Practical and efficient synthesis of α-Aminophosphonic acids containing 1,2,3,4-Tetrahydroquinoline or 1,2,3,4-Tetrahydroisoquinoline heterocycles

Article abstract of DOI:10.3390/molecules21091140

We report here a practical and efficient synthesis of α-aminophosphonic acid incorporated into 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline heterocycles, which could be considered to be conformationally constrained analogues of pipecolic acid. The principal contribution of this synthesis is the introduction of the phosphonate group in the N-acyliminium ion intermediates, obtained from activation of the quinoline and isoquinoline heterocycles or from the appropriate ?-lactam with benzyl chloroformate. Finally, the hydrolysis of phosphonate moiety with simultaneous cleavage of the carbamate afforded the target compounds.

Full text of DOI:10.3390/molecules21091140

molecules
Article
Practical and Efficient Synthesis of
α-Aminophosphonic Acids Containing
1,2,3,4-Tetrahydroquinoline or
1,2,3,4-Tetrahydroisoquinoline Heterocycles
Mario Ordóñez 1,*, Alicia Arizpe 2, Fracisco J. Sayago 2, Ana I. Jiménez 2 and Carlos Cativiela 2,
*
1
Centro de Investigaciones Químicas-IICBA, Universidad Autónoma del Estado de Morelos,
Av. Universidad 1001, Cuernavaca 62209, Morelos, Mexico
Departamento de Química Orgánica, Universidad de Zaragoza-CSIC, ISQCH, Zaragoza 50009, Spain;
2
aliceiw@gmail.com (A.A.); jsayago@unizar.es (F.J.S.); anisjim@unizar.es (A.I.J.)
*
Correspondence: palacios@uaem.mx (M.O.); cativiela@unizar.es (C.C.);
Tel.: +52-777-329-7997 (M.O.); +34-976-761-210 (C.C.)
Academic Editor: György Keglevich
Received: 25 July 2016; Accepted: 25 August 2016; Published: 31 August 2016
Abstract: We report here a practical and efficient synthesis of α-aminophosphonic acid incorporated
into 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline heterocycles, which could be
considered to be conformationally constrained analogues of pipecolic acid. The principal contribution
of this synthesis is the introduction of the phosphonate group in the N-acyliminium ion intermediates,
obtained from activation of the quinoline and isoquinoline heterocycles or from the appropriate
δ-lactam with benzyl chloroformate. Finally, the hydrolysis of phosphonate moiety with simultaneous
cleavage of the carbamate afforded the target compounds.
Keywords: α-aminophosphonic acids; N-acyliminium ions; conformationally constrained
1. Introduction
There is a continuously growing interest in the development of new peptidomimetics, compounds
that mimic the bioactive conformation and action of therapeutic peptides while possessing greater
bioavailability and stability and less undesirable effects. In this regard, the incorporation of
rigid unusual secondary
in significant consequences for the conformation of peptidomimetics as synthetic tools for drug
discovery [ ]. Some of the most important molecules are the 1,2,3,4-tetrahydroquinoline-2-carboxylic
acid ] and 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid ], which are conformationally
constrained analogues of unnatural pipecolic acid, and 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
(Tic) ], which is considered a conformationally constrained analogue of phenylalanine (Phe).
These compounds are important unnatural -amino acids, and they are used as key intermediates in
α-amino acids, where the nitrogen is involved in a ring, may result
1,2
1
[
3,4
2 [5,6
3 [7,8
α
organic synthesis for the preparation of biologically active compounds. Therefore, much effort has
been dedicated to the preparation of these compounds.
On the other hand, the
α-aminoalkylphosphonic acids are probably the most important
analogues of the -amino acids, obtained by isosteric substitution of the planar and less bulky
α
carboxylic acid (CO2H) by a tetrahedral phosphonic acid functionality (PO3H2). This class of
compounds is currently attracting interest in organic and medicinal chemistry, due to their
important biological and pharmacological properties [
of compound has prompted organic chemists to report numerous procedures for their racemic
or stereoselective synthesis [13 18], principally using the diastereoselective and enantioselective
9–12]. The great importance of this type
–
Molecules 2016, 21, 1140; doi:10.3390/molecules21091140
www.mdpi.com/journal/molecules

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Pudovik [19
,
20] and Kabachnik–Fields [21–25] reactions for acyclic
α
-aminoalkylphosphonates,
and through N-acyl iminium ions for the synthesis of cyclic derivatives [26
the best of our knowledge, the synthesis of 1,2,3,4-tetrahydroquinoline-2-phosphonic acid
1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid analogues [35 38] has not yet been described in
–
34]. However, to
4
and
5
–
the literature, whereas the synthesis of 1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid
recently described by our research group [39,40] (Figure 1).
6 has been
Figure 1. α-Amino acids characterized by a tetrahydroquinoline or tetrahydroisoquinoline heterocyles
and their α-amino phosphonic analogues.
Considering the high value of these non-coded compounds in connection with our current research
interest in the synthesis of novel conformationally restricted
we now report herein the practical and efficient synthesis of
α
-aminophosphonic acids [26
-aminophosphonic acids incorporating
and , which could be
–28,41–43],
α
1,2,3,4-tetrahydroquinoline
4
, and 1,2,3,4-tetrahydroisoquinoline rings
5
6
considered to be conformationally constrained analogues of pipecolic acid. The principal contribution
of this work is the regioselective introduction of the phosphonate group in the N-acyliminium ions
derivatives obtained from activation of the quinoline and isoquinoline nucleous or from the appropriate
δ-lactams with benzyl chloroformate.
2. Results and Discussion
For the synthesis of 1,2,3,4-tetrahydroquinoline-2-phosphonic acid
N-acyliminium ions as suitable precursors, considering that the well-known reduction of the
carbonyl group of lactams such as the 3,4-dihydro-2(1H)-quinolinone , and their subsequent
transformation into a N-acyliminium ion, is one of the methods that allows the incorporation of
the phosphonate functionality into the position of the nitrogen atom such as we have previously
described [26 28]. These proposals prompted us to explore further application of the N-acyliminium
strategy for the synthesis of the target compound. In this context, the commercially available
4, we proposed the
7
α
–
3,4-dihydro-2(1H)-quinolinone
a base and benzyl chloroformate in THF at
7
was reacted◦with lithium bis(trimethylsilyl)amide (LiHMDS) as
−
78 C, to obtain the N-Cbz-3,4-dihydro-2(1H)-quinolinone
8
in 91% yield. Reduction of the carbonyl group in
subsequent reaction with methanol and catalytic amounts of pyridinium p-toluenesulfonate (PPTS),
gave the methoxyaminal , which was treated immediately with trimethyl phosphite in the presence of
BF3 OEt2, obtaining the dimethyl N-Cbz-1,2,3,4-tetrahydroquinoline-2-phosphonate 11 in 62% via the
N-acyliminium ion 10 in 62% yield from . Treatment of this N-Cbz-protected phosphonate with a 33%
8 with diisobutylaluminium hydride (DIBAL-H) and
9
·
8
solution of hydrogen bromide in acetic acid, afforded the 1,2,3,4-tetrahydroquinoline-2-phosphonic
acid 4 as hydrobromide in quantitative yield (Scheme 1).

