A polymer-supported [1,3,2]oxazaphospholidine for the conversion of isothiocyanates to isocyanides and their subsequent use in an ugi reaction.

Article abstract of DOI:10.1016/S0960-894X(02)00269-X

The design and synthesis of a new polymer supported reagent for the clean conversion of isothiocyanates to isocyanides under microwave conditions was accomplished. The structurally diverse isocyanides generated were used in an Ugi 3CC, allowing the rapid generation of 2-isoindolinone-7-carboxamide analogues.

Full text of DOI:10.1016/S0960-894X(02)00269-X

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1813–1816
A Polymer-Supported [1,3,2]Oxazaphospholidine for the
Conversion of Isothiocyanates to Isocyanides and Their
Subsequent Use in an Ugi Reaction
Steven V. Ley* and Stephen J. Taylor
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Received 10 December 2001; accepted 14 February 2002
Abstract—The design and synthesis of a new polymer supported reagent for the clean conversion of isothiocyanates to isocyanides
under microwave conditions was accomplished. The structurally diverse isocyanides generated were used in an Ugi 3CC, allowing
the rapid generation of 2-isoindolinone-7-carboxamide analogues. # 2002 Elsevier Science Ltd. All rights reserved.
The generation of compound collections for evaluation
as enzyme or receptor ligands is an important compo-
nent of the modern drug industry. This revolution in
high-throughput synthesis enables the delivery of func-
tionally diverse compounds in a rapid and efficient
fashion. The methods, however, rely on the availability
of large monomer sets as primary building blocks. Also,
multicomponent reactions (MCRs), that enable the
simultaneous combination of certain of these reactive
monomers, are proving to be particularly useful in the
generation of combinatorial arrays.1 Nevertheless, these
routes are often constrained by the commercial avail-
ability of the starting materials and consequently this cre-
ates a demand for new structures and alternative synthesis
methods. For this reason solid-supported reagents (SSRs)
offer an attractive alternative to conventional solution-
phase procedures for molecular assembly.2 The successful
application of SSRs to the synthesis of complex librar-
ies,3 natural products,4À6 and drug molecules7 has
established some of the advantages of these methods for
parallel synthesis.
products.9À11 Not surprisingly these valuable compounds
are under represented in the directories of available che-
micals. We have therefore chosen to develop a supported
reagent to generate isocyanides ‘on-demand’ from readily
available isothiocyanates. The results of this study,
along with some applications of the use of the products
in an Ugi 3CC reaction are reported below.
Mukaiyama demonstrated that 3-methyl-2-phenyl-[1,3,2]
oxazaphospholidine 1 mediates the efficient conversion of
isothiocyanates to their corresponding isocyanides
(Scheme 1).12
Despite the mild reaction conditions employed in this
conversion, the approach was not generally accepted
due to the toxicity and instability of the phosphorus
derived reagent. Moreover, the necessity to isolate the
products from a complex crude mixture, using vacuum
distillation, was frequently complicated by the volatility
and extreme malodor of many isocyanides. We decided
therefore to covalently attach the active [1,3,2]oxaza-
phospholidine to a polymer support matrix and thereby
circumvent some of the drawbacks of the solution phase
method.
Since isocyanides represent an important class of mono-
mers, due to their unique reactivity in MCRs these have
become ideal targets for synthesis.8 However, despite
this, general solution-phase methods for their prepara-
tion are not always satisfactory and often result in the
use of toxic reagents and can often generate malodorous
Reaction of commercial Merrifield resin 2, suspended in
N,N-dimethylformamide at 80 ꢀC, with 2-aminoethanol
3 in the presence of excess potassium carbonate yielded
2-(polystyrylmethylamino) ethanol 4 (Scheme 2). While
this compound has been described previously in the lit-
erature,13 the new route, using an excess of potassium
carbonate, gives a significant reaction rate enhancement.
*Corresponding author. Tel.: +44-1223-336398; fax: +44-1223-
336442; e-mail: svl1000@cus.cam.ac.uk
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00269-X

