Spontaneous reaction of malonyl peroxides with methanol

Article abstract of DOI:10.1016/j.mencom.2017.05.008

The spontaneous reaction of disubstituted malonyl peroxides (MPOs) with methanol affording monopermalonic acid monomethyl esters is fast (minutes) for lower homologues but is sharply decelerated (days) for the higher ones. Spirocyclopropyl-MPO is an excep

Full text of DOI:10.1016/j.mencom.2017.05.008

Mendeleev
Communications
Mendeleev Commun., 2017, 27, 243–245
Spontaneous reaction of malonyl peroxides with methanol
Margarita A. Lapitskaya, Vera A. Vil’, Ludmila L. Vasil’eva,
Elena D. Daeva, Alexander O. Terent’ev and Kasimir K. Pivnitsky*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 8824; e-mail: kpiv@mail.ru
DOI: 10.1016/j.mencom.2017.05.008
The spontaneous reaction of disubstituted malonyl peroxides
MPOs) with methanol affording monopermalonic acid
monomethyl esters is fast (minutes) for lower homologues
but is sharply decelerated (days) for the higher ones. Spiro­
cyclopropyl­MPO is an exception in which the nucleophilic
opening of the spiroactivated cyclopropane ring leads to
(
R
R
R
R
MeOH
O
O
MeOH
2 2 2 2
MeOCH CH C(CO H)
R + R = (CH2)2
MeO2C
R = Me, Et, Bu
R + R = (CH2)3, (CH2)4
CO3H
OMe
O
O
2
,4­dimethoxy­2­carboxybutanoic acid.
1
Within the first decade after their discovery in 1971, malonyl
peroxides (MPOs, stable cyclic diacylperoxides, e.g., com­
pounds of type 1e–f in Scheme 1) were intensively investigated
as convenient substrates for generation of a­lactones, malonic
anhydrides, and other types of low­stable compounds by photolysis
unexpectedly found that spirocyclobutyl­MPO 1b rapidly reacts
with methanol without any catalysts giving the same mixture of
products 2b and 3b as those with potassium acetate catalysis
‡
(Table 1). This transformation proceeds equally well in carefully
purified (from traces of basic impurities) methanol (Method A)
as well as in methanol acidified to pH 2–3 (Method B). Similar
2
or thermolysis. Interest in MPOs returned in 2010 with the
discovery of their capability of the cis­dihydroxylating of olefins
without using reagents with heavy metals. In recent years, the
§
results were obtained with methanolysis of MPOs 1c,d (see
3
Table 1, entries 5 and 6). Due to the high volatility of the lowest
use of MPOs as oxidizing agents is expanding, as exemplified by
4
5
†
3(a),6,10
trans­dihydroxylation of olefins, hydroxylation of arenes and
Starting MPOs 1a–c,e,f were synthesized as described.
The
acyloxylation of b­dicarbonyl compounds.6
,7
1,2(a),10
use of compound 1d was multiply reported
without its synthesis
and properties. In ref. 2(d) an attempted preparation of 1d by the standard
for MPOs procedure was reported to give the product to which dimeric
structure 5 was ascribed on the basis of cryo­ and ebullioscopic data. On
repeating this synthesis (with minor modification), we obtained the product
which was identical with the already described one by melting point, IR
At the same time, the transformations of MPOs themselves,
other than photolysis and thermolysis, are little known. Slow
solvolysis (up to 2500 h at 22°C) of di­n­butyl­MPO (1f, see
Scheme 1) with methanol gave monomethyl ester 3f as a main
product, whereas with ethanol it resulted in free di­n­butylmalonic
1
and H NMR spectra (see below). However, the monomeric structure of
8
acid. Recently, we described fast (15 min at 25°C) alcoholysis
the product was proved as its methanolysis brings about only monoesters
of diacids 2d and 3d. In case of dimeric structure 5, other dimethylmalonic
acid derivatives should also be expected, namely, diester, bisperacid and
reduction products of the latter.
of MPOs 1a–c catalyzed by potassium acetate, which led to
monoesters (at carboxyl group) of monopermalonic acids 2a–c
partially converted into monoesters 3a–c under mild reaction
‡
9
Literature statement of the fast (10 min at room temperature) reaction
conditions.
of MPO 1b with methanol1 is erroneous. In fact, it was performed with
1(a)
Herein, we report our results of more thorough investigations
11(b)
a MeONa/MeOH solution.
