Chiral N-phosphonyl imine chemistry: An efficient asymmetric synthesis of chiral N-phosphonyl propargylamines

Article abstract of DOI:10.1039/b923914f

A variety of substituted chiral propargylamines have been synthesized by reacting chiral N-phosphonylimines with lithium aryl/alkyl acetylides. Seventeen examples were studied to give excellent yields (>90%) and diastereoselectivities (96:4 to 99:1). It was found that the types of bases for generating acetylides and solvents are crucial for effectiveness of this asymmetric reaction. In addition, N,N-isopropyl group on chiral N-phosphonylimine auxiliary was proven to be superior to other protecting groups in controlling diastereoselectivity. The Royal Society of Chemistry.

Full text of DOI:10.1039/b923914f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Chiral N-phosphonyl imine chemistry: an efficient asymmetric synthesis of
chiral N-phosphonyl propargylamines†
Parminder Kaur,a Gaurav Shakya,a Hao Sun,b Yi Pan*b and Guigen Li*a
Received 13th November 2009, Accepted 25th November 2009
First published as an Advance Article on the web 5th January 2010
DOI: 10.1039/b923914f
A variety of substituted chiral propargylamines have been synthesized by reacting chiral
N-phosphonylimines with lithium aryl/alkyl acetylides. Seventeen examples were studied to give
excellent yields (>90%) and diastereoselectivities (96 : 4 to 99 : 1). It was found that the types of bases
for generating acetylides and solvents are crucial for effectiveness of this asymmetric reaction. In
addition, N,N-isopropyl group on chiral N-phosphonylimine auxiliary was proven to be superior to
other protecting groups in controlling diastereoselectivity.
1. Introduction
Chiral propargylamines are versatile building blocks for the
synthesis of chemically and biologically important compounds.1
The addition of terminal alkynes to imines and iminiums has
been serving as a common approach to chiral and achiral
propargylamines.2–4 In the past several years, asymmetric catalysis
for this synthesis has been actively pursued5–8 by using various
Scheme 1
catalysts,9–14 such as Au(II)salen complex, Cu(I)-i-Pr-Pybox-diPh
and Cu(I)-PINAP complexes.14 Although great progress has been
made on this asymmetric catalysis, the development of chiral
imine-based methodologies is still highly sought after for larger
scale synthesis.
resulting mixture was slowly added chiral N-phosphonyl imine 1
which was dissolved in THF. The reaction was stirred at -78 ◦C for
2 h and constantly monitored by TLC (6 : 4 hexane–EtOAc) before
it was quenched with saturated ammonium chloride solution. The
The use of chiral sulfinylimines, N-p-tolylsulfinylimines and N-
product 8 was isolated in a good yield (85%) although modest
tert-butylsulfinylimines offered a practical approach to a series of
diastereoselectivity (dr = 70 : 30) was observed.
propargylamines.15–19 In this synthesis, Lewis acids (e.g. AlMe3)
are sometimes required to activate sulfinylimine electrophiles for
additions by lithium and magnesium acetylides.17 In the past year,
our group reported the design and synthesis of new chiral N-
phosphonyl imines and has successfully utilized them in a variety
of nucleophilic addition reactions to give very useful chiral amino
products in good yields and excellent diastereoselectivities.20 In
continuation of our work on chiral N-phosphonyl imine chemistry,
we would like to report herein the efficient additions of metal
aromatic/aliphatic acetylides onto chiral N-phosphonyl imines
without the use of Lewis acid promoters.
We next investigated the effects of metal ions of acetylides on the
diastereoselectivity by using three other metal cations including
sodium, magnesium, aluminium for acetylide formation.
It was found that both sodium and magnesium phenyl acetylides
resulted in poor diastereoselectivities of dr = 60 : 40 (for Na) and
dr = 65 : 35 (for Mg), respectively. The use of aluminium acetylide
did not improve diastereoselectivity (dr = 63 : 37) either. Based
on these observations, lithium acetylide was thus chosen as the
nucleophile.
We then explored the effects of different N,N¢-R groups on
the chiral N-phosphonyl auxiliary (Scheme 2). These protecting
groups include benzyl, isobutyl, neopentyl, 1-naphthylmethyl,
cyclopentylmethyl and isopropyl groups. As shown in Table 1,
cyclopentylmethyl and isopropyl group-attached chiral N-phos-
phonyl imines resulted in high chemical yields of 92% and 97%,
respectively and excellent diastereoselectivities, dr = 95 : 5 and
2. Results and discussion
In our initial attempt, the chiral N-phosphonyl imine at-
tached with N-benzyl group 1 was employed as the electrophile
(Scheme 1). The lithium phenyl acetylide was generated by treating
phenyl acetylene 7 with LDA in THF at -78 ◦C for 1 h. Into the
aDepartment of Chemistry and Biochemistry, Texas Tech University, Lub-
bock, Texas 79409-1061, USA. E-mail: guigen.li@ttu.edu; Fax: +1-806-
742-3015
bSchool of Chemistry and Chemical Engineering, and the State Key Lab of
Coordination Chemistry, Nanjing University, Nanjing, 210093, PR China.
