Convenient Synthesis of Cyclic a-Aminophosphonates by Alkylation-Cyclization Reaction of Iminophosphoglycinates Using Phase-Transfer Catalysis

Article abstract of DOI:10.1002/ejoc.201501203

The alkylation reaction of diethyl N-(diphenylmethylene)aminomethylphosphonate (6) with alkyl dihalides under phase-transfer catalysis followed by hydrolysis of the benzophenone imine moiety and subsequent cyclization provides a simple and convenient meth

Full text of DOI:10.1002/ejoc.201501203

DOI: 10.1002/ejoc.201501203
Full Paper
α-Amino Phosphonates
Convenient Synthesis of Cyclic α-Aminophosphonates by
Alkylation–Cyclization Reaction of Iminophosphoglycinates
Using Phase-Transfer Catalysis
Oscar Abelardo Ramírez-Marroquín,[a] Iván Romero-Estudillo,[a]
José Luis Viveros-Ceballos,[b] Carlos Cativiela,[c] and Mario Ordóñez*[a]
Abstract: The alkylation reaction of diethyl N-(diphenylmethyl- simple and convenient method for the synthesis of known and
ene)aminomethylphosphonate (6) with alkyl dihalides under
phase-transfer catalysis followed by hydrolysis of the benzo-
phenone imine moiety and subsequent cyclization provides a
new cyclic α-aminophosphonates 1–5 in moderate to good
yields.
Introduction
cant role in designing peptidomimetics and peptide modifica-
tion.
α-Aminoalkylphosphonic acids and their derivatives are struc-
tural analogues of α-amino acids. They are obtained by the iso-
steric substitution of the planar less bulky carboxylic acid
(CO2H) with a tetrahedral phosphonic acid functionality (PO3H2)
and are considered as stable mimics of the tetrahedral transi-
tion-state that forms during peptide hydrolysis.[1] This class of
compounds has wide applications in medicinal, bioorganic, ag-
ricultural, and organic synthesis.[2–5] Many α-aminophosphon-
ates and derivatives have applications as antibacterial,[6] anti-
cancer,[7] anti-HIV,[8] antimalarial,[9] and antifungal agents,[10]
and some also exhibit pesticidal, insecticidal, and herbicidal ac-
tivities[11] as well as function as plant growth regulators.[12] Fur-
thermore, α-aminophosphonates have been used as key syn-
thetic intermediates in the preparation of more complex com-
pounds and more recently as organocatalysts.[13,14]
Because of the relevant properties of α-aminophosphonates
and their derivatives, numerous useful synthetic approaches
have been developed over the past decades for their prepara-
tion in both racemic and optically pure forms,[15,16] primarily for
the syntheses of the α-aminophosphonic acid analogues of the
20 proteinogenic α-amino acids.[17] A convenient synthesis for
new α-aminophosphonates such as conformationally con-
strained α-aminophosphonates 1–5 could thus play a signifi-
Several methods have been reported for the preparation of
phosphonic analogues of proline (i.e., 1)[18] and pipecolic acid
(i.e., 2).[19] The syntheses of the conformationally constrained α-
aminophosphonates 3–5, however, have not yet been de-
scribed in the literature, despite the importance of these com-
pounds to medicinal chemistry and organic synthesis. Hence,
the development of convenient methods for their preparation
is of great significance. In this context, and in connection with
our current research interest in the synthesis of new conforma-
tionally constrained α-aminophosphonates,[20] we herein report
the first convenient synthesis of diethyl azepan-2-ylphosphon-
ate (3, n = 2), diethyl decahydroisoquinoline-3-phosphonate (4),
and diethyl 1,2,3,4-tetrahydroisoquinoline-3-phosphonate [( )-
5] as well as an alternative approach for the synthesis of diethyl
phosphoprolinate (1, n = 0) and diethyl phosphopipecolate (2,
n = 1). The procedure involves the alkylation of N-(diphenyl-
methylene)aminomethylphosphonate (6) under phase-transfer
catalysis (PTC) conditions followed by hydrolysis of the imine
moiety and a subsequent intramolecular cyclization reaction.
