Simple preparation process of syn phenylpropanolamines from racemic O-TBDPS cyanohydrins

Article abstract of DOI:10.1080/00397911.2013.862835

In this article, a practically interesting route for the diastereoselective synthesis of phenylpropanolamines has been demonstrated for the first time. Using racemic O-tert-butyldiphenylsilyl (TBDPS) cyanohydrins as the starting materials, various syn phenylpropanolamines and derivatives (e.g., norpseudophedrine) have been successfully prepared in exellent diastereoselectivity via a practically interesting process.

Full text of DOI:10.1080/00397911.2013.862835

This article was downloaded by: [Newcastle University]
On: 02 May 2014, At: 08:37
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
A Simple Preparation Process of Syn
phenylpropanolamines From Racemic O-TBDPS
Cyanohydrins
Shi Tang a , Dong Zhou a , Qing-lan Li a & Xin-mei Tang a
a College of Chemistry and Chemical Engineering , Jishou University , Jishou , 416000 , China
Accepted author version posted online: 10 Feb 2014.Published online: 10 Feb 2014.
To cite this article: Shi Tang , Dong Zhou , Qing-lan Li & Xin-mei Tang (2014): A Simple Preparation Process of Syn
phenylpropanolamines From Racemic O-TBDPS Cyanohydrins, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2013.862835
To link to this article: http://dx.doi.org/10.1080/00397911.2013.862835
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

ACCEPTED MANUSCRIPT
Shi Tang
A simple preparation process
A simple preparation process of syn phenylpropanolamines from racemic O-TBDPS
cyanohydrins
Shi Tang1,, Dong Zhou1, Qing-lan Li1, Xin-mei Tang1
1College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000,
China
College of Chemistry and Chemical Engineering, Jishou University, Jishou 416000,
China, Tel.: +86-743-8563911; fax: +86-743-8563911; email: Shitang@126.com
Abstract
In this article, a practically interesting route for the diastereoselective synthesis of
phenylpropanolamines has been demonstrated for the first time. Using racemic O-TBDPS
(tert-butyldiphenylsilyl) cyanohydrins as the starting materials, various syn
phenylpropanolamines and derivatives (e.g. norpseudophedrine) have been successfully
prepared in exellent diastereoselectivity via a practically interesting process.
KEYWORDS: diastereoselective, O-TBDPS cyanohydrins, alkylation,
phenylpropanolamines, practically interesting
ACCEPTED MANUSCRIPT
1

ACCEPTED MANUSCRIPT
INTRODUCTION
Phenylpropanolamines (stereoisomers norephedrine and norpseudophedrine) and
derivatives are pharmacologically interesting compounds that display great potential
bioactivity in many major therapeutic areas, such as stimulants, 5HT2-receptor agonist,
bronchodilators, and antidepressants (Figure 1).[1-5] Moreover, phenylpropanolamines and
derivatives are widely used as chiral ligands and/or catalysts in a variety of asymmetric
reactions, such as ketone reduction or addition[6], aldol reaction,[7] amino acids
synthesis,[8] and rearrangement of epoxides.[9] In addition, these compounds are also of
great importantance as starting materials for the preparation of pharmaceutically
interesting chiral 2-oxazoline, piperidines.[10]
Given the growing therapeutic and synthetic importance of phenylpropanolamines and
derivatives, stereoselective synthetic approaches to those compounds are popularly
noteworthy target. In the past decade, a wide variety of methods have been reported in
this regard, including bioreduction of 2-azido-1-phenyl propanone,[11] asymmetric
reduction of 2-N-protected amino-1-phenylpropanone by chiral boronic reagents,[12]
regioselective azidolysis of chiral cis-β-methylstyrene oxides,[13] diastereoselective
reduction of chiral 2-hydroxyamino-1-phenylpropanone and/or
1-hydroxy-1-phenyl-2-propanone-2-O-methyloxime,[14] diastereoselective phenylation of
N-protectedalaninal derivatives,[15] etc. Among these methods, this method via sequential
alkylation/reduction of optically pure O-silyl protecting cyanohydrin represents one of
the most efficient routes for the synthesis of phenylpropanolamines and derivatives.[16]
ACCEPTED MANUSCRIPT
2

