N, O -nucleosides from ene reactions of nitrosocarbonyl intermediates with the 3-methyl-2-buten-1-ol

Article abstract of DOI:10.1021/jo302346a

Nitrosocarbonyl intermediates undergo ene reactions with allylic alcohols, affording regioisomeric adducts in fair yields. Nitrosocarbonyl benzene reacts with 3-methyl-2-buten-1-ol and follows a Markovnikov orientation and abstracts preferentially the twi

Full text of DOI:10.1021/jo302346a

Article
pubs.acs.org/joc
N,O‑Nucleosides from Ene Reactions of Nitrosocarbonyl
Intermediates with the 3‑Methyl-2-buten-1-ol
Paolo Quadrelli,* Mariella Mella, Serena Carosso, and Bruna Bovio
̀
Dipartimento di Chimica, Universita degli Studi di Pavia, Viale Taramelli 12, 27100, Pavia, Italy
S
* Supporting Information
ABSTRACT: Nitrosocarbonyl intermediates undergo ene reactions with allylic alcohols, affording regioisomeric adducts in fair
yields. Nitrosocarbonyl benzene reacts with 3-methyl-2-buten-1-ol and follows a Markovnikov orientation and abstracts
preferentially the twix hydrogens over the lone ones. With the more sterically demanding nitrosocarbonyl mesitylene and
anthracene, the Markovnikov directing effect is relieved and lone abstraction is observed, affording the 5-hydroxy-isoxazolidines
that serve as synthons for the preparation of N,O-nucleoside analogues according to the Vorbruggen protocol.
̈
Recently, we have proposed the synthesis of a new class of
INTRODUCTION
■
carbocyclic nucleosides starting from cyclopentadiene using the
nitrosocarbonyl intermediates (RCONO, 1) chemistry.6 These
intermediates, generated by the mild oxidation of nitrile oxides
with tertiary amine N-oxides or by oxidation of hydroxamic
acids, are efficiently trapped by cyclopentadiene (Scheme 1) to
afford the hetero Diels−Alder (HDA) cycloadducts 2 that are
highly reactivity dipolarophiles and were employed to
synthesize the conformationally restricted carbocyclic moiety
aminols 4 through amide hydrolysis and N−O bond cleavage of
the cycloadducts 3.7 Aminols 4 were useful for the linear
construction of purine and pyrimidine nucleosides 5. These
nucleosides are characterized by the presence of a secondary
hydroxy group on the cyclopentane moiety and by an
isoxazoline ring fused to the carbocyclic unit and were found
moderately active against human Herpes (types 1 and 2) and
Varicella viruses.8 Recently, anthryl derivatives were found
active with no cellular toxicity at the dose tested against the
Human Papilloma virus (HPV).9
The discovery of several new series of nucleosides analogues
with antiviral activity altered the classical way of thinking about
nucleosides analogues as antiviral agents.1 These derivatives
play a fundamental role in viral chemotherapy and modification
of the sugar fragment and its replacement with a carbocyclic
moiety resulted in the syntheses of interesting nucleosides
analogues that have shown remarkable activity toward a variety
of viruses.2
Methods for the synthesis of sugar- and sugar-modified and
carbocyclic-nucleosides were studied extensively.3 However,
various synthetic problems were frequently encountered, such
as low yields, low stereoselectivity, and toxicity problems of the
obtained compounds, which are just some of the problems that
characterize these synthetic approaches.
Among the various synthetic strategies, the heteroatom
substitution produced a series of compounds where the sugar
moiety was replaced by alternative heterocyclic rings.
Furthermore, the introduction of a side chain on the sugar
led to several branched nucleosides that were found to be
potential antitumoral or antiviral agents.4 In this field, the
Chiacchio and Romeo groups have described the synthesis of
4′-α-C-branched N,O-nucleosides based on the 1,3-dipolar
cycloadditions of nitrones with vinyl acetate, followed by
coupling with silylated nucleobases. The obtained compounds
were evaluated for their activity against various viruses as well as
cytoxicity and apoptotic activity.5
Applications of nitrosocarbonyls to the syntheses of
biologically active molecules are well-known, essentially due,
first, to the variety of generating methods available (oxidation
of hydroxamic acids10 and nitrile oxides11 and thermal12 or
photochemical13 cycloreversions of 1,2,4-oxadiazole-4-oxides)
Received: October 29, 2012
Published: December 17, 2012
© 2012 American Chemical Society
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Scheme 1. Synthetic Pathway of Isoxazoline-Carbocyclic Nucleosides through Nitrosocarbonyl Chemistry and Linear
Construction of the Heterobases
Scheme 2. Ene Reactions of Aromatic Nitrosocarbonyl Intermediates with Trisubstituted Olefins
Scheme 3. Ene Reactions of Aromatic Nitrosocarbonyl Intermediates with the 3-Methyl-2-buten-1-ol and Its Methyl Ether and
Acetyl Derivatives
and, second, to the exceptional reactivity of these intermediates
in HDA reactions. Nevertheless, nitrocarbonyl intermediates
are also powerful enophiles,14 but no applications of ene
reactions toward the synthesis of nucleosides are actually
reported.15 We have detailed that nitrosocarbonyl intermedi-
ates, generated at r.t. by the mild oxidation of nitrile oxides,
undergo clean ene reactions with trisubstituted olefins 9. Allylic
hydrogens on the more congested side of the alkene are
exclusively abstracted (the “cis effect”), thus resembling the
singlet oxygen behavior. Nitrosocarbonyl benzene 8P (P =
phenyl) follows a Markovnikov (M) orientation and abstracts
preferentially the twix hydrogens over the lone ones. With the
more sterically demanding nitrosocarbonyl mesitylene 8M (M
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= mesityl), the M-directing effect is relieved and comparable
twix and lone abstraction are observed (Scheme 2).16
addition of the nitrosocarbonyl benzene 8P to the less-
substituted carbon atom of the double bond, in full accordance
with a M orientation.14,16 Adduct 13Pd derives from 10Pd
simply upon water elimination.
On pursuing our research in nitrosocarbonyl ene reactions,
we extended the studies to other trisubstituted olefins and, in
particular, to allylic alcohols (R = OH). The 3-methyl-2-buten-
1-ol was found to be the proper model to investigate the
selectivity outcome in the ene reaction with nitrosocarbonyls
bearing more sterically demanding substituents. An unexpected
isoxazolidine deriving from the anti-Markovnikov (AM)
addition to the alcohol is presented as a valuable synthon
toward the preparation of new N,O-nucleoside analogues
When the hydroxy group of the alcohol 9d is protected as an
ether in 9e or an ester in 9f, the ene reactions with the
nitrosocarbonyl benzene 8P proceed straight to single ene
adducts 10Pe and 10Pf, respectively, which are obtained in
good yields according to the addition of the nitrosocarbonyl
electrophilic nitrogen to the alkene in an M fashion.19
Moving to the nitrosocarbonyl mesitylene 8M case, the
experimental conditions were even simpler and cleaner.
Mesitonitrile oxide 7 was added to a stirred solution of
NMO (1.1 equiv) in DCM in the presence of an excess (5
equiv) of 3-methyl-2-buten-1-ol 9d at r.t. After stirring
overnight and column chromatographic separation, the ene
adduct 10Md was isolated in 50% yield along with an
unexpected second compound, 11Md, in only, but remarkable,
25% yield.
through the Vonbruggen protocol.
̈
RESULTS
■
Ene Reactions with Nitrosocarbonyl Benzene and
Mesitylene. Addition of a dichloromethane (DCM) solution
of benzohydroximoyl chloride 6 to a stirred solution of N-
methyl-morpholine N-oxide (NMO, 1.1 equiv) and Et3N (1
equiv or a catalytic amount) in DCM in the presence of an
excess (5 equiv) of 3-methyl-2-buten-1-ol 9d afforded, after
standing overnight at r.t., the ene adducts 10Pd and 13Pd
(Scheme 3) that were isolated upon chromatographic
separation of the reaction mixture in the reported yields
(Table 1). The same procedure was followed for the allylic
ether 9e17 and acetate 9f,18 which were prepared according to
the reported syntheses.
