1-Hydroxy-2-methyl-2-propyl Isocyanide (HMPI) as a new convertible isocyanide for the ugi four-component-coupling reaction

Article abstract of DOI:10.1055/s-0033-1338967

The Ugi reaction is a useful four-component coupling reaction for α-(acylamino)amide. However, selective transformation of the two amides is generally difficult. Here, we report 1-hydroxy-2-methyl-2-propyl isocyanide (HMPI) as a new member of a 'convertible isocyanide' class used to solve the problem. HMPI is odorless and shows good reactivity in the Ugi reaction to give N-(1-hydroxy-2-methyl-2-propyl) amides, which are smoothly converted into esters upon Zn(OTf)₂-mediated solvolysis. Overall, structurally diverse α-amino acid esters are readily accessible in two steps by using HMPI. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1338967

2014▌
LETTER
letter
1-Hydroxy-2-methyl-2-propyl Isocyanide (HMPI) as a New Convertible Iso-
cyanide for the Ugi Four-Component-Coupling Reaction
Convertible Isocyanide for Ugi Reaction
Masato Oikawa,* Yutaro Sugamata, Manami Chiba, Koichi Fukushima, Yuichi Ishikawa
Yokohama City University, Seto 22-2, Kanazawa-ku, Yokohama 236-0027, Japan
Fax +81(45)7872403; E-mail: moikawa@yokohama-cu.ac.jp
Received: 05.06.2013; Accepted: 27.06.2013
in the presence of a second amide B (derived from the car-
Abstract: The Ugi reaction is a useful four-component coupling re-
boxylic acid) is often difficult to realize, and thus has been
action for α-(acylamino)amide. However, selective transformation
recognized as a significant challenge.
of the two amides is generally difficult. Here, we report 1-hydroxy-
2-methyl-2-propyl isocyanide (HMPI) as a new member of a ‘con-
vertible isocyanide’ class used to solve the problem. HMPI is odor-
less and shows good reactivity in the Ugi reaction to give N-(1-
lysis, in our synthetic study of AMPA receptor-selective
hydroxy-2-methyl-2-propyl) amides, which are smoothly converted
into esters upon Zn(OTf)2-mediated solvolysis. Overall, structurally
To realize the selective transformation, we have employed
formation of N-Boc imide followed by alkaline methano-
antagonist IKM-159.5 While the methodology is operative
in most cases,6 there are still problems; for example, the
diverse α-amino acid esters are readily accessible in two steps by us-
N-Boc group sometimes migrates intramolecularly to an
intimate functional group such as the hydroxyl group un-
der methanolic alkaline conditions.7 On the other hand,
several isocyanides have been developed to realize che-
moselective transformation of amides derived from isocy-
anide components after MCRs. Such isocyanides, termed
‘convertible isocyanide’,4 include Armstrong’s 1-isocya-
nocyclohexene,8 Ugi’s 2-isocyano-2-methylpropyl car-
bonates,9 Fukuyama’s 2-isocyano-2-methylpropyl phenyl
carbonate,10 Kobayashi’s 1-isocyano-2-(2,2-dimethoxy-
ethyl)benzene,11 and 2-nitrophenyl isocyanide,12 and oth-
ers.13
ing HMPI.
Key words: amides, chemoselectivity, multicomponent reactions,
zinc, esters
The Ugi reaction1 is one of the most popular isocyanide-
based multi-component coupling reactions (MCRs).2 As a
four-component coupling reaction of isocyanide with al-
dehyde, amine, and carboxylic acid, the Ugi reaction has
been recognized as a promising methodology with which
to construct α-(acylamino)amides in a one-pot operation.
Furthermore, a structurally diverse collection of α-(acyl-
amino)amides can be obtained by combination of various
compounds as building blocks.3 One of the problems of
isocyanide-based MCRs is the difficulty in controlling the
selective transformation of the amide functionality gener-
ated.4 That is, chemoselective transformation of amide A
(derived from the isocyanide component, see Scheme 1)
In this paper, we report our preliminary results on a new
isocyanide 1 (1-hydroxy-2-methyl-2-propyl isocyanide,
HMPI) as a novel entry for the convertible isocyanide.
