Synthesis of topologically constrained naphthalimide appended palladium(ii)-N-heterocyclic carbene complexes-insights into additive controlled product selectivity

Article abstract of DOI:10.1039/c8ob00616d

Topologically constrained naphthalimide appended Pd-NHCs were synthesized and characterized. These structurally related complexes were catalytically compared with previously synthesized Pd-NHCs in the regioselective heteroannulation of o-haloanilines and

Full text of DOI:10.1039/c8ob00616d

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ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Synthesis of topologically constrained naphthalimide appended
Palladium(II)-N-Heterocyclic carbene complexes- Insights into
additive controlled product selectivity
Received 00th January 20xx,
Accepted 00th January 20xx
Pradeep Kumar Reddy Panyam,[a] Ramdas Sreedharan[a] and Thirumanavelan Gandhi*[a]
DOI: 10.1039/x0xx00000x
www.rsc.org/
Topologically constrained naphthalimide appended Pd-NHCs were synthesized and characterized. These structurally
related complexes were catalytically compared with the previously synthesized Pd-NHC in the regioselective
heteroannulation of o-haloanilines and arylethynyl-trimethylsilane. The unique effect of the additive on the product
selectivity has been clearly demonstrated. The scope of the reaction with respect to different TMS protected alkynes and
o-haloanilines are presented. Importantly, the step- economic regioselective synthesis of N-alkyl-3-aryl-indoles from o-
haloanilines and arylethynyl-trimethylsilane assisted by Pd(II)-NHC has been clearly demonstrated via one-pot
heteroannulation, TMS deprotection and N-alkylation. In addition, synthetic utility was demonstrated with several
derivatizations.
heteroannulation of o-haloanilines and arylethynyl-
trimethylsilane with apropos additives and catalyst yields 3-
aryl-2-(trimethylsilyl)-1H-indoles 23 and N-butyl-3-phenyl-
Introduction
The indole scaffolds are recurring heterocycles in many
biologically active natural products, pharmaceuticals,
agrochemical and functional materials.[1] In that event, its
supremacy is further validated by 3-arylindoles viz.
dragmacidin D, meridianins, nortosentins, hemacanthins B
which are bestowed with a multitude of medicinal properties
such as antitumor, antifungal, antiviral, antibacterial and
antagonists to progesterone receptor (PR).[2] Recently, the
efficacy of transition-metal-catalyzed annulation to produce a
plethora of heterocycles have been recognized and its
constant development in organic synthesis is highly
demanded.[3] Traditionally, 3-arylindoles were synthesized by
Fischer indole synthesis involving arylhydrazines and
aldehydes.[4] Recent reports show Pd-catalyzed reductive
amination of nitroalkenes in the presence of carbon monoxide,
reductive cyclization of 2-(2-nitroaryl)acetonitriles (Rh & Pt),[5]
annulation of o-haloanilines with aldehydes or alkynes,[6] and
direct arylation of indoles.[7] Besides, 3-arylindoles were
synthesized by gold-catalyzed annulation of nitrosoarenes and
alkynes.[8] Helleday et al reported two-step synthesis:
vinylation of ortho-nitrohaloarenes using MIDA and
indoles 25
. Moreover, heteroarylsilanes proved to be
important synthon in organic synthesis and find applications in
medicinal chemistry, advanced materials and polymer
synthesis. Common strategies to facilitate the C-Si bond
construction entail the intervention of heteroaryl lithium or
magnesium reagents with silicon electrophiles or cross-
dehydrogenative coupling of aromatic heterocycles with
hydrosilanes catalyzed by KOt-Bu.[10]
R1
Br
R2
R2
NH2
21
Pd-NHC
Pd-NHC (4 mol %)
K2CO3 (2 equiv)
TBAB (2.2 equiv)
(4 mol %)
K2CO3 (2 equiv)
LiBr (1 equiv)
R1
R1
Si
Si
Dioxane (2 mL)
120 oC, 12 h
Dioxane (2 mL)
120 oC, 8 h
N
H
N
Bu
25
23
R2
22
Figure 1. Outline of the present work
subsequent
cyclization
under
phosphite-mediated
conditions.[9] However, the reported reactions demand harsh
reaction conditions, high H2 pressure, involving CO, long
reaction time, assembling multi-components and demanding
pre-functionalized substrates. To oust such challenges,
Remarkably strong σ-binding and steric tunability of NHCs,
makes them versatile ligands in the area of homogenous
catalysis.[11] Lately, our research group have effectively
harnessed the π-stacking approach in enhancing the catalytic
properties – synthesis of 2-alkenylindoles catalyzed by Pd-NHC
appended with naphthalimide or bisnaphthalimide moieties
from o-haloanilines and tertiary propargyl alcohols.[12] We
have reasoned that enhanced catalytic efficiency of these
complexes is attributed to the π-stacking nature of
naphthalimide coupled with the flexible alkyl linker. In this
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regard, we have decided to further study the structure and wingtip substituent to imidazole, whereas, in 13 it is a part of
catalytic activity of various palladium complexes with benzimidazole backbone.
