Ruthenium-Catalyzed Aminomethylation and Methylation of Phenol Derivatives Utilizing Methanol as the C1 Source

Article abstract of DOI:10.1002/adsc.201601117

A reaction involving ortho-aminomethylation of phenol was developed via ruthenium-catalyzed dehydrogenation of methanol, an environmentally benign C₁ building block, without the use of reactive reagents. The reaction was successfully applied to a range of substrates. When naphthol was employed instead of phenol, only methylation was observed. On the basis of various mechanistic studies, we propose that formamide barely participates in the reaction, which mainly occurs through an iminium cation intermediate. The difference in the reactivities of phenol and naphthol is attributable to stronger basicity of naphtholate as a conjugate base owing to its lower aromaticity. Plausible reaction pathways were proposed for both reactions. (Figure presented.).

Full text of DOI:10.1002/adsc.201601117

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DOI: 10.1002/adsc.201601117
Ruthenium-Catalyzed Aminomethylation and Methylation of
Phenol Derivatives Utilizing Methanol as the C1 Source
Seoksun Kima and Soon Hyeok Honga,*
a
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08826, Republic of Korea
Fax : (+82)-2-889-1568; Phone: (+82)-2-880-6655; e-mail: soonhong@snu.ac.kr
Received: October 10, 2016; Revised: November 27, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201601117.
Abstract: A reaction involving ortho-aminomethyla- reaction, which mainly occurs through an iminium
tion of phenol was developed via ruthenium-cata- cation intermediate. The difference in the reactivities
lyzed dehydrogenation of methanol, an environmen- of phenol and naphthol is attributable to stronger ba-
tally benign C1 building block, without the use of re- sicity of naphtholate as a conjugate base owing to its
active reagents. The reaction was successfully applied lower aromaticity. Plausible reaction pathways were
to a range of substrates. When naphthol was em- proposed for both reactions.
ployed instead of phenol, only methylation was ob-
served. On the basis of various mechanistic studies, Keywords: aminomethylation; dehydrogenation;
we propose that formamide barely participates in the methanol; phenols; ruthenium
Introduction
tated rather than dehydrogenation, an X=CH2 (X=
CR2, NR, NR2 ) type of intermediate is formed,
+
Since the discovery of the Friedel–Crafts reaction,[1] which could be further converted to a methyl[12] or
a number of phenol functionalization methods has methylene group.[13]
been extensively developed. Among those transfor-
In this context, we envisioned that ortho-aminome-
mations, preparation of ortho-aminomethylated thylation of phenol can be achieved by using metha-
phenol structures, which can be found in various com- nol and an amine through an activated intermediate
pounds such as pharmaceuticals[2] and ligands for such as an iminium cation formed by successive dehy-
transition metals,[3] is one of the most important types drogenation and dehydration reactions.[14] Formalde-
of phenol functionalization. Classically, this structure hyde generated in situ from methanol can be captured
could be obtained by utilizing Eschenmoserꢀs salt as by two nucleophiles, phenol and the amine. Reactions
a common intermediate,[4] but unfortunately, stoichio- between nucleophiles and formaldehyde often suffer
metric amounts of reactive species such as pre-gener- from unwanted side reactions such as dimerization or
ated salt itself, N-oxide, or BrCCl3 are required for oligomerization
the reaction to proceed (Scheme 1).
through
bridging
methylene
groups.[13b,15] In this case, the desired 3-component re-
In pursuit of environmentally benign synthesis[5] action was successfully controlled without significant
without pre-activation of substrates,[6] we designed formation of possible side products such as 2,2’-meth-
a catalytic ortho-aminomethylation of phenol utilizing ylenediphenol. The recently developed hydroamino-
methanol as the methylation source. Methanol has methylation and dehydrogenation sequence can also
emerged as a potential renewable resource[7] as the be considered as a possible reaction pathway for this
development of CO2 reduction[8] and biomass conver- transformation.[16] In the case of naphthol, we ob-
sion chemistry.[9] In the utilization of methanol as a C1 served methylation instead of aminomethylation.
source, a commonly used strategy is in situ generation Only a few methods were reported for the catalytic
of formaldehyde via dehydrogenative activation of methylation of naphthol with methanol, using hetero-
methanol. The formaldehyde intermediate generated, geneous catalysts under harsh reaction conditions (ꢀ
which acts as an electrophile, can be transformed to 2008C).[17] Plausible intermediates and reaction path-
a hydroxymethyl group through nucleophilic attack.[10] ways were proposed for each reaction on the basis of
Further dehydrogenation could afford compounds the mechanistic studies.
containing carbonyl groups.[11] If dehydration is facili-
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equivalents of the amine and elevated temperatures
were used, 78% of 4a could be obtained (Table 1,
entry 10). The developed reaction showed exclusive
ortho-selectivity, no other regioisomers being formed.
Other tested solvents did not show better reactivity
than toluene (Table 1, entries 11–14). We also con-
firmed that the reaction was tolerant to moisture
(Table 1, entry 15). Lower temperature gave a moder-
ate yield of 4a (Table 1, entry 16). The reaction under
air exhibited lower efficiency (Table 1, entry 17).