This convertible isocyanide is odorless14 and structurally
simple compared to the precedents, can be readily pre-
pared, shows moderate to high reactivity in the Ugi four-
amide A
AL
CHO
OH
isocyanide 1
O
CN
aldehyde
AL
OH
Ugi reaction
MeOH
N
H
(HMPI)
CA
OH
N
CA
AM
H2N
AM
amine
O
O
amide B
carboxylic acid
Ugi product X
selective
solvolysis
O
AL
R
alcohol (ROH)
O
CA
N
Zn(OTf)2
(EtO)2C=O
AM
O
ester Y
Scheme 1 Overview of the Ugi reaction followed by selective transformation using new isocyanide 1
SYNLETT 21709013, 2415, 2014–2018
Advanced online publication: 08.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338967; Art ID: ST-2013-U0521-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Convertible Isocyanide for Ugi Reaction
2015
component coupling reaction, and can be directly and lections of 7-oxanorbornenes with appendage diversity.22
smoothly converted into esters without affecting another He reported that the reaction between benzylamine, ben-
unfunctionalized amide moieties located elsewhere as, for zyl isocyanide, fumaric acid monoethyl ester, and 2-fural-
example, amide B (see Scheme 1).
dehyde proceeds in 89% yield (structures not shown
here).21 Our results for two UDA reactions employing
HMPI (1) are shown in Table 1 (entries 5 and 6). The
UDA reactions were carried out at 50 °C to facilitate the
Diels–Alder reaction. First, employment of HMPI (1) in-
stead of benzyl isocyanide in the domino reaction gave 7-
oxanorbornene 7X in 56% yield as a single diastereomer
(entry 5). The structure was determined by comparison to
the known compound.21 In this combination, 1 was shown
to be less reactive than benzyl isocyanide.
The overview of our strategy for the generation of α-acyl-
aminoester Y through Ugi and post-Ugi reactions, by em-
ploying HMPI (1), is shown in Scheme 1. Here, the Ugi
product X was expected to be converted into ester Y by
Zn(OTf)2-mediated solvolysis that was recently report-
ed.15 Since non-hydroxylated N,N-(dialkyl)amide has
been reported to be inert under the solvolysis conditions,
we anticipated that chemoselective transformation at am-
ide A over amide B would be possible.
We had studied the UDA reaction employing cis-3-iodo-
acrylic acid23 and 4-methoxybenzylamine as carboxylic
acid and amine components, respectively, in combination
with benzyl isocyanide and 2-furaldehyde to develop neu-
roactive agents.5a,b In those studies, we reported that the
UDA reaction proceeded in 68% yield. When benzyl iso-
cyanide was changed to HMPI (1) in the present study, 7-
oxanorbornene 8X was obtained in better yield (82%; Ta-
ble 1, entry 6).
HMPI (1) has been reported in a polymer-bound form in
2005 for the study of polymer-bound Fischer tungsten car-
bene complexes.16 Isocyanide 1 was not, however, isolat-
ed or characterized in solution phase. Therefore, the
reactivity and usefulness of HMPI (1) in MCRs in the so-
lution phase remained unknown.
HMPI (1) can be readily synthesized by treatment of the
known oxazoline 217 with BuLi (Scheme 2), according to
the procedure for the synthesis of the O-phenyloxycar-
bonyl derivative reported by Ugi et al. in 1999.9 The puri-
fication is performed by silica gel column
chromatography (72% yield). Gratifyingly, 1 was found
to be odorless.18
Solvolysis of the Ugi reaction products 3X–8X was then
investigated. Recently, the group of Mashima reported
Zn(OTf)2-catalyzed solvolysis of more simple N-(2-hy-
droxyethyl) amides by 1-butanol.15 Since they demon-
strated chemoselective solvolysis of peptides, we
anticipated that solvolysis by 1-butanol would be realized
at amide A of the Ugi products X (Table 1), and would be
selective in some cases. All solvolysis reactions were car-
ried out by using a catalytic amount (0.05 equiv) of
Zn(OTf)2 and two equivalents of diethyl carbonate
[(EtO)2C=O] in 1-butanol at reflux temperature for 13–40
hours.24 The results are summarized in Table 1. As shown
in Table 1 (entry 1), butanolysis of diamide 3X was
achieved exclusively at the amide A moiety to give 3Y in
moderate yield (83% conversion, 62% isolated yield). No
other products were observed. Complete selectivity was
also observed for 4X (Table 1, entry 2), which gave butyl
ester 4Y in 60% yield (>98% conversion), wherein the oc-
tanamide residue remained intact. Thus, an apparent reac-
O
BuLi
OH
THF
–78 °C
CN
N
1
2
72%
Scheme 2 Preparation of 1-hydroxy-2-methyl-2-propyl isocyanide
(HMPI, 1)
The Ugi reaction of HMPI (1) was then explored (Table
1). The reaction was performed in MeOH at between
room temperature and 50 °C by mixing the four compo-
nents in the ratio indicated.19 Although the investigation
was preliminary, we did not observe any clear influence of
the ratio of the components on the reaction yield. With
poorly reactive formic acid (entry 1), the Ugi reaction pro-
ceeded quite slowly at room temperature to provide 3X in
moderate yield (55%) after 40 hours. When the carboxylic
acid component was changed to octanoic acid, which gen-
erally shows better reactivity, the yield improved to 66%
4X (entry 2). With 2-aminoethanol as an amine compo-
nent, the yield for 5X was comparable (65%, entry 3). Di-
astereoselectivity was slightly induced when chiral amine
2-amino-2-(4-methoxyphenyl)ethanol20 was employed
(62%, dr 5:2; entry 4). Separation and structural analysis
of the latter are under investigation.
