Strain-release electrophilic activation via E-cycloalkenones

Article abstract of DOI:10.1021/ol701496b

UVA irradiation (ca. 350 nm) of a mixture of cyclic enones and nitrogen heterocycles leads to efficient formation of the 1,4-adducts in a variety of solvents, at room temperature. These reactions likely proceed through strained E-cycloalkenone intermediates, as suggested by lowtemperature generation/trapping experiments monitored by ¹H NMR. These results demonstrate that E-cycloalkenones are good electrophiles despite their known tendency to favor a conformation in which the carbonyl is not fully conjugated with the double bond.

Full text of DOI:10.1021/ol701496b

ORGANIC
LETTERS
2007
Vol. 9, No. 20
3893-3896
Strain-Release Electrophilic Activation
via E-Cycloalkenones
Joseph Moran, Peter Dornan, and Andre´ M. Beauchemin*
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie, Ottawa,
Ontario, Canada, K1N 6N5
andre.beauchemin@uottawa.ca
Received June 22, 2007
ABSTRACT
UVA irradiation (ca. 350 nm) of a mixture of cyclic enones and nitrogen heterocycles leads to efficient formation of the 1,4-adducts in a variety
of solvents, at room temperature. These reactions likely proceed through strained E-cycloalkenone intermediates, as suggested by low-
temperature generation/trapping experiments monitored by 1H NMR. These results demonstrate that E-cycloalkenones are good electrophiles
despite their known tendency to favor a conformation in which the carbonyl is not fully conjugated with the double bond.
Strained organic molecules often display high reactivity,
consistent with high ground-state energy and low-activation
energy for a variety of transformations.1 Six- to eight-
membered E-cycloalkenes2 and E-cycloalkenones,3 highly
reactive yet readily accessible intermediates via photoisomer-
ization, are representative examples. In seminal work on
E-cycloalkenones, Corey and Eaton showed their unique
dienophile reactivity in Diels-Alder additions.3 Other ex-
amples have been documented over the years,4 yet this
reactivity remains largely unexploited by synthetic chemists.
Notably, the ability of E-cycloalkenones to act as activated
electrophiles has not been demonstrated, and in solution these
enones favor a conformation in which the carbonyl is not
fully conjugated with the double bond (i.e., their UV and
IR spectroscopic data is consistent with saturated ketones).3
Only MeOH (eq 1), EtOH, i-PrOH, and Et2NH give the 1,4-
adducts in moderate yield upon photoisomerization of the
cycloalkenone in the presence of these reagents as solVents.5
As part of a program directed toward developing new
reactivity of these strained intermediates, we suggest this ap-
proach could enable the 1,4-addition of a variety of nucleo-
philes under very mild conditions. Herein we report results
demonstrating that efficient strain-release activation via
E-cycloalkenones is possible, and leads to near stoichiometric
1,4-addition of various nitrogen heterocycles to cyclohept-
2-enones and cyclooct-2-enone upon photoisomerization at
room temperature in a variety of solvents (eq 2).
(1) (a) Liebman, J. F.; Greenberg, A. A. Chem. ReV. 1976, 76, 311. (b)
Wiberg, K. B. Angew. Chem., Int. Ed. Engl. 1986, 25, 312.
(2) (a) Kropp, P. J. J. Am. Chem. Soc. 1966, 89, 4091. (b) Marshall, J.
A.; Carroll, R. D. J. Am. Chem. Soc. 1966, 89, 4092.
(3) (a) Eaton, P. E.; Lin, K. J. Am. Chem. Soc. 1964, 86, 2087. (b) Corey,
E. J.; Tada, M.; LaMahieu, R.; Libit, L. J. Am. Chem. Soc. 1965, 87, 2051.
(c) Eaton, P. E.; Lin, K. J. Am. Chem. Soc. 1965, 87, 2052.
(4) For selected examples, see: Nazarov: (a) Crandall, J. K.; Haseltine,
R. P. J. Am. Chem. Soc. 1968, 90, 6251. (b) Noyori, R.; Katoˆ, M.
Tetrahedron Lett. 1968, 5075. (c) Photodeconjugation: Noyori, R.; Inoue,
H.; Katoˆ, M. J. Am. Chem. Soc. 1970, 92, 6699. (d) Intramolecular [2+2]:
Noyori, R.; Inoue, H.; Katoˆ, M. J. Chem. Soc., Chem. Commun. 1970, 1695.
(e) Intramolecular Diels-Alder: Dorr, H.; Rawal, V. H. J. Am. Chem. Soc.
1999, 121, 10229. For a recent application of in synthesis, see: Davies, H.
M. L.; Loe, Ø.; Stafford, D. G. Org. Lett. 2005, 7, 5561.
Initial experiments showed that benzimidazole (2) reacts
efficiently with cyclohept-2-enone (1) upon irradiation with
UVA lamps (ca. 350 nm) in a CH2Cl2/MeCN (8:1) mixture,
10.1021/ol701496b CCC: $37.00
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Published on Web 09/05/2007

