4-Phenylspiro[2.2]pentane-1,1-dicarboxylate: synthesis and reactions with EtAlCl2 and 4,5-diazaspiro[2.4]hept-4-ene derivative

Article abstract of DOI:10.1016/j.mencom.2019.07.020

Cyclopropanation of 1-methylidene-2-phenylcyclopropane with dimethyl diazomalonate affords new dimethyl 4-phenyl-spiro[2.2]pentane-1,1-dicarboxylate. On contact with EtAlCl2, this compound undergoes opening of both cyclopropane rings to give dimethyl (2-chloromethyl-3-phenylallyl)malonate. Its EtAlCl2-assisted reaction with methyl 5′-methylspiro[cyclo-propane-1,3′-pyrazoline]-5′-carboxylate proceeds as the 1,3:1′,5′-addition to afford mainly 3-(2-chloroethyl)-1-cyclo-propylmethyl-1H-pyrazoline derivative.

Full text of DOI:10.1016/j.mencom.2019.07.020

Mendeleev
Communications
Mendeleev Commun., 2019, 29, 417–418
4-Phenylspiro[2.2]pentane-1,1-dicarboxylate: synthesis and reactions
with EtAlCl and 4,5-diazaspiro[2.4]hept-4-ene derivative
2
Dmitry A. Denisov, Denis D. Borisov, Konstantin V. Potapov, Roman A. Novikov and Yury V. Tomilov*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 6390; e-mail: tom@ioc.ac.ru
DOI: 10.1016/j.mencom.2019.07.020
Cyclopropanation of 1-methylidene-2-phenylcyclopropane
with dimethyl diazomalonate affords new dimethyl 4-phenyl-
spiro[2.2]pentane-1,1-dicarboxylate. On contact with EtAlCl2,
this compound undergoes opening of both cyclopropane rings
Cl
CO2Me
Me
Cl
CO2Me
Ph
Nu =
N
EtAlCl2
2
CO Me
N
to give dimethyl (2-chloromethyl-3-phenylallyl)malonate. Its
Me
CO2Me
Nu
Nu
EtAlCl -assisted reaction with methyl 5'-methylspiro[cyclo-
Ph
2
N N
propane-1,3'-pyrazoline]-5'-carboxylate proceeds as the
CO2Me
CO Me
2
+
CO2Me
EtAlCl2
CO2Me
CO2Me
Ph
1
,3:1',5'-addition to afford mainly 3-(2-chloroethyl)-1-cyclo-
Ph
D–A spiropentane
~ 6 : 1
CO2Me
propylmethyl-1H-pyrazoline derivative.
Incorporation of donor and acceptor substituents at vicinal posi­
tions of cyclopropane strongly activates this three­membered
ring thus ensuring its easy opening. 2­Arylcyclopropane­1,1­di­
substrate that can react with various DACs as 1,3­zwitterions
1
9
(Scheme 2). With substrate 5, even bicyclopropane 2 reacts as a
1,3­zwitterion. In this process, spiro[cyclopropanepyrazoline] 5
also undergoes cyclopropane ring opening that occurs as 1,5­addi­
1
carboxylates, and primarily phenylcyclopropanedicarboxylate 1,
20,21
are among the most abundant donor–acceptor cyclopropanes
tion.
The overall process can be represented as 1,3:1',5'­addition
2
–6
(
DACs). Their activation is commonly performed by catalysis
that eventually results in polysubstituted 2­pyrazolines 6 (see
Scheme 2).
7–10
with Lewis acids
to promote reactions with diverse substrates, in
11
particular with N­nucleophiles. Various types of DAC reactivity
are also documented.1
2,13
i
Br
ii
Br
One of the trends of DAC chemistry14,15 involves expanding
the reactive carbocyclic system by adding further three­membered
rings with retention of the concept of activation by donor and
acceptor substituents. For example, we have recently synthesized
new donor–acceptor bicyclopropane 216 which proved to be
a highly reactive compound whose bicyclopropyl system was
strongly activated due to a favorable arrangement of donor and
acceptor substituents and its entire six­membered system could
react as an integral whole. Nucleophilic 1,6­addition with the opening
Ph
Ph
Ph
Br
1%
Me
7
93%, E + Z
iii
iv
CO Me
CO2Me
2
Ph
Ph
4
(54%)
3 (43%, dr 10:1)
Scheme 1 Reagents and conditions: i, CHBr , NaOH, Et BnNCl, EtOH–H O
;
2
3
3
t
ii, BuLi, then MeI; iii, Bu OK, DMSO; iv, N =C(CO Me) , Rh (OAc) (cat.).
2
2
2
2
4
1
6
of both cyclopropane rings was typical of such a system.
