Ugi-post functionalization, from a single set of Ugi-adducts to two distinct heterocycles by microwave-assisted palladium-catalyzed cyclizations: Tuning the reaction pathways by ligand switch

Article abstract of DOI:10.1021/jo900210x

Linear amides 4, prepared in one step by the Ugi four-component reaction, were converted to 3,4-dihydroquinoxalin-3-ones (5) or to 2-(2-oxoindolin-1-yl) acetamides (6) dependent on the catalytic conditions. While microwave irradiation was found to be dete

Full text of DOI:10.1021/jo900210x

Ugi-Post Functionalization, from a Single Set of Ugi-Adducts to Two
Distinct Heterocycles by Microwave-Assisted Palladium-Catalyzed
Cyclizations: Tuning the Reaction Pathways by Ligand Switch
William Erb, Luc Neuville,* and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-YVette Cedex, France
zhu@icsn.cnrs-gif.fr; neuVille@icsn.cnrs-gif.fr
ReceiVed January 30, 2009
Linear amides 4, prepared in one step by the Ugi four-component reaction, were converted to
3,4-dihydroquinoxalin-3-ones (5) or to 2-(2-oxoindolin-1-yl)acetamides (6) dependent on the catalytic
conditions. While microwave irradiation was found to be determinant on the reaction efficiency, the
choice of ligand diverged the reaction pathways. Heating a solution of 4 in dioxane/MeCN (v/v ) 85/
15) under microwave irradiation conditions in the presence of Pd(dba)2 (0.05 equiv) and Cs2CO3 (2
equiv), using XPhos as a supporting ligand, afforded the 3,4-dihydroquinoxalin-3-ones (5) via an
intramolecular N-arylation of the secondary amide. On the other hand, using BINAP as ligand under
otherwise identical conditions, intramolecular R-CH arylation of tertiary amide occurred to furnish the
oxindoles (6).
Introduction
Isonitrile-based MCRs, represented by the Passerini three-
component reaction4 and Ugi four-component reaction,5 are
among the most powerful transformations that have been
extensively investigated for the past 20 years.6 Because of the
mildness of reaction conditions, the wide application scope, and
the high variability (four diversity points for U-4CR), they
provided perfect tools for generating multifunctional adducts.
The postfunctionalization of multicomponent reaction (MCR)1
adducts has received considerable attention in recent years.2
Indeed, MCR is not only a valuable tool for rapidly creating
molecular complexity and diversity suitable for biological
evaluation but is also capable of providing scaffolds with
appropriate functionalities paired for further transformations,
expanding consequently the chemical space accessible by this
enabling technology.3
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10.1021/jo900210x CCC: $40.75
Published on Web 03/13/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3109–3115 3109

Erb et al.
SCHEME 1. From Single Ugi Adduct to Different Set of
Naturally, these reactions have been associated with a number
of post-transformations such as cyclocondensation,7 ring-closure
metathesis,8 cycloaddition,9 macrolactonization,10 SNAr,11 SN2
reaction,12 radical cyclization13 etc. for the synthesis of various
cyclic scaffolds. The association of rich and diverse palladium-
catalyzed chemistry14 with the Ugi reaction has also been
investigated. Indeed, performing the Heck reactions,15 the
N-arylations,16 the C-arylation of benzylic carbon,17 the C-H
funcationalization,18 the Suzuki-Miyaura reaction,19 and the
Sonogashira couplings20 on the properly functionalized Ugi-
adducts allowed the facile access to a number of medicinally
relevant heterocycles.21
Heterocycles by Metal Switch
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Notwithstanding the effiency of these reaction sequences, the
functionalized Ugi-adducts in most of these processes were
designed and synthesized for participation in a single defined
chemical process. Therefore, each of these two-step sequences
generally led to a single set of heterocyclic system. The power
of the MCR/postfunctionalization would be reinforced if the
same MCR-adduct could be diverged to different heterocyclic
scaffolds by exploiting its multifunctionalities.22 Toward this
end, we have recently reported that the linear Ugi-adduct 1 can
be converted to tetracyclic compound 2 or benzodiazepinedione
3 at will by simply switching the metal catalysts (Scheme 1).23,24
As a continuation of this work, we reasoned that it should be
conceivable to assemble a single subset of molecules bearing
multiple reaction sites, which could then undergo, in a selective
manner, different palladium-catalyzed transformations by simply
changing one or two reaction parameters.25 In view of the recent
spectacular advances on the palladium-catalyzed N-arylation of
amides26 and C-arylation of acidic methylene groups,27 we were
interested in the Ugi-adduct 4 and hypothesized that by judicious
