Structure Ligation Relationship of Amino Acids for the Amination Cross-Coupling Reactions

Article abstract of DOI:10.1021/acs.joc.8b03214

The structure ligation relationship (SLR) of amino acids (AAs) for the cross-coupling aminations was examined. While AA ligated C-N cross-couplings under Pd and Ni catalysis were minor or ineffective, the AA ligated Cu-catalyzed C-N cross-couplings were promising particularly with the use of l-methionine. The roles of -NH₂, -CO₂H, and -S- of l-methionine were investigated and found critical for their ligation efficiency. The finding was compatible with aromatic as well as aliphatic amines including tautomerizable N-heteroarenes.

Full text of DOI:10.1021/acs.joc.8b03214

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Note
Structure Ligation Relationship of Amino Acids
for the Amination Cross-Coupling Reactions
Gargi Nikhil Vaidya, Arif Khan, Hansa Verma, Sanjeev Kumar, and Dinesh Kumar
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 08 Feb 2019
Downloaded from http://pubs.acs.org on February 8, 2019
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The Journal of Organic Chemistry
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Structure Ligation Relationship of Amino Acids for the Amination
Cross-Coupling Reactions
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Gargi Nikhil Vaidya, Arif Khan, Hansa Verma, Sanjeev Kumar, Dinesh Kumar*
Department of Medicinal Chemistry,
National Institute of Pharmaceutical Education and Research (NIPER) – Ahmadabad, Palaj, Gandhinagar-382355,
Gujarat, India
ABSTRACT: The Structure Ligation Relationship (SLR) of amino acids (AA) for the cross-coupling aminations was exam-
ined. While AA ligated C–N cross-coupling under Pd- and Ni- catalysis were minor or ineffective, the AA ligated Cu-
catalyzed C–N cross-couplings were promising particularly with the use of L-Methionine. The role –NH2, -CO2H, and –S-
of L-Methionine were investigated and found critical for their ligation efficiency. The finding was compatible with aro-
matic as well as aliphatic amines including tautomerizable N-heteroarenes.
Introduction of nitrogen functionality into carbocyclic
frameworks has been the hot area of research owing to
the ubiquity of amino compounds in pharmaceuticals,
Amino acids (AAs), the fundamental building blocks
of life, have been exploited well in organic synthesis and
7
catalysis including asymmetric reactions and direct C-H
1
8
agrochemicals, and functional materials. While tradition-
functionalizations. The ease of availability and its deri-
al approaches to construct C−N bonds often require mul-
ti-steps procedure, the metal-catalyzed C−N bond for-
mations has opened a new avenue in context of efficiency
vatizations (cost-effectiveness), tolerance toward aerial
oxidation & moisture, and lack of general toxicity is the
key advantages. The use of amino acid ligands in cross-
coupling reactions including C-N bond formation is doc-
2
and applicability. In this regard, the cross coupling of
amine nucleophiles with prefunctionalized arene electro-
9
umented, however their general Structure Ligation Rela-
3
philes (Ullmann reaction and Buchwald−Hartwig reac-
tionship (SLR) or Structure Efficiency Relationship (SER)
have been not investigated. In this context, the present
work aims to evaluate AA ligations (SLR) on C−N bond
formation under Cu-, Pd-, and Ni-catalysis and subse-
quently translate the optimal catalytic combinations for
the general amination cross-couplings.
4
5
tion ) or nucleophiles (Chan−Lam reaction ) constitute
the fundamental building blocks (Scheme 1). Recently,
6
direct C–H aminations emerged as valuable strategy for
C–N bond formation complementing the classical cross
coupling procedures.
Scheme 1: Metal-catalyzed cross coupling C−N Bond
Formation reactions.
The study begun with evaluating different AAs for the
C−N bond formation under metal catalysis (Scheme 2).
For each AA, three parallel reactions were performed,
representing Ni-, Pd-, and Cu-catalysis respectively. The
reason being choosing indole as amine source is the chal-
lenges lie ahead in controlling selectivity as it represents a
reactant with three distinct nucleophilic sites (NH, C3–H,
and C2–H) We initially examined the cross-coupling of
.
iodobenzene (1a) with indole (2a), employing Ni (II) as
metal precursor. No C−N bond formation (3a) was ob-
served in any case, the starting 2a was found intact (no C-
arylation was observed as well).
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Scheme 2. Evaluation of AAs ligation for C−N cross-
Page 2 of 8
scope of AAs ligation for C−N bond formations under Cu
(I)-catalysis was examined subsequently. The formation of
C−N bond was observed with variable yields of 3a in dif-
ferent AAs such as Gly (62%), L-Val (79%), L-Leu (81%),
L-Met (92%), L-Arg (63%), L-Lys (83%), L-Tyrosine (72%),
and L-Proline (76%). In order to obtain the ligation dis-
tinction between these elected AAs, cross coupling of 1a
with 1(2H)-phthalazinone (4a) were performed (Scheme
3). The results were promising, the use of L-Met was
found distinctly superior over others, with 78% yield of
a, b, c
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couplings under metal catalysis.
