1,5-(H, RO, RS) shift/6π-electrocyclic ring closure tandem processes on N-[(α-heterosubstituted)-2-tolyl]ketenimines: A case study of relative migratory aptitudes and activating effects

Article abstract of DOI:10.1039/c2ob27010b

A number of N-aryl ketenimines, substituted at the ortho position either with different non-cyclic acetalic functions (acetals, monothioacetals, dithioacetals) or with only one alkoxymethyl or (alkylthio)methyl group, have been prepared and submitted to thermal treatment in toluene solution. Under smooth heating the ketenimines bearing non-cyclic acetals converted into 3,4-dihydroquinolines following two competitive tandem sequences that involve the alternative 1,5 migration of a hydride or alkoxy group as the first mechanistic step, followed by subsequent 6π electrocyclic ring closure. The heterocumulenes bearing acyclic monothioacetal and dithioacetal functions converted via a unique consecutive process involving the selective migration of the alkanethiolate group. Ketenimines bearing only one ether or thioether group transformed exclusively by the tandem sequence initiated by a 1,5 hydride shift. All these transformations provided as final reaction products a variety of quinoline derivatives with a range of substitution patterns. From these experiments the following order of propensity to migration can be extracted: RS > RO > H. It was also possible to estimate the following order of relative activating activities: RO > RS > H. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob27010b

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
PAPER
1,5-(H, RO, RS) shift/6π-electrocyclic ring closure
tandem processes on N-[(α-heterosubstituted)-2-tolyl]-
ketenimines: a case study of relative migratory
aptitudes and activating effects†
Cite this: Org. Biomol. Chem., 2012, 10,
9523
Mateo Alajarín,*a Baltasar Bonillo,a Raúl-Angel Orenes,b María-Mar Ortína and
Angel Vidal*a
A number of N-aryl ketenimines, substituted at the ortho position either with different non-cyclic acetalic
functions (acetals, monothioacetals, dithioacetals) or with only one alkoxymethyl or (alkylthio)methyl
group, have been prepared and submitted to thermal treatment in toluene solution. Under smooth
heating the ketenimines bearing non-cyclic acetals converted into 3,4-dihydroquinolines following two
competitive tandem sequences that involve the alternative 1,5 migration of a hydride or alkoxy group as
the first mechanistic step, followed by subsequent 6π electrocyclic ring closure. The heterocumulenes
bearing acyclic monothioacetal and dithioacetal functions converted via a unique consecutive process
involving the selective migration of the alkanethiolate group. Ketenimines bearing only one ether or
thioether group transformed exclusively by the tandem sequence initiated by a 1,5 hydride shift. All
these transformations provided as final reaction products a variety of quinoline derivatives with a range
of substitution patterns. From these experiments the following order of propensity to migration can be
extracted: RS > RO > H. It was also possible to estimate the following order of relative activating activities:
RO > RS > H.
Received 16th October 2012,
Accepted 29th October 2012
DOI: 10.1039/c2ob27010b
www.rsc.org/obc
Introduction
The development of new methodologies for the selective repla-
cement of the carbon–hydrogen bond with new bonds (C–H
functionalization) has provided a powerful tool in synthetic
organic chemistry,1 allowing the production of numerous
complex molecules.2 Recently, much attention on this research
topic has been devoted to the functionalization of C(sp3)–H
bonds via the so-called “internal redox process” (Scheme 1).3
This type of process involves as the first step the cleavage of a
C–H bond α to a heteroatom via a 1,5 hydride shift to give a
zwitterionic intermediate 2. Subsequent recombination of the
aDepartamento de Química Orgánica, Universidad de Murcia, Facultad de Química,
Regional Campus of International Excellence “Campus Mare Nostrum”, Espinardo,
30100 Murcia, Spain. E-mail: alajarin@um.es, vidal@um.es; Fax: +34 868 884149;
Tel: +34 868 887497, +34 868 887418
Scheme 1 Typical internal redox process.
reduced and oxidized parts of the molecule takes place to
afford heterocyclic compounds 3. Moreover, the participation
in this type of reaction of benzylic C–H bonds4 without adja-
cent heteroatoms and even of aliphatic non-benzylic C–H
bonds5 has been also reported. These internal redox processes
are commonly activated either thermally or by Brønsted and
Lewis acid catalysis.6
bServicio Universitario de Instrumentación Científica, Universidad de Murcia,
Campus de Espinardo, 30100 Murcia, Spain. E-mail: raorenes@um.es;
Tel: +868 888633
†Electronic supplementary information (ESI) available: ORTEP representation of
the crystal structure of cis-20e. Copy of 1H and 13C NMR spectra of compounds
10, 12, 13, 17, 20, 21, 26, 28, 31, 34, 37 and 39. Copy of 31P NMR spectra of com-
pounds 10, 17, 26, 31 and 37. Cif files of cis-20e. CCDC 905526. For ESI and crys-
tallographic data in CIF or other electronic format see DOI: 10.1039/c2ob27010b
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9523–9537 | 9523

Paper
Organic & Biomolecular Chemistry
View Article Online
Fig. 1 General structure of ketenimines bearing non-cyclic acetalic functions
(A) and ether or thioether groups (B).
structurally related ketenimines bearing ArCH2O groups at the
carbonyl carbon experience evolution by a different pathway:
the addition of the non-carbonylic oxygen atom of the ester
group to the ketenimine followed by oxygen-to-carbon
migration of the benzyl unit.12 Several examples of related 1,5
RO migrations have been also reported involving the electro-
philic carbon atom of carbodiimides as the migration ter-
minus.13 However, in the thermally-induced tandem
transformations of ketenimines 4 bearing cyclic acetalic frag-
ments we always obtained products derived from the exclusive
migration of the benzylic H atom. Most probably, the confor-
mational restrictions imposed on the system by the cyclic
nature of the acetalic groups prevent the alternative anionotro-
pic migration of the RO and/or RS fragments from the acetalic
carbon atom by making more difficult the subsequent cycliza-
tion. We thus reasoned that the acyclic acetalic functions of
ketenimines A in Fig. 1 would probably allow the competitive
migration of all atoms (or groups of atoms) at the acetalic
carbon, and, if so, to establish the relative order of migratory
aptitude of these atoms in such tandem processes, in combi-
nation with the study of the more simple related substrates B.
Herein we disclose that under thermal treatment several
examples of ketenimines A bearing non-cyclic acetal functions
(X = Y = O) converted into mixtures of 4,4-dialkoxyquinolines
and 2,4-dialkoxyquinolines, following two competitive tandem
sequences involving the respective 1,5 migration of hydride
and alkoxy groups. We also document that in similar reactions
of ketenimines A supporting acyclic dithioacetals (X = Y = S)
and monothioacetals (X = O, Y = S) the alkanethiolate group
selectively migrated to give 2-alkylthioquinolines. We also
show that ketenimines B bearing one ether or thioether group
transformed, on heating, exclusively into the quinolines result-
ing from a tandem sequence having as the first step a
1,5 hydride shift.
Scheme 2 Cyclic acetalic fragments facilitating tandem sequences promoted
by initial 1,5 hydride shifts.
Recently, as part of our research program for developing
new reactions involving ketenimines we discovered that under
thermal activation the acetal-ketenimines 4 converted into qui-
nolones 6 (Scheme 2).7 In these conversions the acetalic C–H
bond serves as a hydride source for translating its H atom to
the central carbon of the pendant ketenimine moiety. After the
hydride transfer, the resulting ortho-azaxylylene intermediates
5 undergo 6π electrocyclic ring closure (6π-ERC) to form the
quinoline ring system. The C(sp3)–H activation step occurring
in these tandem processes is facilitated by the hydricity
(hydride donor ability) of the acetalic functions. Only in one
particular case (X = O, Y = S, n = 1) the course of the one-pot
thermal transformation changed, the final products being
species 7, but the result was also explained by postulating an
initial 1,5 hydride shift.8 We have also previously conducted
similar sequences onto ketenimines bearing triarylmethane
fragments as hydride donors.9
Stimulated by these results we became interested in the
exploration of the thermally-activated transformation that
could undergo N-aryl ketenimines A bearing non-cyclic acetalic
functions at the ortho position of the keteniminic nitrogen
atom, such as acetals, monothioacetals and dithioacetals, and
structurally related N-aryl ketenimines B supporting only one
ether or thioether function at the benzylic carbon (Fig. 1). It is
well known that under high temperature conditions (FVP con-
ditions) oxoketenimines undergo anionotropic 1,3 migration
of electron-donor RO, RS and R2N groups from the carbonyl
carbon to the central heterocumulenic carbon atom, thus equi-
librating with imidoylketenes.10 In our hands N-phenyl keteni-
mines substituted at the ortho position of their N-phenyl ring
with different carboxylic –C(O)Z functions (Z = RS, ArS, ArSe,
ArO and R2N) undergo cyclization, under mild thermal con-
ditions, initiated by 1,5-shifts of these electron-donor frag-
ments Z to the ketenimine central carbon atom.11 In contrast,
Results and discussion
Dimethoxyacetal-ketenimines 11 designed for the initial
studies were prepared via a three step sequence initiated by
the treatment of methanolic solutions of the easily available
2-azidobenzaldehydes 8 with methyl orthoformate, in the pres-
ence of a catalytic amount of para-toluenesulfonic acid at
room temperature, to provide α,α-dimethoxy-2-tolylazides 9.
The Staudinger reaction of acetal-azides 9 with triphenyl-
phosphine, in anhydrous diethyl ether at room temperature,
9524 | Org. Biomol. Chem., 2012, 10, 9523–9537
This journal is © The Royal Society of Chemistry 2012

Organic & Biomolecular Chemistry
Paper
View Article Online
Scheme 3 Reagents and conditions: (a) HC(OCH3)3, p-TsOH cat., CH3OH, r.t.,
24 h. (b) PPh3, Et2O, r.t., 16 h. (c) PhR3CCO, toluene, r.t., 30 min. (d) Toluene,
reflux, 3–24 h.
Scheme 4 Alternative reaction pathways for the conversion of 11 into 12 and
13.
C(2)H proton appears at δ = 7.82–8.49 ppm. Significant 13C
NMR data of quinolines 12 are the chemical shifts of the C4
aliphatic quaternary carbon at δ = 99.9–100.6 ppm and that of
Table 1 4,4-Dimethoxyquinolines 12 and 2,4-dimethoxyquinolines 13
Entry
R1
R2
R3
Combined yield (%)
12 : 13 Ratio
1
the C2 methine carbon at δ = 170.5–172.6 ppm. The H NMR
a
b
c
d
e
f
H
H
Cl
CH3
H
H
CH3
H
H
H
Ph
Ph
Ph
Ph
CH3
CH3
82
88
89
64
90
75
41 : 59
41 : 59
27 : 73
61 : 39
33 : 66
33 : 66
spectra of quinolines 13 show two neatly different methoxy
groups, that linked to C2 resonates at δ = 3.92–3.99 ppm and
that to C4 at δ = 3.01–3.41 ppm. In their 13C NMR spectra the
quaternary C2 resonates at δ = 165.9–169.7 ppm, whereas the
signal of the methine C4 appears at δ = 84.6–85.9 ppm, con-
siderably shifted upfield with respect to the signal of the same
H
CH3
afforded the acetal-iminophosphoranes 10. When toluene sol- carbon in the isomeric quinolines 12 bearing two methoxy
utions of compounds 10 were treated, at room temperature, groups at that carbon.
with diphenylketene and methylphenylketene the acetal-kete-
The 2,4-dimethoxy-3,4-dihydroquinolines 13e,f in which R3
nimines 11 were formed, as corroborated by recording FT-IR is a methyl group were obtained as mixtures of the two poss-
spectra of the final solutions which showed very strong absorp- ible racemic diastereoisomers in relative ratios close to 1 : 1, as
tion bands around 2000 cm−1 distinctive of the ketenimine calculated by integration in the 1H NMR spectra of the final
grouping. By simply heating at reflux temperature for a few reaction mixtures. These mixtures were resolved by column
hours the toluene solutions containing heterocumulenes 11, a chromatography and both diastereoisomers of compounds
clean reaction occurred to provide mixtures of the 4,4- 13e,f could be isolated in a pure form. Thus we were able to
dimethoxy-3,4-dihydroquinolines 12 and the 2,4-dimethoxy- measure two-dimensional NOESY spectra of both diastereo-
3,4-dihydroquinolines 13 (Scheme 3, Table 1).
isomers, but the data extracted from these experiments were
The determination of the structure of dihydroquinolines 12 not conclusive enough in order to assign the relative cis/trans
and 13 was carried out following their spectral data: IR, 1H configuration of the two stereocenters in each isomer.
and 13C NMR and mass spectrometry. In the 1H NMR of the
Obviously two competitive reaction pathways operate in the
4,4-dimethoxy derivatives 12a–d the protons of both methoxy thermal conversion of acetal-ketenimines 11 (Scheme 4). A
groups resonate as one singlet at δ = 2.82–2.91 ppm, whereas 1,5 hydride-like migration of the acetalic H to the central
in examples 12e,f, bearing a chiral C3 carbon atom, the dia- carbon atom of the ketenimine grouping followed by a 6π elec-
stereotopic methoxy groups appear as two singlets at very close trocyclization of the resulting 3-azatriene 14 explains the for-
chemical shifts, δ = 2.89–2.95 ppm. In these compounds the mation of 4,4-dimethoxy-3,4-dihydroquinolines 12. A similar
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9523–9537 | 9525

