Dimethylzinc-initiated radical reaction of cyclic ethers with arylamines, alkoxyamines, and dialkylhydrazines

Article abstract of DOI:10.1016/j.tet.2004.10.080

Dimethylzinc-initiated radical reaction of THF with arylamines afforded aminoalcohols which were derived from the two molecules of THF and one molecule of an arylamine. The reaction seems to proceed via two-consecutive processes, electrophilic and then nucleophilic reactions of THF-derived species. Alkoxyamines and dialkylhydrazines reacted with electrophilic cyclic ether species to give the corresponding oximes and hydrazones of ω- hydroxyalkanal.

Full text of DOI:10.1016/j.tet.2004.10.080

Tetrahedron 61 (2005) 379–384
Dimethylzinc-initiated radical reaction of cyclic ethers with
arylamines, alkoxyamines, and dialkylhydrazines
Yasutomo Yamamoto, Masaru Maekawa, Tito Akindele, Ken-ichi Yamada
*
and Kiyoshi Tomioka
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 14 October 2004; revised 27 October 2004; accepted 28 October 2004
Available online 18 November 2004
Abstract—Dimethylzinc-initiated radical reaction of THF with arylamines afforded aminoalcohols which were derived from the two
molecules of THF and one molecule of an arylamine. The reaction seems to proceed via two-consecutive processes, electrophilic and then
nucleophilic reactions of THF-derived species. Alkoxyamines and dialkylhydrazines reacted with electrophilic cyclic ether species to give
the corresponding oximes and hydrazones of u-hydroxyalkanal.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
It is well recognized that one-pot, consecutive reactions are
powerful and green methodologies for multi-bonds forming
reactions. A highly valued example of these processes is the
tandem conjugate addition–alkylation reaction of metallated
nucleophiles with a,b-unsaturated carbonyl compounds and
their equivalents which play a dual role as an electrophile in
the first step and as a nucleophile in the alkylation step.1 We
describe herein a dual role of THF as an electrophile and as
a nucleophile in the dimethylzinc-initiated radical reaction
with arylamines. Two THF molecules reacted with one
molecule of arylamines to afford amino alcohols through
the consecutive electrophilic amination to give aminals and
then a nucleophilic radical addition to the resulting imines.
Scheme 1. The reaction of THF with aniline 1a and/or benzaldehyde 2.
unexpected THF b-adduct.4 This interesting result led us to
investigate the reaction of aniline 1a with THF. The reaction
Alkoxyamines and dialkylhydrazines reacted with cyclic
ethers to afford the corresponding oximes and hydrazones.
of 1a (1 mmol) in THF (22 mL) was conducted at room
temperature (rt) for 13 h with dimethylzinc (12 mmol)
under continuous air stream (0.5 mL/h) to give 4a in 90%
yield.5
2. Results and discussion
These reactions were discovered during our studies on the
reaction of ether radicals generated from dimethylzinc–air.2
We have already reported that THF radical chemo-
A ca 1:1 mixture of diastereomeric alcohols 4a was
separated by silica gel column chromatography to give
each diastereomer. The diastereomers were then separately
selectively reacted with the imine generated in situ in the
converted to pyrrolidines 5 in high yields through treatment
with tosyl chloride in pyridine (Scheme 2).
three-component reaction of THF, aniline 1a and benzal-
dehyde 2 (Scheme 1).3 Further studies revealed that two-
component reaction of benzaldehyde 2 and THF gave
Various arylamines 1 bearing electron-donating and with-
drawing substituents on the aryl ring were compatible with
Keywords: Radical reaction; Cyclic ethers; Amines; Oximes; Hydrazones.
* Corresponding author. Tel.: C81 757534553; fax: C81 757534604;
e-mail: tomioka@pharm.kyoto-u.ac.jp
1a. 4-Toluidine 1b, p-anisidine 1c, and 4-chloroaniline 1e
gave 4b, 4c, and 4e in 90, 73, and 87% yields, respectively
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.080

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Y. Yamamoto et al. / Tetrahedron 61 (2005) 379–384
arylamines suggested the nucleophilic attack of arylamines
to electrophilic THF species as the first step of the reaction.
