Copper-catalyzed oxidative cleavage of Passerini and Ugi adducts in basic medium yielding α-ketoamides

Article abstract of DOI:10.1039/c9nj03533h

The aerobic oxidative cleavage of Passerini and Ugi adducts in the presence of base and copper(i) iodide is studied in detail. The oxidative cleavage yields α-ketoamides along with acids and amides from Passerini and Ugi adducts respectively. Mechanistic investigations revealed that the reaction proceeds via a radical pathway involving molecular oxygen. Control experiments with ¹⁸O-labeled Passerini adducts confirmed that molecular oxygen is the source of oxygen in α-ketoamides. A variety of Passerini and Ugi adducts were studied to explore the effect of substitution. Overall, the present study provides an insight into the reactivity of Passerini and Ugi adducts in strong basic conditions along with a method to prepare α-ketoamides.

Full text of DOI:10.1039/c9nj03533h

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Copper‐catalyzed oxidative cleavage of Passerini and Ugi adducts
in basic medium yielding α‐ketoamides
Received 00th January 20xx,
Accepted 00th January 20xx
Anirban Ghoshal,a,b,c Mayur Ambule Diliprao,a,b Revoju Sravanthi,c Mohit Tanejac and Ajay Kumar
Srivastava*,a,b
DOI: 10.1039/x0xx00000x
The aerobic oxidative cleavage of Passerini and Ugi adducts in Zhu’s protocol involves the use of hydroxylamine and acetic
presence of base and copper(I) iodide is studied in detail. The acid in the Ugi reaction that helps in the acid‐catalyzed oxygen
oxidative cleavage yields α‐ketoamide along with acid and amide transfer to provide the α‐ketoamide along with some side
from Passerini and Ugi adducts respectively. Mechanistic products.4b The method was further improved by the same
investigations revealed that the reaction proceeds via a radical group, wherein use of ZnCl2 increases the formation of α‐
pathway involving molecular oxygen. Control experiments with ketoamide (Scheme 1b).4c
18O‐labeled Passerini adducts confirmed that the molecular
oxygen is the source of oxygen in α‐ketoamide. A variety of
Passerini and Ugi adducts were studied to explore the effect of
substitution. Overall, the present study provides an insight into
the reactivity of Passerini and Ugi adducts in strong basic
conditions along with a method to prepare α‐ketoamides.
Previous Work
a) El Kaim et al. (2008)
NO2
NO2
R1 CHO
R2
O
H
N
N
MeOH, rt
Pd(OAc)2, PCy3
K2CO3, DMF
R1
R2
+
O
O
R2
N
4-NO2-Ph-OH
NH2
HN
110 o
C
N
-Ketoamide; II
H
R1
MeO
OMe
OMe
I
III
b) Zhu et.al. (2008, 2010)
Introduction
R1 CHO
Me
OH
Me
OAc
H
N
O
N
H
N
H
NaHCO3, ZnCl2
MeOH, rt
N
R2
N
R1
R2
The isocyanide‐based multicomponent reactions (IMCRs)
produce excellent building blocks to develop post‐IMCR
modifications.1 These IMCRs and post‐IMCR modifications are
extremely helpful in constructing diverse small molecule
libraries for drug discovery research.2 Aldehyde‐derived
Passerini and Ugi adducts bear an acidic proton that can be
abstracted to perform intermolecular and intramolecular
addition and cyclization reactions in basic medium. Several
groups have demonstrated that the alpha proton adjacent to
amide carbonyl can be easily abstracted using base such as
K2CO3, DBU, KOtBu and Cs2CO3 or under the microwave
conditions for performing intramolecular cyclizations.3 Efforts
have been made to prepare α‐ketoamides using Isocyanide
based multi‐component reactions (IMCRs).4 El Kaim et al.
reported the oxidative cleavage of Ugi‐Smile adduct on
treatment with Pd(OAc)2 yielding α‐ketoamide (Scheme 1a).4a
N
R1
R2
R1
R2
AcOH
O
O
O
V
-Ketoamide; II
MeNHOH.HCl
IV Minor products
c) Hulme et al. (2017)
CuBr, pyr, TBHP
O
Ph
R1-CHO
H
Toluene, 70 oC, 16 h
NH
N
H
DCM, rt, 3d
R1
R2
N
Ph-NH2
R2
R1
R2
then 1M HCl
70 oC, 16 h
O
N
O
VI
-Ketoamide; II
d) Malkov et al. (2017)
R1
R1
R1
O2
H
R
NaH
O Na
O
R
R
O
H
VIII
H
VII
IX
O
R1
O
e) El Kaim et al. (2017, 2018)
CH2I2
N
R1
R3
Ar
R1
R3
O
O
R2
N
NHR2
O
O
NaH (2.0 eq.)
N
XII
R3
NR2
N
O
O
Ar
R2
Ar
Ar
N
R1
N
R3
Br
X
XI
XIII
Present work
f) Trapping of peptidyl anion with molecular oxygen and oxidative cleavage
O
R1 R2
NH
O
R2
R1
H
O
KOtBu, CuI
O2
H
R3
X
N
NH
R1
R2
R3
X
THF/ACN, rt
O
O
O
(I)Cu
Passerini/Ugi adduct; XIV
-Ketoamide; II
XV
Scheme 1. Base‐mediated aerobic oxidative cleavage and trapping of Ugi‐peptidyl
anion.

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Hulme and co‐workers reported a two‐step MCR‐oxidation reaction did not proceed under argon atmosphere (entry 21,
methodology to access diverse α‐ketoamides via a copper(I)‐ Table 1). The α‐ketoamide 2a was fully characterized by 1H and
mediated C‐N oxidation/acidic hydrolysis of Ugi three‐ 13C NMR spectral analysis in which the characteristic peaks
component and Ugi‐azide reaction products. The reaction (deshielded ortho‐protons of phenyl group) of 2a were
proceeds through enolization followed by palladium‐mediated observed at δ 8.3 ppm (1H NMR, 400 MHz, CDCl3) and two
oxidative cleavage (Scheme 1c).4d Recently, Malkov et al. carbonyls appeared at δ 187.5 and 161.5 ppm (13C NMR, 100
reported dehomologation of aldehydes bearing α‐hydrogen by MHz, CDCl3) respectively.
9
using molecular oxygen as a terminal oxidant in presence of
strong base such as NaH (Scheme 1d).5 Currently, our research
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Table 1. Optimization of the reaction conditionsa
group is engaged in exploring novel post‐Ugi transformations
to identify medicinally important structural frameworks.6 In
this direction, recently we have utilized the Ugi adducts to
perform intramolecular cyclo‐isomerizations in basic medium
leading to the formation of β‐lactams and 2,5‐pyrrolidinones.
The reaction proceeds via formation of peptidyl anion
followed by 4‐exo‐dig cyclization.7 Recently, El Kaim et al.
describe trapping of Ugi derived peptidyl anion with external
electrophiles such as alkyl halides (Scheme 1e).8 The results
prompted us to investigate the fate of Passerini and Ugi
adducts in presence of oxygen and base. We envisioned that
the trapping of Passerini and Ugi adduct derived peptidyl anion
with molecular oxygen might lead to the formation of α‐
ketoamides through oxidative cleavage. Herein, we present a
general method for the oxidative cleavage of Passerini and Ugi
adducts in basic medium yielding α‐ketoamides (Scheme 1f).
Entry
Base
Additive
(mol %)
Solvent
Time
2a; yield (%)c
1.
2.
3.
4.
5.
NaH
NaH
‐
THF
THF
THF
THF
THF
10 min
10 min
10 min
10 min
10 min
trace
trace
15
CuI (5)
CuI (10)
CuI (20)
‐
NaH
NaH
22
KOtBu
12
6.
KOtBu
KOtBu
KOtBu
K2CO3
Cs2CO3
DBU
CuI (5)
CuI (10)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuBr (20)
I2 (20)
THF
THF
10 min
10 min
10 min
12 h
25
41
7.
Results and Discussion
8.
THF
87
At the outset of this investigation, benzoic acid derived
Passerini adduct 1a was treated with different bases such as
NaH and KOtBu in THF under oxygen atmosphere (entries 1
and 5, Table 1). To our delight, the formation of desired α‐
ketoamide 2a was observed albeit in low yields and poor rate
of conversion (entries 1 and 5, Table 1). Next to improve the
yield, CuI was added, as copper (I) helps the oxygen transfer in
such reactions. Addition of 5 mol% CuI alongwith NaH however
did not improve the yield of the product (entry 2, Table 1).
Addition of 10 mol% CuI alongwith NaH in THF resulted the
desired product 2a in 15% yield, showing the expected role of
copper in the transformation (entry 3, Table 1). Increasing the
quantity of CuI to 20 mol% resulted in 22% yield of 2a (entry 4,
Table 1). Addition of 5 mol% CuI alongwith KOtBu resulted in
25% yield of corresponding α‐ketoamide 2a (entry 6, Table 1).
Increasing the quantity of CuI to 10 mol% afforded 2a in 41%
yield (entry 7, Table 1). However, 20 mol% of CuI alongwith
KOtBu yielded 2a in 87% yield (entry 8, Table 1). With bases
such as K2CO3 and Cs2CO3, no formation of 2a was observed
and the Passerini adduct 1a remained unreacted even under
reflux conditions (entries 9 and 10, Table 1). The oxidative
cleavage with organic base such as DBU was also unsuccessful
(entry 11, Table 1). After screening of bases with various
solvents and 20 mol% of CuI (entries 12‐17, Table 1), it was
observed that KOtBu in THF gave the best result with complete
conversion of 1a and formation of 2a in 87% yield (entry 8,
Table 1). With other copper salts, corresponding α‐ketoamide
2a was obtained in low yields (entries 18‐20, Table 1). It was
observed that oxygen is essential for the conversion as the
9.
THF
0
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21b
THF
12 h
0
THF
12 h
0
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
CH3CN
10 min
trace
53
Toluene 10 min
DMF 10 min
Dioxane 10 min
trace
0
DCM
DMSO
THF
10 min
10 min
10 min
10 min
10 min
10 min
38
trace
27
THF
24
NIS (20)
CuI (20)
THF
15
THF
trace
aReaction Conditions: 1a (0.1 mmol), base (0.3 mmol), CuI in solvent (2.0 mL) at rt
under oxygen balloon. bUnder argon. cIsolated yields.
In order to check the scope of the method for the oxidative
cleavage of Passerini adducts, adducts 1a‐l were subjected to
the standard reaction conditions (Table 2). All the Passerini
2 | J. Name., 2012, 00, 1‐3
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adducts 1a‐k reacted well and corresponding α‐ketoamides
COMMUNICATION
1
2
3
4
5
6
7
8
2
11.
12.
were isolated in good‐to‐excellent yields (Table 2). To further
explore the robustness and scope of our methodology, we
tried to perform the oxidative cleavage in aliphatic aldehyde
derived Passerini adducts 1l‐n. Notably, the Passerini adduct 1l
with R1 as benzyl was sluggish and the α‐ketoamide 2k was
obtained in 28% yield along with the hydrolysis product 2k' in
23% yield (entry 12, Table 2). To our disappointment, the other
aliphatic aldehyde derived Passerini adducts 1m and 1n did
not yield the desired α‐ketoamide and only the hydrolysis
products 2l' and 2m' were obtained in 53% and 72% yields
respectively (entries 13 and 14, Table 2). This could be due to
the poor enolizability of such adducts.
1k
1l
2j; 55%
2k; 28%
2k'; 23%
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13.
14.
1m
1l
2l'; 53%
Table 2. Oxidative cleavage of Passerini adductsa
2m'; 72%
aReaction Conditions: 1 (0.2 mmol), KOtBu (0.6 mmol), CuI (20 mol %) in THF (5.0
mL) for 30 min at rt under oxygen balloon. bIsolated yields.
Entry
1.
Passerini adduct
2; yield (%)b)
In order to investigate the reaction mechanism, we subjected
the Passerini adduct 1a to standard reaction conditions in
presence of radical quenchers (2,2,6,6‐Tetramethylpiperidin‐1‐
yl)oxyl (TEMPO) and butylated hydroxytoluene (BHT)
respectively (Scheme 2a). In both the cases, α‐ketoamide 2a
was obtained in traces with sluggish reaction indicating a
radical pathway for the reaction (Scheme 2a).
1a
2a; 87%
2b; 47%
2c; 58%
OBz
2.
3.
H
N
tBu
O
1b
OAc
H
N
CyHex
a) Oxidative cleavage of Passerini adduct 1a in presence of radical
scavangers
O
Me
O
OBz
1c
1d
1e
1f
H
H
N
standard conditions
N
4.
5.
Ph
Bn
Ph
Ph
Bn
Bn
TEMPO (5.0 equiv)
O
O
1a
2a; traces
2d; 46%
2d; 48%
2e; 68%
O
H
OBz
H
N
standard conditions
N
Ph
Bn
BHT (5.0 equiv)
O
O
1a
2a; traces
b) KIE studies
6.
O
OBz
H
H
KOtBu, CuI, O2
THF, rt
N
N
tBu
tBu
H
O
O
MeO
MeO
2d
1d
7.
O
OBz
H
H
KOtBu, CuI, O2
THF, rt
N
N
tBu
tBu
H/D
O
O
1g
1h
1i
2f; 50%
2g; 28%
MeO
MeO
2d
1d / D-1d
(65% D-labeled)
8.
c) Oxidative cleavage of 18O-labeled Passerini adduct 18O-1b
18O
O
H
18O
9.
KOtBu, CuI, O2
THF, rt, 10 min
18O
Ph
H
N
1
tBu
2
+
Ph
18OH
Ph
18O-2b'
[M+H]+ m/z = 127.9792
N
18O
18O-2b
[M+H]+ m/z = 208.1217
tBu
Ph
2h; 45%
2i; 49%
18O
18O-1b
[M+H]+ m/z = 318.1717
10.
51.02% 18O/18
23.98% 18O/16
25% 16O/16
O
O
90.9% 18O/16
9.09% 16O/16
O
O
70.92% 18O/18O/18
29.08% 18O/18O/16
O
O
O
1j
Scheme 2. Control experiments.
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In order to extend the scope of this methodology, the Ugi
adduct 3a was reacted under the standard reaction conditions.
Although formation of the α‐ketoamide 2a was observed on
TLC, the conversion was very low. Subsequent screening of
different reaction conditions revealed that KOtBu (3.0 equiv)
and CuI (20 mol %) in CH3CN provided the best condition for
the formation of α‐ketoamide and amide from the
corresponding Ugi adduct (See Supporting Information for
optimization table).
Next, the kinetic isotope effect was studied by performing
the oxidative cleavage with deuterated Passerini adduct D‐1d
under the standard reaction conditions (Scheme 2b). KH/KD
was found to be 3.14 for the formation of α‐ketoamide 2d
,
reflecting that the proton abstraction is the rate determining
step in this reaction (See Supporting Information). Further, to
rule out the possibility of ester hydrolysis and alcohol
oxidation, we prepared the 18O‐labeled Passerini adduct 18O‐
1b (m/z = 318.1717) by reacting 18O‐labeled benzoic acid9 and
18O‐labeled benzaldehyde.10 When the Passerini adduct 18O‐1b
was subjected to the standard reaction conditions, it yielded
predominantly the 18O‐labeled α‐ketoamide 18O‐2b and
corresponding acid 18O‐2b' in 27% and 38% yields respectively
(Scheme 2c). HRMS analysis revealed that the α‐ketoamide
18O‐2b (having only C‐1 oxygen labeled) has m/z = 208.1217,
while the 18O‐labeled benzoic acid has m/z = 127.9792 (See
Supporting Information). This confirms that the oxygen at C‐2
position of the α‐ketoamide 18O‐2b is coming from molecular
oxygen (Scheme 2c). Notably, this experiment also confirmed
the incorporation of only one 16O oxygen atom in the α‐
ketoamide as there was negligible formation of 2b in the
reaction.11
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Table 3. Oxidative cleavage of Ugi adductsa
Entry
1.
