Hydrogenolysis of the cyclopropyl group into an isopropyl group in the presence of a platinum catalyst and hydrobromic acid

Article abstract of DOI:10.1016/j.tet.2009.10.064

Reduction of cyclopropylmethylamines proceeded under mild reaction conditions in the presence of platinum (IV) oxide catalyst and hydrobromic acid at rt, providing isobutylamines and no linear butylamines. The ring cleavage reaction was widely applicable to cyclopropane rings in various compounds such as N-cyclopropylalkyl, O-cyclopropylalkyl, and C-cyclopropylalkyl derivatives. Although unactivated cyclopropane rings were also cleaved, the cyclobutane ring was tolerated under the same reaction conditions.

Full text of DOI:10.1016/j.tet.2009.10.064

Tetrahedron 65 (2009) 10623–10630
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Hydrogenolysis of the cyclopropyl group into an isopropyl group in the presence
of a platinum catalyst and hydrobromic acid
Hideaki Fujii, Kayoko Okada, Marina Ishihara, Shinichi Hanamura, Yumiko Osa,
*
Toru Nemoto, Hiroshi Nagase
School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2009
Received in revised form 17 October 2009
Accepted 19 October 2009
Available online 22 October 2009
Reduction of cyclopropylmethylamines proceeded under mild reaction conditions in the presence of
platinum (IV) oxide catalyst and hydrobromic acid at rt, providing isobutylamines and no linear butyl-
amines. The ring cleavage reaction was widely applicable to cyclopropane rings in various compounds
such as N-cyclopropylalkyl, O-cyclopropylalkyl, and C-cyclopropylalkyl derivatives. Although unactivated
cyclopropane rings were also cleaved, the cyclobutane ring was tolerated under the same reaction
conditions.
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Hydrogenolysis
Cyclopropane ring
Isopropyl
Platinum catalyst
1. Introduction
2. Results and discussion
The smallest carbocycle, the cyclopropane ring, is so highly
strained that hydrogenolysis of cyclopropane ring can proceed in
the presence of a transition metal catalyst, such as nickel, rhodium,
palladium, iridium, and platinum, etc.1 Catalytic hydrogenolysis of
cyclopropane rings is applied in the total synthesis of natural
products2 or drug candidate research.3,4 However, hydrogenolysis
of unactivated cyclopropane rings generally requires harsh reaction
conditions such as high pressure and/or high temperature, while
cyclopropane rings activated by some conjugated substituent, such
as an aromatic ring, acyl group, or vinyl group react more easily.1a
We have recently reported that hydrogenolysis of the N-cyclo-
propylmethyl group in naltrexone methyl ether 1a in the presence
of platinum (IV) oxide and hydrobromic acid proceeded under mild
reaction conditions (H2 (1 atm), rt).5 Although the cyclopropane
ring in 1a was not activated by any conjugated substituents, the
cyclopropane ring was easily cleaved. Our hydrogenolysis condi-
tions were widely applicable to various cyclopropane rings in-
cluding unactivated ones. Herein, we describe the scope of the
catalytic hydrogenolysis of cyclopropane rings under our reduction
conditions.
2.1. Hydrogenolysis of N-cyclopropylmethyl group in
morphinan derivatives
Treatment of naltrexone methyl ether 1a in the presence of
platinum (IV) oxide and hydrochloric acid under hydrogen (1 atm)
gave N-isobutyl derivative 2a along with compounds 3a and 4a
(Table 1). Although hydrochloric acid effectively facilitated the ring
cleavage of the cyclopropyl group, the reduction of the keto group
Table 1
Hydrogenolysis of naltrexone methyl ether 1a with various amounts of platinum (IV)
oxide
OH
OH
OH
H2 (1 atm)
PtO2
R1
R2
N
N
N
+
O
O
HCl/MeOH
rt
O
O
O
OMe
OMe
OMe
3a: R1=H, R2=OH
1a
2a
4a: R1=OH, R2=H
Entry
PtO2 (equiv)
Reaction Time
Yield (%)
2a
3a
4a
Recovery of 1a
1
2
3
0.1
0.3
0.8
5 days
37 h
20 h
32
52
48
11
14
13
12
46
NDa
20
12
NDa
* Corresponding author. Tel.: þ81 3 5791 6372; fax: þ81 3 3442 5707.
E-mail address: nagaseh@pharm.kitasato-u.ac.jp (H. Nagase).
a
Not detected.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.064

10624
H. Fujii et al. / Tetrahedron 65 (2009) 10623–10630
occurred concomitantly. To achieve chemoselective opening of the
cyclopropane ring, we attempted the reduction of compound 1a in
the presence of various amounts of platinum (IV) oxide. When
0.1 equiv of the catalyst was used, the reaction rate was very slow
and a large amount of the starting material 1a was recovered (Table
1, entry 1). While a three-fold increase in the amount of the catalyst
to 0.3 equiv accelerated the reaction rate (entry 2), a further in-
crease to 0.8 equiv of the catalyst decreased the chemoselectivity
(entry 3). Therefore, we chose to use 0.3 equiv of the catalyst for
further investigations. Our efforts to substitute palladium on car-
bon as a catalyst instead of platinum (IV) oxide resulted in the re-
covery of the compound 1a.
poison.7 As expected, cleavage of the cyclopropane ring occurred at
the less hindered bond to afford the N-isobutyl derivative 2a, and
no detection of the linear butyl derivative. Additionally, a strong
acid may promote intramolecular hemiacetal formation in com-
pound 1a to afford hemiacetal 7 (Fig. 1),8 resulting in the protection
of the ketone moiety from reduction.
14
N
O
OH
O
OMe
We next examined the effect of various acids using 0.3 equiv of
platinum (IV) oxide (Table 2). In the presence of acetic acid or tri-
fluoroacetic acid (TFA), the reduction proceeded nonselectively
(Table 2, entries 3 and 4). Perchloric acid rather improved the
chemoselectivity of the reduction in comparison to acetic acid or
TFA, but the yield of objective compound 2a was low (entry 7). On
the other hand, (ꢀ)-camphorsulfonic acid (CSA) or hydroiodic acid
mainly resulted in recovery of starting material 1a (entries 5 and
11). In the case of methanesulfonic acid, complex mixture products
were obtained and no objective product 2a was detected (entry 6).
In the absence of acid, reduction of the keto group only proceeded
and cleavage of the cyclopropane ring was not observed (entry 12).
Among the investigated acids, hydrobromic acid gave compound 2a
predominantly (entries 8 and 9), with the concentration of hydro-
bromic acid having hardly any influence on the chemoselectivity. In
contrast, variations in the concentration of hydrochloric acid had
a notable effect on chemoselectivity (entries 1 and 2), suggesting
that an optimal acid would be hydrobromic acid. The reaction at
50 ꢁC in the presence of hydrobromic acid gave the objective
product 2a in 54% yield along with 40% recovery of the compound
1a (entry 10). These results suggest that the acidity6 would play an
important role in both facilitation of the ring opening reaction and
the chemoselectivity. Although among the examined acids hydro-
iodic acid is the strongest acid,6 the reaction with hydroiodic acid
never proceeded (entry 11). Hydroiodic acid itself and/or small
amount of iodine included in the acid might function as a catalyst
7
Figure 1. Structure of hemiacetal 7.
To confirm the participation of the 14-hydroxyl group in forma-
tion of the hemiacetal, we attempted the reduction of naltrexone
(1b), having
a 14-hydroxyl group, and N-cyclopropylmethyl-
norhydrocodone (1c),9 lacking the 14-hydroxyl group. Under the
same conditions, the reactions afforded the corresponding products
2b (71%) and 2c (62%) and 3c (12%) (Scheme 1). These results support
the idea that intramolecular hemiacetal formation would participate
in protecting the ketone moiety from reduction.
OH
14
OH
N
N
H2, PtO2
HBr/MeOH
44 h
O
O
1b
+
+
O
O
OH
OH
1b
2b
71 %
H
7%
N
H
14
H
N
N
H2, PtO2
HBr/MeOH
47 h
1c
+
O
O
OH
O
O
O
OMe
OMe
OMe
3c
1c
2c
62 %
12 %
23 %
Scheme 1. Hydrogenolysis of N-cyclopropylmethyl morphinan derivatives 1b and 1c.