topologically constrained naphthalimide carbenes. Herein, we
NH
report a direct, convenient, and one-pot synthesis of 3-aryl-2-
(trimethylsilyl)-1H-indoles 23 and N-butyl-3-phenyl-indoles 25
employing decorated Pd-NHC precatalyst (Figure 1).
N
N
N
NH
N
Benzyl bromide
(1.2 equiv)
K2CO3
Triethylamine
(2 equiv)
O
N
O
(2.5 equiv)
O
N
O
H2
O
N
9
Results and Discussion
Ethanol, 24 h
90 °C
DMF, 24 h
80 °C
O
O
10
; 71%
Initially compounds 3, 4 & 10 were synthesized by the
condensation of amino derivatives of heterocycles (1, 2 & 9)
1:1 ratio of 5(6)-substitution
11; 83%
with 1,8-naphthalic anhydride respectively (Scheme 1 & 2).
Compound 10 was then subjected to N-benzylation employing
the standard protocol of DMF/K2CO3 to afford the designed
compound 11. However, we observed only the 1:1 mixture of
5(6)-substituted derivative due to tautomer effect of NH in
benzimidazole ring. Despite numerous efforts, isolation of a
N
Br
Pd
Br
Bu
N
Bu
N
N
N
Br
PdCl2 (1.05 equiv)
K2CO3 (5 equiv)
KBr (3 equiv)
n-BuBr
(5 equiv)
single isomer was not achieved. Compounds 3, 4 & 11 were
subjected to treatment with n-butyl bromide affording desired
11
O
N
CH3CN, 24 h
110 °C
O
O
N
O
Pyridine
80 °C
16h
imidazolium salts
94% yields).
5
,
6
&
12 respectively in excellent yields (91-
Bu
Br
N
1:1 ratio of 5(6)-substitution
1:1 ratio of 5(6)-substitution
12; 91%
13; 61%
N
N
N
N
N
N
Scheme 2. Synthesis of Pd-PEPPSI NHC complex 13
Triethylamine
(2 equiv)
n-butyl bromide
(5 equiv)
1-2
NH2
O
O
N
O
O
O
Acetonitrile, 24 h
110 °C
Ethanol, 24 h
90 °C
O
O
3; 82%
4; 71%
5
; 94%
6; 93%
Bu
N
Br
Pd
Br
N
N
PdCl2 (1.05 equiv)
K2CO3 (5 equiv)
KBr (3 equiv)
O
N
O
5
6
Pyridine
80 °C
16h
7
; 71%
8; 53%
Scheme 1. Synthesis of Pd-PEPPSI NHC complexes 7 & 8
Figure 2. ORTEP representation of 7 (CCDC1584103, 50% probability
ellipsoids and hydrogens are omitted for clarity)
Finally, Pd-PEPPSI NHC complexes 7, 8 & 13 were conveniently
synthesized by palladation of corresponding imidazolium salts
in 71%, 53% and 61% yields respectively (Scheme 1 & 2). The
synthesized complexes are stable in air and moisture in both
solid and solution state. The chemical structure of the
complexes was confirmed by the multinuclear NMR and mass
Yellow crystals of 7 suitable for single-crystal X-ray diffraction
analysis were obtained by slow evaporation of its
concentrated dichloromethane solution at RT. As shown in the
Fig.2,
pyridine trans to each other. The Pd-Ccarbene bond length in
1.950 Å. However, the lower yield of was ascribed to the
formation of cyclic urea derivative (confirmed by single-crystal
X-ray analysis ORTEP representation in supporting
7
adopts square planar geometry with the carbene and
spectroscopy. The resonances of Pd-Ccarbene of complexes 7, 8
& 13 appear in the range of 149.50 to 165.72 ppm. In contrast
to previously synthesized complexes 14-20 (Structures of 14-
7
is
8