Ugi adduct
2; yield (%)b
2a; 81%
4; yield (%)b
4a; 53%
3a
3b
3c
2.
3.
4.
Considering the observations from above experiments and
previous literature reports,11,12 the oxidative cleavage of
Passerini adducts can be explained by a putative reaction
2b; 60%
2b; 78%
4a; 75%
mechanism as depicted in Scheme 3. Passerini adduct
undergo enolization in presence of base which might be
trapped by Cu(I) to form intermediate . Intermediate could
be oxidized to superoxide radical through radical pathway in
presence of molecular oxygen. Radical species rearranges to
form intermediate , which then forms peroxide intermediate
by regeneration of CuI. Peroxide intermediate then
undergoes homolytic cleavage with elimination of water and
tert‐butoxide radical to form intermediate . Subsequent
A might
‐‐‐‐#
B
B
C
D
E
E
4b; 70%
2n; 35%
2c; 50%
F
elimination of acetate radical
3
affords α‐ketoamide 2 and
3d
corresponding acid.
5.
6.
O
R1
‐‐‐‐#
NHR2
R3
O
KOtBu
CuI
O2
O
(I)Cu
O
B
R1
H
O
R3
O
NHR2
R1
R3
O
NHR2
3e
3f
O
O
O
A
C
O
Cu
‐‐‐‐#
(II)
R1
NHR2
2c; 74%
2o; 45%
O
O
O
O
-Ketoamide; 2
R3
NHR2
O
7.
8.
R1
O
R4
3
O
O
Cu(I)
D
O
O
4a; 44%
4a; 48%
CuI
R4
NHR2
O
R1
O
3g
3h
H2O + tBuO
O
O
O
O
R3
NHR2
F
R1
O
E
2d; 83%
OH
tBuOH
Scheme 3. Proposed reaction mechanism.
4 | J. Name., 2012, 00, 1‐3
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9.
21.
4
5
2p; 78%
2aa; 60%
4d; 67%
4a; 69%
3i
3j
6
7
8
9
3u
10.
11.
12.
13.
14.
aReaction Conditions: 3 (0.2 mmol), KOtBu (0.6 mmol), CuI (20 mol %) in CH3CN
(5.0 mL) for 15 min at rt under oxygen balloon. bIsolated yields. #Complex
mixture.
2q; 75%
2r; 50%
4a; 49%
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To explore the generality of the oxidative cleavage, a wide
variety of Ugi adducts were reacted under the optimized
reaction conditions (Table 3). It was observed that the reaction
worked well with both the aromatic and heteroaromatic
aldehyde derived Ugi adducts. The Ugi adducts with R1 as
electron rich aromatic groups (entries 5, 6, 8, 13, 17, 18; Table
3) reacted well in comparison to the electron deficient
aromatic groups (entries 4, 9, 11, 12, 15, 20, 21; Table 3). It
was interesting to note that the Ugi adducts with R1 as
heteroaromatic groups such as furyl, indolyl and pyrolyl
underwent smooth transformation yielding the corresponding
α‐ketoamides in good yields (entries 10, 14, 16; Table 3). The
‐‐‐‐#
3k
‐‐‐‐#
‐‐‐‐#
2s; 79%
2t; 84%
3l
3m
Ugi adducts with R2 as Bu, CyHex, Bn, Ph and 4‐Br‐C6H4
t
reacted well except with the naphthyl group yielding the
corresponding α‐ketoamide 2o in 45% yield (entry 7, Table 3).
Notably, the Ugi adducts with R3 as phenyl and methyl were
found to be suitable for the oxidative cleavage. However, in
the cases with R3 as methyl, corresponding amides could not
be isolated and formation of a complex mixture was observed
(entries 3, 6, 11‐13; Table 3). Both the aromatic and aliphatic
groups at R4 were well tolerated for the oxidative cleavage.
Next, the cyclic imine derived Ugi adducts 5a‐c were
subjected to the standard reaction conditions (Scheme 4).
Interestingly, the smooth ring cleavage was observed leading
to the formation of corresponding α‐ketoamides 6a‐c in
reasonably good yields (Scheme 4). The complete conversion
4c; 43%
2u; 57%
2v; 65%
3n
3o
15.
16.
4c; 60%
4a; 49%
2w; 75%
3p
3q
of
5 took longer reaction time of 12 h, with formation of
corresponding α‐ketoamide 6c in 29% yield.
17.
18.
H
O
4a; 65%
4a; 74%
N
2x; 87%
2y; 65%
R1
R1
N
KOtBu, CuI, O2
O
N
O
H
N
CH3CN, rt, 12 h
O
R2HN
H
NHR2
O
5a: R1= Ph, R2= tBu
5b: R1= Ph, R2= CyHex
5c: R1= Me, R2= CyHex
6a; 63%
6b; 51%
6c; 29%
3r
3s
3t
19.
20.
Scheme 4. Oxidative cleavage of cyclic U‐3CR adducts. Reaction Conditions: 5 (0.2
mmol), KOtBu (0.6 mmol), CuI (20 mol %) in CH3CN (5.0 mL) for 12 h at rt under oxygen
balloon. Isolated yields.
4a; 45%
4a; 58%
2e; 76%
2z; 79%
Surprisingly, the dihydroisoquinoline derived Ugi adduct
did not undergo the oxidative ring opening, rather a mixture of
deacylated dihydroisoquinoline and isoquinoline were
obtained (Scheme 5). This might have happened
predominantly due to the thermodynamic stability of DHIQ
and isoquinoline . A putative mechanism has been given
wherein the hydroxyl group at C1 in intermediate might have
7
8
9
8
9
C
migrated to the amide carbonyl leading to the formation of
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dihydroisoquinoline 8. Air oxidation of 8 would have generated
the isoquinoline 9 (Scheme 5).
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
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Scheme 5. Unexpected formation of deacylated dihydroisoquinoline and isoquinoline
from THIQ‐derived Ugi adducts. Reaction Conditions: 7 (0.2 mmol), KOtBu (0.6 mmol),
CuI (20 mol %) in CH3CN (5.0 mL) for 12 h at rt under oxygen balloon. Isolated yields.
Scheme 7. Aerobic oxidative cleavage of azaspirotrienone containing Ugi‐type adducts.
Reaction Conditions: 11 (0.2 mmol), KOtBu (0.6 mmol), CuI (20 mol %) in CH3CN (5.0
mL) for 15 min at rt under oxygen balloon. Isolated yields.
In another effort to see the applicability of this oxidative
cleavage, the Ugi‐Smile adduct 10 was reacted under standard
conditions (Scheme 6). Adduct 10 underwent smooth cleavage
affording the α‐ketoamide 2s in 69% yield.
Conclusion
In conclusion, the present study provides an insight into the
reactivity of Passerini and Ugi adducts in strong basic
conditions resulting in the formation of α‐ketoamides. A
detailed mechanistic investigation established the role of
copper and confirmed the incorporation of single oxygen atom
in the product from molecular oxygen. This method is general
and tolerates a variety of functionalities making it suitable for
a diverse set of Passerini and Ugi adducts. The present study
would be of great importance in designing novel post‐
functionalization of Passerini and Ugi adducts.
Scheme 6. Aerobic oxidative cleavage of Ugi‐Smile adduct 10. Reaction Conditions: 10
(0.2 mmol), KOtBu (0.6 mmol), CuI (20 mol %) in CH3CN (5.0 mL) for 12 h at rt
under oxygen balloon. Isolated yields.
We further investigated the scope of the oxidative cleavage
in azaspirotrienone containing Ugi adducts 11a‐f, that were
readily available in our lab through our reported one‐pot
procedure.6b The reaction proceeded well and clean formation
of the corresponding α‐ketoamides were observed in good
yields (Scheme 7). Formation of a byproduct 2ad was noticed
with all the substrates, but the characterizable quantity of 2ad
could be isolated only with 11e. Structure of 2ad was
established on the basis of 1H‐, 13C‐NMR and Mass data. It can
be postulated that the ring cleavage of amide 3ac might have
happened in the presence of copper leading to the formation
of 2ad as shown in the plausible mechanism (Scheme 7).13
Experimental Section
A. General Information. All the reagents and solvents were
used as received from commercial sources without further
purification. All air and moisture sensitive reactions were
conducted under inert atmosphere of nitrogen. Reactions
were monitored by thin‐layer chromatography carried out on
silica plates (Silica gel 60 F254, Merck) using uv‐light, iodine,
ninhydrin and p‐anisaldehyde for visualization. Column
chromatography was carried out using silica gel (100‐200 and
230‐400 mesh) packed in glass columns. Technical grade ethyl
acetate and petroleum ether used for column chromatography
were distilled prior to use. 1H NMR and 13C NMR spectra were
recorded in CDCl3 or DMSO‐d6 as solvent (300 and 75 MHz /
400 and 100 MHz
/ 500 and 125 MHz) at ambient
temperature. The coupling constant J is given in Hz. The
chemical shifts (δ) are reported in ppm on scale downfield
from TMS and using the residual solvent peak in CDCl3 (H: δ =
7.26 ppm and C: δ = 77.00 ppm) or TMS (δ = 0.00) as internal
standard and signal patterns are indicated as follows: s =
singlet, d = doublet, dd = doublet of doublet, ddd = doublet of
doublet of doublet, dt = doublet of triplet, t = triplet, q =
quartet, m = multiplet. High‐resolution mass spectra (HRMS)
were recorded on a Thermo Scientific Exactive ORBITRAP
6 | J. Name., 2012, 00, 1‐3
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spectrometer using H2O/MeOH mixed with 0.1% formic acid as 167.6, 163.2, 160.7, 159.9, 128.9, 127.9, 114.0, 75.2, 55.2,
mobile phase. All the known compounds were in accordance 51.4, 28.7, 28.5, 20.9; HRMS (ESI): calcd. for C15H22NO4 [M+H]+:
with the data reported in the literatures.
280.1549, found: 280.1555.
B. Experimental Procedures
2‐((4‐bromophenyl)amino)‐2‐oxo‐1‐phenylethyl benzoate (1f).
I. General Procedure for the synthesis of Passerini adducts Yellow solid (200.0 mg, 60%); m.p: 142 °C; Rf = 0.38 (30%
1a‐l. Equimolar mixture of aldehyde (1.0 equiv, 0.8 mmol), acid EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 8.16 – 8.12 (m,
(1.0 equiv, 0.8 mmol) and isocyanide (1.0 equiv, 0.8 mmol) in 2H), 7.91 (s, 1H), 7.66 – 7.59 (m, 3H), 7.51 (t, J = 7.7 Hz, 2H),
water was stirred at room temperature for 6 h. After 7.45 – 7.40 (m, 7H), 6.43 (s, 1H); 13C NMR (125 MHz, CDCl3): δ
completion of the reaction (based on TLC), reaction mixture 166.4, 165.2, 136.0, 134.8, 133.9, 131.9, 129.9, 129.4, 129.0,
was diluted with ethyl acetate and washed with saturated 128.7, 127.5, 121.6, 117.5, 76.1; HRMS (ESI): calcd. for
sodium bicarbonate solution. Aqueous layer was extracted C21H17BrNO3 [M+H]+: 410.0392, found: 410.0385.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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48
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53
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58
59
60
with ethyl acetate and the combined organic layers were dried 2‐(tert‐butylamino)‐2‐oxo‐1‐(p‐tolyl)ethyl acetate (1g). White
over anhydrous sodium sulfate followed by evaporation of solid (176.0 mg, 82%); m.p: 138 °C; Rf = 0.35 (30% EtOAc in
1
solvent in vacuo. The crude was purified by silica gel column hexane); H NMR (500 MHz, CDCl3): δ 7.30 (d, J = 8.1 Hz, 2H),
chromatography to afford the desired product
1
.
7.17 (d, J = 7.9 Hz, 2H), 5.92 (s, 1H), 5.89 (s, 1H), 2.34 (s, 3H),
2‐(benzylamino)‐2‐oxo‐1‐phenylethyl benzoate (1a). White 2.15 (s, 3H), 1.35 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 169.2,
solid (200.0 mg, 72%); m.p: 84 °C, Rf = 0.35 (30% EtOAc in 167.5, 138.7, 132.9, 129.4, 127.4, 75.5, 51.5, 28.6, 21.2, 21.0;
hexane); 1H NMR (300 MHz, CDCl3): δ 8.09 (dd, J = 1.8, 1.2 Hz, HRMS (ESI): calcd. for C15H22NO3 [M+H]+: 264.1600, found:
1H), 8.07 (t, J = 1.7 Hz, 1H), 7.62 – 7.53 (m, 3H), 7.48 – 7.37 (m, 264.1595.
5H), 7.31 – 7.24 (m, 3H), 7.24 – 7.18 (m, 2H), 6.50 (s, 1H), 6.37 2‐(naphthalen‐1‐ylamino)‐2‐oxo‐1‐phenylethyl benzoate (1h)
.
(s, 1H), 4.58 – 4.42 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 168.4, White solid (220.0 mg, 72%); m.p: 170 °C; Rf = 0.45 (40% EtOAc
165.0, 137.7, 135.5, 133.6, 129.8, 129.2, 129.0, 128.8, 128.7, in hexane); 1H NMR (500 MHz, CDCl3): δ 8.38 (s, 1H), 8.21 (d, J
128.6, 127.5, 127.5, 127.3, 75.9, 43.3; HRMS (ESI): calcd. for = 7.3 Hz, 2H), 7.98 (d, J = 7.1 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H),
C22H20NO3 [M+H]+: 346.1443, found: 346.1431.
7.70 (d, J = 6.5 Hz, 3H), 7.65 (t, J = 10.4 Hz, 2H), 7.52 (t, J = 7.2
2‐(tert‐butylamino)‐2‐oxo‐1‐phenylethyl benzoate (1b). White Hz, 2H), 7.48 – 7.42 (m, 6H), 6.62 (s, 1H); 13C NMR (125 MHz,
solid (205.0 mg, 82%); m.p: 148 °C; Rf = 0.32 (30% EtOAc in CDCl3): δ 166.9, 165.0, 135.3, 134.0, 133.8, 131.2, 129.9, 129.3,
hexane); 1H NMR (400 MHz, CDCl3): δ 8.12 – 8.06 (m, 2H), 7.63 129.1, 129.0, 128.81, 128.7, 127.5, 126.5, 126.2, 125.9, 125.7,
– 7.58 (m, 1H), 7.54 – 7.46 (m, 4H), 7.42 – 7.33 (m, 3H), 6.22 (s, 120.7, 120.0, 76.4; HRMS (ESI): calcd. for C25H20NO3 [M+H]+:
1H), 5.98 (s, 1H), 1.37 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 382.1443, found: 382.1444.