E-mail: yipan@nju.edu.cn; Fax: +86-25-83314502
† Electronic supplementary information (ESI) available: 31P NMR spectra
of compounds 13b–e, 17–21, 23 and 26. See DOI: 10.1039/b923914f
Scheme 2
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Table 1 Effect of different R groups on asymmetric additions of chiral
N-phosphonyl imine with lithium phenyl acetylidea
Table 2 Results of the synthesis of N-phosphonyl substituted propargy-
lamines 13a-f (7)a
Entry Substrate
R
Product Yield (%)b drc
Entry
Substrate
R
Product
Yield (%)b
drc
1
2
3
4
5
6
1
Benzyl
Isobutyl
Neopentyl
1-Naphthylmethyl
Cyclopentylmethyl 12
Isopropyl 13a
8
85
70
60
90
92
97
70 : 30
50 : 50
50 : 50
85 : 15
95 : 5
1
2
3
4
5
6a
6b
6c
6d
6e
H
13a
13b
13c
13d
13e
97
95
96
95
96
99 : 1
98 : 2
96 : 4
100 : 0
100 : 0
2
9
p-Fluoro
o-Fluoro
o-Bromo
o-Methyl
3
10
11
4
5
6a
99 : 1
a All reactions were carried out at -78 ◦C in 0.06 M solution of imine in
THF. b Combined yields of both isomers. c Diastereomeric ratio has been
determined by using 31P-NMR and 1H-NMR of crude products.
a All reactions were carried out at -78 ◦C in 0.05 M solution of imine in
THF. b Combined yields of both isomers. c Diastereomeric ratio has been
determined by using 31P-NMR and 1H-NMR of crude products.
99 : 1, respectively (Table 1, entries 5 & 6) as determined by
Table 3 Results for the synthesis of N-phosphonyl-substituted propargy-
lamines 16–26 using lithium aliphatic acetylides 14 and 15a
1
31P and H-NMR analysis of crude products. In our previous
ketone enolate-based addition to chiral N-phosphonyl imines,
the 1-naphthylmethyl group gave the highest diastereoselectivity.20e
However, this group resulted in a modest diastereoselectivity of dr
= 85 : 15 in the present system, albeit the yield is still excellent
(90%, Table 1, entry 4). Surprisingly, isobutyl and neopentyl
groups did not give any diastereoselectivity (Table 1, entries 2 & 3).
The isopropyl group was thus proven to be the most efficient one
for the present asymmetric induction, which is similar to several
of our previous asymmetric reactions using chiral N-phosphonyl
imines.20b-d Obviously, the secondary alkyl substituent (isopropyl)
group on chiral N-phosphonyl imine (entry 6, Table 1) is superior
to its counterparts that are primary alkyl groups (entries 1–5,
Table 1), and should be chosen for the present asymmetric control.
After the optimal conditions were realized, the substrate scope
was then studied. Several chiral N-phosphonyl imines derived
from different aldehydes were synthesized and subjected to
the addition reaction with lithium phenyl acetylide which was
generated by treating with 2.0 M of LDA in THF (Scheme 3). As
indicated in Table 2, substitution on the phenyl rings of chiral
N-phosphonyl imines has no significant effect on either yield
or diastereoselectivity. Single isomeric products were obtained in
the cases of ortho-bromo and ortho-methyl chiral N-phosphonyl
imines (Table 2, entries 4–5).
Entry Substrateb R1
R2
Product Yield (%)c Drd
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6g
6h
6a
H
n-C4H9- 16
n-C4H9- 17
n-C4H9- 18
n-C4H9- 19
n-C4H9- 20
n-C4H9- 21
95
97
93
95
96
98
90
92
97
98 : 2
100 : 0
98 : 2
98 : 2
98 : 2
100 : 0
99 : 1
98 : 2
99 : 1
p-Fluoro
o-Fluoro
o-Chloro
o-Bromo
o-Methyl
o-Methoxy n-C4H9- 22
o-Nitro
H
n-C4H9- 23
24
10
11
6c
6e
o-Fluoro
o-Bromo
25
26
98
96
99 : 1
98 : 2
a All reactions were carried out at -78 ◦C in 0.06 M solution of imine
in THF. b For optical rotation data of these starting materials, see
ref. 21 c Combined yields of both isomers. d Diastereomeric ratio has been
determined by using 31P-NMR and 1H-NMR of crude products.
Scheme 3
Scheme 4
Besides the use of lithium phenyl acetylide, two lithium aliphatic
acetylides derived from 1-hexyne (14) and 3,3-diethoxy-prop-1-
yne (15) were also employed as the nucleophiles (Scheme 4). The
generation of these lithium aliphatic acetylides was conducted
by treating aliphatic alkynes with 1.6 M n-BuLi in THF at
-78 ◦C. The reaction was stirred for 2 h after it was quenched
with saturated solution of NH4Cl (Scheme 4). Excellent yields (90–
98%) and diastereoselectivities (98 : 2 to >99 : 1) were obtained for
all cases that were examined as shown in Table 3. In two cases
(Table 3, entries 2 and 6), essentially single isomeric products
were observed in crude NMR analysis. For all of these cases, the
substitutions on phenyl rings showed no significant effect on yield
and diastereoselectivity.
The absolute configuration of asymmetric induction for this
asymmetric reaction has been determined by cleaving the phos-
phonyl group of product 13a with 3 N aqueous HCl in methanol
followed by N-acetylation to give acetamide 27 (Scheme 5). The S
absolute configuration of the isolated acetamide 27 was deduced
from its optical rotation, of opposite sign to that of the literature
compound which has R configuration.19,22
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C◦ompound 13a. White solid; yield (0.251 g, 97%); mp 164–
166 C; [a]2D5 = -80.5 (c 0.50, CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.60 (d, J = 7.5 Hz, 2H), 7.41–7.39 (m, 2H), 7.36 (t, J = 7.5 Hz,
2H), 7.31–7.26 (m, 4H), 5.50 (t, J = 10.0 Hz, 1H), 3.68–3.58 (m,
1H), 3.56–3.47 (m, 1H), 2.99 (t, J = 11.5 Hz, 1H), 2.83–2.76 (m,
2H), 2.05 (t, J = 10.5 Hz, 2H), 1.77 (d, J = 11.0 Hz, 2H), 1.38–1.31
(m, 3H), 1.29 (d, J = 7.0 Hz, 3H), 1.23 (d, J = 7.0 Hz, 4H), 1.17
(dd, J = 3.0, 6.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) d 141.8
(d, J = 5.3 Hz), 131.4 (2C), 128.5 (2C), 128.2 (2C), 128.1, 127.5,
126.7 (2C), 123.0, 90.6 (d, J = 4.3 Hz), 84.1, 60.0 (d, J = 10.3 Hz),
59.1 (d, J = 10.3 Hz), 48.1 (d, J = 1.5 Hz), 44.4 (d, J = 3.0 Hz),
43.7 (t, J = 4.3 Hz), 30.9, 30.8, 30.6 (d, J = 9.3 Hz), 24.3 23.0 (d,
Scheme 5
Conclusions
Chiral N-phosphonyl imines were found to react with lithium
phenyl and alkyl acetylides smoothly to give substituted chiral
propargylamines. Effects on asymmetric induction of different
N,N¢-alkyl substituents on chiral N-phosphonyl imines and metal
ions were carefully investigated; and isopropyl group-attached
chiral N-phosphonyl imine and metal lithium were found to be
highly efficient in terms of yields and diastereoselectivities. The
applications of the resulting N-phosphonyl-substituted propargyl-
amines will be studied in our laboratories in the future.