20 are shown in table 1), the movement of the naphthalimide
moiety is restricted in 13 which is parted by benzene
spacer. In case of , the naphthalimide moiety is a
&
7, 8 &
information) via sequential deprotonation and oxidation of
NHC as observed previously by other authors.[13]
7
and 8
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as an additive with 1,4-dioxane as solvent at 120 °C. Surprisingly,
we obtained mixture of annulated products 3-phenyl-2-
(trimethylsilyl)-1H-indoles 23a (17%) and 3-phenyl-1H-indole 24
(50%) (Table 1 entry-1). Intention to obtain selectively 23a was
realized by replacing TBAB with various salts viz. NaBr, LiBr and
KBr, (entries 2-4) among these LiBr found to be best (71%, entry
3). Replacement of K2CO3 with other bases such as Na2CO3,
KOt-Bu, NaOH, triethylamine, DIPEA & KOH proved less
effective or not effective (entries 5-11). The temperature of
above 120 °C failed to improve yield further. Among a variety
of solvents, which includes DMF, DMSO, ethanol, dioxane and
NMP, we found out that dioxane is very effective (entries 12-
15). Extending the optimized reaction condition to other Pd-
Table 1. Optimization details[a,b]
NHC’s 14
increment in the yield of 23a (entries 16-24). However, modest
catalytic performance has been observed with (entries
, 15, 17-20, 7, 8 & 13 could not furnish profound
7
& 8
22-23) which could be attributed to restricted movement of
naphthalimide moiety appended to the Pd-NHC. Having
realized the selective formation of 23a, we turned our
attention to investigate the formation of 24a
& 25a. To our
delight, an increment in the loading of TBAB from 1 to 2
equivalents (entry 25) leads to the generation of 25a, and it
was further furnished that 2.2 equivalents are the best (entry
26). Thus it is conceived that TBAB plays multiple roles as an
additive, deprotecting and an alkylating agent.
Yield (%)
Entry
[Pd]
Base
Additive
23a
25a
1[c, d]
2
3
4
5
6
7
8
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
14
15
17
18
19
20
7
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
KOt-Bu
NaOH
TEA
TBAB
NaBr
LiBr
KBr
17
63
71
55
65
71
50
52
11[c]
14[c]
50
64
31
52
60
63
65
70
70
70
68
64
67
70
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
Table 2. Scope for the synthesis of 3-aryl 2-trimethylsilyl indoles[a,b]
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
TBAB[i]
TBAB[j]
-
9
10
11
12[e]
13[f]
14[g]
15[h]
16
17
18
19
20
21
22
23
24
25
26
27
DIPEA
KOH
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
8
13
16
16
16
58
65
-
-
46
[a] 21 (1 mmol), 22 (2 mmol), [Pd] (4 mol %), base (2 mmol),
additive (1 mmol), 1,4-dioxane (2 mL), 120 °C, 8 h. [b] Isolated
yields. [c] GC yields determined using n-decane as internal
standard. [d] 24 was observed in 50% yield. [e] DMF as solvent. [f]
DMSO as solvent. [g] Ethanol as solvent. [h] NMP as solvent. [i] 2
mmol of TBAB was used. [j] 2.2 mmol of TBAB was used.
