Formation of 3-Aminophenols from Cyclohexane-1,3-diones

Article abstract of DOI:10.1021/acs.joc.0c02284

meta-Aminophenols are formed by the action of DBU on 3-amino-2-chlorocyclohex-2-en-1-ones at room temperature in MeCN. The chloro compounds are generated by treating 3-aminocyclohex-2-en-1-ones with the easily prepared halogenating agent BnNMe3·ICl2 in Me

Full text of DOI:10.1021/acs.joc.0c02284

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Formation of 3‑Aminophenols from Cyclohexane-1,3-diones
̀
Damian Szymor-Pietrzak, Muhammad N. Khan, Anaïs Pages, Ajay Kumar, Noah Depner,
and Derrick L. J. Clive*
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ABSTRACT: meta-Aminophenols are formed by the action of DBU on 3-
amino-2-chlorocyclohex-2-en-1-ones at room temperature in MeCN. The
chloro compounds are generated by treating 3-aminocyclohex-2-en-1-ones
with the easily prepared halogenating agent BnNMe3·ICl2 in MeOH-
CH2Cl2. The amino group must carry two substituents, either two aryl, one
aryl and one alkyl, or two alkyl groups; 3-aminocyclohex-2-en-1-ones of
this type are readily made from cyclohex-2-en-1-one and a primary or
secondary amine.
1 → 2 → 4 → 6), and the last paper4 dealt with the formation
of meta-sulfanylphenols (Scheme 2, 7 → 8 → 9 → 10 → 11).
All these transformations were carried out under mild
conditions and without metal catalysis.
INTRODUCTION
■
The synthesis of meta-substituted phenols (as well as the
corresponding ethers) is made difficult by the ortho-para
directing properties of the phenolic oxygen. In those cases
where the meta substituent is itself ortho-para directing, similar
complications thwart the alternative approach of direct meta-
oxygenation. Solutions to such problems have been addressed
in four publications from this laboratory. The first two1,2
reported procedures along the lines shown in Scheme 1 for
converting readily available 3-methoxycyclohex-2-en-1-ones
(1) into 3-methoxyphenols (5) that can carry a variety of
carbon, nitrogen, sulfur, or oxygen substituents (E). The third
publication3 explained how to introduce a carbon unit, either
aliphatic or aromatic, meta to the phenolic oxygen (Scheme 1,
Scheme 2. Formation of meta-Sulfanylphenols
Scheme 1. Formation of meta-Substituted Phenols
We have now incorporated the above principles into a
procedure for making meta-aminophenols (Scheme 3, A and B
= aryl or alkyl groups). As indicated in this generic scheme,
cyclohexane-1,3-dione (7) is converted into a 3-amino-
cyclohex-2-en-1-one (13), either directly or in two steps via
the secondary enaminone 12. The tertiary enaminone 13 is
then halogenated at C(2) and the product treated with DBU to
Received: September 24, 2020
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alkaloids9 and some carbazole alkaloids,10 and they are used as
precursors of dyes.11
Scheme 3. Our Approach to meta-Aminophenols
RESULTS AND DISCUSSION
■
Preparation of Starting Materials. The required starting
materials, 3-aminocyclohex-2-en-1-ones (13), were made from
cyclohexane-1,3-dione and the appropriate amine. We
examined several standard methods12 for condensing the
amine and the dione: the use of refluxing PhH or PhMe and a
Dean-Stark apparatus with or without catalytic p-TsOH·H2O,
the use of catalytic AcOH in PhMe,13 and the use of catalytic
14
Yb(OTf)3 in MeCN. We find that the most reliable
procedure is to use AcOH as the solvent at 80−95 °C;
under these conditions, the reaction works with both primary
and secondary amines, is usually over in 2−6 h, and does not
require removal of water. Diphenylamine was an exception,
and a much longer time was needed (ca. 50 h). Diluting the
reaction mixture with THF (1:1 AcOH-THF) resulted in a
lower yield, 20% versus 65% in the one case we tested (28, see
Table 1 for structure).
effect elimination of HX and form the meta-aminophenol 15.
Simple meta-aminophenols of therapeutic or agrochemical
value are phentolamine5 (an anti-hypertensive), demecarium
bromide (formally used in treating glaucoma),6 phenmedip-
ham (a herbicide),7 and formetanate (a miticide and
insecticide).8 Benzene rings with oxygen and nitrogen
substitution in a 1,3 relationship are subunits of quinolinone
When cyclohexanedione was condensed with a primary
amine the next step required N-alkylation, and this was
a
Table 1. Preparation of Tertiary 3-Aminocyclohex-2-en-1-ones
a
Reaction of the amines with cyclohexane-1,3-dione were done in AcOH, except for the preparation of 30 and 32 where no acid was used.
b
Reaction done without acid gave almost the same yield (59%).
B
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Table 2. Formation of meta-Aminophenols
a
b
c
d
BnNMe3ICl2, NaHCO3, CH2Cl2-MeOH, room temp. DBU, MeCN, room temp. Reaction done in the presence of LiCl. 2-Iodo enaminone
e
(12%) and 4-iodo enaminone (31%) also isolated. Reaction at a higher than normal concentration.
achieved by deprotonation with NaH in DMF followed by
addition of an alkyl or benzyl halide (MeI, BnCl).15
of 32 is not a general reaction and did not work with the
corresponding pyrrolidino or diethylamino cyclohexenones.
The 3-aminocyclohex-2-en-1-ones we have studied are listed
in Table 1. In the two cases where the same product was made
by direct use of a secondary amine and also by the two-step
method involving a primary amine followed by N-alkylation,
the single step process gave a higher yield.
Halogenation Studies. The initial halogenation studies
were attempts at bromination because our prior experience1−4
was based on the introduction of bromine.16 A suitable test
appeared to be the preparation of bromide 33, which was
reported to be available as a hydrobromide by treatment of 3-
(piperidin-1-yl)cyclohex-2-en-1-one (32, Table 1)17 with
Br2.18 It turns out that the compound is not a 2-bromo
derivative but the hydrobromide of the structural isomer 34.
This assignment was clear from the 1H NMR spectrum, and an
X-ray structure determination indicated that the material is
best regarded as the bromide salt19 of an O-protonated
enaminone. The compound readily gives the expected phenol
(90% yield) on treatment with DBU in MeCN at room
temperature, but, unfortunately, the smooth C(4) bromination
Consequently, other halogenation methods were tested on a
variety of enaminones. The action of NBS20 or Br2 (both in
19
CH2Cl2) on 30 (see Table 1 for structure) gave a complex
mixture in both cases, as did I2 in MeCN.21 t-BuOCl22 failed to
afford the desired chloride with 3-(pyrrolidin-1-yl)cyclohex-2-
en-1-one, and the use of NCS, tried with 19 (see Table 1), was
also unsatisfactory; it led to the desired product in 59% yield as
C
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well as the byproduct 35 (27%). It is not clear whether the
formation of 35 is the result of an ionic reaction via an
extended enolate or is the product of a free radical allylic
chlorination. However, BrCH(CN)2,23 which is known to
work well with secondary enaminones,24 seemed promising
(68% yield) when tried with 36 in DMF. We soon found,
however, that the yields of the required bromides were lower
and erratic with other tertiary enaminones. Finally, we turned
to the easily prepared and crystalline reagent BnNMe3·ICl2,25
which had been reported to convert 17 into the corresponding
2-chloro compound under very mild conditions and in good
yield (83%).26 Likewise, the tertiary enaminone 37 had also
been chlorinated27 (no yield given). The generality of this
chlorination of tertiary enaminones was unestablished as these
were the only examples. The reagent has the curious property
of iodinating secondary enaminones.26,28 In the event,
BnNMe3·ICl2 proved to be satisfactory for the chlorinations
we needed, although we have found one case, the N,N-
diphenyl enaminone 29 (see Table 2), where iodination is a
competing reaction and we isolated (see the Experimental
Section) the 2-iodo compound 29b′ (12% yield), the desired
chloro compound 29b (48%), and the 4-iodo compound 29b″
(31%). All three of these products were again formed when the
halogenation of 29 was done with protection from light.
Presumably, the electron density on the nitrogen or the
conformation about the N−C(3) bond are factors responsible
for this behavior. In general, the optimum conditions for
chlorination with BnNMe3·ICl2 are the use of 1.2−1.5 equiv of
the reagent and a reaction time of 1−12 h; with this procedure,
the average yield for the chlorination of our 12 examples
(Table 1) is 83%.
(Scheme 4), but we were unable to isolate it for character-
ization. In an attempt to clarify what was happening, we
Scheme 4. Reaction Mechanism
evaporated the reaction mixture from 19b and kept the residue
under oil pump vacuum (ca. 0.005 mmHg) overnight to
remove DBU and then ran NMR spectra in THF-d8, but at
that stage, all the material was the aminophenol 19c.
In early experiments aimed at optimizing the conditions for
aromatization of 20b, we arbitrarily added the weak Lewis acid
LiCl to the reaction mixture in the hope that it might facilitate
an enolization step (see Scheme 4), and we observed an
improvement in the yield of the phenol from 38% to 73%. LiCl
was again used for aromatization of 28b, giving a yield of 84%
after a reaction period of 48 h; in the absence of LiCl, the yield
was 74%, again after 48 h.
We have also examined the possibility of aromatizing an
enaminone having one hydrogen on the nitrogen since
halogenation is then very easy.19 The compound used was 2-
bromo-3-[(4-chlorophenyl)amino]cyclohex-2-en-1-one, but
the action of DBU failed to produce the aromatic system,
probably because of preferential deprotonation of the nitrogen.
In two experiments,30 N-acylation of the nitrogen with Boc2O
or AcCl after chlorination was also unpromising.31
The mechanism of the aromatization presumably occurs via
the process summarized in Scheme 4,1,32 but we were unable
to isolate what may be the enamine 39 in the one case we
examined (19b) where TLC monitoring of the aromatization
revealed the formation of a precursor to the aminophenol.
Related Approaches to meta-Aminophenols. meta-
Aminophenols can be prepared from cyclohexanone systems
by several methods reported in the literature. Heating a 3-
aminocyclohex-2-en-1-one with Pd/C to 150−220 °C effects
aromatization.33 The two enaminones 40 (Scheme 5), on
All the 2-chloro enaminones should be used promptly after
isolation; those that were not solids turned black at room
temperature after about 1 week.
Aromatization by Base Treatment. For the aromatiza-
tion step, we examined several bases (pyridine, Et3N, i-Pr2NEt,
DBN, and DBU) but only DBU was satisfactory. The slightly
less basic29 analog DBN was less effective (26% in a test with
19b, Table 2). There appeared to be little if any reaction with
i-Pr2NEt in the case of 19b. The action of DBU was examined
in several solvents (PhMe, THF, and MeCN), and we
established that DBU in MeCN at room temperature is the
best, as judged by isolated yields from 30b. Generally, we use 2
equiv DBU and arbitrarily leave the reaction mixtures for 24 h.
In a few cases, e.g., 20c (48 h), 21c (48 h), 23c (70 h), and
30c (42 h) (Table 2), a longer time was required. Our results
for the complete sequence of halogenation and aromatization
are listed in Table 2. With the formation of 19c as a test case,
the yield was 63% with 1.2 equiv DBU after 22 h
(concentration of 19b = 0.21 mmol/mL) and 75% with 2
equiv DBU after 20 h (concentration of 19b = 0.15 mmol/
mL). In the case of 30c, the yield was improved by running the
aromatization at a concentration of 0.25 molar in starting
chloro enaminone (59%) rather than 0.11 molar (36%), a
reaction time of 42 h being used for both experiments.
In the aromatization of 17b, 19b, and 27b, we noticed by
TLC examination of the reaction mixtures that two products
were formed; these were eluted from the flash chromatography
column in successive fractions, but the NMR spectra of the
content of these fractions were identical, as was their TLC
behavior. Clearly, one of the initial products changes into the
desired meta-aminophenol during the chromatography.
