Isocyanide addition to acylphosphonates: A formal Passerini reaction of acyl chlorides

Article abstract of DOI:10.1055/s-2008-1072726

Acylphosphonates behave as carbonyl components in Passerini reactions with isocyanides and carboxylic acids. Under saponification, the adducts undergo a phospha-Brook rearrangement to form α-amidophosphates. As acylphosphonates are quantitatively formed from carboxylic derivatives, this new reductive procedure allows acyl chlorides to react as aldehydes in a Passerini-type reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072726

LETTER
1133
Isocyanide Addition to Acylphosphonates: A Formal Passerini Reaction of
Acyl Chlorides
Isocyanide
A
dditio
i
n
to
A
c
ylphosphon
i
ates er Coffinier, Laurent El Kaim,* Laurence Grimaud*
Laboratoire Chimie et Procédés, Ecole Nationale Supérieure de Techniques Avancées, 32 Bd Victor, 75739 Paris Cedex 15, France
Fax +33(1)45525587; E-mail: laurent.elkaim@ensta.fr; E-mail: laurence.grimaud@ensta.fr
Received 21 February 2008
O
OPO(OR2)2
CONHR3
Abstract: Acylphosphonates behave as carbonyl components in
Passerini reactions with isocyanides and carboxylic acids. Under sa-
ponification, the adducts undergo a phospha-Brook rearrangement
to form a-amidophosphates. As acylphosphonates are quantitative-
ly formed from carboxylic derivatives, this new reductive procedure
allows acyl chlorides to react as aldehydes in a Passerini-type reac-
tion.
H
R1
P(OR2)2
O
R1
Passerini
H+
R3NC, AcOH
phospha-
Brook
(OR2)2
OPO(OR2)2
CONHR3
PO(OR2)2
CONHR3
AcO
R1
O
P
Key words: phosphonate, isocyanide, multicomponent reaction,
Passerini reaction
O
R1
R1
CONHR3
Scheme 1 Passerini reaction coupled with phospha-Brook rearran-
gement
The synthetic interest in isocyanides is traditionally asso-
ciated with their interaction with aldehydes and ketones as
disclosed in the Ugi and Passerini reactions.1 Discovered
much earlier by Nef,2 the reaction of isocyanides with acyl
chlorides is, however, less documented.3 Reinvestigated
more recently by Ugi,3a this reaction gives imidoyl chlo-
ride intermediates which can be either hydrolyzed to ke-
toamides or trapped to form various cyclic adducts. In
contrast to the Ugi and Passerini reactions, the interaction
between isocyanides and acyl chlorides often requires
heating to give adducts in moderate yield due to partial
Acylphosphonate 2a was quantitatively formed under
treatment of acyl chloride 1a with trimethyl phosphite in
a solvent-free Arbuzov-type reaction. Toluene was then
added to 2a, followed by cyclohexylisocyanide (3a) and
acetic acid (4a). After 24 hours under an argon atmo-
sphere at room temperature, the Passerini adduct 5a was
formed in a 74% isolated yield showing that the carbon–
phosphorous bond is relatively stable in the process
(Table 1).
polymerization under these conditions.4 More efficient Different acyl chlorides 1a–f behaved similarly with var-
Nef-type reactions could be obtained with highly electro- ious isocyanides and carboxylic acids forming hydroxy-
philic acid derivatives such as trifluoroacetic anhydride5 phosphonoamide derivatives 5a–n in moderate to good
or acyl bromides which were shown to be more reactive yields. Aliphatic as well as aromatic acyl chloride reacted
than the corresponding chlorides.3b
under these additions. The aromatic acyl chlorides (entries
12–14) were, however, less efficient and the addition with
isocyanides required heating for the reaction to reach
completion. The formation of aryl-substituted phospho-
nates such as 5l, 5m or 5n was most noteworthy as these
compounds have never been prepared before (the related
esters are unknown as well). Dimethyl acylphosphonates
were the most efficient acyl intermediates; the diethyl and
diisopropyl analogues gave adducts in lower yields prob-
ably due to steric factors.
We envisioned that the choice of a leaving group less
prone to nucleophilic displacement on the acyl moiety
could allow the acyl derivative to react as a ketone with
isocyanides in a Passerini-type reaction. The removal of
the leaving group could then be performed directly from
the Passerini adduct. Interesting work in this direction has
been achieved recently with acyl cyanides. Indeed, the cy-
ano group allows the starting material to react as an acti-
vated ketone, the resulting cyano amide being selectively
reduced to an amine in a further step.6
a-Hydroxyphosphonate derivatives are interesting com-
pounds displaying both pharmaceutical and agrochemical
activities.8 These compounds are usually prepared by ba-
sic treatment of carbonyl derivatives with dialkyl phos-
phites.9 These additions are highly efficient except for
carbonyl derivatives substituted with electron-withdraw-
ing groups; in these latter cases, phosphate derivatives are
easily obtained along with the expected phosphonates.10
Indeed, under basic treatment, hydroxyphosphonates may
undergo a 1,2-shift of the phosphoryl group to give phos-
phates. Close to the Brook rearrangement of silyl deriva-
tives, this phosphoryl migration discovered more than 50
Following our studies on a-hydroxyphosphonate–phos-
phate rearrangement (phospha-Brook),7 we surmised that
a Passerini reaction of acylphosphonate could settle the
proper functionalities for efficient phospha-Brook rear-
rangements (Scheme 1).
SYNLETT 2008, No. 8, pp 1133–1136
x
x.
x
x.
2
0
0
8
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072726; Art ID: D05608ST
© Georg Thieme Verlag Stuttgart · New York

