4-lithiosydnone imines: Generation and stability. Plant growth regulating activity of 4-hydroxymethyl derivatives of sydnone imines

Article abstract of DOI:10.1016/j.jorganchem.2021.121841

The C(4)-deprotonation of N₆-substituted sydnone imines with lithium hexamethyldisilazide (LHDMS), lithium diisopropylamide (LDA), lithium diethylamide (LDEA), and n-BuLi was studied. A thermal stability of 4-lithiosydnone imines was investigated and an efficiency of subsequent reactions of the generated C(4)-lithio derivatives with electrophiles was shown to depend on the exploited deprotonating reagent. It was found that 4-(α-arylhydroxymethyl)sydnone imines, when used for pre-sowing treatment of corn seeds at very low doses (0.25-5 g t^?1), promoted a plant growth up to 60%.

Full text of DOI:10.1016/j.jorganchem.2021.121841

Journal of Organometallic Chemistry 943 (2021) 121841
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
4-lithiosydnone imines: Generation and stability. Plant growth
regulating activity of 4-hydroxymethyl derivatives of sydnone imines
Ilya A. Cherepanova, Ekaterina V. Shevaldinaa, Dmitry A. Lapshinb, Yury Ya. Spiridonovc,
Vladimir A. Abubikerovc, Sergey K. Moiseeva,∗
a A.N.Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences, ul. Vavilova 28, Moscow119991, Russia
b D. Mendeleev University of Chemical Technology of Russia, Miusskaya square, 9, Moscow125047, Russia
c All-Russian Research Institute of Phytopatology, ul. Institut 5, Bolshie Vyazemy, Moscow Region, Moscow 143050, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The C(4)-deprotonation of N6-substituted sydnone imines with lithium hexamethyldisilazide (LHDMS),
lithium diisopropylamide (LDA), lithium diethylamide (LDEA), and n-BuLi was studied. A thermal stability
of 4-lithiosydnone imines was investigated and an efficiency of subsequent reactions of the generated
C(4)-lithio derivatives with electrophiles was shown to depend on the exploited deprotonating reagent.
It was found that 4-(α-arylhydroxymethyl)sydnone imines, when used for pre-sowing treatment of corn
seeds at very low doses (0.25-5 g t−1), promoted a plant growth up to 60%.
Received 11 February 2021
Revised 9 April 2021
Accepted 12 April 2021
Available online 15 April 2021
Keywords:
sydnone imines
© 2021 Elsevier B.V. All rights reserved.
deprotonation
lithium amides
4-lithiosydnone imines
1-methoxy-N,N-dimethylmethanaminium
methylsulfate
plant growth regulators
1. Introduction
tives 2. Sydnone imines are of special interest primarily due to the
wide spectrum of their biological activities [3,4]. These compounds
Sydnone imines (1a,b and 2) are important representatives of
mesoionic heterocyclic compounds [1-4]. Compounds that are un-
substituted on the exocyclic N6 atom are not stable as free bases
1a, but they can form stable salts 1b or the N6-substituted deriva-
have manifested themselves as effective exogenous donors of nitric
oxide (NO), the signaling molecule playing a role in a variety of
biological processes [5-9]. Some of sydnone imine derivatives are
used as medicines (Molsidomine, Sydnophen, Mesocarb). Resently,
sydnone imines have been shown to exhibit plant growth regulat-
ing properties [10-12].
Therefore, a search for new biologically active sydnone imine
based molecules is being actual. So, effective synthetic methods
for preparation of the diversity of these heterocyclic compounds
∗
Corresponding author.
E-mail address: skm@ineos.ac.ru (S.K. Moiseev).
https://doi.org/10.1016/j.jorganchem.2021.121841
0022-328X/© 2021 Elsevier B.V. All rights reserved.

I.A. Cherepanov, E.V. Shevaldina, D.A. Lapshin et al.
Journal of Organometallic Chemistry 943 (2021) 121841
Scheme 1. Cyclization of N-nitroso derivatives 3 to sydnone imine derivatives 1b, 2.
Scheme 2. Formation of 4-lithio derivatives by a deprotonation of sydnone imines with n-BuLi or LHMDS.
are highly desirable. Nowadays, there are two main approaches to
in THF (Scheme 2). The 4-lithio derivatives 4 are stable only at the
temperature below -80°С. According to our data, lithium amides
cannot be used for production of compounds 4 at -90°С. However,
some recent papers [21-23] reported about deprotonation of syd-
none imines with lithium hexamethyldisilazide (LHMDS) at room
temperature in THF (Scheme 2). The authors argued that 4-lithio
derivatives 4 are formed quantitatively under these conditions and
are stable at room temperature for several weeks [21]. These data
are contradictory to our observations.
the preparation of sydnone imine derivatives. The first one is cy-
clization of the appropriately substituted N-nitroso derivatives of
α-aminoacetonitriles 3 (Scheme 1) and the alternative approach is
modification of the pre-synthesized sydnone imine framework [4].
The second way seems to be more preferable for preparation of
families of the structurally similar derivatives for SAR studies.
4-Lithio derivatives are among the most important conventional
reactive intermediates in the sydnone imine chemistry providing
the way to a diversity of the C(4)-substituted sydnone imines [4].
However, the molecular structures of 4-lithio sydnone imines are
still not known in detail because of the lack of single crystal X-
ray studies data for these compounds. This is due to the fact that
4-lithio sydnone imines are stable only in solutions at low temper-
ature and do not survive in a solid state. Nevertheless, the fact that
the C(4)-H deprotonation in sydnone imines with strong lithiated
bases leads to a formation of the corresponding 4-lithio derivatives
has never been questioned by experts in the art. There have been
numerous reports on the use of 4-lithio sydnone imines for the
preparation of a variety of C(4)-substituted derivatives. Specifically,
they have been exploited in the syntheses of 4-hydroxymethyl [13-
15], 4-alkoxycarbonyl [13,14], 4-thioalkyl [15-17], 4-formyl [18,19]
and 4-diphenylphosphino sydnone imines [20]. In some cases the
molecular structures of the resulting products, i. a. substitution at
C(4), have been proven by X-ray single crystal studies or X-ray
powder diffraction analysis (for examples, see [15,17,18,20]). More-
over, the transmetalation reactions of 4-lithio sydnone imines were
used to prepare the corresponding cuprio [13,14], selenio, aurio,
and palladio derivatives [21]. Further Pd-catalyzed cross-coupling
reactions of the cuprio derivatives were found to produce the cor-
responding 4-substituted sydnone imines [13,14]. As for the sele-
nio, aurio, and palladio derivatives, a presence of the direct bonds
of C(4) with Se, Au or Pd in these molecules was shown [21], with
the Au-C(4) and Pd-C(4) bonds were proved by X-ray study.
Taking into account the great importance of this issue for prac-
tice of synthesis, it was decided to thoroughly reexamine the pro-
cess of generation of the lithio derivatives 4 from sydnone imines
5 under the action of various deprotonating reagents and the ther-
mal stability of compounds 4. Aims of this study were to compare
lithium hexamethyldisilazide, lithium diisopropylamide, lithium di-
ethylamide and n-BuLi as deprotonating agents for generation of 4-
lithio derivatives 4, to evaluate the stability of the last ones, and to
use them for preparation of 4-formyl and 4-(α-arylhydroxymethyl)
derivatives, the putative plant growth regulating compounds.
2. Results and discussion
2.1. C(4)-Deprotonation of sydnone imines and stability of 4-lithio
derivatives
2.1.1. Deprotonation procedure and stability monitoring
As sydnone imines unsubstituted at N6 position are unstable
(see above), the direct C(4)-lithiation of compounds 1b is impos-
sible. So, N6-substituted derivatives 5 were used as the starting
materials for deprotonation. Because the direct evaluation of the
yields of the resultant 4-lithio derivatives 4was impossible, the re-
action mixtures after the deprotonation step were treated with
4-chlorbenzadehyde to form, after hydrolytic work-up, the corre-
sponding alcohols 6 (Scheme 3).
We have previously shown [13,14], that 4-lithio derivatives of
sydnone imines (4) can be easily generated by direct deprotona-
tion of sydnone imines 5 unsubstituted at C4 with n-BuLi at -90°С
As one could expect [15], the lithium derivative 4j reacted with
4-chlorobenzaldehyde affording the bicyclic derivative 7 instead
2