Paper
Organic & Biomolecular Chemistry
View Article Online
sequence involving the alternative 1,5 shift of one of the dithioacetal-ketenimines 18 were dependent on the nature of
methoxy substituents of the acetalic function in turn explains the R3 substituent. Whereas ketenimines 18a–c bearing R3
the formation of 2,4-dimethoxy-3,4-dihydroquinolines 13.
Ph required heating in refluxing toluene, those with R3 = CH3
=
Most of the entries of Table 1 show that quinolines 13 18d,e transformed just by keeping their dichloromethane sol-
slightly predominate over 12 in the final reaction mixtures (the ution at room temperature. The reaction products obtained in
only rare exception is entry d). For briefly analysing these the thermal treatment of dithioacetal-ketenimines 18 were, in
results we must bring into play the results of our previous all the cases, the 2,4-dialkylthio-3,4-dihydroquinolines 20
computational analyses on the closely related two-step pro- (Scheme 5, Table 2), which formed by the habitual two-step
cesses shown in Scheme 2, showing that the first step, the sequence: the selective 1,5 shift of one alkanethiolate group
hydride transfer from the benzylic carbon to the central one of from the acetalic carbon to the ketenimine central carbon
the ketenimine, is always the rate-determining one with the atom followed by the 6π electrocyclization of the 3-azahexa-
higher activation energy.7,8 Thus, in a reasonable approxi- triene intermediates 19.
mation our analysis will deal with the first migratory step. In
With the aim of extending the synthetic scope of this 1,5-SR
our interpretation of the experimental results in Table 1, the shift/6π-ERC tandem process to the preparation of additional
composition of the mixtures of compounds 12 and 13 quinolines with different substitution patterns, a mixture of
obtained from 11 should be explained as resulting from a com- iminophosphorane 17a and S-phenyl 2-diazoethanethiolate in
bination of two electronic effects: first, the “pushing” power of anhydrous toluene was heated at 80 °C, giving rise to the
the substituents at the benzylic carbon for contributing to 2-ethylthio-3-phenylthioquinoline 21. The full mechanistic
“expel” the migrating atom or group in an anion-like form, sequence explaining the formation of quinoline 21 is also
and second, the anionotropic migratory aptitude of the shown in Scheme 5, involving as the last step the aromatiza-
“expelled” atom or group. The first one can be also viewed as tion of the pyridine ring of the 1,5-SR/6π-ERC product 23 by
the ability of the atoms or groups at the benzylic carbon to the β-elimination of volatile ethanethiol.
stabilise the developing electronic deficiency at that atom. In
Quinolines 20d,e (R3 = CH3) having two sterocenters, C3
this respect the ability of an RO group to stabilise positive and C4 carbon atoms, were obtained as mixtures of the cis and
charges, via lone pair conjugation, at the carbon atom to trans diastereoisomers in unexpectedly good diastereomeric
which it is linked is well known. In other words, the lone pairs ratios (up to 90 : 10). The fractional crystallization of the major
at the oxygen atoms of 11 contribute to detach the migrating isomer of compound 20e yielded good quality single crystals
group (H or CH3O) from the benzylic carbon in an anion-like suitable for X-ray structure determination. The X-ray structural
form.14 By contrast, the H atom should not play a comparable data indicate that in this diastereoisomer of 20e the phenyl
activating role in this respect. Concerning the second elec- group at C3 and the ethylthio group at C4 are in a relative cis
tronic effect, the migratory aptitude of the groups in anion-like disposition (see ESI†). A relative cis configuration was also
form, it is also of fundamental chemical knowledge that elec- assigned to the major diastereoisomer of quinoline 20d as it
tronegative atoms, such as oxygen, better accommodate nega- showed 1H and 13C NMR data similar to those of cis-20e.
tive charges than the simplest H atom. The results of the
As shown in Scheme 5 and Table 2, the migrating group in
thermal conversions of ketenimines 11, yielding mixtures of the thermal conversion of dithioacetal-ketenimines 18 is
quinolines 12 and 13 not very far from the 1 : 1 ratio, should always an alkylthio group, whereas products derived from the
thus be reasoned as resulting from a compromise situation alternative migration of the acetalic H atom were neither iso-
between the facilitation of the H migration path by the two lated nor even detected in the reaction crudes, in sharp con-
methoxy groups, and the better migratory aptitude of the trast with the results obtained with acetal-ketenimines 11.
detached CH3O when compared with H, but in this last case From the exclusive formation of 3,4-dihydroquinolines 20 by
being activated by only one methoxy group. This compromise thermal treatment of dithioacetal-ketenimines 18, and also by
situation between the two alternative reaction paths seems to taking our background in this research into account, we can
be slightly unbalanced toward the second one in most of the estimate that the RS groups of ketenimines 18 possess better
cases collected in Table 1.
migratory aptitude than the CH3O of ketenimines 11. To reach
We next examined the thermal evolution of ketenimines this conclusion, one key point is that we have previously
bearing non-cyclic dithioacetal functionalities. The reaction of proved that a cyclic dithioacetal fragment is less effective than
2-azidobenzaldehydes 8a,e with ethanethiol or 2-phenyletha- a similar cyclic acetal in promoting the 1,5 H migrations rep-
nethiol, in anhydrous chloroform at room temperature in the resented in Scheme 2. That is, alkoxy groups have better
presence of trimethylsilyl chloride, yielded the corresponding “pushing” ability than their thioanalogues in order to “expel”
dithioacetal-azides 16, which in a further step by treatment the migrating atom or group. This is why the contrasting
with triphenylphosphine, in diethyl ether solution at room results of the thermal treatment of ketenimines 11 and 18 can
temperature, were converted into the iminophosphoranes 17. be rationalized by accounting for the poorer activating power
The dithioacetal-ketenimines 18 were prepared by the usual of the RS groups in comparison with that of the methoxy
methodology, the aza-Wittig reaction of the iminophosphor- group, and the better migratory aptitude of the RS ones.15
anes 17 with diphenylketene or methylphenylketene. The
Nevertheless, with the aim of directly testing the above esti-
thermal conditions required to promote the conversion of the mations on the relative migratory aptitudes of the different
9526 | Org. Biomol. Chem., 2012, 10, 9523–9537
This journal is © The Royal Society of Chemistry 2012

Organic & Biomolecular Chemistry
Paper
View Article Online
Scheme 6 Reagents and conditions: (a) SOCl2, r.t., 16 h. (b) KSC(S)OEt, Et2O,
reflux, 1 h. (c) CH3I, NaOCH3, Et2O, 15 °C, 5 h. (d) PPh3, Et2O, r.t., 16 h. (e)
PhR1CCO, toluene, r.t., 30 min. (f) Toluene, reflux, 1 h.
carbon atom. Thus, hemithioacetal-ketenimines 27 were pre-
pared in a simple five-step synthetic sequence starting from
α,α-dimethoxy-2-tolylazide 9a. The consecutive treatment of
compound 9a with thionyl chloride and potassium O-ethyl
dithiocarbonate afforded the xanthate 24. Next, xanthate 24
was reacted with methyl iodide in the presence of sodium
methoxide leading to hemithioacetal-azide 25, which by the
habitual methodology was converted into a pair of hemithio-
acetal-ketenimines 27. The heating at reflux temperature of
toluene solutions of ketenimines 27 provided 4-methoxy-2-
methylthioquinolines 28 as the only reaction products
(Scheme 6). The 3-methyl-3,4-dihydroquinoline 28b (R1 = CH3)
was obtained as a mixture of the two expected cis/trans diaster-
eoisomers, in a relative ratio close to 2 : 1, which could be sep-
arated by column chromatography on silica gel. Unfortunately,
the recorded NMR experiments for both diastereoisomers of
compound 28b did not allow us a reliable stereochemical
assignment of the relative cis/trans configuration of the two
stereocenters in each isomer.
Scheme 5 Reagents and conditions: (a) R2SH, TMSCl, CHCl3, r.t., 1 h. (b) PPh3,
Et2O, r.t., 16 h. (c) PhR3CCO, toluene, r.t., 30 min. (d) 18a–c: toluene, reflux, 1 h;
18d,e: CH2Cl2, r.t., 3–16 h. (e) PhSC(O)CH(N2), toluene, 80 °C, 1 h.
Table 2 2,4-Dialkylthioquinolines 20
Compound
R1
R2
R3
Yield (%)
Cis/trans ratio
Clearly the conversions summarized in Scheme 6 took
place through the exclusive 1,5 migration of the methylthio
group. These results are in accord with our previous esti-
mations: the most favourable 1,5 anionotropic shift should be
the one involving the best migrating group, methylthio, being
promoted by the most powerful activating one, the methoxy
group.
All 1,5-X shift/6π-ERC tandem sequences examined so far in
this work deal with acetalic substrates, that is species bearing
one hydrogen atom and two heteroatom-linked groups (RO,
20a
20b
20c
20d
20e
H
Br
H
H
Br
CH3CH2
CH3CH2
PhCH2CH2
CH3CH2
CH3CH2
Ph
Ph
Ph
CH3
CH3
94
81
99
97
99
90 : 10
72 : 28
groups, we next tackled the preparation of ketenimines
bearing non-cyclic monothioacetal functions, substrates with
one hydrogen atom, one alkoxy group and one alkylthio group
simultaneously placed at the migration origin, the benzylic
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9523–9537 | 9527

Paper
Organic & Biomolecular Chemistry
View Article Online
Scheme 8 Reagents and conditions: (a) EtSH, KOH, DMSO, r.t., 2 h. (b) PPh3,
Et2O, r.t., 16 h. (c) Ph2CCO, toluene, r.t., 30 min. (d) Toluene, reflux, 6 d (50%) or
ortho-xylene, reflux, 24 h (85%).
Scheme 7 Reagents and conditions: (a) CH3I, KOH, DMSO, r.t., 30 min. (b)
PPh3, Et2O, r.t., 16 h. (c) PhR3CCO, toluene, r.t., 30 min. (d) Toluene, reflux,
12–36 h.
32 were heated at reflux temperature. The conversions of 32
into 34 were complete in an interval of 12–36 h (Scheme 7,
Table 3).
Table 3 4-Methoxyquinolines 34
The formation of dihydroquinolines 34 is the consequence
of tandem 1,5-H/6π-ERC processes, these results proving that
in the absence of a second heteroatom-linked group able to
facilitate the migration placed at the benzylic carbon, the
methoxy group remained at that position playing the role of an
activating group.
Ketenimine 38, prepared similarly to 32 and containing the
good-migrating ethylthio group, heated in toluene solution at
reflux temperature gave rise, after 6 days, to a 50% yield of
4-ethylthio-3,4-dihydroquinoline 39, as a result of a tandem
1,5-H/6π-ERC process (Scheme 8). A better yield, 85%, was
obtained when carrying out the thermal treatment in refluxing
ortho-xylene for 24 h.
It became thus clear that even a group with good migratory
aptitude, such as EtS, would require the activation of a second
heteroatom-linked group at the benzylic position for under-
going a 1,5 shift to the central ketenimine carbon of this type
of heterocumulene. Otherwise, the H migration promoted by
the activating group is the only observed shift. By comparing
the reaction conditions of the 32 into 34 and 38 into 39 trans-
formations, the better activating characteristics of the alkoxy
groups over the alkylthio ones are once again highlighted.
Compound
R1
R2
R3
Yield (%)
34a
34b
34c
34d
34ea
34fa
H
H
Cl
CH3
H
H
CH3
H
H
H
Ph
Ph
Ph
Ph
CH3
CH3
51
99
70
61
69
50
H
CH3
a Obtained as mixtures of diastereoisomers in a relative ratio close
to 2 : 1.
RS) at the benzylic carbon. In all cases, at least one of these
groups could migrate in the first step whereas the second one
activates the migration by the participation of the lone pairs at
its heteroatom. Still some questions remained unanswered. If
the ketenimine bears only one of these groups, would it be
able to experience the 1,5 shift in the absence of the second
RO or RS as the activating group? Only if this group is the one
with the best migratory aptitude? Would the H migration
compete? The following, final experiments were carried out
aiming to answer these questions, by using substrates bearing
only one alkoxy or alkylthio group at the benzylic carbon
atom.16
Methylation of the hydroxyl group of the 2-azidobenzyl alco-
hols 29, followed by consecutive treatment of the resulting
azido-ethers 30 with triphenylphosphine and methylphenyl-
ketene or diphenylketene under the usual conditions afforded
ketenimines 32. 4-Methoxy-3,4-dihydroquinolines 34 were the
only products formed when toluene solutions of ketenimines
Conclusions
In conclusion, ketenimines bearing acyclic acetal functions as
hydride donor units have been shown to undergo competitive
1,5-H/6π-ERC and 1,5-OR/6π-ERC tandem processes, leading to
9528 | Org. Biomol. Chem., 2012, 10, 9523–9537
This journal is © The Royal Society of Chemistry 2012

