Practical synthesis of N-aryl-o-hydroxyaryl ketimines

Article abstract of DOI:10.1080/00397911.2011.564341

(Chemical Equation Presented) Heating o-hydroxyacetophenones and anilines under solvent-free conditions afforded the corresponding aryl ketimines in good to excellent yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.564341

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Practical Synthesis of N-Aryl-o-
hydroxyaryl Ketimines
Thanh Binh Nguyen a , Qian Wang a b & Françoise Guéritte a
a Centre de Recherche de Gif, Institut de Chimie des Substances
Naturelles, CNRS, Gif-sur-Yvette, France
b Institute of Chemical Sciences and Engineering, Ecole
Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
Accepted author version posted online: 31 Oct 2011.Published
online: 29 May 2012.
To cite this article: Thanh Binh Nguyen , Qian Wang & Françoise Guéritte (2012) Practical
Synthesis of N-Aryl-o-hydroxyaryl Ketimines, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:18, 2648-2663, DOI:
10.1080/00397911.2011.564341
To link to this article: http://dx.doi.org/10.1080/00397911.2011.564341
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Synthetic Communications1, 42: 2648–2663, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.564341
PRACTICAL SYNTHESIS OF N-ARYL-o-HYDROXYARYL
KETIMINES
1
Thanh Binh Nguyen,1 Qian Wang,1,2 and Franc¸oise Gueritte
´
1Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles,
CNRS, Gif-sur-Yvette, France
2Institute of Chemical Sciences and Engineering, Ecole Polytechnique
´ ´
Federale de Lausanne, Lausanne, Switzerland
GRAPHICAL ABSTRACT
Abstract Heating o-hydroxyacetophenones and anilines under solvent-free conditions
afforded the corresponding aryl ketimines in good to excellent yields.
Keywords Aniline; N-aryl-o-hydroxyaryl ketimine; o-hydroxyacetophenone
INTRODUCTION
Imines are important precursors of nitrogen-containing heterocyclic
compounds,[1] and they serve as valuable starting materials for the synthesis of
enantiomerically enriched amines, natural products, and medicinally relevant com-
pounds.[2,3] The o-hydroxyaryl ketimines, a subclass of imines, are excellent ligands
for transition metals[4] and showed interesting bioactivities.[5] In addition, they also
have been used in the syntheses of a number of biologically active heterocycles,
such as 4H-chromen-4-ylidenamines,[6a] 1,4-benzothiazines,[6b] 4-alkylcoumarin-3-
carboxylic acids,[6c] 3,4-dihydro-2H-1,3-benzoxazines,[6d] and 4-methyl-3-nitro-2-
trihalomethyl-2H-chromenes.[6e] They are also precursors of aminophenols,
an important class of ligands for transition-metal-mediated and catalyzed
processes.[7,8]
Received August 28, 2010.
Address correspondence to Qian Wang, Centre de Recherche de Gif, Institut de Chimie des
Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France. E-mail:
qian.wang@icsn.cnrs-gif.fr; q.wang@epfl.ch
2648

N-ARYL-o-HYDROXYARYL KETIMINES
2649
RESULTS AND DISCUSSION
o-Hydroxyaryl ketimines are commonly prepared by refluxing primary amines
and o-hydroxyacetophenones in benzene, toluene, or xylene with azeotropic removal
of water[9] in the presence of Brønsted[10] or Lewis acids (ZnCl2)[11] as catalysts.
Palmieri et al. reported a solvent-free preparation of ketimines derived from o-
hydroxyacetophenone and aliphatic amines at room temperature.[12] However, these
conditions are not applicable to aniline. Perlmutter et al. prepared N-unsubstituted
ketimines from o-hydroxyarylketones using ammonium iodide=piperidine as an
ammonia surrogate.[13] The corresponding NH-ketimines were also prepared from
o-hydroxyacetophenones and ammonia in methanol.[6e] Recently, Ra¨isa¨nen et al.
reported the synthesis of N-aryl-o-hydroxyphenylketimines in moderate yield
(<48%).[14] under harsh conditions (formic acid, sodium sulfate, 200 ꢀC, autoclave).
The condensations of o-hydroxyacetophenone and aniline under microwave condi-
tions,[15a] in dry n-butanol under reflux in the presence of para-toluenesulfonic acid
(PTSA),[15b] in methanol,[5b] or in CH2Cl2 in the presence of TiCl4[15c] also have been
reported. We report herein a convenient and general synthesis of N-aryl-o-hydro-
xyaryl ketimines by heating o-hydroxyacetophenones and anilines under solvent-free
conditions (Scheme 1).
In connection with our ongoing project dealing with the synthesis of a flavonoi-
dal alkaloid library, we needed easy access to a large collection of o-hydroxyaryl
ketimines. After an initial survey of reaction conditions, we found that simply heat-
ing a mixture of o-hydroxyacetophenone and p-MeOC6H4NH2 under solvent-free
conditions (120 ꢀC) afforded the corresponding o-hydroxyphenyl ketimines in good
yield. The conditions were found to be general and applicable to a variety of anilines
(Table 1). As is seen, anilines having electron-donating and electron-withdrawing
groups participated equally well in this reaction to afford the corresponding imines
in good to excellent yields. With o-phenylenediamine (2 eq.), a monocondensed pro-
duct was isolated in essentially quantitative yield. Formation of benzimidazoline was
not observed. It is interesting to note that sterically hindered 2,6-disubstituted ani-
lines were also accepted as substrates (compounds 7–9, entries 5–7). In the case of
2,6-diisopropylaniline (2g), heating at higher temperature (160 ꢀC) was required to
drive the reaction to completion (entry 7).
To further examine the scope of the present reaction, diversely substituted
o-hydroxyacetophenones were allowed to react with p-MeOC6H4NH2 (PMPNH2,
2a), and the results are summarized in Table 2. As is seen, 1-(2-hydroxyphenyl)-
propan-1-one (entry 12), 1-(2-hydroxyphenyl)butan-1-one (entry 13), o-hydroxyben-
zophenones (entries 14–16), 1-(2-hydroxynaphthalen-1-yl)ethanone (entry 17), and
Scheme 1. Ketimines from o-hydroxyacetophenones and anilines.

