A new access to substituted tetraethyl N-Boc 2-aminoethylidene-1,1-bisphosphonates and phosphonyl-substituted aza-Morita-Baylis-Hillman-type adducts

Article abstract of DOI:10.1016/j.tet.2007.11.072

A general one-pot synthesis of substituted 2-aminoethylidene-1,1-bisphosphonates has been developed. The protocol involves base-induced addition of sodium tetraethyl methylenebisphosphonate to N-Boc imines generated in situ from N-Boc-α-amidoalkyl-p-tolyl

Full text of DOI:10.1016/j.tet.2007.11.072

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1233e1241
www.elsevier.com/locate/tet
A new access to substituted tetraethyl N-Boc 2-aminoethylidene-1,1-
bisphosphonates and phosphonyl-substituted aza-Moritae
BayliseHillman-type adducts
*
Anna Gajda, Tadeusz Gajda
_
Institute of Organic Chemistry, Technical University of Lodz, Zeromskiego St. 116, 90-924 Lodz, Poland
Received 3 September 2007; received in revised form 5 November 2007; accepted 22 November 2007
Available online 23 November 2007
This paper is dedicated to Professor Andrzej Zwierzak on the occasion of his 75th birthday
Abstract
A general one-pot synthesis of substituted 2-aminoethylidene-1,1-bisphosphonates has been developed. The protocol involves base-induced
addition of sodium tetraethyl methylenebisphosphonate to N-Boc imines generated in situ from N-Boc-a-amidoalkyl-p-tolylsulfones by the
action of sodium hydride. The direct and efficient conversion of the title compounds into aza-MoritaeBayliseHillman-type adducts has
been also elaborated.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Bisphosphonates; Nucleophilic addition; N-Boc imines; a-Amidosulfones; Aza-MoritaeBayliseHillman-type adducts
1. Introduction
are shown to be the most potent compounds.1a Increasing inter-
est in the nitrogen-containing bisphosphonates resulted in the
development of different strategies for their synthesis. The
standard route to 2-aminoethylidene-1,1-bisphosphonates 6
exploits the Michael-type addition of amines2a,2b,5 or amides6
to tetraethyl vinylidenebisphosphonate (5) by the method elab-
orated by Hutchinson and Thornton5a (Scheme 1). The addition
Geminal bisphosphonates are hydrolytically stable analogs
of naturally occurring inorganic pyrophosphates and constitute
an important class of biologically active compounds. A num-
ber of these compounds have found application in treatment of
bone diseases such as Paget’s disease, myeloma, bone metas-
tases, and osteoporosis1 (Fig. 1). Recently, bisphosphonates
have also been used as antiprotozoan1f,2 agents and are found
to stimulate human gd T cells.3
Current investigations prove that mevalonate pathway en-
zyme, farnesyl pyrophosphate synthase (FPPS), is a principal
molecular target of the bisphosphonates action.4 Bioactivity
of bisphosphonates is determined by the structure of the side-
chain as well as the nature of the functional groups connected
with the methylenebisphosphonate moiety. Among numerous
bisphosphonates the nitrogen-containing derivatives (N-BPs)
P(O)(OH)2
P(O)(OH)2
H2N
H2N
HO P(O)(OH)2
HO P(O)(OH)2
1 Alendronate
2 Pamidronate
P(O)(OH)2
P(O)(OH)2
N
N
P(O)(OH)
HO P(O)(OH)2
HO
2
N
3 Risedronate
4 Zoledronate
Figure 1. Representative members of the second- and third generation of
bisphosphonates 1e4 used in treatment of bone diseases (the common names
given here refer to their salts).
* Corresponding author. Tel.: þ48 42 6313146; fax: þ48 42 6365530.
E-mail address: tmgajda@p.lodz.pl (T. Gajda).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.072

1234
A. Gajda, T. Gajda / Tetrahedron 64 (2008) 1233e1241
of nitrogen-containing nucleophiles to homologs of the above-
mentioned Michael acceptor has not been hitherto reported.
elimination have been recently the subject of extensive
research.10
Herein we report on the synthesis of novel b-functionalized
bisphosphonates using N-Boc-a-amidoalkyl-p-tolylsulfones as
imine precursors for the b-aminoalkylation of tetraethyl meth-
ylenebisphosphonate. To the best of our knowledge this
approach to 2-aminoethylidene-1,1-bisphosphonate deriva-
tives has not been hitherto reported.
O
O
O
O
R1R2NH
(EtO)2P
P(OEt)2
(EtO)2P
P(OEt)2
NR1R2
5
6
R1R2NH = ArNH2, AlkylNH2, Et2NH, c-C6H11NH2,
c-C7H13NH2, H2N(CH2)2NH2, H2NCH2CO2H,
2. Results and discussion
N
NH
HO(CH2)2N(Me)H
We established a new and efficient route to diethyl 2-
substituted [2-tert-butoxycarbonylamino-1-(diethoxyphospho-
ryl)-ethyl]phosphonates 11 via addition of sodium tetraethyl
methylenebisphosphonate (9) to N-Boc imines 10, both gener-
ated in situ from tetraethyl methylenebisphosphonate (7) and
N-Boc-a-amidoalkyl-p-tolylsulfones 8, by the action of sodium
hydride (Scheme 2).
As shown in Scheme 2, the reaction was performed by add-
ing 7 (1 equiv) to the suspension of sodium hydride (2 equiv)
in THF at rt, followed by the addition of a-amidosulfones 8 in
THF at ꢀ20 ꢁC. The reaction was completed within 3 h. The
corresponding adducts 11aej were isolated in high yields
and purity. The reaction was general and a number of diverse
alkyl, aryl, or heteroaryl substituted bisphosphonates 11 were
obtained in this way. The results are summarized in Table 1.
The reactions of a-amidosulfones 8 with 7 were temperature
sensitive and in order to avoid the formation of side-products
the temperature regime should be strictly obeyed. When the
reactions were carried out at rt diethyl 1-alkenylphosphonates
N
H
O
NH
N
NH2
NH2
NH2
N
OBn OBn
NH
R
BnO
N
X
N
C(O)NH2
OBn
NHBoc
HO2C
F
O
EtO2C
C(O)NH2
X = C, N: R = Et, c-C3H5
Scheme 1. Preparation of aminoethylidene-1,1-bisphosphonate derivatives 6
from the tetraethyl vinylidenebisphosphonate (5) and amine derivatives.
Some N-BPs are also available via reductive (Pd/ammonium
formate) ring-opening of N-(p-toluenesulfonyl)-2,2-(diethoxy-
phosphoryl)aziridine,5f or by Curtius rearrangement of 2,2-
bis(diethoxyphosphoryl)cyclopropanecarboxylic acid.7 Another
well documented methodology, leading, however, only to 2-
amino-1-hydroxyethylidene-1,1-bisphosphonate derivatives, is
based on the reaction of the corresponding carboxylic acid
with a mixture of phosphorus trichloride and phosphorous
acid,2a,2b,4e,8 followed by hydrolysis. Alternatively, phosphorus
oxychloride/phosphorous acid2a,4b or phosphorus trichloride/
phosphoric acid1e system can be applied. In turn, N-methyl
and N,N-dimethyl analogs of 2-amino-1-hydroxyethylidene-
1,1-bisphosphonate can be obtained via addition of dimethyl
phosphite to 2-(N-phthaloylamino)acetylphosphonic acid di-
methyl ester, followed by hydrolysis with hydrobromic acid
and subsequent methylation with formic acid/formaldehyde.9
N-Boc-a-amidoalkyl-p-tolylsulfones can be considered as a
stable and easy to handle equivalents of N-Boc imines. There-
fore, nucleophilic additions to N-Boc imines generated in situ
from the a-amidosulfones mentioned above by base-induced
Table 1
Diethyl 2-substituted [2-tert-butoxycarbonylamino-1-(diethoxyphosphoryl)-
ethyl]phosphonates 11aej prepared
Entry
Product
R
Yielda (%)
1
2
3
4
5
6
7
8
9
10
a
11a
11b
11c
11d
11e
11f
11g
11h
11i
Me
92
90
92
93
93
82
98
87
88
92
Et
i-Pr
Bu
c-Hex
2-Furyl
Ph
2-Py
3-Py
1-Naphthyl
11j
Yields of pure, isolated products.
