On the formation of a side product with hexahydroaporphine-like structure in the Grewe cyclization of dextromethorphan

Article abstract of DOI:10.1007/s11164-016-2723-4

Factors leading to the formation of a hexahydroaporphine-like cyclizing side product were studied systematically for the first time and the ratio of this side product was controlled effectively. To understand better the electronic effect of substrates on the formation of side products, different 1-benzyloctahydroisoquinolines with substituted groups on nitrogen or benzene ring were compared. A plausible mechanism of cyclizing reaction was proposed, and key intermediates as well as transition states were analyzed using DFT calculations.

Full text of DOI:10.1007/s11164-016-2723-4

Res Chem Intermed (2017) 43:1689–1708
DOI 10.1007/s11164-016-2723-4
On the formation of a side product with hexahy-
droaporphine-like structure in the Grewe cyclization
of dextromethorphan
Qiao Zhao1 Kai Zhao1 Sheng-ying Wu1,2,3,4
•
•
•
Bo-xue Tian2 Leif A. Eriksson3,4 Li-min Wang1
Na An4 Zhong-zhu Long4 Shui-hong Cai4
•
•
•
•
•
Received: 15 April 2016 / Accepted: 31 August 2016 / Published online: 16 September 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract Factors leading to the formation of a hexahydroaporphine-like cyclizing
side product were studied systematically for the first time and the ratio of this side
product was controlled effectively. To understand better the electronic effect of
substrates on the formation of side products, different 1-benzyloctahydroisoquino-
lines with substituted groups on nitrogen or benzene ring were compared. A plau-
sible mechanism of cyclizing reaction was proposed, and key intermediates as well
as transition states were analyzed using DFT calculations.
Keywords Grewe cyclization Á Dextromethorphan Á Hexahydroaporphine-like side
product Á DFT calculation
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2723-4)
contains supplementary material, which is available to authorized users.
&
Li-min Wang
wanglimin@ecust.edu.cn
Leif A. Eriksson
leif.eriksson@chem.gu.se
1
2
3
4
Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University
of Science and Technology, 130 Meilong Road, Shanghai 200237, People’s Republic of China
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California,
San Francisco, CA 94158, USA
¨
Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Goteborg,
Sweden
Dongyue Pharma Ltd. Co., Shanghai, People’s Republic of China
123

1690
Q. Zhao et al.
Introduction
Dextromethorphan [(?)-3-methoxy-17-methy-(9a,13a,14a)-morphinan, DXM], a
non-narcotic morphinan derivative, has been widely used as an antitussive for
almost 50 years and has recently attracted considerable attention because of its
anticonvulsant and neuroprotective properties [1–5]. Its application in medicine
ranges from pain relief to psychological applications. Dextromethorphan as an oral
drug is available as lozenges, capsules, tablets, and cough syrups, in a variety of
prescription medications and over-the-counter cough and cold remedies.
The key reaction in the preparation of DXM is Grewe cyclization. Grewe [6–8]
achieved the first cyclization transformation, as postulated by Robinson [9–13] and
Schopf [14–17], of 1-benzylisoquinoline derivatives into compounds with a ring
system of morphine alkaloids with 65 % yield [6]. Subsequently, Schinider [18],
Koelsch [19], Ochiai [20, 21], Sasamoto [22], Meyers [23], and Tian [24] chose N-
methyl-1-benzylisoquinoline derivatives as precursors to react with phosphoric acid,
hydrochloric acid, or hydrobromic acid at higher temperatures (130–160 °C or
reflux in phosphoric acid), where the corresponding N-methylmorphinan or
3-hydroxy-N-methylmorphinan was obtained as the major product, along with
several side products. Since the discovery by Leimgruber et al. [25] that N-formyl
derivatives of octahydroisoquinoline in concentrated phosphoric acid cyclizes to
classical morphinans almost 400 times faster than N-methyl derivatives, another
route with N-formyl-1-benzylisoquinoline derivatives as precursors in the cycliza-
tion reactions to afford the corresponding morphinans in higher yields has been
employed [26–33].
Fadnavis and co-workers offered an improved cyclization procedure to achieve
N-formylated morphinan in higher purity using solid acid ([98 % purity by HPLC)
[34]. However, when we repeated the experiment described in this literature,
significant amounts (4 %) of unidentified side product was discovered by HPLC
analysis. To elucidate the structure of this side product, the side product was
deformylated, and the deformylated side product was isolated by preparative HPLC,
NMR spectroscopy and LC–MS of the deformylated side product showed that this
side product was (6a,S)-10-methoxy-2,3,3a,3a’,4,5,6,6a,7,11b-decahydro-1H-diben-
zo[de,g]-quinolone, 3–2 (Scheme 1; see also Supporting Information). This
compound, formed as a side product in the cyclization of 1-benzyloctahydroiso-
quinolines, was first proven to possess the apomorphine-like structure by Hoffmann
degradation [35]. It was later isolated in the form of hydrobromide or d-tartrate by
Sawa et al. and proven from the degradation products to have the hexahydroapor-
phine structure [36].
Scheme 1 Deformylation of
the hexahydroaporphine-like
side product
123

On the formation of a side product with…
1691
Two mechanistic pathways have been outlined for the formation of this
hexahydroaporphine-like side product: one by olefinic isomerization in the Grewe
cyclization reaction, [25] the other through a Wagner-Meerwein type rearrangement
[37–41]. To reduce the amount of side product, we investigate various cyclization
conditions and discuss the electronic effect of 1-benzyloctahydroisoquinolines with
substituents on the nitrogen or the benzene ring on the cyclizing reaction and side
product formation, respectively. It is necessary to pointed out that apart from the
hexahydroaporphine side product discussed in this paper, another potential side
product may be demethylated product [34]. A possible mechanism of the cyclization
reaction is also presented.
Results and discussion
Based on previous reports, [25] (?)-1-(p-methoxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-
octahydroisoquinoline (1a) was chosen as the precursor to react with a variety of
Brønsted acids in order to find the optimal cyclization reagent (Table 1). The initial
experiment was carried out at 10 °C in CF3SO3H and the reaction was completed
quickly with the side product in significant amounts (18 % yield) detected by HPLC
analysis (Table 1, entry 1). When the reaction was performed in typical sulfonic
acids (H2SO4, CH3SO3H, Eaton’s reagent [42]), it took longer time to complete, but
was accompanied by a relatively smaller amount of the side product (Table 1,
entries 2–4). When phosphoric acids were employed as cyclization reagent
(Table 1, entries 6–7), we observed a higher purity of N-formylated product (2a-
1), especially for the reaction in anhydrous phosphoric acid providing the side
product (2a-2) in less than 4 %. However, carboxylic acids, solid acids, and
hydrogen acids failed to induce the cyclizing reaction (Table 1, entries 5, 8–14).
Further variations of the reaction conditions (temperature, concentration, and
amounts of phosphoric acid) revealed that 60 °C was suitable for this reaction
(Table 2, entries 1–4); 93 % phosphoric acid (5:1 V/W) was the best in terms of
price and side product ratio (Table 2, entries 5–11). Interestingly, in toluene, the
reaction proceeded smoothly, but when EtOH, THF, DMF, or DCM was employed,
respectively, cyclization was distinctly inhibited rather than promoted (Table 2,
entries 12–16). Moreover, the addition of Lewis acid was less effective (Table 2,
entries 17–22). Thus, the optimized reaction conditions for Grewe cyclization of 1a
involved a 93 % concentration of phosphoric acid (5:1 V/W) in air at 60 °C and
without additional organic solvent or Lewis acid.
After optimizing the reaction conditions, we investigated the dependence of the
precursor on the cyclization reaction by employing a variety of 1-benzyloctahy-
droisoquinolines with substituents on the nitrogen and the benzene ring of the
substrate, respectively (Table 3). Remarkably, (?)-1-(p-methoxybenzyl)-2-methyl-
1,2,3,4,5,6,7,8-octahydroiso-quinoline hardly converted to the corresponding mor-
phinan under optimized reaction conditions, which could be attributed to high
electron density at the nitrogen (Table 3, entry 2). As electron-withdrawing groups
drastically reduce the basicity of the nitrogen atom, [26, 27] we speculated that N-
acyl or N-sulfonyl 1-benzyloctahydroisoquinolines with electron-rich substituents
123

