A dimethylzinc/diphenylphosphinoylimine approach to the asymmetric synthesis of the calcimimetic agent NPS R-568

Article abstract of DOI:10.1002/aoc.1723

An asymmetric synthesis of the calcimimetic agent NPS R-568 using a (1R,2S)-N-benzylephedrine-promoted addition of dimethylzinc to a diphenylphosphinoylimine derived from 3-methoxybenzaldehyde is described. The enantiomeric ratio of the key amine fragment was determined to be 93:7 (86% ee), favoring the (R)-enantiomer by derivatization and chiral stationary phase HPLC analysis.

Full text of DOI:10.1002/aoc.1723

Full Paper
Received: 19 February 2010
Revised: 28 July 2010
Accepted: 30 July 2010
Published online in Wiley Online Library: 14 October 2010
(wileyonlinelibrary.com) DOI 10.1002/aoc.1723
A dimethylzinc/diphenylphosphinoylimine
approach to the asymmetric synthesis of the
calcimimetic agent NPS R-568
Sucharita Banerjee, Brad Smith and Shawn R. Hitchcock∗
An asymmetric synthesis of the calcimimetic agent NPS R-568 using a (1R,2S)-N-benzylephedrine-promoted addition of
dimethylzinc to a diphenylphosphinoylimine derived from 3-methoxybenzaldehyde is described. The enantiomeric ratio of the
key amine fragment was determined to be 93 : 7 (86% ee), favoring the (R)-enantiomer by derivatization and chiral stationary
c
phase HPLC analysis. Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: asymmetric addition; dimethylzinc; diphenylphosphinoylimine; NPS R-568; calcimimetic
Introduction
synthetic preparation. In this context, NPS R-568 is a phenylalky-
lamine that has been shown to be clinically effective[2] and the
subject of synthetic preparation.[3–6] In particular, the asymmetric
synthesisofthismedicinalagentisofinterestasithasbeendemon-
strated that the (R)-enantiomer is considerably more active than
the corresponding (S)-enantiomer.[2] The reported methods for
the preparation of NPS R-568 vary in terms of synthetic design and
asymmetric induction. The first literature report on the synthesis of
NPS R-568 by Van Wagenen and coworkers was focused primarily
on a coupling process that required the use of two equivalents of
the chiral, non-racemic amine component for the synthesis of the
calcimimetic agent from a diisobutylaluminum-imine complex.[3]
Hansen and Buchwald developed a very efficient synthesis of NPS
R-568 by using a chiral, non-racemic ansa-titanocene, ethylene
bis(tetrahydroindenyl)titanium difluoride as a catalyst precursor in
the hydrosilylation of an imine precursor to afford 1 (Scheme 1).[4]
Kibayashiandcoworkersusedanapproachinvolvingtheuseofa
chiraloximeetherwithmethyllithiumfortheasymmetricinduction
process to form the amine component of the calcimimetic.[5]
Khiar and coworkers pursued a similar pathway but employed
a chiral N-isopropylsulfinylimine as the template forming the
chiral amine.[6] Based on our ongoing interest in the use of
Ephedra alkaloids in asymmetric synthesis, we became focused
on developing an N-benzylephedrine promoted dimethylzinc
addition to a diphenylphosphinoylimine. Herein, we report our
efforts on the first diorganozinc approach to the synthesis of NPS
R-568.
NPS R-568 (1), also known by the generic name of tecalcet
and the tradename norcalcin, is an active calcimimetic agent
of medicinal utility that was initially developed by NPS Phar-
maceutics, Inc. in the early 1990s for the treatment of primary
and secondary hyperparathyroidism (HPT) (Figure 1).[1] Primary
hyperparathyroidism originates in the parathyroid gland and is
often manifested through a parathyroid adenoma. In contrast,
secondary hyperparathyroidism originates externally from this
gland and is commonly associated with chronic renal failure.
