Palladium catalyzed N-H bond insertion and intramolecular cyclization cascade: The divergent synthesis of heterocyclics

Article abstract of DOI:10.1039/c4ob00001c

The palladium catalyzed carbenoid based N-H insertion and electronic effect controlled 5-exo-trig or 6-endo-trig mode Heck cyclization in one-pot has been realized for ortho-iodoanilines, in which PdCl₂ was used as the single palladium resource

Full text of DOI:10.1039/c4ob00001c

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Palladium catalyzed N–H bond insertion and
intramolecular cyclization cascade: the divergent
synthesis of heterocyclics†
Cite this: Org. Biomol. Chem., 2014,
12, 2533
Received 1st January 2014,
Accepted 21st February 2014
Dong Ding,a Gang Liu,a Guangyang Xu,a Jian Li,a Guoping Wangb and
Jiangtao Sun*a
DOI: 10.1039/c4ob00001c
www.rsc.org/obc
The palladium catalyzed carbenoid based N–H insertion and elec-
tronic effect controlled 5-exo-trig or 6-endo-trig mode Heck
cyclization in one-pot has been realized for ortho-iodoanilines, in
which PdCl2 was used as the single palladium resource. The
corresponding indoles and quinolines were obtained respectively.
However, for ortho-triflateanilines, base promoted cyclization is
preferred and the lactones were obtained.
Increased focus has been placed on the development of
different types of organic transformations in one pot, which
allows rapid construction of highly functionalized molecules
with a multiple catalytic system.1 Undoubtedly, this atom econ-
omic approach is time and cost saving. In view of the ability to
be converted easily between different oxidation states, palla-
dium complexes could be selected as good candidates to cata-
lyze different reactions in one pot.2 Inspired by this strategy
and our own investigations on carbenoid chemistry of diazo
compounds,3 we envisioned that the combination of palla-
dium catalyzed N–H insertion and Heck cyclization in one pot
would facilitate the development of novel methodologies.
In another part, palladium catalyzed C–C bond formations
from diazo compounds have received considerable attention
during the past decade;4 in contrast to rhodium, copper and
other metal complexes,5 the application of palladium catalysts
in N–H insertion remains relatively unexplored.6 Recently, we
reported the first palladium-catalyzed stereoselective N–H
insertion from diazo substrates to prepare chiral α-amino
esters.3a Just recently, Feng and co-workers described the
highly enantioselective N–H insertion catalyzed by a palladium
and chiral guanidine catalytic system.7 In early 2013, Liang
Scheme 1 Pd-catalyzed one-pot synthesis of heterocyclics.
and co-workers reported
a palladium catalyzed reaction
between vinyldiazoacetates and N-substituted-ortho-iodo-
anilines, in which Pd(0)-catalyzed C–C bond formation was
postulated as the first step (Scheme 1).8 During our investi-
gation on the utilization of similar substrates to Liang’s report,
we imagined that the C–N bond could have formed firstly
rather than the C–C bond in the presence of Pd(II) complexes
under specific reaction conditions. Moreover, the insertion
products are potential substrates for Heck cyclization. So, fol-
lowed by Pd(0)-catalyzed intramolecular Heck cyclization, ring-
closing would take place logically. In view of the fact that these
two independent reactions could be catalyzed by different
palladium species, it is reasonable to postulate that the two
different transformations could be completed in one pot just
by controlling the oxidation of palladium (Scheme 1). In this
communication, we wish to present the utilization of arylvinyl
aSchool of Pharmaceutical Engineering & Life Science, Changzhou University,
Changzhou 213164, P. R. China. E-mail: jtsun08@gmail.com;
Fax: +86 519 86334598; Tel: +86 519 86334597
bSchool of Petroleum Engineering, Changzhou University, Changzhou 213164,
P. R. China
†Electronic supplementary information (ESI) available: Details of experiment
procedures, NMR and HRMS data for new compounds. CCDC 944907 for 10p.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ob00001c
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Table 1 Optimization of the reaction conditionsa
Table 2 Substrate scopea,b,c
Entry
Pd complexes
Solventb
5ac (yield%)
6ac (yield%)
1
2
3
4
5
6
7
8
PdCl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMSO
DCE
74
—
32
45
12
—
13
54
16
40
0
—
0
0
0
—
0
0
<5%
0
Pd(PPh3)4
Pd(OAc)2
Pd2(dba)3
Pd(TFA)2
Pd(dppf)Cl2
PdCl2
PdCl2
PdCl2
PdCl2
9
DMF
CH2Cl2
10d
a All reactions were carried out with 1a (0.52 mmol), 3a (0.5 mmol),
PdCl2 (5 mol%), and solvent (2 mL) at r.t. for 3 hours unless otherwise
noted; then PPh3 (0.05 mmol, 10 mol%), NaHCO3 (0.75 mmol) and
DMF (2 mL) were added and the mixture was continued to be stirred at
80 °C for 2 hours. b Solvents were examined for the N–H insertion step.