Possibly, this compound is the intermediate enamine 39
Scheme 5. Silylation Route
silylation and heating (50 °C) with stoichiometric
PdCl2(MeCN)2, affording the corresponding O-silylated
meta-aminophenols 42 in poor yield.34 The action of
palladium(II) on 3-(arylamino)cyclohex-2-en-1-ones does not
seem to lead to aromatization however.35 Another palladium-
based method involves in situ dehydrogenation of cyclo-
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3-(Phenylamino)cyclohex-2-en-1-one (16).13 Aniline (0.4549
mL, 15 mmol) was added to AcOH (6 mL) followed by cyclohexane-
1,3-dione (560 mg, 5.0 mmol), and the mixture was stirred at 90 °C
(N2 atmosphere) for 6 h. The solvent was then evaporated at 40 °C,
and the residue was dissolved in the minimum of EtOAc and applied
to the top of a chromatography column made up with silica gel (2 ×
20 cm) and hexane. Flash chromatography, using first hexane (ca. 250
mL) and then 1:9 hexane-EtOAc, gave 16 (830 mg, 88%) as a yellow
hexanone at 100 °C in the presence of an amine, Cu2O, I2,
TEMPO, t-BuOOH, and air to afford the meta-aminophenols
resulting from sequential conjugate addition of the amine to
the intermediate cyclohexenone followed by dehydrogen-
ation.36 In the few examples reported for this method, yields
varied from 40% to 51%.
The closest procedure to our own approach is the report
that secondary 3-aminocyclohex-2-en-1-ones react with
aryliododiacetates [Ar(I(OAc)2] in the presence of K2CO3
to give meta-aminophenols in which the nitrogen now carries
the aryl group that was initially part of the hypervalent iodine
reagent.37 The reaction proceeds at 100 °C via an intermediate
3-amino-2-iodocyclohex-2-en-1-one, and yields in this process
were generally very high.38
The meta-aminophenol unit has been generated at 130 °C in
the form of hydroxyphenanthridinones by aromatization of 3-
aminocyclohex-2-en-1-ones in the presence of stoichiometric
Cu(OAc)2 and air.40
meta-Aminophenols are formed (32−78% yield) when 3-
aminocyclohex-2-en-1-ones are treated with 1 equiv (or more)
of Hg(OAc)2 in refluxing MeCN or AcOH for 1−20 h.41,42
Two 3-aminocyclohex-2-en-1-ones have been aromatized at
150 °C in the presence of both Pd/C and H2 (0.2 atm).43
Several secondary 3-aminocyclohex-2-en-1-ones have been
aromatized by heating with Pd/C at 210−300 °C for 12 to
48 h,10,44 and 3-aminophenol itself can be obtained by heating
3-aminocyclohex-2-en-1-one with 5% Pd/C and AcOK in
refluxing N-methylpyrrolidinone.45
1
solid: mp 179−181 °C; H NMR (CDCl3, 400 MHz) δ 7.36 (t, J =
7.59 Hz, 2 H), 7.22−7.16 (m, 3 H), 6.13 (br s, 1 H), 5.61 (s, 1 H),
2.52 (t, J = 6.24 Hz, 2 H), 2.39 (t, J = 7.12 Hz, 2 H), 2.07 (quint, J =
6.6 Hz, 2 H); 13C{1H} NMR (CDCl3, 175 MHz) δ 198.2 (s), 162.5
(s), 138.1 (s), 129.2 (d), 125.5 (d), 123.9 (d), 99.6 (d), 36.4 (t), 29.6
(t), 21.8 (t).
3-[Methyl(phenyl)amino]cyclohex-2-en-1-one (17).35 Dry
DMF (30 mL) was injected into a flask containing the enaminone
16 (2.02 g, 10.8 mmol) (N2 atmosphere), and the stirred mixture was
cooled in an ice bath. NaH (60% w/w dispersion in oil, 968 mg, 24.3
mmol) was tipped into the resulting solution under a stream on N2,
the ice bath was removed, and stirring was continued for 2 h. MeI (1.7
mL, 27.3 mmol) was then injected dropwise over about 2 min, and
stirring was continued overnight. The mixture was poured into water
(300 mL) and extracted with EtOAc (5 × 50 mL). The combined
organic extracts were washed with brine (2 × 50 mL), dried
(Na2SO4), and evaporated. Flash chromatography of the residue over
silica gel (3 × 15 cm), using 19:1 CH2Cl2-MeOH, gave 17 (1.33 g,
61%) as a beige solid. For characterization data, see the next
experiment.
3-[Methyl(phenyl)amino]cyclohex-2-en-1-one (17).35 N-
Methylaniline (0.54 mL, 5.0 mmol) was added to AcOH (6.5 mL)
followed by cyclohexane-1,3-dione (560 mg, 5.0 mmol), and the
mixture was stirred at 85 °C (N2 atmosphere) for 6 h. The solvent
was then evaporated at 40 °C, and the residue was dissolved in the
minimum of EtOAc and applied to the top of a chromatography
column made up with silica gel (2 × 15 cm) and hexane. Flash
chromatography, using first hexane (ca. 250 mL) and then 1:9
hexane-EtOAc, gave 17 (950 mg, 94%) as an oil, which slowly
solidified: mp 81−83 °C; 1H NMR (CDCl3, 500 MHz) δ 7.42 (t, J =
7.36 Hz, 2 H), 7.36−7.31 (m, 1 H), 7.15 (d, J = 7.42 Hz, 2 H), 5.34
(s, 1 H), 3.25 (s, 3 H), 2.32 (t, J = 5.0 Hz, 2 H), 2.23 (t, J = 6.23 Hz,
2 H), 1.91 (quint, J = 8.15 Hz, 2 H); 13C{1H} NMR (CDCl3, 175
MHz) δ 197.5 (s), 164.9 (s), 145.3 (s), 129.6 (d), 127.4 (d), 127.1
(d), 100.5 (d), 40.7 (q), 36.0 (t), 28.4 (t), 22.4 (t).
2-Chloro-3-[methyl(phenyl)amino]cyclohex-2-en-1-one
(17b).26 BnNMe3·ICl2 (450 mg, 1.29 mmol) was tipped into a stirred
solution of 17 (217 mg, 1.08 mmol) in a mixture of dry CH2Cl2 (8
mL) and dry MeOH (4 mL) followed immediately by NaHCO3 (634
mg, 7.54 mmol), which was also added in one portion (N2
atmosphere). Stirring was continued for 45 min, and the mixture
was then filtered through a sintered disc. Evaporation of the filtrate
and flash chromatography of the residue over silica gel (2 × 15 cm),
using 19:1 CH2Cl2-MeOH, gave 17b (236 mg, 93%) as an oil
containing trace impurities (1H NMR): FTIR (CDCl3, cast film)
2949, 2825, 1647, 1596, 1584, 1543, 1293, 1188, 1035, 769 cm−1; 1H
NMR (CDCl3, 500 MHz) δ 7.42−7.34 (m, 2 H), 7.26−7.17 (m, 1
H), 7.12−7.06 (m, 2 H), 3.55 (s, 3 H), 2.592−2.52 (m, 4 H), 1.94
(quint, J = 6.5 Hz, 2 H); 13C{1H} NMR (CDCl3, 176 MHz) δ 191.1
(s), 160.6 (s), 146.4 (s), 129.4 (d), 125.3 (d), 124.2 (d), 42.8 (q),
37.6 (t), 31.8 (t), 20.7 (t); exact mass (ESI) m/z calcd for
C13H14ClNO (M + Na)+ 258.0656, found 258.0656.
Halogenated meta-aminophenols are available by successive
reaction of 3-aminocyclohex-2-en-1-ones with (Me3Si)2NLi
and TsCl (or TsBr) and again with (Me3Si)2NLi.46,47
Certain 3-aminocyclohex-2-en-1-ones have been deproto-
nated regioselectively and silylated to generate a diene system
that undergoes Diels−Alder cycloaddition followed by retro-
Diels−Alder reaction to afford O-silyl derivatives of meta-
aminophenols.48
CONCLUSIONS
■
Cyclohexane-1,3-dione is readily converted into 3-amino-
cyclohex-2-en-1-ones in which the nitrogen carries two
substituents, which are both aryl or alkyl units, or one of
each type. Such compounds can be chlorinated at C(2) with
the crystalline reagent BnNMe3·ICl2, and the resulting chloro
enaminones undergo aromatization at room temperature on
treatment with DBU in MeCN. The average yield for the
chlorination was 83% (12 examples); the average yield for the
aromatization was 73%.
EXPERIMENTAL SECTION
■
Solvents used for chromatography were distilled before use.
Commercial thin layer chromatography plates (silica gel, Merck
60F-254) were used. Silica gel for flash chromatography was Merck
type 60 (230−400 mesh). Dry solvents were prepared under an inert
atmosphere (N2) and transferred by a syringe or cannula. The
symbols s, d, t, and q used for13C{1H} NMR spectra indicate zero,
one, two, or three attached hydrogens, respectively, the assignments
being made from APT spectra. Solutions were evaporated under water
pump vacuum, and the residue was then kept under oil pump vacuum.
In the formation of enaminones, a heating mantle was used; in all
other cases, the heat source was a temperature-controlled oil bath.
High-resolution electrospray mass spectrometric analyses were
done with an orthogonal time-of-flight analyzer, and electron
ionization mass spectra were measured with a double-focusing sector
mass spectrometer.
3-[Methyl(phenyl)amino]phenol (17c).49 DBU (0.1257 mL,
0.840 mmol) was injected at a fast dropwise rate into a stirred
solution of 17b (98.8 mg, 0.420 mmol) in dry MeCN (3 mL) (N2
atmosphere), and stirring was continued for 16 h. At this stage,
examination of the reaction mixture by TLC (silica, 99:1 CH2Cl2-
MeOH) showed two new spots and examination in two dimensions
suggested that the less polar material was decomposing into the more
polar on the silica. Evaporation of the solvent and flash
chromatography of the residue over silica gel (2 × 15 cm), using
99:1 CH2Cl2-MeOH, gave 17c (68.6 mg, 82%) as a yellow liquid: 1H
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NMR (CDCl3, 500 MHz) δ 7.33 (t, J = 7.24 Hz, 2 H), 7.16−7.09 (m,
3 H), 7.06 (t, J = 7.47 Hz, 1 H), 6.56 (dd, J = 8.15, 2.11 Hz, 1 H),
6.45 (t, J = 2.29 Hz, 1 H), 6.39 (ddd, J = 7.99, 2.40, 0.78 Hz, 1 H),
4.63 (br d, J = 15.75 Hz, 1 H), 3.32 (s, 3 H); 13C{1H} NMR (CDCl3,
125 MHz) δ 156.3 (s), 150.6 (s), 148.7 (s), 130.0 (d), 129.3 (d),
122.60 (d), 122.58 (d), 111.2 (d), 107.1 (d), 105.5 (d), 40.2 (q).
3-[(4-Methylphenyl)amino]cyclohex-2-en-1-one (18).13 4-
MeC6H4NH2 (330 mg, 2.924 mmol) was added to AcOH (6 mL)
followed by cyclohexane-1,3-dione (327 mg, 2.92 mmol), and the
mixture was stirred at 88−90 °C (N2 atmosphere) for 4 h. The
solvent was then evaporated at 40 °C, and the residue was dissolved in
the minimum of EtOAc and applied to the top of a chromatography
column made up with silica gel (2 × 22 cm) and hexane. Flash
chromatography, using first hexane (ca. 250 mL) and then 1:9
hexane-EtOAc, gave 18 (557 mg, 94%) as a yellow solid: mp 139−
dry MeCN (2 mL) (N2 atmosphere), and stirring was continued
overnight. Evaporation of the solvent and flash chromatography of the
residue over silica gel (1 × 15 cm), using EtOAc, gave 19c (50.3 mg,
75%) as an oil: FTIR (CH2Cl2 ,cast film) 3369, 2919, 2874, 2813,
1602, 1510, 1349, 1129, 956, 819 cm−1; 1H NMR (CDCl3, 400 MHz)
δ 7.20−7.12 (m, 2 H), 7.12−7.02 (m, 3 H), 6.46 (ddd, J = 8.2, 2.3,
0.8 Hz, 1 H), 6.37−6.28 (m, 2 H), 4.53 (s, 1 H), 3.28 (s, 3 H), 2.36
(s, 3 H); 13C{1H} NMR (CDCl3, 176 MHz) δ 156.2 (s), 150.9 (s),
146.2 (s), 133.3 (s), 130.0 (d), 129.8 (d), 124.2 (d), 109.3 (d), 105.8
(d), 103.6 (d), 40.3 (q), 20.8 (q); exact mass (ESI) m/z calcd for
C14H15NO (M − H)− 212.1081, found 212.1079.