tivity
difference
between
N-(2-hydroxy-1,1-
dimethyl)ethyl amide (present as the amide A, Scheme 1)
and other unfunctionalized amides (present as the amide
B), in the Zn(OTf)2-catalyzed butanolysis is clear (Table
1, entries 1 and 2).15
We next examined butanolysis of diamide 5X, bearing N-
(2-hydroxyethyl)-N-alkyl amide as the amide B moiety,
which was originally derived from 2-aminoethanol used
in the Ugi reaction (Table 1, entry 3). Here, bis-solvolysis
at amides A and B was expected to serve as a new meth-
odology for the generation of α-aminoesters, which have
not been readily accessible by MCRs so far. However, af-
ter extensive exploration of the conditions required for si-
multaneous butanolysis of amides A and B, all attempts
gave only complex mixtures and no product was isolated
cleanly; the expected product that underwent bis-solvoly-
sis was detected only in trace amounts (<5%) by LC–MS
Domino Ugi/Diels–Alder (UDA) reaction was also at-
tempted in the present study by using HMPI (1). Reported
first by Paulvannan in 1999,21 the UDA reaction employ-
ing acrylic acid derivative and 2-furaldehyde has been an
important method with which to generate compound col-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2014–2018

2016
M. Oikawa et al.
LETTER
Table 1 Ugi Reaction Using HMPI (1) followed by Solvolysis by 1-Butanol
amide A
AL
CHO
OH
O
O
CN
aldehyde
Ugi
reaction
solvolysis
1-butanol
AL
OH
AL
1
N
OBu
AM
H
CA
OH
MeOH
CA
N
CA
N
Zn(OTf)2
(EtO)2C=O
AM
H2N
AM
O
O
O
amide B
Ugi product X
amine
carboxylic
acid
ester Y
Entry
Components used for Ugi reaction (equiv) Product and yield (%) for Ugi reactiona
Product and yield (%)
for solvolysis
O
H
O
H
Ph
Ph
O
OH
benzaldehyde (2.0)
HMPI (1) (1.0)
formic acid (2.6)
N
H
OBu
H
N
H
N
1
4-methoxybenzylamine (2.0)
C6H4-4-OMe
O
C6H4-4-OMe
3X (55)
3Y (62,a 83b)
O
H
O
H
Ph
OH
Ph
benzaldehyde (1.5)
HMPI (1) (1.4)
octanoic acid (1.0)
benzylamine (1.0)
N
OBu
H
N
H15C7
N
H15C7
2
3
4
O
Ph
Ph
O
4Y (60,a >98b)
4X (66)
O
H
Ph
OH
benzaldehyde (1.5)
HMPI (1) (1.4)
octanoic acid (1.0)
ethanolamine (1.0)
N
H
N
H15C7
complex mixture
OH
O
5X (65)
O
O
H
H
Ph
Ph
OH
N
benzaldehyde (1.5)
HMPI (1) (1.0)
formic acid (2.0)
2-amino-2-(4-methoxyphenyl)ethanol (1.5)
OBu
H
H
N
N
OH
C6H4-4-OMe
H
OH
O
C6H4-4-OMe
6Y (64,a 80b) dr = 5:2
6X (62) dr = 5:2
HO
Ph
H
Ph
O
BuO
O
O
H
NH
O
O
N
2-furaldehyde (1.7)
N
HMPI (1) (1.7)
fumaric acid monoethyl ester (1.1)
benzylamine (1.0)
5
O
H
H
H
H
CO2Et
CO2Bu
7Y (44,a 75b)
7X (56)
C6H4-4-OMe
H
HO
BuO
C6H4-4-OMe
H
O
NH
N
O
O
2-furaldehyde (1.5)
N
O
HMPI (1) (1.5)
cis-3-iodoacrylic acid (1.0)
4-methoxybenzylamine (1.0)
I
O
6
H
H
O
I
H
H
H
H
8Y (65,a 83b)
8X (82)
a Isolated yield.