167.3, 164.9, 135.9, 133.6, 129.7, 129.4, 128.9, 128.8, 128.6, 2‐oxo‐1‐phenyl‐2‐(phenylamino)ethyl benzoate (1i). Yellow
127.4, 76.0, 51.6, 28.7; HRMS (ESI): calcd. for C19H22NO3 solid (200.0 mg, 75%); m.p: 177 °C; Rf = 0.30 (30% EtOAc in
[M+H]+: 312.1600, found: 312.1591.
hexane); 1H NMR (400 MHz, CDCl3): δ 8.17 – 8.15 (m, 1H), 8.14
2‐(cyclohexylamino)‐2‐oxo‐1‐(p‐tolyl)ethyl acetate (1c). White (d, J = 1.4 Hz, 1H), 7.88 (s, 1H), 7.66 – 7.60 (m, 3H), 7.50 (dd, J =
solid (256.0 mg, 81%); m.p: 153 °C; Rf = 0.36 (30% EtOAc in 10.8, 4.6 Hz, 4H), 7.45 – 7.38 (m, 3H), 7.33 – 7.28 (m, 2H), 7.12
hexane); 1H NMR (400 MHz, CDCl3): δ 7.98 – 7.96 (m, 1H), 7.40 (t, J = 7.4 Hz, 1H), 6.46 (s, 1H); 13C NMR (125 MHz, CDCl3): δ
(d, J = 8.1 Hz, 1H), 7.28 (s, 1H), 7.18 (d, J = 7.9 Hz, 1H), 6.26 (s, 166.3, 165.0, 136.9, 135.1, 133.8, 129.9, 129.2, 129.1, 129.0,
1H), 6.10 – 5.97 (m, 1H), 3.87 – 3.77 (m, 1H), 2.42 (s, 3H), 2.34 128.9, 128.7, 127.5, 124.9, 120.1, 76.1; HRMS (ESI): calcd. for
(s, 3H), 1.97 – 1.86 (m, 2H), 1.68 (ddd, J = 17.2, 8.8, 4.7 Hz, 2H), C21H18NO3 [M+H]+: 332.1287, found: 332.1284.
1.35 (m, 2H), 1.15 (tdd, J = 27.3, 11.7, 3.6 Hz, 4H); 13C NMR 2‐(tert‐butylamino)‐1‐(4‐cyanophenyl)‐2‐oxoethyl benzoate
(125 MHz, CDCl3): δ 167.6, 164.9, 144.3, 138.7, 132.9, 129.8, (1j). White solid (216.0 mg, 80%); m.p: 150 °C; Rf = 0.45 (30%
1
129.4, 129.3, 127.4, 126.7, 75.7, 48.1, 32.9, 32.8, 25.4, 24.7, EtOAc in hexane); H NMR (300 MHz, CDCl3): δ 8.10 (s, 1H),
24.6, 21.7, 21.2; HRMS (ESI): calcd. for C17H24NO3 [M+H]+: 8.07 (t, J = 1.7 Hz, 1H), 7.68 – 7.65 (m, 4H), 7.55 – 7.47 (m, 3H),
290.1756, found: 290.1750.
6.25 (s, 1H), 6.15 (s, 1H), 1.37 (s, 9H); 13C NMR (75 MHz, CDCl3):
2‐(tert‐butylamino)‐1‐(4‐methoxyphenyl)‐2‐oxoethyl
δ 166.3, 164.5, 140.9, 134.0, 133.6, 132.5, 130.1, 129.7, 128.8,
benzoate (1d). White solid (212.0 mg, 77%); m.p: 145 °C; Rf = 128.7, 128.4, 127.9, 118.4, 112.7, 75.1, 51.9, 28.6; HRMS (ESI):
0.30 (30% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 8.13 calcd. for C20H21N2O3 [M+H]+: 337.1552, found: 337.1556.
– 8.01 (m, 2H), 7.62 – 7.57 (m, 1H), 7.45 (ddd, J = 9.4, 6.4, 2.2 2‐(cyclohexylamino)‐1‐(naphthalen‐1‐yl)‐2‐oxoethyl benzoate
Hz, 4H), 6.97 – 6.85 (m, 2H), 6.17 (s, 1H), 5.96 (s, 1H), 3.80 (s, (1k). White solid (275.0 mg, 70%); m.p: 140 °C; Rf = 0.30 (30%
3H), 1.37 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 167.6, 164.9, EtOAc in hexane); 1H NMR (300 MHz, CDCl3): δ 8.27 (d, J = 8.3
160.0, 133.5, 129.7, 129.5, 129.0, 128.6, 128.1, 114.2, 75.7, Hz, 1H), 8.14 – 8.01 (m, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.68 (d, J =
55.3, 51.5, 28.7; HRMS (ESI): calcd. for C20H23NNaO4 [M+Na]+: 7.0 Hz, 1H), 7.52 (ddt, J = 22.2, 15.1, 6.4 Hz, 6H), 6.97 (s, 1H),
364.1525, found: 364.1526.
5.89 (d, J = 8.0 Hz, 1H), 3.85 (dtt, J = 12.1, 8.1, 3.9 Hz, 1H), 1.94
2‐(tert‐butylamino)‐1‐(4‐methoxyphenyl)‐2‐oxoethyl acetate (d, J = 9.2 Hz, 1H), 1.88 – 1.76 (m, 1H), 1.67 (d, J = 4.0 Hz, 1H),
(1e). Yellow solid (156.0 mg, 69% ); m.p: 129 °C; Rf = 0.32 (30% 1.56 (s, 2H), 1.39 – 1.21 (m, 2H), 1.08 (m, 3H); 13C NMR (75
EtOAc in hexane); 1H NMR (500 MHz, CDCl3): δ 7.36 – 7.32 (m, MHz, CDCl3): δ 167.5, 165.3, 134.1, 133.5, 131.6, 131.4, 130.1,
2H), 6.90 – 6.87 (m, 2H), 6.00 (s, 1H), 5.91 (s, 1H), 3.79 (s, 3H), 129.9, 129.4, 128.8, 128.5, 127.3, 126.9, 126.1, 125.1, 123.9,
2.15 (s, 3H), 1.35 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 169.3,
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74.2, 48.4, 32.8, 32.7, 25.4, 24.7, 24.6; HRMS (ESI): calcd. for 128.3, 51.6, 28.3; HRMS (ESI): calcd. for C12H16NO2 [M+H]+:
C25H26NO3 [M+H]+: 388.1913, found: 388.1888.
206.1181, found: 206.1169.
1‐(cyclohexylamino)‐1‐oxo‐3‐phenylpropan‐2‐yl acetate (1l)
.
N‐cyclohexyl‐2‐oxo‐2‐(p‐tolyl)acetamide (2c)14. Yellow sticky
1
White solid (216.0 mg, 68%); m.p: 82 °C; Rf = 0.30 (40% EtOAc solid (24.6 mg, 50%); Rf = 0.65 (30% EtOAc in hexane); H NMR
1
6
in hexane); H NMR (300 MHz, CDCl3): δ 7.33 – 7.24 (m, 3H), (300 MHz, CDCl3): δ 8.31 – 8.19 (m, 2H), 7.29 (s, 1H), 7.26 (s,
7
8
9
7.23 – 7.15 (m, 2H), 5.68 (d, J = 7.6 Hz, 1H), 5.34 (t, J = 5.8 Hz, 1H), 6.95 (s, 1H), 3.92 – 3.78 (m, 1H), 2.42 (s, 3H), 2.04 – 1.92
1H), 3.75 (ttd, J = 12.2, 8.2, 3.9 Hz, 1H), 3.27 – 3.11 (m, 2H), (m, 2H), 1.82 – 1.71 (m, 2H), 1.70 – 1.61 (m, 1H), 1.50 – 1.38
2.10 (s, 3H), 1.86 – 1.75 (m, 2H), 1.64 (dd, J = 9.6, 3.7 Hz, 2H), (m, 2H), 1.38 – 1.27 (m, 3H); 13C NMR (75 MHz, CDCl3): δ 187.6,
1.43 – 1.26 (m, 3H), 1.14 (ddd, J = 14.8, 8.1, 3.7 Hz, 1H), 1.02 161.1, 145.5, 131.4, 130.9, 129.2, 48.4, 32.7, 25.4, 24.7, 21.9;
(ddd, J = 15.1, 7.2, 3.3 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ HRMS (ESI): calcd. for C15H20NO2 [M+H]+: 246.1494, found:
169.3, 167.7, 135.8, 129.6, 128.3, 126.8, 74.3, 47.8, 37.6, 32.8, 246.1487.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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36
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39
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48
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50
51
52
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59
60
32.7, 25.4, 24.7, 24.6, 20.9; HRMS (ESI): calcd. for C17H24NO3 N‐(tert‐butyl)‐2‐(4‐methoxyphenyl)‐2‐oxoacetamide
(2d)14
Yellow solid (39.1 mg, 83%); m.p: 61 °C; Rf = 0.65 (30% EtOAc in
.
[M+H]+: 290.1756, found: 290.1745.
1‐(benzylamino)‐1‐oxo‐3‐phenylpropan‐2‐yl benzoate (1m)
.
hexane); 1H NMR (400 MHz, CDCl3): δ 8.42 – 8.35 (m, 2H), 6.97
White solid (200.0 mg, 70%), m.p: 122 °C; Rf = 0.30 (40% EtOAc (s, 1H), 6.96 – 6.91 (m, 2H), 3.88 (s, 3H), 1.45 (s, 9H); 13C NMR
1
in hexane); H NMR (300 MHz, CDCl3): δ 8.00 – 7.92 (m, 2H), (100 MHz, CDCl3): δ 186.6, 164.5, 161.7, 133.9, 126.4, 113.7,
7.62 – 7.53 (m, 1H), 7.48 – 7.38 (m, 2H), 7.30 – 7.21 (m, 8H), 55.5, 51.5; HRMS (ESI): calcd. for C13H18NO3 [M+H]+: 236.1287,
7.14 – 6.97 (m, 2H), 6.21 (s, 1H), 5.70 (t, J = 5.6 Hz, 1H), 4.48 found: 236.1278.
(dd, J = 15.0, 6.2 Hz, 1H), 4.35 (dd, J = 15.0, 5.6 Hz, 1H), 3.35 (d, N‐(4‐bromophenyl)‐2‐oxo‐2‐phenylacetamide (2e)15
. Yellow
J = 5.6 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ 168.9, 165.2, 137.5, sticky solid (46.3 mg, 76%); Rf = 0.65 (30% EtOAc in hexane); 1H
135.8, 133.6, 129.8, 129.7, 129.1, 128.6, 128.4, 127.4, 126.9, NMR (400 MHz, CDCl3): δ 8.97 (s, 1H), 8.44 – 8.38 (m, 2H), 7.69
74.8, 43.1, 37.8; HRMS (ESI): calcd. for C23H22NO3 [M+H]+: – 7.65 (m, 1H), 7.63 – 7.59 (m, 2H), 7.55 – 7.49 (m, 4H); 13C
360.1600, found: 360.1600.
NMR (125 MHz, CDCl3): δ 187.0, 158.8, 135.7, 134.8, 132.9,
1‐cyclohexyl‐2‐oxo‐2‐(phenylamino)ethyl benzoate
(1n)
.
132.2, 131.5, 128.6, 121.4, 118.1; HRMS (ESI): calcd. for
White solid (100.0 mg, 37%), m.p: 102 °C; Rf = 0.30 (40% EtOAc C14H11BrNO2 [M+H]+: 303.9973, found: 303.9964.
1
in hexane); H NMR (300 MHz, CDCl3): δ 8.15 (dd, J = 1.9, 1.2 N‐(tert‐butyl)‐2‐oxo‐2‐(p‐tolyl)acetamide (2f)4c
. Yellow oil
Hz, 1H), 8.12 (t, J = 1.7 Hz, 1H), 7.74 (s, 1H), 7.68 – 7.62 (m, (29.9 mg, 68%); Rf = 0.65 (30% EtOAc in hexane); 1H NMR (400
1H), 7.56 – 7.48 (m, 4H), 7.35 – 7.27 (m, 2H), 7.12 (ddd, J = 8.5, MHz, CDCl3): δ 8.23 (d, J = 8.3 Hz, 2H), 7.28 – 7.25 (m, 2H), 6.93
2.2, 1.1 Hz, 1H), 5.41 (d, J = 4.7 Hz, 1H), 2.29 – 2.15 (m, 1H), (s, 1H), 2.42 (s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
1.90 – 1.75 (m, 4H), 1.69 (d, J = 12.1 Hz, 1H), 1.38 – 1.23 (m, 188.0, 161.4, 145.3, 131.4, 130.9, 129.1, 51.6, 28.4, 28.2, 21.8;
3H), 1.23 – 1.11 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 167.5, HRMS (ESI): calcd. for C13H18NO2 [M+H]+: 220.1338, found:
165.4, 136.8, 133.7, 129.8, 129.2, 128.9, 128.8, 124.8, 120.2, 220.1331.
78.4, 40.4, 29.3, 27.5, 26.0, 25.9, 25.9; HRMS (ESI): calcd. for N‐(naphthalen‐1‐yl)‐2‐oxo‐2‐phenylacetamide (2g)16. Yellow
1
C21H24NO3 [M+H]+: 338.1756, found: 338.1747.
oil (15.5 mg, 28%); Rf = 0.69 (30% EtOAc in hexane); H NMR
II. General procedure for the oxidative cleavage of Passerini (500 MHz, CDCl3): δ 9.55 (s, 1H), 8.50 (d, J = 7.6 Hz, 2H), 8.25
adducts 1a‐n. To the solution of
1 (1.0 equiv, 0.2 mmol) in dry (d, J = 7.5 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 7.9 Hz,
THF was added KOtBu (3.0 equiv, 0.6 mmol) and CuI (0.2 equiv, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.69 (t, J = 7.3 Hz, 1H), 7.60 (t, J =
20 mol %) at room temperature and the reaction vessel was 7.4 Hz, 1H), 7.54 (d, J = 6.2 Hz, 4H); 13C NMR (100 MHz, CDCl3):
flushed with O2. The resulting reaction mixture was stirred at δ 187.5, 159.3, 134.7, 134.1, 133.2, 131.6, 131.1, 128.9, 128.6,
room temperature. After completion of the reaction (based on 126.7, 126.5, 126.3, 125.7, 120.2, 119.5; HRMS (ESI): calcd. for
TLC) in 10 minutes, the reaction mixture was quenched with C18H14NO2 [M+H]+: 276.1025, found: 276.1023.
water and the crude product was extracted with ethyl acetate. 2‐oxo‐N,2‐diphenylacetamide (2h)17. Yellow oil (20.2 mg, 45%);
The organic layer was dried over anhydrous sodium sulfate, Rf = 0.67 (30% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ
concentrated in vacuo and the crude was purified by silica gel 8.94 (s, 1H), 8.43 (d, J = 7.4 Hz, 2H), 7.71 (d, J = 7.8 Hz, 2H),
column chromatography to afford the desired α‐ketoamide
2
.
7.66 (d, J = 7.5 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 7.41 (t, J = 7.9
N‐benzyl‐2‐oxo‐2‐phenylacetamide (2a)4c. White solid (39.0 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ
mg, 81%); m.p: 96 °C; Rf = 0.65 (30% EtOAc in hexane); 1H NMR 187.4, 158.9, 136.7, 134.6, 133.1, 131.5, 129.2, 128.6, 125.3,
(400 MHz, CDCl3): δ 8.36 (dd, J = 8.2, 1.0 Hz, 2H), 7.66 – 7.60 119.9; HRMS (ESI): calcd. for C14H12NO2 [M+H]+: 226.0868,
(m, 1H), 7.49 (t, J = 7.8 Hz, 2H), 7.44 – 7.27 (m, 6H), 4.58 (d, J = found: 226.0863.
6.1 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 187.5, 161.5, 137.1, N‐(tert‐butyl)‐2‐(4‐cyanophenyl)‐2‐oxoacetamide
(2i)18
.