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Scheme 1. Synthesis of 1,2,3,4-tetrahydroquinoline-2-phosphonic acid 4 from lactam 7.
The literature has described the hydrophosphonylation of quinoline derivatives to obtain the
1,2-dihydroquinolin-2-ylphosphonate and 2,4-diphosphono-1,2,3,4-tetrahydroquinoline derivatives
using activating agents [44–48]. These reactions proceed via quinolinium ions that can be viewed
as counterparts of the above-mentioned iminium species. Thus, the addition of an acyl chloride
to quinoline can be considered as a way to generate the iminium ion necessary for subsequent
regioselective incorporation of the phosphonate functionality α to the nitrogen atom.
Based on this precedent, we decided to compare the efficiency of the N-acylquinolinium salts as
intermediates in the synthesis of α-aminophosphonic acid 4. For this purpose, benzyl chloroformate
was added to quinoline and the N-Cbz-quinolinium chloride formed 12 was reacted with trimethyl
◦
phosphite in acetonitrile at 50 C, obtaining the dimethyl N-Cbz-1,2-dihydroquinoline-2-phosphonate
derivative 13 in 74% yield from quinolone. The diphosphonylation products at the 2- and 4-positions
of the quinoline ring were not detected. The regioselectivity observed in the addition of trimethyl
phosphite to the N-acylquinolinium ion 12 may be attributed to the electron-withdrawing character
of the benzyloxycarbonyl group, which increases the electrophilic nature of the carbon adjacent to
the nitrogen atom. Additionally, the benzyloxycarbonyl group was selected for its easy incorporation
and removal under mild conditions. Thus, the catalytic hydrogenation resulted in simultaneous
removal of the Cbz group and reduction of the double bond at positions 3,4 to afford the
α
-aminophosphonate 14, which, by treatment with hydrogen bromide in acetic acid, gave the
1,2,3,4-tetrahydroquinoline-2-phosphonic acid as hydrobromide. The latter two steps proceeded
quantitatively and obviated the need for purification (Scheme 2).
4
(MeO)3P
CbzCl
-
+
Cl
CH3CN, 0 ºC
CH3CN, 50 ºC
74%
N
N
P(OMe)2
O
N
Cbz
Cbz
12
13
H2, Pd/C
100%
AcOEt, r.t.
-
Br
HBr / AcOH
+
N
P(OH)2
O
H
r.t.
N
H
P(OMe)2
100%
H
O
4
14
Scheme 2. Synthesis of 1,2,3,4-tetrahydroquinoline-2-phosphonic acid 4 from quinoline.

Molecules 2016, 21, 1140
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The 1,2,3,4-tetrahydroquinoline-2-phosphonic acid
4
was obtained in 74% overall yield from
quinoline following the synthetic strategy in Scheme 2, which compares favorably with the 56% global
yield achieved in Scheme 1, when starting from quinolinone . Accordingly, the superior global yield,
together with the much lower price of quinoline in comparison with 3,4-dihydro-2(1H)-quinolinone
makes the methodology in Scheme 2 more advantageous than the lactam-based one for the preparation
of -aminophosphonic acid . From an operational viewpoint, both routes required few purification
1
7
,
α
4
steps—by column chromatography—of intermediate compounds.
We next addressed the preparation of 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid
5.
Similarly to that described above for the quinoline counterpart, the preparation of N-substituted-1,2-
dihydroisoquinoline-1-phosphonates through the isoquinolinium salts formed by reaction of isoquinoline
with acyl chlorides and subsequent addition of trialkyl phosphites has been described [49,50]. Thus,
the synthesis of dimethyl N-Cbz-1,2-dihydroisoquinoline-1-phosphonate should be straightforward,
as shown above for the preparation of dimethyl N-Cbz-1,2-dihydroquinoline-2-phosphonate 13.
On the other hand, the lactam to be used as a starting product for the preparation of the target
amino acid
the advantageous preparation of amino acid
5
is not easily available from commercial sources in this case. This fact together with
via the formation of quinolinium salt prompted us to
4
undertake the synthesis of 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid following an analogous
synthetic route.
Thus, using the reaction conditions described above, the isoquinoline was reacted with benzyl
◦
chloroformate followed by the addition of trimethyl phosphite in acetonitrile at 50 C. However,
under these reaction conditions, the desired compound 16 was not obtained. It is noteworthy that
during the addition of benzyl chloroformate to isoquinoline, a yellow solid was formed, which was
later identified as the isoquinolinium salt 15. This compound remained unaltered upon addition of
trimethyl phosphite so that the formation of the expected 1,2-dihydroisoquinoline-1-phosphonate 16
did not take place. We reasoned that if the trimethyl phosphite was present in the reaction medium
before benzyl chloroformate was added, the isoquinolinium ion formed 16 would immediately
react with it, thus preventing precipitation. To our delight, when the order of addition of these
reagents was exchanged (that is, trimethyl phosphite prior to benzyl chloroformate), the dimethyl
N-Cbz-1,2-dihydroisoquinoline-1-phosphonate 16 was obtained at 92% yield. In the next step, we
carried out the catalytic hydrogenation of the double bond in 16 under an atmospheric pressure of
hydrogen gas and using Pd/C as a catalyst, to generate the tetrahydroisoquinoline moiety. However,
the Cbz group in 16 was readily eliminated at room temperature, whereas the double bond at positions
3,4 was only partially hydrogenated even after long reaction times. As a consequence, mixtures of
the desired tetrahydroisoquinoline derivative 17 and the analogous dihydroisoquinoline 18 were
obtained. Attempts to improve this result by changing the solvent as well as by increasing the reaction
temperature or hydrogen gas pressure proved unsuccessful and a mixture of 17 and 18 was always
obtained (Scheme 3).
