The aza Arndt-Eistert reaction based on N-trifluoromethylsulfonylarenecarboximidoyl chlorides

Article abstract of DOI:10.1016/j.jfluchem.2009.10.019

The aza analogues of carboxylic acids chlorides containing the {double bond, long}NSO₂CF₃ and {double bond, long}NSO₂CH₃ groups instead of oxygen atom were used in the Arndt-Eistert reaction. It was found that N

Full text of DOI:10.1016/j.jfluchem.2009.10.019

Journal of Fluorine Chemistry 131 (2010) 238–247
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
The aza Arndt–Eistert reaction based on N-
trifluoromethylsulfonylarenecarboximidoyl chlorides
a
a,1
Lev M. Yagupolskii a, Irina I. Maletina a, , Liubov V. Sokolenko , Yurii G. Vlasenko
,
*
Maria V. Drozdova b,2, Vitaliy V. Polovinko c,3
a Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanskaya Str. 5, Kiev 02094, Ukraine
b Life Chemicals Inc, Ukraine, Murmanskaya Str. 5, Kiev 02094, Ukraine
c Enamine Ltd., Matrosova Str. 23A, Kiev 01103, Ukraine
A R T I C L E I N F O
A B S T R A C T
Article history:
The aza analogues of carboxylic acids chlorides containing the55NSO2CF3 and55NSO2CH3 groups instead
of oxygen atom were used in the Arndt–Eistert reaction. It was found that N-trifluoromethylsulfonyl-(4-
fluorophenyl)-carboximidoyl chloride 1 reacts with diazomethane vigorously even at ꢀ70 8C with
formation of 1-trifluoromethylsulfonylamino-2-(4-fluorophenyl)-2,3-dimorpholine-4-yl-propane 3,
2-trifluoromethylsulfonylamino-2-(4-fluorobenzyl)-7-oxa-4-azonia-spiro[3.5]nonane 4, 2-trifluoro-
methylsulfonylamino-2-(4-fluorobenzyl)-1,3-dimorpholine-4-yl-propane 5 and 1-trifluoromethylsul-
fonylamino-2-(4-fluorobenzyl)-2,3-dimorpholine-4-yl-propane 6. Reaction of N-methylsulfonylbenz-
carboximidoyl chloride 8 with diazomethane proceeds at ꢀ15 8C yielding 4-chloro-4-methylsulfony-
laminomethyl-3-phenyl-4,5-dihydro-1H-pyrazoline 9.
Received 29 July 2009
Received in revised form 29 October 2009
Accepted 30 October 2009
Available online 16 December 2009
Keywords:
N-trifluoromethylsulfonylarenecar-
boximidoyl chlorides
Rearrangements
ß 2009 Elsevier B.V. All rights reserved.
X-ray structure
Two-dimensional NMR spectra
1. Introduction
the action of (diacyloxyiodo)arenes to form carbodiimides. All these
reactions proceed via nucleophilic migration of a substituent from
In a course of a systematic research on nucleophilic rearrange-
ments of carbonyl compounds analogues in which the sp2-
hybridized oxygen atom is replaced by a trifluoromethylsulfony-
limino group, we previously reported that aza analogues of acid
azides, arenehydroxamic acids and carboxamides undergo the aza
Curtius [1], Lossen [2] and Hofmann [3] rearrangements. The aza
Curtius reaction was shown to proceed under mild conditions
yielding the carbodiimides containing the 55NSO2CF3 group [1]. In
contrast acid azides with fluorine-free sulfonylimino groups
react with sodium azide yielding heterocyclic compounds and no
Curtius rearrangement was observed [1]. Trifluoromethylsulfony-
limides of arenehydroxamic acids undergo a Lossen-type rearrange-
ment to form N-trifluoromethylsulfonyl-N0-arylcarbodiimides or N-
trifluoromethylsulfonyl-N0-arylchloroformamidines depending on
the reaction conditions [2]. N-Trifluoromethylsulfonyl arenecarbox-
amidines undergo an oxidative aza Hofmann rearrangement under
carbon atom to nitrogen atom (Scheme 1).
Bearing in mind specific effects of the 55NSO2CF3 group in
various rearrangements mentioned above, in the present research
we have studied the influence of the trifluoromethylsulfonylimino
group on the known Wolff rearrangement. In the key step of this
process a substituent undergoes C–C migration via carbene
intermediate formation. The Wolff rearrangement is the second
stage of the Arndt–Eistert reaction, which includes the following
stages: (1) reaction of acid chloride with diazomethane in
appropriate solvent yielding
a stable diazoketone; (2) the
Wolff rearrangement of isolated or crude diazoketone in the
presence of suitable reagents. With water the corresponding acid is
formed, an ester is produced in an alcohol, and an amide results
when ammonia or an amine is used. The Wolff rearrangement
of diazoketones is triggered by metal catalyst, irradiation or
heating [4].