N-[(4-Methoxyphenyl)methyl]-4-methylaniline.50−52 4-
MeOC6H4CHO (27.4 μL, 2.25 mmol) was added dropwise to a
stirred solution of 4-methylaniline (290 mg, 2.7 mmol) in anhydrous
EtOH (18 mL). CeCl3·7H2O (16 mg, 0.045 mmol) was added, the
reaction flask was stoppered, and stirring was continued for an
arbitrary period of 2 h. At that stage, NaBH4 (170 mg, 4.50 mmol)
was added in one portion. Immediate bubbling was observed, and
stirring was continued overnight with the flask open to the
atmosphere. Evaporation of EtOH gave a residue, which was
partitioned between EtOAc and water. The aqueous phase was
washed twice with EtOAc, and the combined organic extracts were
dried (Na2SO4) and evaporated. Flash chromatography of the residue
over silica gel (2 × 15 cm), using 19:1 hexane-EtOAc, gave N-[(4-
methoxyphenyl)methyl]-4-methylaniline (410 mg, 80%) as a pale
1
141 °C; H NMR (CDCl3, 400 MHz) δ 7.15 (d, J = 8.22 Hz, 2 H),
7.06 (d, J = 8.36 Hz, 2 H), 6.19 (br s, 1 H), 5.53 (s, 1 H), 2.50 (t, J =
6.24 Hz, 2 H), 2.39−2.33 (m including a singlet, 5 H), 2.05 (quint, J
= 6.31 Hz, 2 H); 13C{1H} NMR (CDCl3, 175 MHz) δ 198.0 (s),
162.3 (s), 135.55 (s), 135.32 (s), 129.8 (d), 124.1 (d), 99.7 (d), 36.4
(t), 29.7 (t), 21.8 (t), 20.9 (q).
3-[Methyl(4-methylphenyl)amino]cyclohex-2-en-1-one
(19).35 Dry DMF (15 mL) was injected into a flask containing
enaminone 18 (1.02 g, 5.51 mmol) (N2 atmosphere), and the stirred
mixture was cooled in an ice bath. NaH (60% w/w dispersion in oil,
530 mg, 13.3 mmol) was tipped into the resulting solution under a
stream of N2, the ice bath was removed, and stirring was continued for
2 h. MeI (0.86 mL, 13.8 mmol) was then injected dropwise over
about 2 min, and stirring was continued overnight. The mixture was
poured into water (125 mL) and extracted with EtOAc (4 × 25 mL).
The combined organic extracts were washed with brine (2 × 25 mL),
dried (Na2SO4), and evaporated. Flash chromatography of the residue
over silica gel (2 × 15 cm), using 19:1 CH2Cl2-MeOH, gave 19 (78.7
mg, 72%) as a beige solid: 1H NMR (CDCl3, 600 MHz) δ 7.25−7.20
(m, 2 H), 7.05−7.01 (m, 2 H), 5.33 (s, 1 H), 3.23 (s, 3 H), 2.39 (s, 3
H), 2.32 (dd, J = 7.1, 5.9 Hz, 2 H), 2.22 (t, J = 6.2 Hz, 2 H), 1.90
(quint, J = 6.4 Hz, 2 H); 13C{1H} NMR (CDCl3, 176 MHz,) δ 197.5
(s), 165.2 (s), 142.8 (s), 137.4 (s), 130.2 (d), 126.9 (d), 100.3 (d),
40.8 (d), 36.1 (t), 28.5 (t), 22.5 (t), 21.0 (q).
2-Chloro-3-[methyl(4-methylphenyl)amino]cyclohex-2-en-
1-one (19b). BnNMe3·ICl2 (333.8 mg, 0.959 mmol) was tipped into
a stirred solution of 19 (137 mg, 0.636 mmol) in a mixture of dry
CH2Cl2 (8 mL) and dry MeOH (4 mL) followed immediately by
NaHCO3 (381.9 mg, 4.55 mmol), which was also added in one
portion (N2 atmosphere). Stirring was continued for 45 min, and the
mixture was then filtered through a sintered disc. Evaporation of the
filtrate and flash chromatography of the residue over silica gel (2 × 15
cm), using 1:1 hexane-EtOAc, gave 19b (151.9 mg, 96%) as an oil:
FTIR (CH2Cl2, cast film) 2921, 1649, 1545, 1452, 1275, 1188, 1135,
1110, 1001, 825 cm−1; 1H NMR (CDCl3, 600 MHz) δ 7.21−7.16 (m,
2 H), 7.03−6.99 (m, 2 H), 3.55 (s, 3 H), 2.56−2.48 (m, 4 H), 2.37 (s,
3 H), 1.90 (tt, J = 6.6, 5.6 Hz, 2 H); 13C{1H} NMR (CDCl3, 176
MHz) δ 191.0 (s), 160.8 (s), 144.0 (s), 135.8 (s), 130.1 (d), 124.9
(d), 110.0 (s), 43.6 (q), 37.5 (t), 32.0 (t), 20.9 (t), 20.7 (q); exact
mass (ESI) m/z calcd for C14H16ClNO (M + Na)+ 272.0813, found
272.0815.
3-[Methyl(4-methylphenyl)amino]phenol (19c). DBU
(0.0427 mL, 0.2859 mmol) was injected at a fast dropwise rate into
a stirred solution of 19b (35.7 mg, 0.143 mmol) in dry MeCN (4 mL)
(N2 atmosphere), and stirring was continued for 24 h. At this point,
TLC (silica, 99:1 CH2Cl2-MeOH) showed two spots but no 19b.
Evaporation of the solvent and flash chromatography of the residue
over silica gel (2 × 25 cm), using 99:1 CH2Cl2-MeOH, gave 19c as
two successive fractions with identical NMR spectra (20.4 mg in total,
67%) as clear, viscous liquids. The two fractions now had the same
TLC Rf values and the same NMR spectra and were combined.
When this experiment was repeated on a larger scale (by a different
experimentalist), the development of two fractions in the flash
chromatography was not observed: DBU (93 μL, 0.623 mmol) was
added dropwise to a stirred solution of 19b (77.7 mg, 0.278 mmol) in
1
yellow solid: H NMR (CDCl3, 400 MHz) δ 7.31 (d, J = 8.66 Hz, 2
H), 7.01 (d, J = 8.07 Hz, 2 H), 6.92−6.88 (m, 2 H), 6.59 (d, J = 7.53
Hz, 2 H), 4.26 (s, 2 H), 3.85 (br s, 1 H), 3.82 (s, 3 H), 2.26 (s, 3 H).
3-{[(4-Methoxyphenyl)methyl](4-methylphenyl)amino}-
cyclohex-2-en-1-one (20). N-[4-Methoxybenzyl]-4-methylaniline
(prepared as in the previous experiment, 366 mg, 1.61 mmol) was
added to AcOH (6 mL) followed by cyclohexane-1,3-dione (180 mg,
1.61 mmol), and the mixture was stirred at 95 °C (N2 atmosphere)
for 2 h (TLC monitoring, silica, EtOAc). At this point, more
cyclohexane-1,3-dione (45.0 mg, 0.40 mmol) was added and heating
was continued for 2 h. Some starting amine was still present (TLC,
silica, EtOAc), and so a further portion of cyclohexane-1,3-dione
(46.0 mg, 0.41 mmol) was added. Heating was continued for 1 h, by
which stage all the amine had reacted. The solvent was evaporated at
40 °C, and the residue was dissolved in the minimum of EtOAc and
applied to the top of a chromatography column made up with silica
gel (2 × 15 cm) and hexane. Flash chromatography, using first hexane
(ca. 200 mL) and then EtOAc, gave 20 (474 mg, 91%) as a dark
yellow, viscous liquid. This material was further purified by flash
chromatography over silica gel (1 × 21 cm), using 98.5:1.5 CH2Cl2-
MeOH, to give 20 (410 mg, 79%) as a solid: mp 124−126 °C; FTIR
(CH2Cl2 cast film) 3031, 2946, 2835, 1620, 1557, 1248, 727 cm−1; 1H
NMR (CDCl3, 500 MHz) δ 7.17−7.09 (m, 4 H), 6.97 (d, J = 7.46
Hz, 2 H), 6.82 (d, J = 7.69 Hz, 2 H), 5.42 (s, 1 H), 4.73 (s, 2 H), 3.77
(s, 3 H), 2.34 (s, 3 H), 2.31−2.26 (m, 4 H), 1.90 (quint, J = 6.78 Hz,
2 H); 13C{1H} NMR (CDCl3, 125 MHz) δ 197.5 (s), 165.1 (s),
158.9 (s), 141.7 (s), 137.4 (s), 130.2 (d), 128.49 (s), 128.43 (d),
127.7 (d), 114.0 (d), 101.1 (d), 56.1 (t), 55.2 (q), 36.1 (t), 28.7 (t),
22.5 (t), 21.0 (q); exact mass (ESI) m/z calcd for C21H23NNaO2 (M
+ Na)+ 344.1621, found 344.1621.
2-Chloro-3-{[(4-methoxyphenyl)methyl](4-methylphenyl)-
amino}cyclohex-2-en-1-one (20b). NaHCO3 (146 mg, 1.74
mmol) and BnNMe3·ICl2 (129 mg, 0.328 mmol) were tipped into
a flask containing 20 (79.9 mg, 0.249 mmol) and a magnetic stir bar.
The flask was closed with a septum, flushed with N2, and kept under a
static pressure of N2. A 2:1 mixture of CH2Cl2 and MeOH (4.5 mL in
total) was injected, and the mixture was stirred at room temperature
for 1 h. At this stage, TLC (silica, 24:1 CH2Cl2-MeOH) showed the
presence of 20. Stirring was continued overnight by which time all of
the starting enaminone had been consumed. The mixture was filtered
through a sintered disc and evaporated. Flash chromatography of the
residue over silica gel (2 × 25 cm), using 99:1 CH2Cl2-MeOH, gave
20b (65.9 mg, 74%) as a light brown solid: mp 133−135 °C; FTIR
(CH2Cl2 cast film) 3030, 2951, 2835, 1652, 1580, 1542, 1510, 1183,
1033, 821 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.22 (d, J = 8.61 Hz,
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2 H), 7.11 (d, J = 8.15 Hz, 2 H) , 6.94 (d, J = 8.33 Hz, 2 H), 6.88 (d, J
= 8.61 Hz, 2 H), 5.09 (s, 2 H), 3.82 (s, 3 H), 2.61 (t, J = 6.09 Hz, 2
H), 2.53 (t, J = 6.96 Hz, 2 H), 2.33 (s, 3 H), 1.89 (quint, J = 6.34 Hz,
2 H); 13C{1H} NMR (CDCl3, 125 MHz) δ 191.1 (s), 159.6 (s),
158.9 (s), 143.8 (s), 134.8 (s), 129.8 (d), 129.7 (s), 127.9 (d), 124.0
(d), 114.1 (d), 112.8 (s), 56.7 (t), 55.2 (q), 37.5 (t), 31.9 (t), 20.9
(q), 20.8 (t); exact mass (ESI) m/z calcd for C21H23ClNO2 (M + H)+
356.1412, found 356.1412.
(CH2Cl2 cast film) 3057, 2946, 2866, 1637, 1573, 1488, 1363, 1182,
1011, 749 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, J = 7.91 Hz,
2 H), 7.41 (d, J = 7.04 Hz, 2 H), 7.30−7.25 (m, 2 H), 7.21−7.13 (m,
3 H), 5.41 (s, 1 H), 2.44−2.15 (m, 6 H), 2.10−2.02 (m, 2 H), 1.97−
1.75 (m, 4 H); 13C{1H} NMR (CDCl3, 125 MHz) δ 195.8 (s), 150.9
(s), 146.2 (s), 138.1 (s), 128.2 (d), 127.7 (d), 126.0 (d), 123.4 (s),
115.8 (s), 36.7 (t), 31.9 (d), 30.9 (d), 28.3 (t), 21.1 (t); exact mass
(ESI) m/z calcd for C25H22BrNNaO2 (M + Na)+ 470.0726, found
470.0728. A sample was recrystallized from chloroform-hexane for X-
ray analysis.