Compound 10Md is the M adduct, and its structure is in
accordance with the analytical and spectroscopic data. The
1
structure of 11Md was not immediately clear. The H NMR
spectrum indicates the presence of one deshielded proton at
5.44 δ coupled with two protons at 2.14 and 2.35 δ, while an
OH group gives a singlet at 6.98 δ, as confirmed by the
corresponding IR spectrum. The 13C NMR spectrum presents a
signal at 95.3 δ resembling an acetal-type carbon atom. The
structure assignment as shown in Scheme 3 came from the X-
ray analysis (see the Supporting Information). These types of 5-
hydroxy-isoxazolidines are usually prepared by reaction of
hydroxamic acids and α,β-unsaturated aldehydes.20 The origin
of the isoxazolidine 11Md was undoubtedly attributed to a
relief in the M addition determined by the more sterically
demanding mesityl group that activates the AM path.16 As the
addition of the nitrosocarbonyl moiety occurs on the more
substituted carbon atom of the allylic alcohol 9d, the primary
adduct is the enol 14 that evolves into the nonisolable aldehyde
15, which undergoes cyclization to the hemiacetal 11Md
(Scheme 4). In fact, when the protected alcohols 9e,f were used
and the reactions were carried out in the same conditions,
adducts 10Me and 10Mf were obtained in 63% and 56% yields,
respectively, along with the enol ethers 12Me and 12Mf in 35%
and 32% yields, respectively (Scheme 3 and Table 1).
Table 1. Yields of Adducts in the Reactions of
Nitrosocarbonyls 8P,M with Alkenes 9d−9f
Ar-CONO
alkene
10
11
12
13
8P
9d
9e
9f
50
70
60
50
63
56
8
8M
9d
9e
9f
25
35
32
The structures of all isolated ene adducts rely upon the
1
corresponding analytical and spectroscopic data. In the H
NMR spectra, the typical olefinic methylene signals are found
in the range between 5.00 and 5.43 δ for adducts 10Pd−10Pf
and more shielded between 4.89 and 5.00 δ for the derivative
13Pd. The N-OH group is evident when the spectrum is
recorded in DMSO and is found strongly deshielded in the
range 8.2−8.4 δ for 10Pd−10Pf and even more (9.3−9.5 δ) for
adduct 13Pd. In the reaction with the allylic alcohol 9d,
compound 13Pd is related to 10Pd and both derive from the
The structures of the adducts obtained from alkenes 9e,f rely
1
upon their analytical and spectroscopic data. The H NMR
spectra of adducts 10Me and 10Mf show the olefinic
methylenes as singlets at 4.90 and 5.00 δ for 10Me and at
4.96 and 5.04 δ for 10Mf. The N-OH singlets are found at 9.07
Scheme 4. AM Pathway: The Formation of Isoxazolidine Ring
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Scheme 5. Ene Reaction of Anthryl Nitrosocarbonyl Intermediate with the 3-Methyl-2-buten-1-ol
Scheme 6. Synthesis of Isoxazolidine-Nucleoside Analogues through the Vorbruggen Protocol
̈
and 9.27 δ for the two products, respectively. The enol-ether
12Me showed the double bond signals at 5.23 and 6.52 δ and
the N-OH singlet at 9.10 δ while the enol-acetate 12Mf showed
the double bond signals at 5.88 and 7.21 δ and the N-OH
singlet at 9.38 δ.
The results of the reactions of nitrosocarbonyls 8P,M and
olefins 9d−9f seem to show that hydrogen bonding is
ineffective with respect to the selectivity. To verify
experimentally the influence of the substitution pattern on
the reactivity of the double bond, we performed control
experiments by means of intermolecular competition reactions
of the alkenes 9d versus 9e and 9f, respectively, in the presence
of the nitrosocarbonyl benzene 8P and mesitylene 8M. The
results showed that the expected compounds (as shown in
Table 1) from the competitive reactions were isolated in all the
cases with the same ratios (see the Experimental Section). The
allylic alcohol 9d was not found somehow more reactive than
the others, and the selectiviy outcomes were maintained.
Enforcing the AM Path. We explored the ene reaction of
another typical stable nitrile oxide,21 the anthracenenitrile oxide
17 obtained from the 9-anthraldeyde oxime 16 according to the
preparation reported in the literature22 by treating a chloroform
solution of 16 with NCS and catalytic pyridine at 0 °C for 2 h.
The solid nitrile oxide 17 was added portionwise to a stirred
DCM solution of 5 equiv of the allylic alcohol 9d in the
presence of 2 equiv of NMO at r.t. for 48 h. After the usual
workup, the residue was submitted to column chromatography,
and two products were isolated and identified as compounds 19
and 20 in 27% and 52% yields, respectively (Scheme 5).
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Their structures rely upon the relative spectroscopic data. In
particular, the H NMR spectrum of the major compound 20
easily detectable. In the 1H NMR spectrum of the uracil
derivative 22Aa, the doublets (J = 8 Hz) at 5.49 and 7.86 δ are
clearly related to the uracil double bond while the imide NH is
found highly deshielded at 11.22 δ as a singlet. In the 1H NMR
spectrum of the cytosine derivative 22Mg, the double bond
doublets (J = 8 Hz) are found at 5.53 and 7.39 δ. Again, when,
in the uracil ring, the CH−C proton is replaced by a halogen
(b, c, d, e) or by a methyl, as in the case of tymine (f), a single
proton corresponding to the N−CH is observed in the range
of 7.29−7.86 δ, while the imide NH singlets remain strongly
deshielded in the range of 11.23−11.75 δ.
Nucleoside analogues 22M,A can be submitted for biological
evaluation without any further structural modification, either
for their antiviral behavior or, in other cases, in order to
compare their activities with those of reported carbocyclic and
heterocyclic structures.5,8,24,28 In particular, in nucleoside
analogues 22A, the presence of an anthracene ring adds
fluorescent properties to these compounds, a further tool for
our future studies. The use of fluorescent moieties in the
nucleoside synthesis has attracted the interest of various
research groups as marker molecules or in the field of imaging
to follow their path inside the cells in order to achieve a better
understanding of the “in vivo” mechanisms.29 Fluorescent
structures can be considered “molecular labels”30 to be
assembled in specific oligofluorosides, as sensors31 or indicators
of the behavior of the DNA.32 New fluorophores are constantly
developed as well as their applications.33 Fluorescent
polyaromatic groups may be active through their ability to
establish π-stacking interactions with themselves34 as well as
DNA intercalators;35 these mechanisms are in action in
different cases depending upon the biological targets.
1
showed a deshielded proton as a triplet at 5.22 δ, coupled with
two protons at 2.20 and 2.44 δ. Just before the aromatic signals
(7.5−8.6 δ), a doublet was found at 6.84 δ corresponding to the
OH group (exchange with D2O) and whose presence was
confirmed by the IR spectrum (νOH = 3200 cm−1). The 13C
NMR spectrum showed significantly the acetal-type carbon at
95.8 δ.
The experiment performed with anthracene nitrosocarbonyl
18 and alcohol 9d confirms the relief of the M control observed
in the addition of 8M to enes 9d−9f (Table 1), and the results
show the remarkable influence of the nitrosocarbonyl
substituent on the selectivities. The approach of the bulkier
anthracene group determines a strong steric hindrance that
disfavors the M path enforcing the AM selectivity.