2. Results and discussion
* Corresponding author. Tel.: +38 044 559 0349; fax: +38 044 573 2643.
It is well known that the aromatic fluorine atom is a very helpful
mark in product identification, therefore we have selected the N-
trifluoromethylsulfonyl-(4-fluorophenyl)-carboximidoyl chloride
1 [1] as a model compound for our study. Morpholine was chosen
E-mail address: imaletina@yandex.ru (I.I. Maletina).
1
Crystal structure analysis.
2
HPLC separation.
3
Two-dimensional NMR spectra analysis.
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.10.019

L.M. Yagupolskii et al. / Journal of Fluorine Chemistry 131 (2010) 238–247
239
Scheme 1.
as nucleophile and was added to the reaction mixture after the
evolution of nitrogen finished. Ether, THF and glyme were used as
solvents in this reaction; it is noteworthy to mention that positive
results were achieved only in glyme. Besides, for other rearrange-
ments of N-trifluoromethylsulfonyl derivatives of carbonyl com-
pounds (the aza Curtius, aza Lossen and aza Hofmann
rearrangements) glyme was preferred to other solvents due to
its coordinating effect on the compounds of this type [1]. Taking
into account these observations we had also preferred glyme for
the Arndt–Eistert reaction.
Remarkably, the reaction between N-trifluoromethylsulfonyl-
(4-fluorophenyl)-carboximidoyl chloride 1 and diazomethane
occurs vigorously even at low temperature (ꢀ70 8C). The resulting
diazoketone was found to be a very unstable compound which
underwent further transformations at ꢀ70 8C yielding a mixture
of four products 3–6 in total 5% yield (Scheme 2). Reaction is
attended by significant resinification. A product of morpholine
addition to N-trifluoromethylsulfonyl-4-fluorophenylketenimine
2 does not form.
line as a nucleophile was carried out. Similar reactions were
performed using lithium chloride [6] for stabilization of the partial
positive charge on the central carbon atom of 2.
We have found that stabilization of 2 by three equivalents of
phenylazide or lithium chloride and usage of three equivalents of
diazomethane led to higher overall yield of four products 3–6 (40–
55%) (Scheme 3).
There is dependence between yields of products 3–6 and the
reagent (PhN3 or LiCl) used. These data are summarized in Table 1.
Compounds 3–6 were separated by crystallization and HPLC,
and their structure was determined by X-ray analysis (Figs. 1–4).
Only tarry products were obtained if one equivalent of phenylazide
or lithium chloride with three equivalents of diazomethane was
used in these conditions. It is interesting that using of two
equivalents of diazomethane in the presence of one equivalent of
phenylazide or lithium chloride leads to compound 4 only with 5–
10% yield.
As a result of X-ray diffraction study it was found, that in the
compound 3 there is very strong [7] intramolecular hydrogen bond
˚
˚
Probably, there is a partial positive charge on the central carbon
atom of the ketenimine 2 induced by the strong electron acceptor—
the 55NSO2CF3 group. This may be the reason of its high reactivity
and instability.
Phenylazide is known to be an efficient trapping agent for
compounds with unstable and highly reactive double bonds [5].
Nevertheless, attempts to use phenylazide instead of morpholine
to obtain stable heterocyclic products from keteneimine 2 failed.
On the other hand, in this case no resinification has been observed.
We supposed that phenylazide can stabilize the partial positive
charge in 2 and to verify this assumption the reaction between 1
and diazomethane in the presence of phenylazide using morpho-
N(1)–Hꢁ ꢁ ꢁN(3) [N(1)–N(3) 2.593(5) A, N(3)–H 1.80(4)A, N(1)–H(1)
˚
0.92(4)A, N(1)HN(3) 144(4)8], which forms 6-membered cycle
N(3)C(14)C(7)C(8)N(1)H(1). The N(1) atom has a trigonal-planar
bond configuration (sum of the bond angles 358.0(6)8). The atoms
N(2) and N(3) have pyramidal bond configuration (sum of the bond
angles 336.7(6)8 and 333.6(6)8, respectively).