I.A. Cherepanov, E.V. Shevaldina, D.A. Lapshin et al.
Journal of Organometallic Chemistry 943 (2021) 121841
Scheme 3. Preparation of alcohols 6 from sydnone imines 5via an intermediate formation of 4-lithiosydnone imines 4.
Scheme 4. Formation of bicyclic derivative 7 from 4j.
of the alcohol 6 as a result of the cyclization reaction shown in
Scheme 4.
Since reactions of organolithium derivatives with aromatic alde-
pholyl), and aryl (phenyl), were used as the starting materials
(Table 1). In addition, starting sydnone imines 5 had the most
important substituents (acetyl, trifluoroacetyl, benzoyl, ethoxycar-
bonyl, tert-butoxycarbonyl, p-toluenesulfonyl, diphenylphosphinyl,
and diphenylphosphoryl) on the exocyclic N6 nitrogen.
hydes usually give high yields and are not accompanied by side
processes (see, for example, [24]), a content of alcohol 6 among the
reaction products after hydrolysis should generally corresponds to
the content of the lithio derivative 4 in the reaction mixture. Quan-
tities of alcohol 6 and the unreacted starting sydnone imine 5 in
reaction mixtures were calculated from the 1H NMR data after hy-
drolysis and evaporation of the solvent using hexamethylbenzene
Lithium diisopropylamide (LDA) and diethylamide (LDEA) were
used as the deprotonating agents along with lithium hexamethyl-
disilazide (LHDMS); the application of the last one was described
earlier [21-23]. The use of cheaper LDA or LDEA for the deproto-
nation instead of LHMDS makes the preparation of lithium deriva-
tives 4 less expensive. Deprotonations of sydnone imines 5 with
lithium amides were carried out under the conditions reported in
ref. [22] (5: lithium amide ratio was 1: 1.2, THF, 20°С, 10 min). De-
protonations of compounds 5 using n-BuLi (1.1 eq.) were carried
out in THF at -80°С for 10 min. The 4-lithio derivatives 4 were
quenched with 4-chlorobenzaldehyde either at -80°С or at 20°С,
with the retention times of 4 at 20°С before the addition of 4-
chlorobenzaldehyde varied within 1-480 min interval. The results
are shown in Table 1.
ꢀ
(HMB) or 4,4 -bis-tert-butyldiphenyl (DTBBP) as the internal stan-
dard. The standard was added to the reaction mixtures after hy-
drolysis.
Stability of lithium derivatives 4 was deduced from their de-
composition rates at room temperature. These rates were evalu-
ated by the time dependent decrease of the yields of alcohols 6.
Measurements were carried out using the 1H NMR as described
above. In the case of deprotonations with lithium amides, a lithium
amide was added to a solution of sydnone imine 5, the mixture
was kept at 20°C and quenched with 4-chlorbenzadehyde 10-720
min after adding the amide. With n-BuLi, deprotonation was car-
ried out at -80°C for 10 min followed by either an addition of 4-
chlorbenzadehyde at -80°C, keeping the mixture for 5 min at this
temperature, warming it to 20°C and keeping for an additional 10
min before the hydrolytic work-up, or quick (1 min) heating of the
5/n-BuLi mixture to 20°C, keeping it for 1-480 minutes at this tem-
perature, and quenching with 4-chlorobenzaldehyde followed by
hydrolysis after additional stirring for 20 minutes. The results are
presented in Table 1.
The data presented in Table 1 obviously allows to divide the
examined sydnone imines into the following three groups: 5a,h,i
(1st group), 5b,c,e,j (2nd group), and 5d,f,g (3rd group). In the first
group of compounds, yields of alcohols 6 are high and do not de-
pend on a type of the deprotonating agent although the use of
lithium amides usually afforded some higher yields than the use of
n-BuLi. In the second group, yields of alcohols are generally slightly
lower than those in the first group (excepting 5i) and the best
results in the most cases were observed when n-BuLi was used
as the deprotonating agent, especially in comparison with LDA or
LDEA. As for the third group of the sydnone imines, alcohols 6
were prepared in moderate yields (25-78%) using only n-BuLi. The
use of LHMDS, LDA or LDEA as the deprotonating reagents gave
very poor yields (1-6%) of compounds 6, if any. These results can
be explained by the difference in the stabilities of 4-lithio deriva-
tives 4a-j.
2.1.2. Generation of 4-lithiosydnone imines
To study the deprotonation reaction and to examine stabili-
ties of the arising 4-lithio derivatives 4, sydnone imines 5 bear-
ing conventional types of substituents on the N(3) nitrogen of
the oxadiazole ring, such as alkyl (isopropyl), dialkylamino (mor-
3

I.A. Cherepanov, E.V. Shevaldina, D.A. Lapshin et al.
Journal of Organometallic Chemistry 943 (2021) 121841
Table 1
Deprotonation of sydnone imines 5 with lithium amides or n-BuLi followed by a derivatization of 4-lithiosydnone imines 4 with 4-chlorobenzaldehyde.
Starting sydnone imine
Deprotonation with R2NLi
Deprotonation with n-BuLi
Method Aa
R2NLi, yields of 4(5), %b
Method Bc
Method Cd
5
R’
R”
Time period, min
LHDMS
i-Pr2NLi
Et2NLi
96(3)
Time period, min
Yields of 4(5), %b
Yields of 4(5), %b
5a
i-Pr
CO-Ph
10
96(1)
93(1)
93(1)
84(5)
57(8)
53(7)
34(7)
0(9)
5
93(6)
-
30
15
85(11)
60
24(25)
1(38)
120
180
360
600
10
30
60
77(6)
89(5)
60(13)
0(20)
28(25)
5b
5c
i-Pr
i-Pr
CO-CH3
CO-CF3
85(12)
66(11)
2(41)
34(23)
1(15)
27(40)
0(14)
5
62(17)
25(33)
0(48)
76(22)
60(19)
30
15
30
0
60
10
58(14)
32(29)
22(41)
6(9)
1(34)
30
60
5d
5e
i-Pr
i-Pr
SO2-C6H4-
CH3
10
1(34)
0(17)
1(24)
0(20)
0
1(65)
77(15)
80(20)
CO-
10
30
63(13)
0(29)
1
67(30)
50(20)
0(28)
1(33)
0(24)
94(3)
OC(CH3)3
10
30
0
5f
i-Pr
P(O)Ph2
10
4(36)
0(12)
93(2)
93(6)
87(2)
54(8)
35(20)
0(11)
53(8)
50(13)
49(17)
40(22)
14(29)
0(0)
0(0)
25(72)
78(1)
-
5g
5h
i-Pr
P(O)(OPh)2
CO-OEt
10
0(27)
85(9)
0(43)
86(3)
0
N-morpholine
10
10
60
120
240
360
720
10
60
57(14)
45(18)
120
5i
Ph
Ph
CO-
59(25)
58(34)
5
58(14)
45(38)
40(39)
24(51)
22(42)
8(54)
-
OC(CH3)3
60
30
120
240
480
60
120
240
480
30
5j
P(O)(OPh)2
10
36e(47)
25e(40)
3e(56)
17e(69)
20e(52)
21e(17)
7e(60)
45e(18)
60
60
120
a
Method A. A mixture of5 and LiNR2 was stirred at 20°C for the time period indicated in the table and 4-chlorobenzaldehyde was added. The mixture was
stirred for 20 min and quenched with water.
b
Calculated from the 1H MNR data using the internal standard.
c
Method B. A mixture of5 and n-BuLi was stirred at -80°C for 10 min, warmed up to 20°C for 1 min and kept at 20°C for the time period indicated in the table
followed by an addition of 4-chlorobenzaldehyde. The mixture was stirred for 20 min and quenched with water.
d
Method C. A mixture of5 and n-BuLi was stirred at -80°C for 10 min and 4-chlorobenzaldehyde was added. Themixturewas warmed up to 20°C stirred for 20
min and quenched with water.
e
Yieldofcompound7.
Taken together, the data presented in Table 1 outline the suit-
ability of the 4-lithio derivatives derived from structurally varied
sydnone imines for synthetic purposes.
position while keeping at 20°C for 2-3 h. However, they fully de-
composed at room temperature within 10 h. These data contradict
the statement [21,22] that 4-lithio derivatives of sydnone imines
(including those generated from 5h) are stable for several weeks.
It is convenient to use the “half-decomposition” time (T1/2
)
2.1.3. Stability of 4-lithiosydnone imines
at 20°C as a measure of the apparent thermal stability of the
4-lithio derivatives 4. T1/2 is the time period for which the re-
action mixture prepared by mixing a sydnone imine 5 and a
lithium amide should be kept at 20°C before the addition of 4-
chlorobenzaldehyde to reduce the yield of the corresponding alco-
hol 6 by two folds. In the case of deprotonations with n-BuLi, T1/2
is the time of keeping the reaction mixture at 20°C after warming
it from -80°C to 20°C before the addition of 4-chlorobenzaldehyde.
The experimental data presented in Table 1 show that the sta-
bility of lithio derivatives 4 depends on the substituents at N(3)
and N6. It additionally depends on the deprotonating reagent used
to obtain compounds 4. Some of 4-lithio derivatives suddenly
turned out to be rather stable. Unlike the majority of the 4-lithio
derivatives, which rapidly decomposed at room temperature, that
ones generated from the 1st group of sydnone imines (5a,h,i) by
the action of LHMDS were found to undergo only minor decom-
4