Thus, the reaction of benzyl carbamate 6 did not give the
expected two-THF adduct, instead one-THF adduct 77 was
produced in 12% yield, apparently indicating that the
nucleophilicity of nitrogen is critical in the first step and its
electron donating nature to generate C]N double bond in
the second step (Scheme 3).
Scheme 2. Conversion of 4a to bicyclic pyrrolidine 5.
(Table 1, entries 2, 3, and 5). o-Anisidine 1d reacted more
slowly, probably due to the ortho-substitution, to give 4d in
58% yield (entry 4). Amine 1f with the much more electron-
withdrawing 4-trifluoromethyl group reacted sluggishly to
give 4f in 36% yield (entry 6). Diphenylamine 1g failed to
react with THF, resulting in the recovery of 1g (entry 7).6
Radical initiator, dimethylzinc, is also critical to the
reaction. For example, the reaction with diethylzinc,2 in
place of dimethylzinc, gave aminoalcohol 4a in 37% yield
after 75 h reaction time at rt. Triethylborane8 gave 4a in
17% yield after 48 h (Scheme 4).
The reaction of cyclic ethers with alkoxyamines 8 and di-
alkylhydrazines 9 gave O-alkyloximes 10 and hydrazones
11 by the one-THF reaction (Table 2). The reaction of
methoxyamine 8a and benzyloxyamine 8b with THF gave
10a and 10b in 77 and 90% yields, respectively (entries 1
and 2). Cyclic ethers of 4-, 6- and 7-membered rings are also
good partners of the reaction with 8b to give 10c, 10d, and
10e in 45, 80, and 72% yields, respectively (entries 3–5).
The reaction of N,N-diphenyl- and N,N-dimethylhydrazines
9a and 9b with THF gave the corresponding hydrazones 11a
and 11b in moderate yields also by the one-THF reaction
(entries 6 and 7). Treatment of O-benzyl-oxime 10b with
THF under the radical reaction conditions recovered 10b
unchanged, indicating poorer reactivity of oxime C]N
double bond in the present conditions.
The dependency of the reaction on the electronic nature of
Scheme 3. The reaction of benzyl carbamate 6 with THF giving 7.
Scheme 4. Diethylzinc and triethylborane-initiated reaction of 1a giving
4a.
The reaction of 1a with tetrahydropyran (THP) provided a
Table 1. Dimethylzinc-mediated reaction of 1 with THF
Entry
1
R1
R2
Time (h)
4
Yield (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Ph
H
H
H
H
H
13
20
26
24
20
15
72
4a
4b
4c
4d
4e
4f
90
90
73
58
87
36
0
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-ClC6H4
4-CF3C6H4
Ph
H
Ph
1g
4g
Table 2. The reaction of alkoxyamines 8 and hydrazines 9 with cyclic ethers
Entry
8/9
X
n
Me2Zn (equiv)
Time (h)
10/11
Yield (%)
1
2
3
4
5
6
7
8a
8b
8b
8b
8b
9a
9b
MeO
BnO
BnO
BnO
BnO
Ph2N
Me2N
5
5
4
6
7
5
5
12
12
12
18
12
24
12
120
18
20
70
22
120
24
10a
10b
10c
10d
10e
11a
11b
77
90
45
80
72
33
42

Y. Yamamoto et al. / Tetrahedron 61 (2005) 379–384
381
clue to a mechanistic aspect. The reaction mixture contain-
4. Experimental
ing aminoalcohol 12 and aminal 13 was treated with sodium
cyanoborohydride to give 12 in 21% yield along with 14 in
58% yield (Scheme 5). The reaction of 139 with THP under
the same radical conditions as the reaction of 1a with THP
gave, after reduction, 12 in 34% yield and 14 in 28% yield.
These results indicated that aminal intermediate 13 is
involved in the reaction of arylamines 1 with cyclic ethers.