The peculiarity of the compound 4 is the presence of 4-
membered cycle C(8)–C(9)–N(2)–C(10), which is almost planar—
the average deviation from the least square plane does not exceed
0.012 A. The bond lengths and angles in this cycle are similar to the
corresponding values in picrate 2-hydroxy-7-oxa-4-azoniaspir-
o[3.5]nonane [8].
˚
Scheme 2.

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L.M. Yagupolskii et al. / Journal of Fluorine Chemistry 131 (2010) 238–247
Scheme 3.
In the molecule of the compound 5 the atom N(3) has a trigonal-
hydrogen bonds N(3)–H(3)ꢁ ꢁ ꢁO(4) with the following parameters:
˚
˚
˚
planar bond configuration (sum of the bond angles 359.1(4)8). The
N(1) and N(2) atoms have pyramidal bond configuration (sum of
the bond angles 333.6(5)8 and 332.6(5)8, respectively). In the solid
state molecules 5 are organized in chains by the intermolecular
N(3)ꢁ ꢁ ꢁO(4) 2.824(2) A, N(3)–H(3) 0.80(2) A, H(3)ꢁ ꢁ ꢁO(4) 2.04(2) A,
N(3)H(3)O(4) 171(2)8 (Fig. 5).
It was found that the main peculiarity of the compound 6 is the
strong [7] intramolecular hydrogen bond N(2)–Hꢁ ꢁ ꢁN(3) [N(2)–
˚
˚
˚
N(3) 2.650(3) A, N(3)–H 1.83(3) A, N(2)–H 0.88(3) A, N(2)HN(3)
153(3)8],
which
forms
the
6-membered
ring
Table 1
Yields of products 3–6 depending on the reaction conditions.
N(2)C(9)C(8)C(18)N(3)H(2). The N(1) atom has a pyramidal bond
configuration (sum of the bond angles 337.2(5)8).
Reagent
Yields of products [%]
Substance 3 results from diazoketone transformations without
Wolff rearrangement. For its formation we can propose the
following scheme (Scheme 4).
Compounds 4–6 are formed as a result of the Wolff rearrange-
ment followed by interaction of N-trifluoromethylsulfonyl-4-
fluorophenylketenimine 2 with diazomethane and morpholine.
3
4
5
6
Overall
PhN3
LiCl
15
18
10
8
20
2
10
12
55
40
˚
˚
Fig. 1. Molecular structure of compound 3. Selected bond lengths [A] and angles [8]:
S(1)–N(1) 1.553(2), N(1)–C(8) 1.465(4), C(7)–C(8) 1.551(3), C(7)–C(14) 1.548(4),
N(3)–C(14) 1.483(4), N(2)–C(7) 1.491(3), S(1)–C(9) 1.819(4); N(1)S(1)C(9) 106.2(2),
S(1)N(1)C(8) 125.0(2), N(2)C(7)C8) 110.0(2), N(2)C(7)C(14) 109.1(2), C(7)C(8)N(1)
109.5(2), C(7)C(14)N(3) 114.9(2), C(8)C(7)C(14) 107.2(2).
Fig. 2. Molecular structure of compound 4. Selected bond lengths [A] and angles [8]:
C(7)–C(8) 1.533(3), C(8)–C(9) 1.557(3), N(2)–C(9) 1.517(2), N(2)–C(10) 1.530(2),
C(8)–C(10) 1.548(2), N(1)–C(8) 1.453(2), S(1)–N(1) 1.515(1); S(1)N(1)C(8) 126.5(1),
C(7)C(8)N(1) 112.3(2), N(1)C(8)C(9) 118.8(2), C(8)C(9)N(2) 91.2(1), C(9)N(2)C(10)
89.9(1), C(8)C(10)N(2) 91.0(1).

L.M. Yagupolskii et al. / Journal of Fluorine Chemistry 131 (2010) 238–247
241
Fig. 5. Fragment of the crystal packing of compound 5. Substituents not
˚
Fig. 3. Molecular structure of compound 5. Selected bond lengths [A] and angles [8]:
participating in the intermolecular hydrogen bonds are omitted for clarity.
S(1)–N(3) 1.585(2), N(3)–C(8) 1.499(2), C(8)–C(10) 1.550(2), N(1)–C(10) 1.460(3),
C(7)–C(8) 1.553(3), C(8)–C(15) 1.531(3), N(2)–C(15) 1.476(2), F(1)–C(1) 1.353(3);
S(1)N(3)C(8) 128.7(1), N(3)C(8)C(10) 106.7(1), N(3)C(8)C(15) 109.4(2),
C(7)C(8)N(3) 110.7(1), C(8)C(10)N(1) 116.2(2), C(8)C(15)N(2) 112.1(2).
without addition of phenylazide or lithium chloride, the only
isolated product was 4-fluorophenacyl chloride in minor amounts.
