Copper(i) catalyzed oxidative hydrolysis of Ugi 3-component and Ugi-azide reaction products towards 2° α-ketoamides and α-ketotetrazoles

Article abstract of DOI:10.1039/c7ob00881c

Herein, a two-step MCR-oxidation methodology accessing decorated 2° α-ketoamides and α-ketotetrazoles is described via a catalytic copper(i)-mediated C-N oxidation/acidic hydrolysis of Ugi-three-component and Ugi-azide reaction products. The ability to in

Full text of DOI:10.1039/c7ob00881c

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C7OB00881C
Organic & Biomolecular Chemistry
Copper (I) Catalyzed Oxidative Hydrolysis of Ugi 3-Component and
Ugi-Azide Reaction Products towards 2o α-Ketoamides and α-
Ketotetrazoles
Jurriën W. Colleta,b, Christopher Foley,a Arthur Y. Shaw,a Romano V.A. Orru,b Eelco Ruijter,b and
Christopher Hulmea*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Thus, herein we describe the synthesis of 2o α-ketoamides and
α-ketotetrazoles via a catalytic oxidation of the corresponding
Herein, two-step MCR-Oxidation methodology accessing
decorated 2o α-ketoamides and α-ketotetrazoles, is described via
a catalytic Copper (I)-mediated C-N oxidation/acidic hydrolysis of
Ugi-three-component and Ugi-azide reaction products. The ability
to install diversity from aldehyde and isocyanide synthons allows
rapid complexity generation. Of note, 1. 2o α-ketoamides are
traditionally difficult to access and moreso reminiscent of
endogenous peptide bonds. 2. The route to α-keto-tetrazoles is
significantly shorter to previous reports.
α-amino-amides
4 and α-amino-tetrazoles 13, derived
respectively from the Ugi 3-component10 and Ugi-azide11
multi-component reactions.12 Note: this approach was inspired
by a previously reported discovery of a side reaction involving
an oxidative deisatinylation of α-aryl-α-isatinylamides and α-
aryl-α-isatinyltetrazoles which serendipitously afforded both
target chemotypes in nominal yields.13 Encouraged by these
observations, initial studies focused on development of an
MCR-oxidation sequence utilizing an amine as a pro-ketone
moiety.
Over the past two decades, α-ketoamides have proven to be
valuable synthetic targets as biologically active motifs and
building blocks for diversification. The most thoroughly
investigated applications of these compounds include HIV/HCV
serine protease inhibitors,1 cysteine protease inhibitors,2 and
thrombosis inhibitors.3 Although a wide variety of synthetic
methods to substituted α-ketoamides have been developed,
substrate scope is limited and few methods truly utilize
catalytic oxidants.4 More importantly, much of the currently
available methodology only affords access to 3o α-ketoamides,
requiring aryl ketones, aryl diketones, and aryl diketone
derivatives as starting materials alongside a given 2o amine.
The power of this methodology lies in the capability to
produce 2o α-ketoamides from aldehydes and isocyanides,
which are more readily available. This limitation to generating
3o α-ketoamides has also deleteriously effected the use of 2o
α-ketoamides as building blocks to afford 2o amide handles in
biologically active small molecule libraries.
Thus, study of the compatibility of amines
the Ugi-3CR was undertaken, Table 1. Unhindered aliphatic
amines afforded low to moderate yields of (Table 1, entries
1-6). Aniline ultimately proved optimal (Table 1, entry 8),
affording in consistently high yields whilst the electron-rich
1 (entries 1 – 9) in
4
4
p-aniside (entry 9) gave lower yields of desired product. Note
the cost effectiveness of using aniline (<10$/mol) as the
oxidizable surrogate is deemed highly attractive. Subsequently,
we explored various oxidants capable of oxidizing the C-N
bond of the α-aminoamide 5, derived from the Ugi 3-
component reaction of benzaldehyde, aniline, and t-butyl
isocyanide (Table 2). Hypervalent iodine species (IBA and IBX,
Table 1. Optimization of amine input in Ugi-3CR .
R
Equally noteworthy, α-ketotetrazoles, which display bio-
isosterism with both 2o α-keto-(cis)-amides5 and cis-chalcones6
are amenable to production in two steps via the methodology
described herein, the former having shown prior utility as
protease inhibitors.7,8 This compares highly favourably to
earlier optimal routes, comprised of six steps.9
O
NH
PhP(OH)2
(30 mol%)
NC
H
N
NH2
R
+
+
DCM, rt, 3d
O
1
2
3
4
entry
R
yield 7 (%)a
~30
~30
~30
~30
56
1
2
3
4
5
6
7
8
9
Me
c-Pr
n-Bu
i-Bu
MeO(CH2)2
c-HexCH2
Bn
~50
50
Ph
89b
4-MeOC6H4
61
a Yield determined by LCMS. b Isolated yield.