1814
S. V. Ley, S. J. Taylor / Bioorg. Med. Chem. Lett. 12 (2002) 1813–1816
competing rearrangement process, generating the corre-
sponding nitriles after prolonged heating.15
Microwave irradiation of chemical reactions is known
to greatly enhance the rate of many thermal reaction
processes.16 It was proposed that this rate enhancement
may increase the production of the desired isocyanide at
the expense of the competing thermal rearrangement
pathway.
Scheme 1.
Optimization of the microwave protocol indicated that
the most effective conditions for isocyanide formation
were produced by the irradiation of a mixture contain-
ing the isothiocyanate substrate 7a–f and 6 (1.5–
3.0 equiv) suspended in toluene (Scheme 4).
Scheme 2.
Although polymers containing 1.1, 4.4, and 5.9 mmol
gÀ1 (chlorine) were subjected to this amination proce-
dure, the results indicated that an optimal product
loading was achieved with a 1.1 mmol gÀ1 (chlorine)
starting material. In addition, the lower loading Merri-
field resin reduced the potential for polymer-backbone
crosslinking, providing an opportunity for enhanced
functional activity in the target polymer.
The successful reduction of the parent isothiocyanates
7a–f (Table 1) enabled the preparation of primary, sec-
ondary and tertiary alkyl isocyanides, and three less
stable aromatic analogues, 8a–f, exhibiting diverse ste-
reo and electronic environments. The isocyanides were
produced in excellent yields and high purity, although
The condensation of 4 with bis(diethylamino)phenyl
phosphine14 5 was achieved by the controlled addition of
the phosphine to an anhydrous suspension of 4 in toluene
at 115 ꢀC, producing 3-polystyrylmethyl-2-phenyl[1,3,2]
oxazaphospholidine 6 (Scheme 3).
The polymer product was isolated, washed under anhy-
drous and anaerobic conditions and then dried in vacuo,
prior to a new solid phase purification strategy. The crude
resin product, suspended in toluene, was stirred with
excess macroporous tosic acid resin (MP-TsOH, Argo-
naut Technologies), isolated within IRORI Kans. This
efficiently scavenged residual diethylamine trapped
within the polymer matrix of 6, whilst the utilization of
IRORI Kans enabled the facile separation of product
and scavenger polymer beads. Subsequent Soxhlet
extraction yielded 6 in high purity. Elemental analysis
indicated 6 to contain 0.78 mmol gÀ1 (phosphorus). Gel-
phase 31P NMR confirmed the presence of a phospho-
rus (III) atom (d 144 ppm), whilst magic angle spinning
1H, 13C, and COSY NMR were used to confirm the pre-
sence of the [1,3,2]oxazaphospholidine methylene pro-
tons. In contrast to the solution phase reagent 1, the
supported variant 6 was found to be stable for over
1 month, when stored under an inert atmosphere at
À60ꢀC. Moreover, the solid reagent was not malodorous
and was easily handled in air under ambient conditions.
Scheme 4.
Table 1. Isothiocyanate substrates 7a–f
Ref Substrate isothiocyanate Microwavea Equivb Yield (purity)c
a
b
c
140, 1800
140, 2700
140, 9000
2.0
2.0
3.0
85 (100)
87 (100)
96 (100)
d
140, 1800
1.5
84 (94)
e
f
140, 1800
140, 1800
2.0
2.0
96 (98)
The new solid supported reagent 6 was initially applied to
the conversion of isothiocyanates to isocyanides under
conventional thermal conditions. Whilst isocyanides were
successfully produced, the products were susceptible to a
54 (78)d
aMicrowave conditions described as temperature/(ꢀC), time/(s).
bResin equivalents, based on an active loading of 0.4 mmol gÀ1
cYield based on isolated mass. Purity determined by GC and 1H
NMR.
.
Scheme 3.
d2-Chlorophenyl isocyanide 7f was found to be extremely unstable.