[a] Centro de Investigaciones Químicas CIQ-IICBA, Universidad Autónoma del
Estado de Morelos,
62209 Cuernavaca, Morelos, Mexico
E-mail: palacios@uaem.mx
http://www.ciq.uaem.mx/nosotros/jose-mario-ordonez-palacios/
[b] Secretaría Académica, Universidad Autónoma del Estado de Morelos,
62209 Cuernavaca, Morelos, Mexico
Results and Discussion
[c] Departamento de Química Orgánica, ISQCH, Universidad de Zaragoza –
CSIC,
For the synthesis of conformationally constrained α-
aminophosphonates 1–5, we proposed diethyl α-haloalkyl
phosphoglycinate derivatives 7–9, 11, and 13 as suitable pre-
cursors (Scheme 1), as the well-known acid hydrolysis and sub-
50009 Zaragoza, Spain
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501203.
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sequent ring-closure or N-alkylation of α-haloalkyl amino acid
derivatives provides easy access to cyclic α-amino acids.[21] In
this context, diethyl α-haloalkyl phosphoglycinate derivatives
7–9, 11, and 13 could be obtained by C-alkylation of diethyl
iminophosphoglycinate 6 under phase-transfer catalysis.
Table 1. Alkylation of 6 with 1,4-dibromobutane.
Entry
Base
Catalyst
Yield [%]
1
2
3
4
5
6
KOH
KOH
NaOH
CsOH[c]
NaOH
CsOH[c]
TBAB
10[a]
62[a]
73[a]
81[a]
72[b]
89[b]
Aliquat 336
Aliquat 336
Aliquat 336
Aliquat 336
Aliquat 336
[a] Dihalide (1.5 equiv.) was used. [b] Dihalide (2.5 equiv.) was used.
[c] CsOH·H2O (100 % w/w) was used.
After finding the best reaction conditions, we examined the
scope of the alkylation reaction of protected diethyl iminophos-
phoglycinate 6 with other alkylating agents to obtain the corre-
sponding alkylated products, which are intermediates in the
preparation of cyclic α-aminophosphonates 1–5. Surprisingly,
the alkylation of 6 with 1,3-dibromopropane in the presence of
CsOH·H2O and Aliquat 336 as the catalyst did not give the de-
sired α-alkylated phosphoglycinate derivative 8a. Instead, the
reaction afforded diethyl α-allyl phosphoglycinate 8b in 54 %
yield, which was produced by the elimination reaction under
basic conditions of α-bromoalkyl phosphoglycinate 8a
(Scheme 2). This complication was overcome by using an alk-
ylating agent that is less likely to undergo an elimination reac-
tion. Therefore, the reaction of diethyl iminophosphoglycinate
6 was carried out by using 1-bromo-3-chloropropane, instead,
as the alkylating agent along with CsOH·H2O (100 % w/w) as
the base and Aliquat 336 as the phase-transfer catalyst at room
temperature. Under these conditions, the desired α-alkylated
phosphoglycinate 8c was obtained in 67 % yield, whereas elimi-
nation product 8b was detected in only 8 % yield. The alkyl-
ation reaction of diethyl iminophosphoglycinate 6 with 1,5-di-
bromopentane under the identical conditions afforded the ex-
pected product 9 in 68 % yield (Scheme 2).
Scheme 1. Retrosynthetic analysis of 1–5.
Considering the retrosynthetic analysis described above, we
chose diethyl iminophosphoglycinate 6 as the starting material
for the synthesis of target compounds 1–5. Although com-
pound 6 is not commercially available, it was easily prepared
by the condensation of diethyl phosphoglycinate[22] with ben-
zophenone as described in the literature.[23] Initially we carried
out the synthesis of the diethyl α-bromoalkyl phosphoglycinate
7 by using 1,4-dibromobutane as the alkylating agent.
