Pd(0)-catalyzed regio- and stereoselective cyclization of alkynes: Selective synthesis of (E)-4-(isobenzofuran-1(3H)-ylidene)-1,2,3,4- tetrahydroisoquinolines and aze/oxepinoindoles

Article abstract of DOI:10.1039/c3ob42314j

Palladium-catalyzed highly regio- and stereoselective 6-exo-dig and 7-endo-dig cyclization of functionalized propargylic compounds has been developed for the synthesis of (E)-4-(isobenzofuran-1(3H)-ylidene)-1,2,3,4- tetrahydroisoquinolines and aze/oxepinoindoles.

Full text of DOI:10.1039/c3ob42314j

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Pd(0)-catalyzed regio- and stereoselective
cyclization of alkynes: selective synthesis of
(E)-4-(isobenzofuran-1(3H)-ylidene)-1,2,3,4-
tetrahydroisoquinolines and aze/oxepinoindoles†
Cite this: DOI: 10.1039/c3ob42314j
Received 20th November 2013,
Accepted 3rd December 2013
DOI: 10.1039/c3ob42314j
Avanashiappan Nandakumar, Selvarangam E. Kiruthika, Kanagaraj Naveen and
Paramasivan Thirumalai Perumal*
www.rsc.org/obc
Palladium-catalyzed highly regio- and stereoselective 6-exo-dig
and 7-endo-dig cyclization of functionalized propargylic compounds
has been developed for the synthesis of (E)-4-(isobenzofuran-1(3H)-
ylidene)-1,2,3,4-tetrahydroisoquinolines and aze/oxepinoindoles.
The carbon–carbon triple bond is one of the most important
functional groups in organic chemistry and has been widely
utilized in organic synthesis.1 During the past few decades,
palladium-catalyzed sequential reaction of functionalized
alkynes has emerged as a powerful tool for the construction of
a variety of heterocycles.2 In this regard, highly regio- and
stereoselective transformation of alkynes to tetrasubstituted
olefins utilizing palladium has generated more interest among
organic chemists due to their intriguing selectivity and toler-
ance towards many organic functional groups.3
Fig. 1 Biologically active indole fused seven member rings.
Scheme 1 Proposed scheme for the palladium-catalyzed synthesis of
heterocycles.
1,2,3,4-Tetrahydroisoquinolines (THIQ) and 1,3-dihydro-
isobenzofurans form an important class of heterocyclic
compounds as they are found in numerous alkaloids and bio-
logically active compounds.4,5 Furthermore, THIQ act as key
intermediates for the synthesis of an array of substances.6 In
general, tetrahydroisoquinolines have been constructed by
various methods like the Pictet–Spengler reaction,7 intramole-
cular Friedel–Crafts alkylation,8 transition metal catalyzed C–C
bond formation,9 etc.
The indole fused seven member ring core is a ubiquitous
structural motif found in biologically active compounds10 and
natural products such as subincanadine F10a and Paullone
derivatives,10c and recently, structurally related indolo-
benzazepin-7-ones also showed anti-tumor properties as
inhibitors of tubulin polymerization (Fig. 1).11 Their structural
importance in medicinal chemistry and drug discovery is
stimulating growing insights towards the synthesis of this
heterocyclic moiety.12 Most of the reported transformations
required the use of functionalized indole as the starting material
for the synthesis of indole fused to a seven membered ring.
Previously, we have developed the palladium-catalyzed
regio- and stereoselective protocol for the synthesis of hetero-
cyclic compounds using functionalized propargylic com-
pounds as building blocks.13 Herein we have made an attempt
to explore the palladium-catalyzed strategy for the synthesis of
(E)-4-(isobenzofuran-1(3H)-ylidene)-1,2,3,4 tetrahydroisoquino-
lines and aze/oxepinoindoles through 6-exo-dig and 7-endo-dig
cyclization of internal alkynes containing a proximate aryl
halide and nucleophiles (Scheme 1).
