Zinc-acetic acid promoted reductive carbon-nitrogen bond cleavage reaction of α-aminoketones

Article abstract of DOI:10.3987/COM-13-S(S)64

Scope and limitation of the reductive cleavage reaction of α-aminoketone systems with zinc-acetic acid are described. The carbon-nitrogen bond cleavage reaction was applicable to a wide range of α-aminoalkyl aryl ketones possessing various substituents on the aromatic ring. In contrast, α-aminoalkyl alkyl ketones with protons at the α'-position or α-aminoesters were sluggish to the carbon-nitrogen cleavage reaction.

Full text of DOI:10.3987/COM-13-S(S)64

HETEROCYCLES, Vol. 88, No. 2, 2014
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HETEROCYCLES, Vol. 88, No. 2, 2014, pp. 1051 - 1063. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 29th June, 2013, Accepted, 7th August, 2013, Published online, 8th August, 2013
DOI: 10.3987/COM-13-S(S)64
ZINC-ACETIC ACID PROMOTED REDUCTIVE CARBON-NITROGEN
BOND CLEAVAGE REACTION OF -AMINOKETONES
Kyoko Ishikawa, Miyuki Tomatsu, Hiroshi Nagase,§ and Hideaki Fujii*
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo
108-8641, Japan; e-MAIL: fujiih@pharm.kitasato-u.ac.jp
§International Institute for Integrative Sleep Medicine, Tsukuba University, Life
Science Center of Tsukuba Advanced Research Alliance (TARA center) C-1F,
1-1-1 Tenoudai, Tsukuba, Ibaraki 305-8577, Japan
Abstract – Scope and limitation of the reductive cleavage reaction of
-aminoketone systems with zinc-acetic acid are described. The carbon-nitrogen
bond cleavage reaction was applicable to a wide range of -aminoalkyl aryl
ketones possessing various substituents on the aromatic ring. In contrast,
-aminoalkyl alkyl ketones with protons at the '-position or -aminoesters were
sluggish to the carbon-nitrogen cleavage reaction.
INTRODUCTION
We have developed ligands selective for the opioid receptor types with a 4,5-epoxymorphinan structure1
and have reported many novel reactions using 4,5-epoxymorphinan derivatives.2 In the course of our
investigations, we found that attempts to remove the Troc (2,2,2-trichloroethoxycarbonyl) protecting
group in the presence of zinc and acetic acid led to cleavage of the carbon-nitrogen bond of 1 (Scheme 1).
Although carbon-nitrogen cleavage reactions of -aminoketones have been reported previously,3-6 many
reactions included a ring-opening reaction of an aziridine ring.3 Therefore, the scope of such reactions
appeared to be limited. Among the reported methods, deamination reactions of -aminoketones by
samarium diiodide have been intensively investigated and utilized in a wide range of compounds.3k,l,o,4
Although carbon-nitrogen cleavage reactions using zinc as a reducing agent have also been reported,5 in
almost all such reports the substrates possessed quaternary ammonium5i or pyridinium5a-e moieties or
strained polycyclic system (Scheme 2).5f,i Therefore, we attempted to clarify the scope and limitation of

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HETEROCYCLES, Vol. 88, No. 2, 2014
the reductive cleavage reaction of -aminoketones with zinc-acetic acid. Herein, we report the scope and
limitation of the reaction.