Table 2
Hydrogenolysis of naltrexone methyl ether 1a catalyzed by platinum (IV) oxide in the presence of various acids
OH
OH
OH
OH
H2 (1 atm)
N
N
N
N
PtO2 (0.3 eq)
R1
R2
R1
R2
+
O
+
O
H+, MeOH
rt
O
O
O
O
OMe
OMe
OMe
OMe
1a
2a
3a: R1=H, R2=OH
5a: R1=H, R2=OH
4a: R1=OH, R2=H
6a: R1=OH, R2=H
Entry
Acida
Reaction Time (h)
Yield (%)
2a
3a
4a
5a
6a
Recovery of 1a
1
2
3
4
5
6
7
8
1 M HCl
37% HCl
AcOH
20
37
48
24
37
34
14
37
37
36
39
56
62
52
4
18
27
12
6
11
NDe
NDe
70
NDe
NDe
12
NDe
12
8
15
36
2
NDe
NDe
12
TFAc
24
4
14
(ꢀ)-CSAd
MeSO3H
70% HClO4
1 M HBr
48% HBr
48% HBr
57% HI
14
NDe
9
NDe
18
NDe
NDe
NDe
NDe
NDe
NDe
NDe
77
NDe
18
NDe
20
NDe
NDe
NDe
NDe
NDe
7
NDe
NDe
NDe
40
100
NDe
c
33
47
61
76
NDe
2
NDe
NDe
NDe
NDe
NDe
9
10b
11
12
54
NDe
NDe
NDe
NDe
NDe
None
a
A ratio of acid to MeOH is 1:1.2.
b
c
The reaction was carried out at 50 ꢁC.
Only acid was used as a solvent.
1 equiv of (ꢀ)-CSA was used.
Not detected.
d
e

H. Fujii et al. / Tetrahedron 65 (2009) 10623–10630
10625
2.2. Hydrogenolysis of the N-cyclopropylalkyl group
2.3. Hydrogenolysis of the O- or C-cyclopropylalkyl group
We next attempted hydrogenolysis of general cyclopropyl-
alkylamines. In the first attempt using cyclopropylmethylamine 8
(Fig. 2), not only cleavage of the cyclopropane ring but also re-
duction of the naphthyl group proceeded. Therefore, compounds 9
having the dimethoxyphenyl group were used to prevent the re-
duction of the aromatic ring (Table 3). After 12 h of reaction,
cyclopropylmethylamine 9awas converted to isobutylamine 10a in
59% yield with recovery of 9a (19%) (Table 3, entry 1), while pro-
longation of the reaction time to 24 h increased the yield of iso-
butylamine 10a (entry 2).
To investigate the scope of this reaction, cleavage of the cyclo-
propane ring in O-cyclopropylalkyl and C-cyclopropylalkyl de-
rivatives 12,15, and 17,19 was attempted to afford the corresponding
ring opening products 13, 16, and 18, 20 in moderate to good yields,
respectively (Scheme 2). Neither linear O-alkyl nor C-alkyl de-
rivatives were detected. In the case of O-cyclopropylmethyl de-
rivative 12, alcohol 14 was obtained as a by-product.12 Why alcohol
14 was obtained is not clear, but the stability of the cyclo-
propylcarbinyl cation13 may affect the preparation of alcohol 14. The
examples in Scheme 2 indicate that the reaction conditions would be
widely applicable to various compounds possessing a cyclopropane
ring.
N
O
O
OH
N
H2 (1 atm)
PtO2 (0.3 eq)
+
+
12
48% HBr/MeOH
rt, 12 h
OMe
OMe
OMe
OMe
12
OMe
13
OMe
14
OMe
OMe
59%
9%
8%
O
O
H
2 (1 atm)
8
11
PtO2 (0.15 eq)
Figure 2. Structures of cyclopropylmethylamine 8 and cyclobutylmethylamine 11.
48% HBr/MeOH
rt, 12 h
OMe
OMe
15
OMe
OMe
16
Table 3
69%
Hydrogenolysis of N-cyclopropylalkylamines 9
OMe
OMe
OMe
OMe
H2 (1 atm)
PtO2 (0.3 eq)
n
n
N
N
H
2 (1 atm)
48% HBr/MeOH
rt, 24 h
PtO2 (0.3 eq)
OMe
OMe
17
OMe
OMe
18
48% HBr/MeOH
rt, 12 h
OMe
OMe
86%
OMe
OMe
OMe
OMe
OMe
OMe
H
2 (1 atm)
9a - c
10a - c
PtO2 (0.15 eq)
48% HBr/MeOH
rt, 9 h
Entry
9
n
Product
Yield (%)
OMe
OMe
19
OMe
OMe
20
1
a
a
b
c
1
1
2
3
10a
10a
10b
10c
59a
65
94
76
2b
3
76%
4
Scheme 2. Hydrogenolysis of O-cyclopropylalkyl and C-cyclopropylalkyl derivatives
12, 15, 17, and 19.
a
Cyclopropylmethylamine 9a was also recovered in 19% yield.
The reaction was carried out for 24 h.
b
Although hydrogenolysis of the cyclopropane ring has been
frequently carried out using platinum (IV) oxide in the presence of
acetic acid,2–4 these reaction conditions in the presence of acetic
acid were not optimal in our investigation using naltrexone methyl
ether 1a (Table 2). Therefore, we repeated the attempted hydro-
genolysis of cyclopropane ring in cyclopropylmethylamine 9a in the
presence of acetic acid instead of hydrobromic acid (Scheme 3). The
reduction of cyclopropylmethylamine 9a gave isobutylamine 10a
(24%) along with linear butylamine 21 (5%) and starting material 9a
(17%). Moreover, reduction of the benzene ring was also observed.14
This outcome indicates that the hydrogenolysis reaction conditions
We first hypothesized that the s-electrons between the nitrogen
and the carbon of the cyclopropylmethyl group would be donated
to the protonated nitrogen, a process that is facilitated by the ex-
treme stability of the cyclopropylcarbinyl cation10,11 which may
promote the activation of the cyclopropane ring (Fig. 3). Therefore,
we presumed that this hydrogenolysis of the cyclopropane ring
would be applicable to only the cyclopropylmethylamines. How-
ever, the reduction of both cyclopropylethylamine 9b and cyclo-
propylpropylamine 9c gave the respective branched alkylamines
10b and 10c in good to excellent yield (Table 3, entries 3 and 4) and
no linear alkylamines were detected in all cases. These unexpected
results may suggest the direct activation of the cyclopropane ring
by hydrobromic acid. The attempted ring cleavage of cyclo-
butylmethylamine 11 (Fig. 2) resulted in recovery of 11.
R
N
N
N
N
H2 (1 atm)
PtO2 (0.3 eq)
+
+
+
9a
AcOH, rt, 24 h
H
N
OMe
OMe
OMe
OMe
OMe
22
OMe
OMe
OMe
δ+
R
9a
10a
21
R
24%
5%
17%
Figure 3. Diagram of the activated cyclopropane ring. The
nitrogen and carbon in the cyclopropylmethyl group may be released to the protonated
nitrogen (red arrow) because of the extremely stable cyclopropylcarbinyl cation.
s
-electrons between the
Scheme 3. Hydrogenolysis of cyclopropylmethylamine 9a in the presence of acetic
acid instead of hydrobromic acid. The yield of 22 was not determined. For details, see
the Experimental section and Ref. 14.

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H. Fujii et al. / Tetrahedron 65 (2009) 10623–10630
in the presence of hydrobromic acid were more chemo- and
regioselective. Of the reported methods for this transformation, the
reaction protocol that we present in this study for cleavage of the
cyclopropane ring appears to be the optimal conditions.
2955, 2833, 1729, 1504, 1440, 1282, 1257. HRMS (ESI): [MþNa]þ
Calcd for C21H27NNaO4: 380.1838. Found: 380.1820.
4.4. 4,5
a-Epoxy-17-isobutyl-3-methoxymorphinan-6a,14b-
diol (3a)
3. Conclusion
A colorless oil. 1H NMR (300 MHz, CDCl3)
d
0.91 (d, J¼6.5 Hz,
We found that reduction of cyclopropylmethylamines proceeded
under mild reaction conditions in the presence of platinum (IV)
oxide catalyst and hydrobromic acid at rt to provide isobutylamines
without the production of linear butylamines. The ring cleavage re-
action was widely applicable to cyclopropane rings in various com-
pounds such as N-cyclopropylalkyl, O-cyclopropylalkyl, and
C-cyclopropylalkyl derivatives. Unactivated cyclopropane rings were
readily cleaved, and the cyclobutane ring was tolerated under the
same reaction conditions. Hydrogenolysis of cyclopropane rings has
been frequently carried out using platinum (IV) oxide in the presence
of acetic acid, but our attempted reduction of cyclopropylmethyl-
amine in the presence of acetic acid instead of hydrobromic acid gave
isobutylamine along with linear butylamine. Moreover, reduction of
the benzene ring occurred concomitantly. Our reaction protocol for
the chemo- and regioselective cleavage of various cyclopropane
rings, including unactivated rings, appears to be one of the best
conditions among all the methods reported to date.
3H), 0.92 (d, J¼6.3 Hz, 3H), 1.10–1.26 (m, 1H), 1.40–1.86 (m, 5H),
2.10–2.31 (m, 4H), 2.44–2.52 (m, 1H), 2.63 (dd, J¼6.3, 18.5 Hz, 1H),
2.82 (d, J¼6.3 Hz, 1H), 3.10 (d, J¼18.5 Hz, 1H), 3.86 (s, 3H), 4.13–4.24
(m, 1H), 4.64 (d, J¼4.7 Hz, 1H), 5.02 (br s, 1H), 6.60 (d, J¼8.2 Hz, 1H),
6.72 (d, J¼8.2 Hz, 1H). (A proton of OH group was not observed.) IR
(neat, cmꢂ1): 3397, 2953, 2833, 1634, 1606, 1504, 1453, 1381, 1336,
1282. HRMS (ESI): [MþNa]þ Calcd for C21H29NNaO4: 382.1994.
Found: 382.2002.