3-[Benzyl(4-bromophenyl)amino]-2-chlorocyclohex-2-en-1-
one (21b). BnNMe3·ICl2 (163 mg, 0.468 mmol) was tipped into a
stirred solution of 21 (139.7 mg, 0.392 mmol) in a mixture of dry
CH2Cl2 (8 mL) and dry MeOH (4 mL) followed immediately by
NaHCO3 (239 mg, 2.84 mmol), which was also added in one portion
(N2 atmosphere). Stirring was continued for 80 min, and the mixture
was then filtered through a sintered disc. Evaporation of the filtrate
and flash chromatography of the residue over silica gel (2 × 15 cm),
using 19:1 CH2Cl2-MeOH, gave 21b (123 mg, 80%) as a yellow solid:
FTIR (CDCl3, cast film) 3030, 2951, 2870, 1658, 1544, 1487, 1452,
1280, 1185, 733 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.41−7.32 (m,
4 H), 7.32−7.21 (m, 3 H), 6.89−6.83 (m, 2 H), 5.06 (s, 2 H), 2.66 (t,
J = 6.0 Hz, 2 H), 2.54 (dd, J = 7.3, 5.9 Hz, 2 H), 1.93 (quint, J = 6.3
Hz, 2 H); 13C{1H} NMR (CDCl3, 126 MHz) δ 191.2 (s), 158.7 (s),
145.3 (s), 137.4 (s), 132.2 (d), 129.0 (d), 127.7 (d), 126.3 (d), 124.1
(d), 117.0 (s), 116.3 (s), 56.5 (t), 37.6 (t), 31.3 (t), 20.8 (t); exact
mass (ESI) m/z calcd for C19H17BrClNO (M + Na)+ 412.0074, found
412.0072.
3-{[(4-Methoxyphenyl)methyl](4-methylphenyl)amino}-
phenol (20c). DBU (7.31 μL, 0.0489 mmol) was injected at a fast
dropwise rate into a stirred mixture of LiCl (1.52 mg, 0.037 mmol),
20b (8.7 mg, 0.024 mmol), and dry MeCN (2 mL) (N2 atmosphere),
and stirring was continued for 24 h. Examination of the mixture by
TLC (silica, 99.5:0.5 CH2Cl2-MeOH) showed the presence of 20b,
and so stirring was continued for a further 24 h. The mixture was
filtered through a sintered disc, and the filtrate was evaporated. Flash
chromatography of the residue over silica gel (1.5 × 15 cm), using
99.5:0.5 CH2Cl2-MeOH, gave 20c (5.7 mg, 73%) as a thick oil: FTIR
(CH2Cl2 cast film) 3405, 3027, 2919, 2835, 1607, 1511, 1245, 1171,
822 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.26 (d, J = 8.61 Hz, 2 H),
7.15−7.09 (m, 4 H), 7.04 (t, J = 8.15 Hz, 1 H), 6.88−6.84 (m, 2 H),
6.48 (dd, J = 8.24, 1.74 Hz, 1 H), 6.36 (t, J = 2.33 Hz, 1 H), 6.29 (dd,
J = 8.01, 1.79 Hz, 1 H), 4.89 (s, 2 H), 4.52 (s, 1 H), 3.80 (s, 3 H),
2.34 (s, 3 H); 13C{1H} NMR (CDCl3, 125 MHz) δ 158.4 (s), 156.3
(s), 150.2 (s), 145.2 (s), 133.2 (s), 131.1 (s), 130.1 (d), 129.9 (d),
127.7 (d), 124.4 (d), 114.0 (d), 109.9 (d), 106.1 (d), 104.1 (d), 55.9
(t), 55.3 (q), 20.8 (q); exact mass (ESI) m/z calcd for C21H22NO2
(M + H)+ 320.1645, found 320.1641. A similar experiment done
without LiCl gave a poor yield (38%).
3-[Benzyl(4-bromophenyl)amino]phenol (21c). DBU (70 μL,
0.469 mmol) was added dropwise to a stirred solution of 21b (91.6
mg, 0.234 mmol) in dry MeCN (3 mL) (N2 atmosphere), and stirring
was continued for 48 h. Evaporation of the solvent and flash
chromatography of the residue over silica gel (1 × 10 cm), using 1:1
hexane-EtOAc, gave 21c (76.2 mg, 92%) as a purplish oil: FTIR
(CDCl3, cast film) 3521, 3390, 3087, 3062, 3029, 2923, 2855, 1585,
N-Benzyl-4-bromoaniline.51 4-Bromoaniline (1.198 g, 7.00
mmol), PhCHO (0.59 mL, 5.84 mmol), and CeCl3·7H2O (43.5 g,
0.116 mmol) were added in that order to anhydrous EtOH (12 mL).
The reaction flask was stoppered, and stirring was continued for 2.5 h
(TLC monitoring, silica, 4:1 EtOAc-hexane). At that stage, NaBH4
(441 mg, 11.68 mmol) was added in one portion to cause immediate
bubbling. Stirring was continued overnight with the flask open to the
atmosphere. Evaporation of EtOH gave a residue, which was
partitioned between EtOAc and water. The aqueous phase was
washed twice with EtOAc, and the combined organic extracts were
dried (Na2SO4) and evaporated. Flash chromatography of the residue
over silica gel (2 × 15 cm), using first hexane (ca. 200 mL) and then
1:4 hexane-EtOAc, gave N-benzyl-4-bromoaniline (1.286 g, 84%) as a
solid: 1H NMR (CDCl3, 400 MHz) δ 7.40−7.25 (m, 7 H), 6.54 (d, J
= 7.90 Hz, 2 H), 4.33 (d, J = 3.89 Hz, 2 H), 4.11 (br s, 1 H); 13C{1H}
NMR (CDCl3, 175 MHz) δ 147.0 (s), 138.5 (s), 131.9 (d), 128.6 (d),
127.38 (d), 127.36 (d), 114.4 (d), 109.1 (s), 48.2 (t).
3-[Benzyl(4-bromophenyl)amino]cyclohex-2-en-1-one (21).
N-Benzyl-4-bromoaniline (prepared as in the previous experiment,
1.286 g, 4.90 mmol) was added to AcOH (12 mL) followed by
cyclohexane-1,3-dione (550 mg, 4.90 mmol), and the mixture was
stirred at 85 °C (N2 atmosphere) for 4 h (TLC monitoring, silica,
EtOAc). At this stage, more cyclohexane-1,3-dione (275 mg, 2.45
mmol) was added and heating was continued for 3 h (TLC
monitoring, silica, EtOAc). The solvent was then evaporated at 40 °C,
and the residue was dissolved in the minimum of EtOAc and applied
to the top of a chromatography column made up with silica gel (2 ×
15 cm) and hexane. Flash chromatography, using first hexane (ca. 250
mL) and then 1:9 hexane-EtOAc, gave 21 (1.340 g, 76%) as a solid,
together with cyclohexane-1,3-dione (150 mg, 8.6%) and compound
(i) (15 mg, 0.9%), which was visible as a bright spot on TLC under
UV light. Enaminone 21: mp 90−92 °C; 1H NMR (CDCl3, 500
MHz) δ 7.50 (d, J = 8.52 Hz, 2 H), 7.35−7.27 (m, 3 H), 7.20 (br d, J
= 7.23 Hz, 2 H), 7.03 (d, J = 8.52 Hz, 2 H), 5.42 (s, 1 H), 4.82 (s, 2
H), 2.35−2.32 (m, 4 H), 1.99−1.94 (m, 2 H); 13C{1H} NMR
(CDCl3, 125 MHz) δ 197.7 (s), 164.4 (s), 143.4 (s), 136.0 (s), 132.8
(d), 129.5 (d), 128.8 (d), 127.6 (d), 126.9 (d), 121.2 (s), 102.3 (d),
56.5 (t), 36.1 (t), 28.6 (t), 22.5 (t); exact mass (ESI) m/z calcd for
C19H18BrNO (M + Na)+ 378.0464, found 378.0461.
1
1490, 1452 cm−1; H NMR (CDCl3, 500 MHz) δ 7.39−7.31 (m, 6
H), 7.30−7.22 (m, 1 H), 7.13 (t, J = 8.1 Hz, 1 H), 7.01−6.94 (m, 2
H), 6.67 (ddd, J = 8.2, 2.2, 0.9 Hz, 1 H), 6.56 (t, J = 2.3 Hz, 1 H),
6.46 (ddd, J = 8.1, 2.4, 0.9 Hz, 1 H), 4.97 (s, 2 H), 4.77−4.73 (m, 1
H); 13C{1H} NMR (CDCl3, 126 MHz) δ 156.5 (s), 149.3 (s), 146.8
(s), 138.6 (s), 132.2 (d), 130.3 (d), 128.7 (d), 127.0 (d), 126.5 (d),
122.7 (d), 114.1 (s), 113.2 (d), 108.9 (d), 107.6 (d), 56.3 (t); exact
mass (ESI) m/z calcd for C19H15BrNO (M − H)− 352.0343, found
352.0340.
3-[(2-Methylphenyl)amino]cyclohex-2-en-1-one (22).54 2-
Methylaniline (0.40 mL, 3.75 mmol) was added to AcOH (6 mL)
followed by cyclohexane-1,3-dione (0.420 g, 3.75 mmol), and the
mixture was stirred at 97 °C (N2 atmosphere) for 4 h (TLC
monitoring). The solvent was then evaporated at 40 °C, and the
residue was dissolved in the minimum of CHCl3 and applied to the
top of a chromatography column made up with silica gel (2.5 × 20
cm) and hexane. Flash chromatography, using first 1:1 EtOAc-hexane
(ca. 250 mL), then 1:1 hexane-EtOAc, and finally pure EtOAc, gave
1
22 (0.580 g, 77%) as a cream colored solid: mp 162−166 °C; H
NMR (CDCl3, 400 MHz) δ 7.26−7.16 (m, 4 H), 5.90 (br s, 1 H),
5.10 (s, 1 H), 2.53 (t, J = 6.20 Hz, 2 H), 2.37 (t, J = 6.53 Hz, 2 H),
2.24 (s, 3 H), 2.11−2.04 (m, 2 H); 13C{1H} NMR (CDCl3, 125
MHz) δ 197.8 (s), 162.9 (s), 136.0 (s), 134.1 (s), 131.1 (s), 127.2
(d), 126.92 (d), 126.87 (d), 99.7 (d), 36.4 (t), 29.4 (t), 22.0 (t), 17.7
(q).
3-[Benzyl(2-methylphenyl)amino]cyclohex-2-en-1-one (23).
NaH (60% w/w in mineral oil, 60 mg, 1.5 mmol) was tipped into a
stirred solution of 22 (200 mg, 0.994 mmol) in dry DMF (6 mL) (N2
atmosphere), and stirring was continued for 2 h. There was gas
evolution initially, and the mixture gradually became dark. BnCl
(0.145 mL, 1.15 mmol) was injected at a fast dropwise rate, and
stirring was continued overnight, by which time reaction was
complete (TLC, silica, 1:1 EtOAc-hexane). The mixture was diluted
with EtOAc, water was added, and the aqueous phase was extracted
with EtOAc. The combined organic extracts were dried (MgSO4) and
10-(4-Bromophenyl)-9-phenyl-1,2,3,4,5,6,7,8,9,10-decahy-
droacridin-1,8-dione (i).53 Compound (i): mp 262−265 °C; FTIR
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evaporated. Flash chromatography of the residue over silica gel (2 ×
25 cm), using 1:1 hexane-EtOAc (300 mL) and then EtOAc, gave 23
(225 mg, 78%) as a thick, bright yellow liquid: FTIR (CH2Cl2 cast
film) 3060, 2946, 2868, 1622, 1554, 1185, 1081, 726 cm−1; 1H NMR
(CDCl3, 500 MHz) δ 7.33−7.21 (m, 7 H), 7.16 (br t, J = 7.42 Hz, 1
H), 7.02 (d, J = 7.78 Hz, 1 H), 5.59 (br s, 1 H), 4.96 (br d, J = 13.55
Hz, 1 H), 4.48 (br d, J = 15.84 Hz, 1 H), 2.32 (t, J = 6.41 Hz, 2 H),
2.13 (s, 3 H), 1.94 (br s, 3 H); 13C{1H} NMR (CDCl3, 125 MHz) δ
197.5 (s), 165.0 (s), 142.7 (s), 131.5 (d), 128.6 (d), 128.2 (d), 127.6
(d), 127.1 (d), 55.6 (t), 36.1 (t), 22.4 (t), 17.6 (q); exact mass (ESI)
m/z calcd for C20H21NNaO (M + Na)+ 314.1515, found 314.1515.