I.A. Cherepanov, E.V. Shevaldina, D.A. Lapshin et al.
Journal of Organometallic Chemistry 943 (2021) 121841
Table 2
The apparent “half-decomposition” time (T1/2, min) of 4-lithio derivatives 4a-j generated from 5a-jby the action of LHMDS or n-BuLi.
Compound 4
RLi
R’, R”
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
R’
i-Pr
i-Pr
i-Pr
-CO-CF3
40
i-Pr
i-Pr
i-Pr
i-Pr
N-morphlyl
-CO-OEt
300
Ph
Ph
R”
-CO-Ph
450
-CO-CH3
40
-SO2-C6H4-CH3
a
-CO-OC(CH3)3
-P(O)Ph2
a
-P(O)(OPh)2
a
-CO-OC(CH3)3
-P(O)(OPh)2
LHMDS
-
0b
15
15
-
0b
-
0b
300
120
100
20
n-BuLi
45
10
0b
120
a
Alcohol 6 was not formed.
b
The lithio derivative was completely decomposing while warming up to 20°C.
The approximate apparent T1/2 values of 4-lithio derivatives 4a-j
generated from compounds 5a-j by treatment with LHMDS or n-
BuLi are shown in Table 2. As on can see, the stability values given
in Table 2 for a specific lithio derivative vary depending on the de-
protonating reagent used for generation of the compound. As a re-
sult, the features of the specific deprotonation process (see below
in this section) affect the values. Therefore, it should be specially
noted, that these are the apparent, not true, values.
LHDMS, as the deprotonating agents leads to a shift of the equilib-
rium towards the lithio derivatives 4, thus decreasing the apparent
stability of compounds 4. In the case of n-BuLi, the deprotonation
reaction is irreversible.
Our assumption that the equilibrium at deprotonation of 5 un-
der the action of LHMDS is shifted towards the starting materi-
als contradicts the statement[16, 17] that 4-lithio derivatives 4 are
formedin this reaction quantitatively. It should be taken into ac-
count that the quantitative formation of 4 was deduced [21,22]
only from the NMR data, although this method is not applicable to
the fast dynamic processes. The almost quantitative yields of the
products in some reactions of 4 with electrophiles both reported
in [21,22] and observed by us can be easily explained by a gradual
shift of the equilibrium “to the right” as the lithio derivatives 4 are
consumed by the electrophiles.
The data presented in Table 2 show that the substituent on
the N6 nitrogen exerts a significant impact on the stability of
4-lithio derivatives generated from 3-alkyl substituted sydnone
imines. Among them, the most stable is the N6-benzoyl derivative
4a. The corresponding alkylcarbonyl and alkoxycarbonyl derivatives
are less stable. The 4-lithio derivatives bearing a heteroatomic sub-
stituent, such as 4-tolylsulfonyl (4d), diphenylphosphinyl (4f) or
diphenylphosphoryl (4g) groups, at N6 have the least stability and
were completely decomposing while warming up to room temper-
ature.
Lithium dialkylamides have been reported to add the car-
bonyl group of benzaldehydes affording the lithium α-dialkylamino
alkoxides [25,26]. In turn, LHMDS reacts with benzaldehyde to
form the corresponding N-trimethylsilyl imine [27]. However, these
reactions proceed at moderate rates taking in some cases more
then 10 minutes at room temperature. Therefore, an addition re-
action of lithium amides to the carbonyl group of benzaldehydes
is only weakly able to compete with both the deprotonation of
compounds 5 and the reaction of the 4-lithio derivative 4 with
benzaldehyde. In addition, it should be taken into account that
we used the excesses of both lithium amides (1.2 equiv) and p-
chlorobenzaldehyde (1.3 equiv) in the reactions under considera-
tion. This also reduces the possible effect of the side reaction of
the deprotonating reagent with the electrophile on the reaction
consequence5→ 4→6.
A stability of 4-lithio derivatives 4 also strongly depends on the
substituent at N(3) of the oxadiazole ring. With N6-alkoxycarbonyl
derivatives, the thermal stability of the N6-ethoxycarbonyl substi-
tuted compound 4h bearing an amino functionality at N(3) is sig-
nificantly higher than that of the N(3)-isopropyl substituted deriva-
tive 4e with the tert-butoxycarbonyl group at the N6 nitrogen. The
phenyl substituent at N(3) of the oxadiazole ring increases the sta-
bility of 4. The 3-phenyl derivatives 4i and 4j are significantly more
stable than their 3-alkyl analogs4e and 4g.
It should be noted that compounds 4 obtained by deprotonation
of 5 with n-BuLi exhibited lower apparent stability then their rel-
atives prepared using LHMDS as the base. This observation would
be explained by stabilization of lithio derivatives 4 upon their co-
ordination with the amine formed from LHMDS during the depro-
tonation reaction. However, the use of LDA or LDEA as deprotonat-
ing reagents resulted in a formation of compound 4a that demon-
strated the low apparent stability (Table 1) comparable to that
one exhibited by this lithio compound obtained using n-BuLi as
the base. In our opinion, the equilibrium character of the depro-
tonation process can explain the higher apparent stability of com-
pounds 4 obtained using LHMDS. Unlike the reaction with n-BuLi,
the equilibrium in the case of LHMDS is shifted towards the start-
ing compound 5, so that the low concentration of the generated
4-lithio derivative 4 leads to a decrease in the rate of the decom-
position reaction and, consequently, to an increase of the appar-
ent stability. The use LDA or LDEA, the stronger bases compared to
As one can see from the data presented in Table 1 the first
group sydnone imines (5a,h,i) that give the relatively stable 4-
lithio derivatives produce the alcohols 6a,h,i in very similar yields
irrespectively the type of the deprotonating reagent used for gen-
eration of the lithium intermediates 4a,h,i. So, the use of LDA
or LDEA in these cases compares favorably with more expen-
sive LHDMS and allows deprotonation at room temperature, thus
greatly simplifying the synthetic procedure. In contrast, the depro-
tonation of 4 with n-BuLi can be carried out only at low tem-
perature (-80°C), since our attempts to carry out this reaction at
room temperature resulted in resinification of the reaction mix-
tures. However, the sydnone imines of the second (5b,c,e,j) and,
especially, the third (5d,f,g) groups producing the much less stable
4-lithio derivatives should be deprotonated with n-BuLi at -80°C,
5

I.A. Cherepanov, E.V. Shevaldina, D.A. Lapshin et al.
Journal of Organometallic Chemistry 943 (2021) 121841
Table 3
Preparation of 4-formylsydnone imines 9.
Deprotonation with R2NLi
Deprotonation with n-BuLi
Compound
R2NLi, yields of 9(5), %a,b
Temperature,
Yields of
9(5), %a
5
°C
LHDMS
i-Pr2NLi
Et2NLi
5a
5b
69(10)
28(3)
66(35)
17(6)
26(73)
0(38)
20c
-80
20c
-80
-80
-80
-80
-80
20c
20c
-80
80(18)
42(2)
34(4)
5c
5d
5e
5f
16(26)
0(12)
9(39)
0(22)
0(17)
66(9)
29(30)
1(74)
0(57)
-
0(74)
-
19(63)
52(16)
60(37)
6(21)
-
-
0(57)
0(63)
55(20)
21(51)
0(84)
0(51)
0(50)
19(73)
12(65)
1(79)
5g
5h
5i
38(50)
66(33)
28(62)
26(62)
5j
a
Calculated from 1H MNR data using the internal standard.
b
c
The percentages of the unreacted starting compounds 5 are given in parentheses.
A solution of the lithio derivative 4 was heated from -80°C to 20°C for 1 min before adding the reagent 8.
because the use of LHMDS at room temperature leads to lower
yields of the products 6. Both LDA and LDEA are inapplicable in
these cases due to very poor yields of the alcohols 6, if any.
2.3. Synthesis of 4-(α-substitutedhydroxymethyl) derivatives sydnone
imines for plant growth regulation studies
We prepared the α-substituted 4-hydroxymethyl derivatives of
sydnone imines 10 and 11 from the corresponding 4-lithiosydnone
imines (Scheme 5) to evaluate their plant growth regulating prop-
erties (see Section 2.4). To conduct SAR studies in this family, the
compounds with variable substituents on the C(4) carbon were
necessary, as well as both N6-unsubstituted compounds (the syd-
none imine salts) and their N6-substituted relatives. Since syd-
none imines unsubstituted at N6 are stable only as salts, the direct
C(4)-lithiation of such salts is impossible. So, we used the N6-Boc-
protected derivatives 12 as the starting materials and metalated
them according the previously reported method [28].
2.2. Synthesis of 4-formyl derivatives of sydnone imines
We have proposed previously a method for preparation of 4-
formylsydnone imines by the reaction of 4-lithiosydnone imines
with an adduct of dimethylformamide with dimethyl sulfate
(1-methoxy-N,N-dimethylmethanaminium methylsulfate, 8) [18,19]
inasmuch as these compounds cannot be obtained by a con-
ventional reaction of the organolithiums with DMF due to an
insufficient reactivity of 4-lithiosidnone imines. In addition, 4-
formylsydnone imines can be exploited as the starting materials
in an alternative approach to preparation of the α-substituted or
unsubstituted 4-(hydroxymethyl) derivatives similar to the alcohols
reported in section 2.3, the putative plant growth regulators (see
section 2.4). Herein, we compared the applicability of various de-
protonating agents (LHMDS, LDA, LDEA, and n-BuLi) for production
of lithium intermediates 4 in the syntheses of 4-formyl derivatives
of sydnone imines 9. The results are shown in Table 3.
The reaction of aromatic aldehydes with C(4)-lithiated interme-
diates formed on the deprotonation of compounds 12a-f under the
action of n-BuLi followed by the hydrolytic workup of the reac-
tion mixtures led to the formation of the corresponding N6-Boc-
substituted derivatives 10. Subsequent removal of the protective
Boc-group proceeded smoothly [28] and furnished the required N6-
unsubstituted compounds 11 as the hydrochlorides.
In all cases, the use of LDEA, as compared to other deprotonat-
ing reagents, lead to lower yields of 4-formyl derivatives 9. This
may be explained by the competitive side reaction of LDEA with
the highly reactive reagent 8. In this case, the rate of the reaction
of LDEA with the electrophile is comparable or exceeds the rate
of the deprotonation reaction thus notably decreasing the yield of
the aldehydes 9. With the 1st group sydnone imines (5a,h,i), the
use of sterically hindered bases (LHMDS, LDA) allows a prepara-
tion of aldehydes 9 in high yields. In contrast, with the 2nd and
3rd group sydnone imines, n-BuLi turned out to be the only reagent
applicable for the preparation of 4-formyl derivatives, since the use
of lithium amide deprotonating reagents delivered only very poor
yields of 9, if any.
2.4. Plant growth regulating activity of sydnone imines
Recently we were the first to show that derivatives of syd-
none imine have a pronounced effect on the growth and devel-
opment of plants [11,12]. Specifically, compounds 12 and 13 with
dimethylamino or N-morpholyl groups attached to the N(3) nitro-
gen showed a herbicidal effect in very small doses (1 g and 10 g
per 1 ton of seeds) negatively affecting the germination of sun-
flower seeds [11]. In contrast, C(4)-unsubstituted N(3)-alkyl and
N(3)-amino derivatives of sydnone imines 14 taken as either hy-
drochlorides or N6-acylated relatives in the experiments on corn
6