Thus, we found that the reaction of diethyl iminophospho-
glycinate 6 and 1,4-dibromobutane (1.5 equiv.) with KOH
(5 equiv.) as the base and tetra-n-butylammonium bromide
(TBAB) as the phase-transfer catalyst at room temperature un-
der solvent-free conditions afforded the corresponding α-alk-
ylated phosphoglycinate derivative 7 in 10 % yield (Table 1, En-
try 1). In the next step, we carried out the alkylation reaction
with Aliquat 336 as the phase-transfer catalyst and obtained
alkylated product 7 in a clearly increased yield of 62 % (Table 1,
Entry 2). This improvement was attributed to the liquid-liquid
transfer process, which favored the reaction between the sub-
strate and the alkylating reagent. Using Aliquat 336 as the
phase-transfer catalyst, we proceeded to evaluate other bases
such as NaOH and CsOH (Table 1, Entries 3 and 4) to determine
the best results. When diethyl iminophosphoglycinate 6 was
alkylated by 1,4-dibromobutane (1.5 equiv.) in the presence of
CsOH·H2O (100 % w/w) as the base and Aliquat 336 as the
phase-transfer catalyst, C-bromoalkyl derivative 7 was obtained
in 81 % yield (Table 1, Entry 4). Additionally, the alkylation reac-
tion of diethyl iminophosphoglycinate 6 by using an excess
amount of 1,4-dibromobutane (2.5 equiv.) with NaOH as the
base and Aliquat 336 (10 mol-%) at room temperature afforded
alkylated product 7 in 72 % yield (Table 1, Entry 5). Our best
results were achieved when the reaction was carried out under
the same conditions but with CsOH·H2O (100 % w/w) as the
Scheme 2. Synthesis of the compounds 8a, 8c, and 9.
Motivated by these results, we decided to use these opti-
base. In this case, α-alkylated derivative 7 was obtained in 89 % mized conditions in the alkylation reaction of diethyl imino-
yield (Table 1, Entry 6).
phosphoglycinate 6 with ( )-1,2-bis(bromomethyl)cyclohexane
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(10), which was readily obtained by the reduction of 1,2-cyclo- and the equatorial H-1 proton at δ = 2.87 ppm as doublet of
hexanedicarboxylic anhydride followed by treatment with PBr3 doublet of doublets (ddd, Jgem = 12.4 Hz, Jgauche = 4.4 Hz, JH,P
in diethyl ether as described in the literature.[24] Thus, the reac- 2.0 Hz). Additionally, the signal for the H-3 proton appears at
tion of diethyl iminophosphoglycinate 6 and ( )-1,2-bis(bromo- δ = 2.95 ppm as a ddd (JH,P = 13.2 Hz, Janti = 12.0 Hz, Jgauche
=
=
methyl)cyclohexane (2.5 equiv.) with CsOH·H2O (100 % w/w) as 2.8 Hz). These coupling patterns demonstrate that the H-8a and
the base and Aliquat 336 as the phase-transfer catalyst at room axial H-1 protons are in the gauche conformation, and the
temperature gave the desired alkylated product 11 in 50 % phosphonate group is in the equatorial position. Finally, an nOe
yield with a diastereomeric ratio of 94:6 (Scheme 3).
signal was observed between the axial H-3 and axial H-1 pro-
tons, which indicates that they are located on the same side of
piperidine ring, as shown in Figure 1.
Scheme 3. Synthesis of the compound 11.
Figure 1. Determination of cis stereochemistry of 4 by 1H NMR spectroscopic
analysis.
