A long-range tautomeric effect on a new Schiff isoniazid analogue, evidenced by NMR study and X-ray crystallography

Article abstract of DOI:10.1039/c8nj01680a

Long-range tautomerism to a N,O-aminal thereby closing a tetrahydrofuran ring was evidenced for an isoniazid analogue, whose accidental synthesis is presented in the paper. The isoniazid analogue was synthesized by the reaction of isoniazid with 2-hydroxy-tetrahydrofuran which was demonstrated to exist in old THF together with other peroxides, especially 2-HOO-THF. The same compound was efficiently obtained from a THF containing 2-HOO-THF, by reducing this peroxide in the presence of isoniazid. The 2,4-dinitrophenylhydrazone was also synthesized. The oxidation of 1,4-butanediol and the reaction of the resulting mono-aldehyde with isoniazid gave the same compound. The existence of the linear tautomer was evidenced in the NMR spectra in DMSO-d₆ and was confirmed by X-ray analysis to be the single tautomer in the crystal. The cyclic N,O-aminal tautomer was found in the NMR spectra in CDCl₃, resulting from an intramolecular HCl-catalyzed addition of the hydroxyl group to the double bond CHN of the linear tautomer, thereby closing a tetrahydrofuran ring. This is a favoured cyclization according to Baldwin's rules (5-exo-trig). The same tautomerism was also present for two isoniazid analogues obtained from two lactols, used in prostaglandin synthesis. The compounds 1, 4, 6 and INH had no antibacterial or antifungal activity.

Full text of DOI:10.1039/c8nj01680a

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Volume 40 Number
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January 2016 Pages 1–846
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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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antibacterial or antifungal activity.
1
. Introduction
Received 00th January 20xx,
Accepted 00th January 20xx
N,O-aminals are compounds with a carbon atom geminally
substituted by an amine and a hydroxy or alkoxy group [1, 2]. These
compounds are important structural fragments encountered in
many natural products [3-5], and in active substances studied in
different clinical phases [5, 6]. Classified by Huang et al [2] into
acyclic and cyclic-types, the N,O-aminals were observed to be more
stable than imines in many chemical structures, a feature which
DOI: 10.1039/x0xx00000x
www.rsc.org/
A long range tautomeric effect on a new
Schiff isoniazid analogue, NMR study and makes the N,O- aminals more convenient to use in subsequent
synthesis steps as a masked form of imines. In particular, the N,O-
aminals are suitable to (un)catalytically generate in situ the reactive
X-ray crystallography
imines, which can then be used in the next specific reactions, for
example in catalytic asymmetric reactions [2, 8].
a
b
c
Constantin I. Tănase, *Constantin Drăghic, Sergiu Shova,
b
d
Anamaria Hanganu, Emese Gal, and Cristian V. A.
N,O-aminals were found to be valuable reagents for the
regio/stereoselective formation of C-C or C-N bonds, in asymmetric
catalytic reactions [2], and for obtaining chiral complex chemical
structures [2-7, 9]. The non-stereoselective synthesis of N,O-
aminals or the catalytic asymmetric synthesis of chiral N,O-aminals
are widely discussed in the literature [2, 10-15]. N,O-alkoxy-aminals
are obtained from the corresponding imines by the nucleophilic
addition of an alkoxy group [15,16] or by the substitution of a
sulfonyl group of an α-amido sulfone by an alkoxy group [2, see ref.
e
Munteanu
A long range tautomerism to a N,O-aminal by closing a tetrahydrofuran ring
was put in evidence for an isoniazid analogue, whose accidental synthesis is
presented in the paper. The isoniazid analogue was synthesized by the
reaction of isoniazid with 2-hydroxy-tetrahydrofuran which was
demonstrated to exist in old THF together with other peroxides, especially
2
]. N,O-aminals with a hydroxy group are described as
2
-HOO-THF. The same compound was efficiently obtained from a THF
intermediates in the synthesis of imines, by the nucleophilic
addition of an amine to aldehydes and ketones (followed by proton
transfer) [17, 18, 2], but their synthesis is also described by the
addition of an alcohol to the corresponding imines [18, 19]. The
latter method is relevant for this paper.
The tautomerism of N,O-aminals is presented in some depth in the
literature: Schiff base-oxazolidine (with two (un)substituted carbon
atoms between the amine and the OH group) [17-18], Schiff base-
containing 2-HOO-THF, by reducing this peroxide in the presence of
isoniazid. The 2,4-dinitrophenylhydrazone was also synthesized. The
oxidation of 1,4-butanediol and the reaction of the resulted mono-aldehyde
with isoniazid gave the same compound. The linear tautomer was put in
evidence in the NMR spectra in DMSO-d6 and confirmed to be the single
tautomer in the crystal, by X-ray analysis. The cyclic N,O-aminal tautomer
3
was found in the NMR spectra in CDCl , resulted by intramolecular HCl-
catalyzed addition of the hydroxyl group to the double bond CH=N of the oxazolidine/1,3-oxazine (with two/three carbon atoms between the
linear tautomer, by closing a tetrahydrofurane ring. This is a favoured amine and the OH group) [20, 21], bisimine of 4-
cyclization according to Baldwin’s rules (5-exo-trig). The same tautomerism chlorobenzaldehyde with 1,3-diamino-2-propanol in equilibrium
was also present for two isoniazid analogues obtained from two lactols, with cis-and trans-mono-oxazolidines [22], in hydroxylated
used in prostaglandin synthesis. The compounds 1, 4, 6 and INH had no isoflavones [23], etc. The influence of the steric and/or electronic
effects of the substituents (including positions and electron
withdrawing/donating substituents) of the amine moiety or
aromatic aldehyde/ketone moiety was also taken into account in
explaining the sometimes complex tautomeric mixture of the Schiff
base form, the oxazolidine or the 1,3-oxazine forms. Some
theoretical calculations in this direction were described in [19, 20,
2
2, 24]. The ratio of the cyclized and open chain forms of the
tautomeric equilibria was conveniently determined by NMR, by the
integration of the O-CH-N and -CH=N protons which appeared as
singlets. In many publications, the N,O-aminals are presented as
intermediates, reagents, or starting compounds for asymmetric
catalysis, or in the final structures [2, 20, 24], however, to our
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New Journal of Chemistry
_
knowledge, a similar cyclic N,O-aminal has not been encountered in
the isoniazid analogues.
In the present paper, we put in evidence a tautomerization of some
isoniazid analogues from the Schiff form to a cyclic N,O-aminal,
formed by the intramolecular acid catalysis addition of an alcohol
group to the C=N double bond which closes a tetrahydrofuran ring.
Cl
H
O
H Cl
H
O
+
(HCl in CDCl
DMSO
3
)
N
NH
N
O
NH NH OC
N
1
-iminium
1a
Cl
H
O
.
.
N
NH
N
H
O
2. Results and discussion
1
A
long range tautomerism to a N,O aminal by closing a
tetrahydrofuran ring was put in evidence for a few isoniazid
analogues. In a reaction of isoniazid (INH) with a sterically hindered
ketone [25] in an old anh. tetrahydrofuran (THF ) (See
experimental), we discovered the formation of a secondary
compound which did not look to originate from the skeleton of the
ketone compound.
_
Cl
H
H
Cl
H
OH
O
H
O
O
.
.
