Dibromomethane as one-carbon source in organic synthesis: The Mannich base formation from the reaction of phenolic compounds with a preheated mixture of dibromomethane and diethylamine

Article abstract of DOI:10.1081/SCC-120038509

The salt formed from the reaction of dihalomomethane and diethylamine reacted with phenolic compounds to give the corresponding Mannich bases in modest to good yields. As for the relative rates and yields are in the following order: CH₂Br₂ > CH₂Cl₂. The CD₂Cl₂ is also applicable to prepare the deuterated analogues. At higher temperature, the elimination of diethylamine from Mannich base occurred to give the corresponding o-quinone methide intermediate, which was then trapped by another phenolic compound to give bis(2-hydroxy-1-aryl) methanes.

Full text of DOI:10.1081/SCC-120038509

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Dibromomethane as One‐Carbon Source in Organic
Synthesis: The Mannich Base Formation from the
Reaction of Phenolic Compounds with a Preheated
Mixture of Dibromomethane and Diethylamine
a b
a
a
Yung‐Son Hon
, Yu‐Yu Chou & I‐Che Wu
a
Department of Chemistry and Biochemistry, National Chung Cheng University, Chia‐Yi,
Taiwan, R.O.C, 621
b
Institute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan, R.O.C.
Version of record first published: 17 Aug 2006.
To cite this article: Yung‐Son Hon , Yu‐Yu Chou & I‐Che Wu (2004): Dibromomethane as One‐Carbon Source in Organic
Synthesis: The Mannich Base Formation from the Reaction of Phenolic Compounds with a Preheated Mixture of
Dibromomethane and Diethylamine, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:12, 2253-2267
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 12, pp. 2253–2267, 2004
Dibromomethane as One-Carbon Source in
Organic Synthesis: The Mannich Base
Formation from the Reaction of Phenolic
Compounds with a Preheated Mixture of
Dibromomethane and Diethylamine
1
,2,
1
1
Yung-Son Hon, * Yu-Yu Chou, and I-Che Wu
1
Department of Chemistry and Biochemistry, National Chung Cheng
University, Chia-Yi, Taiwan, R.O.C.
2
Institute of Chemistry, Academia Sinica, Nankang, Taipei,
Taiwan, R.O.C.
ABSTRACT
The salt formed from the reaction of dihalomomethane and diethylamine
reacted with phenolic compounds to give the corresponding Mannich
bases in modest to good yields. As for the relative rates and yields are
2 2 2 2 2 2
in the following order: CH Br . CH Cl . The CD Cl is also applicable
to prepare the deuterated analogues. At higher temperature, the elimi-
nation of diethylamine from Mannich base occurred to give the
*
Correspondence: Yung-Son Hon, Department of Chemistry and Biochemistry,
National Chung Cheng University, Chia-Yi, Taiwan 621, R.O.C.; E-mail: cheysh@
ccu.edu.tw.
2
253
DOI: 10.1081/SCC-120038509
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
2
254
Hon, Chou, and Wu
corresponding o-quinone methide intermediate, which was then trapped
by another phenolic compound to give bis(2-hydroxy-1-aryl)methanes.
Key Words: Mannich base; o-Quinone methide; o-Naphthoquinone
methide; Naphthol; Dibromomethane; Diethylamine.
INTRODUCTION
We found that the treatment of ozonide 2 or the corresponding aldehyde 3
with a preheated mixture of dihalomethane and diethylamine gave acrolein 4
in modest to good yields [Eqs. (1) and (2)], the b-carbon of the acrolein being
derived from dihalomethane; the relative rates and yields are in the following
[
1]
order: CH I . CH Br . CH Cl . The reactivity of aryl alkyl ketone 5 to
2
2
2
2
2
2
the preheated mixture of CH Br and Et NH is poor. Interestingly, it can be
2
2
2
accelerated dramatically by microwave irradiation to give the corresponding
[2]
a-methylene ketone 6 [Eq. (3)]. The b-carbon of the conjugated carbonyl
compounds was derived from CH Br . The characteristic feature of the reac-
2
2
tive intermediate formed from CH Br and Et NH is described as follows.
2
2
2
Both reagents are cheap. Their salts were prepared in situ very easily and
were used in the same flask to carry out further reactions. The reaction
condition was usually mild and it was carried out in nonaqueous media.
Therefore, in comparison with the reported methods, (using Eschenmoser’s
[
3a,b]
salt, see, Ref.
; using methylenedimethylaminoammonium chloride, see
[
3c,d]
Ref.
Ref.
; Using Dimethylamine hydrogen chloride, formaldehyde, see:
a preheated mixture of CH Br and Et NH is a convenient and
[
3e]
2
2
2
economic reagent as one-carbon synthon in organic synthesis.
We are interesting in exploring its further synthetic applications to the
[
4]
Mannich base formation. There are two major methods to prepare the