Synthesis of N,O-Nucleosides. The 5-hydroxy-isoxazoli-
dines 11Bd and 20 obtained from the ene reaction of
nitrosocarbonyl mesitylene 8M and nitrosocarbonyl anthracene
18 with the allylic alcohol 9d were used as synthons to prepare
N,O-nucleoside analogues by adapting the Vorbruggen
̈
protocol23 as well as the Chiacchio’s procedures for similar
compounds.5,24 The acetyl derivatives of 21M,A were prepared
according to standard procedures (Scheme 6).25 The acetylated
compound was obtained in nearly quantitative yield and fully
1
characterized. In the H NMR spectrum of 21M, the presence
of the acetyl group is shown by the presence of a singlet at 2.09
δ while the OH signal, previously found at 6.98 δ, disappeared.
Similarly, in the 1H NMR spectrum of 21A, the acetyl group is
found as a singlet at 2.15 δ while the OH signal at 6.84 δ is now
absent.
The Vorbruggen protocol can be applied on both previously
̈
DISCUSSION AND CONCLUSIONS
silylated heterobases or commercial compounds in the presence
of silylating agents.23,26 In the cases at hand, we report the
syntheses conducted on commercial heterobases of the uracil
family used in the presence of the in situ silylating agent, the
bis(trimethylsilyl)acetamide (BSA), and trimethylsilyl trifluor-
omethanesulfonate (TMSO-Tf) as reaction promoter.27 The
acetylated isoxazolidine 21M,A were added under a nitrogen
atmosphere at r.t. to a solution of the selected heterobases (2
equiv) and BSA (2 equiv), and the solutions became clear after
boiling in DCM for a couple of hours. The mixtures were then
ice-cooled at 0 °C, TMSO-Tf was added, and the reactions
were refluxed overnight (Scheme 6). The desired compounds
22M,A(a−g) were obtained as white solids by simple
crystallization or column chromatographic purification.
■
We have investigated the ene reactions of aromatic nitro-
socarbonyls, generated through the mild oxidative protocol
with NMO, with allylic alkoxy olefins. The faster oxidation
process of nitrile oxide to nitrosocarbonyl intermediate
prevents a possible side reaction, that is, the addition of the
allylic alcohol to the electrophilic nitrile oxide. From the
reaction mixtures, the presence of adducts between the
aromatic nitrile oxides and the 3-methyl-2-buten-1-ol 9d was
not observed.
The nitrosocarbonyl benzene 8P adds the 3-methyl-2-buten-
1-ol 9d, affording adducts 10Pd and 13, which derive from the
preferred M path in ene reactions of trisubstituted olefins.13,16
If hydroxy-protected allylic ether 9e or ester 9f are used, the
reactions proceed straightforwardly to single ene adducts
Nucleoside analogues 22M,A(a−g) were isolated from good
to excellent yields (48−99%), and their structures rely upon the
analytical and spectroscopic data. All the reactions gave single
products belonging to the family of uracil derivatives.
10Pe,f in accordance with the prevailing HOMO(olefin)
−
LUMO(nitrosocarbonyl) interaction, somewhat enforced by the
polarization of the CC double bond induced by the CH2OR
group.36 Furthermore, no hydrogen-bonding effects are found
in directing the selectivity in the reactions at hand.
The uracil derivative 22Ma is representative of a general
1
trend in the H NMR spectra of this type of compound, and
the doublets (J = 8 Hz) at 5.67 and 7.64 δ are clearly related to
the uracil double bond while the imide NH is found highly
deshielded at 10.10 δ as a singlet. The same features were found
in cytosine derivative 22Mg. When, in the uracil ring, the 
CH−C proton is replaced by a halogen (b, c, d, e) or by a
methyl, as in the case of tymine (f), a single proton
corresponding to the N−CH is observed in the range of
7.43−7.80 δ, while the imide NH singlets remain strongly
deshielded in the range of 10.08−10.51 δ.
When bulkier substituents replace the phenyl group (Figure
1), as in nitrosocarbonyl intermediates 8M and 18, in the ene
reactions with the 3-methyl-2-buten-1-ol 9d, the M path is risen
energetically because of a steric effect and the AM path is
favored, affording a mixture of regioisomeric compounds. We
have recently detailed the selectivity outcome in ene reactions
of nitrosocarbonyl mesitylene 8M with trisubstituted olefins,16
and the results show the remarkable influence of the
nitrosocarbonyl substituent on the selectivities in ene reactions.
Model calculations on the reaction of 8P,M with tetramethyl-
ethylene (TME) shed light on the factors involved in the
1
In H NMR spectra of nucleosides 22A(a−g), the signals
corresponding to the anthracene and isoxazolidine moieties are
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group is twisted out of the nitrosocarbonyl plane as usual,
causing unfavorable steric crowding between its ortho methyl
and the “trans” distal TME methyl, as depicted in Figure 2.
This crowding should slow down the M approach of 8M to a
trisubstituted ethene and compensates somewhat the M
electronic bias. Figure 3 reports the same features in the case
of the allylic alcohol 9d. From the M approach point of view, it
seems quite clear that the OH group is not playing any role in
directing the addition of the nitrosocarbonyl intermediates,
both in the cases depicted in the TS M and M′, as the top view
of the structures shows (Figure 3).
The steric clashes at work in the M case drift the addition to
the AM path that is the prelude to the enol formation and
subsequent cyclization to the isoxazolidine structures.
The structures of the 5-hydroxy-isozaxolidine 11 and 20
resemble those obtainable through nitrone additions to vinyl
ether derivatives and constitute useful synthons toward the
prepartion of N,O-nucleoside analogues. By adapting the
Vorbruggen protocol23 as well as known procedures for similar
̈
compounds,5,24 we have prepared a selection of uracil
derivatives 22M,A(a−g) from good to excellent yields. These
products constitute a new class of nucleoside analogues with a
variety of different heterobases, easily inserted on the
isoxazolidine ring. Their potentialities in terms of biological
activity are totally unexplored, but we believe in future
promising results if we compare the new nucleoside structures
with those of known compounds, both hetero- and carbocyclic,
recently reported in the literature, which were found to be
interesting adenosine receptor agonists.37 The insertion of a
fluorecent chromophore allows for planning future applications
as fluorescent markers in different biological targets.
The uracil derivatives 22M,A(a−g) were sent to the
Southern Research Institute (SRI) of Birmingham (AL, USA)
within the Tuberculosis Antimicrobial Acquisition and
Coordinating Facility (TAACF) program and tested against
the Mycobacterium tuberculosis H37Rv in BACTEC 12B
medium using the microplate Alamar Blue Assay.38 The
minimum inhibition concentration (MIC μg/mL) was found
to be >6.25 for all the compounds with the %Inh in the range
of 22−34. Further antiviral and antitumoral tests are currently
under evaluation.
Figure 1. Effect of substituents on ene reaction selectivity.
varying selectivities. In these reactions of trimethylethylenes,
the M path is favored in the case of nitrosocarbonyl benzene 8P
while steric hindrance in the approach of 8M compensates
somewhat its electronic preference, and mixtures of M and AM
adducts are formed. This mechanism is at work also in the case
of 3-methyl-2-buten-1-ol 9d as well as the corresponding
hydroxy-protected derivatives 9e,f (Figure 2) and remarkably
influences and enforces the selectivity in the reaction of
nitrosocarbonyl anthracene 18 with 3-methyl-2-buten-1-ol 9d.
The steric hindrance produced by the anthracene group
reverses the selectivity in the ene reaction, and the
corresponding 5-hydroxy-isoxazolidine becomes the major
product and a convenient intermediate for nucleoside analogue
synthesis.
As we have demonstrated,16 in the reactions of nitro-
socarbonyl 8P with TME, the transition structure (TS) of the
addition step of 8P to TME shows no special hindrance
between the addends, whereas in the TS of 8M, the mesityl
Figure 2. Side view of the B3LYP/6-31G* TS's for the reactions of tetramethylethylene with nitrosocarbonyl benzene and 2,6-dimethylbenzene.16
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Figure 3. Side views and top views of the M and AM ene additions to the 3-methyl-2-buten-1-ol of the nitrosocarbonyl mesitylene.
10Pd: (1.42 g, 50%) White crystals from ethanol, mp 157−159 °C.
