates bearing an electron-
withdrawing group at C5. For example, substrate 23 also fur-
nished the corresponding oxidized product 24 in good yield
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Synthesis of 4-Alkylidene Cyclopentenones
FULL PAPER
one substrates undergo the
usual 4p-electrocyclization fol-
lowed by [1,2]-alkyl or -aryl
shift to produce cationic inter-
mediate 30. Then, loss of the
acidic C5 proton occurs to give
the extended enol 31, which
suffers oxidation by copper(II)
to give an enol cation radical.[10]
Interception of the radical by
dioxygen produces the unstable
hydroperoxide 32,[11] which is
Scheme 4. Cyclization/rearrangement of 26 under aerobic and anaerobic conditions.
readily reduced to the alcohol 33 through a Fenton-type
fragmentation.[12] Finally, the acid-promoted dehydration
generates the 4-alkylidene cyclopentenones; see [Eq. (6)].
To further investigate this proposed mechanism, we con-
ducted electron paramagnetic resonance (EPR) studies. The
anaerobic reaction of 26 with the active copper catalyst was
performed to determine whether reduction of CuII (d9, S=
1
= , EPR active) to CuI (d10, S=0, EPR silent) occurred
Figure 1. ORTEP drawing of 27.
2
shown in Scheme 4 (see below for a detailed discussion of
the mechanism).
We have been able to gain some insight into the mecha-
nism of the reaction through further experimentation with
substrates 19 and 26. Interestingly, if the reaction of sub-
strate 19 is stopped after 2 h [Eq. (5)], two products are iso-
lated: 4-methylidenecyclopentenone 20 (36%), and g-hy-
droxycyclopentenone 29 (22%).
We found that dehydration of 29 can be triggered by a
catalytic amount of HSbF6 (10 mol%), with quantitative
production of 20 after 30 min [Eq. (6)]. This suggests that
tertiary alcohol intermediates undergo efficient dehydration
to the product 4-alkylidene cyclopentenones upon exposure
to adventitious Brønsted acid in the reaction mixture.
A mechanistic hypothesis that accounts for the oxidation
of the various substrates is presented in Scheme 5. The dien-
Scheme 5. Cyclization/rearrangement/oxidation sequence.
during the reaction.[13] Addition
of one equivalent of substrate
to [(MeCN)5CuACHTNUGRTNEUNG(SbF6)2] in di-
chloromethane (t=0 h sample)
led to the immediate formation
of an axial CuII site with gll =
2.365, g ? =2.076 (All =144ꢂ
10ꢀ4 cmꢀ1, A ? =0 cmꢀ1).
A
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A. J. Frontier et al.
small (ꢁ1.5%) additional isotropic g=2.003 CuII signal is
also present, possibly indicating a copper species that is not
complexed with the substrate. Importantly, the reduction of
the CuII can be quantified using the integrated area of the
CuII EPR signal, which directly corresponds to the amount
of CuII in solution. Taking the initial t=0 h reaction point as
purely CuII, the amount of CuII remaining as a function of
reaction time is found to be 36% of the initial t=0 h
amount after 24 h (see the Supporting Information, Fig-
ure S2) and 5% after 2 days (Figure 2). No additional reduc-
tion in signal occurred between 48 and 72 h of reaction time,
indicating that the reaction has effectively reached comple-
tion. Thus, the EPR results are consistent with a mechanistic
hypothesis involving the reduction of CuII to CuI. Lastly, the
exposure of the reduced sample to air leads to partial re-oxi-
dation of the CuI to CuII (see the Supporting Information,
Figure S3). No substrate radical could clearly be identified
in these measurements, possibly because the spectrum is
complicated by the broad copper signals in the g=2 region.
It is also possible that the radical is rapidly consumed in a
side reaction process that occurs in the absence of oxygen.
may facilitate enol formation ([Eq. (3)] vs. [Eq. (4)]). In
ꢀ
compound 26, the projected C5 C1 hydride shift would gen-
erate
a
highly strained [5,6]-trans fused-ring system
(Scheme 6). In this case, it is plausible that elimination of
the C5 proton is more favorable than a hydride shift, which
would produce enol 35 and subsequently, oxidation to give
27.
Scheme 6. Rationale for the unexpected oxidation of compound 26.
Conclusion
We have reported an efficient protocol for the synthesis of
4-alkylidene cyclopentenones by using a copper(II) complex
as promoter. The substrate isomerization, cyclization, and
chemoselectivity of the subsequent migration were accurate-
ly anticipated by using DFT. The mechanistic hypothesis
proposed for the final oxidation is consistent with EPR
data. Further experimentation focused on understanding
and characterizing the unique reactivity of the copper(II)
complex is ongoing.