These two diseases are characterized by both elevated levels of
plasma parathyroid hormone (PTH), a polypeptide containing 84
α-amino acid residues, and serum Ca2+. PTH is a key endocrine
regulator secreted from parathyroid cells. PTH acts on bone,
kidney and the intestinal tract via the kidneys to release Ca2+
into the blood stream. Elevated levels of Ca2+ are detected by
cell-surface Ca2+ receptors (i.e. seven transmembrane G-coupled
receptors) on the cells of parathyroid glands. Activation of the
Ca2+ receptor by these elevated levels of Ca2+ initiates a complex
cellular response (involving the increase of intracellular Ca2+
)
which ultimately results in the inhibition of PTH secretion from
these cells. Thus, there is an inverse relationship between the
concentration of extracellular Ca2+ and PTH which serves as the
foundation for the regulation of bodily Ca2+ homeostasis.[2]
Calcimimetics, such as NPS R-568, are agonists and activate the
Ca2+ receptor in a non-competitive fashion. They do not compete
directly with Ca2+ that activates the receptor through binding in
theextracellulardomainofthesereceptors, butrather, calcimimet-
ics such as NPS R-568, bind allosterically in the seven transmem-
brane to ‘sensitize’ the receptor to extracellular Ca2+. Compounds
Results and Discussion
of this type do not activate Ca2+ receptors in the absence of Ca2+
.
We initiated our work with the synthesis of the N-benzylephedrine
(7) as the chiral agent for the promotion of the asymmet-
In this context, enantiomerically enriched phenylalkyl amines,
such as NPS R-568, have been found to activate the Ca2+ receptor
in the presence of Ca2+ in bovine parathyroid cells, evidenced
by increasing intracellular calcium and inhibiting the secretion of
PTH. As such, calcimimetics have clinical utility in treating diseases
such as primary and secondary HPT and therefore the subject of
∗
Correspondenceto:Shawn R. Hitchcock,DepartmentofChemistry,IllinoisState
University, Normal, IL, USA. E-mail: hitchcock@ilstu.edu
Department of Chemistry, Illinois State University, Normal, IL, USA
c
Appl. Organometal. Chem. 2011, 25, 105–109
Copyright ꢀ 2010 John Wiley & Sons, Ltd.

S. Banerjee, B. Smith and S. R. Hitchcock
TiF2
Me
MeO
Buchwald4
N
1
PhSiH3, PMHS, methanol
pyrrolidine
Cl
2
H
Me
OCH3
H
MeO
O
1. MeLi, toluene
MeO
Kibayashi et al.5
NH2
N
1
2. Zn, AcOH, THF
Ph
4
3
5
H
O
S
MeO
1. MeMgBr, toluene
2. CF3CO2H
Khiar et al.6
N
4
1
Scheme 1. Asymmetric syntheses of NPS R-568.
The amide (R)-14 was reduced using diisobutylaluminum
hydride (Dibal-H) in dichloromethane as described in the ex-
perimental procedure established by Kibayashi and coworkers
(Scheme 5).[5a] It was determined that the use of 4 equivalents
of the reducing agent was optimal and in the case of (R)-13
afforded the corresponding amine (R)-15 in 60% yield after purifi-
cation. Using these conditions on amide (R)-14, we were able to
isolate the calcimimetic NPS R-568 (1) in 68% yield after chromato-
graphic purification in ∼86% ee based on the prior analysis of the
amide precursor (R)-14. The specific rotation was determined to
H
Me
MeO
N
H
Cl
Figure 1. Calcimimetic agent NPS R-568 (1).[1,2]
ric addition reaction with dimethylzinc. N-Benzylephedrine was
selected for its ease of preparation and successful applica-
tion in diorganozinc reactions with aldehydes[7a] and with
diphenylphosphinoylimines.[7b] Thus, (1R,2S)-ephedrine (6) was
alkylated at nitrogen with benzyl bromide to afford 7 in 82%
yield after chromatographic purification (Scheme 2). The req-
uisite diphenyl phosphinoylimine 9 was prepared from 1-(3ꢁ-
methoxyphenyl)-1-ethylamine using the method of Lovely and
coworkers.[8] At this stage, the asymmetric addition of dimethylz-
inc to 9 was conducted with 7 to afford the addition product 10
in 81% yield with a enantiomeric ratio of 95.4 : 4.6 (R : S, ∼90% ee)
via proposed transition state TS-9. The addition product was then
hydrolyzed with concentrated HCl in methanol to afford the key
amine component of the calcimimetic agent in 84% yield. The spe-
24
20
be [α]D = +39.3 (c 1.20, CHCl3) [lit.[5b] [α]D = +41.9 (c 1.10,
CHCl3); lit.[4] [α]D = +38.6 (c 1.10, CHCl3)].