ORDER
REPRINTS
Dibromomethane as One-Carbon Source in Organic Synthesis
2255
Mannich base. First, phenols were condensed with formaldehyde and second-
[5]
ary amines in protic solvent. Second, phenols reacted with Eschenmoser’s
[6]
iminium salts in aprotic media in the presence of base. In this report,
we will describe our effort in understanding the reactivity of the preheated
mixture of CH Br and Et NH with phenolic compounds.
2
2
2
RESULTS AND DISCUSSION
A mixture of CH Br (15 mol equiv.) and Et NH (4 mol equiv.) was
2
2
2
heated at 558C for 1.5 hr. This preheated mixture was treated with 2-naphthol
9) (1 mol equiv.) in CH Cl at RT and stirred at RT for 3 hr to give the corres-
ponding Mannich base 9a in 82% yield (entry 1, Table 1). The characteristic
(
2
2
chemical shifts of compound 9a are the benzylic protons that appeared at d
1
.20 ppm as a singlet in H-NMR and the benzylic carbon that appeared at
4
d 52.32 ppm in C-NMR.
1
3
Due to the lower boiling point and electrophilicity of CH Cl in com-
2
2
parison with CH Br , the reactive intermediate was generated by heating
2
2
the mixture of CH Cl (15 mol equiv.) and Et NH (4 mol equiv.) in a
2
2
2
sealed tube at 808C for 2.5 hr. The preheated mixture was then treated
with 2-naphthol (9) in CH Cl at RT for 4 hr to give the corresponding
2
2
Mannich base 9a in 80% yield (entry 2). Since the benzylic carbon of
the Mannich base 9a is derived from dihalomethane, we are interested
in employing CD Cl in order to introduce the D-labeled Mannich base.
2
2
0
Indeed, we had prepared dideutero-Mannich base 9a in 63% yield when
CD Cl was used as the reagent (entry 3). There is no absorption at d
2
2
1
.20 ppm in H-NMR for compound 9a . The chemical shift of the
0
4
benzylic carbon appears at d 52.32 ppm as a quintet ( J
1
¼ 20.4 Hz). It
C-D
0
indicates that the deuterium-enrichment is almost 100% in compound 9a
and our method is useful and convenient to prepare the deuterium-labeled
Mannich bases. If the preheated mixture of CH Br and Et NH was mixed
2
2
2
with 2-naphthol (9) in CH Cl and heated in a sealed tube at 1108C for
2
2
2
7 hr, it afforded bis(2-hydroxy-1-naphthyl)methane (9b) in 55% yield
entry 4). The mechanism of this reaction is described as follows. At
higher temperature, Et NH will be eliminated from the primary product
(
2
[5c]
Mannich base 9a to give o-naphtoquinone methide 9a-1, which undergo
Friedel–Crafts reaction with 2-naphthol to give the product 9b (Sch. 1).
When primary amine such as allylamine is treated with CH Br , 3,4-dihy-
2
2
dro-2H-benzo[e][1,3]oxazine 9c is formed in 50% yield from 2-naphthol
[
7]
9) (entry 5). The preheated mixture of allylamine and CH Br reacts
2 2
(
with 2-naphthol (9) to give the secondary amine 9c-1, which further reacts
with CH Br to give the iminium brominde 9c-2. Intermediate 9c-2
2
2

ORDER
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2
256
Hon, Chou, and Wu

ORDER
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Dibromomethane as One-Carbon Source in Organic Synthesis
2257

ORDER
REPRINTS
2
258
Hon, Chou, and Wu
Scheme 1.
undergo intramolecular cyclization to give benzo[e][1,3]oxazine 10c
(
Sch. 2).
The preheated mixture of CH Br (15 mol equiv.) and Et NH
2
2
2
(
RT and stirred at RT for 3 hr to give the corresponding Mannich base 10a
4 mol equiv.) was treated with 1-naphthol (10) (1 mol equiv.) in CH Cl at
2
2
in 75% yield (entry 6). Only 2-substituted Mannich base was isolated. On
the other hand, treatment of the preheated mixture of Et NH (8 mol equiv.)
2
and CH Br (30 mol equiv.) with 1-naphthol (10) (1 mol equiv.) in CH Cl
2
2
2
2
at 558C for 10 hr gave the corresponding Mannich base 10c in 76% yield
entry 7). The sequential diethylaminomethylation at 2- and 4-position of
(
1
-naphthol occurred to give intermediate 10b. Compound 10b underwent
,4-elimination to give the corresponding p-naphthoquinone methide 10b-1,
1
Scheme 2.

ORDER
REPRINTS
Dibromomethane as One-Carbon Source in Organic Synthesis
2259
which was then trapped with Mannich base 10a to give bis(2-diethylamino-
methyl-2-hydroxy-4-naphthyl)methane (10c) (Sch. 3).
The preheated mixture of CH Br and Et NH also reacted with phenol
2
2
2
(
11), 4-benzyloxyphenol (12), 2-allylphenol (13) and bisphenol A (14), respec-
tively, to give the corresponding Mannich bases in good yields (entries 8–11).
Interestingly, 2-allylphenol (13) afforded both mono-diethylaminomethylated
product 13a in 38% yield and bis-diethylaminomethylated product 13b in 43%
yield (entry 10). Similarly, quinolin-8-ol (15) also afforded both mono-
Mannich base 15a (20% yield) and di-Mannich base 15b (32% yield) under
similar condition (entry 12). We have tried to vary the mole ratio of CH Br2
2
and Et NH, however, we failed to obtain the mono-Mannich base product 15a
2
only. When the mole equiv. ratio of CH Br and Et NH was changed from
2
2
2
15 : 4 to 60 : 16, 5,7-bis-Mannich base 15b was formed as the sole product
in 50% yield (entry 13). Since we needed mono-diethylaminomethylated pro-
duct 15a for further application, we followed the reported method by heating
quinolin-8-ol (15), formaldehyde, and diethylammonium chloride in ethanol
[
8]
at 708C for 96 hr. Under this reaction condition, we did not obtain Mannich
base 15a, but obtained the 5,7-bis(ethoxymethyl)quinolin-8-ol (15b ) in 35%
yield and a bis(quinolinol)methane 15d in 6% yield. Mannich bases 15a and
0
15b are proposed to be formed as the primary products in which the diethyl-
amino groups are replaced by ethoxy groups to give 15a and 15b . This
exchange process probably occurs via the corresponding naphthoquinone
0
0
Scheme 3.