O
O
Ts
NHBoc
P(O)(OEt)2
(EtO)2P
(EtO)2P
a
b
Na
R
NBoc
R
NHBoc
R
82−98%
(EtO)2P
O
(EtO)2P
O
P(O)(OEt)2
11
7
8
9
10
8,10,11 R
8,10,11 R
a
b
c
d
e
Me
f
2-Furyl
Et
g Ph
h 2-Py
i-Pr
Bu
i
3-Py
1-Naphthyl
c-Hex
j
Scheme 2. Reagents and conditions: (a) NaH (2 equiv), ꢀ20 ꢁC to ꢀ10 ꢁC, 3 h, THF; (b) aq NH4Cl, ꢀ10 ꢁC.

A. Gajda, T. Gajda / Tetrahedron 64 (2008) 1233e1241
1235
were identified as one of the by-products, as determined by 1H
11g
Base
and 31P NMR.
The structure of final products was unequivocally con-
firmed by NMR, mass spectra, and elemental analyses. Due
to anisochronicity of diethoxyphosphoryl groups in 11aej,
two separate signals could be observed in their proton de-
coupled 31P NMR spectra, sometimes accompanied (11c,e)
by additional peaks of rotamers.
Boc
Ph
O
P
N
Boc
Ph
N
(OEt)2
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
13
14
Unfortunately, under the conditions mentioned above the
a-amidosulfone 8k, derived from formaldehyde, afforded the
mixture of mono- and bis-adducts 11k and 12 in 1:4 ratio
(31P NMR, dP¼21.67 and 23.28, respectively), together with
starting compound 7 (Scheme 3). Attempted synthesis of
pure 11k failed.
H3O
P(O)(OEt)2
15
BocNHP(O)(OEt)2
Ph
16
Scheme 4. A plausible pathway of base-induced rearrangement of bisphos-
phonate 11g.
Ts
a
NHBoc
7
NHBoc
8k
P(O)(OEt)2
R
P(O)(OEt)2
BocHN
BocHN
P(O)(OEt)2
P(O)(OEt)2
P(O)(OEt)2
11
BocHN
P(O)(OEt)2
11k
12
a
b or c
Scheme 3. Reagents and conditions: (a) NaH (2 equiv), ꢀ20 ꢁC to ꢀ10 ꢁC,
3 h, THF then satd aq NH4Cl, ꢀ10 ꢁC.
NH3Cl
P(O)(OEt)2
NH3Cl
P(O)(OH)2
R
R
The final aminobisphosphonates 11aej are stable com-
pounds and can be stored for unlimited time at rt. They are,
however, base sensitive to some extent. Thus, when the solution
of pure diethyl [2-tert-butoxycarbonylamino-1-(diethoxyphos-
phoryl)-ethyl]phosphonate (11g, R¼Ph) in THF is subjected
to the action of stoichiometric amount of sodium hydride for
12 h at rt, partial rearrangement of 11g occurred, and the
mixture of diethyl (E)-styrylphosphonate11 (15) (dP¼20.45)
and diethyl N-Boc phosphoramidate12 (16) (dP¼ꢀ2.7) accom-
panied by starting 11g (dP¼20.89, 21.25) has been obtained in
1:1:1.5 ratio, as confirmed by 1H and 31P NMR analyses of the
reaction mixture. The NMR data of the crude reaction mixture
agree with those collected for the original samples of 1511 and
1612 prepared by an independent way, what confirms the above
assumption. This result can also explain the side formation of
diethyl 1-alkenylphosphonates in the reactions of a-amidosul-
fones 8 with 7 carried out at rt. The plausible pathway of this
rearrangement is shown in Scheme 4. Thus, the intermediate
anion 13, formed under basic conditions from 11g, can
decompose via transient azaphosphetane 14 to give diethyl
(E)-styrylphosphonate (15) and diethyl N-Boc phosphorami-
date (16) on quenching.
P(O)(OEt)2
P(O)(OH)2
17a R = Bu
17b R = Ph
18a R = Me
18b R = Ph
18c R = 1-Naphthyl
18d R = 3-Py
Scheme 5. Reagents and conditions: (a) 3.5 M HCl/AcOEt, rt, 1 h; (b) 20% aq
HCl, reflux, 10 h; (c) TMSBr, CH2Cl2, rt, 48 h, followed by CH3OH, rt, 2 h.
Table 2
Aminobisphosphonate hydrochlorides 17a,b and aminobisphosphonic acid
hydrochlorides 18aed prepared
Entry
Product
R
Yielda (%)
1
2
3
4
5
6
a
17a
17b
18a
18b
18c
18d
Bu
Ph
100b
100b
50c
Me
Ph
68c
1-Naphthyl
3-Py
52c
35d
Yields of pure, isolated products.
Obtained by the action of 3.5 M HCl in anhydrous EtOH.
Prepared by the action of 20% aq HCl. The products were isolated after
b
c
lyophilization as hydrochlorides.
d
Prepared by the action of TMSBr, followed by methanolysis. The product
was isolated after lyophilization as dihydrobromide.
The synthetic versatility of the diethyl [2-tert-butoxycar-
bonylamino-1-(diethoxyphosphoryl)ethyl]phosphonate deriva-
tives 11 was confirmed by the following transformations. As
shown in Scheme 5, treatment of the model phosphonates
11d and 11g with 3.5 M HCl solution in anhydrous ethanol at
rt resulted in the smooth and selective cleavage of the N-Boc
group13 to give analytically pure 17a,b in quantitative yields
(Table 2, entries 1 and 2).
bisphosphonic acid ester functions in 11. The aminobisphos-
phonic acid hydrochlorides 18aec were prepared by refluxing
the mixture of the aminobisphosphonates 11a,g,j and 20% aq
HCl solution for 10 h (Scheme 5). Analytically pure 18aec
were obtained in satisfactory yields (50e68%) after their pre-
cipitation from the reaction mixture with acetone, followed by
redissolving in water and lyophilization (Table 2, entries 3e5).
Pyridine derivative11i underwent, however, thecomplete degra-
dation under these hydrolytic conditions. Aminobisphosphonic
In turn, aq HCl solution was the reagent of choice for
simultaneous Boc group deprotection and the dealkylation of

1236
A. Gajda, T. Gajda / Tetrahedron 64 (2008) 1233e1241
acid dihydrobromide 18d was obtained from 11i in 35% yield
using bromotrimethylsilane14 in CH2Cl2 at rt for 48 h, followed
by methanolysis of the intermediate trimethylsilyl esters (entry
6). The structures of the aminobisphosphonates 17a,b and
aminobisphosphonic acid 18aed were fully confirmed by H,
13C and 31P NMR as well as elemental analyses and mass
spectra.
However, Burger et al. have demonstrated that the aza-MBH
reaction of diethyl vinyl phosphonate with N-Boc fluoroalkyl
substituted imines proceeds slowly, giving unsatisfactory yields
of products.18 Therefore, the number of aza-MBH adducts
derived from diethyl vinyl phosphonate is limited19 and there
are only a few alternative routes to their synthesis. The aza-
MBH-type adducts have been obtained via the aldol-type reac-
tion of diethyl 2-(N,N-dimethylamino)ethylphosphonate with
trifluoromethyl substituted imines, followed by treatment of
the intermediate adducts with m-chloroperbenzoic acid.18 Loreto
and collaborates have described the synthesis of a-methylene
N-(ethoxycarbonyl) b-aminophosphonic esters20 via aziridina-
tion of (1-trimethylsilanylmethyl-vinyl)phosphonic acid esters
with ethyl N-{[(4-nitrobenzene)sulfonyl]oxy}carbamate, fol-
lowed by silyl group elimination and aziridine ring-opening.