I.A. Cherepanov, E.V. Shevaldina, D.A. Lapshin et al.
Journal of Organometallic Chemistry 943 (2021) 121841
Scheme 5. Synthesis of α-aryl substituted 4-hydroxymethyl derivatives 10a-f and 11a-c.
seeds stimulated the seed germination and the development of
both shoots and roots [12].
But this influence is not unambiguous. For example, the growth
These results have proved sydnone imines to emerge as a new
family of plant growth regulating compounds. So, the data on the
relationship between the molecular structures of sydnone imine
derivatives and their plant growth regulating properties are of
undoubted interest. As noted above, the plant growth regulating
sydnone imine derivatives have so far been exemplified only by
the C(4) unsubstituted compounds. Therefore, it was of interest to
disclose whether the derivatives substituted at C(4) possess the
growth regulating properties, and, if it would be the case, how
these properties are affected by the substituents both at C(4) and
at N(3) and N6. With this background, we examined α-arylated 4-
hydroxymethylsydnone imines 10a-f, 11a-c readily available from
the reaction of 4-lithiosidnone imines with aromatic aldehydes
(see Section 2.3) for pre-sowing treatment of corn seeds, which
were than evaluated in the pot experiments. The results (see the
Table in Supporting Information) showed that all examined com-
pounds, except 10e,f, exhibited the corn growth stimulation at
very low doses (0.25-5 g t−1 of seeds). The increase in the shoots
weight of the plants compared to the control (Ctrlaq.) reached 64%
and was dose depended in many cases.
stimulating effect is the maximum for the unprotected compound
11a (57-64%) at higher doses (0.5 and 1.0 g t−1) and essentially
decreases (23%) at a dose of 0.25 g t−1, whereas the corresponding
Boc-protected compound 10a is notably less active, but the activity
of the last is the same at all doses (36-40%). On the contrary, the
stimulating effects of compounds 10b and 11b at a dose of 1 g
t−1 are similar (45-49%), with the effect of 10b decreased with the
decrease of the dose while the effect of 11b decreased as the dose
increased.
At doses of 0.5 g t−1, the growth stimulating effect of the Boc-
derivative 10c was approximately 2 times higher than that of the
unprotected compound 11c (38% and 20%, respectively) and de-
creased to the same value (14%) at higher doses. The effect of the
N(3)-isopropyl substituted derivatives 10a,b and 11a,b was more
pronounced than that of the corresponding N(3)-morpholyl deriva-
tives 10c and 11c. This testifies that the substituent at N(3) affects
the growth stimulating ability of sydnone imines. Therefore, the
relative activity of N(3)-alkyl substituted compounds was screened.
It was found that among compounds 10b,d,e bearing the identi-
cal substituents both at C(4) and at N6, the substituent at N(3)
strongly influenced the growth regulating effect. The N(3)-ethyl
substituted compound 10d turned to be less active than the iso-
propyl derivative 10b, and the 2-metoxyethyl derivative 10e con-
taining the heteroatom in the N(3)-alkyl chain was found to be
A comparison of N6-Boc protected compounds 10a-c with their
unprotected counterparts 11a-c proved that a Boc group can affect
the activity of the compounds both qualitatively and quantitatively.
7

I.A. Cherepanov, E.V. Shevaldina, D.A. Lapshin et al.
Journal of Organometallic Chemistry 943 (2021) 121841
inactive. The aromatic auxiliary in the substituent at C(4) also has
some effect on the growth regulation (compounds 10a,b). We were
surprised to found that the imidazole derivative 10f was inactive.
This result may indicate that the replacement of an aryl group at
the α-position to C(4) of sydnone imines with a heteroaryl sub-
stituent may affect either bioavailability of these compounds or
their metabolism.
umn liquid chromatography was performed using silica gel (parti-
cle size 80 μm).
All solvents were purified (dried and distilled) before use
according to literature methods. All reactions were performed
in an argon atmosphere in dried glassware. All reagents were
used as supplied by commercial sources unless otherwise
stated. Starting sydnone imines were prepared as described 5a,b
[29], 5c,d [19], 5e,i [28], 5f,g,j [15], 5h [30].1-Methoxy-N,N-
dimethylmethanaminium methylsulphate (8) was obtained accord-
ing to the known method [31].
All in all, C(4)-substituted sydnone imines are promising plant
growth regulating compounds. Specifically, the majority of the 4-
hydroxymethyl derivatives investigated in this work stimulated the
corn development in pot experiments (up to 64% increase of the
shoots weight). This effect was shown to have, as a rule, a dose
dependent character, along with the magnitude of the effect de-
pends on a molecular structure of the sydnone imine derivative,
specifically, on the substituents at N(3) and N6 as well as the
nature of the aromatic group in the substituent at C(4). Obvi-
ously, the structure-activity relationship data of biologically active
compounds can be correctly interpreted only with the informa-
tion on their mode of action in hands. At the moment, we asso-
ciate the mode of action of the sydnone imine derivatives as the
plant growth regulators with the above mentioned role of sydnone
imines as the exogenous donors of nitrogen(II) oxide molecules.
However, this needs the unambiguous proofs. The relative studies
are now in progress and the results will be published anywhere.
4.2. Generation of 4-lithio derivatives of sydnonimines 4a-j by the
action of different deprotonating agents and study of their stability
4.2.1. Deprotonation of sydnone imines with n-BuLi
To a solution of sydnone imine 5 (0.60 mmol) in THF (20 ml)
was added 1.9M solution of n-BuLi (0.32 ml, 0.66 mmol) in hex-
ane at -80°С. The mixture was stirred at -80°С for 10 min and
1M solution of p-chlorobenzaldehyde (0.72 ml, 0.72 mmol) in THF
was added. The mixture was stirred for 5 min. The reaction mix-
ture was heated on a water bath to room temperature, stirred for
another 20 min, then quenched with H2O (1 ml) and the inter-
ꢀ
nal standard (0.60 ml, 0.1 mmol, 0,167М solution of 4,4 -di-tert-
butylbiphenyl or hexamethylbenzene in THF) was added. The sol-
vent was evaporated under reduced pressure.
For the stability evaluation of the 4-lithio derivatives of sydnone
imines 4, the addition of n-BuLi to the solution of 5 and keeping
the mixture at -80°С for 10 min was followed by quick heating the
reaction mixture on a water bath to room temperature and keeping
it at this temperature for 0-480 min (Table 1). Then, 1 M solution
of p-chlorobenzaldehyde (0.72 ml, 0.72 mmol) in THF was added,
the mixture was stirred for 20 min and quenched with H2O (1 ml).
3. Conclusion
To conclude, we re-examined the C(4)-deprotonation of syd-
none imines under the action of lithium amides (LHDMS, LDA,
LDEA) and n-BuLi. As a rule, 4-lithiosydnone imines were found
to exhibit a low thermal stability. However, the stability substan-
tially depends on the nature of the substituents at N(3) and N6 of
the sydnone imines. Some 4-lithiosydnone imines survive on keep-
ing in THF solutions at room temperature for dozens of minutes.
So, lithium amides, LHDMS or cheaper LDA or LDEA, can be uti-
lized for preparation of these organolithiums as the deprotonat-
ing reagents. The use of n-BuLi as the base for this purpose is
more general, however, the too low temperature of the process
complicates it. In addition, we found that α-aryl substituted 4-
hydroxymethylsydnone imines readily available from the reaction
of 4-lithiosidnone imines with aromatic aldehydes exhibit plant
growth regulating properties. Utilized for a pre-sowing treatment
of corn seeds at very low doses (0.25-5 g per ton of seeds), these
compounds in pot experiments showed a stimulation of the corn
development resulting in an increase of the shoots weight up to
64% compared to the control.
ꢀ
An internal standard (0.60 ml, 0.1 mmol, 0,167М solution of 4,4 -di-
tert-butylbiphenyl or hexamethylbenzene in THF) was added. The
solvent was evaporated under reduced pressure.
In both cases, the residue after evaporation of the solvent was
passed through a layer of SiO2 (20 × 20 mm) using EtOAc/CHCl3
(1:1) as the eluent. After removing the solvent at reduced pres-
sure, the residue was analyzed by 1H NMR spectroscopy (see Sup-
plementary materials).
4.2.2. Deprotonation of sydnone imines with LHMDS
To a solution of sydnonimine 5 (0.60 mmol) in THF (20 ml) a
1M solution of LHMDS (0.72 ml, 0.72 mmol) in THF was added. The
mixture was stirred at room temperature for 10-720 min (Table 1)
and 1M solution of p-chlorobenzaldehyde (0.72 ml, 0.72 mmol)
in THF was added. The reaction mixture was stirred for 20 min
and quenched with H2O (1 ml). The internal standard (0.60 ml, 0.1
4. Experimental
ꢀ
mmol 0,167М solution of 4,4 -di-tert-butylbiphenyl or hexamethyl-
benzene in THF) was added. The solvent was evaporated under re-
duced pressure. The residue was passed through a layer of SiO2
(20 × 20 mm) using EtOAc:CHCl3 (1:1) as the eluent. After evapo-
ration of the solvent at reduced pressure, the residue was analyzed
by 1H NMR spectroscopy (see Supplementary materials).
4.1. Materials and instrumentation
NMR spectra were recorded on a Bruker Avance 400 NMR spec-
trometer with basic frequencies of 400.13 MHz for 1H, 100.62 MHz
for 13C, 161.96 MHz for 31P, and 376 MHz for 19 F. All chemical
shifts in 1H and 13C spectra were referenced by TMS and resid-
ual deuterium solvents signals. In 31P spectra, all chemical shifts
were referenced by orthophosphoric acid. In 19 F chemical shifts
were referenced by trichlorofluoromethane. Data are reported as
follows: chemical shifts (δ), multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, br = broad, m = multiplet), coupling con-
stants (J, Hz). Elemental analyses were performed using a Carlo-
Erba CE-1106 elemental analyzer. Melting points were determined
with an Electrorthermal 1002 MEL-TEMP® capillary melting point
apparatus and are uncorrected. TLC was performed on Silufol UV-
254 plates; the spots were visualized in camera with iodine. Col-
4.2.3. Deprotonation of sydnone imines with lithium diethylamide or
diisopropylamide
A 1.9 M solution of n-BuLi (0.38 ml, 0.72 mmol) in hexane was
added to a solution of diethylamine (0.08 ml, 0.78 mmol) or di-
isopropylamine (0.11 ml, 0.78 mmol) in THF (20 ml). The mix-
ture was stirred for 10 min and sydnone imine 5 (0.6 mmol) was
added. The mixture was stirred at room temperature for 10-180
min (Table 1) and 1M solution of p-chlorobenzaldehyde (0.72 ml,
0.72 mmol) in THF was added. The mixture was stirred for 20 min
and quenched with H2O (1 ml). The internal standard (0.60 ml,
8