With the diethyl α-alkylated phosphoglycinate derivatives 7,
8c, 9, and 11 in hand, we attempted the synthesis of cyclic
α-aminophosphonates 1–4 through the acid hydrolysis of the
benzophenone imine moiety and subsequent intramolecular
cyclization reaction. Our studies show that the treatment of
Finally, as a first approach to the synthesis of the diethyl
1,2,3,4-tetrahydroisoquinoline-3-phosphonate (5), diethyl imin-
ophosphoglycinate 6 was alkylated by commercially available
α,α′-dibromo-o-xylene (12) as the alkylating agent (2.5 equiv.)
with CsOH·H2O (100 % w/w) as the base and Aliquat 336
(10 mol-%) as the phase-transfer catalyst in toluene at room
temperature to give the expected product 13 (Scheme 5). The
alkylating agent was a solid in this case, and therefore, toluene
was used as the solvent to incorporate all components within
the reaction mixture. Because of the instability of intermediate
13, it was difficult to determine the yield of the reaction. With-
compound 7 with 2
N HCl in tetrahydrofuran (THF) at room
temperature for 1.0 h followed by a ring-closing N-alkylation
reaction with an excess amount of K2CO3 produced diethyl
phosphopipecolate (2) in 58 % yield (Scheme 4). Under identi-
cal conditions, the hydrolysis and subsequent intramolecular N-
alkylation of α-haloalkyl derivatives 8c, 9, and 11 afforded the
cyclic α-aminophosphonates 1, 3, and 4 in moderate to good
yields (Scheme 4).
out additional purification, 13 was treated with 2
N HCl in THF
followed by treatment with an excess amount of K2CO3 to give
diethyl 1,2,3,4-tetrahydroisoquinoline-3-phosphonate (5) in
41 % overall yield (Scheme 5).
Scheme 4. Synthesis of the target compounds 1–4.
The relative stereochemistry of the phosphonate group in
relation to the cyclohexane ring of 4 was assigned as cis, which
was confirmed by spectroscopic evidence. Because of exten-
sively overlapped signals, it was not initially possible to observe
the nOe correlation between the axial H-3 and axial H-4a pro-
Scheme 5. Synthesis of the target compound 5.
Conclusions
ton at the ring junction. However, it was possible to unambigu- In summary, we have developed an efficient and versatile
ously assign the signal for the axial H-1 proton at δ = 2.77 ppm method for the C-alkylation of diethyl iminophosphoglycinate
as a doublet of doublets (dd, Jgem = 12.4 Hz, Jgauche = 3.6 Hz) 6 under phase-transfer catalysis conditions. The reactions pro-
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fied upon standing; m.p. 93–94 °C. The asterisk denotes compound
8b in the mixture. 1H NMR (400 MHz, CDCl3): δ = 1.29 (t, J = 7.1 Hz,
3 H, CH3CH2O), 1.34 (t, J = 7.2 Hz, 3 H, CH3CH2O), 1.50–1.62 (m, 1
H, CH2), 1.74–1.86 (m, 1 H, CH2), 1.98–2.16 (m, 2 H, CH2), 2.65–2.75*
(m, 2 H, CH2), 3.37–3.43 (m, 2 H, CH2Cl), 3.87 (ddd, J = 12.2, 9.6,
3.8 Hz, 1 H, CHP), 4.05–4.27 (m, 4 H, OCH2CH3), 4.97–5.05* (m, 2 H,
CH2=HC), 5.50–5.59* (m, 1 H, HC=CH2), 7.23–7.50 (m, 8 H, HAr), 7.62–
7.68 (m, 2 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.5 (d, J =
5.8 Hz, CH3CH2O), 28.6 (d, J = 4.8 Hz, CH2), 29.8 (d, J = 14.9 Hz, CH2),
44.4 (CH2Cl), 60.8 (d, J = 159.3 Hz, CHP), 62.7 (d, J = 7.0 Hz,
ceeded smoothly using CsOH·H2O (100 % w/w) as the base and
Aliquat 336 as the phase transfer-catalyst at room temperature
under solvent-free conditions and gave alkylated intermediates
7, 8c, 9, and 11 in moderate to good yields. Upon hydrolysis of
the benzophenone imine moiety and subsequent cyclization
under basic conditions, we successfully obtained the known
and new cyclic α-aminophosphonates 1–4 in good yields. Addi-
tionally, to enhance the efficiency of this method, a sequential
one-pot C,N-alkylation was developed to achieve the synthesis
of diethyl 1,2,3,4-tetrahydroisoquinoline-3-phosphonate (5). OCH2CH3), 62.8 (d, J = 6.7 Hz, OCH2CH3), 128.0 (Ar), 128.1 (Ar), 128.5
(Ar), 128.6 (Ar), 128.7 (Ar), 130.3 (Ar), 135.8 (Ar), 139.3 (d, J = 3.8 Hz,
Ar), 170.9 (d, J = 16.3 Hz, C=N) ppm. 31P NMR (162 MHz, CDCl3): δ =
21.07, 21.21 (93:07) ppm. HRMS (FAB+): calcd. for C21H28ClNO3P [M
+ H]+ 408.1495; found 408.1493.