´
T. B. NGUYEN, Q. WANG, AND F. GUERITTE
2650
a
Table 1. Ketimines of o-hydroxyacetophenone with ArNH2
Entry
Ar
Product
Yield (%)
1
2
4-MeOC6H4 (2a)
2-MeC6H4 (2b)
3a
4
82
81
85
76
67
82
73b
48
52
85
89
92
87
72
76
99c
3
2-MeOC6H4 (2c)
Ph (2d)
5
4
6
5
2,6-Me2C6H3 (2e)
2-Et-6-MeC6H3 (2f)
2,6-(i-Pr)2C6H3 (2g)
4-CNC6H4 (2h)
7
6
8
7
9
8
10
11
12
13
14
15
16
17
18
9
4-NO2C6H4 (2i)
2-HOC6H4 (2j)
10
11
12
13
14
15
16
2-HO-4-MeC6H3 (2k)
2-HO-5-MeC6H3 (2l)
4-HOC6H4 (2 m)
3,4,5-(MeO)3C6H2 (2n)
2,4-(MeO)2C6H3 (2o)
2-NH2C6H4 (2p)
aGeneral conditions: A mixture of 1a and 2 (molar ratio 1=1), 120 ꢀC, solvent-free.
bReaction was performed at 160 ꢀC.
c2 equiv. of amine (2p) was used.
1-(1-hydroxynaphthalen-2-yl)ethanone (entry 18) all participated well in this conden-
sation reaction, and the reaction tolerated the presence of a strong electron-
withdrawing group (NO2) as well as electron-donating group (OMe) in the aromatic
ring. Even the methoxycarbonyl group was well tolerated to give the corresponding
imines with good yields (entries 15 and 16). The presence of electron-withdrawing
groups (nitro or chlorine) accelerated the reaction, as the reaction can be performed
at lower temperature (80 ꢀC, entries 8 and 11).
All of the o-hydroxyarylketimines thus obtained are stable to chromatography
on silica gel, and no hydrolysis has been detected when stored in pure form at room
temperature.
The presence of an o-hydroxy group is essential to the success of the reaction,
as in the case of acetophenone (1q, entry 16), azeotropic removal of water was
needed to drive the reaction to completion. Only 50% of conversion was observed
when an equimolar mixture of acetophenone and PMPNH2 was heated under the
same conditions (120 ꢀC, 16 h), and the corresponding imine (3S) could not be
obtained in pure form by column chromatography on silica gel due to partial
hydrolysis. The formation of an internal H-bond between the o-hydroxy and the
ketone carbonyl group might activate the latter toward the nucleophilic addition
of amine (A, Fig. 1). The same H-bond formed between the o-hydroxy and resulting

N-ARYL-o-HYDROXYARYL KETIMINES
2651
a
Table 2. Ketimines of o-hydroxyarylketones with PMPNH2
Entry
Substrate
Imine
Yield (%)
1
3b
64
2
3c
60
3
4
5
6
3d
3e
3f
86
87
89
60
3g
7
3h
85
(Continued )

´
T. B. NGUYEN, Q. WANG, AND F. GUERITTE
2652
Table 2. Continued
Entry
Substrate
Imine
Yield (%)
8
3i
89b
9
3j
65c
10
3k
56c
11
3l
95d
12
13
14
3m
3n
3o
84
82
93
15
3p–a
88
(Continued )

N-ARYL-o-HYDROXYARYL KETIMINES
Table 2. Continued
2653
Entry
Substrate
Imine
Yield (%)
16
3p–b
75e
17
18
19
3q
3r
3s
45
77
50f
aGeneral conditions: A mixture of 1 and 2a (molar ratio 1=1), 120 ꢀC, solvent-free.
bReaction was performed at 80 ꢀC for 1 h.
cReaction was performed at 130 ꢀC.
dReaction was performed at 80 ꢀC for 16 h.
eUsing 3,4,5-trimethoxyaniline as the amine partner.
fConversion.
Figure 1. Hypothesis on activation of carbonyl group and stabilization of imine function by ortho-
hydroxyl group.