ORDER
REPRINTS
2
260
Hon, Chou, and Wu
Scheme 4.
methide intermediates followed by the addition of ethanol. Besides, the minor
0
product 15d was derived from the addition of quinolinol 15a to the p-quino-
0
linone methide 15b (Sch. 4). In our joined research program, Wu et al. use our
protocol to prepare the azacrown-quinol-7-ol 16 from quinolin-7-ol in high
[9]
yield. It has been applied as a highly sensitive metal cation probe.
CONCLUSIONS
The aryl alcohol reacted with a preheated mixture of CH Br and Et NH
2
2
2
to afford the corresponding Mannich bases in modest to good yields. If the

ORDER
REPRINTS
Dibromomethane as One-Carbon Source in Organic Synthesis
2261
reaction was carried out at higher temperature, the elimination of Et NH
2
occurred to give the corresponding quinone methide intermediate, which
was then trapped by Mannich base to give bis(2-hydroxy-1-aryl)methanes.
EXPERIMENTAL
All reactions were carried out under nitrogen. Unless otherwise noted,
materials were obtained from commercial suppliers and used without further
purification. Melting points were determined by using a Thomas–Hoover
1
13
melting point apparatus and were uncorrected. The H and C NMR spectra
were recorded on a Bruker Avance APX-400 and chemical shifts were given
in ppm downfield from tetramethylsilane (TMS). IR spectra were taken with a
Perkin–Elmer 682 spectrophotometer and only noteworthy absorption was
listed. Mass spectra were measured on a VG-Trio-2000GC/MS spectrometer
(
National Chia-Tung University) by electronic impact at 70 eV (unless other-
wise indicated). High Resolution Mass Spectroscopy (HRMS) was measured
on a Finnigan/Thermo Quest MAT (National Chung Hsing University). The
elemental analyses were measured on Heraeus NCH-RAPID and Perkin–
Elmer 2400 CHN analyzer.
Typical Procedure to Work Up the Reaction of the Mannich
Base Formation
After the reaction was completed, the reaction mixture was concentrated
to give the crude residues. To the crude mixture, ether was added and most of
the ammonium salts were precipitated out. After filtration and washing, the
filtrate was concentrated and chromatographed on the silica gel column to
give the desired product.
General Procedure for the Diethylaminomethylation of Aryl Alcohol at
RT by Using CH Br as One Carbon Source
2
2
A mixture of CH Br (0.73 mL, 10.41 mmol) and Et NH (0.29 mL,
2
2
2
2
.78 mmol) was heated to 558C under nitrogen for 1.5 hr and then cooled to
RT. A yellow solution was formed. To a solution of 2-naphthol (9) (0.10 g,
.69 mmol) in 5 mL of CH Cl , a preheated mixture of CH Br –Et NH was
0
2
2
2
2
2
added at RT and stirred at RT for 3 hr. Using standard work up procedure
described above, the desired product 9a (0.13 g, 0.55 mmol) was isolated in
82% yield as a pale yellow oil.