1692
Q. Zhao et al.
Table 1 Screening of Brønsted acids in Grewe cyclization
Entry
Brønsted acids
Time (h)
Conversion
of 1a (%)
Purity
Ratio
(2a-1/2a-2)
2a-1 (%)
2a-2 (%)
1a
2a
3
CF3SO3H
H2SO4
1 min
24
6
100
82
54.2
70.5
84.3
83.0
3.2
17.7
5.0
75.4/24.6
93.4/6.6
87.9/12.1
88.4/11.6
91.4/8.6
93.5/6.5
96.2/3.8
–
CH3SO3H
Eaton’s reagent
TsOH
100
100
4
11.6
10.9
0.3
4
5b
4
48
17
32
32
32
48
48
48
48
24
6
PPA
100
100
\2
12
89.9
91.7
Trace
7.0
6.3
7
H3PO4 (100 %)
CH3PO3H2
H3PO3
3.6
N.Dc
8b
9b
10
11
12
13
14d
0.5
93.3/6.7
–
CF3COOH
HCOOH
\2
\2
\2
52
Trace
N.D
N.D
15.4
Trace
N.D
N.D
N.D
1.1
–
CH3COOH
HCl (37 %)
HBr solution (33 %)
–
93.3/6.7
–
100
Trace
Unless otherwise specified, the reaction was carried out in the presence of 1a (1.0 g), Brønsted acids
(5.0 mL) at 60 °C. Conversion, purity and ratio were based on HPLC analysis
a
Reaction temperature was 10 °C
Solid acid was dissolved in acetic acid
b
c
N.D. = not detected
d
Hydrogen bromide was dissolved in acetic acid and (?)-N-formyl-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-
octahydroisoquinoline was the major product
might increase the yield (Table 3, entries 3–9). Interestingly, a variation of
substituents such as acetyl, propionyl, ethoxycarbonyl, and trifluoroacetyl groups on
the nitrogen did not affect the ratio of the side product (Table 3, entries 3–6).
Unexpectedly,
(?)-N-trichloroacetyl-1-(p-methoxybenzyl)octahydroisoquinoline
produced the corresponding cyclization product (2g) in considerably lower isolated
yield even though the amount of side product was very little. For the structures with
sulfonyl groups on the nitrogen, the reaction proceeded well (Table 3, entries 8–9).
The best overall performance was obtained with the trifluoromethylsulfonyl
substituent, which gave 2i in 87 % yield with the lowest amount of side product.
In addition, structures with different substituent groups on the aromatic ring were
investigated (Table 3, entries 1, 10–14). In general, the reactivity of the substrates
123

On the formation of a side product with…
1693
Table 2 Screening of other conditions in Grewe cyclization
Entry Acid
Additive
Sol-vent Conversion Purity
of 1a (%)
Ratio
(2a-1/2a-2)
2a-1 2a-2
(%) (%)
1a
2
3b
4c
5
H3PO4 (100 %)
–
–
90
83.6 2.7
91.7 3.6
91.3 4.6
87.3 5.2
60.1 2.1
80.2 1.9
90.3 2.3
89.6 2.5
92.3 2.4
91.5 2.4
86.5 2.7
N.Df N.D
N.D N.D
N.D N.D
49.0 0.9
89.4 2.3
88.4 2.6
87.6 2.6
87.4 2.6
88.4 2.6
87.3 2.6
89.1 2.7
96.8/3.2
96.2/3.8
95.2/4.8
94.4/5.6
96.6/3.4
97.7/2.3
97.6/2.4
97.2/2.8
97.5/2.5
97.4/2.6
97.0/3.0
–
H3PO4 (100 %)
H3PO4 (100 %)
H3PO4 (100 %)
H3PO4 (85 %)
–
–
100
100
100
65
–
–
–
–
–
–
6
H3PO4 (90 %)
–
–
87
7
H3PO4 (93 %)
–
–
100
100
100
100
98
8
H3PO4 (95 %)
–
–
9
H3PO4 (93 %): 1a = 9:1
H3PO4 (93 %): 1a = 7:1
H3PO4 (93 %): 1a = 3:1
H3PO4 (93 %)
–
–
10
11
12d
13
14
15
16
17e
18
19
20
21
22
–
–
–
–
–
EtOH
\1
\1
\1
52
H3PO4 (93 %)
–
THF
–
H3PO4 (93 %)
–
DMF
–
H3PO4 (93 %)
–
DCM
98.2/1.8
97.5/2.5
97.1/2.9
97.3/2.9
97.1/2.9
97.1/2.9
97.1/2.9
97.1/2.9
H3PO4 (93 %)
–
Toluene
100
100
100
100
100
100
100
H3PO4 (93 %)
Cu(OAc)2ÁH2O
Ni(OAc)2Á4H2O
Co(OAc)2Á4H2O
Zn3(PO4)2
FePO4
–
–
–
–
–
–
H3PO4 (93 %)
H3PO4 (93 %)
H3PO4 (93 %)
H3PO4 (93 %)
H3PO4 (93 %)
AlPO4
The reaction was carried out in the presence of 1a (1.0 g) and corresponding concentration phosphoric
acids (5.0 mL) at 60 °C for 32 h. Conversion, purity, and ratio were based on HPLC analysis
a
The reaction was carried out at 50 °C
70 °C
b
c
80 °C, respectively
The reaction was carried out in the presence of 1a (0.5 g), H3PO4 (93 %, 2.5 mL), and solvent
d
(2.5 mL) at 60 °C for 32 h
e
The reaction was carried out in the presence of 1a (0.5 g), H3PO4 (93 %, 2.5 mL), and Lewis acid
(5 mol %) at 60 °C for 32 h
f
N.D. = not detected
123

1694
Q. Zhao et al.
Table 3 Acid-catalyzed cyclization of N-acyl-1-benzyloctahydroisoquinolines
Entry R1
R2
Time (h) Product 2a-2m Yielda (%) Ratio (2-1/2-2)
1
CHO
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OH
32
32
12
12
12
8
2a
2b
2c
2d
2e
2f
90
N.Db
85
84
86
93
55
70
87
87
89
91
89
57
97.6/2.5
–
2
CH3
3
CH3CO
CH3CH2CO
EtOCO
CF3CO
CCl3CO
CH3SO2
CF3SO2
CHO
98.6/1.4
98.6/1.4
98.4/1.6
98.4/1.6
99.6/0.4
98.7/1.3
[99.9/0.1
96.9/3.0
97.9/2.1
98.3/1.7
98.9/1.1
93.6/6.4
4
5
6
7
72
4
2g
2h
2i
8
9
120
12
32
32
24
96
10
11
12
13
14
2j
CHO
OCH2CH3
OCH2CH2CH3
CH3
2k
2l
CHO
CHO
2m
2n
CHO
Cl
Reaction was carried out in the presence of 1 (1.0 g), H3PO4 (93 %, 5.0 mL) at 60 °C. Ratio was based on
HPLC analysis
a
Isolated yield
b
N.D. = not detected
with an electron-donating group (e.g. OH, OMe, OEt, OCH2CH2CH3, Me) on the
benzene ring was higher than that with an electron-withdrawing group (e.g. Cl), and
morphinan with chlorine on the para-position resulted in 6.4 % cyclization side
product while the product with methyl substituent was associated with only of 1.1 %
undesired side product based on HPLC analysis.
On the basis of reported work [34, 38–42] and the current experiments, a
plausible mechanism is proposed with model substrate 1a as outlined in Scheme 2.
As the aldehyde group on the nitrogen is essential for the reaction, and
N-methylated substrate won’t react with any of the acid, the initial protonation
site is probably at the aldehyde oxygen. First, the reaction of N-formyl
benzylisoquinoline (1a) is initiated by addition of the phosphoric acid to generate
the highly reactive quaternary ammonium intermediate I0. Intermediate I0 reacts
further with phosphoric acid to give the carbocation intermediate I1, which may
follow two pathways. In pathway a, the desired product 2a-1 is formed directly by
nucleophilic attack from the aromatic ring. In pathway b, carbocation I2 is produced
123

On the formation of a side product with…
1695
Scheme 2 A plausible cyclization mechanism induced by phosphoric acid
by ortho-hydrogen migration. Subsequent to the hydride transfer step, the resulting
intermediate I2 undergoes [1–8] –H migration once again forming an unstable car-
bocation (I4), and the aromatic ring is attacking the carbocation affording side
product 2a-2.
However, it was difficult to capture the cyclization intermediates experimentally.
To confirm our hypothesis further, DFT calculations were performed to explore the
energies of the key intermediates and transition states of both reaction pathways
(Scheme 2 and Figs. 1, 2). According to our calculations, in pathway b, the rate
limiting step is the conversion from I2 to I5, the energy barrier for the conversion
from I2 to I5 is 21.0 kcal/mol, while the energy barrier for the conversion from I1 to
I3 (rate limiting step in pathway a) is only 5.0 kcal/mol. These results suggest that
pathway a is kinetically more favorable than pathway b. Therefore, under low
temperature conditions, the rate determining step for byproduct formation (from I2
to I4) should not be easily passed, and the side product formation effectively
123

1696
Q. Zhao et al.
24
22
20
18
16
14
12
10
8
TS4
Pathway a
Pathway b
TS5
21.0
TS3
10.0
TS2
I5
6
2a-2
4
5.0
I2
I3
2
0
I1
-2
-4
-6
2a-1
Reaction Coordinates
Fig. 1 Comparison of relative free energies for the product 2a-1 and side product 2a-2
22
TS7
I2
20
18
16
14
12
10
8
3.6
I2
I2
I2
TS7
I1
I1
I1
I1
TS6
TS6
TS7
2.2
TS7
3.2
2.3
16.2
6
H3PO4
13.7
CF3SO3H
CF3COOH
HCl
4
2
I0
0
-2
Reaction Coordinates
Fig. 2 Reaction barrier profiles for different acids
controlled. This is consistent with our experimental data (Table 2, entries 1–4). In
addition, we also compared the energies of the final products of both pathways. As
expected, the energy of the main product 2a-1 is much lower than that of the side
product 2a-2 (-5.3 vs. ?4.3 kcal/mol).
Motivated by our computational results, experiments at lower temperature
(40 °C) was employed in order to further reduce the amount of the side product, and
the solid acid Amberyst 15 was used as the catalyst in order to increase the reaction
performance at low temperature according to Fadnavis et al. [34] (Table 4). After
optimization of the phosphoric acid concentration, we obtained the best reaction
conditions by using phosphoric acid (98 %) as the cyclization acid, reactant ratio of
123