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entries 1-3), demonstrated only poor reactivity and other
oxidants (entries 4-5) were unable to facilitate reaction in a
short time frame, additionally affording undesired chlorinated
products of the aniline ring. Attempts to employ catalytic SeO2
with two co-oxidants (H2O2 and TBHP) failed to reliably
increase yield (Table 2, entries 6-7). Avoiding toxic,
stoichiometric SeO2 was viewed as critical for a robust process-
ready procedure. Based on earlier reports, we thus
rationalized that use of copper halide salts would prove fruitful
in promoting oxidation of 5
to an intermediary imine14,15 which
in turn could be hydrolysed in expeditious fashion.
Satisfyingly, at first attempt, the relatively benign CuBr proved
5
moderately effective in the oxidation of α-amino-amide
(Table 1, entry 8). After a solvent screen, toluene proved
Table 2. Optimization of oxidant and conditions
entry
oxidant
(mol%)
Cooxidant
(equiv.)
T
t
conv.a
(°C) (h)
120 0.5
25
100 0.5
60
25
1b,c
2d
o-IBA (100)
IBX (110)
IBX (110)
Oxone® (200)
Ca(ClO)2 (200)
SeO2 (20)
SeO2 (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr (10)
CuBr2 (10)
-
-
-
-
-
-
-
-
18
3b,d
4e
32% (-)
trace
35% (-)
9
45
43
51
9
91
42
42
Scheme 1. Diversification of U-3CR/oxidative hydrolysis substrates. a Isolated yields are
reported.
5e
6b,c
7b,c
8e
H2O2 (2) 130 0.5
Moreover, the isocyanide-derived amide functionality (R2) did
not significantly influence yields for either the Ugi-3CR or the
oxidative hydrolysis. The catalytic oxidation/hydrolysis method
was also amenable to heterocyclic 2-furfural, exemplified by
diketoamide 11i, and the densely functionalized nitropiperonal
TBHP (2)
Air
Air
H2O2 (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
160 0.5
60
60
60
60
70
70
70
70
70
60
42
42
42
9f
10
11
12
13f
14
15
16g
24 >99 (90)
affording 11h
Encouraged with these results, we investigated the
.
24
24
48
24
96
96
10
>99
amenability of Ugi-azide derived α-aminotetrazoles 13 to the
oxidative-hydrolysis
methodology.
Exposure
of
α-
CuBr (10)
aminotetrazole 13a to optimized conditions delivered the
imine congener of 14a in 24 hours and acidic hydrolysis
garnered the keto-tetrazole 14a (58% yield). Scope exploration
demonstrated MCR compatibility with various isocyanides and
a
b
Yields determined by LCMS, isolated yields are displayed in brackets.
c
Microwave irradiation was applied. Reaction performed in DCM. d) Reaction
e
f
performed in H2O. Reaction performed in 1,4-dioxane : H2O (9:1). Reaction
g
performed in DCE. Reaction was perfomed under argon. CuBr was used in
aldehydes, rendering
a diverse collection of α-aryl-α-
combination with pyridine (1.0 eq.)
aminotetrazoles 13a-13o. Yields did not appear to correlate
with the electronic nature of either the aldehyde or isocyanide
substituent. Oxidative hydrolysis towards 5-(hetero)aroyl
tetrazoles 14 proceeded smoothly to 14b-14o in high yields.
Unfortunately, conversion to nicotinaldehyde-derived product
14k proved incompatible with the reaction conditions, forming
complex mixtures, possibly due to interference with the
copper/pyridine catalytic complex. To our delight, cyclopropyl
carboxaldehyde-derived aminotetrazole 13j was readily
converted to the corresponding ketotetrazole 14j (51% yield),
although slightly elevated temperatures and prolonged
reaction times were required (40h, 80οC).
optimal at elevated temperatures (Table 2, entry 10-13).
Additionally, TBHP (Table 2, entry 11-16) was found to be a
superior co-oxidant to H2O2 (Table 2, entry 10). It should be
noted that CuBr2 is also capable of facilitating the same
reaction (Table 2, entry 14). With an optimized protocol in-
hand (0.1 eq. CuBr/1 eq. pyridine/2 eq. TBHP in toluene at
70οC for 16h, followed by hydrolysis of the crude product by
addition of 1M HCl at 70οC, 1h), we thus explored the scope of
the oxidation/hydrolysis protocol
(Scheme 1). Excellent
conversions were obtained with diverse aromatic aldehyde
derived α-aminoamides, although aliphatic α-aminoamides
proved difficult, 11a
.