J = 6.5 Hz), 22.8 (d, J = 4.0 Hz), 20.0, 19.8 (d, J = 1.5 Hz); 31
NMR (202 MHz; CDCl3) d 22.3; LCMS (m/z): 450 (M + H)+.
P
Compound 13b. White solid; yield (0.247 g, 95%); mp 186–
188 ◦C; 1H NMR (500 MHz, CDCl3) d 7.59–7.56 (m, 2H), 7.41–
7.39 (m, 2H), 7.31–7.29 (m, 3H), 7.04 (t, J = 8.5 Hz, 2H), 5.51 (t,
J = 10.0 Hz, 1H), 3.66–3.58 (m, 1H), 3.52–3.44 (m, 1H), 2.98 (t,
J = 11.0 Hz, 1H), 2.77 (t, J = 10.5 Hz, 2H), 2.06–2.04 (m, 2H),
1.78–1.75 (m, 3H), 1.39–1.29 (m, 3H), 1.26 (t, J = 6.5 Hz, 6H),
1.19 (d, J = 7.0 Hz, 3H), 1.16 (d, J = 7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 163.1, 137.8, 131.4 (2C), 128.4, 128.3, 128.28
(2C), 128.26, 122.8, 115.3, 115.1, 90.2 (d, J = 3.8 Hz), 84.3, 59.9
(d, J = 10.8 Hz), 59.1 (d, J = 9.8 Hz), 47.5, 44.3 (d, J = 3.0 Hz),
43.7 (d, J = 3.8 Hz), 30.9, 30.8, 30.6 (d, J = 9.8 Hz), 24.3, 23.0 (d,
Experimental
General methods
All commercially available solvents, unless otherwise mentioned,
were used without purification. THF was distilled from sodium–
benzophenone ketyl. All the glassware used was dried overnight
at 100 ◦C. All the melting points are uncorrected. The NMR
spectra were recorded at 500, 125, 202 MHz for 1H, 13C and
31P respectively. Shifts are reported in ppm based on an internal
TMS standard (for 1H/CDCl3) or on residual solvent peaks
(for 13C/CDCl3). 31P NMR spectra were referenced to external
H3PO4 (0.00 ppm). 1.6 M solution of n-butyl lithium solution in
hexanes, 2 M solution of lithium diisopropylamide in THF, phenyl
acetylene, 3,3-diethoxy-prop-1-yne and 1-hexyne were obtained
from Aldrich and used as obtained from commercial sources
without any further purification.
J = 5.8 Hz), 22.8 (d, J = 3.8 Hz), 20.0, 19.9 (d, J = 2.0 Hz); 31
NMR (202 MHz; CDCl3) d 22.2; LCMS: m/z 468.0 (M + H)+.
P
1
Compound 13c. Yellow oil; yield (0.249 g, 96%); H NMR
(500 MHz, CDCl3) d 7.59 (d, J = 7.5 Hz, 1H), 7.37–7.34 (m,
3H), 7.31–7.21 (m, 5H), 5.65 (t, J = 10.5 Hz, 1H), 3.54–3.39
(m, 3H), 3.00–2.96 (t, J = 10.0 Hz, 1H), 2.85 (t, J = 16.5 Hz,
1H), 2.10–2.02 (m, 3H), 1.38–1.19 (m, 13H), 1.08 (dd, J =
7.0, 14.0 Hz, 4H); 13C NMR (125 MHz, CDCl3) d 139.3 (d,
J = 4.5 Hz), 132.3, 131.55, 131.51 (2C), 129.8, 128.7, 128.4,
128.1 (2C), 127.2, 122.8, 89.2 (d, J = 5.8 Hz), 83.5, 60.1 (d,
J = 10.8 Hz), 59.2 (d, J = 10.3 Hz), 46.1, 44.3 (d, J = 2.8 Hz),
43.7 (d, J = 4.3 Hz), 30.8, 30.7 (d, J = 2.8 Hz), 30.6, 24.3, 24.2 (d,
J = 2.8 Hz), 22.8 (d, J = 3.5 Hz), 19.9, 19.4 (d, J = 2.0 Hz); 31
NMR (202 MHz; CDCl3) d 22.4.
