A one-pot procedure for the synthesis of α-amino phosphonates from alkynes

Article abstract of DOI:10.1002/1099-0690(20022)2002:3<457::AID-EJOC457>3.0.CO;2-B

A new and highly flexible procedure for the synthesis of α,α-disubstituted α-amino phosphonates is described with disubstituted alkynes, primary amines and diethyl or dimethyl phosphite as starting materials. The reaction sequence, which is performed as a

Full text of DOI:10.1002/1099-0690(20022)2002:3<457::AID-EJOC457>3.0.CO;2-B

FULL PAPER
A One-Pot Procedure for the Synthesis of α-Amino Phosphonates from
Alkynes
Edgar Haak,[a] Igor Bytschkov,[a] and Sven Doye*[a]
Keywords: Alkynes / Amination / Homogeneous catalysis / Phosphorus / Titanium
A new and highly flexible procedure for the synthesis of α,α-
disubstituted α-amino phosphonates is described with disub-
sequent nucleophilic addition of diethyl or dimethyl phos-
phite to the resulting imine, performed in the presence of
stituted alkynes, primary amines and diethyl or dimethyl catalytic amounts of Me2AlCl, gives the desired α-amino
phosphite as starting materials. The reaction sequence, phosphonate. The application of intermolecular and intramo-
which is performed as a one-pot operation, starts with a
Cp2TiMe2-catalyzed hydroamination of the alkyne. A sub-
lecular hydroamination reactions leads to the formation of
both, cyclic and acyclic α-amino phosphonates.
Introduction
Due to their potential biological activity and their use as
building blocks for phosphorus-containing peptide mi-
metics, derivatives of phosphonic and phosphinic acid ana-
logues of α-amino acids (Figure 1) are of considerable cur-
rent interest. Several α-aminophosphonic and -phosphinic
acid derivatives show activity as enzyme inhibitors, antibi-
otics, herbicides, fungicides or plant growth regulators.[1]
For example, the phosphonic acid analogues of phenylala-
nine and histidine inhibit the corresponding ammonia-
lyases in plants, yeasts and bacteria.[2] Other α-aminophos-
phonic acid derivatives are specific suicide inhibitors of
phosphatases which are important in signal transduction
processes.[3] In particular, phosphorus-containing peptide
mimetics, in which the tetrahedral phosphorus moiety acts
as a transition-state analogue of the peptide cleavage, select-
ively inhibit peptidases and proteinases (e. g. HIV-pro-
tease,[4] pepsin,[5] penicillopepsin[6] and serine protease[7]) as
well as ligases involved in the peptidoglycan biosynthesis of
bacteria cell walls.[8]
Figure 1. Comparison between α-aminophosphinic, α-aminophos-
phonic and α-amino acids
can only be achieved in special cases. Furthermore, both
methods have drawbacks regarding the diversity of the syn-
thesized products and their use in automated synthesis (e.g.
reactions are run at Ϫ78 °C or use unstable starting mat-
erials). Due to these drawbacks we focused on the develop-
ment of a highly flexible procedure for the synthesis of α,α-
disubstituted α-aminophosphonic acid derivatives that is
easy to perform and can be adapted for an automated syn-
thesis. For diversity reasons, it was our goal to employ start-
ing materials that are inexpensive and readily available in
various forms. Furthermore, it was desirable to use starting
materials that have never been used before for the synthesis
of the target compounds. Due to these points, the fact that
a wide variety of alkynes is easily accessible by cross-coup-
ling[10] and metathesis[11] techniques, and that the use of
alkynes for the synthesis of nitrogen-containing products
has become well-established with the development of mod-
ern hydroamination protocols,[12] we decided to use disub-
stituted alkynes as suitable starting materials for the syn-
thesis of α,α-disubstituted α-aminophosphonic acid derivat-
ives.
Because of the above-mentioned biological effects many
procedures for the synthesis of α-aminophosphonic and α-
aminophosphinic acid derivatives have been developed.[9]
Among these methods nucleophilic and electrophilic trans-
formations
of
1-aminomethylphosphonic
acid
derivatives[9bϪ9d] and nucleophilic additions of dialkyl
phosphites to imines[9eϪ9j] are the most general and power-
ful procedures. While both methods are useful for the syn-
thesis of analogues of naturally occurring α-substituted α-
amino acids, the synthesis of α,α-disubstituted derivatives
[a]
Institut für Organische Chemie der Universität Hannover
Schneiderberg 1B, 30167 Hannover, Germany
Fax: (internat.) ϩ49-(0)511/762-3011
E-mail: sven.doye@oci.uni-hannover.de
Eur. J. Org. Chem. 2002, 457Ϫ463
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0203Ϫ0457 $ 17.50ϩ.50/0
457

E. Haak, I. Bytschkov, S. Doye
FULL PAPER
Table 1. One-pot procedure for the synthesis of acyclic α-amino
phosphonates by intermolecular hydroamination and subsequent
nucleophilic addition of phosphites
Results and Discussion
In this publication we describe a new and highly flexible
procedure for the synthesis of cyclic and acyclic α,α-disub-
stituted α-amino phosphonates. Using the new procedure,
the desired products can be obtained in good to excellent
yields. Disubstituted alkynes, which are easily accessible in
a wide variety, primary amines and diethyl or dimethyl
phosphite are employed as starting materials. The reaction
sequence, which is performed as a one-pot operation, starts
with a Cp2TiMe2[13]-catalyzed hydroamination of the
alkyne.[12jϪ12n] A subsequent nucleophilic addition of di-
ethyl or dimethyl phosphite to the resulting imine, per-
formed in the presence of catalytic amounts of Me2AlCl,
gives access to the desired α-amino phosphonate. The de-
scribed one-pot procedure can be used for the synthesis of
acyclic (intermolecular hydroamination[12jϪ12n]) and cyclic
(intramolecular hydroamination[14]) products. The general
synthetic strategy is shown in Scheme 1.
[a]
Reaction conditions: a) 1.4 mmol alkyne, 1.4 mmol amine, 3.0
mol % Cp2TiMe2, 0.5 mL toluene, 110 °C, 72 h (reaction times have
not been optimized); b) 1.4 mmol HP(O)(OEt)2 (7), 5.0 mol %
Me2AlCl, 25 °C, 2 h. Unless otherwise noted, yields represent iso-
[b]
lated yields of pure compounds.