4.1. General
1H- and 13C NMR spectra were taken in CDCl3. Chemical
shift values are expressed in ppm relative to internal tetra-
methylsilane. Coupling constants J values are presented in
Hz. Abbreviations are as follows: s, singlet; d, doublet; t,
triplet; m, multiplet. IR spectroscopy of oil sample was
measured as neat liquid film. The wave-numbers of
maximum absorption peaks of IR spectroscopy are
presented in cmK1. MS (EI) is presented in m/z. Extracts
were washed with brine and then dried over sodium sulfate.
Silica gel column chromatography was used for purification.
4.2. Typical procedure for the reaction of an amine with
THF
To a solution of an amine (1 mmol) in THF (22 mL,
0.27 mol) was added the indicated amount of dimethylzinc
(1.0 M solution in hexane) at rt. The reaction mixture was
stirred at rt with continuous air bubbling (flow rate;
0.5 mL/h). After the indicated period, saturated aqueous
NaHCO3 was added to the mixture, and the organic layer
was separated. The aqueous layer was extracted with ethyl
acetate three times. After concentration the crude mixture
was purified by column chromatography.
Scheme 5. Reaction of 1a with THP giving 12–14.
Based on the results above, a plausible mechanism is
shown in Scheme 6. In the first step of the THF reaction,
a-alkoxyalkyl radical 15, generated by a-hydrogen atom
abstraction by a methyl radical, undergoes further oxidation
to an electrophilic a-alkoxyalkyl cation10,11 16 and 17
which is nucleophilically attacked by an amine nitrogen 1,
6, 8, and 9 to give aminal 18.12 If the electron-donating
power of the nitrogen atom of 18 is high enough, imine 19 is
formed, which in turn accepts nucleophilic attack by 15 to
complete the second step.13 The reaction of benzyl
carbamate 6 stops at the first step to produce 7 due to the
delocalization of nitrogen lone pair electron with a carbonyl
group. The reactions of alkoxyamines 8 and hydrazines 9
also stop at the first step due to the poor reactivity of C]N
double bonds of oximes 10 and hydrazones 11 in the present
conditions.14
4.2.1. 4-(Oxolan-2-yl)-4-(phenylamino)butan-1-ol (4a)
(Table 1, entry 1). A 1:1 diastereomer mixture was
separated by chromatography (CHCl3/EtOAcZ2/1). The
less polar isomer (4a-1) as a pale yellow oil. 1H NMR: 1.60–
1.85 (m, 8H), 3.40–3.50 (m, 1H), 3.57–3.59 (m, 2H), 3.72–
3.76 (m, 1H), 3.86–3.89 (m, 1H), 3.98–3.99 (m, 1H), 6.58
(d, JZ7.7 Hz, 2H), 6.63 (t, JZ7.4 Hz, 1H), 7.11–7.13 (m,
2H). 13C NMR: 26.0, 28.0, 29.3, 29.4, 55.0, 62.6, 68.6, 80.7,
112.7, 116.7, 129.2, 148.3. IR: 3390, 1600, 1500, 1060. MS:
235 (MC), 164 (MCKC4H7O), 71 (C4H7O). HRMS: calcd
for C14H21NO2, 235.1572; found, 235.1569. The more polar
isomer (4a-2) as a pale yellow oil. 1H NMR: 1.40–1.95 (m,
8H), 3.07 (brs, 2H), 3.39–3.43 (m, 1H), 3.56–3.59 (m, 2H),
3.68–3.72 (m, 1H), 3.79–3.89 (m, 2H), 6.61–6.67 (m, 3H),
7.11–7.14 (m, 2H). 13C NMR: 25.7, 28.0, 28.1, 29.2, 56.6,
62.5, 68.2, 81.5, 113.3, 117.0, 129.1, 148.0. IR: 3360, 1600,
1500, 1060. MS: 235 (MC), 164 (MCKC4H7O), 71
(C4H7O). HRMS: calcd for C14H21NO2, 235.1572; found,
235.1573.
