Four-Electron Electrocyclic Ring-Opening/Intermolecular [4+2] Cycloadditions of α-Hydroxycyclobutenones: Stereoselective Synthesis of Multiple Substituted δ-Lactams

Article abstract of DOI:10.1002/adsc.201501152

A four-electron electrocyclic ring-opening/intermolecular [4+2] cycloaddition of α-hydroxycyclobutenones is reported. The reaction represents the first example for the intermolecular cycloaddition of the extensively studied enol-ketene intermediate, and provides a new synthetic route to multiply substituted δ-lactams in high stereoselectivity.

Full text of DOI:10.1002/adsc.201501152

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DOI: 10.1002/adsc.201501152
Very Important Publication
Four-Electron Electrocyclic Ring-Opening/Intermolecular
4+2]Cycloadditions of a-Hydroxycyclobutenones:
Stereoselective Synthesis of Multiple Substituted d-Lactams
[
a
a
a
a
a
a
Peidong Song, Qing Li, Congcong Wang, Wenfa Wu, Xu Mao, Jiajia Wang,
a,
and Xiangdong Hu *
School of Chemistry & Material Science, Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of
a
Ministry of Education of China, Northwest University, Xi’an 710127, Peopleꢀs Republic of China
E-mail: xiangdonghu@nwu.edu.cn
Received: December 17, 2015; Revised: January 29, 2016; Published online: March 17, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501152.
Abstract: A four-electron electrocyclic ring-open-
ing/intermolecular [4+2]cycloaddition of a-
a number of interesting transformations of small ring
[1]
compounds. As a unique family in transformations
of all-carbon four-membered ring compounds, the
ring-opening and subsequent transformations of a-hy-
droxycyclobutenones are an attractive topic. The
hydroxycyclobutenones is reported. The reaction
represents the first example for the intermolecular
cycloaddition of the extensively studied enol-ketene
intermediate, and provides a new synthetic route to
multiply substituted d-lactams in high stereoselec-
tivity.
[2]
[3]
seminal studies from Moore and Liberskind re-
vealed that, through a four-electron electrocyclic ring-
opening process under thermal conditions, a-hydroxy-
cyclobutenones can be readily transformed into an
enol-ketene intermediate A with high torquoselectivi-
Keywords: enol-ketene intermediates; a-hydroxycy-
clobutenones; intermolecular [4+2]cycloaddition;
d-lactams; stereoselectivity
[4]
ty. Moreover, depending on the structure of the sub-
1
stituent R , intermediate A can go through different
1
subsequent transformations (Scheme 1). When R is
an alkene or alkyne group, quinols and benzoqui-
nones will be generated, respectively, through a 6p-
electrocyclization process [Eqs. (a) and (b)]. As pow-
By virtue of the release of ring strain, the ring-open- erful strategies, these transformations have been used
[5]
ing process affords a powerful driving force to in the synthesis of natural products. In addition,
Scheme 1. Previous reports on four-electron electrocyclic ring opening/intramolecular domino reactions of a-hydroxycyclo-
butenones.
1
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COMMUNICATIONS Four-Electron Electrocyclic Ring-Opening/Intermolecular [4+2]Cycloaddition
1
Harrowvenꢀs group disclosed that, when R is an lar [4+2]cycloaddition of a-hydroxycyclobutenones,
[8]
alkene group containing an allylic hydrogen atom, in- which were prepared according to Mooreꢀs methods.
termediate A can go through a carbonyl-ene reaction, To avoid the known intramolecular reaction pathways,
1
generating multiply substituted cyclopentenones in substituents R of the a-hydroxycyclobutenones were
[
6]
1
the end [Eq. (c)]. When R is an o-vinyl aromatic prepared as alkyl groups rather than the active func-
ring, an intramolecular [2+2]cycloaddition or an in- tional groups mentioned above. The reaction of a-hy-
tramolecular [2+2]cycloaddition/rearrangement pro- droxycyclobutenones and imines was tested in p-
cess will happen and furnish benzobicyclo[4.2.0]octen- xylene under thermal conditions. To our delight, vari-
ones and benzobicyclo[3.2.1]octenones, respectively ous a-hydroxycyclobutenones and imines reacted
[
6]
[
Eq. (d)]. Although the various transformations of smoothly through the expected four-electron electro-
enol-ketene intermediate A are a very interesting cyclic ring-opening/intermolecular [4+2]cycloaddition
field, to date, all reports on transformations of inter- pathway, generating multi-substituted d-lactams with
mediate A, after the in situ generation from four-elec- moderate to excellent yields (Table 1). It was ob-
tron electrocyclic ring-openings of a-hydroxycyclobu- served that imines containing electron-rich aromatic
tenones, went through intramolecular pathways.
rings could facilitate the [4+2]cycloaddition process
We are currently interested in the chemistry of by decreasing the reaction temperature, and such re-
[9]
ring-opening and subsequent transformations of cy- actions generated d-lactams 3b, 3c and 3i. Imines
clobutenedione derivatives and their applications in bearing electron-withdrawing groups on the aromatic
[
5a,7]
the synthesis of bioactive natural products.
Follow- ring (formation of 3d), by contrast, reacted much
[9]
ing our interest, we wonder if the in situ formed enol- more slowly. Interestingly, 3,4-dihydroisoquinoline,
ketene intermediate A could take part in intermolec- as a Z-configuration imine, has been proven to be an
ular cycloadditions with imines, which would demon- excellent reactant for this process, generating d-lac-
strate more synthetic value for practical applications. tams 3j and 3s in 98% and 95% yields, respectively.
Theoretically, the intermolecular cycloaddition be- However, alkylimines, such as n-butyraldehyde N-
tween imines and enol-ketene intermediate A could methylimine, did not show reactivity in the test with
follow three different pathways (Scheme 2): (i) a-hydroxycyclobutenone 1a.
[
2+2]cycloaddition between the ketene motif of inter-
Particularly noteworthy is the high stereoselectivity
mediate A and imines, (ii) [3+2]cycloaddition be- of the cycloaddition reported herein. All lactams
tween enol-ketene intermediate A, as a 1,3-dipole, were obtained as only one stereoisomer. In order to
and imines, and (iii) [4+2]cycloaddition between assign the relative configuration of these lactams,
enol-ketene intermediate A, as a diene, and imines.
crystals of 3d, 3j and 3o were obtained and submitted
[10]
Mindful of this, we started the exploration on the to X-ray crystallographic analysis. The cis-configu-
four-electron electrocyclic ring-opening/intermolecu- ration of the hydroxy group and the aromatic ring has
been confirmed consistently (Figure 1).
Figure 1. X-ray structures of d-lactams 3d, 3j and 3o.
It should be noted that the four-electron electrocy-
clic ring-opening/intermolecular [2+2]cycloaddition is
another feasible reaction pathway of a-hydroxycyclo-
butenones. In reactions of a,b-unsaturated imine 2k
and 1a, and 2b and 1h, the products obtained were b-
lactam 3t and 3x, respectively, rather than d-lactams
for unknown reasons (Scheme 3). Besides, in the reac-
tion of all alkyl-substituted a-hydroxycyclobutenone
1
g and 2b, the major product was b-lactam 3v, with d-
Scheme 2. Our anticipation of the four-electron electrocyclic
ring-opening/intermolecular [4+2]cycloaddition of a-hy- lactam 3w generated as the minor product. Notably,
droxycyclobutenones.
b-lactams 3t and 3v were generated in three stereoiso-
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Peidong Song et al.
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[a]
Table 1. Study on the scope.
Scheme 3. The four-electron electrocyclic ring-opening/inter-
molecular [2 ++ 2]cycloaddition of a-hydroxycyclobutenones.
garding the proposed [3+2]pathway of intermediate
A, no related product was observed in any event.
During our exploration on the four-electron elec-
trocyclic ring-opening/intermolecular [4+2]cycloaddi-
tion of a-hydroxycyclobutenones, other types of dien-
ophiles, including alkenes, alkynes, enol ethers and
enamines (such as a-methylstyrene, phenylacetylene,
dimethyl acetylenedicarboxylate and a-methoxystyr-
ene), were tested as well. However, no reaction was
observed in most cases. Only enamine 2m displayed
mild reactivity at elongated reaction time, generating
bicyclo[4.4.0]decanone 3u in high stereoselectivity
(
Scheme 4). The trans-configuration of the hydroxy
and amine group was assigned through X-ray diffrac-
[
12]
tion of 3u.
[a]
Reaction conditions: under an argon atmosphere, a-hy-
droxycyclobutenone (1 mmol) and imine (2 mmol) in p-
xylene (3 mL) were stirred at 120–1408C for 2–4.5 h;
yields of isolated products are given.
To reach a better understanding of the high stereo-
selectivity and the relative configuration outcome of
the transformation, a plausible mechanism has been
proposed (Scheme 5). The enol-ketene intermediate
A is first generated in high torquoselectivity through
mers, respectively, and b-lactam 3x was formed as a four-electron conrotatory electrocyclic ring-opening
four stereoisomers. This phenomenon is highly sug- process of a-hydroxycyclobutenones 1 under thermal
gestive that, in these cases, the intermolecular conditions. During the subsequent intermolecular
[
2+2]cycloaddition between in situ generated enol- [4+2]cycloaddition, the endo transition state is fa-
ketene intermediates and imines should be a stepwise vored because of the p–p interaction between the ar-
[11]
process as known for the Staudinger reaction. Re- omatic ring of the imine and the diene. As a result,
1
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Adv. Synth. Catal. 2016, 358, 1208 – 1212