ORDER
REPRINTS
2
262
Hon, Chou, and Wu
General Procedure for the Diethylaminomethylation of Aryl Alcohol by
Using CH Cl as One-Carbon Source
2
2
A mixture of CH Cl (1.20 mL, 18.72 mmol) and Et NH (0.29 mL,
2
2
2
2
.78 mmol) in a sealed tube was heated to 808C for 4 hr and then cooled to
RT. A pale yellow solution was formed. To a solution of 2-naphthol
9) (0.10 g, 0.69 mmol) in 5 mL of CH Cl , a preheated mixture of CH Cl –
(
2
2
2
2
Et NH was added at RT and stirred at RT for 4 hr. Using standard work up
2
procedure described above, the desired product 9a (0.11 g, 0.48 mmol) was
isolated in 69% yield as a pale yellow oil.
General Procedure for the Diethylaminomethylation of Aryl Alcohol by
Using CD Cl as One-Carbon Source
2
2
A mixture of CD Cl (1.50 mL, 23.49 mmol, 99.9% D) and Et NH
2
2
2
(0.31 mL, 3.00 mmol) in a sealed tube was heated to 808C for 4 hr and then
cooled to RT. To a solution of 2-naphthol (9) (0.10 g, 0.69 mmol) in 5 mL of
CH Cl , a preheated mixture of CD Cl –Et NH was added at RT and stirred
2
2
2
2
2
at RT for 4 hr. Using standard work up procedure described above, the desired
0
product 9a (0.104 g, 0.45 mmol) was isolated in 65% yield as a pale yellow oil.
General Procedure for the bis(2-Hydroxy-1-naphthyl)methane by Using
CH Br as One-Carbon Source
2
2
A mixture of CH Br (1.46 mL, 20.82 mmol) and Et NH (0.57 mL,
2
2
2
5.55 mmol) was heated under nitrogen to 558C for 1.5 hr and then cooled to
RT. A preheated mixture of Et NH–CH Cl and 2-naphthol (9) (0.10 g,
2
2
2
0
2
9
.69 mmol) in 5 mL of CH Cl was heated at 1108C in a sealed tube for
7 hr. Using standard work up procedure described above, the desired product
b (0.12 g, 0.38 mmol) was isolated in 55% yield as a white solid. Besides
2
2
CH Cl , anhydrous ethanol, benzene were also tried to be the solvents during
2
2
heating in the sealed tube. Their chemical yields are more or less the same.
TLC R ¼ 0.51 (EtOAc/
[
10]
1
-Diethylaminomethyl-2-naphthol (9a).
1
f
hexane ¼ 1/5); H NMR (400 MHz, CDCl )d 7.78 (d, J ¼ 8.4 Hz, 1H),
3
7
7
.74 (d, J ¼ 8.0 Hz, 1H), 7.66 (d, J ¼ 8.8 Hz, 1H), 7.40–7.42 (m, 1H),
.24–7.28 (m, 1H), 7.07 (d, J ¼ 8.8 Hz, 1H), 4.20 (s, 2H, ArCH N), 2.71
2
1
3
(
(
(
(
q, J ¼ 7.2 Hz, 4H, –NCH –), 1.17 (t, J ¼ 7.2 Hz, 6H, –CH ); C NMR
2
3
100 MHz, CDCl ) d157.1 (48), 132.6 (48), 128.9 (38), 128.9 (38), 128.4
3
48), 126.2 (38), 122.2 (38), 120.8 (38), 119.4 (38), 111.4 (48), 52.3 (28), 47.0
28), 11.4 (18); IR (KBr, neat): 3300 (br, O–H), 1646, 1591, 1461, 1391 cm
MS (m/z, relative intensity) 230 (M þ 1, 100), 229 (M , 84), 157
2
1
;
þ
þ