The substrate scope was subsequently explored
(Table 2). Electron-rich phenols as well as a conjugat-
ed phenol smoothly participate in the developed reac-
tion (4b–4e). The reaction efficiency was not signifi-
cantly affected by halide substituents on phenol (4f–
4h). The ortho-aminomethylated product of ortho-
substituted phenol could also be obtained in a moder-
ate yield (4i). When anisole was employed as a sub-
strate, the desired transformation was not observed,
indicating that deprotonation of the acidic proton by
the amine is an important step in the reaction. The re-
actions involving various acyclic secondary amines
were also efficient (4j–4l). Unfortunately, when the
steric hindrance of the amine was increased, the de-
sired product was not observed (4m). Diverse cyclic
secondary amines were tested with from 5- to 7-mem-
bered rings (4n–4t). Regardless of the ring size, good
yields of the desired products were obtained. When
a primary amine was employed, poor reactivity was
observed (4u). The formation of the imine rather than
the iminium cation might be the reason for this obser-
vation, which could be attributed to the low electro-
philicity of the former (Scheme 5). In low yielding
cases such as 4h, 4s, 4u, poor conversion of starting
materials was observed.
Scheme 1. Classical and developed synthetic methods for
ortho-aminomethylation of phenol derivatives.
Results and Discussion
Methylation of Naphthol
ortho-Aminomethylation of Phenol
Interestingly, when similar reaction conditions were
applied to 2-naphthol, 1-methyl-2-naphthol (6a) was
We began our study on the ortho-aminomethylation obtained almost quantitatively, with the production of
of phenol with in situ generated (IiPr)- 7 from 3a (Table 3, entry 2). The reaction without
RuH2(CO)(PPh3)2, which was used as a dehydrogena- methanol did not give 6a (Table 3, entry 3). This
tion catalyst in our previous report.[18] In the initial at- result implies that methanol, rather than 3a, is the
tempt, 4a was obtained in 8% yield (Table 1, entry 1). methyl source for the product. The yield significantly
N-Methyl-N-benzylformamide (7) was observed as dropped when a reduced temperature was applied
the major by-product. Various dehydrogenation cata- (Table 3, entry 4). Surprisingly, 3a showed superior ef-
lysts were then tested (Table 1, entries 2–9). The iridi- ficiency compared to other inorganic bases (Table 3,
um complex, which is highly active for the dehydro- entries 5–7). When the more economical pyrrolidine
genation of alcohols, did not afford the desired prod- was introduced as a base, a quantitative yield was ob-
uct,[19] while Milsteinꢀs catalyst[14f] and Shvoꢀs cata- tained, while the tertiary amine showed no reactivity
lyst[20] did not catalyze the reaction at all (Table 1, en- (Table 3, entries 8 and 10). Substoichiometric amounts
tries 2–4). Ru(acac)3 as catalyst with triphos as ligand of pyrrolidine gave a reasonable, but slightly de-
system[21] gave a 49% yield (Table 1, entry 8). Among creased, yield of the product (Table 3, entry 11).
the catalysts tested, Ru-MACHO-BH exhibited the We then investigated the substrate scope for the
highest efficiency (Table 1, entry 9). When increased methylation of 2-naphthol (Table 4). Biaryl substrates
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Table 1. Optimization of the reaction conditions.[a]
Entry
[M]
Base
Solvent
Yield[b] [%]
1
2
3
4
5
6
7
8
RuH2(CO)(PPh3)3/IiPr·HBr
[Cp*IrCl2]2
Milsteinꢀs catalyst
Shvoꢀs catalyst
[Ru(p-cymene)Cl]2/2 dppb
RuH2(PPh3)4
RuHCl(CO)(PPh3)4
Ru(acac)3/2 triphos
Ru-MACHO-BH
Ru-MACHO-BH
Ru-MACHO-BH
Ru-MACHO-BH
Ru-MACHO-BH
Ru-MACHO-BH
Ru-MACHO-BH
Ru-MACHO-BH
Ru-MACHO-BH
2 NaH
NaOAc
–
–
KO-t-Bu
–
KO-t-Bu
–
–
–
–
–
–
–
–
–
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
toluene
toluene
THF
DCE
MeCN
neat
8
0
0
0
5
5
10
49
61
78
65
0
9
10[c]
11[c]
12[c]
13[c]
14[c]
15[c,d]
16[e]
17[c,f]
0
46
72
56
37
toluene
toluene
toluene
[a]
Reaction conditions: 1a (0.50 mmol, 1.0 equiv.), 2 (2.50 mmol, 5.0 equiv.), 3a (0.50 mmol, 1.0 equiv.), [M] (0.01 mmol per
metal center, 2 mol%), base (0.01 mmol, 2 mol%), 1408C, 20 h in toluene (1.0 mL, 0.5M), in a sealed tube. IiPr·HBr=
1,3-diisopropylimidazolium bromide.
[b]
[c]
[d]
[e]
[f]
1
Yields were determined by H NMR with CH3NO2 as an internal standard.
2.0 equiv. of 3a were used at 1508C.
1.0 equiv. of H2O was added.
2.0 equiv. of 3a were used at 1308C.
Under air.
with various kinds of substituents gave good yields of Mechanistic Study
the desired products (6b–6e). When 1-naphthol was
employed with an increased amount of 2, a moderate The possible reaction pathways for each reaction
yield of the dimethylated product was obtained (6f). were investigated by observing the reactivities of
Compared to the previous catalytic methods utilizing phenol and naphthol. First, changes in the levels of
methanol for the methylation of naphthols, our each substrate and product in the ortho-aminomethy-
method operates under relatively milder reaction con- lation of phenol over time were measured by
ditions and shows better substrate scope.[17] Further- 1H NMR spectroscopy (Figure 1). The production of
more, the overall reaction yields were better than for 4b was observed as 1b and 3a were consumed. At the
those methods utilizing stoichiometric amount of same time, the gradual accumulation of formamide 7
methyl iodide or diiodomethane.[22]
was observed.
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Table 2. Scope of the ortho-aminomethylation reaction.[a]
[a]
Reaction conditions: 1 (0.50 mmol, 1.0 equiv.), 2 (2.50 mmol, 5.0 equiv.), 3 (1.0 mmol, 2.0 equiv.), Ru-MACHO-BH
(0.01 mmol, 2 mol%), 1508C, 20 h in toluene (1.0 mL, 0.5M), in a sealed tube. N. D.=not determined. Isolated yields re-
poprted.