c Isolated yields. d The reaction temperature is 40 °C; DCE = 1,2-
dichloroethane, DMF = N,N-dimethylformamide, DMSO = dimethyl
sulfoxide.
a All reactions were carried out with 1 (0.52 mmol), 3a (0.5 mmol),
PdCl2 (5 mol%), and CH2Cl2 (2 mL) at r.t. for 3 hours; then PPh3
(0.05 mmol, 10 mol%), NaHCO3 (0.75 mmol) and DMF (2 mL) were
added and the mixture was continued to be stirred at 80 °C for
2 hours. b The ratios were determined by 1H-NMR analysis of crude
products. c Isolated yields of the major products.
diazoacetates and ortho-iodo/triflate-anilines to construct three
different types of heterocyclics. It is noteworthy that different
from Liang’s procedure, our investigation featured the Pd-cata-
lyzed C–N bond rather than C–C bond formation as the first
step. Moreover, the N-nonsubstituted iodoanilines work well in
our approach but are totally inert in Liang’s procedure.8
following Heck cyclization step, the 5-exo-trig and 6-endo-trig
modes of annulations are both favored to afford the corres-
ponding five or six member ring-closing products (Scheme 1).9
However, for the reaction of 1a and 3a, the 6-endo-trig ring-
closing product (6a) was not observed and the indole (5a) was
isolated as the single isomer.
With the optimized reaction conditions in hand, we next
investigated the reaction of different substituted anilines with
3a (Table 2). As observed, for the electron-donating and weak
electron-withdrawing substituted ortho-iodoanilines, the 5-exo-
trig annulation was preferred and the indoles were obtained
as the major products (Table 2, from 5a to 5j). However,
the anilines bearing strong electron-withdrawing groups (such
as NO2 and CN) afforded quinolines as the major isomers
(Table 2, 6l and 6m) in which the 6-endo-trig annulation
was the prior ring-closing mode. However, the carboxylate
substituted aniline rendered the indole as the major product
(Table 2, 5k), probably owing to the relatively weaker electron-
Our investigation started from the reaction of aniline (1a)
with phenylvinyldiazoacetate (3a) in the presence of different
palladium complexes. Upon optimizing the reaction para-
meters aiming at getting high selectivity, the best result was
obtained when the reaction was performed with PdCl2 (5 mol%)
in dichloromethane at room temperature for 3 hours fol-
lowed by Heck reaction (PPh3 and NaHCO3 in DMF). The
indole (5a) was obtained in 74% isolated yield in two steps
(Table 1, entry 1). For the palladium complexes examined,
Pd(PPh3)4 and Pd(dppf)Cl2 were totally inert to the process,
which meant that these two catalysts cannot initiate the first
insertion step (Table 1, entries 2 and 6). This phenomenon
was consistent with our former report that the presence of
phosphorus ligands was detrimental to the palladium-cata-
lyzed N–H insertion.3a Other palladium complexes gave low
yields in the one-pot procedure too. High temperature resulted
in a decreased yield (Table 1, entry 10). Generally, for the
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Table 3 Substrate scopea,b,c
Scheme 2 Control experiments. Reaction conditions: route A: (i) PdCl2
(5 mol%), CH2Cl2, r.t. for 3 hours and then PPh3 (10 mol%), NaHCO3 (1.5
eq.), DMF, 80 °C, 2 hours. Route B: (i) PdCl2 (5 mol%), and CH2Cl2, r.t. for
3 hours and then NaHCO3 (1.5 eq.), DMF, 80 °C, 2 hours. Route C: (i)
PdCl2 (5 mol%), and CH2Cl2, r.t. for 3 hours. (ii) NaHCO3 (1.5 eq.), DMF,
80 °C, 2 hours.