(HCl in CDCl
DMSO
3
)
X
+
H
N
NH
N
HO
HN NH
N
O
1-iminium
1b
This compound was isolated by low pressure chromatography (LPC), Scheme 2. The cyclized tautomers 1a, formed in CDCl3 in the
crystallized in needles from acetonitrile, mp 146.3-147.5 ˚C, and presence of catalytic HCl from 1, and linear N,O-aminal 1b formed
analyzed by IR and NMR in CDCl
3
. Its NMR spectrum in CDCl
3
by acid catalyzed addition of water to the C=N double bond through
showed, in addition to the INH fragment, the signals of four carbon the iminium ion.
atoms and 7 protons, indicating that we have probably a compound
with formula 1 which could have resulted by the reaction of INH The signal at δ 96.36 ppm, could be attributed to a linear N,O-
with the 2-hydroxy-tetrahydrofuran (2-HO-THF) (Scheme 1), aminal 1b (Scheme 2, 1b) formed by hydrochloric acid catalyzed
X
present in THF :
addition of water to the double bond of the Schiff base (1 → 1b);
the water was later observed co-crystalized with 1, from the X-ray
crystallography. The addition of alcohols to imines, in the presence
of an acid catalyst, is mentioned in the literature [29, 18, 19].
O
O
3
' 2'
2
N
N
N
HO 4 3 2
1
N
N
H
4'
N
1'
H
H
H
O
OH
1
4
1
+
Isoniazid
N'-(4-hydroxybutylidene)
isonicotinohydrazide
3
2
In the meantime, another compound was isolated from the reaction
X
6'
5' 4'
2
-HO-THF
N
N
H
NO
of an aldehyde [25] with INH in the same THF , and the NMR
2
2
HO
N
N
H
NO
2
1' 2' 3'
spectra in an anhydrous DMSO-d6 confirmed its structure to be that
of compound 1 (ex. 1.2, NMR copies in ESI, 1.2). The same Rf and
mp were obtained for this compound as for the previous one.
We analyzed the crystals by X-ray crystallography and found that
the structure of compound 1 is in agreement with the one
2
NO
,4-dinitrophenylhydrazine
2
NO
4-(2-(2,4-dinitrophenyl)hydrazineylidene)butan-1-ol
2
2
Scheme 1. The reaction of 2-Hydroxy-tetrahydrofuran with INH and presented in Scheme 1 (See also Fig. 3 to X-ray data).
X
2
,4-dinitrophenylhydrazine
Then we used an aliquot of 50 mL THF to react with INH. We added
INH in portions until 24 mmoles reacted (ex. 1.3). The main
compound was 1 but it is worth mentioning that a less polar
compound was also formed in the reaction, with Rf = 0.42, active in
2-HO-THF is an intermediate in the synthesis of butyrolactone from
THF [26-28], and in our case, it was formed by the air oxidation of
THF through the corresponding peroxides, followed by their
decomposition in time on sodium wire or during the THF
distillation. The signals for all carbon atoms were in a ratio of ~1:1,
and, for C-1 two signals were at δ 96.36, 91.59 ppm, which did not
confirm the presence of a CH=N group for a hydrazone in 1 [ex. 1.1.
and Electronic Supplementary Information (ESI), 1.1-NMR spectra].
These signals seemed to agree more with the structures of N,O-
aminals, as described in the literature [ 20, 22]. The signal at δ 91.59
ppm could be attributed to a cyclic N,O-aminal 1a resulting from
the internal cyclization of compound 1 (1 → 1a), catalyzed by the
2 4
UV and DNFH, but inactive to H SO , which decomposed during the
LPC purification (dichloromethane-methanol, 9:1, I) of the reaction
mixture. Compound 1 was obtained in 43.4% yield based on INH,
and crystallized from acetonitrile had mp 146.3-147.5 ˚C, similar to
that of the previous compounds. The experiment was repeated
three times and was reproducible. The NMR spectra of this
3
compound in CDCl (see ESI, 1.5.) presented the carbon atoms as
double signals and the proton profile was similar to the one
mentioned above for the cyclic N,O-aminal 1a and the linear
compound 1b. These new crystals were analyzed by NMR in DMSO-
d6, which confirmed the Schiff structure of the isoniazid analogue 1,
presented in Scheme 1. The same crystals were then analyzed by X-
ray crystallography and the molecular structure 1 was undoubtedly
confirmed (Fig. 3).
traces of HCl in CDCl , both enantiomers giving the same NMR
spectra (Scheme 2, 1a).
3
These experimental results indicate that compound 1 was formed,
X
in all the reactions above, from the 2-HO-THF present in THF ,
through the intermediate 4-hydroxy-butanal, because these forms
are known to be in equilibrium (Fig. 1) [26, 27, 30].
2
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and of the resulting triphenylphosphinoxide, the crude 2-HO-THF
was reacted with INH in methanol, at r.t. overnight. After removing
the solvent under reduced pressure, the crude compound
crystallized from acetonitrile and 1 was directly obtained in a
O
OH
OHC
OH
X
quantity of 24.8 mmol; this means that in THF at least 14.4 mmol
2
-Hydroxy-tetrahydrofuran
4-hydroxy-butanal
2
-HOO-THF from the all peroxides were reduced to 2-HO-THF to
react with INH.
Figure 1. The equilibrium of 2-HO-THF and 4-hydroxy-butanal
An interesting fact is that the reduction of 2-HOO-THF (existing in
Y
the THF ) in the presence of INH with Ph P was a very efficient way
X
3
To prove this fact (the existence of 2-HO-THF in THF ), we purified
to obtain the isoniazid analogue 1 (Experimental, ex. 1.5.2.). During
the reaction we did not observe the formation of 2-HO-THF,
probably due to the rapid reaction of the 4-hydroxybutanal (in
equilibrium with 2-HO-THF) with INH at ~ 50 ˚C, a temperature
X
an aliquot from THF by LPC and analyzed the two isolated
compounds, [which we believed to be responsible for the reaction
with INH to the less polar (Rf = 0.44) and the more polar (Rf
.21) isoniazid compounds]. The less polar compound (Rf = 0.76),
was isolated as an oil and was identified as 2-hydroperoxide-
tetrahydrofuran (2-HOO-THF) [31-33]. The more polar (Rf = 0.51)
was isolated also as an oil and was proven to be 2-HO-THF [26-28,
1
=
0
3
which was maintained during the Ph P reduction.
This finding is important because it shows that 2-HOO-THF from old
THF with peroxides (and also pure 2-HOO-THF or made from THF as
mentioned in the literature [35]) could be also used as a source of
3
0] (ex.1.4; ESI, NMR-spectra: 1.3-1.4). Surely, the presence of
2
-HO-THF for similar reactions with other functional groups in
peroxides with higher boiling point was limited by distillation of THF
which, the reduction of the peroxide to 2-HO-THF with Ph P does
3
X
Y
until its boiling point, for THF and then until 68 ˚C, for THF . In the
TLC studies, we than realized that the presence of 2-HO-THF and 2-
HOO-THF could be simply checked on silica gel plates (eluent:
not disturb; the catalog price of 2-HO-THF is extremely high.
However, the presence of 2-HO-THF and also of 2-HOO-THF, in the
old THF with peroxides can be easily checked by TLC in the systems:
dichloromethane-methanol, 9:1, 95:5 (or others) by visualization
with DNFH at rt (yellow color) and then by heating at 110 ˚C (gray-
black spots) (ESI, 4.1.).
2 2
CH Cl -Methanol, 9:1 or 95:5, or others) and visualized with 2,4-
dinitrophenyl hydrazine reagent at r.t. (yellow spots for both
compounds, more intense being that of 2-HO-THF), followed by
heating at 110 ˚C, when both spots became very intensive gray-
black). This finding is an easy method to verify the extent of 2-HO-
THF and 2-HOO-THF in THF with greater content of peroxides.
In the literature, the 2-HOO-THF was found to be the major
peroxide in the THF oxidation during prolonged exposure to air
during storage, and was isolated by careful distillation [34, 35].
Moreover, 2-HOO-THF was obtained by the autoxidation of fresh
THF for 24 h at 25˚C [35] or 65˚C [32] under UV light and isolated by
vacuum distillation. Though 2-HOO-THF was stable in its purification
by distillation, Criegee [35] assumed that it is the decomposition of
1
The compound 1, obtained above, had the same signals in H- and
13
3
C-NMR in CDCl and in DMSO-d6 (Experimental, ex. 1.5.1; ESI 1.6-
1
.7). The following NMR studies were performed, all supporting the
tautomerism:
3
. the NMR tube with substance in CDCl was heated for 5 min
1
and we observed the tautomerization of the compound 1 to 1a, and
the reaction product of 1 with water, 1b (ESI, 1.7. NMR spectra).