Figure 2. Electron paramagnetic resonance spectra of the reaction of 26
with copper(II) at different reaction time intervals: t=0 h and t=48 h.
In previous work with related substrates,[3] we found that
stereochemical outcomes were consistent with a suprafacial
[1,2]-hydride shift (from C5 to C1). In these studies, the
mechanism presented in Scheme 3 is proposed instead, to
account for the facile oxidation. In contrast to our earlier
studies, cation 30 (Ar=EWG) will possess a more acidic C5
proton, and the C5 to C1 hydride shift would produce a less
stable C5 cation. Thus, proton elimination might be expect-
ed to compete with [1,2]-hydride shift for these substrates.
Experimental Section
General procedure for the cyclization: The copper complex [L-Cu-
AHCTUNTGREG(NUNN SbF6)2] (1 equiv) was added to a stirred solution of a-alkylidene b-keto
esters in CH2Cl2 or (CH2Cl)2 (0.03m) under air. The reaction mixture was
stirred at room temperature or heated at reflux until completion of the
reaction and then quenched with aqueous NH4OH and extracted with di-
ethyl ether. The combined organic layers were washed with brine, dried
over magnesium sulfate, and filtered. After removal of the solvents
under reduced pressure, the crude product was purified by flash column
chromatography by using different gradients of pentane and ethyl acetate
to obtain the pure desired products.
Compound 8: Yellow oil. 1H NMR (400 MHz, CDCl3): d=8.37 (d, J=
8.4 Hz, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.38–7.26 (m, 5H), 5.57 (s, 1H),
5.47 (s, 1H), 3.71 (s, 3H), 1.74 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=201.0, 167.9, 154.1, 148.6, 140.0, 138.4, 131.4, 129.3, 128.8, 127.5, 126.4,
123.6, 119.5, 54.9, 52.4, 22.9; IR (neat): n˜ =2947, 1713, 1574, 1520, 1493,
ꢀ
However, we cannot rule out C5 C1 hydride shift, with sub-
sequent formation of enol species 31.
Since oxidation and/or epimerization at C1 has not been
observed during our earlier Nazarov cyclization/Wagner–
Meerwein rearrangement studies,[3] the outcome of the cycli-
zation rearrangement of substrates 23 and 26 (which contain
electron-rich aryl groups) was surprising. We suggest that
the formation of enols of type 31 is especially favorable in
these systems, and that these enol species are highly suscep-
tible to oxidation. For substrate 23, elevated temperatures
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Synthesis of 4-Alkylidene Cyclopentenones
FULL PAPER
1435, 1346, 1261, 1204 cmꢀ1; HRMS (EI+): m/z calcd for C21H18NO5:
364.1185 [M+H+]; found: 364.1189.
3H), 1.27 (s, 3H), 1.26–1.20 (m, 1H), 0.78 ppm (s, 3H). 13C NMR
(100 MHz, CDCl3): d=205.5, 167.6, 164.1, 162.5, 158.1, 158.0, 144.4,
128.6, 126.5, 103.9, 91.1, 90.8, 56.0, 55.8, 55.4, 52.1, 51.4, 34.2, 32.8, 24.7,
24.1, 22.1, 22.0 ppm; IR (neat): n˜ =2943, 2875, 2841, 1736, 1701, 1609,
1586, 1458, 1515, 1366, 1335, 1227, 1204, 1127 cmꢀ1; HRMS (EI+): m/z
calcd for C23H28O6: 400.1886 [M+H+]; found: 400.1892.
Compound 10: Yellow oil. 1H NMR (400 MHz, CDCl3): d=7.63 (d, J=
8.4 Hz, 2H), 7.37–7.26 (m, 7H), 5.56 (s, 1H), 5.52 (s, 1H), 3.72 (s, 3H),
1.71 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): d=201.5, 168.5, 163.5,
154.2, 140.4, 131.7, 130.9, 130.5, 129.9, 128.7, 127.3, 126.5, 124.5, 119.0,
54.8, 52.3, 22.8 ppm; IR (neat): n˜ =2928, 1734, 1721, 1601, 1489, 1435,
Compound 29: Yellow oil. 1H NMR (400 MHz, CDCl3): d=8.10 (d, J=
8.1 Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 3.95 (s, 3H), 3.67 (s, 3H), 1.79 (s,
1H), 1.34 (s, 3H), 1.26 (s, 3H), 1.19 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=204.6, 174.1, 166.4, 163.6, 136.8, 131.2 (2 C), 129.4, 128.1,
81.4, 53.3, 52.4, 52.3, 24.3. 21.8, 20.6 ppm; IR (neat): n˜ =3476, 2951, 2932,
1362, 1269, 1231, 1207, 1010 cmꢀ1
; HRMS (EI+): m/z calcd for
C21H18O3Br: 397.0439 [M+H+]; found: 397.0438.