Results and discussion
Organic Chemistry Division, CSIR-Central Leather Research Institute, Adyar,
Chennai-600020, Tamil Nadu, India. E-mail: ptperumal@gmail.com;
The initial reaction was carried out with substrate 2a using
5 mol% Pd(PPh3)4 and 5 equiv. K2CO3 as a base in DMF at
100 °C (Table 1). The desired cyclization product 3a was
obtained in 66% yield within 3 h (Table 1, entry 1). The
choice of solvents such as dioxane, CH3CN, and toluene and
Fax: +91 44 24911589; Tel: +91 44 24437223
†Electronic supplementary information (ESI) available: Experimental section
and 1H and 13C NMR spectra of all compounds. CCDC 884176. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c3ob42314j
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Table 1 Optimization of the palladium-catalyzed cyclization reaction
Table 2 Synthesis
of
(E)-4-(isobenzofuran-1(3H)-ylidene)-1,2,3,4-
tetrahydroisoquinolinesa
Time Yielda,b
(min) (%)
Entry Catalyst (mol%)
Base
Solvent
DMF
1
2
3
4
5
6
7
8
9
Pd(PPh3)4(5)
Pd(PPh3)4(5)
Pd(PPh3)4(5)
Pd(PPh3)4(5)
Pd(PPh3)4(5)
Pd(PPh3)4(5)
Pd(PPh3)4(5)
K2CO3
K2CO3
K2CO3
K2CO3
NEt3
Cs2CO3 DMF
K3PO4
180
66
50
65
60
30
64
60
30
78
Dioxane 180
CH3CN 180
Toluene 180
DMF
180
180
180
180
45
DMF
DMF
DMF
Pd(OAc)2(5) + PPh3(10) K2CO3
Pd(PPh3)4(10) K2CO3
a The reactions were carried out with propargylamine 2a (0.3 mmol) in
the presence of a Pd source and a base (5 equiv.) at 100 °C under an
N2 atmosphere. b Isolated yields after column chromatography.
bases like NEt3, Cs2CO3 and K3PO4 did not improve the rate
and yield of the product formation (Table 1, entries 2–7). The
generation of in situ Pd(0) employing Pd(OAc)2 and PPh3 also
did not help in improving the reaction yield (Table 1, entry 8).
On increasing the catalyst amount from 5 mol% to 10 mol%,
the reaction rate was dramatically increased and the yield of
the product was also improved to 78% (Table 1, entry 9). Thus
the desired product 3a was obtained in 78% yield when the
reaction was carried out using 10 mol% of Pd(PPh3)4 and 5
equiv. of K2CO3 in DMF at 100 °C for 45 min.
a Isolated yields after column chromatography.
Table 2. The reaction is found to possess a broad substrate
scope as the yield and reaction rate did not depend on the
nature of the substrate. The presence of a substituent at
the benzylic position adjacent to alcohol had accountable
effects on the cyclization; primary alcohols underwent
cyclization significantly (Table 2, 3a–m) in terms of shorter
reaction times and higher yields than the secondary
alcohols (Table 2, 3o–q), which in turn reacted more efficiently
than their tertiary counterpart (Table 2, 3n). The propargylic
aromatic ring having methyl, methoxy, and chloro substituents
produced high yields of the tetrahydroisoquinoline derivatives
(Table 2, 3b–d, 3h and 3i). Fused aromatic rings incorporated
propargylic compounds (2e–g, 2j) were cyclized to give corres-
ponding compounds 3e–g and 3j (Table 2). Heterocycles such
as 2-thienyl- and 3-furyl-substituted propargyl compounds 2l
and 2m led to the desired products 3l and 3m in 75 and 76%
yields respectively (Table 2). Similarly, the benzyl alcohol con-
taining dimethoxy group 2r was converted to the corres-
ponding product 3r in moderate yield (Table 2).