4.2.2. Cyclization of aminoalcohol 4a (Scheme 2). To a
solution of 4a-2 (7.1 mg, 0.03 mmol) in pyridine (0.03 mL)
was added TsCl (10.3 mg, 0.054 mmol) at rt. After the
reaction mixture was stirred at rt for 4 h, 10% aqueous
NaOH (0.5 mL) was added to the mixture, and the organic
layer was separated. The aqueous layer was extracted with
diethyl ether three times. After concentration the crude
mixture was purified by chromatography (hexane/Et2OZ
Scheme 6. Plausible mechanism of the reaction of amines with ethers.
1
5/1) to afford 5-2 as a pale yellow oil (6.6 mg, quant). H
3. Conclusion
NMR: 1.60–1.70 (m, 1H), 1.80–2.05 (m, 6H), 2.10–2.20 (m,
1H), 3.13–3.18 (m, 1H), 3.54 (ddd, JZ1.8, 8.9, 8.9 Hz, 1H),
3.70–3.74 (m, 1H), 3.82–3.86 (m, 1H), 3.91–3.93 (m, 1H),
4.09 (ddd, JZ3.0, 6.7, 8.8 Hz, 1H), 6.65–6.70 (m, 3H),
7.19–7.22 (m, 2H). 13C NMR: 24.0, 25.9, 27.1, 28.5, 49.6,
61.1, 68.3, 80.8, 112.4, 115.7, 129.0, 148.1. IR: 1600, 1500,
We have found one-pot, two-consecutive reaction of aryl-
amines with dimethylzinc-generated cyclic ether radicals.15
It is highly probable that the polarity reversal of a-alkoxy-
alkyl radicals by one electron oxidation is involved.

382
Y. Yamamoto et al. / Tetrahedron 61 (2005) 379–384
1
less polar isomer as a pale yellow oil. H NMR: 1.60–1.75
1070. MS: 217 (MC), 146 (MCKC4H7O), 77 (Ph). HRMS:
calcd for C14H19NO, 217.1467; found, 217.1462.
(m, 5H), 1.84–1.92 (m, 3H), 3.40–3.43 (m, 1H), 3.63–3.65
(m, 2H), 3.74–3.78 (m, 1H), 3.87–3.91 (m, 1H), 3.96–4.00
(m, 1H), 6.52 (d, JZ8.9 Hz, 2H), 7.08 (d, JZ8.9 Hz, 2H).
13C NMR: 26.0, 28.1, 29.3, 29.4, 55.4, 62.7, 68.7, 80.7,
113.9, 121.2, 129.1, 147.1. IR: 3371, 1601, 1504, 1057. MS:
269 (MC), 198 (MCKC4H7O), 111 (C6H4Cl), 71 (C4H7O).
HRMS: calcd for C14H20ClNO2, 269.1183; found,
The other isomer 4a-1 was converted to 5-1 as a pale yellow
oil in 89% yield. H NMR: 1.56–1.64 (m, 1H), 1.82–2.10
1
(m, 7H), 3.13–3.18 (m, 1H), 3.52–3.56 (m, 1H), 3.72–3.77
(m, 1H), 3.89–3.93 (m, 2H), 4.02 (ddd, JZ5.9, 5.9, 8.5 Hz,
1H), 6.67–6.77 (m, 3H), 7.19–7.22 (m, 2H). 13C NMR: 24.2,
26.0, 27.7, 28.1, 49.7, 61.6, 68.1, 81.3, 112.7, 116.0, 128.8,
148.7. IR: 1600, 1500, 1070. MS: 217 (MC), 146 (MCK
C4H7O), 77 (Ph). HRMS: calcd for C14H19NO, 217.1467;
found, 217.1472.
1
269.1185. The more polar isomer as a pale yellow oil. H
NMR: 1.42–1.49 (m, 1H), 1.58–1.97 (m, 7H), 3.38–3.42 (m,
1H), 3.62–3.64 (m, 2H), 3.70–3.74 (m, 1H), 3.80–3.84 (m,
1H), 3.87–3.91 (m, 1H), 6.57 (d, JZ8.9 Hz, 2H), 7.08 (d,
JZ8.9 Hz, 2H). 13C NMR: 25.8, 27.95, 27.98, 29.2, 57.0,
62.7, 68.3, 81.5, 114.5, 121.7, 129.1, 146.8. IR: 3352, 1601,
1497, 1057. MS: 269 (MC), 198 (MCKC4H7O), 111
(C6H4Cl), 71 (C4H7O). HRMS: calcd for C14H20ClNO2,
269.1183; found, 269.1179.