It is likely, that formation of diazoketone takes place, but it reacts
with HCl and hydrolysis of trifluoromethylsulfonylimino group
occurs during separation.
Trimethylsilyldiazomethane is known to be less reactive than
diazomethane (the most probably for steric effects) [9]. There are
many examples of the Arndt–Eistert reaction using TMS-diazo-
methane or its lithium salt [9]. Reaction of acyl chloride with TMS-
diazomethane proceeds in the presence of base or without base
yielding the corresponding diazoketone or TMS-diazoketone
depending on solvent used. In ether or THF TMS-diazoketone is
formed. Usage of THF:acetonitrile 1:1 mixture leads to diazoke-
tone. But it was the single example of TMS-diazoketone formation
[10]. We carried out reaction of N-trifluoromethylsulfonyl-(4-
fluorophenyl)-carboximidoyl chloride with TMS-diazomethane in
the presence of triethylamine in THF. Reaction proceeds vigorously
as well as with diazomethane. The isolated products were 4-
fluorophenacyl chloride and trifluoromethanesulfonamide.
Attempts to use TMS-diazomethane lithium salt in glyme gave
no positive results also. It is likely, that formation of TMS-
diazoketone takes place (starting imidoyl chloride disappears from
the reaction mixture) but no rearrangement was observed. The
only isolated product was N-trifluoromethylsulfonyl-(4-fluoro-
phenyl)-imidoyl morpholide 7.
˚
Fig. 4. Molecular structure of compound 6. Selected bond lengths [A] and angles [8]:
S(1)–N(3) 1.529(2), N(3)–C(18) 1.476(3), C(8)–C(18) 1.538(3), C(7)–C(8) 1.556(3),
C(8)–C(9) 1.529(3), N(2)–C(9) 1.508(3), N(1)–C(8) 1.491(3); S(1)N(3)C(18)
118.7(2), C(8)C(18)N(3) 111.2(2), C(7)C(8)C(18) 108.1(2), N(1)C(8)C(9) 108.1(2),
C(7)C(8)N(1) 112.5(2), C(8)C(9)N(2) 112.9(2), C(7)C(8)C(9) 108.2(2).
Faced with these difficulties, we also attempted to carry out the
Arndt–Eistert reaction using ethyl diazoacetate instead of diazo-
methane. In contrast to previous cases reaction of 1 with ethyl
diazoacetate proceeds slowly at room temperature. Starting
imidoyl chloride disappears from reaction mixture (monitoring
by TLC and 19F NMR spectra) after stirring for 24 h. Attempts to
isolate diazoketone formed in this reaction were unsuccessful.
Heating of the reaction mixture to 60 8C in presence of the excess of
morpholine leads to evolution of nitrogen being the result of
diazoketone decomposition. However, the only isolated product
was 7 and no Wolff rearrangement was observed (Scheme 7). It is
likely, that 7 is formed by substitution of diazoacetate residue with
morpholine. If diazoketone decomposition was induced by the
action of silver oxide or dirhodium tetraacetate only tarry products
have been obtained. UV-irradiation of the diazoketone with Hg
lamp (PRK-4, 950 W) leads to the compound 7. In these conditions
reactions begin only at 60 8C as well, so we can assume that
Their formation the most likely proceeds according to Schemes 5
and 6. Probably, the reaction occurs through the formation of
intermediate A. Interaction of A with HCl and then with morpho-
line yields compounds 4 and 5 (Scheme 5).
Intermediate A can also undergo an intramolecular rearrange-
ment via formation of carbenoid transition state. This route leads
to formation of product 6 (Scheme 6).
We suppose that hydrogen chloride formed from 1 and
diazomethane takes part in further transformations (see Schemes
4–6). Formation of morpholine hydrochloride in quantitative yield
observed in these reactions may be the evidence of our
assumption.
If 1 was treated with diazomethane in ether solution in the
presence of triethylamine (for trapping of hydrogen chloride) and

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L.M. Yagupolskii et al. / Journal of Fluorine Chemistry 131 (2010) 238–247
Scheme 4.
Scheme 5.
transition metals or irradiation have not the influence on the
reaction course.
was isolated from the reaction mixture in nearly quantitative
amount.