Conclusions
We have developed an asymmetric pathway to the synthesis of
the clinically effective calcimimetic agent NPS R-568 through the
use of an N-benzylephedrine promoted dimethylzinc addition to
a phosphinoylimine. The hydrolysis of the diphenylphosphinoy-
lamine yielded the key amine fragment in 86% ee, favoring the
(R)-enantiomer as determined by analysis of the derivatized amine
by CSP HPLC. This synthesis represents the first application of
diorganozinc reagent to the preparation of NPS R-568.
20
cific rotation of the amine was determined to be [α]D = +12.4 (c
20
20
0.72, MeOH), lit. [α]D = +23.6 (c 0.8, MeOH);[5b] [α]D = +17.6
(c 2, MeOH).[9]
There was a concern that the measured specific rotation of
11 was not an accurate reflection of its enantiomeric purity.
Thus, commercially available rac-1-phenyl-1-ethylamine and (R)-
1-phenyl-1-ethylamine [rac-12/(R)-12] were each coupled with 2-
chlorophenylpropanoicacidusingEDCandDMAP(Scheme 3). The
resultant amides [rac-13/(R)-13] were analyzed by chiral stationary
phase (CSP) HPLC and it was determined that the (R)-enantiomer
elutes first based on the comparison between the racemic mixture
and the amide derived from the commercial (R)-amine.
With a reliable method for the analysis, the enantiomerically
enriched 3ꢁ-methoxyphenyl-1-ethylamine (11) and its racemic
variant (rac-11) were coupled with 2-chlorophenylpropanoic acid
using EDC and DMAP (Scheme 4). The analysis of the resultant
amides [rac-13 and (R)-13] by CSP HPLC revealed that, by analogy
with the analysis of 12, the (R)-enantiomer eluted first and the
ratio of enantiomers was 93 : 7 (86% ee).
Experimental
General Remarks
All reactions were run under a nitrogen atmosphere. Anhy-
drous toluene was purchased and stored under a nitrogen
atmosphere. Dimethylzinc was purchased in 1.2 M solution
in hexanes. Dichloromethane was purchased as an anhydrous
reagent. All 1H and 13C NMR spectra were recorded on Var-
ian spectrometer at 25 ◦C in CDCl3 operating in 500 MHz and
125 MHz respectively. Chemical shifts are recorded in parts
per million (δ scale), and the coupling constant (J values) are
listed in hertz. Optical activities are measured using 589 nm us-
ing Jasco digital polarimeter. Infrared spectra were reported in
reciprocal centimeters (cm−1). Flash chromatography was con-
ducted with an Analogix chromatograph. Mass spectral analyses
c
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Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 105–109

Asymmetric synthesis of the calcimimetic agent NPS R-568
OH
OH Bn
N
BnBr, THF
K2CO3
82%
NHCH3
Ph
Ph
CH3
CH3
CH3
7
(1R,2S)-ephedrine (6)
P(O)Ph2
N
CHO
H3CO
H3CO
Ph2PONH2,TEA
H
CH2Cl2
80%
8
9
H
CH3
H
N
Ph
CH3
CH3
NHP(O)Ph2
CH3
O
Zn
H3C
H3C
H3CO
Zn
7, Me2Zn, toluene
O
9
N
P
81%
Ph
Ph
H
10
CH3O
proposed TS-9
NH2
CH3
H3CO
conc. HCl, MeOH
84%
11
Scheme 2. Synthesis of the amine fragment of NPS R-568.
Cl
Cl
Cl
CO2H
NH2
Dibal-H, CH Cl
2
2
(R)-13 or (R)-14
HN
25°C
HN
O
Ph
CH3
EDC, CH2Cl2
R
CH3
Ph
CH3
rac-12/(R)-12
rac-13/(R)-13
(R)-15:R = -H (60%)
(R)-1:R = -OCH3 (68%)
Scheme 3. Formation of racemic 13 and (R)-13.
Scheme 5. Synthesis of NPS R-568.