4.2.3. 4-(4-Methylphenylamino)-4-(oxolan-2-yl)butan-1-
ol (4b) (Table 1, entry 2). A 1:1 diastereomer mixture was
separated by chromatography (CHCl3/EtOAcZ2/1). The
1
less polar isomer as a pale yellow oil. H NMR: 1.60–1.89
(m, 8H), 2.21 (s, 3H), 2.80 (brs, 2H), 3.41–3.44 (m, 1H),
3.59–3.62 (m, 2H), 3.73–3.77 (m, 1H), 3.86–3.91 (m, 1H),
3.98–4.01 (m, 1H), 6.52 (d, JZ8.3 Hz, 2H), 6.95 (d, JZ
8.3 Hz, 2H). 13C NMR: 20.2, 26.0, 27.8, 29.45, 29.51, 55.5,
62.8, 68.6, 80.7, 113.1, 126.1, 129.8, 146.1. IR: 3391, 1616,
1520, 1057. MS: 249 (MC), 178 (MCKC4H7O), 91 (tolyl),
71 (C4H7O). HRMS: calcd for C15H23NO2, 249.1729;
found, 249.1735. The more polar isomer as a pale yellow
4.2.7. 4-(4-Trifluoromethylphenylamino)-4-(oxolan-2-
yl)-butan-1-ol (4f) (Table 1, entry 6). A 3:2 diastereomer
mixture was separated by chromatography. The major
isomer as a yellow oil. 1H NMR: 1.60–2.00 (m, 8H), 3.45–
3.55 (m, 1H), 3.64 (t, JZ5.6 Hz, 2H), 3.70–3.80 (m, 1H),
3.85–4.05 (m, 2H), 6.59 (d, JZ8.6 Hz, 2H), 7.36 (d, JZ
8.6 Hz, 2H). 13C NMR: 26.0, 28.3, 29.3, 29.7, 54.8, 62.8,
1
3
1
oil. H NMR: 1.41–1.49 (m, 1H), 1.59–1.96 (m, 7H), 2.22
68.7, 80.7, 111.8, 116.8 (q, JCFZ34.0), 125.0 (q, JCFZ
3
(s, 3H), 2.77 (brs, 2H), 3.36–3.39 (m, 1H), 3.58–3.65 (m,
2H), 3.69–3.73 (m, 1H), 3.81–3.90 (m, 2H), 6.57 (d, JZ
8.3 Hz, 2H), 6.96 (d, JZ8.3 Hz, 2H). 13C NMR: 20.2, 25.8,
28.1, 28.2, 29.4, 57.2, 62.8, 68.3, 81.5, 113.8, 126.7, 129.8,
145.7. IR: 3387, 1616, 1520, 1061. MS: 249 (MC), 178
(MCKC4H7O), 91 (tolyl), 71 (C4H7O). HRMS: calcd for
C15H23NO2, 249.1729; found, 249.1724.
208), 126.7 (q, JCFZ3.0), 150.9. The minor isomer as a
yellow oil. 1H NMR: 1.40–2.00 (m, 8H), 3.45–3.55 (m, 1H),
3.63 (t, JZ5.8 Hz, 2H), 3.70–4.00 (m, 3H), 6.64 (d, JZ
8.6 Hz, 2H), 7.36 (d, JZ8.6 Hz, 2H). 13C NMR: 25.8, 27.9,
3
28.0, 29.1, 56.1, 62.6, 68.3, 81.6, 112.2, 116.8 (q, JCF
Z
34.0), 125.0 (q, 1JCFZ208), 126.6 (q, 3JCFZ3.0), 150.7. IR
and MS were measured as a mixture of diastereomers. IR:
3380, 1620, 1060. MS: 303 (MC), 232 (MCKC4H7O), 71
(C4H7O). HRMS: calcd for C15H20F3NO2, 303.1446; found,
303.1457.