Fig. 1 X-ray crystal structure of 10p.
Further investigation on the use of ortho-triflateanilines
in this reaction revealed a different ring-closing mode with
ortho-iodoanilines. Surprisingly, the annulations did not
proceed via the Heck cyclization. The NMR analysis of the
final product of the reaction between 2a and 3a gave different
spectra to indole and quinoline. In contrast, the lactone (10a)
was isolated as a unique product in 71% yield (Scheme 2,
route A). Moreover, the structure of the lactone was further
confirmed by X-ray crystallographic analysis of 10p (Fig. 1).
The formation of the lactone rather than indole or quino-
line for the triflateaniline (2a) indicated that the annulation
did not proceed via Pd-catalyzed Heck reaction. To further
understand this reaction process, we only added NaHCO3 to
the reaction mixture during the second step in the absence of
triphenylphosphine (Scheme 2, route B). As expected, only the
lactone was obtained. Furthermore, the N–H insertion inter-
mediate 9a has been separated in pure form and treated with
NaHCO3 directly (Scheme 2, route C), and 10a was obtained
cleanly. The controlled experiments disclosed that the base-
promoted annulation was superior to the Heck cyclization
even under the Heck reaction conditions when triflateanilines
were utilized in the one-pot procedure.
a Same reaction conditions with Table 2. b The ratios were the major
isomer to the minor one, which were determined by 1H-NMR analysis
of crude products. c Isolated yields of the major products.
withdrawing ability of the carboxylate group compared with
nitro and cyano groups.
Next, the substrate scope of the one-pot reaction has been
further investigated (Table 3). Similar to the above ob-
servations, for iodoanilines bearing the electron-donating or
weak electron-withdrawing substitutes, the indoles were
obtained as the major products (Table 3, 7a to 7m). For the
strong electron-withdrawing nitro-substituted anilines, the qui-
nolines were isolated as the major isomers in high yields
(Table 3, 8e to 8g). However, the carboxylate substituted iodo-
aniline afforded the indole and quinoline nearly in a 1 : 1 ratio
when reacted with meta-chloro-phenyldiazoacetate (Table 3,
7o/8a), which indicated that the 5-exo-trig and 6-endo-trig
annulations had equal opportunity in the ring-closing
process. The same phenomenon was observed for the reaction
between para-cyano-iodoaniline and para-methyl-phenyldi-
azoacetate (Table 3, 7p/8b). The above experiments disclosed
the fact that the 5-exo-trig and 6-endo-trig annulations were
affected by both the diazo compounds and the anilines.
With the standard reaction conditions in hand, the influ-
ence of substitutes of the two substrates had been investigated
(Table 4). Generally, the reaction proceeded smoothly to
deliver the lactones in moderate to high yields. The electron-
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Table 4 One-pot reaction of 2 and 3a,b
Notes and references
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In summary, the palladium-catalyzed one-pot process of
N–H insertion followed by electronic effect controlled Heck
cyclization between ortho-iodoanilines and vinyldiazoacetates
has been realized. For the iodoanilines, the corresponding
indoles and quinolines were obtained respectively through
5-exo-trig or 6-endo-trig ring-closing mode. For the triflate-
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base promoted annulation rather than Heck cyclization. As
a result, three different heterocyclics were obtained respecti-
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insertion into other X–H bonds are ongoing, as well as further
investigation into the reaction mechanism and synthetic
applications.
We gratefully acknowledge the National Natural Science
Foundation of China (21172023), a project funded by the
Priority Academic Program Development of Jiangsu Higher
Education Institutions (PAPD) and the Science & Technology
Agency of Jiangsu Province (BY2012096) for their financial
support.
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