Cl
Cl
CO2H
(1R,2S)-2-(Benzyl(methyl)amino)-1-phenyl-1-propanol (7)
rac-11/(R)-11
HN
O
EDC, CH2Cl2
The title compound was obtained from the alkylation of (1R,2S)-
ephedrine with benzyl bromide (1.1 equiv.) dissolved in refluxing
anhydrous THF and potassium carbonate (3 equiv.) in 82% yield
H3CO
CH3
1
as a colorless oil after flash chromatography. H NMR (400 MHz,
CDCl3) δ (ppm): 0.98 (3H, d, J = 6.9 Hz), 2.18 (3H, s), 2.91 (1H,
dq, J = 6.9, 4.9 Hz), 3.57 (1H, d, J = 13.4 Hz), 3.63 (1H, d,
J = 13.4 Hz), 4.85 (1H, d, J = 4.9 Hz), 7.21–7.32 (10H, m). 13C
NMR (100 MHz, CDCl3) δ 9.7, 38.5, 59.0, 63.3, 73.6, 126.1, 126.8,
127.9, 128.6, 139.4, 142.6. FT-IR (neat) 3081, 1599, 1061, 1006,
rac-14/(R)-14
Scheme 4. Synthesis of racemic 14 and (R)-14.
were conducted by the mass spectrometry analytical labora-
tories of the University of Illinois at Urbana–Champaign us-
ing quadruple time of flight mass spectrometer hybrid with
MS/MS capability. Enantiomeric ratios were determined using
a Shimadzu HPLC with chiral stationary phase chiralcel AD col-
umn.
23
733, 700 cm−1. [α]D − 22.2 (c 1.03, CH2Cl2). HRMS (M + H)+
calcd for C17H22NO: 256.3627; found: 256.3625. Anal. calcd for
C
17H21NO: C, 79.96; H, 8.29; N, 5.30; found: C, 79.31; H, 8.46;
N, 5.30. This material was identical to that of known literature
examples.[8]
c
Appl. Organometal. Chem. 2011, 25, 105–109
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

S. Banerjee, B. Smith and S. R. Hitchcock
N-(3-Methoxybenzylidene)-P,P-diphenylphosphinicamide(9)
reconstituted with dichloromethane (50 ml) was added. The so-
lution was washed with brine (50 ml) and dried (MgSO4). The
solvent was evaporated via rotary evaporation. Colorless oil (84%).
In a 250 ml round bottom flask were placed diphenylphosphi-
namide (3.00 g, 13.8 mmol) and dichloromethane (55 ml) and then
cooled to 0 ◦C. At this point, triethylamine (5.80 ml, 41.3 mmol),
titanium tetrachloride (0.90 ml, 8.3 mmol) and m-anisaldehyde
(1.70 ml, 13.8 mmol) were added. The reaction mixture was al-
lowed to warm to 25 ◦C and was stirred for 1.5 h and then gravity
filtered to remove titanium dioxide. The filtrate was collected
and the solvent was removed by rotary evaporation. The residue
was treated with diethyl ether (40 ml) and filtered to remove
triethylammonium chloride. The filtrate from this process was
collected and the solvent was removed by rotary evaporation.
The resultant yellow residue was purified by flash chromatog-
raphy (hexanes : EtOAc, 4 : 6); yellow oil (80%). IR (nujol): 3100,
25
[α]D = +15.6 (c 0.90, CHCl3). IR (nujol): 3500, 3000, 2900, 1590,
1200, 760, 695 (cm−1). 1H NMR (500 MHz, CDCl3) δ (ppm): 1.38
(d, J = 6.7 Hz, 3H), 3.82 (s, 3H), 4.06–4.12 (m, 1H) 6.77–6.79 (m,
1H), 6.91–6.93 (m, 1H) and 7.23–7.26 (m, 2H). The protons asso-
ciated with the amino group (-NH2) were not observed. 13C NMR
(125 MHz, CDCl3): 25.6, 51.3, 55.2, 111.4, 112.0, 118.0, 129.5, 149.6,
159.8. ESI-HRMS calcd for C9H14NO (M + H+): 152.1075; found:
152.1070. Anal. calcd for C9H13NO: C, 71.49; H, 8.67; N, 9.26; found:
C, 71.35; H, 8.71; N, 8.52.