4.2.4. 4-(4-Methoxyphenylamino)-4-(oxolan-2-yl)butan-
1-ol (4c) (Table 1, entry 3). A 1:1 mixture of diastereomers
as a pale brown oil. 1H NMR: 1.42–1.96 (m, 8H), 3.29–3.37
(m, 1H), 3.59–3.77 (m, 3H), 3.74 (s, 3H), 3.81–4.00 (m,
2H), 6.56–6.65 (m, 2H), 6.74–6.76 (m, 2H). 13C NMR: 25.9,
26.1, 28.0, 28.1, 28.2, 29.4, 29.56, 29.60, 55.75, 55.78, 56.5,
58.4, 62.9 (overlap), 68.3, 68.6, 80.8, 81.2, 114.6, 114.9,
115.0, 115.6, 142.0, 142.5, 151.9, 152.4. IR: 3380, 1510,
1040. MS: 265 (MC), 194 (MCKC4H7O), 107
(C6H4OCH3), 71 (C4H7O). HRMS: calcd for C15H23NO3,
265.1678; found, 265.1671.
4.2.8. 4-Hydroxybutanal O-methyloxime (10a) (Table 2,
entry 1). A 3:2 mixture of E- and Z-isomer as a colorless oil.
1H NMR E-isomer: 1.71–1.81 (m, 2H), 2.31 (dt, JZ5.8 Hz,
7.3, 2H), 3.70 (t, JZ6.1 Hz, 2H), 3.82 (s, 3H), 7.42 (t, JZ
5.8 Hz, 1H). Z-isomer: 1.71–1.81 (m, 2H), 2.43 (dt, JZ
6.1 Hz, 7.3, 2H), 3.65 (t, JZ6.1 Hz, 2H), 3.88 (s, 3H), 6.70
(t, JZ6.1 Hz, 1H). 13C NMR: 21.9, 26.0, 28.8, 29.2, 61.1,
61.50, 61.53, 61.6, 150.5, 151.2. IR: 3391, 1636, 1053. MS:
117 (MC). HRMS: calcd for C5H11NO2, 117.0790; found,
117.0793.
4.2.5. 4-(2-Methoxyphenylamino)-4-(oxolan-2-yl)butan-
1-ol (4d) (Table 1, entry 4). A 56:44 mixture of
diastereomers as a yellow oil. 1H NMR: 1.47–1.99 (m,
8H), 3.42–3.50 (m, 1H), 3.61–3.64 (m, 2H), 3.71–3.93 (m,
major 3H and minor 2H), 3.83 (s, 3H), 4.02–4.06 (m, minor
1H), 6.59–6.65 (m, major 1H and minor 2H), 6.69–6.71 (m,
major 1H), 6.75–6.76 (m, 1H), 6.81–6.85 (m, 1H). 13C
NMR: 25.8, 26.1, 27.9, 28.3, 28.4, 29.2, 29.3, 29.6, 55.1,
55.4, 56.7, 62.9, 63.0, 68.3, 68.7, 80.8, 81.9, 109.66, 109.73,
109.8, 110.6, 115.8, 116.1, 121.23, 121.27, 138.0, 138.3,
146.7, 146.8. IR: 3422, 1601, 1516, 1460, 1246, 1223, 1053,
1030. MS: 265 (MC), 194 (MCKC4H7O), 71 (C4H7O).
HRMS: calcd for C15H23NO3, 265.1678; found, 265.1672.
4.2.9. 4-Hydroxybutanal O-benzyloxime (10b) (Table 2,
entry 2). A 3:2 mixture of E- and Z-isomer as a colorless oil.