4.5. 4,5
a-Epoxy-17-isobutyl-3-methoxymorphinan-6b,14b-
diol (4a)
A colorless oil. 1H NMR (300 MHz, CDCl3)
d
0.90 (d, J¼6.4 Hz,
3H), 0.91 (d, J¼6.4 Hz, 3H), 1.29–1.40 (m, 1H), 1.44–1.84 (m, 4H),
1.86–2.01 (m, 1H), 2.05–2.32 (m, 4H), 2.42–2.50 (m, 1H), 2.62 (dd,
J¼5.9, 18.6 Hz, 1H), 2.83 (d, J¼5.9 Hz, 1H), 3.08 (d, J¼18.3 Hz, 1H),
3.54–3.63 (m, 1H), 3.86 (s, 3H), 4.48 (d, J¼5.6 Hz, 1H), 6.61 (d,
J¼8.2 Hz, 1H), 6.71 (d, J¼8.2 Hz, 1H) (Two protons of OH groups
were not observed.) IR (neat, cmꢂ1): 3492, 2963, 2923, 2822, 1637,
1510, 1439, 1286. HRMS (ESI): [MþNa]þ Calcd for C21H29NNaO4:
382.1994. Found: 382.1989.
4. Experimental section
4.1. General
Melting points were measured on a Yazawa BY–10 melting point
apparatus. Infrared (IR) spectra were measured on a JASCO FT/IR–
460Plus. Nuclear magnetic resonance (NMR) spectra were recorded
on a Varian Mercury–300 (300 MHz) spectrometer. Chemical shifts
4.6. 17-Cyclopropylmethyl-4,5
a-epoxy-3-
methoxymorphinan-6 ,14 -diol (5a)
a
b
A colorless oil. 1H NMR (300 MHz, CDCl3)
d 0.07–0.17 (m, 2H),
were reported as
d
values (ppm) related to tetramethylsilane (TMS).
0.47–0.59 (m, 2H), 0.77–0.92 (m, 1H), 1.10–1.27 (m, 1H), 1.41–1.71
(m, 3H), 1.73–1.86 (m, 1H), 2.15–2.30 (m, 3H), 2.33 (dd, J¼6.3,
12.8 Hz, 1H), 2.36 (dd, J¼6.5, 12.7 Hz, 1H), 2.58–2.70 (m, 1H), 2.60
(dd, J¼6.6, 18.6 Hz, 1H), 3.04 (d, J¼18.6 Hz, 1H), 3.08 (d, J¼6.6 Hz,
1H), 3.86 (s, 3H), 4.14–4.27 (m, 1H), 4.65 (d, J¼4.5 Hz, 1H), 5.02 (br s,
1H), 6.59 (d, J¼8.2 Hz, 1H), 6.72 (d, J¼8.2 Hz, 1H). IR (neat, cmꢂ1):
3397, 2938, 1504, 1452, 1281. HRMS (ESI): [MþNa]þ Calcd for
C21H27NNaO4: 380.1838. Found: 380.1847.
Mass spectra (MS) were measured on a JMS–AX505HA or JMS–
700 M Station instruments by applying a fast atom bombardment
(FAB), electron ionization (EI), or electron splay ionization (ESI)
method. The progress of the reaction was determined on Merck
Silica Gel Art. 5715. Column chromatographies were carried out
using Kanto Silica Gel 60 N or Fuji Silysia DM2035 (The surface of
the silica gel was modified by amino group). Preparative TLCs were
performed using Merck Silica Gel Art. 5744 or Fuji Silysia NH TLC
plate.
4.7. 17-Cyclopropylmethyl-4,5
a-epoxy-3-
methoxymorphinan-6 ,14 -diol (6a)
b
b
4.2. General procedure of catalytic hydrogenolysis
A colorless oil. 1H NMR (300 MHz, CDCl3)
d 0.07–0.17 (m, 2H),
To the solution of compound 9a (51 mg, 0.19 mmol) in 48% HBr
(0.33 mL) and MeOH (0.4 mL) was added PtO2 (15 mg, 0.054 mmol)
and stirred at rt for 24 h under H2. The catalyst was removed by
filtration and the filtrate was concentrated under reduced pressure.
To the obtained residue was added 2 M NaOH solution and
extracted with AcOEt. The combined organic layers were washed
with brine and dried over anhydrous Na2SO4. After removing the
solvent under reduced pressure, the residue was purified by pre-
parative TLC (CHCl3/MeOH¼15/1) to give compound 10a (33 mg,
65%) as a colorless oil.
0.47–0.59 (m, 2H), 0.76–0.91 (m, 1H), 1.30–1.43 (m, 1H), 1.45–1.70
(m, 3H),1.87–2.02 (m,1H), 2.07–2.30 (m, 2H), 2.36 (d, J¼6.5 Hz, 2H),
2.59–2.69(m, 1H), 2.61 (dd, J¼5.9, 18.5 Hz, 1H), 2.94 (br s, 1H), 3.04
(d, J¼18.6 Hz, 1H), 3.10 (d, J¼5.9 Hz, 1H), 3.54–3.66 (m, 1H), 3.86 (s,
3H), 4.49 (d, J¼5.6 Hz,1H), 5.17 (br s,1H), 6.61 (d, J¼8.2 Hz,1H), 6.71
(d, J¼8.2 Hz, 1H). IR (neat, cmꢂ1): 3392, 2934, 1502, 1439, 1280,
1257. HRMS (ESI): [MþH]þ Calcd for C21H28NO4: 358.2018. Found:
358.2004.
4.8. 4,5
a-Epoxy-3,14b-dihydroxy-17-isobutylmorphinan-6-
one (2b)
4.3. 4,5a-Epoxy-14b-hydroxy-17-isobutyl-3-
methoxymorphinan-6-one (2a)
A white crystal. Mp: 187–190 ꢁC. 1H NMR (300 MHz, CDCl3)
d
0.93 (d, J¼6.6 Hz, 3H), 0.95 (d, J¼6.7 Hz, 3H), 1.52–1.70 (m, 2H),
A colorless oil. 1H NMR (300 MHz, CDCl3)
d
0.87 (d, J¼6.7 Hz,
1.71–1.84 (m, 1H), 1.87 (ddd, J¼3.1, 4.9, 13.4 Hz, 1H), 2.11–2.25 (m,
2H), 2.26–2.64 (m, 6H), 2.91 (d, J¼5.9 Hz, 1H), 3.03 (dt, J¼5.1,
14.5 Hz, 1H), 3.09 (d, J¼18.5 Hz, 1H), 4.70 (s, 1H), 6.59 (d, J¼8.1 Hz,
1H), 6.71 (d, J¼8.2 Hz, 1H). (A proton of OH group was not ob-
served.) IR (KBr, cmꢂ1): 3198, 2957, 1721, 1620, 1462, 1243. HRMS
(ESI): [MþNa]þ Calcd for C20H25NNaO4: 366.1681. Found: 366.1675.
3H), 0.88 (d, J¼6.7 Hz, 3H),1.44–1.63 (m, 2H),1.65–1.80 (m,1H),1.80
(ddd, J¼2.9, 4.9, 13.4 Hz, 1H), 2.02–2.40 (m, 5H), 2.42–2.60 (m, 2H),
2.84 (d, J¼5.9 Hz, 1H), 2.94 (dt, J¼5.1, 14.4 Hz, 1H), 3.04 (d,
J¼18.5 Hz, 1H), 3.83 (s, 3H), 4.60 (s, 1H), 5.13 (br s, 1H), 6.56 (d,
J¼8.2 Hz, 1H), 6.63 (d, J¼8.2 Hz, 1H). IR (neat, cmꢂ1): 3380, 3017,

H. Fujii et al. / Tetrahedron 65 (2009) 10623–10630
10627
4.9. 4,5
a
-Epoxy-17-isobutyl-3-methoxymorphinan-6-one (2c)
4.16. 4-(3-Isopentyloxypropyl)-1,2-dimethoxybenzene (16)
A colorless oil. 1H NMR (300 MHz, CDCl3)
6H),1.48 (q, J¼6.9 Hz, 2H),1.61–1.79 (m,1H),1.80–1.93 (m, 2H), 2.64
(t, J¼7.7 Hz, 2H), 3.41 (t, J¼6.3 Hz, 2H), 3.43 (t, J¼6.9 Hz, 2H), 3.85 (s,
3H), 3.86 (s, 3H) 6.67–6.83 (m, 3H). IR (neat, cmꢂ1): 2952, 2867,
1516, 1465, 1262, 1237, 1156, 1141, 1112, 1032. HRMS (FAB): [M]þ
Calcd for C16H26O3: 266.1882. Found: 266.1877.
