Synthesis of an advanced precursor of Rivastigmine: Cinchona-derived quaternary ammonium salts as organocatalysts for stereoselective imine reductions

Article abstract of DOI:10.1016/j.tetlet.2015.08.086

The enantioselective reduction of ketoimines has been successfully realized, using trichlorosilane as the stoichiometric reducing agent in the presence of catalytic amounts of a Lewis base, specifically a Cinchona derivative. For the first time, a novel c

Full text of DOI:10.1016/j.tetlet.2015.08.086

Tetrahedron Letters 56 (2015) 5752–5756
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Tetrahedron Letters
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Synthesis of an advanced precursor of Rivastigmine:
Cinchona-derived quaternary ammonium salts as organocatalysts
for stereoselective imine reductions
a
a
a
Andrea Genoni a, Maurizio Benaglia a,b, , Emanuele Mattiolo , Sergio Rossi , Laura Raimondi ,
⇑
Pedro C. Barrulas c, Anthony J. Burke c,
⇑
a Dipartimento di Chimica, Universita’ degli Studi di Milano, via Golgi 19, I-20133 Milano, Italy
b Istituto di Scienze e Tecnologie Molecolari, ISTM-CNR, via Golgi 19, I-20133 Milano, Italy
c Department of Chemistry and Chemistry Center of Évora, University of Évora, Rua Romão Ramalho, 59, 7000 Évora, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective reduction of ketoimines has been successfully realized, using trichlorosilane as the
stoichiometric reducing agent in the presence of catalytic amounts of a Lewis base, specifically a Cinchona
derivative. For the first time, a novel class of derivatives was studied, featuring a picolinamide unit bound
to the alkaloid scaffold, further functionalized as quaternary ammonium salt at the quinuclidine ring.
Excellent yields and from good to high enantioselectivities (up to 92% ee) were obtained in the reduction
of ketoimines. The novel catalysts were successfully employed in the synthesis of an enantiomerically
pure advanced precursor of the blockbuster drug Rivastigmine.
Received 30 June 2015
Revised 10 August 2015
Accepted 31 August 2015
Available online 1 September 2015
Keywords:
Ketoimine reduction
Chiral amines
Ó 2015 Elsevier Ltd. All rights reserved.
Cinchona alkaloid derivatives
Rivastigmine
Trichlorosilane
The reduction of carbon–carbon and carbon–nitrogen double
bonds is one of the most important chemical transformations since
it leads very often to the generation of new stereocenters in the
molecule. The control of the stereochemical outcome of the
reduction process, in an attempt to obtain preferentially one
stereoisomer over the other ones, requires the use of a ‘chiral tech-
nology’. Despite several difficulties and many open questions,
enantioselective catalysis is the modern answer to this question
and the key of all future technologies.1 The replacement of
organometallic systems with equally efficient metal-free catalysts2
represents a further attractive opportunity, in view of possible
applications in the future of non toxic, low cost, and environmen-
tally friendly promoters on industrial scale.3
This holds true also in the case of enantioselective reduction of
carbon–nitrogen double bond, that leads to the formation of chiral
amines, compounds of extraordinary importance in different
fields,4 specially as pharmaceutical products, where complexity
and multifunctionality call for methodologies with high chemo-,
regio-, diastereo-, and enantiocontrol. Catalytic asymmetric
hydrogenation5 of imines represents a versatile method for access
to chiral nitrogen-containing substrates;6 however, stereoselective
hydrogenation of carbon–nitrogen double bonds is not very well
explored, due also to the possible deactivation and/or poisoning
of catalysts by molecules containing nitrogen and sulfur atoms.
Therefore organocatalytic methodologies7 offer an appealing alter-
native, since they may avoid problems due to the presence of toxic
metal, whose leaching could contaminate the product, a key point
for pharmaceuticals, agrochemicals, and fragrances.
One of the most developed metal-free methodologies to enan-
tioselectively reduce ketoimines relies on the use of the very cheap
and readily available trichlorosilane as the reducing agent in the
presence of a chiral Lewis base.8 Among the most successful basic
ligands used to activate HSiCl3, picolinamides have found great
success,9 due also to the easiness of their preparation, simply con-
necting picolinic acid to a chiral carbon skeleton.10
We have recently reported a novel group of Cinchona-based
picolinamides, which gave excellent results in the ketoimine
hydrosilylation.11 Noteworthy, remarkably high TOFs and very
short reaction times for imine hydrosilylation were observed, the
catalyst of choice being successfully active even at 1 mol % only.