On the formation of a side product with…
1697
Table 4 Grewe cyclization reaction conducted at 40 °C
Entry Proton acid
Additive
Time Conversion Purity
(h)
Ratio
(2a-1/2a–2)
of 1a (%)
2a-1 2a-2
(%)
(%)
1
2
3
H3PO4 (93 %)
H3PO4 (98 %)
Amberyst 15 (50 %) 70
Amberyst 15 (50 %) 34
88
100
100
84.6
95.0
94.1
1.4
1.9
2.3
98.4/1.6
98.0/2.0
97.6/2.4
H3PO4 (100 %) Amberyst 15 (50 %) 34
Reaction was carried out in the presence of 1a (1.0 g), H3PO4 (5.0 mL), Amberlyst 15 (50 %) at 40 °C.
Conversion, purity, and ratio were based on HPLC analysis
Scheme 3 Two pathways of the product and side product
5:1 (V/W), an addition of Amberlyst 15 (50 %), and performed the reaction in air at
40 °C for 34 h. This resulted in a cyclization product of 95 % purity concomitantly
with 2.0 % of the side product.
To understand why H3PO4 is better than the other acids in terms of catalytic
efficiency, DFT calculations were also employed to evaluate the reaction barriers of
the proton transfer steps of different acids. In our calculations, acids first protonate
the keto oxygen (I0). Different acids then function as proton shuttles to mediate the
proton transfer from the hydroxyl to the olefin carbon (Scheme 3, Table 5). We
found that the reaction barriers for H3PO4 and CF3SO3H were lower than those of
CF3COOH and HCl (13.7 vs 16.2 kcal/mol; Table 5), which is consistent with our
experimental data listed in Table 1. After proton transfer, 1,2-hydride shift can
occur to give I2, which is the precursor of the side product. In principle, a higher
reaction barrier of this step should give lower side product ratio. We found that the
reaction barrier in presence of H3PO4 (17.1 kcal/mol) is higher than those using
CF3COOH (16.1 kcal/mol) or CF3SO3H (15.4 kcal/mol), implying that H3PO4
should give lower side product ratio. For HCl, although the barrier of the 1,2-
hydride shift step is high, the barrier for the proton transfer is also high, which leads
to low conversion rate (Table 5). Overall, the calculations are fully consistent with
our experimental findings.
123

1698
Q. Zhao et al.
Table 5 Reaction barriers of TS1 and TS2 for different acids
Acid
I0
TS6
I1a
TS7
I2a
H3PO4
0.0
0.0
0.0
0.0
13.7
13.7
16.2
16.2
14.9
13.1
12.9
16.6
17.1
15.4
16.1
20.2
17.3b
16.3b
16.0
CF3SO3H
CF3COOH
HCl
20.3b
Relative energy, in kcal/mol
a
Intermediates in presence of the acid
b
Free energies of I2 become higher than TS2 after adding the Gibbs corrections
Conclusions
In summary, we have provided the first systematic investigation of the leading
factors to form the hexahydroaporphine-like cyclizing side product in Grewe
cyclization. In this case, the ratio of the side product was controlled effectively
(2.0 %) with the corresponding product (N-formyl-3-methoxymorphinan) in 95 %
purity. Furthermore, it is suggested that the electronic effect of 1-benzyloctahy-
droisoquinolines with different substituent groups on the nitrogen and the benzene
ring has great influence on the amount of cyclizing side product, among which N-
trifluoromethylsulfonyl benzylisoquinoline generated the corresponding side pro-
duct in the lowest ratio (\0.1 %). Finally, a novel cyclization mechanism is
proposed based on the experimental results and DFT calculations, which supports
and explains the rationalization of the observed cyclization reaction.
Experimental section
General
Unless otherwise noted, all the reactions were run under air in oven-dried parallel
reaction tube and were heated on hot plates to an internal thermometer in Aplus
PTC07B. All the solvents and reagents were purchased from the suppliers and used
1
without additional purification. The H NMR spectra were recorded at 400 MHz
and the 13C NMR spectra were recorded at 100/400 MHz in CDCl3 or d4-MeOH
with TMS as internal standard. All shifts were given in ppm. All coupling constants
(J values) were reported in Hertz (Hz). Column chromatography was performed on
silica gel 200–300 mesh. Melting points were uncorrected and were obtained on a
Laboratory Devices Mel-Temp II instrument.
HPLC analysis
Column Cadenza CD-18 (250 mm 9 4.6 mm, 3 lm), Imtakt, Japan; Injection
volume 1.0 lL. Detection wavelength and column temperature were 280 nm and
30 °C, respectively. At the start of analysis the mobile phase was consisted of 30 %
acetonitrile -70 % water containing 0.1 % H3PO4. This was changed to 80 %
123

On the formation of a side product with…
1699
acetonitrile -20 % water containing 0.1 % H3PO4 in 45 min with total flow rate of
1.0 mL/min. Side product 3–2 was purified by America semipreparative high
performance liquid chromatography (Gilson 281) and analyzed by Agela MP C18
(250 mm 9 4.6 mm, 5.0 lm), Shimadzu LC-20AB.
Procedure for preparation of (6a,S)-10-methoxy-2,3,3a,3a1,4,5,6,6a,7,11b-
decahydro-1H-dibenzo[de,g]quinolone (3–2)
The crude product of Grewe Cyclization of 1a 0.5 g was added to the methanol
solution of NaOH (0.4 g NaOH in 10 mL MeOH), the mixture was refluxed for 5 h,
solvent was evaporated under reduced pressure. The crude product was purified by
semipreparative high performance liquid chromatography. 1H NMR (400 MHz, d4-
MeOH) d: 1.08–1.15 (m, 1H), 1.23–1.30 (m, 1H), 1.38–1.60 (m, 5H), 1.66–1.71 (m,
1H), 1.81–1.90 (m, 1H), 1.98 (d, J = 12.4 Hz, 1H), 2.46 (d, J = 12.4 Hz, 1H),
2.72–2.75 (m, 1H), 2.96–2.99 (m, 1H), 3.02–3.11 (m, 1H), 3.24–3.29 (m, 1H), 3.69
(s, 1H), 3.78 (s, 3H), 3.82 (m, 1H), 6.83 (dd, J = 2.0 Hz, 8.8 Hz, 1H), 6.88 (d,
J = 2.0 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H); 13C NMR (400 MHz, d4-MeOH) d:
20.3, 25.0, 28.2, 28.4, 29.6, 32.4, 36.3, 38.2, 41.0, 51.4, 54.3, 110.9, 112.0, 123.9,
130.2, 136.6, 158.9. LC–MS (ESI) calcd for C17H24NO?([M ? H]?): 258.2, found:
258.2.
General procedure for preparation of (1)-N-formyl-1-(4-substituted)
benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (1a, 1m-n)
(?)-Octabase-mandelate salt (15.0 g) was added to solution of 10 % sodium
hydroxide (100 mL), and the mixture was stirred for 0.5 h. After that, the mixture
was extracted with DCM (100 mL 9 3), washed with brine, and dried over
anhydrous Na2SO4. The solvent was evaporated and concentrated to dryness to
afford (?)-1-(4-substituted)benzyl-1,2,3,4,5,6,7,8- octahydroisoquinoline.
(?)-1-(4-substituted)benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (19.5 mmol)
was added to a mixture of toluene (70 mL) and formic acid (29.25 mmol) in an
oven-dried flask equipped with a stir bar and water segregator. The mixture was
stirred at reflux until no water was separated. After cooling to room temperature,
water (50 mL) was added to the mixture, and the organic phase was separated. The
aqueous phase was extracted with toluene (50 mL 9 2), and the combined organic
layer was dried over anhydrous Na2SO4, filtered, and concentrated to dryness. The
crude material was purified by column chromatography with cyclohexane: ethyl
acetate (10:1–5:1) as eluent.
(?)-N-Formyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (1a) Pale-
yellow oil, yield: 95 %. 1H NMR (400 MHz, CDCl3) d: 1.66–1.69 (m, 4H),
1.81–1.93 (m, 4H), 2.08–2.26 (m, 2H), 2.60–2.67 (m, 0.6H), 2.80 (dd, J = 6.9 Hz,
14.1 Hz, 0.4H), 2.85–3.05 (m, 2 H), 3.30 (dd, J = 6.5 Hz, 13.2 Hz, 0.4H), 3.58 (d,
J = 10.1 Hz, 0.6H), 3.76 (s, 3H), 4.37 (dd, J = 6.5 Hz, 13.2 Hz, 0.6H), 4.67 (bs,
0.4H), 6.78–6.83 (m, 2H), 6.97–7.06 (m, 2H), 7.38 (s, 0.6H), 7.92 (s, 0.4H); 13C
NMR (100 MHz, CDCl3) d: 22.7, 22.8, 22.9, 27.6, 27.7, 29.7, 30.0, 30.1, 30.8, 33.3,
123