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The above studies concluded that AA ligation suits
best with Cu-catalysis for C−N cross-coupling reactions,
the L-Met being the distinctly superior over others nota-
ble AAs such as Gly, L-Val, L-Leu, L-Lys, L-Arg, L-Tyr,
and L-Pro. The AA-ligated Pd-catalysis was capable of
C−N bond formations; however selectivity was an issue as
it forms the competitive side products (C−arylation) sig-
nificantly. The AAs as ligand were ineffective for C−N
cross-coupling reaction under Ni-catalysis.
For the catalytic system consisting of Cu (I)/α-amino
acid, rate and yields is induced by the structure of the α-
amino acid. The greater ability of L-Met, a sulfur-
containing AA, to promote coupling reactions might be
dependent on the presence of thioether sulfur donors in
its structure, in addition to the N and O donor groups,
which may lead to more active and stable Cu (I) species in
the reaction medium. To gain insight further, structural
analogs of L-Met such as N-Acetyl-L-Met (L-Met-NAc), L-
Met ethyl ester (L-Met-OEt), L-Met sulfoxide [L-Met-
(
S=O)], Seleno-L-Met (L-Met-Se), and L-Norleucine were
investigated under optimized conditions to elucidate the
role of –NH2, -CO2H, and –S- (Scheme 4). The yield of 3a
was significantly decreased in case of L-Met-NAc (21%), L-
Met-OEt (22%), L-Met-Se (20%), and L-norLeu (28%)
suggesting the simultaneous involvement of free -NH2, -
CO2H, and –S-. The L-Met-(S=O) was ligable to provide
excellent yield (78%), however inferior compared to L-
Met (85 %). A similar yield was obtained using isomeric
D-Met (83%) indicating chirality of AAs insignificant.
Scheme 3. Ligation distinction of elected AAs for C−N
cross-coupling reactions under metal catalysis.
a, b
Scheme 4. Investigation of role of L-Met as ligand
Next, the AA ligation for C−N bond formation was
examined under Pd (II)-catalysis. The results were quite
interesting as we observed the formation of both, the C−N
bond (see, L-Arg, L-Lys, L-Pro) and C−C bond (see, L-
Asp), however the yields were very poor (< 10%). The
Ligation of L-Met for the C−N cross-couplings with
other metal-catalysis such as iron, manganese, rutheni-
2
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The Journal of Organic Chemistry
um, rhodium were re-investigated; however, it was dis-
couraging as no desired 3a was formed in any case as
various indoles bearing e-withdrawing groups, e-releasing
groups, halogens etc. were reacted well with electronically
different iodobenzenes affording excellent yields of N-
arylated indoles. Wide range of functional groups (–OMe,
-OBn, –F, –Br, –NO ,–CF , –OCH O–) tolerated well, vali-
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shown in scheme 5.
Scheme 5. Re-investigation of L-Met ligation for
cross-coupling amination reaction under Fe-, Mn-,
Ru-, Rh- catalysis.
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2
dating the robustness of protocol. The applicability of this
protocol was further extended to other biologically rele-
vant N-heteroarenes. Gratifyingly, N-arylation of electron-
deficient tautomerizable bioactive N-heteroarenes such as
phthalazine 5a, quinazoline 5b, and pyridine 5c proceed-
ed well with excellent yields and chemoselectivity. The
efficiency of the developed protocol with aliphatic amines
was showcased using representative examples (5d and 5e)
with excellent yields.
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We took this opportunity to discover a general high
yielding protocol for the synthesis of high value N-aryl
indoles. A full optimization of different reaction parame-
ters revealed the use of 5 mol % of CuI with 10 mol% of L-
Met in presence of K CO (2 equiv) at 100 °C in DMF was
Scheme 7. Demonstration of gram scale reaction
2
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optimal with 92% yield of 3a. Variations in the Cu-source
using L-Met as ligand resulted inferior results (see ESI).
Scheme 6. C−N cross-couplings of various amines
under optimized conditions unless otherwise noted.
To demonstrate the scalability and utility of the proto-
col, the reaction was also performed on a gram scale.
Treatment of 2a (1 g, 8.54 mmol) with 1a under optimized
condition resulted the formation of 3a in 91%. A 52% of 3a
was obtained using 1 mol% of CuI and 2 mol% of L-Met
(
Scheme 7).
In conclusion, the present work reports the scope and
limitations of the amino acids (AAs) ligation for the cross-
coupling amination reactions under commonly exercised
metal (Cu-, Pd-, & Ni-) catalysis. While AAs were ineffec-
tive ligand for C−N cross-coupling under Ni-catalysis,
their ligation under Pd- and Cu-catalysis were capable for
C−N bond construction. However, AA-ligated C–N cross-
coupling under Pd-catalysis is markedly inferior com-
pared to Cu-catalysis in term of chemoselectivity and
yields. While several AAs were found effective for C−N
cross-couplings under Cu-catalysis, the use of L-Met is
distinctly superior and versatile. The finding was applied
to construct the varieties of N-aryl indoles in excellent
yields with high functional group tolerance. Notably, the
methodology was found effective for C−N cross-couplings
using electron deficient tautomerizable N-heteroarenes
and aliphatic amines as well. The mechanistic studies
indicated the simultaneous involvement of the NH2, -
CO2H, and –S- of L-Met is critical for effective ligation.