I.A. Cherepanov, E.V. Shevaldina, D.A. Lapshin et al.
Journal of Organometallic Chemistry 943 (2021) 121841
ꢀ
0.1 mmol 0,167М solution of 4,4 -di-tert-butylbiphenyl or hexam-
White solid, m. p. 142-143°C. Calculated for C14 H16 ClN3O3: C,
54.29; H, 5.21; Cl, 11.45; N, 13.57 %. Found C, 54.41; H, 5.33; N,
13.68 %. 1H NMR (400 MHz, CDCl3) δ 1.26 (d, 3H, J = 6.7 Hz,
CH(CH3)2); 1.67 (d, 3H, J = 6.6 Hz, CH(CH3)2); 2.11 (s, 3H, CH3CO);
4.99 (hept, 1H, J = 6.6 Hz, CH(CH3)2); 6.27 (s, 1H, CH-OH); 7.06
(sbr, 1H, CH-OH), 7.32-7.39 (m, 4H, C6H4). 13C NMR (101 MHz,
CDCl3) δ 21.6 (C10, C10’), 22.0 (C10, C10’), 26.8 (C11 ), 57.6 (C9), 63.3
(C11 ), 118.7 (C4), 126.9 (C13), 128.8 (C14 ), 133.8 (C15), 137.9 (C12),
169.0 (C5), 179.4 (C7). (2D1H13C-HMQC and 2D1H13C-HMBC corre-
lation of 6b – See Supplementary materials)
ethylbenzene in THF) was added. The solvent was evaporated un-
der reduced pressure and the residue was passed through a layer
of SiO2 (20 × 20 mm) using EtOAc:CHCl3 (1:1) as eluent. The sol-
vent was evaporated at reduced pressure and analyzed by 1H NMR
spectroscopy (see Supplementary materials).
4.3. Preparation of 4-formyl derivatives of sydnone imines (9)
(general procedure)
A
1M solution of 1-methoxy-N,N-dimethylmethanaminium
4-[(4’-Chlorophenyl)hydroxymethyl]-3-isopropyl–N6-
methylsulphate 8 (0.72 ml, 0.72 mmol) in DMF was added to a
solution of the 4-lithio derivative of sydnone imine 4 (0.6 mmol)
in THF (20 ml) prepared by one of the methods described above
(see Table 1). The reaction mixture was stirred for 20 min and
quenched with H2O (1 ml). The internal standard (0.60 ml, 0.1
trifluoroacetylsydnone imine (6c).
ꢀ
mmol, 0,167М solution of 4,4 -di-tert-butylbiphenyl or hexamethyl-
benzene in THF) was added. The solvent was evaporated at re-
duced pressure. The residue was dissolved in ethyl acetate (20
ml) and washed with water (20 ml). The organic layer was sep-
arated and passed through a layer of SiO2 (20 × 20 mm) using
EtOAc:CHCl3 (1:1) as the eluent. The solvent was evaporated at re-
duced pressure and analyzed by 1H NMR spectroscopy (see Sup-
plementary materials).
White solid, m. p. 134-135°C. Calculated for C14 H13ClF3N3O3: C,
46.23; H, 3.60; Cl, 9.75; F, 15.67; N, 11.55 %. Found C, 46.36; H,
3.73; N, 11.62 %. 1H NMR (400 MHz, CDCl3) δ 1.32 (d, 3H J = 6.6
Hz, CH(CH3)2); 1.74 (d, 3H, J = 6.6 Hz, CH(CH3)2); 5.10 (hept,
1H, J = 6.5 Hz, CH(CH3)2), 6.40 (s, 1H, CH-OH), 7.32-7.41 (m, 4H,
C6H4). 13C NMR (101 MHz, CDCl3) δ 21.7, 22.1, 58.9, 63.3, 118.3
(q, J = 285.9 Hz), 121.3, 126.7, 129.1, 134.3, 136.7, 142.5, 162.6 (q,
J = 36.3 Hz), 170.0. 19 F NMR (376 MHz, CDCl3) δ -75.57.
4-[(4’-Chlorophenyl)hydroxymethyl]-3-isopropyl-N6-
The analytical samples of compounds 6a-i, 7, 9a-j were
obtained by column chromatography (SiO2, 20
×
150 mm,
EtOAc:CHCl3 (from 1:9 to 1:1)) followed by crystallization from,
unless otherwise indicated, isopropanol/hexanes.
4.4. Analytical data for compounds 6a-i, 7, 9a-j
4-[(4’-Chlorophenyl)-hydroxymethyl]-3-isopropyl-N6-
tosylsydnone imine (6d).
benzoylsydnone imine (6a).
White solid, m. p. 162-163°C. Calculated for C19 H18 ClN3O3: C,
61.37; H, 4.88; Cl, 9.54; N, 11.30 %. Found C, 61.40; H, 4.91; N, 11.28
%. 1H NMR (400 MHz, CDCl3) δ 1.24 (d, 3H, J = 6.7 Hz, CH(CH3)2);
1.76 (d, 3H, J = 6.6 Hz, CH(CH3)2); 5.14 (hept, 1H, J = 6.4 Hz,
CH(CH3)2); 6.14 (s, 1H, CH-OH); 6.73 (s, 1H, CH-OH); 7.34-7.37 (m,
5H + 1H, C6H4Cl + m-C6H5); 7.45 (t, 1H, J = 7.3 Hz, p-C6H5); 8.05
(d, 2H, J = 7.4 Hz, o-C6H5). 13C NMR (101 MHz, CDCl3) δ 21.7, 22.0,
57.2, 63.5, 119.1, 126.8, 127.9, 128.8, 129.6, 131.5, 133.7, 137.0, 138.0,
168.3, 173.6.
White solid, m. p. 183-184°C. Calculated for C19 H20ClN3O4S: C,
54.09; H, 4.78; Cl, 8.40; N, 9.96; S, 7.60 %. Found C, 54.17; H, 4.85;
N, 10.07 %. 1H NMR (400 MHz, DMSO-d6) δ 1.22 (d, 3H, J = 6.7
Hz, CH(CH3)2); 1.55 (d, 3H, J = 6.6 Hz, CH(CH3)2); 2.37 (s, 3H,
CH3-C6H4); 5.09 (hept, 1H, J = 6.6 Hz, CH(CH3)2); 5.95 (d, 1H,
J = 4.3 Hz, CH-OH); 6.87 (d, 1H, J = 4.3 Hz, CH-OH); 7.35 (d,
2H, J = 8.1 Hz, C6H4-CH3); 7.40 (d, 2H, J = 8.6 Hz, C6H4-Cl); 7.45
(d, 2H, J = 8.6 Hz, C6H4-Cl); 7.74 (d, 2H, J = 8.2 Hz, C6H4-CH3).
13C NMR (101 MHz, DMSO-d6) δ 21.4, 21.8, 22.0, 58.0, 62.9, 116.3,
126.8, 127.8, 128.9, 129.8, 132.9, 138.9, 140.7, 142.6, 163.2.
4-[(4’-Chlorophenyl)hydroxymethyl]-3-isopropyl-N6-tert-
butoxycarbonylsydnone imine (6e).
4-[(4’-Chlorophenyl)hydroxymethyl]-3-isopropyl–N6-
acetylsydnone imine (6b).
9