[a] 21 (1 mmol), 22 (2 mmol), 16 (4 mol %), K2CO3 (2 mmol), LiBr (1
mmol), dioxane (2 mL), 120 °C, 8 h. [b] Isolated yields. [c] Gram-
scale reaction
Having established the set of optimized reaction conditions,
first, we set out to evaluate the substrate scope with respect
to different o-haloanilines and arylethynyl-trimethylsilane to
In pursuit of 3-phenyl-2-(trimethylsilyl)-1H-indoles 23a, we
reacted the 22 with 21 by adopting our previously reported
optimized conditions[12], 16 as a catalyst, K2CO3 as a base, TBAB
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yield 3-aryl-2-(trimethylsilyl)-1H-indoles 23 (Table 2). which can undergo subsequent transformation via transition
Heteroannulation reaction was compatible with different o- metal catalysis. Even the sterically encumbered naphthyl
haloanilines namely iodo, bromo, chloro whereas o- group were well tolerated affording the corresponding indole
fluoroaniline was non-reactive. It is noteworthy that gram derivative in synthetically useful yields 25f. It should be noted
scale reaction of 21 with 22 afforded the 23a without erosion that broad functional group tolerance highlights the synthetic
in yield, which is highly significant in scalability. Henceforth, by potential of the protocol in late-stage derivatization. Even the
employing o-bromoaniline derivatives, a wide variety of 3-aryl- reaction proceeded exceedingly well when TBAB was replaced
2-(trimethylsilyl)-1H-indoles 23a-23e were synthesized. with TBAF affording 25a in good yields (67%). It is noteworthy
Reactive functional groups such as cyano, acetyl and ester that, when the reaction of 21 and 22 was performed under the
were well tolerated furnishing the desired products in optimized conditions in the presence of different ammonium
synthetically useful yields 23c-23e. Incongruent to the salts, the corresponding desired products 26a-28a were
literature, N-acetyl bromoanilines failed to react with 22 to the successfully obtained. However, the yield of 28a was low when
afford desired indole. Subsequently, we examined the scope of aliquat 336 was employed.
arylethynyl-trimethylsilane. Both electron-donating 23f & 23g
and electron-withdrawing substituents 23h 23i on the aryl The synthetic utility of the current protocol was further
&
moiety were found to proceed smoothly under the optimized demonstrated through different derivatizations as evident
conditions. Likewise, this protocol was amenable to substrates from scheme 3. TMS-deprotection from 23a enables the
containing naphthalene 23j and thiophene 23k
.
formation of 3-phenylindoles 24 in good yield. Furthermore,
bromination[14] of 23a assisted by NBS to affords 29, indicating
the potential for further synthetic elaboration. Likewise, 25a
was transformed into synthetically useful products 30 and 31
employing suitable reaction conditions as reported earlier[15]
(Scheme 3).
Table 3. Scope for the synthesis of N-butyl-3-aryl indoles [a,b]
Scheme 3. Derivatizations.
To gain more insights into the mechanism involving the
formation of 25a, the reaction of 21 with 22 under the
optimized conditions was carefully monitored by GC-MS
analysis. As assumed, tributylamine was detected by GC-MS
along with 25a (Scheme 4) which suggested the thermal
decomposition of tetrabutylammonium bromide to yield n-
butyl bromide and tributylamine which thereby assists in the
N-alkylation of the in situ formed 24. Even the reaction of
isolated 24 with TBAB under the optimized conditions yielded
25a as the sole product which corroborates the in situ
formation of 24 followed by alkylation. In addition, reaction of
23a with TBAB under the optimized conditions to yield 25a
.
[a] 21 (1 mmol), 22 (2 mmol), 16 (4 mol %), K2CO3 (2 mmol), TBAB
(2.2 mmol), dioxane (2 mL), 120 °C, 12 h. [b] Isolated yields. [c]
Tetrabutylammonium fluoride (TBAF) [d] Tetraethylammonium
bromide as additive. [e] Tetrapropylammonium bromide as
additive. [f] Aliquat 336 (Methyltrioctylammonium chloride) as
additive. [g] tetramethylammonium chloride as additive.
Using the second set of conditions, the N-butyl-3-aryl indoles
25 were obtained with excellent regioselectivity (Table 3). o-
bromoanilines bearing electron-donating (-CH3) 25b was
successfully employed without any detrimental effect on the
reactivity and they are well tolerated. This strategy was
employed for aniline substrates bearing various reactive
functional groups such as cyano, acetyl and ester 25c-25e,
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Flash chromatographic technique on silica gel (100-200 mesh)
was used for the purification of the products. Thin layer
chromatography was conducted with 0.25mm silica plates
1
(60F254) and visualized by exposure to UV light (254 nm). H
NMR spectra were recorded on Bruker spectrometer (400
MHz) and are reported in units ppm (parts per million) relative
to the signals for residual chloroform (7.26 ppm) and DMSO
(2.54 ppm) in the deuterated solvent. 13C NMR spectra were
recorded on Bruker spectrometer (100 MHz) and are reported
in ppm relative to deuterated chloroform (77.23 ppm) and
DMSO (39.52 ppm). Coupling constants (J) are reported in Hz;
splitting patterns are assigned s = singlet, d = doublet, t =
triplet, q = quartet, br = broad signal. High-resolution mass
spectra (HRMS) and ESI mass were performed on TOF-Q
analyser.