EXPERIMENTAL SECTION
■
1
IR: νOH 3450, νCO 1715 cm−1. H NMR (DMSO) δ: 1.70 (s, 3H,
All melting points (mp's) are uncorrected. Elemental analyses were
done on n elemental analyzer available at the Departmen of
CH3); 4.70 (m, 2H, CH2-O); 5.15 (s, 1H + 1H, CH2); 5.30 (m, 1H,
CH-N); 7.2−7.9 (m, 5H, Ph); 8.21 (s, 1H, OH). 13C NMR (DMSO)
δ: 23.8; 66.0; 79.9; 120.4; 132.6; 132.9; 133.1; 133.2; 137.5; 142.7;
169.0. Anal. Calcd for C12H15NO3 (221.25): C, 65.14; H, 6.83; N,
6.33. Found: C, 65.15; H, 6.83; N, 6.25.
1
Chemistryt. H and 13C NMR spectra were recorded on a 300 MHz
spectrometer (solvents specified). Chemical shifts are expressed in
parts per million (ppm) from internal tetramethylsilane (δ), and
coupling constants (J) are in hertz (Hz): b, broad; s, singlet; bs, broad
singlet; d, doublet; t, triplet; m, multiplet. IR spectra (Nujol mulls)
were recorded on a spectrophotometer available at the Department,
and absorbtions (ν) are in cm−1. Column chromatography and tlc:
silica gel H60 and GF254, respectively. Eluants: cyclohexane/ethyl
acetate 9:1 to pure ethyl acetate; pure CHCl3 to CHCl3/MeOH 9/1
for the nucleoside syntheses. The identification of samples from
different experiments was secured by mixed mp's and superimposable
IR spectra.
10Pe: (2.12 g, 70%) Yellowish oil. IR: νOH 3203, νCO 1626 cm−1.
1H NMR (DMSO) δ: 1.75 (s, 3H, CH3); 3.33 (s, 3H, OCH3); 3.56
(dd, J = 10, 4 Hz, 2H, CH-N); 3.74 (t, J = 10 Hz, 2H, CH2-O); 4.89
and 4.97 (s, 1H + 1H, CH2); 7.3−7.6 (m, 5H, Ph); 9.50 (s, 1H, OH).
13C NMR (DMSO) δ: 21.0; 58.1; 69.2; 113.4; 126.0; 127.8; 128.0;
128.2; 128.5; 129.2; 135.4; 140.9; 169.2. Anal. Calcd for C13H17NO3
(235.27): C, 66.36; H, 7.28; N, 5.95. Found: C, 66.35; H, 7.25; N,
5.94.
Starting and Reference Materials. 3-Methyl-2-buten-1-ol (99%)
9d was purchased from chemical suppliers.
10Pf: (1.81 g, 60%) Yellowish oil. IR: νOH 3206, νCO 1742, 1612
cm−1. 1H NMR (DMSO at 80 °C) δ: 1.80 (s, 3H, CH3); 2.01 (s, 3H,
CH3CO); 4.35 (d, J = 7 Hz, 2H, CH-O); 4.91 and 5.00 (s, 1H + 1H,
CH2); 5.03 (m, 1H, CH-N); 7.39 (m, 3H, arom.); 7.57 (m, 2H,
arom.); 9.35 (s, 1H, OH). 13C NMR (DMSO at 80 °C) δ: 13.5; 20.4;
57.8; 61.9; 113.5; 126.0; 128.3; 128.7; 129.1; 130.0; 140.6; 165.5;
171.5. Anal. Calcd for C13H17NO3 (235.27): C, 66.36; H, 7.28; N,
5.95. Found: C, 66.34; H, 7.25; N, 5.94.
3-Methyl-2-butenyl methyl ether 9e was prepared from 4-bromo-2-
methyl-2-butene and MeONa according to the reported synthesis.17
1-Acetoxy-3-methyl-2-butene 9f was prepared from the alcohol 9d
and acetic anhydride as reported.18
Benzhydroximoyl chloride was obtained by treatment of benzaldox-
ime with sodium hypochlorite.39 Addition of a slight excess of Et3N to
a DCM solution of benzhydroximoyl chloride furnished in situ BNO.
Mesitonitrile oxide 7 was obtained by oxidation of 2,4,6-
trimethylbenzaldoxime with bromine.21
13Pd: (0.21 g, 8%) Yellowish oil. IR: νOH 3393, νCO 1723 cm−1.
1H NMR (CDCl3) δ: 1.90 (s, 3H, CH3); 5.22 (m, 2H, CH2); 5.32 and
5.43 (s, 1H + 1H, CH2); 7.2−8.0 (m, 5H, Ph). 13C NMR (CDCl3) δ:
19.3; 54.1; 118.6; 128.3; 129.3; 129.6; 133.0; 138.5; 154.9; 166.1. Anal.
Calcd for C12H13NO2 (203.23): C, 70.91; H, 6.45; N, 6.89. Found: C,
70.85; H, 6.45; N, 6.85.
The 9-anthraldeyde oxime 16 has been purchased from chemical
suppliers.
General Procedure for the Ene Reactions of Nitrosocarbonyl
Benzene 8A with Alkenes 9d−9f. To an ice-cooled DCM (200
mL) solution of alkenes 9d−9f (5 equiv) were added 1.9 g (1.3 equiv)
of NMO and 2 mL (1.1 equiv) of Et3N under stirring. A solution of
2.0 g (12.9 mmol) of benzhydroxymoyl chloride 6 in 100 mL of DCM
was added dropwise, and the reaction was left under stirring at r.t. for
24 h. After dilution with an equivalent volume of DCM, the organic
phase was washed with water and dried over anhydrous Na2SO4. After
filtration, the solvent was then evaporated and the reaction mixture
was separated by column chromatography, affording the ene adducts.
General Procedure for the Ene Reactions of Nitrosocarbonyl
Mesitylene 8M with Alkenes 9d−9f. To an ice-cooled DCM (200
mL) solution of alkenes 9d−9f (5 equiv) was added 1.8 g (1.3 equiv)
of NMO under stirring. A solution of 2.0 g (12.4 mmol) of
mesitonitrile oxide 7 in 100 mL of DCM was added dropwise, and the
reaction was left under stirring at r.t. for 24 h. After dilution with an
equivalent volume of DCM, the organic phase was washed with water
and dried over anhydrous Na2SO4. After filtration, the solvent was
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then evaporated and the reaction mixture was separated by column
chromatography, affording the ene adducts.
20: (1.52 g, 52%) Straw yellow crystals from ethanol, mp 229 °C
(dec.). IR: νOH 3200, νCO 1588 cm−1. 1H NMR (DMSO) δ: 1.83 (s,
3H, CH3); 1.97 (s, 3H, CH3); 2.22 (d, 1H, J = 13 Hz, CH); 2.44 (dd,
1H, J = 13, 5 Hz, CH); 5.23 (b, 1H, CH-OH); 6.84 (b, 1H, OH, exch.
with D2O); 7.56 (m, 4H, arom.); 7.89 (m, 1H, arom.); 7.99 (m, 1H,
arom.); 8.11 (m, 2H, arom.); 8.62 (s, 1H, arom.). 13C NMR (DMSO)
δ: 25.7; 26.6; 50.0; 61.6; 95.8; 124.8; 125.3; 125.5; 125.6; 126.3; 126.4;
126.6; 126.7; 126.8; 128.2; 128.4; 130.6; 130.8; 131.9; 161.8. Anal.
Calcd for C20H19NO3 (321.38): C, 74.75; H, 5.96; N, 4.36. Found: C,
74.76; H, 6.00; N, 4.37.