b Yield estimated from 1H NMR spectroscopic analysis of the crude material.
Synlett 2013, 24, 2014–2018
© Georg Thieme Verlag Stuttgart · New York

LETTER
Convertible Isocyanide for Ugi Reaction
2017
analysis. In Mashima’s paper,15 no solvolysis reaction Finally, solvolysis reactions using other alcohols were ex-
was reported on ‘hydroxylated N,N-dialkyl amide’. How- amined with diamide 4X. It had been reported that 1-bu-
ever, based on their proposed mechanism, which involves tanol (bp 117 °C) and 1-pentanol (bp 137 °C) are good
N,O-acyl rearrangement, solvolysis of amide B was ex- solvolysis agents, whereas more volatile alcohols such as
pected to occur. We therefore next examined the butanol- methanol and ethanol are inefficient. As shown in Scheme
ysis of diamide 6X, bearing N-[2-hydroxy-1-(4- 3, we first examined benzyl alcohol (bp 203–205 °C) for
methoxyphenyl)]ethyl amide as amide B, which may solvolysis. To our delight, the reaction proceeded quite
smoothly undergo the N,O-acyl rearrangement via a five- smoothly at 120 °C over 44 hours to give benzyl ester 4Y′
membered transition state (entry 4). Gratifyingly, butano- in the highest isolated yield (83%). Since benzyl ester can
lysis of 6X at both amides A and B was found to proceed be readily transformed into carboxylic acid upon hydroge-
cleanly, giving rise to 6Y in 64% yield (80% conversion). nolysis, this would serve as a promising methodology for
In addition, the diastereomeric ratio was found to be re- the three-step synthesis of structurally diverse α-acylami-
tained, indicating that no epimerization had taken place. nocarboxylic acids.
Here, the formyl group might enhance the reactivity of the
We further investigated the reaction with poly(ethylene
butanolysis at amide B. It should also be noted that forma-
glycol) methyl ether (MPEG-OH, average Mn ca. 550).26
tion of cyclic carbamate was reported to take place by re-
In this case, we needed to establish conditions for stoi-
action between liberated 2-aminoethanol analogues and
chiometric reaction. It was found that o-dichlorobenzene
was suitable as solvent, and the amount of MPEG-OH
could be reduced to 0.95 equiv relative to amide 4X. The
(EtO)2C=O after solvolysis.15 Indeed, we generally detect
4,4-dimethyloxazolidin-2-one (structure not shown) de-
rived from 2-methyl-2-aminopropanol released from the
reaction was performed at 120 °C for 22 hours, then the
amide A moiety, in the product mixture. Product 6Y, how-
mixture was directly subjected to silica gel flash column
ever, does not undergo cyclic carbamate formation (entry
chromatography.26a Fractions that contain polymer were
4), indicating that the reactivity of the secondary amine is
collected, and the loading yield was determined to be 48%
lower than the primary amine in oxazolidinone formation
(1.0 mmol/g) on the basis of 1H NMR spectroscopic anal-
with (EtO)2C=O.
ysis.