Scheme 3. First attempt to synthetize 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acids derivatives.

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To circumvent this problem, we synthesized the compound analogous to 16 that bears the
less acid-sensitive diethyl phosphonate group 19. A procedure identical to that established for the
dimethyl derivative but using triethyl phosphite as the phosphorus source provided the desired diethyl
N-Cbz-1,2-dihydroisoquinoline-1-phosphonate 19 in 98% yield from isoquinoline. Taking into account
the fact that compound 19 can be considered not only as an N-acyl-
as an enamide, we decided to perform the reduction of the double bond using trifluoroacetic acid
and triethylsilane as the reducing agent, following the conditions described by Jacobsen et al. [51
α-aminophosphonate, but also
]
for cyclic enamides. In this case, the diethyl N-Cbz-1,2,3,4-tetrahydroisoquinoline-1-phosphonate
20 was readily obtained in quantitative yield by reaction with triethylsilane and trifluoroacetic acid.
Subsequent cleavage of the protecting groups in 20 by treatment with hydrogen bromide in acetic acid,
afforded the 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid
5 as hydrobromide in quantitative yield.
This compound was isolated in 97% overall yield from isoquinoline (Scheme 4).
Scheme 4. Synthesis of 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid 5 from isoquinoline.
Finally, we focused on the preparation of 1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid 6,
that is, the phosphonic analogue of Tic (TicP). This compound exhibits a tetrahydroisoquinoline
core, as does the aminophosphonic acid 5
. However, in the case of TicP, the phosphonate group
is at the 3-position. However, the isoquinoline selectively provides the phosphonate group at the
1-position of the ring. Therefore, we believe that the generation of a suitable iminium ion for the
introduction of the phosphonate moiety at the desired 3-position, the lactam precursor was the only
route to consider in this case. It should be noted that, following this strategy, the position of the
carbonyl group in the starting lactam determines with complete regiocontrol the introduction of the
phosphonate substituent, which is a distinctive advantage of this methodology. The adequate lactam 21
used in the synthesis of the target amino acid was easily prepared following reported procedures that
involved reaction of 2-phenylacetyl chloride with aqueous ammonia to give 2-phenylacetamide [52
and subsequent condensation with formaldehyde [53]. Lactam 21 was readily transformed into
1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid (TicP,
) following the synthetic route strictly similar
to that reported above for the preparation of the -aminophosphonic acid from lactam (Scheme 1).
The 1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid was thus obtained as hydrobromide in 52%
]
6
α
4
7
6
global yield from the starting substrate 21, with isolation and purification of only two synthetic
intermediates 22, 25 (Scheme 5).

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Scheme 5. Synthesis of 1,2,3,4-tetrahydroisoquinoline-3-phosphonic acid, TicP 6.
The results obtained show the successful use of the lactam 21 to generate the key intermediate
N-acyliminium ion, which by phosphonylation, afforded the desired diethyl N-Cbz-1,2,3,4-
tetrahydroisoquinoline-3-phosphonate 25, demonstrating thus the versatility of this methodology in
the preparation of α-aminophosphonic acids structurally related to pipecolic acid.
3. Materials and Methods
3.1. General
All reagents were used as received from commercial suppliers (Sigma-Aldrich Chemie GmbH,
Buchs, Switzerland) without further purification. Thin-layer chromatography (TLC) was performed
on Macherey-Nagel Polygram® SIL G/UV254 (Macherey-Nagel, Duren, Germany) precoated silica gel
polyester plates. The products were visualized by exposure to UV light (254 nm), iodine vapour or
ethanolic solution of phosphomolybdic acid. Column chromatography was performed using 60 M
(0.04–0.063 mm) silica gel from Macherey-Nagel. Melting points were determined on a Gallenkamp
apparatus (Weiss Gallenkamp, Loughborough, UK). IR spectra were registered on a Nicolet Avatar
360 FTIR spectrophotometer (Thermo Electron Corporation, Madison, WI, USA);
ν
is given for
max
the main absorption bands. 1H-, 13C- and 31P-NMR spectra were recorded on Bruker AV-400 or
AV-300 instruments (Bruker BioSpin GmbH, Rheinstetten, Germany) at room temperature, unless
otherwise indicated, using the residual solvent signal as the internal standard; chemical shifts (
δ) are
expressed in ppm and coupling constants (J) in Hertz. High-resolution mass spectra were obtained on
a Bruker Microtof-Q spectrometer. Compound 22 was prepared by reaction of 2-phenylacetamide [52
]
1
with formaldehyde [53]. H-, 13C- and 31P- NMR spectra of all final compounds are showed in the
supplementary material (Figures S1–S34).
3.2. Synthesis of N-Benzyloxycarbonyl-3,4-dihydro-2-quinolinone 8
A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.80 mL, 2.80 mmol) was
slowly added to a solution of 3,4-dihydro-2(1H)-quinolinone
7 (400 mg, 2.72 mmol) in anhydrous
tetrahydrofuran (10 mL) kept at
−
78 ◦C under argon. After 30 min, benzyl chloroformate (0.39 mL,
464 mg, 2.72 mmol) was added dropwise and stirring was continued for additional 3 h. The reaction
mixture was then treated with saturated aqueous ammonium chloride (10 mL) and allowed to warm
to room temperature. The two layers were separated and the aqueous phase was extracted with
dichloromethane (2
Purification by column chromatography (eluent:hexanes/ethyl acetate 4:1) afforded
oil (694 mg, 2.47 mmol, 91% yield). IR (neat)
1773, 1699 cm−1 1H-NMR (400 MHz, CDCl3):
= 7.48–7.33 (m, 5H, Ar), 7.20–7.13 (m, 2H, Ar), 7.10–7.04 (m, 1H, Ar), 6.92–6.88 (m, 1H, Ar), 5.41
(s, 2H, CH2Ph), 2.98–2.92 (m, 2H, H-4), 2.72–2.67 (m, 2H, H-3) ppm. 13C-NMR (100 MHz, CDCl3):
= 169.90 (CO), 153.46 (COO), 136.94 (Ar), 134.52 (Ar), 128.85 (Ar), 128.76 (Ar), 128.75 (Ar), 127.95 (Ar),
×
20 mL). The combined organic extracts were dried, filtered, and concentrated.
8
as a colourless
ν
.
max
δ
δ

Molecules 2016, 21, 1140
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127.39 (Ar), 126.95 (Ar), 124.78 (Ar), 118.65 (Ar), 70.05 (CH2Ph), 33.05 (C-3), 25.55 (C-4) ppm. HRMS
(ESI): calcd. for C17H15NNaO3 [M + Na]+ 304.0944; found 304.0947.