1H NMR E-isomer: 1.55–1.65 (m, 1H), 1.71–1.80 (m, 2H),
2.31 (dt, JZ6.1 Hz, 7.2, 2H), 3.61–3.68 (m, 2H), 5.05 (s,
2H), 7.27–7.36 (m, 5H), 7.50 (t, JZ6.1 Hz, 1H). Z-isomer:
1.55–1.65 (m, 1H), 1.71–1.80 (m, 2H), 2.47 (dt, JZ5.8 Hz,
7.3, 2H), 3.61–3.68 (m, 2H), 5.11 (s, 2H), 6.74 (t, JZ
5.8 Hz, 1H), 7.27–7.36 (m, 5H). 13C NMR: 22.2, 26.2, 28.9,
29.1, 61.7, 61.8, 75.6, 75.8, 127.9, 128.1, 128.3, 128.42,
128.44, 137.6, 137.7, 151.1, 151.7. IR: 3391, 1632, 1454,
1369, 1042. MS: 193 (MC), 149, 91 (benzyl), 77 (phenyl).
HRMS: calcd for C11H15NO2, 193.1103; found, 193.1107.
4.2.6. 4-(4-Chlorophenylamino)-4-(oxolan-2-yl)butan-1-
ol (4e) (Table 1, entry 5). A 1:1 diastereomer mixture was
separated by chromatography (CHCl3/EtOAcZ1/1). The
4.2.10. 3-Hydroxypropanal O-benzyloxime (10c)
(Table 2, entry 3). A 4:1 mixture of E- and Z-isomer as a

Y. Yamamoto et al. / Tetrahedron 61 (2005) 379–384
383
colorless oil. 1H NMR E-isomer: 2.40–2.43 (m, 2H), 3.74–
3.90 (m, 2H), 5.06 (s, 2H), 7.25–7.36 (m, 5H), 7.52 (t, JZ
5.2 Hz, 1H). Z-isomer: 2.60–2.63 (m, 2H), 3.74–3.90 (m,
2H), 5.12 (s, 2H), 6.83 (t, JZ5.5 Hz, 1H), 7.25–7.36 (m,
5H). 13C NMR: 29.4, 32.6, 59.4, 75.77, 75.83, 127.86,
127.96, 128.00, 128.3, 128.41, 128.44, 137.4, 137.8, 149.2.
IR: 3379, 1632, 1454, 1369, 1049. MS: 179 (MC), 162
(MCKOH), 91 (benzyl), 77 (phenyl). HRMS: calcd for
C10H13NO2, 179.0946; found, 179.0943.
6.59 (d, JZ7.9 Hz, 2H), 6.65 (t, JZ7.3 Hz, 1H), 7.10–7.20
(m, 2H). 13C NMR: 22.6, 23.6, 26.2, 28.7, 30.4, 32.8, 57.1,
62.8, 68.8, 80.1, 113.2, 116.9, 129.2, 148.2. IR: 3400, 1600,
1500, 1080, 1050. MS: 263 (MC), 178 (MCKC5H9O), 85
(C5H9O). HRMS: calcd for C16H25NO2, 263.1885; found,
263.1888.
4.3. Reduction of aminal 12
To the mixture, obtained by the reaction of aniline (93.1 mg,
1.0 mmol) and THP (26 mL, 270 mmol), in CH3CN
(3.0 mL) was added sodium cyano-borohydride (94.3 mg,
1.5 mmol). After stirring for 15 min, acetic acid (0.06 mL)
was added and the mixture was stirred for 1 h, and
concentrated. The residue was dissolved in CH2Cl2, and
was successively washed with 5% KOH and brine, dried
over Na2SO4. Concentration and purification by column
chromatography (hexane/EtOACZ4/3) afford 12 (55.5 mg,
21%) and 1417 (104.1 mg, 58%).
4.2.11. 5-Hydroxypentanal O-benzyloxime (10d)
(Table 2, entry 4). A 16:9 mixture of E- and Z-isomer as
a colorless oil. 1H NMR E-isomer: 1.50–1.61 (m, 4H), 2.21–
2.25 (m, 2H), 3.61–3.65 (m, 2H), 5.05 (s, 2H), 7.29–7.37
(m, 5H), 7.46 (t, JZ6.1 Hz, 1H). Z-isomer: 1.50–1.61 (m,
4H), 2.40 (dt, JZ5.5 Hz, 7.2, 2H), 3.61–3.65 (m, 2H), 5.10
(s, 2H), 6.69 (t, JZ5.5 Hz, 1H), 7.29–7.37 (m, 5H). 13C
NMR: 22.4, 22.6, 25.4, 29.1, 31.9, 32.1, 62.25, 62.30, 75.5,
75.7, 127.78, 127.85, 128.0, 128.3, 128.4, 137.6, 138.0,
151.3, 152.2. IR: 3379, 1632, 1454, 1369, 1049. MS: 207
(MC), 190 (MCKOH), 149, 91 (benzyl), 77 (phenyl). Anal.