ORDER
REPRINTS
Dibromomethane as One-Carbon Source in Organic Synthesis
2263
þ
(
Found: 229.1465.
56, M 2 NEt ), 72 (44), 58 (35); HRMS calcd for C H NO: 229.1467;
15 19
2
0
1
-Diethylaminodideuteromethyl-2-naphthol (9a ). R ¼ 0.76 (hexane/
f
1
EtOAc ¼ 3/1); H NMR (400 MHz, CDCl ) d 7.79 (d, J ¼ 8.8 Hz, 1H),
3
7
7
.76 (d, J ¼ 8.3 Hz, 1H), 7.68 (d, J ¼ 8.8 Hz, 1H), 7.45–7.41 (m, 1H),
.30–7.26 (m, 1H), 7.09 (d, J ¼ 8.8 Hz, 1H), 2.72 (q, J ¼ 7.2 Hz, 4H, –
1
3
NCH –) 1.18 (t, J ¼ 7.2 Hz, 6H, –CH ); C NMR (100 MHz, CDCl )
2
3
3
d157.2 (48), 132.7 (48), 128.94 (38), 128.91 (38), 128.4 (48), 126.3 (38),
22.2 (38), 120.8 (38), 119.4 (38), 111.3 (38), 51.7 (JC-D ¼ 20.4 Hz, –
PhCD N–), 46.9 (28), 11.4 (18); IR (KBr, neat): 2500–3300 (br, OH), 2359
1
2
2
1
(
C-D), 1631, 1601, 1472, 1252, 1123 cm ; MS (m/z, relative intensity):
þ þ
31 (M , 12), 158 (M 2 Et NH, 55), 130 (100), 58 (47); HRMS calcd for
2
2
C H D NO: 231.1590; Found: 231.1594.
1
5 17 2
0
[11]
1
1,1 -Methylenedi-2-naphthol (9b).
White solid; mp 200–2018C; H
NMR (400 MHz, CDCl ) d8.21 (d, J ¼ 8.5 Hz, 2H), 7.78 (d, J ¼ 7.9 Hz, 2H),
3
7
.66 (d, J ¼ 8.8 Hz, 2H), 7.45 (t, J ¼ 8.3 Hz, 2H), 7.35–7.31 (m, 2H), 7.06
1
3
(
d, J ¼ 8.8 Hz, 2H) 4.82 (s, 2H, ArCH Ar); C NMR (100 MHz, CDCl )
2 3
d151.6 (48), 133.5 (48), 129.7 (48), 128.9 (38), 126.9 (38), 123.3 (38),
1
1
5
23.1 (38), 118.1 (38), 117.1 (48), 21.8 (28); MS (m/z, relative intensity):
58 (M 2 142, 100), 144 (M 2 156, 91), 129 (56), 115 (91), 84 (51),
1 (72).
þ
þ
2-Allyl-2,3-dihydro-1H-naphth[1,2-e]-1,3-oxazine (9c). A mixture of
allylamine (0.42 mL, 5.55 mmol) and CH Br (1.46 mL, 20.82 mmol) was
2
2
heated under nitrogen to 558C for 3 hr and then cooled to RT. To a solution
of 2-naphthol (9) (0.10 g, 0.69 mmol) in 5 mL of CH Cl , a preheated mixture
of Et NH–CH Br was added; the desired product 9a (0.08 g, 0.34 mmol) was
2
2
2
2
2
isolated in 50% yield as a pale yellow oil. R ¼ 0.69 (hexane/EtOAc ¼ 10/1);
f
1
H NMR (400 MHz, CDCl ) d7.78 (d, J ¼ 8.1 Hz, 1H), 7.67–7.50 (m, 2H),
3
7
.49–7.46 (m, 1H), 7.39–7.34 (m, 1H), 7.05 (d, J ¼ 8.8 Hz, 1H), 6.01–
.94 (m, 1H, –CH 55 CH ), 5.27–5.21 (m, 2H, –CH 55 CH ), 4.95 (s, 2H, –
5
2
2
OCH N–), 4.34 (s, 2H, ArCH N–), 3.47 (d, J ¼ 6.3 Hz, 2H, –NCH
2
2
2-
1
3
CH 55 CH ); C NMR (100 MHz, CDCl ) d154.0 (48), 133.8 (48), 127.2,
2
3
126.4, 125.8, 125.1 (48), 124.6, 122.0, 117.9, 114.3 (48), 57.1 (28), 46.5
(
28), 11.2 (28); IR (KBr, neat): 3077, 2877, 1631, 1606, 1237, 1143, 938,
2
1
þ
þ
8
3
4
19, 754 cm ; MS (m/z, relative intensity): 225 (M , 42), 224 (M 21,
þ
6), 184 (M 2CH CH 55 CH –, 9), 156 (64), 128 (100), 127 (40), 102 (22),
2
2
1 (22); HRMS calcd for C H NO: 225.1154: Found 225.1161.
1
5 15
[10b,12]
2
-Diethylaminomethyl-1-naphthol
1
(10a).
TLC
R ¼ 0.50
f
(
EtOAc/hexane ¼ 1/5); H NMR (400 MHz, CDCl ) d 8.24–8.22 (m, 1H),
3
7
.74–7.72 (m, 1H), 7.43–7.41 (m, 2H), 7.26 (d, J ¼ 8.3 Hz, 1H), 7.05
(
d, J ¼ 8.3 Hz, 1H), 4.00 (s, 2H, ArCH N), 2.66 (q, J ¼ 7.1 Hz,
2
1
3
4
H, –NCH ), 1.13 (t, J ¼ 7.1 Hz, 6H, –CH ); C NMR (100 MHz, CDCl )
2
3
3