EXPERIMENTAL SECTION
Unless otherwise noted, all manipulations (reactions)
were carried out in oven-dried glasswares under nitrogen
conditions. All commercially obtained reagents/solvents
were used as received; chemicals were purchased from
Alfa Aesar®, Sigma-Aldrich®, Acros®, and were used as
With optimized conditions, the scope of developed
protocol was examined. As summarized in Scheme 6,
1
13
received without further purification. NMR and C NMR
3
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Page 4 of 8
+
spectra were recorded on Brukar 400 MHz and 100 spec-
trometers respectively using TMS as an internal standard.
Both H and C NMR chemical shifts were reported in
HRMS (ESI-TOF) m/z: [M + H] Calcd for C H NO
21 18
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
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6
300.1383, Found 300.1387.
-(4-Nitrophenyl)-1H-indole
39.23 mg, 82%); purified by column chromatography
using PE/EA: 9/1, R = 0.45; NMR (400 MHz, CDCl ): δ 8.35
1
13
10d
1
(3e): White solid
parts per million downfield from tetramethylsilane ( =
(
1
0). Data for H NMR are reported as chemical shift (δ
f
3
ppm) with the corresponding integration values. Cou-
pling constants (J) are reported in hertz (Hz). Standard
abbreviations indicating multiplicity were used as follows:
s (singlet), b (broad), d (doublet), t (triplet), q (quartet)
(
Hz, 3H), 7.36 (d, J = 3.4 Hz, 1H), 7.25 (dtd, J = 24.0, 7.1, 1.2
d, J = 9.0 Hz, 2H), 7.69 (d, J = 7.0 Hz, 1H), 7.63 (d, J = 8.9
13
Hz, 2H), 6.76 (dd, J = 3.4, 0.9 Hz, 1H); C { H} NMR (101
1
MHz, CDCl ) δ 145.2, 145.0, 135.3, 130.1, 127.1, 125.5, 123.5,
123.3, 121.7, 121.6, 110.5, 106.2; HRMS (ESI-TOF) m/z: [M +
H] Calcd for C H N O 239.0821, Found 239.0807.
1
3
3
and m (multiplet). Data for C NMR spectra are reported
in terms of chemical shift (δ ppm). High-resolution mass
spectra of unknown products were obtained at Agilent
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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7
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9
0
1
2
3
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8
9
0
1
2
3
4
5
6
7
8
9
0
+
1
4
11
2
2
+
10e
1-(4-Fluorophenyl)-5-methoxy-1H-indole (3f):
White solid (41.00 mg, 85%); purified by column chroma-
QTOFs spectrometer in positive (ESI ) ion mode.
1
tography using PE/EA: 8/1, R = 0.57; H NMR (400 MHz,
Representative procedure for C-N bond formation: To
dried tube equipped with a stir bar, CuI (1.90 mg, 0.01 mmol,
f
CDCl ): δ 7.44 – 7.38 (m, 2H), 7.36 (d, J = 9.0 Hz, 1H), 7.24
d, J = 3.2 Hz, 1H), 7.21 – 7.15 (m, 2H), 7.13 (d, J = 2.5 Hz,
H), 6.87 (dd, J = 9.0, 2.5 Hz, 1H), 6.59 (dd, J = 3.2, 0.9 Hz,
H), 3.86 (s, 3H): C { H} NMR (101 MHz, CDCl ): δ 160.9
d, J = 246.0 Hz), 154.6, 136.0 (d, J = 2.9 Hz), 131.3, 129.7,
28.5, 125.9 (d, J = 8.4 Hz), 116.5 (d, J = 22.8 Hz), 112.6, 111.1,
03.3, 102.7, 55.9; HRMS (ESI-TOF) m/z: [M + H] Calcd
for C H FNO 242.0981, Found 242.0977.
3
5
mol%), L-Met (2.98 mg, 0.02 mmol, 10 mol%), Indole 2a
23.43 mg, 0.2 mmol), iodobenzene 1a (33.57 L, 61.20 mg, 0.3
mmol, 1.5 equiv), K CO (55.28 mg, 0.4 mmol, 2.0 equiv)
(
(
1
1
13
1
2
3
3
followed by DMF (1 mL) was added and the resulting reac-
tion mixture was stirred at 100 °C (oil bath). After 24 h, the
reaction mixture was cooled to rt, adsorbed on to silica gel
and purified by column chromatography using petroleum
(
1
1
+
1
5
13
ether (PE) and ethyl acetate (EA) (6/1, R = 0.52) as mobile
f
10a
phase to get analytically pure 3a (35.57 mg, 92%) as white
5-(Benzyloxy)-1-(4-fluorophenyl)-1H-indole (3g):
White solid (56.47 mg, 89%); purified by column chroma-
tography using PE/EA: 19/1, R = 0.56; H NMR (400 MHz,
CDCl ): δ 7.52 – 7.31 (m, 9H), 7.24 – 7.17 (m, 3H), 6.97 (d, J
8.9 Hz, 1H), 6.60 (s, 1H), 5.14 (s, 2H); C { H} NMR (101
MHz, CDCl ) δ 160.9 (d, J = 245.8 Hz), 153.7, 137.5, 135.9,
31.4, 129.6, 128.5, 128.4, 127.7, 127.4, 125.8 (d, J = 8.6 Hz),
116.4 (d, J = 22.9 Hz), 113.3, 110.9, 104.3, 103.2, 70.8; HRMS
1
solid; H NMR (400 MHz, CDCl ): δ 7.93 (d, J = 7.1 Hz, 1H),
3
7
.79 (d, J = 8.2 Hz, 1H), 7.70 – 7.65 (m, 4H), 7.54-7.49 (m, 2H),
1
f
1
3
1
7.47 – 7.38 (m, 2H), 6.90 (d, J = 3.2 Hz, 1H); C { H} NMR (101
3
MHz, CDCl ): δ 140.00, 136.04, 129.81, 129.57, 128.15, 126.61,
13
1
3
=
124.52, 122.60, 121.38, 120.61, 110.75, 103.83; HRMS (ESI-TOF)
m/z: [M + H] Calcd for C H N 194.0964, Found 194.0966.