1700
Q. Zhao et al.
36.2, 37.4, 40.3, 53.2, 55.1, 60.7, 113.5, 114.0, 127.6, 127.8, 127.8, 128.8, 129.8,
129.9, 130.2, 130.4, 158.1, 158.3, 160.8, 161.0. HRMS (ESI) calcd for C18H24-
NO2?([M ? H]?): 286.1807, found: 286.1812.
(?)-N-Formyl-1-(p-methylbenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (1m) Pale-
yellow oil, yield: 92 %. 1H NMR (400 MHz, CDCl3) d: 1.64–1.93 (m, 8H),
2.06–2.21 (m, 2H), 2.28 (s, 3H), 2.64 (dd, J = 10.4 Hz, 13.6 Hz, 0.6H), 2.76 (dd,
J = 7.2 Hz, 14.0 Hz, 0.4H), 2.85–3.06 (m, 2H), 3.28 (dd, J = 6.8 Hz, 13.2 Hz,
0.4H), 3.59 (d, J = 10.0 Hz, 0.6H), 4.36 (dd, J = 6.8 Hz, 13.2 Hz, 0.6H), 4.69 (bs,
0.4H), 6.94 (d, J = 8.0 Hz, 1.3H), 7.03 (s, 1.3H), 7.07 (d, J = 8.0 Hz, 1.4H), 7.35
(s, 0.6H), 7.89 (s, 0.4H); 13C NMR (100 MHz, CDCl3) d: 21.1, 22.7, 22.8, 22.9,
27.7, 29.7, 30.0, 30.1, 30.9, 33.3, 36.8, 38.0, 40.3, 53.2, 60.7, 127.8, 128.8, 128.9,
129.1, 129.4, 134.7, 134.9, 135.7, 136.2, 160.8, 161.0. HRMS (ESI) calcd for
C18H24NO? ([M ? H]?): 270.1858, found: 270.1860.
(?)-N-Formyl-1-(p-chlorobenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline
(1n)
1
Pale-yellow oil, yield: 90 %. H NMR (400 MHz, CDCl3) d: 1.64–2.25 (m, 10H),
2.68 (dd, J = 10.4 Hz, 14.0 Hz, 0.6H), 2.80 (dd, J = 7.2 Hz, 14.0 Hz, 0.4H),
2.84–3.08 (m, 2H), 3.33 (dd, J = 7.2 Hz, 13.2 Hz, 0.4H), 3.60 (d, J = 10.4 Hz,
0.6H), 4.37 (dd, J = 7.2 Hz, 13.2 Hz, 0.6H), 4.70 (bs, 0.4H), 7.01 (d, J = 8.0 Hz,
1H), 7.08 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 8.0 Hz, 16.4 Hz, 2H), 7.41 (s, 0.6H),
7.91 (s, 0.4H); 13C NMR (100 MHz, CDCl3) d: 22.6, 22.7, 22.8, 27.6, 27.7, 29.6,
29.9, 30.1, 30.8, 33.4, 36.7, 37.7, 40.3, 53.0, 60.4, 127.5, 128.2, 128.8, 129.2, 130.6,
130.8, 132.1, 132.6, 136.4, 136.6, 160.8, 160.9. HRMS (ESI) calcd for C17H21-
NOCl? ([M ? H]?): 290.1312, found: 290.1303.
(?)-N-Methyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (1b)
Formaldehyde (40 % dispersion in water, 1.76 g, 23.4 mmol) was added in a
mixture solution of methanol (50 mL) and (?)-1-(4-methoxyl)benzyl-
1,2,3,4,5,6,7,8-octahydroisoquinoline (5.0 g, 19.5 mmol) in an oven-dried flask
equipped with a stir bar. The solution was then heated to 40 °C and stirred for 1 h
and allowed to cool to ambient temperature. After that, KBH4 (0.63 g, 11.7 mmol)
was added in batches and stirred for 1 h. The reaction was poured into H2O (50 mL)
and organic solvent was evaporated under reduced pressure. Then the resulting
mixture was diluted with CH2Cl2, combined organic layers were washed with water,
dried (Na2SO4), and concentrated to dryness. The crude material was purified by
column chromatography (hexane/AcOEt/Et3N = 10:1:0.01) to afford the desired
product 1b, yield 94 %. 1H NMR (400 MHz, CDCl3) d: 1.50–2.00 (m, 10H), 2.37
(s, 3H), 2.48–2.54 (m, 1H), 2.79 (t, J = 4.2 Hz, 2H), 2.88–2.95 (m, 2H), 3.77 (s,
3H), 6.80 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) d: 23.0, 23.3, 28.1, 28.3, 30.2, 35.8, 43.0, 47.6, 54.9, 66.4, 113.3, 127.3,
129.3, 130.1, 133.0, 157.7. HRMS (ESI) calcd for C18H26NO?([M ? H]?):
272.2014, found: 272.2020.
123

On the formation of a side product with…
1701
General procedure for preparation of (1)-N-Acyl-1-(4-methoxy)benzyl-
1,2,3,4,5,6,7,8-octahydroisoquinoline (1c-i)
The first step
(?)-Octabase-mandelate salt (15.0 g) was added to solution of 10 % sodium
hydroxide (100 mL), and the mixture was stirred for 0.5 h. After that, the mixture
was extracted with DCM (100 mL 9 3), washed with brine, and dried over
anhydrous Na2SO4. The solvent was evaporated and concentrated to dryness to
afford (?)-1-(4-methoxyl)benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline.
The second step
Et3N (2.95 g, 29.25 mmol) was added in a mixture solution of DCM (50 mL) and
(?)-1-(4-methoxyl)benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline
(5.0 g,
19.5 mmol) in an oven-dried flask equipped with a stir bar. Acyl chlorides or
anhydrides (23.4 mmol) were then added dropwise and stirred at 0 °C or ambient
temperature, until TLC indicated the total consumption of octahydroisoquinoline
derivative. After the reaction was completed, approximately 50 mL water was
added, and the organic phase was separated. The aqueous phase was extracted with
DCM (50 mL 9 2), and the combined organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated to dryness again. The crude material was purified
by column chromatography with cyclohexane: ethyl acetate (15:1–5:1) as eluent.
(?)-N-Acetyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline
(1c)
1
Pale-yellow oil, yield: 94 %. H NMR (400 MHz, CDCl3) d: 1.25 (s, 1.5H), 1.35
(s, 1.5H), 1.63–1.70 (m, 4H), 1.78 (d, J = 16.0 Hz, 1H), 1.92 (d, J = 18.4 Hz, 3H),
2.04–2.26 (m, 2H), 2.69–2.81 (m, 1H), 2.84–3.04 (m, 2H), 3.46 (dd, J = 5.6 Hz,
13.2 Hz, 0.4 H), 3.78 (s, 3H), 3.82 (d, J = 10.0 Hz, 0.6H), 4.67 (dd, J = 5.6 Hz,
13.2 Hz, 0.6H), 4.89 (bs, 0.4H), 6.77–6.83 (m, 2H), 7.01–7.06 (m, 2H); 13C NMR
(100 MHz, CDCl3) d: 20.8, 21.6, 22.7, 22.8, 22.9, 27.8, 28.0, 29.7, 29.9, 30.0, 30.4,
34.1, 36.4, 37.2, 40.5, 54.2, 55.1, 55.2, 61.0, 113.4, 113.9, 127.8, 128.2, 129.0,
129.3, 130.3, 130.4, 130.5, 158.0, 158.4, 168.4, 169.3. HRMS (ESI) calcd for
C19H26NO2 ([M ? H]?): 300.1964, found: 300.1968.
?
(?)-N-Propionyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (1d)
1
Pale-yellow oil, yield: 93 %. H NMR (400 MHz, CDCl3) d: 0.68 (t, J = 7.6 Hz,
1.5H), 0.95 (t, J = 7.6 Hz, 1.5H), 1.53–2.17 (m, 12H), 2.60–2.71 (m, 1H),
2.77–2.95 (m, 2H), 3.41 (dd, J = 5.6 Hz, 13.2 Hz, 0.5H), 3.66 (s, 3H), 3.79 (d,
J = 9.6 Hz, 0.5H), 4.59 (dd, J = 5.6 Hz, 13.2 Hz, 0.5H), 4.81 (bs, 0.5H),
6.67–6.73 (m, 2H), 6.91–6.97 (m, 2H); 13C NMR (100 MHz, CDCl3) d: 8.3, 8.6,
21.7, 21.8, 21.9, 24.7, 25.7, 26.8, 27.1, 28.9, 29.0, 29.5, 33.3, 35.6, 36.2, 38.6, 53.1,
54.1, 54.2, 58.8, 112.3, 112.9, 126.6, 127.3, 128.2, 128.3, 129.4, 129.5, 129.6,
?
157.0, 157.3, 170.8, 171.6. HRMS (ESI) calcd for C20H28NO2 ([M ? H]?):
314.2120, found: 314.2111.
123