ORDER
REPRINTS
2
264
Hon, Chou, and Wu
d 135.2 (48), 131.9 (48), 129.0 (38), 128.6 (38), 128.0 (38), 126.5 (48), 123.4
(
38), 121.0 (38), 118.6 (38), 118.2 (38), 55.1 (28), 53.4 (28), 47.2 (18); IR
21
(
relative intensity): 229 (M , 2), 156 (66, M 2 HNEt ), 128 (100), 127
KBr, neat): 3500 (br, OH), 1626, 1606, 1531, 1477, 1277 cm ; MS (m/z,
þ
þ
2
(
30), 102 (25), 58 (49); HRMS calcd for C H NO: 229.1467; Found:
15 19
229.1469.
bis(2-Diethylaminomethyl-1-hydroxy-4-naphthyl)methane (10c). Pale
1
yellow solid: mp 161–1638C; H NMR (400MHz, CDCl ) d1.12
3
(
t, J ¼ 7.1 Hz, 12H, NCH CH ), 2.64 (q, J ¼ 7.2 Hz, 8H, NCH –), 3.76
2
3
2
(s, 4H, ArCH N–), 4.66 (s, 2H, ArCH Ar), 6.67 (s, 1H), 7.39–7.52 (m, 2H),
2 2
1
3
7
.94 (d, J ¼ 8.2 Hz, 1H), 8.34 (d, J ¼ 8.0 Hz, 1H); C NMR (100MHz,
CDCl ) d11.2 (18), 34.6 (28), 46.5 (28), 57.1 (28), 113.9 (48), 122.5, 123.7,
3
1
24.5, 125.4 (48), 125.8, 126.3 (48), 127.4, 132.2 (48), 152.6 (48); IR
21
KBr, neat): 3478 (br, OH), 1624, 1607, 1530, 1476, 1275cm ; Anal.
(
calcd for C H N O : C, 79.11; H, 8.14; N, 5.95; Found: C, 79.08; H, 8.26;
3
1 38 2 2
N, 5.74.
-Diethylaminomethyl-1-phenol (11a).
[13]
2
TLC R ¼ 0.65 (EtOAc/
f
1
hexane ¼ 1/5); H NMR (400 MHz, CDCl ) d 7.15 (dd, J ¼ 7.4, 6.3 Hz,
3
1
2
H), 6.88 (d, J ¼ 7.4 Hz, 1H), 6.81–6.74 (m, 2H), 3.76 (s, 2H, PhCH N),
2
1
3
.62 (q, J ¼ 7.3 Hz, 4H, –NCH CH ), 1.11 (t, J ¼ 7.2 Hz, 6H, –CH );
C
2
3
3
NMR (100 MHz, CDCl ) d 158.3 (48), 128.4 (38), 128.2 (38), 122.1 (48),
3
1
2
1
18.8 (38), 116.0 (38), 56.9 (28), 46.3 (28), 11.2 (18); IR (KBr, neat): 3100–
21
500 (br, OH), 1596, 1492, 1447, 1267 cm ; MS (m/z, relative intensity):
þ
þ
79 (M , 45), 164 (M 2 CH , 58), 107 (87), 77 (31), 58 (100), 29 (28), 27
3
(
17); HRMS calcd for C H NO: 179.1310 Found: 179.1309.
11 17
4
-Benzyloxy-2-diethylaminomethylphenol (12a). TLC R ¼ 0.56
f
1
(
EtOAc/hexane ¼ 1/5); H NMR (400 MHz, CDCl )d 7.43–7.30 (m, 5H),
3
6
.78–6.63 (m, 3H), 4.98 (s, 2H, Ar-CH ), 3.72 (s, 2H, –CH –NEt ), 2.62
2 2 2
1
3
(
q, J ¼ 7.2 Hz, 4H, –NCH CH ), 1.10 (t, J ¼ 7.0 Hz, 6H, –NCH CH );
C
2
3
2
3
NMR (100 MHz, CDCl ) d 152.4 (48), 151.6 (48), 137.5 (48), 128.5 (38),
3
127.8 (38), 127.5 (38), 122.9 (48), 116.3 (38), 115.6 (38), 114.5 (38), 70.9
(
28), 57.0 (28), 46.4 (28), 11.2 (18); IR (KBr, neat): 3186 (br,-OH), 3033,
2
1
2
972, 1597, 1494, 1250, 1026 cm ; MS (m/z, relative intensity): 285
þ
(
M , 7), 213 (3), 194 (100), 91 (15); HRMS calcd for C H NO :
1
8
23
2
285.1729; Found: 285.1730.
6
-Diethylaminomethyl-2-allylphenol (13a). Pale yellow oil, R ¼ 0.47
f
(
hexane/EtOAc ¼ 10/1); pale yellow oil, R ¼ 0.09 (hexane/
f
1
EtOAc ¼ 10/1). H NMR (400 MHz, CDCl ) d7.05–7.03 (m, 1H),
3
6
5
2
.86–6.84 (m, 1H), 6.73 (t, J ¼ 7.5 Hz, 1H), 6.08–6.01 (m, 1H, CH 55 CH ),
2
.09–5.03 (m, 2H, –CH ¼ CH ), 3.77 (s, 2H, ArCH N–), 3.40 (d, J ¼ 6.5 Hz,
2
2
H, –CH CH 55 CH ), 2.63 (q, J ¼ 7.2 Hz, 4H, –NCH CH ), 1.11
2
2
2
3
1
3
(
t, J ¼ 7.2 Hz, 6H, NCH CH ); C NMR (100 MHz, CDCl )d155.9 (48),
2
3
3