I.A. Cherepanov, E.V. Shevaldina, D.A. Lapshin et al.
Journal of Organometallic Chemistry 943 (2021) 121841
White solid, m. p. 159-160°C. Calculated for C17 H22ClN3O4: C,
55.51; H, 6.03; Cl, 9.64; N, 11.42 %. Found C, 55.58; H, 6.09; N, 11.46
%. 1H NMR (400 MHz, CDCl3) δ 1.18 (d, 3H J = 6.7 Hz, CH(CH3)2);
1.49 (s, 9H, C(CH3)3); 1.62 (d, 3H, J = 6.6 Hz, CH(CH3)2); 4.96 (hept,
1H, J = 6.3 Hz, CH(CH3)2); 6.32 (sbr, 1H, CH-OH); 6.17 (s, 1H, CH-
OH); 7.28-7.35 (m, 4H, C6H4). 13C NMR (101 MHz, CDCl3) δ 21.5,
22.1, 28.2, 57.3, 62.9, 79.8, 117.2, 126.9, 128.8, 133.7, 138.4, 158.6,
167.4.
4-[(4’-Chlorophenyl)hydroxymethyl]-3-morpholyl-N6-
ethoxycarbonylsydnone imine (6h).
4-[(4’-Chlorophenyl)hydroxymethyl]-3-isopropyl-N6-
diphenylphosphinylsydnone imine (6f).
White solid, m. p. 155.5-156.5°C. Calculated for C16 H19 ClN4O5:
C, 50.20; H, 5.00; Cl, 9.26; N, 14.64 %. Found C, 50.33; H, 5.11; N,
14.71 %. 1H NMR (400 MHz, CDCl3) δ 1.15 (t, 3H, J = 7.1 Hz, CH3-
CH2); 3.46-3.47 (m, 4H, CH2-CH2); 3.82 (m, 4H, CH2-CH2); 3.89-
3.99 (m, 2H, CH3-CH2); 6.08 (sbr, 2H, CH-OH + CH-OH); 7.22-7.43
(m, 4H, C6H4). 13C NMR (101 MHz, CDCl3) δ 14.3, 55.9, 61.7, 64.1,
66.0, 114.3, 126.9, 128.6, 133.7, 137.5, 160.7, 169.5.
4-[(4’-Chlorophenyl)hydroxymethyl]-3-phenyl-N6-tert-
butoxycarbonylsydnone imine (6i).
White solid, m. p. 202-203°C. Calculated for C24H23ClN3O3P: C,
61.61; H, 4.95; Cl, 7.58; N, 8.98; P, 6.62 %. Found C, 61.74; H, 5.07;
N, 9.14 %. 1H NMR (400 MHz, CDCl3) δ 1.14 (d, 3H, J = 6.7 Hz,
CH(CH3)2); 1.62 (d, 3H, J = 6.6 Hz, CH(CH3)2); 5.20 (hept, 1H,
J = 6.6 Hz, CH(CH3)2); 6.15 (s, 1H, CH-OH); 7.20-7.42 (m, 10H,
C6H4 + C6H5); 7.72-7.77 (m, 2H, C6H5); 7.83-7.88 (m, 2H, C6H5).
13C NMR (101 MHz, CDCl3) δ 21.7, 21.9, 56.8, 63.3, 116.4 (d, J = 12.9
Hz), 126.8, 128.1 (d, J = 5.1 Hz), 128.3 (d, J = 5.5 Hz), 128.5, 130.9
(d, J = 2.4 Hz), 131.0 (d, J = 2.7 Hz), 131.22 (d, J = 10.0 Hz), 131.48
(d, J = 9.8 Hz), 133.2, 135.2 (d, J = 139.7 Hz), 135.4 (d, J = 126.2
Hz), 139.5, 165.22 (d, J = 3.1 Hz). 31P NMR (162 MHz, CDCl3) δ
16.8.
4-[(4’-Chlorophenyl)hydroxymethyl]-3-isopropyl-N6-
diphenylphosphorylsydnone imine (6g).
White solid, m. p. 163-164°C. Calculated for C20H20ClN3O4: C,
59.78; H, 5.02; Cl, 8.82; N, 10.46 %. Found C, 59.89; H, 5.20; N,
10.51 %. 1H NMR (400 MHz, CDCl3) δ 1.35 (s, 9H, C(CH3)3); 5.80 (s,
1H, CH-OH); 6.55 (sbr, 1H, CH-OH); 7.12 (d, 2H, J = 8.3 Hz, C6H4);
7.21 (d, 2H, J = 8.4 Hz, C6H4); 7.53-7.77 (m, 5H, C6H5). 13C NMR
(101 MHz, CDCl3) δ 28.0, 64.8, 79.7, 117.5, 125.2, 126.8, 128.7, 130.2,
132.5, 132.9, 133.6, 137.5, 159.8, 169.7.
9-(4-Chlorophenyl)-8-oxa-7-oxo-7-phenoxy-3-phenyl-7-
phospha-6,4-propanosydnone imine (7).
White solid, m. p. 132-133°C. Calculated for C24H23ClN3O5P: C,
57.66; H, 4.64; Cl, 7.09; N, 8.41; P, 6.20 %. Found C, 57.71; H, 4.68;
N, 8.47 %. 1H NMR (400 MHz, DMSO-d6) δ 1.21 (d, 3H J = 6.0
Hz, CH(CH3)2); 1.58 (d, 3H, J = 5.9 Hz, CH(CH3)2); 5.00-5.18 (m,
1H, CH(CH3)2); 5.97 (sbr, 1H, OH); 6.85 (d, J = 2.3 Hz, 1H, CH);
7.11-7.26 (m, 6H, C6H5 + C6H4); 7.27-7.48 (m, 8H, C6H5+ C6H4).
13C NMR (101 MHz, DMSO-d6) δ 21.7, 22.0, 57.6, 63.0, 115.6, 115.8,
120.6 (d, J = 4.7 Hz), 120.7 (d, J = 4.7 Hz), 124.8 (d, J = 4.4), 127.7,
128.9, 130.1, 132.8, 139.3, 151.7 (d, J = 7.2 Hz), 151.8 (d, J = 7.4 Hz),
164.8. 31P NMR (162 MHz, CDCl3) δ 7.6.
White solid, m. p. 136-137°C (dec.). Calculated for
C21H15ClN3O4P: C, 57.35; H, 3.44; Cl, 8.06; N, 9.55; P, 7.04 %.
Found C, 57.43; H, 3.50; N, 9.62 %. 1H NMR (400 MHz, DMSO-d6)
δ 6.85 (s, 1H, CH); 7.20 (m, 3H); 7.30-7.47 (m, 8H); 7.48-7.59 (m,
3H). 13C NMR (101 MHz, DMSO-d6) δ 74.2 (d, J = 7.9 Hz), 110.0 (d,
J = 14.5 Hz), 121.0 (d, J = 4.5 Hz), 125.11, 125.34, 128.76, 129.93,
130.21, 131.40, 132.33, 132.83, 133.2 (d, J = 7.5 Hz), 134.88, 151.1
(d, J = 7.7 Hz), 172.1 (d, J = 12.3 Hz). 31P NMR (162 MHz, CDCl3)
δ -1.51.
10

