A simple, cheap alternative to 'designer convertible isonitriles' expedited with microwaves

Article abstract of DOI:10.1016/j.tetlet.2009.04.095

Interest in designer convertible isonitriles has increased in recent years with the growing recognition that isonitrile-based multi-component reactions (IMCRs) are highly effective in rapidly accessing, new and pharmacologically relevant diversity space.

Full text of DOI:10.1016/j.tetlet.2009.04.095

Tetrahedron Letters 50 (2009) 4054–4057
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Tetrahedron Letters
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A simple, cheap alternative to ‘designer convertible isonitriles’ expedited
with microwaves
*
Christopher Hulme , Shashi Chappeta, Justin Dietrich
College of Pharmacy, Department of Pharmacology and Toxicology, Division of Medicinal Chemistry, University of Arizona, Tucson, AZ 85721, United states
a r t i c l e i n f o
a b s t r a c t
Article history:
Interest in designer convertible isonitriles has increased in recent years with the growing recognition that
isonitrile-based multi-component reactions (IMCRs) are highly effective in rapidly accessing, new and
pharmacologically relevant diversity space. This Letter reports on the novel use of n-butylisonitrile as
a cheaper and more atom-economical alternative to currently reported ‘designer convertible isonitriles’,
facilitated by the advent of microwave-assisted organic synthesis (MAOS).
Received 7 April 2009
Revised 22 April 2009
Accepted 23 April 2009
Available online 3 May 2009
Published by Elsevier Ltd.
Since the completion of the human genome project it has be-
come evident that more efficient, cost-effective exploration of
chemical diversity space is required to enable small molecule val-
idation of new macromolecular targets with potential disease
modifying effects. As such, the design of new MCRs and post-
MCR transformations are now recognized as powerful library gen-
erating tools that facilitate the discovery of novel pharmacologi-
cally rich molecular probes.1 Isonitrile-based MCRs (IMCRs)2 have
proven extremely fruitful, and many groups have developed
post-condensation strategies with the classical Ugi reaction3 which
employ so-called ‘convertible’ isonitriles.4 This set of specialized
reagents includes cyclohexynlisonitrile 1, and close analogs 2, 3,
and 5 that function as acid activated leaving groups in the Ugi con-
densation product. Isonitriles 4, 6, and 8 utilize ‘safety-catch’
mechanisms to the same end, Figure 1.5 Their value was recently
nicely exemplified in a report from a clinical candidate develop-
ment program, where molecules progressed into man without
chemistry deviating from original hit generation ‘convertible isoni-
trile’ based methodology. One such molecule, AplavirocTM 9, a CCR5
inhibitor developed for the treatment of HIV infection, was discov-
ered from a two-step IMCR based diketopiperazine library using
convertible isonitrile 7.6 The same strategy with 1 was originally
published in 19987 at a time when only 12 isonitriles were com-
mercially available and microwave-assisted organic synthesis
was in its infancy.8 This communication follows recent reports
from our laboratory that re-examined the application of ‘designer
convertible isonitriles’ in IMCRs. For example, in studies of the
Bienayme–Blackburn–Groebke reaction,9 it was shown that the
relatively expensive Walborsky reagent (1,1,3,3-tetramethylbutyl-
isonitrile) was replaceable with trimethylsilylcyanide, rendering
deprotection obsolete and free amino bicyclic imidazo[1,2-x]-het-
erocycles directly.10 Herein, we present studies driven by an obser-
vation detailed in a previous article describing a two-step UDC
(Ugi/Deprotect/Cyclize)11 route to benzimidazoles 17 (Pathway
A), Scheme 1.12 It was noted that when sterically hindered acids
11 were used in conjunction with n-butylisonitrile 14, dihydroqui-
noxalinones 18 emerged from an alternate pathway (Pathway B),
Scheme 1.
AplavirocTM, discontinued Phase II
O
HO
O
O
NH
N
OH
N
HCl
O
9
In the majority of reactions monitored Pathway B was insignif-
icant, producing only trace amounts of the side product. Significant
however was the new potential application of n-butylisonitrile as a
simple, cheap, more atom-economical alternative to convertible
isonitriles in UDC transformations (note with a >10-fold price dif-
ferential from isonitriles 1 and 3)13—ironically an isonitrile from
the original set of commercially available 12 in the late 1990s.
The AplavirocTM diketopiperazine ring forming strategy was initially
evaluated. Thus, the Ugi reaction was run under microwave-as-
sisted conditions with N-Boc-a-amino acids 19, n-butylisonitrile
14 and supporting reagents utilizing a Biotage Initiator8TM system.
After solvent evaporation, the crude Ugi product 20 was dissolved
in 10% TFA in DCE and was irradiated at 120 °C for 20 min, Scheme
2. Six examples were purified in automated fashion on a Biotage
IsoleraTM, and are shown with reported isolated yields for the over-
all two-step process, Figure 2.
* Corresponding author. Tel.: +1 520 626 5322.
E-mail address: hulme@pharmacy.arizona.edu (C. Hulme).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.04.095