†
on methanolysis of some representative MPOs 1a–f. We have
§
Dimethylmalonyl peroxide 1d. A suspension of dimethylmalonic acid
(
6
1.98 g, 15 mmol) in solution of H O ·OC(NH ) (6.27 g of 90% purity,
0 mmol) in methanesulfonic acid (10 ml) was stirred at room temperature
2
2
2 2
R
R
O
O
MeOH
2–25 °C
R
R
until total dissolution (2.5 h), and the mixture was left overnight. The
formed colourless solution was cooled in an ice bath and treated with
saturated ammonium sulfate aqueous solution (2 ml) pre­cooled to 4°C.
The white precipitate thus formed was filtered, washed with the same
ammonium sulfate solution, dissolved in chloroform (20 ml), and the
small aqueous layer thus emerged was discarded. The organic layer after
2
MeO2C
2a–f
CO3H
O
1
O
a–f
1
a
2
2–25 °C
MeOH
R
R
MeO
CO2R
CO2R
rapid drying (with MgSO + 10% MgO) was concentrated on a rotary
4
MeO C
2
CO H
2
evaporator without warming to leave a semi­crystalline mass. This was
dissolved in minimum methyl tert­butyl ether, the solution was diluted
(3–4 fold) with hexane. After the crystallization ceased, the suspension was
evaporated in vacuo (no longer than 1 min at 1 Torr) to afford white
crystals of 1d with a strong pungent odour (be careful!), yield 800 mg
(41%), mp 49–51°C (lit.,
CDCl ) d: 1.59 (s). C NMR (75.48 MHz, CDCl ) d: 21.6 (Me), 39.0 (C),
174.6 (CO). IR (CHCl , n/cm ): 1800, 1815 (1:2). Mass spectrum of 1d
corresponds to a monomer.
evaporating in air at 21°C within 15 min. Probably, this volatility distorted
MeO
3
a–f
4
4
a R = H
b R = Me
Me3SiCHN2
a R + R = (CH2)2
b R + R = (CH2)3
c R + R = (CH2)4
d R = Me
e R = Et
R = Bu
O
O
O
2(d)
mp 48–49°C). 1H NMR (300.13 MHz,
O
O
O
O
Me
Me
Me
13
3
3
Me
O
–1
3
f
2
(d)
The substance is volatile, small crystals
5
Scheme 1
the results of cryo­ and ebullioscopic methods in ref. 2(d).
©
2017 Mendeleev Communications. Published by ELSEVIER B.V.
–
243 –
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.

Mendeleev Commun., 2017, 27, 243–245
Table 1 Spontaneous reaction of MPOs with methanol.
ones 1b–d is remarkable. This can be caused by the effect of
gem­dialkyl groups which create steric shielding of carbonyl
groups being attacked in the course of methanolysis.
Time of 50%
Entry MPO Methoda conversionb
c
d
P
r
o
d
u
c
t
s
a
n
d
t
h
e
i
r
r
a
t
i
o
s
In an attempt to assess the role of these substituents, energy of
transition states during methanolysis was calculated by ab initio
method (for details, see Online Supplementary Materials). Energy
barriers for the reaction of MPOs 1d and 1e with one MeOH
at 25°C/h
1
1a
A
6
2a + 3a + 4a + polymer,
4
:11:49:36
2
3
4
5
6
7
8
9
0
1a
1b
1b
1c
1d
1d
1d
1e
1f
B
A, Be
6
3a + 4a + polymer, 10:53:37
2b + 3b, 56:44
none
–1
molecule were found to be correspondingly 41.9 and 44.3 kcal mol
0.06
>500f
0.25
0.05
1.0f
>500f
41
–1
in a vacuum, 30.6 and 33.5 kcal mol in methanol environment,
D
–
1
and 28.1 and 31.4 kcal mol for the reaction model with the
simultaneous participation of two MeOH molecules. For the
much slower reacting MPO 1e, the energy barrier is higher by
A, Be
A, Be
C
2c, ~100
2d + 3dg
1d + 2d + 3d, 24:72:4
none
–
1
~
8
3 kcal mol . This difference is not large enough for more than
00­fold slowing the reaction.