+
3
14
12
1
1
0b
5
-Methoxy-1-phenyl-1H-indole (3b): White solid
+
(
40.18 mg, 90%); purified by column chromatography
(ESI-TOF) m/z: [M + H] Calcd for C21
H17FNO 318.1289,
1
using PE/EA: 9/1, R = 0.58; H NMR (400 MHz, CDCl ): δ
Found 318.1293.
f
3
7
.48 – 7.39 (m, 5H), 7.33 – 7.23 (m, 2H), 7.12 (d, J = 2.5 Hz,
10f
1-(4-Fluorophenyl)-5-nitro-1H-indole (3h): White
1
1
1
1
H), 6.86 (dd, J = 9.0, 2.5 Hz, 1H), 6.57 (dd, J = 3.3, 0.8 Hz,
H), 3.83 (s, 3H); C { H} NMR (101 MHz, CDCl ) δ δ154.7,
40.0, 131.1, 130.0,129.71, 128.4, 126.3, 124.08, 112.6, 111.5,
03.4, 102.8, 55.9; HRMS (ESI-TOF) m/z: [M + H] Calcd
1
3
1
solid (61.72 mg, 82%); purified by column chromatog-
3
1
raphy using PE/EA: 9/1, R = 0.47; H NMR (400 MHz,
f
+
CDCl ): δ 8.64 (d, J = 2.3 Hz, 1H), 8.11 (dd, J = 9.1, 2.3 Hz,
3
1H), 7.57 – 7.35 (m, 4H), 7.27 (t, J = 8.4 Hz, 2H), 6.86 (d, J
for C H NO 224.1075, Found 224.1078.
13
1
1
5
14
= 3.4 Hz, 1H); C { H} NMR (101 MHz, CDCl ): δ 161.8 (d, J
3
1
0c
5-Nitro-1-phenyl-1H-indole
(50.40 mg, 72%); purified by column chromatography
using PE/EA: 9/1, R = 0.42; H NMR (400 MHz, CDCl ): δ
(3c): White solid
= 248.3 Hz), 142.2, 138.9, 134.6 (d, J = 3.1 Hz), 131.4, 128.3,
126.6 (d, J = 8.5 Hz), 118.4, 118.1, 116.9 (d, J = 23.1 Hz), 110.2,
105.7; HRMS (ESI-TOF) m/z: [M + H] Calcd for
1
+
f
3
8
.63 (d, J = 2.3 Hz, 1H), 8.10 (dd, J = 9.1, 2.3 Hz, 1H), 7.59 –
C
14
H10FN O
2
2
257.0726, Found 257.0727.
1
3
1
7
.44 (m, 7H), 6.85 (d, J = 3.3 Hz, 1H); C { H} NMR (101
MHz, CDCl ): δ 142.2, 138.7, 138.6, 131.3, 130.0, 128.5, 127.8,
10g
-Fluoro-1-(4-fluorophenyl)-1H-indole (3i): White
5
solid (37.13 mg, 81%); purified by column chromatography
3
124.7, 118.3, 117.9, 110.5, 105.6; HRMS (ESI-TOF) m/z: [M +
H] Calcd for C H N O 239.0821, Found 239.0807.