choice of the base we would be able to orient the reaction
pathways toward the formation of either dihydroquinoxalinones
5 or oxindoles 6 (Scheme 2). While a divergent synthesis of
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3110 J. Org. Chem. Vol. 74, No. 8, 2009

Ugi-Post Functionalization
TABLE 1. Palladium-Catalyzed Intramolecular N-Arylation:
SCHEME 2. From Single Ugi Adduct to Different Set of
Heterocycles by Ligand Switch
Survey of Reaction Conditionsa
entry
Pd
ligand
XPhos
Xantphos
XPhos
XPhos
XPhos
XPhos
XPhos
solvent
dioxane
dioxane
dioxane
DMF
T (°C) yieldb (%)
1
2
3
4
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(OAc)2
PdCl2(dppf)
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
reflux
reflux
MWc
MWc
40
55
44
77
91
28
67
58
87
78
60
0
these two heterocycles from the same linear amide 4 was indeed
achieved, we observed that it was not the base, but the structure
of ligand that determined the reaction manifold. Thus under
microwave irradiation conditions, palladium-catalyzed intramo-
lecular N-arylation of amide 4 in the presence of Xphos ligand
afforded the 3,4-dihydroquinoxalin-3-ones (5).28 On the other
hand, when BINAP was used as ligand under otherwise identical
conditions, amide 4 was converted to 2-(2-oxoindolin-1-
yl)acetamides (6) by an intramolecular arylation of enolate.29
5
dioxane/CH3CNd MWc
dioxane/CH3CNd MWc
dioxane/CH3CNd MWc
dioxane/CH3CNd MWc
dioxane/CH3CNd MWc
dioxane/CH3CNd MWc
dioxane/CH3CNd MWc
6e
7
8
9
10
11
12
Me-Phos
Xantphos
Rac BINAP dioxane/CH3CNd MWc
13f Pd(dba)2
14g Pd(dba)2
XPhos
XPhos
dioxane/CH3CNd MWc
dioxane/CH3CNd MWc
81
34
a General conditions: 4a (1.0 equiv), palladium (0.05 equiv), ligand
(0.05 equiv), and Cs2CO3 (2.0 equiv), C ) 0.015 M. b Referred to
chromatographically pure product. c Microwave irradiation power: 300
W, 150 °C. Microwave experiments were conducted using a Discover
microwave reactor from CEM. All experiments were performed in
sealed tubes (capacity 10 mL) under argon atmosphere. Microwave
irradiation of 300 W was used, the temperature being ramped from
room temperature to 150 °C in 1 min. Once this temperature was
Results and Discussion
Synthesis of 3,4-Dihydroquinoxalin-2-ones. 3,4-Dihydro-
quinoxalin-2-ones (benzopiperazinones) are attractive synthetic
targets in medicinal chemistry. These compounds have been
reported to present antidiabetic30 or antiviral activities,31 to act
as multiple drug resistance antagonists,32 and to be inhibitors
of aldose reductase,33 agonists of the γ-aminobutyric acid
(GABA)/benzodiazepine receptor complex,34 and antagonists
of the AMPA and angiotensin II receptors.35 Because of their
significant biological activities, they are considered as priv-
iledged scaffolds in medicinal chemistry.36
Recently, Kalinski and co-workers reported an Ugi/Pd-
catalyzed amidation sequence for the synthesis of such
heterocycles.16a Whereas the viability of the sequence was
demonstrated, the reported process suffered from the poor yield
obtained in the Pd-catalyzed amidation reaction (3-50%) and
the limited number of examples investigated (5 examples). This
prompted us to re-evaluate the sequence using amide 4a (R1 )
C2H5, R2 ) i-Pr, R3) t-Bu, X ) I) as a model compound, and
the results are summarized in Table 1.
reached, the reaction mixture was held at 150 °C for
2 h. The
temperature in the MW experiments was measured by an external IR
sensor. d v/v ) 85/15. e K2CO3 was used as a base. f Bromide 7 was
used as starting material. g Chloride 8 was used as starting material.
A bidentate ligand, Xantphos,37 and a monodentate biaryl
monophosphine, Xphos,38 were initially used in combination
with Pd(dba)2 (5% equiv) and Cs2CO3 (2.0 equiv) in refluxing
dioxane for the cyclization of 4a. Indeed, both ligands were
found to be effective to afford cyclized product in moderate
yield (entries 1, 2). Since microwave heating was known to be
beneficial to the palladium-catalyzed intramolecular N-arylation
reaction,26,39 we next carried out the reaction under microwave
irradiation using XPhos as ligand.40 In dioxane, performing the
reaction under microwave irradiation did not have significant
impact on the reaction outcome (entry 3). However, when DMF
or a mixture of solvent dioxane/acetonitrile (v/v ) 85/15) was
used, the reaction proceeded more efficiently to provide 5a in
yields of 77% and 91%, respectively (entries 4 and 5). Variation
of the base (entry 6), the palladium sources (entries 7, 8), and
ligands (entries 9-12) invariably reduced the yield of cyclic
product. It should be noted that under microwave irradiation
cyclization of 4a took place under ligandless conditions using
Pd(dba)2 as catalyst to afford 5a in 87% (entry 9). These latter
(28) For the synthesis of 3,4-dihydroquinoxalin-2-ones from an Ugi adduct
but using different ring closure reactions, see: Hulme, C.; Cherrier, M.-P.