3.3. Synthesis of Dimethyl N-benzyloxycarbonyl-1,2,3,4-tetrahydroquinoline-2-phosphonate 11
A 1 M solution of diisobutylaluminium hydride in hexanes (2.40 mL, 2.40 mmol) was slowly
added to a solution of
8
(448 mg, 1.59 mmol) in anhydrous tetrahydrofuran (8 mL) kept at
−
78 ◦C
under argon. After stirring at this temperature for 2 h, the reaction was treated with saturated aqueous
sodium acetate (5 mL) and warmed to room temperature. A 3:1 mixture of diethyl ether and saturated
aqueous ammonium chloride (16 mL) was then added and the resulting mixture was stirred at room
temperature until a suspension was formed. The solid was filtered off under reduced pressure and
washed with diethyl ether (2
extracted with diethyl ether (2
(20 mL), dried, filtered, and evaporated to provide the hemiaminal as an oil. It was dissolved in
methanol (6 mL) and treated with pyridinium p-toluenesulfonate (40 mg, 0.16 mmol). After stirring
at room temperature for 2 h, triethylamine (0.10 mL, 74 mg, 0.73 mmol) was added. The solvent
×
10 mL). The organic layer was separated and the aqueous phase was
20 mL). The combined organic extracts were washed with brine
×
was evaporated and the crude methoxyaminal
dichloromethane (7 mL) and kept under argon. Trimethyl phosphite (0.19 mL, 198 mg, 1.59 mmol)
was added and the resulting solution was cooled to
20 ◦C. Boron trifluoride-diethyl ether
9 thus obtained was dissolved in anhydrous
−
(0.20 mL, 226 mg, 1.59 mmol) was added dropwise and the reaction mixture was slowly warmed
to room temperature and stirred for 12 h. After quenching with water (2 mL), the two layers were
separated and the aqueous phase was extracted with dichloromethane (2
organic extracts were dried, filtered, and concentrated. Purification by column chromatography
×
10 mL). The combined
(eluent:ethyl acetate/hexanes 4:1) afforded 11 as a colourless oil (372 mg, 0.99 mmol, 62% yield). IR
1
(neat)
ν
max 1702, 1279, 1029 cm−1. H-NMR (400 MHz, CDCl3):
δ
= 7.53–7.46 (m, 1H, Ar), 7.37–7.28
(m, 5H, Ar), 7.22–7.16 (m, 1H, Ar), 7.14–7.06 (m, 2H, Ar), 5.31 (d, J = 12.5 Hz, 1H, CH2Ph), 5.16
(d, J = 12.5 Hz, 1H, CH2Ph), 5.04 (ddd, J = 13.4, 8.7, 7.3 Hz, 1H, H-2), 3.63 (d, J = 10.6 Hz, 3H, OMe),
3.51 (d, J = 10.6 Hz, 3H, OMe), 2.85–2.75 (m, 1H, H-4), 2.67–2.57 (m, 1H, H-40), 2.54–2.40 (m, 1H, H-3),
2.17–2.03 (m, 1H, H-30) ppm. 13C-NMR (100 MHz, CDCl3):
δ = 154.68 (CO), 136.84 (Ar), 136.08 (Ar),
132.78 (Ar), 128.54 (Ar), 128.16 (Ar), 127.88 (Ar), 127.56 (Ar), 126.36 (Ar), 125.97 (Ar), 125.22 (Ar), 68.11
(CH2Ph), 53.07 (d, J = 6.2 Hz, OMe), 52.82 (d, J = 7.2 Hz, OMe), 49.33 (d, J = 158.2 Hz, C-2), 25.75 (C-3),
25.66 (C-4) ppm. 31P-NMR (162 MHz, CDCl3):
[M + Na]+ 398.1128; found 398.1145.
δ = 26.39 ppm. HRMS (ESI): calcd. for C19H22NNaO5P
3.4. Synthesis of Dimethyl N-Benzyloxycarbonyl-1,2-dihydroquinoline-2-phosphonate 13
Benzyl chloroformate (0.61 mL, 726 mg, 4.26 mmol) was added dropwise to a solution of quinoline
◦
(0.46 mL, 500 mg, 3.87 mmol) in anhydrous acetonitrile (6 mL) kept at 0 C under argon. After stirring
at this temperature for 10 min, trimethyl phosphite (0.50 mL, 528 mg, 4.26 mmol) was slowly added
◦
followed by sodium iodide (853 mg, 5.69 mmol). The mixture was heated at 50 C for 10 min.
The solvent was evaporated and the crude product was partitioned between dichloromethane (15 mL)
and saturated aqueous sodium bicarbonate (15 mL). The organic phase was separated and the aqueous
layer was further extracted with dichloromethane (3
washed with brine (10 mL), dried, filtered, and concentrated. Purification by column chromatography
×
15 mL). The combined organic extracts were
(eluent:ethyl acetate/hexanes 4:1) afforded 13 as a colourless oil (1.07 g, 2.87 mmol, 74% yield).
1
◦
1706, 1653, 1603, 1263, 1125, 1026 cm−1. H-NMR (400 MHz, DMSO-d6, 80 C):
max
IR (neat)
= 7.58–7.52 (m, 1H, Ar), 7.44–7.30 (m, 5H, Ar), 7.25–7.07 (m, 3H, Ar), 6.71–6.65 (m, 1H, H-4), 6.07
(ddd, J = 9.5, 6.3, 4.5 Hz, 1H, H-3), 5.61 (ddd, J = 21.4, 6.3, 1.2 Hz, 1H, H-2), 5.27 (s, 2H, CH2Ph), 3.47
(d, J = 10.6 Hz, 6H, OMe) ppm. 13C-NMR (100 MHz, DMSO-d6, 80 ◦C):
= 152.90 (d, J = 4.7 Hz, CO),
ν
δ
δ
135.68 (Ar), 134.66 (Ar), 128.05 (Ar), 127.70 (Ar), 127.40 (Ar), 127.35 (Ar), 127.01 (d, J = 9.7 Hz, C-4),
126.77 (d, J = 4.0 Hz, Ar), 126.06 (d, J = 1.5 Hz, Ar), 124.35 (Ar), 123.66 (Ar), 122.55 (d, J = 3.0 Hz, C-3),
67.44 (CH2Ph), 52.70 (d, J = 7.0 Hz, OMe), 52.39 (d, J = 6.6 Hz, OMe), 50.84 (d, J = 151.5 Hz, C-2) ppm
.