Benzene assisted shift (BAS) of signals in H NMR spectra
D
A
1e + 2e + 3e, 20:18:62
1f + 2f + 3f, 50:33:17
1
1
A
96
13,14
is particularly significant for carbonyl compounds.
Nature of
aMethod A. A solution of MPO 1a–f (0.05–0.1 mmol) in carefully purified
methanol (1.00 ml) was stored at 22–25°C under control of the MPO
conversion and the corresponding peracid 2 formation (TLC, visualization
by aqueous sodium iodide). After complete (or partial) MPO conversion,
the solution was evaporated to dryness without warming, and the residue was
BAS consists in formation of a complex in which the benzene
molecule is associated and coordinated with the carbonyl group of
substrate. For our case, benzene may be considered as a probe
allowing one to estimate accessibility of MPO carbonyl groups
towards methanol. Compound 1a manifested the unusually high
dissolved immediately in CDCl . The product composition was analyzed
3
1
by H NMR. Method B. As Method A, but 0.01 m solution of CF COOH
2(f)
3
BAS, the greatest one observed for compounds with CHO
in methanol (pH 2–3) was used. Method C. As Method A, but 2.3 m con­
centration of MPO was used. Method D. A solution of MPO (0.05 mmol)
and methanol (0.1 mmol) in dichloromethane (1.00 ml) was stored at 22–25°C
composition. Table 2 shows BAS values measured for b­located
protons with respect to the carbonyl groups in MPOs 1a–f and
some reference compounds 6–9 (for full NMR spectral data
for benzene solutions, see Online Supplementary Materials). For
compounds 1b–e and 6 BAS values are also unusually large.
This fact can be attributed to two features of the structures in
question: two identical carbonyl groups situated with respect to
the observed proton induce a double effect, and 1,2­dioxolane
cycle of MPOs or 1,3­dioxane cycle in 6 and 7 can make a small
contribution to the total BAS. The value of this contribution
can be estimated by noticeable BAS in 1,3­dioxanes 8 and some
b
under control as in Method A. Assuming quasi­first order in MPO reaction
c
rate. Products 2a–c and 3a–c were identified by comparison with the pre­
9
d
e
viously obtained samples. Yields of product sums ~100%. Results on
f
using Methods A and B are the same. These values are for comparison only
because the reaction rate order was higher in Methods C and D due to
g
MeOH:MPO ratios <10:1. Product isolation was impossible due to its
volatility with methanol.
homologue 2d with methanol vapors, its isolation from the
resulting 0.1 m solution was impossible (complete volatilazing
during evaporation of the solution). Isolation of peracid 2d turned
possible from 2.3 m methanolic solution (Method C), however,
at this concentration the methanolysis rate drops sharply (entry 7).
With 0.1 m solution of methanol in dichloromethane (Method D),
MPOs 1b,d do not react at all (entries 4 and 8), as reported for
1
5
other related molecules, as compared with the absence of BAS
for b­protons in acyclic malonate 9.
O
O
O
O
O
O
O
O
O
O
O
O
OEt
OEt
Me Me
Me Me
Me Me
Me Me
Me Me
Me Me
9
compound 1a.