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(32) Lawrence, D. S.; Copper, J. E.; Smith, C. D. J. Med. Chem. 2001, 44,
594–601.
(33) (a) Sarges, R.; Lyga, J. W. J. Heterocycl. Chem. 1988, 25, 1475–1479.
(b) Bunin, B. A.; Ellman, J. A. J. Am. Chem. Soc. 1992, 114, 10997–10998.
(34) (a) Lee, L.; Murray, W. V.; Rivero, R. A. J. Org. Chem. 1997, 62,
3874–3879, and references therein. (b) Jacobsen, E. J.; Stelzer, L. S.; Belonga,
K. L.; Carter, D. B.; Im, W. B.; Sethy, V. H.; Tang, A. H.; VonVoigtlander,
P. F.; Petke, J. D. J. Med. Chem. 1996, 39, 3820–3836.
(35) Morales, G. A.; Corbett, J. W.; DeGrado, W. F. J. Org. Chem. 1998,
63, 1172–1177.
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893–930.
J. Org. Chem. Vol. 74, No. 8, 2009 3111

Erb et al.
TABLE 2. UGI-4CR/Palladium-Catalyzed Intramolecular N-Arylation: Synthesis of Benzopiperazinones
a General conditions: 4 (1.0 equiv), palladium (0.05 equiv), XPhos (0.05 equiv), and Cs2CO3 (2.0 equiv) in dioxane/MeCN ) 85/15 (v/v), C )
0.015M, MW (300 W, 150 °C). b Referred to chromatographically pure product. c Two separable diastereoisomers. d Pure diastereomer 4j was used for
the cyclization.
SCHEME 3. Ligand-Directed Reaction Divergency
conditions were subsequently found to be substrate dependent
and have only limited application scope. Overall, the optimized
conditions for this cyclization were as follows: Pd(dba)2 (0.05
equiv), XPhos (0.05 equiv), and Cs2CO3 (2.0 equiv) in dioxane/
CH3CN (v/v ) 85/15) under microwave irradiation (entry 5).
The aryl bromide 7 participated in the reaction efficiently to
afford the desired product 5a in 81% yield (entry 13). On the
other hand, the aryl chloride 8 was much less reactive under
these conditions providing the benzopiperazinone 5a in only
standard conditions (entry 14). Amides synthesized from linear
34% yield together with unreacted starting materials (54%
and R-branched aliphatic aldehydes and carboxylic acid all
recovered) (entry 14).
cyclized without event. Surprisingly, in the cyclization of acetyl
With the appropriate conditions in hand, the scope of this
derivative 4o, the desired 3,4-dihydroquinoxalin-2-one (5o) was
two-step synthesis of 3,4-dihydroquinoxalin-3-ones was explored
isolated in only 25% yield together with oxindole 6d in 54%
by combined use of Ugi-4CR and Pd-catalyzed intramolecular
yield (vide infra). The aryl bromide 4k, as demonstrated in the
amidation. The results are summarized in Table 2. As expected,
optimization phase, is reactive enough to afford compound 5k
the Ugi reaction proceeded uneventfully under standard condi-
in 78% yield.
tions (MeOH, rt) with a wide range of substrates. From three
Synthesis of Indolin-2-ones. During the optimization of the
aldehydes, seven anilines, six carboxylic acids, and three
Pd-catalyzed N-arylation reaction (Table 1), we frequently
isonitriles, 15 amides were synthesized in yields ranging from
observed the formation of oxindole 6 as a side product when
42 to 90%. The low yield obtained with 4-fluoroaniline (entry
ligands other than XPhos were used. This product was very
8) is understandable considering the reduced nucleophilicity of
likely derived from competitive intramolecular palladium-
the nitrogen and the low basicity of the resulting imine.41 The
catalyzed R-arylation of the tertiary amide.27,29,42 While use of
intramolecular palladium-catalyzed amidation worked well with
XPhos as a supporting ligand suppressed completely the
most of the substrates examined. The benzyl amide, cyclohexyl
oxindole formation, we found that cyclization of 4a in the
amide, and tert-butyl amide cyclized efficiently, indicating that
presence of Binap completely reVersed the benzopiperazinones/
the reaction was insensititve to the steric hindrance around the
oxindole selectiVity leading to the formation of oxindole 6a as
secondary amide unit. The electronic properties of the aromatic
a mixture of two diastereoisomers (Scheme 3). The optimal
ring have no significant impact on the reaction outcome as the
conditions found consisted of using Pd(dba)2 (0.05 equiv) as a
presence of methyl, methoxy, and fluorine substituents were well
palladium source, rac-Binap (0.05 equiv) as a ligand, and
tolerated. The reaction was, however, found to be sensitive to
steric hindrance ortho to the iodide as a Ugi-adduct derived
from 3-methoxy-2-iodo aniline (4n) failed to cyclize under
(42) (a) Marsden, S. P.; Watson, E. L.; Raw, S. A. Org. Lett. 2008, 10, 2905–
2908. (b) Jia, X. Y.; Hillgren, J. M.; Watson, E. L.; Marsden, S. P.; Ku¨ndig,
E. P. Chem. Commun. 2008, 4040–4042. (c) J. Hillgren, M.; Marsden, S. P. J.
Org. Chem. 2008, 73, 6459–6461.
