A practical and inexpensive 'convertible' isonitrile for use in multicomponent reactions

Article abstract of DOI:10.1016/j.tetlet.2010.11.156

N-tert-Butylamides are readily converted into the corresponding carboxylic acids by simple nitrosation. The process, which occurs under mild nonaqueous conditions, leaves carboxylic esters untouched and transforms multicomponent reaction products into useful building blocks for further synthetic elaboration.

Full text of DOI:10.1016/j.tetlet.2010.11.156

Tetrahedron Letters 52 (2011) 2209–2211
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A practical and inexpensive ‘convertible’ isonitrile
for use in multicomponent reactions
⇑
Hoang V. Le, Lijun Fan, Bruce Ganem
Department of Chemistry & Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 15 December 2010
N-tert-Butylamides are readily converted into the corresponding carboxylic acids by simple nitrosation.
The process, which occurs under mild nonaqueous conditions, leaves carboxylic esters untouched and
transforms multicomponent reaction products into useful building blocks for further synthetic
elaboration.
This Letter is dedicated to our dear friend
and colleague, Harry H. Wasserman, in
honor of his many years of service to
Tetrahedron Publications and on the
occasion of his 90th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Isonitrile-based multicomponent reactions
t-Butylisonitrile
Amides to acids
Carboxyl protecting group
Combinatorial chemistry
The use of multicomponent reactions (MCRs) in generating
complex small molecule arrays continues to play an important role
in drug discovery and development.1 By concurrently forming sev-
eral new bonds in a one-pot procedure and with high atom econ-
omy, MCRs provide rapid access to chemically diverse structures
in an operationally simple manner. Recently, the ability to perform
iterative2 as well as higher-order3 MCRs has significantly increased
the molecular complexity that can be obtained in chemical
libraries.
Passerini reaction products, which already contain hydrolyzable
ester functionality.
We recognized that t-butylisonitrile might serve as a useful
convertible isonitrile in Passerini and related reactions. Among
other advantages, t-butylisonitrile gives rise in MCRs to N-t-butyla-
mides, whose characteristic NMR singlet simplifies the analysis of
multicomponent reaction products. We now demonstrate that
nitrosation of various N-t-butylamides affords carboxylic acids un-
der non-hydrolytic conditions.
The most versatile MCRs typically incorporate an isonitrile as
one reactant,4 which leads to a new secondary carboxamide group
in the product. Mild methods for converting such amides into car-
boxylic acids or esters would enhance the utility of MCR products
for example, as building blocks in iterative MCRs or in other syn-
thetic transformations.
To date, several ‘convertible’ isonitriles have been developed,
including 1-cyclohexenylisonitrile,5 (b-isocyanoethyl)alkylcarbon-
ates,6 and various fragrant oxazole- and benzoxazole-derived iso-
nitriles.7 While these isonitriles have all demonstrated utility in
The nitrosation of secondary carboxamides and thermal trans-
formations of the derived N-alkyl-N-nitrosamides, first investi-
gated systematically by White,8 have been the subject of
extensive mechanistic study over the past half-century, including
recent theoretical calculations.9 N-Alkyl-N-nitrosamides undergo
a highly solvent-dependent thermal rearrangement at 80–100 °C
via diazenes to products derived either from diazoalkane or carbo-
cation intermediates. By controlling and/or intercepting such inter-
mediates, our laboratory several years ago developed several new
synthetic transformations of amines via their derived nitrosamides
to alcohols, phosphotriesters alkenes, alkynes, enol acetates, and
aldehydes.10
the Ugi reaction, none has been shown to be ‘convertible’ in a-acyl-
oxyamide (i.e., Passerini) products. Moreover isonitriles whose
amides convert into esters create a new selectivity problem in
Building on those earlier findings, we reasoned that the rear-
rangement of N-nitroso-N-t-butylamides should strongly favor
the carbocationic pathway shown in Eq. 1, thus achieving a mild
amide-to-acid conversion while releasing innocuous gaseous
byproducts.
⇑
Corresponding author. Tel.: +1 607 255 7360.
E-mail address: bg18@cornell.edu (B. Ganem).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.156