1702
Q. Zhao et al.
(?)-N-Ethoxycarbonyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline
(1e) Pale-yellow oil, yield: 89 %. 1H NMR (400 MHz, CDCl3) d: 0.94 (t,
J = 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 1H), 1.57–1.72 (m, 5H), 1.88–2.15 (m, 5H),
2.63–3.01 (m, 3H), 3.64–3.68 (m, 0.6H), 3.74 (s, 3H), 3.78–3.82 (m, 1H), 4.01–4.04
(m, 0.8H), 4.12 (dd, J = 6.0 Hz, 13.2 Hz, 0.6H), 4.25 (d, J = 7.2 Hz, 0.6H), 4.47
(bs, 0.4H), 6.78 (d, J = 8.0 Hz, 2H), 7.01–7.07 (m, 2H); 13C NMR (100 MHz,
CDCl3) d: 14.3, 14.7, 23.0, 27.9, 30.0, 30.1, 36.5, 36.9, 37.2, 37.6, 55.2, 56.5, 57.3,
60.7, 113.5, 128.1, 128.5, 128.9, 130.3, 130.7, 131.0, 155.2, 155.3, 158.0, 158.1.
HRMS (ESI) calcd for C20H28NO3 ([M ? H]?): 330.2069, found: 330.2064.
?
(?)-N-Trifluoroacetyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline
1
(1f) Pale-yellow oil, yield: 92 %. H NMR (400 MHz, CDCl3) d: 1.60–1.92 (m,
8H), 2.14–2.21 (m, 2H), 2.82 (dd, J = 7.6 Hz, 14.0 Hz, 1H), 3.01–3.09 (m, 2H),
3.72 (dd, J = 4.8 Hz, 14.0 Hz, 1H), 3.77 (s, 3H), 4.78 (bs, 1H), 6.79 (d,
J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) d: 22.6,
22.8, 27.6, 29.8, 30.6, 36.2, 39.7, 55.1, 56.1, 113.7, 127.8, 128.1, 129.1, 130.3,
155.0, 155.3, 158.4. HRMS (ESI) calcd for C19H22NO2F3Na? ([M ? Na]?):
376.1500, found: 376.1494.
(?)-N-Trichloroacetyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline
1
(1g) Pale-yellow powder, yield: 86 %. m.p. 101–102 °C; H NMR (400 MHz,
CDCl3) d: 1.65–1.72 (m, 5H), 1.86–1.93 (m, 3H), 2.17–2.31 (m, 2H), 2.87 (dd,
J = 6.8 Hz, 14.4 Hz, 1H), 2.94–3.02 (m, 1H), 3.09 (dd, J = 5.2 Hz, 14.4 Hz, 1H),
3.77 (s, 3H), 4.27 (dd, J = 5.2 Hz, 14.0 Hz, 1H), 4.79 (bs, 1H), 6.78 (d,
J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) d: 22.7,
22.9, 27.8, 29.8, 30.0, 36.4, 42.2, 55.2, 57.9, 93.6, 113.6, 128.0, 128.0, 129.4, 130.6,
158.3, 158.8. HRMS (ESI) calcd for C19H22NO2Cl3Na? ([M ? Na]?): 424.0614,
found: 424.0606.
(?)-N-Methylsulfonyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline
1
(1h) Pale-yellow powder, yield: 83 %. m.p. 130–132 °C; H NMR (400 MHz,
CDCl3) d: 1.61–1.72 (m, 5H), 1.92 (d, J = 5.6 Hz, 3H), 2.14 (d, J = 16.8 Hz, 1H),
2.25 (bs, 4H), 2.68 (dd, J = 9.6 Hz, 14.0 Hz, 1H), 2.98 (dd, J = 4.0 Hz, 14.4 Hz,
1H), 3.06–3.10 (m, 1H), 3.67 (dd, J = 6.4 Hz, 14.4 Hz, 1H), 3.76 (s, 3H), 4.11 (d,
J = 8.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d: 22.7, 23.0, 28.0, 29.4, 30.1, 37.8, 38.5, 39.8, 55.2, 58.8,
113.7, 128.1, 128.8, 130.5, 130.8, 158.3. HRMS (ESI) calcd for C18H26NO3S?
([M ? H]?): 336.1633, found: 336.1636.
(?)-N-Trifluoromethylsulfonyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroiso-
quinoline (1i) Pale-yellow powder, yield: 82 %. m.p. 65–67 °C; 1H NMR
(400 MHz, CDCl3) d: 1.61–1.73 (m, 5H), 1.82–1.98 (m, 3H), 2.10–2.21 (m, 2H),
2.90–2.99 (m, 3H), 3.72 (dd, J = 7.2 Hz, 14.4 Hz, 1H), 3.78 (s, 3H), 4.16 (bs, 1H),
6.83 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3)
d: 22.6, 22.8, 28.0, 30.0, 38.2, 40.4, 55.2, 59.9, 113.9, 128.3, 128.9, 130.6, 158.6.
HRMS (ESI) calcd for C18H23F3NO3S?([M ? H]?): 390.1351, found: 390.1345.
123

On the formation of a side product with…
1703
(?)-N-Formyl-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (1j)(?)-
Octabase-mandelate salt (20.0 g) was added to solution of 10 % sodium hydroxide
(150 mL), and the mixture was stirred for 0.5 h. After that, the mixture was
extracted with DCM (150 mL 9 3), washed with brine, and dried over anhydrous
Na2SO4. The solvent was evaporated and concentrated to dryness to afford (?)-1-
(4-methoxyl)benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline.
A mixture of (?)-1-(4-methoxyl)benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline
(10.0 g, 38.9 mmol) and 40 mL of 48 % hydrobromic acid was heated to reflux
for 12 h. After cooling to room temperature, NaHCO3 was added to reaction system
until no bubble appeared. The mixture was then extracted with toluene
(50 mL 9 3), and the combined organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated to dryness. The crude material was added to a mixture of
toluene (70 mL) and formic acid (3.45 g, 46.68 mmol) in an oven-dried flask
equipped with a stir bar and water segregator. The mixture was stirred at reflux until
no water was separated. After cooling to room temperature, water (50 mL) was
added to the mixture with stirring and 10 % aq. NaOH (10 mL) was then added. The
aqueous layer was separated, and the organic one was washed with water
(50 mL 9 2). The combined aqueous layers were added 2 M HCl until amounts of
insoluble solid appeared, and the solid was filtered under reduced pressure to give
the product as a yellow solid (1j). yield: 84 %, m.p. 178–180 °C; 1H NMR
(400 MHz, CDCl3) d: 1.65–1.68 (m, 4H), 1.82–1.95 (m, 4H), 2.08–2.27 (m, 2H),
2.55–2.67 (m, 1H), 2.93–3.08 (m, 1.7H), 3.22–3.29 (m, 0.3H), 3.36–3.40 (m, 0.3H),
3.54 (d, J = 10.8 Hz, 0.7H), 4.41 (dd, J = 10.8 Hz, 13.2 Hz, 0.7H), 4.70 (d,
J = 5.6 Hz, 0.3H), 6.68 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.0 Hz, 1.4H), 6.99 (d,
J = 8.0 Hz, 0.6H), 7.32 (s, 0.7H), 7.84 (s, 0.3H), 8.14 (s, 0.3H), 8.71 (s, 0.7H); 13
C
NMR (100 MHz, CDCl3) d: 22.7, 22.8, 27.6, 29.7, 29.9, 30.0, 31.0, 33.7, 36.8, 37.5,
40.4, 53.8, 61.5, 115.3, 115.8, 127.3, 127.6, 128.2, 128.6, 130.3, 155.6, 156.1,
161.1, 161.8. HRMS (ESI) calcd for C17H22NO2 ([M ? H]?): 272.1651, found:
?
272.1655.
General procedure for preparation of (1)-N-Formyl-1-(4-Alkoxy)benzyl-
1,2,3,4,5,6,7,8-octahydroisoquinoline (1k-l)
Sodium hydroxide (0.81 g, 20.3 mmol) was added to a solution mixture of DMF
(50 mL) and (?)-N-formyl-1-(p-hydroxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquino-
line (5.0 g, 18.4 mmol) in an oven-dried flask equipped with a stir bar. The solution
was stirred for 1 h at ambient temperature and alkyl chloride (20.3 mmol) was then
added dropwise to the reaction mixture. After the starting material was completely
consumed by TLC monitoring, the organic solvent was evaporated under reduced
pressure. Then, the residual mixture was diluted with DCM (30 mL) and H2O
(30 mL), and the organic layer was seperated. The aqueous one was extracted with
DCM (30 mL 9 2), and combined organic layers were washed with water, dried
(Na2SO4), and concentrated to dryness. The crude material was purified by column
chromatography to afford corresponding product.
123