2
3
. the CDCl was then evaporated with a nitrogen stream, the
2
2 3 2 n
-HOO-THF to a polymer hydroxy-acetal, [HO-(CH ) CH(O-) ] , that
residue was dissolved in DMSO-d6 and the NMR spectroscopy
showed very well the return of the cyclized tautomer 1a to the
tautomer with the linear structure 1 (1a → 1), presented in Scheme
is responsible for the explosion of peroxides from old THF. Other
peroxides or impurities from THF were discovered in the researches
on 2-HOO-THF. For example, in the treatment of 2-HOO-THF with
ferrous sulphate or sodium hydroxide, γ-butyrolactone was found
to be formed [34]. Muroi [36] identified γ-butyrolactone, but also
hexane-1,6-diol diformate and only small amounts of 4-hydroxy
butanal. Certainly, peroxides with greater molecular weight, or
products resulted from the decomposition of the peroxides, are
present in the THF with high peroxide content, and their
1
, and also the elimination of water from 1b giving 1; this analysis
confirmed that in DMSO this linear structure 1 is favored (ESI, 1.7.
NMR spectra).
3
. by adding D O over DMSO-d6, the 4-OH was deuterated
2
and the corresponding triplet at 4.55 ppm disappeared and H-4
simplified to a triplet (J = 6.3 Hz) (ESI, 1.8.).
4
. by heating then for two hours at 100 ˚C, the CH=N proton
identification
is
waiting
to
be
discovered.
2,2’-
was partially deuterated and more evidently, the H -protons were
2
Peroxybis(tetrahydrofuran) was recently discovered in the crystal
complex of perfluoro-o-phenylmercury, formed in time (a month on
air) [37] or in a co-crystal with a polycyclitol [38]. Generally, the THF
with more than 0.05% peroxides must be carefully checked before
use, as it is well known in the art (see also ref. 1-7 in [42]).
almost entirely deuterated (~ 85% deuterated) and the H-3 protons
appeared as triplet (J = 6.3 Hz). Of course, the profile of the carbon
atoms was not modified (ESI, 1.8).
It is clear that in DMSO, in DMSO + D
crystal) from X-ray analysis, the compound has the linear structure
, presented in the Scheme 2, while in the slightly acidic CDCl a
2
O, like in the solid state
X
After proving that 2-HOO-THF was present in THF , we decided to
(
X
reduce it from a 50mL aliquot of THF . Aqueous reducing reagents
1
3
like ferrous sulfate [36] or sodium sulfite/bisulfit [39] are not
attractive because of the solubility of THF in water; the reflux of the
long range tautomerization takes place to the cyclic forms of N,O-
aminals 1a.
THF over solid cuprous chloride [40], stannous chloride, or LiAlH
41] and molecular sieve [42] are also mentioned in the literature.
The absorption of peroxides on other absorbers is also mentioned:
alumina, activated alumina, 13X molecular sieves, ion-exchange
resins (see ref. 10-14 in [42]). We have chosen to reduce the
4
A tautomerism was observed in the literature between the amide-
carbonyl and the vicinal NH (Fig. 2, line a) [44], in the chelates with
metals [45], to over a few atoms, like in Schiff bases of 2-hydroxy-1-
naphthylaldehyde (Fig. 2, line b, A ↔ B) [46], a Schiff base to a
cyclized aminal with a primary alcohol (Fig. 2, line c, C↔ D) or a bis-
Schiff base to a cyclized aminal with a secondary alcohol (Fig. 2, line
d, F ↔ E ↔ G):
[
peroxides (including 2-HOO-THF) with triphenylphosphine (Ph
3
P)
[
43] to 2-HO-THF and after a rough separation of the excess Ph P
3
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O
C
OH
C
sterical hindrance and the traces isomer has the endo-form. These
findings strengthen the above mentioned facts that the acidity
a).
R
C
N
NH
N
R
C
N
N
N
[
44]
R
R
presented in CDCl
3
favoured the cyclic N,O-aminal form of the
N
N
R1
N
R1
H
H
isoniazid analogues, like in the case of compound 1.
R1
R1
H
O
O
c). HO
b).
O
R
N
R
[18]
[
46]
R
3'2'
R
C
OH
NH NHOC
N
1'
4
'
A
B
D
6
O
HO
CH NHNOC
O
Cl
Cl
INH
7
+
9
8
Cl
Cl
10
11
OH
E
OTBDMS
13 OTBDMS
2
OTBDMS
1
H
N
H
N
N
OTBDMS
OTBDMS
4b
OTBDMS
H+ (CDCl
3
)
N
N
d).
[22]
4a
3
DMSO
H
O
H
O
H
H
OH
NH NHOC
N
N
HN
O
O
HO
6
3' 2'
4'
H
INH
7
CH NHNOC
N
1'
Cl
Cl
+
9
8
(
cis-tautomer)
(trans-tautomer)
10
1
1
13
15
17
O
19 20
F
G
O
12
14
16
21
O
18 23
OH
OH
OH
OH
OH
OH
22
Cl
Cl
Cl
5
H+ (CDCl
)
3
6a
6b
Figure 2. The tautomerism of different Schiff bases
DMSO
In our case there is a long range tautomerism (over 4 carbon Scheme 3. The Schiff and N,O-aminal forms of the isoniazid
atoms), from to 1a, due to the addition of the 4-hydroxyl proton analogues obtained from prostaglandin intermediates of lactol
to the Schiff double bond, with the concomitant formation of a types,
and ; the carbon atoms are numbered as in the
tetrahydrofuran ring and the disappearance of the sp character of prostaglandins field.
1
3
5
2
13
the C-1 carbon atom, like in a N,O-aminal, as observed in C-NMR
in CDCl ; the addition of the water, present in the crystal, to
gave X-Ray crystallography of the compound
also a linear N,O-aminal 1b
crystal X-ray diffraction study, compound
3
1
1
: According to the single
1 crystallizes in P1 space
.
N,O-Aminals with an exocyclic hydroxy or alkoxy group [2] and group of triclinic system. Its asymmetric part comprises four
cyclic N,O-aminals like that presented in Fig. 2 (lines c and d) [18, crystallographic independent but chemically equivalent molecular
2
2] are mentioned in the literature, but our study presents an entities (denoted A B
easier transform of the linear tautomer
to the cyclic tautomer 1a molecules. Due to their similarity, the perspective view of the
favoured by the formation of a 5-atoms cycle, like in
-butyrolactol molecule is only shown in Figure 3.
2-HO-THF), in agreement with the Baldwin’s rule (5-exo-trig) [47,
, C and D) and four co-crystalizes water
1
γ
A
(
4
8], and, to our knowledge, such a tautomerization was never
mentioned in the literature for an isoniazid analogue.
Finally, we oxidized 1,4-butanediol [49-51] with PDC and the
resulting crude carbonyl compound was reacted with INH (ex. 1.6.);
the product obtained was identical to compound 1.
X
We then reacted the same aliquot of THF with the more reactive
,4-dinitrophenylhydrazine and obtained 4-(2-(2,4-
dinitrophenyl)hydrazineylidene)butan-1-ol, (Scheme 1), in almost
the same level as for (ex. 1.7.); in CDCl we did not observe an
aminal formation for this compound. The NMR spectra in DMSO,
and in CDCl (at r.t and 60˚C) of the compound show only a Schiff
, in agreement with the
2
2
1
3
2
3
structure (ESI, 1.9), as for compound
1
Figure 3. X-ray molecular structure of isoniazid analogue
(molecule ) with atom labeling scheme and thermal ellipsoids at
50% probability level. Selected bond and torsion angles (deg.): O1-
1
stronger linkage of the CH=N bond in 2,4-dinitrophenylhydrazone
than in isonicotinoylhydrazone.