(41) Marcaccini, S.; Torroba, T. Nature Protocols 2007, 2, 632–639.
3112 J. Org. Chem. Vol. 74, No. 8, 2009

Ugi-Post Functionalization
SCHEME 4. Synthesis of Oxindoles through r-Arylation
SCHEME 5. Ligand-Dependent Reaction Divergence:
Mechanistic Hypothesis
monodentate ligands.43 Thus, if complex C was formed in the
case where BINAP was used as a ligand, the reductive
elimination should occurr to deliver the N-arylamide. This is,
however, not the case, and we concluded that the role of
supporting ligand on the partition of reaction pathways cannot
be explained on this step either. Overall, we hypothesized that
it is the transmetalation step that determined the reaction
outcome.44 It is reasonable to assume that the N-H of the
secondary amide would be deprotonated first in the presence
of a weak base (Cs2CO3) leading to the intermediate B. When
XPhos was used as a ligand, the availability of a vacant
coordination site of metal would facilitate the coordination of
amidate to Pd, thus accelerating the transmetalation step (from
B to C). Reductive elimination from C would then afford the
benzopiperizinone 5. It has to be noted that formation of a k2-
amidate palladium complex, often associated with the mono-
dentate ligand, is known to inhibit the reductive elimination in
an intermolecular amidation reaction.43,44 However, we assumed
that in the intramolecular version leading to the formation of a
six-membered ring, the formation of such complex may not be
so pronunced due to the geometry constraint.45 In addition, the
anilide nitrogen atom can also serve as a ligating site for Pd(II)
species46 to favor the formation of k1-amidate palladium
complex even with a monodentate ligand. On the other hand
with sterically hindered secondary amide (tert-butyl amide) in
the presence of a bidentate BINAP, the coordination of the
secondary amide or the attack of the amidate on the tetracoor-
dinated Pd(II) species B leading to C would be slowed down
for steric reasons. Consequently, intramolecular proton shift
from complex B could become competitive leading to the
formation of enolate D. Transmetalation would subsequently
take place to afford palladacycle E, which upon reductive
elimination would produce oxindole 6.
Cs2CO3 (2 equiv) as a base in dioxane-CH3CN (v/v ) 85/15)
under microwave irradiation. The conditions turned out to be
generally applicable to amides with different susbsituent pat-
terns. It can be applied to the synthesis of 3-unsubstituted,
3-substituted, and 3,3-disubstituted oxindoles. However, in the
latter case, the intramolecular N-arylation became competitive
probably due to the increased steric hindrance associated with
the creation of the quaternary carbon center. Using bulky tert-
butylamide derived from tert-butyl isocyanide was important
in order to ensure the occurrence of the R-arylation. Indeed,
submitting the benzyl amide 4f to the above conditions afforded
the dihydroquinoxalinone 5f as the only isolable product in 78%
yield. Finally, aryl bromide 4k also proved to be reactive,
leading to the formation of oxindole 6g in 47% yield together
with recoved starting materials (44%).
Effect of Ligand on the Reaction Divergence: Mechanistic
Implication. The palladium-catalyzed cross-coupling reaction
is initiated by oxidative addition of haloarene to Pd(0) species,
followed by transmetalation and reductive elimination to afford
the coupled product with concurrent regeneration of Pd catalyst.
A classic mechanism accounting for the formation of products
5 and 6 from 4 is illustrated in Scheme 5. The R-arylation of
tertiary amides usually required strong bases like NaO-t-Bu and
LiHMDS. Indeed, under thermal conditions, Cs2CO3 is known
to be inefficient for promotion of oxindole formation through
R-arylation of tertiary amide.29a The key questions we asked
with regard to the reaction divergency were as follows: (a) How
can ligand switch modulate so efficiently the two different
reaction pathways? (b) How can the enolate of tertiary amide
be formed?
Conclusions
In conclusion, we have demonstrated that ligand can not only
influence the reaction efficiency of a given palladium-catalyzed
The oxidative addition of aryl iodide to Pd(0) species leading
to A is a common step for both the N-arylation and the R-C-
arylation reactions and should thus have no consequence on
the subsequent reaction pathways. With regard to the reductive
elimination step of N-arylation, it is known that this step is faster
from Pd complexes with bidentate ligands than from those with
(43) Fujita, K.-I.; Yamashita, M.; Puschmann, F.; Alvarez-Falcon, M. M.;
Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 9044–9045.