134.4, 133.3, 131.2, 128.8, 128.5, 127.9, 127.8, 43.5; HRMS Yellow solid (22.6 mg, 49%); m.p: 120 °C; Rf = 0.65 (30% EtOAc
(ESI): calcd. for C15H14NO2 [M+H]+: 240.1025, found: 240.1017.
in hexane); 1H NMR (300 MHz, CDCl3): δ 8.43 (d, J = 1.8 Hz, 1H),
N‐(tert‐butyl)‐2‐oxo‐2‐phenylacetamide (2b)4d. Yellow solid 8.41 (d, J = 1.8 Hz, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.75 (d, J = 1.8
(24.7 mg, 60%); m.p: 77 °C; Rf = 0.65 (30% EtOAc in hexane); 1H Hz, 1H), 6.96 (s, 1H), 1.46 (s, 9H); 13C NMR (125 MHz, CDCl3): δ
NMR (500 MHz, CDCl3): δ 8.30 (d, J = 7.5 Hz, 2H), 7.60 (t, J = 7.4 187.1, 159.9, 136.6, 132.0, 131.6, 117.9, 117.1, 51.9, 28.3;
Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 6.92 (s, 1H), 1.46 (s, 9H); 13C HRMS (ESI): calcd. for C13H15N2O2 [M+H]+: 231.1134, found:
NMR (100 MHz, CDCl3): δ 188.5, 161.1, 134.1, 133.4, 131.2, 231.1127.
8 | J. Name., 2012, 00, 1‐3
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N‐cyclohexyl‐2‐(naphthalen‐2‐yl)‐2‐oxoacetamide (2j). White N‐(naphthalen‐1‐yl)‐2‐oxo‐2‐(p‐tolyl)acetamide (2o). Yellow
1
sticky solid (41.9 mg, 55%); Rf = 0.65 (30% EtOAc in hexane); 1H oil (26.2 mg, 45%); Rf = 0.75 (20% EtOAc in hexane); H NMR
NMR (300 MHz, CDCl3): δ 8.56 (d, J = 8.5 Hz, 1H), 8.30 (dd, J = (400 MHz, CDCl3): δ 9.57 (s, 1H), 8.43 (d, J = 8.3 Hz, 2H), 8.24
7.3, 1.2 Hz, 1H), 8.07 (d, J = 8.2 Hz, 1H), 7.92 – 7.87 (m, 1H), (d, J = 7.5 Hz, 1H), 7.97 (d, J = 8.3 Hz, 1H), 7.91 (d, J = 7.5 Hz,
7.62 (ddd, J = 8.5, 6.9, 1.6 Hz, 1H), 7.58 – 7.51 (m, 2H), 7.06 (s, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.62 – 7.52 (m, 3H), 7.34 (d, J = 8.1
1H), 3.98 – 3.83 (m, 1H), 2.05 (dd, J = 9.4, 5.2 Hz, 2H), 1.85 – Hz, 2H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 186.9,
1.75 (m, 2H), 1.49 – 1.41 (m, 2H), 1.40 – 1.33 (m, 3H), 1.31 (m, 159.5, 146.1, 134.1, 131.8, 131.2, 130.7, 129.4, 128.9, 126.7,
1H); 13C NMR (125 MHz, CDCl3): δ 190.9, 161.2, 134.4, 133.9, 126.5, 126.3, 126.2, 125.7, 120.2, 119.4, 21.9; HRMS (ESI):
133.0, 131.2, 129.9, 128.7, 128.3, 126.5, 125.3, 124.2, 48.7, calcd. for C19H16NO2 [M+H]+: 290.1181, found: 290.1175.
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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32.8, 25.4, 24.8; HRMS (ESI): calcd. for C18H20NO2 [M+H]+: 2‐(4‐bromophenyl)‐N‐(tert‐butyl)‐2‐oxoacetamide
282.1494, found: 282.1482.
(2p)18
.
Yellow oil (44.6 mg, 78%); Rf = 0.65 (30% EtOAc in hexane); 1H
N‐cyclohexyl‐2‐oxo‐3‐phenylpropanamide (2k). White sticky NMR (300 MHz, CDCl3): δ 8.26 – 8.18 (m, 2H), 7.64 – 7.58 (m,
solid (13.5 mg, 28%); Rf = 0.75 (30% EtOAc in hexane); 1H NMR 2H), 6.95 (s, 1H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3): δ
(400 MHz, CDCl3): δ 7.36 – 7.30 (m, 2H), 7.29 – 7.24 (m, 3H), 187.4, 160.7, 132.8, 132.1, 131.8, 129.8, 51.7, 28.3; HRMS
6.81 (s, 1H), 4.22 (s, 2H), 3.74 (tdd, J = 8.6, 7.5, 4.2 Hz, 1H), (ESI): calcd. for C12H15BrNO2 [M+H]+: 284.0286, found:
1.93 – 1.87 (m, 2H), 1.76 – 1.69 (m, 2H), 1.38 (dd, J = 10.0, 6.7 284.0282.
Hz, 2H), 1.23 – 1.13 (m, 4H); 13C NMR (100 MHz, CDCl3): δ N‐benzyl‐2‐(furan‐2‐yl)‐2‐oxoacetamide (2q)4d. Light yellow
196.4, 158.9, 132.9, 129.8, 128.6, 127.2, 48.5, 43.1, 32.6, 25.3, solid (34.4 mg, 75%); m.p: 95 °C; Rf = 0.69 (20% EtOAc in
1
24.7; HRMS (ESI): calcd. for C15H19NNaO2 [M+Na]+: 268.1313, hexane); H NMR (400 MHz, CDCl3): δ 8.98 (d, J = 0.6 Hz, 1H),
found: 268.1299.
N‐cyclohexyl‐2‐hydroxy‐3‐phenylpropanamide (2k')
7.54 (s, 1H), 7.46 (t, J = 1.4 Hz, 1H), 7.37 – 7.33 (m, 2H), 7.33 –
.
White 7.30 (m, 3H), 6.90 (d, J = 1.9 Hz, 1H), 4.54 (d, J = 6.1 Hz, 2H); 13
C
solid (11.5 mg, 23%), m.p: 82 °C; Rf = 0.30 (30% EtOAc in NMR (100 MHz, CDCl3): δ 181.6, 160.3, 153.5, 143.6, 136.9,
hexane); 1H NMR (300 MHz, CDCl3): δ 7.39 – 7.23 (m, 5H), 6.24 128.9, 127.9, 127.8, 122.7, 109.2, 43.4; HRMS (ESI): calcd. for
(d, J = 6.8 Hz, 1H), 4.28 (dt, J = 7.9, 4.7 Hz, 1H), 3.77 (tdt, J = C13H12NO3 [M+H]+: 230.0817, found: 230.0810.
12.3, 8.2, 3.9 Hz, 1H), 3.21 (dd, J = 13.9, 4.6 Hz, 1H), 2.95 (dd, J 2‐(4‐bromophenyl)‐N‐cyclohexyl‐2‐oxoacetamide (2r). White
= 13.9, 7.8 Hz, 1H), 2.60 (d, J = 4.9 Hz, 1H), 1.85 (dd, J = 14.3, solid (31.1 mg, 50%); m.p: 105 °C; Rf = 0.65 (30% EtOAc in
6.3 Hz, 2H), 1.71 (d, J = 3.9 Hz, 1H), 1.60 (d, J = 3.8 Hz, 1H), 1.48 hexane); 1H NMR (300 MHz, CDCl3): δ 8.28 – 8.22 (m, 2H), 7.65
– 1.23 (m, 3H), 1.23 – 1.00 (m, 3H); 13C NMR (75 MHz, CDCl3): δ – 7.59 (m, 2H), 6.99 (s, 1H), 3.91 – 3.76 (m, 1H), 1.98 (dd, J =
171.6, 136.8, 129.6, 128.6, 126.9, 72.6, 47.8, 40.9, 32.9, 32.9, 12.2, 3.2 Hz, 2H), 1.82 – 1.72 (m, 2H), 1.71 – 1.62 (m, 1H), 1.46
25.4, 24.7, 24.6; HRMS (ESI): calcd. for C15H22NO2 [M+H]+: – 1.23 (m, 5H); 13C NMR (75 MHz, CDCl3): δ 186.9, 160.4, 132.7,
248.1651, found: 248.1640.
132.2, 131.8, 129.9, 48.5, 32.7, 25.4, 24.7; HRMS (ESI): calcd.
N‐benzyl‐2‐hydroxy‐3‐phenylpropanamide (2l')19. White solid for C14H17BrNO2 [M+H]+: 310.0443, found: 310.0436.
(27.0 mg, 53%), m.p: 104 °C; Rf = 0.30 (30% EtOAc in hexane); 2‐(4‐chlorophenyl)‐N‐cyclohexyl‐2‐oxoacetamide (2s)21. White
1H NMR (300 MHz, CDCl3): δ 7.33 – 7.14 (m, 10H), 6.82 (s, 1H), solid (42.0 mg, 79%); m.p: 100 °C; Rf = 0.65 (30% EtOAc in
4.49 – 4.29 (m, 3H), 3.23 (dd, J = 13.9, 4.1 Hz, 1H), 2.92 (dd, J = hexane); 1H NMR (400 MHz, CDCl3): δ 8.36 – 8.34 (m, 1H), 8.33
13.9, 8.1 Hz, 1H), 2.78 (d, J = 4.9 Hz, 1H); 13C NMR (75 MHz, – 8.32 (m, 1H), 7.47 – 7.45 (m, 1H), 7.45 – 7.43 (m, 1H), 6.99 (s,
CDCl3): δ 172.5, 137.8, 136.7, 129.6, 128.7, 128.6, 127.7, 127.5, 1H), 3.89 – 3.79 (m, 1H), 2.01 – 1.95 (m, 2H), 1.80 – 1.74 (m,
126.9, 72.9, 43.1, 40.8; HRMS (ESI): calcd. for C16H18NO2 2H), 1.68 – 1.63 (m, 1H), 1.48 – 1.36 (m, 3H), 1.29 (d, J = 3.3 Hz,
[M+H]+: 256.1338, found: 256.1333.
2H); 13C NMR (125 MHz, CDCl3): δ 186.7, 160.4, 141.1, 132.7,
White 131.8, 128.8, 48.5, 32.7, 25.4, 24.7; HRMS (ESI): calcd. for
2‐cyclohexyl‐2‐hydroxy‐N‐phenylacetamide (2m')20
.
solid (33.5 mg, 72%), m.p: 150 °C; Rf = 0.30 (30% EtOAc in C14H17ClNO2 [M+H]+: 266.0948, found: 266.0936.
hexane); 1H NMR (300 MHz, CDCl3): δ 8.43 (s, 1H), 7.59 (dt, J = N‐cyclohexyl‐2‐(4‐methoxyphenyl)‐2‐oxoacetamide
(2t)22
.
8.7, 1.7 Hz, 2H), 7.40 – 7.31 (m, 2H), 7.19 – 7.09 (m, 1H), 4.10 White sticky solid (44.0 mg, 84%); Rf = 0.65 (30% EtOAc in
(dd, J = 5.0, 3.2 Hz, 1H), 2.81 (d, J = 5.0 Hz, 1H), 1.97 (tt, J = hexane); 1H NMR (400 MHz, CDCl3): δ 8.44 – 8.41 (m, 1H), 8.41
11.8, 3.3 Hz, 1H), 1.79 (dd, J = 12.0, 9.2 Hz, 3H), 1.62 (dd, J = – 8.39 (m, 1H), 7.02 (d, J = 5.5 Hz, 1H), 6.96 – 6.95 (m, 1H), 6.94
14.5, 9.9 Hz, 2H), 1.38 – 1.14 (m, 5H); 13C NMR (75 MHz, – 6.92 (m, 1H), 3.89 (s, 3H), 3.86 – 3.80 (m, 1H), 2.01 – 1.95 (m,
CDCl3): δ 171.3, 137.2, 129.0, 124.5, 119.8, 76.7, 41.8, 29.6, 2H), 1.76 (ddd, J = 10.7, 7.3, 3.6 Hz, 3H), 1.68 – 1.61 (m, 2H),
26.3, 26.0, 25.9; HRMS (ESI): calcd. for C14H20NO2 [M+H]+: 1.47 – 1.36 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 186.0, 164.6,
234.1494, found: 234.1490.
161.3, 133.9, 126.5, 113.8, 55.5, 48.4, 32.7, 25.4, 24.7; HRMS
N‐(tert‐butyl)‐2‐(4‐nitrophenyl)‐2‐oxoacetamide (2n)21. Yellow (ESI): calcd. for C15H20NO3 [M+H]+: 262.1443, found: 262.1437.
solid (17.6 mg, 35%); m.p: 88 °C; Rf = 0.65 (30% EtOAc in N‐benzyl‐2‐(1H‐indol‐3‐yl)‐2‐oxoacetamide (2u). Yellow oil
hexane); 1H NMR (400 MHz, CDCl3): δ 8.52 – 8.47 (m, 2H), 8.32 (31.8 mg, 57%); Rf = 0.75 (30% EtOAc in hexane); 1H NMR (400
– 8.27 (m, 2H), 6.98 (s, 1H), 1.47 (s, 9H); 13C NMR (75 MHz, MHz, CDCl3): δ 9.11 (d, J = 3.2 Hz, 1H), 8.96 (s, 1H), 8.42 (dd, J =
CDCl3): δ 186.9, 159.8, 150.7, 138.1, 132.4, 123.3, 52.0, 28.3; 6.7, 2.3 Hz, 1H), 7.86 (s, 1H), 7.43 (dt, J = 7.4, 3.2 Hz, 1H), 7.39
HRMS (ESI): calcd. for C12H15N2O4 [M+H]+: 251.1032, found: – 7.28 (m, 7H), 4.58 (d, J = 6.1 Hz, 2H); 13C NMR (125 MHz,
251.1026.
CDCl3): δ 180.5, 162.3, 138.2, 137.4, 135.7, 128.8, 127.7, 127.7,
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126.6, 124.3, 123.4, 122.5, 113.5, 111.6, 43.4; HRMS (ESI): N‐benzyl‐2‐(4‐(methylthio)phenyl)‐2‐oxoacetamide
calcd. for C17H15N2O2 [M+H]+: 279.1134, found: 279.1129.
Yellow solid (29.2 mg, 51%); m.p: 100 °C; Rf = 0.68 (30% EtOAc
N‐benzyl‐2‐(4‐fluorophenyl)‐2‐oxoacetamide (2v)23 White in hexane); 1H NMR (300 MHz, CDCl3): δ 8.37 – 8.29 (m, 2H),
(2ac).
.
solid (33.5 mg, 65%); m.p: 65 °C; Rf = 0.68 (30% EtOAc in 7.44 (s, 1H), 7.39 – 7.29 (m, 5H), 7.28 (d, J = 1.9 Hz, 1H), 7.25 (t,
hexane); 1H NMR (500 MHz, CDCl3): δ 8.51 – 8.42 (m, 2H), 7.46 J = 1.6 Hz, 1H), 4.56 (d, J = 6.1 Hz, 2H), 2.53 (s, 3H); 13C NMR
(s, 1H), 7.39 – 7.29 (m, 5H), 7.18 – 7.12 (m, 2H), 4.56 (d, J = 6.1 (75 MHz, CDCl3): δ 186.0, 161.8, 148.3, 137.1, 131.6, 129.5,
Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 185.6, 167.9, 165.4, 128.8, 127.9, 127.8, 124.6, 43.4, 14.6; HRMS (ESI): calcd. for
161.3, 136.9, 134.3, 134.3, 129.8, 129.8, 128.9, 127.9, 115.9, C16H16NO2S [M+H]+: 286.0902, found: 286.0896.