The hydroamination reaction
was run without solvent (toluene). HP(O)(OMe)2 (8) was used for
the nucleophilic addition of phosphite.
Scheme 1. One-pot procedure for the synthesis of α-amino phos-
phonates from disubstituted alkynes, primary amines and dialkyl
phosphites: a) 3.0Ϫ5.0 mol % Cp2TiMe2, 110 °C; b) HPO(OR4)2,
5.0 mol % Me2AlCl, 25 °C
at room temperature the desired products 9Ϫ12 could be
isolated in good to excellent yields (Table 1).
Due to the fact that Cp2TiMe2-catalyzed hydroamination
reactions of arylalkylamines are highly regioselective the
To demonstrate the efficiency of the developed one-pot unsymmetrically substituted alkynes 3 and 4 could be se-
process we first synthesized acyclic α-amino phosphonates lectively converted into α-alkylated phosphonic ester ana-
from representative symmetrically substituted [diphenylac- logues (11, 12) of phenylalanine (Table 1, entries 3,4). While
etylene (1), 3-hexyne (2)] and unsymmetrically substituted 11 and 12 are stable compounds, the obtained 4-methoxy-
[1-phenylpropyne (3), 1-phenylbutyne (4)] alkynes. As aniline derivatives 9 and 10 tend to eliminate diethyl phos-
amines we chose 4-methoxyaniline (5)[15] and benzhydryla- phite, for example during chromatography on SiO2. The
mine (6)[12l,16] because both amines allow a final deprotec- reason for this behavior is probably the electron-donating
tion of the incorporated NH2 groups. However, in principle ability of the methoxy group located on the aromatic ring,
any other amine which is suitable for the Cp2TiMe2-cata- which destabilizes the carbon phosphorus bonds in 9 and
lyzed intermolecular hydroamination of alkynes[12jϪ12n] can 10.
be used as well. The nucleophilic phosphite additions were
In addition to the described synthesis of 9Ϫ12, we were
performed using diethyl phosphite (7) or dimethyl phos- able to remove the 4-methoxyphenyl protecting groups in 9
phite (8). In general, the hydroamination reactions were and 10 under standard oxidative reaction conditions [ceric
performed in the presence of 3.0 mol % Cp2TiMe2 at 110 ammonium nitrate (CAN)].[15] Furthermore, the benzhydryl
°C for 72 h (the reaction times have not been optimized). groups in 11 and 12 could be removed reductively (H2, Pd/
Reactions employing 4-methoxyaniline (5) were run in tolu- C) (Scheme 2).[12l,16]
ene whereas no solvent was added to reactions employing
While the deprotected derivative 14 was formed smoothly
benzhydrylamine (6).[12l] Once the crude reaction mixtures in the presence of CAN, deprotection of the diphenyl-sub-
obtained from the hydroamination step had been cooled to stituted compound 9 was only possible with low yield (26%)
0 °C the phosphite and 5.0 mol % Me2AlCl were added due to the initial formation of a stable intermediate under
directly to the reaction flask. After a reaction time of 2 h the oxidative reaction conditions. Further cleavage of this
458
Eur. J. Org. Chem. 2002, 457Ϫ463

A One-Pot Procedure for the Synthesis of α-Amino Phosphonates from Alkynes
FULL PAPER
intermediate, which was identified as the corresponding
mono-imine of 1,4-quinone, is very slow. To obtain the re-
ductively deprotected compounds 15 and 16 in acceptable
yields long reaction times for the cleavage (1 atm. H2, 10
mol % Pd/C) of 11 and 12 were necessary. Even after seven
days the obtained yields were only about 50%. A possible
explanation for this observation is that trace amounts of
dimethyl phosphite which can be present in the starting
materials or can be formed during the reaction poison the
palladium catalyst.
Finally, we tried to use the developed one-pot procedure
for the synthesis of cyclic α-amino phosphonates. For that
purpose, we first cyclized the easily accessible aminoalkynes
17Ϫ22[17] in the presence of 5.0 mol % Cp2TiMe2 at 110
°C.[14] A subsequent nucleophilic addition of diethyl phos-
phite (7) to the formed imines gave the desired cyclic α-
amino phosphonates 23Ϫ28 in good yields (Table 2).
Among the products shown in Table 2, the derivatives 23,
27 and 28 (Table 2, entries 1,5,6) are particularly interesting
since they represent α-alkylated phosphonic ester analogues
Scheme 2. Oxidative and reductive deprotection of the NH2 groups
Table 2. One-pot procedure for the synthesis of cyclic α-amino of the naturally occurring amino acid proline. However, the
phosphonates by intramolecular hydroamination and subsequent
nucleophilic addition of phosphite
synthesis of piperidine derivatives (24, 25, 26) could also
be achieved in good yields. In contrast to 24 and 25 the
isoquinoline derivative 26 could only be obtained as a 5:1
mixture with the corresponding imine. Attempts to further
purify 26 have so far failed.
Conclusion
In summary, the presented studies clearly indicate that
the Cp2TiMe2-catalyzed hydroamination of alkynes com-
bined with a nucleophilic addition of dialkyl phosphites to
imines allows the synthesis of α,α-disubstituted α-amino
phosphonates in good to excellent yields. Since acyclic and
cyclic products can be synthesized from easily accessible
starting materials, the developed procedure is characterized
by a very high diversity. Therefore, an application for the
generation of libraries of α-aminophosphonic acid derivat-
ives is imaginable. Another important advantage of the de-
scribed method is that only metal-catalyzed addition reac-
tions are used for the synthesis of the target compounds,
and no undesired side products are formed during the pre-
sented process. Furthermore, the simple experimental one-
pot protocol should allow its use for automated synthesis.
Using the presented method, an enantioselective approach
towards α-aminophosphonic acid derivatives should be pos-
sible as well.
