Electrooxidative cyclization of hydroquinolyl alcohols

Article abstract of DOI:10.3987/COM-06-10881

Several hydroquinolyl, hydroisoquinolyl, and indolinyl alcohols were electrochemically oxidized in methanol in the presence of sodium methoxide and potassium iodide. The hydroquinolyl and hydroisoquinolyl alcohols afforded the corresponding intramolecular cyclization products through the bond formation between the α-carbon of the nitrogen atom and the oxygen atom of the hydroxy group. In contrast, the indolinyl alcohols underwent dehydrogenation to give the corresponding indolyl alcohols. Presumably, in all cases, the electrooxidation involves a two-electron oxidation process.{A figure is presented}. Quinoline Amino-Alcohol Dehydrogenation Cyclization Oxidation.

Full text of DOI:10.3987/COM-06-10881

HETEROCYCLES, Vol. 68, No. 12, 2006
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HETEROCYCLES, Vol. 68, No. 12, 2006, pp. 2563 - 2570. © The Japan Institute of Heterocyclic Chemistry
Received, 8th September, 2006, Accepted, 23rd October, 2006, Published online, 27th October, 2006. COM-06-10881
ELECTROOXIDATIVE CYCLIZATION OF HYDROQUINOLYL
ALCOHOLS (MS WORD STYLE “01 HET-TITLE”)
Mitsuhiro Okimoto,* Takashi Yoshida, Masayuki Hoshi, Kazuyuki Hattori,
Masashi Komata, Kaori Numata, and Kenta Tomozawa (MS Word Style
“
02 Het-Author’s name”)
Department of Applied and Environmental Chemistry
Kitami Institute of Technology, Koen-cho 165, Kitami, Hokkaido 090-8507,
Japan
E-mail: oki@chem.kitami-it.ac.jp (MS Word Style “03 Het-Author’s
address”)
Abstract – Several hydroquinolyl, hydroisoquinolyl, and indolinyl alcohols were
electrochemically oxidized in methanol in the presence of sodium methoxide and potassium
iodide. The hydroquinolyl and hydroisoquinolyl alcohols afforded the corresponding
intramolecular cyclization products through the bond formation between the ꢀ-carbon of the
nitrogen atom and the oxygen atom of the hydroxy group. In contrast, the indolinyl alcohols
underwent dehydrogenation to give the corresponding indolyl alcohols. Presumably, in all
cases, the electrooxidation involves a two-electron oxidation process. (MS Word
Style “04 Het-Abstract”)
INTRODUCTION (MS Word Style “06 Het-Sub-heading”)
In our most recent study, we reported the electrochemical cyclization of dimethyl aminomalonates A to
1
, 2
afford the corresponding heterobicyclic compounds B, as illustrated in Scheme 1.
MeO C
CO Me
2
2
CO Me
2
2e, - 2H+
-
(
CH )
(CH2)m
N
2 n
(
CH )
CO Me NaCN/MeOH
(CH
)
N
2 n
2
2
m
A
B
m = 3 or 4
n = 2 or 3
Scheme 1 Electrochemical cyclization of dimethyl aminomalonates
In a basic media, the ꢀ-carbon of the nitrogen atom of A is subjected to a nucleophilic attack by the