Molecules 2016, 21, 1140
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◦
31P-NMR (162 MHz, DMSO-d6, 80 C):
δ
= 20.41 ppm. HRMS (ESI): calcd. for C19H20NNaO5P
[M + Na]+ 396.0971; found 396.0991.
3.5. Synthesis of Dimethyl 1,2,3,4-Tetrahydroquinoline-2-phosphonate 14
A mixture of 13 (200 mg, 0.54 mmol) and 10% Pd/C (20 mg) in ethyl acetate (10 mL) was stirred
at room temperature under an atmospheric pressure of hydrogen gas for 12 h. Filtration of the catalyst
and evaporation of the solvent provided pure 14 as a colourless oil (130 mg, 0.54 mmol, 100% yield).
1
IR (neat)
ν
3316, 1231, 1057, 1029 cm−1. H-NMR (400 MHz, CDCl3): δ = 7.02–6.93 (m, 2H, Ar),
max
6.70–6.63 (m, 1H, Ar), 6.58–6.53 (m, 1H, Ar), 4.16 (br s, 1H, NH), 3.82 (d, J = 10.3 Hz, 3H, OMe), 3.81
(d, J = 10.5 Hz, 3H, OMe), 3.71 (dd0d, J = 10.1, 6.7, 3.4 Hz, 1H, H-2), 2.88–2.75 (m, 2H, H-4), 2.29–2.19
(m, 1H, H-3), 2.12–1.98 (m, 1H, H-3 ) ppm. 13C-NMR (100 MHz, CDCl3): δ = 143.08 (d, J = 10.9 Hz, Ar),
129.40 (Ar), 127.11 (Ar), 121.05 (Ar), 118.26 (Ar), 114.97 (Ar), 53.83 (d, J = 6.7 Hz, OMe), 53.08
(d, J = 7.3 Hz, OMe), 49.05 (d, J = 161.5 Hz, C-2), 26.09 (d, J = 13.7 Hz, C-4), 22.39 (d, J = 5.2 Hz,
C-3) ppm. 31P-NMR (162 MHz, CDCl3):
[M + Na]+ 264.0760; found 264.0752.
δ = 27.39 ppm. HRMS (ESI): calcd. for C11H16NNaO3P
3.6. Synthesis of 1,2,3,4-Tetrahydroquinoline-2-phosphonic Acid Hydrobromide 4
From 11: A 33% solution of hydrogen bromide in acetic acid (2 mL) was added to compound 11
(110 mg, 0.29 mmol) and the reaction mixture was stirred at room temperature for 3 h. The solvent
was evaporated and the residue was taken up in water and lyophilised to afford
4 as a white solid
(86 mg, 0.29 mmol, 100% yield). M.p. 94–96 ◦C (dec.). IR (nujol) 3381, 1171, 1077, 1057 cm−1
ν
.
max
1H-NMR (400 MHz, CD3OD):
3.08–3.01 (m, 2H, H-4), 2.52–2.43 (m, 1H, H-3), 2.19–2.06 (m, 1H, H-30) ppm. 13C-NMR (100 MHz,
CD3OD): = 132.21 (d, J = 0.7 Hz, Ar), 131.87 (Ar), 131.78 (Ar), 130.25 (Ar), 128.64 (Ar), 124.49 (Ar),
52.52 (d, J = 153.2 Hz, C-2), 25.94 (d, J = 12.4 Hz, C-4), 22.37 (d, J = 2.2 Hz, C-3) ppm. 31P-NMR
δ = 7.40–7.28 (m, 4H, Ar), 3.78 (ddd, J = 13.1, 12.1, 2.5 Hz, 1H, H-2),
δ
(162 MHz, CD3OD):
found 214.0632.
δ
= 14.61 ppm. HRMS (ESI): calcd. for C9H13NO3P [M
−
Br]+ 214.0628;
From 14: A 33% solution of hydrogen bromide in acetic acid (2 mL) was added to compound 14
(130 mg, 0.54 mmol) and the reaction mixture was stirred at room temperature for 3 h. The solvent
was evaporated and the residue was taken up in water and lyophilised to afford
4 as a white solid
(158 mg, 0.54 mmol, 100% yield). Spectroscopic data were identical to those described above.
3.7. Synthesis of Dimethyl N-Benzyloxycarbonyl-1,2-dihydroisoquinoline-1-phosphonate 16
Benzyl chloroformate (0.61 mL, 726 mg, 4.26 mmol) was added dropwise to a solution of
isoquinoline (500 mg, 3.87 mmol) and trimethyl phosphite (0.50 mL, 528 mg, 4.26 mmol) in anhydrous
acetonitrile (6 mL) kept at 0 ◦C under argon. Sodium iodide (853 mg, 5.69 mmol) was slowly added
and the mixture was heated at 50 ◦C for 10 min. The solvent was evaporated and the crude product
was partitioned between dichloromethane (15 mL) and saturated aqueous sodium bicarbonate (15 mL).
The organic phase was separated and the aqueous layer was further extracted with dichloromethane
(3
×
15 mL). The combined organic extracts were washed with brine (10 mL), dried, filtered, and
concentrated. Purification by column chromatography (eluent: ethyl acetate/hexanes 4:1) afforded
16 as a colourless oil (1.33 g, 3.56 mmol, 92% yield). IR (neat)
ν
1715, 1342, 1295, 1238, 1121,
max
1
1028 cm−1. H-NMR (300 MHz, DMSO-d6, 50 ◦C):
δ
= 7.51–7.11 (m, 9H, Ar), 6.91 (d, J = 7.7 Hz, 1H,
H-3), 6.08–5.94 (m, 1H, H-4), 5.83 (d, J = 15.8 Hz, 1H, H-1), 5.27 (s, 2H, CH2Ph), 3.57–3.38 (m, 6H, OMe)
ppm. 13C-NMR (100 MHz, DMSO-d6):
δ
= (duplicate signals are observed for some carbons; asterisks
indicate those corresponding to the minor rotamer) 152.37* (CO), 151.88 (CO), 136.01 (Ar), 135.91* (Ar),
131.03* (d, J = 3.6 Hz, Ar), 130.84 (d, J = 3.6 Hz, Ar), 128.75* (d J = 3.0 Hz, Ar), 128.68 (d, J = 3.1 Hz,
Ar), 128.54 (Ar), 128.47* (Ar), 128.26 (Ar), 128.11* (Ar), 127.92 (Ar), 127.55 (d, J = 5.2 Hz, Ar), 127.30
(d, J = 2.3 Hz, Ar), 127.18 (d, J = 2.0 Hz, Ar), 125.43 (Ar), 125.35 (Ar), 124.86 (d, J = 2.9 Hz, C-3), 124.79*
(C-3), 109.86 (C-4), 67.86* (CH2Ph), 67.77 (CH2Ph), 53.40* (d, J = 148.4 Hz, C-1), 53.16* (d, J = 6.1 Hz,

Molecules 2016, 21, 1140
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OMe), 53.12 (d, J = 7.0 Hz, OMe), 52.64 (d, J = 149.6 Hz, C-1) ppm. 31P-NMR (122 MHz, DMSO-d6,
50 ◦C): δ = 21.34 ppm. HRMS (ESI): calcd. for C19H20NNaO5P [M + Na]+ 396.0971; found 396.0982.