A
We then synthesized the isoniazid analogues
complex structures than , from two different single enantiomer
lactol-compounds, and originated from the total = 119.8; C6-N2-N3-C7 = -178.3(2); N2-N3-C7-C8 = - 178.6(2); N3-N2-
4
and
6
, with more C6-N2 = 123.9(2); O1-C6-C3 = 119.3(2); N2-C6-C3 = 116.8(2); N3-C7-
1
γ-
C8 = 120.4(2); C6-N2-N3 = 118.2(2); C7-N3-N2 = 115.4(2); N3-C7-H7
3
5,
stereocontrolled sequence for obtaining prostaglandins, to see if a
similar tautomerism could be observed (Scheme 3). In both cases,
C-NMR in DMSO shows the presence of the Schiff analogues 4a Bond distances and angles are summarized in Table 1S and Tables
C6-C3 = - 176.8(2).
1
3
and 6a [δ 153.86, respectively 153.72 ppm for CH=N] as in the case 4-6 (cifreport) (ESI). The structure of the molecule shows the E-
of compound
, but also the presence of the cyclic N,O-aminals 4b configuration of the substituents linked to the double bond N3-C7,
and 6b [δ 91.72 (traces at 93.36), respectively 91.62 ppm for O-CH- proved by the C6-N2-N3-C7 torsion angle of -178.3(2). This fact was
1
13
NH], a little more favoured being the Schiff form. In CDCl
shows almost exclusively the presence of the N,O-aminals 4b and 6b the hydrazone N3 atom are cis-linked to the C6-N2 bond and N2
3
,
C-NMR observed in the literature in another case [52]. The O1 atom and
[
δ 92.57 (traces 94.17), respectively 92.57 (traces 93.70) ppm] and C8 are trans-linked to the double bond N3-C7. The whole
(
Scheme 3) (ESI, 1.10-1.11), a favoured cyclization as predicted by crystallographic data are presented in Tables 1-8 (ESI) and selected
Baldwin’s rules (5-exo-trig) [47-48]. It is to be mentioned that in the angles are presented in Figure 4.
case of the cyclic N,O-aminals, 4b and 6b, the two isomers are All the components of the structure are interacting through
present, the major being probably the exo-form due to the less numerous O-H···N, N-H···O, and N-H···N hydrogen bonds (Table 2S),
which are completely realized in the crystal. These bonds determine
4
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ARTICLE
the formation of two dimensional supramolecular layers running NMR signals. The numbering of the atoms in the compounds is
parallel to the 110 plane, as shown in Figure 5. There are two presented in Schemes 1 and 3.
crystallographic distinct layers formed by molecules
A
+
B
and
C +
D
, respectively. In turn, these layers are further linked via
π
-
π
-
X-Ray crystallographic measurements were carried out with
a
centroid-to-centroid an Oxford-Diffraction XCALIBUR E CCD diffractometer equipped
stacking interactions (Figure 6S) with
distance of 3.622(6) Å. As the result, the main crystal structure with graphite-monochromated Mo-Kα radiation. Single crystals
packing motif can be characterized as
supramolecular arrangement.
a
tree-dimensional were positioned at 40 mm from the detector and 716 frames were
measured each for 5 s over 1° scan width. The unit cell
determination and data integration were carried out using the
CrysAlis package of Oxford Diffraction [53]. The structure was
solved by direct methods using Olex2 [54] and refined by full-matrix
least-squares on F² with SHELXL-97 [55]. Atomic displacements for
non-hydrogen atoms were refined using an anisotropic model. All H
atoms attached to carbon were introduced in idealized positions
(dCH = 0.96 Å) using the riding model with their isotropic
displacement parameters fixed at 120% of the riding atom.
Hydrogen atoms for OH and NH groups have been placed by Fourier
Difference and refined accounting for hydrogen bonds parameters.
In the absence of significant anomalous scattering, the absolute
configuration of structure could not be reliably determined. As a
result, Friedel pairs were merged and any references to the Flack
parameter were removed. The molecular plots were obtained using
the Olex2 program. Crystallographic data have been deposited at
the Cambridge Crystallographic Data Centre as Supplementary
Publication No. CCDC- 1561067. Copies of the data can be obtained
free of charge from CCDC (12 Union Road, Cambridge CB2 1EZ, UK;
Tel.: + 44 1223 336 408; fax: +44 1223 336 033; e-mail:
deposit@ccdc.cam.ac.uk; www:http://ccdc.cam.ac.uk).
Figure
4
.
One of the two independent two-dimensional
and molecules). H-bonds are
supramolecular layers (formed by
A
B
shown in dashed lines. Non-relevant H-atoms are omitted for
clarity.
X
THF was obtained from old THF kept on sodium wire, (left for some
years in small quantities in bottles) by distilling the solvent with a
distillation column with Raschig rings not exceeding the boiling
point of THF and then added sodium wire. We continued the
The compounds 1, 4, 6, and INH as standard were sent to CO-ADD
Community for Open Antimicrobial Drug Discovery (Institute for
Molecular Biosciences, The University of Queensland, 4072 St Lucia
Y
distillation until 68 ˚C and obtained a THF , containing 2-HOO-THF.
We observed that it is easy to check and qualitatively evaluate the
THFs with peroxides for 2-HO-THF or 2-HOO-THF simply by TLC in
the solvent system dichloromethane-methanol 9:1 (or 95:5 for
example) and to view the spots by spraying with 2,4-dinitrophenyl
QLD Australia
cell growth inhibition assays, at a single concentration, in duplicate
n=2). The inhibition of growth was measured against 5 bacteria:
Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii,
Pseudomonas aeruginosa and Staphylococcus aureus, and 2 fungi:
Candida albicans and Cryptococcus neoformans (ESI, Table 3S). The
) for primary antimicrobial screening study by whole
(
hydrazine reagent at r.t. (yellow spots), then heating to 110 ˚C
X
(
~
gray-black spots) (ESI, 4.). By iodide/thiosulfate titration, THF had
Y
0.3 mequiv/mL and THF had ~2.9 mequiv/mL, with TLC mentioned
in ESI, 4.1. No unusual sign was observed, even after its use in a
Corey type -lactone to a -lactol reduction with DIBAL.
compounds 1, 4, 6 and INH were found to be inactive.
γ
γ
4
. Experimental
Example 1.1. NMR spectra of compound 1 isolated from a reaction
of INH with a hindered ketone, in THF .
Melting points (uncorrected) were determined in open capillary on
an OptiMelt melting point apparatus. The progress of the reaction
was monitored by TLC on silica gel 60F254 plates (Merck) eluted with
X
Compound
visualized with dinitrophenylhydrazine and H
15 min. heating at 110˚C) and isolated by LPC (eluent, I) in the
1
was obtained as a by-product (active in UV light, and
the solvent system:
I
(Dichloromethane-methanol, 9:1), II
2
4
SO /MeOH reagent
(
dichloromethane-methanol, 95:5). Spots were developed in UV,
(
2
,4-dinitrophenylhydrazine reagent or with 15% H SO4 in MeOH
2
purification of a crude product (reaction of INH with a ketone) as
oil, which crystallized from acetonitrile, mp 146.0-147.6 ˚C, FT-IR
(
heating at 110˚C, 10 min). IR spectra were recorded on FT-IR-100
Perkin Elmer spectrometer, in solid phase by ATR and frequencies
-1
spectrum: 3185 s, 2963m, 1653s, 1627m, 1552s, 1410m, 1345m,
expressed in cm , with the following abbreviations: w = weak, m =
medium, s = strong, v = very, br = broad. MS were recorded on 1200
L/MS/MS triple-quadrupole Varian with ESI interface, fragments,
obtained by collision with Ar and relative abundances (%) are given
1
1
296m, 1051m, 1025m, 666w, H-NMR-500 MHz (CDCl , δ ppm, J
3
Hz): 9.35 (br s, CONH), 8.74 (d, 2H, H-2’, 6.0), 7.62 (d, 2H, H-3’, 6.0),
.12 (t, ~0.3H, H-1, 6.3), 4.97 (dd, ~0.6H, H-1, 4.9, 6.3), 4.00-3.68
5
13
1
13
(4m, 2H, H-4), 3.73 (br s, OH), 2.57-1.70 (m, 4H, 2H-2, 2H-3), C-
NMR-125 MHz (CDCl , δ ppm): 165.74, 164.87 (CON), 150.79,
in parenthesis. H-NMR and C-NMR spectra are recorded on
1
3
Varian Gemini 300 BB spectrometer (300 MHz for H and 75 MHz
1
3
150.63 (C-2’), 140.20, 140.02 (C-4’), 121.01, 120.88, 120.73 (C-3’),
96.36, 91.57 (C-1), 68.96, 67.26 (C-4), 29.74, 29.32 (C-2), 25.05,
for C), or Bruker Avance III 500 MHz spectrometer (500 MHz for
1
13
H and 125 MHz for C), spectrometer chemical shifts are given in
ppm relative to TMS as internal standard. Complementary spectra:
D-NMR and decoupling were done for the correct assignment of
2
4.84 (C-3) (See ESI for all NMR spectra, 2.1.).