Compound 12: Pale yellow oil. 1H NMR (400 MHz, CDCl3): d=8.16 (d,
J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.40–7.28 (m, 5H), 5.53 (s, 2H),
3.96 (s, 3H), 3.68 (s, 3H), 1.73 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=201.4, 168.9, 166.4, 163.3, 154.2, 140.3, 136.3, 131.4, 131.1, 129.6, 128.7,
128.3, 127.3, 126.5, 119.2, 54.8, 52.4, 52.2, 22.8 ppm; IR (neat): n˜ =2951,
1720, 1589, 1435, 1362, 1277, 1230, 1107 cmꢀ1; HRMS (EI+): m/z calcd
for C23H20O5: 376.1311 [M+H+]; found: 376.1317.
1721, 1636, 1605, 1435, 1335, 1277, 1231, 1161, 1107, 1014, 995 cmꢀ1
;
HRMS (EI+): m/z calcd for C18H20O6: 332.1560 [M+H+]; found:
332.1550.
Compound 14: Yellow oil. 1H NMR (400 MHz, CDCl3): d=8.36 (d, J=
8.8 Hz, 2H), 7.55 (d, J=8.7 Hz, 2H), 7.37–7.25 (m, 5H), 5.89 (q, J=
7.5 Hz, 1H), 3.66 (s, 3H), 1.80 (s, 3H), 1.61 ppm (d, J=7.5 Hz, 3H).
13C NMR (100 MHz, CDCl3): d=201.5, 171.3, 163.1, 148.3, 147.4, 139.5,
138.9, 134.9, 129.1, 128.8, 128.5, 127.3, 126.2, 123.5, 54.2, 52.2, 21.3,
15.9 ppm; IR (neat): n˜ =2947, 1735, 1713, 1574, 1520, 1493, 1435, 1346,
1261, 1204, 1177 cmꢀ1; HRMS (EI+): m/z calcd for C22H20NO5: 378.1341
[M+H+]; found: 378.1345.
Compound 16: Yellow oil. 1H NMR (400 MHz, CDCl3): d=7.76 (d, J=
8.0 Hz, 2H), 7.49 (d, J=7.8 Hz, 2H), 7.37–7.31 (m, 5H), 5.92 (q, J=
7.5 Hz, 1H), 3.66 (s, 3H), 1.80 (s, 3H), 1.60 ppm (d, J=7.5 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=201.8, 171.9, 163.3, 147.5, 139.2, 136.4,
134.5, 128.8, 128.5, 127.2, 126.3, 125.2, 54.1, 52.1, 21.3, 15.8 ppm; IR
(neat): n˜ =2958, 2924, 1705, 1589, 1570, 1435, 1319, 1261, 1203, 1165,
1122, 1065 cmꢀ1; HRMS (EI+): m/z calcd for C23H19F3O3: 400.1286 [M+
H+]; found: 400.1290.
Acknowledgements
We thank the National Science Foundation (Grant CHE-0847851, sup-
porting D. L.) and the NIGMS (R01 GM079364, supporting E. T.) for
funding this work. We used the computing facility of the CRIHAN (proj-
ect 2006–013). We are grateful to Dr. W. Brennessel (University of Ro-
chester) for solving structures by X-Ray crystallography. We thank Prof.
J. P Dinnocenzo (University of Rochester) for helpful discussions.
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1
Compound 18: Yellow oil. H NMR (400 MHz, CDCl3): d=7.50–7.26 (m,
10H), 5.61 (s, 1H), 5.51 (s, 1H), 3.69 (s, 3H), 1.72 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=201.7, 169.6, 163.7, 154.4, 140.6, 131.7, 130.9,
130.0, 128.6, 128.4, 128.3, 127.2, 126.5, 119.0, 54.7, 52.1, 22.8 ppm; IR
(neat): n˜ =3059, 2974, 1736, 1713, 1605, 1574, 1492, 1435, 1362, 1273,
1230, 1203, 1176 cmꢀ1; HRMS (EI+): m/z calcd for C21H19O3: 319.1334
[M+H+]; found: 319.1335.