Mechanistically, the formation of compound 3 consists of
the following steps. First, aryl bromide 2 undergoes oxidative
addition with Pd(0) leading to palladium–aryl bromide
complex A. Intramolecular coordination of complex A with
internal alkyne [(η-alkyne)organopalladium complex B] fol-
lowed by insertion of the alkyne results in the formation of
carbo-palladation complex C, which determines the ring size
of the product as six. Complex C undergoes an internal cross
coupling reaction with alcohol leading to the formation of a
six-membered palladium cycle and subsequent reductive elimi-
nation of palladium results in the formation of compound 3
with regeneration of the catalyst (Scheme 2).
The highly regio- and stereoselective formation of single
isomer 3a was confirmed using 1D and 2D NMR experiments.
1
In the H NMR spectrum, the singlet at δ 5.23 confirmed the
presence of a methine (–CH–) proton. Disappearance of two
acetylenic peaks in the 13C NMR spectrum confirmed the con-
version of the alkyne to a cyclized compound. On irradiating
the methine proton at δ 5.23, the aromatic protons at δ 7.02
showed an enhancement in the 1D nOe experiment and the
vice versa also provided the same result at δ 5.23. The protons
resonating at δ 7.02 in the 1H NMR spectrum correspond to
the ring C protons which was firmly established through
HMBC and HSQC experiments. Based on the nOe observation,
the aromatic ring C and methine proton are present on the
same side (3a) which ruled out the formation of six membered
Z-isomer 3a′ and seven membered ring 3a″ (Table 1). Thus,
this observation confirmed the formation of the six membered
E-isomer. Moreover the regio- and stereoselectivity of the
product formation is highly determined by the syn insertion of
palladium into the triple bond. The high resolution mass spec-
trum of compound 3a also showed a peak at 520.2457 which
corresponded to [M + H]+.
On the onset of optimized reaction conditions, we next
explored the substrate scope of the reaction by various substi-
tuted alkynes 2a–r and obtained the corresponding 1,2,3,4-
tetrahydroisoquinolines 3a–r in good yields as shown in
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Our initial study started with the reaction of 2-(3-(benzyl-
(2-bromo-4,5-dimethoxybenzyl)amino)prop-1-ynyl)aniline
4
(0.3 mmol) and 10 mol% Pd(PPh3)4 in the presence of K2CO3
in DMF at 100 °C under an N2 atmosphere (Table 3). The sub-
strate 4 remained unconsumed and was recovered completely
(Table 3, entry 1). A dramatic change was observed in the reac-
tivity of the aniline moiety when a strong electron withdrawing
group (CF3CO–) was introduced at the amino terminal. The
desired product 5a was obtained in 55% yield (Table 3, entry 2).
Most probably, the favourable effect of the trifluoroacetyl
group on the cyclization step may be due to its ability to stabi-
lize the anionic nitrogen nucleophile leading to the cyclization
adduct under mild basic conditions.15 Thus, the low yield of
the product prompted us to investigate other bases, solvents
and palladium conditions (Table 3, entries 3–9). The optimum
reaction conditions for the formation of 5a employ 1.0 equiv.
of 4a, 10 mol% of Pd(PPh3)4 and 5.0 equiv. of K2CO3 in CH3CN
at 100 °C under a N2 atmosphere to obtain the product in 62%
yield (Table 3, entry 7).
Having established the optimal reaction conditions for the
conversion of 4a, we synthesized analogues of azepinoindoles
(5a–d) and oxepinoindoles (5e–g) in moderate yields (Table 4).
Among the substrates explored, both the reaction rate and the
reaction yield were found to be higher with trifluoroacetanilide
containing the nitro moiety (5c and 5g). For all other substrates
bearing methyl, or chloro groups (5a–b, 5d–f), the reactions
were found to proceed moderately. The formation of com-
pounds (5a–f) was confirmed by 1H and 13C NMR experiments.