ORDER
REPRINTS
Dibromomethane as One-Carbon Source in Organic Synthesis
2265
137.2, 128.9, 126.5, 121.7, 118.6, 115.1, 56.8 (28), 46.2 (28), 33.9 (28), 11.0
(
18); IR (KBr, neat): 2500–3500 (br, OH), 1645, 1604, 1466, 1420, 1277,
2
1
þ
1
254, 1074, 1055 cm ; MS (m/z, relative intensity): 219 (M , 20), 204
þ
(M 2 CH , 13), 147 (51), 131 (10), 119 (12), 91 (21), 72 (32), 58 (100);
HRMS calcd for C H NO: 219.1623: Found: 219.1631.
3
1
4 21
1
-Allyl-4,6-bis(diethylaminomethyl)phenol (13b). H NMR (400 MHz,
2
CDCl ) d6.93 (s, 1H), 6.81 (s, 1H), 6.11–5.97 (m, 1H), 5.11–4.98 (m, 2H),
3
3
.74 (s, 2H, ArCH N–), 3.43 (s, 2H), 3.37 (d, J ¼ 6.5 Hz, 2H, –CH CH 55 CH ),
2 3
2
2
2
2
.60 (q, J ¼ 7.2 Hz, 4H, –NCH CH ), 2.50 (q, J ¼ 7.1 Hz, 4H), 1.09
1
3
(
(
t, J ¼ 7.2 Hz, 6H, –NCH CH ), 1.03 (t, J ¼ 7.1 Hz, 6H); C NMR
3
2
3
100 MHz, CDCl ) d150.1, 132.8, 129.3, 128.4, 127.9, 126.3, 123.4, 121.9,
1
18.7, 111.5, 96.4, 62.5, 31.7, 26.0, 24.4, 23.8; IR (KBr, neat): 2500–3500
1
2
(
br, OH), 1641, 1618, 1480, 1392, 1295, 1254, 1203, 1180, 1065 cm
,2-bis(4-Hydroxy-3-diethylaminomethylphenyl)propane (14a). TLC
.
2
1
R ¼ 0.23 (EtOAc/hexane ¼ 1/3); H NMR (400 MHz, CDCl ) d7.03 (dd,
f
3
J ¼ 8.4, 2.5 Hz, 2H), 6.79 (d, J ¼ 2.4 Hz, 2H), 6.70 (d, J ¼ 8.4 Hz, 2H),
3
–
.70 (s, 4H, ArCH N), 2.60 (q, J ¼ 7.2 Hz, 8H, –NCH CH ), 1.60 (s, 6H,
3 2 3 3
2
2
3
1
3
(CH ) C), 1.10 (t, J ¼ 7.2 Hz, 12H, –CH ); C NMR (100 MHz, CDCl )
d155.7 (48), 141.4 (48), 126.7 (38), 126.4 (38), 121.2 (48), 115.1 (38), 57.3
(
(
(
28), 46.3 (28), 41.4 (48), 31.2 (18), 11.2 (18); IR (KBr, neat): 3000–2500
21
br, OH), 1611, 1502, 1392, 1277 cm ; MS (m/z, relative intensity): 398
þ
M , 43), 327 (100), 310 (88), 253 (60), 84 (42), 58 (74), 49 (55), 28 (24);
HRMS calcd for C H N O : 398.2933; Found: 398.2931.
5 38 2 2
2
5
,7-bis-Diethylaminomethylquinolin-8-ol (15b). Mp 53–558C; TLC
1
R ¼ 0.06 (EtOAc); H NMR (400 MHz, CDCl ) d 8.83–8.81 (m, 1H),
f
3
8
.63–8.59 (m, 1H), 7.32–7.30 (m, 1H), 7.08 (d, J ¼ 5.4 Hz, 1H), 3.88
(
d, J ¼ 6.7 Hz, 2H, Ar-CH ), 3.79 (d, J ¼ 6.5 Hz, 2H, Ar-CH ), 2.68–2.61
2
2
(
m, 2H, –NCH CH ), 2.52–2.46 (m, 2H, –NCH CH ), 1.15–1.09 (m, 3H,
2 3 2 3
1
3
–
NCH CH ), 1.02–0.97 (m, 3H, –NCH CH ); C NMR (100 MHz,
2 3 2 3
CDCl ) d 153.0 (48), 148.4 (38), 139.8 (48), 133.1 (38), 128.2 (38), 127.5
3
(
48), 125.0 (48), 120.4 (38), 117.3 (48), 56.4 (28), 55.5 (28), 46.6 (28), 46.5
28), 11.4 (18), 11.4 (18); IR (KBr, neat): 3374 (br, OH), 3051, 2971, 2812,
(
2
1
1
570, 1462, 1265, 1120, 739 cm ; MS (m/z, relative intensity): 315
þ
(M , 2), 286 (36), 244 (64), 172 (100), 72 (27); HRMS calcd for
C H N O: 315.2311; Found: 315.2313.
1
9 29 3
5,7-bis-Ethoxymethylquinolin-8-ol (15c) and 5-ethoxymethyl-7-(7-
ethoxymethyl-8-hydroxy-5-quinolinyl)methyl)-8-hydroxyquinoline (15d). A
mixture of quinolin-8-ol (15) (2.0 g, 13.7 mmol), paraformaldehyde (4.9 g,
55.1 mmol), diethylammonium chloride (4.5 g, 13.7 mmol) in 150 mL of the
absolute ethanol was heated to 708C for 4 days. The reaction mixture was
cooled to RT and concentrated to give a crude residue. The crude residue
was chromatographed on the silica gel column to give the major product