1
+
using PE/EA: 9/1, R
.39–7.26 (m, 4H), 7.24 (d, J = 3.3 Hz, 1H), 7.15 (t, J = 8.5
Hz, 2H), 6.92 (td, J = 9.0, 2.6 Hz, 1H), 6.59 (d, J = 3.2 Hz,
f
= 0.5; H NMR (400 MHz, CDCl ): δ
3
1
4
11
2
2
7
5-(Benzyloxy)-1-phenyl-1H-indole (3d): White solid
52.68 mg, 88%); purified by column chromatography
1
3
1
(
1H); C { H} NMR (101 MHz, CDCl ): δ 161.2 (d, J = 246.7
3
1
using PE/EA: 6/1, R = 0.45; H NMR (400 MHz, CDCl ): δ
Hz), 159.5, 157.1, 135.7 (d, J = 3.0 Hz), 132.8, 129.6, 126.2 (d, J
= 8.5 Hz), 116.6 (d, J = 22.8 Hz), 111.0 (d, J = 9.0 Hz), 110.7,
105.9 (d, J = 23.5 Hz), 103.5 (d, J = 4.5 Hz); HRMS (ESI-
f
3
7.57 – 7.46 (m, 7H), 7.45 – 7.38 (m, 2H), 7.39 – 7.30 (m,
3H), 7.24 (d, J = 2.4 Hz, 1H), 6.99 (dd, J = 8.9, 2.5 Hz, 1H),
6.62 (dd, J = 3.3, 0.9 Hz, 1H), 5.16 (s, 2H); C { H} NMR (101
MHz, CDCL ) δ 153.7, 139.9, 137.6, 131.2, 129.8, 129.6, 128.6,
128.4, 127.8, 127.6, 126.3, 124.1, 113.2, 111.4, 104.3, 103.3, 70.8;
1
3
1
+
TOF) m/z: [M + H] Calcd for C14
230.0785
H
10
F
N 230.0781, Found
2
3
4
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5-Methoxy-1-(4-(trifluoromethyl)phenyl)-1H-
indole (3j): White solid (45.83 mg, 79%); purified by
1-(Benzo[d][1,3]dioxol-5-yl)-5-bromo-1H-indole
(3o): White solid (51.00 mg, 81%); purified by column
1
2
3
4
5
6
7
8
9
1
column chromatography using PE/EA: 19/1, R = 0.56; H
1
chromatography using PE/EA: 30/1, R = 0.5; H NMR (400
f
f
NMR (400 MHz, CDCl ): δ 7.78 (d, J = 8.3 Hz, 2H), 7.61 (d,
MHz, CDCl ): δ 7.82 (d, J = 1.9 Hz, 1H), 7.38 – 7.21 (m, 4H),
3
3
J = 8.3 Hz, 2H), 7.51 (d, J = 9.0 Hz, 1H), 7.33 (d, J = 3.3 Hz,
1H), 7.17 (d, J = 2.5 Hz, 1H), 6.93 (dd, J = 9.0, 2.5 Hz, 1H),
6.67 (d, J = 3.3 Hz, 1H), 3.90 (s, 3H); C { H} NMR (101
6.97 – 6.88 (m, 3H), 6.60 (dd, J = 3.2, 0.8 Hz, 1H), 6.09 (s,
1
3
1
2H); C { H} NMR (101 MHz, CDCl ): δ 148.5, 146.6, 135.0,
3
1
3
1
133.4, 130.6, 129.4, 125.1, 123.5, 118., 113.4, 111. 9, 108.7, 106.2,
102.5, 101.8; HRMS (ESI-TOF) m/z: [M + H] Calcd for
+
MHz, CDCl ): δ 154.9, 142.9, 130.6, 130.4, 127.85 (q, J = 32.6
3
Hz), 127.82, 126.8 (q, J = 3.8 Hz), 124.0 (q, J = 275 Hz), 123.3,
112.9, 111.2, 104,6, 103.0, 55.8; HRMS (ESI-TOF) m/z: [M +
Na] Calcd for C H F NONa 314.0763, Found 314.0769.
C H BrNO 315.9968, Found 315.9972.
1
5
11
2
+
1-(Benzo[d][1,3]dioxol-5-yl)-5-methoxy-1H-indole
3p): White solid (43.83 mg, 82%); purified by column
chromatography using PE/EA: 30/1, R = 0.5; H NMR (400
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
16 12 3
(
10h
1
5
-Bromo-1-(4-fluorophenyl)-1H-indole
(3k):
White solid (50.80 mg, 85%); purified by column chroma-
f
MHz, CDCl ): δ 7.39 (d, J = 8.9 Hz, 1H), 7.24 (d, J = 3.2 Hz,
3
1
tography using PE/EA: 19/1, R = 0.57; H NMR (400 MHz,
1H), 7.13 (d, J = 2.5 Hz, 1H), 6.97 (d, J = 1.7 Hz, 1H), 6.92 (d,
J = 2.0 Hz, 2H), 6.88 (dd, J = 9.0, 2.6 Hz, 1H), 6.57 (d, J =
3.1 Hz, 1H), 6.05 (s, 2H), 3.88 (s, 3H); C { H} NMR (101
f
CDCl ): δ 7.82 (s, 1H), 7.43 (dd, J = 8.9, 4.7 Hz, 2H), 7.35 –
3
1
3
1
7
2
.30 (m, 2H), 7.28 (d, J = 3.3 Hz, 1H), 7.22 (t, J = 8.5 Hz,
1
H), 6.62 (d, J = 3.2 Hz, 1H); C { H} NMR (101 MHz,
3
1
MHz, CDCl ): δ 154.5, 148.3, 146.2, 134.1, 131.5, 129.5, 128.7,
3
CDCl ): δ 161.3 (d, J = 247.0 Hz), 135.4 (d, J = 3.1 Hz), 134.8,
117.7, 112.5, 111.2, 108.6, 106.1, 102.7, 101.7, 55.9, 29.7; HRMS
3
+
130.8, 129.2, 126.2 (d, J = 8.5 Hz), 125.3, 123.6, 116.6 (d, J =
22.8 Hz), 113.6, 111.7, 103.1; HRMS (ESI-TOF) m/z: [M +
(ESI-TOF) m/z: [M + H] Calcd for C H NO 268.0968,
1
6
14
3
Found 268.0969.
+
H] Calcd for C H BrFN 298.9981, Found 298.9985.