A colorless oil. 1H NMR (300 MHz, CDCl3)
d
0.84 (d, J¼6.3 Hz,
d
0.91 (d, J¼6.6 Hz,
3H), 0.85 (d, J¼6.4 Hz, 3H),1.09–1.25 (m,1H),1.58–1.80 (m, 3H),1.96
(dt, J¼4.6, 11.9 Hz, 1H), 2.02–2.38 (m, 6H), 2.44–2.56 (m, 2H), 2.87
(d, J¼18.3 Hz, 1H), 3.08 (dd, J¼2.8, 5.3 Hz, 1H), 3.83 (s, 3H), 4.56 (s,
1H), 6.55 (d, J¼8.1 Hz, 1H), 6.62 (d, J¼8.2 Hz, 1H). IR (neat, cmꢂ1):
2950, 1728, 1503, 1439, 1274, 1258. HRMS (ESI): [MþNa]þ Calcd for
C21H27NNaO3: 364.1889. Found: 364.1888.
4.17. 4,40-(3-Methylbutane-1,1-diyl)bis(1,2-
dimethoxybenzene) (18)
4.10. 4,5
a-Epoxy-17-isobutyl-3-methoxymorphinan-
6
a
-ol (3c)
A colorless oil. 1H NMR (300 MHz, CDCl3)
d
0.92 (d, J¼6.6 Hz,
A colorless oil. 1H NMR (300 MHz, CDCl3)
d
0.90 (d, J¼6.6 Hz,
6H), 1.38–1.55 (m, 1H), 1.85 (t, J¼7.5 Hz, 2H), 3.71–3.95 (m, 1H), 3.83
(s, 6H), 3.84 (s, 6H), 6.73 (br s, 2H), 6.75–6.83 (m, 4H). IR (neat,
cmꢂ1): 3000, 2953, 2867, 2834, 1604, 1590, 1514, 1464, 1415, 1260,
1144, 1029, 759. HRMS (EI): [M]þ Calcd for C21H28O4: 344.1988.
Found: 344.2001.
3H), 0.91 (d, J¼6.6 Hz, 3H), 1.00–1.18 (m, 1H), 1.36–1.59 (m, 3H),
1.60–1.79 (m, 2H), 1.87 (dt, J¼4.2, 12.0 Hz, 1H), 2.07 (br s, 1H), 2.14–
2.30 (m, 4H), 2.30–2.45 (m, 1H), 2.52 (dd, J¼3.7, 11.6 Hz,1H), 2.91 (d,
J¼18.3 Hz, 1H), 3.06 (br d, J¼2.7 Hz, 1H), 3.87 (s, 3H), 3.96–4.07 (m,
1H), 4.59 (d, J¼5.1 Hz, 1H), 6.61 (d, J¼7.8 Hz, 1H), 6.71 (d, J¼8.4 Hz,
1H). IR (neat, cmꢂ1): 3427, 2948, 1636, 1503, 1450, 1278. HRMS
(ESI): [MþNa]þ Calcd for C21H29NNaO3: 366.2045. Found:
366.2042.
4.18. 4,40-(4-Methylpentane-1,1-diyl)bis(1,2-
dimethoxybenzene) (20)
The reaction was carried out using 10-fold amount of MeOH
compared to the general procedure because compound 19 did not
dissolve in the general procedure solvent. A colorless oil. 1H NMR
4.11. 1-Isobutyl-4-(3,4-dimethoxyphenyl)piperidine (10a)
A colorless oil. 1H NMR (300 MHz, CDCl3)
d
0.92 (d, J¼6.6 Hz,
(300 MHz, CDCl3)
d
0.87 (d, J¼6.6 Hz, 6H), 1.10–1.21 (m, 2H), 1.47–
6H), 1.71–2.05 (m, 7H), 2.11 (d, J¼7.2 Hz, 2H), 2.35–2.51 (m, 1H),
2.98 (br d, J¼11.7 Hz, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 6.74–6.84 (m,
3H). IR (neat, cmꢂ1): 2950, 2869, 2833, 2802, 2773,1606,1590,1516,
1465, 1417, 1380, 1338, 1260, 1158, 1142, 1118, 1095, 1031, 1004, 804.
HRMS (EI): [M]þ Calcd for C17H27NO2: 277.2042. Found: 277.2051.
1.67 (m, 1H), 1.89–2.40 (m, 2H), 3.68–3.80 (m, 1H), 3.84 (s, 6H), 3.85
(s, 6H), 6.69–6.83 (m, 6H). IR (neat, cmꢂ1): 2952, 1590, 1514, 1464,
1415, 1257, 1144, 1030. HRMS (FAB): [M]þ Calcd for C22H30O4:
358.2144. Found: 358.2142.
4.19. Hydrogenolysis of cyclopropylmethylamine 9a in the
presence of AcOH
4.12. 1-Isopentyl-4-(3,4-dimethoxyphenyl)piperidine (10b)
A colorless oil. 1H NMR (300 MHz, CDCl3)
d
0.92 (d, J¼6.6 Hz,
To the solution of cyclopropylmethylamine 9a (50 mg,
0.18 mmol) in AcOH (0.7 mL) was added PtO2 (16 mg) and stirred at
rt under H2. After removing catalyst by filtration, the filtrate was
poured into 2 M NaOH solution and extracted with AcOEt. The
combined organic layers were washed with brine and dried over
anhydrous Na2SO4 followed by removing the solvent under re-
duced pressure to give crude product (49 mg). The residue was
purified by preparative TLC (CHCl3/MeOH/NH4OH¼50/1/0.1) to
give isobutylamine 10a (12.1 mg, 24%) and linear butylamine 21
(2.3 mg, 5%) along with recovery of 9a (8.3 mg, 17%).
6H), 1.38–1.69 (m, 3H), 1.73–1.95 (m, 4H), 1.97–2.18 (m, 2H), 2.28–
2.58 (m, 3H), 3.11 (br d, J¼11.1 Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H),
6.73–6.85 (m, 3H). IR (neat, cmꢂ1): 2996, 2932, 2869, 2803, 2766,
1590, 1517, 1465, 1260, 1233, 1142, 1029. HRMS (EI): [M]þ Calcd for
C18H29NO2: 291.2198. Found: 291.2205.
4.13. 4-(3,4-Dimethoxyphenyl)-1-(4-methylpentyl)
piperidine (10c)
A colorless oil. 1H NMR (300 MHz, CDCl3)
d
0.89 (d, J¼6.6 Hz,
6H), 1.12–1.37 (m, 2H), 1.45–1.66 (m, 3H), 1.68–1.89 (m, 4H), 2.01
(dt, J¼3.9, 11.1 Hz, 2H), 2.26–2.52 (m, 3H), 3.06 (br d, J¼11.7 Hz, 2H),
3.85 (s, 3H), 3.86 (s, 3H), 6.73–6.84 (m, 3H). IR (neat, cmꢂ1): 2934,
2869, 2801, 2763, 1590, 1517, 1466, 1417, 1374, 1261, 1142, 1031.
HRMS (EI): [M]þ Calcd for C19H31NO2: 305.2355. Found: 305.2352.
4.19.1. 1-Butyl-4-(3,4-dimethoxyphenyl)piperidine (21). A colorless
oil. 1H NMR (300 MHz, CDCl3)
d
0.93 (t, J¼7.4 Hz, 3H), 1.22–1.41 (m,
2H), 1.46–1.59 (m, 2H), 1.75–1.87 (m, 4H), 1.94–2.10 (m, 2H), 2.32–
2.52 (m, 3H), 3.07 (br d, J¼11.4 Hz, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 6.72–
6.86(m, 3H). IR(neat, cmꢂ1):2932, 2871, 2802, 2764,1590,1517,1465,
1417, 1375, 1261, 1232, 1141, 1031. HRMS (ESI): [MþH]þ Calcd for
C17H28NO2: 278.2120. Found: 278.2123.
4.14. 4-(3-Isobutoxypropyl)-1,2-dimethoxybenzene (13)
A colorless oil. 1H NMR (300 MHz, CDCl3)
d
0.92 (d, J¼6.9 Hz, 6H),
4.20. Preparation of 1-(cyclopropylmethyl)-4-(3,4-
dimethoxyphenyl)piperidine (9a)
1.79–1.95 (m, 3H), 2.60–2.69 (m, 2H), 3.17 (d, J¼6.6 Hz, 2H), 3.41 (t,
J¼6.5 Hz, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 6.69–6.82 (m, 3H). IR (neat,
cmꢂ1): 2952, 2854, 1516, 1466, 1261, 1237, 1156, 1141, 1114, 1032.
HRMS (FAB): [M]þ Calcd for C15H24O3: 252.1725. Found: 252.1725.