ORDER
REPRINTS
2
266
Hon, Chou, and Wu
15c (1.05 g) in 35% yield as a pale green solid and product 15d (0.51 g) in 6%
yield as a pale green solid. Compound 15c: mp 34–358C; TLC R ¼ 0.79
f
1
(
EtOAc/Hexane ¼ 1/5); H NMR (400 MHz, CDCl ) d 8.74 (dd, J ¼ 4.2,
3
1
4
.4 Hz, 1H), 8.44 (dd, J ¼ 8.6, 1.5 Hz, 2H), 7.55 (s, 1H), 7.39 (dd, J ¼ 8.4,
.2 Hz, 1H), 4.80 (s, 2H, Ar-CH O), 4.79 (s, 2H, Ar-CH O), 3.63 (q,
2
2
J ¼ 7.0 Hz, 2H, O–CH CH ), 3.53 (q, J ¼ 7.0 Hz, 2H, O–CH CH ), 1.27
2
3
2
3
(
1
t, J ¼ 7.0 Hz, 3H, O–CH –CH ), 1.22 (t, J ¼ 7.0 Hz, 3H, O–CH –CH );
3
2
3
2
3
3
C NMR (100 MHz, CDCl ) d 149.5 (48), 147.6 (38), 138.4 (48), 133.3
(
38), 129.0 (48), 126.7 (38), 124.2 (48), 121.5 (48), 118.8 (38), 70.7 (28, Ar-
CH –O), 66.5 (28, Ar-CH –O), 65.8 (28, Ar-CH –O–CH ), 65.3 (28, Ar-
2
2
2
2
CH –O–CH ), 15.2 (18, O–CH –CH ), 15.1 (18, O–CH –CH ); IR (KBr,
2
2
2
3
2
3
2
neat): 3374 (br, –OH), 2975, 2868, 1504, 1464, 1127, 1092 cm ; MS
1
þ
(
m/z, relative intensity): 261 (M , 7), 232 (14), 217 (100), 172 (75), 170
(
26); HRMS calcd for C H NO : 261.1365; Found: 261.1363. Compound
1
5
19
3
1
1
2
5d: H NMR (400 MHz, CDCl ) d 8.80–8.70 (m, 2H), 8.43 (t, J ¼ 8.4 Hz,
3
H), 7.57 (s, 1H), 7.44 (q, J ¼ 4.4 Hz, 1H), 7.34 (q, J ¼ 4.4 Hz, 1H), 7.12
(
s, 1H), 4.82 (s, 2H, ArCH –), 4.63 (s, 2H, ArCH O), 4.53 (s, 2H,
2 2
ArCH O), 3.66 (q, J ¼ 6.8 Hz, 2H, –OCH CH ), 3.45 (q, J ¼ 7.0 Hz, 2H, –
2
2
3
OCH CH ), 1.28 (t, J ¼ 6.8 Hz, 3H, –OCH CH ), 1.15 (t, J ¼ 7.0 Hz, 3H,
2
3
2
3
1
3
–
OCH CH ); C NMR (100 MHz, CDCl ) d 148.5 (48), 158.5 (48), 147.7
2
3
3
(
38), 147.4 (38), 138.6 (48), 138.6 (48), 133.4 (38), 129.9 (38), 129.1 (38),
26.8 (48), 126.6 (48), 126.0 (48), 124.3 (48), 121.4 (48), 121.3 (48), 120.9
38), 119.2 (48), 70.7 (28), 66.8 (28), 65.9 (28), 65.5 (28), 31.2 (28), 15.3 (18),
1
(
1
5.1 (18); IR (KBr, neat): 3382 (br,OH), 3052, 2976, 2929, 2869, 1578, 1463,
265, 1092 cm ; MS (m/z, relative intensity): 418 (M , 39), 374 (100), 372
21
þ
1
(
50), 327 (51), 164 (49); HRMS calcd for C H N O : 418.1893; Found:
25 26 2 4
418.1891.
ACKNOWLEDGMENTS
We are grateful to the National Science Council, National Chung Cheng
University, and Academia Sinica, Republic of China for financial support.
REFERENCES
1
. (a) Hon, Y.S.; Chang, F.J.; Lu, L. Chem. Commun. 1994, 2041–2042;
b) Hon, Y.S.; Chang, F.J.; Lu, L.; Lin, W.C. Tetrahedron 1998, 54,
233–5246.
(
5
2. Hon, Y.S.; Hsu, T.R.; Chen, C.Y.; Lin, Y.H.; Chang, F.R.; Hsieh, C.H.;
Szu, P.H. Tetrahedron 2003, 59, 1509–1520.

ORDER
REPRINTS
Dibromomethane as One-Carbon Source in Organic Synthesis
2267
3. (a) Nicolaou, K.C.; Reddy, K.R.; Skokotas, G.; Sato, F.; Xiao, X.Y. J. Am.
Chem.Soc.1992,114,7935–7936;(b)Takano,S.;Inomata,K.;Samizu,K.;
Tomita, S.; Yanase, M. Chem. Lett. 1989, 1283–1284; (c) Takano, S.;
Iwabichi, Y.; Ogasawara, K. Chem. Commun. 1988, 1204–1206;
(
d) Herdewijn, P.; Claes, P.J.; Vanderhaeghe, H. J. Med. Chem. 1986, 29,
61–664; (e) Nakatsuji, Y.; Nakamura, T.; Yonetani, M.; Yuya, H.;
Okahara, M. J. Am. Chem. Soc. 1988, 110, 531–538.
6
4
5
. (a) Tramontini, M. Synthesis 1973, 703; (b) Kleinman, E.F. Comprehen-
sive Organic Synthesis; Trost, B.M., Ed.; Pergamon Press: New York,
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991; Vol. 2, 893.
. (a) Grillot, G.F.; Gormley, W.T., Jr. J. Am. Chem. Soc. 1945, 67,
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Chem. Soc. 1946, 68, 946–947; (c) Snyder, H.R.; Brewster, J.H. J. Am.
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. Pochoni, A.; Puglia, G.; Ungaro, R. Synthesis 1983, 906–907.
. Burke, W.J.; Nasutavicus, W.A.; Weatherbee, C. J. Org. Chem. 1964, 29,
7
407–410.
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. Phillip, J.P.; Fernando, Q. J. Am. Chem. Soc. 1953, 75, 3768–3769.
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5
Ungaro, R.; Sartori, G. Synthesis 1981, 143–146.
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1
1
1982, 841–848.
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Received in Japan December 15, 2003

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