Experimental Section
General Remarks: All reactions were performed under an inert at-
mosphere of argon in flame dried Duran glassware (e.g. Schlenk
tubes fitted with Teflon stopcocks). Toluene was distilled from mol-
ten sodium under argon. Dimethyltitanocene was synthesized ac-
cording to ref.[13a] Unless otherwise noted, all reagents were pur-
chased from commercial sources and were used without further
purification. All products were characterized by 1H NMR, 13C
[a]
Reaction conditions: a) 1.0 mmol aminoalkyne, 5.0 mol %
Cp2TiMe2, 1.0 mL toluene, 110 °C, 9 h; b) 1.0 mmol HP(O)(OEt)2
(7), 5.0 mol % Me2AlCl, 25 °C, 2 h. Unless otherwise noted, yields
represent isolated yields of pure compounds. [b] Contaminated with
the corresponding imine. A further purification could not be
achieved.
Eur. J. Org. Chem. 2002, 457Ϫ463
459

E. Haak, I. Bytschkov, S. Doye
FULL PAPER
NMR, and IR spectroscopy, and mass spectrometry (MS). New
C), 154.1 (C). IR: ν
˜ ϭ 3337, 2962, 2873, 2833, 1722, 1613, 1509,
compounds were further characterized by C, H N elemental ana- 1464, 1442, 1390, 1292, 1232, 1164, 1097, 1022, 955, 826, 788, 760,
lysis or high resolution mass spectrometry (HRMS). Unless other-
638, 555 cmϪ1. MS (25 °C): m/z (%) ϭ 343 (8) [Mϩ], 206 (100),
wise noted, NMR spectra were recorded in CDCl3 on a Bruker
Avance 400 MHz spectrometer. All H NMR spectra are reported 343.1912; found 343.1922.
176 (25), 162 (20), 134 (5), 111 (6), 83 (5), 65 (4). HRMS: calcd.
1
in δ units downfield from tetramethylsilane as internal standard.
Compound 11 (C24H28NO3P, M ϭ 409.46 g/mol): General proced-
All 13C NMR spectra are reported in δ units relative to the central
line of the triplet for CDCl3 at δ ϭ 77.0. Infrared spectra were
recorded on a Bruker Vector 22 spectrometer using an attenuated
total reflection (ATR) method (neat). Mass spectra were recorded
on a Finnigan MAT 312 or a VG Autospec (EI) with an ionization
potential of 70 eV. Elemental analysis was carried out on an
Elementar Vario EL machine. PE: light petroleum ether, b.p.
40Ϫ60 °C.
ure A was used to convert 1-phenylpropyne (3) and benzhydrylam-
ine (6) into the title compound. No solvent was used for the reac-
tion and HP(O)(OMe)2 (8) was used instead of HP(O)(OEt)2 (7).
Purification by flash chromatography (PE/EtOAc, 1:1) afforded 11
(556 mg, 1.36 mmol, 97%) as a colorless solid. 1H NMR (400 MHz,
CDCl3): δ ϭ 1.03 (d, J ϭ 17.7 Hz, 3 H), 1.87 (br. s, 1 H), 2.94 (d,
J ϭ 9.6 Hz, 2 H), 3.72 (d, J ϭ 3.3 Hz, 3 H), 3.74 (d, J ϭ 3.3 Hz,
3 H), 5.41 (d, J ϭ 3.0 Hz, 1 H), 7.03Ϫ7.40 (m, 15 H). 13C NMR
(100.6 MHz, DEPT, CDCl3): δ ϭ 19.0 (CH3), 43.5 (d, J ϭ 5.0 Hz,
CH2), 52.7 (d, J ϭ 8.0 Hz, CH3), 53.1 (d, J ϭ 8.0 Hz, CH3), 58.3
(d, J ϭ 143 Hz, C), 61.5 (CH), 126.3 (CH), 126.5 (CH), 126.7 (CH),
127.0 (CH), 127.4 (CH), 127.6 (CH), 128.0 (CH), 128.4 (CH), 131.5
(CH), 135.9 (d, J ϭ 11.0 Hz, C), 145.9 (C), 146.1 (d, J ϭ 2.0 Hz,
One-Pot Synthesis of Acyclic α-Amino Phosphonates from Alkynes.
General Procedure A: The alkyne (1.40 mmol), the amine
(1.40 mmol), toluene (0.5 mL) and
a solution of Cp2TiMe2
(0.074 mL, 0.57 mol/L in toluene, 0.042 mmol, 3.0 mol %) were
added to a Schlenk tube. The Schlenk tube was sealed with a Teflon
stopcock and heated to 110 °C for 72 h. Then the mixture was
cooled to 0 °C and HP(O)(OEt)2 (7; 193 mg, 1.40 mmol) and a
solution of Me2AlCl (0.07 mL, 1.0 mol/L in hexane, 0.07 mmol,
5.0 mol %) were added. After 2 h of stirring at room temperature
the mixture was diluted with water and 2.0  KOH was added until
pH 9 was reached. Then the mixture was extracted four times with
CH2Cl2 (50 mL). The combined organic layers were washed with
brine and dried over MgSO4. Evaporation of the solvent under
vacuum and flash chromatography on silica gel afforded the pure
α-amino phosphonate.
˜
C). IR: ν ϭ 3329, 3061, 3026, 2999, 2947, 2844, 1599, 1492, 1450,
1375, 1230, 1179, 1115, 1046, 1018, 910, 882, 820, 798, 784, 751,
697 cmϪ1. MS (120 °C): m/z (%) ϭ 410 (1) [Mϩ ϩ 1], 319 (47), 301
(17), 300 (52), 221 (12), 167 (100), 152 (35), 115 (7), 91 (12), 80
(26), 79 (26). HRMS: calcd. 409.1807; found 409.1815.