3.8. Synthesis of Diethyl N-Benzyloxycarbonyl-1,2-dihydroisoquinoline-1-phosphonate 19
Benzyl chloroformate (0.61 mL, 726 mg, 4.26 mmol) was added dropwise to a solution of
isoquinoline (500 mg, 3.87 mmol) and triethyl phosphite (0.73 mL, 708 mg, 4.26 mmol) in anhydrous
acetonitrile (6 mL) kept at 0 ◦C under argon. Sodium iodide (853 mg, 5.69 mmol) was slowly added
and the mixture was heated at 50 ◦C for 10 min. The solvent was evaporated and the crude product
was partitioned between dichloromethane (15 mL) and saturated aqueous sodium bicarbonate (15 mL).
The organic phase was separated and the aqueous layer was further extracted with dichloromethane
(3
concentrated. Purification by column chromatography (eluent:ethyl acetate/hexanes 3:2) afforded
19 as a colourless oil (1.52 g, 3.79 mmol, 98% yield). IR (neat)
max 1715, 1294, 1253, 1120, 1023 cm−1
1H-NMR (300 MHz, DMSO-d6, 70 ◦C):
= 7.50–7.10 (m, 9H, Ar), 6.91 (d, J = 7.8 Hz, 1H, H-3), 5.98
(d, J = 7.8 Hz, 1H, H-4), 5.77 (d, J = 15.9 Hz, 1H, H-1), 5.26 (s, 2H, CH2Ph), 3.95–3.69 (m, 4H, OCH2), 1.08
(t, J = 7.0 Hz, 3H, Me), 1.07 (t, J = 7.0 Hz, 3H, Me) ppm. 13C-NMR (100 MHz, DMSO-d6):
= (duplicate
×
15 mL). The combined organic extracts were washed with brine (10 mL), dried, filtered, and
ν
.
δ
δ
signals are observed for some carbons; asterisks indicate those corresponding to the minor rotamer)
152.48* (CO), 151.91 (CO), 136.05 (Ar), 135.88* (Ar), 131.15* (d, J = 3.6 Hz, Ar), 130.98 (d, J = 3.7 Hz,
Ar), 128.69* (d, J = 3.3 Hz, Ar), 128.61 (d, J = 3.3 Hz, Ar), 128.56 (Ar), 128.47* (Ar), 128.28 (Ar),
128.25* (Ar), 128.13* (Ar), 127.97 (Ar), 127.53 (d, J = 5.2 Hz, Ar), 127.22 (d, J = 2.6 Hz, Ar), 127.11* (d,
J = 2.7 Hz, Ar), 125.59 (d, J = 1.8 Hz, Ar), 125.56* (d, J = 2.4 Hz, Ar), 125.42 (Ar), 124.84* (C-3), 124.81
(C-3), 109.95 (C-4), 67.84* (CH2Ph), 67.71 (CH2Ph), 62.54 (d, J = 7.1 Hz, OCH2), 62.42* (d, J = 6.6 Hz,
OCH2), 62.38* (d, J = 7.1 Hz, OCH2), 53.97* (d, J = 148.9 Hz, C-1), 53.15 (d, J = 15◦0.2 Hz, C-1), 16.17
(d, J = 5.3 Hz, Me), 16.15* (d, J = 5.7 Hz, Me) ppm. 31P-NMR (122 MHz, DMSO-d6, 70 C): δ = 18.77 ppm
.
HRMS (ESI): calcd. for C21H25NO5P [M + H]+ 402.1465; found 402.1466.
3.9. Synthesis of Diethyl N-Benzyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-1-phosphonate 20
Triethylsilane (1.0 mL, 730 mg, 6.28 mmol) and trifluoroacetic acid (0.48 mL, 716 mg, 6.28 mm◦ol)
were added to a solution of 19 (300 mg, 0.75 mmol) in anhydrous dichloromethane (15 mL) kept at 0 C
under argon. The solution was allowed to warm to room temperature and stirred for 18 h. Evaporation
of the solvent followed by column chromatography (eluent:hexanes/ethyl acetate 1:1) afforded 20 as a
colourless oil (298 mg, 0.74 mmol, 99% yield). IR (neat)
1H-NMR (300 MHz, DMSO-d6, 70 ◦C):
ν .
max 1701, 1294, 1249, 1230, 1051, 1022 cm−1
= 7.44–7.16 (m, 9H, Ar), 5.53 (d, J = 20.4 Hz, 1H, H-1), 5.17
(s, 2H, CH2Ph), 4.14–3.77 (m, 5H, H-3, OCH2), 3.72–3.52 (m, 1H, H-30), 2.98–2.78 (m, 2H, H-4), 1.17
δ
(t, J = 7.0 Hz, 3H, Me), 1.08 (t, J = 6.9 Hz, 3H, Me) ppm. 13C-NMR (100 MHz, DMSO-d6):
δ
= (duplicate signals are observed for some carbons; asterisks indicate those corresponding to
the minor rotamer) 154.60 (d, J = 3.9 Hz, CO), 154.18* (d, J = 2.4 Hz, CO), 136.66 (Ar), 136.46* (Ar),
134.73 (d, J = 5.6 Hz, Ar), 134.63* (d, J = 5.6 Hz, Ar), 129.22 (Ar), 129.13* (d, J = 2.2 Hz, Ar), 128.95
(d, J = 2.3 Hz, Ar), 128.85 (Ar), 128.38 (Ar), 128.33* (Ar), 127.94* (Ar), 127.91 (Ar), 127.86* (Ar), 127.67
(d, J = 4.0 Hz, Ar), 127.58 (Ar), 127.38 (Ar), 125.88 (d, J = 2.8 Hz, Ar), 125.83* (d, J = 2.8 Hz, Ar),
66.92* (CH2Ph), 66.82 (CH2Ph), 62.58 (d, J = 7.2 Hz, OCH2), 62.19 (d, J = 7.1 Hz, OCH2), 52.76*
(d, J = 149.9 Hz, C-1), 52.34 (d, J = 152.0 Hz, C-1), 39.05* (C-3), 38.84 (C-3), 27.43 (C-4), 27.15* (C-4),
16.08* (d, J = 5.6 Hz, Me), 16.05 (d, J = 5.3 Hz, Me). 31P-NMR (122 MHz, DMSO-d6, 70 ◦C):
δ = 20.75.
