Reductive cyclization of halo-ketones to form 3-hydroxy-2-oxindoles via palladium catalyzed hydrogenation: a hydrogen-mediated Grignard addition

Article abstract of DOI:10.1016/j.tet.2015.05.085

Abstract The reductive cyclization of N-oxoacyl ortho-bromoanilides to form 3-hydroxy-2-oxindoles under the conditions of palladium catalyzed hydrogenation is described. This work may be viewed as a prelude to intermolecular hydrogen-mediated Grignard-typ

Full text of DOI:10.1016/j.tet.2015.05.085

Tetrahedron 71 (2015) 5776e5780
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Reductive cyclization of halo-ketones to form 3-hydroxy-2-
oxindoles via palladium catalyzed hydrogenation: a hydrogen-
mediated Grignard addition
*
Inji Shin, Stephen D. Ramgren, Michael J. Krische
Department of Chemistry, University of Texas at Austin, Austin, TX 78712, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The reductive cyclization of N-oxoacyl ortho-bromoanilides to form 3-hydroxy-2-oxindoles under the
conditions of palladium catalyzed hydrogenation is described. This work may be viewed as a prelude to
intermolecular hydrogen-mediated Grignard-type reductive couplings of organic halides with carbonyl
compounds.
Received 9 March 2015
Received in revised form 15 May 2015
Accepted 25 May 2015
Available online 3 June 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Hydrogenation
Carbonyl addition
Reductive coupling
Hydroxyl oxindole
Palladium
1. Introduction
Carbonyl addition is a cornerstone of chemical synthesis.1 The
Grignard reaction,2 the magnesium mediated reductive coupling
of organic halides and carbonyl compounds, persists as one of the
most broadly utilized methods for carbonyl addition. Despite its
broad scope, operational simplicity and cost-effective nature, the
Grignard reaction requires organomagnesium reagents, which are
highly basic and, hence, moisture sensitive, and which generate
stoichiometric quantities of metallic byproducts, posing chal-
lenges for use on scale.3e5 Additionally, enantioselective variants
of the Grignard addition have proven elusive.6 These limitations
are potentially addressed through the development of metal cat-
alyzed organic halide-carbonyl reductive couplings, especially
those employing non-metallic low molecular weight terminal
reductants (Scheme 1).7 The Nozaki-Hiyama-Kishi (NHK) reaction
is perhaps the most notable metal catalyzed reaction of this type.8
While enantioselective variants of the NHK reaction have been
developed,8 this process employs toxic chromium base catalysts
and, as elemental manganese is used as terminal reductant, it
does not circumvent generation of stoichiometric metallic
byproducts.
Scheme 1. Transition metal catalyzed reductive carbonyl addition.
We have developed the first ‘CeC bond forming hydrogenations’
beyond hydroformylation, the largest volume application of ho-
mogeneous catalysis.9 In these processes,
p-unsaturated reactants
are hydrogenated in the presence of carbonyl compounds or imines
to furnish products of reductive coupling.10 As catalytic hydroge-
nation is used routinely for the reduction of organic halides to form
the corresponding CeH compounds,11 we became attracted to the
prospect of capturing the intervening organometallic species via
carbonyl addition. Such hydrogen-mediated organic halide-
carbonyl reductive couplings would bypass the generation of stoi-
chiometric metallic byproducts and potentially provide a conduit to
enantiomerically enriched adducts. The feasibility of hydrogen-
mediated Grignard-type reactions is supported by reports of re-
lated halo-ketone reductive cyclizations under the conditions of
transfer hydrogenation, wherein alcohols12 or tertiary amines13e15
are utilized as terminal reductants (Scheme 2, Eq. 1e3).16,17 Here,
we demonstrate palladium catalyzed hydrogenation of N-oxoacyl
* Corresponding author. Tel.: þ1 512 232 5892; fax: þ1 512 471 8696; e-mail
address: mkrische@cm.utexas.edu (M.J. Krische).
http://dx.doi.org/10.1016/j.tet.2015.05.085
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

I. Shin et al. / Tetrahedron 71 (2015) 5776e5780
5777
ortho-bromoanilides promotes reductive cyclization to form 3-
hydroxy-2-oxindoles in good to excellent yield with complete
suppression of conventional aryl halide hydrogenolysis pathways
(Scheme 2, Eq. 4).