Based on those very encouraging results, we decided to take
advantage of the great richness of functionalities featuring the
Cinchona alkaloids and explore a further structure variation of this
new family of catalysts.
⇑
Corresponding authors. Tel.: +39 0250314171; fax: +39 0250314159 (M.B.).
E-mail address: maurizio.benaglia@unimi.it (M. Benaglia).
http://dx.doi.org/10.1016/j.tetlet.2015.08.086
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

A. Genoni et al. / Tetrahedron Letters 56 (2015) 5752–5756
5753
Indeed, quinine (and quinidine) derivatives are small yet com-
N
N
plex molecules containing five stereogenic centers, a basic and
nucleophilic quinuclidine, a quinoline unit, a secondary alcohol,
an aryl methyl ether, and a terminal olefin (Fig. 1).12
OH
NH2
R
R
R = H or OMe
All of these points of molecular variety have been extensively
exploited for the facile modification of the naturally occurring
alkaloids to develop synthetic, tailor-made compounds for specific
applications. It is also known that Cinchona alkaloids can adopt in
solution several conformations; solvent change, protonation, or
quaternarization of the N-quinuclidine moiety may induce three-
dimensional structural modifications. Therefore we decided to
exploit the unique molecular recognition abilities of this natural
scaffold and to further explore the catalytic behavior of newly
modified Cinchona-derived picolinamides, characterized by the
presence of quaternary ammonium salt as additional steric and
electronic element of stereocontrol (Fig. 1).
N
N
Ar
Br
N
H
N
H
N
N
N
N
O
R
O
R
N
N
Scheme 1. Synthetic sequence for the preparation of novel Cinchona-based
catalysts for enantioselective hydrosilylation of imines.
In synthesizing the novel metal-free catalysts, we followed the
synthetic plan described in Scheme 1. Starting from the naturally
occurring alkaloid, the C9-hydroxyl group was easily converted
into the corresponding amine in a three step preparation and a sin-
gle purification;13 the amino-Cinchona derivative was then reacted
with picolinic acid to afford an enantiomerically pure picoli-
namide.11 Finally the reaction with benzyl bromide (or analog acti-
vated bromide) afforded the desired novel chiral Lewis base,
featuring a quaternary ammonium salt.
This straightforward and experimentally very simple synthesis
allowed the preparation of different Cinchona alkaloid derivatives
in good and reliable yields. Some representatives of this new fam-
ily of catalysts for enantioselective hydrosilylation of ketoimines
are reported in Figure 2. Epi-cinchonine and epi-cinchonidine qua-
ternary ammonium salts 1–3 were prepared, as well as analogous
epi-quinidine derivatives 4–6, typically by quaternarization of the
quinuclidine ring by reaction with benzyl or methyl bromide.14
For the sake of comparison in picolinamides 7–9, non functional-
ized at the quinuclidine ring, are reported in Figure 2.15
thus confirming the trend already observed in our previous work.11
However, poorer results were obtained with compound 3, which
features a more sterically hindering arylmethyl moiety at the quin-
uclidine nitrogen, clearly showing that it is not possible to directly
correlate the catalyst stereochemical efficiency with the bulkiness
of the ammonium salt substituent.
It is worth noting that molecules 1–9 are representatives of a
wide class of multifunctional chiral Lewis bases, as chiral catalysts
for stereoselective reductions, characterized by multiple possible
modes of action. Indeed, while compounds 7–8 feature the picoli-
namide group as coordinating unit to HSiCl3, and the basic quinu-
clidine ring that can also play a role in the activation of the
reducing agent, catalyst 2 has the only picolinamides as activating
unit of trichlorosilane. Furthermore, catalyst 9 might still behave as
a bifunctional catalyst, presenting a different coordination mode,
with the carboxyamide group and the quinuclidine nitrogen atom,
while catalyst 6 probably functions as a monodentate catalyst.
Further studies are required in order to further determine the dif-
ferent possibilities that the Cinchona scaffold can offer, principally
for tuning the catalyst behavior by exploiting steric and electronic
modifications in the catalyst structure.
All the catalysts were preliminarily tested in the model reac-
tion, the hydrosilylation of the N-phenyl-imine of acetophenone
(Table 1), using 3 mol equiv of trichlorosilane and 10 mol% of the
catalyst in dry DCM, for 18 h at 0 °C (Scheme 2).
Once 2 was identified as the most promising catalyst, a screen-
ing of the reaction conditions, that is, solvent and temperature, was
performed; the results are reported in Table 2.