4.20.1. 1-Benzyl-4-(3,4-dimethoxyphenyl)-1,2,3,6-tetrahydropyridine
(23). Under Ar, to the solution of 4-bromoveratrole (0.1 mL,
0.7 mmol) in THF (0.7 mL) was added 1.63 M solution of n-BuLi in
hexane (0.43 mL, 0.7 mmol) dropwise at ꢂ78 ꢁC. After 1 h, to the
mixture was added the solution of 1-benzyl-4-piperidone (0.12 mL,
0.6 mmol) in THF (0.6 mL) and stirred at the same temperature for
1 h, then stirred at rt for 2.5 h. The reaction mixture was poured into
saturated NaHCO3 solution and extracted with AcOEt. The combined
organic layers were washed with distillated water and brine, and
dried over anhydrous Na2SO4 followed by removing the solvent
4.15. 3-(3,4-Dimethoxyphenyl)propan-1-ol (14)
A colorless oil. 1H NMR (300 MHz, CDCl3)
d 1.81–1.93 (m, 2H),
2.65 (t, J¼7.7 Hz, 2H), 3.67 (t, J¼6.5 Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H),
6.68–6.82 (m, 3H) (A proton of OH group was not observed.) IR
(neat, cmꢂ1): 3388, 2937, 1516, 1465, 1260, 1236, 1154, 1141, 1028.
HRMS (FAB): [M]þ Calcd for C11H16O3: 196.1099. Found: 196.1103.

10628
H. Fujii et al. / Tetrahedron 65 (2009) 10623–10630
under reduced pressure. The resulting residue was roughly purified
by silica gel column chromatography (CHCl3/MeOH¼50/1–30/1) to
give an oily yellow material (143 mg). The obtained material
(143 mg) was dissolved in 85% phosphoric acid (5 mL) and stirred at
80 ꢁC for 2 h. The reaction mixture was poured into 7 M ammonia
and extracted with CHCl3. The combined organic layers were washed
with distillated water and dried over anhydrous Na2SO4 followed by
removing the solvent under reduced pressure. The residue was pu-
rified by silica gel column chromatography (NH silica gel, hexane/
AcOEt¼50/1–30/1) to give the title compound 23 (81 mg, 41%) as
3.85 (s, 3H), 3.87 (s, 3H), 4.34 (br d, J¼12.6 Hz, 1H), 4.76 (br d,
J¼12.3 Hz, 1H), 6.64–6.86 (m, 3H). IR (neat, cmꢂ1): 3005, 2935,
2849, 1633, 1517, 1451, 1254, 1213. HRMS (FAB): [MþH]þ Calcd for
C17H24NO3: 290.1756. Found: 290.1750.
4.20.5. 1-(Cyclopropylmethyl)-4-(3,4-dimethoxyphenyl)piperidine
(9a). Under Ar, to the suspension of LiAlH4 (3 g, 11 mmol) in THF
(15 mL) was added the solution of compound 26 (528 mg,
1.8 mmol) in THF (5 mL) dropwise at 0 ꢁC and stirred at rt for 2 h. To
the reaction mixture was added saturated Na2SO4 solution drop-
wise at 0 ꢁC for decomposition of the excess LiAlH4 and then added
anhydrous Na2SO4. The resulting insoluble materials were removed
by filtration. After concentration of the filtrate, the residue was
purified by silica gel column chromatography (NH silica gel, hex-
ane/AcOEt¼10/1–4/1) to give the title compound 9a (311 mg, 62%)
a white powder. 1H NMR (300 MHz, CDCl3)
d 2.43–2.52 (m, 2H),
2.60–2.71 (m, 2H), 3.07–3.14 (m, 2H), 3.57 (s, 2H), 3.79 (s, 3H), 3.81 (s,
3H), 5.88–5.93 (m, 1H), 6.72–6.76 (m, 1H), 6.83–6.88 (m, 2H), 7.16–
7.34 (m, 5H). IR (KBr, cmꢂ1): 1517, 1249, 1142, 1028. HRMS (ESI):
[MþH]þ Calcd for C20H24NO2: 310.1807. Found: 310.1793.
as a colorless oil. 1H NMR (300 MHz, CDCl3)
d 0.09–0.17 (m, 2H),
4.20.2. 1-Benzyl-4-(3,4-dimethoxyphenyl)piperidine (24). To the
solution of compound 23 (81 mg, 0.3 mmol) in MeOH (0.5 mL) and
10% HCl–MeOH (0.5 mL) was added 10% Pd/C (12 mg) and stirred at
rt for 24 h under H2. The catalyst was removed by filtration and the
resulting filtrate was concentrated under reduced pressure. The
residue was purified by preparative TLC (NH silica gel, hexane/
AcOEt¼3/1) to give the title compound 24 (48 mg, 58%) as a white
0.49–0.58 (m, 2H), 0.85–1.00 (m, 1H), 1.83 (ddd, J¼3.3, 6.0, 12.5 Hz,
4H), 1.98–2.15 (m, 2H), 2.30 (d, J¼6.3 Hz, 2H), 2.36–2.54 (m, 1H),
3.21 (br d, J¼11.7 Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 6.74–6.84 (m,
3H). IR (neat, cmꢂ1): 2930, 2912,1518,1232,1140,1026. HRMS (ESI):
[MþH]þ Calcd for C17H26NO2: 276.1962. Found: 276.1964.
4.21. Preparation of 1-(2-cyclopropylethyl)-4-(3,4-
dimethoxyphenyl)piperidine (9b)
amorphous solid. 1H NMR (300 MHz, CDCl3)
d 1.73–1.86 (m, 4H),
2.00–2.14 (m, 2H), 2.38–2.52 (m,1H), 3.02 (br d, J¼11.7 Hz, 2H), 3.56
(s, 2H), 3.85 (s, 3H), 3.87 (s, 3H), 6.74–6.84 (m, 3H), 7.22–7.40 (m,
5H). IR (KBr, cmꢂ1): 2931, 2754, 1519, 1451, 1255, 1231, 1137, 1028.
HRMS (EI): [M]þ Calcd for C20H25NO2: 311.1885. Found: 311.1895.
4.21.1. 2-Cyclopropyl-1-(4-(3,4-dimethoxyphenyl)piperidin-1-yl)-
ethanone (27). To the solution of compound 25 (1.6 g, 4.1 mmol) in
AcOH (35 mL) was added Zn powder (18 g, 275 mmol) and stirred at
rt for 17 h under Ar. The Znpowder was removed by filtration and the
resulting filtrate was poured into ammonia solution, and then
extracted with CHCl3/i-PrOH¼2/1. The combined organic layers were
washed with distillated water and brine, and dried over anhydrous
Na2SO4 followed by removing the solvent under reduced pressure to
give the crude product (802 mg) as awhite powder. To the solution of
the crude product (802 mg), Et3N (0.67 mL, 4.8 mmol), and EDCI
hydrochloride (932 mg, 4.9 mmol) in CH2Cl2 (11 mL) was added
cyclopropylacetic acid (531 mg, 5.3 mmol) at 0 ꢁC and stirred at rt for
14 h. The reaction mixture was poured into 2M HCl and extracted
with CHCl3. The combined organic layers were washed with satu-
rated NaHCO3 solution and distillated water, and dried over anhy-
drous Na2SO4 followed by removing the solvent under reduced
pressure. The residue was purified by silica gel column chromatog-
raphy (hexane/AcOEt¼100/0–1/2) to give the title compound 27
4.20.3. 2,2,2-Trichloroethyl
4-(3,4-dimethoxyphenyl)piperidine-1-
carboxylate (25). To the solution of compound 24 (662 mg,
2.1 mmol) in 1,1,2,2-tetrachloroethane (2 mL) were added K2CO3
(588 mg, 4.3 mmol) and 2,2,2-trichloroethyl chloroformate (0.6 mL,
4.4 mmol), and refluxed for 23 h under Ar. The reaction mixture
was poured into 2 M HCl solution and extracted with CHCl3. The
combined organic layers were washed with distillated water and
dried over anhydrous Na2SO4 followed by removing the solvent
under reduced pressure. The residue was purified by silica gel
column chromatography (CHCl3) to give the title compound 25
(805 mg, 94%) as a yellow oil. 1H NMR (300 MHz, CDCl3)
d 1.66 (dq,
J¼4.1, 12.8 Hz, 2H), 1.88 (br d, J¼12.9 Hz, 2H), 2.66 (tt, J¼3.6, 12.0 Hz,
1H), 2.80–3.10 (m, 2H), 3.85 (s, 3H), 3.87 (s, 3H), 4.35 (br d,
J¼13.2 Hz, 2H), 4.78 (d, J¼2.7 Hz, 2H), 6.70–6.86 (m, 3H). IR (neat,
cmꢂ1): 2938, 1715, 1517, 1440, 1254, 1215. HRMS (ESI): [MþNa]þ
Calcd for C16H20Cl3NNaO4: 418.0356. Found: 418.0357.