For 44 h.
15 mol% of NaOMe were added.
5 mol% of catalyst was used.
[b]
[c]
[d]
[e]
4 equiv. of amine were used.
The reactions between the nucleophiles and 7 were entry 2). These experimental results strongly support
performed to determine if formamide 7 acts as an our hypothesis that free secondary amine, and not for-
electrophile in the reaction (Table 5 and Table 6). For mamide, is involved in both reactions.
each reaction, the remaining amount of 7, and yields
The involvement of formamide was further exam-
of 3a and the desired products were measured via ined by deuterium labelling (Scheme 2). When reac-
1H NMR spectroscopy. When 1a was employed with- tions were conducted with deuterated methanol (2-D)
out base or with DIPEA, only marginal conversion of in the presence of 7, the deuterated products, 8-D and
7 was observed, with a poor yields of 4a (Table 5, en- 6a-D, were obtained without formation of 8 and 6a.
tries 1 and 2). When piperidine was added, the ortho- Concurrently, deuterium scrambling on 7 occurred to
aminomethylated product and the formamide of pi- a minimal extent. These results demonstrate that for-
peridine were obtained in 60% and 27% yields, re- mamide formation is almost irreversible under the de-
spectively. However, production of 4a was still poor veloped reaction conditions. Based on the control ex-
(Table 5, entry 3). The reactions between 5a and 7 periments and the deuterium labelling study, we con-
also gave poor yield of 6a without significant conver- clude that formamide forms almost irreversibly and
sion of 7 (Table 6, entry 1). When pyrrolidine was barely participates in both alkylation reactions.
added, the yield of 6a significantly increased (Table 6,
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Table 3. Effect of base on the methylation of 2-naphthol.[a]
Table 4. Scope of the methylation reaction.[a]
Entry
Base
Yield[b] [%]
1[c]
2
BnMeNH (3a)
BnMeNH (3a)
BnMeNH (3a)
BnMeNH (3a)
K2CO3
24
98
0
39
0
3[d]
4[e]
5
6
KOH
8
7
8
NaHCO3
DIPEA
16
0
9
hexamethyleneimine
pyrrolidine
pyrrolidine
49
>99
92
10[f]
11[g]
[a]
Reaction conditions: 5a (0.50 mmol, 1.0 equiv.),
2
(2.50 mmol, 5.0 equiv.), Ru(acac)3 (0.01 mmol, 2 mol%),
triphos (0.02 mmol, 4 mol%), base (1.00 mmol,
2.0 equiv.), 1508C, 20 h in THF (1.0 mL, 0.5M), in
a sealed tube.
Yields were determined by H NMR with CH3NO2 as an
internal standard.
Ru-MACHO-BH (2 mol%) and toluene (1.0 mL, 0.5M)
were used instead of Ru(acac)3, triphos, and THF.
2 was not added.
[b]
[c]
1
[a]
Reaction conditions:
5
(0.50 mmol, 1.0 equiv.),
2
(2.00 mmol, 4.0 equiv.), Ru(acac)3 (0.01 mmol, 2 mol%),
triphos (0.02 mmol, 4 mol%), pyrrolidine (0.50 mmol,
1.0 equiv.), 1508C, 20 h in THF (1.0 mL, 0.5M), in
a sealed tube. Isolated yields reported.
[d]
[e]
[f]
At 1408C.
[b]
10.0 equiv. of 2 were used.
1.0 equiv. of amine and 4.0 equiv. of 2 were used.
0.5 equiv of amine and 4.0 equiv of 2 were used.
[g]
We then hypothesized that formaldehyde or the
iminium cation might react with nucleophiles in both
reactions. If phenol reacts with the iminium cation,
the aminomethylated product can be formed directly.
Hence, in the case of phenol, involvement of formal-
dehyde was considered via control experiments
(Scheme 3). Firstly, we examined the reactivity of 2-
hydroxybenzyl alcohol (9) which can be formed from
formaldehyde and phenol; 9 could be transformed to
4a quantitatively under the standard reaction condi-
tions (Scheme 3A). Noticeably, a significant amount
of 4a was still formed in the absence of Ru catalyst
and methanol, possibly through dehydrative transfor-
mation to ortho-quinone methide.[23] Accordingly, we
assumed that both the dehydrogenative pathway via
reductive amination[24] and the dehydrative pathway
via ortho-quinone methide[23] can significantly contrib-
ute to the reaction if 9 is generated during the reac-
tion. The dehydrogenative pathway was previously re-
ported,[24] and the feasibility of the dehydrative path-
way was investigated by capturing ortho-quinone me-
thide (A) from 9 via the Diels–Alder reaction
(Scheme 3B).[25] However, when we started from 1a,
attempts to capture A with ethyl vinyl ether
(Scheme 3C) or several nucleophiles, such as imida-
Scheme 2. Deuterium labelling study
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Figure 1. Kinetic profile of ortho-aminomethylation of 1b. Error bars were calculated from three repetitions.
zole, 2-phenylethanethiol and 2,5-dimethylpyrrole, all base.[26] However, transformation of 10 into 6a gave
failed, contrary to the reaction involving naphthol only 38% yield under the standard reaction condi-
(Scheme 4D). In addition, we could not observe 9 and tions (Scheme 4A). In contrast, 11, which can be
2-methylphenol via the spectroscopic analyses done formed from naphthol and iminium cation,[27] gave
during the reaction. Reaction between phenol and a quantitative yield of 6a (Scheme 4B). We postulated
formaldehyde also did not give any meaningful prod- that a deaminative pathway occurs via ortho-naphtho-
uct such as 9. Thus, we conclude that involvement of quinone methide (B) as an intermediate. Indeed, it
9 is not likely in the case of phenol.
could be captured by ethyl vinyl ether
In the case of 2-naphthol, it is known that the reac- (Scheme 4C).[25] B can also be captured during the re-
tion between formaldehyde and 2-naphthol forms 1- action (Scheme 4D), which further proves that B acts
hydroxymethyl-2-naphthol (10) in the presence of as a real intermediate.