´
T. B. NGUYEN, Q. WANG, AND F. GUERITTE
2654
imine function can in turn stabilize the condensation product (B, Fig. 1).[6e] Only the
E isomer was obtained for all the ketimines even in the case of o-hydroxybenzophe-
1
nones (Table 2, entries 14–16). The observed H NMR chemical shifts of the o-OH
protons are between 13.52 and 16.74 ppm, indicating a strong hydrogen bond
formed between OH and the neighboring imine function.
CONCLUSION
In summary, N-aryl-o-hydroxyaryl ketimines were readily synthesized by heat-
ing o-hydroxyacetophenones with anilines under solvent-free conditions. The experi-
mental simplicity and good to excellent yields are the main attributes of the present
protocol.
EXPERIMENTAL
Reagents were obtained from a commercial supplier and used without further
purification unless otherwise noted. Analytical thin-layer chromatography (TLC)
used silica gel 60 F254, purchased from Merck KGaA. Flash column chromato-
graphy was carried out using kieselgel silica gel (35–70 mm particle size,
230–400 mesh). NMR spectra were recorded on Bruker Avance 300 spectrometer.
Proton chemical shifts are reported in parts per million (ppm) from tetramethylsilane
(TMS). Coupling constants (J) are reported in hertz (Hz). Melting points were mea-
sured on a Buchi melting-point B-540 instrument. High-resolution mass spectra
¨
(HRMS) were determined on a MALDI-TOF spectrometer (Voyager-De STR; Per-
spective Biosystems).
Synthesis of N-Aryl-o-hydroxyketimines: Typical Procedure
A mixture of o-hydroxyacetophenone (1, 10 mmol) and arylamine (2, 10 mmol)
was heated under argon at 120 ꢀC (160 ꢀC when 2g was used as amine, 150 ꢀC in the
cases of 1i and 1j) for 16 h. The crude product was purified by column chromato-
graphy (CH2Cl2=heptanes) to afford the corresponding imine.
2-(1-(4-Methoxyphenylimino)ethyl)phenol (3a)[16]
Yield 82%. Yellow crystals; mp 122–123 ꢀC (CH2Cl2=heptanes). 1H NMR
(CDCl3) d 15.05 (s, 1H), 7.63 (dd, 1H, J ¼ 7.9, 1.6 Hz), 7.38 (ddd, 1H, J ¼ 8.4, 7.2,
1.6 Hz), 7.04 (dd, 1H, J ¼ 8.4, 1.6), 6.98–6.86 (m, 5H), 3.85 (s, 3H), 2.37 (s, 3H).
13C NMR (CDCl3) d 171.2, 162.2, 157.0, 139.9, 132.9, 128.9, 122.7, 119.9, 118.3,
118.0, 114.3, 55.5, 16.9.
2-(1-(o-Tolylimino)ethyl)phenol (4)[15c]
Yield 81%. Yellow crystals; mp 55–56 ꢀC (heptanes).

N-ARYL-o-HYDROXYARYL KETIMINES
2655
2-(1-(2-Methoxyphenylimino)ethyl)phenol (5)
1
Yield 85%. Yellow oil. H NMR (CDCl3): d 14.87 (s, 1H), 7.65 (dd, 1H,
J ¼ 7.9, 1.6 Hz), 7.38 (ddd, 1H, J ¼ 9.4, 7.2, 1.7 Hz), 7.19 (ddd, 1H, J ¼ 7.9, 7.7,
1.7 Hz), 7.06–6.97 (m, 3H), 6.90 (ddd, 1H, J ¼ 7.1, 7.2, 1.7 Hz), 3.82 (s, 3H), 2.30
(s, 3H). 13C NMR (CDCl3): d 172.3, 162.2, 150.3, 135.8, 132.9, 128.9, 125.9,
122.5, 120.7, 120.0, 118.3, 117.9, 111.7, 55.7, 17.4.
2-(1-(Phenylimino)ethyl)phenol (6)[15b,16]
1
Yield 76%. Yellow crystals; mp 84 ꢀC (heptanes) (lit.15b 80–81 ꢀC). H NMR
(CDCl3) d 14.71 (s, 1H), 7.65 (dd, 1H, J ¼ 8.1, 1.7 Hz), 7.44–7.37 (m, 3H),
7.24–7.18 (m, 1H), 7.04 (dd, 1H, J ¼ 8.3, 1.3 Hz), 6.95–6.89 (m, 3H), 2.36 (s, 3H).
13C NMR (CDCl3) d 171.2, 162.0, 147.0, 133.1, 129.1, 128.9, 124.8, 121.3, 119.8,
118.3, 118.1, 17.1.
2-(1-(2,6-Dimethylphenylimino)ethyl)phenol (7)[14,15c]
Yield 67%. Yellow crystals; mp 72–73 ꢀC (heptanes).
2-(1-(2-Ethyl-6-methylphenylimino)ethyl)phenol (8)
1
Yield 82%. Yellow oil. H NMR (CDCl3): d 14.78 (s, 1H), 7.66 (dd, 1H,
J ¼ 8.0, 1.7 Hz), 7.41 (ddd, 1H, J ¼ 8.2, 7.2, 1.7 Hz), 7.17–7.05 (m, 4H), 6.92 (ddd,
1H, J ¼ 8.2, 7.2, 1.7 Hz), 2.54–2.34 (m, 2H), 2.19 (s, 3H), 2.08 (s, 3H), 1.15 (t, 3H,
J ¼ 7.6 Hz). 13C NMR (CDCl3): d 171.8, 162.4, 144.5, 133.7, 133.1, 128.9, 128.1,
127.5, 126.3, 124.7, 119.3, 118.3, 118.1, 24.8, 18.2, 17.1, 14.1. Anal. calcd. for
C17H19NO: C, 80.60; H, 7.56; N, 5.53. Found: C, 80.60; H, 7.74; N, 5.53.
2-(1-(2,6-Diisopropylphenylimino)ethyl)phenol (9)[14]
Yield 73%. Pale yellow oil that crystallizes on standing.
4-(1-(2-Hydroxyphenyl)ethylideneamino)benzonitrile (10)
1
Yield 48%. Yellow crystals; mp 156–157 ꢀC (heptanes). H NMR (CDCl3): d
13.55 (s, 1H), 7.63–7.58 (m, 2H), 7.56 (dd, 1H, J ¼ 8.1, 1.7 Hz), 7.33 (ddd, 1H,
J ¼ 8.6, 7.3, 1.7 Hz), 6.96–6.89 (m, 3H), 6.84 (ddd, 1H, J ¼ 8.1, 7.3, 1.2 Hz), 2.52
(s, 3H). 13C NMR (CDCl3): d 171.9, 161.6, 151.4, 133.9, 133.3, 129.2, 122.0,
119.3, 118.8, 118.6, 118.3, 108.3, 17.7. HRMS (ESþ): m=z [M þ H]þ calcd. for
C25H13N2O: 237.1028. Found: 237.1017.
2-(1-(4-Nitrophenylimino)ethyl)phenol (11)[17]
1
Yield 52%. Yellow crystals; mp 169–170 ꢀC (heptanes). H NMR (CDCl3): d
13.52 (s, 1H), 8.32–8.27 (m, 2H), 7.67 (dd, 1H, J ¼ 8.1, 1.7 Hz), 7.44 (ddd, 1H,
J ¼ 8.5, 7.2, 1.7 Hz), 7.07–7.02 (m, 3H), 6.94 (ddd, 1H, J ¼ 8.1, 7.2, 1.2 Hz), 2.37