Using the following conditions, Pd2(dba)3ꢀCHCl3 (2.5 mol %),
DiPPF (5 mol %), Cs2CO3 (200 mol %) in toluene (0.05 M) at 80 ꢁC in
the presence of H2 (1 atm) the reductive cyclization of a-ketoamides
1ae1f was explored (Table 1). The hydroxy oxindoles 2ae2f were
obtained in moderate to excellent yields. Aryl 2ae2c, alkyl 2de2e,
and heteroaryl 2f groups at the C3 position of the resulting oxin-
doles 2ae2f were tolerated. Reactants 1ae1c that incorporate aryl
substituents gave uniformly better results compared to reactants
incorporating alkyl groups (1de1e) or heteroaryl groups (2f).18
Table 1
Reductive cyclization of
a
-ketoamides 1ae1f under the conditions of palladium
catalyzed hydrogenationa
Scheme 2. Reductive cyclization of aromatic halo-ketones in the absence of stoi-
chiometric metals.
2. Results and discussion
Initial experiments focused on the reductive cyclization of a-
b
aYields are of material isolated by silica gel chromatography. K2CO3
ketoamides 1a (X]Br) under hydrogenation conditions using
Pd2(dba)3ꢀCHCl3 as precatalyst in combination with various phos-
phine ligands (Eq. 5). Gaseous hydrogen was introduced simply
using balloons. Several phosphine ligands were tested for this
transformation, for example, 1,10-bis(di-tert-butylphosphino)ferro-
cene (DtBPF, 55% yield), XPhos (64% yield), and 1,2-
bis(dicyclohexylphosphino)ethane (DCyPE, 68% yield). The palla-
dium catalyst modified by the chelating phosphine ligand 1,10-
bis(di-iso-propylphosphino)ferrocene (DiPPF) provided the best
results, enabling formation of 3-hydroxy-2-oxindole 2a in 95% yield
after isolation by silica gel flash column chromatography. The use of
Cs2CO3 as base is important, as substantially diminished isolated
yields were observed in reactions using Na2CO3 (trace conversion),
K2CO3 (47% yield) or K3PO4 (20% yield) under otherwise identical
conditions, which may, in part, be due to solubility. Under the in-
dicated conditions (Eq. 5), the corresponding ortho-chloro ketoa-
mide 1a (X]Cl) provided 2a in 30% yield due to a combination of
incomplete conversion and hydrogenolysis of the chloride. The
triflyl derivative of ketoamide 1a (X]OTf) did not convert to
oxindoles 2a under these conditions due to hydrolysis to form the
phenol.14
(200 mol%).18
To further probe the scope of this process, compounds 1g and
1h, derived from 2-amino-3-bromopyridine and 4-amino-3-
bromopyridine, respectively, were subjected to standard condi-
tions for reductive cyclization (Eq. 6,7). Compound 1g was trans-
formed to 6-aza-3-hydroxy-2-oxindole 2g in good yield (Eq. 6). For
compound 1h, only trace quantities of the 4-aza-3-hydroxy-2-
oxindole 2h were observed under standard conditions. Elevated
temperatures (130 ꢁC) were required to enforce conversion to the
4-aza-3-hydroxy-2-oxindole 2h, which was isolated in 30% yield
along with dehalogenated material (Eq. 7).18 The diminished re-
activity of 1h may be due to coordination of the less hindered
pyridyl nitrogen to the palladium catalyst.