2
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ARTICLE
New Journal of Chemistry
Example 1.2. NMR spectra of compound 1 isolated from a reaction and 283 mg of the compound with Rf = 0.51 (which gave compound
X
of INH with a cyclopentane aldehyde, in the same THF .
1
), identified to be 2-HO-THF, as oil, IR: 3400 brs, 2954s, 2885s,
1
720s, 1181m, 1031vs, 985vs, 918s, 3400 br s, 2954s, 2885s,
1
Compound
1
(coded: Cp-Clo-bis-INI for NMR spectra) was isolated 1443m, 1342m, 1260m, 1181m, 1031s, 985s, H-NMR-300 MHz
as above by purification of a crude product obtained by the reaction (CDCl , δ ppm, J Hz): 5.49 (d, 1H, H-1, 3.7), 3.80 (t, 2H, H-4, 6.6),
3
X
1
of INH with a cyclopentane aldehyde in THF , H-NMR-500 MHz 4.01 (t, 1H, H-4, 6.2), 2.18 (t, 1H, H-2, 7.8), 2.05-1.70 (m, 3H, H-2,
13
(
6
3
DMSO-d , δ ppm, J Hz): 11.65 (s, 1H, CONH), 8.745 (d, 2H, H-2’, 2H-3), C-NMR-75 MHz (CDCl , δ ppm): 103.92m, 98.53 (C-1),
5
5
.6), 7.78 (t, 1H, CH=N, 5.3), 7.75 (d, 2H, H-3’, 5.6), 4.54 (t, 1H, OH, 67.52, 67.08m (C-4), 32.25, 32.41m (C-2), 23.55 (C-3), (ESI, 2.4.).
.1), 3.45 (q, 2H, H-4, 6.1), 2.32 (dt, 2H, H-2, 5.7, 7.3), 1.65 (dt, 2H, MS: C H O , Mwt: 88.11, MS 88.05, HRMS calc. for C H O , [M+H]:
4
8
2
4
9
2
13
H-3, 6.6, 14.2), C-NMR-125 MHz (DMSO-d6, δ ppm): 161.22 (CO), 89.05971, measured APCI 91.0542.
1
2
53.83 (C-1), 150.24 (C-2’), 140.67 (C-4’), 121.47 (C-3’), 60.13 (C-4),
9.30, 28.94 (C-2, C-3) (ESI, 2.2.).
Example 1.4.2. Synthesis of 2-HOO-THF.
Example
1.3.
Synthesis
of
N'-(4- 2-HOO-THF was synthesized by introducing a low stream of oxygen
hydroxybutylidene)isonicotinohydrazide
in THF at 65 ˚C overnight (without an UV lamp), as described by
Criegee R. [35]. The THF was distilled at rotavapor, the residue was
X
INH (5 mmol, 685 mg) was added to 50 mL tetrahydrofuran THF , co-evaporated with benzene and 2-HOO-THF was used as so
and the mixture was heated to slight reflux under stirring for 90 obtained.
min., monitoring the reaction by TLC (I, Rf
1
= 0.21). The INH was
X
consumed and another INH (2.1 g) was added in portions and the Example 1.5.1. Treatment of THF with triphenylphosphine to
mixture was stirred for 1h at slight reflux. TLC showed that all INH reduce peroxides and reaction of 2-hydroxytetrahydrofurane with
was reacted and that another compound was formed, active in UV INH
and dinitrophenylhydrazine reagent, but inactive to 15% H
MeOH reagent, Rf by-product = 0.44, See SM, 4.2). Another 500 mg INH Ph
total 24 mmol) were added, reacted at slight reflux for 1 h and under stirring. The solution warmed from 18˚C to 35˚C and then the
then at r.t. overnight. The products were adsorbed on 5 g silica gel stirring was continued overnight (80h), monitoring the reaction by
2 4
SO in
X
3
P (3.935 g, 15 mmol) was added to 50 mL tetrahydrofuran (THF )
(
and purified by LPC (eluent, II), resulting 2.16 g (10.42 mmol, 43.4% TLC (I, Rf Triphenylphosphine = 0.91, Rf Triphenylphosphinoxid = 0.69, Rf 2-OH-THF
=
based on INH) of pure compound
acetonitrile, mp 146.3-147.5 ˚C, IR as in ex. 1, H-NMR-500 MHz crude product was absorbed on 12 g silica gel and roughly purified
CDCl
, δ ppm, J Hz): 9.41, 9.06 (2s in a ratio of 2:1, CONH), 8.74 (d, by LPC (eluent, dichloromethane-methanol, 10:0.2), resulting 3.167
H, H-2’, 6.0), 7.63 (d, 2H, H-3’, 6.0), 5.12 (t, ~0.3H, H-1, 6.3), 4.97 g of crude product containing ~ 70% 2-HO-THF by TLC (roughly
dd, ~0.6H, H-1, 4.9, 6.3), 4.00-3.68 (4m, 2H, H-4), 3.37 (br s, OH), densitometric).
1
, which was crystallized from 0.50). Triphenylphosphinoxide did not crystallize from ether and the
1
(
3
2
(
1
3
2
1
1
.57-1.70 (m, 4H, 2H-2, 2H-3), C-NMR-125 MHz (CDCl
3
, δ ppm): The crude product was dissolved in methanol (70 mL), INH (3.46 g,
65.75, 164.87 (CON), 150.77, 150.71 (C-2’), 140.02 (C-4’), 121.02, 25.2 mmol) was added and stirred overnight at r.t. TLC showed the
20.89, 120.74 (C-3’), 96.36, 91.59 (C-1), 68.95, 67.27 (C-4), 29.73, disappearance of the 2-hydroxy-tetrahydrofurane and the presence
2
9.31 (C-2), 25.05, 24.84 (C-3),
of some excess of INH. The solvent was removed under reduced
, δ ppm, J Hz): 11.65 (s, 1H, NH), 8.75 pressure, taken in hot acetonitrile (70 mL), filtered and the filtrate
d, 2H, H-2’, 6.1), 7.78 (t, 1H, CH=N, 5.2), 7.75 (d, 2H, H-3’, 6.1), 4.54 was left at r.t. (18˚C) over weekend. The crystallized compound was
t, 1H, OH, 6.0), 3.45 (br dt, 2H, H-4, 6.0, 4.7), 2.33 (dd, 1H, H-2, 5.2, filtered, washed with a little acetonitrile, dried at r.t., resulting 3.40
1
H-NMR-300 MHz (DMSO-d
6
(
(
1
3
7
.7), 2.30 (dd, 1H, H-2, 5.5, 7.7), 1.65 (dt, 2H, H-3, 6.6, 14.8), C- g (24.8 mmol) of pure compound 1, crystallized in needles, mp
NMR-75 MHz (DMSO-d6, δ ppm): 161.21 (CO), 153.81 (C-1), 150.25 142.9-143.2 ˚C. By recrystallization from acetonitrile, the compound
C-2’), 140.67 (C-4’), 121.48 (C-3’), 60.13 (C-4), 29.31, 28.95 (C-2, C- has mp 146.3-147.4˚C, Rf, IR and NMR in DMSO-d6 identical with
(
3
2
), (See ESI, 2.3.), MS 207.23 calcd. for C10
08.10805, found 208.10796 [121 (C O), 138 (C
NO), 79 (C N)].