Typical Procedure for the Synthesis of Precursors (3, 4 & 10)
Scheme 4. Control studies
To a stirred suspension of 1,8-naphthalic anhydride and amine
derivatives of heterocycles (1, 2 & 9) in ethanol, triethylamine
Based on the control experiments discussed above and the
earlier works,[12,16] we envision the pathway involved in the
heteroannulation reaction (Scheme 5). Initial oxidative
(2 equiv) was charged. After stirring for 24 h at 90 °C, the mass
was cooled to room temperature and the solids formed were
filtered and washed with a minimum quantity of ethanol to
washout the unwanted impurities. The solids were dried under
vacuum and used without further purification.
addition to Pd(0) complex forms NHC-Pd(II)-aryl complex
followed by sequential coordination and selective insertion of
trimethyl(phenylethynyl)silane resulting in intermediate with
A
B
the release of HBr which eventually lead to 23a. The halide
ligation step is believed to stabilize the intermediate.[16,17]
Synthesis of 11: To a stirred suspension of 10 (1 equiv), K2CO3
(2.5 equiv) and DMF (5 mL), benzyl bromide (1.2 equiv) was
added and the resulting mixture was stirred at 80 °C for 24 h.
The reaction mass was then poured into ice-cold water and
extracted with 3 × 25 mL ethyl acetate. The combined organic
layers were washed with water, dried over Na2SO4 and the
solvent was concentrated under reduced pressure. The crude
was purified using column chromatography to afford 11. 1:1
inseparable mixture of 5(6)-substituted derivatives were
observed due to tautomer effect of NH in benzimidazole ring.
Yield: 83%; White coloured solid. Rf=0.60 (MeOH/DCM 1:49).
Purified by column chromatography on silica gel
1
(DCM/Methanol = 97/3). H NMR (400 MHz, DMSO-d6) δ 8.58
– 8.54 (m, 10H), 7.97 – 7.93 (t, J = 7.74 Hz, 4H), 7.84 (d, J = 8.48
Hz, 1H), 7.76 (dd, J = 1.56, 11.36 Hz, 2H), 7.69 (d, J = 8.52 Hz,
1H), 7.47 – 7.41 (m, 4H), 7.39 – 7.37 (m, 6H), 7.28 (dd, J = 1.8,
8.48 Hz, 2H), 5.63 (s, 2H), 5.54 (s, 2H); 13C NMR (100 MHz,
DMSO-d6) 164.50, 164.47, 137.33, 137.28, 134.90, 134.81,
131.92, 131.29, 131.22, 131.18, 130.51, 129.25, 129.20,
128.33, 128.28, 128.03, 127.91, 127.70, 123.96, 123.42,
123.23, 123.13, 120.65, 119.93, 111.86, 111.17, 48.33, 48.13;
HRMS [M+H+] Calcd. for C26H18N3O2: 404.1399, found:
404.1406.
General Procedure for the Synthesis of Imidazolium salts (5, 6
& 12)
To a suspension of 3, 4 & 11 in acetonitrile solution, 5
Scheme 5. Plausible Mechanism
equivalents of n-butyl bromide were added and stirred at 100
°C until completion of starting material as indicated by thin
layer chromatography. The reaction mixture was cooled and
concentrated under reduced pressure. Ethylacetate was then
added, stirred for 30 min and the solids formed are filtered,
dried under vacuum.
Experimental Section
Unless otherwise mentioned, all the reactions were carried out
in screw cap reaction tubes and all the chemicals were
purchased commercially and used without purification.
Different palladium salts and the reagents were purchased at
the highest commercial quality and used without purification.