115.7, 43.5; HRMS (ESI): calcd. for C15H13FNO2 [M+H]+: (E)‐3‐(4‐hydroxyphenyl)‐2‐iodo‐3‐phenylacrylamide
(2ad)
.
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258.0930, found: 258.0905.
N‐benzyl‐2‐oxo‐2‐(1H‐pyrrol‐2‐yl)acetamide (2w)
Yellow sticky solid (22.0 mg, 30%); Rf = 0.20 (50% EtOAc in
White hexane); H NMR (300 MHz, DMSO‐d6): δ 9.60 (s, 1H), 7.55 (s,
1
.
sticky solid (34.3 mg, 75%); Rf = 0.70 (30% EtOAc in hexane); 1H 1H), 7.42 – 7.36 (m, 2H), 7.34 – 7.28 (m, 1H), 7.17 (dd, J = 5.1,
NMR (400 MHz, CDCl3): δ 7.88 – 7.84 (m, 2H), 7.79 (s, 1H), 7.54 3.2 Hz, 2H), 7.08 (s, 1H), 7.05 – 7.03 (m, 1H), 7.02 – 7.00 (m,
(dt, J = 4.9, 2.8 Hz, 3H), 7.50 – 7.45 (m, 2H), 6.93 – 6.91 (m, 1H), 6.67 – 6.60 (m, 2H); 13C NMR (75 MHz, DMSO‐d6): δ 169.8,
1H), 6.90 – 6.88 (m, 1H), 3.81 (s, 2H); 13C NMR (100 MHz, 157.3, 148.0, 144.7, 130.2, 130.1, 128.7, 128.3, 127.7, 114.8,
CDCl3): δ 165.6, 156.6, 135.0, 131.7, 131.0, 128.7, 126.9, 122.1, 93.2; HRMS (ESI): calcd. for C15H13INO2 [M+H]+: 365.9991,
114.2, 55.5; HRMS (ESI): calcd. for C13H13N2O2 [M+H]+: found: 365.9961.
229.0977, found: 229.1043.
N‐(tert‐butyl)‐2‐(4‐isopropylphenyl)‐2‐oxoacetamide (2ae)4c
.
2‐(4‐methoxyphenyl)‐2‐oxo‐N‐phenylacetamide (2x)17. Yellow Pale yellow solid (31.7 mg, 64%); m.p: 39 °C; Rf = 0.68 (30%
sticky solid (44.5 mg, 87%); Rf = 0.65 (30% EtOAc in hexane); 1H EtOAc in hexane); 1H NMR (300 MHz, CDCl3): δ 8.27 – 8.25 (m,
NMR (300 MHz, CDCl3): δ 9.00 (s, 1H), 8.54 – 8.51 (m, 1H), 8.51 1H), 8.24 – 8.23 (m, 1H), 7.33 (d, J = 1.5 Hz, 1H), 7.31 – 7.29 (m,
– 8.48 (m, 1H), 7.71 (t, J = 1.6 Hz, 1H), 7.68 (t, J = 1.6 Hz, 1H), 1H), 6.92 (s, 1H), 3.04 – 2.89 (m, 1H), 1.45 (s, 9H), 1.28 (s, 3H),
7.43 – 7.36 (m, 2H), 7.19 (ddd, J = 8.6, 2.3, 1.1 Hz, 1H), 7.01 – 1.25 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 188.2, 161.4, 155.9,
6.98 (m, 1H), 6.98 – 6.95 (m, 1H), 3.91 (s, 3H); 13C NMR (75 131.5, 131.2, 126.5, 51.6, 34.4, 28.4, 23.5; HRMS (ESI): calcd.
MHz, CDCl3): δ 185.2, 164.9, 159.5, 136.8, 134.3, 129.2, 126.1, for C15H22NO2 [M+H]+: 248.1651, found: 248.1645.
125.2, 119.9, 113.9, 55.6; HRMS (ESI): calcd. for C15H14NO3 III. General Procedure for the synthesis of Ugi adducts 3a‐u
.
[M+H]+: 256.0974, found: 256.0964.
Equimolar mixture of amine (1.0 equiv, 0.8 mmol), aldehyde
(1.0 equiv, 0.8 mmol), acid (1.0 equiv, 0.8 mmol) and
N‐(tert‐butyl)‐2‐oxo‐2‐(2,4,6‐trimethoxyphenyl)acetamide
(2y). Yellow oil (38.5 mg, 65%); Rf = 0.67 (30% EtOAc in isocyanide (1.0 equiv, 0.8 mmol) in methanol (MeOH) was
hexane); 1H NMR (300 MHz, CDCl3): δ 7.74 (s, 2H), 6.98 (s, 1H), stirred at room temperature for 12 h. After completion of the
3.95 (s, 3H), 3.92 (s, 6H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3): reaction (based on TLC), MeOH was removed in vacuo,
δ 186.6, 161.3, 152.7, 143.9, 128.3, 108.9, 60.9, 56.3, 51.6, reaction mixture was diluted with ethyl acetate and washed
28.4; HRMS (ESI): calcd. for C15H22NO5 [M+H]+: 296.1498, with saturated sodium bicarbonate solution. Aqueous layer
found: 296.1519.
was extracted with ethyl acetate and the combined organic
Light layers were dried over anhydrous sodium sulfate followed by
N‐benzyl‐2‐(4‐bromophenyl)‐2‐oxoacetamide (2z)24
.
yellow solid (50.0 mg, 79%); m.p: 114 °C; Rf = 0.65 (30% EtOAc evaporation of solvent in vacuo. The crude was purified by
1
in hexane); H NMR (400 MHz, CDCl3): δ 8.30 – 8.26 (m, 2H), silica gel column chromatography to afford the desired
7.65 – 7.62 (m, 2H), 7.43 (s, J = 3.9 Hz, 1H), 7.39 – 7.31 (m, 5H), product 3.
4.57 (d, J = 6.1 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 186.3, N‐(2‐(benzylamino)‐2‐oxo‐1‐phenylethyl)‐N‐(4‐
161.1, 136.9, 132.8, 132.1, 131.9, 130.2, 128.9, 127.9, 127.9, methoxyphenyl)benzamide (3a). White solid (310.0 mg, 85%);
43.6; HRMS (ESI): calcd. for C15H13BrNO2 [M+H]+: 318.0130, m.p: 155 °C; Rf = 0.45 (40% EtOAc in hexane); H NMR (300
1
found: 318.0114.
N‐benzyl‐2‐(4‐cyanophenyl)‐2‐oxoacetamide (2aa)
MHz, CDCl3): δ 7.33 – 7.31 (m, 1H), 7.31 – 7.29 (m, 2H), 7.27 (d,
Yellow J = 2.4 Hz, 3H), 7.25 – 7.19 (m, 6H), 7.19 – 7.14 (m, 2H), 7.14 –
.
sticky solid (31.8 mg, 60%); Rf = 0.65 (30% EtOAc in hexane); 1H 7.09 (m, 1H), 6.86 (d, J = 8.2 Hz, 2H), 6.50 (dd, J = 7.8, 1.4 Hz,
NMR (300 MHz, CDCl3): δ 8.52 – 8.44 (m, 2H), 7.81 – 7.78 (m, 2H), 6.26 (t, J = 5.5 Hz, 1H), 6.21 (s, 1H), 4.53 (d, J = 5.8 Hz, 2H),
1H), 7.77 (t, J = 1.7 Hz, 1H), 7.43 (s, 1H), 7.39 – 7.31 (m, 5H), 3.64 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 171.5, 169.6, 158.2,
4.57 (d, J = 6.1 Hz, 2H); 13C NMR (75 MHz, CDCl3): δ 186.1, 138.1, 136.1, 134.6, 133.8, 131.4, 130.3, 129.3, 128.6, 128.4,
160.4, 136.7, 136.4, 132.2, 131.6, 128.9, 128.0, 127.9, 117.8, 128.4, 127.6, 127.3, 113.4, 66.5, 55.1, 43.7; HRMS (ESI): calcd.
117.4, 43.6; HRMS (ESI): calcd. for C16H13N2O2 [M+H]+: for C29H27N2O3 [M+H]+: 451.2022, found: 451.1999.
265.0977, found: 265.0999.
2‐(2‐bromophenyl)‐N‐(tert‐butyl)‐2‐oxoacetamide
N‐(2‐(tert‐butylamino)‐2‐oxo‐1‐phenylethyl)‐N‐(4‐
(2ab)
.
methoxyphenyl)benzamide (3b). White solid (236.0 mg, 70%);
1
White solid (39.8 mg, 70%); m.p: 85 °C; Rf = 0.68 (30% EtOAc in m.p: 154 °C; Rf = 0.45 (40% EtOAc in hexane); H NMR (400
hexane); 1H NMR (500 MHz, CDCl3): δ 7.64 – 7.57 (m, 2H), 7.42 MHz, CDCl3): δ 7.32 – 7.29 (m, 2H), 7.26 – 7.19 (m, 5H), 7.19 –
– 7.34 (m, 2H), 6.84 (s, 1H), 1.45 (s, 9H); 13C NMR (125 MHz, 7.10 (m, 3H), 6.88 (d, J = 7.1 Hz, 2H), 6.50 (d, J = 9.1 Hz, 2H),
CDCl3): δ 191.9, 159.5, 136.4, 133.3, 132.7, 130.9, 127.0, 120.7, 6.10 (s, 1H), 5.78 (s, 1H), 3.64 (s, 3H), 1.37 (s, 9H); 13C NMR
51.8, 28.3; HRMS (ESI): calcd. for C12H15BrNO2 [M+H]+: (100 MHz, CDCl3): δ 171.2, 168.7, 158.1, 136.2, 135.0, 133.8,
284.0286, found: 284.0279.
131.3, 130.1, 129.1, 128.4, 128.3, 128.2, 127.5, 113.3, 66.7,
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55.1, 51.5, 28.6; HRMS (ESI): calcd. for C26H29N2O3 [M+H]+: CDCl3): δ 7.29 (dd, J = 8.1, 1.4 Hz, 2H), 7.16 (dd, J = 4.7, 2.3 Hz,
417.2178, found: 417.2176.
N‐(tert‐butyl)‐2‐(N‐(4‐methoxyphenyl)acetamido)‐2‐
2H), 7.15 – 7.12 (m, 3H), 6.87 (d, J = 4.6 Hz, 2H), 6.76 (d, J = 2.9
Hz, 1H), 6.75 – 6.73 (m, 1H), 6.51 (d, J = 9.0 Hz, 2H), 6.09 (s,
phenylacetamide (3c). White solid (200.0 mg, 70%); m.p: 150 1H), 5.76 (s, 1H), 3.76 (s, 3H), 3.65 (s, 3H), 1.37 (s, 9H); 13C
°C; Rf = 0.45 (40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): NMR (100 MHz, CDCl3): δ 171.3, 169.0, 159.4, 158.2, 136.4,
δ 7.34 – 7.01 (m, 7H), 6.68 (s, 2H), 5.97 (s, 1H), 5.56 (s, 1H), 133.7, 131.6, 131.5, 129.1, 128.4, 127.6, 127.0, 116.5, 114.8,
3.74 (s, 3H), 1.85 (s, 3H), 1.33 (s, 9H); 13C NMR (100 MHz, 113.7, 113.3, 65.8, 55.2, 55.1, 51.5, 28.7; HRMS (ESI): calcd. for
CDCl3): δ 171.5, 168.9, 158.8, 135.0, 133.3, 131.3, 130.3, 128.2, C27H31N2O4 [M+H]+: 447.2284, found: 447.2264.
128.2, 113.8, 65.1, 55.3, 51.5, 28.6, 23.2; HRMS (ESI): calcd. for N‐(1‐(4‐bromophenyl)‐2‐(tert‐butylamino)‐2‐oxoethyl)‐N‐(4‐
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C21H27N2O3 [M+H]+: 355.2022, found: 355.2013.
N‐(2‐(tert‐butylamino)‐1‐(4‐nitrophenyl)‐2‐oxoethyl)‐N‐(4‐
methoxyphenyl)benzamide (3i). Yellow sticky solid (350.0 mg,
85%); Rf = 0.45 (40% EtOAc in hexane); H NMR (400 MHz,
1
methoxyphenyl)benzamide (3d). Pale yellow oil (280.0 mg CDCl3): δ 7.36 (d, J = 8.5 Hz, 2H), 7.30 – 7.27 (m, 2H), 7.22 –
1
80%); Rf = 0.65 (30% EtOAc in hexane); H NMR (400 MHz, 7.17 (m, 1H), 7.16 – 7.13 (m, 3H), 6.86 (d, J = 7.7 Hz, 2H), 6.78 –
CDCl3): δ 8.12 – 8.06 (m, 2H), 7.52 (d, J = 8.6 Hz, 2H), 7.33 – 6.64 (m, 1H), 6.54 (d, J = 9.0 Hz, 2H), 6.08 (s, 1H), 5.91 (s, 1H),
7.28 (m, 2H), 7.25 – 7.20 (m, 1H), 7.18 – 7.12 (m, 2H), 7.07 (dd, 3.67 (s, 3H), 1.38 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 171.4,
J = 6.9, 3.0 Hz, 3H), 7.03 – 6.94 (m, 2H), 6.20 (d, J = 6.1 Hz, 2H), 168.4, 158.4, 135.9, 133.9, 133.4, 131.9, 131.5, 131.3, 129.4,
1.40 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 171.4, 167.6, 147.6, 128.4, 127.7, 122.6, 116.7, 114.8, 113.6, 65.8, 55.2, 51.7, 28.7.;
142.1, 140.9, 135.2, 130.7, 129.9, 129.7, 128.9, 128.5, 127.8, HRMS (ESI): calcd. for C26H28BrN2O3 [M+H]+: 495.1283, found:
127.7, 123.4, 66.4, 51.9, 28.7; HRMS (ESI): calcd. for 495.1274.
C25H26N3O4 [M+H]+: 432.1923, found: 432.1896.
N‐(2‐(benzylamino)‐1‐(furan‐2‐yl)‐2‐oxoethyl)‐N‐(4‐
N‐(2‐(cyclohexylamino)‐2‐oxo‐1‐(p‐tolyl)ethyl)‐4‐methoxy‐N‐
methoxyphenyl)benzamide (3j). Brown sticky solid (230.0 mg,
1
phenylbenzamide (3e). White solid (300.0 mg, 81%); m.p: 210 64%); Rf = 0.52 (40% EtOAc in hexane); H NMR (300 MHz,
°C; Rf = 0.52 (40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): CDCl3): δ 7.51 (s, 1H), 7.34 – 7.25 (m, 8H), 7.21 – 7.10 (m, 3H),
δ 7.28 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 7.4 6.84 (d, J = 8.8 Hz, 2H), 6.66 (s, 1H), 6.58 (d, J = 9.1 Hz, 2H),
Hz, 7H), 6.62 (d, J = 8.8 Hz, 2H), 6.06 (s, 1H), 5.90 (d, J = 7.7 Hz, 6.25 (d, J = 1.1 Hz, 1H), 6.16 (s, 1H), 4.60 – 4.44 (m, 2H), 3.68
1H), 3.91 – 3.81 (m, 1H), 3.71 (s, 3H), 2.29 (s, 3H), 2.00 – 1.87 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 171.3, 168.9, 158.5, 143.2,
(m, 2H), 1.72 (s, 2H), 1.60 (ddd, J = 17.1, 8.9, 4.1 Hz, 1H), 1.42 – 142.9, 138.1, 135.8, 133.6, 130.9, 129.5, 128.6, 128.4, 127.7,
1.29 (m, 2H), 1.20 – 1.02 (m, 3H); 13C NMR (75 MHz, CDCl3): δ 127.6, 127.4, 119.1, 113.7, 111.4, 57.9, 55.2, 43.7; HRMS (ESI):
170.7, 168.9, 160.5, 142.2, 138.1, 132.1, 130.8, 129.9, 129.8, calcd. for C27H25N2O4 [M+H]+: 441.1814, found: 441.1794.
