Utilization of aminophosphonates in the petasis boronic acid mannich reaction

Article abstract of DOI:10.1055/s-0029-1218386

Aminophosphonates were used as amine components in the Petasis boronic acid Mannich reaction. With the use of α-aminophosphonates, several N-phosphonomethylglycine derivatives were prepared in modest to good yields and high diastereoselectivities. The met

Full text of DOI:10.1055/s-0029-1218386

LETTER
73
Utilization of Aminophosphonates in the Petasis Boronic Acid Mannich
Reaction
P
etasis Boronic Acid M
i
annic
c
h Reaction hael V. Shevchuk,a,b Alexander E. Sorochinsky,a Volodymyr P. Khilya,b Vadim D. Romanenko,a
Valery P. Kukhar*a
a
Department of Fine Organic Synthesis, Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
Murmanska 1, Kyiv-94, 02660, Ukraine
Fax +38(44)5732552; E-mail: kukhar@bpci.kiev.ua
Department of Organic Chemistry, Faculty of Chemistry, Taras Shevchenko National University of Kyiv,
Volodymyrska 62A, Kyiv-33, 01033, Ukraine
b
Received 28 September 2009
R2
X
R3
R1
R3
R2
Abstract: Aminophosphonates were used as amine components in
the Petasis boronic acid Mannich reaction. With the use of a-ami-
nophosphonates, several N-phosphonomethylglycine derivatives
were prepared in modest to good yields and high diastereoselectiv-
ities. The method affords the possibility of variation for the substit-
uents in the position a to the phosphorus and nitrogen atoms. By
using the same methodology, highly functionalized amino acids
were prepared starting from (R)-b-amino-a,a-difluoromethylphos-
phonate.
O
N
N
H
R1B(OH)2
+
+
– B(OH)3
X
H
CH2OH, COOH,
X =
OH
Scheme 1 Typical examples of the Petasis one-pot, three-compo-
nent coupling
Key words: boronic acids, aminophosphonates, multicomponent
reaction, amino acids, stereoselective synthesis
trolled synthesis of the angiotensin converting enzyme
(ACE) inhibitor enalapril.6
Multicomponent reactions (MCR), in which at least three
chemical entities are brought together to produce a poly-
functional compound, play an increasingly significant
role in the development of modern synthetic organic and
bioorganic chemistry.1 Among these, the Petasis three-
component boronic acid Mannich reaction has been the
focus of attention in the last decade because of some fea-
tures of the organoboron compounds such as (i) compati-
bility with many functional groups allowing the facile
synthesis of multifunctional molecules without the exces-
sive use of protective groups, (ii) availability of reagents
in a large variety of structural configurations, (iii) possi-
bility of using water and alcohols as the reaction medium,
and (iv) low toxicity and environmental friendliness.2 In
most of the described cases, the Petasis reaction includes
the interaction of an organoboronic acid, an amine, and
certain carbonyl compounds, such as a-hydroxy alde-
hydes, a-keto acids, and salicylaldehydes, leading to a-
amino acids, b-amino alcohols, and aminophenol deriva-
tives, correspondingly (Scheme 1).3 It is believed that the
reaction proceeds through condensation of an amine and
an aldehyde to give a transient iminium species followed
by intramolecular transfer of the organyl ligand from the
activated ‘ate’ complex of organoboronic acid.4 Several
biologically important imino biscarboxylic acid deriva-
tives have been obtained via the one-step reaction among
Aminophosphonic acids are a class of amino acid isoster-
es in which the carboxylic acid group has been replaced
by a phosphonic group.7 Phosphonate derivatives are able
to mimic the tetrahedral transition states of enzyme-medi-
ated peptide-bond hydrolysis. Such structural feature
causes a unique enzyme response which led to the discov-
ery of herbicides, antifungal, antibacterial, and antihyper-
tensive agents, inhibitors of proteases, including HIV-
protease, and haptens of catalytic antibodies.7,8 Different
synthetic routes to aminophosphonic acid derivatives
have been reported in the literature.9 The most frequently
used are nucleophilic addition of a dialkyl phosphite to an
imine (Pudovik reaction) or condensation of an aldehyde,
an amine, and a dialkyl phosphite (Kabachnik–Fields
reaction), but for the preparation of functionalized N-
phosphonomethylglycines the use of catalysts, protective
groups, and multistep processes are necessary. To the best
of our knowledge, aminophosphonic acid derivatives
have not been studied as substrates for the Petasis boronic
acid reaction. Herein, we report an easy and efficient
method for the synthesis of compounds of the general for-
mula 2, 4, and 7 based on the reaction of aminophospho-
nates with glyoxylic acid in the presence of organoboronic
acids.