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Compound 5: Yield: 94%; White coloured solid. Rf=0.40 (t, J = 7.74 Hz, 2H), 2.21 – 2.13 (m, 2H), 1.62 – 1.53 (m, 2H),
1
(MeOH/DCM 4:46). H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1.10 – 1.06 (t, J = 7.36 Hz, 3H); 13C NMR (100 MHz, CDCl3)
1H), 8.57 – 8.53 (t, J = 8.00 Hz, 4H), 8.45 (s, 1H), 8.13 (s, 1H), 164.18, 152.64, 149.50, 139.63, 137.64, 135.65, 134.47,
7.99 – 7.92 (m, 4H), 7.76 (d, J = 8.68 Hz, 2H), 4.32 – 4.29 (t, J = 131.81, 131.75, 129.78, 128.58, 127.53, 127.12, 124.52,
7.2 Hz, 2H), 1.96 – 1.88 (m, 2H), 1.42 – 1.33 (m, 2H), 0.98 – 123.40, 122.73, 122.14, 51.49, 32.03, 20.09, 13.84; Anal. Calcd
0.95 (t, J = 7.36 Hz, 3H); 13C NMR (100 MHz, DMSO-d6) 164.16, for C30H26Br2N4O2Pd: C, 48.64; H, 3.54; N, 7.56. Found: C,
137.74, 136.10, 135.15, 134.94, 131.97, 131.51, 131.31, 48.62; H, 3.57; N, 7.51. HRMS (ESI) m/z: [M–2Br-Py] Calcd for
128.37, 127.78, 123.87, 123.04, 122.99, 121.81, 49.66, 31.62, C25H21N3O2Pd 503.0673; Found, 503.0743.
19.35, 13.84; HRMS (ESI) m/z: [M–Br+H]+ Calcd for C25H23N3O
397.1790; Found, 397.1805.
Complex 8: Yield: 53%; Yellow coloured solid. Rf=0.25
(MeOH/DCM 2:98). Purified by column chromatography on
Compound 6: Yield: 93%; White coloured solid. Rf=0.40 silica gel (DCM/Methanol = 97/3). 1H NMR (400 MHz, CDCl3) δ
(MeOH/DCM 4:46). H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 8.88 (d, J = 5.8 Hz, 2H), 8.71 (d, J = 7.24 Hz, 2H), 8.32 (d, J = 8.2
1
1H), 8.64 – 8.61 (m, 4H), 8.35 (d, J = 7.84 Hz, 1H), 8.12 (d, J = Hz, 2H), 8.16 (d, J = 8.4 Hz, 2H), 7.85 – 7.81 (t, J = 7.74 Hz, 2H),
8.12 Hz, 2H), 8.06 – 7.99 (m, 3H), 7.91 – 7.82 (m, 4H), 4.70 – 7.74 – 7.70 (t, J = 7.7 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.51 (d, J
4.67 (t, J = 6.94 Hz, 2H), 2.11 – 2.05 (m, 2H), 1.56 – 1.49 (m, = 7.96 Hz, 1H), 7.39 – 7.29 (m, 5H), 4.94 – 4.90 (t, J = 8.02 Hz,
2H), 1.07 – 1.03 (t, J = 7.18 Hz, 3H); 13C NMR (100 MHz, DMSO- 2H), 2.36 – 2.28 (m, 2H), 1.71 – 1.63 (m, 2H), 1.15 – 1.11 (t, J =
d6) 164.20, 143.20, 138.32, 135.16, 133.44, 131.99, 131.85, 7.34 Hz, 3H); 13C NMR (100 MHz, CDCl3) 164.16, 154.37,
131.78, 131.42, 131.32, 128.41, 128.03, 127.79, 127.50, 152.56, 138.37, 137.65, 137.28, 136.22, 136.04, 134.45,
126.11, 123.04, 114.61, 114.11, 47.37, 30.98, 19.67, 13.96; 134.40, 131.85, 131.70, 130.10, 129.62, 128.63, 127.13,
HRMS (ESI) m/z: [M–Br]+ Calcd for C29H24N3O2 446.1863; 125.00, 124.58, 123.55, 123.50, 122.81, 111.22, 110.46, 48.93,
Found, 446.1885.
31.04, 20.48, 13.87; Anal. Calcd for C34H28Br2N4O2Pd: C, 51.64;
H, 3.57; N, 7.08. Found: C, 51.67; H, 3.55; N, 7.10. HRMS (ESI)
Compound 12: 1:1 mixture of 5(6)-substituted derivatives m/z: [M–2Br–Py-H] Calcd for C29H23N3O2Pd 550.0747; Found,
were observed. Yield: 91%; White coloured solid. Rf=0.35 550.0748;.