In 2006 Krische et al. have reported a concise approach to
the phosphonyl-substituted aza-MBH adducts via phosphine-
catalyzed allylic substitution of diethyl 1-substituted [1-(acetyl-
amino-methyl)-vinyl]phosphonates (MBH acetates), employing
4,5-dichlorophthalimide as a nucleophile.21 Recently, the aza-
MBH-type adducts derived from vinyl phosphonates have
found application as a building blocks in the synthesis of
b-amino-a-hydroxyphosphonates.20b
1
Straightforward conversion of N-Boc derivatives 11 to
substituted [1-(tert-butoxycarbonylamino-methyl)vinyl]phos-
phonates 19aef by HornereWadswortheEmmons (HWE)
olefination of formaldehyde11,15,16 was also accomplished.
On account of the base sensitivity of the phosphonates 11
(vide supra), repeated attempts were made to find optimal re-
action conditions, under which a side formation of the diethyl
1-alkenylphosphonates could be avoided. As shown in Scheme
6, these transformations were performed using potassium tert-
butoxide as a base and paraformaldehyde at ꢀ10 ꢁC in anhy-
drous THF. Under these conditions clean conversion of 11 to
the desired aminomethylene derivatives 19 took place and
the final products 19aef were obtained in high yields (73e
89%) and in spectroscopic purity. The results are summarized
in Table 3. The structures of 19aef were unambiguously con-
1
firmed by H, 13C and 31P NMR spectroscopies as well as
elemental analyses and mass spectra. The HWE reaction was
limited to formaldehyde. Attempted olefinations of the higher
aldehydes failed. Under the reaction condition mentioned
above only the unreacted 11 was present in the reaction mix-
ture on quenching.
The conversion of 11 to 19 established by us is an alterna-
tive to the aza-MoritaeBayliseHillman reaction17 (aza-MBH
reaction) whereby polyfunctional adducts can be prepared in
a single step by the nucleophile-catalyzed condensation of
N-acyl imines with electron-deficient olefins. The aza-MBH
adducts have proven to be useful intermediates in organic
synthesis.17
3. Conclusions
The protocol described here provides a new and operation-
ally simple one-pot access to substituted N-Boc 2-aminoethyl-
idene-1,1-bisphosphonate derivatives from easily available
tetraethyl methylenebisphosphonate and N-Boc-a-amidoalkyl-
p-tolylsulfones. The reaction is general and structurally diverse
aminobisphosphonates have been thus obtained under mild con-
ditions and in good yields. The title products are also versatile
synthetic intermediates for further transformations, including
selective Boc group deprotection, conversion to free amino-
bisphosphonic acids, and direct synthesis of the aza-Moritae
BayliseHillman-type adducts.
NHBoc
P(O)(OEt)2
NHBoc
P(O)(OEt)2
a, b, c
R
R
73−89%
4. Experimental
P(O)(OEt)2
11a-c,e,g,j
19a R = Me
19b R = Et
4.1. General
19c R = i-Pr
19d R = c-Hex
19e R = Ph
NMR spectra were recorded on a Bruker Avance DPX 250
1
instrument at 250.13 MHz for H NMR, 62.90 MHz for 13C
19f R = 1-Naphthyl
NMR, and 101.3 MHz for 31P NMR in CDCl3 solution, using
either tetramethylsilane as an internal or 85% H3PO4 as an
external standard. Positive chemical shifts are downfield
from external 85% H3PO4 for 31P NMR spectra. Chemical
shifts (d) are indicated in parts per million and coupling con-
stants (J) in hertz. For 13C NMR spectra, the peak assignments
were made with the assistance of CH-COSY experiments. Par-
tially overlapped signals are assigned by asterisks (*). Elemen-
tal analyses were performed on a PerkineElmer PE 2400
Analyzer. High- and low-resolution mass spectra (m/z) were
recorded on a Finnigan MAT 95 spectrometer (FAB, glycerol
matrix or CI, isobutane). IR spectra were measured on a
Scheme 6. Reagents and condition: (a) t-BuOK (1.2 equiv), THF, ꢀ10 ꢁC,
10 min; (b) (CH2O)n (8 equiv), ꢀ10 ꢁC, 5 h; (c) satd aq NH4Cl at ꢀ10 ꢁC to rt.
Table 3
Aza-MoritaeBayliseHillman-type adducts 19aef prepared
Entry
Product
R
Yielda (%)
1
2
3
4
5
6
a
19a
19b
19c
19d
19e
19f
Me
73
87
89
89
78
73
Et
i-Pr
c-Hex
Ph
1-Naphthyl
Yields of pure, isolated products.
Specord M80 (Zeiss) instrument and are reported in cmꢀ1
.

A. Gajda, T. Gajda / Tetrahedron 64 (2008) 1233e1241
1237
Melting points were determined in open capillaries and are
4.2.3. Diethyl [2-tert-butoxycarbonylamino-1-
uncorrected. All reagents were purchased from Fluka and
were used without further purification. Tetraethyl methylene-
bisphosphonate,22 diethyl (E)-styrylphosphonate,11 diethyl
N-Boc phosphoramidate,12 and N-Boc a-amidoalkyl-p-tolyl-
sulfones23,24 were prepared as described previously.
(diethoxyphosphoryl)-3-methyl-butyl]phosphonate (11c)
Yield: 254 mg (92%); colorless oil; [Found: C, 47.20; H,
8.70; N, 3.09. C18H39NO8P2 requires: C, 47.05; H, 8.56; N,
3.05%]; nmax (film) 3384, 2976, 1720, 1612, 1508, 1392, 1368,
1292, 1280, 1252, 1172, 1096, 1088, 1032, 992, 968 cmꢀ1; dH
(250 MHz, CDCl3) 5.99 (d, 1H, J 10.3 Hz, NH), 4.30e4.09
(m, 8H*, 4ꢂCH2O), 4.09e3.87 (m, 1H*, CHN), 2.74 (dt, 1H,
JHP 26.4 Hz, J 2.4 Hz, CHP), 2.07e1.92 (m, 1H, CH(CH3)2),
1.43 (s, 9H*, 3ꢂCH3), 1.44e1.31 (m, 12H*, 4ꢂCH3), 0.95 (d,
6H, J 7.5 Hz, 2ꢂCH3); dC (63 MHz, CDCl3) 155.0, 78.3, 63.3
4.2. Preparation of substituted tetraethyl N-Boc
2-aminoethylidene-1,1-bisphosphonates 11; general
procedure
2
2
2
A solution of tetraethyl methylenebisphosphonate (7,
173 mg, 0.6 mmol) in anhydrous THF (1 mL) was added with
stirring to a suspension of NaH (29 mg, 1.2 mmol) in anhydrous
THF (1 mL) at rt. The resulting mixture was stirred at rt for
10 min, cooled to ꢀ20 ꢁC, and a solution of a-amidosulfones
(8, 0.6 mmol) in THF (10 mL) was then added dropwise over
30 min. The reaction mixture was stirred at ꢀ20 ꢁC for 1 h
and at ꢀ10 ꢁC for 2 h. The mixture was quenched with satd aq
NH4Cl (10 mL). CH2Cl2 (30 mL) was added, the organic layer
was separated, and the aqueous phase was extracted with
CH2Cl2 (15 mL). The combined organic phases were washed
with water (2ꢂ10 mL), dried over MgSO4, and evaporated to
give spectroscopically pure 11aej (Table 1). All impurities
were water soluble and remained in the aqueous phase.
(d, JCP 6.8 Hz), 62.3 (d, JCP 7.1 Hz), 62.1 (d, JCP 6.79 Hz),
2
2
1
61.7 (d, JCP 7.0 Hz), 54.2 (t, JCP 5.7 Hz), 39.4 (t, JCP
3
132.4 Hz), 33.4 (dd, JCP 1.5, 11.7 Hz), 28.2, 20.0, 19.1, 16.1
3
3
(d, JCP 6.3 Hz), 16.0 (d, JCP 6.9 Hz); dP (101 MHz, CDCl3)
22.8, 22.0 (23.0, 22.4, rotamers) (1:1:0.15:0.15); m/z (CI, isobu-
tane) 460.3 (100, MHþ), 360.2 (80%).