(R)-3-(2-Chlorophenyl)-N-(1-phenylethyl)propanamide (13)
1
2998, 1600, 1200 cm−1. H NMR (500 MHz, CDCl3) δ (ppm): 3.85
In a 250 ml round bottom flask were placed dichloromethane
(17 ml), EDC (1.2 g, 5.5 mmol), 4-dimethylaminopyridine (0.12 g,
1.1 mmol) and 3-(2-chlorophenyl)propanoic acid (1.0 g, 5.5 mmol).
Thereactionmixturewasstirredfor30 min.Commerciallyavailable
(R)-1-(phenyl)-1-ethylamine(0.70 ml, 5.5 mmol)wasthenaddedto
the reaction mixture. The reaction mixture was stirred overnight at
roomtemperatureandquenchedwithanaqueous1M HClsolution
(50 ml). The reaction mixture was diluted with dichloromethane
(50 ml), washed with brine (50 ml), and dried (MgSO4). The solvent
was removed via rotary evaporation and the product was purified
by flash chromatography (hexanes : EtOAc, 8 : 2). White solid
(s, 3H), 7.09–7.12 (m, 1H), 7.43–7.58 (m, 9H) 7.92–7.96 (m, 4H),
9.29 (d, JPH = 30.0 Hz, 1H). 13C NMR (125 MHz, CDCl3, 13C–31
P
coupling observed) 55.3, 113.5, 119.9, 123.5, 128.3, 128.4, 129.8,
131.4, 131.5, 131.6, 131.7, 132.2, 133.2, 136.9, 137.1, 159.9, 173.5,
173.6. ESI- HRMS calcd for C20H19NO2P (M + H+): 336.1153. Found:
336.1148. Anal. calcd for C18H20NOP· 0.2 CHCl3 (multiple analyses
fromdifferentsamplesyieldedresultsconsistentwiththepresence
of 0.2 equiv. of CHCl3 for every 1 equiv. of the phosphinoylimine
substrate): C, 67.54; H, 5.11; N, 3.90; found: C, 67.05; H, 5.17; N,
3.87.
(74%). M.p.: 102–104 ◦C. [α]D = +39.8 (c 0.90, CHCl3). HPLC
25
(Chiralcel AD column, 95 : 5 (hexanes : isopropanol), 1.0 ml min−1):
tR = 12.9 min. and tS = 19.9 min. IR (nujol): 3300, 2990, 1600, 790,
650 cm−1. 1H NMR (500 MHz, CDCl3) δ (ppm): 1.40 (d, J = 7.0 Hz,
3H), 2.43–2.53 (m, 2H), 3.06 (t, J = 7.5 Hz, 2H), 5.08 (p, J = 7.0 Hz,
1H), 5.78 (s, 1H), 7.12–7.32 (m, 9H). 13C NMR (125 MHz CDCl3):
21.6, 29.6, 36.3, 48.6, 126.0, 126.9, 127.2, 127.7, 128.5, 129.4, 130.8,
133.7, 138.2, 143.0, 170.8. ESI- HRMS calcd for C17H19NOCl (M +
H+): 288.1155; found: 288.1159. Anal. calcd for C17H19NOCl: C,
70.95; H, 6.30; N, 4.87; found: C, 69.75; H, 6.13; N, 4.91. The racemic
mixture of 13 was prepared in the same fashion had the same
physical properties as (R)-13 with the exception of polarimetry.
(R)-N-(1-(3-Methoxyphenyl)ethyl)-P,P-diphenylphosphinic
amide (10)
In a 100 ml round bottom flask were placed anhydrous toluene
(7.5 ml), (1R,2S)-N-benzylephedrine (0.380 g, 1.49 mmol), N-(3-
methoxybenzylidene)-P,P-diphenylphosphinic amide (9) (0.50 g,
1.5 mmol) and dimethylzinc (6.30 ml, 7.5 mmol). The reaction
mixture stirred for 48 h and was quenched by the addition of
an saturated aqueous solution of ammonium chloride (50 ml). The
organic layer was diluted with ethyl acetate (50 ml), washed
with brine (50 ml), and dried (MgSO4). The solvents were
removed via rotary evaporation and the product was purified by
flash chromatography (hexanes : EtOAc, 4 : 6). Colorless oil (81%).