Table 5. Reaction between phenol and formamide.
Table 6. Reaction between naphthol and formamide.
Entry
Amine
7
3a
4a
Entry
Amine
7
3a
6a
1
2
3
none
DIPEA
piperidine
93%
94%
84%
1%
0%
4%
6%
6%
3%
1
2
none
pyrrolidine
100%
90%
0%
10%
20%
89%
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Scheme 3. Possible intermediates in ortho-aminomethylation of phenol.
Notably, deamination occurred only with 11 and ous reports even though the applied reaction temper-
not with 4a, presumably due to the stronger basicity atures were as high (up to 1408C) as in our reaction
of naphtholate as a conjugate base, which in turn re- conditions.[16] Hence, we believe that an enolate-in-
sults from its lower aromaticity. Capturing of ortho- volved nucleophilic attack operates in our case rather
quinone methide (A) from 4a by ethyl vinyl ether did than ruthenium-catalyzed sequential reactions.
not occur.
On the basis of the experimental results, possible
Since an iminium cation is a plausible intermediate reaction pathways were proposed (Scheme 5). It is
in both transformations, involvement of the rutheni- well known that methanol (2) can be dehydrogenated
um catalyst in the reaction between nucleophiles and by ruthenium catalysts.[28] The generated formalde-
iminium cation, such as hydroaminomethylation and hyde (C) is attacked by 3a to form the hemiaminal in-
dehydrogenation sequence, could be considered. termediate (D). Via subsequent dehydration, the imi-
However, the ruthenium-catalyzed hydroaminomethy- nium cation (E) is formed. Formamide 7 is also pro-
lation reaction occurs usually with terminal ole- duced from dehydrogenation of D.[11a,b] However, for-
fins,[16b–e] and only a few examples are known with in- mamide does not directly participate in the reaction.
ternal olefins.[16f,g] Furthermore, reactivity with the ar- In the case of the ortho-aminomethylation of phenol,
omatic multiple bond was not observed in the previ- the iminium cation is attacked by the phenolate anion
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Scheme 4. Possible intermediates in methylation of naphthol.
([1a-H]À), generating 4a. In the case of the methyla- tion to successfully form 6a.[29] In this pathway, 3a is
tion of 2-naphthol, both formaldehyde and the imini- liberated and can participate in the generation of 11.
um cation react with the 2-naphtholate anion ([5a- The amine acts as a catalyst as well as a base in the
H]À). However, compound 10, resulting from formal- methylation of naphthol, and this suggestion is consis-
dehyde and [5a-H]À, is not efficiently converted to 6a. tent with the previous experimental results (Table 3,
On the other hand, compound 11 undergoes reversi- entry 11).
ble deamination via an E1cB mechanism and reduc-
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Scheme 5. Plausible mechanism
0.01 mmol),
1 (0.50 mmol), 2 (101 mL, 2.50 mmol), 3
(1.00 mmol) and anhydrous toluene (1.0 mL) were added
inside a glovebox. The reaction tube was then taken out of
the box and the mixture stirred for 20–44 h at 1508C. The
resulting reaction mixture was cooled to room temperature
and concentrated under reduced pressure. The crude prod-
ucts were purified via silica gel column chromatography.
Conclusions
We have developed novel alkylation reactions of
phenol derivatives by using methanol as the C1
source. Initiated by dehydrogenation of methanol and
subsequent nucleophilic attack on formaldehyde,
methanol could be directly incorporated into the or-
ganic molecules, phenol and naphthol. The developed
reactions could be applied to a range of substrates
with good yields. Based on our mechanistic studies,
the iminium cation is proposed to be the key electro-
phile in both reactions. In the case of the methylation
of naphthol, an ortho-naphthoquinone methide inter-
mediate and the dual role of the amine as a catalyst
and a base, were suggested.
General Procedure for Methylation of Naphthol
To an oven-dried, 50-mL, screw capped round-bottom flask
equipped with a stirring bar, Ru(acac)3 (4.0 mg, 0.01 mmol),
triphos (12.5 mg, 0.02 mmol),
5 (0.50 mmol), 2 (81 mL,
2.00 mmol), pyrrolidine (42 mL, 0.50 mmol) and anhydrous
toluene (1.0 mL) were added inside a glovebox. The reac-
tion tube was then taken out of the box and the mixture
stirred for 20 h at 1508C. The resulting reaction mixture was
cooled to room temperature and concentrated under re-
duced pressure. The crude products were purified via silica
gel column chromatography.
Experimental Section
General Procedure for the Capture of ortho-Quinone
Methide (Scheme 3B)
General Information
Unless otherwise noted, all reactions were carried out using
standard Schlenk techniques or in an argon-filled glove box.
All anhydrous solvents were purchased from commercial
suppliers and degassed with dry argon before usage. 1c,[30]
5b–5e,[31] 10,[26] and 11[27] were prepared by the methods re-
ported in the literature, and all other substrates and catalysts
were purchased from commercial suppliers and used as re-
ceived without purification. HR-MS analyses were per-
formed at the Organic Chemistry Research Center of
Sogang University.