3-[Benzyl(2-methylphenyl)amino]-2-chlorocyclohex-2-en-
1-one (23b). NaHCO3 (155 mg, 1.85 mmol) and BnNMe3·ICl2 (138
mg, 0.397 mmol) were tipped into a flask containing 23 (77.3 mg,
0.265 mmol) and a magnetic stir bar. The flask was closed with a
septum, flushed with N2, and kept under a static pressure of N2. A 2:1
mixture of CH2Cl2 and MeOH (3 mL in total) was injected, and the
mixture was stirred at room temperature for 3 h. At this stage, TLC
(silica, 24:1 CH2Cl2-MeOH) showed no 23. The mixture was filtered
through a sintered disc and evaporated. Flash chromatography of the
residue over silica gel (2 × 15 cm), using 99.5:0.5 CH2Cl2-MeOH,
gave 23b (83.9 mg, 97%) as a thick, yellow oil: FTIR (neat film)
chromatography, using first hexane (ca 100 mL) and then pure
EtOAc, gave 24 (535 mg, 59%) as a yellow solid.
4-[Benzyl(3-oxocyclohex-1-en-1-yl)amino]benzonitrile (25).
NaH (60% w/w in mineral oil, 112 mg, 2.80 mmol) was tipped into a
stirred solution of 24 (400 mg, 1.88 mmol) in dry DMF (8 mL) (N2
atmosphere), and stirring was continued for 2 h. There was gas
evolution initially, and the mixture gradually became dark. BnCl
(0.247 mL, 2.15 mmol) was injected at a fast dropwise rate, and
stirring was continued overnight. The mixture was diluted with
EtOAc, water was added, and the aqueous phase was extracted with
EtOAc. The combined organic extracts were dried (MgSO4) and
evaporated. Flash chromatography of the residue over silica gel (2 ×
20 cm), using 97.5:2.5 CH2Cl2-MeOH, gave 25 (295 mg, 52%) as a
thick, yellow oil, which slowly solidified: mp 94−96 °C; FTIR
(CH2Cl2 cast film) 3059, 2946, 2872, 2227, 1628, 1559, 1186, 733
1
cm−1; H NMR (CDCl3, 500 MHz) δ 7.64 (d, J = 8.61 Hz, 2 H),
7.32−7.26 (m, 5 H), 7.18 (d, J = 7.14 Hz, 2 H), 5.43 (s, 1 H), 4.87 (s,
2 H), 2.38 (t. J = 5.04 Hz, 2 H), 2.32 (t, J = 6.96 Hz, 2 H), 1.9 (quint,
J = 6.32 Hz, 2 H); 13C{1H} NMR (CDCl3, 125 MHz) δ 197.7 (s),
163.4 (s), 148.5 (s), 135.8 (s), 133.5 (d), 128.9 (d), 128.0 (d), 127.8
(d), 126.6 (d), 118.0 (s), 110.5 (s), 104.4 (d), 56.3 (t), 36.2 (t), 28.7
(t), 22.6 (t); exact mass (ESI) m/z calcd for C20H18N2NaO (M +
Na)+ 325.1311, found 325.1312.
1
3061, 2951, 2868, 1649, 1536, 1276, 721 cm−1; H NMR (CDCl3,
4-[Benzyl(2-chloro-3-oxocyclohex-1-en-1-yl)amino]-
benzonitrile (25b). NaHCO3 (84.0 mg, 1.00 mmol) and BnNMe3·
ICl2 (73.7 mg, 0.212 mmol) were tipped into a flask containing 25
(42.7 mg, 0.141 mmol) and a magnetic stir bar. The flask was closed
with a septum, flushed with N2, and kept under a static pressure of N2.
A 2:1 mixture of CH2Cl2 and MeOH (3 mL in total) was injected,
and the mixture was stirred at room temperature for 3 h. At this stage,
TLC (silica, 24:1 CH2Cl2-MeOH) showed the presence of only a
trace of 25. Even so, the mixture was filtered through a sintered disc
and evaporated. Flash chromatography of the residue over silica gel (2
× 18 cm), using 99.5:0.5 CH2Cl2-MeOH, gave 25b (38.8 mg, 82%) as
a light brown solid: mp 48−50 °C; FTIR (liquid film) 3063, 2953,
500 MHz) δ 7.36−7.27 (m, 5 H), 7.21−7.11 (m, 4 H), 5.13 (br s, 2
H), 2.52−2.48 (m, 4 H), 2.17 (s, 3 H), 1.85 (quint, J = 6.34 Hz, 2 H);
13C{1H} NMR (CDCl3, 125 MHz) δ 190.9 (s), 159.4 (s), 145.1 (s),
137.4 (s), 134.8 (s), 131.1 (d), 128.7 (d), 127.6 (d), 127.1 (d), 127.0
(d), 126.9 (d), 109.5 (s), 58.0 (t), 37.4 (t), 31.9 (t), 20.5 (t), 18.1
(q); exact mass (ESI) m/z calcd for C20H20ClNNaO (M + H)+
348.1126, found 348.1128.
3-[Benzyl(2-methylphenyl)amino]phenol (23c). DBU (21 μL,
0.14 mmol) was injected at a fast dropwise rate into a stirred solution
of 23b (22.7 mg, 0.070 mmol) in dry MeCN (2 mL) (N2
atmosphere), and stirring was continued for 40 h at which point
some 23b remained (TLC, silica, CH2Cl2). Stirring was continued for
a further 30 h at which point TLC showed that only a trace of 23b
was left. Evaporation of the solvent and flash chromatography of the
residue over silica gel (2 × 20 cm), using CH2Cl2, gave 23c (14.6 mg,
72%) as a pale mauve solid: mp 94−95 °C; FTIR (solid) 3507, 3056,
1
2872, 2220, 1675, 1584, 1293, 1045, 734 cm−1; H NMR (CDCl3,
500 MHz) δ 7.54−7.52 (m, 2 H), 7.40−7.37 (m, 2 H), 7.34−7.27
(m, 3 H), 6.91−6.89 (m, 2 H), 5.02 (s, 2 H), 2.73 (t, J = 6.00 Hz, 2
H), 2.62 (t, J = 6.23 Hz, 2 H), 2.04 (quint, J = 6.41 Hz, 2 H);
13C{1H} NMR (CDCl3, 125 MHz) δ 191.2 (s), 157.7 (s), 148.9 (s),
136.5 (s), 133.4 (d), 129.1 (d), 127.8 (d), 126.2 (d), 123.0 (s), 119.1
(s), 118.9 (d), 104.5 (s), 54.8 (t), 37.7 (t), 31.0 (t), 20.8 (t); exact
mass (ESI) m/z calcd for C20H17ClN2NaO (M + H)+ 359.0922,
found 359.0919.
1
2923, 2852, 1618, 1575, 1164, 727 cm−1; H NMR (CDCl3, 500
MHz) δ 7.40 (d, J = 7.32 Hz, 2 H), 7.36−7.32 (m, 3 H), 7.29−7.25
(m, 4 H), 7.01 (t, J = 8.15 Hz, 1 H), 6.19 (br dd, J = 11.35, 1.83 Hz, 2
H), 6.01 (t, J = 2.29 Hz, 1 H), 4.84 (s, 2 H), 4.58 (s, 1 H), 2.19 (s, 3
H); 13C{1H} NMR (CDCl3, 125 MHz) δ 156.4 (s), 150.2 (s), 145.6
(s), 138.9 (s), 137.0 (s), 131.7 (d), 130.0 (d), 129.3 (d), 128.5 (d),
127.5 (d), 127.0 (d), 126.8 (d), 106.2 (d), 104.2 (d), 100.4 (d), 56.2
(t), 18.3 (q); exact mass (ESI) m/z calcd for C20H18NO (M − H)−
288.1394, found 288.1391.
4-[Benzyl(3-hydroxyphenyl)amino]benzonitrile (25c). DBU
(31.6 μL, 0.212 mmol) was injected at a fast dropwise rate into a
stirred solution of 25b (35.6 mg, 0.106 mmol) in dry MeCN (3 mL)
(N2 atmosphere), and stirring was continued for 24 h. Evaporation of
the solvent and flash chromatography of the residue over silica gel (2
× 20 cm), using 99.5:0.5 CH2Cl2-MeOH, gave 25c (19.8 mg, 62%) as
a solid: mp 114−116 °C; FTIR (solid) 3336, 3032, 2880, 2221, 1592,
4-[(3-Oxocyclohex-1-en-1-yl)amino]benzonitrile (24).13 4-
Aminobenzonitrile (500 mg, 4.23 mmol) was added to AcOH (7
mL) followed by cyclohexane-1,3-dione (474 mg, 4.23 mmol), and
the mixture was stirred at 97 °C (N2 atmosphere) overnight. The
solvent was then evaporated at 40 °C, and the residue was dissolved in
the minimum of EtOAc and applied to the top of a chromatography
column made up with silica gel (2 × 20 cm) and hexane. Flash
chromatography, using first hexane (ca. 100 mL) and then pure
EtOAc, gave 24 (0.517 g, 57%) as a yellow solid: mp 216−218 °C; 1H
NMR (CDCl3, 500 MHz) δ 7.66−7.62 (m, 2 H), 7.29−7.25 (m, 2
H), 5.81 (s, 1 H), 6.23 (br s, 1 H), 2.55 (t, J = 6.18 Hz, 2 H), 2.43 (t,
J = 7.14 Hz, 2 H), 2.13−2.07 (m, 2 H); 13C{1H} NMR (CDCl3, 125
MHz) δ 198.3 (s), 158.7 (s), 142.7 (s), 133.5 (d), 122.0 (d), 118.4
(s), 107.5 (s), 103.0 (d), 36.5 (t), 30.0 (t), 21.6 (t).
1
1510, 1376, 1201, 699 cm−1; H NMR (CDCl3, 500 MHz) δ 7.40−
7.33 (m, 4 H), 7.31−7.26 (m, 4 H), 6.87 (dd, J = 7.97, 1.19 Hz, 1 H),
6.82−6.80 (m, 3 H), 6.75 (d, J = 8.08 Hz, 1 H), 5.35 (br s, 1 H), 5.00
(s, 2 H); 13C{1H} NMR (CDCl3, 125 MHz) δ 157.1 (s), 151.2 (s),
147.4 (s), 137.4 (s), 133.3 (d), 130.9 (d), 128.8 (d), 127.3 (d), 126.3
(d), 120.1 (s), 118.3 (d), 115.0 (d), 113.29 (d), 113.25 (d), 99.8 (s),
56.3 (t); exact mass (ESI) m/z calcd for C20H16N2NaO (M + Na)+
323.1155, found 323.1159.
3-[(4-Bromophenyl)amino]cyclohex-2-en-1-one (26).13
PhMe (20 mL) followed by AcOH (ca. 1 mL) was added to a flask
containing cyclohexane-1,3-dione (1.04 g, 9.45 mmol) and 4-
bromoaniline (1.62 g, 9.35 mmol), and the mixture was refluxed
overnight under a Dean-Stark trap. The solution was cooled and
evaporated, and flash chromatography of the residue over silica gel (3
× 15 cm), using 9:1 CH2Cl2-MeOH, gave 26 (2.19 g, 88%) as a
yellow solid: mp 174−176 °C; 1H NMR (CDCl3, 400 MHz) δ 7.50−
7.46 (m, 2 H), 7.09−7.05 (m, 2 H), 5.98 (br s, 1 H), 5.57 (s, 1 H),
2.51 (t, J = 6.20 Hz, 2 H), 2.39 (t, J = 6.82 Hz, 2 H), 2.07 (quint, J =
6.6 Hz, 2 H); 13C{1H} NMR (CDCl3, 175 MHz) δ 198.1 (s), 161.1
The preparation of 24 was repeated without acetic acid: 4-
Aminobenzonitrile (508 mg, 4.30 mmol) was added to PhH (7 mL)
followed by cyclohexane-1,3-dione (0.482 g, 4.299 mmol), and the
mixture was refluxed (N2 atmosphere) overnight. The solvent was
then evaporated at 40 °C, and the residue was dissolved in the
minimum of EtOAc and applied to the top of a chromatography
column made up with silica gel (2 × 21 cm) and hexane. Flash
H
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(s), 137.1 (s), 132.4 (d), 125.3 (d), 118.4 (s), 100.5 (d), 36.4 (t),
29.7 (t), 21.7 (t).