Scheme 1. Cleavage reaction of a carbon-nitrogen bond of 1
Scheme 2. Representative examples of reductive cleavage reactions of the carbon-nitrogen bond in the
presence of zinc and acetic acid. Attempted ring-opening reaction of the corresponding tertiary cyclic
amine furnished poor yield.5i
RESULTS AND DISCUSSION
We attempted the cleavage of carbon-nitrogen bonds of various -aminoketones 3 in the presence of zinc
and acetic acid (Table 1). The reactions of unsubstituted aryl ketones 3a and 3b and aryl ketones 3c and
3d with electron donating group smoothly proceeded to give the corresponding acetophenone derivatives
4a-d in good to excellent yield (entries 1-4). The position of the substituent had little effect on the
isolated yields (entries 4, 7, and 8). In contrast to the electron donating substituents, some electron
withdrawing groups tended to decrease the isolated yields (entries 5 and 6) except for carbomethoxy
group (entry 9). Although 3l required reflux reaction conditions, the carbon-nitrogen cleavage reaction
was tolerated by the substituents on the nitrogen (entries 10-15). In the reaction of 3n, dibenzylamine was

HETEROCYCLES, Vol. 88, No. 2, 2014
1053
Table 1. Reductive cleavage of the carbon-nitrogen bonds of various ketones 3
R4
O
O
H
N
Zn (5 eq)
AcOH, rt
R5
R2 R3
R2 R3
R1
R1
3a-u
4a-u
Reaction Yield
Entry
SM
R1
R2
R3
R4
R5
Time (h)
1.0
1.0
1.0
1.5
1.0
1.0
1.0
1.0
1.0
1.0
3.0
1.0
2.0
1.0
1.0
24
(%)
80
85
94
78
68
33
71
68
1
2
3
4
5
6
7
8
9
10
11
12a
13
14
15
16a
17a
18
19 a
20c
21
22
23d
24a
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Et
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
Bn
Bn
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
p-Me
p-OMe
p-F
p-CF3
m-OMe
o-OMe
p-CO2Me
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
-(CH2)-O-(CH2)-
H
H
H
Me
Bn
-(CH2)-O-(CH2)-
H
H
H
H
86
86
69
75
75
84
92
3j
3k
3l
H
Me
Ph
Bn
Bn
3m
3n
3o
3p
3q
3r
3r
3r
3s
Ac
NRb
NRb
NRb
65
Cbz
Boc
Boc
Boc
Me
24
24
1.0
1.0
1.0
1.0
1.0
2.0
H
Me
67
77
92
99
3t
3u
3u
H
-(CH2)-O-(CH2)-
Me
Me
p-morpholino
p-morpholino
Me
Me
96
a A reaction was carried out at the reflux temperature of AcOH.
b NR: no reaction.
c Trifluoroacetic acid was used instead of acetic acid.
d A reaction was carried out using 20 eq. of zinc.7
isolated in 90% yield along with the acetophenone derivative 4n. It is noteworthy that the reactions of
ketones 3p-r with the acetyl, Cbz, or Boc group as an N-substituent did not proceed (entries 16-18) and
that the reaction of 3p and 3q did not proceed, furnishing only starting material even under the reflux
reaction conditions (entries 16 and 17). On the other hand, the elevation of the reaction temperature to the
boiling point and the use of trifluoroacetic acid instead of acetic acid facilitated the cleavage of the
carbon-nitrogen bond of 3r to provide 4r in 65% and 67% yield, respectively (entries 19 and 20). The
results of entries 18 and 19 indicated that the cleavage reaction of the carbon-nitrogen bond could proceed

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HETEROCYCLES, Vol. 88, No. 2, 2014
Me
N
O
O
O
O
N
O
O
O
O
N
O
O
N
N
N
N
N
O
N
Ts
5d
(13.5 h, 40%)
Ts
5e
(1.0 h, 33%)
5a
5b
(1.0 h, 54%*)
5c
(1.0 h, 35%)
(2.0 h, 79%)
Figure 1. Structures of examined aryl or heteroaryl ketones 5. The reaction time and the isolated yield are
indicated in the parentheses. The asterisk “*” indicates the yield of 1-(pyridin-3-yl)ethan-1-ol.