11a
1
4
10
2-Phenylphthalazin-1(2H)-one
(5a): White solid
10i
5
-Methoxy-1-(4-nitrophenyl)-1H-indole
(3l):
(36.00 mg, 81%); purified by column chromatography
1
White solid (41.81 mg, 78%); purified by column chroma-
using PE/EA: 3/1, R = 0.40; H NMR (400 MHz, CDCl ): δ
f
3
1
tography using PE/EA: 4/1, R = 0.47; H NMR (400 MHz,
8.50 (dt, J = 7.6, 1.0 Hz, 1H), 8.28 (d, J = 0.8 Hz, 1H), 7.88 –
f
CDCl ): δ 8.40 (d, J = 9.1 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H),
7.76 (m, 2H), 7.76 – 7.70 (m, 1H), 7.67 (dd, J = 8.6, 1.2 Hz,
3
13
7
2
.56 (d, J = 8.9 Hz, 1H), 7.36 (d, J = 3.4 Hz, 1H), 7.15 (d, J =
.6 Hz, 1H), 6.94 (dd, J = 8.9, 2.6 Hz, 1H), 6.70 (d, J = 3.4
2H), 7.49 (t, J = 7.8 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H);
C
1
{ H} NMR (101 MHz, CDCl ): δ 159.2, 141.9, 138.5, 133.5,
3
13
1
Hz, 1H), 3.89 (s, 3H); C { H} NMR (101 MHz CDCl ): δ
132.0, 129.5, 128.8, 128.6, 127.8, 127.3, 126.2, 125.7; HRMS
3
+
1
1
55.3, 145.4, 144.8, 130.9, 130.3, 127.5, 125.6, 122.8, 113.2, 111.4,
06.0, 103.3, 55.8; HRMS (ESI-TOF) m/z: [M + H] Calcd
(ESI-TOF) m/z: [M + H] Calcd for C H N O 223.0871,
1
4
11
2
+
Found 223.0873.
for C H N O 269.0926, Found 269.0926
11b
1
5
13
2
3
3
-Phenylquinazolin-4(3H)-one (5b): White solid
5
-(Benzyloxy)-1-(4-nitrophenyl)-1H-indole
(3m):
(35.55 mg, 80%); purified by column chromatography
1
White solid (55.50 mg, 83%); purified by column chroma-
using PE/EA: 1/1, R = 0.52; H NMR (400 MHz, CDCl ): δ
f
3
1
tography using PE/EA: 12/1, R = 0.5; H NMR (400 MHz,
8.37 (d, J = 7.5 Hz, 1H), 8.14 (s, 1H), 7.84 – 7.74 (m, 2H),
7.59 – 7.52 (m, 3H), 7.52 – 7.47 (m, 1H), 7.46 – 7.40 (m,
f
CDCl ): δ 8.37 (d, J = 8.9 Hz, 2H), 7.63 (d, J = 8.9 Hz, 2H),
3
1
3
1
7
7
7
.56 (d, J = 9.0 Hz, 1H), 7.50 (d, J = 7.1 Hz, 2H), 7.42 (t, J =
.3 Hz, 2H), 7.38 – 7.32 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H),
.03 (dd, J = 9.0, 2.5 Hz, 1H), 6.70 (d, J = 3.3 Hz, 1H), 5.15
2H); C { H} NMR (101 MHz, ,CDCl ): δ 160.7, 147.7, 146.1,
3
137.5, 134.6, 129.7, 129.2, 127.7, 127.5, 127.2, 127.0, 122.3;
+
HRMS (ESI-TOF) m/z: [M + H] Calcd for C H N O
1
4
11
2
13
1
(
s, 2H); C { H} NMR (101 MHz, CDCl ): δ 154.5, 145.3,
223.0871, Found 223.0873.
3
1
1
[
44.8, 137.3, 130.9, 130.4, 128.6, 128.0, 127.6, 127.5, 125.6,
22.8, 113.9, 111.4, 106.1, 104.9, 70.7; HRMS (ESI-TOF) m/z:
11c
1-Phenylpyridin-2(1H)-one (5c): White solid (28.00
mg, 82%); purified by column chromatography using
+
M + H] Calcd for C H N O 345.1234, Found 345.1236.
21
17
2
3
1
PE/EA: 1/9, R = 0.52; H NMR (400 MHz, CDCl ): δ 7.49
f
3
5-Fluoro-1-(4-nitrophenyl)-1H-indole (3n): White
solid (43.55 mg, 85%); purified by column chromatog-
(t, J = 7.4 Hz, 2H), 7.45 – 7.35 (m, 4H), 7.33 (d, J = 6.9 Hz,
1H), 6.67 (d, J = 9.2 Hz, 1H), 6.24 (td, J = 6.7, 1.4 Hz, 1H);
1
raphy using PE/EA: 6/1, R = 0.5; H NMR (400 MHz,
13
1
C { H} NMR (101 MHz, CDCl ): δ 162.4, 140.9, 139.9, 138.0,
f
3
CDCl ): δ 8.43 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 9.0 Hz, 2H),
129.4, 128.5, 126.5, 121.9, 105.9; HRMS (ESI-TOF) m/z: [M +
H] Calcd for C H NO 172.0762, Found 172.0763.