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HETEROCYCLES, Vol. 68, No. 12, 2006
carbanion of the dimethyl malonate moiety to give B. Moreover, the electrooxidative cyanation of
tertiary aliphatic amines, in which the reaction mechanism is similar to that of Scheme 1, was previously
3
reported. The beginning of this study, we reasoned that the oxygen atom of the intramolecular hydroxy
group of tertiary amine C would initiate a similar nucleophilic attack to form the corresponding
cyclization product D, as illustrated in Scheme 2.
O
oxidation
(
CH ) OH
(CH )
N
2 n
N
2 n
n = 2 or 3
C
D
Scheme 2 Electrochemical cyclization of amino alcohols
Due to the simple synthetic procedures, and because the corresponding products (cyclic N, O-acetal) are
presumably stable against methanolysis and hydrolysis, hydroquinolyl alcohol (1), hydroisoquinolyl
alcohol (3), and indolinyl alcohol (5) were chosen as the starting substrates. As expected, 1 and 3
afforded heterocyclic 2 and 4, respectively, through the formation of an intramoleclar carbon-oxygen
bond (Table 2). Schneider and co-worker first reported the formation of 4a using 3,4-dihydroquinoline
4
5
as the starting substrate. The conversion of 4a into several derivatives were investigated. Lohray and
6
co-workers were able to obtain 2a in a yield of 56% by reduction of the amide esters. On the other
hand, Shono and co-workers reported the cyclization of carbamates that employ similar electrochemical
7
techniques. To the best of our knowledge, however, the systematic electrochemical preparation of this
class of compounds using 1, 3, or 5 as the starting substrate has yet to be reported.
RESULTS AND DISCUSSION
To determine the optimal reaction conditions, the electrooxidation reaction of a model substrate,
hydroquinolyl ethanol (1a), to yield the corresponding fused-ring heterocyclic compound (2a), was
examined. The reactions were carried in the presence of various supporting electrolytes, as listed in
Table 1. The presence of basic electrolytes, such as NaOAc, NaCN, NaOH, and NaOMe (Runs 1-4)
afforded 2a in yields of 25 to 80%. In contrast, the use of neutral electrolytes, such as LiClO4,
tetraethylammonium p-toluenesulfonate, KBr, and KI (Runs 5-8) gave 2a in poor yields; in these cases,
the purification procedures resulted in the recovery of unreacted 1a and/or the deposit of considerable
amounts of dark brownish material on the silica gel column (see general procedure section). It is
noteworthy that, although the presence of NaOMe or KI afforded 2a with yields of 80 and 23% (Runs 4
and 8, respectively), the concurrent use of both electrolytes resulted in an improved yield of 93% (Run 9)
–
in contrast, the concurrent use of KBr or KCl did not exhibit such improvements.

HETEROCYCLES, Vol. 68, No. 12, 2006
2565
a
Table 1 Influence of supporting electrolytes
oxidation
in MeOH
N
O
N
OH
1a
2a
b
Supporting
Electrolyte
Recovery
of 1a
Yield (%)
Runs
(mmol)
of 2a
1
2
3
4
5
6
7
8
9
NaOAc
NaCN
10
10
37
14
4
25
50
70
80
1
NaOH
10
NaOMe
10
17
59
15
23
22
4
LiClO
4
10
p-TsON(Et)
4
8
2
KBr
KI
10
7
10
23
93
KI + NaOMe
5 + 5
a
Reaction conditions: 1a (5 mmol), MeOH (40 mL), current passed (2.0 F/mol),
constant current (0.3 A), temperature (ca. 15 ˚C).
b
Recovery of 1a and yields of 2a were determined by GC analysis.
Our studies showed that the amount of KI, over a range of 2 to 10 mmol, did not affect the yield of 2a (90
and 91%, respectively), whereas an excessive amount of NaOMe (20 vs. 5 mmol) decreased the yield of
2
a (73 vs. 93%, respectively). Because halide ion sources such as KBr (Run 7) and KI (Run 8), which
can act as electron carriers (indirect oxidation), did not affect the yield of the product, it can be assumed
that the electrooxidation proceeds via direct electron transfer from the substrate to the anode.ꢀ
Preliminary electrooxidations revealed that the formation of 2a was in proportion almost quantitatively to
the current passed (24%, 0.5 F/mol; 49%, 1.0 F/mol; 93%, 2.0 F/mol). The maximum yield of 96% was
obtained after passage of 2.3 F/mol (reaction time, 62 min; current efficiency, 83%), at which point, the