While high chemical yields could be obtained in different reac-
tion media, chlorinated solvents seem to be the best option to guar-
antee high levels of enantioselectivity at 0 °C; while the reaction at
22 °C led to the formation of the chiral amine in lower enantioselec-
tion, by decreasing the temperature it was possibly to further
improve the enantioselection of the process, up to 92% ee, although
with a harsh drop in chemical yield. Finally, the catalyst loading was
In all cases excellent yields were obtained; as expected,
Cinchonine and Cinchonidine derivatives behaved as quasi-
enantiomers and led to the formation of the products with opposite
absolute configuration. Enantioselectivities range from modest to
very good (up to 87% ee), with epi-cinchonine derivative 2 per-
forming clearly better than epi-quininidine-derived catalysts 4–6
(Table 1). From the reported results, it can be noted that the benzyl
salt 2 showed an improvement compared to the parent catalyst 7
and that the picolinamides derived from Cinchonine (2) performed
slightly better than the catalyst synthesized from Cinchonidine 1,
(R)
(R)
R
H
R
N+
H
Structural modification by
- Salification of the tertiary amine
N
(R)
(R)
(R)
(R)
Ar
N
NH
NH
N
N
N
O
O
Quaternary ammonium salt
Additional stereocontrol element
- Electrostatic perturbation of the
secondary amine/amide
R = OAlk : higher steric hindrance
R = OH : hydrogen-bonding interactions
- Tuning of the steric shielding by
modulation of the anion
Figure 1. Novel Cinchona-based picolinamides featuring quaternary ammonium salts.

5754
A. Genoni et al. / Tetrahedron Letters 56 (2015) 5752–5756
Br
Br
Cl
N
H
N
H
N
N
H
N
N
N
N
N
O
O
O
N
N
N
1
2
3
I
Br
BF4
I
N
H
N
H
N
H
N
N
N
N
N
N
O
MeO
O
MeO
O
MeO
N
N
N
6
4
5
BF4
O
N
N
H
N
N
H
H
N
N
N
N
N
O
O
MeO
N
N
N
7
8
9
Figure 2. Cinchona alkaloid quaternary ammonium salts and analogs as catalysts for enantioselective trichlorosilane addition to imines.
Table 1
In the attempt to test the applicability of the new catalysts in
Stereoselective hydrosilylation of N-phenyl-imine of acetophenone promoted by
the synthesis of a product of pharmaceutical interest, we per-
formed a preliminary investigation directed at the synthesis of an
advanced Rivastigmine precursor.16
catalyst 1–9a
Entry
Catalyst
Yield %b
ee %c
At the beginning of our studies, we investigated the possibility
to perform the enantioselective reduction directly on the N-PMP
imine 13 easily obtained from the commercially available ketone
12. However the modest enantioselectivities observed prompted
us to protect the phenolic group as benzyl ether, to give ketone
15 (Scheme 3).
1
2
3
4
5
6
1
2
3
4
5
6
7
8
9
91
98
67
93
91
87
97
98
75
75 (S)
87 (R)
67 (R)
43 (R)
51 (R)
65 (R)
77 (R)
87 (R)
90 (S)
7
8d
9d
a
Typical experimental conditions: 0.1 mol equiv of catalyst, 1 mol equiv of
imine, 3,5 mol equiv of trichlorosilane, 18 h reaction time in DCM at 0 °C.
b
Table 2
Yields of isolated products.
As determined by HPLC on a chiral stationary phase; yields and ee are average
c
Optimization studies for the enantioselective reduction of N-phenyl-imine of
acetophenone 10 catalyzed by 2a
of duplicate experiments.
d
Entry
T (°C)
Solvent
Yield %b
ee %c
As reported in the literature (see Ref. 13).
1
2
3
4
5
6
7
0
0
0
0
0
À20
À40
0
0
22
22
DCM
CHCl3
Et2O
98
95
97
98
98
67
33
95
83
91
92
87
87
31
23
53
83
92
86
85
71
73
also briefly investigated; we were happy to see that catalyst 2 could
maintain its activity also when used at loadings of 5 mol% or even
1 mol% (entries 8 and 9 of Table 2), always affording the chiral amine
with comparable enantioselectivity.