S. V. Ley, S. J. Taylor / Bioorg. Med. Chem. Lett. 12 (2002) 1813–1816
1815
2-chlorophenyl isocyanide 8f decomposed rapidly, due
to its intrinsic instability.
incorporation of non-commercial isocyanides in the
combinatorial array synthesis produced several com-
pounds possessing novel structures, illustrating the con-
cept of monomer set expansion and its application to
the enrichment of established library syntheses. In a
further development of this methodology, it was shown
that the crude product from the polymer assisted isocy-
anide syntheses could be directly incorporated into the
Ugi process. Therefore, isocyanides 8a and 8b, used to
synthesize products 11a and 11e, were isolated by fil-
tration alone. Despite the omission of both the silica frit
and the solvent evaporation steps from the protocol,
products 11a and 11e were produced in yields and purity
comparable to those previously obtained.
This procedure offers several key advantages. The reac-
tions are simple to perform and are therefore suitable
for high-throughput and parallel synthesis programs. If
necessary, product purification can be achieved by simple
filtration through a frit of silica, yielding the isocyanide
monomers for direct utilization. Moreover, user expo-
sure is minimized as the volatile and malodorous iso-
cyanides are produced in sealed microwave vessels,
simplifying the handling of these noxious materials. Sub-
sequent in situ manipulation of the isocyanide products
was also investigated.
To demonstrate the application of 6 in the production
of monomers for library synthesis, the isocyanides 8a–e,
derived from the supported reagent protocol, were com-
bined with a collection of amines 9a–f (Table 2) in an Ugi
3CC procedure based on a 2-carboxybenzaldehyde 10
scaffold (Scheme 5).17
The novel polymer supported reagent 6 was successfully
synthesized and shown to effect the conversion of six
diverse isothiocyanates to their corresponding iso-
cyanides. The reaction proceeded in excellent yields,
generating products of high purity. The procedure was
simple to perform, efficient and the products required
minimal purification. Operator exposure to the volatile
and malodorous isocyanides was minimized and the
toxic phosphorus components remained isolated on the
reagent support matrix further limiting toxicity and
malodor. The isocyanides generated using 6 were intro-
duced into an MCR process, constructing a library of
drug-like molecules based upon the 2-isoindolinone-7-
carboxamide core template 11. This highlighted the
potential value of SSR technology in the enrichment of
monomer sets for combinatorial compound synthesis.
Given the scope and versatility of isocyanide MCR
reactions, the parallel synthesis of isocyanides using
SSR 6 provides an effective approach to these valuable
monomers.
These reactions were performed in a parallel fashion using
generic conditions (see experimental section), leading to
the one-pot formation of the decorated 2-isoindolinone-7-
carboxamide core structures 11a–r (Table 3). The reac-
tions were high yielding, and the target molecules were
isolated in excellent purity following reverse-phase auto-
preparative chromatography.
The compound collection produced serves to highlight
the power of supported reagent and MCR technologies
in the rapid generation of small-molecule libraries. The
Experimental
Reagents and solvents were purified and rigorously
dried by standard techniques. Microwave irradiation
was performed using a Personal Chemistry ‘Smith
Scheme 5.
Table 2. Isocyanide and amine monomers employed in the Ugi 3CC
Table 3. Array of 2-isoindolinone-7-carboxamides
Isocyanidea
Aminea
Product reference
Yield
Monomer structures
Entry
1
2
3
4
5
6
7
8
8a
8a
8a
8a
8b
8b
8b
8b
8b
8c
8c
8c
8c
8d
8e
8e
8e
8e
9a
9b
9c
9d
9a
9b
9c
9d
9e
9a
9b
9c
9f
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
11m
11n
11o
11p
11q
11r
84
92
89
95
93
88
97
98
91
86
83
91
82
74
78
86
78
72
Isocyanides
(R2-NC)
9
10
11
12
13
14
15
16
17
18
9b
9a
9b
9c
9f
Amines
(R1-NH2)
aRefer to Table 2 for monomer structures.