Organic & Biomolecular Chemistry
Paper
View Article Online
quinolines, whereas their monothioacetal and dithioacetal (1 H, s), 7.11–7.18 (2 H, m), 7.41–7.44 (1 H, m); δC (100 MHz,
analogues experience cyclization through tandem processes CDCl3) 18.1, 53.8, 100.8, 125.5, 125.7, 131.6, 131.9 (s), 132.9
involving as the first step the selective migration of an (s), 136.4 (s).
alkylthio group. We have herein also demonstrated that a
2-AZIDO-5-CHLORO-1-(DIMETHOXYMETHYL)BENZENE 9C (R1 = CL; R2 =
single ether or thioether function is also able to impart hydri- H). Eluent for column chromatography: hexanes–diethyl ether
city facilitating intramolecular H shifts, but in no case the (7 : 3, v/v); (2.25 g, 99%); colourless oil; νmax(neat)/cm−1 2129
migration of the heteroatom-based function is amenable. Thus (vs), 2098 (vs); δH (400 MHz, CDCl3) 3.35 (6 H, s), 5.47 (1 H, s),
the thermal treatment of N-aryl ketenimines, supporting one 7.09 (1 H, d, J 8.5), 7.33 (1 H, dd, J 8.5, 2.5), 7.57 (1 H, d, J 2.5);
ether or thioether function at the benzylic carbon at the ortho δC (100 MHz, CDCl3) 53.6, 98.7, 119.5, 128.2, 130.2 (s), 130.7
position, provides the quinolines resulting from the exclusive (s), 136.4 (s).
1,5-H migration in the first mechanistic step. The analysis of
2-AZIDO-1-(DIMETHOXYMETHYL)-5-METHYLBENZENE 9D (R1 = CH3;
all these experiments revealed the following order of migratory R2 = H). Eluent for column chromatography: hexanes–diethyl
aptitude RS > RO > H, accounting for the anionotropic nature ether (4 : 1, v/v); (2.03 g, 98%); yellow oil; νmax(neat)/cm−1 2129
of the migratory step. The order of activating power follows the (vs), 2105 (vs); δH (300 MHz, CDCl3) 2.33 (3 H, s), 3.35 (6 H, s),
sequence RO > RS > H, reflecting the relative power for stabiliz- 5.49 (1 H, s), 7.05 (1 H, d, J 8.1), 7.17 (1 H, dd, J 8.1, 1.9), 7.38
ing the developing carbocationic characteristics at the benzylic (1 H, d, J 1.9); δC (75 MHz, CDCl3) 21.0, 53.8, 99.5, 118.1,
carbon atom in the rearrangement.
128.3, 128.8 (s), 130.5, 134.4 (s), 135.0 (s).
Preparation of 1-(dimethoxymethyl)-2-
triphenylphosphoranylideneaminobenzenes 10
Experimental
To
a solution of 2-azido-1-(dimethoxymethyl)benzene 9
All melting points are uncorrected. Infrared (IR) spectra were
recorded neat or as Nujol emulsions. 1H NMR spectra were
recorded at 300 or 400 MHz. 13C NMR spectra were recorded at
75 or 100 MHz. The chemical shifts in the 1H NMR spectra are
expressed in ppm relative to Me4Si at δ = 0.00. The chemical
shifts in the 13C NMR spectra are reported relative to the reson-
ance of CDCl3 at δ = 77.1 ppm. J values are given in Hz.
2-Azidobenzaldehyde 8a,17 2-azido-3-methylbenzaldehyde
8b,18 2-azido-5-chlorobenzaldehyde 8c,19 2-azido-5-methylben-
zaldehyde 8d,18 2-azido-5-bromobenzaldehyde 8e,19 2-azido-
benzyl alcohol 29a,20 2-azido-3-methylbenzyl alcohol 29b,18 2-
azido-5-chlorobenzyl alcohol 29c,21 2-azido-5-methylbenzyl-
alcohol 29d,18 2-azidobenzyl iodide 35,21 methylphenyl-
ketene22 and diphenylketene23 were prepared following
published experimental procedures.
(5 mmol) in anhydrous diethyl ether (20 mL), under nitrogen
at room temperature, triphenylphosphine (1.30 g, 5 mmol) was
added in small portions. The reaction mixture was stirred at
room temperature for 16 h. Then the precipitated compounds
10 were isolated by filtration and washed with anhydrous
diethyl ether (10 mL). These compounds were used in the fol-
lowing step without further purification.
For analytical samples iminophosphoranes 10 were recrys-
tallized from diethyl ether.
1-(DIMETHOXYMETHYL)-2-TRIPHENYLPHOSPHORANYLIDENEAMINOBENZENE
10A (R1 = R2 = H). (2.09 g, 98%); mp 125–126 °C (from Et2O);
νmax(Nujol)/cm−1 1435 (vs), 1321 (vs), 1103 (s); δH (400 MHz,
CDCl3) 3.36 (6 H, s), 6.16 (1 H, s), 6.47 (1 H, d, J 8.0), 6.68 (1 H,
t, J 7.4), 6.83 (1 H, t, J 7.4), 7.41–7.45 (7 H, m), 7.48–7.54 (3 H,
m), 7.73–7.78 (6 H, m); δC (100 MHz, CDCl3) 54.1, 101.9, 117.3,
121.8 (d, J 9.6), 126.8, 128.3, 128.6 (d, J 12.0), 131.6 (d, J 2.4),
131.7 (d, J 99.7) (s), 131.8 (s), 132.6 (d, J 9.7), 149.4 (s); δP
Preparation of 2-azido-1-(dimethoxymethyl)benzenes 9
To a solution of the 2-azidobenzaldehyde 8 (10 mmol) in anhy- (161.9 MHz, CDCl3, H3PO4) 1.5; HRMS (ESI): Calcd for
drous methanol (15 mL) methyl orthoformate (2.12 g, C27H27NO2P [M + H]+ 428.1774, found 428.1780.
20 mmol) and a catalytic amount of para-toluenesulfonic acid
1-(DIMETHOXYMETHYL)-3-METHYL-2-TRIPHENYLPHOSPHORANYLIDENEAMI-
(0.01 g) were added. The reaction mixture was stirred at room NOBENZENE 10B (R1 = H; R2 = CH3). (2.03 g, 92%); mp
temperature for 24 h. Then, the solvent was removed under 118–119 °C (from Et2O); νmax(Nujol)/cm−1 1435 (vs), 1381 (vs),
reduced pressure, and the crude material was purified by 1105 (s); δH (400 MHz, CDCl3) 1.90 (3 H, s), 2.95 (6 H, s), 5.56
column chromatography on silica gel.
(1 H, s), 6.72 (1 H, td, J 7.4, 2.1), 6.96 (1 H, d, J 7.4), 7.26 (1 H,
2-AZIDO-1-(DIMETHOXYMETHYL)BENZENE 9A (R1 = R2 = H). Eluent d, J 7.4), 7.36–7.40 (6 H, m), 7.44–7.52 (3 H, m), 7.58–7.68 (6 H,
for column chromatography: hexanes–diethyl ether (4 : 1, v/v); m); δC (100 MHz, CDCl3) 21.3, 52.9, 101.3, 118.7 (d, J 3.2),
(1.83 g, 95%); yellow oil; νmax(neat)/cm−1 2127 (vs), 2089 (s); δH 124.4 (d, J 1.9), 128.3 (d, J 12.0), 130.1 (d, J 2.5), 131.2 (d, J 2.4),
(400 MHz, CDCl3) 3.35 (6 H, s), 5.52 (1 H, s), 7.14–7.18 (2 H, 132.4 (d, J 9.5), 132.6 (d, J 100.8) (s), 133.5 (d, J 4.0) (s), 147.1
m), 7.37 (1 H, ddd, J 8.2, 7.2, 1.6), 7.57–7.59 (1 H, m); δC (s); δP (161.9 MHz, CDCl3, H3PO4) – 3.8; HRMS (ESI): Calcd for
(100 MHz, CDCl3) 53.6, 99.3, 118.2, 124.5, 127.9, 129.1 (s), C28H29NO2P [M + H]+ 442.1930, found 442.1936.
129.9, 137.8 (s).
5-CHLORO-1-(DIMETHOXYMETHYL)-2-TRIPHENYLPHOSPHORANYLIDENEAMI-
2-AZIDO-1-(DIMETHOXYMETHYL)-3-METHYLBENZENE 9B (R1 = H; R2
=
NOBENZENE 10C (R1 = CL; R2 = H). (2.10 g, 91%); mp 117–118 °C
CH3). Eluent for column chromatography: hexanes–diethyl (from Et2O); νmax(Nujol)/cm−1 1346 (vs), 1321 (s), 1108 (s); δH
ether (9 : 1, v/v); (1.51 g, 73%); colourless oil; νmax(neat)/cm−1 (400 MHz, CDCl3) 3.35 (6 H, s), 6.06 (1 H, s), 6.36 (1 H, dd, J
2113 (vs); δH (400 MHz, CDCl3) 2.41 (3 H, s), 3.37 (6 H, s), 5.60 8.5, 1.4), 6.77 (1 H, dd, J 8.5, 2.8), 7.39–7.53 (10 H, m),
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9523–9537 | 9529