Compound 12 (C25H30NO3P, M ϭ 423.49 g/mol): General proced-
ure A was used to convert 1-phenylbutyne (4) and benzhydrylamine
(6) into the title compound. No solvent was used for the reaction
and HP(O)(OMe)2 (8) was used instead of HP(O)(OEt)2 (7). Puri-
fication by flash chromatography (PE/EtOAc, 1:1) afforded 12
1
Compound 9 (C25H30NO4P, M ϭ 439.49 g/mol): General procedure
A was used to convert diphenylacetylene (1) and 4-methoxyaniline
(5) into the title compound. Purification by flash chromatography
(PE/EtOAc, 2:1) afforded 9 (418 mg, 0.95 mmol, 68%) as a color-
(522 mg, 1.23 mmol, 88%) as a colorless oil. H NMR (400 MHz,
CDCl3): δ ϭ 1.00 (t, J ϭ 7.5 Hz, 3 H), 1.25Ϫ1.43 (m, 1 H),
1.65Ϫ1.78 (m, 1 H), 1.98 (br. s, 1 H), 2.82 (dd, J ϭ 16.2, 13.8 Hz,
1 H), 3.04 (dd, J ϭ 13.5, 12.3 Hz, 1 H), 3.57 (d, J ϭ 10.4 Hz, 3
H), 3.61 (d, J ϭ 10.5 Hz, 3 H), 5.45 (d, J ϭ 2.6 Hz, 1 H), 7.08Ϫ7.40
(m, 15 H). 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 8.7 (d, J ϭ
4.0 Hz, CH3), 25.9 (d, J ϭ 4.0 Hz, CH2), 39.7 (d, J ϭ 6.0 Hz, CH2),
51.9 (d, J ϭ 8.0 Hz, CH3), 52.6 (d, J ϭ 8.0 Hz, CH3), 61.5 (CH),
63.0 (d, J ϭ 136 Hz, C), 126.4 (CH), 126.5 (CH), 126.7 (CH), 127.1
(CH), 127.3 (CH), 127.7 (CH), 128.1 (CH), 128.4 (CH), 131.4
1
less oil. H NMR (400 MHz, CDCl3): δ ϭ 1.00 (t, J ϭ 5.6 Hz, 6
H), 3.03Ϫ3.12 (m, 1 H), 3.53Ϫ3.63 (m, 1 H), 3.68Ϫ3.79 (m, 2 H),
3.71 (s, 3 H), 3.83Ϫ3.92 (m, 2 H), 4.49 (d, J ϭ 7.7 Hz, 1 H), 6.35
(d, J ϭ 7.2 Hz, 2 H), 6.66 (d, J ϭ 7.1 Hz, 2 H), 7.11Ϫ7.20 (m, 5
H), 7.29Ϫ7.35 (m, 1 H), 7.38 (t, J ϭ 6.0 Hz, 2 H), 7.73 (br. d, J ϭ
6.5 Hz, 2 H). 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 15.8 (d,
J ϭ 5.0 Hz, CH3), 16.3 (d, J ϭ 4.0 Hz, CH3), 37.7 (CH2), 55.5
(CH3), 61.8 (d, J ϭ 7.0 Hz, CH2), 63.6 (d, J ϭ 6.0 Hz, CH2), 64.5
(d, J ϭ 117 Hz, C), 114.3 (CH), 117.7 (CH), 126.5 (CH), 127.5
(CH), 127.5 (CH), 128.2 (d, J ϭ 2.0 Hz, CH), 128.7 (d, J ϭ 4.0 Hz,
CH), 131.4 (CH), 136.3 (d, J ϭ 2.0 Hz, C), 137.5 (d, J ϭ 6.0 Hz,
˜
(CH), 136.3 (d, J ϭ 8.0 Hz, C), 146.2 (C), 146.4 (C). IR: ν ϭ 3467,
3060, 3027, 2950, 2848, 1736, 1600, 1494, 1453, 1373, 1235, 1182,
1024, 920, 815, 767, 744, 698 cmϪ1. MS (80 °C): m/z (%) ϭ 332 (8)
[Mϩ Ϫ Bn], 314 (17), 235 (3), 167 (100), 152 (8), 148 (8), 106 (6),
91 (21), 80 (9). HRMS: calcd. 423.1963; found 423.1963.
˜
C), 138.6 (d, J ϭ 12.0 Hz, C), 152.1 (C). IR: ν ϭ 3404, 3059, 3031,
Deprotection of the NH2 Groups. Oxidative Cleavage. General Pro-
cedure B: At 0 °C a solution of ceric ammonium nitrate (1.64 g,
3.00 mmol) in water (5.0 mL) was added dropwise to a solution of
the 4-methoxyaniline derivative (1.00 mmol) in CH3CN (5.0 mL).
The mixture was stirred for 20 min at 0 °C and then for 30 min at
25 °C. Then 2  KOH was added until pH 12 was reached. After
four extractions with CH2Cl2 (100 mL), the combined organic
layers were washed with an aqueous solution of Na2S2O3 (10%)
and brine, dried over MgSO4 and concentrated under vacuum.
Flash chromatography on silica gel afforded the pure deprotected
α-amino phosphonate.
2980, 2930, 2906, 2832, 1735, 1509, 1444, 1391, 1296, 1235, 1180,
1097, 1020, 960, 821, 803, 774, 755, 731, 698, 642, 567 cmϪ1. MS
(110 °C): m/z (%) ϭ 439 (4) [Mϩ], 348 (10), 302 (23), 210 (40), 123
(100), 108 (98), 80 (20). HRMS: calcd. 439.1912; found 439.1910.