Further, the structure and optimized geometry of compound
5e were confirmed by X-ray single crystal analysis (Table 4).‡
A plausible mechanism for the formation of indole can be
accounted for as follows. The formation of compound 5 also
starts with oxidative addition of 4 with Pd(0) followed by
coordination with the alkyne to form (η-alkyne)organopalla-
dium complex F. Instead of insertion of the alkyne, complex F
undergoes an intramolecular nucleophilic attack by the
Scheme 2 Plausible mechanism for the formation of product
through 6-exo-dig cyclization.
3
As described in Scheme 1, the introduction of a proximate
nucleophile (–NH2) instead of –CH2OH in the substrate 2k
might lead to the formation of indole (4′) followed by 7-endo-
dig cyclization product 5a (Scheme 3). In the presence of a
proximate nucleophile (–NH2), carbopalladation complexes
appeared to be less effective than organopalladium complexes
in activating the carbon–carbon triple bond towards an intra-
molecular nucleophilic attack towards the formation of a
stable indole moiety.3i,14
Scheme 3 Proposed scheme for the synthesis of azepinoindole.
Table 3 Optimization of the synthesis of azepinoindole 5aa
Entry
R
Pd-catalyst (mol%)
Base
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
H (4)
Pd(PPh3)4(10)
Pd(PPh3)4(10)
Pd(PPh3)4(10)
Pd(PPh3)4(10)
Pd(PPh3)4(10)
Pd(PPh3)4(10)
K2CO3
K2CO3
Cs2CO3
NEt3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
Dioxane
Toluene
CH3CN
CH3CN
CH3CN
8
8
8
10
10
10
5
—
55
53
30
40
Trace
62
COCF3 (4a)
COCF3 (4a)
COCF3 (4a)
COCF3 (4a)
COCF3 (4a)
COCF3 (4a)
COCF3 (4a)
COCF3 (4a)
Pd(PPh3)4(10)
Pd2(dba)3(5) + DPPFb
Pd(OAc)2(10)/PPh3(20)
8
8
50
c
—
a The reactions were carried out with propargylamine 4a (0.3 mmol) in the presence of a Pd source and a base (5 equiv.) at 100 °C under an N2
atmosphere. b DPPF = 1,1′-bis(diphenylphosphino)ferrocene. c 5-endo-dig cyclization occurred.
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Table 4 Synthesis of aze/oxepinoindolesa
research fellowship. The authors thank the Department of
Chemistry, IITM, Chennai for single crystal XRD analysis.
Notes and references
‡Crystallographic data of compound 5e, CCDC 884176, C18H17NO3, M = 295.33,
orthorhombic, a = 9.3972(2), b = 16.1308(3), c = 19.6022(3) Å, U = 2971.39(10) Å3,
T = 298 K, space group P2(1)2(1)2(1), Z = 8, 14 312 reflections measured, 7154
unique (Rint = 0.0178) which were used in all calculations. The final wR(F2) was
0.0994.
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Scheme 4 Plausible mechanism for the formation of 5.
nitrogen atom across the carbon–carbon triple bond. Sub-
sequently, the resulting indolyl palladium intermediate G
affords the desired product 5 by a reductive elimination fol-
lowed by deacylation. A nucleophilic attack across the carbon–
carbon triple bond follows 5-endo-dig cyclization which deter-
mines the regioselectivity of the final product 5 (Scheme 4).
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Conclusion
In summary, we have studied the regioselectivity of substituted
propargylic compounds through palladium-catalyzed oxoaryla-
tion and aminoarylation reactions. The cascade reaction
resulted in the formation of highly selective (E)-4-(isobenzo-
furan-1(3H)-ylidene)-1,2,3,4-tetrahydroisoquinoline and aze/
oxepinoindole derivatives. This methodology serves as a new
platform for the synthesis of aze/oxepinoindoles from simple
starting materials in addition to the existing methods.
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