1704
Q. Zhao et al.
(?)-N-Formyl-1-(p-ethoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (1k) Yield:
94 %. 1H NMR (400 MHz, CDCl3) d: 1.30 (t, J = 6.8 Hz, 3H), 1.58–1.85 (m, 8H),
1.99–2.17 (m, 2H), 2.51–2.58 (m, 0.6H), 2.72 (dd, J = 7.2 Hz, 14.4 Hz, 0.4H),
2.77–2.96 (m, 2H), 3.21 (dd, J = 5.6 Hz, 13.2 Hz, 0.4H), 3.50 (d, J = 10.0 Hz,
0.6H), 3.90 (q, J = 7.2 Hz, 2H), 4.28 (dd, J = 5.6 Hz, 13.2 Hz, 0.6H), 4.59 (bs,
0.4H), 6.68–6.74 (m, 2H), 6.87–6.96 (m, 2H), 7.30 (s, 0.6H), 7.83 (s, 0.4H); 13C
NMR (100 MHz, CDCl3) d: 13.8, 21.7, 21.8, 26.7, 28.9, 29.1, 29.8, 32.3, 35.2, 36.5,
39.4, 52.2, 59.8, 62.2, 62.3, 113.1, 113.6, 126.6, 126.7, 126.8, 127.8, 128.6, 128.8,
?
129.2, 129.4, 156.5, 156.8, 159.9, 160.1. HRMS (ESI) calcd for C19H26NO2
([M ? H]?): 300.1964, found: 300.1967.
(?)-N-Formyl-1-(p-propoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline
(1l)
1
Yield: 92 %. H NMR (400 MHz, CDCl3) d: 1.02 (t, J = 7.6 Hz, 3H), 1.64–1.93
(m, 10H), 2.06–2.26 (m, 2H), 2.62 (dd, J = 10.4 Hz, 14.0 Hz, 0.6H), 2.80 (dd,
J = 6.4 Hz, 14.4 Hz, 0.4H), 2.85–3.04 (m, 2H), 2.90 (dd, J = 6.4 Hz, 13.2 Hz,
0.4H), 3.57 (d, J = 10.0 Hz, 0.6H), 3.87 (t, J = 6.4 Hz, 2H), 4.36 (dd, J = 6.4 Hz,
13.2 Hz, 0.6H), 4.67 (bs, 0.4H), 6.77–6.82 (m, 2H), 6.95–7.05 (m, 2H), 7.38 (s,
0.6H), 7.91 (s, 0.4H); 13C NMR (100 MHz, CDCl3) d: 9.5, 21.6, 21.7, 21.9, 26.7,
28.7, 29.0, 29.1, 29.8, 32.3, 35.2, 36.5, 39.4, 52.2, 59.8, 68.3, 68.4, 113.1, 113.6,
126.7, 126.8, 127.8, 128.7, 129.2, 129.4, 157.0, 159.8, 160.1. HRMS (ESI) calcd for
C20H28NO2 ([M ? H]?): 314.2120, found: 314.2127.
?
General procedure for Grewe cyclization reaction of (1)-N-acyl-1-(4-
substituted)benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline
A mixture of phosphorus pentoxide (4.0 g) and phosphoric acid (10 mL) was stirred
in an ice-water bath until a homogeneous solution was formed. A solution of (?)-N-
acyl-1-(4-substituented)benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline 1 (1.0 g) in
pre-prepared homogeneous phosphoric acid (5 mL) was added to a parallel reaction
tube equipped with a magnetic stirrer, as well as temperature controller. The
reaction mixture was stirred at 60 °C until starting material almost disappeared
monitored by TLC. To quench the reaction, 5 mL ice-water was added to mixture
system. Then resulting suspension was extracted with ethyl acetate (10 mL 9 3),
the combined organic phases were washed with brine, dried by Na2SO4, and
concentrated to dryness. Column chromatography on silica gel eluted with a mixture
of petroleum ether and EtOAc gave the almost corresponding product 2 and the ratio
of product 2-1 and side product 2-2 was followed by HPLC analysis.
(?)-3-Methoxy-17-formylmorphinan (2a–1) Pale-yellow oil, yield: 90 %. 1H
NMR (400 MHz, CDCl3) d: 1.08–1.70 (m, 10H), 2.37 (d, J = 9.6 Hz, 1H), 2.42 (t,
J = 12.8 Hz, 0.5H), 2.66 (t, J = 17.6 Hz, 1H), 2.95 (t, J = 12.8 Hz, 0.5H),
3.11–3.21 (m, 1H), 3.27 (dd, J = 4.0 Hz, 12.8 Hz, 0.5H), 3.69 (bs, 0.5 H), 3.79 (s,
3H), 4.17 (dd, J = 4.0 Hz, 12.8 Hz, 0.5H), 4.63 (bs, 0.5 H), 6.74 (d, J = 8.4 Hz,
1H), 6.84 (s, 1H), 7.02 (t, J = 8.4 Hz, 1H), 7.99 (s, 0.5H), 8.15 (s, 0.5H); 13C NMR
(100 MHz, CDCl3) d: 21.9, 26.2, 26.3, 30.8, 32.2, 34.9, 36.4, 36.5, 38.7, 38.8, 40.8,
123

On the formation of a side product with…
1705
41.1, 42.0, 43.7, 45.0, 46.3, 53.7, 55.2, 111.3, 111.4, 127.5, 128.0, 129.0, 129.1,
140.1, 158.6, 158.7, 160.6, 160.7. HRMS (ESI) calcd for C18H24NO2?([M ? H]?):
286.1807, found: 286.1812.
(?)-3-Methoxy-17-acetylmorphinan (2c–1) Pale-yellow oil, yield: 85 %. 1H
NMR (400 MHz, CDCl3) d: 1.05–1.71 (m, 10H), 2.05 (s, 2H), 2.15 (s, 1H), 2.34
(d, J = 10.4 Hz, 1H), 2.59–2.70 (m, 1H), 2.91 (t, J = 13.2 Hz, 0.6H), 3.08–3.19
(m, 1H), 3.47 (d, J = 14.0 Hz, 0.6H), 3.78 (s, 3H), 3.91 (bs, 0.4H), 4.36 (d,
J = 14.0 Hz, 0.4H), 4.85 (bs, 0.6H), 6.72 (d, J = 8.4 Hz, 1H), 6.83 (s, 1H), 7.01 (d,
J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) d: 20.9, 21.0, 25.2, 25.3, 25.7, 28.6,
30.0, 30.6, 34.6, 35.3, 36.6, 39.8, 40.1, 41.0, 42.7, 43.5, 45.9, 52.0, 54.1, 110.1,
110.3, 126.5, 127.4, 127.9, 128.0, 139.2, 157.4, 157.5, 167.7, 167.9. HRMS (ESI)
calcd for C19H26NO2 ([M ? H]?): 300.1964, found: 300.1968.
?
1
(?)-3-Methoxy-17-propionylmorphinan (2d–1) Pale-yellow oil, yield: 84 %. H
NMR (400 MHz, CDCl3) d: 1.02–1.11 (m, 4H), 1.21–1.61 (m, 9H), 2.14–2.22 (m,
0.4H), 2.24–2.36 (m, 3H), 2.49–2.60 (m, 1H), 2.79 (td, J = 3.2 Hz, 13.2 Hz, 0.6 H),
3.00–3.09 (m, 1H), 3.43 (dd, J = 4.4 Hz, 13.6 Hz, 0.6H), 3.70 (s, 3H), 3.88 (bs,
0.4H), 4.30 (dd, J = 4.4 Hz, 13.6 Hz, 0.4H), 4.78 (bs, 0.6H), 6.64 (d, J = 8.4 Hz,
1H), 6.75 (d, J = 2.4 Hz, 1H), 6.92 (t, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d: 14.3, 16.3, 16.4, 29.7, 61.6, 62.4, 62.5, 115.9, 116.0, 123.8, 127.2, 129.3,
131.7, 132.2, 134.5, 135.7, 135.8, 152.8, 156.1, 165.3. HRMS (ESI) calcd for
C20H28NO2 ([M ? H]?): 314.2120, found: 314.2111.
?
(?)-3-Methoxy-17-ethoxycarbonylmorphinan (2e–1) Pale-yellow oil, yield:
1
86 %. H NMR (400 MHz, CDCl3) d: 1.08 (t, J = 12.4 Hz, 1H), 1.22–1.36 (m,
7H), 1.48–1.67 (m, 5H), 2.36 (d, J = 10.8 Hz, 1H), 2.63–2.69 (m, 2H), 3.05–3.13
(m, 1H), 3.79 (s, 3H), 3.90 (d, J = 13.6 Hz, 0.5H), 4.09–4.17 (m, 2.5H), 4.25 (bs,
0.5H), 4.39 (bs, 0.5H), 6.71 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 6.83 (d, J = 2.4 Hz, 1H),
7.00 (t, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) d: 14.2, 14.7, 14.8, 22.1,
26.4, 31.3, 31.6, 36.6, 37.6, 38.2, 41.4, 41.7, 43.9, 44.0, 49.7, 50.0, 55.2, 61.1, 61.2,
?
111.0, 111.1, 111.3, 129.1, 140.5, 155.7, 158.4. HRMS (ESI) calcd for C20H28NO3
([M ? H]?): 330.2069, found: 330.2064
(?)-3-Methoxy-17-trifluoroacetylmorphinan (2f–1) Pale-yellow oil, yield: 93 %.
1H NMR (400 MHz, CDCl3) d: 1.05–1.14 (m, 1H), 1.26–1.76 (m, 9H), 2.39 (d,
J = 10.4 Hz, 1H), 2.61–2.65 (m, 0.4H), 2.67–2.78 (m, 1H), 3.02 (td, J = 3.2 Hz,
13.6 Hz, 0.6H), 3.17–3.25 (m, 1H), 3.69 (d, J = 13.6 Hz, 0.6H), 3.80 (s, 3H), 4.10
(bs, 0.4H), 4.29 (dd, J = 4.8 Hz, 13.6 Hz, 0.4H), 4.78 (bs, 0.6H), 6.76 (dd,
J = 2.4 Hz, 8.4 Hz, 1H), 6.85 (t, J = 2.4 Hz, 1H), 7.05 (t, J = 8.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d: 20.8, 25.1, 25.2, 25.5, 29.5, 30.5, 35.0, 36.7, 39.8, 40.9,
42.6, 43.4, 48.4, 54.2, 110.4, 110.5, 126.0, 126.4, 128.1, 138.8, 157.7. HRMS (ESI)
calcd for C19H22NO2F3Na? ([M ? Na]?): 376.1500, found: 376.1494.
(?)-3-Methoxy-17-trichloroacetylmorphinan (2g–1) Pale-yellow oil, yield: 55 %.
1H NMR (400 MHz, CDCl3) d: 0.95–1.03 (m, 1H), 1.16–1.60 (m, 9H), 2.30 (d,
J = 9.6 Hz, 1H), 2.63 (d, J = 17.6 Hz, 1H), 2.80 (d, J = 17.6 Hz, 0.5H), 2.96 (t,
123