To compare the reactivity of fluorine-containing imidoyl
chlorides to that of analogous fluorine-free ones, we carried out
reactions between N-methyl- and N-phenylsulfonylbenzcarbox-
imidoyl chlorides and diazomethane in the presence of phenyla-
zide or lithium chloride and morpholine. Only tarry products were
obtained from N-phenylsulfonylbenzcarboximidoyl chloride if
phenylazide was used. In the presence of lithium chloride
destruction of molecule was observed and benzenesulfonamide
Interaction between N-methylsulfonylbenzcarboximidoyl
chloride 8 and diazomethane in the presence of phenylazide or
lithium chloride and morpholine is more controllable. It was found
that reaction proceeds at ꢀ15 8C with formation of compound 9 as
main product (Scheme 8). This transformation needs only two
equivalents of diazomethane and gives better yield of 9 in the
presence of lithium chloride (45% by LC–MS of reaction mixture). If
morpholine was not added to the reaction mixture, yield of 9

L.M. Yagupolskii et al. / Journal of Fluorine Chemistry 131 (2010) 238–247
243
Scheme 6.
Scheme 7.
Scheme 8.
Fig. 6. APT spectrum of compound 9.
Fig. 7. HMQC spectrum of compound 9.

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L.M. Yagupolskii et al. / Journal of Fluorine Chemistry 131 (2010) 238–247
Fig. 8. COSY spectrum of compound 9.
Fig. 9. NOESY spectrum of compound 9.
decreased. Usage of triethylamine instead of morpholine leads to
the analogous results. If penylazide was used, yield of product was
only 12–20%.
Unfortunately, all attempts to obtain suitable single crystals of
compound 9 failed. We believe that structure of 9 shown in Scheme
8 is the most probable. It agrees with data obtained from IR-
spectrum, LC–MS and one- and two-dimensional NMR spectra (1H,
13C, APT, 1H–13C HMQC, COSY and NOESY) (Figs. 6–9). Presence of
two molecular ions (M and M + 2) with intensity ratio 3:1 in mass-
spectra establishes that this molecule contains one chlorine atom
[11]. APT spectrum (Fig. 6) indicates the presence of CH3, 2CH2 and
C sites in compound 9 besides benzene ring. 1H NMR and HMQC
(Fig. 7) spectra show that there are two different NH-groups in
molecule. The single 1H–1H correlation (Fig. 8) shows that more
acidic NH-group (evidently, it is NHSO2CH3 group) is attached
directly to one of the methylene sites. Thus, molecule of 9 should
Scheme 9.

L.M. Yagupolskii et al. / Journal of Fluorine Chemistry 131 (2010) 238–247
245
contain the CH2NHSO2CH3 fragment. The other CH2 site is isolated.
Chemical shift of this group in 1H NMR spectrum indicates that it is
attached to the nitrogen atom. It can be the nitrogen atom of
pyrazoline ring. NOESY spectrum shows that CH2NHSO2CH3
fragment is located close to the second methylene site and o-
protons of benzene ring. Such NOE pattern does not contradict to
the structure of 9 shown in Scheme 8.
lithium chloride) was filtered off and anhydrous ether (ca.
30 mL) was added to the filtrate. Solution obtained was left to
stand overnight. Precipitate of 4 was filtered off and filtrate was
evaporated to dryness in vacuo. Residue was crystallized (from
methanol/water 1:1) gave the mixture of 3, 5, 6. Compound 6 was
separated in pure state by crystallization from ether. HPLC of
mixture gave pure compounds
(RT = 3.95 min).
3
(RT = 4.55 min) and
5
It is likely, that formation of product 9 proceeds according to the
following scheme (Scheme 9).
4.2.1. 1-Trifluoromethylsulfonylamino-2-(4-fluorophenyl)-2,3-
3. Conclusions
dimorpholine-4-yl-propane 3
m.p. 170–171 8C. 1H NMR ([D6]acetone):
d 2.4–3.05 (11H, m,
The Arndt–Eistert reaction based on N-trifluoromethylsulfonyl-
(4-fluorophenyl)-carboximidoyl chloride 1 has been studied. It
was shown that reaction proceeds vigorously even at low
temperatures. It was found that the presence of substances being
able to stabilize the positive charge at the central carbon atom of
resulting ketenimine is needed. Comparison of the reactivity of
imidoyl chlorides containing the55NSO2CF3 and55NSO2CH3 groups
was made.