´
T. B. NGUYEN, Q. WANG, AND F. GUERITTE
2656
(s, 3H). 13C NMR (CDCl3): d 172.0, 161.6, 153.3, 144.9, 134.0, 129.2, 125.1, 121.8,
119.2, 118.7, 118.4, 17.8. HRMS (ESþ): m=z [M þ H]þ calcd. for C14H13N2O3:
257.0926. Found: 257.0916.
2-(1-(2-Hydroxyphenyl)ethylideneamino)phenol (12)[18]
1
Yield 95%. Yellow crystals; mp 198–199 ꢀC (EtOH). H NMR (DMSO-d6): d
14.92 (s, 1H), 9.52 (s, 1H), 7.75 (dd, 1H, J ¼ 8.6, 1.8 Hz), 7.38 (ddd, 1H, J ¼ 8.6,
7.7, 1.6 Hz), 7.05 (ddd, 1H, J ¼ 8.6, 6.4, 2.6 Hz), 6.96–6.82 (m, 5H), 2.28 (s, 3H).
13C NMR (DMSO-d6,): d 172.6, 161.5, 148.0, 133.8, 132.9, 129.5, 126.0, 122.5,
119.6, 119.2, 118.0, 117.4, 116.1, 17.2. HRMS (ESþ): m=z [M þ H]þ calcd. for
C14H14NO2: 228.1025. Found: 228.1018.
2-(1-(2-Hydroxyphenyl)ethylideneamino)-4-methylphenol (13)
Yield 89%. Yellow crystals; mp 178–179 ꢀC (Et2O=heptanes). 1H NMR
(CDCl3): d 14.68 (s, 1H), 7.61 (dd, 1H, J ¼ 8.1, 1.7 Hz), 7.38 (ddd, 1H, J ¼ 8.3,
7.2, 1.6 Hz), 7.01 (dd, 1H, J ¼ 8.3, 1.3 Hz), 6.92–6.85 (m, 2H), 6.76–6.69 (m, 2H),
5.17 (s, 1H), 2.41 (s, 3H), 2.35 (s, 3H). 13C NMR (CDCl3): d 175.1, 162.1, 147.3,
137.0, 133.5, 131.0, 129.1, 121.9, 121.2, 119.7, 118.4, 116.7, 21.1, 17.4. HRMS
(ESþ): m=z [M þ Na]þ calcd. for C15H15NO2Na: 264.1000. Found: 264.0997.
2-(1-(2-Hydroxyphenyl)ethylideneamino)-5-methylphenol (14)
Yield 92%. Yellow crystals; mp 178–179 ꢀC (Et2O=heptanes). 1H NMR
(DMSO-d6): d 14.94 (s, 1H), 9.27 (s, 1H), 7.74 (dd, 1H, J ¼ 8.4, 1.6 Hz), 7.38 (ddd,
1H, J ¼ 8.5, 7.5,1.6 Hz), 6.92–6.84 (m, 4H), 6.68 (s, 1H), 2.28 (s, 3H), 2.22 (s, 3H).
13C NMR (DMSO-d6): d 172.5, 161.5, 145.5, 133.5, 132.8, 129.4, 127.9, 126.3,
122.8, 119.6, 117.9, 117.4, 116.0, 20.1, 17.3. HRMS (ESþ): m=z [M þ Na]þ calcd.
for C15H15NO2Na: 264.1000. Found: 264.0994.
2-(1-(4-Hydroxyphenylimino)ethyl)phenol (15)[16]
Yield 87%. Yellow crystals; mp 205 ꢀC (EtOH). 1H NMR (DMSO-d6): d 15.13
(s, 1H), 9.44 (s, 1H), 7.71 (dd, 1H, J ¼ 8.3, 1.5 Hz), 7.36 (ddd, 1H, J ¼ 8.1, 7.7,
1.5 Hz), 6.91-6.81 (m, 6H), 2.35 (s, 3H). 13C NMR (DMSO-d6): d 171.5, 161.5,
154.9, 137.5, 132.7, 129.5, 122.9, 119.6, 117.9, 117.5, 115.6, 16.7. HRMS (ESþ):
m=z [M þ H]þ calcd. for C14H14NO2: 228.1025. Found: 228.1020.
2-(1-(3,4,5-Trimethoxyphenylimino)ethyl)phenol (16)
Yield 72%. Yellow crystals; mp 131 ꢀC (CH2Cl2=heptanes). 1H NMR (CDCl3):
d 14.54 (s, 1H), 7.63 (dd, 1H, J ¼ 8.1, 1.5 Hz), 7.38 (dd, 1H, J ¼ 8.4, 7.3, 1.5 Hz), 7.03
(dd, 1H, J ¼ 8.4, 1.1 Hz), 6.90 (ddd, 1H, J ¼ 8.1, 7.3, 1.1 Hz), 6.15 (s, 2H), 3.88 (s,
3H), 3.86 (s, 6H), 2.39 (s, 3H). 13C NMR (CDCl3): d 171.6, 161.9, 153.6, 143.2,
135.1, 133.1, 128.9, 119.7, 118.3, 118.2, 98.6, 61.6, 56.2, 17.2. HRMS (ESþ): m=z
[M þ Na]þ calcd. for C17H19NO4Na: 324.1219. Found: 324.1212.