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HETEROCYCLES, Vol. 68, No. 12, 2006
majority of 1a was consumed. Subsequently, using the optimal reaction conditions as described above,
the electrooxidation reactions were carried out using hydroquinolyl alcohol (1b), hydroisoquinolyl
alcohols (3a and 3b), and indolinyl alcohols (5a and 5b), as shown in Table 2.
Table 2 Electrooxidation of tetrahydroquinolyl alcohols,
a
tetrahydroisoquinolyl alcohols, and indolinyl alcohols
oxidation
a: n = 2
b: n = 3
N
O
N
OH
CH2)n
(
(CH )
2 n
1a, 1b
2a = 87 % ( 2.3 F/mol ), 2b = 88 % ( 3.0 F/mol )
oxidation
OH
N
N
O
(
CH2)n
(
CH2)n
3
a, 3b
4a = 62 % ( 6.2 F/mol ), 4b = 73 % ( 7ꢀꢁ F/mol )
oxidation
OH
CH2)n
OH
(CH )
2 n
N
N
(
5a, 5b
6a = 65 % ( 2.5 F/mol ), 6b = 63 % ( 2.7 F/mol )
a
Reaction conditions: substrate (5 mmol), NaOMe (5 mmol), KI (5 mmol),
MeOH (40 mL), constant current (0.3 A), temperature (ca. 15 ˚C).
Isolated yields are shown.
The substrates required significantly different amounts of electrical current – for example, substrates (1a
and 1b) required electric currents of 2.3 and 3.0 F/mol, respectively, to form the corresponding
heterocyclic products in good yields (2a, 87% and 2b, 88%, respectively), whereas substrates (3a and 3b)
required currents of 6.2 and 7.8 F/mol, respectively, to form the products in moderate yields (4a, 62% and
4
b, 73%, respectively). In the cases of 3a and 3b, the oxygen atom on the hydroxy group carried out the
nucleophilic attack only on the benzylic carbon, presumably due to the stable molecular structure of the
radical and/or cationic intermediate which forms conjugate system (Scheme 3). The products were
obtained as a slightly yellow viscous oily liquid; in the cases of 2b and 4a, the viscous oil solidified upon

HETEROCYCLES, Vol. 68, No. 12, 2006
2567
storage in a refrigerator for several days. Under similar reaction conditions, the electrooxidation of
indolinyl alcohols (5a and 5b) resulted in the dehydrogenation products (6a, 65% and 6b, 63%,
respectively) instead of the expected cyclized products. Apparently, the electrooxidation of 5 favor
8
aromatization over cyclization to afford the corresponding indolyl alcohol (6). As a note, purification
of 6a and 6b by distillation resulted in considerable amounts of tar-like material that remained in the
distilling flask. Although details of the reaction mechanism remain unclear, a reasonable reaction
pathway (as shown in Scheme 3) describes the cyclization of tetrahydroisoquinoline (3) to 4 as: 1) the
loss of one electron from the lone electron pair of the nitrogen of substrate (3) to the anode to form
cationic radical E, 2) the further one-electron oxidation and deprotonation to form immonium ion F, then
3) the subsequent nucleophilic attack by the oxygen of the hydroxy group. Essentially, substrate 3 loses
two protons and two electrons during the course of the reaction. During these steps, NaOMe would
serve as the base in facilitating the deprotonation of both cation radical E and the hydroxy group of F.
-
e
- e, - H+
N
N
(
CH ) OH
base
2
n
(CH ) OH
2
n
H
H
H
3
E
H
-
H+
n = 2 or 3
N
N
base
(
CH )
(CH )
2 n
H
2 n
O
F
4
O
H
Scheme 3 Proposed scheme of the oxidative cyclization
In conclusion, our studies have demonstrated the electrooxidation of hydroquinolyl alcohols,
hydroisoquinolyl alcohols, and indolinyl alcohols toward the synthesis of several heterocyclic compounds.
Although the yields depend upon the structure of the substrate, our methodology is advantageous due to:
1
) the absence of oxidants and/or special reagents, 2) the mild reaction conditions, 3) the availability of
the substrates, and 4) the simple, one-pot procedure. Further investigations using substrates having
various carbon chain lengths of the alcohol moiety and /or substituted aromatic moiety are currently
underway in our laboratories.
EXPERIMENTAL
Preparative-scale electrooxidations were carried out in a tall 50-mL beaker equipped with a fine frit cup
(
porosity, ca. 100 μm) as the cathode compartment with nickel or stainless steel coil (diameter, 0.8 mm;