(44) (a) Ikawara, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 13001–13007.
(45) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35–37.
(46) Sole´, D.; Vallverdu´, L.; Solans, X.; Font-Bardia´, M.; Bonjoch, J. J. Am.
Chem. Soc. 2003, 125, 1587–1594.
J. Org. Chem. Vol. 74, No. 8, 2009 3113

Erb et al.
N-tert-Butyl-2-(N-(2-chlorophenyl)butyramido)-3-methylbu-
tanamide (8): light brown solid; Rf ) 0.59 (3:2 hexanes/EtOAc);
mp 95-97 °C; IR (neat, cm-1) ν 3335, 2964, 1668, 1641, 1541,
1481, 1385, 1245, 1217, 769; 1H NMR (CDCl3, 500 MHz) rotamers
δ 7.60-7.46 (d, J ) 7.9 Hz, 1H), 7.52 and 6.38 (broad s, 1H,
NH), 7.43-7.37 (m, 1H), 7.33-7.18 (m, 2H), 4.30 and 3.55 (d, J
) 10.5 Hz, 1H), 2.58 and 2.41 (m, 1H), 2.10-1.95 (m, 1H),
1.93-1.83 (m, 1H), 1.61-1.47 (m, 2H), 1.33 and 1.27 (s, 9H),
1.07 and 0.97 (d, J ) 6.5 Hz, 3H), 0.90 (d, J ) 6.5 Hz, 3H),
0.79-0.77 (2t, J ) 7.4 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
rotamers 174.9 and 174.5, 170.1 and 168.4, 140.7 and 138.4, 134.3
and 133.8, 130.4 and 130.3, 130.4 and 129.5, 129.9 and 129.3,
128.2 and 127.8, 76.2 and 69.2, 51.1 and 50.7, 36.9 and 36.6, 29.2
and 28.6, 28.4 and 27.4, 20.8 and 19.81, 19.7 and 19.4, 18.6 and
15.8, 13.8 and 13.7; MS (m/z, ESI+) 729 and 727 (2 M + Na), 377
and 375 (M + Na). Anal. Calcd for C19H29ClN2O2: C, 64.67; H,
8.28; N 7.84. Found: C, 64.61; H, 8.45; N 7.83.
General Procedure for the Preparation of 3,4-Dihydroqui-
noxalin-3-ones 5. To a solution of Ugi adduct 4 (0.034 mmol, 1.0
equiv) in dioxane/acetonitrile (v/v ) 85/15; 0.015 M) were added
Cs2CO3 (0.068 mmol, 2.0 equiv), Pd(dba)2 (0.0017 mmol, 0.05
equiv), and Xphos (0.0017 mmol, 0.05 equiv) in a Teflon-capped
vial. The vial was degazed under vacuum, refilled with argon, and
subjected to microwave heating (300 W, 150 °C) for 2 h. After the
reaction mixture was cooled to room temperature, the reaction
mixture was concentrated to dryness and purified by preparative
TLC (eluent: EtOAc/heptane) to give 3,4-dihydroquinoxalin-3-ones.
1-tert-Butyl-4-butyryl-3-isopropyl-3,4-dihydroquinoxalin-2(1H)-
one (5a): light brown solid; Rf ) 0.40 (7:3 hexanes/EtOAc); mp
81-83 °C; IR (neat, cm-1) ν 2961, 2933, 2871, 1665, 1652, 1495,
1463, 1395, 1330, 1287, 1218, 1190, 1001, 960; 1H NMR (CDCl3,
500 MHz) δ 7.17-7.19 (m, 3H), 7.13 (t, J ) 7.2 Hz, 1H), 5.03 (d,
J ) 9.4 Hz, 1H), 2.54 (t, J ) 7.3 Hz, 2H), 1.65 (m, 2H), 1.60 (s,
9H), 1.44 (m, 1H), 0.97 (d, J ) 6.6 Hz, 3H), 0.88 (t, J ) 7.5 Hz,
3H), 0.69 (d, J ) 6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) 173.7,
171.9, 134.8, 131.8, 125.8, 125.6, 123.9, 122.7, 64.7, 58.6, 35.4,
29.9, 28.2, 19.2, 19.1 (2C), 13.7; MS (m/z, ESI+) 339 (M + Na).