The new cyclic α-aminophosphonates obtained herein will pro-
vide excellent opportunity for future studies.
Diethyl
6-Bromo-1-[(diphenylmethylene)amino]hexylphos-
Experimental Section
phonate (9): Clear yellow liquid (196 mg, 68 %). 1H NMR (400 MHz,
CDCl3): δ = 1.01–1.12 (m, 1 H, CH2), 1.26–1.37 (m, 3 H, CH2), 1.30 (t,
J = 7.1 Hz, 3 H, CH3CH2O), 1.33 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.74–
1.83 (m, 2 H, CH2), 1.83–1.94 (m, 1 H, CH2), 1.94–2.05 (m, 1 H, CH2),
3.32 (t, J = 6.8 Hz, 2 H, CH2Br), 3.87 (ddd, J = 11.8, 10.2, 3.2 Hz, 1 H,
CHP), 4.06–4.24 (m, 4 H, OCH2CH3), 7.23–7.49 (m, 8 H, HAr), 7.61–
7.67 (m, 2 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.6 (d, J =
5.5 Hz, CH3CH2O), 26.0 (d, J = 15.1 Hz, CH2), 28.0 (CH2), 30.9 (d, J =
4.7 Hz, CH2), 32.7 (CH2), 33.7 (CH2Br), 61.5 (d, J = 158.2 Hz, CHP),
62.4 (d, J = 7.4 Hz, OCH2CH3), 62.5 (d, J = 8.0 Hz, OCH2CH3), 128.1
(Ar), 128.3 (Ar), 128.5 (Ar), 128.7 (Ar), 128.8 (Ar), 130.3 (Ar), 136.0
(Ar), 139.6 (Ar), 170.6 (d, J = 16.7 Hz, C=N) ppm. 31P NMR (162 MHz,
CDCl3): δ = 21.93 ppm. HRMS (FAB+): calcd. for C23H32BrNO3P [M +
H]+ 480.1303; found 480.1310.
General Methods: All commercial materials were used as received
unless otherwise noted. Melting points were measured with a
Fisher–Johns apparatus, Flash chromatography was performed by
using 230–400 mesh Silica Flash 60®. Thin-layer chromatography
was done on TLC sheets that were precoated with silica gel 60 F254
(E. Merck). The NMR spectroscopic data were recorded with a Varian
System instrument (400 and 200 MHz). CDCl3 was used as the NMR
solvent along with TMS and Ph3PO as the internal standards. Chemi-
cal shifts (δ) are reported in parts per million. Multiplicities are re-
ported as s (singlet), d (doublet), t (triplet), dd (doublet of doublets),
td (triplet of doublets), br. s (broad singlet), q (quartet), and m (mul-
tiplet). Coupling constants (J) are given in Hz. High resolution mass
spectrometry (CI+ and FAB+) experiments were carried out with a
JEOL HRMStation JHRMS-700. The 1H and 13C NMR spectroscopic
data for compound 6[23] are identical to those reported in the litera-
ture.