129.1, 128.4, 128.2, 126.8, 112.8, 67.1, 55.1, 48.6, 32.8, 25.5, 2‐(4‐bromophenyl)‐N‐cyclohexyl‐2‐(N‐
24.8, 24.7, 21.1; HRMS (ESI): calcd. for C29H33N2O3 [M+H]+: phenylacetamido)acetamide (3k). White solid (270.0 mg,
1
457.2491, found: 457.2458.
78%); m.p: 230 °C; Rf = 0.45 (40% EtOAc in hexane); H NMR
N‐cyclohexyl‐2‐(N‐phenylacetamido)‐2‐(p‐tolyl)acetamide
(500 MHz, CDCl3): δ 7.31 (d, J = 8.4 Hz, 2H), 7.28 – 7.15 (m, 4H),
(3f). White solid (212.0 mg, 72%); m.p: 181 °C; Rf = 0.52 (40% 7.08 (s, 1H), 7.02 (d, J = 8.4 Hz, 2H), 5.97 (s, 1H), 5.72 (d, J = 7.5
EtOAc in hexane); 1H NMR (500 MHz, CDCl3): δ 7.20 (d, J = 2.7 Hz, 1H), 3.85 – 3.77 (m, 1H), 1.96 (d, J = 9.5 Hz, 1H), 1.86 (s,
Hz, 4H), 6.99 (q, J = 8.3 Hz, 5H), 5.97 (s, 1H), 5.57 (d, J = 7.8 Hz, 3H), 1.72 – 1.63 (m, 4H), 1.61 – 1.55 (m, 1H), 1.42 – 1.28 (m,
1H), 3.81 (tdt, J = 11.8, 8.0, 3.9 Hz, 1H), 2.26 (s, 3H), 1.94 (d, J = 2H), 1.20 – 1.09 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 171.3,
10.5 Hz, 1H), 1.85 (s, 3H), 1.67 – 1.52 (m, 3H), 1.43 – 1.27 (m, 168.3, 140.4, 133.8, 131.9, 131.4, 130.2, 129.1, 128.3, 122.6,
3H), 1.23 – 0.92 (m, 3H); 13C NMR (125 MHz, CDCl3): δ 171.1, 64.2, 48.8, 32.8, 32.8, 25.5, 24.8, 24.7, 23.2; HRMS (ESI): calcd.
168.9, 140.9, 138.1, 131.8, 130.3, 130.2, 129.0, 128.8, 127.9, for C22H26BrN2O2 [M+H]+: 429.1178, found: 429.1132.
64.9, 48.7, 32.8, 32.8, 25.5, 24.8, 24.7, 23.2, 21.1; HRMS (ESI): 2‐(4‐chlorophenyl)‐N‐cyclohexyl‐2‐(N‐phenyl
acetamido)
calcd. for C23H29N2O2 [M+H]+: 365.2229, found: 365.2216.
acetamide (3l). White solid (212.0 mg, 68%); m.p: 220 °C; Rf =
N‐(4‐methoxyphenyl)‐N‐(2‐(naphthalen‐1‐ylamino)‐2‐oxo‐1‐
0.45 (40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.25
(p‐tolyl)ethyl)benzamide (3g). Brown solid (348.0 mg, 85%); (d, J = 1.6 Hz, 1H), 7.23 (d, J = 2.2 Hz, 1H), 7.21 (s, 2H), 7.11 (d, J
1
m.p: 140 °C; Rf = 0.50 (30% EtOAc in hexane); H NMR (300 = 1.7 Hz, 1H), 7.09 (d, J = 1.7 Hz, 1H), 7.07 – 7.05 (m, 2H), 6.98
MHz, CDCl3): δ 8.49 (s, 1H), 8.02 (d, J = 7.2 Hz, 1H), 7.81 (ddd, J (s, 1H), 6.10 (s, 1H), 5.75 (d, J = 8.0 Hz, 1H), 3.91 – 3.81 (m, 1H),
= 9.7, 5.8, 3.3 Hz, 2H), 7.69 (d, J = 8.2 Hz, 1H), 7.50 – 7.44 (m, 1.97 (d, J = 12.7 Hz, 1H), 1.89 (d, J = 12.4 Hz, 1H), 1.74 – 1.60
3H), 7.39 – 7.32 (m, 4H), 7.21 – 7.11 (m, 5H), 6.94 (d, J = 8.0 Hz, (m, 3H), 1.59 (s, 3H), 1.36 (ddd, J = 13.1, 8.1, 3.5 Hz, 2H), 1.19 –
2H), 6.56 (d, J = 8.8 Hz, 2H), 6.38 (s, 1H), 3.67 (s, 3H), 2.35 (s, 1.05 (m, 3H); 13C NMR (75 MHz, CDCl3): δ 171.3, 168.4, 140.4,
3H); 13C NMR (100 MHz, CDCl3): δ 171.8, 168.8, 158.4, 138.6, 134.4, 133.2, 131.7, 130.2, 129.1, 128.5, 128.3, 64.1, 48.8,
135.9, 134.2, 134.1, 132.4, 131.5, 131.2, 129.9, 129.5, 129.4, 32.8, 25.5, 24.8, 24.7, 23.2; HRMS (ESI): calcd. for C22H26ClN2O2
128.5, 127.6, 127.3, 126.3, 125.9, 125.7, 125.6, 121.0, 120.6, [M+H]+: 385.1683, found: 385.0380.
116.4, 114.8, 113.7, 67.9, 55.2, 21.2; HRMS (ESI): calcd. for N‐cyclohexyl‐2‐(4‐methoxyphenyl)‐2‐(N‐phenyl
acetamido)
acetamide (3m). White solid (230.0 mg, 75%); m.p: 160 °C; Rf =
0.45 (40% EtOAc in hexane); 1H NMR (400 MHz, CDCl3): δ 7.20
C33H29N2O3 [M+H]+: 501.2178, found: 501.2163.
N‐(2‐(tert‐butylamino)‐1‐(4‐methoxyphenyl)‐2‐oxoethyl)‐N‐
(4‐methoxyphenyl) benzamide (3h). Yellow sticky solid (296.0 (d, J = 2.6 Hz, 4H), 7.11 – 6.89 (m, 3H), 6.75 – 6.62 (m, 2H), 6.00
mg, 81%); Rf = 0.45 (40% EtOAc in hexane); 1H NMR (400 MHz, (s, 1H), 5.59 (d, J = 7.8 Hz, 1H), 3.85 – 3.77 (m, 1H), 3.75 (d, J =
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8.8 Hz, 3H), 1.95 (d, J = 8.8 Hz, 1H), 1.85 (s, 3H), 1.71 – 1.54 (m, (40% EtOAc in hexane); H NMR (300 MHz, CDCl3): δ 7.33 –
4H), 1.39 – 1.27 (m, 2H), 1.18 – 1.00 (m, 3H); 13C NMR (125 7.28 (m, 2H), 7.20 – 7.09 (m, 3H), 6.88 (d, J = 6.8 Hz, 2H), 6.52
MHz, CDCl3): δ 171.2, 168.9, 159.5, 140.7, 131.6, 130.4, 128.8, (dd, J = 7.8, 1.3 Hz, 2H), 6.45 (s, 2H), 6.09 (s, 1H), 5.85 (s, 1H),
127.9, 126.8, 113.7, 64.3, 55.2, 48.7, 32.8, 32.8, 25.5, 24.8, 3.80 (s, 3H), 3.70 (s, 6H), 3.65 (s, 3H), 1.39 (s, 9H); 13C NMR (75
24.7, 23.2; HRMS (ESI): calcd. for C23H29N2O3 [M+H]+: MHz, CDCl3): δ 171.4, 168.7, 158.3, 152.8, 137.9, 136.2, 133.5,
6
7
8
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381.2178, found: 381.2168.
131.6, 130.2, 129.2, 128.3, 127.6, 113.3, 107.8, 65.9, 60.8,
56.1, 55.2, 51.6, 28.7; HRMS (ESI): calcd. for C29H35N2O6
N‐(2‐(benzylamino)‐1‐(1H‐indol‐3‐yl)‐2‐oxoethyl)‐N‐(2,2‐
dimethoxyethyl)benzamide (3n). Light yellow solid (243.0 mg, [M+H]+: 507.2495, found: 507.2486.
63%); m.p: 100 °C, Rf = 0.45 (40% EtOAc in hexane); the N‐(2‐((4‐bromophenyl)amino)‐2‐oxo‐1‐phenylethyl)‐N‐(4‐
product may contain rotamers; H NMR (400 MHz, CDCl3): δ methoxyphenyl)benzamide (3s). Light brown solid (320.0 mg,
8.99 (s, 1H), 8.47 (s, 1H), 7.57 (s, 2H), 7.42 (d, J = 15.5 Hz, 8H), 76%); m.p: 156 °C; Rf = 0.55 (40% EtOAc in hexane); H NMR
7.34 (s, 2H), 7.21 (s, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 5.87 (s, 1H), (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.42 – 7.34 (m, 4H), 7.32 –
5.04 (s, 1H), 4.54 (s, 1H), 4.45 (s, 1H), 3.36 (d, J = 30.1 Hz, 6H), 7.26 (m, 6H), 7.23 – 7.11 (m, 4H), 6.88 (d, J = 6.8 Hz, 2H), 6.53
3.00 (s, 2H); 13C NMR (100 MHz, CDCl3): δ 174.6, 169.9, 138.1, (d, J = 9.1 Hz, 2H), 6.34 (s, 1H), 3.66 (s, 3H); 13C NMR (100 MHz,
136.2, 130.8, 128.9, 128.7, 127.5, 127.1, 126.3, 125.1, 122.3, CDCl3): δ 171.8, 168.4, 158.4, 137.1, 135.8, 133.9, 133.4, 131.7,
120.2, 117.9, 111.6, 109.5, 102.7, 62.6, 55.8, 47.6, 43.9; HRMS 131.5, 130.3, 129.6, 128.7, 128.6, 128.5, 128.1, 127.7, 121.4,
(ESI): calcd. for C28H29N3NaO4 [M+Na]+: 494.2056, found: 116.7, 113.5, 67.3, 55.2; HRMS (ESI): calcd. for C28H24BrN2O3
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494.2022.
[M+H]+: 515.0970, found: 515.0969.
N‐(2‐(benzylamino)‐1‐(4‐bromophenyl)‐2‐oxoethyl)‐N‐(4‐
N‐(2‐(benzylamino)‐1‐(4‐fluorophenyl)‐2‐oxoethyl)‐N‐(2,2‐
dimethoxyethyl)benzamide (3o). White sticky solid (280.0 mg, methoxyphenyl)benzamide (3t). White solid (320.0 mg, 74%);
1
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76%); Rf = 0.45 (40% EtOAc in hexane); H NMR (400 MHz, m.p: 160 °C; Rf = 0.45 (40% EtOAc in hexane); H NMR (300
CDCl3): δ 9.05 (s, 1H), 7.46 (d, J = 7.2 Hz, 4H), 7.44 – 7.40 (m, MHz, CDCl3): δ 7.39 – 7.23 (m, 9H), 7.16 (t, J = 10.2 Hz, 5H),
6H), 7.34 (d, J = 6.0 Hz, 1H), 7.02 (t, J = 8.2 Hz, 3H), 5.68 (s, 1H), 6.82 (d, J = 7.7 Hz, 2H), 6.53 (d, J = 8.6 Hz, 2H), 6.42 (s, 1H),
5.01 (s, 1H), 4.83 (s, 1H), 4.42 (d, J = 12.4 Hz, 1H), 3.32 (s, 2H), 6.17 (s, 1H), 4.52 (d, J = 3.1 Hz, 2H), 3.66 (s, 3H); 13C NMR (125
3.12 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 168.6, 163.7, 161.2, MHz, CDCl3): δ 171.5, 169.2, 158.5, 137.9, 135.8, 133.6, 133.4,
138.1, 131.2, 130.8, 128.9, 128.8, 128.3, 127.7, 127.1, 115.9, 131.9, 131.6, 131.4, 129.5, 128.7, 128.4, 127.7, 127.4, 122.8,
115.7, 102.5, 67.6, 55.8, 48.9, 43.9; HRMS (ESI): calcd. for 113.6, 65.5, 55.2, 43.8; HRMS (ESI): calcd. for C29H26BrN2O3
C26H28FN2O4 [M+H]+: 451.2033, found: 451.2038.
N‐(2‐(benzylamino)‐2‐oxo‐1‐(1H‐pyrrol‐2‐yl)ethyl)‐N‐(4‐
methoxyphenyl)benzamide (3p). White solid (259.0 mg, 72%); phenylbenzamide (3u). Light brown solid (390.0 mg, 84%);
[M+H]+: 529.1127, found: 529.1122.
N‐(2‐(benzylamino)‐1‐(4‐cyanophenyl)‐2‐oxoethyl)‐3‐iodo‐N‐
1
1
m.p: 161 °C; Rf = 0.45 (40% EtOAc in hexane); H NMR (300 m.p: 187 °C; Rf = 0.45 (40% EtOAc in hexane); H NMR (400
MHz, CDCl3): δ 9.80 (s, 1H), 7.33 (dd, J = 2.9, 1.9 Hz, 1H), 7.30 MHz, CDCl3): δ 7.66 (t, J = 1.6 Hz, 1H), 7.57 – 7.46 (m, 3H), 7.38
(d, J = 1.4 Hz, 4H), 7.28 (t, J = 1.9 Hz, 2H), 7.22 – 7.18 (m, 1H), (d, J = 8.3 Hz, 2H), 7.35 – 7.30 (m, 2H), 7.27 (dd, J = 6.4, 2.8 Hz,
7.17 (d, J = 1.3 Hz, 1H), 7.14 (t, J = 1.8 Hz, 1H), 6.88 (s, 1H), 6.84 3H), 7.19 – 7.15 (m, 1H), 7.13 – 7.03 (m, 3H), 6.92 (d, J = 6.0 Hz,
(d, J = 3.3 Hz, 1H), 6.75 (dd, J = 4.1, 2.6 Hz, 1H), 6.65 – 6.63 (m, 2H), 6.84 (t, J = 7.9 Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H), 6.22 (s, 1H),
1H), 6.62 – 6.59 (m, 1H), 6.43 (s, 1H), 6.22 (dd, J = 4.3, 3.0 Hz, 4.53 (qd, J = 14.8, 5.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ
1H), 6.14 (dd, J = 6.0, 2.7 Hz, 1H), 5.67 (s, 1H), 4.50 (d, J = 6.0 169.6, 168.4, 140.0, 139.3, 138.8, 137.7, 137.4, 137.0, 132.0,
Hz, 2H), 3.70 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 171.8, 168.7, 130.8, 130.0, 129.3, 128.9, 128.7, 128.0, 127.6, 127.6, 127.5,
158.5, 138.1, 135.7, 135.5, 129.7, 128.6, 128.6, 127.7, 127.5, 118.2, 112.4, 93.3, 65.8, 43.9; HRMS (ESI): calcd. for
127.3, 125.1, 119.5, 114.0, 111.1, 107.9, 62.5, 55.3, 43.7; C29H23IN3O2 [M+H]+: 572.0835, found: 572.0813.