Anal. Calcd for C19H28N2O2: C, 72.12; H, 8.92; N, 8.85. Found: C,
72.11; H, 9.00; N, 8.81.
transformation, but also completely switch the reaction mani-
folds with multifunctional substrates. Thus, from a single set
of Ugi-adducts, two different heterocycles were readily syn-
thesized by palladium-catalyzed intramolecular N-arylation and
C-arylation processes. While microwave irradiation was im-
portant to the reaction efficiency, the choice of ligand determined
the reaction pathways. Using monodentate XPhos as a support-
ing ligand, cyclization of 4 afforded the 3,4-dihydroquinoxalin-
3-ones (5) via an intramolecular N-arylation of the secondary
amide. On the other hand, in the presence of BINAP under
otherwise identical conditions, intramolecular R-CH arylation
of tertiary amide occurred to furnish the oxindole 6. Combining
with the versatile Ugi four-component reaction, these two
medicinally relevant heterocycles can now be prepared in only
two steps from the same, readily accessible starting materials.
We assumed that high responsiveness of palladium chemistry
to reaction parameters could be taken for granted for the similar
reactivity switches with other substrates having more than one
set of paired functional groups.
Experimental Section
General Procedure for the Preparation of Ugi Adducts 4.
Iodoaniline (0.34 mmol, 1.2 equiv) and aldehyde (0.34 mmol, 1.2
equiv) were mixed together in dry methanol (0.2 M) under argon
and stirred for 45 min. Isocyanide (0.285 mmol, 1.0 equiv) and
carboxylic acid (0.34 mmol, 1.2 equiv) were then added, and the
mixture was stirred for 2 days at room temperature. The reaction
mixture was quenched by addition of saturated aqueous NaHCO3
solution. The aqueous layer was extracted three times with EtOAc,
and the organic layers were combined, backwashed with saturated
aqueous NaHCO3 solution and brine, dried over sodium sulfate,
and evaporated under reduced pressure. Purification by preparative
TLC (eluent: EtOAc/heptane) afforded the desired Ugi aduct.
N-tert-Butyl-2-(N-(2-iodophenyl)butyramido)-3-methylbutan-
amide (4a): white solid; Rf ) 0.53 (7:3 hexanes/EtOAc); mp
122-124 °C; IR (neat, cm-1) ν 3339, 2961, 1641, 1536, 1466, 1388,
1
1362, 1243, 1225, 1017, 737, 720; H NMR (CDCl3, 300 MHz)
1-tert-Butyl-4-butyryl-3-phenethyl-3,4-dihydroquinoxalin-
2(1H)-one (5b): colorless oil; Rf ) 0.30 (9:1 hexanes/EtOAc); IR
(neat, cm-1) ν 2963, 1672, 1493, 1454, 1385, 1366, 1325, 1285,
1215, 754, 698; 1H NMR (CDCl3, 500 MHz) δ 7.31-7.20 (m, 4H),
7.20-7.09 (m, 3H), 7.09-7.02 (m, 2H), 5.46 (dd, J ) 11.0, 4.1
Hz, 1H), 2.75-2.63 (m, 1H), 2.61-2.54 (m, 1H), 2.54-2.46 (m,
2H), 1.98-1.86 (m, 1H), 1.72-1.64 (m, 2H), 1.61 (s, 9H),
1.40-1.32 (m, 1H), 0.89 (t, J ) 7.4 Hz, 3H); 13C NMR (CDCl3,
125 MHz) 175.6, 172.4, 141.5, 135.3, 131.2, 128.8 (2C), 128.6,
126.6, 126.3, 124.3, 122.8, 60.0, 58.9, 35.9, 32.6, 30.9, 30.2, 19.4,
14.1; HRMS (m/z, ESI+) calcd for C24H30N2O2 ([M + Na]+)
401.2205, found 401.2202.
1-tert-Butyl-4-butyryl-3-methyl-3,4-dihydroquinoxalin-2(1H)-
one (5c): white solid; Rf ) 0.39 (4:1 hexanes/EtOAc); mp 107-109
°C; IR (neat, cm-1) ν 2965, 1664, 1496, 1389, 1365, 1328, 1263,
1210, 1189, 1030, 771, 761, 740, 663; 1H NMR (CDCl3, 500 MHz)
δ 7.29 (d, J ) 7.8 Hz, 1H), 7.24 (t, J ) 7.2 Hz, 1H), 7.20 (d, J )
7.2 Hz, 1H), 7.14 (t, J ) 7.8 Hz, 1H), 5.47 (q, J ) 7.0 Hz, 1H),
2.53 (m, 2H), 1.73-1.64 (m, 2H), 1.62 (s, 9H), 1.05 (d, J ) 7.0
Hz, 3H), 0.89 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
175.9, 171.4, 134.8, 130.9, 126.2, 125.8, 123.9, 122.4, 58.4, 55.4,
35.5, 29.7, 19.1, 14.7, 13.7; HRMS (m/z, ESI+) calcd for
C17H24N2O2 ([M + Na]+) 311.1735, found 311. 1730.