THF
CH3CN
DCM
DCM
DCM
DCM
DCM
CHCl3
8d
9e
10
11
Ph
Ph
N
HN
*
HSiCl3 (3.5 eq.), cat.
a
CH2Cl2, 18 h, 0 °C
Unless different specifications, typical experimental conditions were:
0.1 mol equiv of catalyst, 1 mol equiv of imine, 3,5 mol equiv of trichlorosilane, 18 h
reaction time at 0 °C.
b
10
11
Yields of isolated products.
Enantiomeric excess determined by HPLC analysis on a chiral stationary phase.
Reaction was run with 5 mol% cat. at 0 °C.
c
d
Scheme 2. Screening of catalysts 1–9 in the enantioselective hydrosilylation of
N-phenyl imine of acetophenone.
e
Reaction was run with 1 mol% cat. at 0 °C.

A. Genoni et al. / Tetrahedron Letters 56 (2015) 5752–5756
5755
NMe2
N
O
O
RIVASTIGMINE
PMP
PMP
PMP
Ph
O
N
HN
HO
HO
HO
13
16
14
12
PMP
N
HN
BnO
BnO
O
17
BnO
Ph
15
N
HN
BnO
BnO
18
19
Scheme 3. Preliminary studies on the synthesis of Rivastigmine.
The O-benzyl protected ketone was then converted into two
different ketimines, the N-PMP protected imine 16 and imine 18
obtained through the reaction with (S)-phenyl ethylamine.17 The
reduction of imine 16 afforded the product in good yield but
modest enantioselectivity,18 even at a lower reaction temperature
(entries 3 and 4, Table 3).19
However, the reduction of imine 18 led to the formation of the
expected chiral amine 19 in 81% yield with virtually complete
diastereocontrol as observed by NMR spectroscopy.20 The same
chiral amine was obtained with high stereoselectivity using cata-
lyst 9, while, as expected, less stereocontrol was observed when
the mismatch combination of imine 18 and catalyst 8 was
employed. The deprotection by hydrogenolysis of intermediate
19 would afford an advanced precursor of the target molecule,21
thus providing a very promising and straightforward route to
enantiomerically pure Rivastigmine.
In conclusion, we have reported a new class of Cinchona deriva-
tives, featuring a picolinamide unit bound to the alkaloid scaffold,
further functionalized as a quaternary ammonium salt at the
quinuclidine ring. The best catalyst was able to promote the reduc-
tion of N-phenyl imine of acetophenone in up to 92% ee. The new
catalysts were also successfully employed in preliminary studies
aimed at the development of an easy and straightforward prepara-
tion of the blockbuster drug Rivastigmine. The main feature of the
described class of catalysts is their high tunability, coupled with
the capacity to modulate both the electronic and the steric
properties as well as to explore different coordination modes,
experimenting with different combinations of the coordinating
units (carboxyamide, pyridine ring, and quinuclidine moiety).
Acknowledgments
M.B. thanks COST action CM9505 ‘ORCA’ Organocatalysis. A.G.
acknowledges University of Milano for a PhD fellowship. S.R.
acknowledges University of Milano for a Postdoctoral fellowship.
Table 3
Preliminary investigation on the possible synthetic strategies for the enantioselective
synthesis of Rivastigminea
PCB is grateful for the award of
a PhD Grant (SFRH/
Entry
Catalyst
Substrate
Reduction product
Yield %b
ee %c
BD/61913/2009) from the Fundação para a Ciência e a Tecnologia
(FCT). This work was financed from the strategic project PEst-OE/
QUI/UI0619/2014. A.J.B. is grateful for a Grant from INMOLFAR-
Molecular Innovation and Drug Discovery (ALENT-57-2011-20)
financed from the FEDER-INALENTEJO program ALENT-07-0224-
FEDER-001743.
1
2
1
13
13
16
16
18
18
18
14
14
17
17
19
19
19
44
35
85
51
81
73
65
65
55
43
Ent-8
3
1
1
1
8
9
4d
5
65
>96e
68e
94e
6
7
a
Unless different specifications, typical experimental conditions were:
Supplementary data
0.1 mol equiv of catalyst, 1 mol equiv of imine, 3,5 mol equiv of trichlorosilane, 18 h
reaction time at 0 °C.
b
Supplementary data (copies of 1H and 13C NMR spectra of new
catalysts. 1H NMR spectra and HPLC chromatograms on chiral
stationary phase of products of reduction of ketoimines) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2015.08.086.
Yields of isolated products.
As determined by HPLC on a chiral stationary phase; yields and ee are average
c
of duplicate experiments.
d
Reaction was run at À20 °C.
e
dr ratio was determined by 1H MR spectroscopic on the crude reaction mixture
and confirmed after chromatographic purification.