Hz, 1 H), 6.93−6.88 (m, 2 H), 6.56 (ddd, J = 8.2, 2.2, 0.9 Hz, 1 H),
6.46 (t, J = 2.3 Hz, 1 H), 6.43 (ddd, J = 8.1, 2.4, 0.9 Hz, 1 H), 4.62 (s,
1 H), 3.25 (s, 3 H); 13C{1H} NMR (CDCl3, 176 MHz) δ 156.4 (s),
150.1 (s), 147.8 (s), 132.1 (d), 130.2 (d), 122.6 (d), 114.1 (s), 112.7
(d), 108.5 (d), 107.1 (d), 40.2 (q); exact mass (ESI) m/z calcd for
C13H12BrNO (M − H)− 276.0030, found 276.0029.
3-[(4-Bromophenyl)(methyl)amino]cyclohex-2-en-1-one
(27).35 Dry DMF (20 mL) was injected into a flask containing the
enaminone 26 (0.90 g, 3.39 mmol) (N2 atmosphere), and the stirred
mixture was cooled in an ice bath. NaH (60% w/w dispersion in oil,
0.27 g, 6.75 mmol) was tipped into the resulting solution under a
stream on N2, the ice bath was removed, and stirring was continued
for 2 h. MeI (0.53 mL, 8.51 mmol) was then injected dropwise over
about 2 min, and stirring was continued overnight. The mixture was
poured into water (250 mL) and extracted with EtOAc (4 × 50 mL).
The combined organic extracts were washed with brine (2 × 25 mL),
dried (Na2SO4), and evaporated. Flash chromatography of the residue
over silica gel (2 × 15 cm), using 49:1 CH2Cl2-MeOH, gave 27 (0.52
g, 55%) as a beige solid.
4-Bromo-N-[(4-methoxyphenyl)methyl]aniline.56 4-
MeOC6H4CHO (0.71 mL, 5.84 mmol) was added dropwise to a
stirred solution of 4-bromoaniline (1.198 g, 7.00 mmol) in anhydrous
EtOH (30 mL). A pale greenish precipitate formed. CeCl3·7H2O (44
mg, 0.12 mmol) was added, the reaction flask was stoppered, and
stirring was continued for an arbitrary period of 3 h. At that stage,
NaBH4 (442 mg, 11.7 mmol) was added in one portion. Immediate
bubbling was observed, the precipitate dissolved, and the mixture
became light brown. Stirring was continued overnight with the flask
open to the atmosphere. Evaporation of EtOH gave a residue, which
was partitioned between EtOAc and water. The aqueous phase was
washed twice with EtOAc, and the combined organic extracts were
dried (Na2SO4) and evaporated. Flash chromatography of the residue
over silica gel (2 × 15 cm), using first hexane (ca. 200 mL) and then
1:4 hexane-EtOAc, gave 4-bromo-N-[(4-methoxyphenyl)methyl]-
aniline (1.59 g, 77%) as a white solid: mp 79−81 °C; 1H NMR
(CDCl3, 500 MHz) δ 7.32−7.25 (m, 2 H), 6.93−6.89 (m, 2 H),
6.54−6.51 (m, 2 H), 4.25 (s, 2 H), 4.03 (br s, 1 H), 3.83 (s, 3 H);
13C{1H} NMR (CDCl3, 175 MHz) δ 159.0 (s), 146.8 (s), 131.9 (d),
4-Bromo-N-methylaniline.55 Oven-dried K2CO3 (2.433 g, 17.61
mmol) was added to a solution of 4-BrC6H4NH2 (2.00 g, 11.70
mmol) in dry THF (18 mL), then MeI (1.46 mL, 23.4 mmol) was
injected, and the mixture was stirred overnight at room temperature.
Examination of the mixture by TLC (silica, 5:95 EtOAc-hexane)
showed 4-BrC6H4NH2 and two new spots. The mixture was diluted
with EtOAc and water, and the aqueous phase was extracted with
EtOAc. The combined organic extracts were dried (MgSO4) and
evaporated. Flash chromatography of the residue over gel (2 × 22
cm), using 19:1 hexane-EtOAc, gave 4-bromo-N-methylaniline (419.9
1
mg, 19.4%) as a pale yellow liquid: H NMR (CDCl3, 500 MHz) δ
130.6 (s), 128.7 (d), 114.5 (d), 114.0 (d), 109.2 (s), 55.2 (q), 47.8
(t).
7.30 (d, J = 8.15 Hz, 2 H), 6.51 (d, J = 8.97 Hz, 2 H), 3.71 (br s, 1
H), 2.83 (s, 3 H); 13C{1H} NMR (CDCl3, 125 MHz) δ 148.3 (d),
131.8 (d), 113.9 (d), 108.7 (s), 30.7 (q).
3-[(4-Bromophenyl)[(4-methoxyphenyl)methyl]amino]-
cyclohex-2-ene-1-one (28). N-[4-Methoxybenzyl]-4-bromoaniline
(150 mg, 0.513 mmol) was added to AcOH (6 mL) followed by
cyclohexane-1,3-dione (57.5 mg, 0.513 mmol), and the mixture was
stirred at 95 °C (N2 atmosphere) for 4 h (TLC monitoring, silica,
EtOAc). The solvent was then evaporated at 40 °C, and the residue
was dissolved in the minimum of EtOAc and applied to the top of a
chromatography column made up with silica gel (2 × 15 cm) and
hexane. Flash chromatography, using first hexane (ca 200 mL) and
then 1:9 hexane-EtOAc, gave 28 (0.130 g, 65%) as a bright yellow
solid: mp 89−91 °C; FTIR (CH2Cl2 cast film) 2946, 2834, 1623,
3-[(4-Bromophenyl)(methyl)amino]cyclohex-2-en-1-one
(27).35 4-Bromo-N-methyl-aniline (419.9 mg, 2.269 mmol) was
added to AcOH (7 mL) followed by cyclohexane-1,3-dione (254.4
mg, 2.269 mmol), and the mixture was stirred at 95 °C (N2
atmosphere) for 6 h. The solvent was then evaporated at 40 °C,
and the residue was dissolved in the minimum of CH2Cl2 and applied
to the top of a chromatography column made up with silica gel (2 ×
25 cm) and CH2Cl2. Flash chromatography, using 24:1 CH2Cl2-
MeOH, gave 27 (546.9 mg, 86%) as a pinkish white solid: mp 162−
1
1
1556, 1186, 819 cm−1; H NMR (CDCl3, 400 MHz) δ 7.48 (d, J =
164 °C; H NMR (CDCl3, 500 MHz) δ 7.51−7.49 (m, 2 H), 7.03−
6.98 (m, 2 H), 5.27 (s, 1 H), 3.18 (s, 3 H), 2.27 (t, J = 6.23 Hz, 2 H),
2.19 (t, J = 6.18 Hz, 2 H), 1.88 (quint, J = 6.41 Hz, 2 H); 13C{1H}
NMR (CDCl3, 125 MHz) δ 197.5 (s), 164.4 (s), 144.3 (s), 132.8 (d),
128.8 (d), 120.9 (s), 101.2 (d), 40.6 (q), 36.0 (t), 28.4 (t), 22.4 (t).
3-[(4-Bromophenyl)(methyl)amino]-2-chlorocyclohex-2-en-
1-one (27b). BnNMe3·ICl2 (365.1 mg, 1.05 mmol) was tipped into a
stirred solution of 27 (195.0 mg, 0.696 mmol) in a mixture of dry
CH2Cl2 (8 mL) and dry MeOH (4 mL) followed immediately by
NaHCO3 (418.9 mg, 4.99 mmol), which was also added in one
portion (N2 atmosphere). Stirring was continued for 45 min, and the
mixture was then filtered through a sintered disc. Evaporation of the
filtrate and flash chromatography of the residue over silica gel (2 × 15
cm), using 1:1 hexane-EtOAc, gave 27b (195.7 mg, 89%) as a yellow
solid: FTIR (CDCl3, cast film) 2956, 2924, 1651, 1542, 1488, 1322,
8.00 Hz, 2 H), 7.09 (d, J = 8.66 Hz, 2 H), 7.01−6.96 (m, 2 H), 6.84
(d, J = 7.97 Hz, 2 H), 5.43 (s, 1 H), 4.74 (s, 2 H), 3.80 (s, 3 H),
2.35−2.28 (m, 4 H), 1.98−1.91 (m, 2 H); 13C{1H} NMR (CDCl3,
125 MHz) δ 197.7 (s), 164.5 (s), 159.1 (s), 143.2 (s), 132.8 (d),
129.6 (d), 128.5 (d), 127.9 (s), 121.2 (s), 114.2 (d), 101.9 (d), 55.9
(t), 55.3 (q), 36.0 (t), 28.6 (t), 22.4 (t); exact mass (ESI) m/z calcd
for C20H21BrNNaO2 (M + Na)+408.0570, found 408.0571.0749.
3-[(4-Bromophenyl)[(4-methoxyphenyl)methyl]amino]-2-
chlorocyclohex-2-en-1-one (28b). BnNMe3·ICl2 (216.2 mg, 0.621
mmol) was tipped into a stirred solution of 28 (197.1 mg, 0.510
mmol) in a mixture of dry CH2Cl2 (8 mL) and dry MeOH (2 mL)
followed immediately by NaHCO3 (306.2 mg, 3.64 mmol), which was
also added in one portion (N2 atmosphere). Stirring was continued
for 1 h, and the mixture was then filtered through a sintered disc.
Evaporation of the filtrate and flash chromatography of the residue
over silica gel (2 × 15 cm), using 1:1 hexane-EtOAc, gave 28b (157.0
mg, 73%) as a solid: mp 134−136 °C; FTIR (CH2Cl2, cast film)
2954, 2835, 2244, 1655, 1574, 1487, 1248, 1184, 1006, 731 cm−1; 1H
NMR (CDCl3, 700 MHz) δ 7.34 (d, J = 8.4 Hz, 2 H), 7.15 (d, J = 8.2
Hz, 2 H), 6.84 (t, J = 7.6 Hz, 4 H), 4.97 (s, 2 H), 3.77 (s, 3 H), 2.62
(t, J = 6.0 Hz, 2 H), 2.50 (t, J = 6.5 Hz, 2 H), 1.89 (quint, J = 6.2 Hz,
2 H); 13C{1H} NMR (CDCl3, 176 MHz) δ 191.1 (s), 159.0 (s),
158.9 (s), 145.3 (s), 132.1 (d), 129.1 (s), 127.6 (d), 124.3 (d), 117.0
(s), 115.9 (s), 114.3 (d), 55.9 (t), 55.3 (q), 37.5 (t), 31.3 (t), 20.7
(t); exact mass (ESI) m/z calcd for C20H19BrClNO2 (M + Na)+
442.0180, found 442.0181.
1
1266, 1187, 1007, 824 cm−1; H NMR (CDCl3, 400 MHz) δ 7.51−
7.43 (m, 2 H), 6.96−6.88 (m, 2 H), 3.47 (s, 3 H), 2.59 (q, J = 6.6, 6.2
Hz, 4 H), 2.09−1.93 (m, 2 H); 13C{1H} NMR (CDCl3, 176 MHz) δ
191.1 (s), 160.0 (s), 145.3 (s), 132.4 (d), 124.7 (d), 117.6 (s), 114.3
(s), 41.8 (q), 37.6 (t), 31.3 (t), 20.8 (t); exact mass (ESI) m/z calcd
for C13H13BrClNO (M + Na)+ 335.9761, found 335.9761.
3-[(4-Bromophenyl)(methyl)amino]phenol (27c). DBU (62.5
μL, 0.419 mmol) was injected at a fast dropwise rate into a stirred
solution of 27b (65.5 mg, 0.209 mmol) in dry MeCN (3 mL) (N2
atmosphere), and stirring was continued for 20 h. At this point, TLC
(silica, 99:1 CH2Cl2-MeOH) showed two spots but no 27b.
Evaporation of the solvent and flash chromatography of the residue
over silica gel (2 × 19.5 cm), using 99:1 CH2Cl2-MeOH, gave 27c as
two successive fractions with identical TLC Rf values and NMR
spectra (42.7 mg, 74% in total) as viscous liquids: FTIR (CH2Cl2, cast
film) 3371, 2882, 2814, 1583, 1489, 1348, 1127, 1008, 943, 814 cm−1;
1H NMR (CDCl3, 700 MHz) δ 7.38−7.33 (m, 2 H), 7.11 (t, J = 8.1
3-[(4-Bromophenyl)[(4-methoxyphenyl)methyl]amino]-
phenol (28c). DBU (93 μL, 0.62 mmol) was injected at a fast
dropwise rate into a stirred solution of 28b (131.1 mg, 0.311 mmol)
and LiCl (27 mg, 0.64 mmol) in dry MeCN (3 mL) (N2
atmosphere), and stirring was continued for 48 h. Evaporation of
I
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the solvent and flash chromatography of the residue over silica gel (1
× 10 cm), using 1:1 hexane-EtOAc, gave 28c (101.7 mg, 84%) as a
purplish oil: FTIR (CH2Cl2, cast film) 3399, 2999, 2953, 2933, 2835,
126.8 (d), 126.6 (d), 109.9 (d), 35.5 (t), 31.9 (t), 25.0 (d); low-
resolution mass (ESI) m/z calcd for C18H16INaO (M + Na)+
412.0169, found 412.0. The location of the iodine at C(4) was
established by a 1D ROESY experiment, which showed that the ortho
aromatic hydrogens are close to the C(4) hydrogen.