4.2.4. Diethyl [2-tert-butoxycarbonylamino-1-
(diethoxyphosphoryl)hexyl]phosphonate (11d)
Yield: 264 mg(93%); colorlessoil;[Found: C, 48.36;H, 8.64;
N, 3.11. C19H41NO8P2 requires: C, 48.20; H, 8.73; N, 2.96%];
nmax (film) 3384, 2976, 2872, 1712, 1504, 1392, 1368, 1252,
1168, 1096, 1088, 1032, 992, 968 cmꢀ1; dH (250 MHz,
CDCl3) 5.72 (d, 1H, J 10.0 Hz, NH), 4.23e4.13 (m, 9H,
4ꢂCH2O, CHN), 2.73 (dt, 1H, JHP 26.4 Hz, J 2.4 Hz, CHP),
1.85e1.43 (m, 6H, 3ꢂCH2), 1.42 (s, H, 3ꢂCH3), 1.35 (t, 12H,
J 7.05 Hz, 4ꢂCH3), 0.90 (distorted t, 3H, J 6.5 Hz, CH3); dC
4.2.1. Diethyl [2-tert-butoxycarbonylamino-1-
(diethoxyphosphoryl)propyl]phosphonate (11a)
2
Yield: 238 mg (92%); colorless oil; [Found: C, 44.46; H,
8.29; N, 3.40. C16H35NO8P2 requires: C, 44.55; H, 8.18; N,
3.25%]; nmax (film) 3384, 2984, 1712, 1504, 1392, 1368,
1252, 1168, 1024, 968 cmꢀ1; dH (250 MHz, CDCl3) 5.78 (d,
1H, J 9.7 Hz, NH), 4.44e4.38 (m, 1H, CHN), 4.30e4.12
(m, 8H, 4ꢂCH2O), 2.74 (dt, 1H, JHP 26.4 Hz, J 2.4 Hz,
CHP), 1.45 (d, 3H*, J 7.4 Hz, CH3), 1.43 (s, 9H*, 3ꢂCH3),
1.35 (t, 12H, J 7.0 Hz, 4ꢂCH3); dC (63 MHz, CDCl3) 154.3,
(63 MHz, CDCl3) 155.0, 78.6, 62.9 (d, JCP 6.6 Hz), 62.3 (d,
2JCP 6.3 Hz), 62.2 (d, 2JCP 6.1 Hz), 62.0 (d, 2JCP 7.0 Hz), 48.6,
1
3
41.8 (dd, JCP 129.8, 131.5 Hz), 33.9 (d, JCP 7.5 Hz), 28.6,
3
28.1, 22.0, 16.1 (d, JCP 6.1 Hz), 13.8; dP (101 MHz, CDCl3):
22.1, 21.1; m/z (CI, isobutane) 474.3 (100, MHþ), 374.2 (50%).
4.2.5. Diethyl [2-tert-butoxycarbonylamino-2-cyclohexyl-1-
(diethoxyphosphoryl)ethyl]phosphonate (11e)
2
2
79.0, 62.8 (d, JCP 6.6 Hz), 62.4 (d, JCP 6.4 Hz), 62.2 (d,
Yield: 279 mg (93%); colorless oil; [Found: C, 50.59; H,
8.80; N, 2.94. C21H43NO8P2 requires: C, 50.49; H, 8.68; N,
2.80%]; nmax (film) 3384, 2976, 2960, 2928, 2856, 1720,
1508, 1448, 1392, 1368, 1288, 1252, 1172, 1024, 992,
964 cmꢀ1; dH (250 MHz, CDCl3) 5.97 (d, 1H, J 10.5 Hz,
NH), 4.27e3.95 (m, 9H, 4ꢂCH2O, CHN), 2.83 (dt, 1H, JHP
25.4 Hz, J 2.2 Hz, CHP), 1.91e1.58 (m, 9H, 4ꢂCH2, CH),
1.82 (s, 9H*, 3ꢂCH3), 1.48e1.31 (m, 12H, 4ꢂCH3), 1.25e
1.09 (m, 2H, CH2); dC (63 MHz, CDCl3) 154.6, 77.8, 62.9
2JCP 6.7 Hz), 62.2 (d, JCP 6.9 Hz), 44.1, 42.1 (t, JCP
130.3 Hz), 27.9, 19.3 (d, JCP 6.6 Hz), 15.9 (d, JCP 6.2 Hz);
dP (101 MHz, CDCl3) 22.2, 21.6; m/z (CI, isobutane) 432.2
(100, MHþ), 332 (90%).
2
1
3
3
4.2.2. Diethyl [2-tert-butoxycarbonylamino-1-
(diethoxyphosphoryl)butyl]phosphonate (11b)
Yield: 240 mg (90%); colorless oil; [Found: C, 45.65; H,
8.46; N, 3.18. C17H37NO8P2 requires: C, 45.84; H, 8.37; N,
3.14%]; nmax (film) 3400, 2976, 2936, 1716, 1504, 1456,
2
2
2
(d, JCP 6.8 Hz), 62.0 (d, JCP 6.9 Hz), 61.8 (d, JCP 6.9 Hz),
2
3
61.2 (d, JCP 6.9 Hz), 52.6, 41.8 (d, JCP 11.5 Hz), 38.2 (t,
1JCP 132.6 Hz), 30.0, 28.5, 27.8, 25.4, 25.3, 15.7 (d, JCP
1393, 1368, 1252, 1168, 1028, 996, 972 cmꢀ1
;
dH
3
(250 MHz, CDCl3) 5.74 (d, 1H, J 10.0 Hz, NH), 4.25e4.10
(m, 9H, 4ꢂCH2, CHN), 2.73 (dt, 1H, JHP 25.1 Hz, J 2.4 Hz,
CHP), 1.92e1.68 (m, 2H, CH2), 1.42 (s, 9H, 3ꢂCH3), 1.35
(t, 12H, J 7.0 Hz, 4ꢂCH3), 0.94 (t, 3H, J 7.5 Hz, CH3); dC
6.1 Hz); dP (101 MHz, CDCl3) 22.9, 22.3 (22.5, 23.2,
rotamers) (1:1:0.15:0.15); m/z (CI, isobutane) 500.2 (100,
MHþ), 400.1 (40%).
2
(63 MHz, CDCl3) 155.0, 78.5, 62.9 (d, JCP 6.9 Hz), 62.8 (d,
4.2.6. Diethyl [2-tert-butoxycarbonylamino-1-(diethoxy-
phosphoryl)-2-furan-2-yl-ethyl]phosphonate (11f)
Yield: 238 mg (82%); pale yellow solid; mp 42e45 ꢁC;
[Found: C, 47.09; H, 7.46; N, 3.05. C19H35NO9P2 requires:
C, 47.21; H, 7.30; N, 2.90%]; nmax (film) 3368, 2984, 2928,
2
2
2JCP 6.8 Hz), 62.2 (d, JCP 6.4 Hz), 62.2 (d, JCP 6.5 Hz),
1
50.2, 41.4 (t, JCP 130.1 Hz), 28.0, 27.3 (d, JCP 8.2 Hz,),
16.0 (d, JCP 6.2 Hz), 10.9; dP (101 MHz, CDCl3) 22.3,
3
3
21.4; m/z (CI, isobutane), 446.3 (100, MHþ), 346.2 (20%).

