Palladium-catalyzed expedient Heck annulations in 1-bromo-1,5-dien-3-ols: Exceptional formation of fused bicycles

Article abstract of DOI:10.1016/j.tetlet.2019.02.043

An unprecedented Pd-catalyzed intramolecular Heck cyclization has been investigated on halogenated diene scaffolds undergoing various mode of cyclization and termination leading to the formation of structurally differing fused cyclopenta(e)none and aromatic analogue. The discrimination in the fate of palladium intermediates formed in situ undergoing Heck cyclization preferentially arises out of the difference in reaction temperature as well as substrate architecture. Sequential Heck reaction of 1-Bromo-5-methyl-1-aryl-hexa-1,5-dien-3-ol derivatives followed by oxidation or termination via sp² C–]H activation in aromatic ring led to the formation of fused cyclopentanes. However, the similar reaction at elevated temperature showed predominance towards the formation of aromatic analogues via one pot cyclization and dehydroxylation. The mechanism for the formation of cyclopentanone fused with cyclopropane ring system is supported by density functional theory based calculations.

Full text of DOI:10.1016/j.tetlet.2019.02.043

Accepted Manuscript
Palladium-catalyzed expedient Heck annulations in 1-bromo-1,5-dien-3-ols:
Exceptional formation of fused bicycles
Jayanta K. Ray, Raju Singha, Devalina Ray, Paramita Ray, Davuluri Yogeswara
Rao, Anakuthil Anoop
PII:
S0040-4039(19)30186-8
https://doi.org/10.1016/j.tetlet.2019.02.043
TETL 50637
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Accepted Date:
23 January 2019
22 February 2019
Please cite this article as: Ray, J.K., Singha, R., Ray, D., Ray, P., Rao, D.Y., Anoop, A., Palladium-catalyzed
expedient Heck annulations in 1-bromo-1,5-dien-3-ols: Exceptional formation of fused bicycles, Tetrahedron
Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.02.043
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Palladium catalyzed expedient Heck
annulations in 1-bromo-1,5-dien-3-ols:
Exceptional formation of fused bicycles
Leave this area blank for abstract info.
Jayanta K. Ray, Raju Singha, Devalina Ray, Paramita Ray, Davuluri Yogeswara Rao, Anakuthil Anoop
O
C-H
Pd (II) catalyzed
6-endo-dig
cyclization,
activation Pd (II) catalyzed
Br
5
-exo-trig
cyclization
Aromatization
Me
OH
Cyclo-
propanation
H
O

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Palladium-catalyzed expedient Heck annulations in 1-bromo-1,5-dien-3-ols:
Exceptional formation of fused bicycles
a,
b
c
a
a
Jayanta K. Ray  , Raju Singha and Devalina Ray , Paramita Ray , Davuluri Yogeswara Rao , Anakuthil
Anoop
a*
a
Department of chemistry, IIT Kharagpur, Kharagpur-721302, india
Panskura Banamali College, Panskura R.S.-721152, India
b
c
Amity Institute of Biotechnology, Amity University, Sector-125, Noida-201313, UP, India
—
——
ARTICLE INFO
ABSTRACT