Paper
Organic & Biomolecular Chemistry
View Article Online
7.70–7.75 (6 H, m); δC (100 MHz, CDCl3) 54.0, 101.2, 122.1 (s), 140.9 (s), 141.8 (s), 172.6; HRMS (ESI): Calcd for C23H21ClNO2
122.6 (d, J 9.6), 126.8, 128.1, 128.7 (d, J 11.9), 131.1 (d, J 99.3) [M + H]+ 378.1255, found 378.1262.
(s), 131.8 (d, J 2.4), 32.5 (d, J 9.6), 133.2 (d, J 20.1) (s), 148.1 (s);
δP (161.9 MHz, CDCl3, H3PO4) 2.7; HRMS (ESI): Calcd for (R1 = CH3; R2 = H; R3 = PH). Eluent for column chromato-
C27H26ClNO2P [M + H]+ 462.1384, found 462.1389.
graphy: hexanes–diethyl ether (1 : 1, v/v); (0.14 g, 39%); mp
4,4-DIMETHOXY-6-METHYL-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 12D
1-(DIMETHOXYMETHYL)-5-METHYL-2-TRIPHENYLPHOSPHORANYLIDENEAMI- 113–114 °C (from Et2O); νmax(Nujol)/cm−1 1621 (m); δH
NOBENZENE 10D (R1 = CH3; R2 = H). (1.85 g, 84%); mp (400 MHz, CDCl3, 57 °C) 2.36 (3 H, s), 2.90 (6 H, s), 7.03 (1 H,
128–129 °C (from Et2O); νmax(Nujol)/cm−1 1489 (vs), 1344 (s), dd, J 7.8, 1.2), 7.10 (1 H, d, J = 7.8), 7.16–7.18 (6 H, m),
1107 (s); δH (400 MHz, CDCl3) 2.19 (3 H, s), 3.37 (6 H, s), 6.14 7.40–7.43 (4 H, m), 7.56–7.57 (1 H, m), 8.39 (1 H, s); δC
(1 H, s), 6.39 (1 H, dd, J 81, 1.4), 6.65 (1 H, dd, J 8.1, 2.0), (100 MHz, CDCl3) 21.6, 50.9, 59.1 (s), 100.3 (s), 126.6, 126.8,
7.23–7.25 (1 H, m), 7.40–7.44 (6 H, m), 7.47–7.49 (3 H, m), 127.0, 127.5, 129.0 (s), 129.8, 131.1, 137.1 (s), 141.0 (s), 141.5
7.72–7.77 (6 H, m); δC (100 MHz, CDCl3) 20.7, 54.2, 101.9, (s), 170.9; HRMS (ESI): Calcd for C24H24NO2 [M + H]+
121.5 (d, J 9.3), 126.4 (s), 127.2, 128.5 (d, J 11.9), 129.0, 131.5 358.1802, found 358.1808.
(d, J 2.5), 131.8 (d, J 99.6) (s), 132.6 (d, J 9.6), 146.6 (s); δP
4,4-DIMETHOXY-3-METHYL-3-PHENYL-3,4-DIHYDROQUINOLINE 12E (R1 =
(161.9 MHz, CDCl3, H3PO4) 1.6; HRMS (ESI): Calcd for R2 = H; R3 = CH3). Eluent for column chromatography:
C28H29NO2P [M + H]+ 442.1930, found 442.1936.
dichloromethane; (0.08 g, 30%); colourless oil; νmax(neat)/cm−1
1610 (m); δH (400 MHz, CDCl3) 1.52 (3 H, s), 2.91 (3 H, s), 2.95
(3 H, s), 7.26–7.44 (6 H, m), 7.54–7.57 (2 H, m), 7.64–7.66 (1 H,
m), 7.82 (1 H, s); δC (100 MHz, CDCl3) 16.9, 50.5, 51.0, 51.2 (s),
100.0 (s), 126.7, 127.1, 127.3, 127.4, 127.5 (s), 127.8, 129.6,
Preparation of 4,4-dimethoxyquinolines 12 and
2,4-dimethoxyquinolines 13
To a solution of the 1-(dimethoxymethyl)-2-triphenylphosphor- 129.9, 140.2 (s), 172.2.
anylideneaminobenzene 10 (1 mmol) in anhydrous toluene
4,4-DIMETHOXY-3,8-DIMETHYL-3-PHENYL-3,4-DIHYDROQUINOLINE
12F
(20 mL) a solution of methylphenylketene (0.13 g, 1 mmol) or (R1 = H; R2 = CH3; R3 = CH3). Eluent for column chromato-
diphenylketene (0.19 g, 1 mmol) in the same solvent (5 mL) graphy: hexanes–diethyl ether (9 : 1, v/v); (0.07 g, 25%); colour-
was added. The reaction mixture was stirred under nitrogen at less oil; νmax(neat)/cm−1 1630 (m); δH (300 MHz, CDCl3) 1.50 (3
room temperature for 30 min, and next heated at reflux temp- H, s), 2.52 (3 H, s), 2.89 (3 H, s), 2.92 (3 H, s), 7.14–7.22 (1 H,
erature for 3–24 h. After cooling at room temperature, the m), 7.23–7.38 (4 H, m), 7.48–7.51 (1 H, m), 7.56–7.59 (2 H, m),
solvent was removed under reduced pressure, and the resulting 7.85 (1 H, s); δC (100 MHz, CDCl3) 16.9, 17.8, 50.4, 50.6 (s),
crude material was purified by column chromatography on 51.0, 100.2 (s), 124.3, 126.7, 127.2, 128.7, 129.9, 131.3, 134.9
silica gel.
(s), 140.4 (s), 140.5 (s), 170.7; HRMS (ESI): Calcd for
4,4-DIMETHOXY-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 12A (R1 = R2 = C19H22NO2 [M + H]+ 296.1645, found 296.1655.
H; R3 = PH). Eluent for column chromatography: hexanes–
2,4-DIMETHOXY-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 13A (R1 = R2 =
diethyl ether (4 : 1, v/v); (0.12 g, 34%); mp 131–132 °C (from H; R3 = PH). Eluent for column chromatography: hexanes–
Et2O); νmax(Nujol)/cm−1 1628 (m); δH (400 MHz, CDCl3) 2.82 (6 diethyl ether (9 : 1, v/v); (0.16 g, 48%); mp 146–147 °C (from
H, s), 7.09–7.12 (6 H, m), 7.13–7.17 (3 H, m), 7.32–7.36 (4 H, Et2O); νmax(Nujol)/cm−1 1629 (vs); δH (400 MHz, CDCl3) 3.01 (3
m), 7.67–7.70 (1 H, m), 8.38 (1 H, s); δC (100 MHz, CDCl3) 50.9, H, s), 3.92 (3 H, s), 4.63 (1 H, s), 6.96–7.00 (1 H, m), 7.03–7.05
59.0 (s), 100.2 (s), 126.1, 127.0, 127.1, 127.2, 127.5, 129.3, 129.4 (1 H, m), 7.09–7.13 (9 H, m), 7.21 (1 H, d, J 7.4), 7.24–7.26 (2
(s), 131.1, 141.4 (s), 143.2 (s), 172.0; HRMS (ESI): Calcd for H, m); δC (100 MHz, CDCl3) 54.2, 58.5 (s), 58.7, 84.9, 124.6,
C23H22NO2 [M + H]+ 344.1645, found 344.1649.
125.1, 125.9, 126.8, 127.0, 127.3, 127.9 (s), 128.0, 128.8, 128.9,
4,4-DIMETHOXY-8-METHYL-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 12B 130.7, 139.3 (s), 141.5 (s), 141.9 (s), 167.5 (s); HRMS (ESI):
(R1 =H; R2 = CH3; R3 = PH). Eluent for column chromato- Calcd for C23H22NO2 [M + H]+ 344.1645, found 344.1655.
graphy: hexanes–diethyl ether (9 : 1, v/v); (0.13 g, 36%); colour-
2,4-DIMETHOXY-8-METHYL-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE
13B
less oil; νmax(neat)/cm−1 1587 (m); δH (300 MHz, CDCl3) 2.33 (3 (R1 = H; R2 = CH3; R3 = PH). Eluent for column chromato-
H, s), 2.88 (6 H, s), 7.05–7.09 (2 H, m), 7.14–7.16 (6 H, m), graphy: hexanes–diethyl ether (9 : 1, v/v); (0.18 g, 52%); mp
7.40–7.43 (4 H, m), 7.57–7.60 (1 H, m), 8.49 (1 H, s); δC 173–174 °C (from Et2O); νmax(Nujol)/cm−1 1666 (m); δH
(75 MHz, CDCl3) 17.4, 50.9, 58.5 (s), 100.6 (s), 123.8, 126.6, (400 MHz, CDCl3) 2.32 (3 H, m), 3.07 (3 H, m), 3.99 (3 H, m),
127.0, 127.5, 129.1 (s), 131.1, 131.2, 134.9 (s), 141.3 (s), 141.7 4.65 (1 H, s), 6.94 (1 H, t, J 7.4), 7.05 (1 H, d, J 7.4), 7.12 (1 H,
(s), 170.5; HRMS (ESI): Calcd for C24H24NO2 [M + H]+ d, J 7.4), 7.17–7.21 (8 H, m), 7.30–7.33 (2 H, m); δC (100 MHz,
358.1802, found 358.1817.
CDCl3) 17.3, 54.0, 58.2 (s), 58.6, 85.2, 123.7, 124.1, 126.7,
6-CHLORO-4,4-DIMETHOXY-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 12C 126.9, 127.2, 127.4 (s), 127.9, 128.9, 130.3, 130.7, 133.3 (s),
(R1 = CL; R2 = H; R3 = PH). Eluent for column chromatography: 139.7 (s), 139.8 (s), 141.6 (s), 165.9 (s); HRMS (ESI): Calcd for
hexanes–diethyl ether (9 : 1, v/v); (0.09 g, 24%); colourless oil; C24H24NO2 [M + H]+ 358.1802, found 358.1806.
νmax(neat)/cm−1 1621 (m); δH (300 MHz, CDCl3, 55 °C) 2.91 (6
6-CHLORO-2,4-DIMETHOXY-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE
13C
H, s), 7.12–7.23 (8 H, m), 7.38–7.41 (4 H, m), 7.75 (1 H, d, J (R1 = CL; R2 = H; R3 = PH). Eluent for column chromatography:
2.2), 8.46 (1 H, s); δC (75 MHz, CDCl3, 55 °C) 51.0, 58.8 (s), 99.9 hexanes–diethyl ether (9 : 1, v/v); (0.25 g, 65%); mp 150–151 °C
(s), 126.3, 127.3, 127.7, 128.2, 129.3, 131.0, 131.2 (s), 133.0 (s), (from Et2O); νmax(Nujol)/cm−1 1614 (vs); δH (400 MHz, CDCl3)
9530 | Org. Biomol. Chem., 2012, 10, 9523–9537
This journal is © The Royal Society of Chemistry 2012

Organic & Biomolecular Chemistry
Paper
View Article Online
3.01 (3 H, s), 3.98 (3 H, s), 4.71 (1 H, s), 7.03 (1 H, d, J 8.3), 140.0 (s), 168.2 (s); HRMS (ESI): Calcd for C19H22NO2 [M + H]+
7.13–7.15 (3 H, m), 7.18–7.24 (6 H, m), 7.29–7.33 (3 H, m); δC 296.1645, found 296.1652.
(100 MHz, CDCl3) 54.4, 58.4 (s), 59.3, 84.9, 125.5, 126.3, 127.1,
Preparation of 2-azido-1-[bis(alkylthio)methyl]benzenes 16
127.2, 127.5, 128.1, 128.6, 129.0, 129.8 (s), 130.1 (s), 130.5,
138.5 (s), 140.4 (s), 141.3 (s), 168.0 (s); HRMS (ESI): Calcd for To a solution of the 2-azidobenzaldehyde 8 (8 mmol) in anhy-
C23H21ClNO2 [M + H]+ 378.1255, found 378.1263.
drous chloroform (20 mL) at room temperature ethanethiol
2,4-DIMETHOXY-6-METHYL-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 13D (0.99 g, 16 mmol) or 2-phenylethanethiol (2.21 g, 16 mmol)
(R1 = CH3; R2 = H; R3 = PH). Eluent for column chromato- was added. Next, trimethylchlorosilane (1.19 g, 11 mmol) was
graphy: hexanes–diethyl ether (9 : 1, v/v); (0.09 g, 25%); mp added dropwise for 20 min, and the stirring at room tempera-
176–177 °C (from Et2O); νmax(Nujol)/cm−1 1630 (vs); δH ture was continued for 1 h. Then Na2CO3 5% aqueous solution
(400 MHz, CDCl3) 2.31 (3 H, s), 3.07 (3 H, s), 3.97 (3 H, s), 4.67 (50 mL) was added. The organic phase was separated and
(1 H, s), 6.98–7.01 (2 H, m), 7.09–7.10 (1 H, m), 7.17–7.21 (8 H, dried over anhydrous magnesium sulphate. The solvent was
m), 7.31–7.33 (2 H, m); δC (100 MHz, CDCl3) 21.3, 54.1, 58.5 removed under reduced pressure and the resulting material
(s), 58.8, 85.1, 124.9, 126.5, 126.8, 127.0, 127.2, 127.7 (s), 127.9, was purified by column chromatography on silica gel, using
129.0, 129.3, 130.7, 134.2 (s), 139.3 (s), 139.4 (s), 141.7 (s), hexanes–dichloromethane (7 : 3, v/v) as the eluent.
166.8 (s); HRMS (ESI): Calcd for C24H24NO2 [M + H]+ 358.1802,
found 358.1806.
2-AZIDO-1-[BIS(ETHYLTHIO)METHYL]BENZENE 16A (R1 = H; R2
=
CH3CH2). (2.00 g, 99%); colourless oil; νmax(neat)/cm−1 2121
DIASTEREOISOMER 1 OF 2,4-DIMETHOXY-3-METHYL-3-PHENYL-3,4-DIHY- (vs), 2088 (vs); δH (300 MHz, CDCl3) 1.24 (6 H, t, J 7.4),
DROQUINOLINE 13E (R1 = R2 = H; R3 = CH3). Eluent for column 2.46–2.67 (4 H, m), 5.32 (1 H, s), 7.10–7.17 (2 H, m), 7.28 (1 H,
chromatography: dichloromethane; (0.08 g, 30%); colourless td, J 7.7, 1.6), 7.67 (1 H, dd, J 7.7, 1.6); δC (75 MHz, CDCl3)
oil; νmax(neat)/cm−1 1630 (s); δH (400 MHz, CDCl3) 1.66 (3 H, 14.4, 26.3, 45.6, 117.9, 125.1, 128.8, 129.3, 132.0 (s), 136.7 (s).
s), 3.19 (3 H, s), 3.99 (3 H, s), 4.15 (1 H, s), 6.89–6.94 (2 H, m),
2-AZIDO-5-BROMO-1-[BIS(ETHYLTHIO)METHYL]BENZENE 16B (R1 = BR;
7.00 (1 H, d, J 5.1), 7.06–7.20 (6 H, m); δC (100 MHz, CDCl3) R2 = CH3CH2). (2.47 g, 93%); colourless oil; νmax(neat)/cm−1
20.5, 49.1 (s), 53.9, 56.6, 84.6, 123.9, 125.0, 125.1 (s), 126.2, 2125 (vs), 2086 (vs); δH (400 MHz, CDCl3) 1.25 (6 H, t, J 7.4),
126.9, 128.4, 128.5, 129.3, 141.2 (s), 143.3 (s), 169.0 (s); 2.50–2.58 (2 H, m), 2.60–2.65 (2 H, m), 5.23 (1 H, s), 6.99 (1 H,
HRMS (ESI): Calcd for C18H20NO2 [M + H]+ 282.1489, found d, J 8.5), 7.39 (1 H, dd, J 8.5, 2.3), 7.80 (1 H, d, J 2.3); δC
282.1495.
(75 MHz, CDCl3) 14.3, 26.4, 118.2 (s), 119.5, 131.8, 132.3, 134.1
DIASTEREOISOMER 2 OF 2,4-DIMETHOXY-3-METHYL-3-PHENYL-3,4-DIHY- (s), 136.0 (s).
DROQUINOLINE 13E (R1 = R2 = H; R3 = CH3). Eluent for column
2-AZIDO-1-[BIS(2-PHENYLETHYLTHIO)METHYL]BENZENE 16C (R1 = H; R2
chromatography: dichloromethane; (0.08 g, 30%); colourless = PHCH2CH2). (3.21 g, 99%); colourless oil; νmax(neat)/cm−1
oil; νmax(neat)/cm−1 1625 (s); δH (400 MHz, CDCl3) 1.63 (3 H, 2121 (vs), 2088 (vs); δH (400 MHz, CDCl3) 2.68–2.77 (2 H, m),
s), 3.41 (3 H, s), 3.93 (3 H, s), 4.14 (1 H, s), 7.06 (1 H, td, J 6.8, 2.80–2.88 (6 H, m), 5.29 (1 H, s), 7.09–7.15 (6 H, m), 7.18–7.21
0.8), 7.16–7.23 (6 H, m), 7.25–7.28 (2 H, m); δC (100 MHz, (2 H, m), 7.25–7.28 (5 H, m), 7.64 (1 H, d, J 7.7, 1.4); δC
CDCl3) 21.8, 48.8 (s), 54.0, 59.9, 85.4, 124.7, 124.9, 125.6, (100 MHz, CDCl3) 33.7, 36.0, 46.5, 118.0, 125.2, 126.4, 128.5,
126.9, 127.6, 127.9 (s), 128.4, 128.7, 138.5 (s), 142.3 (s), 169.7 128.6, 129.1, 129.4, 131.7 (s), 136.8 (s), 140.3 (s).
(s); HRMS (ESI): Calcd for C18H20NO2 [M + H]+ 282.1489,
Preparation of 1-[bis(alkylthio)methyl]-2-
triphenylphosphoranylideneaminobenzenes 17
found 282.1499.
DIASTEREOISOMER
1 OF 2,4-DIMETHOXY-3,8-DIMETHYL-3-PHENYL-3,4-
DIHYDROQUINOLINE 13F (R1 = H; R2 = R3 = CH3). Eluent for To a solution of the 2-azido-1-[bis(alkylthio)methyl]benzene 16
column chromatography: hexanes–diethyl ether (9 : 1, v/v); (5 mmol) in anhydrous diethyl ether (20 mL), under nitrogen
(0.07 g, 25%); colourless oil; νmax(neat)/cm−1 1633 (vs); δH at room temperature, triphenylphosphine (1.30 g, 5 mmol) was
(300 MHz, CDCl3) 1.66 (3 H, s), 2.39 (3 H, s), 3.20 (3 H, s), 3.98 added in small portions. The reaction mixture was stirred at
(3 H, s), 4.11 (1 H, s), 6.79–6.85 (2 H, m), 7.05–7.20 (6 H, m); δC room temperature for 16 h. Then the precipitated compounds
(75 MHz, CDCl3) 17.5, 20.5, 48.8 (s), 53.7, 56.8, 85.1, 123.4, 17 were isolated by filtration and washed with anhydrous
124.8 (s), 126.1, 126.2, 126.9, 128.4, 130.8, 133.2 (s), 141.2 (s), diethyl ether (10 mL). These compounds were used in the fol-
141.4 (s), 167.5 (s); HRMS (ESI): Calcd for C19H22NO2 [M + H]+ lowing step without further purification.
296.1645, found 296.1651.
DIASTEREOISOMER
For analytical samples iminophosphoranes 17 were recrys-
OF 2,4-DIMETHOXY-3,8-DIMETHYL-3-PHENYL-3,4- tallized from diethyl ether.
2
DIHYDROQUINOLINE 13F (R1 = H; R2 = R3 = CH3). Eluent for
1-[BIS(ETHYLTHIO)METHYL]-2-TRIPHENYLPHOSPHORANYLIDENEAMINOBEN-
column chromatography: hexanes–diethyl ether (9 : 1, v/v); ZENE 17A (R1 = H; R2 = CH3CH2). (2.07 g, 85%); mp 106–107 °C
(0.07 g, 25%); colourless oil; νmax(neat)/cm−1 1633 (vs); δH (from Et2O); νmax(Nujol)/cm−1 1580 (s), 1110 (s); δH (400 MHz,
(300 MHz, CDCl3) 1.59 (3 H, s), 2.42 (3 H, s), 3.34 (3 H, s), 3.92 CDCl3) 1.18 (6 H, t, J 7.4), 2.48–2.64 (4 H, m), 6.34 (1 H, s), 6.42
(3 H, s), 4.05 (1 H, s), 6.93–7.00 (1 H, m), 7.02 (1 H, d, J 6.0), (1 H, d, J 7.0), 6.66 (1 H, t, J 7.0), 6.74 (1 H, td, J 7.5, 1.8),
7.11–7.14 (1 H, m), 7.16–7.24 (3 H, m), 7.26–7.30 (2 H, m); δC 7.40–7.45 (6 H, m), 7.48–7.52 (3 H, m), 7.55 (1 H, dt, J 7.5, 2.2),
(75 MHz, CDCl3) 17.4, 21.7, 48.4 (s), 53.8, 59.6, 85.9, 123.5, 7.73–7.78 (6 H, m); δC (100 MHz, CDCl3) 14.8, 26.2, 46.5, 117.6,
124.1, 126.8, 127.3 (s), 127.5, 128.5, 130.1, 133.1 (s), 138.8 (s), 120.9 (d, J 10.0), 127.2, 128.4, 128.6 (d, J 11.9), 131.4 (d, J 99.0)
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9523–9537 | 9531