N-ARYL-o-HYDROXYARYL KETIMINES
2657
2-(1-(2,4-Dimethoxyphenylimino)ethyl)phenol (17)
Yield 76%. Yellow crystals; mp 96–97 ꢀC (heptanes=CH2Cl2). 1H NMR
(CDCl3): d 15.2 (s, 1H), 7.62 (dd, 1H, J ¼ 8.1, 1.5 Hz), 7.38 (ddd, 1H, J ¼ 8.4, 7.3,
1.5 Hz), 7.03 (dd, 1H, J ¼ 8.4, 1.1 Hz), 6.88 (ddd, 1H, J ¼ 8.1, 7.3, 1.1 Hz), 6.83 (d,
1H, J ¼ 8.6 Hz), 6.56 (d, 1H, J ¼ 2.6 Hz), 6.53 (dd, 1H, J ¼ 8.6, 2.6 Hz), 3.85 (s,
3H), 3.81 (s, 3H), 2.31 (s, 3H). 13C NMR (CDCl3): d 172.2, 162.4, 158.3, 151.5,
132.7, 129.0, 128.8, 122.9, 120,1. 118.3, 117.8, 104,2. 99.5, 55.7, 55.6, 17.2. HRMS
(ESþ): m=z [M þ Na]þ calcd. for C16H17NO3Na: 294.1106. Found: 294.1104.
2-(1-(2-Aminophenylimino)ethyl)phenol (18)[19]
o-Phenylenediamine (2 equiv.) was used. Yield 100%. Yellow crystals; mp
1
102–103 ꢀC (CH2Cl2=heptanes). H NMR (DMSO-d6): d 14.99 (s, 1H), 7.75 (ddd,
1H, J ¼ 8.5, 1.7 Hz), 7.39 (ddd, 1H, J ¼ 8.4, 7.5, 1.2 Hz), 6.96–6.88 (m, 3H), 6.78
(dd, 1H, J ¼ 7.9, 1.2 Hz), 6.69 (dd, 1H, J ¼ 7.6, 1.5 Hz), 6.60 (ddd, 1H, J ¼ 7.5, 7.4,
1.2 Hz), 4.77 (s, 2H), 2.32 (s, 3H). 13C NMR (DMSO-d6): d 173.2, 161.6, 139.8,
132.8, 131.8, 129.6, 125.8, 121.3, 119.8, 117.9, 117.4, 116.2, 115.1, 17.0. HRMS
(ESþ): m=z [M þ Na]þ calcd. for C14H14N2ONa: 249.0997. Found: 249.1004.
5-Methoxy-2-(1-(4-methoxyphenylimino)ethyl)phenol (3b)
1
Yield 60%. Yellow crystals; mp 87–88 ꢀC (heptanes). H NMR (CDCl3): d
14.41 (s, 1H), 7.14 (d, 1H, J ¼ 2.7 Hz), 7.03–6.86 (m, 6H), 3.84 (s, 3H), 3.82 (s,
3H), 2.34 (s, 3H). 13C NMR (CDCl3): d 170.8, 157.0, 156.3, 151.4, 140.1, 122.6,
119.7, 119.5, 118.7, 114.3, 113.4, 56.1, 55.5, 17.0. HRMS (ESþ): m=z [M þ H]þ
calcd. for C16H18NO3: 272.1287. Found: 272.1277.
5-Fluoro-2-(1-(4-methoxyphenylimino)ethyl)phenol (3c)
Yield 86%. Yellow crystals; mp 106–107 ꢀC (CH2Cl2=heptanes). 1H NMR
(CDCl3) d 15.72 (s, 1H), 7.59 (dd, 1H, J ¼ 8.8, 6.5 Hz), 6.98–6.86 (m, 4H), 6.70
(dd, 1H, J ¼ 10.6, 2.6 Hz), 6.58 (ddd, 1H, J ¼ 8.8, 8.6, 2.6 Hz), 3.85 (s, 3H), 2.35
(s, 3H). 13C NMR (CDCl3) d 170.6, 165.5 (d, J ¼ 252 Hz), 165.1 (d, J ¼ 13.7 Hz),
157.2, 139.0, 130.6 (d, J ¼ 11.5 Hz), 122.9, 116.6, 114.4, 105.6 (d, J ¼ 22.5 Hz),
104.9 (d, J ¼ 23.0 Hz), 55.5, 16.9. HRMS (ESþ): m=z [M þ H]þ calcd. for
C15H14FNO2: 260.1087. Found: 260.1093. Anal. calcd. for C15H14FNO2: C, 69.49;
H, 5.44; N, 5.40. Found: C, 69.55; H, 5.42; N, 5.40.
2-(1-(4-Methoxyphenylimino)ethyl)-4-methylphenol (3d)[20]
1
Yield 86%. Yellow crystals; mp 125-126 ꢀC (heptanes). H NMR (CDCl3): d
14.73 (s, 1H), 7.42 (d, 1H, J ¼ 2.2 Hz), 7.19 (dd, 1H, J ¼ 8.4, 2.2 Hz), 6.97–6.86 (m,
5H), 3.85 (s, 3H), 2.36 (s, 3H), 2.34 (s, 3H). 13C NMR (CDCl3): d 171.2, 159.9,
157.0, 140.1, 133.8, 128.9, 126.9, 122.6, 119.5, 118.0, 114.3, 55.5, 20.7, 16.9. HRMS
(ESþ): m=z [M þ H]þ calcd. for C16H18NO2: 256.1338. Found: 256.1338.