2568
HETEROCYCLES, Vol. 68, No. 12, 2006
length, 250 mm) as the cathode, and an insert cylindrical platinum net (diameter, 32 mm; height, 35 mm;
5 mesh) as the anode. Electrooxidations of the substrates (1, 3, or 5) (5 mmol) were carried in a
5
solution of powdered KI (0.83 g, 5 mmol) in MeOH (40 mL) containing NaOMe (5 mmol) under a
constant current (0.3 A). During the course of the electrooxidation, the anolyte was magnetically stirred
and the temperature of the cell was maintained at approximately 15 ˚C. Upon passage of electricity, the
reaction mixture was concentrated in vacuo at approximately 40 ˚C to remove most of the methanol.
The residue was treated with water (ca. 15 mL), and the resulting oily layer was extracted with diethyl
ether (4 x 60 mL), which were combined, and dried over magnesium sulfate. Following the removal of
the solvent, the product was isolated by silica gel column chromatography (diameter, 20 mm; length, 400
mm; diethyl ether as the elution solvent) or by distillation under reduced pressure.
2
7
3
a bp 108–110 ˚C /2 mmHg. IR (neat) : 2939, 2864, 1605, 1504, 1460, 1346, 1312, 1061, 1053, 1001,
-
1 1
46 cm . H NMR (CDCl
.8–4.3 (m, 2H), 4.7–4.9 (m, 1H), 6.4–6.8 (m, 2H, Arom), 6.9–7.3 (m, 2H, Arom). C NMR (CDCl
24.76 (CH ), 26.18 (CH ), 47.36 (CH ), 65.68 (CH ), 87.96 (CH), 111.90 (CH), 116.99 (CH), 122.33
3
):ꢀ=1.4–1.9 (m, 1H), 2.1–2.4 (m, 1H), 2.6–2.9 (m, 2H), 3.2–3.6 (m, 2H),
13
3
):ꢀ
=
2
2
2
2
+
(
C), 127.37 (CH), 128.07 (CH), 143.87 (C). MS m/z (%) : 175 (M , 87), 174 (100), 145 (26), 144 (25),
+
1
32 (21), 130 (17), 118 (14), 117 (27), 91 (18), 77 (13). HRMS m/z found : 175.0993 (M ), calcd. for
11
C H13NO : 175.0997.
2
1
3
b bp 110–112 ˚C /1.5 mmHg. mp 39~41˚C (recrystallized from EtOH). IR (neat) : 2953, 2845, 1603,
-
1 1
495, 1458, 1315, 1263, 1171, 1076, 1061, 748 cm . H NMR (CDCl
3
) :ꢀ=1.2–1.5 (m, 1H), 1.7–2.1 (m,
H), 2.4–3.4 (m, 3H), 3.7–4.3 (m, 3H), 4.6–4.8 (m, 1H), 6.4–6.8 (m, 2H, Arom), 6.9–7.3 (m, 2H, Arom).
1
3
C NMR (CDCl
3
) :ꢀ= 23.67 (CH
2
), 24.43 (CH
2
), 28.38 (CH
2
), 46.91 (CH
2
2
), 67.84 (CH ), 85.96 (CH),
+
1
12.84 (CH), 118.13 (CH), 125.62 (C), 127.09 (CH), 128.68 (CH), 143.91 (C). MS m/z (%) : 189 (M ,
100), 188 (50), 170 (13), 158 (26), 146 (29), 132 (36), 131 (72), 130 (52), 91 (13), 77 (11). HRMS m/z
+
found : 189.1179 (M ), calcd. for C12
H15NO : 189.1154.
4
a mp 50~52˚C (recrystallized from EtOH). IR (neat) : 1464, 1394, 1290, 1078, 1057, 1016, 991, 889,
-
1
1
13
7
77, 746 cm . H NMR (CDCl
3
) :ꢀ= 2.5–4.0 (m, 8H), 5.19 (s, 1H), 6.8–7.5 (m, 4H). C NMR
(
(
(
CDCl
3
) :ꢀ= 29.73 (CH ), 45.65 (CH
2
2
), 54.73 (CH
2
), 62.18 (CH
2
), 90.40 (CH), 126.28 (CH), 128.07
+
CH), 128.23 (CH), 128.84 (CH), 132.14 (C), 134.95 (C). MS m/z (%) : 175 (M , 69), 174 (100), 145
+
53), 130 (25), 117 (53), 115 (26), 103 (15), 91 (21), 77 (17), 56 (16). HRMS m/z found : 175.0973 (M ),
13NO : 175.0997.
calcd. for C11
H