Paper
Organic & Biomolecular Chemistry
View Article Online
(s), 131.7 (d, J 2.4), 132.5 (d, J 9.7), 133.9 (d, J 21.5) (s), 148.4 141.7 (s), 142.0 (s), 174.8 (s); HRMS (ESI): Calcd for
(s); δP (161.9 MHz, CDCl3, H3PO4) 1.9; HRMS (ESI): Calcd for C25H25BrNS2 [M + H]+ 482.0606, found 482.0608.
C29H31NPS2 [M + H]+ 488.1630, found 488.1634.
2,4-BIS(2-PHENYLETHYLTHIO)-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 20C
1-[BIS(ETHYLTHIO)METHYL]-5-BROMO-2-TRIPHENYLPHOSPHORANYLIDENE- (R1 = H; R2 = PHCH2CH2; R3 = PH). (0.55 g, 99%); colourless
AMINOBENZENE 17B (R1 = BR; R2 = CH3CH2). (2.49 g, 88%); mp oil; νmax(neat)/cm−1 1552 (vs); δH (400 MHz, CDCl3) 2.41–2.48
117–118 °C (from Et2O); νmax(Nujol)/cm−1 1436 (vs), 1112 (vs); (2 H, m), 2.63–2.70 (2 H, m), 2.93–2.98 (2 H, m), 3.28–3.42 (2
δH (300 MHz, CDCl3) 1.18 (6 H, t, J 7.4), 2.46–2.65 (4 H, m), H, m), 4.69 (1 H, s), 7.01–7.29 (20 H, m), 7.42–7.48 (3 H, m),
6.23 (1 H, s), 6.25 (1 H, dd, J 8.5, 1.2), 6.81 (1 H, dd, J 8.5, 2.6), 7.54–7.56 (1 H, m); δC (100 MHz, CDCl3) 32.8, 35.2, 35.5, 36.0,
7.41–7.47 (6 H, m), 7.50–7.55 (3 H, m), 7.65 (1 H, t, J 2.6), 55.2, 60.3 (s), 125.4, 126.1, 126.4, 126.7, 127.4, 127.5, 128.1,
7.69–7.76 (6 H, m); δC (75 MHz, CDCl3) 14.7, 26.2, 46.1, 109.5 128.5, 128.7, 129.0 (s), 130.3, 130.5, 137.2 (s), 140.2 (s), 140.9
(s), 122.1 (d, J 10.0), 128.7 (d, J 11.9), 130.1, 130.8 (d, J 99.5) (s), (s), 142.1 (s), 142.9 (s), 173.0 (s); HRMS (ESI): Calcd for
131.0 (d, J 1.0), 131.9 (d, J 2.8), 132.5 (d, J 9.7), 136.2 (d, J 21.8) C35H34NS2 [M + H]+ 556.2127, found 556.2132.
(s), 147.7 (s); δP (161.9 MHz, CDCl3, H3PO4) 3.8; HRMS (ESI):
Calcd for C29H30BrNPS2 [M + H]+ 566.0735, found 566.0740.
Preparation of 2,4-bis(alkylthio)quinolines 20d,e
1-[BIS(2-PHENYLETHYLTHIO)METHYL]-2-TRIPHENYLPHOSPHORANYLIDENE-
To a solution of the 1-[bis(alkylthio)methyl]-2-triphenylphos-
AMINOBENZENE 17C (R1 = H; R2 = PHCH2CH2). (2.24 g, 70%); mp
phoranylideneaminobenzene 17 (1 mmol) in anhydrous
109–110 °C (from Et2O); νmax(Nujol)/cm−1 1436 (vs), 1110 (vs);
dichloromethane (20 mL) a solution of methylphenylketene
δH (400 MHz, CDCl3) 2.75–2.89 (8 H, m), 6.42 (1 H, d, J 7.5),
(0.13 g, 1 mmol) in the same solvent (5 mL) was added. The
6.52 (1 H, s), 6.68 (1 H, t, J 7.5), 6.76 (1 H, td, J 7.5, 1.7),
reaction mixture was stirred under nitrogen at room tempera-
7.00–7.02 (4 H, m), 7.10–7.14 (6 H, m), 7.34–7.39 (6 H, m),
ture for 3–16 h. Next, the solvent was removed under reduced
7.45–7.49 (3 H, m), 7.59 (1 H, dt, J 7.5, 2.1), 7.69–7.74 (6 H, m);
pressure, and the resulting crude material was purified by
δC (100 MHz, CDCl3) 33.7, 36.3, 46.9, 117.7, 120.9 (d, J 10.1),
column chromatography on silica gel, using hexanes–diethyl
126.0, 127.5, 128.3, 128.6, 128.7 (d, J 12.0), 131.2 (d, J 98.9) (s),
ether (9 : 1, v/v) as the eluent.
131.7, 132.5 (d, J 9.6), 133.5 (d, J 22.0) (s), 141.1 (s), 148.6 (s); δP
CIS-2,4-BIS(ETHYLTHIO)-3-METHYL-3-PHENYL-3,4-DIHYDROQUINOLINE 20D
(161.9 MHz, CDCl3, H3PO4) 3.0; HRMS (ESI): Calcd for
(R1 = H; R2 = CH3CH2; R3 = CH3). (0.33 g, 97%); colourless oil;
C41H39NPS2 [M + H]+ 640.2256, found 640.2264.
νmax(neat)/cm−1 1581 (vs); δH (400 MHz, CDCl3) 1.14 (3 H, t, J
7.4), 1.30 (3 H, t, J 7.4), 1.87 (3 H, s), 2.21–2.32 (2 H, m), 3.12 (2
H, q, J 7.2), 3.92 (1 H, s), 7.11–7.15 (1 H, m), 7.16–7.19 (3
H, m), 7.24–7.29 (3 H, m), 7.33 (1 H, d, J 7.6), 7.45–7.47 (1 H,
m); δC (100 MHz, CDCl3) 13.9, 14.8, 24.6, 24.9, 27.6, 49.9 (s),
55.4, 125.7, 126.2, 127.5, 127.6, 127.7 (s), 127.8, 128.0, 128.2,
138.0 (s), 142.9 (s), 175.1 (s); HRMS (ESI): Calcd for C20H24NS2
[M + H]+ 342.1345, found 342.1352.
CIS-2,4-BIS(ETHYLTHIO)-6-BROMO-3-METHYL-3-PHENYL-3,4-DIHYDROQUINO-
LINE 20E (R1 = BR; R2 = CH3CH2; R3 = CH3). (0.30 g, 72%); mp
94–95 °C (from Et2O); νmax(Nujol)/cm−1 1593 (vs); δH
(300 MHz, CDCl3) 1.19 (3 H, t, J 7.4), 1.29 (3 H, t, J 7.4), 1.87 (3
H, s), 2.33 (2 H, q, J 7.4), 3.09 (2 H, q, J 7.4), 3.86 (1 H, s),
7.18–7.26 (6 H, m), 7.40 (1 H, dd, J 8.2, 2.0), 7.62–7.63 (1 H,
m); δC (75 MHz, CDCl3) 13.8, 14.8, 24.6, 25.0, 27.9, 49.6 (s),
55.1, 119.3 (s), 127.2, 127.7, 127.8, 127.9, 130.2 (s), 130.8,
131.2, 137.5 (s), 142.1 (s), 176.2 (s); HRMS (ESI): Calcd for
C20H23BrNS2 [M + H]+ 420.0450, found 420.0453.
Preparation of 2,4-bis(alkylthio)quinolines 20a–c
To a solution of the 1-[bis(alkylthio)methyl]-2-triphenylphos-
phoranylideneaminobenzene 17 (1 mmol) in anhydrous
toluene (20 mL) a solution of diphenylketene (0.19 g, 1 mmol)
in the same solvent (5 mL) was added. The reaction mixture
was stirred under nitrogen at room temperature for 30 min.
Next, the solution was heated at reflux temperature for 1 h.
After cooling at room temperature, the solvent was removed
under reduced pressure, and the resulting crude material was
purified by column chromatography on silica gel, using
hexanes–diethyl ether (9 : 1, v/v) as the eluent.
2,4-BIS(ETHYLTHIO)-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 20A (R1
=
-
H; R2 = CH3CH2; R3 = PH). (0.38 g, 94%); colourless oil; νmax
(neat)/cm−1 1552 (vs); δH (400 MHz, CDCl3) 1.15 (3 H, t, J 7.4),
1.35 (3 H, t, J 7.4), 2.27–2.38 (2 H, m), 3.10–3.25 (2 H, m), 4.69
(1 H, s), 7.10–7.14 (1 H, m), 7.20–7.34 (10 H, m), 7.47–7.50 (2
H, m), 7.63 (1 H, d, J 7.4); δC (100 MHz, CDCl3) 13.7, 14.5, 26.0,
28.3, 54.5, 60.2 (s), 125.2, 125.9, 126.6, 127.3, 127.4, 127.5,
128.0, 129.1 (s), 130.3, 130.4, 137.3 (s), 142.1 (s), 143.1 (s),
Preparation of quinoline 21
173.7 (s); HRMS (ESI): Calcd for C25H26NS2 [M + H]+ 404.1501, To a solution of 1-[bis(ethylthio)methyl]-2-triphenylphosphora-
found 404.1504. nylideneaminobenzene 17a (0.25 g, 0.5 mmol) in anhydrous
2,4-BIS(ETHYLTHIO)-6-BROMO-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 20B toluene, heated at 80 °C, under nitrogen, a solution of
(R1 = BR; R2 = CH3CH2; R3 = PH). (0.39 g, 81%); colourless oil; S-phenyl 2-diazoethanethiolate (0.1 g, 0.5 mmol) in the same
νmax(neat)/cm−1 1566 (vs); δH (400 MHz, CDCl3) 1.10 (3 H, t, J solvent (10 mL) was added dropwise for 10 min, and the
7.4), 1.28 (3 H, t, J 7.4), 2.22–2.34 (2 H, m), 3.03–3.17 (2 H, m), heating at 80 °C was continued for 1 h. After cooling at room
4.58 (1 H, s), 7.04–7.07 (1 H, m), 7.17–7.19 (3 H, m), 7.26–7.32 temperature the solvent was removed under reduced pressure.
(6 H, m), 7.39–7.43 (2 H, m), 7.77 (1 H, s); δC (100 MHz, CDCl3) The resulting material was purified by column chromato-
13.6, 14.4, 26.0, 28.5, 54.3, 59.9 (s), 119.0 (s), 126.8, 127.5, graphy on silica gel using hexanes–diethyl ether (9.5 : 0.5, v/v)
127.6, 128.6, 129.5, 130.2, 130.3, 131.0, 131.5 (s), 136.7 (s), as the eluent.
9532 | Org. Biomol. Chem., 2012, 10, 9523–9537
This journal is © The Royal Society of Chemistry 2012