ð6Þ
ð7Þ
ð5Þ

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I. Shin et al. / Tetrahedron 71 (2015) 5776e5780
To probe the feasibility of engaging less activated carbonyl
transformations foreshadows the principal challenge associated
with this endeavor.
partners, compounds 1i and 1j were subjected to standard con-
ditions for reductive cyclization (Eq. 8,9). Compound 1i delivered
3-phenyl indole 2i due to dehydration-aromatization of the ter-
tiary alcohol derived upon reductive cyclization (Eq. 8).18 The
relatively low isolated yield of 2i stems from competing dehalo-
genation of 1i. For compound 1j, reductive cyclization to form 2j
occurred in 32% isolated yield (Eq. 9).18 Dehydration-aromatization
to form the corresponding benzofuran was not observed. However,
dehalogenation of 1j again contributed to a relatively low isolated
yield of 2j.
4. Experimental
4.1. General experimental
Tetrahydrofuran (THF) and toluene (PhMe) were distilled from
sodium/benzophenone, and dichloromethane (CH2Cl2) and mesi-
tylene were distilled from calcium hydride under a nitrogen at-
mosphere. Unless otherwise stated, commercially obtained
reagents were used as received. 1H and 13C NMR spectra were
recorded at 400 and 100 MHz with a Varian Gemini spectrometer.
Chemical shifts are reported as parts per million (ppm) from tet-
ramethylsilane (TMS) or ppm relative to the deuteriochloroform
(CDCl3), 7.26 ppm for 1H NMR and 77.16 ppm for 13C NMR, re-
spectively. Melting points (ꢁC) are uncorrected. Infrared spectra
were recorded on a Thermo Nicolet 380 spectrometer. Analytical
thin layer chromatography (TLC) was performed on TLC silica gel
ð8Þ
ð9Þ
plates (250
flash column chromatography procedures were followed using
40e63 m silica gel. Visualization was effected with p-anisalde-
mm) precoated with a fluorescent indicator. Standard
m
hyde, potassium permanganate, and iodine stains.
4.2. General experimental procedure for palladium catalyzed
reductive cyclization
The collective data suggest a catalytic mechanism involving
oxidative addition of a palladium(0) complex to ortho-haloarenes
1ae1f to form the square planer s-arylpalladium(II) complex A (Eq.
10). Insertion of the tethered carbonyl followed by hydrogen acti-
vation delivers products of reductive cyclization 2ae2f. Use of
chiral chelating phosphine ligands, Josiphos or Walphos type li-
gands, DuPhos, and BINAP, did not result in enantiomeric enrich-
ment (>1% ee), suggesting loss of chelating ligand in advance of
carbonyl insertion. Competing dehalogenation of 1ae1f pre-
sumably stems from the reaction of complex A with elemental
To a flask charged with Pd2(dba)3ꢀCHCl3 (2.6 mg, 0.0025 mmol,
2.5 mol %), DiPPF (2.1 mg, 0.005 mmol, 5 mol %), and Cs2CO3
(65.2 mg, 0.2 mmol, 200 mol %) under an argon atmosphere was
added freshly distilled toluene (2 mL, 0.05 M). The mixture was
allowed to stir at 80 ꢁC for 1 h, during which time the color of the
solution changed from purple to orange or brown. N-Acyl ortho-
bromoanilides 1 (0.1 mmol, 100 mol %) was added in one portion to
the flask, then an argon balloon was switched to H2 balloon, and the
reaction mixture was allowed to stir at 80 ꢁC for 20 h. The reaction
mixture was evaporated and the residue was subjected to flash
silica gel column chromatography to furnish the title compound 2.
hydrogen via pathways involving
s-bond metathesis-CeH re-
ductive elimination.11 The identification of second generation cat-
alysts that promote rapid carbonyl insertion with respect to
hydrogen activation is currently under investigation in our
laboratory.