P
Typical procedure for the synthesis of N-phosphonyl substituted
propargylamines using chiral N-phosphonyl imines and phenyl
acetylene
C◦ompound 13d. White solid; yield: 0.239 g (95%); mp 174–
176 C; [a]2D5 = -81.3 (c 0.51, CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.60 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.36–7.33
(m, 3H), 7.27–7.23 (m, 3H), 7.14 (t, J = 8.0 Hz, 1H), 5.64 (t, J =
11.0 Hz, 1H), 3.60–3.50 (m, 2H), 3.44–3.36 (m, 1H), 3.00 (t, J =
10.0 Hz, 1H), 2.86 (t, J = 10.0 Hz, 1H), 2.11 (d, J = 8.5 Hz,
1H), 2.01 (d, J = 7.0 Hz, 1H), 1.77 (m, 2H), 1.33 (d, J = 6.5 Hz,
7H), 1.27 (d, J = 6.5 Hz, 3H), 1.00 (d, J = 6.5 Hz, 3H), 0.953 (d,
J = 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 140.9 (d, J = 4.3
Hz), 133.0, 131.4 (2C), 128.9 (2C), 128.5, 128.1 (2C), 127.8, 122.8,
122.2, 89.2 (d, J = 5.5 Hz), 83.7, 60.0 (d, J = 11.3 Hz), 59.2 (d,
J = 9.8 Hz), 48.3 (d, J = 2.5 Hz), 44.3 (d, J = 3.0 Hz), 43.7 (d,
J = 4.3 Hz), 30.8, 30.7 (d, J = 8.75 Hz), 24.3, 24.2 (d, J = 1.0 Hz),
22.95, 22.92 (d, J = 2.5 Hz), 19.9, 19.3 (d, J = 2.0 Hz); 31P NMR
(202 MHz; CDCl3) d 22.4; LCMS: m/z 530.0 (M + H)+.
In a dry vial, under inert gas protection, phenyl acetylene 7 (1.0
mmol) was dissolved in 3 mL THF. The vial was cooled to -78 ◦C
and into the resulting solution lithium diisopropylamide (2.0 M
in THF, 1.0 mmol) was added dropwise. The reaction solution
was stirred at -78 ◦C for 1 h and phosphonyl imine 6 (0.50 mmol
in 3 ml THF) was added to the reaction mixture. The reaction
mixture was stirred for another 2 h before it was quenched by
adding saturated ammonium chloride solution followed by 10 mL
water. The reaction mixture was then extracted with 2 ¥ 10 mL
of diethyl ether. Combined organic layers were washed with water
(1 ¥ 20 mL), and dried over anhydrous sodium sulfate. Sodium
sulfate was filtered off and the organic layer was evaporated to
obtain the desired product as pale yellow solid which on washing
with hexanes gave pure product as white solid. In a few cases,
a yellow oil was obtained which was further purified by column
chromatography (solvent system: EtOAc–hexanes 70 : 30).
C◦ompound 13e. White solid; yield (0.250 g, 96%); mp 154–
156 C; [a]2D5 = -84.6 (c 0.50, CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.53 (d, J = 7.5 Hz, 1H), 7.35–7.32 (m, 2H), 7.26–7.15 (m, 6H),
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5.51 (t, J = 10.0 Hz, 1H), 3.60–3.44 (m, 2H), 3.06–2.96 (m, 2H),
2.76 (t, J = 10.0 Hz, 1H), 2.52 (s, 3H), 2.09–2.01 (m, 2H), 1.77 (d,
J = 6.5 Hz, 2H), 1.37–1.23 (m, 7H), 1.21 (d, J = 7.0 Hz, 3H), 1.08
(dd, J = 6.5, 9.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) d 139.9
(d, J = 4.3 Hz), 134.9, 131.3 (2C), 130.6, 128.1 (2C), 127.9, 127.3,
126.1, 125.9, 123.0, 90.2 (d, J = 5.3 Hz), 83.1, 60.1 (d, J = 11.3
Hz), 59.1 (d, J = 9.8 Hz), 45.6 (d, J = 1.5 Hz), 44.3 (d, J = 3.0
Hz), 43.7 (d, J = 4.5 Hz), 30.9 (d, J = 11.3 Hz), 30.7 (d, J = 9.3
Hz), 24.2 23.0, 22.9, 22.8 (d, J = 3.8 Hz), 19.8, 19.4 (d, J = 2.0
Hz), 19.3; 31P NMR (202 MHz; CDCl3) d 22.6.
Hz), 31.5, 30.9 (d, J = 11.3 Hz), 30.7, 30.6 (d, J = 6.8 Hz), 24.3,
23.0 (d, J = 6.3 Hz), 22.7 (d, J = 4.0 Hz), 21.9, 19.9, 19.7 (d, J =
1.5 Hz), 18.4, 13.5; 31P NMR (202 MHz; CDCl3) d 22.6.
C◦ompound 17. White solid; yield (0.239 g, 97%); mp 164–
166 C; [a]2D5 = -68.1 (c 0.51, CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.51–7.48 (m, 2H), 7.00 (t, J = 5 Hz, 2H), 5.23 (t, J = 9.5 Hz,
1H), 3.61–3.50 (m, 1H), 3.48–3.38 (m, 1H), 2.96 (t, J = 12.5 Hz,
1H), 2.73 (t, J = 10.0 Hz, 1H), 2.63 (t, J = 10.0 Hz, 1H), 2.20 (t,
J = 7.0 Hz, 2H), 2.05–2.02 (m, 2H), 1.77–1.75 (m, 2H), 1.50–1.44
(m, 2H), 1.43–1.27 (m, 5H), 1.25 (d, J = 6.5 Hz, 4H), 1.21 (d, J =
7.0 Hz, 3H), 1.15 (dd, J = 7.0, 13.5 Hz, 6H), 0.90 (t, J = 7.5 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 162.9, 161.0, 138.6, 128.3 (d,
J = 8.0 Hz), 115.1, 115.0, 84.8, 81.1 (d, J = 4.8 Hz), 59.9 (d, J =
10.7 Hz), 59.0, 58.9, 47.1, 44.3 (d, J = 3.0 Hz), 43.8 (d, J = 4.3
Hz), 31.0 (d, J = 11.3 Hz), 30.7, 30.6 (d, J = 9.8 Hz), 24.3, 23.1
(d, J = 6.5 Hz), 22.6 (d, J = 4.0 Hz), 21.9, 19.9, 19.8 (d, J = 1.5
Hz), 18.4, 13.5; 31P NMR (202 MHz; CDCl3) d 22.4; LCMS: m/z
448.0 (M + H)+.