Organic & Biomolecular Chemistry
Paper
View Article Online
2-ETHYLTHIO-3-PHENYLTHIOQUINOLINE 21. (0.14 g, 91%); colour- Preparation of 1-[(1′-methoxy)methylthiomethyl]-2-
less oil; νmax(neat)/cm−1 1612 (s); δH (400 MHz, CDCl3) 1.42 (3 triphenylphosphoranylideneaminobenzene 26
H, t, J 7.6), 3.33 (2 H, q, J 7.6), 7.23–7.35 (5 H, m), 7.38 (1 H, d,
To
a
solution of 2-azido-1-[methoxy(methylthio)methyl]-
J 8.0), 7.57 (1 H, d, J 8.0), 7.61 (1 H, t, J 8.0), 7.84 (1 H, s), 7.92
(1 H, d, J 8.0); δC (100 MHz, CDCl3) 14.2, 25.2, 125.5, 126.1 (s),
127.2, 127.5, 127.8, 128.4 (s), 129.5, 129.8, 130.7, 134.1 (s),
138.5, 147.2 (s), 160.9 (s); HRMS (ESI): Calcd for C17H16NS2
[M + H]+ 298.0719, found 298.0725.
benzene 25 (0.62 g, 3 mmol) in anhydrous diethyl ether
(15 mL), under nitrogen at room temperature, triphenylpho-
sphine (0.80 g, 3 mmol) was added in small portions. The reac-
tion mixture was stirred at room temperature for 16 h. Then
the solvent was removed under reduced pressure and the
crude material was purified by column chromatography on
silica gel deactivated with triethylamine, using hexanes–
diethyl ether (1 : 1, v/v) as the eluent.
Preparation of xanthate 24
1-[(1′-METHOXY)METHYLTHIOMETHYL]-2-TRIPHENYLPHOSPHORANYLIDENE-
AMINOBENZENE 26. (0.88 g, 66%); colourless oil; νmax(neat)/cm−1
1591 (vs), 1351 (vs), 1107 (vs); δH (300 MHz, CDCl3) 1.99 (3 H,
s), 3.45 (3 H, s), 6.22 (1 H, s), 6.43–6.46 (1 H, m), 6.67 (1 H, t, J
7.5), 6.80 (1 H, td, J 7.5, 1.7), 7.32–7.35 (1 H, m), 7.40–7.51 (9
H, m), 7.72–7.79 (6 H, m); δC (75 MHz, CDCl3) 11.6, 56.4, 84.5,
117.0, 121.4 (d, J 9.7), 126.2 (d, J 1.7), 127.5, 128.6 (d, J 11.9),
131.5 (d, J 99.1) (s), 131.6 (d, J 2.8), 132.6 (d, J 9.7), 132.8 (d, J
20.4 (s), 147.7 (s); δP (161.9 MHz, CDCl3, H3PO4) 2.2; HRMS
(ESI): Calcd for C27H27NOPS [M + H]+ 444.1545, found
444.1564.
A mixture of 2-azido-1-(dimethoxymethyl)benzene 9a (2.91 g,
15 mmol) and thionyl chloride (15 mL) was heated at reflux
temperature for 30 min, followed by stirring at room tempera-
ture for 16 h. Then the remaining thionyl chloride was
removed to dryness under reduced pressure to give 2-azido-1-
[(1′-chloro)methoxymethyl]benzene, which was used in the fol-
lowing step without further purification.
A mixture of 2-azido-1-[(1′-chloro)methoxymethyl]benzene
(2.97 g, 15 mmol) and potassium O-ethyl dithiocarbonate
(2.43 g, 15 mmol) in anhydrous diethyl ether (30 mL) was
heated at reflux temperature for 1.5 h. After cooling at room
temperature water (50 mL) was added. The organic phase was
separated and dried over anhydrous magnesium sulphate. The
solvent was removed under reduced pressure and the crude
Preparation of 4-methoxy-2-methylthioquinolines 28
material was purified by column chromatography on silica gel, To a solution of 1-[(1′-methoxy)methylthiomethyl]-2-triphenyl-
using hexanes–diethyl ether (9.5 : 0.5, v/v) as the eluent. phosphoranylideneaminobenzene 26 (0.58 g, 1.3 mmol) in
XANTHATE 24. (3.27 g, 77%); colourless oil; νmax(neat)/cm−1 anhydrous toluene (15 mL) a solution of methylphenylketene
2127 (vs), 2096 (vs); δH (300 MHz, CDCl3) 1.45 (3 H, t, J 7.1), (0.17 g, 1.3 mmol) or diphenylketene (0.25 g, 1.3 mmol) in the
3.52 (3 H, s), 4.70 (2 H, q, J 7.1), 6.60 (1 H, s), 7.12–7.16 (2 H, same solvent (5 mL) was added. The reaction mixture was
m), 7.32–7.38 (1 H, m), 7.51–7.54 (1 H, m); δC (75 MHz, CDCl3) stirred under nitrogen at room temperature for 30 min. Next,
13.8, 57.4, 70.0, 87.6, 118.3, 125.0, 127.9, 129.0 (s), 129.9, 136.8 the solution was heated at reflux temperature for 1 h. After
(s), 212.6 (s).
cooling at room temperature, the solvent was removed under
reduced pressure, and the resulting crude material was puri-
fied by column chromatography on silica gel, using hexanes–
diethyl ether (9 : 1, v/v) as the eluent.
Preparation of 2-azido-1-[(1′-methoxy)methylthiomethyl]-
benzene 25
4-METHOXY-2-METHYLTHIO-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 28A
(R1 = PH). (0.37 g, 80%); mp 146–147 °C (from Et2O); νmax
-
To a solution of xanthate 24 (1.42 g, 5 mmol) in anhydrous (Nujol)/cm−1 1554 (vs), 1539 (vs); δH (300 MHz, CDCl3) 2.49
diethyl ether (25 mL), at 15 °C, a solution of methyl iodide (3 H, s), 3.36 (3 H, s), 4.98 (1 H, s), 6.96 (1 H, td, J 7.3, 1.0),
(1.06 g, 7.5 mmol) in the same solvent (20 mL) was added 7.09 (1 H, d, J 7.3), 7.14–7.23 (10 H, m), 7.44–7.46 (2 H, m); δC
dropwise for 20 min. Next, the reaction mixture was stirred at (100 MHz, CDCl3) 14.8, 58.7, 60.6 (s), 83.8, 125.0, 125.3, 125.4,
room temperature for 30 min and sodium methoxide (0.49 g, 127.3, 127.4, 127.9, 128.0 (s), 128.6, 129.6, 131.2, 138.7 (s),
9 mmol) was added. The stirring at room temperature was con- 140.7 (s), 143.1 (s), 175.2 (s); HRMS (ESI): Calcd for C23H22NOS
tinued for 5 h before the addition of water (25 mL). The [M + H]+ 360.1417, found 360.1421.
organic phase was separated and dried over anhydrous mag-
DIASTEREOISOMER 1 OF 4-METHOXY-3-METHYL-2-METHYLTHIO-3-PHENYL-
nesium sulphate. The solvent was removed under reduced 3,4-DIHYDROQUINOLINE 28B (R1
= CH3). (0.19 g, 50%); mp
pressure and the resulting oil was purified by column chrom- 100–101 °C (from Et2O); νmax(Nujol)/cm−1 1554 (vs); δH
atography on silica gel, using hexanes–diethyl ether (9.5 : 0.5, (400 MHz, CDCl3) 1.59 (3 H, s), 2.48 (3 H, s), 3.31 (3 H, s), 4.01
v/v) as the eluent.
(1 H, s), 7.11 (1 H, td, J 7.2, 1.4), 7.15–7.17 (1 H, m), 7.21–7.25
2-AZIDO-1-[(1′-METHOXY)METHYLTHIOMETHYL]BENZENE 25. (0.75 g, (3 H, m), 7.31 (1 H, td, J 7.7, 1.7), 7.35 (1 H, dd, J 7.7, 1.3),
72%); colourless oil; νmax(neat)/cm−1 2127 (vs); δH (300 MHz, 7.39–7.42 (2 H, m); δC (100 MHz, CDCl3) 13.8, 22.2, 51.2 (s),
CDCl3) 1.95 (3 H, s), 3.44 (3 H, s), 5.57 (1 H, s), 7.11–7.16 (2 H, 59.1, 84.3, 125.7, 125.8, 126.3, 127.0 (s), 127.3, 127.4, 128.9,
m), 7.28–7.34 (1 H, m), 7.45–7.48 (1 H, m); δC (75 MHz, CDCl3) 129.4, 138.1 (s), 142.4 (s), 176.6 (s); HRMS (ESI): Calcd for
10.9, 56.2, 82.0, 118.1, 124.3, 127.2, 128.8, 130.6 (s), 135.9 (s).
C18H20NOS [M + H]+ 298.1260, found 298.1267.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9523–9537 | 9533