4.2.1. 3-Hydroxy-1-methyl-3-phenylindolin-2-one (2a). According
to general procedure for palladium catalyzed reductive cyclization
with 1a (31.8 mg, 0.1 mmol, 100 mol %), the title product 2a was
obtained as a white solid in 95% yield (22.7 mg, 0.095 mmol) after
flash column chromatography (hexanes/EtOAc¼1:1). 1H NMR
(400 MHz, CDCl3):
d
7.36e7.18 (m, 7H), 7.01 (td, J¼7.6,1.0 Hz,1H), 6.84
(dt, J¼7.8, 0.8 Hz,1H), 3.46 (br s,1H), 3.18 (s, 3H); 13C NMR (100 MHz,
ð10Þ
CDCl3): d 177.4, 143.5, 140.0, 131.5, 129.8, 128.5, 128.2, 125.3, 124.9,
123.5,108.6, 77.9, 26.5. Data is consistent with reported literature.12b
4.2.2. 3-(3,5-Difluorophenyl)-3-hydroxy-1-methylindolin-2-one
(2b). According to general procedure for palladium catalyzed re-
ductive cyclization with 1b (35.4 mg, 0.1 mmol, 100 mol %), the title
product 2b was obtained as a white solid in 95% yield (26.1 mg,
0.095 mmol) after flash column chromatography (hexanes/
3. Conclusions
In summary, we report that palladium catalyzed hydrogenation
of ortho-bromoaryl
zation to form 3-substituted-3-hydroxy-2-oxindoles 2ae2f in good
to excellent isolated yields. Additionally, as illustrated in the con-
EtOAc¼1:1). Mp: 45 ꢁC; 1H NMR (400 MHz, CDCl3)
7.40 (td, J¼7.7,
d
a
-ketoamides 1ae1f results in reductive cycli-
1.3 Hz, 1H), 7.26 (ddd, J¼7.4, 1.4, 0.6 Hz, 1H), 7.12 (td, J¼7.6, 1.0 Hz,
1H), 6.96e6.93 (m, 1H), 6.93e6.87 (m, 2H), 6.74 (tt, J¼8.7, 2.3 Hz,
1H), 3.27 (s, 3H), 3.22 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 176.5,
version of 2-amino-3-bromopyridine derived
a
-ketoamides 1g and
163.9 (d, J¼12.6 Hz), 162.2 (d, J¼12.6 Hz), 144.1 (t, J¼8.6 Hz), 143.3,
130.7, 130.4, 129.1, 124.8, 123.9, 109.0, 108.7 (dd, J¼21.1, 5.6 Hz),
103.7 (t, J¼25.4 Hz), 77.4 (t, J¼2.2 Hz), 26.7; IR (neat) 3410, 1701,
1610, 1595, 1450, 1111 cmꢂ1; HRMS (ESIþ) calcd for C15H11F2NO2Na
[MþNa]þ 298.0650, found 298.0649.
4-amino-3-bromopyridine derived -ketoamides 1h to compounds
a
2g and 2h, respectively, this method also provides access to aza-3-
hydroxy-2-oxindoles. These results may be viewed as proof-of-
concept with respect to the long term objective of developing
general intermolecular hydrogen-mediated Grignard type addi-
tions of organic halides and carbonyl partners. The observation of
competing aryl halide hydrogenolysis in the present
4.2.3. 3-(Benzo[d][1,3]dioxol-5-yl)-3-hydroxy-1-methylindolin-2-
one (2c). According to general procedure for palladium catalyzed

I. Shin et al. / Tetrahedron 71 (2015) 5776e5780
5779
reductive cyclization with 1c (36.2 mg, 0.1 mmol, 100 mol %), the
title product 2c was obtained as a colorless oil in 72% yield (19.8 mg,
0.072 mmol) after flash column chromatography (hexanes/
obtained as a colorless oil in 30% yield (7.2 mg, 0.03 mmol) after
flash column chromatography (100% EtOAc). 1H NMR (400 MHz,
CDCl3)
d
8.45 (d, J¼5.4 Hz, 1H), 8.26 (d, J¼0.9 Hz, 1H), 7.42e7.31 (m,
EtOAc¼1:1). 1H NMR (400 MHz, CDCl3)
d
7.35 (td, J¼7.8, 1.3, 1H),
5H), 6.83 (dd, J¼5.4, 0.8 Hz,1H), 3.22 (s, 3H),1.28 (br s,1H); 13C NMR
7.29 (ddd, J¼7.4, 1.3, 0.6 Hz, 1H), 7.10 (td, J¼7.5, 1.0 Hz, 1H),
6.91e6.89 (m, 2H), 6.83 (dd, J¼8.1, 1.8 Hz, 1H), 6.73 (dd, J¼8.1,
0.5 Hz, 1H), 5.93 (q, J¼1.4 Hz, 2H), 3.35 (s, 3H), 3.34 (s, 1H); 13C NMR
(100 MHz, CDCl3) 177.2, 147.9, 147.7, 143.1, 133.8, 131.3, 129.9, 124.8,
123.5, 118.9, 108.7, 108.1, 106.3, 101.2, 29.6, 26.5. Data is consistent
with reported literature.12b
(100 MHz, CDCl3) d 177.3, 151.4, 151.2, 145.1, 139.0, 131.1, 129.0, 127.5,
125.5, 123.4, 104.5, 26.7; IR (neat) 3350, 1630, 1466, 1359 cmꢂ1
;
HRMS (ESIþ) calcd for C14H12N2O2Na [MþNa]þ 263.0791, found
263.0789.