The coupling of diethyl 1-amino-(4-methoxyphenyl)-
methylphosphonate (1a) with glyoxylic acid monohydrate
and styrylboronic acid was selected as a model reaction.
In this process, the interaction of reagents at room temper-
ature or higher in a variety of solvents (toluene, dichlo-
rometane, dioxane, acetonitrile, ethyl acetate, ethanol,
methanol) proceeded to furnish the corresponding
organoboronic acids, glyoxylic acid, and amino acids.3,5
specific example is an efficient and highly stereocon-
A
SYNLETT 2010, No. 1, pp 0073–0076
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x.
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x.
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Advanced online publication: 27.11.2009
DOI: 10.1055/s-0029-1218386; Art ID: G30809ST
© Georg Thieme Verlag Stuttgart · New York

74
M. V. Shevchuk et al.
LETTER
Table 1 Reaction of Aminophosphonates and Glyoxylic Acid with Various Boronic Acids
O
R1
O
∗
HO
R3
R2
R3
P(O)(OEt)2
∗
H
R1B(OH)2
+
+
HO
N
P(O)(OEt)2
∗
EtOAc,
reflux, 2.5-4 h
NH
O
R2
1a: R2 = 4-MeOC6H4, R3 = H
1b: R2 = Ph, R3 = Bn
1a,b
2a–h
Entry
Producta R1
R2
R3
H
Reaction conditionsb drc
Isolated yield (%)d
1
2
2a
4-MeOC6H4
4-MeOC6H4
A
A
9:1
75
76
Ph
2b
4-MeOC6H4
H
9:1
O
3
4
2c
4-MeOC6H4
4-MeOC6H4
H
H
B
B
9:1
53e
43e
O
S
2d
9:1
5
6
2e
2f
Ph
Ph
Bn
Bn
A
A
>95:5
>95:5
80
95
Ph
4-MeOC6H4
O
7
8
2g
2h
Ph
Ph
Bn
Bn
A
B
>95:5
>95:5
88
69
O
S
a All compounds have been characterized by microanalytical, LC-MS, 1H NMR, 13C NMR, and 31P NMR data.
b Glyoxylic acid monohydrate (1.05 equiv), R1B(OH)2 (1.05 equiv), R2CH(NHR3)PO3Et2 (1.0 equiv). A: EtOAc, reflux for 2.5 h, product was
purified by recrystallization from EtOAc–hexane (4:1, v/v). B: EtOAc, reflux for 4 h, product was purified by flash chromatography on silica
gel (CHCl3–EtOAc–MeOH, 35:55:10, v/v).
c Determined by 1H NMR and 31P NMR of the unpurified reaction mixture.
d Isolated yield of the major diastereomer, unless otherwise stated.
e Diastereomeric mixture isolated.