1
Compound 13f. Colorless oil; yield (0.248 g, 97%); H NMR
(500 MHz, CDCl3) d 7.41–7.39 (m, 1H), 7.35–7.32 (m, 2H), 7.27–
7.24 (m, 4H), 6.95 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H),
5.51 (t, J = 10.5 Hz, 1H), 3.90 (s, 3H), 3.53–3.41 (m, 3H), 2.97 (t,
J = 11.0 Hz, 1H), 2.83 (t, J = 9.5 Hz, 1H), 2.08-2.01 (m, 3H), 1.78
(d, J = 7.5 Hz, 2H), 1.38-1.29 (m, 2H), 1.28 (d, J = 7.0 Hz, 4H),
1.20 (d, J = 7.0 Hz, 3H), 1.12 (d, J = 7.0 Hz, 3H), 1.07 (d, J =
7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 156.6, 131.4 (2C),
130.1, 128.7, 128.0 (2C), 127.9, 127.7, 123.4, 120.7, 111.2, 91.0 (d,
J = 3.7 Hz), 82.2, 60.0 (d, J = 10.3 Hz, 3H), 59.2 (d, J = 10.3 Hz,
3H), 55.5, 44.6 (d, J = 1.5 Hz), 44.3 (d, J = 3.3 Hz), 43.7 (t, J =
4.3 Hz), 30.7, 30.6, 30.5, 24.3, 22.8 (d, J = 5.8 Hz), 22.6 (d, J =
3.5 Hz), 19.9, 19.7 (d, J = 1.5 Hz); 31P NMR (202 MHz; CDCl3)
d 22.3.
Compound 18. White solid; yield (0.235 g, 93%); mp 138–
140 ◦C; 1H NMR (500 MHz, CDCl3) d 7.44 (t, J = 7.5 Hz, 1H),
7.25–7.21 (m, 1H), 7.11 (t, J = 6.5 Hz, 1H), 7.02 (t, J = 10.5 Hz,
1H), 5.31 (t, J = 10.5 Hz, 1H), 3.47–3.37 (m, 2H), 3.01 (t, J =
10.5 Hz, 1H), 2.95 (t, J = 11.5 Hz, 1H), 2.77 (t, J = 10.0 Hz,
1H), 2.15 (t, J = 7.0 Hz, 2H), 2.06–2.00 (m, 2H), 1.76 (m, 2H),
1.46–1.41 (m, 2H), 1.40–1.25 (m, 6H), 1.24 (d, J = 6.5 Hz, 3H),
1.17 (d, J = 7.0 Hz, 3H), 1.08 (dd, J = 6.5, 10.0 Hz, 6H), 0.87 (t,
J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 160.9, 130.2 (d,
J = 3.8 Hz), 128.9 (d, J = 8.3 Hz), 128.2 (d, J = 3.8 Hz), 124.2
(d, J = 3.3 Hz), 115.7 (d, J = 21.2 Hz), 83.9, 80.3 (d, J = 5.8 Hz),
59.99, 59.90, 59.1 (d, J = 9.8 Hz), 44.3 (d, J = 3.0 Hz), 43.7 (d,
J = 4.3 Hz), 42.9 (t, J = 2.5 Hz), 30.7 (d, J = 11.2 Hz), 30.6, 30.5,
24.3 (d, J = 5.5 Hz), 22.7 (d, J = 6.5 Hz), 22.5 (d, J = 3.3 Hz),
21.8, 19.8, 19.6 (d, J = 1.5 Hz), 18.3, 13.5; 31P NMR (202 MHz;
CDCl3) d 22.1; LCMS: m/z 448.0 (M + H)+.
Typical procedure for the synthesis of N-phosphonyl-substituted
propargylamines using chiral N-phosphonyl imines and aliphatic
alkynes
In a dry vial, under inert gas protection, was taken 1-hexyne 14
(1.0 mmol) in 3 mL of THF. The reaction vial was cooled to
-78 ◦C, and into the resulting solution n-BuLi (2.0 M in hexanes,
1.0 mmol) was added dropwise. The reaction solution was stirred
at -78 ◦C for 1 h and phosphonyl imine 6 (0.5 mmol in 3 ml
THF) was added to the reaction mixture. The reaction mixture
was stirred for another 2 h before it was quenched by adding
saturated ammonium chloride solution followed by 10 mL water.
The reaction mixture was then transferred to the separatory funnel
and extracted with 2 ¥ 10 mL of diethyl ether. Combined organic
layers were washed with water (1 ¥ 20 mL), dried over anhydrous
sodium sulfate which was filtered off and the organic layer was
evaporated to obtain the desired product as pale yellow solid which
on washing with hexanes gave pure product as white solid in most
cases except in few cases where yellow or colorless oil was obtained
which was further purified by column chromatography (solvent
system: EtOAc–hexanes 70 : 30). A similar procedure was used for
the synthesis of compounds 24–26 with the only exception being
that 3,3-diethoxy-prop-1-yne 15 was used instead of hexyne 14.