4.2.9. 1-Methyl-3-phenyl-1H-indole (2i). According to general pro-
cedure for palladium catalyzed reductive cyclization with 1i
(30.4 mg, 0.1 mmol, 100 mol %), the title product 2i was obtained as
a yellow oil in 28% yield (5.8 mg, 0.028 mmol) after flash column
chromatography (hexanes/EtOAc¼3:1). 1H NMR (400 MHz, CDCl3)
4.2.4. 3-Hydroxy-1,3-dimethylindolin-2-one (2d). According to
general procedure for palladium catalyzed reductive cyclization
with 1d (25.6 mg, 0.1 mmol, 100 mol %), the title product 2d was
obtained as a white solid in 76% yield (13.5 mg, 0.076 mmol) after
flash column chromatography (hexanes/EtOAc¼1:1). Mp:
d
7.88 (dt, J¼8.0, 1.0 Hz, 1H), 7.62e7.57 (m, 2H), 7.41e7.34 (m, 2H),
7.30 (dt, J¼8.3, 1.0 Hz, 1H), 7.24e7.17 (m, 3H), 7.12 (ddd, J¼8.0, 7.0,
141e143 ꢁC (lit.: 141e143 ꢁC); 1H NMR (400 MHz, CDCl3)
d
7.43
1.1 Hz, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
137.7, 136.6,
(d, J¼7.5 Hz, 1H), 7.34 (td, J¼8.0 Hz, 1.5 Hz, 1H), 7.12 (t, J¼7.5 Hz,
127.8, 127.9, 126.1, 125.6, 121.8, 120.0, 119.9, 117.0, 109.1, 32.9. Data is
consistent with reported literature.20
1H), 6.86 (d, J¼8.0 Hz, 1H), 3.23 (s, 1H), 3.21 (s, 3H), 3.93 (s, 3H);
13C NMR (100 MHz, CDCl3)
d 187.9, 143.0, 131.4, 129.6, 123.4,
123.0, 108.0, 74.0, 26.1, 25.0. Data is consistent with reported
4.2.10. 3-Phenyl-2,3-dihydrobenzofuran-3-ol (2j). According to
general procedure for palladium catalyzed reductive cyclization
with 1j (29.1 mg, 0.1 mmol, 100 mol %), the title product 2j was
obtained as a light yellow oil in 32% yield (6.8 mg, 0.032 mmol)
after flash column chromatography (hexanes/EtOAc¼25:1). 1H
literature.19
4.2.5. 3-Cyclopropyl-3-hydroxy-1-methylindolin-2-one
(2e). According to general procedure for palladium catalyzed re-
ductive cyclization with 1e (28.2 mg, 0.1 mmol, 100 mol %), the title
product 2e was obtained as a white solid in 50% yield (10.2 mg,
0.050 mmol) after flash column chromatography (hexanes/
EtOAc¼15:1 to 2:1). Mp: 179e183 ꢁC; 1H NMR (400 MHz, CDCl3)
NMR (400 MHz, CDCl3)
d 7.46e7.41 (m, 2H), 7.33e7.27 (m, 2H),