Corresponding author. Tel.: +91-3222-283-326; fax: +91-3222-283-352; e-mail: jkray@chem.iitkgp.ernet.in
Article history:
Received
Received in revised form
Accepted
An unprecedented Pd-catalyzed intramolecular Heck cyclization has been investigated on
halogenated diene scaffolds undergoing various mode of cyclization and termination leading to
the formation of structurally differing fused cyclopenta(e)none and aromatic analogue. The
discrimination in the fate of palladium intermediates formed in situ undergoing heck cyclization
preferentially arises out of the difference in reaction temperature as well as substrate
architecture. Sequential heck reaction of 1-Bromo-5-methyl-1-aryl-hexa-1,5-dien-3-ol
Available online
2
derivatives followed by oxidation or termination via sp C-H activation in aromatic ring led to
the formation of fused cyclopentanes. However, the similar reaction at elevated temperature
showed predominance towards the formation of aromatic analogues via one pot cyclization and
dehydroxylation. The mechanism for the formation of cyclopentanone fused with cyclopropane
ring system is supported by density functional theory based calculations.
Keywords:
Palladium catalyst
Cascade Heck Reaction
C-H activation
DFT calculation
2
009 Elsevier Ltd. All rights reserved.
9
Palladium catalysts are bestowed with evolutionary capability
to construct carbon-carbon bonds for the synthesis of complex
framework from simple precursors.1 The cross-coupling of
hexa-1,5-dien-3-ol derivatives (Scheme 1a). In continuation with
the previous work, we were keen in further exploration of tandem
intra-molecular Heck reaction in condensed ring scaffold related
to acenaphthenene and deoxybenzoin derivatives (Scheme 1b).
unsaturated electrophilic substrates with
a
nucleophilic
counterpart using Pd-catalyzed Heck reaction is of fundamental
importance for the direct access to various natural products.1d, 1f, 5
Recently Shang and Fu delineated an irradiation-induced
intermolecular heck reaction of unactivated alkyl halides at room
Herein we present our relevant contribution towards an
unprecedented palladium-catalyzed annulation leading to diverse
mode of termination resulting in the formation of fused
cyclopentanone as well as aromatic analogues. The targeted
synthetic scaffold 1-(2-bromoacenaphthylene-1-yl)-3-methyl-but-
3
temperature. Liu and coworkers introduced a palladium-
catalyzed intramolecular 6-endo selective alkyl-heck reactions to
3
-en-1-ol (5), was subjected to Pd-catalyzed intramolecular Heck
4
access 5-Phenyl-1,2,3,6-tetrahydropyridine derivatives. The
reaction utilizing reaction conditions developed in our prior
reports.
generation of oligocyclic compounds via tandem cyclization of
suitably substituted polyenes/enynes using these catalysts has
been hallmarked as an important synthetic strategy in last two
Unlike the previous cases, here we ended up with a
cyclopropane ring fused with the carbocycle (6) involving a
series of transformations in a single pot. The amenable substrates
undergoes simultaneous intramolecular 5-exo-trig cyclization,
cyclopropanation with exclusive cis stereochemistry conferring
5,3 ring system followed by the oxidation of secondary alcohol
to ketone. The unique pathway for one pot synthesis of these
complexities involving multiple phenomenons is uncommon.
Interestingly, the reaction underwent different mode of
cyclization with variation in temperature (Scheme 2).
5
decades. Nemoto and coworkers established Pd-catalyzed
cascade cyclization by intramolecular Heck insertion of an
allene−allylic amination sequence to access 3,4-Fused Tricyclic
Indoles (Scheme 1a).6 However, formation of fused bicyclic
systems such as cyclopropane-cyclopentane rings through
palladium catalyzed Heck reaction have limited popularity due to
the ring strain associated with the product formation.7 In this
regard, Meijere and coworkers have advented an unprecedented
palladium catalyzed domino polycyclization of dienynes leading
to a new type of tetracyclic skeleton containing a cyclopropane
8
ring. In our antecedent studies, we have synthesized the
sesquiterpene natural product, β-cuparenone via palladium
catalyzed tandem Heck cyclization of 1-Bromo-5-methyl-1-aryl-

2
Tetrahedron
a) Previous work
Y
Y
n
n
Pd(dba)2
P(2-furyl)3
A plausible mechanistic interpretation for cascade annulation
has been outlined in Scheme 3. The Pd(0) catalyst obtained
through in situ reduction of Pd(II) in presence of PPh , undergoes
I
R2
R2
NHR1
K CO
3
N
R1
3
2
DMSO, 90 oC
oxidative addition into the substrate (5) to afford the intermediate
I. A dual possibility of cyclization for intermediate I via heck
reaction arise out of either 5-exo-trig or 6-endo-dig pathway. 5-
exo-trig cyclization of the intermediate (I) afforded the 5-
membered cyclic Pd-intermediate II which undergo
cyclopropanation via addition to the internal double bond
situated at ring junction furnishing intermediate III. The β-
elimination of intermediate (III) followed by keto-enol
tautomerization accounts for the formation of cyclopropane-
fused-cyclopentanone (6) as the final product
Nemoto and coworkers
R
Br
Br
Pd(OAc)2, PPh3
Pd(OAc)2, PPh3
O
OH
OH Na2CO3, DMF
o
Na CO3 or HCOONa
DMF, 80 C, 5h
2
o
80
C, 5h
Our work
Our work
R = CH3, H
b) Present Work
Cyclo-
propanation,
Table 1: Optimization studies for formation of products 6 and
Br
7a
Me
H
oxidation
O
Pd (II)
Pd (II)
Me
O
6
-endo-dig
5-exo-trig
cyclization
O
OH
Br
cyclization,
Pd(OAc) , PPh
2
3
H
Aromatization
OH
This work
+
C-H
This work
activation,
Na CO , DMF,
Ph
2
3
oxidation
heat
5
6
7
b
Sl. No.
Temp. (°C)
Yield(%)
6
Trace
35
7
1
2
3
4
5
6
7
60
0
Scheme 1: Synthetic approaches for Pd-catalyzed cascade
cyclization reactions
70
0
0
80
72
100
120
140
150
46
Trace
41
Br
CHO
O
OH
Pd(OAc)2, PPh3
Br
Br
Trace
00
H
68
Na2CO3, DMF,
80 C, 5h
In, DMF, NaI
r.t., 6h
o
00
63
4
aReaction condition:
5
6
Pd(OAc)2, PPh3
b
Isolated yield
Na2CO3, DMF,
o
140 C, 5h
Me
Pd(II)
PPh3
H
O
Br
6
Pd(0)
7
O
a
6
xid
d
OH
Scheme 2: Varied mode of cyclization
different temperature
under
d
a
it
tiv
e
io
HPdBr
n
PdBr