HRMS (ESI): calcd. for C27H26N3O3 [M+H]+: 440.1974, found: IV. General procedure for the oxidative cleavage of Ugi
440.1964.
N‐(4‐methoxyphenyl)‐N‐(1‐(4‐methoxyphenyl)‐2‐oxo‐2‐
(phenylamino)ethyl)benzamide (3q). Red solid (256.0 mg, equiv, 20 mol %) at room temperature and the reaction vessel
adducts 3a‐u. To the solution of
3 (1.0 equiv, 0.2 mmol) in dry
CH3CN was added KOtBu (3.0 equiv, 0.6 mmol) and CuI (0.2
1
67%); m.p: 110 °C; Rf = 0.45 (40% EtOAc in hexane); H NMR was flushed with O2. The resulting reaction mixture was stirred
(300 MHz, CDCl3): δ 7.94 (s, 1H), 7.50 (d, J = 7.8 Hz, 2H), 7.34 – at room temperature. After completion of the reaction (based
7.28 (m, 4H), 7.20 (dd, J = 9.5, 5.7 Hz, 3H), 7.17 (dd, J = 3.9, 2.1 on TLC) in 15‐30 minutes, the reaction mixture was quenched
Hz, 1H), 7.13 (d, J = 1.4 Hz, 1H), 7.12 – 7.05 (m, 1H), 6.88 (d, J = with water and the crude product was extracted with ethyl
8.0 Hz, 2H), 6.80 (s, 1H), 6.77 (s, 1H), 6.54 (d, J = 9.1 Hz, 2H), acetate. The organic layer was dried over anhydrous sodium
6.35 (s, 1H), 3.77 (s, 3H), 3.66 (s, 3H); 13C NMR (100 MHz, sulfate, concentrated in vacuo and the crude was purified by
CDCl3): δ 171.7, 168.2, 159.8, 158.4, 137.8, 135.9, 133.5, 131.8, silica gel column chromatography to afford the desired
131.6, 129.4, 128.9, 128.5, 127.6, 126.1, 124.3, 120.0, 113.9, products 2 and 4 respectively.
113.5, 66.3, 55.2, 55.2; HRMS (ESI): calcd. for C29H27N2O4 N‐(4‐methoxyphenyl)benzamide (4a)25. Yellow solid (34.1 mg,
[M+H]+: 467.1971, found: 467.1963.
75%); m.p: 152 °C; Rf = 0.52 (30% EtOAc in hexane); H NMR
(400 MHz, CDCl3): δ 7.88 – 7.83 (m, 2H), 7.80 (s, 1H), 7.56 –
1
N‐(2‐(tert‐butylamino)‐2‐oxo‐1‐(2,4,6‐
trimethoxyphenyl)ethyl)‐N‐(4‐methoxyphenyl)
benzamide 7.51 (m, 3H), 7.49 – 7.44 (m, 2H), 6.92 – 6.87 (m, 2H), 3.81 (s,
(3r). Light yellow solid (326.0 mg, 79%); m.p: 120 °C; Rf = 0.45 3H); 13C NMR (100 MHz, CDCl3): δ 165.8, 156.8, 135.2, 131.8,
12 | J. Name., 2012, 00, 1‐3
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1
2
3
4
5
6
7
8
9
131.2, 128.9, 127.1, 122.3, 114.4, 55.6; HRMS (ESI): calcd. for 2‐benzoyl‐N‐(tert‐butyl)‐2,3,4,9‐tetrahydro‐1H‐pyrido[3,4‐
C14H14NO2 [M+H]+: 228.1025, found: 228.1011.
b]indole‐1‐carboxamide (5a). Yellow solid (136.0 mg, 60%);
1
N‐phenylbenzamide (4b)26. White solid (27.7 mg, 70%); m.p: m.p: 243 °C; Rf = 0.45 (30% EtOAc in hexane); H NMR (400
1
160 °C; Rf = 0.53 (30% EtOAc in hexane); H NMR (400 MHz, MHz, DMSO‐d6): δ 10.68 (s, 1H), 7.81 (s, 1H), 7.50 (dd, J = 12.6,
CDCl3): δ 7.87 (dd, J = 5.2, 3.3 Hz, 3H), 7.68 – 7.61 (m, 2H), 7.58 4.8 Hz, 5H), 7.46 – 7.42 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 7.01 (t,
– 7.46 (m, 3H), 7.40 – 7.34 (m, 2H), 7.19 – 7.13 (m, 1H); 13C J = 7.2 Hz, 1H), 5.93 (s, 1H), 3.89 (dd, J = 15.3, 8.6 Hz, 2H), 2.77
NMR (100 MHz, CDCl3): δ 165.8, 137.9, 134.9, 131.8, 129.1, (dd, J = 21.0, 10.9 Hz, 2H), 1.34 (s, 9H); 13C NMR (125 MHz,
128.8, 127.0, 124.6, 120.2; HRMS (ESI): calcd. for C13H12NO DMSO‐d6): δ 170.5, 167.7, 136.1, 136.0, 129.8, 129.3, 128.5,
[M+H]+: 198.0919, found: 198.0900.
126.8, 126.1, 121.3, 118.7, 117.7, 111.5, 53.5, 50.8, 44.1, 28.4,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N‐(2,2‐dimethoxyethyl)benzamide (4c)27. White solid (25.2 21.0; HRMS (ESI): calcd. for C23H26N3O2 [M+H]+: 376.2025,
1
mg, 60%); m.p: 114 °C; Rf = 0.35 (30% EtOAc in hexane); H found: 376.2010.
NMR (400 MHz, CDCl3): δ 7.78 (d, J = 7.5 Hz, 2H), 7.54 – 7.48 2‐benzoyl‐N‐cyclohexyl‐2,3,4,9‐tetrahydro‐1H‐pyrido[3,4‐
(m, 1H), 7.43 (t, J = 7.4 Hz, 2H), 6.39 (s, 1H), 4.49 (t, J = 5.2 Hz, b]indole‐1‐carboxamide (5b). Yellow solid (169.0 mg, 70 %);
1
1H), 3.61 (t, J = 5.5 Hz, 2H), 3.44 (s, 6H); 13C NMR (100 MHz, m.p: 249 °C; Rf = 0.45 (30% EtOAc in hexane); H NMR (400
CDCl3): δ 167.6, 134.3, 131.5, 128.5, 126.9, 102.7, 54.6, 41.5; MHz, DMSO‐d6): δ 10.66 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.46
HRMS (ESI): calcd. for C11H16NO3 [M+H]+: 210.1130, found: (d, J = 2.8 Hz, 3H), 7.43 – 7.37 (m, 3H), 7.33 (s, 1H), 7.06 (t, J =
210.1114.
7.5 Hz, 1H), 6.96 (t, J = 7.3 Hz, 1H), 5.91 (s, 1H), 3.87 – 3.75 (m,
3‐iodo‐N‐phenylbenzamide (4d). White sticky solid (43.4 mg, 2H), 3.56 (s, 1H), 2.75 (dd, J = 8.9, 5.4 Hz, 1H), 2.66 (d, J = 15.1
1
67%); Rf = 0.59 (30% EtOAc in hexane); H NMR (300 MHz, Hz, 1H), 1.80 (d, J = 9.2 Hz, 1H), 1.69 (d, J = 15.3 Hz, 3H), 1.54
CDCl3): δ 8.19 (t, J = 1.7 Hz, 1H), 7.90 – 7.85 (m, 1H), 7.81 (ddd, (d, J = 11.4 Hz, 1H), 1.26 (dd, J = 17.8, 9.2 Hz, 5H); 13C NMR
J = 5.8, 3.5, 2.2 Hz, 2H), 7.66 – 7.58 (m, 2H), 7.42 – 7.33 (m, (100 MHz, DMSO‐d6): δ 170.6, 167.2, 136.1, 135.9, 129.9,
2H), 7.25 – 7.13 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 164.2, 129.1, 128.6, 126.9, 126.3, 126.0, 121.4, 118.8, 117.8, 111.5,
140.7, 137.6, 136.9, 136.0, 130.4, 129.1, 126.2, 124.9, 120.3, 107.9, 53.3, 48.2, 44.2, 32.3, 32.1, 25.2, 24.6, 24.5, 21.1; HRMS
94.4; HRMS (ESI): calcd. for C13H11INO [M+H]+: 323.9885, (ESI): calcd. for C25H28N3O2 [M+H]+: 402.2182, found: 402.2178.
found: 323.9876.
2‐acetyl‐N‐cyclohexyl‐2,3,4,9‐tetrahydro‐1H‐pyrido[3,4‐
V. General Procedure for the synthesis of Ugi adducts 5a‐c
Ugi adducts 5a‐c were prepared by performing U‐3CR using m.p: 220 °C; Rf = 0.47 (30% EtOAc in hexane); H NMR (500
4,9‐dihydro‐3H‐pyrido[3,4‐b]indole that was prepared in two MHz, CDCl3): δ 8.88 (s, 1H), 7.47 (dd, J = 19.0, 7.6 Hz, 1H), 7.34
.
b]indole‐1‐carboxamide (5c). Yellow solid (138.0 mg, 68%);
1
steps from tryptamine.
a) Preparation of 4,9‐dihydro‐3H‐pyrido[3,4‐b]indole
(dd, J = 14.6, 8.2 Hz, 1H), 7.21 – 7.14 (m, 1H), 7.13 – 7.06 (m,
1H), 6.40 (d, J = 7.0 Hz, 1H), 6.11 (s, 1H), 4.14 (d, J = 13.7 Hz,
.
Tryptamine (1.0 g, 6.24 mmol) and ethyl formate (0.6 ml, 7.49 1H), 3.72 (dd, J = 22.1, 18.6 Hz, 1H), 3.65 – 3.56 (m, 1H), 2.85
mmol) were added in a round bottom flask and refluxed at 60 (s, 2H), 2.32 (s, 3H), 1.90 (d, J = 12.5 Hz, 1H), 1.78 (d, J = 11.6
°C for 12 h. Excess ethyl formate in reaction mixture was Hz, 1H), 1.61 (dd, J = 32.6, 15.3 Hz, 3H), 1.32 (d, J = 11.1 Hz,
removed in vacuo and crude reaction mixture was used for the 2H), 1.14 (dd, J = 22.3, 10.6 Hz, 3H); 13C NMR (100 MHz, CDCl3):
next step. Crude was dissolved in dichloromethane, POCl3 (0.9 δ 170.9, 167.9, 136.5, 128.6, 126.2, 122.1, 119.4, 117.9, 111.3,
ml, 9.36 mmol) was added to it at 0 °C and refluxed for 1 h. 108.6, 53.5, 48.5, 43.6, 32.7, 32.6, 25.4, 24.6, 24.6, 21.9; HRMS
After completion of reaction (based on TLC), the reaction (ESI): calcd. for C20H26N3O2 [M+H]+: 340.2025, found: 340.2018.
mixture was cooled to room temperature. Excess POCl3 was VI. General Procedure for the oxidative cleavage of Ugi
removed in vacuo. The crude mixture was dissolved in 10% adducts 5a‐c. To the solution of
5 (1.0 equiv, 0.2 mmol) in dry
K2CO3 solution and the aqueous phase was extracted with CH3CN was added KOtBu (3.0 equiv, 0.6 mmol) and CuI (0.2
dichloromethane. The combined organic layers were dried equiv, 20 mol %) at room temperature and the reaction vessel
over anhydrous Na2SO4, concentrated in vacuo and crude was was flushed with O2. The resulting reaction mixture was stirred
purified by silica gel column chromatography to afford 4,9‐ at room temperature. After completion of the reaction (based
dihydro‐3H‐pyrido[3,4‐b]indole as a brown solid (810.0 mg, on TLC) in 12 h, the reaction mixture was filtered through a
76%). The spectral data matched with literature reports.28
short pad of celite, quenched with water and the crude
b) Preparation of Ugi adduct 5. To a solution of 4,9‐dihydro‐ product was extracted with ethyl acetate. The organic layer
3H‐pyrido[3,4‐b]indole (1.0 equiv, 0.6 mmol) in dry DCM, acid was dried over anhydrous sodium sulfate, concentrated in
(1.3 equiv, 0.8 mmol) and isocyanide (1.3 equiv, 0.8 mmol) vacuo and the crude was purified by silica gel column
were added and stirred at room temperature for 12 h. On chromatography to afford the desired product 6.
completion of the reaction (based on TLC), the reaction N‐(2‐(2‐(2‐(tert‐butylamino)‐2‐oxoacetyl)‐1H‐indol‐3‐
mixture was diluted with dichloromethane and washed with yl)ethyl)benzamide (6a). Yellow oil (49.0 mg, 63%); Rf = 0.52
1
saturated sodium bicarbonate solution. The aqueous layer was (30% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 11.37 (s,
extracted with dichloromethane and the combined organic 1H), 7.75 (dd, J = 8.3, 0.8 Hz, 1H), 7.63 (dd, J = 5.2, 3.3 Hz, 2H),
layers were dried over anhydrous sodium sulfate followed by 7.44 (ddd, J = 6.7, 3.8, 1.3 Hz, 2H), 7.41 – 7.31 (m, 4H), 7.12
evaporation of solvent in vacuo. The crude product was (ddd, J = 8.1, 4.8, 3.0 Hz, 1H), 6.63 (s, 1H), 3.86 – 3.76 (m, 2H),
purified by silica gel column chromatography to afford the 3.53 (t, J = 6.5 Hz, 2H), 1.47 (s, 9H); 13C NMR (100 MHz, DMSO‐
desired product
5
.
d6): δ 176.6, 167.6, 162.2, 137.5, 134.6, 131.2, 129.3, 128.5,
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1
2
3
4
5
6
7
8
128.3, 128.2, 127.2, 126.9, 121.2, 121.1, 112.9, 51.7, 40.9, 127.1, 126.7, 124.1, 48.3, 33.1, 25.7, 24.9; HRMS (ESI): calcd.
29.7, 28.3; HRMS (ESI): calcd. for C23H26N3O3 [M+H]+: 392.1974, for C16H19N2O [M+H]+: 255.1497, found: 255.1491.
found: 392.1972.