ACCEPTED MANUSCRIPT
However, success is currently limited to the preparation of anti phenylpropanolamines
(e.g. norephedrine), as well as in need of optically pure cyanohydrin as starting material
and tedious purifying procedures. With our continuing interest to prepare various
phenylpropanolamines,[17] we herein want to demonstrate a simple route for the
preparation of various phenylpropanolamines derivatives (e.g. norpseudophedrine) with a
syn configuration from simple racemic O-TBDPS cyanohydrins (Scheme 1).
RESULTS AND DISCUSSION
The synthesis route of desired phenylpropanolamines 3 was outlined as Scheme 2.
Initially, we studied the reaction parameters of alkylation reaction with alkyl Grignard
reagents. We found that O-silyl protecting group of cyanohydrin 1 played a crucial role in
the alkylation reaction with Grignard reagent (Table 1). Obvious desilylprotonation was
detected when using TMS as an O-silyl group (entry 1). Next screening discovered that
some more bulk O-silyl groups (e.g. TBDPS) were robust enough to tolerate strong base
RMgBr/I. Moreover, we were happy to find that the sequential alkylation/reduction, in
the presence of tert-butyldiphenylsilyl (TBDPS) group, underwent smoothly to provide
the syn phenylpropanolamine 2 unexpectedly (entries 2 and 3)[18]. The effect of the
Grignard reagents in the alkylation process was next examined, and the results showed
that halo anion and solvent were also important for the success (entries 3-6). Using
MeMgX (X = I/Br) as methylation reagent, the methylation of cyano group proceeded
smoothly, and provide desired O-silyl phenylpropanolamine in excellent
diatereoselectivity (92%, d.r. > 95:5), whereas MeMgCl, a more strong base than
ACCEPTED MANUSCRIPT
3

ACCEPTED MANUSCRIPT
MeMgX (X = I/Br), was observed to remove the O-silyl group of cyanohydrin seriously.
Subsequential screening discovered the solvent dissolving MeMgX was also of great
importance. Diethyl ether was the most efficient solvent for the alkylation reaction
(entries 4-6). Note that methylation by using MeMgI/Br in THF yielded many
unidentified side-products.
Next, we examined the deprotection of O-silyl group (Scheme 3). First, TBAF
(tetrabutylammonium fluoride), a typical fluoride reagent removing O-silyl group, was
examined, and the deprotection of the bulky O-TBDPS proceeded sluggishly, and was
also accompanied by extensive racemization and formation of unidentified byproduct.
Thus, we switched our efforts to screen other fluoride reagents including HF-pyridine,
aqueous HF. Delightedly, HF (aq. 30%) in acetonitrile was proved to be highly effective,
and provided nearly pure norpseudophedrine without above-mentioned undesired effects
(e.g. racemization, formation of unidentified by-product).
The norpseudophedrine could be readily converted to their HCl salts by treating them
with hydrogen chloride gas in Et2O (Scheme 4). Note that the resulting HCl salts (a white
flocky precipitate) was obtained in good yield with high diastereoselectivity (d.r. > 95:5)
by 1H NMR analysis.
With optimal reaction parameters for the synthesis of phenylpropanolamines HCl salts in
mind, we focused on the development of synthetic route through a simple process without
tedious purifying operation. After screening various effect parameters, we finally
obtained a practical cascade process (Scheme 5). At the outset, silylation protection with
ACCEPTED MANUSCRIPT
4

ACCEPTED MANUSCRIPT
tBu(Ph)2SiCl reagent, using the mixture of cyanohydrin stereoisomers 1a as starting
material, proceeded smoothly to afford the O-silyl compound 1b in good yelds (> 90%).
After simple work-up, the resulted crude compound 1b was treated with MeMgI in Et2O,
and thus obtained imine via the methylation process could be reduced by NaBH4 to
provide desired O-silyl phenylpropanolamine. Finally, the crude norpseudophedrine was
converted into its HCl salt by treating with a HCl gas, and then recrystallizing in
Et2O/EtOH (v:v = 20:1) would give pure norpseudophedrine HCl salt with good
diastereoselectivity.
With practically interesting cascade process in hand, we next examed the substrate
scope (Scheme 6). Expectedly, we successfully synthesized a series of
phenylpropanolamines bearing different substituents. Through a similar synthetic process
for 3a, the reactions of O-TBDPS cyanohydrin with EtMgBr and BnMgBr provided
corresponding phenylpropanolamine derivatives 3b and 3c in 51 and 43% yield
repectively. Noteworthily, the process using cyanohydrin 1d aslo provided the desired
phenylpropanolamine 3d in a practical-accepted yield (52%). However, the attempt to
prepare phenyl substituted phenylpropanolamine 3e did not succeed.
The controllably stereoselective alkylation reaction is understood in term of the
catalytic cycles shown in Scheme 7.[16][19] For the stereoisomer 1a’ of O-TBDPS
cyanohydrin 1a, the insertion of MeMgI into cyano group of O-silyl cyanohydrin would,
owing to substantial collision between bulk siyl group (O-TBDPS) and Mg species, be
difficulty to form five-membered intermediate B’ via the coordination of Mg2+ species to
ACCEPTED MANUSCRIPT
5