Calcd for C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C,
69.25; H, 8.30; N, 6.67.
Acknowledgements
This research was partially supported by the 21st Century
COE (Center of excellence) Program ‘Knowledge Infor-
mation Infrastructure for Genome Science’, a Grant-in-Aid
for Young Scientists (B) and a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘Exploitation of Multi-
Element Cyclic Molecules’ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
4.2.12. 6-Hydroxyhexanal O-benzyloxime (10e) (Table 2,
entry 5). A 3:1 mixture of E- and Z-isomer as a colorless oil.
1H NMR E-isomer: 1.35–1.60 (m, 7H), 2.18–2.23 (m, 2H),
3.62 (t, JZ6.6 Hz, 2H), 5.05 (s, 2H), 7.28–7.37 (m, 5H),
7.45 (t, JZ6.1 Hz, 1H). Z-isomer: 1.35–1.60 (m, 7H), 2.38
(dt, JZ5.5 Hz, 7.5, 2H), 3.62 (t, JZ6.6 Hz, 2H), 5.10 (s,
2H), 6.68 (t, JZ5.5 Hz, 1H), 7.28–7.37 (m, 5H). 13C NMR:
25.1, 25.4, 25.7, 25.9, 26.3, 29.3, 32.3, 62.6, 75.5, 127.75,
127.82, 127.9, 128.2, 128.4, 137.7, 151.4, 152.3. IR: 3368,
1454, 1366, 1053, 1018. MS: 221 (MC), 204 (MCKOH),
149, 91 (benzyl), 77 (phenyl). HRMS: calcd for C13H19NO2,
221.1416; found, 221.1411.
References and notes
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4.2.13. 4-Hydroxybutanal N,N-diphenylhydrazone (11a).
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were identical to those reported.16
4.2.14. 4-Hydroxybutanal N,N-dimethylhydrazone (11b)
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2. (a) Yamada, K.; Yamamoto, Y.; Maekawa, M.; Chen, J.-b.;
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1
oil. H NMR: 1.77–1.82 (m, 2H), 2.36–2.40 (m, 2H), 2.73
(s, 6H), 3.68 (t, JZ6.1 Hz, 2H), 6.72 (t, JZ4.9 Hz, 1H). 13C
NMR: 29.8, 29.9, 43.2 (overlap), 62.1, 138.7. IR: 3375,
1610, 1470, 1447, 1254, 1142, 1038. MS: 130 (MC).
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4.2.15. 5-(Phenylamino)-5-(tetrahydro-2H-pyran-2-
yl)pentan-1-ol (12) (Scheme 5). A 2:3 diastereomer
mixture was separated by chromatography (benzen/
EtOAcZ4/1). The less polar isomer as a pale yellow oil.
1H NMR: 1.35–1.75 (m, 11H), 1.75–1.90 (m, 1H), 3.28
(ddd, JZ2.3, 6.5, 6.5 Hz, 1H), 3.35–3.50 (m, 2H), 3.62 (t,
JZ7.3 Hz, 2H), 3.90–4.10 (m, 1H), 6.57 (d, JZ7.6 Hz, 2H),
6.62 (t, JZ7.3 Hz, 1H), 7.10–7.20 (m, 2H). 13C NMR: 22.8,
23.4, 26.1, 28.1, 31.7, 32.8, 56.6, 62.8, 68.8, 78.6, 112.6,
116.4, 129.3, 148.4. IR: 3400, 1500, 1080, 1050. MS: 263
(MC), 178 (MCKC5H9O), 85 (C5H9O). HRMS: calcd for
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1
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384
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