Diethyl
2-[(cis-1,2)-2-(Bromomethyl)cyclohexyl]-1-[(diphenyl-
methylene)amino]ethylphosphonate (11): Colorless oil (157 mg,
1
50 %). H NMR (400 MHz, CDCl3): δ = 0.81–0.99 (m, 2 H), 1.10–1.21
General Procedure for the Preparation of 7, 8c, 9, and 11: Di-
ethyl iminophosphoglycinate 6 (1.0 equiv.) was treated successively
with the corresponding alkyl dihalide (2.5 equiv.), Aliquat 336
(10 mol-%), and CsOH·H2O (100 % w/w). The reaction mixture was
stirred at room temperature for 17 to 23 h. After this time, the crude
product was purified by flash column chromatography (hexane/
AcOEt, 55:45 or CH2Cl2/iPrOH, 95:05).
(m, 1 H), 1.24–1.37 (m, 2 H), 1.29 (t, J = 7.0 Hz, 3 H, CH3CH2O), 1.35
(t, J = 7.0 Hz, 3 H, CH3CH2O), 1.49 (br. s, 3 H), 1.58–1.64 (m, 1 H),
1.77–1.95 (m, 3 H), 3.30–3.42 (m, 2 H, CH2Br), 3.92 (ddd, J = 12.2,
10.2, 2.8 Hz, 1 H, CHP), 4.05–4.27 (m, 4 H, OCH2CH3), 7.29–7.49 (m,
8 H, HAr), 7.64–7.68 (m, 2 H, HAr) ppm. 13C NMR (100 MHz, CDCl3):
δ = 16.7 (d, J = 5.6 Hz, CH3CH2O), 22.6, 23.7, 27.2, 27.4, 29.8, 34.2
(d, J = 15.3 Hz), 36.0, 42.9 (CH2Br), 58.9 (d, J = 159.1 Hz, CHP), 62.7
(d, J = 6.5 Hz, OCH2CH3), 62.8 (d, J = 6.1 Hz, OCH2CH3), 128.1 (Ar),
128.5 (Ar), 128.5 (Ar), 128.8 (Ar), 129.0 (Ar), 130.4 (Ar), 136.0 (d, J =
2.8 Hz, Ar), 139.6 (d, J = 3.8 Hz, Ar), 170.8 (d, J = 16.6 Hz, C=N) ppm.
31P NMR (162 MHz, CDCl3): δ = 22.18 ppm. HRMS (FAB+): calcd. for
C26H36BrNO3P [M + H]+ 520.1616; found 520.1633.
Diethyl
5-Bromo-1-[(diphenylmethylene)amino]pentylphos-
phonate (7): Colorless oil (248 mg, 89 %). 1H NMR (400 MHz, CDCl3):
δ = 1.14–1.24 (m, 1 H, CH2), 1.30 (t, J = 6.8 Hz, 3 H, CH3CH2O), 1.33
(t, J = 7.0 Hz, 3 H, CH3CH2O), 1.39–1.50 (m, 1 H, CH2), 1.66–1.80 (m,
2 H, CH2), 1.85–2.08 (m, 2 H, CH2), 3.30–3.36 (m, 2 H, CH2Br), 3.87
(ddd, J = 11.8, 10.1, 3.2 Hz, 1 H, CHP), 4.07–4.24 (m, 4 H, OCH2CH3),
7.26–7.28 (m, 2 H, HAr), 7.30–7.35 (m, 2 H, HAr), 7.37–7.49 (m, 4 H,
HAr), 7.63–7.66 (m, 2 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ =
16.7 (d, J = 5.7 Hz, CH3CH2O), 25.6 (d, J = 15.1 Hz, CH2), 30.4 (d, J =
5.2 Hz, CH2), 32.5 (CH2), 33.4 (CH2Br), 61.6 (d, J = 158.7 Hz, CHP),
62.6 (d, J = 6.3 Hz, OCH2CH3), 62.7 (d, J = 6.3 Hz, OCH2CH3), 128.2
(Ar), 128.4 (Ar), 128.6 (Ar), 128.8 (Ar), 128.9 (Ar), 130.4 (Ar), 136.1 (d,
J = 2.4 Hz, Ar), 139.7 (d, J = 3.6 Hz, Ar), 170.9 (d, J = 16.8 Hz, C=
N) ppm. 31P NMR (81 MHz, CDCl3): δ = 24.50 ppm. HRMS (FAB+):
calcd. for C22H30NO3BrP [M + H]+ 466.1147; found 466.1143.