1816
S. V. Ley, S. J. Taylor / Bioorg. Med. Chem. Lett. 12 (2002) 1813–1816
Synthesizer’ multimode machine [the heating protocol is
defined as: temperature/(ꢀC), time/(s)]. Microwave
reactions were performed in sealed tubes supplied by
Personal Chemistry, Uppsala, Sweden.
0.5 cm3) and the resulting mixture was stirred until
complete consumption of the isocyanide was observed
by TLC (usually 12–48 h). If a white precipitate formed,
a minimum volume of dimethylsulfoxide (<0.5 cm3)
was added until the solid redissolved. The reaction
mixture was subsequently diluted with acetonitrile
(1.0 cm3) and directly purified by reverse-phase auto-
preparative HPLC, yielding the target molecules 11a–r
as white solids or colorless oils.
3-Polystyrylmethyl-2-phenyl[1,3,2]oxazaphos-pholidine 6.
Compound 5 (3.0 g, 12.0 mmol) was added via syringe
pump (6.2 h, 0.5 cm3 hÀ1) to a rigorously dried suspen-
sion of 4 (4.0 g, ca. 4.0 mmol) in toluene (25 cm3) at
115 ꢀC. After stirring for a further 4 h, the mixture was
cooled to room temperature and the supernatant sol-
vent was drawn off through a dry fritted glass tube
under a positive pressure of argon gas. Using the same
equipment, the residual solid was consecutively washed
with toluene, dichloromethane, diethyl ether, dichloro-
methane, diethyl ether and dichloromethane (4Â25 cm3
each) then dried in vacuo. The resulting polymer was
suspended in toluene (50 cm3) and stirred with IRORI
Kans containing a macroporous tosic acid resin (2.0 g,
1.40 mmol gÀ1, MP-TsOH Argonaut Technologies) for
7.5 h. The resin was collected by filtration, under an
inert atmosphere, and then further purified by Soxhlet
extraction using dichloromethane [continuously distilled
from molecular sieves (10.0 g) and MP-TsOH (2.0 g,
1.40 mmol gÀ1, Argonaut Technologies)] for 2 days. The
isolated polymer was dried under a stream of argon and
then in vacuo (1Â10À3 mm Hg) to give 6 as a pale yel-
low resin (3.4 g). dH (400 MHz, MAS-NMR, CDCl3)
7.91 (ArH), 7.73 (ArH), 7.65 (ArH), [3.12, 3.04, 3.00,
2.65 (4H, NCH2CH2)]; dC (100 MHz, MAS-NMR,
CDCl3) 145 (ArC), 65 (OCH2), 16 (NCH2); dP (243 MHz,
gel-phase NMR, CDCl3) 144; elemental analysis: P
(0.78 mmol gÀ1).
Acknowledgements
We gratefully acknowledge the financial support pro-
vided by GlaxoSmithKline (S.J.T.), BP endowment
(S.V.L.) and Novartis Research Fellowship (S.V.L.).
References and Notes
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Isocyanide synthesis, 8a–f. The appropriate iso-
thiocyanate 7a–f (30–90 mmol) was added to a suspen-
sion of 6 (300–600 mg) in toluene (2–3 cm3) and the
reaction mixture exposed to microwave radiation for
1800–9000 s at 140 ꢀC. The mixture was then filtered
and the residue washed with toluene (3Â10 cm3). The
combined organic phases were concentrated in vacuo.
The resulting residue was dissolved in 5% diethyl ether
in light petroleum and purified by filtration through a
silica frit. Solvents were removed under reduced pres-
sure to yield the target isocyanides 8a–f as colorless
solids or oils (84–96%).
2-Isoindolinone-7-carboxamide synthesis, 11a–r. A solu-
tion of 10 (50 mg, 0.31 mmol) and the amine component
(Table 2, 0.31 mmol) in methanol (1.0 cm3), was added
to a solution of the isocyanide component (Table 2,
0.31 mmol) in a minimum volume of methanol (ca.
16. (a) Caddick, S. Tetrahedron 1995, 51, 10403. (b) Lidstrom,
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