N‐(2‐(2‐(2‐(cyclohexylamino)‐2‐oxoacetyl)‐1H‐indol‐3‐
IX. Procedure for the synthesis of Substrate 10. Substrate 10
was prepared according to reported procedure.32
yl)ethyl)benzamide (6b). Yellow oil (43.0 mg, 51%); Rf = 0.52 2‐(benzyl(2‐nitrophenyl)amino)‐2‐(4‐chlorophenyl)‐N‐
1
(30% EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 11.36 (s, cyclohexylacetamide (10). Yellow solid (180.0 mg, 27%); m.p:
1
1H), 7.75 (d, J = 7.9 Hz, 1H), 7.65 – 7.62 (m, 2H), 7.48 (s, 1H), 201 °C; Rf = 0.40 (30% EtOAc in hexane); H NMR (500 MHz,
9
7.43 (d, J = 7.5 Hz, 1H), 7.41 – 7.39 (m, 2H), 7.36 (d, J = 7.8 Hz, CDCl3): δ 7.63 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.33
2H), 7.13 (ddd, J = 8.0, 5.2, 2.5 Hz, 1H), 6.67 (s, 1H), 3.85 – 3.78 (d, J = 8.4 Hz, 3H), 7.21 (q, J = 7.9 Hz, 3H), 7.16 (t, J = 7.4 Hz,
(m, 3H), 3.54 (t, J = 6.5 Hz, 2H), 1.88 (dd, J = 13.3, 3.9 Hz, 2H), 2H), 6.93 (d, J = 8.1 Hz, 1H), 6.70 (d, J = 7.2 Hz, 2H), 4.82 (s,
1.82 – 1.76 (m, 3H), 1.56 (d, J = 15.6 Hz, 3H), 1.47 – 1.42 (m, 1H), 4.03 – 3.95 (m, 2H), 3.57 – 3.49 (m, 1H), 1.71 – 1.60 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 176.2, 167.6, 161.9, 137.5, 2H), 1.52 (d, J = 6.5 Hz, 2H), 1.40 (d, J = 11.2 Hz, 1H), 1.34 –
134.6, 131.2, 129.4, 128.5, 128.37, 128.2, 127.3, 126.8, 121.2, 1.18 (m, 3H), 1.09 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 168.8,
121.1, 112.9, 48.6, 40.9, 34.3, 33.1, 32.5, 29.7; HRMS (ESI): 147.4, 141.8, 134.9, 134.3, 133.9, 132.5, 129.9, 129.5, 128.9,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
calcd. for C25H28N3O3 [M+H]+: 418.2131, found: 418.2105.
128.2, 127.9, 127.1, 125.6, 124.4, 70.8, 57.6, 47.8, 32.4, 32.3,
2‐(3‐(2‐acetamidoethyl)‐1H‐indol‐2‐yl)‐N‐cyclohexyl‐2‐
25.3, 24.6, 24.5; HRMS (ESI): calcd. for C27H29ClN3O3 [M+H]+:
oxoacetamide (6c). Yellow oil (21.0 mg, 29%); Rf = 0.55 (30% 478.1897, found: 478.1891.
1
EtOAc in hexane); H NMR (400 MHz, CDCl3): δ 11.35 (s, 1H), X. General Procedure for the synthesis of substrate 11
.
7.71 (d, J = 8.3 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.43 – 7.38 (m, Substrate 11 was prepared according to the procedure
2H), 7.15 (ddd, J = 8.1, 5.2, 2.6 Hz, 1H), 5.87 (s, 1H), 3.89 – 3.79 previously reported by our research group.6b To a solution of p‐
(m, 1H), 3.58 (dd, J = 12.4, 6.3 Hz, 2H), 3.39 (dd, J = 11.1, 4.7 anisidine (1.0 equiv, 0.4 mmol) in CH3CN (3.0 mL) and water
Hz, 2H), 2.01 – 1.96 (m, 2H), 1.87 (s, 3H), 1.82 – 1.76 (m, 4H), (0.1 mL), aldehyde (1.0 equiv, 0.4 mmol) was added with
1.67 (m, 3H), 1.61 – 1.55 (m, 1H); 13C NMR (100 MHz, CDCl3): δ continuous stirring at rt and allowed to stir for 4‐5 minutes To
176.0, 170.3, 161.9, 137.4, 129.3, 128.3, 128.1, 127.4, 121.2, that mixture, phenyl propiolic acid (1.0 equiv, 0.4 mmol),
121.0, 112.9, 48.6, 40.2, 32.5, 25.3, 25.1, 24.6, 23.2; HRMS followed by isocyanide (1.0 equiv, 0.4 mmol), was added and
(ESI): calcd. for C20H26N3O3 [M+H]+: 356.1974, found: 356.1966. stirred for 12‐18 h. After consumption of all the substrates
VII. General Procedure for the synthesis of THIQ‐derived Ugi (based on TLC), acetonitrile was added (3.0 mL) to dilute the
adducts 7. Substrate
procedure.29 Compounds 7a‐c were in accordance with the added, and the mixture was allowed to stir for 5‐6 h at rt. After
data reported in the literature. completion of the reaction, reaction mixture was diluted with
VIII. General Procedure for the oxidative cleavage of Ugi ethyl acetate and washed with sodium thiosulfate solution
7 was prepared according to reported reaction mixture. To this, iodine (2.0 equiv, 0.8 mmol) was
adducts 7. To the solution of
7 (1.0 equiv, 0.2 mmol) in dry (10% w/v). Aqueous layer was extracted with ethyl acetate and
CH3CN was added KOtBu (3.0 equiv, 0.6 mmol) and CuI (0.2 the combined organic layers was dried over anhydrous sodium
equiv, 20 mol %) at room temperature and the reaction vessel sulfate. After evaporation of ethyl acetate in vacuo, crude was
was flushed with O2. The resulting reaction mixture was stirred dissolved in dichloromethane and distilled hexane was added
at room temperature. After completion of the reaction (based to precipitate the product. Solid portion was filtered and dried
on TLC) in 12 h, the reaction mixture was quenched with water in high vacuum to afford the desired product 11
and the crude product was extracted with ethyl acetate. The N‐(tert‐butyl)‐2‐(3‐iodo‐2,8‐dioxo‐4‐phenyl‐1‐
.
organic layer was dried over anhydrous sodium sulfate, azaspiro[4.5]deca‐3,6,9‐trien‐1‐yl)‐2‐phenylacetamide (11a)
.
concentrated in vacuo and the crude was purified by silica gel Pale yellow solid (184.0 mg, 82%); m.p: 170 °C; Rf = 0.45 (30%
column chromatography to afford the product
8
or
9.
EtOAc in hexane); 1H NMR (400 MHz, DMSO‐d6): δ 7.70 (s, 1H),
7.38 – 7.33 (m, 3H), 7.32 – 7.28 (m, 2H), 7.28 – 7.25 (m, 1H),
N‐(tert‐butyl)‐3,4‐dihydroisoquinoline‐1‐carboxamide (8a)30
.
1
Yellow oil (18.0 mg, 39%); Rf = 0.5 (20% EtOAc in hexane); H 7.25 – 7.23 (m, 1H), 7.19 (t, J = 7.3 Hz, 2H), 7.11 (dd, J = 6.5, 3.2
NMR (300 MHz, CDCl3): δ 8.18 (dd, J = 7.6, 1.3 Hz, 1H), 7.41 – Hz, 2H), 6.49 (dd, J = 10.0, 3.0 Hz, 1H), 6.12 (dd, J = 10.1, 1.9
7.26 (m, 3H), 7.20 – 7.14 (m, 1H), 3.79 – 3.70 (m, 2H), 2.74 – Hz, 1H), 5.52 (dd, J = 9.9, 1.9 Hz, 2H), 1.27 (s, 9H); 13C NMR
2.66 (m, 2H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 163.7, (125 MHz, DMSO‐d6): δ 183.6, 167.7, 166.9, 159.1, 145.3,
160.5, 138.1, 131.1, 128.6, 127.0, 126.8, 126.3, 51.0, 47.1, 144.9, 134.2, 132.2, 130.5, 130.4, 129.1, 128.7, 128.5, 128.3,
28.6, 25.9; HRMS (ESI): calcd. for C14H19N2O [M+H]+: 231.1497, 127.9, 127.5, 99.8, 71.2, 61.1, 50.5, 28.3; HRMS (ESI): calcd. for
found: 231.1494.
C27H26IN2O3 [M+H]+: 553.0988, found: 553.0984.
N‐cyclohexylisoquinoline‐1‐carboxamide (9b)31. White solid 2‐(4‐chlorophenyl)‐N‐cyclohexyl‐2‐(3‐iodo‐2,8‐dioxo‐4‐phenyl‐
(13.0 mg, 26%); m.p: 118 °C; Rf = 0.7 (10% EtOAc in hexane); 1H 1‐azaspiro[4.5]deca‐3,6,9‐trien‐1‐yl)acetamide (11b). White
NMR (500 MHz, CDCl3): δ 9.61 (d, J = 8.5 Hz, 1H), 8.46 (d, J = solid (217.0 mg, 87%); m.p: 182 °C; Rf = 0.45 (30% EtOAc in
1
5.5 Hz, 1H), 8.10 (s, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 5.5 hexane); H NMR (300 MHz, CDCl3+DMSO‐d6): δ 7.93 (s, 1H),
Hz, 1H), 7.69 (dtd, J = 16.8, 6.8, 1.3 Hz, 2H), 4.07 – 3.99 (m, 7.50 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 8.1 Hz, 5H), 7.21 (s, 1H),
1H), 2.08 (dd, J = 12.3, 3.3 Hz, 2H), 1.83 – 1.78 (m, 2H), 1.71 – 7.15 – 7.04 (m, 3H), 6.50 (dd, J = 10.0, 2.8 Hz, 1H), 6.17 (d, J =
1.64 (m, 1H), 1.50 – 1.45 (m, 2H), 1.38 (m, 3H); 13C NMR (100 10.0 Hz, 1H), 5.82 (d, J = 10.0 Hz, 1H), 5.42 (s, 1H), 3.77 – 3.62
MHz, CDCl3): δ 165.2, 148.7, 140.1, 137.4, 130.4, 128.5, 128.0, (m, 1H), 1.80 (s, 2H), 1.63 (d, J = 34.5 Hz, 3H), 1.34 – 1.23 (m,
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2H), 1.14 (dd, J = 24.1, 12.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): The authors declare no competing financial interests
δ 182.3, 170.1, 165.7, 157.9, 143.4, 142.9, 130.7, 130.0, 129.2,
.
128.2, 126.9, 126.8, 120.2, 97.5, 70.2, 59.4, 47.5, 43.8, 31.1,
28.1, 24.0, 23.4; HRMS (ESI): calcd. for C29H27ClIN2O3 [M+H]+:
613.0755, found: 613.0740.
Acknowledgement
Financial support from SERB, New Delhi (Grant No.
CRG/2018/001897) and CSIR‐New Delhi (XIIth FYP Project
‘THUNDER’ Grant No. BSC0102) is highly acknowledged. AG
thanks ICMR, AMD and RS thank CSIR for providing fellowship.
The authors are grateful to SAIF, CSIR‐CDRI for analytical
support.
N‐(tert‐butyl)‐2‐(3‐iodo‐2,8‐dioxo‐4‐phenyl‐1‐
azaspiro[4.5]deca‐3,6,9‐trien‐1‐yl)‐2‐(p‐tolyl)acetamide (11c)
.
White solid (180.0 mg, 78%); m.p: 178 °C; Rf = 0.45 (30% EtOAc
1
in hexane); H NMR (500 MHz, CDCl3): δ 7.40 – 7.31 (m, 5H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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34
35
36
37
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39
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60
7.15 (t, J = 7.9 Hz, 4H), 6.73 (dd, J = 9.9, 3.0 Hz, 1H), 6.53 (dd, J
= 9.9, 3.0 Hz, 1H), 6.26 – 6.16 (m, 2H), 5.52 (s, 1H), 4.80 (s, 1H),
2.35 (s, 3H), 1.30 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 183.9,
167.1, 166.8, 158.8, 144.3, 144.2, 139.2, 132.2, 132.1, 131.9,
131.9, 129.8, 129.6, 129.4, 128.4, 127.7, 98.6, 71.6, 62.6, 51.8,
28.5, 21.1; HRMS (ESI): calcd. for C28H28IN2O3 [M+H]+:
567.1145, found: 567.1138.
Notes and references
1
2
3
a) A. Domling, Chem. Rev., 2006, 106, 17; b) S. Sadjadi, M.M.
Heravi and N. Nazari, RSC Adv., 2016, , 53203; c) A. Varadi,
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6
2‐(2‐bromophenyl)‐N‐(tert‐butyl)‐2‐(3‐iodo‐2,8‐dioxo‐4‐
phenyl‐1‐azaspiro[4.5]deca‐3,6,9‐trien‐1‐yl)acetamide (11d)
.
White solid (244.0 mg, 95%); m.p: 187 °C; Rf = 0.45 (30% EtOAc
in hexane); 1H NMR (500 MHz, CDCl3): δ 7.67 (d, J = 7.4 Hz, 1H),
7.59 – 7.53 (m, 1H), 7.35 (ddd, J = 22.2, 12.2, 7.2 Hz, 3H), 7.23
(dt, J = 7.3, 6.7 Hz, 2H), 7.17 – 7.11 (m, 2H), 6.71 (dd, J = 10.0,
2.9 Hz, 1H), 6.64 (dd, J = 9.8, 2.3 Hz, 1H), 6.14 (dd, J = 10.1, 1.3
Hz, 1H), 6.06 (dd, J = 9.9, 2.0 Hz, 1H), 5.59 (s, 1H), 5.30 (t, J =
5.2 Hz, 1H), 1.32 (s, 9H); 13C NMR (75 MHz, CDCl3): δ 183.9,
167.5, 165.9, 159.5, 144.0, 143.9, 134.4, 133.0, 131.8, 131.6,
131.1, 130.8, 129.9, 128.4, 128.1, 127.8, 126.1, 97.8, 71.4,
61.6, 52.1, 28.4; HRMS (ESI): calcd. for C27H25BrIN2O3 [M+H]+:
631.0093, found: 631.0089.
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3,6,9‐trien‐1‐yl)‐2‐(4‐(methylthio)phenyl)acetamide
(11e).
White solid (226.0 mg, 88%); m.p: 230 °C; Rf = 0.42 (30% EtOAc
in hexane); 1H NMR (300 MHz, DMSO‐d6): δ 8.36 (t, J = 5.9 Hz,
1H), 7.30 – 7.25 (m, 3H), 7.25 – 7.14 (m, 7H), 7.07 – 6.99 (m,
4H), 6.95 (dd, J = 10.1, 3.0 Hz, 1H), 6.56 (dd, J = 10.0, 3.0 Hz,
1H), 6.06 (dd, J = 10.1, 1.9 Hz, 1H), 5.65 (dd, J = 10.0, 1.9 Hz,
1H), 5.34 (s, 1H), 4.33 – 4.18 (m, 2H), 2.33 (s, 3H); 13C NMR (75
MHz, DMSO‐d6): δ 183.8, 168.3, 167.2, 159.2, 145.22, 144.7,
139.2, 132.3, 131.4, 130.9, 130.9, 129.8, 129.4, 128.3, 128.2,
127.2, 126.9, 125.2, 99.8, 71.3, 60.7, 42.6, 14.7; HRMS (ESI):
calcd. for C31H26IN2O3S [M+H]+: 633.0709, found: 633.0648.
N‐(tert‐butyl)‐2‐(3‐iodo‐2,8‐dioxo‐4‐phenyl‐1‐
4
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(300 MHz, CDCl3): δ 7.37 – 7.29 (m, 5H), 7.18 (s, 1H), 7.16 –
7.11 (m, 3H), 6.63 (ddd, J = 9.7, 7.4, 2.9 Hz, 2H), 6.24 – 6.18 (m,
1H), 6.13 – 6.07 (m, 1H), 5.53 (s, 1H), 4.93 (s, 1H), 2.98 – 2.82
(m, 1H), 1.32 (s, 9H), 1.25 (d, J = 0.5 Hz, 3H), 1.22 (d, J = 0.5 Hz,
3H); 13C NMR (75 MHz, CDCl3): δ 184.1, 167.3, 167.1, 159.1,
150.4, 144.2, 144.2, 132.2, 131.9, 131.9, 131.6, 129.8, 128.5,
127.9, 126.9, 98.5, 71.7, 62.6, 51.9, 33.8, 28.6, 23.9, 23.7;
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595.1457.
6
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Conflicts of interest
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The present study provides an insight into the reactivity of Passerini and Ugi adducts in basic
medium leading to α-ketoamides.