affording the 1,4-adduct in 94% isolated yield. To our delight,
the reactivity proved general in a variety of solvents (Table
1), with little or no thermal reaction observed in samples
Table 2. Nucleophile Scope
Table 1. Solvent Effect
entry
solvent
PhCF3
Et2O
THF
EtOAc
CH2Cl2/MeCN (8:1)
MeCN
i-PrOH
DMSO
conversion (%)a
1
2
3
4
5
6
7
8
37
58
86
91
94
94
71
55
a Samples not subjected to UVA irradiation showed no conversion, except
in i-PrOH (11%) and THF (<5%)
not exposed to UV light. The use of a 8:1 mixture of
CH2Cl2/MeCN was selected for substrate scope determination
as these conditions allow solubilization of most heterocycles
while minimizing the likelihood of a thermal reaction
involving the cis form of the cycloalkenone.
The substrate scope with respect to various nitrogen
heterocycles is shown in Table 2.6,7 Various imidazoles
reacted to afford the 1,4-adducts in good yield (entries 1-4).8
Substitution at the 2 and 4 positions was tolerated (entries
2-4), and a 7:1 selectivity is observed for 4-methylimidazole,
favoring attack from the least hindered nitrogen atom (entry
4). This reaction is also efficient with pyrazoles, with
pyrazole and benzopyrazole affording the desired product
in 99 and 92% yield, respectively (entries 5-6). Triazoles
also add efficiently under the reaction conditions (entries
7-8). The observed selectivity for the reaction of benzot-
riazole (entry 8) is in agreement with that typically observed
for related reactions.9
a Isolated yield after column chromatography. b 7 (R1 ) H, R2 ) Me):1
(R1 ) Me, R2 ) H) inseperable mixture of isomers. c 11% of the parent
N2 isomer was also isolated.
As shown in Table 3, the enone substrate scope is
consistent with that of other reactions involving E-cycloalk-
enones.3,4 For entries 1-6, benzimidazole was selected as
nucleophile as only a very slow thermal reaction, if any, is
observed at room temperature in a CH2Cl2/MeCN mixture
with these substrates. However, upon irradiation, a very clean
conversion to the 1,4-adducts is observed. Cyclohept-2-enone
and cyclooct-2-enone afford these products in 94 and 90%
yield, respectively (entries 1-2). Substituted cyclohept-2-
enones also react efficently (entries 3-4), and cyclohepta-
dienone affords the monoadduct in 51% yield (entry 5),
despite the possibility of double addition or Nazarov cy-
clization.10 In addition, substitution at the 4 position is also
tolerated, and affords the 1,4-adducts as mixtures of dia-
stereoisomers (entries 6-7). Notably, irradiation of a cyclo-
hex-2-enone and benzimidazole mixture under identical
reaction conditions does not lead to any photoinduced
reactivity, in agreement with the expected propensity of the
highly strained E-cyclohex-2-enone to isomerize back to
Z-cyclohex-2-enone (if formed).11 Similarly, no photoinduced
(5) MeOH: (a) Hart, H.; Dunkelblum, E. J. Am. Chem. Soc. 1978, 100,
5141. For precedence, see: (b) Nozaki, H.; Kurita, M.; Noyori, R.
Tetrahedron Lett. 1968, 2025. Et2NH: (c) Noyori, R.; Katoˆ, M. Bull. Chem.
Soc. Jpn. 1974, 47, 1460. For related studies, see: (d) Dunkelblum, E.;
Hart, H.; Jeffares, M. J. Org. Chem. 1978, 43, 3409.
(6) Typical experimental procedure: 3-(2-methylimidazol-1-yl)cyclo-
heptanone (Table 2, entry 2). A borosilicate tube was charged with a stir
bar, cyclohept-2-enone (0.050 g, 0.45 mmol), and 2-methylimidazole (0.112
g, 1.38 mmol). A volume of 8.0 mL of CH2Cl2 and 1.0 mL of MeCN was
added to the mixture. The tube was capped with a septum and was sparged
with a nitrogen balloon and an outlet for 10 minutes while stirring. The
tube was then placed in a Rayonet photoreactor equipped with eight 8W
UV-A bulbs for 18 hours. The reaction was monitored by TLC. The crude
mixture was then transferred to a round bottom flask and concentrated under
reduced pressure. The resulting oil was purified by column chromatography
(6% MeOH/CH2Cl2), affording the product as a yellow oil (61 mg, 70%).
(7) In control experiments, no 1,4-addition was observed with 2, 4, 5,
7-10 under identical conditions but in the absence of UV light. In contrast,
6 led to 53% conversion (vs >99% conversion upon UV irradiation).
(8) In contrast with the nucleophiles shown in Table 2, imidazole
underwent a high yielding thermal addition with Z-cycloheptenone.
(9) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Denisko, O. V. Chem. ReV.
1998, 98, 409.
(10) Nozaki, H.; Kurita, M.; Noyori, R. Tetrahedron Lett. 1968, 3635.
Org. Lett., Vol. 9, No. 20, 2007
3894