1238
A. Gajda, T. Gajda / Tetrahedron 64 (2008) 1233e1241
1720, 1508, 1392, 1368, 1252, 1168, 1096, 1088, 1024, 992,
972 cmꢀ1; dH (250 MHz, CDCl3) 7.32 (s, 1Harom), 6.65 (d,
1H, J 9.7 Hz, NH), 6.28e6.25 (m, 2Harom), 5.58 (ddt, 1H,
JHP 32.4 Hz, J 9.7, 2.8 Hz, CHN), 4.27e4.11 (m, 6H,
3ꢂCH2O), 3.89e3.77 (m, 2H, CH2O), 3.16 (dt, JHP 24.5 Hz,
J 2.6 Hz, CHP), 1.45 (s, 9H, 3ꢂCH3), 1.39e1.28 (m, 9H,
3ꢂCH3), 1.11 (t, 3H, J 7.5 Hz, CH3); dC (63 MHz, CDCl3)
C, 48.58; H, 7.34; N, 5.67%]; nmax (film) 3984, 3432, 2984,
2952, 2896, 1712, 1500, 1468, 1432, 1392, 1368, 1328,
1248, 1208, 1160, 1124, 1104, 1088, 1024, 996, 976 cmꢀ1
dH (250 MHz, CDCl3) 8.62 (s, 1Harom.), 8.49 (d, 1Harom
;
,
J 4.3 Hz), 7.73 (d, 1Harom, J 7.0 Hz), 7.25 (dd, 1Harom, J
7.0, 4.3 Hz), 6.87 (d, J 9.3 Hz, NH), 5.71e5.56 (m, 1H,
CHN), 4.29e4.08 (m, 6H, 3ꢂCH2O), 3.83e3.55 (m, 2H,
CH2O), 2.90 (dt, 1H, JHP 24.5 Hz, J 2.6 Hz, CHP), 1.43 (s,
9H, 3ꢂCH3), 1.36 (t, 6H, J 7.0 Hz, 2ꢂCH3), 1.28 (t, 3H, J
7.0 Hz, CH3), 0.95 (t, 3H, J 7.0 Hz, CH3); dC (63 MHz,
3
154.6, 153.1 (d, JCP 13.8 Hz), 141.4, 110.2, 106.1, 79.2,
2
2
2
63.4 (d, JCP 6.8 Hz), 62.7 (d, JCP 6.8 Hz), 62.5 (d, JCP
2
1
6.8 Hz), 61.7 (d, JCP 6.8 Hz), 46.8, 40.7 (t, JCP 131.8 Hz),
3
3
3
28.1, 16.2, 16.1 (2ꢂd, JCP 6.1 Hz), 15.8 (d, JCP 6.7 Hz); dP
(101 MHz, CDCl3) 21.0, 20.2; m/z (CI, isobutane) 484.3
(100, MHþ), 384.2 (60%).
CDCl3) 154.0, 135.7 (d, JCP 12.6 Hz), 147.8, 133.5, 122.3,
2
2
78.8, 63.2 (d, JCP 6.7 Hz), 62.3 (d, JCP 6.6 Hz), 62.1 (d,
2JCP 6.4 Hz), 61.0 (d, JCP 6.9 Hz), 49.3, 42.9 (t, JCP
130.9 Hz), 27.7, 15.7 (d*, JCP 6.1 Hz), 15.7 (d*, JCP
6.2 Hz), 15.6 (d*, JCP 6.1 Hz), 15.0 (d, JCP 6.9 Hz); dP
(101 MHz, CDCl3) 21.0, 20.6; m/z (CI, isobutane) 495.4
(100, MHþ), 439.3 (35), 395.3 (40%).
2
1
3
3
3
3
4.2.7. Diethyl [2-tert-butoxycarbonylamino-1-(diethoxy-
phosphoryl)-2-phenyl-ethyl]phosphonate (11g)
Yield: 290 mg (98%); white solid; mp 79e83 ꢁC; [Found:
C, 51.18; H, 7.71; N, 2.92. C21H37NO8P2 requires: C, 51.11;
H, 7.56; N, 2.84%]; nmax (film) 3432, 2984, 2936, 1716,
4.2.10. Diethyl [2-tert-butoxycarbonylamino-1-(diethoxy-
phosphoryl)-2-naphthalen-1-yl-ethyl]phosphonate (11j)
1500, 1392, 1368, 1256, 1168, 1096, 1032, 996, 972 cmꢀ1
;
dH (250 MHz, CDCl3) 7.40e7.18 (m, 5Harom), 6.86 (d, 1H, J
9.3 Hz, NH), 5.68e5.30 (m, 1H, CHN), 4.3e4.01 (m, 6H,
3ꢂCH2O), 3.77e3.40 (m, 2H, CH2O), 2.95 (dt, JHP 24.5 Hz,
J 3.0 Hz, CHP), 1.43 (s, 9H, 3ꢂCH3), 1.38 (t, 3H*, J
7.1 Hz, CH3), 1.36 (t, 3H*, J 7.2 Hz, CH3), 1.27, 0.90 (2ꢂt,
6H, J 7.05 Hz, 2ꢂCH3); dC (63 MHz, CDCl3) 154.5, 140.5
Yield: 300 mg (92%); white solid; mp 69e73 ꢁC; [Found:
C, 55.51; H, 7.05; N, 2.77. C25H39NO8P2 requires: C, 55.24;
H, 7.23; N, 2.58%]; nmax (film) 3368, 2984, 1720, 1508,
1392, 1368, 1256, 1172, 1024, 972 cmꢀ1; dH (250 MHz,
CDCl3) 8.03e7.30 (m, 7Harom), 7.20 (d, 1H, J 9.0 Hz, NH),
6.49e6.31 (m, 1H, CHN), 4.40e4.03 (m, 6H, 3ꢂCH2O),
3.44e3.41 (m, 2H, CH2O), 3.21 (dt, JHP 24.7 Hz, J 2.6 Hz,
CHP), 1.54e1.41 (m, 15H, 5ꢂCH3), 1.25 (t, 3H, J 7.1 Hz,
CH3), 0.66 (t, 3H, J 7.1 Hz, CH3); dC (63 MHz, CDCl3)
3
2
(d, JCP 13.6 Hz), 127.9, 126.8, 126.0, 78.8, 63.2 (d, JCP
2
2
6.8 Hz), 62.7 (d, JCP 6.6 Hz), 62.3 (d, JCP 6.4 Hz), 61.3 (d,
2JCP 6.9 Hz), 51.2, 43.7 (t, JCP 130.5 Hz), 28.0, 16.1 (d,
3JCP 7.4 Hz), 16.1 (d, JCP 6.1 Hz), 16.0 (d, JCP 6.1 Hz),
15.4 (d, JCP 7.0 Hz); dP (101 MHz, CDCl3) 21.3, 20.9; m/z
(CI, isobutane) 494.3 (90, MHþ), 394.2 (100%).
1
3
3
3
153.0, 134.5 (d, JCP 15.5 Hz), 132.0, 127.3, 127.1, 126.2,
3
2
124.7, 123.6, 123.3, 122.2, 120.3, 77.4, 61.9 (d, JCP
2
2
7.2 Hz), 61.4 (d, JCP 6.9 Hz), 60.9 (d, JCP 5.8 Hz), 59.6 (d,
2JCP 6.8 Hz), 47.0, 40.1 (t, JCP 130.8 Hz), 26.6, 14.5 (d,
1
3
3
4.2.8. Diethyl [2-tert-butoxycarbonylamino-1-(diethoxy-
phosphoryl)-2-pyridin-2-yl-ethyl]phosphonate (11h)
3JCP 5.6 Hz), 14.4 (d, JCP 6.4 Hz), 13.6 (d, JCP 7.3 Hz); dP
(101 MHz, CDCl3) 21.5, 21.4; m/z (CI, isobutane) 544
(100%, MHþ).