I.A. Cherepanov, E.V. Shevaldina, D.A. Lapshin et al.
Journal of Organometallic Chemistry 943 (2021) 121841
4-Formyl-3-isopropyl-N6-benzoylsydnone imine (9a).
White solid, m. p. 139-140°C. Calculated for C13H15N3O4S: C,
50.47; H, 4.89; N, 13.58; S, 10.37 %. Found C, 50.51; H, 4.93; N,
13.61 %. 1H NMR (400 MHz, CDCl3) δ 1.66 (d, 6H, J = 6.6 Hz,
CH(CH3)2); 2.42 (s, 3H, CH3-C6H4); 5.65 (hept, 1H, J = 6.6 Hz,
CH(CH3)2); 7.31 (d, 2H, J = 8.2 Hz, C6H4); 7.94 (d, 2H, J = 8.2 Hz,
C6H4); 9.65 (s, 1H, CHO). 13C NMR (101 MHz, CDCl3) δ 21.2, 21.6,
60.6, 109.7, 127.2, 129.5, 138.5, 143.4, 163.6, 176.1.
4-Formyl-3-isopropyl-N6-tert-butoxycarbonylsydnone imine
(9e).
White solid, m. p. 117-118°C. Calculated for C13H13N3O3: C,
60.22; H, 5.05; N, 16.21 %. Found C, 60.32; H, 5.16; N, 16.29 %. 1H
NMR (400 MHz, CDCl3) δ 1.72 (d, 6H, J = 6.6 Hz, CH(CH3)2); 5.76
(hept, 1H, J = 6.6 Hz, CH(CH3)2); 7.46 (t, 2H, J = 7.6 Hz, m-C6H5);
7.54 (t, 1H, J = 7.2 Hz, p-C6H5); 8.27 (d, 2H, J = 7.5 Hz, o-C6H5);
10.13 (s, 1H, CHO). 13C NMR (101 MHz, CDCl3) δ 21.4, 51.1, 54.5,
60.1, 110.9, 128.2, 129.9, 132.3, 136.1, 167.2, 173.4, 177.7.
4-Formyl-3-isopropyl-N6-acetylsydnone imine (9b).
White solid, m. p. 63-64°C. Calculated for C11 H17 N3O4: C, 51.76;
H, 6.71; N, 16.46 %. Found C, 51.88; H, 6.83; N, 16.54 %. 1H NMR
(400 MHz, CDCl3) δ 1.53 (s, 9H, C(CH3)3); 1.67 (d, 6H, J = 6.6
Hz, CH(CH3)2); 5.69 (hept, 1H, J = 6.5 Hz, CH(CH3)2); 9.81 (s, 1H,
CHO). 13C NMR (101 MHz, CDCl3) δ 21.3, 28.0, 59.8, 80.5, 109.5,
157.8, 165.7, 176.8.
4-Formyl-3-isopropyl-N6-diphenylphosphinylsydnone imine
(9f).
Pale yellow oil. Calculated for C8H11 N3O3: C, 48.73; H, 5.62; N,
21.31 %. Found C, 48.99; H, 5.43; N, 21.11 %. 1H NMR (400 MHz,
CDCl3) δ 1.70 (d, 6H, J = 6.6 Hz, CH(CH3)2); 2.28 (s, 3H, CH3CO);
5.74 (hept, 1H, J = 6.6 Hz, CH(CH3)2); 9.99 (s, 1H, CHO). 13C NMR
(101 MHz, CDCl3) δ 21.4, 27.5, 60.1, 110.3, 165.5, 177.6, 179.9.
4-Formyl-3-isopropyl-N6-trifluoroacetylsydnone imine (9c).
White solid, m. p. 121-122.5°C. Calculated for C18 H18 N3O3P: C,
60.84; H, 5.11; N, 11.83; P, 8.72 %. Found C, 60.91; H, 5.22; N, 11.91
%. 1H NMR (400 MHz, CDCl3) δ 1.61 (d, 6H, J = 6.6 Hz, CH(CH3)2);
5.63 (hept, 1H, J = 6.5 Hz, CH(CH3)2); 7.42-7.46 (m, 6H, С6H5);
7.89-7.95 (m, 4H, С6H5); 9.93 (s, 1H, CHO). 13C NMR (101 MHz,
CDCl3) δ 21.1, 59.7, 109.5 (d, J = 9.9 Hz), 128.3 (d, J = 12.9 Hz),
131.3 (d, J = 9.9 Hz), 131.3 (d, J = 2.8 Hz), 135.0 (d, J = 131.6 Hz),
164.3, 177.4. 31P NMR (162 MHz, CDCl3) δ 17.1.
White solid, m. p. 73-74°C. Calculated for C8H8F3N3O3: C, 38.26;
H, 3.21; F, 22.69; N, 16.73 %. Found C, 38.28; H, 3.26; N, 16.80 %.
1H NMR (400 MHz, CDCl3) δ 1.77 (d, 6H, J = 6.6 Hz, CH(CH3)2);
5.81 (hept, 1H, J = 6.5 Hz, CH(CH3)2); 10.16 (s, 1H, CHO). 13C NMR
(101 MHz, CDCl3) δ 21.4, 61.4, 112.8, 116.4 (q, J = 287.8 Hz), 163.2
(q, J = 37.7 Hz), 170.9, 177.5. 19 F NMR (376 MHz, CDCl3) δ -76.21.
4-Formyl-3-isopropyl-N6-tosylsydnone imine (9d).
4-Formyl-3-isopropyl-N6-diphenylphosphorylsydnone imine
(9g).
Pale yellow oil. Calculated for C18 H18 N3O5P: C, 55.82; H, 4.68;
N, 10.85; P, 8.00 %. Found C, 55.92; H, 4.83; N, 10.98 %. 1H NMR
(400 MHz, CDCl3) δ 1.65 (d, 6H, J = 6.6 Hz, CH(CH3)2); 5.63 (hept,
1H, J = 6.6 Hz, CH(CH3)2); 7.14-7.17 (m, 2H, C6H5); 7.29-7.37 (m,
8H, C6H5); 9.68 (s, 1H, CHO). 13C NMR (101 MHz, CDCl3) δ 21.2,
11

I.A. Cherepanov, E.V. Shevaldina, D.A. Lapshin et al.
Journal of Organometallic Chemistry 943 (2021) 121841
60.2, 109.5, 109.7, 120.5, 120.5, 124.8, 129.6, 151.1, 151.2, 165.2,
4.5. Preparation of sydnone imine derivatives for biological studies
165.2, 176.7. 31P NMR (162 MHz, CDCl3) δ -9.1.
4-Formyl-3-morpholino-N6-ethoxycarbonylsydnone
(9h).
imine
Compounds 10b-e, 11b,c were prepared according to the re-
ported methods [28].
3-Isopropyl-4-[(phenyl)hydroxymethyl]-N6-tert-
butoxycarbonylsydnone imine (10a).
White solid, m. p. 145-146°C. Calculated for C10H14 N4O5: C,
44.44; H, 5.22; N, 20.73 %. Found C, 44.55; H, 5.32; N, 20.86 %. 1H
NMR (400 MHz, CDCl3) δ 1.35 (t, 3H, J = 7.1 Hz, CH3-CH2); 3.58
(m, 4H, CH2-CH2); 3.87-4.07 (m, 4H, CH2-CH2); 4.24 (q, 2H, J = 7.1
Hz, CH3-CH2); 9.76 (s, 1H, CHO). 13C NMR (101 MHz, CDCl3) δ 14.4,
55.5, 62.1, 65.6, 106.9, 158.6, 165.8, 174.2.
A 1.6 M solution of n-BuLi in hexane (2.06 ml, 3.3 mmol) was
added at -80°C to a solution of 3-isopropyl-N6-tert-butoxycarbonyl
sydnone imine(0.68 g, 3.0 mmol) in THF (50 mL). The mixture was
stirred at -80°C for 10 min and benzaldehyde (0.34 ml, 3.3 mmol)
was added. The mixture was warmed to room temperature and
water (1 ml) was added. The solvent was removed under reduced
pressure and the products were separated by column chromatog-
raphy on silica gel (CHCl3:EtOAc [5:1]).
4-Formyl-3-phenyl-N6-tert-butoxycarbonylsydnone
(9i).
imine
The product was obtained as a white solid in 85% (0.85 g) yield.
M. p. 119-120°C. Calculated for C17 H23N3O4: C, 61.25; H, 6.95; N,
12.60 %. Found C, 61.30; H, 6.99; N, 12.63 %. 1H NMR (400 MHz,
CDCl3) δ 1.09 (d, 3H, J = 6.7 Hz, CH(CH3)2); 1.50 (s, 9H, C(CH3)3);
1.58 (d, 3H, J = 6.6 Hz, CH(CH3)2); 4.91 (hept, 1H, J = 6.2 Hz,
CH(CH3)2); 6.31 (s, 1H, CH-OH); 7.23-7.27 (m, 1H, C6H5); 7.30-7.33
(m, 2H, C6H5); 7.39 (d, 2H, J = 7.5 Hz, о-C6H5). 13C NMR (101
MHz, CDCl3) δ 21.25, 22.11, 28.26, 56.95, 63.31, 79.17, 117.12, 125.36,
127.77, 128.57, 139.99, 159.35, 167.88.
3-Methyl-4-[(1-ethyl-1H-imidazole-2-yl)hydroxymethyl]-N6-
tert-butoxycarbonylsydnone imine (10f).
White solid, m. p. 170-171°C (dec.). Calculated for C14 H15N3O4:
C, 58.13; H, 5.23; N, 14.53 %. Found C, 58.23; H, 5.30; N, 14.62 %.
1H NMR (400 MHz, CDCl3) δ 1.57 (s, 9H, C(CH3)3); 7.50-7.82 (m,
5H, C6H5); 9.81 (s, 1H, CHO). 13C NMR (101 MHz, CDCl3) δ 28.1,
80.8, 110.7, 124.9, 129.9, 132.7, 133.3, 164.9, 175.2, 189.6.
4-Formyl-3-phenyl-N6-diphenylphosphorylsydnone
(9j).
imine
To a solution of 3-methyl-N6-tert-butoxycarbonylsydnone imine
(0.5 g, 2.5 mmol) in THF (20 ml) was added 2M solution of n-BuLi
(1.38 ml, 2.75 mmol) in hexane at -80°С. The mixture was stirred
at -80°С for 10 min and then 1-ethyl-2-formylimidazole (0.34 g,
2.75 mmol) was added. The mixture was warmed to room temper-
ature and H2O (1 mL) was added. The solvent was removed un-
der reduced pressure. The product was purified by column chro-
matography on silica gel (CHCl3:CH3OH [9:1]) and recrystallized
from toluene.
White solid, m. p. 128-128.5°C. Calculated for C21H16 N3O5P: C,
59.86; H, 3.83; N, 9.97; P, 7.35 %. Found C, 59.93; H, 3.94; N, 10.07
%. 1H NMR (400 MHz, CDCl3) δ 7.13-7.21 (m, 2H); 7.35 (m, 8H);
7.54-7.78 (m, 5H); 9.70 (s, 1H, CHO). 13C NMR (101 MHz, CDCl3) δ
110.6 (d, J = 16.2 Hz), 120.6 (d, J = 5.0 Hz), 124.76, 124.88, 129.65,
129.88, 132.66, 133.44, 151.2 (d, J = 7.8 Hz), 164.6 (d, J = 1.2 Hz),
175.10. 31P NMR (162 MHz, CDCl3) δ -9.24.
The product was obtained as a white solid in 45% (0.36 g) yield.
M. p. 169-170°C (dec.). Calculated for C14 H21N5O4: C, 52.00; H,
6.55; N, 21.66 %. Found C, 52.17; H, 6.63; N, 21.72 %. 1H NMR (400
MHz, CDCl3) δ 1.38 (m, 3H, CH3-CH2); 1.48 (s, 9H, C(CH3)3); 3.81
12