1134
D. Coffinier et al.
LETTER
years ago is often coined as the phospha-Brook (PB) rear- The phospha-Brook rearrangement is observed when sim-
rangement (Scheme 1).11
ple acylphosphonates are treated with nucleophiles such
as dialkyl phosphite12 and cyanide anion.13 By using tri-
methylsilyl cyanide, the intermediate oxyphosphonates
can be trapped as silyloxycyanophosphonates before any
This equilibrium is shifted toward the phosphate only if
anion-stabilizing groups are tethered to the carbon bearing
the phosphonate.
Table 1 Preparation of Hydroxyphosphonoamide Derivatives 5a–n from Acyl Chlorides 1a–f
P(OR2)3
(1 equiv)
R4CO2H (1 equiv)
4
OR2
OR2
R4OCO
R1
Cl
PO(OR2)2
NHR3
O
P
R1
1
O
R3NC (1 equiv)
3
neat
r.t.
R1
O
O
2
5
toluene (1 M), r.t.
Entry
1
R1COCl
R2
R3NC
R4CO2H
5 [Yield (%)]
Ph
CyNC
3a
AcOH
4a
Me
5a (74)a
COCl
1a
1a
2
3
Et
Et
3a
3a
4a
5b (61)a
5c (58)a
ClCH2CO2H
4b
1a
4
5
1a
1a
Et
t-BuNC 3b
4a
4a
5d (63)a
5e (67)a
i-Pr
3a
t-OctNC
3c
6
7
1a
i-Pr
i-Pr
4a
4a
5f (59)a
5g (40)a
COCl
3b
Cl
8
9
i-Pr
3b
3a
4a
4a
5h (56)a
5i (78)a
COCl
1c
1c
Me
CO2Me
10
11
Me
Et
3b
3b
4a
5j (73)a
5k (59)a
COCl
1d
1a
Me3CCO2H
4c
COCl
12
13
14
Et
3b
3a
3b
4a
4a
4a
5l (56)b
5m (76)b
5n (54)b
F
1e
1e
Me
Et
COCl
Me
1f
a Equimolar amount of phosphite was added to neat acyl chloride. After 1 h at r.t., evaporation of residual alkyl chloride was followed by the
addition of toluene (1 M) and an equimolar amount of isocyanide and carboxylic acid. The Passerini adduct was obtained after 24 h at r.t.
b The Passerini reaction was performed at 80 °C for 24 h.
Synlett 2008, No. 8, 1133–1136 © Thieme Stuttgart · New York