1
1610, 1584, 1489, 1245, 819 cm−1; H NMR (CDCl3, 500 MHz) δ
7.34−7.28 (m, 2 H), 7.23−7.17 (m, 2 H), 7.09 (t, J = 8.1 Hz, 1 H),
6.97−6.90 (m, 2 H), 6.87−6.81 (m, 2 H), 6.63 (dd, J = 8.2, 2.2 Hz, 1
H), 6.52 (t, J = 2.3 Hz, 1 H), 6.43 (dd, J = 8.0, 2.4 Hz, 1 H), 4.92 (s, 1
H), 4.87 (s, 2 H), 3.78 (s, 3 H); 13C{1H} NMR (CDCl3, 176 MHz) δ
158.6 (s), 156.5 (s), 149.3 (s), 146.8 (s), 132.1 (d), 130.4 (s), 130.3
(d), 127.6 (d), 122.6 (d), 114.1 (d), 113.9 (s), 113.2 (d), 108.8 (d),
107.7 (d), 55.6 (t), 55.3 (q); exact mass (ESI) m/z calcd for
C20H18BrNO2 (M − H)− 382.0448, found 382.045.
3-(Diphenylamino)phenol (29c).37 DBU (16.6 μL, 0.111
mmol) was injected at a fast dropwise rate into a stirred solution of
29b (16.5 mg, 0.055 mmol) in dry MeCN (3 mL) (N2 atmosphere),
and stirring was continued for 24 h. Evaporation of the solvent and
flash chromatography of the residue over silica gel (2 × 24 cm), using
99:1 CH2Cl2-MeOH, gave 29c (11.4 mg, 79%) as a white solid: mp
110−112 °C; FTIR (CH2Cl2 cast film) 3523, 3035, 2923, 2849, 1589,
3-(Diphenylamino)cyclohex-2-en-1-one (29).13 Diphenyl-
amine (0.507 g, 3.00 mmol) was added to AcOH (6 mL) followed
by cyclohexane-1,3-dione (0.336 g, 3.00 mmol), and the mixture was
stirred at 96 °C (N2 atmosphere) for 52 h (TLC monitoring, silica,
EtOAc). Although the reaction was still not complete (TLC), the
solvent was evaporated at 40 °C and the residue was dissolved in the
minimum of EtOAc and applied to the top of a chromatography
column made up with silica gel (2 × 15 cm) and hexane. Flash
chromatography, using first hexane (ca. 200 mL), then 1:1 hexane-
EtOAc, and finally pure EtOAc, gave 29 (0.573 g, 72%) as a cream-
colored solid: mp 156−158 °C; 1H NMR (CDCl3, 500 MHz) δ
7.40−7.35 (m, 4 H), 7.29−7.24 (m, 2 H), 7.22−7.19 (m, 4 H), 5.32
(s, 1 H), 2.42 (t, J = 6.13 Hz, 2 H), 2.37 (t, J = 6.5 Hz, 2 H), 2.01
(quint, J = 6.34 Hz, 2 H);13C{1H} NMR (CDCl3, 175 MHz) δ 198.0
(s), 165.2 (s), 144.0 (s), 129.6 (d), 127.8 (d), 126.9 (d), 105.7 (d),
36.4 (t), 29.1 (t), 22.8 (t).
1
1492, 1275, 1148, 754, 697 cm−1; H NMR (CDCl3, 500 MHz) δ
7.31−7.26 (m, 4 H), 7.14−7.09 (m, 5 H), 7.05 (t, J = 7.23 Hz, 2 H),
6.66 (ddd, J = 8.13, 2.04, 0.73 Hz, 1 H), 6.55 (t, J = 2.24 Hz, 1 H),
6.49 (ddd, J = 8.03, 2.45, 0.78 Hz, 1 H), 4.63 (br s, 1 H); 13C{1H}
NMR (CDCl3, 100 MHz) δ 155.8 (s), 148.9 (s), 147.2 (s), 129.6 (d),
128.8 (d), 124.2 (d), 122.6 (d), 115.6 (d), 109.9 (d), 108.9 (d); exact
mass (EI) m/z calcd for C18H14NO (M − H)− 260.1081, found
260.1079.
The corresponding 2-iodo enaminone (29b′), when subjected to
the same conditions, afforded 29c in 42% yield, and the 4-iodo
enaminone (29b″) gave 29c in 54% yield.
3-[Benzyl(methyl)amino]cyclohex-2-en-1-one (30). N-Meth-
ylbenzylamine (3.1 mL, 4.32 g, 35.7 mmol) was added to a solution of
cyclohexane-1,3-dione (4.03 g, 35.9 mmol) in PhMe (100 mL), and
the mixture was refluxed for 5 h under a Dean-Stark trap. The
resulting dark red solution was cooled and evaporated, and flash
chromatography of the residue over silica gel (5 × 15 cm), using first
1:1 CH2Cl2-EtOAc and then pure MeOH, gave 30 (from the MeOH
fractions) (6.61 g, 96%) as a dark orange oil that solidified at room
temperature: mp 65−67 °C; FTIR (CDCl3, cast film) 3028, 2942,
1620, 1585, 1555, 1452, 1263, 1190, 938, 736 cm−1; 1H NMR
(CDCl3, 700 MHz) δ 7.35 (t, J = 7.6 Hz, 2 H), 7.28 (t, J = 7.4 Hz, 1
H), 7.10 (d, J = 7.6 Hz, 2 H), 5.27 (s, 1 H), 4.51 (s, 2 H), 2.96 (s, 3
H), 2.49 (t, J = 6.2 Hz, 2 H), 2.30 (dd, J = 7.2, 5.9 Hz, 2 H), 1.98
(quint, J = 6.4 Hz, 2 H); 13C{1H} NMR (CDCl3, 176 MHz) δ 197.0
(s), 165.4 (s), 129.0 (d), 127.6 (d), 99.4 (d), 55.1 (t), 38.4 (q), 35.6
(t), 26.8 (t), 22.3 (t); exact mass (ESI) m/z calcd for C14H17NO (M
+ H)+ 216.1383, 216.1381.
3-[Benzyl(methyl)amino]-2-chlorocyclohex-2-en-1-one
(30b). NaHCO3 (606.8 mg, 7.224 mmol) and BnNMe3·ICl2 (538.7
mg, 1.548 mmol) were tipped into a flask containing 30 (222.2 mg,
1.032 mmol) and a magnetic stir bar. The flask was closed with a
septum, flushed with N2, and kept under a static pressure of N2. A 2:1
mixture of CH2Cl2 and MeOH (6 mL in total) was injected, and the
mixture was stirred at room temperature for 75 min. At this stage,
TLC (silica, 24:1 CH2Cl2-MeOH) showed no 30. The mixture was
filtered through a sintered disc and evaporated. Flash chromatography
of the residue over silica gel (2 × 25 cm), using 99:1 CH2Cl2-MeOH,
gave 30b (239.2 mg, 94%) as a thick, dark brown oil: FTIR (CDCl3,
cast film) 3060, 2943, 1640, 1541, 1495, 1354, 1323, 1289, 1068, 734
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.46−7.37 (m, 2 H), 7.36−7.30
(m, 1 H), 7.28−7.22 (m, 2 H), 4.71 (s, 2 H), 3.17 (s, 3 H), 2.67 (t, J
= 6.1 Hz, 2 H), 2.55−2.49 (m, 2 H), 1.99−1.90 (m, 2 H); 13C{1H}
NMR (CDCl3, 126 MHz) δ 190.4 (s), 162.3 (s), 136.8 (s), 128.9 (d),
127.7 (d), 126.7 (d), 106.1 (s), 57.4 (t), 41.6 (q), 37.1 (t), 31.0 (t),
20.4 (t); exact mass (ESI) m/z calcd for C14H16ClNO (M + Na)+
272.0813, found 272.0812.
2-Chloro-3-(diphenylamino)cyclohex-2-en-1-one (29b).
NaHCO3 (210 mg, 2.50 mmol) and BnNMe3·ICl2 (188 mg, 0.541
mmol) were tipped into a flask containing 29 (95 mg, 0.36 mmol)
and a magnetic stir bar. The flask was closed with a septum, flushed
with N2, and kept under a static pressure of N2. A 2:1 mixture of
CH2Cl2 and MeOH (4.5 mL in total) was injected, and the mixture
was stirred at room temperature for an arbitrary period of 15 h. At this
stage, TLC (silica, 24:1 CH2Cl2-MeOH) showed no 29. The mixture
was filtered through a sintered disc and evaporated. Flash
chromatography of the residue over silica gel (2 × 24 cm), using
first 17:3 hexane-EtOAc (ca. 200 mL), then 3:1 hexane-EtOAc (ca
200 mL), and finally 1:1 hexane-EtOAc, gave 29b (51.8 mg, 48%) as a
pale green solid, the corresponding iodide (29b′) (18 mg, 12%) as a
pale brown solid and the corresponding 4-iodo enaminone (29b″)
(33 mg, 31%) as a brown solid. Compound 29b: mp 139−141 °C;
FTIR (CH2Cl2 cast film) 3062, 2951, 2867, 1663, 1557, 1263, 1009,
756 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.31−7.36 (m, 4 H), 7.18
(t, J = 8.70 Hz, 2 H), 7.05−7.01 (m, 4 H), 2.66−2.61 (m, 4 H), 2.01
(quint, J = 6.96 Hz, 2 H); 13C{1H} NMR (CDCl3, 125 MHz) δ 191.5
(s), 158.2 (s), 145.2 (s), 129.3 (d), 125.3 (d), 125.2 (d), 118.5 (s),
38.1 (t), 32.4 (t), 21.2 (t); exact mass (ESI) m/z calcd for
C18H16ClNNaO (M + Na)+ 320.0813, found 320.0812.
The reaction was repeated in the dark, but again all three products
were formed (TLC monitoring).
3-(Diphenylamino)-2-iodocyclohex-2-en-1-one (29b′).37 3-
(Diphenylamino)-2-iodocyclohex-2-en-1-one (29b′): mp 113−115
°C; FTIR (CH2Cl2 cast film) 3061, 2948, 2865, 1658, 1586, 1544,
1252, 754, 693 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.37−7.32 (m,
4 H), 7.17 (t, J = 7.45 Hz, 2 H), 7.06−7.02 (m, 4 H), 2.73 (t, J = 7.14
Hz, 2 H), 2.61 (t, J = 6.00 Hz, 2 H), 2.03−1.97 (m, 2 H); 13C{1H}
NMR (CDCl3, 125 MHz) δ 193.3 (s), 166.9 (s), 145.0 (s), 129.4 (d),
125.4 (d), 124.9 (d), 95.5 (s), 37.0 (t), 34.0 (t), 21.7 (t); exact mass
(ESI) m/z calcd for C18H16INNaO (M + Na)+ 412.0169, found
412.0169.