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A. Genoni et al. / Tetrahedron Letters 56 (2015) 5752–5756
11. Barrulas, P. C.; Genoni, A.; Benaglia, M.; Burke, A. J. Eur. J. Org. Chem. 2014,
References and notes
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12. Reviews: (a) Marcelli, T.; Hiemstra, H. Synthesis 2010, 8, 1229–1279; (b)
Melchiorre, P. Angew. Chem., Int. Ed. 2012, 51, 9748–9770.
13. Song, C. E. Cinchona Alkaloids in Synthesis and Catalysis; Wiley-VCH: Weinheim,
2009.
14. For details on the synthesis, isolation and characterization of the novel catalyst
see the Supporting information.
15. See Ref. 11 and also (a) Barrulas, P.C.; Burke, A. J. Patent Application, PCT/
IB2014/065128. 8–10–2013; (b) Barrulas, P.C. (PhD Dissertation), Univ. Evora,
2014.
16. (a) Polinsky, R. J. Clin. Ther. 1998, 20, 634–647; (b) Farlow, M. R.; Cummings, J.
L. Am. J. Med. 2007, 120, 388–397; For different strategies for the synthesis of
Rivastigmine see: Yan, P. C.; Zhu, G. L.; Xie, J. H.; Zhang, X. D.; Zhou, Q. L.; Li, Y.
Q.; Shen, W. Q.; Che, D. Q. Org. Process Res. Dev. 2013, 17, 307–312.
17. For the use of a chiral auxiliary in combination with a chiral catalyst as highly
efficient method to synthesize virtually enantiomerically pure chiral amines,
see Ref. 9d and also Guizzetti, S.; Biaggi, C.; Benaglia, M.; Celentano, G. Synlett
2010, 134–136. and; Guizzetti, S.; Benaglia, M.; Bonsignore, M.; Raimondi, L.
Org. Biomol. Chem. 2011, 9, 739–743.
1. (a) Okhuma, T.; Noyori, R. In Comprehensive Asymmetric Catalysis, Suppl. 1;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 2004; (b)
Trindade, A. F.; Afonso, C. A. M. Chem. Rev. 2009, 109, 3401.
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3. Review: Busacca, C. A.; Fandrick, D. R.; Song, J. J.; Senanayake, C. H. Adv. Synth.
Catal. 2011, 252, 1825–1864.
4. For a recent review on chiral amine synthesis see: Nugent, T. C.; El-Shazly, M.
Adv. Synth. Catal. 2010, 352, 753–819.
5. For general reviews on asymmetric hydrogenation, see: (a) Palmer, A. M.;
Zanotti-Gerosa, A. Curr. Opin. Drug Discovery Dev. 2010, 13, 698; (b) Shang, G.;
Li, W.; Zhang, X. Transition Metal-Catalyzed Homogeneous Asymmetric
Hydrogenation. In Catalytic Asymmetric Synthesis; Ojima, I., Ed., third ed.;
Wiley: Hoboken, 2010; pp 343–436.
6. For reviews on metal-catalyzed hydrogenation of imines and heteroaromatic
systems see: Fleury-Bregeot, N.; de le Fuente, V.; Castillon, S.; Claver, C. Chem.
Cat. Chem. 2010, 2, 1346; Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357–1371; See
also: Glorius, F. Org. Biomol. Chem. 2005, 3, 4171–4175.
18. Typical imine reduction: the catalyst (0.02 mmol, 0.1 equiv) and a solution
0.9 M of the imine in dry CH2Cl2 (0.2 mmol, 1 equiv) were introduced in a
10 mL vial under N2 atmosphere and further diluted in 2 mL of dry CH2Cl2. The
mixture was cooled to the desired temperature and stirred for 15 min, after
which a solution 1.6 M in CH2Cl2 of HSiCl3 (0.7 mmol, 3.5 equiv) was added.
The mixture was stirred for 18 h, then quenched with NaOH 10% aq. until a
basic pH was reached, stirred at room temperature for 30 min, filtered over
celite pad, and washed with CH2Cl2 (10 mL) and ethyl acetate (10 mL). The
solvent was removed under reduced pressure and the desired amines were
purified by flash column chromatography on silica gel. Absolute configuration
was determined by comparison of the sign of the optical rotation of the
product with literature data.