Bn
N
O
O
H
Zn (5 eq)
N
Bn
AcOH, reflux
1.0 h, 93%
6
7
O
O
Me
MeO
MeO
MeO
MeO
MeO
MeO
Me
NH2
Zn (5 eq)
N
NH
AcOH, reflux
1.0 h
8
9
10
47%
O
O
Zn (5 eq)
NBn2
Me
AcOH, reflux
24 h, 45%
11
12
Scheme 3. Reactions of benzoylpiperidine 6, cyclic ketone 8, and t-butyl ketone 11
after the deprotection of the nitrogen by removal of the Boc group. Taken together, a basic -amino
group was essential in the reaction. Under the reaction conditions, the conversion of the amino group into
the ammonium functionality, which is a better leaving group than an amino group, would be important for
the reaction to progress. In the case of 4,5-epoxymorphinan derivative 1 (Scheme 1), the Troc group
would be firstly removed under the reaction conditions and then the carbon-nitrogen bond would be
cleaved. The carbon-nitrogen cleavage reaction was applicable to the ketones 3s-u possessing substituents
at the -position (entries 21-24), however 3u with the quaternary carbon center at the -position required
a large amount of zinc (entry 23) or reflux reaction conditions (entry 24).
We next examined the reaction of other aryl or heteroaryl ketones 5 (Figure 1). The reaction of 5 provided
the corresponding ketones in moderate to good yields except for the case of 5b. The treatment of 5b with
zinc and acetic acid gave 1-(pyridin-3-yl)ethan-1-ol in 54% yield. In the reaction of 5e, the detosylation
was observed to proceed concomitantly with the carbon-nitrogen bond cleavage. The reductive cleavage
reaction of the carbon-nitrogen bond was also applicable to benzoylpiperidine 6, cyclic ketone 8, and
t-butyl ketone 11, although reflux reaction conditions were required (Scheme 3). After the cleavage of the
carbon-nitrogen bond of 8, the reaction further proceeded to provide imine 10 in 47% yield. Contrary to

HETEROCYCLES, Vol. 88, No. 2, 2014
1055
O
O
NH2
Ph
13
N
O
Me
NMe2
Bn
14
BnO
15
Figure 2. Structures of the investigated -aminoalkyl alkyl ketones 13 and 14, and -aminoester 15
the case of aryl or t-butyl ketones lacking protons at the '-position, the reaction of alkyl ketones 13 and
14 with protons at the '-position (Figure 2) were sluggish to the carbon-nitrogen cleavage reaction. The
reaction of 13 or 14 in the presence of five equivalents of zinc at room temperature furnished the recovery
of the starting ketones. The elevation of the reaction temperature to 118 ºC (a reflux temperature)
decomposed the starting materials. Although the treatment of 14 with a large excess of zinc at room
temperature for 12 hours afforded the corresponding ketone in 77% yield, the same treatment of 13
resulted in only a trace of the corresponding ketone with the bulk of the product being unreacted 13, as
observed by TLC analysis. Taking into account these results and the outcomes of -acylamino or
-carbamoylketones (Table 1, entries 16-18), the progress of the reaction was critically affected by the
-amino functionality. The electron-withdrawing group generally lowers the energy of the LUMO of the
carbonyl  bond and activates the carbonyl group for the nucleophilic or one-electron attack.8 A strong
electron withdrawing property of the quaternary ammonium group such as the methiodide5i or
pyridinum5e group or a protonated amino group would sufficiently activate the carbonyl group, as
compared with the acylamino or carbamoyl group.9
The -aminoester 15 (Figure 2) also resisted the progress of the carbon-nitrogen cleavage reaction at
room temperature. The treatment of 15 with zinc and acetic acid even at reflux temperature for 12 h gave
a mixture of benzyl acetate and the starting ester 15 in 51% and 46% yield, respectively. This result was a
clear contrast to that using samarium diiodide, which is known to cleave the carbon-nitrogen bond not
only of -aminoketones but also of -aminoesters.3l,4a,e This result also suggests that the treatment with
zinc-acetic acid can selectively cleave the carbon-nitrogen bond of -aminoketones in the presence of
-aminoesters. Indeed, the treatment of compound 16, which has -aminoketone and -aminoester
moieties in a molecule, with zinc-acetic acid provided the corresponding ketone 4d and -aminoester 17
in 96% and 48% yield, respectively (Scheme 4). Benzyl acetate was not detected in the reaction mixture
by TLC analysis.