3
+
7.58 (dd, J = 9.0, 4.3 Hz, 1H), 7.44 (d, J = 3.4 Hz, 1H), 7.36
1
1
10
(
(
dd, J = 9.1, 2.5 Hz, 1H), 7.06 (td, J = 9.0, 2.6 Hz, 1H), 6.76
11d
4-Phenylmorpholine (5d): White solid (23.50 mg,
72%); purified by column chromatography using PE/EA:
1
3
1
dd, J = 3.3, 0.8 Hz, 1H); C { H} NMR (101 MHz CDCl ): δ
3
158.6 (d, J = 237.5 Hz), 145.1 (d, J = 26.3 Hz), 131.8, 130.7 (d,
J = 10.2 Hz), 128.7, 125.6, 123.4, 111.8, 111.5, 111.3 (d, J = 9.6
1
4/1, R = 0.4; H NMR (400 MHz, CDCl ): δ7.29 (dd, J = 8.7,
f
3
7.3 Hz, 2H), 6.91 (dd, J = 18.4, 7.7 Hz, 3H), 3.87 (t, J = 9.6
Hz, 4H), 3.16 (t, J = 10 Hz, 4H); C { H} NMR (101 MHz,
Hz), 106.6 (d, J = 23.5 Hz), 105.9 (d, J = 4.4 Hz); HRMS
(
13
1
+
ESI-TOF) m/z: [M + Na] Calcd for C H FN O Na
1
4
9
2
2
CDCl ): δ 151.2, 129.2, 120.1, 115.7, 66.9, 49.4; HRMS (ESI-
3
279.0546, Found 279.0549.
+
TOF) m/z: [M + H] Calcd for C H NO 164.1075, Found
164.1077.
1
0
14
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1
N-(3-Phenylpropyl)aniline (5e): White solid (33.80
1e
Amines: Synthesis Properties and Applications. Cambridge Uni-
versity Press: Cambridge, 2004; pp 265. (c) Craig, P. N. In Com-
prehensive Medicinal Chemistry; Drayton, C. J., Ed.; Pergamon
Press: New York, 1991. (c) Hili, R.; Yudin, A. K. Making Carbon-
Nitrogen Bonds in Biological and Chemical Synthesis. Nat.
Chem. Biol. 2006, 2, 284-287. (d) Liang, M.; Chen, J. Arylamine
Organic Dyes for Dye-Sensitized Solar Cells. Chem. Soc. Rev.
2013, 42, 3453-3488.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
mg, 75%); purified by column chromatography using
1
PE/EA: 9/1, R = 0.60; H NMR (400 MHz, CDCl ): δ 7.35 –
f
3
7.27 (m, 2H), 7.24 – 7.15 (m, 5H), 6.71 (t, J = 7.3 Hz, 1H),
6.61 (d, J = 7.7 Hz, 2H), 3.15 (t, J = 6.9 Hz, 2H), 2.68 (t, J =
1
3
1
7.5 Hz, 2H), 1.92 – 1.58 (m, 4H); C { H} NMR (101 MHz,
CDCl ): δ 145.9, 139.7, 126.7, 125.9, 125.8, 123.3, 114.6, 110.2,
3
+
41.3, 33.1, 26.6, 26.4; HRMS (ESI-TOF) m/z: [M + H] Calcd
(
2) Recent review: (a) Park, Y.; Kim, Y.; Chang, S. Transition
for C H N 212.1439, Found 212.1436
Metal-Catalyzed C–H Amination: Scope, Mechanism, and Appli-
cations. Chem. Rev. 2017, 117, 9247-9301. (b) Hendrick, C. E.;
Wang, Q. Emerging Developments using Nitrogen–Heteroatom
Bonds as Amination Reagents in the Synthesis of Aminoarenes. J.
Org. Chem. 2017, 82, 839-847. (c) Ruiz-Castillo, P.; Buchwald, S.
L. Applications of Palladium-Catalyzed C–N Cross-Coupling
Reactions. Chem. Rev. 2016, 116, 12564-12649. (d) Jiao, J.; Mura-
kami, K.; Itami, K. Catalytic Methods for Aromatic C–H Amina-
tion: An Ideal Strategy for Nitrogen-Based Functional Molecules.
ACS Catal. 2016, 6, 610-633. (e) Kim, H.; Chang, S. Transition-
Metal-Mediated Direct C–H Amination of Hydrocarbons with
Amine Reactants: The Most Desirable but Challenging C–N
Bond-Formation Approach. ACS Catal. 2016, 6, 2341-2351.
1
5
18
11f
-Phenyl-1H-indole as white solid; purified by col-
3
umn chromatography using PE/EA: 4/1, R = 0.35; H NMR
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
f
(
400 MHz CDCl ): δ 8.16 (s, 1H, NH), 7.93 (d, J = 6.0 Hz,
3
1
2
H), 7.66 (d, J = 7.2 Hz, 1H), 7.46-7.38 (m, 3H), 7.32 (d, J =
1
.0 Hz, 1H), 7.30-7.17 (m, 4H); C { H} NMR (100 MHz,
3
1
CDCl ): δ 136.7, 135.6, 128.7, 127.5, 126.0, 125.7, 122.5, 121.8,
3
1
20.4, 119.8, 116.3, 111.4; HRMS (ESI-TOF) m/z: [M +
H] Calcd for C H N 194.0964, Found 194.0967.
+
1
4
12
Representative procedure for the gram-scale reac-
tion: To dried tube equipped with a stir bar, CuI (81.32
mg, 0.43 mmol, 5 mol%), L-Met (126.82 mg, 0.85 mmol, 10
mol%, 2 equiv), Indole 2a (1.0 g, 8.54 mmol), iodobenzene
(
3) (a) Li, Y.; Peng, J.; Chen, X.; Mo, B.; Li, X.; Sun, P.; Chen, C.