Compound 10 (C17H30NO4P, M ϭ 343.40 g/mol): General proced-
ure A was used to convert 3-hexyne (2) and 4-methoxyaniline (5)
into the title compound. Purification by flash chromatography (PE/
EtOAc, 1:1) afforded 10 (365 mg, 1.06 mmol, 76%) as a colorless
1
oil. H NMR (400 MHz, CDCl3): δ ϭ 0.92 (t, J ϭ 7.3 Hz, 3 H),
1.01 (t, J ϭ 7.5 Hz, 3 H), 1.22 (t, J ϭ 7.2 Hz, 3 H), 1.23 (t, J ϭ
7.2 Hz, 3 H), 1.42Ϫ1.54 (m, 2 H), 1.68Ϫ1.93 (m, 4 H), 3.56 (br. s,
1 H), 3.75 (s, 3 H), 3.92Ϫ4.10 (m, 4 H), 6.74 (d, J ϭ 8.9 Hz, 2 H), Compound 13 (C18H24NO3P, M ϭ 333.37 g/mol): General proced-
6.93 (d, J ϭ 8.9 Hz, 2 H). 13C NMR (100.6 MHz, DEPT, CDCl3): ure B was used to convert 9 into the title compound. The reaction
δ ϭ 7.8 (d, J ϭ 6.0 Hz, CH3), 14.4 (CH3), 16.2 (d, J ϭ 6.0 Hz, was stirred for 20 h at 25 °C. Purification by flash chromatography
CH3), 16.3 (d, J ϭ 6.0 Hz, CH2), 26.7 (d, J ϭ 3.0 Hz, CH2), 35.8 (CH2Cl2/MeOH, 10:1) afforded 13 (87 mg, 0.26 mmol, 26%) as a
(d, J ϭ 3.0 Hz, CH2), 55.3 (CH3), 61.2 (d, J ϭ 147 Hz, C), 61.6 (d, colorless solid. 1H NMR (400 MHz, CDCl3): δ ϭ 1.06 (t, J ϭ
J ϭ 2.0 Hz, CH2), 113.7 (CH), 122.6 (CH), 138.5 (d, J ϭ 4.0 Hz, 7.1 Hz, 3 H), 1.28 (t, J ϭ 7.0 Hz, 3 H), 1.84 (br. s, 2 H), 3.31 (dd,
460
Eur. J. Org. Chem. 2002, 457Ϫ463

A One-Pot Procedure for the Synthesis of α-Amino Phosphonates from Alkynes
FULL PAPER
J ϭ 13.6, 8.3 Hz, 1 H), 3.55Ϫ3.67 (m, 2 H), 3.84Ϫ3.94 (m, 1 H), CH2), 40.8 (d, J ϭ 4.0 Hz, CH2), 53.1 (d, J ϭ 8.0 Hz, CH3), 53.2
4.13 (quin, J ϭ 7.1 Hz, 2 H), 6.89 (br. d, J ϭ 7.6 Hz, 2 H), (d, J ϭ 8.0 Hz, CH3), 56.5 (d, J ϭ 150 Hz, C), 126.8 (CH), 128.0
˜
7.08Ϫ7.16 (m, 3 H), 7.23Ϫ7.29 (m, 1 H), 7.34 (t, J ϭ 7.5 Hz, 2 H), (CH), 131.0 (CH), 135.5 (d, J ϭ 11.0 Hz, C). IR: ν ϭ 3377, 3028,
7.66 (br. d, J ϭ 8.0 Hz, 2 H). 13C NMR (100.6 MHz, DEPT, 2951, 2850, 1712, 1601, 1495, 1454, 1380, 1349, 1233, 1182, 1107,
CDCl3): δ ϭ 16.3 (d, J ϭ 5.0 Hz, CH3), 16.4 (d, J ϭ 6.0 Hz, CH3), 1053, 1024, 818, 768, 741, 701, 669 cmϪ1. MS (25 °C): m/z (%) ϭ
44.3 (CH2), 59.3 (d, J ϭ 202 Hz, C), 62.4 (d, J ϭ 8.0 Hz, CH2),
257 (4) [Mϩ], 228 (15), 183 (9), 166 (80), 148 (98), 134 (10), 105
63.5 (d, J ϭ 7.0 Hz, CH2), 126.6 (CH), 127.2 (CH), 127.3 (CH), (15), 91 (100), 83 (37), 80 (32), 79 (37), 77 (11), 65 (22). HRMS:
127.7 (CH), 128.0 (d, J ϭ 3.0 Hz, CH), 130.8 (CH), 135.1 (d, J ϭ calcd. 257.1181; found 257.1177.
˜
13.0 Hz, C), 139.0 (d, J ϭ 2.0 Hz, C). IR: ν ϭ 3377, 3060, 3029,
One-Pot Synthesis of Cyclic α-Amino Phosphonates from Aminoal-
kynes. General Procedure D: The aminoalkyne (1.0 mmol), a solu-
tion of Cp2TiMe2 (0.11 mL, 0.45 mol/L in toluene, 0.05 mmol, 5.0
mol %) and toluene (1.0 mL) were added to a Schlenk tube. The
Schlenk tube was sealed with a Teflon stopcock and heated to 110
°C for 9 h. Then the mixture was cooled to 0 °C and HP(O)(OEt)2
(7; 138 mg, 1.00 mmol) and a solution of Me2AlCl (0.05 mL, 1.0
2979, 2928, 1601, 1495, 1446, 1390, 1233, 1161, 1097, 1050, 1020,
955, 846, 786, 765, 737, 699, 601, 571, 549 cmϪ1. MS (50 °C): m/z
(%) ϭ 333 (1) [Mϩ], 263 (1), 242 (76), 196 (100), 178 (6), 149 (6),
121 (8), 111 (10), 105 (52), 104 (52), 91 (21), 83 (13), 81 (10), 77
(23). HRMS: calcd. 333.1494; found 333.1497.
Compound 14 (C10H24NO3P, M ϭ 237.28 g/mol): General proced-
ure B was used to convert 10 into the title compound. Purification mol/L in hexane, 0.05 mmol, 5.0 mol %) were added. After 2 h of
by flash chromatography (CH2Cl2/MeOH, 10:1) afforded 14
stirring at room temperature the mixture was diluted with EtOAc
(173 mg, 0.73 mmol, 73%) as a colorless solid. 1H NMR (400 MHz, and filtered through SiO2 (prior to its use the SiO2 was washed with
CDCl3): δ ϭ 0.92 (t, J ϭ 7.2 Hz, 3 H), 0.97 (t, J ϭ 7.5 Hz, 3 H), EtOAc/NEt3, 100:1). Evaporation of the solvent under vacuum and
1.33 (t, J ϭ 7.0 Hz, 6 H), 1.37Ϫ1.78 (m, 6 H), 4.14 (quin, J ϭ
flash chromatography on silica gel afforded the pure (unless other-
7.2 Hz, 4 H). 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 7.4 (d, wise noted) α-amino phosphonate.
J ϭ 6.0 Hz, CH3), 14.4 (CH3), 16.0 (d, J ϭ 6.0 Hz, CH2), 16.3 (d,
Compound 23 (C15H24NO3P, M ϭ 297.33 g/mol): General proced-
J ϭ 6.0 Hz, CH3), 27.7 (d, J ϭ 4.0 Hz, CH2), 36.9 (d, J ϭ 3.0 Hz,
CH2), 54.7 (d, J ϭ 145 Hz, C), 61.7 (d, J ϭ 8.0 Hz, CH2). IR: ν˜ ϭ
3377, 2962, 2934, 2873, 1602, 1461, 1390, 1294, 1223, 1162, 1097,
1050, 1021, 951, 825, 785, 749, 680, 654, 559, 519 cmϪ1. MS (25
°C): m/z (%) ϭ 237 (1) [Mϩ], 208 (2), 194 (3), 123 (2), 111 (37),
100 (100), 98 (35), 83 (43), 70 (20), 65 (27). HRMS: calcd. 237.1494;
found 237.1492.