5CH2 + NH), 2.5–2.7 (m, 8H, 4CH2), 3.85 (1H, d, CH2, 2JHH = 12 Hz),
2
4.12 (1H, d, CH2, JHH = 12 Hz), 7.14–7.20 (2H, m, ArH), 7.53–7.57
(2H, m, ArH); 19F NMR ([D6]acetone):
d
ꢀ77.3 (s, 3F, SO2CF3),
ꢀ115.3 (s, 1F, ArF); 13C {1H} NMR ([D6]acetone):
d 163.8 (d,
1JCF = 243.8 Hz), 136.2, 130.9 (d, 3JCF = 7.5 Hz), 122.1 (q,
2
1JCF = 320.0 Hz), 116.6 (d, JCF = 21.3 Hz), 68.8, 68.1, 64.5, 63.4,
56.8, 49.0, 48.6. LC–MS (m/z): 456.2 [M]+. Anal. calcd for
C18H25F4N3O4S: C 47.5, H 5.5, N 9.2. Found C 47.7, H 5.3, N 9.3.
4. Experimental
4.2.2. 2-Trifluoromethylsulfonylamino-2-(4-fluorobenzyl)-7-oxa-4-
azonia-spiro[3.5]nonane 4
4.1. General
m.p. 180–190 8C. 1H NMR ([D6]DMSO):
d
3.10 (2H, s, CH2), 3.45–
3.82 (m, 8H, 4CH2), 4.28 (2H, d, CH2, 2JHH = 10 Hz), 4.34 (2H, d, CH2,
All reactions were carried out under dry argon using flame-
dried glassware. Solvents were distilled from appropriate drying
agents immediately prior to use. Phenylazide was prepared as
described in [12]. Lithium chloride was dried at 200 8C in
vacuum (0.03 Torr). Reactions were monitored by thin-layer
chromatography (TLC) on precoated silica gel Kieselgel 60 F/
UV254 plates (Merck); spots were visualized with UV light.
Purification of some products was carried out using column
chromatography (CC) on silica gel, 70–230 mesh 60A (Aldrich).
Purification of most products was performed by preparative
HPLC with SHIMADZU instrument equipped with two LS-8A
2JHH = 10 Hz), 7.00–7.20 (2H, m, ArH), 7.35–7.52 (2H, m, ArH); 19
F
NMR ([D6]DMSO):
d
ꢀ78.2 (s, 3F, SO2CF3), ꢀ117.6 (s, 1F, ArF); 13
C
1
{1H} NMR ([D6]DMSO):
d
161.0 (d, JCF = 241.4 Hz), 133.1, 132.0,
125.2 (q, 1JCF = 340.0 Hz), 114.3 (d, 2JCF = 21.0 Hz), 73.6, 61.2, 60.8,
60.1, 59.8, 53.6, 46.2. LC–MS (m/z): 383.2 [M]+. Anal. calcd for
C
15H19F4N2O3S: C 47.0, H 5.0, N 7.3. Found C 47.2, H 4.9, N 7.6.
4.2.3. 2-Trifluoromethylsulfonylamino-2-(4-fluorobenzyl)-1,3-
dimorpholine-4-yl-propane 5
m.p. 140 8C. 1H NMR ([D6]acetone):
d
2.63–2.78 (12H, m, 6CH2),
3.1 (1H, br s, NH), 3.26 (2H, s, CH2), 3.63 (m, 8H, 4CH2), 7.03–7.09
pumps, CBM-20A controller and SPD-20A UV-detector (
and 254 nm) using Waters 30 mm ꢂ 75 mm silica column
(stationary phase—SunFire Prep C18 5 m with gradient elution
l
= 215
(2H, m, ArH), 7.39–7.47 (2H, m, ArH); 19F NMR ([D6]acetone):
d
ꢀ78.1 (s, 3F, SO2CF3), ꢀ116.7 (s, 1F, ArF); 13C {1H} NMR
1
3
m
([D6]acetone): d 163.7 (d, JCF = 250.0 Hz), 134.8 (d, JCF = 7.5 Hz),
by acetonitrile/water (0–100%)). 13C NMR spectra and two-
dimensional NMR spectra were recorded on a Bruker AVANCE
DRX 500 instrument at 125 and 500.13 MHz, respectively, 1H
and 19F NMR spectra were recorded at 299.5 and 282.2 MHz,
respectively, with a Varian VXR-300 spectrometer, and chemical
shifts are given in ppm relative to Me4Si and CCl3F, respectively,
as internal standards. LCMS spectra were registered on ‘‘Agilent
1100 Series’’ instrument with diode-matrix and mass-selective
134.0, 121.3 (q, 1JCF = 320.0 Hz), 116.6 (d, 2JCF = 21.2 Hz), 68.3, 68.2,
64.9, 57.4, 42.7. LC–MS (m/z): 470.1 [M]+. Anal. calcd for
C
19H27F4N3O4S: C 24.3, H 2.9, N 4.5. Found C 24.6, H 2.5, N 4.6.