In conclusion, we examined the scope and limitation of the zinc-acetic acid promoted reductive
carbon-nitrogen bond cleavage reaction of -aminoketones. The reaction was applicable to a wide range

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HETEROCYCLES, Vol. 88, No. 2, 2014
Scheme 4. Reaction of compound 16
of -aminoalkyl aryl ketones possessing various substituents on the aromatic ring, -position, or -amino
group. In the reaction, a basic -amino group, which was converted into a protonated ammonium group
under the acidic reaction conditions, would be essential because protection of an -amino group by an
acyl or alkoxycarbonyl group prevented the reaction from proceeding. On the other hand, -aminoalkyl
alkyl ketones with protons at the '-position or -aminoesters were sluggish to the carbon-nitrogen
cleavage reaction.
EXPERIMENTAL
Nuclear magnetic resonance (NMR) spectra were recorded on an Agilent Technologies Mercury-300 or
Agilent Technologies NMR System-400. Chemical shifts were reported as  values (ppm) related to
tetramethylsilane (TMS). Mass spectra (MS) were obtained on a JMS-100LP instrument by applying an
electrospray ionization (ESI) or fast atom bombardment (FAB) method. Infrared (IR) spectra were
recorded on a JASCO FT/IR-460Plus. The progress of the reaction was determined on Merck Silica Gel
Art. 5715 (TLC). Column chromatographies were carried out using Kanto Silica Gel 60 N (40–100 m).
Zinc powder was used after the activation by a general procedure.10
Registry numbers of the described products are following; 3a (613-89-8), 3b (3319-03-7), 3c
(80354-58-1), 3d (53250-07-0), 3e (709-23-9), 3f (1266166-47-5), 3g (99985-55-4), 3h (31543-50-7), 3i
(1266216-21-0), 3j·HCl (3883-94-1), 3k·HCl (29705-80-4), 3l (6037-64-5), 3m (108976-12-1), 3n
(140420-07-1), 3o (20099-92-7), 3p (3755-89-3), 3q (178888-27-2), 3r (778617-61-1), 3s (91564-39-5),
3t (794-06-9), 3u (119313-12-1), 4a (98-86-2), 4c (122-00-9), 4d (100-06-1), 4e (403-42-9), 4f
(709-63-7), 4g (586-37-8), 4h (579-74-8), 4i (3609-53-8), 4t (451-40-1), 5a (119270-39-2), 5b
(46440-89-5), 5c (106272-36-0), 6 (729553-31-5), 8 (1416064-72-6), 10 (4721-98-6), 11 (1338492-73-1),
12 (75-97-8), 13·HCl (19389-43-6), 14 (19134-47-5), 15 (30379-57-8), 17 (54384-05-3),
1-(naphthalen-2-yl)ethan-1-one (93-08-3), 1-(pyridin-3-yl)ethan-1-ol (4754-27-2), 1-(benzofuran-2-yl)ethan-
1-one (1646-26-0), and benzyl acetate (140-11-4).
General procedure of reductive carbon-nitrogen bond cleavage reaction
To a solution of an -aminoketone in acetic acid (2 mL) was added zinc powder (5.0 mmol) and stirred at

HETEROCYCLES, Vol. 88, No. 2, 2014
1057
the indicated temperature for the indicated time. After a filtration, the reaction mixture was poured into a
saturated aqueous solution of sodium hydrogen carbonate and extracted with Et2O. The combined organic
layers were washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography to give the corresponding ketone
in the indicated yield.