´
T. B. NGUYEN, Q. WANG, AND F. GUERITTE
2658
4-Chloro-2-(1-(4-methoxyphenylimino)ethyl)phenol (3e)[20]
Yield 87%. Yellow crystals; mp 141–142 ꢀC (CH2Cl2=heptanes) (lit16b mp
1
131 ꢀC). H NMR (CDCl3) d 15.02 (s, 1H), 7.58 (d, 1H, J ¼ 2.5 Hz), 7.31 (dd, 1H,
J ¼ 8.8, 2.5 Hz), 6.96 (d, 1H, J ¼ 8.8 Hz), 6.96–6.85 (m, 4H), 3.85 (s, 3H), 2.36
(s, 3H). 13C NMR (CDCl3) d 170.3, 160.8, 157.3, 139.4, 132.6, 128.3, 122.7, 122.5,
120.6, 119.7, 114.4, 55.5, 16.9.
4-Bromo-2-(1-(4-methoxyphenylimino)ethyl)phenol (3f)[21]
Yield 89%. Yellow crystals; mp 147–148 ꢀC (CH2Cl2=heptanes). 1H NMR
(CDCl3) d 15.07 (s, 1H), 7.72 (d, 1H, J ¼ 2.5 Hz), 7.43 (dd, 1H, J ¼ 8.7, 2.5 Hz),
6.98–6.85 (m, 4H), 6.92 (d, 1H, J ¼ 8.7 Hz), 3.85 (s, 3H), 2.35 (s, 3H). 13C NMR
(CDCl3) d 170.2, 161.3, 157.3, 139.3, 135.5, 131.2, 122.7, 121.3, 120 .2, 114.4,
109.5, 55.5, 16.9.
4-Methoxy-2-(1-(4-methoxyphenylimino)ethyl)phenol (3g)
1
Yield 64%. Yellow crystals; mp 156 ꢀC (heptanes). H NMR (CDCl3): d 15.70
(s, 1H), 7.51 (d, 1H, J ¼ 8.9 Hz), 6.95–6.87 (m, 4H), 6.51 (s, 1H), 6.44 (d, 1H,
J ¼ 8.9 Hz), 3.84 (s, 3H), 3.83 (s, 3H), 2.34 (s, 3H). 13C NMR (CDCl3): d 170.5,
165.4, 163.6, 157.0, 139.3, 130.1, 123.1, 114.3, 113.4, 106.1, 101.6, 55.5, 55.4, 16.6.
Anal. calcd. for C16H17NO3: C, 70.83; H, 6.32; N, 5.07. Found: C, 70.70; H, 6.36;
N, 5.07.
2-(1-(4-Methoxyphenylimino)ethyl)-4-nitrophenol (3h)
1
Yield 85%. Yellow crystals; mp 173–174 ꢀC (heptanes). H NMR (CDCl3): d
16.74 (s, 1H), 8.59 (d, 1H, J ¼ 2.7 Hz), 8.22 (dd, 1H, J ¼ 9.2, 2.7 Hz), 7.02 (d, 1H,
J ¼ 9.2 Hz), 7.00–6.94 (m, 4H), 3.86 (s, 3H), 2.49 (s, 3H). 13C NMR (CDCl3): d
171.1, 169.8, 158.0, 138.3, 137.0, 128.3, 125.9, 123.3, 119.7, 118.0, 114.6, 56.6,
16.7. HRMS (ESþ): m=z [M þ H]þ calcd. for C15H15N2O4: 287.1032. Found:
287.1031.
2-(1-(4-Methoxyphenylimino)ethyl)-5-nitrophenol (3i)
1
Yield 89%. Orange crystals; mp 153–154 ꢀC. H NMR (CDCl3) d 15.54 (br s,
1H), 7.78 (d, 1H, J ¼ 2.3 Hz), 7.73 (d, 1H, J ¼ 8.9 Hz), 7.65 (dd, 1H, J ¼ 8.9,
2.3 Hz), 6.96–6.87 (m, 4H), 3.82 (s, 3H), 2.41 (s, 3H). 13C NMR (CDCl3) d 170.4,
163.1, 157.9, 150.2, 138.8, 129.8, 124.5, 123.0, 114.7, 113.6, 112.4, 55.8, 17.5. HRMS
(ESIþ) m=z M þ H]þ calculated for C15H15N2O4 287.1032. Found: 287.1026.
3-Ethoxy-2-(1-(4-methoxyphenylimino)ethyl)phenol (3j)
Yield 65%. Yellow oil. 1H NMR (CDCl3): d 15.67 (s, 1H), 7.19 (t, 1H,
J ¼ 8.2 Hz), 6.93–6.84 (m, 4H), 6.59 (dd, 1H, J ¼ 8.2, 1.0 Hz), 6.33 (d, 1H, J ¼ 8.2,
1.0 Hz), 4.07 (q, 2H, J ¼ 7.0 Hz), 3.81 (s, 3H), 2.42 (s, 3H), 1.43 (t, 3H, J ¼ 7.0 Hz).