ure D was used to convert 17 into the title compound. Purification
by flash chromatography (PE/EtOAc/NEt3, 500:100:1) afforded 23
1
(232 mg, 0.78 mmol, 78%) as a colorless oil. H NMR (400 MHz,
CDCl3): δ ϭ 1.29 (t, J ϭ 7.1 Hz, 3 H), 1.30 (t, J ϭ 7.0 Hz, 3
H), 1.62Ϫ1.73 (m, 1 H), 1.80Ϫ1.94 (m, 2 H), 2.10Ϫ2.23 (m, 1 H),
2.68Ϫ2.75 (m, 1 H), 2.82Ϫ2.89 (m, 1 H), 2.95 (dd, J ϭ 13.6,
10.2 Hz, 1 H), 3.04 (dd, J ϭ 13.7, 9.4 Hz, 1 H), 4.08Ϫ4.20 (m, 4
Deprotection of the NH2 Groups. Reductive Cleavage. General Pro- H), 7.23Ϫ7.32 (m, 5 H). 13C NMR (100.6 MHz, DEPT, CDCl3):
cedure C: Pd/C (212 mg, 5% Pd, 10.6 mg Pd, 0.10 mmol Pd, 10.0
δ ϭ 16.4 (CH3), 25.7 (CH2), 31.3 (CH2), 41.1 (d, J ϭ 8.0 Hz, CH2),
mol %) was stirred in THF (5.0 mL) at 25 °C under 1 atm. of H2 47.1 (d, J ϭ 7.0 Hz, CH2), 62.1 (d, J ϭ 8.0 Hz, CH2), 62.4 (d, J ϭ
for 30 min. Then a solution of the benzhydrylamine derivative
(1.00 mmol) in THF (3.0 mL) was added. The resulting mixture
8.0 Hz, CH2), 63.2 (d, J ϭ 166 Hz, C), 64.0 (C), 126.6 (CH), 128.0
˜
(CH), 130.8 (CH), 136.3 (C). IR: ν ϭ 3462, 2980, 2908, 2423, 1495,
was stirred under 1 atm. H2 at 25 °C for seven days. Filtration, 1479, 1444, 1392, 1251, 1163, 1098, 1028, 958, 784, 748, 704, 600,
concentration and purification by flash chromatography on silica
gel afforded the pure α-amino phosphonate.
547 cmϪ1. MS (25 °C): m/z (%) ϭ 297 (1) [Mϩ], 240 (1), 206 (59),
178 (8), 160 (100), 150 (15), 111 (15), 91 (31), 83 (16), 65 (12).
C15H24NO3P (297.3): calcd. C 60.06, H 8.14, N 4.71; found C
60.86, H 7.68, N 4.67.
Compound 15 (C11H18NO3P, M ϭ 243.24 g/mol): General proced-
ure C was used to convert 11 into the title compound. Purification
by flash chromatography (CH2Cl2/MeOH, 10:1) afforded 15
Compound 24 (C16H26NO3P, M ϭ 311.36 g/mol): General proced-
(114 mg, 0.47 mmol, 47%) as a colorless solid. 1H NMR (400 MHz, ure D was used to convert 18 into the title compound. Purification
CDCl3): δ ϭ 1.22 (d, J ϭ 18.0 Hz, 3 H), 1.77 (br. s, 2 H), 2.92 (dd, by flash chromatography (PE/EtOAc/NEt3, 100:100:1) afforded 24
J ϭ 13.4, 9.1 Hz, 1 H), 2.99 (dd, J ϭ 13.3, 9.3 Hz, 1 H), 3.80 (d, (268 mg, 0.86 mmol, 86%) as a colorless oil. The product was con-
J ϭ 5.6 Hz, 3 H), 3.82 (d, J ϭ 5.5 Hz, 3 H), 7.20Ϫ7.34 (m, 5 H). taminated with trace amounts of HP(O)(OEt)2 (7). 1H NMR
13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 22.2 (CH3), 42.7 (d, (400 MHz, CDCl3): δ ϭ 1.10 (t, J ϭ 7.2 Hz, 3 H), 1.24 (t, J ϭ
J ϭ 4.0 Hz, CH2), 53.0 (d, J ϭ 154 Hz, C), 53.4 (d, J ϭ 5.0 Hz, 7.0 Hz, 3 H), 1.43Ϫ1.57 (m, 2 H), 1.60Ϫ1.70 (m, 2 H), 1.75Ϫ2.05
CH3), 53.6 (d, J ϭ 4.0 Hz, CH3), 126.8 (CH), 128.0 (CH), 131.0 (m, 3 H), 2.93Ϫ3.06 (m, 3 H), 3.18 (dd, J ϭ 24.6, 13.9 Hz, 1 H),
(CH), 135.1 (d, J ϭ 13.0 Hz, C). IR: ν ϭ 3374, 3028, 2953, 2851, 3.82Ϫ4.00 (m, 2 H), 4.02Ϫ4.12 (m, 2 H). 13C NMR (100.6 MHz,
1603, 1496, 1455, 1373, 1227, 1182, 1124, 1053, 1027, 822, 776, DEPT, CDCl3): δ ϭ 16.1 (d, J ϭ 6.0 Hz, CH3), 16.4 (d, J ϭ 6.0 Hz,
750, 705, 686 cmϪ1. MS (25 °C): m/z (%) ϭ 243 (1) [Mϩ], 228 (1), CH3), 19.8 (d, J ϭ 8.0 Hz, CH2), 25.4 (CH2), 29.5 (CH2), 38.9 (d,
212 (1), 178 (1), 166 (2), 152 (100), 134 (80), 111 (18), 93 (26), 92 J ϭ 4.0 Hz, CH2), 41.0 (d, J ϭ 9.0 Hz, CH2), 57.1 (d, J ϭ 154 Hz,
(28), 91 (30), 80 (20), 79 (41). HRMS: calcd. 243.1024; found C), 61.4 (d, J ϭ 8.0 Hz, CH2), 62.1 (d, J ϭ 8.0 Hz, CH2), 126.2
˜
˜
243.1020.