Paper
Organic & Biomolecular Chemistry
View Article Online
DIASTEREOISOMER 2 OF 4-METHOXY-3-METHYL-2-METHYLTHIO-3-PHENYL- temperature for 16 h. Then the precipitated compounds 31
3,4-DIHYDROQUINOLINE 28B (R1 = CH3). (0.09 g, 24%); yellow oil; were isolated by filtration and washed with anhydrous diethyl
νmax(neat)/cm−1 1556 (vs); δH (400 MHz, CDCl3) 1.71 (3 H, s), ether (10 mL). These compounds were used in the following
2.55 (3 H, s), 3.18 (3 H, s), 4.29 (1 H, s), 7.02–7.06 (1 H, m), step without further purification.
7.07–7.09 (1 H, m), 7.17–7.30 (6 H, m), 7.32–7.34 (1 H, m); δC
For analytical samples iminophosphoranes 31 were recrys-
(100 MHz, CDCl3) 13.5, 19.9, 51.5 (s), 57.7, 84.4, 125.3, 125.5, tallized from diethyl ether.
125.6 (s), 127.1, 127.2, 127.6, 128.3, 129.3, 141.2 (s), 142.9 (s),
1-METHOXYMETHYL-2-TRIPHENYLPHOSPHORANYLIDENEAMINOBENZENE 31A
176.0 (s); HRMS (ESI): Calcd for C18H20NOS [M + H]+ 298.1260, (R1 = R2 = H). (1.81 g, 91%); mp 127–128 °C (from Et2O); νmax
-
found 298.1265.
(Nujol)/cm−1 1324 (vs), 1105 (vs); δH (400 MHz, CDCl3) 3.45
(3 H, s), 4.83 (2 H, s), 6.46 (1 H, dd, J 7.9, 1.1), 6.68 (1 H, d, J
7.3), 6.81 (1 H, t, J 7.3), 7.30 (1 H, d, J 7.3), 7.40–7.45 (6 H, m),
Preparation of azido-methoxymethylbenzenes 30
To a suspension of potassium hydroxide (1.12 g, 20 mmol) in 7.47–7.52 (3 H, m), 7.72–7.77 (6 H, m); δC (75 MHz, CDCl3)
dimethylsulfoxide (20 mL) the corresponding 2-azidobenzyl 58.3, 72.2, 117.4, 121.1 (d, J 9.8), 127.2, 127.7, 128.6 (d, J 12.0),
alcohol 29 (5 mmol) and methyl iodide (1.42 g, 10 mmol) were 131.6 (d, J 2.5), 131.7 (d, J 99.6) (s), 132.4 (s), 132.6 (d, J 9.6),
added, and the reaction mixture was stirred at room tempera- 148.8 (s); δP (161.9 MHz, CDCl3, H3PO4) 0.9; HRMS (ESI): Calcd
ture for 30 min. Next, water was added (100 mL) and the for C26H25NOP [M + H]+ 398.1668, found 398.1670.
mixture was extracted with dichloromethane (3 × 50 mL). The
1-METHOXYMETHYL-3-METHYL-2-TRIPHENYLPHOSPHORANYLIDENEAMINOBEN-
combined organic phase was washed with water (3 × 50 mL) ZENE 31B (R1 = H; R2 = CH3). (1.54 g, 75%); mp 100–101 °C
and dried over anhydrous magnesium sulphate. The solvent (from Et2O); νmax(Nujol)/cm−1 1379 (vs), 1109 (vs); δH
was removed under reduced pressure and the resulting (400 MHz, CDCl3) 1.92 (3 H, d, J 1.5), 3.00 (3 H, s); 4.22 (2 H,
material was purified by column chromatography on silica gel. s); 6.72 (1 H, td, J 7.4, 2.4), 6.94 (1 H, d, J 7.4), 7.09 (1 H, d; J
1-AZIDO-2-METHOXYMETHYLBENZENE 30A (R1 = R2 = H). Eluent for 7.4), 7.37–7.42 (6 H, m), 7.47–7.49 (3 H, m), 7.55–7.61 (6 H, m);
column chromatography: hexanes–diethyl ether (4 : 1, v/v); δC (100 MHz, CDCl3) 21.0, 57.7, 73.1, 119.0 (d, J 3.3), 125.5 (d, J
(0.77 g, 94%); yellow oil; νmax(neat)/cm−1 2125 (vs); δH 2.2), 128.4 (d, J 12.1), 129.2 (d, J 2.7), 131.3 (d, J 2.5), 132.4 (d, J
(400 MHz, CDCl3) 3.41 (3 H, s), 4.42 (2 H, s), 7.12–7.17 (2 H, 9.5), 132.8 (d, J 101.1) (s), 133.1 (d, J 7.4) (s), 133.4 (d, J 6.2) (s),
m), 7.31–7.36 (1 H, m), 7.38–7.41 (1 H, m); δC (100 MHz, 146.4 (d, J 2.1) (s); δP (161.9 MHz, CDCl3, H3PO4) – 4.5; HRMS
CDCl3) 58.4, 69.9, 118.0, 124.7, 129.0, 129.5 (s), 129.7, (ESI): Calcd for C27H27NOP [M + H]+ 412.1825, found 412.1830.
138.0 (s).
4-CHLORO-2-METHOXYMETHYL-1-TRIPHENYLPHOSPHORANYLIDENEAMINO-
2-AZIDO-1-METHOXYMETHYL-3-METHYLBENZENE 30B (R1 = H; R2
=
BENZENE 31C (R1 = CL; R2 = H). (1.88 g, 87%); mp 103–104 °C
CH3). Eluent for column chromatography: hexanes–diethyl (from Et2O); νmax(Nujol)/cm−1 1374 (vs), 1105 (vs); δH
ether (9 : 1, v/v); (0.50 g, 56%); yellow oil; νmax(neat)/cm−1 2107 (400 MHz, CDCl3) 3.45 (3 H, s), 4.75 (2 H, s), 6.33 (1 H, dd, J
(vs); δH (300 MHz, CDCl3) 2.36 (3 H, s), 3.40 (3 H, s), 4.49 (2 H, 8.4, 1.4), 6.74 (1 H, dd, J 8.4, 2.7), 7.28 (1 H, t, J 2.7), 7.41–7.46
s), 7.02–7.10 (2 H, m), 7.18–7.21 (1 H, m); δC (75 MHz, CDCl3) (6 H, m), 7.49–7.54 (3 H, m), 7.68–7.74 (6 H, m); δC (100 MHz,
17.9, 58.2, 71.1, 125.6, 127.5, 130.8, 131.8 (s), 132.3 (s), CDCl3) 58.5, 71.7, 121.7 (d, J 9.6), 122.2 (s), 126.7, 127.1, 128.7
136.6 (s).
(d, J 11.9), 131.2 (d, J 99.1) (s), 131.8 (d, J 2.5), 132.5 (d, J 9.6),
134.3 (d, J 20.7) (s), 147.3 (s); δP (161.9 MHz, CDCl3, H3PO4)
1-AZIDO-4-CHLORO-2-METHOXYMETHYLBENZENE 30C (R1 = CL; R2
=
H). Eluent for column chromatography: hexanes–diethyl ether 2.3; HRMS (ESI): Calcd for C26H23ClNOP [M + H]+ 432.1279,
(9 : 1, v/v); (0.70 g, 71%); yellow oil; νmax(neat)/cm−1 2131 (vs), found 432.1291.
2090 (vs); δH (300 MHz, CDCl3) 3.39 (3 H, s), 4.32 (2 H, s), 6.99
2-METHOXYMETHYL-4-METHYL-1-TRIPHENYLPHOSPHORANYLIDENEAMINO-
(1 H, dd, J 8.5), 7.22 (1 H, dd, J 8.5, 2.4), 7.37 (1 H, d, J 2.4); δC BENZENE 31D (R1 = CH3; R2 = H). (1.81 g, 88%); mp 119–121 °C
(75 MHz, CDCl3) 58.4, 69.1, 118.9, 128.4, 128.8, 130.1 (s), (from Et2O); νmax(Nujol)/cm−1 1437 (vs), 1107 (vs); δH
131.3 (s), 135.9 (s).
(400 MHz, CDCl3) 2.20 (3 H, s), 3.45 (3 H, s), 4.80 (2 H, s), 6.37
(1 H, d, J 8.0), 6.62 (1 H, dd, J 8.0, 1.7), 7.13 (1 H, s), 7.39–7.44
1-AZIDO-2-METHOXYMETHYL-4-METHYLBENZENE 30D (R1 = CH3; R2
=
H). Eluent for column chromatography: hexanes–diethyl ether (6 H, m), 7.47–7.51 (3 H, m), 7.71–7.76 (6 H, m); δC (100 MHz,
(7 : 3, v/v); (0.57 g, 64%); yellow oil; νmax(neat)/cm−1 2142 (vs), CDCl3) 20.7, 58.3, 72.1, 120.8 (d, J 9.4), 126.4 (s), 127.7, 128.4,
2084 (vs); δH (400 MHz, CDCl3) 2.32 (3 H, s), 3.40 (3 H, s), 4.38 128.5 (d, J 11.9), 131.5 (d, J 2.5), 131.8 (d, J 99.1) (s), 132.1 (s),
(2 H, s), 7.03 (1 H, d, J 8.1), 7.12 (1 H, d, J 81, 1.7), 7.19–7.20 (1 132.6 (d, J 9.6), 146.0 (s); δP (161.9 MHz, CDCl3, H3PO4) 0.5;
H, m); δC (100 MHz, CDCl3) 20.8, 58.5, 69.9, 118.0, 129.1 (s), HRMS (ESI): Calcd for C27H27NOP [M + H]+ 412.1825, found
129.6, 130.4, 134.5 (s), 135.2 (s).
412.1828.
Preparation of methoxymethyl-
Preparation of 4-methoxyquinolines 34
triphenylphosphoranylideneaminobenzenes 31
To a solution of methoxymethyl-triphenylphosphoranylidene-
To a solution of the azido-methoxymethylbenzene 30 (5 mmol) aminobenzene 31 (1.5 mmol) in anhydrous toluene (15 mL) a
in anhydrous diethyl ether (20 mL), under nitrogen at room solution of methylphenylketene (0.2 g, 1.5 mmol) or diphe-
temperature, triphenylphosphine (1.3 g, 5 mmol) was added in nylketene (0.29 g, 1.5 mmol) in the same solvent (5 mL) was
small portions. The reaction mixture was stirred at room added. The reaction mixture was stirred under nitrogen at
9534 | Org. Biomol. Chem., 2012, 10, 9523–9537
This journal is © The Royal Society of Chemistry 2012

Organic & Biomolecular Chemistry
Paper
View Article Online
room temperature for 30 min and next heated at reflux temp- νmax(neat)/cm−1 1620 (s); Major Diastereoisomer: δH (300 MHz,
erature for 12–36 h. Then, after cooling at room temperature, CDCl3) 1.33 (3 H, s), 2.53 (3 H, s), 2.99 (3 H, s), 3.88 (1 H, d, J
the solvent was removed under reduced pressure, and the 1.5), 8.23 (1 H, d, J 1.5); Minor Diastereoisomer: δH (300 MHz,
resulting crude material was purified by column chromato- CDCl3) 1.57 (3 H, s), 2.51 (3 H, s), 3.15 (3 H, s), 4.22 (1 H, d, J
graphy on silica gel.
1.5), 7.92 (1 H, d, J 1.5); HRMS (ESI): Calcd for C18H20NO
4-METHOXY-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 34A (R1 = R2 = H; [M + H]+ 266.1539, found 266.1545.
R3 = PH). Eluent for column chromatography: hexanes–diethyl
Preparation of 1-azido-2-(ethylthio)methylbenzene 36
ether (4 : 1, v/v); (0.24 g, 51%); colourless oil; νmax(neat)/cm−1
1596 (s); δH (400 MHz, CDCl3) 3.08 (3 H, s), 4.66 (1 H, s), To a solution of potassium hydroxide (0.44 g, 8 mmol) in
7.14–7.34 (14 H, m), 8.50 (1 H, d, J 1.1); δC (100 MHz, CDCl3) dimethylsulfoxide (20 mL) was added, dropwise for 20 min, a
54.9 (s), 58.0, 81.9, 126.9, 127.0, 127.1, 127.2 (s), 127.4, 127.7, mixture of 2-azidobenzyl iodide 35 (4.16 g, 16 mmol) and etha-
128.1, 128.3, 128.4, 129.2, 129.3, 141.3 (s), 142.1 (s), 142.2 (s), nethiol (0.48 g, 8 mmol) in the same solvent (25 mL). The reac-
167.2; HRMS (ESI): Calcd for C22H20NO [M + H]+ 314.1539, tion mixture was stirred at room temperature for 2 h. Then
found 314.1545.
water (40 mL) and dichloromethane (40 mL) were added. The
4-METHOXY-8-METHYL-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 34B (R1 = organic phase was separated and dried over anhydrous mag-
H; R2 = CH3; R3 = PH). Eluent for column chromatography: nesium sulphate. The solvent was removed under reduced
hexanes–diethyl ether (9 : 1, v/v); (0.49 g, 99%); mp 95–96 °C pressure and the residue was purified by column chromato-
(from Et2O); νmax(Nujol)/cm−1 1620 (s); δH (400 MHz, CDCl3) graphy on silica gel, using hexanes–ethyl acetate (9 : 1, v/v) as
2.44 (3 H, s), 3.07 (3 H, s), 4.59 (d, 1 H, J 1.1), 7.10–7.18 (8 H, the eluent.
m), 7.19–7.24 (1 H, m), 7.26–7.30 (2 H, m), 7.32–7.35 (2 H, m),
1-AZIDO-2-(ETHYLTHIO)METHYLBENZENE 36. (1.28 g, 83%); yellow
8.55 (1 H, d, J 1.1); δC (100 MHz, CDCl3) 17.6, 54.3 (s), 57.9, oil; νmax(neat)/cm−1 2127 (vs); δH (400 MHz, CDCl3) 1.25 (3 H,
82.0, 124.9, 126.6 (s), 126.8, 127.0, 127.3, 128.1, 128.2, 128.3, t, J 7.4), 2.49 (2 H, q, J 7.4), 3.68 (2 H, s), 7.08 (1 H, td, J 7.7,
129.2, 131.1, 135.5 (s), 140.0 (s), 141.6 (s), 142.2 (s), 165.8; 1.1), 7.14 (1 H, dd, J 7.7, 1.1), 7.25–7.30 (2 H, m); δC (100 MHz,
HRMS (ESI): Calcd for C23H22NO [M + H]+ 328.1696, found CDCl3) 14.5, 25.8, 31.0, 118.4, 124.7, 128.4, 130.2 (s), 138.2 (s).
328.1702.
Preparation of 2-(ethylthio)methyl-1-
triphenylphosphoranylideneaminobenzene 37
6-CHLORO-4-METHOXY-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 34C (R1 =
CL; R2 = H; R3 = PH). Eluent for column chromatography:
hexanes–diethyl ether (7 : 3, v/v); (0.36 g, 70%); mp 125–126 °C To a solution of 1-azido-2-(ethylthio)methylbenzene 36 (1.16 g,
(from Et2O); νmax(Nujol)/cm−1 1620 (s); δH (400 MHz, CDCl3) 6 mmol) in anhydrous diethyl ether (20 mL), under nitrogen at
3.09 (3 H, s), 4.64 (1 H, s), 7.14–7.32 (13 H, m), 8.49 (1 H, s); δC room temperature, triphenylphosphine (1.55 g, 6 mmol) was
(100 MHz, CDCl3) 54.6 (s), 58.6, 81.8, 126.6, 127.1, 127.3, added in small portions. The reaction mixture was stirred at
128.2, 128.3, 128.5, 128.7, 129.1, 129.2, 133.1 (s), 140.4 (s), room temperature for 16 h. Then the solvent was removed
140.5 (s), 142.0 (s), 167.7; HRMS (ESI): Calcd for C22H19ClNO under reduced pressure and the crude material was purified
[M + H]+ 348.1150, found 348.1155.
by column chromatography on silica gel deactivated with tri-
4-METHOXY-6-METHYL-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE 34D (R1 = ethylamine, using hexanes–diethyl ether (1 : 1, v/v) as the
CH3; R2 = H; R3 = PH). Eluent for column chromatography: eluent.
hexanes–diethyl ether (4 : 1, v/v); (0.30 g, 61%); mp 123–124 °C
2-(ETHYLTHIO)METHYL-1-TRIPHENYLPHOSPHORANYLIDENEAMINOBENZENE
(from Et2O); νmax(Nujol)/cm−1 1624 (s); δH (400 MHz, CDCl3) 37. (2.46 g, 96%); yellow oil; νmax(neat)/cm−1 1348 (vs), 1112
2.36 (3 H, s), 3.08 (3 H, s), 4.61 (1 H, s), 7.09–7.34 (13 H, m), (vs); δH (400 MHz, CDCl3) 1.20 (3 H, t, J 7.4), 2.51 (2 H, q, J
8.45 (1 H, s); δC (100 MHz, CDCl3) 21.5, 54.8 (s), 58.0, 81.8, 7.4), 4.08 (2 H, s), 6.46 (1 H, d, J 7.5), 6.61 (1 H, t, J 7.5), 6.77 (1
126.7 (s), 126.9, 127.0, 127.3, 127.7, 128.1, 128.3, 128.4, 129.3, H, t, J 7.5), 7.22–7.24 (1 H, m), 7.38–7.42 (6 H, m), 7.45–7.48 (3
129.7, 137.7 (s), 139.7 (s), 141.4 (s), 142.2 (s), 166.1; HRMS H, m), 7.74–7.79 (6 H, m); δC (100 MHz, CDCl3) 15.0, 25.7,
(ESI): Calcd for C23H22NO [M + H]+ 328.1696, found 328.1701.
33.1, 117.1, 121.2 (d, J 9.9), 126.9, 128.5 (d, J 11.9), 129.6, 131.5
4-METHOXY-3-METHYL-3-PHENYL-3,4-DIHYDROQUINOLINE 34E (R1 = R2 (d, J 98.8) (s), 131.6 (d, J 2.0), 132.6 (d, J 9.6), 132.7 (s), 149.4
= H; R3 = CH3) (MIXTURE OF DIASTEREOISOMERS IN A 2 : 1 CIS/TRANS (s); δP (161.9 MHz, CDCl3, H3PO4) 1.1; HRMS (ESI): Calcd for
RATIO). Eluent for column chromatography: hexanes–diethyl C27H26NPS [M + H]+ 428.1596, found 428.1602.
ether (9 : 1, v/v); (0.26 g, 69%); colourless oil; νmax(neat)/cm−1
Preparation of 4-ethylthio-3,3-diphenyl-3,4-dihydroquinoline
39
1609 (s); Major Diastereoisomer: δH (300 MHz, CDCl3) 1.27 (3
H, s), 2.93 (3 H, s), 3.85 (1 H, s), 8.10 (1 H, s); Minor Diastereo-
isomer: δH (300 MHz, CDCl3) 1.49 (3 H, s), 3.06 (3 H, s), 4.18 (1 To a solution of 2-(ethylthio)methyl-1-triphenylphosphoranyl-
H, s), 7.83 (1 H, s); HRMS (ESI): Calcd for C17H18NO [M + H]+ ideneaminobenzene 37 (0.51 g, 1.2 mmol) in anhydrous ortho-
252.1383, found 252.1390.
xylene (15 mL) a solution of diphenylketene (0.23 g, 1.2 mmol)
4-METHOXY-3,8-DIMETHYL-3-PHENYL-3,4-DIHYDROQUINOLINE 34F (R1 = in the same solvent (5 mL) was added. The reaction mixture
H; R2 = CH3; R3 = CH3) (MIXTURE OF DIASTEREOISOMERS IN A 2 : 1 CIS/ was stirred under nitrogen at room temperature for 30 min
TRANS RATIO). Eluent for column chromatography: hexanes– and next heated at reflux temperature for 24 h. Then, after
diethyl ether (9 : 1, v/v); (0.20 g, 50%); colourless oil; cooling at room temperature, the solvent was removed under
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9523–9537 | 9535