(745 mg, 60%) as a colorless oil.1H NMR (300 MHz, CDCl3)
d 0.11–0.28
(m, 2H), 0.48–0.66 (m, 2H), 0.99–1.14 (m,1H),1.48–1.70 (m, 2H),1.88
(br d, J¼12.9 Hz, 2H), 2.31 (d, J¼6.9 Hz, 2H), 2.52–2.76 (m, 2H), 3.12
(br t, J¼12.3 Hz, 1H), 3.84 (s, 3H), 3.86 (s, 3H), 3.94 (br d, J¼12.9 Hz,
1H), 4.81 (br d, J¼12.9 Hz, 1H), 6.66–6.85 (m, 3H). IR (neat, cmꢂ1):
3001, 2935, 1637, 1517, 1450, 1256. HRMS (FAB): [MþH]þ Calcd for
C18H26NO3: 304.1913. Found: 304.1908.
4.20.4. Cyclopropyl(4-(3,4-dimethoxyphenyl)piperidin-1-yl)metha-
none (26). To the solution of compound 25 (951 mg, 2.4 mmol) in
AcOH (9 mL) was added Zn powder (6.1 g, 92.6 mmol) and stirred at
rt for 11 h under Ar. The Zn powder was removed by filtration and
the resulting filtrate was poured into ammonia solution, and then
extracted with CHCl3/i-PrOH¼2/1. The combined organic layers
were washed with distillated water and brine, and dried over an-
hydrous Na2SO4 followed by removing the solvent under reduced
pressure to give the crude product (530 mg) as a white powder. To
the solution of the crude product (530 mg) in CH2Cl2 (5 mL) were
added Et3N (1 mL, 7.2 mmol) and cyclopropanecarbonyl chloride
(0.6 mL, 12 mmol) at 0 ꢁC and stirred at rt for 17 h under Ar. The
reaction mixture was poured into saturated NaHCO3 solution and
extracted with CHCl3. The combined organic layers were washed
with distillated water and dried over anhydrous Na2SO4 followed
by removing the solvent under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/AcOEt¼100/
0–1/2) to give the title compound 26 (658 mg, 95%) as a colorless
4.21.2. 1-(2-Cyclopropylethyl)-4-(3,4-dimethoxyphenyl)piperidine
(9b). Compound 9b was synthesized from compound 27 in 75%
yield according to the synthetic method of compound 9a from
compound 26. A colorless oil. 1H NMR (300 MHz, CDCl3)
d 0.02–0.10
(m, 2H), 0.38–0.49 (m, 2H), 0.58–0.74 (m, 1H), 1.38–1.51 (m, 2H),
1.69–1.88 (m, 4H), 1.94–2.13 (m, 2H), 2.36–2.55 (m, 3H), 3.06 (br d,
J¼11.7 Hz, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 6.72–6.85 (m, 3H). IR (neat,
cmꢂ1): 2932, 1517, 1464, 1261, 1232, 1142, 1030. HRMS (FAB):
[MþH]þ Calcd for C18H28NO2: 290.2120. Found: 290.2120.
4.22. Preparation of 1-(3-cyclopropylpropyl)-4-(3,4-
dimethoxyphenyl)piperidine (9c)
oil. 1H NMR (300 MHz, CDCl3)
2H), 1.50–2.02 (m, 5H), 2.52–2.78 (m, 2H), 3.18 (br t, J¼12.3 Hz, 1H),
d
0.76 (br d, J¼7.8 Hz, 2H), 0.99 (br s,
4.22.1. 3-Cyclopropyl-1-(4-(3,4-dimethoxyphenyl)piperidin-1-yl)-
propan-1-one (28). To the solution of compound 25 (697 mg,

H. Fujii et al. / Tetrahedron 65 (2009) 10623–10630
10629
1.8 mmol) in AcOH (25 mL) was added Zn powder (7.4 g,
114 mmol) and stirred at rt for 25 h under Ar. The Zn powder was
removed by filtration and the resulting filtrate was poured into
ammonia solution, and then extracted with CHCl3/i-PrOH¼2/1.
The combined organic layers were washed with distillated water
and brine, and dried over anhydrous Na2SO4 followed by re-
moving the solvent under reduced pressure to give the crude
product (323 mg) as a white powder. To the solution of the 3-
cyclopropylpropanoic acid (0.14 mL, 1.2 mmol), Et3N (0.23 mL,
1.7 mmol) in CH2Cl2 (11 mL) was added ethyl chloroformate
(0.2 mL, 1.7 mmol) at 0 ꢁC and stirred at the same temperature for
1 h. To the reaction mixture was added the solution of the
obtained crude product (323 mg) in CH2Cl2 (6 mL) and stirred at
rt for 19 h. The reaction mixture was poured into saturated
NaHCO3 solution and extracted with CHCl3. The combined or-
ganic layers were washed with distillated water and dried over
anhydrous Na2SO4, followed by removing the solvent under re-
duced pressure. The residue was purified by silica gel column
chromatography (hexane/AcOEt¼30/1–1/3) to give the title
compound 28 (297 mg, 64%) as a colorless oil. 1H NMR (300 MHz,
DMF (2 mL) were added the solution of compound 14 (500 mg,
2.5 mmol) in DMF (2 mL) and (bromomethyl)cyclopropane (0.4 mL,
4.1 mmol), and stirred at rt for 7 h. The reaction mixture was
poured into saturated NH4Cl solution and extracted with CHCl3. The
combined organic layers were washed with distillated water and
dried over anhydrous Na2SO4 followed by removing the solvent
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/AcOEt¼2/1) to give the title
compound 12 (454 mg, 71%) as a colorless oil. 1H NMR (300 MHz,
CDCl3)
d 0.12–0.25 (m, 2H), 0.45–0.59 (m, 2H), 0.98–1.15 (m, 1H),
1.80–1.96 (m, 2H), 2.65 (t, J¼7.8 Hz, 2H), 3.26 (d, J¼6.9 Hz, 2H), 3.44
(t, J¼6.6 Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 6.69–6.82 (m, 3H). IR
(neat, cmꢂ1): 3002, 2935, 2856, 1590, 1515, 1464, 1417, 1260, 1155,
1106, 1029, 763. HRMS (FAB): [M]þ Calcd for C15H22O3: 250.1569.
Found: 250.1569.
4.25. 4-(3-(Cyclopropylmethoxy)propyl)-1,2-
dimethoxybenzene (15)
To the solution of 2-cyclopropylethanol (213 mg, 2.5 mmol) and
Et3N (0.65 mL, 4.7 mmol) in CH2Cl2 (3 mL) was added methane-
sulfonyl chloride (0.25 mL, 3.21 mmol) at 0 ꢁC and stirred at the
same temperature for 1 h. After removing the solvent under re-
duced pressure, crude 2-cyclopropylethy methanesulfonate was
obtained as a white solid. Sodium hydride (60% in oil, 424 mg,
10 mmol) was washed with anhydrous hexane, and then sus-
pended with DMF (3 mL). To the DMF suspension of NaH was added
the solution of compound 14 (552 mg, 2.8 mmol) in DMF (3 mL)
and stirred at rt for 40 min. To the obtained reaction mixture was
added the suspension of crude 2-cyclopropylethy methanesulfo-
nate in DMF (5 mL) at 0 ꢁC and stirred at rt for 19 h. The reaction
mixture was poured into saturated NaHCO3 solution and extracted
with CHCl3. The combined organic layers were washed with dis-
tillated water and dried over anhydrous Na2SO4 followed by re-
moving the solvent under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/AcOEt/¼5/
1–4/1) to give the title compound 15 (375 mg, 57%) as a colorless
CDCl3)
d 0.02–0.16 (m, 2H), 0.35–0.50 (m, 2H), 0.67–0.82 (m, 1H),
1.48–1.78 (m, 4H), 1.89 (br d, J¼12.9 Hz, 2H), 2.48 (t, J¼7.8 Hz, 2H),
2.54–2.77 (m, 2H), 2.80–3.21 (m, 1H), 3.86 (s, 3H), 3.87 (s, 3H),
3.92–4.12 (m, 1H), 4.60–4.93 (m, 1H), 6.68–6.85 (m, 3H). IR (neat,
cmꢂ1): 2998, 2934, 2852, 1639, 1518, 1448, 1256, 1142, 1028.
HRMS (ESI): [MþNa]þ Calcd for C19H27NNaO2: 340.1889. Found:
340.1898.