3-[Benzyl(methyl)amino]phenol (30c).57 The following experi-
ment was run at a higher concentration than normally used; under the
standard conditions, the yield was lower (36%) after a reaction time
of 42 h. DBU (0.2247 mL, 1.503 mmol) was injected at a fast
dropwise rate into a stirred solution of 30b (187.3 mg, 0.7519 mmol)
in dry MeCN (3 mL) (N2 atmosphere), and stirring was continued
for 42 h, at which point only a trace of 30b remained (TLC, silica,
CH2Cl2). Evaporation of the solvent and flash chromatography of the
residue over silica gel (2 × 23 cm), using 99.5:0.5 CH2Cl2-MeOH,
gave 30c (106.3 mg, 66%) as a pale yellow liquid containing some
impurities (1H NMR). Rechromatography over silica gel (1 × 20 cm),
3-(Diphenylamino)-4-iodocyclohex-2-en-1-one (29b″). 3-
(Diphenylamino)-4-iodocyclohex-2-en-1-one (29b″): mp 120−122
°C; FTIR (CH2Cl2 cast film) 3021, 2919, 2897, 1616, 1584, 1561,
1274, 758 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.42−7.35 (m, 4 H),
7.30−7.25 (m, 2 H), 7.19 (br d, J = 7.51 Hz, 4 H), 5.52 (s, 1 H), 5.22
(t, J = 3.20 Hz, 1 H), 2.62−2.44 (m, 2 H), 2.28 (ddt, J = 14.89, 4.98,
2.52 Hz, 1 H), 1.97 (ddt, J = 14.82, 12.81, 4.18 Hz, 1 H); 13C{1H}
NMR (CDCl3, 125 MHz) δ 196.6 (s), 164.1 (s), 144.0 (s), 129.7 (d),
J
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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
using 19:1 hexane-EtOAc, gave 30c (94.7 mg, 59%) as a yellow oil:
FTIR (CH2Cl2 cast film) 3374, 3061, 2924, 1618, 1578, 1239, 1169
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.36−7.32 (m, 2 H), 7.30−7.22
(m, 3 H), 7.10 (t, J = 8.15 Hz, 1 H), 6.38 (dd, J = 8.33, 1.92 Hz, 1 H),
6.26 (t, J = 2.33 Hz, 1 H), 6.22 (ddd, J = 7.92, 2.33, 0.64 Hz, 1 H),
4.80 (br s, 1 H), 4.55 (s, 2 H), 3.03 (s, 3 H); 13C{1H} NMR (CDCl3,
125 MHz) δ 156.6 (s), 151.4 (s), 138.8 (s), 130.1 (d), 128.61 (d),
126.9 (d), 126.7 (d), 105.3 (d), 103.5 (d), 99.4 (d), 56.5 (t), 38.6
(q); exact mass (ESI) m/z calcd for C14H14NO (M − H)− 212.1081,
found 212.1081.
(CDCl3, 125 MHz) δ 197.0 (s), 164.5 (s), 99.2 (d), 47.5 (t), 35.5 (t),
26.9 (t), 25.4 (t), 24.2 (t), 22.2 (t).
2-Chloro-3-(piperidin-1-yl)cyclohex-2-en-1-one (32b).
NaHCO3 (840 mg, 10.0 mmol) and BnNMe3·ICl2 (643 mg, 1.85
mmol) were tipped into a flask containing 32 (276 mg, 1.54 mmol)
and a magnetic stir bar. The flask was closed with a septum, flushed
with N2, and kept under a static pressure of N2. A 2:1 mixture of
CH2Cl2 and MeOH (4.5 mL in total) was injected, and the mixture
was stirred at room temperature for 3 h. The mixture was filtered
through a sintered disc and evaporated. Flash chromatography of the
residue over silica gel (2 × 26 cm), using first CH2Cl2 to elute a red
fraction, and then 49:1 CH2Cl2-MeOH, gave 32b (263 mg, 80%) as
an oil that slowly changed to a dark brown semi-solid: FTIR (CH2Cl2
3-(Dibenzylamino)cyclohex-2-en-1-one (31). Bn2NH (0.529
mL, 2.76 mmol) was added to AcOH (8 mL) followed by
cyclohexane-1,3-dione (309 mg, 2.75 mmol), and the mixture was
stirred overnight at 92 °C (N2 atmosphere) (TLC monitoring, silica,
EtOAc after 6 h had shown the presence of both reactants). The
solvent was evaporated at 40 °C, and the residue was dissolved in the
minimum of CHCl3 and applied to the top of a chromatography
column made up with silica gel (2 × 21 cm) and hexane. Flash
chromatography, using first hexane (ca. 200 mL), then 1:1 hexane-
EtOAc (ca 200 mL), and finally 9:1 hexane-EtOAc, gave 31 (515 mg,
64%) as a yellowish-red viscous liquid: FTIR (CH2Cl2 cast film)
3061, 2945, 2878, 1622, 1556, 1187, 734 cm exact mass (ESI) m/z
calcd for C20H21NNaO (M + Na)+ 314.1515, found 314.1515.
2-Chloro-3-(dibenzylamino)cyclohex-2-en-1-one (31b).
NaHCO3 (103 mg, 1.23 mmol) and BnNMe3·ICl2 (73.7 mg, 0.212
mmol) were tipped into a flask containing 31 (51.5 mg, 0.177 mmol)
and a magnetic stir bar. The flask was closed with a septum, flushed
with N2, and kept under a static pressure of N2. A 2:1 mixture of
CH2Cl2 and MeOH (4.5 mL in total) was injected, and the mixture
was stirred at room temperature for 3 h. At this stage, TLC (silica,
49:1 CH2Cl2-MeOH) showed the presence of 31 and so more
BnNMe3·ICl2 (37 mg, 0.11 mmol) was tipped into the reaction flask.
After an additional stirring period of 20 min, all 31 had been
consumed. The mixture was filtered through a sintered disc and
evaporated. Flash chromatography of the residue over silica gel (2 ×
22 cm), using first CH2Cl2 to elute a red fraction, and then 49:1
CH2Cl2-MeOH, gave 31b (51.4 mg, 90%) as a yellow oil: FTIR
(CH2Cl2 cast film) 3028, 2949, 1647, 1539, 1277, 1190, 960, 698
cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.40−7.35 (m, 2 H), 7.34−7.29
(m, 2 H), 7.23 (d, J = 7.26 Hz, 4 H), 4.68 (s, 4 H), 2.67 (t, J = 6.13
Hz, 2 H), 2.53 (t, J = 6.87 Hz, 2 H), 1.88 (quint, J = 6.5 Hz, 2 H);
13C{1H} NMR (CDCl3, 125 MHz) δ 190.7 (s), 162.7 (s), 137.1 (s),
128.9 (d), 127.6 (d), 127.0 (d), 108.7 (s), 55.1 (t), 37.2 (t), 31.2 (t),
20.5 (t); exact mass (ESI) m/z calcd for C20H20ClNNaO (M + Na)+
348.1126, found 348.1122.
1
cast film) 2936, 2857, 1640, 1542, 1289, 1187, 970, 778 cm−1; H
NMR (CDCl3, 400 MHz) δ 3.51 (br s, 4 H), 2.60 (t, J = 6.20 Hz, 2
H), 2.48 (t, J = 6.60 Hz, 2 H), 1.94 (quint, J = 6.68 Hz, 2 H), 1.68 (br
s, 6 H); 13C{1H} NMR (CDCl3, 125 MHz) δ 189.7 (s), 162.6 (s),
105.9 (s), 50.7 (t), 36.8 (t), 30.3 (t), 26.5 (t), 24.1 (t), 20.4 (t); exact
mass (ESI) m/z calcd for C11H16ClNNaO (M + Na)+ 236.0813,
found 236.0813.
3-(Piperidine-1-yl)phenol (32c).49 DBU (0.30 mL, 1.10 mmol)
was injected at a fast dropwise rate into a stirred solution of 32b
(117.6 mg, 0.550 mmol) in dry MeCN (3 mL) (N2 atmosphere), and
stirring was continued for 24 h. Evaporation of the solvent and flash
chromatography of the residue over silica gel (2 × 21 cm), using 4:1
hexane-EtOAc, gave 32c (56.1 mg, 58%) as a beige solid: mp 122−
124 °C; FTIR (CH2Cl2 cast film) 3064, 2938, 2857, 1596, 1446,
1
1242, 1134, 765 cm−1; H NMR (CDCl3, 500 MHz) δ 7.11 (t, J =
8.10 Hz, 1 H), 6.55 (dd, J = 8.24, 1.92 Hz, 1 H), 6.40 (d, J = 2.01 Hz,
1 H), 6.31 (ddd, J = 7.97, 2.29, 0.82 Hz, 1 H), 5.32 (br s, 1 H), 3.16−
3.13 (m, 4 H), 1.74−1.69 (m, 4 H), 1.62−1.57 (m, 2 H); 13C{1H}
NMR (CDCl3, 125 MHz) δ 156.5 (s), 153.5 (s), 129.9 (d), 109.1 (d),
106.4 (d), 103.7 (d), 50.5 (t), 25.6 (t), 24.3 (t); exact mass (ESI) m/
z calcd for C11H14NO (M − H)− 176.1081, found 176.1080.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02284.
■
sı
NMR spectra for compounds in this study (PDF)
X-ray data for compound (i) (PDF)
X-ray data for compound 34 (PDF)
Accession Codes
CCDC 2043613−2043614 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
3-(Dibenzylamino)phenol (31c).58 DBU (47.2 μL, 0.316
mmol) was injected at a fast dropwise rate into a stirred solution of
31b (51.4 mg, 0.158 mmol) in dry MeCN (3 mL) (N2 atmosphere),
and stirring was continued for 24 h. Evaporation of the solvent and
flash chromatography of the residue over silica gel (2 × 23 cm), using
99:1 CH2Cl2-MeOH, gave 31c (32.8 mg, 72%) as a clear, viscous
liquid: FTIR (liquid film) 3520, 3403, 3027, 2906, 2866, 1617, 1580,
1504, 1169, 735 cm−1; 1H NMR (CDCl3, 500 MHz) δ 7.40−7.33 (m,
4 H), 7.32−7.28 (m, 5 H), 7.06 (t, J = 8.10 Hz, 1 H), 6.39 (dd, J =
8.29, 1.97 Hz, 1 H), 6.24 (t, J = 2.29 Hz, 1 H), 6.22 (dd, J = 7.92, 1.69
Hz, 1 H), 4.67 (s, 4 H), 4.61 (s, 1 H); 13C{1H} NMR (CDCl3, 125
MHz) δ 156.6 (s), 150.8 (s), 138.4 (s), 130.2 (d), 128.7 (d), 126.9
(d), 126.6 (d), 105.4 (d), 103.8 (d), 99.5 (d), 54.1 (t); exact mass
(EI) m/z calcd for C20H18NO (M − H)− 288.1394, found 288.1393.
3-(Piperidin-1-yl)cyclohex-2-en-1-one (32).17 Piperidine
(1.548 mL, 15.68 mmol) was added to a solution of cyclohexane-
1,3-dione (1.00 g, 8.92 mmol) in PhMe (12 mL), and the mixture was
refluxed for 24 h under a Dean-Stark trap. The resulting dark red
solution was cooled and evaporated. Flash chromatography of the
residue over silica gel (2.5 × 22 cm), using first CH2Cl2 and then 49:1
CH2Cl2-MeOH, gave 32 (1.269 g, 80%) as a red oil: 1H NMR
(CDCl3, 500 MHz) δ 5.22 (s, 1 H), 3.49−3.22 (m, 4 H), 2.35 (t, J =
6.23 Hz, 2 H), 2.21 (dd, J = 7.10, 6.00 Hz, 2 H), 1.92 (quint, J = 0.37
Hz, 2 H), 1.63−1.59 (m, 2 H), 1.55−1.50 (m, 4 H); 13C{1H} NMR
AUTHOR INFORMATION
Corresponding Author
■
Derrick L. J. Clive − Chemistry Department, University of
Alberta, Edmonton, Alberta T6G 2G2, Canada;
orcid.org/0000-0003-2983-2049; Email: derrick.clive@
ualberta.ca
Authors
Damian Szymor-Pietrzak − Undergraduate research
participant, Chemistry Department, University of Alberta,
Edmonton, Alberta T6G 2G2, Canada
Muhammad N. Khan − Visiting Scholar from the Chemistry
Department, COMSATS University, Islamabad, Abbottabad
Campus, Abbottabad 22010, Pakistan
̀
Anaïs Pages − Research Intern from Ecole Nationale
Supérieure d’Ingénieurs de Caen, Caen 14050, France
K
https://dx.doi.org/10.1021/acs.joc.0c02284
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
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(methyl)amino}cyclohex-2-en-1-one, and 3-[benzyl-(methyl)amino]-
2-bromocyclohex-2-en-1-one.
Noah Depner − Undergraduate research participant,
Chemistry Department, University of Alberta, Edmonton,
Alberta T6G 2G2, Canada
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02284
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSERC for financial support (grant number
29322). M.N.K. thanks the Higher Education Commission,
Pakistan (IRSIP Program) for a scholarship. A.K. thanks the
Shastri Indo-Canadian Institute for a research student
fellowship.
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