4.2.4. 1-Trifluoromethylsulfonylamino-2-(4-fluorobenzyl)-2,3-
dimorpholine-4-yl-propane 6
m.p. 185–186 8C. 1H NMR ([D6]DMSO):
d 2.59–3.60 (22H, m,
11CH2), 7.13–7.25 (4H, m, ArH), 12.72 (1H, br s, NH); 19F NMR
detector ‘‘Agilent 1100 LS/MSD SL’’ (ionization method
–
([D6]DMSO):
NMR ([D6]DMSO):
3JCF = 7.6 Hz), 122.3 (q, JCF = 320.0 Hz), 114.7 (d, JCF = 20.6 Hz),
66.4, 65.2, 59.9, 59.2, 53.7, 48.6, 45.2, 34.4. LC–MS (m/z): 470.1
[M]+. Anal. calcd for C19H27F4N3O4S: C 24.3, H 2.9, N 4.5. Found C
24.1, H 2.3, N 4.1.
d
ꢀ76.6 (s, 3F, SO2CF3), ꢀ116.3 (s, 1F, ArF); 13C {1H}
1
chemical ionization at atmospheric pressure; ionization cham-
ber operation conditions – simultaneous scanning of positive
and negative ions in the range 80–1000 m/z). Melting points
were determined in open capillaries and are uncorrected.
Elemental analysis was performed in the Analytical Laboratory
of the Institute of Organic Chemistry, NAS of Ukraine, Kiev.
d
160.8 (d, JCF = 240.1 Hz), 132.9, 132.1 (d,
1
2
4.3. The Arndt–Eistert reaction of N-trifluoromethylsulfonyl-(4-
4.2. General procedure for the Arndt–Eistert reaction of N-
fluorophenyl)-carboximidoyl chloride 1 with ethyl diazoacetate
trifluoromethylsulfonyl-(4-fluorophenyl)-carboximidoyl chloride 1
Imidoyl chloride 1 (0.87 g, 3 mmol) in glyme (15 mL) was added
dropwise to the stirred solution of ethyl diazoacetate [13] (0.68 g,
6 mmol) in glyme (15 mL) at 0–5 8C over 15 min. The reaction
mixture was stirred at room temperature until nitrogen evolution
(70 mL) ceased (ca. 24 h). Then morpholine (1 mL) was added in
one portion and reaction mixture was heated at 60–65 8C until
nitrogen evolution (70 mL) ceased (about 1 h). Solvent was
evaporated to dryness in vacuo. Column chromatography of
residue (eluent ethylacetate/hexane = 1:2) gave 0.3 g (30%) of
Diazomethane solution in glyme (15 mL, 9 mmol) was added
dropwise to the stirred mixture of imidoyl chloride 1 (0.87 g,
3 mmol) and PhN3 (1.1 g, 9 mmol) or LiCl (0.32 g, 9 mmol) in glyme
(15 mL) at ꢀ70 8C over 30–40 min. The reaction mixture was
stirred at ꢀ70 8C until nitrogen evolution (200–210 mL) ceased (ca.
30 min). Morpholine (2 mL) was added to the reaction mixture at
ꢀ70 8C in one portion. After stirring for 24 h at room temperature
precipitated morpholine hydrochloride (or its mixture with

246
L.M. Yagupolskii et al. / Journal of Fluorine Chemistry 131 (2010) 238–247
Table 2
The main crystallographic parameters of the compounds 3–6.