ACCEPTED MANUSCRIPT
oxygen atom of O-TBDPS group (cram-chelating model) through which to give anti
reduction product.[16][20] Instead, the intermediate B would be favored to form in the
insertion process, which was followed by reduction elimination/deprotection steps to
afford desired syn product 3a’. On the other hand, another stereoisomer 1a” would
provide the syn product 3a” via a similar working mechanism process. Note that bulky
O-silyl group TBDPS is crucial to achieve syn diasteroselectivity in this transformation,
whereas they can also be readily to be removed to give practically important primary
amines.
CONCLUSIONS
In summary, we developed a practically interesting route for the synthesis of
pharmeceutical importance syn phenylpropanolamines for the first time. It would open a
door for the diasteroselective alkylation/reduction of racemic O-silyl cyanohydrin with
alkyl Grignard reaction to prepare syn phenylpropanolamines via a proximal O-TBDPS
sily group. The detail mechanism and application of the practical route to more complex
targets are currently under study in our laboratory.
EXPRRIMENTAL
All reactions were carried out under nitrogen atmosphere in flame-dried glassware.
Syringes which were used to transfer anhydrous solvents or reagents were purged with
argon prior to use. NMR spectra were recorded on solutions in deuterated chloroform
(CDCl3) with residual chloroform (δ 7.26 ppm for 1H NMR and δ 77.0 ppm for 13C
NMR). Abbreviations for signal coupling are as follows: s, singlet; d, doublet; t, triplet; q,
ACCEPTED MANUSCRIPT
6

ACCEPTED MANUSCRIPT
quartet; m, multiplet, br, broad. Column chromatographical purifications were performed
using SiO2 (0.040 – 0.063 mm, 230 – 400 mesh) from Merck. Unless otherwise noted,
commercial available starting materials were purchased from commercial sources and
used without further purification. RMgBr/I was prepared from the insertion of Mg into
alkyl bromide/iodine in Et2O.[21]
Typical Procedure For The Synthesis Of Norpseudophedrine Hcl Salts 3a
To O-silyl cyanohydrin 1a (3.7 g, 10 mmol) in Et2O (10 mL) was added a 1.0 M solution
of MeMgI in Et2O (12 mL), and the resulting mixture was stirred for 2 h at rt, and then
was added dry MeOH (20 mL) slowly over 2 min at 0 0C, and then NaBH4 (0.76g, 20
mmol), and the mixture continued to be stirred for more 12 h at rt. After removal of
solvent in vacuo, the residue was extracted with EtOAc (50 ml x 5), and the combined
organic layers were washed with water and then brine, and dried over anhydrous MgSO4
to provide crude 2a. After concentration in vacuo, the residue was treated with a 30% of
aqueous HF (2 mL) in MeCN (20 mL) in a teflon flask, and stirred at 80 oC for 24 h.
Before extracting with DCM (50 mL x 3), the resulting mixture was neutralized by 6 N
NaOH solution at 0 oC. After work-up, the residue was diluted in Et2O (20 mL), and
treated with a HCl gas untill white flocky precipitate didn’t generate any more. The
resulted white solid was recrystallized in a mixture of Et2O-EtOH (v/v = 20:1) to the
titled compound 3a (0.77 g, 51%) as a white solid. M.p.(oC): 168.5-169.5 oC, 1H NMR
(400 MHz, D2O) δ: 7.51-7.42 (m, 5H), 4.97 (d, J = 4.4 Hz, 1H), 4.79 (br, 3H), 3.72-3.67
(m, 1H), 1.20 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 138.7, 129.2, 128.9,
ACCEPTED MANUSCRIPT
7