4.22.2. 1-(3-Cyclopropylpropyl)-4-(3,4-dimethoxyphenyl)piperidine
(9c). Compound 9c was synthesized from compound 28 in 80%
yield according to the synthetic method of compound 9a from
compound 26. A colorless oil. 1H NMR (300 MHz, CDCl3)
d
ꢂ0.70–
0.09 (m, 2H), 0.31–0.48 (m, 2H), 0.59–0.74 (m, 1H), 1.16–1.28 (m,
2H), 1.56–1.86 (m, 6H), 1.94–2.08 (m, 2H), 2.30–2.70 (m, 3H), 3.05
(br d, J¼11.4 Hz, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 6.72–6.83 (m, 3H). IR
(neat, cmꢂ1): 2932, 1517, 1261, 1233, 1142, 1031. HRMS (ESI):
[MþH]þ Calcd for C19H30NO2: 304.2277. Found: 304.2277.
oil. 1H NMR (300 MHz, CDCl3)
d 0.02–0.1 (m, 2H), 0.34–0.53 (m, 2H),
4.23. 1-(Cyclobutylmethyl)-4-(3,4-dimethoxyphenyl)-
piperidine (11)
0.67–0.83 (m, 1H), 1.48 (q, J¼6.9 Hz, 2H), 1.78–1.94 (m, 2H), 2.64 (t,
J¼7.7 Hz, 2H), 3.43 (t, J¼6.6 Hz, 2H), 3.49 (t, J¼6.9 Hz, 2H), 3.85 (s,
3H), 3.86 (s, 3H), 6.7–6.8 (m, 3H). IR (neat, cmꢂ1): 3435, 2933, 2857,
1516, 1465, 1261, 1237, 1156, 1115, 1031. HRMS (EI): [M]þ Calcd for
C16H24O3: 264.1725. Found: 264.1719.
Compound 11 was synthesized from compound 25 in 49% yield
according to the synthetic method of compound 9a. A colorless oil.
1H NMR (300 MHz, CDCl3)
d 1.63–2.01 (m, 8H), 2.03–2.20 (m, 4H),
2.37–2.55 (m, 3H), 2.56–2.73 (m,1H), 3.03 (br d, J¼11.4 Hz, 2H), 3.85
(s, 3H), 3.86 (s, 3H), 6.72–6.86 (m, 3H). IR (neat, cmꢂ1): 2934, 1519,
1250, 1232, 1138, 1025. HRMS (ESI): [MþH]þ Calcd for C18H28NO2:
290.2120. Found: 290.2124.
4.26. Preparation of 4,40-(2-cyclopropylethane-1,1-
diyl)bis(1,2-dimethoxybenzene) (17)
4.26.1. Naphthalen-1-yl 2-cyclopropylacetate (29). Under Ar, to the
solution of 1-naphthol (1.6 g, 11.4 mmol) in CH2Cl2 (26 mL) were
added Et3N (3.0 mL, 22.2 mmol), EDCI hydrochloride (2.1 g,
11.1 mmol), and cyclopropylacetic acid (0.5 mL, 7.0 mmol) at 0 ꢁC
and stirred at rt for 10 h. The reaction mixture was poured into 2 M
HCl and extracted with CH2Cl2. The combined organic layers were
washed with saturated NaHCO3 solution and distillated water, and
then dried over anhydrous Na2SO4 followed by removing the sol-
vent under reduced pressure. The residue was purified by silica gel
column chromatography (hexane/AcOEt¼30/1–10/1) to give the
title compound 29 (719 mg, 43%) as a colorless oil. 1H NMR
4.24. Preparation of 4-(3-(cyclopropylmethoxy)propyl)-1,2-
dimethoxybenzene (12)
4.24.1. 3-(3,4-Dimethoxyphenyl)propan-1-ol (14). Under Ar, to the
solution of 3-(3,4-dimethoxyphenyl)propanoic acid (3.1 g,14.5 mmol)
in THF (2 mL) was added 1.07 M solution of BH3–THF complex in THF
(46 mL, 49 mmol) dropwise at 0 ꢁC and stirred at 30 ꢁC for 1.5 h.
Aqueous THF (THF/H2O¼1/1, 60 mL) was carefully added to the re-
action mixture at 0 ꢁC, and then K2CO3 was added. After separation
and extraction with Et2O, the organic layers were combined and dried
over anhydrous Na2SO4 followed by removing the solvent under
reduced pressure. The residue was purified by silica gel column
chromatography (hexane/AcOEt¼1/2) to give the title compound 14
(2.7 g, 95%) as a colorless oil.
(300 MHz, CDCl3) d 0.08–0.18 (m, 2H), 0.43–0.53 (m, 2H), 0.99–1.16
(m, 1H), 2.39 (d, J¼7.2 Hz, 2H), 7.05 (dd, J¼1.2, 7.5 Hz, 1H), 7.19–7.33
(m, 3H), 7.50 (d, J¼8.1 Hz, 1H), 7.59–7.75 (m, 2H). IR (neat, cmꢂ1):
3064, 3006, 1767, 1599, 1509, 1462, 1389, 1317, 1256. HRMS (FAB):
[MþNa]þ Calcd for C15H14O2Na: 249.0891. Found: 249.0886.
4.24.2. 4-(3-(Cyclopropylmethoxy)propyl)-1,2-dimethoxybenzene
4.26.2. 2-Cyclopropyl-1,1-bis(3,4-dimethoxyphenyl)ethanol
(12). Under Ar, to the suspension of t-BuOK (360 mg, 3.2 mmol) in
(30). Under Ar, to the solution of (3,4-dimethoxyphenyl)lithium

10630
H. Fujii et al. / Tetrahedron 65 (2009) 10623–10630
in THF (12 mL), which was prepared from 4-bromoveratrole
(1.5 mL, 10.4 mmol) and 1.6 M solution of n-BuLi in hexane
(6.3 mL, 10.1 mmol), was added the solution of compound 29
(1.04 g, 4.5 mmol) in THF (5 mL) dropwise at ꢂ78 ꢁC, and stirred
at the same temperature for 1 h and at rt for 21 h. The reaction
mixture was poured into saturated NaHCO3 solution and extrac-
ted with AcOEt. The combined organic layers were washed with
distillated water and brine, and then dried over anhydrous
Na2SO4 followed by removing the solvent under reduced pres-
sure. The residue was purified by silica gel column chromatog-
raphy (hexane/AcOEt¼3/1) to give the title compound 30
(917 mg, 57%) as a colorless oil. 1H NMR (300 MHz, acetone-d6)
HRMS (ESI): [MþNa]þ Calcd for C22H28NaO4: 379.1885. Found:
379.1874.
Acknowledgements
We acknowledge the Institute of Instrumental Analysis of Kita-
sato University, School of Pharmacy for its facilities. We also ac-
knowledge Grant-in-Aid for Scientific Research (C) (19590105) and
the Uehara Memorial Foundation for financial support.
References and notes
d
ꢂ0.02–0.07 (m, 2H), 0.27–0.37 (m, 2H), 0.68–0.83 (m, 1H), 2.21
1. (a) Freifelder, M. Practical Catalytic Hydrogenation; Wiley & Sons: New York, NY,
1971; p 254–530; (b) Newham, J. Chem. Rev. 1962, 63, 123; (c) Wong, H. N. C.;
Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165.
2. For recent examples: (a) Harmata, M.; Rashatasakhon, P. Org. Lett. 2000, 2, 2913;
(b) Harrowven, D. C.; Lucas, M. C.; Howes, P. D. Tetrahedron 2001, 57, 9157; (c)
Mehta, G.; Murthy, A. S. K.; Umarye, J. D. Tetrahedron Lett. 2002, 43, 8301; (d)
Karimi, S.; Tavares, P. J. Nat. Prod. 2003, 66, 520; (e) Taber, D. F.; Frankowski, K. J. J.
Org. Chem. 2005, 70, 6417; (f) Harmata, M.; Rashatasakhon, P.; Barnes, C. L. Can. J.
Chem. 2006, 84, 1456; (g) Taber, D. F.; Tian, W. J. Org. Chem. 2008, 73, 7560.
3. For recent examples: (a) Robl, J. A.; Cimarusti, M. P.; Simpkins, L. M.; Brown, B.;
Ryono, D. E.; Eileen Bird, J.; Asaad, M. M.; Schaeffer, T. R.; Trippodo, N. C. J. Med.
Chem. 1996, 39, 494; (b) Hendrata, S.; Bennett, F.; Huang, Y.; Sannigrahi, M.;
Pinto, P. A.; Chan, T.; Evans, C. A.; Osterman, R.; Buevich, A.; McPhail, A. T.
Tetrahedron Lett. 2006, 47, 6469; (c) Irie, O.; Yokokawa, F.; Ehara, T.; Iwasaki, A.;
Iwaki, Y.; Hitomi, Y.; Konishi, K.; Kishida, M.; Toyao, A.; Masuya, K.; Gunji, H.;
Sakaki, J.; Iwasaki, G.; Hirao, H.; Kanazawa, T.; Tanabe, K.; Kosaka, T.; Hart, T. W.;
Hallett, A. Bioorg. Med. Chem. Lett. 2008, 18, 4642.
4. For recent other examples: (a) Kozhushkov, S. I.; Kostikov, R. R.; Molchanov, A.
P.; Boese, R.; Benet-Buchholz, J.; Schreiner, P. R.; Rinderspacher, C.; Ghiviriga, I.;
de Meijere, A. Angew. Chem., Int. Ed. 2001, 40, 180; (b) de Meijere, A.; von
Seebach, M.; Zo¨llner, S.; Kozhushkov, S. I.; Belov, V. N.; Boese, R.; Haumann, T.;
Benet-Buchholz, J.; Yufit, D. S.; Howard, J. A. K. Chem.dEur. J. 2001, 7, 4021; (c)
Carrasco, H.; Foces-Foces, C.; Pe´rez, C.; Rodrı´guez, M. L.; Martı´n, J. D. J. Am.