25
[α]D = +26.3 (c 1.03, CHCl3). HPLC [Chiralcel AD coloumn,
(R)-3-(2-Chlorophenyl)-N-(1-(3ꢀ-methoxyphenyl)
ethyl)propanamide (14)
80 : 20 (hexanes : isopropanol), 1.0 ml min−1]: tR = 7.0 min. and
tS = 10.3 min. IR (nujol): 3200, 3010, 2990, 1580, 1200 cm−1
.
1H NMR (500 MHz, CDCl3) δ (ppm): 1.54 (d, J = 6.8 Hz,
3H), 3.45 (s, 1H), 3.75 (s, 3H), 4.31–4.38 (m, 1H), 6.75–6.88
(m, 1H), 7.19–7.47 (m, 9H), 7.79–7.91 (m, 4H). 13C NMR
(125 MHz, CDCl3, 3C–31P coupling observed): 25.9, 51.1, 55.2,
55.5, 111.8, 112.1, 118.1, 128.1, 128.2, 128.3, 129.4, 131.4, 131.5,
131.6, 1321.8, 132.3, 146.6, 146.7, 159.5. ESI-HRMS calcd for
C21H23NO2P (M + H+): 352.1466; found: 352.1463. Anal. calcd
for C21H22NO2P: C, 71.78; H, 6.31; N, 3.99; found: C, 71.79; H, 6.36;
N, 4.17.
In a 100 ml round bottom flask were placed dichloromethane
(9.3 ml), EDC (0.590 g, 3.08 mmol), 4-dimethylaminopyridine
(0.068 g, 0.56 mmol) and 3-(2-chlorophenyl)propanoic acid
(0.517 g, 2.80 mmol). The reaction mixture was stirred for
30 min. and (R)-1-(3ꢁ-methoxy phenyl)ethylamine (11) (0.423 g,
2.80 mmol) was added to the reaction mixture. The reaction mix-
turewasstirredovernightatroomtemperatureandquenchedwith
an aqueous solution 1 M HCl solution (50 ml). The reaction mix-
ture was diluted with dichloromethane (50 ml), washed with brine
(50 ml) and dried (MgSO4). The solvent was removed via rotary
evaporation and the product was purified by flash chromatog-
raphy (hexanes: EtOAc, 8 : 2). White solid (66%). M.p.: 86–88 ◦C.
(R)-1-(3ꢀ-Methoxyphenyl)-1-ethylamine (11)
24
[α]D = +34.9 (c 1.20, CHCl3). HPLC (Chiralcel AD column, 95 : 5
In a 100 ml round bottom flask were placed (R)-N-[1-(3-
methoxyphenyl)ethyl]-P,P-diphenylphosphinic amide (10) (2.0 g,
5.7 mmol), methanol (40 ml) and concentrated HCl (10 ml) at room
temperature. The reaction mixture stirred overnight at room tem-
perature and was quenched by the addition of 1 M NaOH solution
until the reaction mixture was completely neutralized as deter-
mined by the use of pH paper. Methanol was removed from
the reaction mixture via rotary evaporation and the residue was
(hexanes: IPA), 1.0 ml min−1): tR = 17.4 min and tS = 24.7 min. IR
(nujol): 3200, 2990, 1650, 1200 cm−1. 1H NMR (500 MHz, CDCl3) δ
(ppm): 1.39 (d, J = 7.0 Hz, 3H), 2.48 (td, J = 7.6 Hz, 2.2 Hz, 2H),
3.06 (t, J = 7.6 Hz, 2H), 3.77 (s, 3H), 5.05 (p, J = 7.0 Hz, 1H), 5.76
(s, 1H), 6.76–6.80 (m, 3H), 7.11–7.15 (m, 2H), 7.19–7.22 (m, 1H),
7.29–7.33 (m, 2H). 13C NMR (125 MHz, CDCl3): 21.6, 29.5, 36.2, 48.6,
55.1, 112.1, 112.3, 118.3, 126.8, 127.7, 129.3, 129.5, 130.7, 133.6,
c
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Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 105–109

Asymmetric synthesis of the calcimimetic agent NPS R-568
138.2, 144.8, 159.7, 170.8. ESI- HRMS calcd for C18H21NO2Cl (M +
H+): 318.1261; found: 318.1266. Anal. calcd for C18H20NO2Cl: C,
68.03; H, 6.34; N, 4.41; found: C, 67.62; H, 6.46; N, 4.51. The racemic
mixture of 14 was prepared in the same fashion had the same
physical properties as (R)-14 with the exception of polarimetry.