2-Benzyl-1-(4-morpholinophenyl)butan-1-one (4u)
IR (neat, cm-1): 3083, 3460, 3026, 2962, 2926, 2895, 2856, 1661, 1598, 1567, 1554, 1517, 1495, 1451,
1427, 1383, 1304, 1267, 1223, 1193, 1182, 1123, 1115, 1070, 1051, 1029, 1013, 930, 832, 804, 757, 741,
700, 647. 1H NMR (300 MHz, CDCl3) : 0.86 (t, J = 7.4 Hz, 3H), 1.66-1.50 (m, 1H), 1.88-1.70 (m, 1H),
2.74 (dd, J = 6.8, 13.7 Hz, 1H), 3.08 (dd, J = 7.4, 13.7 Hz, 1H), 3.28 (t, J = 5.0 Hz, 4H), 3.64-3.55 (m,
13
1H), 3.84 (t, J = 5.0 Hz, 4H), 6.83 (d, J = 9.0 Hz, 2H), 7.26-7.10 (m, 5H), 7.84 (d, J = 7.2 Hz, 2H). C
NMR (75 MHz, CDCl3) : 12.0, 25.7, 38.2, 202.1, 154.3, 140.6, 130.5, 129.3, 128.6, 128.5, 126.2, 113.5,
66.8, 49.2, 47.7, 38.2, 25.7, 12.0. HR-MS (ESI): [M+Na]+ Calcd for C21H25NNaO2: 346.1783. Found:
346.1792.
1-(1H-Indazol-3-yl)propan-1-one
IR (KBr, cm-1): 3292, 2929, 1724, 1677, 1465, 1380, 1287, 1179, 1129, 1073, 936, 897, 748, 424, 408. 1H
NMR (300 MHz, CDCl3) : 1.30 (t, J = 7.4 Hz, 3H), 3.23 (q, J = 7.4 Hz, 2H), 7.31-7.38 (m, 1H),
7.42-7.49 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 8.1 Hz, 1H). 13C-NMR (100 MHz, CDCl3) : 8.2,
32.3, 109.8, 122.8, 123.7, 127.1, 127.5, 130.2, 141.1, 198.1. HR-MS (EI): [M]+ Calcd for C10H10N2O:
174.2030. Found: 174.0795.
Preparation of 2-morpholino-1-(1-tosyl-1H-indol-3-yl)ethanone (5d)
To a solution of 1-(1-tosyl-1H-indol-3-yl)ethanone11 (387.2 mg, 1.23 mmol) in MeCN (5 mL) were added
iodobenzene (27 L, 0.25 mmol), p-toluenesulfonic acid monohydrate (293 mg, 1.54 mmol), and mCPBA
(65%, 409 mg, 1.54 mmol), and stirred at 50 ºC for 12 h.12 The reaction mixture was poured into a
saturated aqueous sodium hydrogen carbonate solution and extracted with EtOAc. The combined organic
layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced
pressure to give a crude product (590 mg) as a brown amorphous solid. To a solution of the crude product
(590 mg) in THF (3 mL) was added morpholine (1 mL, 11.2 mmol) and the mixture was stirred at rt for
12 h. The reaction mixture was poured into a 4 M aqueous solution of sodium hydroxide and extracted
with EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate,

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HETEROCYCLES, Vol. 88, No. 2, 2014
and concentrated under reduced pressure. The residue was purified by silica gel column chromatography
to give 5d (98 mg, 20%) as a brown amorphous solid.