(MeOH/DCM 4:46). H NMR (400 MHz, DMSO-d6) δ 10.11 (s,
1
2H), 8.58 – 8.52 (m, 8H), 8.33 (d, J = 0.96 Hz, 1H), 8.31 (d, J = Complex 13: Yield: 61%; Yellow coloured solid. Rf=0.45
8.84 Hz, 1H), 8.22 (d, J = 0.96 Hz, 1H), 8.13 (d, J = 8.84 Hz, 1H), (MeOH/DCM 3:97). Purified by column chromatography on
7.96 – 7.92 (m, 4H), 7.80 (dd, J = 1.4, 8.76 Hz, 1H), 7.76 – 7.73 silica gel (DCM/Methanol = 97/3). 1H NMR (400 MHz, CDCl3) δ
(dd, J = 1.36, 8.76 Hz, 1H), 7.63 (d, J = 7.04 Hz, 2H), 7.55 (d, J = 8.99 – 8.96 (m, 4H), 8.58 – 8.55 (dd, J = 0.88, 7.24 Hz, 2H), 8.53
6.64 Hz, 2H), 7.49 – 7.38 (m, 6H), 5.85 (s, 2H), 5.77 (s, 2H), 4.61 – 8.51 (dd, J = 0.88, 7.28 Hz, 2H), 8.21 – 8.17 (m, 4H), 7.73 –
– 4.58 (t, J = 7.20 Hz, 2H), 4.51 – 4.47 (t, J = 7.34 Hz, 2H), 2.03 – 7.66 (m, 6H), 7.56 (d, J = 7.16 Hz, 2H), 7.50 – 7.48 (m, 2H), 7.33
1.89 (m, 4H), 1.49 – 1.34 (m, 4H), 1.01 – 0.97 (t, J = 7.34 Hz, – 7.31 (m, 3H), 7.29 – 7.19 (m, 8H), 7.17 – 7.09 (m, 3H), 6.99 –
3H), 0.96 – 0.92 (t, J = 7.36 Hz, 3H); 13C NMR (100 MHz, DMSO- 6.97 (m, 2H), 6.14 (s, 2H), 6.09 (s, 2H), 4.88 – 4.78 (m, 4H), 2.28
d6) 164.35, 143.92, 135.28, 135.22, 134.39, 134.27, 132.16, – 2.16 (m, 4H), 1.62 – 1.55 (m, 2H), 1.51 – 1.47 (m, 2H), 1.07 –
131.98, 131.74, 131.53, 131.38, 131.35, 131.05, 129.52, 1.04 (t, J = 7.36 Hz, 3H), 1.02 – 0.98 (t, J = 7.34 Hz, 3H); 13C
129.46, 129.31, 129.25, 128.95, 128.77, 128.62, 128.35, NMR (100 MHz, CDCl3) 165.72, 165.55, 164.52, 164.36, 152.67,
127.82, 122.96, 122.89, 115.35, 115.19, 114.83, 114.77, 50.64, 137.97, 135.58, 135.08, 134.95, 134.69, 134.58, 134.52,
50.50, 47.36, 30.94, 30.82, 19.67, 19.60, 13.92, 13.84; HRMS 134.49, 134.40, 131.86, 131.79, 131.74, 130.83, 130.67,
(ESI) m/z: [M – Br]+ Calcd for C30H26N3O2 460.2020; Found, 128.97, 128.89, 128.53, 128.49, 128.28, 128.22, 128.08,
460.2006.
127.11, 127.06, 124.62, 124.60, 124.04, 123.83, 122.58,
112.25, 112.18, 111.10, 111.00, 54.01, 53.73, 49.07, 31.19,
31.04, 20.45, 20.41, 13.92, 13.83; Anal. Calcd for
C35H30Br2N4O2Pd: C, 52.23; H, 3.76; N, 6.96. Found: C, 52.34; H,
3.69; N, 7.05. HRMS (ESI) m/z: [M–Br]+ Calcd for
C35H30BrN4O2Pd 725.0567; Found, 725.0560; [M–Br-Py] Calcd
for C30H25BrN3O2Pd 646.0145; Found, 646.0148.