To an oven-dried 50-mL, screw capped round-bottom flask
equipped with a stirring bar, 9 (62.1 mg, 0.50 mmol), ethyl
vinyl ether (239 mL, 2.50 mmol), pyrrolidine (4.2 mL,
0.05 mmol) and anhydrous toluene (1.0 mL) were added
inside a glovebox. The reaction tube was then taken out of
the box and the mixture stirred for 20 h at 1508C. The re-
sulting reaction mixture was cooled to room temperature
and concentrated under reduced pressure. 25 mL of nitrome-
thane were added as an internal standard. The crude mix-
ture was analyzed by 1H NMR spectroscopy. The experi-
ments of Scheme 3C, Scheme 4B and Scheme 4C were con-
ducted analogously to the method described here.
General Procedure for ortho-Aminomethylation of
Phenol
To an oven-dried, 50-mL, screw capped round-bottom flask
equipped with a stirring bar, Ru-MACHO-BH (5.9 mg,
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2-{[Benzyl(methyl)amino]methyl}-4-chlorophenol
(4g):
Characterization Data
Off-white solid; yield: 83 mg (64%); 1H NMR (499 MHz,
CDCl3): d=11.09 (br. s., 1H), 7.40–7.34 (m, 2H), 7.34–7.28
(m, 3H), 7.14 (dd, J=2.7, 8.6 Hz, 1H), 6.99 (d, J=2.4 Hz,
1H), 6.80 (d, J=8.8 Hz, 1H), 3.71 (s, 2H), 3.60 (s, 2H), 2.25
(s, 3H); 13C NMR (126 MHz, CDCl3): d=156.7, 136.6, 129.4,
128.7, 128.6, 128.3, 127.9, 123.7, 123.4, 117.5, 61.5, 60.5, 41.3;
Reactions were performed in a 0.50 mmol scale. All com-
pounds were identified by 1H, 13C NMR. All new com-
pounds were further identified by HR-MS. All reported
compounds–4l,[32] 4r,[33] 4s,[34] 6a[35] and 6f[36]– were also iden-
tified by spectral comparison with literature data.
[M+H]+,
calcd.
for
2-{[Benzyl(methyl)amino]methyl}phenol (4a): Colourless
liquid; yield: 80 mg (70%); H NMR (300 MHz, CDCl3): d=
HRMS-ESI:
C15H17ClNO: 262.0993.
2-{[Benzyl(methyl)amino]methyl}-4-bromophenol
m/z=262.0993
1
11.12 (br s, 1H), 7.45–7.29 (m, 5H), 7.23 (dt, J=0.9, 7.3 Hz,
1H), 7.05 (d, J=7.0 Hz, 1H), 6.92 (dd, J=0.8, 8.1 Hz, 1H),
6.84 (dt, J=1.1, 7.3 Hz, 1H), 3.79 (s, 2H), 3.63 (s, 2H), 2.28
(s, 3H); 13C NMR (75 MHz, CDCl3): d=157.9, 136.9, 129.4,
128.8, 128.6, 128.6, 127.7, 121.9, 119.2, 116.1, 61.5, 60.9, 41.3;
HR-MS-ESI: m/z=228.1385 [M+H]+, calcd. for C15H18NO:
228.1383.
2-{[Benzyl(methyl)amino]methyl}-4-methoxyphenol (4b):
Light yellow liquid; yield: 98 mg (76%); 1H NMR
(300 MHz, CDCl3): d=10.44 (br. s., 1H), 7.40–7.27 (m, 5H),
6.87–6.72 (m, 2H), 6.62 (d, J=2.6 Hz, 1H), 3.76 (s, 3H),
3.72 (s, 2H), 3.60 (s, 2H), 2.25 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=152.5, 151.6, 136.9, 129.4, 128.6, 127.7, 122.6,
116.4, 114.5, 113.6, 61.4, 61.0, 55.7, 41.3; HR-MS-ESI: m/z=
258.1488 [M+H]+, calcd. for C16H20NO2: 258.1489.
(4h):
White solid; yield: 69 mg (45%); 1H NMR (499 MHz,
CDCl3): d=11.24 (br. s., 1H), 7.38–7.33 (m, 2H), 7.33–7.24
(m, 4H), 7.11 (s, 1H), 6.74 (d, J=8.8 Hz, 1H), 3.71 (s, 2H),
3.60 (s, 2H), 2.24 (s, 3H); 13C NMR (126 MHz, CDCl3): d=
157.2, 136.6, 131.6, 131.2, 129.5, 128.8, 127.9, 124.0, 118.1,
110.9, 61.6, 60.5, 41.4; HR-MS-ESI: m/z=306.0489 [M+
H]+, calcd. for C15H17BrNO: 306.0488.
2-{[Benzyl(methyl)amino]methyl}-6-ethylphenol
(4i):
Light yellow liquid; yield: 64 mg (50%); 1H NMR
(300 MHz, CDCl3): d=11.16 (br. s, 1H), 7.43–7.29 (m, 5H),
7.13 (dd, J=1.5, 7.3 Hz, 1H), 6.91 (dd, J=1.5, 7.3 Hz, 1H),
6.79 (t, J=7.3 Hz, 1H), 3.79 (s, 2H), 3.63 (s, 2H), 2.74 (q,
J=7.4 Hz, 2H), 2.27 (s, 3H), 1.30 (t, J=7.7 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=155.7, 137.1, 131.0, 129.5,
128.7, 128.3, 127.7, 126.3, 121.4, 118.9, 61.5, 61.2, 41.2, 23.0,
14.3; HR-MS-ESI: m/z=256.1697, [M+H]+, calcd. for
C17H22NO: 256.1696.
tert-Butyl
{3-[benzyl(methyl)amino]methyl}-4-hydroxy-
phenyl)carbamate (4c): Beige solid; yield: 95 mg (56%);
1H NMR (300 MHz, CDCl3): d=10.30 (br. s., 1H), 7.38–7.26
(m, 5H), 7.23 (br. s., 1H), 6.99 (dd, J=2.5, 8.6 Hz, 1H), 6.78
(d, J=8.7 Hz, 1H), 6.51 (s, 1H), 3.71 (s, 2H), 3.57 (s, 2H),
2.21 (s, 3H), 1.51 (s, 9H); 13C NMR (75 MHz, CDCl3): d=
153.8, 153.4, 136.9, 130.1, 129.4, 128.6, 127.7, 122.2, 120.0,
120.0, 116.2, 80.1, 61.5, 61.0, 41.2, 28.5; HR-MS-ESI: m/z=
343.2014 [M+H]+, calcd. for C20H27N2O3: 343.2016.