Paper
Organic & Biomolecular Chemistry
View Article Online
reduced pressure, and the resulting crude material was puri-
fied by column chromatography on silica gel, using hexanes–
diethyl ether (7 : 3, v/v) as the eluent.
(m) M. C. Haibach, I. Deb, C. Kanta De and D. Seidel, J. Am.
Chem. Soc., 2011, 133, 2100; (n) B. Bolte and F. Gagosz,
J. Am. Chem. Soc., 2011, 133, 7696; (o) M. Alajarin,
M. Marin-Luna and A. Vidal, Adv. Synth. Catal., 2011, 353,
557; (p) J. Barluenga, M. Fañanás-Mastral, A. Fernández
and F. Aznar, Eur. J. Org. Chem., 2011, 1961.
4 (a) K. Mori, S. Sueoka and T. Akiyama, Chem. Lett., 2011,
40, 1386; (b) M. Tobisu, H. Nakai and N. Chatani, J. Org.
Chem., 2009, 74, 5471; (c) S. Yang, Z. Li, X. Jian and C. He,
Angew. Chem., Int. Ed., 2009, 48, 3999; (d) S. J. Mahoney,
D. T. Moon, J. Hollinger and E. Fillion, Tetrahedron Lett.,
2009, 50, 4706; (e) G. B. Bajracharya, N. K. Pahadi,
I. D. Gridnev and Y. Yamamoto, J. Org. Chem., 2006, 71,
6204.
4-ETHYLTHIO-3,3-DIPHENYL-3,4-DIHYDROQUINOLINE
39. (0.35
g,
85%); mp 99–101 °C (from Et2O); νmax(Nujol)/cm−1 1616 (s); δH
(400 MHz, CDCl3) 0.94 (3 H, t, J 7.4), 1.88–1.98 (2 H, m), 4.60
(1 H, s), 7.13–7.18 (3 H, m), 7.20–7.23 (2 H, m), 7.24–7.30 (3 H,
m), 7.31–7.33 (5 H, m), 7.40–7.42 (1 H, m), 8.63 (1 H, s); δC
(100 MHz, CDCl3) 14.1, 26.2, 50.2, 53.3 (s), 127.0, 127.3, 127.5,
127.8, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5 (s), 128.9, 141.2
(s), 142.1 (s), 143.0 (s), 165.4; HRMS (ESI): Calcd for C23H22NS
[M + H]+ 344.1467, found 344.1472.
5 K. Mori, S. Sueoka and T. Akiyama, J. Am. Chem. Soc., 2011,
133, 2424.
Acknowledgements
This work was supported by the Ministerio de Economía y
Competitividad of Spain (Project CTQ2008-05827/BQU) and
Fundacion Seneca-CARM (Project 08661/PI/08). B. B. also
thanks Fundacion Seneca-CARM for a fellowship.
6 (a) K. Mori, T. Kawasaki and T. Akiyama, Org. Lett., 2012,
14, 1436; (b) K. Mori, K. Ehara, K. Kurihara and T. Akiyama,
J. Am. Chem. Soc., 2011, 133, 6166; (c) K. Mori, T. Kawasaki,
S. Sueoka and T. Akiyama, Org. Lett., 2010, 12, 1732;
(d) G. Zhou and J. Zhang, Chem. Commun., 2010, 46, 6593;
(e) S. Murarka, C. Zhang, M. D. Konieczynska and
D. Seidel, Org. Lett., 2009, 11, 129, and references cited
therein.
Notes and references
1 (a) F. Kakiuchi and N. Chatani, Adv. Synth. Catal., 2003,
345, 1077; (b) K. Godula and D. Sames, Science, 2006, 312,
67; (c) H. M. L. Davies, Angew. Chem., Int. Ed., 2006, 45,
6422; (d) R. G. Bergman, Nature, 2007, 446, 391;
(e) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev.,
2007, 107, 174; (f) H. M. L. Davies and J. R. Manning,
Nature, 2008, 451, 417; (g) X. Chen, K. M. Engle,
D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48,
5094; (h) R. Jazzar, J. Hitce, A. Renaudat, J. Sofack-Kreutzer
and O. Baudoin, Chem.–Eur. J., 2010, 16, 2654;
(i) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110,
1147.
7 (a) M. Alajarin, B. Bonillo, M.-M. Ortin, P. Sanchez-Andrada
and A. Vidal, Org. Lett., 2006, 8, 5645; (b) M. Alajarin,
B. Bonillo, M.-M. Ortin, P. Sanchez-Andrada and A. Vidal,
Eur. J. Org. Chem., 2011, 1896; (c) M. Alajarin, B. Bonillo,
M. Marin-Luna, P. Sanchez-Andrada, A. Vidal and
R.-A. Orenes, Tetrahedron, 2012, 68, 4672.
8 (a) M. Alajarin, B. Bonillo, P. Sanchez-Andrada, A. Vidal
and D. Bautista, Org. Lett., 2009, 11, 1365; (b) M. Alajarin,
B. Bonillo, P. Sanchez-Andrada and A. Vidal, J. Org. Chem.,
2010, 75, 3737.
9 M. Alajarin, B. Bonillo, M.-M. Ortin, P. Sanchez-Andrada,
A. Vidal and R.-A. Orenes, Org. Biomol. Chem., 2010, 8,
4690.
2 (a) L. McMurray, F. O’Hara and M. J. Gaunt, Chem. Soc.
Rev., 2001, 40, 1885; (b) W. R. Gutekunt and P. S. Baran, 10 (a) D. Clarke, R. W. Mares and H. McNab, J. Chem. Soc.,
Chem. Soc. Rev., 2011, 40, 1976.
Chem. Commun., 1993, 1026; (b) B. E. Fulloon,
H. A. A. El-Nabi, G. Kollenz and C. Wentrup, Tetrahedron
Lett., 1995, 36, 6547; (c) C. O. Kappe, G. Kollenz, R. Leung-
Toung and C. Wentrup, J. Chem. Soc., Chem. Commun.,
1992, 487; (d) B. E. Fulloon and C. Wentrup, J. Org. Chem.,
1996, 61, 1363; (e) D. W. J. Moloney, M. W. Wong,
R. Flammang and C. Wentrup, J. Org. Chem., 1997, 62,
4240; (f) C. Wentrup, V. V. Ramana Rao, W. Frank,
B. E. Fulloon, D. W. J. Moloney and T. Mosandl, J. Org.
Chem., 1999, 64, 3608; (g) J. J. Finnerty and C. Wentrup,
J. Org. Chem., 2004, 69, 1909.
3 For selected recent references, see: (a) S. J. Pastine,
K. M. McQuaid and D. Sames, J. Am. Chem. Soc., 2005, 127,
12180; (b) S. J. Pastine and D. Sames, Org. Lett., 2005, 7,
5429; (c) M. Tobisu and N. Chatani, Angew. Chem., Int. Ed.,
2006, 45, 1683; (d) J. Barluenga, M. Fañanás-Mastral,
F. Aznar and C. Valdés, Angew. Chem., Int. Ed., 2008, 47,
6594; (e) K. M. McQuaid and D. Sames, J. Am. Chem. Soc.,
2009, 131, 402; (f) D. Shikanai, H. Murase, T. Hata and
H. Urabe, J. Am. Chem. Soc., 2009, 131, 3166;
(g) P. A. Vadola and D. Sames, J. Am. Chem. Soc., 2009, 131,
16525; (h) N. K. Pahadi, M. Paley, R. Jana, S. R. Waetzig and 11 (a) M. Alajarin, M.-M. Ortin, P. Sanchez-Andrada, A. Vidal
J. A. Tunge, J. Am. Chem. Soc., 2009, 131, 16626;
(i) S. Murarka, I. Deb, C. Zhang and D. Seidel, J. Am. Chem.
Soc., 2009, 131, 13226; ( j) C. Zhan and D. Seidel, J. Am.
Chem. Soc., 2010, 132, 1798; (k) I. Deb and D. Seidel, Tetra-
and D. Bautista, Org. Lett., 2005, 7, 5281; (b) M. Alajarin,
M.-M. Ortin, P. Sánchez-Andrada and A. Vidal, J. Org.
Chem., 2006, 71, 8126; (c) M. Alajarin, A. Vidal and
M.-M. Ortin, Synthesis, 2007, 590.
hedron Lett., 2010, 51, 2945; (l) I. D. Jurberg, Y. Odabachian 12 M. Alajarin, A. Vidal, M.-M. Ortin and D. Bautista, Syn-
and F. Gagosz, J. Am. Chem. Soc., 2010, 132, 3543;
thesis, 2005, 2426.
9536 | Org. Biomol. Chem., 2012, 10, 9523–9537
This journal is © The Royal Society of Chemistry 2012

Organic & Biomolecular Chemistry
Paper
View Article Online
13 (a) H. Wamhoff and J. Muhr, Synthesis, 1988, 919;
(b) H. Wamhoff, H. Wintersohl, S. Stoelben, J. Paasch,
X. Ginesta, D. M. Howells and M. Zaja, Pure Appl. Chem.,
2006, 78, 215.
N. J. Zhu and F. Guo, Liebigs Ann. Chem., 1990, 901; 16 In this respect it should be remarked that when C,C-diphe-
(c) H. Wamhoff and J. Paasch, Liebigs Ann. Chem., 1990,
995.
14 This is commonly interpreted as the result of hyperconju-
gative interactions between the lone pair electrons at het-
eroatoms (the oxygen atom of one CH3O group in this case)
nyl-N-(2-tolyl)ketenimine (a similar substrate but not sub-
stituted by electron-donor groups at the benzylic carbon
atom) was heated in toluene solution at reflux temperature
for 48 h, or at 180 °C in a sealed tube for 24 h, it was recov-
ered unchanged. See ref. 7a.
and the σ*(C–X) orbital where X is the migrating atom 17 M. A. Ardakanis, R. K. Smalley and R. H. Smith, J. Chem.
(H or O in compounds 11). Such interaction induces a Soc., Perkin Trans. 1, 1983, 2501.
weakening of the C–X bond and an increase in negative 18 J. C. Cuevas, J. de Mendoza and P. Prados, J. Org. Chem.,
charge density at the migrating atom. See for instance: 1988, 53, 2055.
P. Brunet and J. D. Wuest, J. Org. Chem., 1996, 61, 2020 and 19 Prepared following procedure
the
experimental
references cited therein.
15 It is commonly assumed that the propensity of an organic
reported for the preparation of similar compounds in
ref. 19.
group to migrate in an anionotropic rearrangement 20 G. Smolinsky, J. Org. Chem., 1961, 26, 4108.
depends, among other factors, on its ability to stabilize a 21 M. Alajarin, A. Lopez-Lazaro, A. Vidal and J. Berna, Chem.–
negative charge. For a summary of the most important
Eur. J., 1998, 4, 2558.
factors that control which group migrates in a representa- 22 H. Pracejus and G. Wallura, J. Prakt. Chem., 1962, 19, 33.
tive case of anionotropic rearrangement (1,2-shifts in orga- 23 E. C. Taylor, A. McKillop and G. H. Hawks, Org. Synth.,
noborate anions) see: V. K. Aggarwal, G. Y. Fang,
1972, 52, 36.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 9523–9537 | 9537