Yield: 258 mg (87%); pale yellow oil; [Found: C, 48.49; H,
7.50; N, 5.85. C20H36N2O8P2 requires: C, 48.58; H, 7.34; N,
5.67%]; nmax (film) 3888, 3368, 2984, 2952, 2936, 1720,
1592, 1504, 1456, 1440, 1392, 1256, 1164, 1040, 996,
976 cmꢀ1; dH (250 MHz, CDCl3) 8.53e8.51 (m, 1Harom),
7.69e7.62 (m, 1Harom), 7.43 (d, 1Harom, J 7.9 Hz), 7.16e7.10
(m, 1Harom), 6.75 (d, 1H, J 9.2 Hz, NH), 5.71e5.48 (m, 1H,
CHN), 4.30e4.07 (m, 6H, 3ꢂCH2O), 3.84 (dt, 1H*, JHP
24.4 Hz, J 2.7 Hz, CHP), 3.77e3.59 (m, 2H*, CH2O), 1.46 (s,
9H, 3ꢂCH3), 1.37 (t, 6H, J 7.1 Hz, 2ꢂCH3), 1.26 (t, 3H, J
7.1 Hz, CH3), 0.93 (t, 3H, J 7.0 Hz, CH3); dC (63 MHz,
4.3. Preparation of aminobisphosphonate hydrochlorides
17a,b; general procedure
A mixture of 11 (0.3 mmol) and 3.5 M HCl in anhydrous
EtOH (4.5 mL) was stirred for 1 h at rt. Evaporation of the
solvent gave spectroscopically pure aminobisphosphonate
hydrochlorides 17 in quantitative yields.
4.3.1. Diethyl [2-amino-1-(diethoxyphosphoryl)hexyl]-
phosphonate hydrochloride (17a)
3
CDCl3) 159.6 (d, JCP 13.6 Hz), 156.1, 148.3, 136.2, 121.5,
2
2
119.7, 79.0, 63.2 (d, JCP 6.7 Hz), 62.6 (d, JCP 6.6 Hz), 62.3
Yield: 123 mg (100%); white solid; mp 120e121 ꢁC;
[Found: C, 41.09; H, 8.52; N, 3.51. C14H34ClNO6P2 requires
(409.82): C, 41.03; H, 8.36; N, 3.42%]; nmax (KBr) 3448,
2984, 2872, 1252, 1028, 996, 972 cmꢀ1; dH (250 MHz,
MeOD) 4.83 (s, NH3), 4.30e4.18 (m, 8H, 4ꢂCH2O), 3.90e
3.58 (m, 1H, CHN), 3.25 (dt, 1H, JHP 25.5 Hz, J 2.9 Hz,
CHP), 2.21e1.37 (m, 6H*, 3ꢂCH2), 1.38 (t, 6H*, J 7.0 Hz,
2ꢂCH3), 1.37 (t, 6H*, J 7.0 Hz, 2ꢂCH3), 0.97 (t, 3H, J
6.9 Hz, CH3); dC (63 MHz, MeOD) 63.4 (d, 2JCP 6.0 Hz), 63.3
(d, 2JCP 7.0 Hz), 48.0 (d, 2JCP 5.7 Hz), 36.8 (t, 1JCP 133.1 Hz),
2
2
1
(d, JCP 6.5 Hz), 61.3 (d, JCP 7.0 Hz), 52.9, 40.2 (t, JCP
3
130.5 Hz), 28.0, 16.0 (d, JCP 6.5 Hz), 15.8 (d, JCP 6.5 Hz),
3
3
15.4 (d, JCP 6.7 Hz); dP (101 MHz, CDCl3) 22.2, 21.6 (2ꢂd,
J
PP 5.1 Hz); m/z (CI, isobutane) 495.4 (100%, MHþ).
4.2.9. Diethyl [2-tert-butoxycarbonylamino-1-(diethoxy-
phosphoryl)-2-pyridin-3-yl-ethyl]phosphonate (11i)
Yield: 262 mg (88%); white solid; mp 117e120 ꢁC;
[Found: C, 48.40; H, 7.49; N, 5.74. C20H36N2O8P2 requires:

A. Gajda, T. Gajda / Tetrahedron 64 (2008) 1233e1241
1239
29.0 (d, 3JCP 5.6 Hz), 25.6, 19.6, 13.8 (d, 3JCP 5.7 Hz), 11.1; dP
(101 MHz, MeOD) 21.5, 20.1 (2ꢂd, JPP 4.0 Hz); m/z (CI,
isobutane) 374.2 (18, MHþꢀHCl), 357.1 (100%).
D2O) 16.0, 15.3; m/z (FAB) 280.1 (100%, MꢀHþꢀHCl);
HRMS (negative ions, glycerol): [MꢀH]ꢀ, found 280.0134.
C8H12NO6P2 requires 280.0140.
4.3.2. Diethyl [2-amino-1-(diethoxyphosphoryl)-2-phenyl-
ethyl]phosphonate hydrochloride (17b)
4.4.3. (2-Amino-2-naphthalen-1-yl-1-phosphono-ethyl)-
phosphonic acid hydrochloride (18c)
Yield: 129 mg (100%); white solid; mp 128e129 ꢁC;
[Found: C, 44.62; H, 7.15; N, 3.34. C16H30ClNO6P2 requires:
C, 44.71; H, 7.04; N, 3.26%]; nmax (KBr) 3448, 3088,
3064, 2984, 1584, 1528, 1480, 1440, 1388, 1236, 1160,
1124, 1024 cmꢀ1; dH (250 MHz, MeOD) 7.65e7.42 (m,
5Harom), 4.96e4.83 (m, 1H, CHN), 4.83 (s, NH3), 4.35e3.84
(m, 8H, 4ꢂCH2O), 3.25 (dt, 1H, JHP 23.9 Hz, J 7.4 Hz,
CHP), 1.36, 1.31, 1.25, 1.20 (4ꢂt, 12H, J 7.1 Hz, 4ꢂCH3);
Yield: 78 mg (52%); white solid; mp 207 ꢁC (dec); [Found:
C, 38.51; H, 4.30; N, 4.81. C12H16ClNO6P2ꢂ0.5H2O requires:
C, 38.26; H, 4.55; N, 3.72%]; nmax (KBr) 3401, 2940, 2360,
1170, 1060, 1012, 950 cmꢀ1; dH (250 MHz, D2O) 8.02e7.50
(m, 7Harom), 5.89e5.74 (m, 1H, CHN), 4.75 (NH3), 3.03e
2.91 (m, 1H, CHP), dC (63 MHz, D2O) 133.6, 131.0, 129.5,
129.3, 129.1, 127.4, 126.4, 125.2, 123.8, 122.0, 49.0, 44.2 (br
1
t, JCP 120.4 Hz); dP (101 MHz, D2O) 16.3, 14.4; m/z (FAB)
3
dC (63 MHz, MeOD) 131.4 (dd, JCP 4.1, 8.7 Hz), 128.3,
330.1 (100%, MꢀHþꢀHCl); HRMS (negative ions, glycerol):
[MꢀH]ꢀ, found 330.0287. C12H14NO6P2 requires 330.0296.
2
2
127.2, 126.2, 63.4 (d, JCP 7.0 Hz), 63.3 (d, JCP 6.9 Hz),
2
1
63.0 (d, JCP 7.0 Hz), 50.8, 38.5 (dd, JCP 132.7, 129.5 Hz),
3
13.7 (d, JCP 6.0 Hz); dP (101 MHz, MeOD) 20.8, 19.5
(2ꢂd, JPP 9.1 Hz); m/z (CI, isobutane) 394 (20, MHþꢀHCl),
4.4.4. (2-Amino-1-phosphono-2-pyridin-3-yl-ethyl)-
phosphonic acid dihydrobromide (18d)
377 (100%).
Bromotrimethylsilane (0.65 mL, 0.765 g, 5 mmol) was
added at rt to a solution of 11i (247 mg, 0.5 mmol) in dry
CH2Cl2 (2 mL). The mixture was stirred at rt for 24 h. Then
the second portion of bromotrimethylsilane (0.65 mL, 0.765 g,
5 mmol) was added to the mixture and the reagents were stirred
at rt for additional 24 h. Dichloromethane and the excess of
bromotrimethylsilane were evaporated under reduced pressure.