Synthesis of the N-Mesitoyl-3,3-dimethyl-5-acetoxy-1,2-
isoxazolidine 21M. To an ice-cooled anhydrous DCM (50 mL)
solution of N-mesitoyl-3,3-dimethyl-5-hydroxy-1,2-isoxazolidine 11Md
(3.60 g, 14 mmol.) was added 2.2 equiv of Ac2O added under stirring
along with 0.34 equiv of DMAP and 2.2 equiv of Et3N. The reaction
was left under stirring at r.t. for 24 h. After dilution with an equivalent
volume of DCM, the organic phase was washed with a saturated
solution of NaHCO3 and dried over anhydrous Na2SO4. After
filtration, the solvent was evaporated and a solid was obtained. The
acetyl derivative 21M (3.68 g) was obtained in 86% yield and
recrystallized from methanol: mp 105−107 °C. IR: νCO 1760 cm−1.
1H NMR (CDCl3) δ: 1.74 and 1.88 (s, 6H, 2CH3); 2.09 (s, 3H,
10Md: (1.63 g, 50%) White crystals from ethanol, mp 162−163 °C.
1
IR: νOH 3163, νCO 1618 cm−1. H NMR (DMSO) δ: 1.78 (s, 3H,
CH3); 2.14, 2.18, and 2.21 (s, 9H, 3CH3-Ar); 3.72 (dd, J = 7, 6 Hz,
2H, CH2-O); 4.68 (m, 1H, CH-N); 4.97 (bs, 1H + 1H, CH2); 5.06 (t,
J = 7 Hz, 1H, OH); 6.80 (m, 2H, Ph); 9.04 (s, 1H, OH). 13C NMR
(DMSO) δ: 18.8; 18.9; 20.6; 21.4; 58.8; 60.5; 113.4; 127.3; 133.3;
133.5; 134.6; 136.5; 141.2; 170.0. Anal. Calcd for C15H21NO3
(263.33): C, 68.41; H, 8.04; N, 5.32. Found: C, 68.47; H, 8.05; N,
5.25.
11Md: (0.82 g, 25%) White crystals from benzene, mp 157−158
1
°C. IR: νOH 3150, νCO 1612 cm−1. H NMR (DMSO) δ: 1.55 and
1.72 (s, 6H, 2CH3); 2.13, 2.19, and 2.22 (s, 9H, 3CH3−Ar); 2.14 and
2.35 (s, 1H + 1H, CH2); 5.44 (m, 1H, CH); 6.79 (m, 2H, Ph); 6.98 (s,
1H, OH). 13C NMR (DMSO) δ: 18.3; 20.6; 25.5; 26.4; 50.2; 60.6;
95.3; 127.2; 127.5; 132.8; 132.9; 134.9; 136.7; 163.2. Anal. Calcd for
C15H21NO3 (263.33): C, 68.41; H, 8.04; N, 5.32. Found: C, 68.47; H,
8.06; N, 5.26.
10Me: (2.17 g, 63%) White crystals from ethanol, mp 127−128 °C.
1
IR: νOH 2920, νCO 1603 cm−1. H NMR (DMSO) δ: 1.79 (s, 3H,
CH3); 2.16, 2.17, and 2.21 (s, 9H, 3CH3-Ar); 3.29 (s, 3H, CH3-O);
3.70 (m, 2H, CH2-O); 4.90 and 5.00 (s, 1H + 1H, CH2); 5.24 (m, 1H,
CH-N); 6.81 (m, 2H, Ph); 9.07 (s, 1H, OH). 13C NMR (DMSO) δ:
18.6; 18.8; 20.1; 20.6; 21.3; 56.8; 57.8; 68.9; 113.4; 127.3; 133.3;
133.5; 134.5; 136.5; 140.7; 170.0. Anal. Calcd for C16H23NO3
(277.35): C, 69.28; H, 8.36; N, 5.05. Found: C, 69.26; H, 8.25; N,
5.08.
CH3CO); 2.28 (s, 9H, 3CH3-Ar); 2.50 (m, 2H, CH2); 6.23 (d, J = 6
Hz, 1H, O-CH-OAc); 6.80 (m, 2H, Ph). 13C NMR (CDCl3) δ: 18.4;
18.6; 20.9; 21.0; 49.8; 60.6; 93.9; 127.7; 127.8; 132.8; 133.5; 138.0;
165.1; 169.1. Anal. Calcd for C17H23NO4 (305.36): C, 66.86; H, 7.59;
N, 4.59. Found: C, 66.75; H, 7.56; N, 4.58.
Synthesis of the N-Anthracenoyl-3,3-dimethyl-5-acetoxy-
1,2-isoxazolidine 21A. To an ice-cooled anhydrous DCM (50 mL)
solution of N-anthracenoyl-3,3-dimethyl-5-hydroxy-1,2-isoxazolidine
20 (1.40 g, 4.78 mmol.) was added 2.2 equiv of Ac2O under stirring
along with 0.34 equiv of DMAP and 2.2 equiv of Et3N. The reaction
was left under stirring at r.t. for 24 h. After dilution with an equivalent
volume of DCM, the organic phase was washed with a saturated
solution of NaHCO3 and dried over anhydrous Na2SO4. The solvent
was then evaporated, and a solid was obtained. The acetyl derivative
21A (1.63 g) was obtained in 94% yield and recrystallized from
ethanol: mp 200−201 °C. IR: νCO 1748 cm−1. 1H NMR (CDCl3) δ:
1.84 and 1.97 (s, 3H + 3H, CH3); 2.15 (s, 3H, CH3CO); 2.47 (d, 1H,
J = 13 Hz, H-CH); 2.64 (dd, 1H, J = 13, 5 Hz, H-CH); 6.04 (d, 1H, J
= 5 Hz, O-CH-O); 7.51 (m, 4H, arom.); 8.04 (m, 4H, arom.); 8.47
(m, 1H, arom.). 13C NMR (CDCl3) δ: 20.8; 26.0; 27.2; 49.5; 61.5;
93.5; 124.7; 124.9; 125.3; 125.8; 126.4; 127.0; 127.5; 127.8; 128.5;
128.6; 130.7; 130.9; 131.1; 164.0; 168.8. Anal. Calcd for C22H21NO4
(363.40): C, 72.71; H, 5.82; N, 3.85. Found: C, 72.71; H, 5.81; N,
3.89.
General Procedure for the Synthesis of Nucleosides 22 by
Coupling of Isoxazolidines 21M,A and Heterobases B(a−g). A
solution of 2 equiv of heterobases B and 2 equiv of bis(trimethylsilyl)-
acetamide (BSA) in anhydrous DCM (50 mL) is refluxed under a
nitrogen atmosphere for 15−20 min until it becomes clear and hence
cooled to ambient. A solution in DCM (10 mL) of isoxazolidines
21M,A (0.20 g, 0.65 mmol) is added dropwise and cooled to 0 °C and
additioned of 0.12 mL (1 equiv) of TMSO-Tf. The reaction is refluxed
under stirring overnight and finally quenched with a saturated solution
of NaHCO3 at pH = 7. The mixture is diluted with an equivalent
volume of DCM and washed with water and finally dried over Na2SO4.
From the residues, nucleosides 22M,A(a−g) are isolated upon
crystallization or column chromatographic purification.
12Me: (1.20 g, 35%) White crystals from ethanol, mp 133−135 °C.
1
IR: νOH 2920, νCO 1656 cm−1. H NMR (DMSO) δ: 1.51 (s, 6H,
CH3); 2.12 and 2.20 (s, 9H, 3CH3-Ar); 3.46 (s, 3H, CH3-O); 5.23 (d,
J = 13 Hz, 1H, C-CH); 6.52 (d, J = 13 Hz, 1H, O-CH); 6.80 (m, 2H,
Ph); 9.10 (s, 1H, OH). 13C NMR (DMSO) δ: 18.5; 20.6; 26.6; 55.5;
61.0; 108.6; 127.2; 132.5; 133.7; 135.9; 136.4; 146.8; 154.5; 170.8.
Anal. Calcd for C16H23NO3 (277.35): C, 69.28; H, 8.36; N, 5.05.
Found: C, 69.25; H, 8.37; N, 5.07.
10Mf: (2.12 g, 56%) White crystals from ethanol, mp 103−104 °C.