IR (neat, cm-1): 2854, 1661, 1596, 1535, 1445, 1379, 1296, 1173, 1135, 1117, 1089, 984, 942, 914, 866,
1
813, 751, 705, 664, 572. H NMR (400 MHz, CDCl3) : 2.37 (s, 3H), 2.61 (t, J = 4.5 Hz, 4H), 3.66 (s,
2H), 3.78 (t, J = 4.7 Hz, 4H), 7.24-7.40 (m, 4H), 7.85 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 7.4 Hz, 1H),
13
8.31-8.35 (m, 1H), 8.66 (s, 1H). C NMR (100 MHz, CDCl3) : 22.2, 54.4, 67.4, 67.5, 113.6, 119.9,
123.6, 125.5, 126.3, 127.7, 127.9, 128.4, 130.4, 130.8, 133.3, 135.07, 135.13, 146.6, 193.5. HR-MS
(ESI): [M+Na]+ Calcd for C21H22N2NaO4S: 421.1198. Found: 421.1233.
Preparation of 2-morpholino-1-(1-tosyl-1H-indazol-3-yl)propan-1-one (5e)
Under an Ar atmosphere, to a solution of N-methoxy-N-methyl-1H-indazole-3-carboxamide13 (313 mg,
1.5 mmol) in THF (5 mL) was added a prepared 1.14 M solution of ethylmagnesium bromide in Et2O (6.6
mL, 7.5 mmol) at 0 ºC. The mixture was stirred at the same temperature for 80 min, and further stirred at
rt for 12 h. The reaction mixture was poured into a 2 M hydrochloric acid and the aqueous layer was
washed with EtOAc. The pH of the aqueous layer was adjusted to basic by a 4 M aqueous solution of
sodium hydroxide and extracted with EtOAc. The combined organic layers were washed with brine, dried
over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography to give 1-(1H-indazol-3-yl)propan-1-one (228 mg, 87%) as a white
amorphous solid. To a solution of 1-(1H-indazol-3-yl)propan-1-one (487 mg, 2.8 mmol) in THF (5 mL)
were added tosyl chloride (800 mg, 4.2 mmol) and triethylamine (1.9 mL, 14 mmol), and the mixture was
stirred at rt for 12 h. The reaction mixture was poured into a 4 M aqueous solution of sodium hydroxide
and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous
sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column
chromatography to give 1-(1-tosyl-1H-indazol-3-yl)propan-1-one (824 mg, 90%) as a white amorphous
solid.
IR (KBr, cm-1): 2982, 2940, 1933, 1693, 1594, 1491, 1476, 1458, 1413, 1380, 1332, 1296, 1253, 1192,
1175, 1128, 1090, 1015, 993, 910, 818, 750, 703, 680, 657, 580, 565, 539, 492, 420. 1H NMR (400 MHz,
CDCl3) : 1.23 (t, J = 7.3 Hz, 3H), 2.38 (s, 3H), 3.21 (q, J = 7.3 Hz, 2H), 7.28 (d, J = 4.0 Hz, 2H), 7.42 (t,
J = 7.6 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 8.21 (d, J = 8.5 Hz, 1H), 8.32 (d, J =
13
8.1 Hz, 1H). C NMR (100 MHz, CDCl3) : 8.3, 22.3, 33.2, 113.5, 123.8, 124.1, 126.2, 128.3, 130.1,
130.6, 134.8, 141.9, 146.6, 147.5, 198.4. HR-MS (ESI): [M+Na]＋ Calcd for C17H16N2NaO3S: 351.0779.
Found: 351.0756.
To a solution of 1-(1-tosyl-1H-indazol-3-yl)propan-1-one (560 mg, 1.7 mmol) in MeCN (5 mL) were

HETEROCYCLES, Vol. 88, No. 2, 2014
1059
added iodobenzene (48.6 L, 0.44 mmol), p-toluenesulfonic acid monohydrate (518 mg, 2.7 mmol), and
mCPBA (65%, 723 mg, 2.7 mmol) and the mixture was stirred at 50 ºC for 12 h.12 The reaction mixture
was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with EtOAc.
The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and
concentrated under reduced pressure. The residue was purified by silica gel column chromatography to
give 1-oxo-1-(1-tosyl-1H-indazol-3-yl)propan-2-yl 4-methylbenzenesulfonate (550 mg, 65%) as a white
amorphous solid.