Anhydrous methanol (4 mL) was added to the residue and the
solution was left for 2 h at rt. The solvent was evaporated under
reduced pressure, the residue was redissolved in methanol
(2 mL) and left for 24 h. The precipitated solid was collected,
redissolved in distilled water (5 mL), and the solution was
lyophilized to give 87 mg (35%) of spectroscopically pure
acid 18d as a white solid; mp 241 ꢁC (dec); [Found: C, 17.02;
H, 4.30; N, 5.91. C7H14Br2N2O6P2ꢂ3H2O requires: C, 16.88;
H, 4.05; N, 5.63%]; nmax (KBr) 3426, 3066, 2963, 2906, 2896,
2361, 1160, 1050, 1015, 962 cmꢀ1; dH (250 MHz, D2O) 8.99
(s, 1Harom), 8.86e8.72 (m, 2Harom), 8.05 (dd, 1Harom, J 6.2,
7.42 Hz), 5.18e4.80 (m, 1H, CHN), 4.74 (NH3), 2.75 (distorted
4.4. Preparation of free aminobisphosphonic acids
18aed; general procedure
A mixture of bisphosphonate 11 (0.4 mmol) and 20% aq
HCl solution (3 mL) was heated at reflux for 10 h. Then the
solution was concentrated under reduced pressure and the res-
idue was co-evaporated with absolute ethanol to remove traces
of water and hydrochloric acid. Acetone (1 mL) was then
added to the residue and the mixture was left for 24 h at rt.
The precipitated solid was collected, redissolved in distilled
water (5 mL), and the solution was lyophilized to give crystal-
line, spectroscopically pure acids 18aec.
4.4.1. (2-Amino-1-phosphono-propyl)phosphonic acid
hydrochloride (18a)
Yield: 53 mg (50%); white solid, mp 240 ꢁC (dec); [Found:
C, 14.20; H, 4.85; N, 5.35. C3H12ClNO6P2ꢂ0.5H2O requires:
C, 14.10; H, 4.73; N, 5.48%]; nmax (KBr) 3220, 3134, 3048,
2360, 1640, 1400, 1195, 1061, 987, 965 cmꢀ1; dH (250 MHz,
D2O) 4.68 (NH3), 3.92e3.75 (m, 1H, CHN), 2.47 (dt, 1H,
1JHP 24.5 Hz, J 3.3 Hz, CHP), 1.45 (d, 3H, J 6.8 Hz, CH3);
1
t, 1H, JHP 20.4 Hz, CHP); dC (63 MHz, D2O) 146.5, 141.6,
1
141.2, 135.5, 127.3, 50.8, 45.4 (br t, JCP 120.9 Hz); dP
(101 MHz, D2O) 13.0 (br s); m/z (FAB) 281.1 (80%,
MꢀHþꢀ2HBr); HRMS (negative ions, glycerol): [MꢀH]ꢀ,
found 281.0103. C7H11N2O6P2 requires 281.0092.
1
dC (63 MHz, D2O) 46.2, 41.6 (t, JCP 120.4 Hz), 17.2; dP
(101 MHz, D2O) 16.7, 16.2; m/z (FAB) 217.9 (50%,
MꢀHþꢀHCl); HRMS (negative ions, glycerol): [MꢀH]ꢀ,
found 217.9991. C3H10NO6P2 requires 217.9983.
4.5. Preparation of aza-MoritaeBayliseHillman-type
adducts 19aef; general procedure
4.4.2. (2-Amino-2-phenyl-1-phosphono-ethyl)phosphonic
acid hydrochloride (18b)
A solution of bisphosphonate 11 (0.5 mmol) in anhydrous
THF (3 mL) was added dropwise to a solution of t-BuOK
(67 mg, 0.6 mmol) in THF (2 mL) at ꢀ10 ꢁC. The reaction
mixture was stirred for 10 min at ꢀ10 ꢁC and paraformalde-
hyde (120 mg, 4 mmol) was then added. Stirring was contin-
ued for 5 h at this temperature. The resultant mixture was
quenched with satd aq NH4Cl solution (ca. 5 mL) until neutral
pH was reached. The mixture was extracted with CH2Cl2
(2ꢂ30 mL), the combined organic extracts were washed
with water (2ꢂ10 mL), and dried over MgSO4. The solvent
Yield: 89 mg (68%); white solid; mp 210 ꢁC (dec); [Found:
C, 29.69; H, 4.90; N, 4.55. C8H14ClNO6P2ꢂ0.5H2O requires:
C, 29.42; H, 4.63; N, 4.29%]; nmax (KBr) 3633, 3383, 2922,
2887, 2359, 2341, 1252, 1234, 1173, 1159, 1130, 1061, 1010,
948 cmꢀ1; dH (250 MHz, D2O) 7.49e7.38 (m, 5Harom),
1
5.20e4.80 (m, 1H CHN), 4.75 (NH3), 2.86 (dt, 1H, JHP
22.0 Hz, J 3.3 Hz, CHP); dC (63 MHz, D2O) 135.1, 129.2,
1
128.8, 127.4, 53.3, 43.2 (br t, JCP 120.4 Hz); dP (101 MHz,

1240
A. Gajda, T. Gajda / Tetrahedron 64 (2008) 1233e1241
was evaporated under reduced pressure and the rest of the
volatile material was removed at 35e40 ꢁC/0.1 mmHg to
give spectroscopically pure 19aef (Table 3).
1448, 1392, 1368, 1252, 1168, 1024, 968 cmꢀ1
; dH
(250 MHz, CDCl3) 5.99 (d, 1Hvin, JHP(cis) 21.6 Hz), 5.86 (d,
1Hvin, JHP(trans) 45.9 Hz), 5.31 (br d, 1H, J 10.2 Hz, NH),
4.15e3.99 (m, 5H, 2ꢂCH2, CHN), 2.02 (m, 1H, CH), 1.42
(s, 9H*, 3ꢂCH3), 1.34, 1.33 (2ꢂt, 6H*, J 7.0 Hz, 2ꢂCH3),
1.85e0.91 (m, 11H*, 5ꢂCH2, CH); dC (63 MHz, CDCl3)
4.5.1. Diethyl (2-tert-butoxycarbonylamino-1-methylene-
propyl)phosphonate (19a)
1
2
Yield:112 mg (73%); colorlessoil; [Found: C, 50.65;H, 8.70;
N, 4.32. C13H26NO5P requires: C, 50.81; H, 8.53; N, 4.56%];
nmax (film) 3296, 2976, 2936, 1712, 1528, 1448, 1392, 1368,
1248, 1172, 1096, 1028, 968 cmꢀ1; dH (250 MHz, CDCl3)
6.01 (d, 1Hvin, JHP(cis) 19.8 Hz), 5.94 (d, 1Hvin, JHP(trans)
45.8 Hz), 5.13 (br d, 1H, J 8.1 Hz, NH), 4.68e4.42 (m, 1H,
CHN), 4.13e4.06 (m, 4H, 2ꢂCH2), 1.43 (t, 6H*, J 7.1 Hz,
2ꢂCH3), 1.37 (d, 3H*, J 7.0 Hz, CH3); dC (63 MHz, CDCl3)
154.4, 137.9 (d, JCP 169.2 Hz), 130.2 (d, JCP 8.1 Hz), 78.0,
2
2
2
61.1 (d, JCP 5.6 Hz), 60.9 (d, JCP 6.0 Hz), 59.4 (d, JCP
11.5 Hz), 39.3, 29.7, 28.0, 27.4, 25.3, 24.9, 15.3 (d, JCP
3
6.6 Hz); dP (101 MHz, CDCl3) 18.3; m/z (CI, isobutane) 376
(100%, MHþ).