1706
Q. Zhao et al.
J = 13.6 Hz, 0.5H), 3.11 (dd, J = 6.4 Hz, 18.4 Hz, 1H), 3.71 (s, 3H), 4.19 (bs, 1H),
4.67 (d, J = 20.8 Hz, 1H), 6.67 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 6.76 (d, J = 2.4 Hz,
1H), 6.97 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) d: 13.2, 20.0, 20.8,
21.7, 25.2, 25.3, 28.7, 30.6, 30.9, 35.0, 36.4, 38.2, 40.5, 41.8, 42.8, 50.4, 53.0, 54.2,
59.3, 92.7, 92.8, 110.3, 126.4, 126.5, 127.9, 128.0, 157.7, 170.1. HRMS (ESI) calcd
for C19H22NO2Cl3Na? ([M ? Na]?): 424.0614, found: 424.0606.
(?)-3-Methoxy-17-methylsulfonylmorphinan (2h–1) Pale-yellow oil, yield: 70 %.
1H NMR (400 MHz, CDCl3) d: 0.93–1.03 (m, 1H), 1.17–1.47 (m, 6H), 1.57–1.65
(m, 2H), 1.72 (d, J = 12.8 Hz, 1H), 2.28 (d, J = 12.8 Hz, 1H), 2.64–2.75 (m, 2H),
2.81 (s, 3H), 3.04 (dd, J = 5.6 Hz, 18 Hz, 1H), 3.44 (dd, J = 4.0 Hz, 4.4 Hz, 1H),
3.71 (s, 3H), 3.98 (bs, 1H), 6.65 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 6.74 (d, J = 2.4 Hz,
1H), 6.95 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) d: 22.0, 26.3, 26.4,
31.1, 36.4, 37.5, 39.4, 39.9, 41.6, 44.7, 51.9, 55.2, 111.3, 111.4, 127.8, 129.0, 140.0,
158.7. HRMS (ESI) calcd for C18H26NO3S? ([M ? H]?): 336.1633, found:
336.1636
(?)-3-Methoxy-17-trifluoromethylsulfonylmorphinan (2i–1) Pale-yellow oil,
yield: 87 %. 1H NMR (400 MHz, CDCl3) d: 1.26–1.84 (m, 10H), 2.38 (d,
J = 12.4 Hz, 1H), 2.83–2.96 (m, 2H), 3.20 (dd, J = 6.0 Hz, 18.4 Hz, 1H), 3.68 (dd,
J = 4.0 Hz, 13.6 Hz, 1H), 3.79 (s, 3H), 4.13 (bs, 1H), 6.76 (dd, J = 2.4 Hz, 8.4 Hz,
1H), 6.83 (d, J = 2.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3) d: 20.8, 25.1, 25.3, 35.2, 36.2, 40.3, 40.5, 53.2, 54.2, 110.3, 110.7, 112.8,
117.4, 120.6, 126.0, 128.2, 129.6, 138.4, 157.9. HRMS (ESI) calcd for C18H23F3-
NO3S?([M ? H]?): 390.1351, found: 390.1345.
(?)-3-Hydroxy-17-formylmorphinan (2j–1) Pale-yellow oil, yield: 87 %. 1H
NMR (400 MHz, CDCl3) d: 1.08–1.14 (m, 1H), 1.26–1.33 (m, 3H), 1.40–1.69
(m, 6H), 2.33 (d, J = 10.0 Hz, 1H), 2.47 (td, J = 4.0 Hz, 13.2 Hz, 0.5H), 2.63 (t,
J = 13.2 Hz, 1H), 2.97 (td, J = 3.6 Hz, 13.2 Hz, 0.5H), 3.09–3.20 (m, 1H), 3.26
(dd, J = 4.4 Hz, 13.2 Hz, 0.5H), 3.69 (s, 0.5H), 4.14 (dd, J = 4.4 Hz, 13.2 Hz,
0.5H), 4.63 (bs, 0.5H), 6.70 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 2.0 Hz, 1H), 6.93 (t,
J = 8.0 Hz, 1H), 7.99 (s, 0.5H), 8.15 (s, 0.5H); 13C NMR (100 MHz, CDCl3) d:
20.9, 25.2, 25.3, 29.7, 31.2, 34.4, 35.3, 35.4, 37.5, 37.6, 39.7, 40.6, 40.9, 42.7, 43.9,
45.9, 52.5, 53.3, 111.2, 112.8, 112.9, 125.2, 125.8, 128.0, 128.1, 138.9, 154.6,
154.7, 160.0, 160.1. HRMS (ESI) calcd for C17H22NO2 ([M ? H]?): 272.1651,
?
found: 272.1655.
(?)-3-Ethoxy-17-formylmorphinan (2k–1) pale-yellow oil, yield: 89 %. 1H NMR
(400 MHz, CDCl3) d: 1.08–1.13 (m, 1H), 1.26–1.70 (m, 12H), 2.37 (d,
J = 10.0 Hz, 1H), 2.46 (td, J = 3.6 Hz, 13.2 Hz, 0.5H), 2.66 (t, J = 17.6 Hz,
1H), 2.95 (t, J = 13.2 Hz, 0.5H), 3.16 (td, J = 5.6 Hz, 17.6 Hz, 1H), 3.24 (dd,
J = 4.4 Hz, 13.2 Hz, 0.5H), 3.69 (bs, 0.5H), 4.01 (q, J = 6.8 Hz, 2H), 4.15 (dd,
J = 4.4 Hz, 13.2 Hz, 0.5H), 4.63 (bs, 0.5H), 6.72 (d, J = 8.4 Hz, 1H), 6.84 (s, 1H),
7.01 (t, J = 8.4 Hz, 1H), 7.99 (s, 0.5H), 8.15 (s, 0.5H); 13C NMR (100 MHz,
CDCl3) d: 13.9, 20.9, 21.0, 25.2, 25.4, 29.8, 31.3, 34.0, 35.4, 35.5, 37.7, 37.8, 39.9,
40.2, 41.1, 42.7, 44.0, 45.4, 52.7, 62.3, 110.8, 111.0, 126.4, 127.0, 128.0, 128.1,
123