(CH), 127.7 (CH), 130.9 (CH), 137.0 (C). IR: ν ϭ 3466, 2980, 2930,
2422, 1495, 1443, 1391, 1367, 1231, 1163, 1098, 1023, 955, 762,
701, 658, 608, 575 cmϪ1. MS (25 °C): m/z (%) ϭ 311 (1) [Mϩ], 220
(42), 192 (4), 174 (100), 172 (64), 148 (8), 117 (16), 111 (20), 91
(28), 83 (17), 65 (13). HRMS: calcd. 311.1650; found 311.1648.
Compound 16 (C12H20NO3P, M ϭ 257.27 g/mol): General proced-
ure C was used to convert 12 into the title compound. Purification
by flash chromatography (CH2Cl2/MeOH, 10:1) afforded 16
(126 mg, 0.49 mmol, 49%) as a colorless solid. 1H NMR (400 MHz,
CDCl3): δ ϭ 1.06 (t, J ϭ 7.6 Hz, 3 H), 1.54Ϫ1.69 (m, 2 H), 1.90
Compound 25 (C10H22NO3P, M ϭ 235.26 g/mol): General proced-
(br. s, 2 H), 2.91Ϫ3.04 (m, 2 H), 3.74 (d, J ϭ 4.8 Hz, 3 H), 3.76 ure D was used to convert 19 into the title compound. Purification
(d, J ϭ 4.8 Hz, 3 H), 7.18Ϫ7.35 (m, 5 H). 13C NMR (100.6 MHz, by flash chromatography (PE/EtOAc/NEt3, 400:100:1) afforded 25
1
DEPT, CDCl3): δ ϭ 8.6 (d, J ϭ 4.0 Hz, CH3), 28.9 (d, J ϭ 2.0 Hz,
Eur. J. Org. Chem. 2002, 457Ϫ463
(200 mg, 0.85 mmol, 85%) as a colorless oil. H NMR (400 MHz,
461

E. Haak, I. Bytschkov, S. Doye
FULL PAPER
CDCl3): δ ϭ 1.31Ϫ1.38 (m, 9 H), 1.55Ϫ1.65 (m, 5 H), 1.68Ϫ1.78 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 16.3 (d, J ϭ 5.0 Hz,
(m, 1 H), 1.83Ϫ1.94 (m, 1 H), 2.80Ϫ2.88 (m, 1 H), 2.92Ϫ3.00 (m, CH3), 16.4 (d, J ϭ 5.0 Hz, CH3), 25.5 (J ϭ 3.0 Hz, CH2), 30.3
1 H), 4.11Ϫ4.21 (m, 4 H). 13C NMR (100.6 MHz, DEPT, CDCl3): (CH2), 36.5 (d, J ϭ 9.0 Hz, CH2), 46.5 (d, J ϭ 3.0 Hz, CH2), 62.1
δ ϭ 16.5 (CH3), 19.5 (d, J ϭ 9.0 Hz, CH2), 20.4 (CH3), 25.8 (CH2), (d, J ϭ 8.0 Hz, CH2), 62.4 (d, J ϭ 8.0 Hz, CH2), 63.1 (d, J ϭ
30.9 (CH2), 40.7 (d, J ϭ 10.0 Hz, CH2), 52.8 (d, J ϭ 316 Hz, C),
155 Hz, C), 124.4 (q, J ϭ 274 Hz, CF3), 125.9 (q, J ϭ 6.0 Hz, CH),
˜
62.0 (d, J ϭ 8.0 Hz, CH2). IR: ν ϭ 3462, 3308, 2977, 2932, 2867, 126.7 (CH), 129.9 (q, J ϭ 29.0 Hz, C), 131.0 (CH), 133.5 (CH),
1442, 1391, 1366, 1232, 1190, 1163, 1123, 1096, 1022, 951, 787,
135.8 (d, J ϭ 13.0 Hz, C). IR: ν˜ ϭ 3335, 2972, 2908, 2860, 2834,
748, 637, 577 cmϪ1. MS (25 °C): m/z (%) ϭ 235 (3) [Mϩ], 220 (1), 1610, 1583, 1512, 1469, 1441, 1428, 1392, 1367, 1303, 1227, 1178,
137 (1), 123 (2), 111 (40), 98 (100), 83 (43), 65 (30). C10H22NO3P 1115, 1099, 1024, 947, 841, 825, 807, 763, 738, 682, 584, 567, 530,
(235.3): calcd. C 51.06, H 9.43, N 5.95; found C 51.42, H 9.17, 513 cmϪ1. MS (25 °C): m/z (%) ϭ 365 (6) [Mϩ], 292 (32), 278 (10),
N 5.71.
252 (13), 240 (15), 228 (88), 199 (31), 183 (20), 158 (100), 130 (16),
111 (88), 93 (31), 91 (13), 83 (87), 77 (8), 65 (67). C16H23NO3PF3
(365.3): calcd. C 52.60, H 6.35, N 3.83; found C 53.08, H 6.04,
N 3.92.
