Synthesis of spiro[2.5]octa-4,7-dien-6-one with consecutive quaternary centers via 1,6-conjugate addition induced dearomatization of para-quinone methides

Article abstract of DOI:10.1039/c5cc06287j

An efficient one-pot approach for the synthesis of spiro[2.5]octa-4,7-dien-6-ones by employing para-quinone methides has been developed. The reaction proceeded smoothly in high yields under mild conditions without the use of metals. Moreover, all products obtained herein contained two or three consecutive quaternary centers.

Full text of DOI:10.1039/c5cc06287j

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DOI: 10.1039/C5CC06287J
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Synthesis of Spiro[2.5]octa-4,7-dien-6-one with Consecutive
Quarternary Centers via 1,6-Conjugate Addition Induced
Dearomatization of para-Quinone Methides
Received 00th January 20xx,
Accepted 00th January 20xx
Kuo Gai,a Xinxin Fang,a Xuanyi Li,a Jinyi Xua, Xiaoming Wua, Aijun Lin*a and Hequan Yao*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient one-pot approach for the synthesis of spiro[2.5]octa-4,7-dien-
6-ones by employing para-quinone methides has been developed. The
reaction proceeded smoothly in high yields under mild conditions without
the use of metals. Moreover, all products obtained herein contained two
or three consecutive quarternary centers.
In present years, much attention has been paid to
spirocyclic compounds due to their unique characteristics and
biological activities[1]. Among the various types of spirocycle
skeletons, spiro[2.5]octa-4,7-dien-6-one core is a privileged
structure found in many natural products, exhibiting antitumor
bioactivities through alkylation of DNA (Figure 1)[2]. Apparently,
design and synthesis of the strained spirocycle is challenging
especially involving the creation of multiple quarternary
centers, which is considered to be a continuing task for
synthetic organic chemistry[3]. To our knowledge, only a few
examples towards the synthesis of spiro[2.5]octa-4,7-dien-6-
one are known, mainly depending on the reaction of para-
quinone diazides with olefins (Scheme 1-a)[4]. In 1967, Pirkle
Scheme 1 Approaches to the synthesis of spiro[2.5]octa-4,7-dien-6-one cores
reported the synthesis of spiro[2.5]octa-4,7-dien-6-one by
photolysis of 3,5-di-t-butylbenzene 1,4-diazooxide with
olefins[5]. In 2014, Baran developed a Rh-catalyzed synthesis of
spiro[2.5]octa-4,7-dien-6-one employing the same starting
materials[6]. Although these methods proved to be useful in
the construction of spirodienone skeletons, the difficulties in
the preparation of diazo compounds, the use of carbene
initiator and heavy metals still restrict their wide applications
in more complex molecule synthesis and medicinal chemistry[7]
Therefore, the development of a simple, efficient, and green
method to access diverse spiro[2.5]octa-4,7-dien-6-ones
remains highly desirable.
.
Para-Quinone methides (p-QMs), consisting of a cyclohexadiene
moiety in para-conjugation with a carbonyl group and an exo-
methylene component[8], existed in many natural products[9] and
have been known as reactive intermediates for more than one
century[10]. Recently, two excellent works of p-QMs have been
reported [11-13], which steered great development prospect in the
future. Given the appeal for exploring new methodology with p-
QMs, we report herein an unprecedented approach towards the
synthesis of spiro[2.5]octa-4,7-dien-6-one skeletons with two or
three consecutive quarternary carbon centers featuring a 1,6-
conjugate addition induced dearomatization of p-QMs
(Scheme 1-b).
Figure 1 Selected natural products with spiro[2.5]octa-4,7-dien-6-one skeletons
a.State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal
Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing,
210009, P .R. China
Email: ajlin@cpu.edu.cn, hyao@cpu.edu.cn
Electronic Supplementary Information (ESI) available: experimenal procedures,
analytical data, and 1H and 13C-NMR spectra for all new compounds. See
DOI: 10.1039/x0xx00000x
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Table 1 Optimization of Reaction Conditionsa
Table 2 Substrate scopea,b
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DOI: 10.1039/C5CC06287J
aReaction Conditions: 1a (0.1 mmol), 2a (0.15 mmol), base (0.2 mmol) in CH2Cl2
(0.5 mL) at ambient temperature for 12 h. bIsolated yields. c0.1 mmol 2a was
used.
We started our investigation by selecting 2,6-di-tert-butyl p-
QM (1a) and diethyl 2-bromomalonate (2a) as the model
substrates[14]. Firstly, a series of bases with 1 equivalent of 2a
were screened (entries 1-4), providing 3aa in low yields with a
lot of unreacted 1a recovered. It seemed that the nature of the
base played an important role on the reaction. Therefore, we
raised 2a to 1.5 equivalent and continued to optimize the
reaction with different bases (entries 5-10). Gratifyingly, the
desired products were obtained in higher yields due to the
effective consumption of 1a. Among the bases tested, Cs2CO3
exhibited best result, affording 3aa in 98% yield (entry 10).
With the optimized condition in hand, we next tested the
substrate scope of the reaction (Table 2). Firstly, a series of p-