HRMS (ESI): calcd. for C21H27NO5P [M + H]+ 404.1621; found 404.1611.
3.10. Synthesis of 1,2,3,4-Tetrahydroisoquinoline-1-phosphonic Acid Hydrobromide 5
A 33% solution of hydrogen bromide in acetic acid (2 mL) was added to 20 (160 mg, 0.40 mmol)
and the reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated and
the residue was taken up in water and lyophilised to afford
100% yield). M.p. 85–87 ◦C (dec.). IR (nujol)
5
as a white solid (117 mg, 0.40 mmol,
1
ν
3421, 1212, 1118, 1019 cm−1. H-NMR (400 MHz,
max

Molecules 2016, 21, 1140
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D2O):
9.2, 6.5 Hz, 1H, H-3), 3.58–3.51 (m, 1H, H-30), 3.18–3.12 (m, 2H, H-4) ppm. 13C-NMR (100 MHz,
CD3OD): = 132.88 (d, J = 5.4 Hz, Ar), 130.40 (d, J = 2.2 Hz, Ar), 129.47 (d, J = 2.7 Hz, Ar), 128.94 (d,
δ = 7.45–7.41 (m, 1H, Ar), 7.37–7.27 (m, 3H, Ar), 4.70 (d, J = 17.6 Hz, 1H, H-1), 3.78 (ddd, J = 12.7,
δ
J = 3.6 Hz, Ar), 127.92 (d, J = 2.6 Hz, Ar), 127.40 (d, J = 5.1 Hz, Ar), 54.00 (d, J = 147.3 Hz, C-1), 41.15 (d,
J = 2.1 Hz, C-3), 25.88 (C-4) ppm. 31P-NMR (162 MHz, D2O):
C9H13NO3P [M − Br]+ 214.0628; found 214.0633.
δ = 10.02 ppm. HRMS (ESI): calcd. for
3.11. Synthesis of N-Benzyloxycarbonyl-1,4-dihydro-3-isoquinolinone 22
A 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.83 mL, 0.83 mmol)
was slowly added to a solution of 1,4-dihydro-3(2H)-isoquinolinone 21 (122 mg, 0.83 mmol) in
anhydrous tetrahydrofuran (5 mL) kept at
−
78 ◦C under argon. After 30 min, benzyl chloroformate
(0.12 mL, 142 mg, 0.83 mmol) was added dropwise and stirring was continued for additional 3 h.
The reaction was then treated with saturated aqueous ammonium chloride (10 mL) and allowed to
warm to room temperature. The two layers were separated and the aqueous phase was extracted with
dichloromethane (2
×
10 mL). The combined organic extracts were dried, filtered, and concentrated.
Purification by column chromatography (eluent:hexanes/ethyl acetate 7:3) afforded 22 as a white
solid (172 mg, 0.61 mmol, 73% yield). M.p. 63–65 ◦C. IR (nujol)
1
ν
max 1692 cm−1. H-NMR (400 MHz,
CDCl3):
δ
= 7.49–7.44 (m, 2H, Ar), 7.40–7.25 (m, 6H, Ar), 7.23–7.19 (m, 1H, Ar), 5.34 (s, 2H, CH2Ph),
= 169.43 (CO), 153.62 (COO),
4.92 (s, 2H, H-1), 3.73 (s, 2H, H-4) ppm. 13C-NMR (100 MHz, CDCl3):
δ
135.38 (Ar), 132.25 (Ar), 132.13 (Ar), 128.74 (Ar), 128.50 (Ar), 128.46 (Ar), 128.22 (Ar), 127.35 (Ar), 126.99
(Ar), 125.81 (Ar), 68.97 (CH2Ph), 48.75 (C-1), 41.53 (C-4) ppm. HRMS (ESI): calcd. for C17H15NNaO3
[M + Na]+ 304.0944; found 304.0943.
3.12. Synthesis of Dimethyl N-Benzyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline-3-phosphonate 25
A 1 M solution of diisobutylaluminium hydride in hexanes (0.78 mL, 0.78 mmol) was slowly
added to a solution of 22 (146 mg, 0.52 mmol) in anhydrous tetrahydrofuran (5 mL) kept at
−
78 ◦C
under argon. After stirring at this temperature for 2 h, the reaction was treated with saturated aqueous
sodium acetate (10 mL) and allowed to warm to room temperature. A 3:1 mixture of diethyl ether
and saturated aqueous ammonium chloride (16 mL) was then added and the resulting mixture was
stirred at room temperature until a suspension was formed. The solid was filtered off under reduced
pressure and washed with diethyl ether (2
phase was extracted with diethyl ether (2
brine (10 mL), dried, filtered, and evaporated to provide the hemiaminal as an oil. It was dissolved in
×
10 mL). The organic layer was separated and the aqueous
10 mL). The combined organic extracts were washed with
×
methanol (5 mL) and treated with pyridinium p-toluenesulfonate (13 mg, 0.05 mmol). After stirring
at room temperature for 2 h, triethylamine (31
evaporated and the crude methoxyaminal obtained 23 was dissolved in anhydrous dichloromethane
(5 mL) and kept under argon. Trimethyl phosphite (61 L, 65 mg, 0.52 mmol) was added and the
resulting solution was cooled to L, 74 mg, 0.52 mmol)
20 ◦C. Boron trifluoride-diethyl ether (65
µL, 22 mg, 0.22 mmol) was added. The solvent was
µ
−
µ
was added and the reaction mixture was slowly warmed to room temperature and stirred for 12 h.