2210
H. V. Le et al. / Tetrahedron Letters 52 (2011) 2209–2211
R3
R3
RCON(NO)—t-Bu
RCO2N=N—t-Bu
RCO2 N2—t-Bu
R1
R1
R2
NH—t-Bu
OH
R2
ð1Þ
O
1
O
RCO2H
isobutene + N2
2
(a) R1= Ph, R2= H, R3= OAc
+
(b) R1= PhCH2CH2, R2= H; R3= OAc
(c) R1= PhCH2CH2, R2= H; R3= OBz
(d) R1= PhCH2CH2, R2= H; R3= OCO(CH2)3CO2CH3
(e) R1,R2= (CH2)5; R3= OAc
The nitrosation of N-cyclohexylamides has been reported in the
literature to afford modest yields of carboxylic acids,8b but to the
best of our knowledge nitrosation of secondary amides bearing ter-
tiary alkyl substituents has not been described. The dealkylation of
N-t-butylamides to acids has only been achieved non-oxidatively
using strong acids.11
Scheme 1.
Table 2
Conversion of Passerini compounds 1 to carboxylic acids
To test our hypothesis, a series of simple N-t-butylamides were
nitrosated using NaNO2 in 1:2 acetic acid/acetic anhydride
(Method A) as first described by White. These conditions were cho-
sen for low cost and ready availability. The results, shown in Table
1, illustrate that nitrosation and rearrangement proceed under
mild conditions to afford the desired carboxylic acid in excellent
yield.
Reactant
Carboxylic acid
% Yield (Method)
1a
1b
1c
2a
2b
2c
79 (A)
95 (A)
52 (A)
81 (B)
63 (A)
95 (B)
33 (A)
89 (B)
1d
1e
2d
2e
Next a representative group of a-acyloxyamides 1a–e (Scheme 1)
was prepared using the Passerini three-component reaction follow-
ing standard procedures for reacting the appropriate carbonyl
compound, carboxylic acid, and t-butylisonitrile.
Initially nitrosation of 1a–e was performed using Method A,
which afforded variable results. The more sterically hindered
Passerini compounds 1c–e reacted sluggishly, but cleanly, using
Method A, with recovered starting material being the only other
product. Superior results were obtained using the more reactive
nitrosating reagent N2O4 with sodium acetate in CCl4 (Method B).
Much higher yields and complete conversion were achieved with
amides 1c–e (Table 2).
Of particular interest was the fact that the t-butylamides in
1a–e were transformed into the corresponding carboxylic acids
without affecting the carboxylic esters present in each substrate.
Notably 1d, which incorporates two ester groups (one of which is
sterically uncongested) was transformed into acid-diester 2d in
excellent yield (Method B), thus highlighting the non-hydrolytic
nature of this transformation.
Table 3
Conversion of hydroxy-t-butylamides to carboxylic acids
Hydroxy-t-butylamide
Carboxylic acid
% Yield
87 (B)
1f
2f
R1,R2 = (CH2)5; R3 = OH
1g
2g
2h
99 (B)
98 (B)
R
R
1 = PhCH2CH2, R2 = H; R3 = OH
1 = CH3(CH2)6, R2 = H; R3 = OH
1h
R3
H
R3
H
R2
O
R2
N
N
NH—t-Bu
OH
R1
R1
Next a series of
a-hydroxy-N-t-butylamides 1f–h (Table 3) were
O
prepared by recently reported variation of the Passerini
a
two-component reaction using boric acid as the Bronsted acid.12
Method A was not compatible with these substrates. When 1f
was nitrosated under those conditions, acetylation of the free
alcohol group afforded acetoxyacid 2e as the major product. How-
ever, Method B furnished the desired hydroxyacids in excellent
yield (Table 3).
3
4
(a) R1= PhCH2CH2, R2= Bz, R3= Bn
(b) R1= PhCH2CH2, R2= Ac, R3= Bn
(c) R1= PhCH2CH2, R2= Ac, R3= CH3
(d) R1= PhCH2CH2, R2= Bz, R3= n-Bu
(e) R1= Ph, R2= Bz, R3= Bn
t-Butylisonitrile has been widely used in Ugi four-component
condensations, thus it was of interest to learn whether the derived
Scheme 2.
secondary/tertiary diamides could be ‘converted’ into the corre-
sponding amidoacids. A test series of diamides were prepared
(Scheme 2) using t-butylisonitrile following the standard Ugi pro-
tocol in methanol. Somewhat surprisingly, we observed no nitrosa-
tion of diamide 3a using Method A conditions. To test whether
steric effects at the tertiary amide group were a factor, diamides
3b and 3c were also subjected to Method A conditions, and in each
case starting material was recovered nearly quantitatively. Diam-
ides 3d–e behaved similarly.
Nitrosations of 3a–e using the more potent nitrosating agent
N2O4 (Method B) were also unpromising, affording at best trace
quantities of acids 4a–e along with (mostly) unreacted diamide
and several uncharacterized byproducts. Difficulties in nitrosating
N-cyclohexyl- and other sterically hindered amides have previ-
ously been reported.13
Table 1
Nitrosation/rearrangement of t-butylamides leading to carboxylic acidsa
N-t-Butylamide
Carboxylic acid
% Yieldb
N-t-Butyl-p-bromobenzamide
N-t-Butyl-p-methoxybenzamide
N-t-Butyl-hydrocinnamide
N-t-Butyl-octanamide
Cyclohexanecarboxylic acid
N-t-butylamide
p-Bromobenzoic acid
p-Methoxybenzoic acid
PhCH2CH2CO2H
Octanoic acid
Cyclohexanecarboxylic
acid
92
99
92
65c
66c
a
Conditions: 2 ꢀ 10 equiv NaNO2; 1:2 acetic acid/acetic anhydride, 0 °C, 3 h;
then stirring 16 h at rt followed by concentration and partitioning between ether
and aq NaHCO3.
b
Reported yields are corrected for small quantities (usually 2–8%) of recovered
starting material.
c
Control workups established that ca. 25% of this volatile product was lost by
rotary evaporation during workup.