ACCEPTED MANUSCRIPT
127.2, 73.2, 52.5, 12.8. IR (KBr, cm-1) ν 3375, 3265. 1227, 1030，955，805，HRMS (EI):
calcd for C9H13NO: 151.0997, found: 151.0994
ACKNOWLEGGMENTS
We thank the Scientific Research Fund of Hunan Provincial Education Department (No.
13B094) and Research-based Learning and Innovative Experiment Project of Joshua
University (No.JSU-CX-2013-03) for financial support.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website. Please
make the words “publisher’s website” a live DOI link.
REFERENCE
[1]
Doe, I. S.; Smith, J.; Roe, P. J. Am. Chem. Soc. 1968, 90, 8234.
Hanson, G. R.; Venturelli, P. J.; Fleckenstein, A. E. Drugs and society. Jones and
Bartlett Publishers. 9th Ed., 2005.
[2]
[3]
[4]
[5]
[6]
Nakamura, M.; Ishii, A.; Nakahara, D. Eur. J. Pharmacol. 1998, 349, 163.
Yang, H. Y.; Neff, N. H. J. Pharmacol. Exp. Ther. 1973, 187, 365.
Maryanoff, B. E.; Nortey, S. O.; Gardocki, G. E. J. Med. Chem. 1984, 27, 1067.
(a) Liu, P. N.; Chen, Y. C.; Li, X. Q.; Tu, Y. Q.; Deng, J. G. Tetrahedron: Asymmetry,
2003, 14, 2481. (b) Balakrishnan, U.; Ananthi, N.; Velmathi, V. Tetrahedron: Asymmetry,
2009, 20, 1150-1153. (c) Unaleroglu, C.; Aydin, A. E.; Demir, A. S. Tetrahedron:
Asymmetry, 2006, 17, 742. (d) Wolf, C.; Hawes, P. A.; J. Org. Chem. 2002, 67, 2727.
ACCEPTED MANUSCRIPT
8

ACCEPTED MANUSCRIPT
[7]
(a) Abiko, A. Org. Synth. 2002, 79, 116. (b) Kurosu, M.; Lorca, M. J. Org. Chem.
2001, 66, 1205. (c) Andrus, M.B.; Soma Sekhar, B. B. V.; Turner, T. M.; Meredith, E. L.
Tetrahedron Lett. 2001, 42, 7197. (d) Ji, Y. Q.; Qi, G..; Judeh, Z. M. A. Tetrahedron:
Asymmetry, 2011, 22, 2065.
[8]
(a) Wiel, M. K. J.; Arnold, M.; Peter, S.; Troltsch, I.; Merget, S.; Glaser, F.;
Schwarm, M.; Bhatti, H. S.; Kuriakose, B.; Pol, S. S.; Balamurugan, M.; Joshi, V. V.,
Tetrahedron: Asymmetry, 2009, 20, 478. (b) Vicario, J. L.; Badía,D.; Carrillo, L. Org.
Lett. 2001, 3, 773. (c) Nagula, G.; Huber, V. J.; Lum, C.; Goodman, B. A. Org. Lett.
2000, 2, 3527. (d) Meyers, A. G.; Gleason, J. L. Org. Synth. 1998, 76, 57 and references
cited therein.
[9]
[10]
[11]
(a) de Sousa, S. E.; O Brien, P.; Pilgram, C. D. Tetrahedron 2002, 58, 4643. (b)
Brookes, P. C.; Milne, D. J.; Murphy, P. J.; Spolaore, B. Tetrahedron 2002, 58, 4675. (c)
Colman, B.; de Sosa, S. E.; O Brien, P.; Towers, T. D.; Waston, W. Tetrahedron:
Asymmetry 1999, 10, 4175.
(a) Kamata, K.; Agata, I.; Meyers, A. I. J. Org. Chem. 1998, 63, 3113. (b) Agami,
C.; Couty, F.; Evano, G. Tetrahedron: Asymmetry 2000, 11, 4639. (c)Van, T. N.; De
Kimpe, N. Tetrahederon 2000, 56, 7299. (d) Boland, N. A.; Casey, M.; Hynes, S. J.;
Matthews, W.; Smyth, M. P. J. Org. Chem. 2002, 67, 3919.
(a) Besse, P.; Veschambre, H.; Dickman, M.; Chênevert, R. J. Org. Chem. 1994, 59,
8288. (b) Moran, P. J. S.; Rodrigues, J. A. R.; Joekes, I.; Brenelli, E. C. S.; Leite, R. A.
ACCEPTED MANUSCRIPT
9