N-ARYL-o-HYDROXYARYL KETIMINES
2659
13C NMR (CDCl3): d 172.8, 163.8, 159.9, 157.0, 139.1, 132.5, 122.9, 114.3, 111.0,
101.3, 64.1, 55.5, 23.1, 14.8 (1C missing due to overlap).
3,5-Dimethoxy-2-(1-(4-methoxyphenylimino)ethyl)phenol (3k)
1
Yield 86%. Pale yellow crystals; mp 122–123 ꢀC (CH2Cl2=heptanes). H NMR
(CDCl3): d 14.12 (s, 1H), 6.95–6.88 (m, 4H), 6.12 (d, 1H, J ¼ 2.5 Hz), 5.89 (d, 1H,
J ¼ 2.5 Hz), 3.83 (s, 3H), 3.83 (s, 3H), 3.82 (s, 3H), 2.41 (s, 3H). 13C NMR (CDCl3):
d 172.2, 168.9, 163.8, 162.0, 157.1, 137.4, 123.8, 114.3, 104.5, 94.7, 89.7, 55.5, 55.3
(2C), 22.0. HRMS (ESþ): m=z [M þ H]þ calcd. for C17H20NO4: 302.1392. Found:
302.1389.
3,5-Dichloro-2-(1-(4-methoxyphenylimino)ethyl)phenol (3l)
1
Yield 97%. Pale yellow crystals; mp 127–128 ꢀC (CH2Cl2=heptanes). H NMR
(CDCl3): d 16.50 (s, 1H), 7.49 (d, 1H, J ¼ 2.4 Hz), 7.45 (d, 1H, J ¼ 2.4 Hz), 6.97–6.89
(m, 4H), 3.84 (s, 3H), 2.39 (s, 3H). 13C NMR (CDCl3) d 170.3, 158.1, 157.8, 137.6,
132.6, 126.8, 123.9, 123.2, 121.5, 120.5, 114.5, 55.5, 16.8. HRMS (ESþ): m=z
[M þ Na]þ calcd. for C15H13NO325Cl2Na: 332.0221. Found: 332.0208.
2-(1-(4-Methoxyphenylimino)propyl)phenol (3m)
Yield 84%. Yellow crystals; mp 79–80 ꢀC (CH2Cl2=heptanes). 1H NMR
(CDCl3): d 15.09 (s, 1H), 7.63 (dd, 1H, J ¼ 8.0; 1.6 Hz), 7.37 (ddd, 1H, J ¼ 8.6,
7.3, 1.6 Hz), 7.04 (dd, 1H, J ¼ 8.6, 1.6 Hz), 6.97–6.92 (m, 3H), 6.90–6.85 (m, 2H),
3.85 (s, 3H), 2.76 (q, 2H, J ¼ 7.7 Hz), 1.24 (t, H, J ¼ 7.7 Hz). 13C NMR (CDCl3): d
176.8, 163.0, 156.9, 139.9, 132.9, 128.9, 122.0, 118.6, 118.0, 114.4, 55.5, 22.7, 13.5.
HRMS (ESþ): m=z [M þ H]þ calcd. for C16H18NO2: 256.1338. Found: 256.1328.
Anal. calcd. for C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.11; H, 6.92;
N, 5.44.
2-(1-(4-Methoxyphenylimino)butyl)phenol (3n)
Yield 82%. Yellow crystals; mp 73 ꢀC (CH2Cl2=heptanes). 1H NMR (CDCl3): d
15.07 (s, 1H), 7.60 (dd, 1H, J ¼ 8.0; 1.2 Hz), 7.37 (ddd, 1H, J ¼ 8.0, 7.1, 1.2 Hz), 7.03
(dd, 1H, J ¼ 7.3, 1.2 Hz), 6.97–6.84 (m, 5H), 3.85 (s, 3H), 2.73–2.68 (m, 2H),
1.73–1.60 (m, 2H), 0.92 (t, 3H, J ¼ 7.2 Hz). 13C NMR (CDCl3): d 175.6, 162.9,
156.9, 139.9, 132.9, 128.9, 122.1, 118.6, 117.9, 114.3, 55.5, 31.4, 22.5, 14.3. HRMS
(ESþ): m=z [M þ H]þ calcd. for C17H20NO2: 269,1416. Found: 269,1418.
2-((4-Methoxyphenylimino)(phenyl)methyl)phenol (3o)
Yield 93%. Yellow crystals; mp 132–133 ꢀC (CH2Cl2=heptanes). 1H NMR
(CDCl3): d 14.96 (s, 1H), 7.41–7.34 (m, 4H), 7.23–7.16 (m, 2H), 7.11–7.09 (m,
1H), 7.08–7.07 (m, 1H), 6.78–6.69 (m, 5H), 3.74 (s, 3H). 13C NMR (CDCl3): d
172.4, 162.7, 156.8, 139.6, 134.5, 133.0, 132.0, 128.9, 128.8, 128.4, 124.0, 120.2,
118.0, 117.9, 113.8, 55.3. HRMS (ESþ): m=z [M þ H]þ calcd. for C20H18NO2:

´
T. B. NGUYEN, Q. WANG, AND F. GUERITTE
2660
304.1338. Found: 304.1330. Anal. calcd. for C20H17NO2: C, 79.19; H, 5.65; N, 4.62.
Found: C, 79.45; H, 5.75; N, 4.59.
Methyl 4-((2-Hydroxyphenyl)((4-methoxyphenyl)imino)methyl)-
benzoate (3p–a)
Yield 66%. Yellow crystals; mp 128 ꢀC1H-NMR (CDCl3) d 14.58 (br s, 1H),
8.02–8.00 (m, 2H), 7.33 (ddd, 1H, J ¼ 8.6, 7.1, 1.7 Hz), 7.25–7.23 (m, 2H), 7.05
(dd, 1H, J ¼ 8.3, 1.3 Hz), 6.93 (dd, 1H, J ¼ 7.9, 1.7 Hz,), 6.73–6.68 (m, 1H), 6.66
(s, 4H), 3.91 (s, 3H), 3.70 (s, 3H). 13C-NMR (CDCl3) d 171.6, 166.6, 162.7, 157.2,
139.6, 139.3, 133.4, 131.9, 130.7, 129.8, 129.2, 124.0, 119.9, 118.3, 114.1, 55.5,
52.5. HRMS (ESIþ) m=z [M þ H]þ calculated for C22H20NO4 362.1392. Found:
362.1395.
Methyl 4-((2-Hydroxyphenyl)((3,4,5-trimethoxyphenl)imino)methyl)-
benzoate (3p–b)
1
Yield 75%. Yellow amorphous powder. HNMR (CDCl3) d 14.58 (br s, 1H),
8.04–8.01 (m, 2H), 7.35 (ddd, 1H, J ¼ 8.6, 7.1, 1.7 Hz), 7.29–7.27 (m, 2H), 7.05
(dd, 1H, J ¼ 8.3, 1.3 Hz), 6.95 (dd, 1H, J ¼ 7.9, 1.7 Hz), 6.75–6.69 (m, 1H), 5.97 (s,
2H), 3.91 (s, 3H), 3.73 (s, 3H), 3.60 (s, 6H). 13C-NMR (CDCl3) d 172.1, 166.4,
162.6, 153.3, 142.4, 139.2, 135.5, 133.7, 132.1, 130.8, 129.8, 129.0, 119.7, 118.5,
118.3, 100.5, 61.1, 56.2, 52.6. HRMS (ESþ): m=z [M þ H]þ calcd. for C24H24NO6:
422.1603. Found 422.1606.
1-(1-(4-Methoxyphenylimino)ethyl)naphthalen-2-ol (3q)
1
Yield 45%. Yellow crystals; mp 94–95 ꢀC (heptanes). H NMR (CDCl3): d
15.85 (s, 1H), 7.91 (dd, 1H, J ¼ 8.0, 1.3 Hz), 7.74 (dd, 1H, J ¼ 8.6, 1.3 Hz) 7.47
(ddd, 1H, J ¼ 8.6, 7.0, 1.3 Hz), 7.31 (ddd, 1H, J ¼ 8.0, 7.0, 1.3 Hz), 7.14 (d, 1H,
J ¼ 9.1 Hz), 7.10–7.05 (m, 2H), 7.01–6.96 (m, 2H), 3.86 (s, 3H), 2.60 (s, 3H). 13C
NMR (CDCl3): d 170.7, 166.6, 157.5, 137.3, 134.7, 132.8, 129.3, 128.3, 127.0,
124.7, 123.9, 122.7, 122.2, 114.6, 113.2, 55.5, 23.5. HRMS (ESþ): m=z [M þ H]þ
calcd. for C19H18NO2: 292.1338. Found: 292.1331. Anal. calcd. for C19H17NO2:
C, 78.33; H, 5.88; N, 4.81. Found: C, 77.95; H, 5.97; N, 4.77.
2-(1-(4-Methoxyphenylimino)ethyl)naphthalen-1-ol (3r)
Yield 77%. Yellow crystals; mp 161–162 ꢀC (CH2Cl2=heptanes). 1H NMR
(CDCl3): d 15.02 (s, 1H), 8.30 (d, 1H, J ¼ 8.0 Hz), 7.47 (d, 1H, J ¼ 8.0 Hz), 7.34
(ddd, 1H, J ¼ 8.3, 6.8, 1.4 Hz), 7.28–7.23 (m, 2H), 6.86–6.81 (m, 3H), 6.77–6.72 (m,
2H), 3.63 (s, 3H), 2.26 (s, 3H). 13C NMR (CDCl3): d 170.6, 169.5, 157.9, 136.7,
135.1, 129.3, 128.5, 125.1, 125.0, 124.8, 124.7, 115.5, 114.5, 110.7, 55.5, 16.5. HRMS
(ESþ): m=z [M þ H]þ calcd. for C19H18NO2: 292.1338. Found: 292.1333. Anal. calcd.
for C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found: C, 78.47; H, 5.95; N, 4.77.

N-ARYL-o-HYDROXYARYL KETIMINES
2661
ACKNOWLEDGMENTS
We thank Institut de Chimie des Substances Naturelles (ICSN)=Centre
National de la Recherche Scientifique (CNRS) for financial support. T. B. N. thanks
ICSN for a postdoctoral fellowship.
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