QMs bearing electron-neutral, electron-rich and electron-
deficient aromatic groups were examined, affording the
spirocycles 3aa-3ga in 90%-98% yields. Besides, the reaction
was also found to be insensitive to the ortho-, meta-, or para-
substituents at the phenyl rings (3ea-3ga). 1k and 1l with
alkynyl or alkenyl at the ortho-position proceeded smoothly to
offer 3ka and 3la in 77% and 62% yields. Substrates carrying
important aryl substituents, such as naphthyl and thienyl,
offered 3ma and 3na in 66% and 54% yields. Alkyl substituents
were also tested, and the product 3oa was obtained in 97%
yield. Particularly to note, the product 3pa (R1 = methyl, R1’ =
ethyl) with three consecutive quarternary carbon centers
could be obtained in 90% yield, which was difficult to be
synthesized from other approaches due to its high steric
hindered characteristic. The generality of R2 was then tested,
producing the desired products 3qa-3sa in moderate to good
yields. Moreover, in order to extend the substrate scope, (E)-4-
benzylidene-naphthalen-1(4H)-one (1t), a special p-QM, was
examined and the product 3ta was achieved in 86% yield. With
regard to electron-withdraw groups, different ester groups
were first tested, affording desired products 3ab-3ae in
aGeneral Reaction Conditions: X = Br,
1 (0.1 mmol), 2 (0.15 mmol) and Cs2CO3
(0.2 mmol) in CH2Cl2 (0.5 mL) for 12h at ambient temperature unless otherwise
noted. bIsolated yield. cX = Cl. dEt3N (2 equiv) was used as base.
68-94% yields. Besides, 2f with a functionalized allyl ester
group also proceeded well to offer the desired product 3af in
82% yield. Other electron-withdraw groups such as cyano and
carbonyl were well tolerated in this reaction, affording 3ag and
3ah in 56% and 65% yield, respectively.
In order to test the synthetic utility of this method, 3aa was
prepared on a gram scale (Scheme 2). The reaction of 1a (5
mmol, 1.47 g) with 2a (7.5 mmol, 1.79 g) at the optimal
reaction condition afforded 3aa in 92% yield (2.09 g).
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DOI: 10.1039/C5CC06287J
Scheme 2 Gram-scale synthesis of 3aa
Scheme 3 Ring-open reaction with Lewis acid
To gain insight into the utility of the reaction, the final
product 3aa could be easily converted into aromatized
derivatives in the presence of Lewis acids (Scheme 3).
Treatment of 3aa with In(OTf)3 afforded 4a in the quantitative
yield through the cleavage of C1-C2-C3 bond. In contrast,
treatment of 3aa with AlCl3 resulted in the formation of 4b in
65% yield through the cleavage of C1-C2 bond, and the
structure was confirmed by single crystal X-ray analysis[15]
.
Scheme 4 Control experiments
Then, we carried out a series of control experiments to
investigate the mechanism of our reaction (Scheme 4). When
excess styrene was added into the reaction mixture, the
product 3aa was obtained in 95% isolated yield without the
formation of compound 5. Besides, 2i could react with 1a
smoothly to give 3ai in 90% yield, while the compound 6 which
could be formed by intramolecular carbene insertion was not
observed[16]. These results indicated that the carbene pathway
might be ruled out in this reaction (eq. a, b). Next, TEMPO and
BHT, two common radical scavengers, were introduced into
the reaction to test the possibility of radical pathway. However,
no significant decline in the yield of 3aa was observed (90%
and 91%, respectively). Moreover, the substrate 2j which was
easily ring-opened in the presence of free radical tolerated
well in the reaction system, affording 3aj in 80% yield without
the formation of ring-open product 7[17]. Therefore, it was
clear that the radical pathway could also be excluded (eq. c, d).
On the basis of the control experiments and previous
Scheme 5 Plausible mechanism
In conclusion, we have developed a 1,6-addition induced
dearomatization strategy for the construction of
spiro[2.5]octa-4,7-dien-6-ones with p-QMs. The method
obviated the need for metal catalysis and proceeded well
under mild conditions. All of the final products contained two
or three consecutive quaternary centers. Further application of
this methodology to the synthesis of natural products and
pharmaceutical agents are in progress in our laboratory.
reports,
a 1,6-addition mechanism was proposed being
responsible for the product formation (Scheme 5)[18,19]
.
Treatment of 2-bromomalonate (2a) with Cs2CO3 formed a
carbanion, which followed by 1,6-addition of p-QM (1a). Then
the aromatization intermediate A underwent intramolecular
dearomatization ring closure reaction to afford the final
product 3aa with the elimination of HBr.
Generous financial support from the National Natural
Science Foundation of China (NSFC21272276 and
NSFC21502232), the Natural Science Foundation of Jiangsu
Province (BK20140655) and the Foundation of State Key
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17 Q.-X. Qin, S.-Y. Yu, Org. Lett., 2015, 17, 1894.
Laboratory of Natural Medicines (ZZJQ201306) is gratefully
acknowledged.
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14 The bulky tert-butyl was introduced for its inherent stability
and facile preparation.
15 CCDC 1414762 contains the supplementary crystallographic
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