General Procedure for the Synthesis of 1–4: To a solution of the
alkylated compound 7, 8c, 9, or 11 (1.0 equiv.) in THF (2 mL) was
added an equal volume of HCl (2
N solution), and the reaction mix-
ture was stirred at room temperature for 1.0 to 1.5 h. The mixture
was made alkaline to pH = 12 by the addition of powdered K2CO3.
The alkaline solution was stirred and heated at 65 °C for 1.0 to
7.0 h. The mixture was then poured into water, and the solution
was extracted with CH2Cl2 or AcOEt. The organic layer was dried
with Na2SO4 and filtered, and the filtrate was concentrated under
reduced pressure. Finally, the crude product was purified by flash
column chromatography.
Diethyl 1-Allyl-1-[(diphenylmethylene)amino]methylphosphon-
ate (8b): Using 1,3-dibromopropane as the alkylating agent af-
forded 8b as a clear yellow oil (121 mg, 54 %). The spectroscopic
data are identical with those reported in the literature.[25]
Diethyl Pyrrolidin-2-ylphosphonate (1): Clear yellow oil (31 mg,
66 %). The spectroscopic data are identical with those reported in
the literature.[18a]
Diethyl
4-Chloro-1-[(diphenylmethylene)amino]butylphos- Diethyl Piperidin-2-ylphosphonate (2): Clear yellow oil (42 mg,
phonate (8c): Using 1-bromo-3-chloropropane as the alkylating
agent afforded 8c (165 mg, 67 %) as a clear yellow oil, which solidi-
58 %). The spectroscopic data are identical with those reported in
the literature.[19]
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Diethyl Azepan-2-ylphosphonate (3): Colorless oil (46 mg, 56 %).
1H NMR (400 MHz, CDCl3): δ = 1.33 (t, J = 7.1 Hz, 3 H, CH3CH2O),
1.34 (t, J = 7.0 Hz, 3 H, CH3CH2O), 1.47–1.74 (m, 6 H, CH2), 1.81–1.91
(m, 1 H, CH2), 1.97 (br. s, 1 H, NH), 2.05–2.15 (m, 1 H, CH2), 2.76
(ddd, J = 14.2, 7.8, 3.7 Hz, 1 H, CH2N), 2.98–3.08 (m, 2 H, CH2N,
CHP), 4.08–4.22 (m, 4 H, OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3):
δ = 16.6 (d, J = 5.7 Hz, CH3CH2O), 27.1 (d, J = 17.0 Hz, CH2), 27.5
(CH2), 30.3 (CH2), 31.8 (CH2), 48.2 (d, J = 15.5 Hz, CH2N), 55.5 (d, J =
156.6 Hz, CHP), 62.1 (d, J = 7.1 Hz, OCH2CH3), 62.5 (d, J = 7.1 Hz,
OCH2CH3) ppm. 31P NMR (162 MHz, CDCl3): δ = 25.70 ppm. HRMS
(FAB+): calcd. for C10H23NO3P [M + H]+ 236.1416; found 236.1404.
FSE (research group E40). We also thank Victoria Labastida for
her valuable technical support in obtaining MS spectra.