Copper-Catalyzed Synthesis of Multisubstituted Indoles through
Tandem Ullmann-Type C–N Formation and Cross-
dehydrogenative Coupling Reactions. J. Org. Chem. 2018, 83,
1
a (1.43 mL, 2.61 g, 12.81 mmol, 1.5 equiv), K CO (2.36 g,
2 3
1
7.08 mmol, 2.0 equiv) followed by DMF (10 mL) was
added and the resulting reaction mixture was stirred at
00 °C (oil bath). After 24 h, the reaction mixture was
5
288-5294. (b) Lo, Q. A.; Sale, D.; Braddock, D. C.; Davies, R. P.
Mechanistic and Performance Studies on the Ligand-Promoted
Ullmann Amination Reaction. ACS Catal. 2018, 8, 101-109. (c)
Zhou, W.; Fan, M.; Yin, J.; Jiang, Y.; Ma, D. CuI/Oxalic Diamide
Catalyzed Coupling Reaction of (Hetero)Aryl Chlorides and
Amines J. Am. Chem. Soc. 2015, 137, 11942-11945. (d) Ziegler, D. T.;
Choi, J.; Muñoz-Molina, J. M. Bissember, A. C.; Peters, J. C.; Fu,
G. C. A Versatile Approach to Ullmann C–N Couplings at Room
Temperature: New Families of Nucleophiles and Electrophiles
for Photoinduced, Copper-Catalyzed Processes. J. Am. Chem.
Soc. 2013, 135, 13107-13112. (e)Giri, R.; Hartwig, J. F. Cu(I)−Amido
Complexes in the Ullmann Reaction: Reactions of Cu(I)−Amido
Complexes with Iodoarenes with and without Autocatalysis by
CuI. J. Am. Chem. Soc. 2010, 132, 15860-15863. (f) Gujadhur, R. K.;
Bates, C. G.; Venkataraman, D. Formation of Aryl−Nitrogen,
Aryl−Oxygen, and Aryl−Carbon Bonds Using Well-Defined
Copper(I)-Based Catalysts. Org. Lett. 2001, 3, 4315-4317. (g) Bhu-
nia, S.; Pawar, G. G.; Kumar, S. V.; Jiang, Y.; Ma, D. Selected
copper-based reactions for C-N, C-O, C-S, and C-C Bond For-
mation. Angew. Chem. Int. Ed. 2017, 56, 16136-16179. (h) Ma, D.;
Cai Q. L-Proline Promoted Ullmann-Type Coupling Reactions of
Aryl Iodides with Indoles, Pyrroles, Imidazoles or Pyrazoles.
Synlett 2004, 128-130. (i) Liu, J.; Yan, J.; Qin, D.; Cai, Q. An Unex-
pected Inversion of Enantioselectivity in a Copper-Catalyzed
Intramolecular- Desymmetric Aryl C–N Coupling Reaction.
Synthesis 2014, 46, 1917-1923.
1
cooled to rt, worked-up with water-EtOAC system, dried
using anhydrous MgSO , adsorbed on to silica gel and
4
purified by column chromatography (PE/EA: 6/1, R =
f
0
.52) to get analytically 3a (1.48 g, 91%) as white solid.
ASSOCIATED CONTENT
Supporting Information. Few experimental details and
1
13
copy of H NMR & C spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: dineshk@niperahm.ac.in
ORCID: Dinesh Kumar: 0000-0003-2680-881X
Notes
The authors declare no competing financial interest
ACKNOWLEDGMENT
We acknowledge the generous financial support from De-
partment of Pharmaceuticals (DoP), Ministry of Chemical &
Fertilizer, GoI. DK hearty acknowledge Prof. Kiran Kalia,
Director NIPER-A for her constant support, encouragement,
and motivation. DK also gratefully acknowledge the DST-
SERB for the award of Ramanujan Fellowship (File No.
SB/S2/RJN-135/2017). Authors thank Ms. Rajeshwari Rathod
for recoding the HRMS spectra.
(
4) (a) Dennis, J. M.; White, N. A.; Liu, R. Y.; Buchwald, S. L.
Breaking the Base Barrier: An Electron-Deficient Palladium
Catalyst Enables the Use of a Common Soluble Base in C–N
Coupling. J. Am. Chem. Soc. 2018, 140, 4721-4725. (b)
Ayothiraman, R.; Rangaswamy, S.; Maity, P.; Simmons, E. M.;
Beutner, G. L.; Janey, J.; Eastgate, M.D.; Vaidyanathan, R. Zinc
Acetate-Promoted Buchwald–Hartwig Couplings of Heteroaro-
matic Amines. J. Org. Chem. 2017, 82, 7420-7427. (c) Zhang, B.;
Zhang, X.; Hao, J.; Yang, C. Direct Approach to N-Substituted-2-
Fluoroindoles by Sequential Construction of C–N Bonds from
gem-Difluorostyrenes. Org. Lett. 2017, 19, 1780-1783. (d) Ramirez-
Lopez, P.; Ros, A.; Romero-Arenas, A.; Iglesias-Siguenza, J.;
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1
1
1
1
1
1
1
1
1
1
2
2
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