N-(phosphonomethyl)-substituted amino acid 2a without An analogous series of reactions was then performed with
detection of any intermediate products.
the sterically hindered tetraethyl (pyrrolidine-2,2-
diyl)bisphosphonate 3. As shown in Scheme 2, the reac-
tions provided modest to good yields of the corresponding
bisphosphonate derivatives 4.10
The best yield and diastereoselectivity (75% yield, ca. 9:1
dr; Table 1, entry 1) was achieved in ethyl acetate at re-
flux. Solvents having a high dielectric constant such as
ethanol, acetonitrile, and THF gave a lower yield of 2a. Finally we expanded our substrates to include b-amino-
Water proved to be also a suitable solvent for this reaction phosphonates. The one-step, three-component reaction of
and afforded the product in 66% yield. In a next step, dif- styrylboronic acid, glyoxylic acid monohydrate and previ-
ferent organoboronic acids were evaluated. The use of ously synthesized (R)-b-amino-a,a-difluoromethylphos-
phenylboronic acid only gave trace amounts of the corre- phonate (6),11 in a variety of solvents, including methanol,
sponding N-phosphonomethylglycine. However, elec- ethyl acetate, and dichloromethane, resulted in the forma-
tron-rich 4-methoxyphenyl-, 3,4-methylenedioxyphenyl-, tion of desired compound 7a in modest isolated yield.
and 2-thiopheneboronic acids were successful as the bo- Dichloromethane provided shorter reaction times and
ron reactants (entries 2–4, Table 1).
slightly higher conversion than methanol and other aprot-
ic solvents. However, in all cases, poor level of diastereo-
selectivity (ca. 60:40 dr) was observed. When pyruvic
acid was used as a carbonyl component, the corresponding
product 7b was obtained in 49% yield with a diastereo-
meric ratio of 75:25 (Scheme 3).12
It was also found that diethyl 1-(N-benzylamino)-1-
phenylmethylphosphonate (1b) containing a secondary
amino group successfully underwent similar transforma-
tions (entries 5–8, Table 1). For these reactions, higher di-
astereoselectivity (>95:5 dr) and slightly higher yields of
products were obtained in good agreement with previous In summary, we have reported a facile multicomponent
experimental findings and DFT calculations.4,9
synthesis of highly functionalized N-phosphonomethyl-
Synlett 2010, No. 1, 73–76 © Thieme Stuttgart · New York

LETTER
Petasis Boronic Acid Mannich Reaction
75
O
O
R
H
N
HO
H
P(O)(OEt)2
P(O)(OEt)2
+
R1
B(OH)2
+
HO
EtOAc,
reflux, 3.5–4 h
P(O)(OEt)2
P(O)(OEt)2
N
O
3
4a-d
S
, 65%;
, 73%;
, 80%.
, 47%;
4b: R =
4c: R =
4d: R =
4a: R =
Ph
O
MeO
O
Scheme 2
(4) Southwood, T. J.; Curry, M. C.; Hutton, C. A. Tetrahedron
2006, 62, 236.
(5) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119,
445.
O
F
F
Ph
OH
B(OH)2
∗
+
+
R
Ph
P(O)(OEt)2
O
NH2
(6) Petasis, N. A.; Zavialov, I. A. US 6,232,467, 2001.
(7) Aminophosphonic and Aminophosphinic Acids; Kukhar,
V. P.; Hudson, H. R., Eds.; John Wiley and Sons:
Chichester, 2000.
(R)-6
F
F
(8) (a) Kafarski, P.; Lejczak, B. Curr. Med. Chem. 2001, 1, 301.
(b) Ordóñez, M.; Rogas-Cabrera, H.; Cativiela, C.
Tetrahedron 2009, 65, 17. (c) Palacios, F.; Alonso, C.;
de los Santos, J. M. Chem. Rev. 2005, 105, 899.
(d) Romanenko, V. D.; Kukhar, V. P. Chem. Rev. 2006, 106,
3868. (e) Moonen, K.; Laureyn, I.; Stevens, C. V. Chem.
Rev. 2004, 104, 6177. (f) Mikolajczyk, M.; Balczewski, P.
Top. Curr. Chem. 2003, 223, 161.
Ph
R
∗
P(O)(OEt)2
Ph
NH
∗
CH2Cl2, r.t.