On the formation of a side product with…
1707
139.1, 157.0, 157.1, 159.6, 159.7. HRMS (ESI) calcd for C19H26NO2? ([M ? H]?):
300.1964, found: 300.1967.
(?)-3-Propoxy-17-formylmorphinan (2l–1)
Pale-yellow oil, yield: 91 %. 1H
NMR (400 MHz, CDCl3) d: 0.97 (t, J = 7.6 Hz, 3H), 1.18–1.63 (m, 10 H),
1.70–1.78 (m, 2H), 2.30 (d, J = 8.0 Hz, 1H), 2.39 (td, J = 4.0 Hz, 12.8 Hz, 0.5H),
2.58 (t, J = 17.6 Hz, 1H), 2.88 (td, J = 4.0 Hz, 12.8 Hz, 0.5H), 3.08 (td,
J = 6.0 Hz, 17.6 Hz, 1H), 3.19 (dd, J = 4.0 Hz, 12.8 Hz, 0.5H), 3.61 (t,
J = 4.4 Hz, 0.5H), 3.82 (t, J = 6.8 Hz, 2H), 4.08 (dd, J = 4.0 Hz, 12.8 Hz,
0.5H), 4.55 (t, J = 4.4 Hz, 0.5H), 6.65 (dd, J = 2.4 Hz, 8.4 Hz, 1H), 6.76 (d,
J = 2.4 Hz, 1H), 6.93 (t, J = 8.4 Hz, 1H), 7.91 (s, 0.5H), 8.07 (s, 0.5H); 13C NMR
(100 MHz, CDCl3) d: 9.6, 20.9, 21.7, 25.2, 25.3, 29.8, 31.2, 33.9, 35.4, 35.5, 37.7,
37.8, 39.8, 40.1, 41.0, 42.7, 44.0, 45.4, 52.7, 68.4, 110.8, 110.9, 111.0, 126.3, 126.8,
?
127.9, 128.0, 139.0, 157.1, 157.2, 159.6, 159.7. HRMS (ESI) calcd for C20H28NO2
([M ? H]?): 314.2120, found: 314.2127.
(?)-3-Methyl-17-formylmorphinan (2m–1)
pale-yellow oil, yield: 89 %. 1H
NMR (400 MHz, CDCl3) d: 0.97–1.02 (m, 1H), 1.20–1.61 (m, 9H), 2.22 (s, 3H),
2.32–2.38 (m, 1.5H), 2.58 (t, J = 18.4 Hz, 1H), 2.83 (t, J = 13.2 Hz, 0.5H),
3.03–3.18 (m, 1.5H), 3.60 (bs, 0.5H), 4.05 (d, J = 9.2 Hz, 0.5H), 4.53 (bs, 0.5H),
6.87 (d, J = 1.2 Hz, 2H), 7.00 (s, 1H), 7.89 (s, 0.5H), 8.05 (s, 0.5H); 13C NMR
(100 MHz, CDCl3) d: 21.4, 21.9, 21.9, 26.2, 26.3, 31.3, 32.7, 34.9, 36.3, 36.4, 38.4,
38.6, 41.0, 41.2, 42.2, 43.9, 45.2, 46.4, 53.8, 126.0, 126.9, 127.0, 128.0, 128.1,
132.4, 132.9, 136.2, 136.3, 138.5, 138.6, 160.6, 160.7. HRMS (ESI) calcd for
C18H24NO? ([M ? H]?): 270.1858, found: 270.1860.
1
(?)-3-Chloro-17-formylmorphinan (2n–1) Pale-yellow oil, yield: 57 %. H NMR
(400 MHz, CDCl3) d: 0.93–0.99 (m, 1H), 1.17–1.65 (m, 9H), 2.26–2.36 (m, 1.5H), 2.61
(t, J = 20.8 Hz, 1H), 2.78–2.83 (m, 0.5H), 3.09 (t, J = 20.8 Hz, 1H), 3.22 (dd,
J = 3.2 Hz, 13.6 Hz, 0.5H), 3.64(bs, 0.5H), 4.08(dd,J = 3.2 Hz, 13.6 Hz, 0.5H), 4.56
(bs, 0.5H), 6.95–6.98 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.91
(s, 0.5H), 8.06 (s, 0.5H); 13C NMR (100 MHz, CDCl3) d: 20.8, 25.0, 25.1, 25.2, 30.1,
31.5, 33.7, 35.2, 35.3, 37.7, 37.8, 39.6, 39.8, 40.8, 42.4, 43.7, 44.9, 52.2, 124.6, 124.7,
125.3, 125.4, 128.6, 128.7, 131.5, 131.6, 133.0, 133.6, 139.9, 140.0, 159.6. HRMS (ESI)
calcd for C17H21NOCl? ([M ? H]?): 290.1312, found: 290.1303.
General procedure for computational modeling
Geometries of all the intermediates and transition states were optimized at the
B3LYP/6-311 ? G(d,p) level, followed by frequency calculations at the same level
of theory to ensure these are stationary points and to extract Gibbs free energy
corrections at 298 K. The Gaussian09 software was used for all DFT calculations.
Acknowledgments The work was supported by the National Nature Science Foundation of China
(NSFC, 21272069, 20672035), the Fundamental Research Funds for the Central Universities, the Key
Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, the Swedish research council, and the Faculty of science at University of Gothenburg.
123

1708
Q. Zhao et al.
References
1. F.C. Tortella, M. Pellicano, N.G. Bowery, Trends Pharmacol. Sci. 10, 501 (1989)
2. H.C. Kim, K. Pennypacker, G. Bing, D. Bronstein, M.K. McMillian, J.S. Hong, Neurotoxicology 17,
375 (1996)
3. H.C. Kim, H.W. Suh, D. Bronstein, G. Bing, B. Wilson, J.S. Hong, Neuropeptides 31, 105 (1997)
4. H.C. Kim, P. H. Lee, W. K. Jhoo, in Symposium on Molecular Monitoring in the Neuroscience Field
(Nagoya, Japan), 3, 1 (1998)
5. H.C. Kim, G. Bing, W.K. Jhoo, K.H. Ko, W.K. Kim, D.C. Lee, E.J. Shin, J.S. Hong, Brain Res. 824,
125 (1999)
6. R. Grewe, Naturwissenschaften 33, 333 (1946)
7. R. Grewe, A. Mondon, Chem. Ber. 81, 279 (1948)
8. R. Grewe, Angew. Chem. 59, 194 (1947)
9. R. Robinson, S. Sugasawa, J. Chem. Soc. 3163 (1931)
10. Z. Kitasato, R. Robinson, J. Chem. Soc. 785 (1932)
11. R. Robinson, S. Sugasawa, J. Chem. Soc. 789 (1932)
12. R. Robinson, S. Sugasawa, J. Chem. Soc. 280 (1933)
13. R. Robinson, The Structural Relations of Natural Products (Clarendon Press, Oxford, 1955)
14. C. Schopf, K. Thierfelder, Ann. Chem. 22, 497 (1932)
15. C. Schopf, K. Thierfelder, Ann. Chem. 143, 537 (1939)
16. C. Schopf, Naturwissenschaften 241, 39 (1952)
17. C. Schopf, H. Perrey, I. Jackh, Ann. Chem. 59, 497 (1932)
18. O. Schnider, A. Griissner, Helv. Chim. Acta. 821 (1949)
19. C.F. Koelsch, N.F. Albertson, J. Am. Chem. Soc. 75, 2095 (1953)
20. E. Ochiai, M. Ikehara, Pharm. Bull. 2, 109 (1954)
21. E. Ochiai, M. Ikehara, Pharm. Bull. 3, 291 (1955)
22. M. Sasamoto, Chem. Pharm. Bull. 8, 324 (1960)
23. A. I. Meyers, T.R. Bailey, J. Org. Chem. 51, 872 (1986)
24. H.-T. Tian, L.-J. Ke, Pharm J Today (chinese), 63 (2008)
25. W. Leimgruber, E. Mohacsi, H. Baruth, L. O. Randall, Raven Press: New York, 8, 45 (1974)
26. W. Leimgruber, E. Mohacsi, U.S. Patent, 3634429 (1972)
27. W. Leimgruber, E. Mohacsi, U.S. Patent 3810899 (1974)
28. E. Mohacsi, U.S. Patent, 4194044 (1980)
29. K.C. Rice, J. Org. Chem. 45, 3135 (1980)
30. P.-X. Wang, F. W. Moser, G. L. Cantrell, C. W. Grote, WO 2008036172A1 (2008)
31. M. Kitamura, Y. Hsiao, R. Noyori, Tetrahedron Lett. 28, 4829 (1987)
32. X.-Q. Wang, F. W. Moser, G. L. Cantrell, J. Bao, U.S. Patent, 7838677 B2 (2010)
33. C. Witterswil, U.S. Patent, 5905153 (1999)
34. T. Kumaraguru, N.W. Fadnavis, Org. Process Res. Dev. 18, 174 (2014)
35. J. Grussner, J. Hellerbach, A. Brossi, O. Schnider, Helv. Chim. Acta 39, 1371 (1956)
36. Y.K. Sawa, K. Kawasaki, S. Mayeda, Pharm. Bull. (Tokyo) 8, 960 (1960)
37. H.L. Goering, M.F. Sloan, J. Am. Chem. Soc. 83, 139 (1961)
38. G.A. Olah, J.M. Bollinger, D.P. Kelly, J. Am. Chem. Soc. 92, 1432 (1970)
39. S.A. Monti, S.-C. Chen, Y.-L. Yang, S.-S. Yuan, O.P. Bourgeois, J. Org. Chem. 43, 4062 (1978)
40. J. Sakurai, T. Kikuchi, O. Takahashi, K. Watanabe, T. Katoh, Eur. J. Org. Chem. 2948 (2011)
41. M. Michalak, K. Michalak, Z. Urbanczyk-Lipkowska, J. Wicha, J. Org. Chem. 76, 7497 (2011)
42. P.E. Eaton, G.R. Carlson, J.T. Lee, J. Org. Chem. 38, 4071 (1973)
123