In this study, spiropentane 3 also reacted very well with spiro­
CO2Me
[cyclopropanepyrazoline] 5 in the presence of EtAlCl (Scheme 3)
2
when pyrazoline 5 was added as a nucleophile and its cyclo­
propane ring underwent opening with addition of a chloride
anion from the Lewis acid. The reaction afforded a mixture of
three products 7–9, indicating different types of reactivity that
donor–acceptor spiropentane 3 manifested in their formation.
Pyrazoline 7 is the main product (yield up to 48%) that is formed
with opening of only one three­membered ring in spiropentane 3.
Note that it is opened with nucleophile addition to the least
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
Ph
Ph
Ph
1
2
3
D–A cyclopropane
D–A bicyclopropane
D–A spiropentane
This work
In this work, we concentrated on another novel promising
chemotype of similar systems, viz., donor–acceptor spiropentanes
of type 3. To obtain the particular compound 3, we developed a
simple and convenient synthetic scheme based on [Rh]­catalyzed
cyclopropanation of 1­methylidene­2­phenylcyclopropane 4 with
Cl
Me
CO2Me
CO2Me
CO2Me
N
Me
diazomalonate (Scheme 1). Compound 4 was easily synthesized
EtAlCl2
CH Cl
+
N
from styrene using reported techniques.1
7,18
The target spiro­
N
CO Me
2
2
2
R
N
R
pentane 3 is mainly formed as the trans­isomer (the trans/cis­
isomer ratio is ~10:1).
The reactivity of donor–acceptor spiropentane 3 was studied
in the model reaction of ordinary DACs with spiro[cyclopropane­
pyrazoline] derivative 5. Compound 5 is a convenient and reactive
R = Ph (1), H2C=CH,
PhCH=CH,
5
MeO2C
CO2Me
PhC C, Ph
(2)
1,3:1',5'-addition
Scheme 2
6
©
2019 Mendeleev Communications. Published by ELSEVIER B.V.
–
417 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2019, 29, 417–418
Cl
Me
CO2Me
i
EtAlCl2
(1 equiv.)
CO2Me
CO2Me
+
+ EtAlCl2
Ph
Ph
N
N
CO Me
CO2Me
CO Me
2
2
4
0 °C, 0.5 h
CH2Cl2
Ph
3
5
Cl
N
Cl
N
3
CO2Me
Cl
N
reacts as 1,4-zwitterion
10 (40%), Z:E = 2.6:1
Me
Me
CO2Me
Me
CO2Me
*
N
Scheme 5
CO2Me
N
N
+
+
*
In conclusion, we synthesized dimethyl 4­phenylspiropentane­
1,1­dicarboxylate (a donor–acceptor spiropentane) and studied
Ph
CO2Me
CO2Me
CO2Me
CO2Me
(48%)
Ph
its reactions with EtAlCl both in the absence and in the presence
2
Ph
CO2Me
CO Me
2
of spiro[cyclopropanepyrazoline] 5. In the presence of EtAlCl2,
a typical process with cleavage of the most substituted 1,3­bond
in the spiropentane moiety occurred, which resulted in instant
opening of the second cyclopropane ring to give an allylic system.
This process also partially occurs if spiro[cyclopropanepyrazoline]
is used in the reaction, but the main path of the reaction with
pyrazoline is the cleavage of the less substituted 1,2­bond that is
non­typical of the majority of DACs, while the second cyclo­
propane ring remains unchanged.
7
8 (~7%)
dr = 1.2:1
9 (~4%)
E:Z = 6:1
cis/trans > 10:1, dr ~1.1:1
Scheme 3 Reagents and conditions: i, 3:5:EtAlCl (1:1.3:2), CH Cl ,
2
2
2
4
0°C, 30 min.
substituted position of the cyclopropanedicarboxylate moiety
Scheme 4, path A and Scheme 5), which is quite untypical of
DACs including strongly substituted ones.
to H, C and 2D NMR spectra, despite three chiral centers,
(
1
,2–6,19,22
According
1
13
2
­pyrazolines 7 are mainly formed as two diastereomers in approxi
­
The work was supported by the Russian President Council
for Grants (grant no. MK­3465.2017.3). High resolution mass
spectra were recorded at the Department of Structural Studies of
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy
of Sciences.
mately equal ratio owing to the retention of the configuration of
the phenylcyclopropane moiety (>10:1) that has mainly trans­
orientation in the starting spiropentane 3.
The formation of minor co­products 8 and 9 is more interesting.
In this process, the entire activated spiropentane system reacts as
an integral whole. The two three­membered rings in spiropentane
Online Supplementary Materials
3
are opened stepwise and in this case DAC acts as a synthetic
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2019.07.020.
equivalent of a 1,4­zwitterion (Scheme 4, path B). After coordina­
tion of the Lewis acid to both ester groups, the cyclopropane ring
bound to them is first opened to give a cyclopropyl cation that is
not trapped by the nucleophile but undergoes instant isomerization
to the corresponding allylic cation. This cation can subsequently
be attacked by the nucleophile (pyrazoline 5) at two positions to
furnish two corresponding unsaturated compounds 8 and 9 in a
total yield of ~11% (see Scheme 3).