1
Compound 19. Colorless oil; yield (0.232 g, 95%); H NMR
(500 MHz, CDCl3) d 7.51 (d, J = 7.0 Hz, 1H), 7.33 (d, J = 8.0 Hz,
1H), 7.27 (t, J = 6.5 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 5.38 (t,
J = 11.0 Hz, 1H), 3.53–3.45 (m, 1H), 3.39–3.31 (m, 1H), 3.27 (t,
J = 9.5 Hz, 1H), 2.96 (t, J = 11.0 Hz, 1H), 2.79 (t, J = 9.5 Hz,
1H), 2.13 (t, J = 7.0 Hz, 2H), 2.09–2.07 (m, 1H), 1.99–1.98 (m,
1H), 1.78–1.76 (m, 2H), 1.45–1.40 (m, 3H), 1.39–1.31 (m, 4H),
1.30 (d, J = 7.0 Hz, 4H), 1.24 (d, J = 7.0 Hz, 3H), 0.98 (d, J =
7.0 Hz, 3H), 0.90–0.85 (m, 6H); 13C NMR (125 MHz, CDCl3) d
140.2 (d, J = 3.8 Hz), 132.1, 129.6, 128.4, 128.2, 127.1, 84.2, 80.0
(d, J = 6.0 Hz), 60.0 (d, J = 10.8 Hz), 59.2 (d, J = 9.8 Hz), 45.5
(d, J = 1.8 Hz), 44.3 (d, J = 2.8 Hz), 43.6 (t, J = 5.0 Hz), 30.8 (d,
J = 4.3 Hz), 30.7 (d, J = 2.3 Hz), 30.5, 24.3 (d, J = 1.0 Hz), 24.2
(d, J = 1.5 Hz), 22.9, 22.8 (d, J = 2.8 Hz), 21.8, 19.8, 19.2 (d, J =
2.0 Hz), 18.3, 13.5; 31P NMR (202 MHz; CDCl3) d 22.5.
Compound 16. White solid; yield (0.236 g, 95%); mp 158–
◦
1
160 C; H NMR (500 MHz, CDCl3) d 7.44 (d, J = 8.0 Hz,
2H), 7.25 (t, J = 7.0 Hz, 2H), 7.19–7.15 (m, 1H), 5.14 (t, J =
10.0 Hz, 1H), 3.52–3.38 (m, 2H), 2.89 (t, J = 9.0 Hz, 1H), 2.63 (t,
J = 10.5 Hz, 1H), 2.12 (t, J = 7.0 Hz, 1H), 1.96 (t, J = 10.5 Hz,
2H), 1.69–1.67 (m, 2H), 1.42–1.37 (m, 2H), 1.34–1.30 (m, 2H),
1.20–1.18 (m, 5H), 1.09 (d, J = 5.5 Hz, 7H), 0.84–0.76 (m, 9H);
13C NMR (125 MHz, CDCl3) d 142.6, 128.3 (2C), 127.2, 126.5
(2C), 84.4, 81.3 (d, J = 4.3 Hz), 59.9 (d, J = 10.8 Hz), 59.0 (d, J =
9.8 Hz), 47.7 (d, J = 1.3 Hz), 44.3 (d, J = 3.0 Hz), 43.8 (d, J = 4.5
1
Compound 20. Colorless oil; yield (0.234 g, 96%); H NMR
(500 MHz, CDCl3) d 7.51 (t, J = 6.5 Hz, 2H), 7.32 (t, J = 7.5 Hz,
1H), 7.11 (t, J = 8.0 Hz, 1H), 5.38 (t, J = 10.5 Hz, 1H), 3.57–3.49
(m, 1H), 3.39–3.28 (m, 2H), 2.97 (t, J = 10.5 Hz, 1H), 2.84 (t,
J = 10.0 Hz, 1H), 2.13 (t, J = 7.0 Hz, 3H), 1.99–1.97 (m, 1H),
1.78–1.73 (m, 2H), 1.45–1.38 (m, 2H), 1.37–1.29 (m, 9H), 1.27 (d,
J = 6.5 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.88–0.82 (m, 6H); 13
C
NMR (125 MHz, CDCl3) d 141.8 (d, J = 4.0 Hz), 132.8, 128.7,
1094 | Org. Biomol. Chem., 2010, 8, 1091–1096
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128.3, 127.8, 122.1, 84.4, 79.9 (d, J = 6.3 Hz), 60.0 (d, J = 10.8
Hz), 59.2 (d, J = 9.8 Hz), 47.7, 44.3 (d, J = 2.8 Hz), 43.6 (t, J =
4.5 Hz), 30.88, 30.80 (d, J = 1.3 Hz), 30.5, 24.3, 24.2, 23.0 (d,
J = 2.8 Hz), 22.9 (d, J = 6.5 Hz), 21.8, 19.9, 19.1 (d, J = 2.0 Hz),
18.3, 13.5; 31P NMR (202 MHz; CDCl3) d 22.6.
J = 10.3 Hz), 59.1 (d, J = 9.8 Hz), 47.5, 44.3 (d, J = 3.0 Hz),
43.8 (d, J = 4.0 Hz), 31.1, 30.8, 30.7, 30.6 (d, J = 9.3 Hz), 24.2,
22.9, 22.8 (d, J = 3.3 Hz), 19.9, 19.7 (d, J = 1.5 Hz), 15.0 (2C);
31P NMR (202 MHz; CDCl3) d 22.2.
Compound 25. Colorless oil; yield (0.237 g, 98%); [a]2D5 = -84.6
(c 0.52, CHCl3); 1H NMR (500 MHz, CDCl3) d 7.39 (t, J = 7.5 Hz,
1H), 7.22 (q, J = 7.5 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.99 (t,
J = 9.5 Hz, 1H), 5.41 (t, J = 10.5 Hz, 1H), 5.21 (d, J = 1.0 Hz,
1H), 3.67–3.61 (m, 2H), 3.53–3.47 (m, 2H), 3.44–3.37 (m, 1H),
3.35–3.29 (m, 1H), 3.03 (t, J = 10.5 Hz, 1H), 2.90 (t, J = 12.0 Hz,
1H), 2.72 (d, J = 10.0 Hz, 1H), 2.01–1.98 (m, 2H), 1.73–1.72 (m,
2H), 1.31–1.24 (m, 2H), 1.17–1.13 (m, 11H), 1.09 (t, J = 7.0 Hz,
6H), 1.053 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) d
161.0, 159.0, 129.3 (d, J = 7.8 Hz), 128.4 (d, J = 4.0 Hz), 124.2
(d, J = 3.3 Hz), 115.7 (d, J = 21.2 Hz), 91.2, 85.2 (d, J = 5.5 Hz),
78.7, 60.6 (2C), 59.8 (d, J = 10.3 Hz), 59.1 (d, J = 9.8 Hz), 44.2
(d, J = 2.8 Hz), 43.8 (d, J = 4.5 Hz), 42.9, 30.5, 30.4, 24.22, 24.20
(d, J = 0.8 Hz), 22.55, 22.52 (d, J = 2.0 Hz), 19.8, 19.6 (d, J = 1.5
Hz), 15.9 (2C); 31P NMR (202 MHz; CDCl3) d 21.7; LCMS: m/z
516.0 (M + Na)+.