No compound with Rf = 0.44 was isolated, as it probably different conditions:
decomposed during purification. The experiment was repeated
-NMR spectra were done in CDCl
, were close to that evaporated and NMR spectra were performed in DMSO (ESI 2.5 and
2.6): NMR spectra in CDCl are in agreement with those presented
H
13
N
3
O
H N
6 8 3
2
[M+1]: th. those of the compound obtained in example 1.
O), 105 Complementary spectra were performed to gain more insight into
the structure of and check the stability of compound under
6
H
5
N
2
(C
6
H
3
5
H
5
1
3
and then the solvent was
three times and the weights of the compound
presented above: 2.12 g, 2.21 g and 2.19 g.
1
3
at ex. 1 and 3 and NMR spectra in DMSO to those presented in ex. 2
X
Example 1.4.1. Purification of an aliquot of THF .
and 3.
1
-
NMR spectra in DMSO-d
6
+D
2
O, at r.t: H-NMR-300 MHz
X
An aliquot of 15 mL THF was purified by LPC (II), resulting a pure (DMSO-d +D O), room temperature, δ ppm, J Hz): 8.72 (d, 2H, H-2’,
6
2
fraction of 234 mg as oil, of the compound with Rf = 0.76, identified 6.3), 7.75 (t, 1H, CH=N, 5.2), 7.73 (d, 2H, H-3’, 6.3), 3.44 (t, 2H, 2H-4,
1
3
to be 2-HOO-THF, IR: 3431 brs, 2953s, 1443w, 1412w, 1324w, 6.6), 2.31 (dt, 2H, H-2, 5.2, 7.3), 1.64 (cv, 2H, H-3, 6.6), C-NMR-75
1
1
3
174s, 1034s, 918s [33], H-NMR-300 MHz (CDCl , δ ppm, J Hz): MHz (DMSO-d6, δ ppm): 161.76 (CO), 154.54 (C-1), 150.57 (C-2’),
8.90 (br s, 1H, OOH), 5.54 (t, 1H, H-1, 6.1), 4.29 (t, 1H, H-4, 7.1), 140.93 (C-4’), 121.89 (C-3’), 60.38 (C-4), 29.40, 29.23 (C-2, C-3), (ESI,
3
.89 (t, 1H, H-4, 6.1), 2.43 (t, 1H, H-2, 8.0), 2.20 (q, 1H, H-2, 7.7), 2.8).
13
2.00-1.75 (m, 2H, H-3), C-NMR-75 MHz (CDCl
3
, δ ppm): 110.13m,
6 2
- NMR spectra in DMSO-d +D O, and warming two hours at
1
1
08.10 (C-1), 68.71m, 67.85 (C-4), 29.26, 27.95m (C-2), 24.05, 100 ˚C: H-NMR-300 MHz (DMSO-d +D O), heating 2 h at 100 ˚C,
6
2
2
2.31m (C-3), (ESI, 2.3) C H O , Mwt: 104.11, MS 104.04, HRMS δ): 8.72 (d, 2H, H-2’, 6.3), 7.74 (t, 1H, CH=N, 5.2), 7.73 (d, 2H, H-3’,
4 8 23
4 8
calc. for C H O23, [M+H]: 105.05462, measured (APCI +) 105.0701 6.3), 3.43 (t, 2H, 2H-4, 6.3), 2.28 (m, ~0.15H non-deuterated, H-2),
[M+H],
6
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ARTICLE
1
3
1
.62 (t, 2H, H-3, 6.3), C-NMR-75 MHz (DMSO-d6, δ ppm): 161.23 The solvent was removed under reduced pressure, and purified by
(
CO), 153.81 (C-1), 150.27 (C-2’), 140.68 (C-4’), 121.50 (C-3’), 60.15 LPC (eluent, I), resulting 2.81
g
(10.6 mmol) 4-(2-(2,4-
, mp 112.3-113.9 ˚C,
(C-4), 29.32, 28.98 (C-2, C-3), (ESI, NMR: 2.8).
dinitrophenyl)hydrazineylidene)butan-1-ol
2
1
6
H-NMR-300 MHz (DMSO-d , δ ppm, J Hz): 11.30 (s, 1H, NH), 8.82
Example 1.5.2. Synthesis of isoniazid analogue 1 by reducing the (d, 1H, H-3’, 2.6), 8.31 (dd, 1H, H-5’, 2.6, 9.7), 8.02 (t, 1H, CH=N,
Y
peroxides (mainly containing 2-HOO-THF) of an old THF with 5.1), 7.83 (d, 1H, H-6’, 9.7), 3.47 (t, 2H, H-4, 6.3), 3.38 (brs, 1H, OH),
1
3
triphenylphosphine in the presence of isoniazid.
2.38 (dt, 2H, H-2, 5.1, 7.3), 1.70 (cv, 2H, H-3, 6.3), C-NMR-75 MHz
(
(
DMSO-d6, δ ppm): 155.00 (C-1), 144.65 (C-1’), 136.34 (C-4’), 129.68
C-5’), 128.50 (C-2’), 122.96 (C-3’), 116.12 (C-6’), 59.92 (C-4), 29.10,
9.02 (2C, C-2, C-3). (ESI, 2.9).
Prior determination of the peroxide content, the reaction
conditions were first tested and the established procedure is
presented below. INH (7.543 g, 55 mmol) was added in a 100 mL
round bottom flask and 25 mL THF with 2-HOO-THF as the major
peroxide and 10 mL good anh. THF were added, and then, under
stirring, triphenylphosphine (14.43 g, 55 mmol) was added in
2
1
H-NMR-500 MHz (CDCl , δ ppm, J Hz): 11.23, 11.03 (2s in a ratio of
3
Y
0
7
.17: 0.83, 1H, NH), 9.10 (s, 1H, H-3’), 8.29 (d, 1H, H-5’, 9.5), 7.95,
.91 (2d, in a ratio of 0.17: 0.83, 1H, H-6’, 9.5), 7.61 (br t, (t, 1H,
CH=N, 5.0), 3.78 (t, 2H, H-4, 5.5), 2.56 (dt, 2H, H-2, 6.4, 6.6), 1.92
(m, 2H, H-3, 6.4), C-NMR-125 MHz (CDCl , δ ppm): 151.98 (C-1),
3
13
portions (the reaction of Ph P with peroxides is exothermic),
3
keeping the temperature of the reaction under 55 ˚C (in 2 h). The
reaction mixture was stirred overnight at ~55˚C, though it looks that
there is no presence of the peroxides by TLC (See ESI, 4.3).
1
44.07 (C-1’), 137.81 (C-4’), 129.97 (C-2’, C-5’), 123.49 (C-3’), 116.44
(
C-6’), 61.97 (C-4), 29.22, 28.98 (2C, C-2, C-3).