Compound 26 (C20H26NO3P, M ϭ 359.40 g/mol): General proced-
ure D was used to convert 20 into the title compound. Purification
by flash chromatography (PE/EtOAc/NEt3, 500:100:1) afforded
1
219 mg of a colorless oil. According to the H NMR spectrum 26
was contaminated with 15% of the corresponding imine. Therefore,
only 186 mg (0.52 mmol, 52%) of 26 were obtained. 1H NMR
(400 MHz, CDCl3): δ ϭ 1.00 (t, J ϭ 7.1 Hz, 3 H), 1.16 (t, J ϭ
7.1 Hz, 3 H), 2.15Ϫ2.50 (br. s, 1 H), 2.47Ϫ2.57 (m, 1 H), 2.68Ϫ2.88
(m, 2 H), 3.12Ϫ3.20 (m, 1 H), 3.34Ϫ3.60 (m, 3 H), 3.82Ϫ4.08 (m,
3 H), 7.03 (d, J ϭ 7.5 Hz, 1 H), 7.05Ϫ7.11 (m, 2 H), 7.12Ϫ7.32
(m, 5 H), 7.90 (d, J ϭ 7.4 Hz, 1 H). 13C NMR (100.6 MHz, DEPT,
CDCl3): δ ϭ 16.2 (CH3), 16.2 (CH3), 30.3 (CH2), 38.9 (CH2), 43.8
(CH2), 60.6 (d, J ϭ 153 Hz, C), 61.8 (d, J ϭ 8.0 Hz, CH2), 63.4 (d,
J ϭ 7.0 Hz, CH2), 125.8 (d, J ϭ 3.0 Hz, CH), 126.6 (CH), 126.8
(d, J ϭ 3.0 Hz, CH), 127.8 (CH), 128.3 (J ϭ 4.0 Hz, CH), 129.3
(d, J ϭ 2.0 Hz, CH), 130.8 (CH), 133.9 (d, J ϭ 2.0 Hz, C), 136.1
(d, J ϭ 10.0 Hz, C), 136.8 (d, J ϭ 7.0 Hz, C). IR: ν˜ ϭ 3359, 3060,
3027, 2979, 2928, 1674, 1622, 1601, 1572, 1494, 1453, 1390, 1365,
1235, 1162, 1049, 1022, 956, 786, 753, 738, 719, 700, 667, 595, 554
cmϪ1. MS (25 °C): m/z (%) ϭ 268 (3) [Mϩ Ϫ Bn], 220 (100), 204
(5), 178 (3), 155 (3), 111 (17), 83 (15), 65 (10).
Acknowledgments
Generous support by Professor E. Winterfeldt is most gratefully
acknowledged. We further thank the Deutsche Forschungsgemein-
schaft, the Fonds der Chemischen Industrie and Bayer AG for fin-
ancial support of our research.
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by flash chromatography (EtOAc/NEt3, 100:1) afforded 27
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A. Peyman, K.-H. Budt, J. Spanig, B. Stowasser, D. Rup-
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B. Stowasser,
1
(216 mg, 0.66 mmol, 66%) as a colorless oil. H NMR (400 MHz,
CDCl3): δ ϭ 1.15Ϫ1.26 (m, 1 H), 1.30 (t, J ϭ 7.0 Hz, 3 H), 1.31
(t, J ϭ 7.0 Hz, 3 H), 1.40Ϫ2.05 (br. s, 1 H), 1.65Ϫ1.75 (m, 1 H),
1.78Ϫ1.88 (m, 1 H), 2.07Ϫ2.21 (m, 1 H), 2.67Ϫ2.77 (m, 1 H),
2.80Ϫ2.94 (m, 2 H), 3.00 (dd, J ϭ 13.8, 9.4 Hz, 1 H), 3.79 (s, 3 H),
4.08Ϫ4.22 (m, 4 H), 6.81 (d, J ϭ 8.6 Hz, 2 H), 7.16 (d, J ϭ 8.6 Hz,
2 H). 13C NMR (100.6 MHz, DEPT, CDCl3): δ ϭ 16.4 (d, J ϭ
2.0 Hz, CH3), 16.4 (d, J ϭ 2.0 Hz, CH3), 25.8 (d, J ϭ 4.0 Hz, CH2),
31.2 (d, J ϭ 2.0 Hz, CH2), 40.1 (d, J ϭ 8.0 Hz, CH2), 41.1 (d, J ϭ
7.0 Hz, CH2), 55.1 (CH3), 62.0 (d, J ϭ 8.0 Hz, CH2), 62.3 (d, J ϭ
7.0 Hz, CH2), 63.2 (d, J ϭ 165 Hz, C), 113.5 (CH), 128.2 (d, J ϭ
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˜
12.0 Hz, C), 131.7 (CH), 158.4 (C). IR: ν ϭ 3377, 2929, 2869, 2838,
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Y. Song, D. Niederer, P. M. Lane-Bell, L. K. P. Lam, S.
1673, 1609, 1582, 1510, 1461, 1442, 1391, 1300, 1244, 1177, 1097,
1022, 957, 834, 788, 756, 673, 663, 637, 578, 527 cmϪ1. MS (80 °C):
m/z (%) ϭ 327 (1) [Mϩ], 271 (4), 225 (7), 206 (100), 190 (77), 178
(59), 150 (72), 121 (73), 103 (5), 91 (13), 83 (19), 65 (17). HRMS:
calcd. 327.1599; found 327.1597.
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Compound 28 (C16H23NO3PF3, M ϭ 365.33 g/mol): General pro-
cedure D was used to convert 22 into the title compound. Purifica-
tion by flash chromatography (EtOAc/NEt3, 100:1) afforded 28
1521Ϫ1542.
J. Rachon, U. Schöllkopf, T. Wintel, Liebigs
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[9e]
J. H. Merrett, W. C. Spurden, W.
1
(212 mg, 0.58 mmol, 58%) as a colorless oil. H NMR (400 MHz,
CDCl3): δ ϭ 1.15Ϫ1.28 (m, 1 H), 1.34 (t, J ϭ 7.0 Hz, 3 H), 1.35
(t, J ϭ 7.0 Hz, 3 H), 1.50Ϫ1.62 (m, 1 H), 1.65Ϫ1.80 (m, 1 H), 1.95
(br. s, 1 H), 2.04Ϫ2.20 (m, 1 H), 2.74Ϫ2.82 (m, 1 H), 2.94Ϫ3.02
(m, 1 H), 3.14 (dd, J ϭ 14.6, 6.3 Hz, 1 H), 3.32 (dd, J ϭ 14.6,
8.3 Hz, 1 H), 4.23Ϫ4.11 (m, 4 H), 7.27Ϫ7.39 (m, 1 H), 7.45 (t, J ϭ
7.3 Hz, 1 H), 7.63 (d, J ϭ 7.7 Hz, 1 H), 7.80 (d, J ϭ 7.8 Hz, 1 H).
[9f]
Perkin Trans. 1 1988, 61Ϫ67.
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and references therein.
See also refs.[1aϪ1c] and
462
Eur. J. Org. Chem. 2002, 457Ϫ463

A One-Pot Procedure for the Synthesis of α-Amino Phosphonates from Alkynes
FULL PAPER
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4411Ϫ4418.
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For intermolecular hydroamination reactions of alkynes, see:
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[12b]
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