2-{[Benzyl(methyl)amino]methyl}-4-(tert-butyl)phenol
(4d): Light yellow liquid; yield: 99 mg (70%); 1H NMR
(300 MHz, CDCl3): d=10.65 (br. s., 1H), 7.42–7.29 (m, 5H),
7.25 (dd, J=2.1, 8.5 Hz, 1H), 7.05 (d, J=1.9 Hz, 1H), 6.85
(d, J=8.5 Hz, 1H), 3.79 (s, 2H), 3.64 (s, 2H), 2.29 (s, 3H),
1.34 (s, 9H); 13C NMR (75 MHz, CDCl3): d=155.4, 141.8,
137.1, 129.4, 128.6, 127.7, 125.5, 125.4, 121.1, 115.5, 61.6,
61.4, 41.4, 34.0, 31.7; HR-MS-ESI: m/z=284.2010 [M+H]+,
calcd. for C19H26NO: 284.2009.
3-{[Benzyl(methyl)amino]methyl}-[1,1’-biphenyl]-4-ol
(4e): Yellow liquid; yield: 118 mg (77%); 1H NMR
(499 MHz, CDCl3): d=11.05 (br. s., 1H), 7.60 (d, J=7.3 Hz,
2H), 7.51–7.32 (m, 9H), 7.31 (d, J=2.0 Hz, 1H), 7.01 (d, J=
8.3 Hz, 1H), 3.86 (s, 2H), 3.67 (s, 2H), 2.32 (s, 3H);
13C NMR (75 MHz, CDCl3): d=157.6, 141.0, 136.8, 132.3,
129.4, 128.8, 128.7, 127.7, 127.5, 127.3, 126.6, 126.5, 122.1,
116.5, 61.5, 61.0, 41.3; HR-MS-ESI: m/z=304.1694 [M+
H]+, calcd. for C21H22NO: 304.1696.
4-Methoxy-2-{[(4-methoxybenzyl)(methyl)amino]methyl}-
phenol (4j): Light yellow liquid; yield: 106mg (74%);
1H NMR (300 MHz, CDCl3): d=9.53 (br. s., 1H), 7.25 (d,
J=8.5 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 6.86–6.74 (m, 3H),
6.63 (d, J=2.8 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.72 (s,
2H), 3.56 (s, 2H), 2.25 (s, 3H); 13C NMR (126 MHz,
CDCl3): d=159.2, 152.6, 151.7, 130.6, 129.0, 122.7, 116.5,
114.6, 114.0, 113.6, 60.8 (2 C), 55.8, 55.3, 41.2; HR-MS-ESI:
m/z=288.1595 [M+H]+, calcd. for C17H22NO3: 288.1594.
2-{[Ethyl(methyl)amino]methyl}-4-methoxyphenol (4k):
Yellow liquid; yield: 73 mg (75%); 1H NMR (300 MHz,
CDCl3): d=9.63 (br. s., 1H), 6.78–6.67 (m, 2H), 6.54 (d, J=
1.7 Hz, 1H), 3.73 (s, 3H), 3.65 (s, 2H), 2.53 (q, J=7.2 Hz,
2H), 2.27 (s, 3H), 1.13 (t, J=7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=152.5, 152.0, 122.8, 116.4, 114.4, 113.4,
61.1, 55.9, 50.8, 40.9, 12.2; HR-MS-ESI: m/z=196.1333 [M+
H]+, calcd. for C11H18NO2: 196.1332.
2-[(Diethylamino)methyl]-4-methoxyphenol
(4l):[32]
Brown liquid; yield: 43 mg (41%); 1H NMR (300 MHz,
CDCl3): d=10.42 (br. s., 1H), 6.72 (s, 2H), 6.55 (s, 1H),
3.77–3.65 (m, 5H), 2.60 (q, J=7.1 Hz, 4H), 1.09 (t, J=
7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=152.5, 152.2,
123.0, 116.4, 114.5, 113.3, 57.2, 55.9, 46.4, 11.3.
4-Methoxy-2-(pyrrolidin-1-ylmethyl)phenol (4n): Dark
yellow liquid; yield: 81 mg (78%); 1H NMR (300 MHz,
CDCl3): d=10.56 (br. s., 1H), 6.81–6.66 (m, 2H), 6.55 (s,
1H), 3.76 (s, 2H), 3.72 (s, 3H), 2.68–2.53 (m, 4H), 1.91–1.76
(m, 4H); 13C NMR (75 MHz, CDCl3): d=152.3, 151.8, 123.2,
116.2, 113.8, 113.3, 58.9, 55.7, 53.5, 23.7; HR-MS-ESI: m/z=
208.1333 [M+H]+, calcd. for C12H18NO2: 208.1332.