Under the most favourable conditions (Method A), MPOs
e,f react 800–2000 times slower (entries 9 and 10). Low speed
1
6
7
8
9
of 1f methanolysis is in accordance with the previously described
8
data (566 h at 50°C for full conversion ). However, methanolysis
The most interesting seems the parallelism between BAS values
(see Table 2) and 50% reaction times (see Table 1, Method A)
in the series of MPOs 1b–f with a correlation coefficient of
0.96. It testifies to the same factor affecting the two phenomena,
which can be only shielding of carbonyl groups by the adjacent
gem­dialkyl groups in malonyl moieties.
An exception from this correlation is MPO 1a exhibiting the
largest BAS value but only a moderate rate of methanolysis
(see Table 1, entries 1 and 2). This is apparently due to geometry
distortion of its 1,2­dioxolane cycle caused by a spiro­annulated
cyclopropane ring (according to X­ray analysis, the value of
9
of MPO 1f catalyzed by potassium acetate proceeds as fast as
those of MPOs 1a–c, with complete conversion in 15 min.
¶
The ratio between peracids 2 and the corresponding carboxylic
acids 3 formed in reactions of MPOs 1 with methanol is strongly
dependent of stability of the peracids. An almost quantitative
formation of peracid 2c from spirocyclopentyl­MPO 1c (entry 5)
is of special note.
Spontaneous alcoholysis of MPOs is not limited to methanol.
Recently described ethanolysis of MPO 1c occurs with 91%
conversion in 6 h at 20°C and produces ethyl homologues of
monoesters 2c and 3c (70:18).7
Such a great difference in the rates of spontaneous methano­
lysis between the MPO higher representatives 1e,f and the lower
Table 2 Benzene­d induced shifts of signals for protons at carbons b­posi­
6
tioned to carbonyl carbon.
a
a
Dd (C D –CDCl ) /
Dd (C D –CDCl ) /
6 6 3
¶
6
6
3
A solution of MPO 1f (20 mg, 0.09 mmol) and AcOK (9 mg, 0.09 mmol)
Compound
Compound
ppm
ppm
in MeOH (1 ml) was stored for 15 min at room temperature (TLC indicated
full conversion). The mixture was acidified with CF COOH to pH 2,
chloroform (3 ml) and water (2 ml) were added, the organic layer was
1a
1b
1c
–1.22
–0.97
–0.81
–0.91
–0.65
1f
6
–0.43
–0.52
–0.31
–0.18
+0.04
3
separated, dried (MgSO ) and evaporated to dryness in vacuo. Yield
4
7
8b
1
2
3 mg (~100%) of a mixture of 2f and 3f (43:57), clear oil. H NMR
1
d
e
(
300 MHz, CDCl ) d: 0.89 (t, ~3H, 2Me in 3f, J 7.2 Hz), 0.91 (t, ~3H,
3
1
9
2
2
Me in 2f, J 6.6 Hz), 1.05–1.25 (m, 4H, 2b­CH ), 1.25–1.40 (m, 4H,
2
a
b
g­CH ), 1.80–2.05 (m, 4H, 2a­CH ), 3.75 (s, 1.3H, OMe in 2f), 3.80
Negative ASIS implies upfield shift. Position of ‘carbonyl carbon’ in 8 is
assumed to be as in 7.
2
2
(s, 1.7H, OMe in 3f).
–
244 –

Mendeleev Commun., 2017, 27, 243–245
OC–C–CO angle in 1a reaches 107.6°, which is significantly
This study was supported by the Presidium of the Russian
Academy of Sciences (grant for 2014–2015) and the Russian
Science Foundation (grant no. 14­23­00150).
higher than those in other MPOs3
(a),(b)
). The other exception
for compound 1a is the direction of its reaction with methanol
leading mainly to dimethoxy diacid 4a, a product of three­mem­
bered and then five­membered cycle disclosures. Product 4a was
characterized as its diester 4b (see Scheme 1).†† Methanolysis
of MPO 1a towards the ‘normal’ products 2a and 3a occurs only
to a minor extent.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2017.05.008.