I.A. Cherepanov, E.V. Shevaldina, D.A. Lapshin et al.
Journal of Organometallic Chemistry 943 (2021) 121841
(dq, 1H, J = 14.3, 7.2 Hz, CH3-CH2); 4.09 (dq, 1H, J = 14.4, 7.2
[7] V.G. Granik, S. Yu. Ryabova, N.B. Grigoriev, Exogenous nitric oxide donors and
inhibitors of its formation (the chemical aspects), Russ. Chem. Rev. 66 (8)
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[8] T. Ro˝szer, in: The Biology of subcellular nitric oxide, Springer, Dordrecht, Hei-
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Hz, CH3-CH2); 4.40 (s, 3H, CH3-N); 6.49 (s, 1H, CH-OH); 6.80 (sbr
,
1H, CH-OH); 6.88 (d, 2H, J = 9.3 Hz, CH=CH). 13C NMR (101 MHz,
CDCl3) δ 16.08, 28.21, 39.60, 40.80, 58.64, 76.73, 77.05, 77.37, 79.34,
116.21, 120.37, 127.22, 144.06, 159.20, 166.84.
3-Isopropyl-4-[(phenyl)hydroxymethyl] sydnone imine hy-
drochloride (11a).
[11] V.A. Ol’shevskaya, I.A. Cherepanov, Yu.Ya. Spiridonov, G.S. Spiridonova,
A.V. Makarenkov, A.S. Samarskaya, A.B. Ponomaryov, S.K. Moiseev, Herbicidal
Activity оf Carboranes, Sydnone Imine аnd Ferrocene Derivatives, Agrokhimiya
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[12] I.A. Cherepanov, Yu.Ya. Spiridonov, O.A. Chichvarina, A.S. Samarskaya, B. Pono-
maryov, S.K. Moiseev, Growth Stimulating Activity of Sydnone Imine Deriva-
tives, Agrokhimiya (Rus.) 9 (2018) 50–55.
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[14] I.A. Cherepanov, V.N. Kalinin, Synthesis and reactivity of 4-lithium and 4-
copper derivatives of sydnone imines, Mendeleev Commun 10 (5) (2000) 181–
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[15] A.S. Samarskaya, I.A. Cherepanov, I.A. Godovikov, A.O. Dmitrienko, S.K. Moi-
seev, V.N. Kalinin, E. Hey-Hawkins, Synthesis of N6 - phosphorylated sydnone
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[16] I.A. Cherepanov, S.N. Lebedev, A.S. Samarskaya, I.A. Godovikov, Y.V. Nelyubina,
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A solution of 10a(1 g, 3.0 mmol) and 4N HCl in dioxane (2.25
ml, 9.0 mmol) in methanol (20 mL) was heated at reflux for 2-3 h.
After cooling to room temperature the solvent was evaporated un-
der reduced pressure. The residue was recrystallized from a mix-
ture of isopropanol and MTBE.
[17] I.A. Cherepanov, A.S. Samarskaya, R.G. Nosov, I.A. Godovikov, Y.V. Nelyubina,
V.N. Kalinin, [4,5]-Bicyclic sydnone imines, Mendeleev Commun 24 (6) (2014)
386–387, doi:10.1016/j.mencom.2014.11.027.
The product was obtained as a white solid in 82% (0.66 g)
yield. M. p. 146-147°C. Calculated for C12H16 ClN3O2: C, 53.43; H,
5.98; Cl, 13.14; N, 15.58 %. Found C, 53.56; H, 6.12; N, 15.64 %. 1H
NMR (400 MHz, DMSO-d6) δ 1.19 (d, 3H, J = 6.4 Hz, CH(CH3)2);
1.53 (d, 3H, J = 6.4 Hz, CH(CH3)2); 5.07-5.13 (m, 1H, CH(CH3)2);
6.51 (s, 1H, CH-OH); 7.38-7.22 (m, 2H, C6H5); 7.46-7.38 (m, 2H,
C6H5); 7.55-7.46 (m, 2H, C6H5); 9.96 (s, 2H, NH2). 13C NMR (101
MHz, DMSO-d6) δ 21.58, 22.03, 58.78, 62.81, 115.22, 126.30, 128.52,
129.06, 139.79, 167.39.
[18] I.A. Cherepanov, E.D. Savin, N.G. Frolova, M.O. Shishkova, I.A. Godovikov,
K.Y. Suponitsky, V.N. Kalinin, 4H-Thiopyrans bearing
a mesoionic ring.
Mendeleev Communications, Mendeleev Commun. 19 (6) (2009) 320–321,
doi:10.1016/j.mencom.2009.11.008.
[19] I.A. Cherepanov, L.H. Kusaeva, I.A. Godovikov, V.N. Kalinin, 4-
Formylsydnonimine derivatives, Russ. Chem. Bull. 58 (12) (2009) 2474–2477,
doi:10.1007/s11172- 009-0346-2.
[20] V.N. Kalinin, S.N. Lebedev, I.A. Cherepanov, I.A. Godovikov, K.A. Lyssenko,
E. Hey-Hawkins, 4-Diphenylphosphinosydnone imines as bidentate ligands,
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A. Schmidt, Anionic N-heterocyclic carbenes derived from sydnone imines such
as molsidomine. Trapping reactions with selenium, palladium, and gold, Tetra-
hedron 73 (36) (2017) 5350–5357, doi:10.1016/j.tet.2017.07.032.
[22] T. Freese, A.-L. Lücke, J.C. Namyslo, M. Nieger, A. Schmidt, Heterocycle Syn-
theses with Anionic N-Heterocyclic Carbenes: Ring Transformations of Syd-
none Imine Anions, Eur. J. Org. Chem. 14 (2018) 1646–1654, doi:10.1002/ejoc.
201800028.
Data availability statement
Data available in article supplementary material.
Declaration of Competing Interest
[23] T. Freese, M. Nieger, J.C. Namyslo, A. Schmidt, Cycloadditions of anionic N-
heterocyclic carbenes of sydnone imines, Tetrahedron Lett 60 (18) (2019)
1272–1276, doi:10.1016/j.tetlet.2019.04.006.
[24] K. Kobayashi, K. Matsumoto, Y. Shirai, H. Ishikawa, H. Inouchi, M. Tan-
matsu, Generation of Aryl(2-lithiophenyl)methanoneO-Methyl Oximes and
Their Use for the Synthesis of N-(3-Alkyl-1-aryl- or 1,3-diaryl-1H-isoindol-
1-yl)-O-methylhydroxylaminesviathe Reaction with Nitriles, Helvetica Chimica
Acta 97 (7) (2014) 915–922, doi:10.1002/hlca.201400067.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
Acknowledgements
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This work was supported by RFBR (grant No. 19-03-00972).
NMR studies were performed with the financial support from Min-
istry of Science and Higher Education of the Russian Federation us-
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13