General Procedure for the Synthesis of PEPPSI complexes (7,
8 & 13)
To an oven-dried screw cap reaction tube equipped with
magnetic stir bar, 5, 6 & 12 (1 equiv), PdCl2 (1.05 equiv), K2CO3
(5 equiv), KBr (3 equiv) and pyridine (5 mL) were charged. The
tube was then capped and placed in a preheated oil bath at 80
°C for 16 h under vigorous stirring. After completion, the General Procedure for the Synthesis of 3-aryl-2-trimethylsilyl
reaction mass was filtered over a short plug of celite using indoles (23)
dichloromethane as washing solvent. The combined organic A flame dried reaction tube was charged with o-haloaniline (1
layers were concentrated under reduced pressure and the mmol), 16 (0.04 mmol), LiBr (1 mmol), anhydrous K2CO3 (2
crude was purified by column chromatography using mmol), TMS protected alkynes (2 mmol) and 1,4-dioxane (2
DCM/Methanol as eluents to afford pure complexes.
mL). The tube was capped and stirred at 120 °C for 8 h. On
completion of the reaction, the mixture was cooled to room
Complex 7: Yield: 71%; Yellow coloured solid. Rf=0.30 temperature, diluted with 15 mL of ethyl acetate and filtered
(MeOH/DCM 2:98). Purified by column chromatography on through a short plug of celite. The organic layers were washed
silica gel (DCM/Methanol = 97/3). 1H NMR (400 MHz, CDCl3) δ with water, dried over sodium sulphate and concentrated in
8.91 (dd, J = 1.44, 6.4 Hz, 2H), 8.69 (d, J = 7.24 Hz, 2H), 8.31 (d, vacuo. The crude mixture was then purified by column
J = 7.84 Hz, 2H), 8.19 (d, J = 8.56 Hz, 2H), 7.84 – 7.80 (t, J = 7.74 chromatography to afford the desired products.
Hz, 2H), 7.73 – 7.69 (m, 1H), 7.55 (d, J = 8.56 Hz, 2H), 7.32 –
7.29 (m, 2H), 7.27 (s, 1H), 7.13 (d, J = 1.96 Hz, 1H), 4.69 – 4.65
6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C8OB00616D
Journal Name
ARTICLE
Tetrahedron Lett. 2017, 58, 445-448; c) F. Zhou, D.-S. Wang,
T. G. Driver, Adv. Synth. Catal. 2015, 357, 3463-3468; d) S.
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General Procedure for the Synthesis of N-alkyl-3-arylindoles
(25)
The aforementioned procedure was applied with o-
bromoaniline (1 mmol), 16 (0.04 mmol), TBAB (2.2 mmol),
anhydrous K2CO3 (2 mmol), TMS protected alkynes (2 mmol)
and 1,4-dioxane (2 mL) to yield the desired products in
excellent yields.
6
7
Y. Jia, J. Zhu, J. Org. Chem. 2006, 71, 7826-7834.
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Conclusions
In conclusion, topologically different Pd-NHCs appended with
naphthalimides have been synthesized, characterized and
evaluated for their catalytic activity. In addition, a unique
effect of the additive on the product selectivity was observed
for the Pd(II)-NHC catalyzed regioselective heteroannulation of
o-haloaniline and TMS protected acetylenes. Electronically and
sterically varied alkynes and o-haloanilines proved to be
competent and the reaction is readily scalable. Late-stage
derivatizations of both the silylated and the alkylated entities
were carried to demonstrate the synthetic applicability.
8
9
10 a) B. Lu, J. R. Falck, Angew. Chem. Int. Ed. 2008, 47, 7508-
7510; b) L. Zhang, Z. Hang, Z.-Q. Liu, Angew. Chem. Int. Ed.
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Conflicts of interest
11 a) W. A. Herrmann, Angew. Chem. Int. Ed. 2002, 41, 1290-
1309; b) M. N. Hopkinson, C. Richter, M. Schedler, F. Glorius,
Nature 2014, 510, 485-496; c) G. C. Fortman, S. P. Nolan,
Chem. Soc. Rev. 2011, 40, 5151-5169; d) C. J. O'Brien, E. A. B.
Kantchev, C. Valente, N. Hadei, G. A. Chass, A. Lough, A. C.
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There are no conflicts to declare.
Acknowledgements
The authors thank DST-SERB (EMR/2016/005461) and Seed
Grant, VIT University, Vellore for the financial support. P. K. R.
P sincerely thanks CSIR-SRF for the fellowship. We also thank
VIT-SIF for instrument facility. The authors thank Dr. C. M.
Nagaraja at IIT Ropar for the assistance in single-crystal XRD.
12 P. K. R. Panyam, T. Gandhi, Adv. Synth. Catal. 2017, 359
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DOI: 10.1039/C8OB00616D
Pd(II)-NHC catalyzed regioselective heteroannulation of o-haloanilines and arylethynyl-trimethylsilane to yield indoles and
additive controlled switchable product selectivity has been demonstrated.