2-{[3,4-Dihydroisoquinolin-2(1H)-yl]methyl}-4-methoxy-
phenol (4o): Light orange solid; yield: 103 mg (77%);
1H NMR (300 MHz, CDCl3): d=9.98 (br. s., 1H), 7.25–7.12
(m, 3H), 7.09–7.00 (m, 1H), 6.87–6.77 (m, 2H), 6.72–6.62
(m, 1H), 3.87 (s, 2H), 3.83–3.74 (m, 5H), 2.98 (t, J=5.6 Hz,
2-{[Benzyl(methyl)amino]methyl}-4-fluorophenol
(4f):
Light yellow liquid; yield: 92 mg (75%); 1H NMR
(499 MHz, CDCl3): d=10.45 (br. s., 1H), 7.39–7.35 (m, 2H),
7.33–7.29 (m, 3H), 6.89 (dt, J=2.9, 8.6 Hz, 1H), 6.80 (dd,
J=4.6, 9.0 Hz, 1H), 6.74 (dd, J=2.9, 8.8 Hz, 1H), 3.71 (s,
2H), 3.60 (s, 2H), 2.25 (s, 3H); 13C NMR (75 MHz, CDCl3):
d=156.07 (d, J=236.4 Hz), 153.84 (d, J=1.8 Hz), 136.68,
129.40, 128.70, 127.83, 122.82 (d, J=7.2 Hz), 116.76 (d, J=
7.8 Hz), 115.14 (d, J=3.6 Hz), 114.83 (d, J=3.0 Hz), 61.48,
60.53, 41.30; HR-MS-ESI: m/z=246.1289 [M+H]+, calcd.
for C15H17NO: 246.1289.
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2H), 2.88 (t, J=5.4 Hz, 2H); 13C NMR (75 MHz, CDCl3):
d=152.6, 151.7, 133.6, 133.4, 128.7, 126.6, 126.6, 126.0, 122.0,
116.6, 114.6, 113.7, 61.2, 55.8, 55.4, 50.0, 28.7; HR-MS-ESI:
m/z=270.1491 [M+H]+, calcd. for C17H20NO2: 270.1489.
4-Methoxy-2-(thiomorpholinomethyl)phenol (4p): White
6-(4-Fluorophenyl)-1-methylnaphthalen-2-ol (6c): White
solid; yield: 91 mg (72%); H NMR (499 MHz, DMSO-d6):
1
d=9.58 (s, 1H), 8.04 (d, J=2.0 Hz, 1H), 7.91 (d, J=8.8 Hz,
1H), 7.81–7.75 (m, 2H), 7.72 (dd, J=2.0, 8.8 Hz, 1H), 7.69
(d, J=8.8 Hz, 1H), 7.32–7.26 (m, 2H), 7.21 (d, J=8.8 Hz,
1H), 2.44 (s, 3H); 13C NMR (126 MHz, DMSO-d6): d=
161.65 (d, J=244.1 Hz), 152.48, 137.05 (d, J=2.9 Hz),
132.95, 132.72, 128.44 (d, J=7.6 Hz), 128.23, 127.19, 125.60,
124.83, 123.62, 118.54, 115.68 (d, J=21.0 Hz), 114.56, 10.44;
HR-MS-ESI: m/z=251.0876, [MÀH]À, calcd. for C17H12FO:
251.0878.
1
solid; yield: 84 mg (76%); H NMR (499 MHz, CDCl3): d=
10.01 (br. s., 1H), 6.75–6.70 (m, 2H), 6.53 (d, J=2.0 Hz,
1H), 3.72 (s, 3H), 3.65 (s, 2H), 2.85–2.76 (m, 4H), 2.72–2.68
(m, 4H); 13C NMR (75 MHz, CDCl3): d=152.6, 151.3, 121.5,
116.5, 114.7, 113.7, 62.3, 55.7, 54.4, 27.9; HR-MS-ESI: m/z=
240.1052, [M+H]+, calcd. for C12H18NO2S: 240.1053.
1-Methyl-6-(p-tolyl)naphthalen-2-ol (6d): White solid;
yield: 86 mg (70%); 1H NMR (499 MHz, DMSO-d6): d=
9.54 (s, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.90 (d, J=8.8 Hz,
1H), 7.74 (dd, J=2.0, 8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H),
7.65 (d, J=7.8 Hz, 2H), 7.27 (d, J=8.3 Hz, 2H), 7.20 (d, J=
8.8 Hz, 1H), 2.44 (s, 3H), 2.35 (s, 3H); 13C NMR (126 MHz,
DMSO-d6): d=152.3, 137.2, 136.2, 133.6, 132.9, 129.5, 128.3,
127.1, 126.4, 125.2, 124.8, 123.5, 118.4, 114.5, 20.7, 10.4; HR-
MS-ESI: m/z=247.113 [MÀH]À, calcd. for C18H15O:
247.1128.
4-Methoxy-2-[(4-methylpiperazin-1-yl)methyl]phenol
(4q): Light yellow liquid; yield: 88 mg (74%); 1H NMR
(499 MHz, CDCl3): d=10.23 (br. s., 1H), 6.72–6.66 (m, 2H),
6.52 (d, J=2.4 Hz, 1H), 3.69 (s, 3H), 3.62 (s, 2H), 2.53 (br.
s., 8H), 2.26 (s, 3H); 13C NMR (75 MHz, CDCl3): d=152.5,
151.4, 121.8, 116.4, 114.4, 113.6, 61.4, 55.7, 54.9, 52.4, 45.8;
HR-MS-ESI:
m/z=237.1596,
[M+H]+,
calcd.
for
C13H21N2O2: 237.1598.
4-Methoxy-2-(piperidin-1-ylmethyl)phenol (4r):[33] Light
brown liquid; yield: 79 mg (71%); 1H NMR (300 MHz,
CDCl3): d=10.05 (br. s., 1H), 6.77–6.70 (m, 2H), 6.55 (s,
1H), 3.72 (s, 3H), 3.61 (s, 2H), 2.67–2.30 (m, 4H), 1.71–1.55
(m, 4H), 1.55–1.30 (m, 2H).