The butanolysis of more complex 7-oxanorbornene ana-
In conclusion, we have demonstrated the synthesis and
logues was next investigated (Table 1, entries 5 and 6).
use of 1-hydroxy-2-methyl-2-propyl isocyanide (HMPI,
While butanolysis of the amide A moiety in 7X cleanly
1) in the Ugi four-component coupling reaction. HMPI (1)
proceeded (entry 5), transesterification at the ethyl ester
is odorless, and the coupling reaction, as well as that fol-
moiety also took place to furnish dibutyl ester 7Y in 44%
lowed by Diels–Alder reaction, proceeded in reasonable
yield (75% conversion). No other products were cleanly
yield. The products were selectively transformed into bu-
isolated. On the other hand, butanolysis of 7-oxanorborn-
tyl esters under conditions mediated by Zn(OTf)2. The
ene analogue 8X, with a labile iodo group, provided butyl
solvolysis was chemoselective to N-(2-hydroxyethyl)am-
ides, and bis-solvolysis was also demonstrated. Thus,
HMPI (1) is an efficient convertible isocyanide that can be
used for two-step synthesis of α-acylaminoesters and ana-
ester 8Y in better yield (83% conversion, 65% upon isola-
tion; entry 6). Although 7-oxanorbornenes are known to
undergo aromatization,25 it is worthy of note that no such
side reaction was observed (entries 5 and 6), indicating the
logues. We also performed solvolysis with other agents
reaction conditions are mild. In general, bisbutanolysis
such as benzyl alcohol and poly(ethylene glycol). Nota-
provided the desired product in lower isolated yield (0–64%,
bly, the latter is expected to be useful for liquid-phase,
entries 3–5) compared to monobutanolysis (60–65%,
rapid organic synthesis. Efforts are currently directed to-
ward optimization of the reaction conditions to improve
entries 1, 2, and 6).
the isolated yield.
O
H
Zn(OTf)2 (0.05 equiv)
(EtO)2C=O (2.0 equiv)
Ph
OBn
BnOH
120 °C, 44 h
C7H15
N
O
H
N
Ph
O
OH
O
Ph
4Y' (83%)
N
H
C7H15
O
Ph
H
Zn(OTf)2 (0.05 equiv)
(EtO)2C=O (2.0 equiv)
Ph
O-MPEG550
4X
C7H15
N
MPEG550-OH (0.95 equiv)
o-dichlorobenzene
120 °C, 22 h
O
Ph
4Y" (48%)
1.0 mmol/g
Scheme 3 Solvolysis of diamide 4X for structurally diverse esters
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2014–2018

2018
M. Oikawa et al.
LETTER
(14) To avoid isolation of unpleasant-smelling isocyanide, an in
situ preparation method has been reported, see: El Kaim, L.;
Grimaud, L.; Schiltz, A. Org. Biomol. Chem. 2009, 7, 3024.
(15) Kita, Y.; Nishii, Y.; Higuchi, T.; Mashima, K. Angew. Chem.
Int. Ed. 2012, 51, 5723.
Acknowledgment
The authors thank Prof. S. Nishiyama (Keio University, Japan) for
access to the HRMS facility. This work was partly supported by the
grant for 2010-2012 Strategic Research Promotion (Nos. T2202,
T2309, T2401) of Yokohama City University, Japan.
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6676.
References and Notes
(18) Spectroscopic data for HMPI (1): IR (film): 3399, 2985,
2941, 2135, 1657 cm–1. 1H NMR (400 MHz, CDCl3): δ =
4.03 (br, 1 H), 3.38 (s, 2 H), 1.29 (s, 6 H); 13C NMR (100
MHz, CDCl3): δ = 152.5, 68.9, 58.9, 25.2 (×2). HRMS (ESI,
+): m/z [M + H]+ calcd for C5H10ON: 100.0762; found:
100.0764.
(19) To a stirred solution of aldehyde (0.0980 mmol) in methanol
(0.5 mL) at r.t., were added amine (0.0650 mmol),
carboxylic acid (0.0650 mmol), and HMPI (1, 9.0 mg, 0.091
mmol). After stirring at r.t. for 40 h, the mixture was
concentrated under reduced pressure. The residue was
dissolved in CHCl3 (1 mL) and washed successively with
sat. aq Na2CO3 (1 mL), sat. aq NH4Cl (1 mL), and brine (1
mL). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (1 g;
hexane–EtOAc) to give the Ugi product X.
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diethyl carbonate (0.0027 mL, 0.022 mmol) in 1-butanol
(0.200 mL) was heated to reflux with stirring for 39 h. The
mixture was then concentrated under reduced pressure,
dissolved in CHCl3 (1 mL), and washed with water (1 mL).
The aqueous layer was extracted with CHCl3 (2 × 1 mL) and
the combined organic layer was washed with brine (1 mL),
dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by column
chromatography on silica gel (0.6 g; hexane–EtOAc) to give
butyl ester Y.
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