Cell parameters
Compound
3
4
5
6
˚
a [A]
10.4894(6)
15.9856(8)
12.5397(8)
90
8.4842(4)
10.1822(5)
11.2630(6)
65.164(3)
70.720(4)
86.073(4)
830.7(1)
13.9124(9)
10.1998(7)
16.6565(10)
90
10.1697(2)
12.3642(3)
17.3192(5)
90
˚
b [A]
˚
c [A]
a
b
g
[8]
[8]
[8]
95.504(2)
90
110.105(3)
90
99.562(1)
90
3
˚
V [A ]
2093.0(2)
2219.6(3)
2147.5(1)
Z
4
2
4
4
D [g cmꢀ3
]
1.45
1.53
Triclinic
Pꢀ1
2.55
396
1.40
1.45
Crystal system
Space group
m
Monoclinic
P21/c
2.20
Monoclinic
P21/n
2.09
Monoclinic
P21/c
2.16
[cmꢀ1
]
F(000)
952
984
984
Indexes
12 ꢃ h ꢃ ꢀ10
19 ꢃ k ꢃ ꢀ15
15 ꢃ l ꢃ ꢀ15
10 ꢃ h ꢃ ꢀ10
12 ꢃ k ꢃ ꢀ12
14 ꢃ l ꢃ ꢀ14
17 ꢃ h ꢃ ꢀ17
12 ꢃ k ꢃ ꢀ11
20 ꢃ l ꢃ ꢀ20
12 ꢃ h ꢃ ꢀ11
15 ꢃ k ꢃ ꢀ13
20 ꢃ l ꢃ ꢀ20
umax [8]
26.5
26.5
26.5
26.4
No. of reflections
Collected
15,289
4,246
1,867
8,453
3,396
2,514
33,411
4,355
2,238
16,466
4,054
2,387
Independent
In refinement (I ꢃ 3
s(I))
R(int)
0.031
275
0.019
226
0.050
284
0.042
284
No. of refined parameters
Obsd./var.
6.79
11.12
7.88
8.40
Final R indices
R1(F)
0.035
0.038
0.035
0.038
0.034
0.031
0.035
0.035
Rw(F)
GOF
1.156
1.123
1.158
1.132
Weighting coefficients
0.70
0.80
0.45
0.68
0.09
0.19
0.75
0.63
0.61
1.16
-0.07
0.87
ꢀ0.14
0.42
ꢀ0.19
Largest peak/hole [e cmꢀ3
CCDC deposition number
]
ꢀ0.21/0.25
ꢀ0.23/0.24
ꢀ0.23/0.30
ꢀ0.34/0.42
739998
739995
739997
739996
pure 7 (Rf = 0.3). m.p. 155–157 8C. 1H NMR ([D6]DMSO):
3.89 (8H, m, 4CH2), 7.38–7.44 (2H, m, ArH), 7.56–7.61 (2H, m, ArH);
19F NMR ([D6]DMSO):
Anal. calcd for C12H12F4N2O3S: C 42.4, H 3.6, N 8.2. Found C 42.5, H
3.4, N 8.3.
d
3.32–
4.5. X-ray crystallography
d
ꢀ79.2 (s, 3F, SO2CF3), ꢀ108.4 (s, 1F, ArF).
All crystallographic measurements were performed at 173 K on
a Bruker Smart Apex II diffractometer (Mo K ). Data were
a
corrected for Lorentz and polarization effects. The SADABS
procedure [14] absorption correction was applied. The structures
were solved by direct methods and refined by the full-matrix least-
squares technique in the anisotropic approximation using the
SHELXS97 and SHELXL97 programs [15,16] and CRYSTALS program
package [17]. In the refinement the Chebychev weighting scheme
[18] was used. All hydrogen atoms were located in the difference
Fourier maps and refined with fixed positional and thermal
parameters (only hydrogen atoms participating in the hydrogen
bonds were refined isotropically).
4.4. The Arndt–Eistert reaction of N-
methylsulfonylbenzcarboximidoyl chloride 8
Diazomethane solution in glyme (12 mL, 7 mmol) was added
dropwise to the stirred mixture of imidoyl chloride 8 (0.76 g,
3.5 mmol) and PhN3 (0.83 g, 7 mmol) or LiCl (0.3 g, 7 mmol) in
glyme (15 mL) at ꢀ15 8C over 30–40 min. The reaction mixture
was stirred at ꢀ15 8C until nitrogen evolution (160 mL) ceased
(ca. 2–3 h) and then allowed to warm to 0 8C. Morpholine (2 mL)
was added to the reaction mixture at 0 8C in one portion. After
stirring for 24 h at room temperature precipitate was filtered off
and filtrate was evaporated to dryness in vacuo. HPLC of residue
gave pure compound 9 (RT = 5.43 min). m.p. 100–105 8C. 1H
Full crystallographic details have been deposited at Cambridge
Crystallographic Data Centre (CCDC) (Table 2).
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d 2.77 (3H, s, SO2CH3), 3.37 (2H, d, CH2,
3JHH = 5 Hz), 3.95 (2H, m, CH2), 5.67 (1H, s, NH), 6.83 (1H, t, NH,
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d
142.8, 128.3, 127.6, 126.7, 75.5, 51.8, 51.2,
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[M]+.
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