rotamers δ 7.89-7.82 (2dd, J ) 7.9, 1.5 Hz, 1H), 7.60 and 7.18
(dd, J ) 7.9, 1.5 Hz, 1H), 7.42 and 6.36 (broad s, 1H, NH),
7.40-7.30 (m, 1H), 7.04-6.94 (2td, J ) 7.9, 1.5 Hz, 1H), 4.36
and 3.59 (d, J ) 10.8 Hz, 1H), 2.60-2.30 (m, 1H), 2,09-1.93 (m,
1H), 1.93-1.77 (m, 1H), 1.66-1.45 (m, 2H), 1.34 and 1.28 (s,
9H), 1.09 and 0.99 (d, J ) 6.6 Hz, 3H), 0.90 and 0.83 (d, J ) 6.6
Hz, 3H), 0.82-0.74 (2t, J ) 7.4 Hz, 3H); 13C NMR (CDCl3, 125
MHz) rotamers 174.9 and 174.7, 170.2 and 168.7, 145.7 and 143.5,
140.6 and 140.5, 130.7 and 129.8, 130.1, 129.9 and 129.6, 103.3
and 102.9, 75.8 and 69.3, 51.6 and 51.3, 38.3 and 38.1, 30.4, 29.0,
29.0, 28.0, 22.2, 20.9, 19.9, 19.8, 19.1, 19.0, 14.2, 14.2; HRMS
(m/z, ES+) calcd for C19H29IN2O2 ([M + Na]+) 467.1165, found
467.1177.
N-tert-Butyl-2-(N-(2-bromophenyl)butyramido)-3-methylbu-
tanamide (7): light brown solid; Rf ) 0.60 (3:2 hexanes/EtOAc);
mp 106-108 °C; IR (neat, cm-1) ν 3339, 2964, 1676, 1642, 1537,
1473, 1395, 1245, 1065, 738; 1H NMR (CDCl3, 500 MHz) rotamers
δ 7.60 (2d, J ) 7.8 Hz, 1H), 7.56 and 7.21 (d, J ) 7.8 Hz, 1H),
7.52 and 6.37 (broad s, 1H, NH), 7.38-7.30 (m, 1H), 7.25-7.13
(m, 1H), 4.33 and 3.53 (d, J ) 10.4 Hz, 1H), 2.58 and 2.42 (m,
1H), 2.10-1.97 and 1.94-1.84 (m, 2H), 1.63-1.47 (m, 2H), 1.34
and 1.28 (s, 9H), 1.09 and 0.99 (d, J ) 6.7 Hz, 3H), 0.90 (m, 3H),
0.79 (m, 3H); 13C NMR (CDCl3, 125 MHz) rotamers 174.9 and
174.5, 170.0 and 168.3, 142.3 and 139.9, 133.8 and 133.7, 130.5
and 129.7, 130,0 and 129.5, 128.9 and 128.4, 125.4 and 124.8,
76.3 and 69.0, 51.2 and 50.8, 37.3 and 37.0, 29.6 and 28.7, 28.5
and 27.5, 21.2 and 20.0, 19.6 and 19.4, 18.7 and 18.6, 13.8 and
13.7; HRMS (m/z, ESI+) calcd for C19H2979BrN2O2 ([M + Na]+)
419.1310, found 419.1325, C19H2981BrN2O2 421.1290, found
421.1310.
General Procedures for the Preparation of 2-(2-Oxoindolin-
1-yl)acetamides 6. To a solution of Ugi adduct 4 (0.034 mmol,
1.0 equiv) in dioxane/acetonitrile (v/v ) 85/15; 0.015 M) were
added Cs2CO3 (0.068 mmol, 2.0 equiv), Pd(dba)2 (0.0017 mmol,
0.05 equiv), and rac-BINAP (0.0017 mmol, 0.05 equiv) in a Teflon-
capped vial. The vial was degassed under vacuum, refilled with
argon, and subjected to microwave heating (300 W, 150 °C) for
3114 J. Org. Chem. Vol. 74, No. 8, 2009

Ugi-Post Functionalization
2 h. After the reaction mixture was cooled to room temperature,
the reaction mixture was concentrated to dryness and purified by
preparative TLC (eluent: EtOAc/heptane) to give 2-(2-oxoindolin-
1-yl)acetamides.
127.6, 126.3, 124.5, 122.9 and 122.9, 106.8 and 106.7, 63.9, 51.4,
45.9 and 45.5, 28.6 and 28.6, 26.0 and 25.7, 24.1, 20.3 and 20.1,
19.0 and 18.7, 9.7 and 9.5; HRMS (m/z, ESI+) calcd for C23H30N2O2
([M + Na]+) 389.2198, found 389.2190.