Compound 20: Pale yellow oil. 1H NMR (400 MHz, CDCl3): d=8.13 (d,
J=8.0 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 5.54 (s, 1H), 5.34 (s, 1H), 3.95
(s, 3H), 3.69 (s, 3H), 1.30 ppm (s, 6H). 13C NMR (100 MHz, CDCl3): d=
204.2, 167.4, 166.4, 154.8, 136.5, 131.2, 131.0, 129.5, 128.3, 116.2, 52.4,
52.2, 46.7, 23.9 ppm, one carbon missed due to overlapping; IR (neat):
n˜ =2955, 2928, 1717, 1620, 1589, 1435, 1408, 1362, 1277, 1234, 1192, 1150,
1107, 1007 cmꢀ1; HRMS (EI+): m/z calcd for C18H18O5: 314.1154 [M+
H+]; found: 314.1447.
Compound 24: Yellow oil. 1H NMR (400 MHz, CDCl3): d=7.42 (dt, J=
8.3, 1.7 Hz, 1H), 7.20 (dd, J=7.5, 1.7 Hz, 1H), 7.04 (t, J=7.5 Hz, 1H),
6.96 (d, J=8.4 Hz), 5.47 (s, 1H), 5.36 (s, 1H), 3.75 (s, 3H), 3.69 (s, 3H),
1.28 ppm (s, 6H); 13C NMR (100 MHz, CDCl3): d=204.7, 166.1, 164.0,
156.3, 155.0, 131.0, 130.7, 129.5, 121.1, 120.1, 115.1, 110.9, 55.3, 51.7, 46.4,
23.9 ppm; IR (neat): n˜ =2947, 2928, 1720, 1615, 1573, 1440, 1356, 1280,
1230, 1203, 1126 cmꢀ1; HRMS (ES+): m/z calcd for C17H19O4: 287.1283
[M+H+]; found: 287.1289.
Compound 25: Yellow oil. 1H NMR (400 MHz, CDCl3): d=7.39 (ddd,
J=8.4, 7.5, 1.7 Hz, 1H), 7.19 (dd, J=7.6, 1.7 Hz, 1H), 7.01 (dt, J=7.5,
1.0 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 3H), 3.19 (q,
J=7.4 Hz, 1H), 1.24 (s, 3H), 1.10 (s, 3H), 0.96 ppm (d, J=7.4 Hz, 3H).
13C NMR (100 MHz, CDCl3): d=208.0, 177.4, 164.4, 156.3, 131.2, 131.0,
128.4, 123.4, 120.5, 111.0, 55.3, 51.7, 48.8, 47.7, 25.9, 20.6, 14.1 ppm; IR
(neat): n˜ =2947, 2924, 1740, 1697, 1612, 1510, 1462, 1346, 1288, 1258,
1230, 1203, 1126, 1022, 995 cmꢀ1; HRMS (EI+): m/z calcd for C17H20O4:
288.1368 [M+H+]; found: 288.1361.
Compound 27: Yellow wax. 1H NMR (400 MHz, CDCl3): d=6.16 (s,
1H), 6.15 (s, 1H), 5.70 (t, J=3.8 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 3H), 3.67
(s, 6H), 2.29–2.25 (m, 1H), 2.20–2.15 (m, 1H), 1.86–1.80 (m, 1H), 1.30 (s,
Chem. Eur. J. 2013, 19, 4842 – 4848
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4847

A. J. Frontier et al.
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[9] The stereochemistry of the ring fusion was not determined, but we
tentatively assume that 28 has a cis ring-fusion, which is significantly
less strained than the alternative trans-fusion.
[7] The geometry optimizations and thermodynamic corrections were
performed with hybrid density functional theory (UB3LYP, doublet
spin state for Cu, +2 overall charge) with the 6-31G
G
[10] M. Schmittel, Top. Curr. Chem. 1994, 169, 183.
The choice of this functional and basis set is justified in the Compu-
tational Methods section of reference [9a] (see references therein).
The B3LYP functional was also used in reference [9b]. The spin
contamination was checked from the final value of <S > for all
structures and found to be very small (<0.76). Solvation corrections
for dichloromethane were computed by using the polarizable contin-
uum model (PCM) with UFF radii using the gas phase optimized
structures. All relative energies presented in this manuscript are free
[11] Such an intermediate has already been observed with a similar com-
pound, through oxidation with oxygen. See reference [2a].
[12] S. Rachmilovich-Calis, A. Masarwa, N. Meyerstein, D. Meyerstein,
R. van Eldik, Chem. Eur. J. 2009, 15, 8303.
2
ˆ
[13] See the Supporting Information for details.
Received: September 21, 2012
Published online: February 21, 2013
4848
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Chem. Eur. J. 2013, 19, 4842 – 4848