ACCEPTED MANUSCRIPT
Biocatalysis 1994, 9, 321. (c) Lee, H.-K.; Kang, S.; Choi, E. B. J. Org. Chem. 2012, 77,
5454.
[12]
Kim, D. J.; Cho, B. B. Bull. Korean Chem. Soc. 2003, 24, 1641. (b) Cho, B. T.,
Chem Soc Rev, 2009, 38, 443
[13]
[14]
Brandes, B. D.; Jacobsen, E. N. Synlett, 2001, 1013.
Kreutz, O. C.; Moran, P. J. S.; Rodrigues, J. A. R. Tetrahedron: Asymmetry, 1997,
8, 2649.
[15]
[16]
[17]
(a) Reddy, G. V.; Rao, G. V.; Sreevani, V.; Iyengar, D. S. Tetrahedron Lett. 2000,
41, 953. (b) Gusselin, F.; Betsbrugge, J. V.; Hatam, M.; Lubell, W. J. Org. Chem. 1999,
64, 2489.
(a) Effenberger, F.; Gutterer, B.; Jäger, J. Tetrahedron: Asymmetry, 1997, 8, 459; (b)
Effenberger, F.; Eichhorn, J. Tetrahedron: Asymmetry, 1997, 8, 469. (c) Effenberger, F.;
Jäger, J. Chem, Eur. J. 1997, 3, 1370.
(a) Tang, S.; Li, S.; Zhou, D.; Zeng, H.; Wang, N.-X. Science China Chemistry,
2013, 57, Online first (doi: 10.1007/s11426-013-4880-2). (b) Tang, S.; Zhou, D.; Li, S.
Wang, N.-X. Chem. Res. Chin. Univ. 2013, 29, 678-681. (c) Tang, S.; Takeda, M.; Nakao,
Y.; Hiyama, T. Chem. Commun. 2011, 47, 307-209.
[18]
The diastereoselectivity (syn and anti) of product 2a was, after removing O-TBDBS
group, determined via 1H NMR analysis comparing with the commercial
norpseudophedrine and norephedrine
ACCEPTED MANUSCRIPT
10

ACCEPTED MANUSCRIPT
[19]
Eliel, E. L. Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York,
1983; Vol. 2, chapter 2 and references cited therein.
[20]
[21]
Seyferth, D. Org. Synth. Coll. Vol. IV, 1963, 258.
Oshima, K. Main group metal in organic synthesis, Eds.: Yamamoto, H.; Oshima,
K. wiley-VHC, Weinheim, 2004.
ACCEPTED MANUSCRIPT
11

ACCEPTED MANUSCRIPT
Table 1. Screening of alkylation/reduction conditions.a
entr Si
X
solven Yield
d.r.
y
t
(%)b
<10
51
(syn/anti)c
n.d.d
1
2
3
4
5
6
TMS
Cl
TBDPS Cl
TBDPS Br
Et2O
Et2O
Et2O
Et2O
THF
THF
91:9
85
>95:5
>95:5
n.dd
TBDPS
TBDPS Br
TBDPS
I
92
54
I
61
n.dd
aReaction conditions: O-silyl cyanohydrin 1 (1 mmol), MeMgX (1.5 mmol) in a solvent
(3 mL) at 0 oC for 10 h, and then MeOH (3 mL) and NaBH4 (2 mmol) for more 12 h at rt,
bDetermined by GC using dodecane as internal stardard , c Determined by GC or 1H
NMR. d n.d.= Not detected.
ACCEPTED MANUSCRIPT
12

ACCEPTED MANUSCRIPT
Figure 1. pharmaceutically interesting phenylpropanolamines
ACCEPTED MANUSCRIPT
13

ACCEPTED MANUSCRIPT
Scheme 1. Stereospecifical Synthesis of phenylpropanolamines
ACCEPTED MANUSCRIPT
14

ACCEPTED MANUSCRIPT
Scheme 2. Synthetic route of DL-norpseudophedrine
ACCEPTED MANUSCRIPT
15

ACCEPTED MANUSCRIPT
Scheme 3. Deprotection of O-TBDPS group
ACCEPTED MANUSCRIPT
16

ACCEPTED MANUSCRIPT
Scheme 4. Preparation of norpseudophedrine HCl salts
ACCEPTED MANUSCRIPT
17

ACCEPTED MANUSCRIPT
Scheme 5. Developing practical process for the synthesis of norpseudoephedrine
ACCEPTED MANUSCRIPT
18

ACCEPTED MANUSCRIPT
Scheme 6. Synthesis of various syn phenylpropanolamines and derivatives.
ACCEPTED MANUSCRIPT
19

ACCEPTED MANUSCRIPT
Scheme 7. Proposed working mechanism process
ACCEPTED MANUSCRIPT
20