C. Hulme et al. / Tetrahedron Letters 50 (2009) 4054–4057
4055
O
O
NC
NC
NC
NC
O
4
2
3
1
O
O
NC
O
O
N
H
O
O
NC
O
NC
O
O
NC
Cyclohexynl Convertible
Isocyanide resin 5
Safety-catch Linker Convertible
Isocyanide resin 6
Carbonate Convertible
Isocyanide resin 8
Rink Convertible
Isocyanide resin 7
Figure 1. Spectrum of convertible isonitriles.
Cl
N
N
H
N
O
H2O
O
Pathway A
Pathway B
H
H
HN
O
Cl O
Cl
N
N
CO2H
Cl
60%
40%
17
(i)
H2N
CN
(iii)
N
O
N
O
A
O
Cl
(ii)
HN
11
13
H2N
12
O
15
O
16
O
B
O
N
H2N
N
H
O
14
18
Scheme 1. Reagents and conditions: (i) 11, 12, 1, 10, rt, 48 h, MeOH; (ii) PS-tosylhydrazine (3 equiv), PS-N-methylmorpholine (3 equiv), THF/CH2Cl2, 24 h; and (iii) 20% TFA/
CH2Cl2, 4 h.
O
O
R1
H
R1
R2
H
H
H
R1 CHO R2 NH2
MeOH, 5 min, MAOS
TFA, DCE
N
N
O
N
CO2H
N
O
CN
N
N
R3
20 min, MAOS
O
R3
R3 R2
O
O
O
20
14
19
21
Scheme 2.
Yields were excellent for the two-step process with no interme-
diate purification of the condensation product 20 required. Ob-
served diastereomeric ratios in molecules 26 and 27 were 1:1.
In similar fashion, N-Boc-anthranilic acids 28 were exposed to
the same protocol employed in Scheme 2. However, mixtures of
the desired 1,4-benzodiazepine-2,4-dione 30 and the trifluoroacet-
ylated analog 31 of the Ugi product 29 were obtained. Conditions
were thus slightly modified to use HCl in MeOH with microwave
irradiation, Scheme 3.14 Isolated yields for the two-step process
were comparable to those reported with cyclohexynlisonitrile7,11g
and furthermore the transformation proceeded well without
work-up or purification of the intermediate Ugi product via simple
addition of a methanolic HCl solution to the on-going Ugi reaction.
Seven examples (32 through 38) are shown in Figure 3 with iso-
lated yields ranging from <5% to 75% for the microwave mediated
ring closing step. The N-methylated anthranilic acid was notice-
ably a poor performer, 38.
Repositioning the internal nucleophile in the condensation
product of mono-Boc protected diamines 39 and supporting Ugi re-
agents, followed by acid treatment interestingly gave the acyclic
salt 41, Scheme 4. Desired ketopiperazine 42 was not observed
even at reaction temperatures in excess of 200 °C.
In summary, the last ten years has witnessed an explosion of
activity in generating new molecular diversity via functional mod-
ifications of MCRs.15 In addition, extensive studies have been per-
formed developing elegant convertible isonitriles that enable
production of large arrays of pharmacologically relevant scaffolds.
These have been particularly directed toward UDC-like methodol-
ogies where an appropriately positioned internal amino nucleo-
phile is utilized to rigidify the flexible Ugi skeleton. Interestingly,
O
O
O
O
O
O
O
O
O
O
O
H
H
H
H
H
H
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
44% (2 steps)
22
59% (2 steps)
23
55% (2 steps)
25
67% (2 steps)
24
47% (2 steps)
26
51% (2 steps)
27
Figure 2.