4.5.5. Diethyl [1-(tert-butoxycarbonylamino-phenyl-
methyl)-vinyl]phosphonate (19e)
Yield: 144 mg (78%); colorless oil; [Found: C, 58.31; H,
7.85; N, 3.58. C18H28NO5P requires: C, 58.53; H, 7.64; N,
3.79%]; nmax (film) 3280, 2976, 1712, 1528, 1520, 1512,
1456, 1392, 1368, 1244, 1200, 1168, 1024, 972 cmꢀ1; dH
1
2
152.9, 140.1 (d, JCP 169.7 Hz), 127.6 (d, JCP 7.2 Hz), 77.5,
2
2
2
60.3 (d, JCP 8.0 Hz), 60.1 (d, JCP 6.0 Hz), 54.1 (d, JCP
3
12.0 Hz), 26.5, 19.5, 14.4 (d, JCP 6.5 Hz); dP (101 MHz,
CDCl3) 17.9; m/z (CI, isobutane) 308.1 (100%, MHþ).
(250 MHz, CDCl3) 7.34e7.25 (m, 5Harom), 6.17 (d, 1Hvin
J
,
HP(cis) 25.9 Hz), 6.01 (d, 1Hvin, JHP(trans) 49.7 Hz), 5.75
4.5.2. Diethyl (2-tert-butoxycarbonylamino-1-methylene-
butyl)phosphonate (19b)
(br s, 1H, NH), 5.57 (dd, 1H, JHP 17.1 Hz, J 8.1 Hz, CHN),
4.88e3.67 (m, 4H, 2ꢂCH2O), 1.44 (s, 9H, 3ꢂCH3), 1.26,
1.05 (2ꢂt, 6H, J 7.0 Hz, 2ꢂCH3); dC (63 MHz, CDCl3)
Yield: 140 mg (87%); colorless oil; [Found: C, 52.11; H
8.90; N 4.19. C14H28NO5P requires: C, 52.33; H, 8.78; N,
4.36%]; nmax (film) 3304, 2976, 2936, 1712, 1528, 1520,
1512, 1456, 1392, 1368, 1240, 1172, 1028, 968 cmꢀ1; dH
(250 MHz, CDCl3) 6.01 (d, 1Hvin, JHP(cis) 21.8 Hz), 5.90 (d,
1Hvin, JHP(trans) 45.8 Hz), 5.20 (br d, 1H, J 11.5 Hz, NH),
4.32e3.98 (m, 5H, 2ꢂCH2, CH), 1.81e1.59 (m, 2H, CH2),
1.43 (s, 9H*, 3ꢂCH3), 1.50e1.23 (m, 6H*, 2ꢂCH3), 0.91 (t,
3H, J 7.5 Hz, CH3); dC (63 MHz, CDCl3) 153.3, 138.0 (d,
1
3
154.5, 139.8 (d, JCP 171.3 Hz), 139.3 (d, JCP 2.5 Hz), 130.6
2
2
(d, JCP 8.3 Hz), 128.2, 127.3, 126.8, 79.4, 61.8 (d, JCP
2
5.6 Hz), 61.6 (d, JCP 5.8 Hz), 57.0 (d, JCP 13.3 Hz), 28.1,
2
3
3
15.9 (d, JCP 6.7 Hz), 15.7 (d, JCP 6.7 Hz); dP (101 MHz,
CDCl3) 17.1; m/z (CI, isobutane) 370 (100%, MHþ).
4.5.6. Diethyl [1-(tert-butoxycarbonylamino-naphthalen-1-
yl-methyl)-vinyl]phosphonate (19f)
2
2
1JCP 168.7 Hz), 128.5 (d, JCP 7.2 Hz), 77.1, 60.2 (d, JCP
2
2
5.7 Hz), 60.0 (d, JCP 6.0 Hz), 54.1 (d, JCP 12.0 Hz), 26.4,
Yield: 153 mg (73%); yellow oil; [Found: C, 62.81; H, 7.32;
N, 3.53. C22H30NO5P requires: C, 63.00; H, 7.21; N, 3.34%];
nmax (film) 3288, 2984, 2928, 1708, 1512, 1464, 1456, 1392,
1380, 1368, 1292, 1280, 1244, 1208, 1168, 1024, 992,
968 cmꢀ1; dH (250 MHz, CDCl3) 8.17e7.30 (m, 7Harom),
6.38 (m, 1H, CHN), 6.31 (d, 1Hvin, JHP(cis) 21.7 Hz), 6.00
(d, 1Hvin, JHP(trans) 45.7 Hz), 5.44 (br s, 1H, NH), 4.39e
3.85 (m, 4H, 2ꢂCH2O), 1.44 (s, 9H, 3ꢂCH3), 1.33 (t, 3H, J
7.1 Hz, CH3), 1.00 (t, 3H, J 6.8 Hz, CH3); dC (63 MHz,
3
25.8, 14.4 (d, JCP 6.5 Hz), 8.7; dP (101 MHz, CDCl3) 18.2;
m/z (CI, isobutane) 322 (100%, MHþ).
4.5.3. Diethyl (2-tert-butoxycarbonylamino-3-methyl-1-
methylene-butyl)phosphonate (19c)
Yield: 149 mg (89%); colorless oil; [Found: C, 53.88; H,
9.25; N, 4.38. C15H30NO5P requires: C, 53.72; H, 9.02; N,
4.18%]; nmax (film) 3294, 2976, 1712, 1512, 1456, 1392,
1368, 1248, 1172, 1028, 992, 968 cmꢀ1; dH (250 MHz,
1
3
CDCl3) 154.4, 139.8 (d, JCP 173.9 Hz), 135.1 (d, JCP
2
3.8 Hz), 133.7, 131.3 (d, JCP 8.3 Hz), 130.7, 128.6, 128.4,
CDCl3) 6.00 (d, 1Hvin, JHP(cis) 20.6 Hz), 5.88 (d, 1Hvin
,
HP(trans) 44.6 Hz), 5.27 (br d, 1H, J 9.5 Hz, NH), 4.16e
2
J
126.2, 125.5, 125.4, 124.9, 124.7, 123.2, 79.6, 62.0 (d, JCP
2
5.8 Hz), 61.8 (d, JCP 6.1 Hz), 52.6 (d, JCP 13.3 Hz), 28.2,
2
4.01 (m, 5H, 2ꢂCH2, CHN), 2.02 (m, 1H, CH), 1.43 (s, 9H,
3ꢂCH3), 1.34, 1.33 (2ꢂt, 6H, J 7.1 Hz, 2ꢂCH3), 0.94 (d,
3H, J 6.7 Hz, CH3), 0.90 (d, 3H, J 6.7 Hz, CH3); dC
3
3
16.1 (d, JCP 6.5 Hz), 15.7 (d, JCP 6.8 Hz); dP (101 MHz,
CDCl3) 17.5; m/z (CI, isobutane) 420 (100%, MHþ).
1
(63 MHz, CDCl3) 153.5, 137.6 (d, JCP 168.0 Hz), 130.0 (d,
2
2
2JCP 8.2 Hz), 77.1, 60.2 (d, JCP 5.5 Hz), 60.0 (d, JCP
Acknowledgements
2
6.1 Hz), 59.2 (d, JCP 12.1 Hz), 29.2, 26.5, 18.3, 16.6, 14.3
3
(d, JCP 6.2 Hz); dP (101 MHz, CDCl3) 17.9; m/z (CI, isobu-
Financial support by a grant 1T 09A 054 30 (2006e2009)
from the Ministry of Education and Science is gratefully
acknowledged.
tane) 336 (100%, MHþ).
4.5.4. Diethyl [1-(tert-butoxycarbonylamino-cyclohexyl-
methyl)-vinyl]phosphonate (19d)
References and notes
Yield: 167 mg (89%); colorless oil; [Found: C, 57.40; H,
9.36; N, 3.49. C18H34NO5P requires: C, 57.58; H, 9.13; N,
3.73%]; nmax (film) 3288, 2976, 2960, 2928, 1712, 1504,
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A. Gajda, T. Gajda / Tetrahedron 64 (2008) 1233e1241
1241
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feger, C.; Kotsikorou, E.; Meints, G. A.; Gomez, A. O.; Gonzalez-
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`
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