CDCl3): 24.4, 30.3, 31.4, 47.3, 55.2, 58.3, 11.9, 112.0, 118.9, 126.6,
127.1, 129.2, 129.3, 130.2, 133.7, 139.6, 147.6 and 159.7. ESI-HRMS
calcd for C18H23NOCl (M + H+): 304.1468; found: 304.1472. Anal.
calcd for C18H22NClO: C, 71.16; H, 7.30; N, 4.61; found: C, 70.29; H,
7.42; N, 4.55.
(R)-3-(2-Chlorophenyl)-N-(1-phenylethyl)propylamine (15)
Acknowledgments
Ina100 mlroundbottomflaskwereplaced(R)-3-(2-chlorophenyl)-
N-(1-phenylethyl) propanamide (13) (0.308 g, 1.07 mmol) and
dichloromethane (4.0 ml). To this mixture was added dibal-H
(4.30 ml, 1.0 M in toluene, 4.30 mmol). The reaction mixture
stirred for 18 h at room temperature. The reaction mixture was
quenched with a saturated aqueous solution of ammonium
chloride (2 × 25 ml), extracted with dichloromethane (2 × 25 ml)
washed with brine (25 ml) and dried (MgSO4). The solvent was
removed via rotary evaporation and the product was purified by
flash chromatography (hexanes: EtOAc, 9 : 1). Yellow oil (60%).
The authors acknowledge helpful and insightful suggestions from
the reviewers. The authors acknowledge support for this work by
the donors of the Petroleum Research Fund as administered by
the American Chemical Society (ACS PRF no. 48367-B1) and the
National Science Foundation (CHE no. 644950).
Supporting information
Supporting information may be found in the online version of this
article.
24
[α]D = +38.8 (c 0.70, CHCl3). IR (nujol): 3200, 3100, 2990,
1
1498, 790, 650 cm−1. H NMR (500 MHz, CDCl3) δ (ppm): 1.34 (d,
References
J = 6.6 Hz,3H),1.70–1.83(m,2H),2.46–2.58(m,2H),2.65–2.78(m,
2H), 3.75 (q, J = 6.6 Hz, 1H), 7.06–7.31(m, 9H). 13C NMR (125 MHz,
CDCl3): 24.3, 30.1. 31.2, 47.2, 58.2, 126.5, 126.6, 126.7, 127.1, 128.3,
129.3, 130.2, 133.8, 139.7, 145.8. ESI-HRMS calcd for C17H21NCl (M
+ H+): 274.1363; found: 274.1361. Anal. calcd for C17H20NCl: C,
74.57; H, 7.36; N, 5.12; found: C, 74.10; H, 7.34; N, 5.00.
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(R)-3-(2-Chlorophenyl)-N-(1-(3ꢀ-methoxyphenyl)
ethyl)propylamine (1)
In
a 100 ml round bottom flask were placed (R)-3-(2-
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(0.120 g, 0.378 mmol) and dichloromethane (1.3 ml). To the re-
action mixture was added dibal-H (1.51 ml, 1.51 mmol) and the
mixture was stirred for 18 h at room temperature. The reaction
mixture was quenched with a saturated aqueous solution of am-
monium chloride (2 × 25 ml), extracted with dichloromethane
(2 × 25 ml), washed with brine (25 ml), and dried (MgSO4). The
solvent was removed via rotary evaporation and the product was
purified by flash chromatography (hexanes : EtOAc, 9 : 1). Clear oil
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24
(68%). [α]D = +39.3 (c 1.20, CHCl3). IR (nujol): 3300, 3010, 2990,
1
1610, 1200, 720, 690 (cm−1). H NMR (500 MHz, CDCl3) δ (ppm):
1.33 (d, J = 6.6 Hz, 3H), 1.70–1.83 (m, 2H), 2.47–2.58 (m, 2H),
2.65–2.79 (m, 2H), 3.73 (q, J = 6.6 Hz, 1H), 3.78 (s, 3H), 6.75–6.77
(m, 1H), 6.8–6.89 (m, 2H), 7.05–7.29 (m, 5H). 13C NMR (125 MHz,
c
Appl. Organometal. Chem. 2011, 25, 105–109
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