IR (KBr, cm-1): 3388, 1706, 1596, 1476, 1392, 1366, 1295, 1251, 1193, 1178, 1129, 1085, 1000, 936, 893,
1
815, 756, 705, 689, 663, 582, 565, 550, 539. H NMR (400 MHz, CDCl3) : 1.61 (d, J = 6.9 Hz, 3H),
2.33 (s, 3H), 2.39 (s, 3H), 6.11 (q, J = 7.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H),
7.39-7.46 (m, 1H), 7.57-7.64 (m, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 8.17-8.26 (m,
2H). 13C NMR (100 MHz, CDCl3) : 19.3, 22.1, 22.3, 77.2, 113.6, 123.5, 124.1, 126.6, 128.5, 128.7,
130.3, 130.5, 130.8, 133.9, 134.5, 141.6, 144.6, 145.5, 147.1, 191.0. HR-MS (ESI): [M+Na]+ Calcd for
C24H22N2NaO6S2: 521.0817. Found: 521.0769.
To a solution of 1-oxo-1-(1-tosyl-1H-indazol-3-yl)propan-2-yl 4-methylbenzenesulfonate (140 mg, 0.28
mmol) in THF (3 mL) was added morpholine (0.5 mL, 5.6 mmol) and the mixture was stirred at rt for 12
h. The reaction mixture was poured into distillated water and extracted with EtOAc. The combined
organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography to give 5e (99 mg, 85%)
as a brown amorphous solid.
IR (neat, cm-1): 2855, 1692, 1596, 1474, 1386, 1292, 1253, 1193, 1179, 1118, 1078, 1000, 957, 901, 853,
814, 754, 704, 685, 663, 580, 564, 538. 1H NMR (400 MHz, CDCl3) : 1.33 (d, J = 7.0 Hz, 3H), 2.38 (s,
3H), 2.52-2.69 (m, 4H), 3.57-3.70 (m, 4H), 4.63 (q, J = 7.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.41-7.47
(m, 1H), 7.57-7.66 (m, 1H), 7.91 (d, J = 8.5 Hz, 2H), 8.23 (d, J = 8.6 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H).
13C NMR (100 MHz, CDCl3) : 13.4, 22.3, 50.7, 63.4, 67.9, 113.6, 123.8, 124.3, 126.4, 128.4, 130.6,
134.8, 141.9, 146.7, 197.2. HR-MS (ESI): [M+Na]+ Calcd for C21H23N3NaO4S1: 436.1307. Found:
436.1312.
Reaction of 6
To a solution of 614 (9.3 mg, 0.033 mmol) in acetic acid (3 mL) was added zinc powder (33 mg, 0.50
mmol) and the mixture was stirred for 1 h with refluxing. After a filtration, the reaction mixture was
concentrated under reduced pressure. The residue was purified by silica gel column chromatography to
give 7 (8.6 mg, 93%) as a brown amorphous solid.

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IR (KBr, cm-1): 3905, 3855, 3842, 3822, 3752, 3737, 3713, 3691, 3678, 3651, 3400, 3061, 3029, 2944,
2801, 2572, 2411, 1813, 1736, 1689,1655, 1579, 1498, 1449, 1435, 1410. 1H NMR (300 MHz, CDCl3) :
1.33-1.47 (m, 2H), 1.57-1.80 (m, 4H), 2.70 (t, J = 7.6 Hz, 2H), 2.95 (t, J = 7.3 Hz, 2H), 3.87 (s, 2H),
7.22-7.63 (m, 8H), 7.94 (d, J = 7.4 Hz, 2H). 13C NMR (100 MHz CDCl3) : 23.8, 26.7, 28.1, 38.3, 47.6,
52.4, 127.9, 128.0, 128.6, 128.7, 128.9, 133.0, 136.4, 137.0, 200.2. HR-MS (ESI): [M+H]+ Calcd for
C19H24NO: 282.1858. Found: 282.1869.