1
IR: νOH 3086, νCO 1747, 1658 cm−1. H NMR (DMSO) δ: 1.80 (s,
3H, CH3); 2.00 (s, 3H, CH3CO); 2.18 and 2.22 (s, 9H, 3CH3-Ar);
4.25 and 4.41 (AB syst, 2H, CH2-O); 4.96 and 5.04 (s, 1H + 1H,
CH2); 5.30 (dd, J = 10, 4 Hz, 1H, CH-N); 6.82 (m, 2H, Ph); 9.27 (s,
1H, OH). 13C NMR (DMSO) δ: 18.7; 18.8; 20.6; 20.7; 21.2; 56.4;
60.8; 114.0; 127.3; 127.4; 133.3; 133.4; 134.2; 136.7; 140.0; 170.1;
170.2. Anal. Calcd for C17H23NO4 (305.36): C, 66.86; H, 7.59; N,
4.59. Found: C, 66.87; H, 7.58; N, 5.00.
12Mf: (1.21 g, 32%) White crystals from ethanol, mp 108−109 °C.
1
IR: νOH 3098, νCO 1754, 1667 cm−1. H NMR (DMSO) δ: 1.52 (s,
6H, CH3); 2.12 and 2.20 (s, 9H, 3CH3-Ar); 2.12 (s, 3H, CH3CO);
5.88 (d, J = 13 Hz, 1H, C-CH); 6.79 (m, 2H, Ph); 7.21 (d, J = 13 Hz,
1H, O-CH); 9.38 (s, 1H, OH). 13C NMR (DMSO) δ: 18.5; 20.5;
20.6; 25.8; 60.4; 120.3; 127.2; 132.7; 134.5; 135.9; 136.2; 168.0; 170.8.
Anal. Calcd for C17H23NO4 (305.36): C, 66.86; H, 7.59; N, 4.59.
Found: C, 66.85; H, 7.55; N, 5.00.
Ene Reaction of Anthracenenitrile Oxide 18 with 3-Methyl-
2-Buten-1-ol 9d. To an anhydrous DCM (80 mL) solution of 3-
methyl-2-buten-1-ol 9d (5 equiv) and NMO (2 equiv) was added 2.0 g
(9 mmol) of anthracenenitrile oxide 18 portionwise under stirring at
r.t. After 48 h, the organic phase was washed with brine and dried over
anhydrous Na2SO4. After filtration and evaporation of the solvent, the
residue was submitted to column chromatography. The two main
fractions were identified as the adducts 19 and 20, which were
characterized as below:
19: (0.79 g, 27%) Pale yellow crystals from ethanol, mp 179−181
°C. IR: νOH 3254, νCO 1603 cm−1. 1H NMR (DMSO) δ: 1.80 (s, 3H,
CH3); 3.35 (s, 2H, CH2OH); 4.41 (m, 3H, OH); 4.67 (m, 2H, CH2);
5.49 (b, 1H, CH); 7.57 (m, 4H, arom.); 8.11 (m, 4H, arom.); 8.59 (s,
1H, arom.); 9.71 (s, 1H, OH). 13C NMR (DMSO) δ: 17.9; 25.5; 61.1;
119.6; 123.6; 125.5; 125.7; 126.0; 126.7; 128.4; 129.1; 131.3; 134.6;
155.6. Anal. Calcd for C20H19NO3 (321.38): C, 74.75; H, 5.96; N,
4.36. Found: C, 74.69; H, 5.94; N, 4.36.
22Ma: (0.22 g, 95%) White solid from ethanol, mp 215 °C (dec.).
IR: νNH 3166, νCO 1690, 1642 cm−1. 1H NMR (CD3COCD3) δ: 1.75
and 1.89 (s, 6H, 2CH3); 2.22 and 2.25 (s, 9H, 3CH3-Ar); 2.72 and
2.90 (dd, J = 14, 7 Hz, 2H, CH2); 5.67 (d, J = 8 Hz, 1H, CO-CH);
6.40 (t, J = 7 Hz, 1H, CH); 6.82 (m, 2H, Ph); 7.64 (d, J = 8, 1H, CH-
N); 10.10 (bs, 1H, NH). 13C NMR (CD3COCD3) δ: 19.5; 21.4; 25.4;
26.9; 48.8; 64.3; 83.4; 103.9; 129.0; 134.4; 134.9; 139.1; 140.5; 151.6;
154.5; 163.4; 168.0; 170.0. Anal. Calcd for C19H23N3O4 (357.40): C,
63.85; H, 6.48; N, 11.76. Found: C, 63.83; H, 6.45; N, 11.75.
22Mb: (0.24 g, 97%) White crystals from acetone, mp 210 °C
1
(dec.). IR: νNH 3167, νCO 1709 cm−1. H NMR (CD3COCD3) δ:
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1.74 and 1.88 (s, 6H, 2CH3); 2.24, 2.25, and 2.28 (s, 9H, 3CH3-Ar);
2.76 and 2.90 (dd, J = 14, 7 Hz, 2H, CH2); 6.35 (dt, J = 7, 1 Hz, 1H,
CH); 6.84 (m, 2H, Ph); 7.70 (d, J = 7 Hz, 1H, CH-N); 10.50 (bs, 1H,
NH). 13C NMR (CD3COCD3) δ: 19.4; 19.5; 21.5; 25.3; 26.9; 49.0;
64.3; 84.1; 124.3; 124.8; 129.1; 134.4; 135.0; 135.4; 139.2; 140.5;
143.6; 150.2; 157.5; 157.8; 167.9. Anal. Calcd for C19H22N3O4F
(375.40): C, 60.79; H, 5.91; N, 11.19. Found: C, 60.81; H, 5.91; N,
11.21.
45.9; 63.8; 82.7; 124.0; 124.3; 124.4; 124.6; 125.7; 126.4; 126.6; 126.8;
126.9; 127.8; 128.5; 129.6; 130.5; 130.6; 138.2; 138.4; 141.5; 148.8;
156.5; 156.8; 164.2. Anal. Calcd for C24H20O4N3F (433.42) C, 66.51;
H, 4.65; N, 9.70. Found: C, 66.51; H, 4.64; N, 9.71.
22Ac: (0.29 g, 97%) White solid from ethanol, mp 185−188 °C. IR:
νNH 3067, νCO 1728 cm−1. 1H NMR (DMSO) δ: 1.83 (s, 3H, CH3);
2.03 (s, 3H, CH3); 2.84 (m, 2H, CH2); 6.12 (1H, t, J = 6 Hz, O-CH-
N); 7.58 (m, 4H, arom.); 7.72 (s, 1H, N-CH); 7.86 (d, 1H, J = 8 Hz,
arom.); 8.00 (d, 1H, J = 8 Hz, arom.); 8.12 (m, 2H, arom.); 8.67 (s,
1H, arom.); 11.78 (s, 1H, NH). 13C NMR (DMSO) δ: 24.8; 25.7;
46.3; 63.7; 83.1; 107.9; 124.3; 125.6; 125.7; 126.4; 126.8; 126.9; 127.9;
128.6; 130.4; 130.5; 130.6; 136.7; 149.2; 158.6; 164.4. Anal. Calcd for
C24H20O4N3Cl (449.89) C, 64.07; H, 4.48; N, 9.34. Found: C, 64.08;
H, 4.49; N, 9.31.
22Mc: (0.24 g, 93%) White crystals from acetone, mp 208−211 °C.
1
IR: νNH 3167, νCO 1709 cm−1. H NMR (CD3COCD3) δ: 1.73 and
1.87 (s, 6H, 2CH3); 2.25, 2.26, and 2.31 (s, 9H, 3CH3-Ar); 2.83 and
2.95 (dd, J = 14, 7 Hz, 2H, CH2); 6.29 (dt, J = 7, 1 Hz, 1H, CH); 6.85
and 6.89 (1, 1H + 1H, Ph); 7.68 (s, 1H, CH-N); 10.60 (bs, 1H, NH).