N-tert-Butyl-2-(5-fluoro-3-methyl-2-oxoindolin-1-yl)-3-meth-
ylbutanamide (6c) (mixture of two diastereoisomers)L. light
yellow solid; Rf ) 0.69 (7:3 hexanes/EtOAc); mp 107-109 °C; IR
(neat, cm-1) ν 2963, 1703, 1698, 1482, 1338, 1220, 1190, 919,
N-tert-Butyl-2-(3-ethyl-2-oxoindolin-1-yl)-3-methylbutana-
mide (6a) (mixture of two diastereoisomers): white solid; Rf )
0.40 (4:1 hexanes/EtOAc); mp 93-95 °C; IR (neat, cm-1) ν 3346,
2960, 2929, 1697, 1609, 1537, 1484, 1460, 1357, 1212, 1097, 1025,
1
1
859, 667; H NMR (CDCl3, 500 MHz) two diastereoisomers, δ
745, 628; H NMR (CDCl3, 500 MHz) two diastereoisomers, δ
7.41-7.26 (m, 1H), 7.01-6.91 (m, 2H), 6.41-5.88 (broad s, 1H,
NH), 4.22 (m, 1H,), 3.49 (q, J ) 7.9 Hz, 1H), 2.85 (m, 1H), 1.49
(d, J ) 7.9 Hz, 3H), 1.31 (2s, 9H), 1.10 (m, 3H), 0.75 (2d, J ) 6.2
Hz, 3H); 13C NMR (CDCl3, 75 MHz) two diastereoisomeres, 179.3
and 179.2, 168.0, 158.7 (d, J ) 241 Hz), 138.1 and 137.9, 131.7
(d, J ) 8 Hz), 114.1 (d, J ) 23 Hz), 112.3 (d, J ) 8 Hz), 112.0 (d,
J ) 8 Hz), 111.3 (d, J ) 23 Hz), 64.3, 51.5 and 51.4, 40.7 and
40.6, 28.6, 26.0, 20.0, 18.7 and 18.5, 16.1 and 15.7; HRMS (m/z,
ESI+) calcd for C18H25FN2O2 ([M + Na]+) 343.1792, found
343.1782.
7.38-7.20 (m, 3H), 7.07 (dd, J ) 7.2, 7.1 Hz, 1H), 6.76-5.89
(broad s, 1H, NH), 4,28 and 4.23 (d, J ) 7.9 Hz, 1H), 3.53 (m,
1H), 2.90 (m, 1H), 2.19-1.99 (m, 2H), 1.30 and 1.27 (2s, 9H),
1.12 (m, 3H), 0.91-0.74 (m, 6H); 13C NMR (CDCl3, 75 MHz)
two diastereoisomers, 178.9 and, 178.8, 168.3 and 168.0, 143.1
and 142.9, 128.2 and 128.1, 128.0, 123.6, 123.6, 122.6 and 122.6,
110.9, 64.6 and 63.7, 51.3, 46.5 and 46.2, 29.7, 28.6 and 28.6, 26.2
and 25.9, 23.7 and 23.6, 20.2 and 20.1, 19.0 and 18.7, 9.7 and 9.5;
HRMS (m/z, ESI+) calcd for C19H28N2O2 ([M + Na]+) 339.2042,
found 339.2037.
N-tert-Butyl-2-(3-ethyl-2-oxo-2,3-dihydro-1H-benzo[f]indol-
1-yl)-3-methylbutanamide (6b) (mixture of two diastereoiso-
mers): light brown solid; Rf ) 0.55 (7:3 hexanes/EtOAc); mp
129-131 °C; IR (neat, cm-1) ν 3348, 2965, 2929, 1697, 1677, 1640,
Acknowledgment. Financial support from CNRS and this
institute is gratefully acknowledged. W.E. thanks the Ministe`re
de l’Enseignement Supe´rieur et de la Recherche for a doctoral
fellowship.
1
1536, 1531, 1454, 1357, 1219, 1203, 868, 746, 607; H NMR
(CDCl3, 500 MHz) two diastereoisomers, δ 7.83 (d, J ) 8.0 Hz,
1H), 7.79 (d, J ) 8.0 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.47 (t,
J ) 8.0 Hz, 1H), 7.40 (t, J ) 8.0 Hz, 1H), 6.80-5.81 (broad s,
1H, NH), 4.38 and 4.34 (d, J ) 9.3 Hz, 1H), 3.68 (m, 1H),
2.96-2.13 (m, 1H), 2.26-2.09 (m, 2H), 1.30-1.27 (2s, 9H), 1.17
(t, J ) 6.0 Hz, 3H), 0.90 and 0.85 (2t, J ) 7.4 Hz, 3H), 0.80 (d,
J ) 6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) two diastereoisomers,
178.5 and 178.4, 168.1 and 167.9, 133.6, 130.2, 129.0, 128.9, 127.7,
Supporting Information Available: Physical and spectra-
scopic data of compounds 4b-o, 5d-o, and 6d-g. Copies of
1H and 13C NMR spectra for compounds 4a-o, 5a-o, 6a-g.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO900210X
J. Org. Chem. Vol. 74, No. 8, 2009 3115