6-(4-Methoxyphenyl)-1-methylnaphthalen-2-ol
(6e):
White solid; yield: 69 mg (52%); 1H NMR (499 MHz,
DMSO-d6): d=9.51 (s, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.89 (d,
J=8.8 Hz, 1H), 7.74–7.65 (m, 4H), 7.19 (d, J=8.8 Hz, 1H),
7.03 (d, J=8.8 Hz, 2H), 3.80 (s, 3H), 2.43 (s, 3H); 13C NMR
(126 MHz, DMSO-d6): d=158.6, 152.2, 133.4, 132.6, 132.5,
128.3, 127.6, 127.0, 124.8, 123.5, 118.4, 114.5, 114.4 (2C),
55.1, 10.4; HR-MS-ESI: m/z=263.1078 [MÀH]À, calcd. for
C18H15O2: 263.1078.
4-Methoxy-2-(morpholinomethyl)phenol (4s):[34] Colour-
less liquid; yield: 47 mg (42%); 1H NMR (300 MHz,
CDCl3): d=10.12 (br. s., 1H), 6.81–6.67 (m, 2H), 6.60–6.50
(m, 1H), 3.76–3.71 (m, 7H), 3.65 (s, 2H), 2.64–2.46 (m,
4H); 13C NMR (75 MHz, CDCl3): d=152.7, 151.3, 121.4,
116.5, 114.7, 113.9, 66.9, 62.0, 55.8, 53.0.
2,4-Dimethylnaphthalen-1-ol (6f):[36] White solid; yield:
2-(Azepan-1-ylmethyl)-4-methoxyphenol
(4t):
Light
1
yellow liquid; yield: 78 mg (66%); 1H NMR (499 MHz,
CDCl3): d=9.79 (br. s., 1H), 6.76–6.70 (m, 2H), 6.53 (d, J=
2.9 Hz, 1H), 3.74–3.71 (m, 5H), 2.69 (t, J=4.9 Hz, 4H),
1.71–1.66 (m, 4H), 1.65–1.60 (m, 4H); 13C NMR (75 MHz,
CDCl3): d=152.4, 152.2, 123.1, 116.4, 114.4, 113.4, 62.2, 55.8,
55.4, 27.8, 26.7; HR-MS-ESI: m/z=236.1645 [M+H]+,
calcd. for C14H22NO2: 236.1645.
35 mg (41%); H NMR (499 MHz, CDCl3): d=8.24–8.19 (m,
1H), 7.99–7.94 (m, 1H), 7.57–7.51 (m, 2H), 7.12 (s, 1H),
5.06 (br. s., 1H), 2.64 (s, 3H), 2.40 (s, 3H); 13C NMR
(126 MHz, CDCl3): d=147.0, 132.2, 129.6, 126.3, 125.3,
125.1, 124.7, 124.3, 121.5, 116.0, 18.8, 15.6.
2-[(Benzylamino)methyl]-4-methoxyphenol (4u): Colour-
less liquid; yield: 36 mg (29%); 1H NMR (300 MHz,
CDCl3): d=7.41–7.27 (m, 5H), 6.83–6.70 (m, 2H), 6.58 (d,
J=2.8 Hz, 1H), 6.08 (br. s., 2H), 3.97 (s, 2H), 3.81 (s, 2H),
3.75 (s, 3H); 13C NMR (75 MHz, CDCl3): d=152.6, 152.0,
138.5, 128.8, 128.5, 127.7, 123.0, 116.9, 114.6, 113.8, 55.9,
52.7, 52.1; HR-MS-ESI: m/z=244.1332, [M+H]+, calcd. for
C15H18NO2: 244.1332.
Acknowledgements
We thank Seung Hyo Kim in our group for helpful discus-
sions. This research was supported by the National Research
Foundation of Korea (NRF-2014R1A2A1A11050028; NRF-
2014R1A5A1011165), Center for New Directions in Organic
Synthesis; NRF-2015M3D3A1A01065480), funded by the
Korea Government.
1-Methylnaphthalen-2-ol (6a):[35] Light yellow solid; yield:
1
69 mg (87%); H NMR (499 MHz, CDCl3) d=7.98 (d, J=
8.8 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.66 (d, J=8.8 Hz,
1H), 7.56 (t, J=8.3 Hz, 1H), 7.42 (t, J=7.3 Hz, 1H), 7.09
(d, J=8.8 Hz, 1H), 5.28 (br. s., 1H), 2.59 (s, 3H); 13C NMR
(126 MHz, CDCl3): d=150.5, 133.9, 129.3, 128.5, 127.4,
126.4, 123.2 (2C), 117.7, 115.5, 10.6.
1-Methyl-6-phenylnaphthalen-2-ol (6b): White solid;
yield: 89 mg (75%); 1H NMR (499 MHz, DMSO-d6): d=
9.57 (s, 1H), 8.11–8.06 (m, 1H), 7.93 (d, J=8.8 Hz, 1H),
7.80–7.74 (m, 3H), 7.71 (d, J=8.8 Hz, 1H), 7.48 (t, J=
7.6 Hz, 2H), 7.35 (t, J=6.8 Hz, 1H), 7.21 (d, J=8.8 Hz,
1H), 2.45 (s, 3H); 13C NMR (126 MHz, DMSO-d6): d=
152.5, 140.1, 133.7, 133.0, 128.9, 128.3, 127.2, 127.0, 126.6,
125.7, 124.9, 123.6, 118.5, 114.6, 10.5; HR-MS-ESI: m/z=
233.0970 [MÀH]À, calcd. for C17H13O: 233.0972.
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