COOH
24 h (7a), 48 h (7b)
7a: (R,R) + (R,S), 55%, 60:40 dr
7b: (R,R) + (R,S), 49%, 75:25 dr
a: R = H, b: R = Me
(9) Candeias, N. R.; Veiros, L. F.; Afonso, C. A. M.; Gois, P. M.
P. Eur. J. Org. Chem. 2009, 1859.
Scheme 3
(10) To a stirred suspension of glyoxylic acid monohydrate (92
mg, 1.00 mmol) in EtOAc (5 mL) tetraethyl pyrrolidine-2,2-
diyldiphosphonate (3, 343 mg, 1.00 mmol) was added
dropwise, after 5 min 2-thiopheneboronic acid (128 mg, 1.00
mmol) was added in one portion, and the reaction mixture
was refluxed over 4 h while monitored by TLC (5% MeOH
in CHCl3). After the completion of the reaction the solvent
was evaporated yielding the crude product as yellow oil.
Flash chromatography using 5% of MeOH in CH2Cl2
afforded 390 mg (80%) of compound 4d as colorless oil.
1H NMR (400 MHz, CDCl3): d = 1.05 (t, 3 H,
glycines and their analogues. The method is shorter and
more convenient than traditional routes.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
OCH2CH3),1.15 (t, 3 H, OCH2CH3), 1.30 (t, 3 H,
OCH2CH3), 1.31 (t, 3 H, OCH2CH3), 1.77–1.84 (m, 2 H,
CH2), 2.19 (m, 2 H, CH2), 3.01–3.07 (m, 1 H, CH2), 3.17–
3.23 (m, 1 H, CH2), 3.78–3.88 (m, 1 H, OCH2CH3), 3.90–
4.10 (m, 3 H, OCH2CH3), 4.14–4.26 (m, 4 H, OCH2CH3),
5.83 (s, 1 H, CHCOOH), 6.87 (dd, JHH = 3.7 Hz, JHH = 5.1
Hz, 1 H, Hthiophene), 7.08 (dd, JHH = 1.0 Hz, JHH = 3.7 Hz, 1 H,
Hthiophene), 7.20 (dd, JHH = 1.0 Hz, JHH = 5.1 Hz, 1 H,
We thank the Science and Technology Center in Ukraine (Project
3558) for financial support.
References and Notes
(1) (a) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
Wiley-VCH: Weinheim, 2005. (b) Yus, M.; Ramón, D. J.
Angew. Chem. Int. Ed. 2005, 44, 1602. (c) Dömling, A.
Chem. Rev. 2006, 106, 17. (d) Dömling, A.; Ugi, I. Angew.
Chem. Int. Ed. 2000, 39, 3168. (e) Simon, C.; Constantieux,
T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957.
(2) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993,
34, 583. (b) Petasis, N. A.; Goodman, A.; Zavialov, I. A.
Tetrahedron 1997, 53, 16463. (c) Petasis, N. A.; Zavialov,
I. A. J. Am. Chem. Soc. 1998, 120, 11798. (d) Petasis, N. A.
Aust. J. Chem. 2007, 60, 795.
H
thiophene). 13C NMR (100 MHz, CDCl3): d = 16.2 (d,
JCP = 6.0 Hz, OCH2CH3), 16.5 (d, JCP = 6.0 Hz, OCH2CH3),
16.5 (d, JCP = 6.0 Hz, OCH2CH3), 16.6 (d, JCP = 6.0 Hz,
OCH2CH3), 24.0 (t, JCP = 3.0 Hz, CH2), 32.3 (t, JCP = 4.0 Hz,
CH2), 48.1 (d, JCP = 4.0 Hz, CH2), 59.8 (s, CHCOOH), 62.3
(d, JCP = 7.0 Hz, OCH2CH3), 63.2 (d, JCP = 7.0 Hz,
OCH2CH3), 63.5 (d, JCP = 7.0 Hz, OCH2CH3), 63.5 (dd,
JCP = 150.0 Hz, JCP = 155.0 Hz, PCP), 64.6 (d, JCP = 7.0 Hz,
OCH2CH3), 125.9, 125.9, 128.7, 138.3, 172.5 (s, COOH).