7.27e7.20 (m, 2H), 7.05e7.02 (m, 1H), 6.93e6.83 (m, 2H), 4.64 (d,
J¼10.2 Hz, 1H), 4.44 (d, J¼10.2 Hz, 1H), 2.23 (br s, 1H); 13C NMR
(100 MHz, CDCl3)
d 160.8, 142.7, 132.3, 130.8, 128.4, 127.7, 126.2,
d
7.37e7.30 (m, 2H), 7.11e7.04 (m, 1H), 6.83 (d, J¼7.8 Hz, 1H), 3.18 (s,
3H), 2.70 (br s,1H),1.39e1.31 (m,1H), 0.66e0.53 (m, 2H), 0.48e0.34
(m, 2H); 13C NMR (100 MHz, CDCl3)
177.6, 143.2, 129.5, 129.3,
123.8, 122.8, 108.2, 75.6, 29.6, 26.1, 17.9; IR (neat) 3331, 2922, 1699,
124.5, 121.6, 110.9, 86.3, 82.7. Data is consistent with that reported
in the literature.21
d
Acknowledgements
1615, 1467, 1260, 1090, 1021 cmꢂ1
C
;
HRMS (ESIþ) calcd for
12H13NO2Na [MþNa]þ 226.0838, found 226.0836.
The Robert A. Welch Foundation (F-0038) and the National In-
stitutes of Health-NIGMS (RO1-GM069445) are acknowledged for
partial support of this research.
4.2.6. 1-methyl-3-(thiophen-2-yl)indolin-2-one (2f). According to
general procedure for palladium catalyzed reductive cyclization
with 1f (32.4 mg, 0.1 mmol, 100 mol %), the title product 2f was
obtained as a yellow solid in 51% yield (12.5 mg, 0.051 mmol) after
flash column chromatography (hexanes/EtOAc¼6:1 to 2:1). Mp:
Supplementary data
Supplementary data (1H and 13C NMR spectra for all new com-
pounds) related to this article can be found at http://dx.doi.org/
10.1016/j.tet.2015.05.085.
119e123 ꢁC; 1H NMR (400 MHz, CDCl3)
d
7.54 (d, J¼7.4 Hz, 1H), 7.38
(dd, J¼7.6, 7.6 Hz, 1H), 7.31 (d, J¼4.9 Hz, 1H), 7.15 (dd, J¼7.4, 7.4 Hz,
1H), 7.01e6.96 (m, 1H), 6.96e6.91 (m, 1H), 6.89 (d, J¼7.8 Hz, 1H),
3.50 (br s, 1H), 3.23 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 176.2,
143.4, 143.3, 130.5, 126.9, 126.1, 125.1, 123.6, 109.0, 75.5, 26.7 (one
carbon was not detected); IR (neat) 3346, 1702, 612, 1469, 1373,
1347, 1093, 1018 cmꢂ1; HRMS (ESIþ) calcd for C13H11NO2SNa
[MþNa]þ 268.0403, found 268.0405.
References and notes
1. (a) Knochel, P.; Molander, G. A.; Comprehensive Organic Synthesis, 2nd ed.;
Elsevier: Oxford, 2014, Vols. 1 and 2; (b) Otera, J. Modern Carbonyl Chemistry;
Wiley-VCH: Weinheim, Germany, 2000.