C◦ompound 21. White solid; yield (0.242 g, 98%); mp 120–
122 C; [a]2D5 = -73.7 (c 0.59, CHCl3); 1H NMR (500 MHz, CDCl3)
d 7.45 (d, J = 7.5 Hz, 1H), 7.20–7.11 (m, 3H), 5.21 (t, J = 10.5 Hz,
1H), 3.51–3.42 (m, 2H), 2.99–2.90 (m, 2H), 2.72 (t, J = 10.5 Hz,
1H), 2.45 (s, 3H), 2.13 (t, J = 7.0 Hz, 2H), 2.09–2.07 (m, 1H),
2.01–1.99 (m, 1H), 1.78–1.76 (m, 2H), 1.44–1.29 (m, 7H), 1.28 (d,
J = 6.5 Hz, 4H), 1.21 (d, J = 6.5 Hz, 3H), 1.05 (d, J = 7.0 Hz,
3H), 0.98 (d, J = 7.0 Hz, 3H), 0.87 (t, J = 7.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 140.8 (d, J = 4.5 Hz), 134.7, 130.5, 127.1,
126.1, 125.7, 83.6, 80.0 (d, J = 6.0 Hz), 60.0 (d, J = 10.8 Hz), 59.2
(d, J = 9.8 Hz), 45.2, 44.2 (d, J = 3.5 Hz), 43.6 (t, J = 4.3 Hz),
31.0, 30.9, 30.8 (d, J = 8.8 Hz), 30.6, 24.3 (d, J = 2.5 Hz), 23.1,
23.0, 22.9 (d, J = 3.8 Hz), 21.8, 19.8, 19.2 (d, J = 1.5 Hz), 18.4,
13.5; 31P NMR (202 MHz; CDCl3) d 22.7; LCMS: m/z 444.0 (M
+ H)+.
Compound 22. Colorless oil; yield (0.230 g, 95%); [a]2D5 = -80.4
(c 0.51, CHCl3); 1H NMR (500 MHz, CDCl3) d 7.32 (d, J = 7.5 Hz,
1H), 7.21 (t, J = 8.0 Hz, 1H), 6.90 (t, J = 7.0 Hz, 1H), 6.85 (t, J
= 8.0 Hz, 1H), 5.24 (t, J = 10.5 Hz, 1H), 3.85 (s, 3H), 3.49–3.33
(m, 2H), 3.28 (t, J = 11.0 Hz, 1H), 2.94 (t, J = 11.0 Hz, 1H), 2.78
(t, J = 10.5 Hz, 1H), 2.11 (t, J = 6.5 Hz, 2H), 2.07–1.98 (m, 2H),
1.74 (m, 2H), 1.42–1.28 (m, 7H), 1.26 (d, J = 7.0 Hz, 4H), 1.19
(d, J = 6.5 Hz, 3H), 1.01 (t, J = 7.0 Hz, 6H), 0.86 (t, J = 7.0 Hz,
3H); 13C NMR (125 MHz, CDCl3) d 156.4, 131.0 (d, J = 4.5 Hz),
128.4, 127.8 (d, J = 15.2 Hz), 120.6, 111.0, 82.5, 81.5 (d, J = 5.3
Hz), 60.0 (d, J = 10.7 Hz), 59.1 (d, J = 9.8 Hz), 55.4, 44.2 (d, J =
3.3 Hz), 43.9, 43.6 (t, J = 4.5 Hz), 30.79, 30.72, 30.68, 30.60, 24.3
(d, J = 1.2 Hz), 22.8 (d, J = 6.0 Hz), 22.7 (d, J = 3.5 Hz), 21.7,
19.9, 19.5 (d, J = 2.0 Hz), 18.4, 13.5; 31P NMR (202 MHz; CDCl3)
d 22.5; LCMS: m/z 460.0 (M + H)+.
1
Compound 26. Colorless oil; yield (0.238 g, 96%); H NMR
(500 MHz, CDCl3) d 7.53–7.50 (m, 2H), 7.32 (t, J = 8.0 Hz, 1H),
7.13 (t, J = 9.0 Hz, 1H), 5.50 (t, J = 10.5 Hz, 1H), 5.23 (d, J =
1.5 Hz, 1H), 3.70–3.64 (m, 2H), 3.54–3.33 (m, 5H), 2.97 (t, J =
10.5 Hz, 1H), 2.82 (t, J = 7.5 Hz, 1H), 2.09 (d, J = 11.0 Hz, 1H),
2.00 (d, J = 7.5 Hz, 1H), 1.78–1.76 (m, 2H), 1.30 (d, J = 7.0 Hz,
6H), 1.23 (d, J = 6.5 Hz, 4H), 1.17 (t, J = 7.0 Hz, 6H), 0.99 (d,
J = 6.5 Hz, 3H), 0.914 (d, J = 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 140.4 (d, J = 4.0 Hz), 133.0, 129.1, 128.6, 127.8, 122.2,
91.2, 84.9 (d, J = 6.3 Hz), 79.2, 60.7, 60.0 (d, J = 10.8 Hz), 59.1
(d, J = 10.3 Hz), 47.7 (d, J = 2.5 Hz), 44.3 (d, J = 3.3 Hz), 43.6
(d, J = 4.3 Hz), 30.8, 30.7 (d, J = 2.0 Hz), 30.6, 24.3, 24.2 (d, J =
1.5 Hz), 23.0 (d, J = 3.5 Hz), 22.8 (d, J = 5.8 Hz), 19.9, 19.2 (d,
J = 2.0 Hz), 14.9 (2C); 31P NMR (202 MHz; CDCl3) d 22.1.