[Observation: In this procedure, the formation of the reduced
1
.8
Synthesis
of
N'-((E)-((1R,2R,3S,5R)-3-((tert-
intermediate 2-HO-THF was not observed, probably at the reaction
temperature, this compound reacted rapidly with isoniazid,
presented in the reaction mixture]. The reaction mixture was
butyldimethylsilyl)oxy)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-
hydroxycyclopentyl)methylene)isonicotinohydrazide, 4
concentrated under reduced pressure, co-evaporated with toluene Starting from 2 mmol ent-Corey lactone 3,2-1’-bis-OTBDMS ether,
and the crystallized residue was extracted with hot by reduction with DIBAL (0.9 mL), the corresponding lactol
dichloromethane-hexane (3
×100 mL). The unified extraction (3aS,4R,5S,6aR)-5-((tert-butyldimethylsilyl)oxy)-4-(((tert-butyl-
solutions were cooled in refrigerator for 1 h, decanted and the dimethylsilyl)oxy)methyl)hexahydro-2H-cyclopenta[b]furan-2-ol,
3
,
residue unified with the previous insoluble, and crystallized and re- was obtained in quantitative yield as oil, [α] = + 31.79 ° (1% in THF);
D
crystalized from acetonitrile. 8.528 g Crystalized compound 1 were TLC (toluene-ethyl acetate 1:1, Rf Corey lactone = 0.73, Rf 3 = 0.63).
obtained. All mother liquors were concentrated, the concentrate The lactol
was purified by LPC (silica gel, eluent: solvent system, I), resulting mg) was added and stirred 72 hrs; TLC (toluene-ethyl acetate 1:1, Rf
.42 g crystalized compound (Total: 10.948 g, 52.83 mmol). This
= 0.63, Rf 4 = 0.12). The crude compound was purified by LPC
result shows that, in 25 mL THF used in the reaction, 52.83 mmol (toluene-ethyl acetate 1:1), resulting a pure fraction of 578 mg
of 2-HOO-THF was reduced to 2-HO-THF, which reacted with INH.
(44.3%) as oil, [α] = +32.03° (1% in THF), IR: 3269brm, 2953vs,
930vs, 2889s, 2857s, 1661s, 1551m, 1467m, 1253s, 1102s, 1004m,
3 was dissolved in MeOH (15 mL), INA (2.2 mmol, 280
2
1
3
Y
4
D
2
1
Example 1.6. Oxidation of 1,4-butanediol and reaction of the 880m, 832vs, 773vs, 667m, H-NMR-500 MHz (DMSO-d , δ ppm, J
6
resulted aldehyde with INH
Hz): 11.61 (s, 1H, NHOC), 10.27m (d, 0.18H, NH, 4.9), 10.22 (d,
.79H, NH, 5.5), 8.80 (d, 1H, H-2’, 4.9), 8.70 (d, 1H, H-2’, 5.7), 7.85
t, ~0.5H, CH=N, 5.2), 7.74 (d, 1H, H-3’, 5.7), 7.73 (d, 1H, H-3’, 4.9),
.63 (t, minor, 5.2), 5.56 (t, major, both OH), 4.97 [(q, M, 4.84 (q,
m), ~0.5H, O-CH-N), 4.8], 4.53 (d, ~0.5H, H-11, 5.0), 4.49-4.41 (m,
.5H, H-11), 4.03-3.93 (m, 1H, H-9), 3.63-3.52 (m, 2H, H-13), 2.35
m, 1H, H-7), 2.20 (m, 1H, H-10), 1.95 (t, 1H, H-7, 5.5), 1.86 (m, H, H-
0
(
5
1,4-Butanediol (20 mmol, 1.80 g) in CH Cl (150 mL) were oxidized
2 2
with PDC (20 mmol, 7.52 g) and molecular sieves under stirring
overnight at r.t., monitoring the reaction by TLC (I, Rf 2-OH-THF = 0.51,
identical with the compound from THF ). The reaction mixture was
X
0
(
diluted with 150 mL ethyl acetate, filtered through a sodium sulfate
bed, the bed was washed with ethyl acetate, the filtrate was
concentrated under reduced pressure, put in benzene, filtered,
concentrated under reduced pressure, resulting 1.24 g crude
product (the ethyl acetate was re-distilled and 120 mg 2-HO-THF
were recovered after solvent concentration). The concentrate (1.36
g) was dissolved in 30 mL methanol, 1.92 g (14 mmol) INH were
added and stirred overnight, TLC showing the end of the reaction.
Methanol was distilled on rotavapor, the concentrate was taken in
warm dichloromethane-methanol (9:1), filtered and concentrated
to opalescent solution, left to crystallize in needles on r.t. and
8
), 1.76, 1.61 (2m, 1H, H-12), 1.49 (m, 1H, H-10), 0.87-0.79 (m, 18H,
1
3
3 3 6
CH C), 0.03, 0.02 (2s, 12H, CH Si), C-NMR-125 MHz (DMSO-d , δ
ppm) (the minor aminal isomer was omitted): 163.51 (CONHNH),
1
4
7
4
61.02 (CONH), 153.86 (CH=N), 150.16 (2C-2’), 140.61, 140.16 (C-
’), 121.56, 121.16 (2C-3’), 93.36m, 91.72 (O-CH-N), 79.68 (C-9),
3.64, 71.94, 69.81 (C-11), 61.43, 60.48 (C-13), 54.96, 52.57 (C-12),
3.54, 40.91 (C-10), 41.88, 41.21 (C-8), 35.17, 31.02 (C-7), 25.72
(
CH
3
-C), 18.93, 17.64 (C-CH
3
), - 4.60, -4.97, -5.55 (ESI 1.10). The
were not purified.
, δ ppm, J Hz): 11.48 (s, 1H, NH), 8.73 (d,
.56H, H-2’, 4.7), 8.71 (d, 0.44H, H-2’, 4.8), the isomers are in a ratio
of 0.78:0.22; 8.06 (s, CH-NH), 7.69m (d, 0.44H, H-3’, 4.8), 7.62 (d,
slightly impure fractions of (-)-
6
1
H-NMR-500 MHz (CDCl
3
filtered, resulting 596 mg pure compound
concentrated (2.19 g) and purified by LPC, as in example 1, resulting
1. The filtrate was
1
a pure fraction of 1.25 g compound
optimized reaction).
1 (total 1.846 g, 8.91 mmol, un-
1
9
7
.56H, H-3’, 4.8), 5.10, 4.95m (2m, 3:1, 1H, O-CH-N), 4.55 (m, 1H, H-
), 3.97 (m, 1H, H-11), 3.57-3.48 (m, 2H H-13), 2.52-1.65 (m, 6H, 2H-
, H-8, H-12, 2H-10), 0.88, 0.86 (2s, 18H, CH
3
C), 0.03, 0.02 (2s, 12H,
, δ ppm) (the minor isomer
omitted): 164.79 (CO), 150.62, (2C-2’), 140.28 (C-4’), 121.49 minor
X
Example 1.7. Treatment of THF with 2,4-dinitrophenylhydrazine
13
3 3
CH Si), C-NMR-125 MHz (CDCl
X
In 50 mL THF , 2,4-dinitrophenylhydrazine (DNFH, 4.76 g, 24 mmol))
(
(
(
C-3’), 121.01 (C-3’), 92.57, 94.17 minor (O-CH-N), 81.30 (C-9), 74.13
C-11), 62.00 (C-13), 55.66 (C-12), 42.48 (C-8), 41.63 (C-10), 35.88
C-7), 25.83 (CH
was added in portions in 30 min. and good THF (50 mL) was added
until a clear solution was obtained. TLC (II, Rf
2
= 0.33, Rf sec. product =
3
-C), 18.26, 17.93 (C-CH
3
),- 4.79, -4.90, -5.57 (ESI
0.81, Rf DNFH = 0.58) showed that after 3 h, no DNFH was present.
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
New Journal of Chemistry
+
1
.10), MS 521.84 calctd. for C H N O Si [M+1] : th. 522.31785, Schiff form
1
is present in DMSO while the N,O-aminal
2
2
47
3
4
2
found 522.31757 [121 (C
6
H
5
N
2
O), 138 (C
6
H
8
N
3
41 3 2
O), 385 (C20H O Si ),
3
tautomers 1a are present in CDCl ; the reverse of 1a to 1 was
2
53 (C H O Si), 209 (C H OSi)].