After quenching with water (10 mL), the two layers were separated and the aqueous phase was
extracted with dichloromethane (2
concentrated. Purification by column chromatography (eluent:ethyl acetate/hexanes 9:1) afforded 25
as a colourless oil (138 mg, 0.37 mmol, 71% yield). IR (neat)
1703, 1410, 1246, 1055, 1031 cm−1
×
10 mL). The combined organic extracts were dried, filtered, and
ν
.
max
1H-NMR (400 MHz, CDCl3):
δ = (duplicate signals are observed for some protons; asterisks indicate
those corresponding to the minor rotamer) 7.42–7.30 (m, 5H, Ar), 7.23–7.04 (m, 4H, Ar), 5.31–5.12
(m, 2H, CH2Ph), 5.11–5.03 (m, 1H, H-3), 5.00–4.86 (m, 1H, H-1) overlapped with 4.97*–4.89*
(m, 1H, H-3), 4.52 (d, J = 16.6 Hz, 1H, H-10), 4.45* (d, J = 16.6 Hz, 1H, H-10), 3.65 (d, J = 10.7 Hz,
3H, OMe), 3.51* (d, J = 10.7 Hz, 3H, OMe), 3.35 (d, J = 10.7 Hz, 3H, OMe), 3.33–3.16 (m, 2H, H-4)
overlapped with 3.24* (d, J = 10.7 Hz, 3H, OMe) ppm. 13C-NMR (100 MHz, CDCl3):
signals are observed for some carbons; asterisks indicate those corresponding to the minor rotamer)
δ = (duplicate

Molecules 2016, 21, 1140
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155.72 (CO), 155.05* (CO), 136.37 (Ar), 136.18* (Ar), 132.61* (Ar), 132.46 (Ar), 131.41 (Ar), 131.00* (Ar),
128.64 (Ar), 128.53 (Ar), 128.45* (Ar), 128.24 (Ar), 128.17* (Ar), 127.95 (Ar), 126.70 (Ar), 126.64* (Ar),
126.60 (Ar), 126.09* (Ar), 125.86 (Ar), 67.79 (CH2Ph), 52.74 (d, J = 6.4 Hz, OMe), 52.58 (d, J = 6.6 Hz,
OMe), 52.34* (d, J = 6.9 Hz, OMe), 47.07* (d, J = 154.2 Hz, C-3), 46.29 (d, J = 154.1 Hz, C-3), 44.37
(C-1), 28.56* (C-4), 28.32 (C-4) ppm. 31P-NMR (162 MHz, CDCl3):
δ = (a duplicate signal is observed;
an asterisk indicates that corresponding to the minor rotamer) 27.67, 27.07* ppm. HRMS (ESI): calcd.
for C19H22NNaO5P [M + Na]+ 398.1128; found 398.1144.
3.13. Synthesis of 1,2,3,4-Tetrahydroisoquinoline-3-phosphonic Acid Hydrobromide 6
A 33% solution of hydrogen bromide in acetic acid (2 mL) was added to 25 (100 mg, 0.27 mmol)
and the reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated and
the residue was taken up in◦water and lyophilised to afford as a white solid (79 mg, 0.27 mmol,
.
3404, 1232, 1010 cm−1 1H-NMR (400 MHz,
max
6
100% yield). M.p. 102–103 C (dec.). IR (nujol)
ν
CD3OD):
δ
= 7.35–7.22 (m, 4H, Ar), 4.52 (d, J = 15.7 Hz, 1H, H-1), 4.42 (dd, J = 15.7, 3.1 Hz, 1H,
= 131.71
H-10), 3.94–3.83 (m, 1H, H-3), 3.34–3.25 (m, 2H, H-4) ppm. 13C-NMR (100 MHz, CD3OD):
δ
(d, J = 12.2 Hz, Ar), 129.97 (Ar), 129.27 (Ar), 128.69 (Ar), 128.32 (Ar), 127.77 (Ar), 51.34 (d, J = 153.1 Hz,
C-3), 47.01 (d, J = 7.7 Hz, C-1), 27.44 (C-4) ppm. 31P-NMR (162 MHz, CD3OD):
HRMS (ESI): calcd. for C9H13NO3P [M − Br]+ 214.0628; found 214.0631.
δ = 14.06 ppm.
4. Conclusions
The synthesis of
tetrahydroisoquinoline heterocycles is described. Specifically, 1,2,3,4-tetrahydroquinoline-2-phosphonic
acid , 1,2,3,4-tetrahydroisoquinoline-1-phosphonic acid , and 1,2,3,4-tetrahydro-isoquinoline-3-
phosphonic acid have been prepared in high overall yields using efficient methods that make use
α-aminophosphonic acids characterized by a tetrahydroquinoline or
4
5
6
of easily available substrates. The compounds obtained can be viewed as higher homologues of
phosphopipecolic acid that bear a benzene ring fused at different positions of the six-membered
piperidine cycle. In particular, the latter is the phosphonic surrogate of Tic, an amino acid of
extraordinary value in the design of pharmacologically useful peptides. The synthetic routes developed
rely on the addition of trialkyl phosphites to iminium ions generated from quinoline/isoquinoline or
from the appropriate
δ-lactam bearing a fused benzene ring. Thus, lactams have proven to be versatile
starting materials for the efficient and selective synthesis of
α
-aminophosphonic acids containing
an azacyclic skeleton. The presence of the carbonyl group in the starting lactam determines, with
full regiocontrol, the position at which the phosphonate substituent is incorporated. Formation of
the intermediate N-acyliminium ion with the adequate regiochemistry has allowed the synthesis of
the phosphonic counterpart of Tic (TicP). Importantly, this
α-aminophosphonic acid is not accessible
through other methodologies traditionally used to generate iminium ions.
Supplementary Materials: 1H-, 13C-, and 31P- (when applicable) NMR spectra of the final compounds and all
key intermediates are available online at http://www.mdpi.com/1420-3049/21/9/1140/s1.
Acknowledgments: Financial support to this work was provided by Consejo Nacional de Ciencia y Tecnología
(CONACYT-Mexico, grants 181816 and 248868). Ministerio Economia y Competitividad (grant CTQ2013-40855-R),
and Gobierno de Aragón-Fondo Social Europeo (research group E40). Consejo Superior de Investigaciones
Científicas (grant 2008MX0044; JAE predoctoral fellowship to A.A).
Author Contributions: M.O., C.C. and A.I.J. provided the concepts of the work, interpreted the results and
prepared the manuscript, A.A., F.J.S., carried out the experimental work, interpreted the results and prepared the
manuscript. All authors read and approved the final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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