13C NMR (CD3COCD3) δ: 19.4; 19.5; 21.5; 25.1; 49.7; 64.2; 84.5;
109.8; 129.1; 129.2; 134.2; 135.0; 135.3; 137.3; 139.3; 150.6; 159.6;
168.2. Anal. Calcd for C19H22N3O4Cl (391.85): C, 58.24; H, 5.66; N,
10.72. Found: C, 58.22; H, 5.69; N, 10.71.
22Ad: (0.31 g, 95%) White solid from ethanol, mp 167−170 °C.
1
IR: νNH 3058, νCO 1726 cm−1. H NMR (DMSO) δ: 1.83 (s, 3H,
CH3); 2.03 (s, 3H, CH3); 2.85 (m, 2H, CH2); 6.12 (t, 1H, J = 6 Hz,
O-CH-N); 7.57 (m, 4H, arom.); 7.81 (s, 1H, N-CH); 7.86 (d, 1H, J =
8 Hz, arom.); 7.97 (d, 1H, J = 8, 4 Hz, arom.); 8.13 (m, 2H, arom.);
8.67 (s, 1H, arom.); 11.73 (s, 1H, NH). 13C NMR (DMSO) δ: 24.9;
25.7; 46.1; 63.7; 83.1; 96.5; 124.3; 125.6; 126.4; 126.9; 127.8; 128.6;
130.4; 130.5; 139.2; 149.4; 158.7; 164.4. Anal. Calcd for
C24H20O4N3Br (494.33) C, 58.31; H, 4.08; N, 8.50. Found: C,
58.31; H, 4.11; N, 8.51.
22Md: (0.27 g, 95%) White crystals from methanol, mp 114−120
1
°C. IR: νNH 3168, νCO 1700 cm−1. H NMR (CD3COCD3) δ: 1.72
and 1.86 (s, 6H, 2CH3); 2.25 and 2.32 (s, 9H, 3CH3-Ar); 2.84 and
2.96 (dd, J = 14, 7 Hz, 2H, CH2); 6.28 (t, J = 6 Hz, 1H, CH); 6.87 (m,
2H, Ph); 7.74 (s, 1H, CH-N); 10.51 (bs, 1H, NH). 13C NMR
(CD3COCD3) δ: 19.5; 19.6; 21.5; 25.1; 26.9; 49.8; 64.2; 84.6; 97.8;
129.0; 129.3; 134.2; 135.0; 135.3; 139.3; 139.8; 150.8; 159.6; 168.3.
Anal. Calcd for C19H22N3O4Br (436.30): C, 52.31; H, 5.08; N, 9.63.
Found: C, 52.25; H, 5.09; N, 9.55.
22Ae: (0.35 g, 99%) White solid from ethanol, mp 164−166 °C. IR:
νNH 3059, νCO 1724 cm−1. 1H NMR (DMSO) δ: 1.83 (s, 3H, CH3);
2.03 (s, 3H, CH3); 2.86 (m, 2H, CH2); 6.13 (t, 1H, J = 6 Hz, O-CH-
N); 7.58 (m, 4H, arom.); 7.85 (d, 2H, J = 7 Hz, arom.); 7.86 (s, 1H,
N-CH); 7.96 (d, 1H, J = 8 Hz, arom.); 8.13 (m, 2H, arom.); 8.67 (s,
1H, arom.); 11.60 (s, 1H, NH). 13C NMR (DMSO) δ: 25.0; 25.7;
45.9; 63.7; 70.6; 82.8; 124.3; 125.6; 126.4; 126.9; 127.0; 127.8; 128.6;
130.4; 130.5; 143.9; 149.8; 160.1; 164.4. Anal. Calcd for C24H20O4N3I
(541.32) C, 53.25; H, 3.72; N, 7.76. Found: C, 53.22; H, 3.72; N, 7.80.
22Af: (0.24 g, 86%) White solid from ethanol, mp 155−157 °C. IR:
νNH 3058, νCO 1719 cm−1. 1H NMR (DMSO) δ: 1.63 (s, 3H, CH3);
1.84 (s, 3H, CH3); 2.05 (s, 3H, CH3); 2.78 (m, 2H, CH2); 6.19 (t, 1H,
J = 7 Hz, O-CH-N); 7.29 (d, 1H, J = 1 Hz, N-CH); 7.59 (m, 4H,
arom.); 7.86 (d, 1H, J = 9 Hz); 8.04 (m, 1H, arom.); 8.13 (m, 2H,
arom.); 8.66 (s, 1H, arom.); 11.23 (s, 1H, NH). 13C NMR (DMSO) δ:
11.5; 24.4; 25.5; 45.9; 63.3; 81.6; 109.7; 123.9; 124.3; 125.2; 126.0;
126.2; 126.4; 126.5; 127.4; 128.1; 128.2; 130.0; 130.1; 134.4; 149.7;
162.9; 163.8. Anal. Calcd for C25H23O4N3 (429.46) C, 69.91; H, 5.40;
N, 9.79. Found: C, 69.91; H, 5.41; N, 9.75.
22Ag: (0.04 g, 48%) White solid from ethanol, mp 188−191 °C. IR:
νNH2 3362, 3171, νCO 1664 cm−1. 1H NMR (DMSO) δ: 1.87 (s, 3H,
CH3); 1.98 (s, 1.98, CH3); 2.59 e 2.84 (m, 1H + 1H, CH2); 5.53 (d,
1H, J = 7 Hz, CH-CN); 6.22 (t, 1H, J = 6 Hz, O-CH-N); 7.18 (d, 2H,
NH2); 7.39 (d, 1H, J = 7 Hz, N-CH); 7.58 (m, 4H, arom.); 7.88 (d,
1H, J = 8 Hz, arom.); 8.00 (m, 1H, arom.); 8.13 (m, 2H, arom.); 8.66
(s, 1H, arom). 13C NMR (DMSO) δ: 22.8; 25.1; 26.0; 47.2; 63.4;
82.7; 94.7; 124.3; 124.8; 125.6; 125.7; 126.4; 126.6; 126.8; 126.9;
127.7; 128.5; 128.6; 130.5; 130.6; 140.0; 154.4; 163.8; 165.3. Anal.
Calcd for C24H22O3N4 (414.45) C, 69.55; H, 5.35; N, 13.52. Found:
C, 69.51; H, 5.31; N, 13.52.
22Me: (0.29 g, 91%) White crystals from methanol, mp 106−110
1
°C. IR: νNH 3169, νCO 1690 cm−1. H NMR (CD3COCD3) δ: 1.72
and 1.87 (s, 6H, 2CH3); 2.25 and 2.34 (s, 9H, 3CH3-Ar); 2.82 and
2.96 (dd, J = 14, 7 Hz, 2H, CH2); 6.27 (t, J = 6 Hz, 1H, CH); 6.85 (m,
2H, Ph); 7.80 (s, 1H, CH-N); 10.45 (bs, 1H, NH). 13C NMR
(CD3COCD3) δ: 19.5; 19.8; 21.5; 25.0; 26.9; 49.9; 64.2; 69.9; 84.4;
129.0; 129.4; 134.1; 135.0; 135.3; 139.2; 144.7; 151.2; 160.8; 168.4.
Anal. Calcd for C19H22N3O4I (483.30): C, 47.22; H, 4.59; N, 8.69.
Found: C, 47.15; H, 4.55; N, 8.49.
22Mf: (0.19 g, 78%) White crystals from ethyl acetate, mp 99−104
1
°C. IR: νNH 3170, νCO 1700 cm−1. H NMR (CD3COCD3) δ: 1.74
and 1.88 (s, 6H, 2CH3); 1.83 (s, 3H, CH3-C); 2.22, 2.25, and 2.27 (s,
9H, 3CH3-Ar); 2.74 and 2.86 (dd, J = 14, 7 Hz, 2H, CH2); 6.39 (t, J =
7 Hz, 1H, CH); 6.82 (m, 2H, Ph); 7.43 (d, J = 1 Hz, 1H, CH-N);
10.08 (bs, 1H, NH). 13C NMR (CD3COCD3) δ: 12.8; 19.5; 21.4;
25.3; 26.9; 48.6; 64.3; 83.3; 112.1; 129.0; 134.3; 134.9; 135.5; 135.8;
139.0; 151.6; 164.2; 167.7. Anal. Calcd for C20H25N3O4 (371.42): C,
64.67; H, 6.78; N, 11.31. Found: C, 64.65; H, 6.75; N, 11.25.