7. For reviews on organocatalyzed enantioselective reductions see: (a) Benaglia,
M.; Genoni, A.; Bonsignore, M. Enantioselective Organocatalytic Reductions. In
Stereoselective Organocatalysis: From C–C to C-heteroatom bond formation; Rios
Torres, R., Ed.; Wiley, 2012; (b) Rossi, S.; Benaglia, M.; Massolo, E.; Raimondi, L.
Catal. Sci. Technol. 2014, 9, 2708–2723.
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Jones, S.; Warner, C. J. A. Org. Biomol. Chem. 2012, 10, 2189–2200.
9. Selected picolinamides catalysts: (a) Onomura, O.; Kouchi, Y.; Iwasaki, F.;
Matsumura, Y. Tetrahedron Lett. 2006, 47, 3751–3754; (b) Zheng, H.; Deng, J.; Li,
W.; Zhang, X. Tetrahedron Lett. 2007, 48, 7934–7937; (c) Guizzetti, S.; Benaglia,
M.; Annunziata, R.; Cozzi, F. Tetrahedron 2009, 65, 6354–6363; (d) Guizzetti, S.;
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M.; Celentano, G. Eur. J. Org. Chem. 2009, 65, 3683–3687; (f) Jiang, Y.; Chen, X.;
Zheng, Y.; Xue, Z.; Shu, C.; Yuan, W.; Zhang, X. Angew. Chem., Int. Ed. 2011, 50,
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Yuan, W.; Zhang, X. Adv. Synth. Catal. 2013, 355, 1931–1936; (h) Genoni, A.;
Benaglia, M.; Massolo, E.; Rossi, S. Chem. Commun. 2013, 8365–8367.
10. Selected, representative references for non picolinamide-based catalysts: (a)
19. The reduction with catalyst 1 of the 3-methoxy-protected N-PMP ketoimine at
0 °C gave comparable results (81% yield, 37% ee).
20. N-(1-(S)-Phenylethyl)-ethan-1-(3-(benzyloxy)phenyl)-1-amine 19. The crude
NMR showed the presence of product with >96% diastereoisomeric ratio. The
product was purified by flash column chromatography on silica gel with a 8:2
hexane/ethyl acetate mixture as eluent. Rf = 0.21. title compound was obtained
in 81% yield. 1H NMR (300 MHz, CDCl3) d: 7.47–7.20 (m, 11H), 6.89–6.87 (m,
ˇ
´
Malkov, A. V.; Mariani, A.; MacDougal, K. N.; Kocovsky, P. Org. Lett. 2004, 6,
2H), 6.81 (d, 1H, J = 7.5 Hz), 5.08 (s, 2H), 3.49 (m, 2H) 1.26 (d, 6H, J = 6.3 Hz). 13
C
2253–2256; (b) Malkov, A. V.; Liddon, A. J. P. S.; Ramírez-López, P.; Bendová, L.;
NMR (75 MHz, CDCl3) d 159.05, 147.72, 145.77, 137.16, 129.42, 128.60, 128.42,
127.95, 127.56, 126.71, 119.41, 113.08, 69.96, 55.11, 24.94. MS (ESI+):
m/z = calcd for C23H25NO+ = 331.19, found 332.0 [M+H].
ˇ
´
Haigh, D.; Kocovsky, P. Angew. Chem., Int. Ed. 2006, 45, 1432–1435; (c) Pei, D.;
Wang, Z.; Wei, S.; Zhang, Y.; Sun, J. Org. Lett. 2006, 25, 5913–5915; (d) Pei, D.;
Wang, Z.; Wei, S.; Zhang, Y.; Sun, J. Adv. Synth. Catal. 2008, 350, 619–623; (e)
Wu, X.; Li, Y.; Wang, C.; Zhou, L.; Lu, X.; Sun, J. Chem. Eur. J. 2011, 17, 2846–
2848; (f) Xiao, Y.-C.; Wang, C.; Yao, Y.; Sun, J.; Chen, Y.-C. Angew. Chem., Int. Ed.
2011, 50, 10661–10664; (g) Jones, S.; Li, X. Org. Biomol. Chem. 2011, 9, 7860–
7866; (h) Wang, Z. Y.; Wang, C.; Zhou, L.; Sun, J. Org. Biomol. Chem. 2013, 11,
787–797.
21. Hu, M.; Zhang, F. L.; Xie, M.-H. Synthetic Commun. 2009, 39, 1527–1533. In
preliminary experiments the hydrogenation of 19 with Pd/C (10% mol) under
10 atm at 60 °C for 12 h led to the formation of the deprotected amine in 40%
yield, along with variable amounts of O-debenzylated products. Optimization
studies are needed.