Keywords: Synthetic methods · Phase-transfer catalysis ·
Alkylation · Cyclization · Phosphorus
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Diethyl (cis-4a,8a)-Decahydroisoquinoline-3-phosphonate (cis-
4): Colorless oil (63 mg, 76 %). 1H NMR (400 MHz, CDCl3): δ = 1.22–
1.31 (m, 2 H), 1.35 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.36 (t, J = 7.1 Hz,
3 H, CH3CH2O), 1.39–1.49 (m, 2 H), 1.51–1.58 (m, 3 H), 1.68–1.94 (m,
6 H), 2.77 (dd, J = 12.4, 3.5 Hz, 1 H, 1-Hax), 2.87 (ddd, J = 12.4, 4.3,
1.8 Hz, 1 H, 1-Heq), 2.95 (ddd, J = 13.8, 11.8, 2.8 Hz, 1 H, CHP), 4.10–
4.23 (m, 4 H, OCH2CH3) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.7
(d, J = 5.4 Hz, CH3CH2O), 20.7, 25.0, 25.8, 26.6, 32.1, 34.7 (d, J =
14.6 Hz, C-4a), 35.9 (C-8a), 53.2 (d, J = 17.6 Hz, CH2N), 54.7 (d, J =
159.4 Hz, CHP), 62.3 (d, J = 8.2 Hz, OCH2CH3), 62.4 (d, J = 7.1 Hz,
OCH2CH3) ppm. 31P NMR (162 MHz, CDCl3): δ = 24.04 ppm. HRMS
(FAB+): calcd. for C13H27NO3P [M + H]+ 276.1729; found 276.1743.
Diethyl (1,2,3,4-Tetrahydroisoquinolin-3-yl)phosphonate (5): A
solution of diethyl iminophosphoglycinate 6 (200 mg, 0.6 mmol) in
toluene (1 mL) was treated successively with α,α′-dibromo-o-xylene
12 (396 mg, 1.5 mmol), Aliquat 336 (27 μL, 0.06 mmol, 10 mol-%),
and CsOH·H2O (100 % w/w, 200 mg). The reaction mixture was
stirred at room temperature for 4.0 h. The solvent was then re-
moved under vacuum, and the crude product was dissolved with-
out further purification in THF (2 mL) and treated with HCl (2
N
solution, 2 mL). The reaction mixture was stirred at room tempera-
ture for 1.0 h and then made alkaline to pH = 12 by the addition
of powdered K2CO3. The mixture was stirred at room temperature
for 2.0 h and then poured into water. The resulting solution was
extracted with AcOEt (2 × 20 mL). The combined organic layers
were dried with Na2SO4 and filtered, and the filtrate was evaporated
under reduced pressure. Finally, the crude product was purified by
flash column chromatography (AcOEt/MeOH) to give cyclic α-ami-
nophosphonate 5 (66 mg, 41 %) as a clear yellow oil. 1H NMR
(400 MHz, CDCl3): δ = 1.36 (t, J = 7.1 Hz, 3 H, CH3CH2O), 1.37 (t, J =
7.1 Hz, 3 H, CH3CH2O), 2.46 (br. s, 1 H, NH), 2.90–3.10 (m, 2 H,
CH2Ph), 3.32 (ddd, J = 15.2, 11.2, 4.2 Hz, 1 H, CHP), 4.07 (s, 2 H,
CH2N), 4.17–4.26 (m, 4 H, OCH2CH3), 6.99–7.03 (m, 1 H, HAr), 7.10–
7.19 (m, 3 H, HAr) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.7 (d, J =
5.5 Hz, CH3CH2O), 28.9 (CH2Ph), 48.4 (d, J = 16.5 Hz, CH2N), 51.2 (d,
J = 161.8 Hz, CHP), 62.6 (d, J = 5.1 Hz, OCH2CH3), 62.7 (d, J = 5.3 Hz,
OCH2CH3), 126.3 (2 Ar), 126.5 (Ar), 129.3 (Ar), 133.2 (d, J = 14.4 Hz,
Ar), 135.0 (Ar) ppm. 31P NMR (162 MHz, CDCl3): δ = 24.02 ppm.
HRMS (FAB+): calcd. for C13H21NO3P [M + H]+ 270.1259; found
270.1257.
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Acknowledgments
Our group wishes to thank the Consejo Nacional de Ciencia y
Tecnología (CONACYT), Mexico for their financial support to
this work (grant 181816; graduate scholarship 251235, to
O. A. R.-M.), the Ministerio de Economía y Competitividad (MEC),
Spain (grant CTQ2013-40855-R), and the Gobierno de Aragón-
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