H. V. Le et al. / Tetrahedron Letters 52 (2011) 2209–2211
2211
R3
R3
R2
O
R2
Acknowledgments
N
N
R1
R1
NH—n-Bu
O—n-Bu
H
The authors thank Messrs. Henry Kaweesi and Alexei Aidan for
helpful experimental assistance. Support of the Cornell NMR Facil-
ity has been provided by NSF (CHE 7904825; PGM 8018643) and
NIH (RR02002).
R1
O
5
6
(a) R1= Ph, R2= Bz, R3= Bn
(b) R1= Ph, R2= Ac, R3= Bn
Supplementary data
Scheme 3.
Supplementary data (representative experimental procedures
and complete spectroscopic data for new reactants and products
shown in Tables 1–3) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.156.
The resistance of Ugi amides 3a–e to nitrosation made it
possible to selectively deprotect a Passerini t-butylamide in the
presence of an Ugi t-butylamide. Nitrosation of a 1:1 mixture of
1b and 3e using Method A afforded 2b in 54% yield (96% based
on recovered 1b) compound 3e was recovered quantitatively.
It was of interest to determine whether n-butylisonitrile might
serve as a convertible isonitrile for Ugi reactions by enabling an
amide-to-ester conversion of the corresponding N-(n-butyl)amide
product.14 Ugi compounds 5a–b (Scheme 3) incorporating n-butyl-
isonitrile underwent smooth nitrosation using Method A to afford
the corresponding N-nitrosoamides (not shown) following the
standard workup. Upon heating to reflux in hexane, the desired
n-butylesters 6a and 6b were produced in 80% and 83% overall
yield, respectively.
In summary, the studies presented herein demonstrate that t-
butylisonitrile can serve as an inexpensive, efficient, and readily
available ‘convertible isonitrile’ in Passerini and related multicom-
ponent reactions. To the best of our knowledge, t-butylisonitrile is
the first isonitrile whose amide-to-acid ‘conversion’ is compatible
with preexisting ester functionality in MCR products. We further
show that n-butylisonitrile may provide a viable alternative to
other convertible isonitriles for amide-to-ester transformations in
Ugi MCR products.
References and notes
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