22Mg: (0.11 g, 46%) White crystals from ethyl acetate, mp 107−
110 °C. IR: νNH2 3360, 3170, νCO 1640 cm−1
.
1H NMR
(CD3COCD3) δ: 1.75 and 1.83 (s, 6H, 2CH3); 2.21, 2.24, and 2.26
(s, 9H, 3CH3-Ar); 2.60 and 2.83 (dd, J = 14, 7 Hz, 2H, CH2); 5.88 (d,
J = 8 Hz, 1H, CH); 6.43 (t, J = 7 Hz, 1H, CH); 6.81 (m, 2H, Ph); 7.38
(s, 2H, NH2); 7.56 (d, J = 8 Hz, 1H, CH-N). 13C NMR (CD3COCD3)
δ: 19.5; 21.4; 23.6; 25.6; 27.1; 49.5; 64.0; 84.2; 95.7; 128.8; 128.9;
129.0; 129.5; 134.3; 134.9; 135.5; 139.0; 141.4; 156.1; 167.3. Anal.
Calcd for C19H24N4O3 (356.41): C, 64.02; H, 6.79; N, 15.72. Found:
C, 63.90; H, 6.65; N, 15.55.
Competition Experiments. Equimolecular amounts (20 equiv) of
3-methyl-2-buten-1-ol and the corresponding acetate and methyl ether
were allowed to react with 1 equiv of either benzonitrile oxide or
mesitonitrile oxide in the presence of 1.2 equiv of NMO in anhydrous
DCM as solvent. After the workup previously described, the reaction
mixtures were submitted to chromatographic separation for the
isolation and quantification of the ene obtained from the yields given
in Table 1 (see Table 2).
Biological Tests. Primary screen (dose response): determination
of a 90% inhibitory concentration (IC90). The initial screen is
conducted against Mycobacterium tuberculosis H37Rv (ATCC 27294)
in BACTEC 12B medium using the microplate Alamar Blue assay
(MABA). Compounds are tested in ten 2-fold dilutions, typically from
100 to 0.19 μg/mL. The IC90 is defined as the concentration effecting
a reduction in fluorescence of 90% relative to controls. This value is
determined from the dose−response curve using a curve-fitting
22Aa: (0.26 g, 97%) White solid from ethanol, mp > 200 °C. IR:
νNH 3167, νCO 1686 cm−1. 1H NMR (DMSO) δ: 1.84 (s, 3H, CH3);
2.03 (s, 3H, CH3); 2.79 (m, 2H, CH2); 5.49 (d, 1H, J = 8 Hz, CH-
CO); 6.17 (dd, 1H, J = 7, 6 Hz, O-CH-N); 7.59 (m, 5H, arom.); 7.86
(d, 1H, J = 8 Hz, N-CH); 7.99 (m, 1H, arom.); 8.12 (m, 2H, arom.);
8.66 (s, 1H, arom.); 11.22 (s, 1H, NH). 13C NMR (DMSO) δ: 25.1;
25.8; 46.2; 63.6; 82.3; 102.3; 124.3; 124.7; 125.6; 126.3; 126.7; 126.8;
126.9; 127.8; 128.5; 128.6; 130.4; 130.5; 140.0; 150.1; 162.6; 164.4.
Anal. Calcd for C24H21O4N3 (415.43) C, 69.38; H, 5.10; N, 10.12.
Found: C, 69.39; H, 5.05; N, 10.13
22Ab: (0.26 g, 93%) White solid from ethanol, mp > 200 °C. IR:
νNH 3168, νCO 1720 cm−1. 1H NMR (DMSO) δ: 1.83 (s, 3H, CH3);
2.04 (s, 3H, CH3); 2.79 (m, 2H, CH2); 6.16 (t, 1H, J = 7 Hz, O-CH-
N); 7.58 (m, 4H, arom.); 7.81 (d, 1H, J = 7 Hz, N-CH); 7.86 (d, 1H, J
= 9 Hz, arom.); 8.04 (m, 1H, arom.); 8.13 (m, 2H, arom.); 8.67 (s,
1H, arom.); 11.75 (s, 1H, NH). 13C NMR (DMSO) δ: 24.9; 25.7;
524
dx.doi.org/10.1021/jo302346a | J. Org. Chem. 2013, 78, 516−526

The Journal of Organic Chemistry
Article
(5) (a) Pistara,
̀
V.; Corsaro, A.; Chiacchio, M. A.; Greco, G.;
Table 2
Quadrelli, P. ARKIVOC 2011, 270−285. (b) Chiacchio, U.; Genovese,
F.; Iannazzo, D.; Piperno, A.; Quadrelli, P.; Corsaro, A.; Romeo, R.;
Valveri, V.; Mastino, A. Bioorg. Med. Chem. 2004, 12, 3903−3909.
(c) Chiacchio, U.; Genovese., F.; Iannazzo, D.; Librando, V.; Merino,
P.; Rescifina, A.; Romeo, R.; Propopio, A.; Romeo, G. Tetrahedron
2004, 60, 441−448. (d) Saita, M. G.; Chiacchio, U.; Iannazzo, D.;
Merino, P.; Piperno, A.; Previtera, T.; Rescifina, A.; Romeo, G.;
Romeo, R. Nucleosides, Nucleotides Nucleic Acids 2003, 22, 739−742.
Ar-CONO
alkene couples
ratios from data of Table1
8P
9d/e 0.86
9d/f 1.00
9d/e 0.77
9d/f 0.85
9d/e 0.77
9d/e 0.87
9d/e 0.67
9d/e 0.75
8M
program. Any IC90 value of ≥10 μg/mL is considered “Active” for
antitubercular activity. For further information, see: http://www.taacf.
org.
X-ray Crystallography. A summary of crystal data, data collection,
and structure refinement of compounds 11Md and 21A is given in
Table S2 of the Supporting Information. The structures are solved by
direct methods. Non-hydrogen atoms were refined anisotropically, and
hydrogen atoms, located from the difference Fourier synthesis, were
refined isotropically.40
CCDC 905532 for compound 11Md and CCDC 905533 for
compound 21A contain the supplementary data. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html
[or from the Cambridge Crystallography Data Centre 12, Union Road,
Cambridge CB2 IEZ, U.K., Fax: +44−1223/336033; E-mail: deposit@
ccdc.cam.ac.uk].41
̀
(e) Chiacchio, U.; Corsaro, A.; Iannazzo, D.; Piperno, A.; Pistara, V.;
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Chem. 2003, 46, 3696−3702.
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(8) For antiviral activity, the manuscript is in preparation. See also:
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Med. Chem. Lett. 2003, 13, 3963−3965. (b) Ramesh, N. G.; Klunder,
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ASSOCIATED CONTENT
* Supporting Information
NMR spectra of new compounds, X-ray crystallographic data,
and crystallographic data in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: paolo.quadrelli@unipv.it.
Notes
■
(9) Moggio, Y.; Legnani, L.; Bovio, B.; Memeo, M. G.; Quadrelli, P.
Tetrahedron 2012, 68, 1384−1392.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the University of Pavia, MIUR (PRIN
2008, CUP: F11J10000010001 and PRIN 2012, CUP:
B11J12002450001) and EUTICALS S.p.a. - V.le Milano, 86/
88- 26900 Lodi, Italy, is gratefully acknowledged. The authors
wish to thank the Fondazione Banca del Monte di Lombardia
for a research grant.
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