2. Grignard, V. Compt. Rend. 1900, 130, 1322.
3. The two largest volume applications of homogenous metal catalysis, alkene
hydroformylation and the carbonylation of methanol, the Monsanto or Cativa
Processes, are byproduct-free CeC bond formations
4.2.7. 3-Hydroxy-1-methyl-3-phenyl-1,3-dihydro-2H-pyrrolo[2,3-b]
pyridin-2-one (2g). According to general procedure for palladium
catalyzed reductive cyclization with 1g (31.9 mg, 0.1 mmol,100 mol
%), the title product 2g was obtained as a colorless oil in 73% yield
(17.6 mg, 0.073 mmol) after flash column chromatography (hex-
4. For selected reviews on hydroformylation, see: (a) Kalck, P.; Peres, Y.; Jenck, J.
Adv. Organomet. Chem. 1991, 32, 121; (b) Breit, B.; Seiche, W. Synthesis 2001, 1;
(c) Van Keeuwen, P. W. N. M.; Claver, C. Rhodium Catalyzed Hydroformylation;
Kluwer Academic: Dordrecht, Netherlands, 2002; (d) Weissermel, K.; Arpe, H. J.
Industrial Organic Chemistry; Wiley-VCH: Weinheim, Germany, 2003; p 127; (e)
anes/EtOAc¼1:1). 1H NMR (400 MHz, CDCl3)
d
8.19 (dd, J¼5.3,
€
Franke, R.; Selent, D.; Borner, A. Chem. Rev. 2012, 112, 5675.
1.6 Hz, 1H), 7.47 (dd, J¼7.3, 1.6 Hz, 1H), 7.38e7.23 (m, 5H), 6.93 (dd,
5. For selected reviews on methanol carbonylation, the Monsanto or Cativa Pro-
cesses, see: (a) Maitlis, P. M.; Haynes, A.; Sunley, G. J.; Howard, M. J. J. Chem. Soc.,
Dalton Trans. 1996, 2187 and references therein; (b) Jones, J. H. Platinum Met.
Rev. 2000, 44, 94; (c) Haynes, A. Top. Organomet. Chem. 2006, 18, 179; (d) Kalck,
P.; Serp, P. Iridium Complexes in Organic Synthesis; Wiley-VCH: Weinheim,
Germany, 2008; p 195.
6. Stoichiometric quantities of chiral modifiers have been employed in Grignard
additions to enforce enantioselectivity: Weber, B.; Seebach, D. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 84.
J¼7.3, 5.3, 1H), 3.29 (s, 3H), 3.18 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
177.2, 157.0, 148.7, 139.2, 132.4, 128.8, 127.7, 125.9, 125.2, 118.9,
77.6, 25.6; IR (neat) 3340, 1635,1467,1351 cmꢂ1; HRMS (ESIþ) calcd
for C14H12N2O2Na [MþNa]þ 263.0791, found 263.0792.
4.2.8. 3-Hydroxy-1-methyl-3-phenyl-1,3-dihydro-2H-pyrrolo[3,2-c]
pyridin-2-one (2h). According to general procedure for palladium
catalyzed reductive cyclization with 1h (31.9 mg, 0.1 mmol,
100 mol %) in mesitylene at 130 ꢁC, the title product 2h was
7. For a recent review on the reductive coupling of organic halides to carbonyl
compounds, see: Moragas, T.; Correa, A.; Martin, R. Chem.dEur. J. 2014, 20,
8242.

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I. Shin et al. / Tetrahedron 71 (2015) 5776e5780
8. For selected reviews on enantioselective carbonyl allylation via Nozaki-
Hiyama-Kishi coupling, see: (a) Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J.
L.; Palacios, J. C. Chem. Soc. Rev. 1999, 28, 169; (b) Bandini, M.; Cozzi, P. G.;
Umani-Ronchi, A. Chem. Commun. 2002, 919; (c) Hargaden, G. C.; Guiry, P. J. Adv.
Synth. Catal. 2007, 349, 2407.
13. For palladium catalyzed reductive cyclization of aryl ortho-halo-ketones me-
ꢀ
ꢀ ꢀ ꢀ
diated by tertiary amines, see: (a) Sole, D.; Vallverdu, L.; Peidro, E.; Bonjoch, J.
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Chem. 2002, 67, 9428; (b) Pletnev, A. A.; Larock, R. C. Tetrahedron Lett. 2002, 43,
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€
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