4056
C. Hulme et al. / Tetrahedron Letters 50 (2009) 4054–4057
F
F
F
10% TFA, DCE,
O
R1
O
NH O
R2
H
N
20 min, MAOS, 160oC
N
N
R3
R1
O
R2
O
N
O
H
R3
R1
O
NH O
CO2H
NH
H
N
R1 CHO R2 NH2
31
30
30
R3
CN
N
R2
O
MeOH, 5 min, MAOS,
O
R2
HCl, MeOH
R3
O
O
80o
C
N
29
R3
R1
14
28
20 min, MAOS,
160oC
N
H
O
Scheme 3.
O
N
N
O
O
O
N
O
O
O
O
N
N
N
N
N
S
N
N
N
N
Cl
N
N
N
N
O
O
O
O
H
H
O
H
H
O
O
H
H
A 80% B 75%
32
A 91% B 69%
33
A 93% B 71%
34
A 83% B 60%
35
A 72% B 64%
37
A 50% B 66%
36
A 62% B < 5%
38
Figure 3. A = Ugi isolated yield, B = cyclization yield.
R1
H
O
HCl, MeOH
N
N
R2
20 min, MAOS,
200oC
O
41
NH2 .HCl
R1
O
H
N
O
R1 CHO R2 CO2H
CN
NH2
N
R2
O
N
H
O
R
MeOH, 5 min, MAOS,
80oC
H
3
N
N
O
NH
O
14
39
40
42
R1
O
O
R2
Scheme 4.
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the work described herein, reveals that many of the same transfor-
mations are feasible with one of the original commercially avail-
able isonitriles, namely n-butylisonitrile and expedited by MAOS
to reduce reaction times. As such, this represents a cost effective13
and more atom-economical alternative to the use of more complex
designer isonitriles and will be a particularly welcome addition to
early stage medicinal chemistry projects developing convertible
isonitrile UDC-derived hits or leads.
Acknowledgments
We would like to thank the Abbott Laboratories Scaffold Ori-
ented Synthesis group for support via a New Faculty Award to C.H.
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2–5 mL microwave vial and was then irradiated for 20 min at 160 °C. Upon
completion of the reaction, the solvent was evaporated in vacuo and crude
material partitioned between NaHCO3 (20 mL) and ethyl acetate (20 mL). The
organic layer was washed with brine (20 mL), dried (MgSO4), and pre-
absorbed onto flash silica. Column purification on a Biotage Isolera system
(20–60% EtOAc/Hex) afforded the desired benzodiazepine, which was
concentrated and dried under high vacuum to yield 34 as a white solid
(174 mg, 71% yield). 1H NMR (300 MHz, CDCl3): d 8.61 (br s, 1H, –NH), 7.82
(s, 1H, –NH), 7.39 (d, 1H, J = 7.6 Hz), 7.19–7.32 (m, 6H), 6.78 (d, 1H,
J = 8.1 Hz), 5.29 (d, 1H, J = 14.4 Hz, benzyl), 4.47 (d, 1H, J = 14.4 Hz, benzyl),
3.62 (d, 1H, J = 11.5 Hz), 2.40 (s, 3H), 1.70 (m, 1H), 0.84 (d, 3H, J = 6.5 Hz),
0.69 (d, 3H, J = 6.5 Hz). 13C NMR (75 MHz, CDCL3): d 172.12, 166.69, 136.91,
135.13, 133.79, 132.67, 131.96, 129.18 (2C), 129.02 (2C), 128.27, 126.93,
120.23, 71.83, 55.74, 27.93, 21.09, 19.99, 19.82.
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13. Scifinder reagent costs were as follows: (a) n-butylisonitrile, 14, $132/5 g. (b)
Cyclohexynl isonitrile, 1, 1060 EUR (ꢀ$1300)/5 g. (c) 4-Phenylcyclohexynl
isonitrile, 3, 1060 EUR (ꢀ$1300)/5 g. (d) Prices for 2 and 4 were not available
requiring specific custom synthesis.
14. For the preparation of 34: To a solution of isobutyraldehyde (86 mg, 109 lL,
1.194 mmol) in methanol (3 mL) contained in a 2.0–5.0 mL microwave vial
were added benzylamine (85 mg, 0.843 mmol), n-butylisonitrile (67.0 mg,
89 lL, 0.843 mmol), and N-Boc-3-methyl-anthranilic acid (200 mg,
0.796 mmol). The reaction mixture was irradiated for 10 min at 90 °C with a
Biotage Initiator8TM system on a low absorption setting. After heating, the
mixture was washed with water and saturated sodium bicarbonate. The crude
material was purified by flash chromatography on
a
Biotage IsoleraTM
automated system equipped with a 25 g silica column and a gradient of 10–
39% EtOAc/Hex. The Ugi product was collected and dried to yield 365 mg
product (93% yield). The Ugi product was dissolved in 3 N HCl/MeOH (5 mL) in