HETEROCYCLES, Vol. 68, No. 12, 2006
2569
4
7
7
b bp 114–116 ˚C /1.5 mmHg. IR (neat) : 2947, 2839, 1464, 1393, 1371, 1294, 1142, 1086, 964, 885,
-
1 1
45 cm . H NMR (CDCl
3
) :ꢀ= 1.2–1.5 (m, 1H), 1.8–3.4 (m, 7H), 3.7–4.3 (m, 2H), 4.87 (s, 1H),
.0–7.4 (m, 4H). C NMR (CDCl ) :ꢀ= 22.97 (CH ), 29.08 (CH ), 46.22 (CH ), 53.22 (CH ), 68.33
), 89.95 (CH), 125.95 (CH), 127.29 (CH), 127.78 (CH), 128.31 (CH), 132.20 (C), 134.83 (C). MS
1
3
3
2
2
2
2
(
CH
2
+
m/z (%) : 189 (M , 38), 188 (77), 158 (37), 146 (100), 145 (31), 133 (46), 132 (66), 131 (42), 130 (35),
+
1
04 (79). HRMS m/z found : 189.1174 (M ), calcd. for C12
H15NO : 189.1154.
6
a bp 141–142 ˚C /2.5 mmHg. IR (neat) : 3380, 1510, 1481, 1464, 1362, 1337, 1315, 1063, 764, 743
-
1 1
cm . H NMR (CDCl ) : ꢀ= 1.94 (bs, 1H), 3.69 (t, J = 7Hz, 2H), 4.07 (t, J = 7Hz, 2H), 6.4–6.5 (m, 1H),
3
1
3
6
.9–7.3 (m, 4H), 7.5–7.7 (m, 1H). C NMR (CDCl
3
) :ꢀ= 48.54 (CH
2
), 61.61 (CH
2
), 101.31 (CH),
109.34 (CH), 119.51 (CH), 120.98 (CH), 121.59 (CH), 128.35 (CH), 128.68 (C), 136.09 (C). MS m/z
+
+
(
%) : 161 (M , 38), 131 (10), 130 (100), 103 (7), 77 (8). HRMS m/z found : 161.0841 (M ), calcd. for
11NO : 161.0841.
C H
10
6
b bp 148–150 ˚C /2 mmHg. IR (neat): 3380, 2941, 1510, 1485, 1464, 1337, 1315, 1065, 1015, 743
-
1 1
cm . H NMR (CDCl
3
) :ꢀ=1.87 (quint, J = 7Hz, 2H), 2.7 (bs, 1H), 3.38 (t, J = 7Hz, 2H), 4.09 (t, J =
1
3
7
Hz, 2H), 6.6–6.7 (m, 1H), 7.1–7.6 (m, 4H), 7.8–7.9 (m, 1H). C NMR (CDCl
3
):ꢀ= 32.58 (CH ), 42.51
2
(
CH
2
), 59.29 (CH
2
), 101.07 (CH), 109.34 (CH), 119.23 (CH), 120.90 (CH), 121.39 (CH), 127.90 (CH),
+
1
28.56 (C), 135.97 (C). MS m/z (%) : 175 (M , 45), 131 (36), 130 (100), 117 (7), 103 (7), 89 (7), 77 (8).
+
HRMS m/z found : 175.0993 (M ), calcd. for C11
H13NO : 175.0997.
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8