COMMUNICATIONS Four-Electron Electrocyclic Ring-Opening/Intermolecular [4+2]Cycloaddition
In conclusion, we have disclosed a four-electron
electrocyclic ring-opening/intermolecular [4+2]cyclo-
addition of a-hydroxycyclobutenones. This is the first
report on the intermolecular cycloaddition of the ex-
tensively studied enol-ketene intermediate. With high
stereoselectivity, this reaction affords a concise syn-
thetic approach to multiply substituted d-lactams.
Experimental Section
General Procedure for the Four-Electron
Scheme 4. The four-electron electrocyclic ring-opening/inter- Electrocyclic Ring-Opening/Intermolecular
molecular [4+2]cycloaddition of 1a and enamine 2m.
[4+2]Cycloaddition of a-Hydroxycyclobutenones
A mixture of a-hydroxycyclobutenone (1 mmol) and imine
(2 mmol) in p-xylene (3 mL) was stirred at 1408C for 2–3 h
in the sealed vessel under an argon atmosphere. After com-
pletion of the reaction as monitored by TLC, the mixture
was cooled to room temperature. After evaporation of the
solvent, the crude product was purified by flash chromatog-
raphy on silica gel using a mixture of EtOAc and petroleum
ether as eluent to afford the pure product.
Acknowledgements
We are grateful for financial support from the National Natu-
ral Science Foundation of China (NSF-21002078, 21372184),
the State Education Ministry Scientific Research Foundation
for the Returned Overseas Chinese Scholars, and Shaanxi
Province Technology Foundation for Selected Overseas Chi-
nese.
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