14 25 2 12 21
also put in evidence, by changing CDCl to DMSO-d6 in the
3
NMR spectra. The X-ray crystallography confirmed that the
1
.9.
Synthesis
of
N'-((Z)-2-((1R,2R,3R,5S)-2-((R,E)-4-(3-
linear structure of compound
that found in the NMR spectra in DMSO and DMSO + D
isoniazid analogues from two single enantiomer
1 in the crystal is the same as
chlorophenoxy)-3-hydroxybut-1-en-1-yl)-3,5-
dihydroxycyclopentyl)ethylidene)isonicotinohydrazide, (-)-6
2
O. Two
-lactols
γ
Prostaglandin lactol
5
(241 mg, 0.71 mmol) and INH (150 mg, 1.09 intermediates in prostaglandin synthesis, were also obtained
mmol) in MeOH (12 mL) were refluxed for 5h; TLC (ethyl acetate- and their NMR spectra shows the presence of the Schiff 4a and
hexane-acetic acid, 5:1:0.1, Rf 5 = 0.32, Rf 6 = 0.07); 253 mg (63.0%) 6a and N,O-aminal 4b and 6b tautomers in DMSO and only of
of pure (-)-6 were obtained as foam, [α]
methanol), IR: 3248vs br, 2929m, 1660vs, 1594vs, 1579s, 1551s,
D
= -23.85° (1% in
N,O-aminals, 4b and 6b, in CDCl
isoniazid analogue , by closing a tetrahydrofurane ring, as
predicted by Baldwin’s rules for cyclization (5-exo-trig).
Compounds and had no antimicrobial and antifungal
activity, like also INH.
3
, like in the case of the
1
1
1
1
479s, 1453m, 1431m, 1412m, 1285s, 1248m, 1230s, 1068m,
033s, 972m, 680m, H-NMR 500 MHz (DMSO-d , δ ppm, J Hz):
1.63 (s, 0.5H, NHOC), 10.27 (d, 0.5H, NHNHOC, 6.1), 8.71 (2d, 2H,
1
6
1,
4
6
H-2’, 4.9), 7.83 (t, 0.5H, H-6, 5.2), 7.75 (d, 2H, H-3’, 4.9), 7.28 (2t,
H, H-22, 8.1), 7.02-6.92 (m, 3H, H-19, H-21, H-23), 5.70 (dd, 0.5H,
H-14, 7.4, 15.4), 5.62-5.52 (m, 0.5H-14, H-13), 5.16 (2d, 1H, OH-15,
1
Conflicts of interest
5
5
1
0
1
1
.1), 4.98 (q, ~0.5H, CH-NH, 5.6), 4.78 and 4.65 (2d, 1H, OH-11, 6.0,
.7), 4.61 (d, 1H, OH-9, 4.8), 4.41 (2m, 1H, H-11), 4.32, 4.03 (2brs, There are no conflicts to declare.
H, H-15), 3.93-3.85 (m, 2H, H-16), 3.71 (m, 1H, H-9, 7.1), (In water
.5H, CH-NH), 2.47-1.98 (3m, 3H, H-7, H-10, H-12), 1.84-1.66 (2m,
1
3
H, H-8), 1.47 (m, 1H, H-10), C-NMR-125MHz (DMSO-d
6
, δ ppm):
Acknowledgements
63.53 (CONHNH), 161.13 (CONH), 159.64, 159.60 (C-18), 153.72
(
CHN, C-6), 150.20 (2C-2’), 140.64, 140.18m (C-4’), 133.66 (Cq, C- We thank CO-ADD Community for Open Antimicrobial Drug
2
1
0), 133.23, 132.25 (C-13), 131.51, 130.55 (C-14), 130.83 (C-22), Discovery (Institute for Molecular Biosciences, The University of
21.44, 121.19 (2C-3’), 120.43 (C-21), 114.64, 114.57 (C-19), 113.77 Queensland, 4072 St Lucia QLD Australia for free antibacterial and
and 6.
)
,
(
C-23), 91.62 (OCH-NH), 78.88, 76.53 (C-11), 75.21 (C-9), 72.44m, antifungal screening of the compounds
1
4
7
4
2.33 (C-16), 69.32, 69.19m (C-15), 55.59m, 54.18 (C-12), 45.97,
5.30m (C-8), 43.96, 40.68m (C-10), 34.32m, 30.39 (C-7) (ESI 1.11),
MS 459.92 calctd. for C23
H
26ClN
3
O
5
[M+1]: th. 460.16490, found Notes and references
4
60.16392 [121 (C O), 138 (C
6
H
5
N
2
6
H
8
N
3
O), 442 (C23
H25ClN
3
O
4
), 424
(
C
23
H
26ClN
3
O
5
)]. The slightly impure fractions of (-)-
6
were not
1
2
3
4
5
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2
1
H-NMR 500 MHz (CDCl
d, 1H, H-3’, 5.3), 7.66, 7.59 (2d, 1H, H-3’, 5.3), 7.21 (t, 1H, H-22,
3
, δ ppm, J Hz): 8.75 (2d, 2H, H-2’, 5.3), 7.63
(
8
8
~
1
.2), 6.96 (d, 1H, H-21, 8.2), 6.91 (s, 1H, H-19), 6.80 (d, 1H, H-23,
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1, H-15), 3.93-3.85 (m, 3H, H-9, 2H-16), 2.64 (m, minor H-12), 2.46
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1
3
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,
7
3
), 1.93 (m, 1H, H-7), 1.81 (m, 1H, H-10), C-NMR-125MHz (CDCl , δ
1
ppm): 164.94 (CONH), 159.10 (C-18), 150.63 (2C-2’), 139.87 (C-4’),
6
7
1
1
9
9
4
1
34.98 (Cq, C-20), 133.76 (C-13), 130.36 (C-22), 130.00 (C-14),
21.54, 121.05 (2C-3’), 120.91 (C-21), 115.07 (C-19), 113.11 (C-23),
3.70m, 92.57 (OCH-NH), 80.91m, 80.78 (C-11), 78.77m, 77.87 (C-
), 71.96 (C-16), 70.60, 70.42m (C-15), 58.24m, 57.06 (C-12),
7.18m, 46.55 (C-8), 41.28m, 40.05 (C-10), 36.10m, 35.30 (C-7) (ESI
.11).
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In conclusion, an isoniazid analogue
1 was synthesized by the
X
reaction of INH with the 2-HO-THF present in an old THF ; The
reduction of 2-HOO-THF prior to the reaction with INH or
2
007, 48, 1967.
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We also obtained it by a two-step reaction from 1,4-
butanediol; the corresponding 2,4-dinitrophenyl hydrazone
was also synthesized and shows no tautomerism. A study of
the tautomer forms by NMR spectroscopy shows that only the
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| NJC., 2018, 00, 1-3
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Pl Ne ae swe Jdoo u nr no at l ao df j Cu sh te mm ai sr tgr iyn s
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DOI: 10.1039/C8NJ01680A
New Journal of Chemistry
ARTICLE
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A long range tautomeric effect on a new Schiff isoniazid analogue, NMR study and X-ray
crystallography
Constantin I. Tănase, Constantin Drăghici, Sergiu Shova, Anamaria Hanganu, Emese Gal, Cristian V. Munteanu
Text
Isoniazid analogues which are cyclized in acid catalysis by closing a THF ring, favoured by Baldwin’s rules (5-exo-
trig)
O
HCl in CDCl3
O
NH NH OC
N
HO
HO
N
N
N
H
N
2-HOO-THF
DMSO
1
2
2-HO-THF
1a
1
,4-butanol
N
H
NO
2
No tautomerism
NO
2
OH
NH NHOC
N
O
HO
CH NHNOC
N
O
INH
+
R
R
OR1
OR1
R
OR1
HCl in CDCl3
DMSO
3, 5
4a, 6a
4b, 6b