Chem. Soc. 2001, 123, 11970; (d) Fo¨hlisch, B.; Bakr, D. A.; Fischer, P. J. Org. Chem.
2002, 67, 3682; (e) Anderson, J. E.; de Meijere, A.; Kozhushkov, S. I.; Lunazzi, L.;
Mazzanti, A. J. Am. Chem. Soc. 2002, 124, 6706; (f) Kozhushkov, S. I.; Yufit, D. S.;
Boese, R.; Bla¨ser, D.; Schreiner, P. R.; de Meijere, A. Eur. J. Org. Chem. 2005, 1409;
(g) Li, W. Z.; Yang, Y. Org. Lett. 2005, 7, 3107; (h) Kuethe, J. T.; Zhao, D.; Hum-
phrey, G. R.; Journet, M.; McKeown, A. E. J. Org. Chem. 2006, 71, 2192.
5. Fujii, H.; Osa, Y.; Ishihara, M.; Hanamura, S.; Nemoto, T.; Nakajima, M.; Hasebe,
K.; Mochizuki, H.; Nagase, H. Bioorg. Med. Chem. Lett. 2008, 18, 4978.
6. pKa values: acetic acid: 4.76, trifluoroacetic acid: ꢂ0.6, methanesulfonic acid:
ꢂ1.9, perchloric acid: ꢂ5.0, hydrochloric acid: ꢂ8, hydrobromic acid: ꢂ9, hy-
droiodic acid: ꢂ10 Miller, A. In Writing Reaction Mechanisms in Organic Chem-
istry; Academic Press: San Diego, 1992; pp 35–42.
(d, J¼6.3 Hz, 2H), 2.84 (s, 1H), 3.75 (s, 6H), 3.77 (s, 6H), 6.84 (d,
J¼8.4 Hz, 2H), 6.99 (dd, J¼2.1, 8.4 Hz, 2H), 7.15 (d, J¼2.1 Hz, 2H). IR
(neat, cmꢂ1): 3519, 3000, 2935, 2835, 1604, 1590, 1514, 1464, 1412,
1329, 1256, 1141, 1027, 763. HRMS (ESI): [MþNa]þ Calcd for
C21H26NaO5: 381.1677. Found: 381.1678.
4.26.3. 4,40-(2-Cyclopropylethane-1,1-diyl)bis(1,2-dimethoxy-
benzene) (17). To the solution of compound 30 (105 mg, 0.3 mmol)
in MeOH (3 mL) was added 10% Pd/C (64 mg) and stirred at rt for
36 h under H2. After removing the catalyst by filtration, the filtrate
was concentrated under reduced pressure. The residue was purified
by preparative TLC (hexane/AcOEt¼2/1) to give the title compound
17 (86 mg, 86%) as a colorless oil. 1H NMR (300 MHz, CDCl3)
d 0.02–
0.11 (m, 2H), 0.35–0.44 (m, 2H), 0.53–0.68 (m, 1H), 1.88 (t, J¼7.4 Hz,
2H), 3.83 (s, 6H), 3.84 (s, 6H), 3.93 (t, J¼7.7 Hz, 1H), 6.70–6.84 (m,
6H). IR (neat, cmꢂ1): 2998, 2932, 2834, 1589, 1515, 1464, 1415, 1260,
1144, 1029. HRMS (FAB): [M]þ Calcd for C21H26O4: 342.1831. Found:
342.1832.
4.27. 4,40-(3-Cyclopropylpropane-1,1-diyl)bis(1,2-
dimethoxybenzene) (19)
4.27.1. Naphthalen-1-yl 3-cyclopropylpropanoate (31). To the solu-
tion of ethyl chloroformate (0.3 mL, 3.1 mmol) and Et3N (2 mL,
14.3 mmol) in CH2Cl2 (10 mL) was added 3-cyclopropylpropanoic
acid (288 mg, 2.5 mmol) at 0 ꢁC and stirred at the same tempera-
ture for 1 h. To the reaction mixture was added the solution of 1-
naphthol (880 mg, 6.1 mmol) and stirred at rt for 15 h. The reaction
mixture was poured into 1 M HCl solution and extracted with
CH2Cl2. The combined organic layers were washed with distillated
water and dried over anhydrous Na2SO4, followed by removing the
solvent under reduced pressure. The residue was purified by silica
gel column chromatography (hexane/AcOEt¼5/1) to give the title
compound 31 (491 mg, 81%) as a colorless oil. 1H NMR (300 MHz,
7. Hydroiodic acid or iodine reportedly functioned as a rhodium or palladium
catalyst poison, respectively; (a) Freedman, L. D.; Doak, G. O.; Petit, E. L. J. Am.
Chem. Soc. 1955, 77, 4262; (b) Caddock, P. D.; Joyner, R. W.; Williams, B. P. Catal.
Lett. 1989, 2, 27.
8. MaloneyHuss, K. E.; Portoghese, P. S. J. Org. Chem. 1990, 55, 2957.
9. (a) Gates, M.; Montzka, T. A. J. Med. Chem. 1964, 7, 127; (b) Osa, Y.; Ida, Y.; Yano,
Y.; Furuhata, K.; Nagase, H. Heterocycles 2006, 69, 271.
10. (a) Gould, E. S. Mechanism and Structure in Organic Chemistry; Henry Holt: New
York, NY, 1959; p 561–617; (b) Richey, H. G., Jr. In Carbonium Ions; Olah, G. A.,
Schleyer, P. R., Eds.; John Wiley & Sons: Canada, 1972; Vol. III, pp 1201–1294; (c)
Olah, G. A.; Prakash Reddy, V.; Surya Prakash, G. K. Chem. Rev. 1992, 92, 69.
11. Nagase, H.; Yamamoto, N.; Nemoto, T.; Yoza, K.; Kamiya, K.; Hirono, S.; Momen, S.;
Izumimoto, N.; Hasebe, K.; Mochizuki, H.; Fujii, H. J. Org. Chem. 2008, 73, 8093.
12. It is known that treatment of aryl cyclopropylmethyl ether with hydrochloric
acid in methanol under reflux conditions resulted in cleavage of cyclo-
propylmethyl ether bond; (a) Wuts, P. G. M.; Greene, T. W. In Greene’s Protective
Groups in Organic Synthesis; John Wiley & Sons: New Jersey, 2007; p 390; (b)
Nagata, W.; Okada, K.; Itazaki, H.; Uyeo, S. Chem. Pharm. Bull. 1975, 23, 2878.
13. Generally speaking, the cyclopropylmethyl tosylate is solvolyzed 106 faster than
isobutyl tosylate because the tosylate ion could be solvolitically eliminated from
the cyclopropylmethyl tosylate to afford the very stable cyclopropylcarbinyl
cation. In Mechanism and Theory in Organic Chemistry, 3rd ed.; Lowry, T. H.,
Richardson, K. S., Eds.; Harper & Row: New York, NY, 1987; p 425–515.
14. The reduction of cyclopropylmethylamine 9a (50 mg) gave 49 mg of crude
product. 1H NMR spectra of crude product showed decrease in signals indicating
cyclopropane ring, but value of integral stemmed from aromatic protons was
smaller than the theoretical value. Aliphatic methoxy signal (around 3.4 ppm)
and increase invalue of integral derived from aliphatic protons(around1–2 ppm)
were also observed. Taken together, these observations strongly suggest that
reduction of benzene ring would proceed concomitantly.
CDCl3)
d 0.12–0.28 (m, 2H), 0.46–0.64 (m, 2H), 0.81–0.99 (m, 1H),
1.79 (q, J¼7.5 Hz, 2H), 2.86 (t, J¼7.5 Hz, 2H), 7.27 (dd, J¼1.1, 7.4 Hz,
1H), 7.45–7.57 (m, 3H), 7.75 (d, J¼8.4 Hz, 1H), 7.84–7.94 (m, 2H). IR
(neat, cmꢂ1): 3068, 3001, 2925, 1760, 1509, 1390, 1358, 1258, 1224,
1115, 1014, 796, 770. HRMS (FAB): [MþH]þ Calcd for C16H17O2:
241.1229. Found: 241.1230.
4.27.2. 4,40-(3-Cyclopropylpropane-1,1-diyl)bis(1,2-dimethox-
ybenzene) (19). Compound 19 was synthesized from compound 31
in 47% yield according to the synthetic method of compound 17 from
29. A colorless oil. 1H NMR (300 MHz, CDCl3)
d
ꢂ0.09–0.01 (m, 2H),
0.30–0.48 (m, 2H), 0.60–0.76 (m,1H),1.10–1.22 (m, 2H), 2.02–2.18 (m,
2H), 3.77–3.87 (m, 1H), 3.83 (s, 12H), 6.71–6.83 (m, 6H). IR (neat,
cmꢂ1): 2997, 2931, 2834, 1589, 1515, 1463, 1415, 1257, 1143, 1029.