of the strained ground-state intermediate upon UV irradiation
of a cyclooct-2-enone solution in CH2Cl2 at -78 °C. After
1 h, the irradiation was stopped, the flask was covered with
aluminum foil, benzimidazole was added, and the mixture
was allowed to warm to room temperature. A modest 18%
conversion to the 1,4-adduct 12 was observed, suggesting
that a long-lived strained E-cycloalkenone ground-state
intermediate is involved in this transformation (eq 4). In the
absence of irradiation, no conversion to the 1,4-adduct was
observed under similar conditions.
Table 3. Electrophile Scope
Seeking a more definitive proof for the likely ground-state
intermediate, we repeated the reaction shown in eq 4 in
CD2Cl2/CD3CN and monitored the reaction by low-temper-
ature NMR. Following enone irradiation at -75 °C in an
NMR tube, benzimidazole was added, and the sample was
inserted in the NMR probe (precooled to -20 °C). An initial
spectra (ii, Figure 1) confirmed that photoisomerization had
a Isolated yield after column chromatography. b Diastereomeric ratio )
12:1 (cis/trans). c Diastereomeric ratio ) 1.3:1 (cis/trans). d Diastereomeric
ratio ) 1.1:1 (cis/trans).
reactivity is observed upon irradiation of a mixture of methyl
vinyl ketone and benzimidazole.
Interestingly, the addition of deuterated benzimidazole 22
to cyclohept-2-enone is stereospecific (eq 3). This result is
in good agreement with the stereochemical outcome of solvo-
lysis reactions outlined in eq 1. A plausible mechanism for
the formation of 3i involves the 1,4-addition to E-cyclohep-
tenone, forming a zwitterionic intermediate analogous to that
shown in eq 1. After conformational relaxation, intermolec-
ular deuteration (likely involving 22) and subsequent proton-
transfer would provide adduct 3i selectively. A similar ration-
ale has been proposed by Hart and Dunkelblum (eq 1).5a
Figure 1. 1H NMR monitoring of low-temperature generation/
trapping experiments (eq 4): (i) spectrum before photoisomerization
(350 nm) at -78 °C; (ii) spectrum after photoisomerization, but
before addition of benzimidazole (2); (iii) spectrum after addition
of excess 2 and warming to 10 °C.
occurred, leading to the appearance of E-cyclooctenone (B,
diagnostic JCHdCH ) 18.0 Hz),3a and only traces of 1,4-adduct
(11) E-Cyclohex-2-enones have been invoked as intermediates in a
number of reactions. However, they have not been observed directly by
low temperature laser flash photolysis and are expected to be very short
lived, if formed. For a discussion, see: Schuster, D. I. In CRC Handbook
of Organic Photochemistry and Photobiology; Horspool, W. M., Song, P.-
S., Eds.; CRC Press: Boca Raton, FL, 1995; Chapter 48.
Despite a substrate scope consistent with the reactivity of
a E-cycloalkenone intermediate, more conclusive evidence
was needed.12 Therefore, we performed low-temperature
generation/trapping experiments,13 which involved generation
Org. Lett., Vol. 9, No. 20, 2007
3895

12 were observed at that temperature. Upon warming to 10
°C (over ca. 10 min), E-cycloalkenone (E)-11 reacted
efficiently to afford 12, as judged by the similar ratios relative
to Z-cyclooctenone [B/A ) 0.29 in spectra ii vs C/A ) 0.28
in spectra iii]. This finding suggests that only little unproduc-
tive E to Z thermal isomerization occurred under the reaction
conditions. Overall, these results support the involvement
of highly strained E-cycloalkenone ground-state intermediates
under the reaction conditions.14
pyrazoles, and triazoles upon UV irradiation of seven- and
eight-membered cycloalkenones. Studies toward new reactiv-
ity of these strained intermediates in other reactions are
underway and will be reported in due course.14
Acknowledgment. We thank the NSERC for generous
support through the discovery grants and research tools and
instrumentation programs, the University of Ottawa for
startup funds, the Canadian Foundation for Innovation and
the Ontario Ministry of Research and Innovation. J.M. also
thanks NSERC for CGS-M and PGS D postgraduate
scholarships and the University of Ottawa for a SAD award.
P.D. thanks NSERC for an Undergraduate Student Research
Award.
In summary, we have demonstrated that significant elec-
trophilic activation can be achieved via E-cycloalkenones,
leading to near stoichiometric 1,4-addition of imidazoles,
(12) E-Cyclohept-2-enone has been observed by laser flash photolysis:
Bonneau, R.; Fornier de Violet, P.; Joussot-Dubien, J. NouV. J. Chim. 1977,
1, 31.
(13) For other low temperature generation/trapping experiments, see
references 3b, 4b, and 5c. Such experiments are based on the longer lifetimes
of ground-state intermediates compared to excited states, which are known
to rapidly decay to the ground state (typically , 1 s).
(14) Over the course of these studies, we discovered that indoles react
with enones, likely via a photoinduced electron transfer mechanism: Moran,
J.; Suen, T.; Beauchemin, A. J. Org. Chem. 2006, 71, 676.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL701496B
3896
Org. Lett., Vol. 9, No. 20, 2007