The easy nucleophilic opening of cyclopropane ring in MPO
References
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a by methanol to form product 4a is a consequence of the
1
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6(b)
the most
rapid reaction for carbanion A is its intramolecular oxidation
by the adjacent peroxide group to form a­lactone B. Methanolic
medium partially protects a­lactone B from polymerization
through the reaction with a second methanol molecule, which
leads (after carboxylate anion protonation) to product 4a. The
direction of methanolysis with formation of a­methoxy acid but
not a­hydroxy acid methyl ester as well as easy polymerization
are typical of a­lactones.1
(
(
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MeO–
MeO
MeO
O
O
O
O
O
MeOH
4
a
COO
O
O
O
O
O
1
a
A
B
2
016, 18, 3102.
Scheme 2
5
6
A. Dragan, T. M. Kubczyk, J. H. Rowley, S. Sproules and N. C. O.
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A. O. Terent’ev, V. A. Vil’, G. I. Nikishin and W. Adam, Synlett, 2015,
The observed spontaneous alcoholysis of MPOs may be used
for a fast in situ generation of peracids 2b–d and should be taken
into consideration when carrying out reactions with MPOs in the
presence of alcohols. Spiro­activation of cyclopropane ring in
MPO 1a was also demonstrated in reactions with other nucleo­
2
6, 802.
7 A. O. Terent’ev, V. A. Vil’, E. S. Gorlov, G. I. Nikishin, K. K. Pivnitsky
7
and W. Adam, J. Org. Chem., 2016, 81, 810.
8
9
W. Adam and R. Rucktäschel, J. Org. Chem., 1972, 37, 4128.
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1
1
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†
†
2
,4-Dimethoxy-2-carboxybutanoic acid 4a was isolated from the crude
product after the conversion of MPA (Method B, see Table 1) by preparative
TLC [Merck silica gel plate, hexane–EtOAc–HCOOH (60:40:5), double
development, R 0.09]. Viscous oil, yield 35%. H NMR (300.13 MHz,
CDCl + 1 equiv. of MeOH) d: 2.42 (t, 2H, C H , J 6.0 Hz), 3.32 (s, 3H,
1
f
3
3
2
12 K. M. Jones, PhD Thesis, Cardiff University, 2010.
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4
2
4
13
C OMe), 3.43 (s, 3H, C OMe), 3.55 (t, 2H, C H , J 6.0 Hz). C NMR
2
3
(75.48 MHz, CDCl + 1 equiv. of MeOH) d: 31.84 (C H ), 53.77 (2­OMe),
3
2
4
2
5
8.59 (4­OMe), 66.92 (C H ), 82.67 (C ), 171.18 (2COOH). MS (ESI,
2
+
+
positive ions), m/z: 193.0707 [M+H ], 210.0973 [M+NH ], 215.0522
4
+
+
[M+Na ], 231.0264 [M+K ] (calc. for C H O , m/z: 193.0707, 210.0972,
7
12 6
2
15.0526, 231.0265).
Diacid 4a was converted into dimethyl ester 4b by a treatment with
1
Me SiCHN in MeOH. Clear oil, yield 68%. H NMR (300.13 MHz,
CDCl ) d: 2.37 (t, 2H, C H , J 6.0 Hz), 3.27 (s, 3H, C OMe), 3.37 (s,
3
3
2
3
4
3
2
2
4
13
H, C OMe), 3.46 (t, 2H, C H , J 6.0 Hz), 3.79 (s, 6H, 2COOMe).
C
2
3
NMR (75.48 MHz, CDCl ) d: 32.90 (C H ), 52.78 (2COOMe), 53.65
3
2
4
2
(2­OMe), 58.82 (4­OMe), 66.84 (C H ), 82.94 (C ), 169.03 (2COOMe).
2
+
+
MS (ESI, positive ions), m/z: 221.1019 [M+H ], 243.0842 [M+Na ],
2
+
59.0574 [M+K ] (calc. for C H O , m/z: 221.1020, 243.0839, 259.0578).
Received: 21st September 2016; Com. 16/5051
9
16 6
–
245 –