1
Compound 23. Colorless oil; yield (0.231 g, 92%); H NMR
Procedure for the removal of auxiliary and synthesis of N-acetyl
(500 MHz, CDCl3) d 7.85 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.5 Hz,
1H), 7.59 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 5.73 (t,
J = 11.0 Hz, 1H), 3.59–3.32 (m, 3H), 2.95 (t, J = 11.0 Hz, 1H),
2.67 (t, J = 10.0 Hz, 1H), 2.09 (t, J = 7.0 Hz, 2H), 1.76 (m, 2H),
1.42–1.23 (m, 10H), 1.21 (d, J = 7.0 Hz, 3H), 1.15 (d, J = 6.5 Hz,
3H), 1.09 (d, J = 6.5 Hz, 6H), 0.86 (t, J = 7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 148.1, 137.2 (d, J = 4.5 Hz), 133.2, 129.8,
128.2, 124.7, 84.2, 78.7 (d, J = 6.0 Hz), 59.8 (d, J = 10.3 Hz), 59.1
(d, J = 10.3 Hz), 45.3 (d, J = 2.8 Hz), 44.3 (d, J = 2.8 Hz), 43.7 (t,
J = 4.3 Hz), 30.58, 30.50 (d, J = 4.8 Hz), 30.4, 30.3, 24.2 (d, J =
1.0 Hz), 24.1 (d, J = 1.0 Hz), 22.5 (d, J = 3.3 Hz), 21.7, 19.9, 19.2
(d, J = 2.0 Hz), 18.1, 13.4; 31P NMR (202 MHz; CDCl3) d 22.5.
Compound 24. Colorless oil; yield (0.238 g, 97%); [a]2D5 = -78.4
(c 0.52, CHCl3); 1H NMR (500 MHz, CDCl3) d 7.51 (d, J = 7.5 Hz,
2H), 7.33 (t, J = 7.5 Hz, 2H), 7.27 (d, J = 7.0 Hz, 1H), 5.35 (t,
J = 9.5 Hz, 1H), 5.29 (d, J = 1.5 Hz, 1H), 3.76–3.68 (m, 3H),
3.61–3.52 (m, 4H), 3.48–3.39 (m, 1H), 2.96 (t, J = 11.5 Hz, 1H),
2.77 (t, J = 10.5 Hz, 2H), 2.05 (d, J = 11.5 Hz, 2H), 1.77 (d,
J = 11.5 Hz, 2H), 1.25–1.19 (m, 14H), 1.16–1.12 (m, 6H); 13C
NMR (125 MHz, CDCl3) d 141.2 (d, J = 4.3 Hz), 128.4 (2C),
127.5, 126.6 (2C), 91.4, 86.4 (d, J = 5.0 Hz), 79.5, 60.7, 59.9 (d,
derivative
In a 50 mL round bottom flask, 0.438 g of product 10a was
dissolved in 6.0 mL methanol. To this solution was added 3 M
◦
◦
HCl (8.0 equiv.) at 0 C and the reaction was stirred at 0 C for
30 min and then at room temperature for 2 h. The reaction was
monitored by TLC and completion of the reaction was indicated
by the disappearance of the starting material on TLC. Volatiles
were evaporated under vacuum and then dichloromethane was
◦
added to the solid residue. The mixture was stirred at 0 C and
diisopropylethylamine and acetic anhydride were added at the
same temperature. The reaction was stirred at 0 ◦C for 30 min and
then at rt for 2 h. After that the resulting mixture was extracted
with water and ethyl acetate. The organic layer was dried over
sodium sulfate. The sodium sulfate was filtered off and the organic
layer was dried under vacuum to get the product which was then
triturated with hexanes to get the pure product as a white solid.
◦
Mp 174 C; [a]2D5 = -40.4 (c 0.50, CHCl3) (reported:19 +36.1, c
0.86, CHCl3); 1H NMR (500 MHz, CDCl3) d 7.58 (d, J = 7.0 Hz,
2H), 7.48–7.46 (m, 2H), 7.47 (t, J = 7.5 Hz, 2H), 7.32 (t, J =
4.5 Hz, 4H), 6.24 (s, 2H), 2.03 (s, 3H); 13C NMR (125 MHz,
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CDCl3) d 168.7, 139.0, 131.7 (2C), 128.6 (2C), 128.5, 128.2 (2C),
128.0, 127.0 (2C), 122.3, 86.9, 84.6, 45.0, 23.1.
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Acknowledgements
We would like to thank the Robert A. Welch Foundation (D-1361,
to GL) and the National Natural Science Foundation of China
(No. 20772056, to Y.P.) for providing us with financial assistance.
The project described was also partially supported by the National
Institute on Drug Abuse (R03DA026960 to GL). The content is
solely the responsibility of the authors and does not necessarily
represent the official views of the National Institute on Drug Abuse
or the National Institutes of Health. We thank our co-workers,
Teng Ai and Briana Lujan, for their assistance. We would like
to thank David W. Purkiss for his assistance with NMR, and we
also thank the University of New Mexico, Albuquerque Mass
Spectrometry Facility for mass analysis of our samples.
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CHIRALCEL OD-H column; isopropanol–hexane (30 : 70) as mobile
phase, 0.6 mL min-1; retention time at 6.626.
1096 | Org. Biomol. Chem., 2010, 8, 1091–1096
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