31P NMR (162 MHz, CDCl3): d = 20.8 (d, JPP = 92.3 Hz, 1
P), 23.3 (d, JPP = 92.3 Hz, 1 P). CI MS (CI, pos.): m/z (%) =
346 (100), 206 (15); MS (CI, neg.): m/z (%) = 482 (100) [M
– H]–, 438 (10), 328 (10), 233 (40), 138 (10), 103 (30), 85
(3) Petasis, N. A. In Multicomponent Reactions; Zhu, J.;
Bienaymé, H., Eds.; Wiley-VCH: Weinheim, 2005, 199–
223.
Synlett 2010, No. 1, 73–76 © Thieme Stuttgart · New York

76
M. V. Shevchuk et al.
LETTER
(t, 3 H, OCH2CH3),1.33 (t, 3 H, OCH2CH3), 1.50 (s, 3 H,
(45). Anal. Calcd for C18H31NO8P2S: C, 44.72; H, 6.46, N,
2.90, S, 6.63. Found: C, 44.61; H, 6.41; N, 2.87; S, 6.68.
CH3), 4.09–4.33 (m, 4 H, OCH2CH3), 4.38 (dd, JHF = 23.0
Hz, JHF = 8.0 Hz, 1 H, CF2CH), 5.94 (d, JHH = 16.0 Hz, 1 H,
PhCH=CH), 6.48 (d, JHH = 16.0 Hz, 1 H, PhCH=CH), 6.40
(br s, NH), 7.07 (d, JHH = 7.0 Hz, 2 H, HPh), 7.18–7.39 (m, 8
H, HPh). 13C NMR (100 MHz, CDCl3): d = 16.4 (m,
OCH2CH3), 22.2 (s, CH3), 63.5 (s, CHCOOH), 64.7 (d,
JCP = 7.0 Hz, OCH2CH3), 65.2 (d, JCP = 7.0 Hz, OCH2CH3),
126.7, 128.07, 128.5, 128.6, 128.6, 129.1, 130.9, 131.5,
136.1. 19F NMR (376 MHz, CDCl3): d = –121.6 (ddd,
JFF = 304.0 Hz, JFP = 108.0 Hz, JFH = 23.0 Hz, 1 F), –110.6
(ddd, JFF = 304.0 Hz, JFP = 104.0 Hz, JFH = 8.0 Hz, 1 F).
19P NMR (162 MHz, CDCl3): d = 6.7 (dd, JPF = 108.0 Hz,
JPF = 104.0 Hz). Anal. Calcd for C23H28F2NO5P: C, 59.10;
H, 6.04. Found: C, 59.06; H, 6.14.
(11) Röschenthaler, G.-V.; Kukhar, V. P.; Belik, M. Yu.;
Mazurenko, K. I.; Sorochinsky, A. E. Tetrahedron 2006, 62,
9902.
(12) To a stirred solution of pyruvic acid (44 mg, 0.50 mmol) in
CH2Cl2 (3 mL) aminophosphonate 6 (147 mg, 0.50 mmol)
was added dropwise, after 5 min (E)-2-phenylethenyl
boronic acid (74 mg, 0.50 mmol) was added in one portion,
and the reaction mixture was stirred for 24 h while
monitored by TLC (5% MeOH in CHCl3). The solvent was
evaporated, and the residual oil was chromatographed using
a gradient of i-PrOH (7 → 13%) in CH2Cl2 to yield 75 mg
(34%) as a mixture of diastereomers 7b, and 35 mg (15%) as
pure major diastereomer. Summary yield 110 mg (49%).
Major diastereomer: 1H NMR (400 MHz, CDCl3): d = 1.26
Synlett 2010, No. 1, 73–76 © Thieme Stuttgart · New York

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