LETTER
Isocyanide Addition to Acylphosphonates
1135
phospha-Brook rearrangement.14 Isocyanides behave sim-
ilarly in conjunction with carboxylic acids. Under sapon-
ification conditions, release of the alkoxide should trigger
the rearrangement. Indeed, when phosphonates 5 were
treated with one equivalent of LiOH in THF and the mix-
ture was heated at 65 °C, the new amidophosphates 6 were
formed in quantitative yield (Table 2).
(8) (a) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.; Free, C.
A.; Rogers, W. L.; Smith, S. A.; DeForrest, J. M.; Oehl, R.
S.; Petrillo, E. W. J. Med. Chem. 1995, 38, 4557. (b) Sun,
F. Y.; Schmid, E.; Baumgartner, A.; Adler, T.-D.
Mutagenesis 2000, 15, 17. (c) Chevrier, C.; Le Nouen, D.;
Defoin, A.; Tarnus, C. Eur. J. Org. Chem. 2006, 2384.
(9) For a review see: Pudovik, A. N.; Konovalova, I. V.
Synthesis 1979, 81.
(10) (a) Pudovik, A. N.; Konovalova, I. V.; Dedova, L. V. Zh.
Obshch. Khim. 1964, 34, 2902. (b) Polezhaeva, N. A.;
Ovodova, O. V.; Litivinov, I. A.; El’shina, E. V.; Naumov,
V. A.; Arbuzov, B. A. Izv. Akad. Nauk. SSSR, Ser. Khim.
1986, 8, 1860. (c) Fokin, A. V.; Studnev, Y. N.; Rapkin, A.
I.; Pasevina, K. I.; Verenikin, O. V.; Kolomiets, A. F. Izv.
Akad. Nauk. SSSR, Ser. Khim. 1981, 7, 1655. (d) Gallagher,
M. J.; Jenkins, I. D. J. Chem. Soc. C 1969, 2605.
(11) (a) Hammerschmidt, F.; Schneyder, E.; Zbiral, E. Chem.
Ber. 1980, 113, 3891. (b) Tromelin, A.; El Manouni, D.;
Burgada, R. Phosphorus Sulfur Relat. Elem. 1986, 27, 301.
(c) Ruel, R.; Bouvier, J.-P.; Young, R. N. J. Org. Chem.
1995, 60, 5209. (d) Barthel, W. F.; Alexander, B. H.; Giang,
P. A.; Hall, S. A. J. Am. Chem. Soc. 1955, 77, 2424.
(e) Bausch, C. C.; Johnson, J. S. Adv. Synth. Catal. 2005,
347, 1207.
Table 2 Phospha-Brook Rearrangement
PO(OR2)2
NHR3
OPO(OR2)2
NHR3
AcO
R1
LiOH (1 equiv)
THF, 65 °C
R1
O
O
5
6
R1
R2
R3
Yield
quant
quant
quant
quant
PhCH2CH2
PhCH2CH2
PhCH2CH2
4-MeC6H4
Et
t-Bu
Cy
Me
i-Pr
Et
Cy
t-Bu
(12) (a) Pudovik, A. N.; Konovalova, I. V. J. Gen. Chem. USSR
(Engl. Transl.) 1963, 33, 3026. (b) Fitch, S. J.; Moedritzer,
K. J. Am. Chem. Soc. 1962, 84, 1876. (c) Hammerschmidt,
F.; Zbiral, E. Monatsh. Chem. 1980, 111, 1015.
In conclusion, we have used acyl chlorides as formal alde-
hyde partners in a Passerini-type reaction with isocya-
nides and phosphoric acids.15 To the best of our
knowledge, Passerini reactions with phosphoric acid de-
rivatives have never been described in the literature. In al-
lowing the preparation of amidophosphonates, important
phosphoryl analogues of amino acids, this new strategy
extends the scope of the Passerini reaction. Further inter-
actions of phosphonates with isocyanides are under study
in our research group.
(d) Nguyen, L. M.; Niesor, E.; Bentzen, C. J. Med. Chem.
1987, 30, 1426.
(13) (a) Hall, L. A. R.; Stephens, C. W.; Drysdale, J. J. J. Am.
Chem. Soc. 1957, 79, 1768. (b) Demir, A. S.; Reis, O.; Igdir,
A. C.; Esiringü, I.; Eymür, S. J. Org. Chem. 2005, 70,
10584. (c) Demir, A. S.; Reis, B.; Reis, O.; Eymür, S.; Göllü,
M.; Tural, S.; Saglam, G. J. Org. Chem. 2007, 72, 7439.
(d) Demir, A. S.; Reis, O.; Esiringu, I.; Reis, B.; Baris, S.
Tetrahedron 2007, 63, 160.
(14) Demir, A. S.; Reis, O.; Kayalar, M.; Eymur, S.; Reis, B.
Synlett 2006, 3329.
References and Notes
(15) General Procedure for the Formation of Phosphonate 5:
To acyl chloride 1 (2 mmol) was added neat trialkyl
phosphite (1 equiv). The mixture was stirred under argon for
30 min. Toluene (1 M), isocyanide (1 equiv) and carboxylic
acid (1 equiv) were then successively added. The mixture
was stirred for 24 h under argon at r.t. (for alkyl acyl
chlorides) or at 80 °C (for aromatic acyl chlorides). The
solvent was then removed under reduced pressure to afford
Passerini products after purification by flash column
chromatography on silica gel. Data for 5a: mp 72–74 °C; Rf
(EtOAc–PE, 50:50): 0.1. 1H NMR (400 MHz, CDCl3): d =
7.26–7.33 (m, 2 H), 7.18–7.24 (m, 3 H), 6.73 (d, J = 8.3 Hz,
1 H), 3.84–3.88 (m, 1 H), 3.88 (d, JH–P = 10.8 Hz, 3 H), 3.84
(d, JH–P = 10.6 Hz, 3 H), 2.69–2.80 (m, 1 H), 2.56–2.69 (m,
3 H), 2.18 (s, 3 H), 1.91–1.99 (m, 2 H), 1.68–1.78 (m, 2 H),
1.59–1.66 (m, 1 H), 1.33–1.47 (m, 2 H), 1.17–1.32 (m, 3 H).
13C NMR (100.6 MHz, CDCl3): d = 169.1 (d, JC–P = 5.9 Hz),
165.2 (d, JC–P = 4.4 Hz), 141.4, 129.0, 128.9, 126.5, 83.3 (d,
JC–P = 152.2 Hz), 55.1 (d, JC–P = 6.6 Hz), 54.5 (d, JC–P = 7.3
Hz), 49.1, 35.6, 33.2, 33.1, 30.5 (d, JC–P = 7.3 Hz), 25.9, 25.1,
21.6. IR (thin film): 3328, 3027, 2987, 1749, 1669, 1531,
1259, 1222, 1020 cm–1. HRMS: m/z calcd for C20H30NO6P:
411.1811; found: 411.1810.
(1) For recent reviews, see: (a) Banfi, L.; Riva, R. Org. React.
(N. Y.) 2005, 65, 1. (b) Zhu, J. Eur. J. Org. Chem. 2003,
1133. (c) Ugi, I.; Werner, B.; Dömling, A. Molecules 2003,
8, 53. (d) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10,
51. (e) Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P.
Chem. Eur. J. 2000, 6, 3321. (f) Dömling, A.; Ugi, I.
Angew. Chem. Int. Ed. 2000, 39, 3168. (g) Dömling, A.
Chem. Rev. 2006, 106, 17.
(2) Nef, J. U. Justus Liebigs Ann. Chem. 1892, 270, 267.
(3) (a) Ugi, I.; Fetzer, U. Chem. Ber. 1961, 94, 1116.
(b) Westling, M.; Smith, R.; Livinghouse, T. J. Org. Chem.
1986, 51, 1159. (c) Lee, C. H.; Westling, M.; Livinghouse,
T.; Williams, A. C. J. Am. Chem. Soc. 1992, 114, 4089.
(d) Livinghouse, T. Tetrahedron 1999, 55, 9947.
(e) VanWangenen, B. C.; Cardellina, J. H. Tetrahedron Lett.
1989, 30, 3605. (f) Adlington, R. M.; Barrett, A. G. M.
Tetrahedron 1981, 37, 3935.
(4) (a) Chen, J. J.; Deshpande, S. V. Tetrahedron Lett. 2003, 44,
8873. (b) See also: ref. 3a and 3f.
(5) El Kaim, L.; Pinot-Périgord, E. Tetrahedron 1998, 54, 3799.
(6) (a) Oaksmith, J. M.; Peters, U.; Ganem, B. J. Am. Chem. Soc.
2004, 126, 13606. (b) Richter, M.; Herrmann, C.; Augustin,
M. J. Prakt. Chem. 1980, 322, 434.
Typical Procedure for the Conversion of 5a to 6a: To a
solution of LiOH (1 mmol) in anhyd THF (0.25 M) was
added 5a (1 equiv). The mixture was heated for 2 d at 65 °C
under argon. After evaporation of the solvent under reduced
pressure, the remaining salts were removed by washing the
(7) El Kaim, L.; Gaultier, L.; Grimaud, L.; Dos Santos, A.
Synlett 2005, 2335.
Synlett 2008, No. 8, 1133–1136 © Thieme Stuttgart · New York