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CuBr (10 mol%),
pyr (1.0 eq.)
TBHP (2.0 eq.)
MePh, 70°C, 24h.
However, the presence of a large excess of molecular oxygen
(1 bar) as a reoxidizing agent, in combination with a solvent
switch to toluene enabled the isolation of 19 in a high yielding
R1 CHO
7
Ph
R2
R2
NH
O
8
Ph NH2
N
N
R1
R1
N
N
R2 NC
MeOH,
rt, 3d
9
then 1M HCl
70°C, 1h.
N
N
one-pot process (Scheme 2
C
, 71% yield).
N
N
12
TMS N3
13
14
CHO
O
O
O
N
N
O
+
+
O
N
N
CuBr (10 mol%)
pyridine (1.0 eq.)
N
NH2
N
N
N
N
NH
N
N
N
N
MeO
N
A
MeOH
RT, 24h.
: THBP (2.0 eq.),
MeOH, 70°C
N
N
N
N
13a
, 91%,
14a
13b
, 60%,
14b
13c
, 92%,
14c
, 96%
, 58%
, 74%
O
N
N
B
16
: THBP (2.0 eq.),
t-Bu NC
O
+
MePh, 70°C
C: O2 (1 bar),
MePh, 70°C
then 1M HCl, 70°C
a
15
A
B
: trace
TMSN3
a
: trace
C: 71%b
O
O
O
F3C
Cl
N
N
N
N
O2N
N
N
N
N
a
N
Scheme 2. Direct one-pot, two-stage synthesis of α-ketotetrazole 16.
determined by LCMS. b Isolated yield.
Yield
N
N
N
13d
, 81%,
14d
13e
, 48%,
14e
13f
, 85%,
14f
, 83%
, 69%
, 82%
In conclusion, we have developed a general protocol for the
synthesis of libraries16 of 2o α-ketoamides and α-
ketotetrazoles, that involves a two-step post-condensation
oxidative-hydrolysis of intermediary MCR products.
Importantly, one must stress that previous related oxidative
processes, amenable to 3o α-ketoamide production, have
often proved unable to garner diverse 2o α-ketoamides.
Indeed, the methodology also shows significant improvement
over previously reported methods toward α-ketotetrazoles, in
particular 1-aryl-5-aroyltetrazoles which have proved
particularly difficult to access.17 Moreover, employment of
molecular oxygen as a stoichiometric oxidant allows for the
O
O
O
MeO
N
N
N
N
O
N
N
N
N
N
N
O2N
N
OMe
N
13g, 81%, 14g, 70%
13h, 86%, 14h, 77%
13i, 50%, 14i, 92%
O
O
O
N
N
N
N
N
N
O
N
N
N
N
N
N
N
O
b
13j
, 85%,
14j
13k
14k
, -
13l
, 74%,
14l
, 91%
, 51%
, 75%,
OMe
OMe
direct one-pot synthesis of α-ketotetrazole 16
.
O
O
O
N
O
N
N
O
N
N
N
Acknowledgements
N
N
N
N
N
O
N
Cl
13m
, 71%,
14m
13n
, 64%,
14n
, 84%
13o
, 67%,
14o
, 67%
, 71%
We thank Elwin Janssen (VU) for technical support, Dr Neil E.
Jacobsen (UA) and Dr. Andreas Ehlers (VU) for NMR support
and maintenance. Furthermore, we thank Dr. David Bishop
(UA) for his organizational prowess, Dr. Sue A. Roberts (UA) for
X-ray analysis, and the HRMS facility for mass analysis. The
research leading to these findings has received financial
support from the Netherlands Organization for Scientific
Research (NWO).
a
Scheme 1. Diversification of Ugi-azide/oxidative hydrolysis substrates. Isolated yields
are given. b Reaction temperature of 80°C maintained for 40 h.
Finally, the direct addition of CuBr, pyridine and TBHP (Scheme
2, A) to an on-going Ugi-azide reaction, was evaluated with the
hope of developing a one-pot two-step protocol, but desired
product was only observed in trace quantities. Evaporating
methanol from the MCR, with dissolution of crude
intermediate 15 in toluene, and concomitant oxidation-
hydrolysis also did not alleviate the issue of low yields of α-
Notes and references
ketotetrazole 16 (Scheme 2,
B
).
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