References
1 H.­U. Reissig and R. Zimmer, Chem. Rev., 2003, 103, 1151.
2 C. A. Carson and M. A. Kerr, Chem. Soc. Rev., 2009, 38, 3051.
3
T. F. Schneider, J. Kaschel and D. B. Werz, Angew. Chem., Int. Ed.,
2
014, 53, 5504.
4
5
6
R. A. Novikov and Yu. V. Tomilov, Mendeleev Commun., 2015, 25, 1.
M. A. Cavitt, L. H. Phun and S. France, Chem. Soc. Rev., 2014, 43, 804.
H.­U. Reissig and D. B. Werz, Isr. J. Chem., 2016, 56, 365.
OMe
OMe
7 A. U. Augustin, M. Busse, P. G. Jones and D. B. Werz, Org. Lett., 2018,
2
0, 820.
+
EtAlCl2
path B
–
O
8
9
A. U. Augustin, M. Sensse, P. G. Jones and D. B. Werz, Angew. Chem.,
Int. Ed., 2017, 56, 14293.
L. K. B. Garve, P. G. Jones and D. B. Werz, Angew. Chem., Int. Ed.,
3
Ph
MeO
O
Ph
MeO
[Al]
O
O
[Al]
path A
2
017, 56, 9226.
B-1
Nu
10 T. N. Nguyen and J. A. May, Org. Lett., 2018, 20, 112.
11 E. M. Budynina, K. L. Ivanov, I. D. Sorokin and M. Ya. Melnikov,
Synthesis, 2017, 49, 3035.
+
Nu
CH2
+
CO2Me
CO2Me
Nu
1,4-zwitterion
–
–
Ph
CO2Me
12 R. A. Novikov, D. D. Borisov, A. V. Tarasova, Y. V. Tkachev and
Ph
B-2
Y. V. Tomilov, Angew. Chem., Int. Ed., 2018, 57, 10293.
CO2Me
,3-zwitterion
1
1
3 D. D. Borisov, R. A. Novikov andY. V. Tomilov, Angew. Chem., Int. Ed.,
016, 55, 12233.
4 D. D. Borisov, R. A. Novikov, A. S. Eltysheva, Y. V. Tkachev and
1
2
path
B-1
path
B-2
Y. V. Tomilov, Org. Lett., 2017, 19, 3731.
7
8
9
15 R.A. Novikov, D.A. Denisov, K.V. Potapov,Y.V. Tkachev, E.V. Shulishov
and Y. V. Tomilov, J. Am. Chem. Soc., 2018, 140, 14381.
Scheme 4 Nu is compound 5.
16 D.A. Denisov, R.A. Novikov, K.V. Potapov,V.A. Korolev, E.V. Shulishov
and Y. V. Tomilov, ChemistrySelect, 2016, 1, 6374.
17 J. Hu, Y. Xie and H. Huang, Angew. Chem., Int. Ed., 2014, 53, 7272.
18 T. Kippo, K. Hamaoka and I. Ryu, J. Am. Chem. Soc., 2013, 135, 632.
9 R.A. Novikov, D. D. Borisov, M.A. Zotova, D.A. Denisov,Y.A. Tkachev,
V. A. Korolev, E. V. Shulishov and Y. V. Tomilov, J. Org. Chem., 2018,
When the reaction of D–A spiropentane 3 with EtAlCl under
the same conditions was performed in the absence of nucleophile
, 2­(chloromethyl)­3­(phenylallyl)malonate 10 was formed as
the main product (see Scheme 5), which was similar in the
mode of formation of compound 9, the very minor product in the
reaction with pyrazoline. Thus, opening of both cyclopropane
rings mostly occurs on treatment of D–A spiropentane 3 with
2
1
5
8
3, 7836.
2
0 Yu.V. Tomilov, G. P. Okonnishnikova, E.V. Shulishov and O. M. Nefedov,
Mendeleev Commun., 1994, 4, 119.
21 Yu.V. Tomilov, G. P. Okonnishnikova, E.V. Shulishov and O. M. Nefedov,
EtAlCl : in this case, the 1,3­bond breaks in the acceptor cyclo­
Russ. Chem. Bull., 1994, 43, 1880 (Izv. Akad. Nauk, Ser. Khim., 1994,
2
1
993).
propane ring and the resulting cyclopropyl cation is instantly
converted to an allylic one with addition of a chloride anion
from the Lewis acid to the least substituted allyl position of the
generated 1,4­zwitterionic intermediate (see Scheme 4, path B­1).
2
2 T. Chidley, N. Vemula, C. A. Carson, M. A. Kerr and B. L. Pagenkopf,
Org. Lett., 2016, 18, 2922.
Received: 28th November 2018; Com. 18/5749
418 –
–