Reaction of 8
To a solution of 815 (74 mg, 0.29 mmol) in acetic acid (3 mL) was added zinc powder (93 mg, 1.4 mmol)
and the mixture was stirred for 1 h with refluxing. After a filtration, the reaction mixture was concentrated
under reduced pressure. The residue was purified by silica gel column chromatography and preparative
TLC to give 10 (27 mg, 47%) as a brown amorphous solid. 1H NMR data of compound 10 were identical
to those of the literature.16
Reaction of 14
To a solution of 14 (32.6 mg, 0.14 mmol) in acetic acid (2 mL) was added zinc powder (622 mg, 9.52
mmol) and the mixture was stirred at rt for 12 h. After a filtration, the reaction mixture was poured into a
4M aqueous solution of sodium hydroxide and extracted with Et2O. The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography to give 4-phenylbutan-2-one (15.9 mg, 77%) as
a pale yellow oil.
Reaction of 15
To a solution of 15 (116 mg, 0.6 mmol) in acetic acid (3 mL) was added zinc powder (196 mg, 3.0 mmol)
and the mixture was stirred for 12 h with refluxing. After a filtration, the reaction mixture was poured into
a 4 M aqueous solution of sodium hydroxide and extracted with EtOAc. The combined organic layers
were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography to give benzyl acetate (46 mg, 51%) as a
colorless oil and recovered 15 (54 mg, 46%).
Preparation of benzyl 2-((2-(4-methoxyphenyl)-2-oxoethyl)(methyl)amino)acetate (16)
To a solution of benzyl 2-(methylamino)acetate 17 (81 mg, 0.45 mmol) in THF (2 mL) were added
4'-methoxyphenacyl bromide (113 mg, 0.50 mmol) and triethylamine (0.19 mL, 1.35 mmol) at 0 ºC and
the mixture was stirred at rt for 4 h. The reaction mixture was poured into a saturated aqueous solution of

HETEROCYCLES, Vol. 88, No. 2, 2014
1061
sodium hydrogen carbonate and extracted with EtOAc. The combined organic layers were washed with
brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was
purified by preparative TLC to give 16 (47 mg, 32%) as a yellow oil.
1
IR (neat, cm-1): 2937, 1742, 1681, 1600, 1511, 1455, 1257, 1171, 1027, 834, 698, 440, 408. H NMR
(400 MHz, CDCl3) : 2.56 (s, 3H), 3.61(s, 2H), 3.86 (s, 3H), 4.10 (s, 2H), 5.17(s, 2H), 6.89-6.94 (m, 2H),
7.31-7.42 (m, 5H), 7.95-8.05 (m, 2H). 13C NMR (100 MHz, CDCl3) : 42.5, 55.5, 57.5, 61.6, 66.3, 113.7,
128.3, 128.6, 128.8, 130.4, 132.1, 135.6, 163.6, 170.7, 195.5. HR-MS (FAB): [M+H]+ Calcd for
C19H22NO4: 328.38. Found: 328.1545.
Reaction of 16
To a solution of 16 (103 mg, 0.31 mmol) in acetic acid (3 mL) was added zinc powder (405 mg, 6.2
mmol) and the mixture was stirred at rt. After 1 h with stirring, benzyl acetate was not detected in the
reaction mixture by TLC analysis. After a filtration, the reaction mixture was concentrated under reduced
pressure. To the residue was added a saturated aqueous solution of potassium carbonate and extracted
with EtOAc.The residue was purified by silica gel column chromatography to give 4d (45 mg, 96%) as a
brown oil and 17 (27 mg, 48%) as a brown oil.
ACKNOWLEDGEMENTS
We acknowledge the Institute of Instrumental Analysis of Kitasato University, School of Pharmacy for its
facilities.
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