1136
D. Coffinier et al.
LETTER
(m, 2 H), 1.10–1.27 (m, 3 H). 13C NMR (100.6 MHz,
CDCl3): d = 168.5 (d, JC–P = 4.4 Hz), 141.1, 128.9, 128.8,
126.5, 78.2 (d, JC–P = 6.6 Hz), 55.2 (d, JC–P = 6.6 Hz), 55.1
(d, JC–P = 6.6 Hz), 48.5, 35.3 (d, JC–P = 4.4 Hz), 33.4, 33.2,
30.8, 25.8, 25.1. IR (thin film): 3298, 2932, 2856, 1668,
1536, 1452, 1267, 1051 cm–1. HRMS: m/z calcd for
C18H28NO5P: 369.1705; found: 369.1700.
residue with a 1:1 mixture of CH2Cl2 and PE followed by
filtration. Evaporation of the solvent gave 6a as a yellow oil
in quantitative yield. 1H NMR (400 MHz, CDCl3): d = 7.22–
7.30 (m, 2 H), 7.13–7.22 (m, 3 H), 6.46 (d, J = 7.6 Hz, 1 H),
4.70–4.78 (m, 1 H), 3.80 (d, JH–P = 10.9 Hz, 6 H), 3.75–3.83
(m, 1 H), 2.65–2.76 (m, 2 H), 2.16–2.25 (m, 2 H), 1.83–1.94
(m, 2 H), 1.65–1.76 (m, 2 H), 1.55–1.65 (m, 1 H), 1.27–1.43
Synlett 2008, No. 8, 1133–1136 © Thieme Stuttgart · New York

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