--hydride
From the crystal structure of the product (6, Scheme 2, CCDC
No: 1829095), it has been established that the cyclopropane is cis
to the hydrogen that is bonded to C(12). This synthetic method
opens up new avenue for one pot protocol to multifunctional
transformations.
O H
IV
elimination
OH
I
rig
t
-
o
H
-ex
5
6-endo-dig
PdBr
OH
OH
PdBr
III
H
The initial screening was started by carrying out the reaction
PdBr
of substrate 5 with Pd(OAc)
2
o
as catalyst, PPh
3
as ligand and
Na CO as base in DMF at 60 C which resulted in the formation
2 3
of product (6) in trace amount (Table 1). Increasing the
II
o
OH
V
temperature till 80 C enhanced yield of 6 to 72% as the sole
o
product. Further increase in temperature of the reaction to 100 C
-hydride
elimination
-Pd0)
HBr
-
led to declination in the yield of product 6 while 8-
methylfluoranthrene (7) started appearing as byproduct in trace
Me
o
-H2O
amount. Attempting the reaction at 140 C resulted in the
formation of 8-methylfluoranthene as the sole product in a
maximum yield of 68%. Further inclination in temperature
endured with declination in yield of product. The results are
shown in table 1.
H
OH VI
7

3
Scheme 3: Plausible mechanistic for the formation of 6 and 7.
An alternative approach for cyclization encompasses 6-endo-
dig cyclization of intermediate I resulting in the formation of 6-
membered Pd-intermediate V. β-hydride elimination of the
Scheme 5: Plausible mechanism for the formation of two
cyclopentane rings
The mechanism of the unexpected cyclopropanation was
analyzed with density functional calculations at B3LYP-D3-
intermediate
aromatization of the precursor leading to 8-methylfluoranthene
7) as the sole product. Thus, in both the cases, a sequential set of
V
followed by dehydroxylation leads to
10-14
BJ/def2-SVP//BP86-D3-BJ/def2-SVP
TURBOMOLE V 6.5
3
level of theory using
package. The intermediate II (Scheme
) has nearly T –shaped geometry at Pd(II) center, i. e., square
(
15,16
Pd-catalyzed transformations for 1-(2-bromoacenaphthylene-1-
yl)-3-methyl-but-3-en-1-ol (5) leads to the formation structurally
distinguished fused scaffolds.
planar geometry with three sites occupied by bromine, phosphine
and terminal carbon(C4) leaving an empty site. The usual β-
hydrogen elimination cannot procced from this intermediate due
to lack of β-hydrogens. Hence the double bond(C1-C2) in the
ring junction of complex (II) gets coordinated to the vacant site
in II to form the intermediate complex (coord_II). The
coordination requires an activation energy 12.10 kcal/mol and is
exergonic by -1.42 kcal/mol. The transition state for the
cyclopropanation from intermediate (coord_II) was identified,
and the activation free energy was found to be 6.89 kcal/mol. The
intermediate (III) with a fused cyclopropane ring is shown in
Figure 2. The cyclopropane and Pd(II) are in the same side of the
five-membered ring.
The scope of cyclization was extended further by employing
the reaction conditions on (Z)-1-bromo-5-methyl-1,2-
diphenylhexa-1,5-dien-3-ol (8), a structural analogue to 1-(2-
bromoacenaphthylene-1-yl)-3-methyl-but-3-en-1-ol (5). The
result juxtaposes formation of prior products and encounter
establishment of alternative mode of termination for the cyclized
intermediate (Scheme 4). Therefore, the Pd-catalyzed cyclization
of 8 ended up in the formation of 8a-methyl-3-phenyl-8,8a-
dihydrocyclopenta[a]inden-2(1H)-one (9) as the only product in
6
7% yield. Notably, no side product was observed on changing
the temperature unlike previous cases.
O
HO
Br
Pd(OAc)2, PPh3
Na2CO3, DMF
o
8
0 C, 5h
9
8
Scheme 4: Intramolecular Heck reaction in deoxybenzoin
system
A related mechanism for the simultaneous formation of fused
five membered rings in product 9 has been described in scheme
. The in situ generated Pd(0) undergoes oxidative addition via
5
migratory insertion into C-Br bond of substrate 8 to form
intermediate VII. The intramolecular Heck cyclization with the
C=C double bond via 5-exo-trig pathway constructs the Pd-
intermediate containing cyclopentane ring VIII. Subsequent
2
ortho Csp -H bond activation of phenyl ring accessible to PdBr
Figure 2: Reaction profile for the cyclopropanation step (Scheme 5).
The energies are in kcal/mol from B3LYP-D3-BJ/def2-SVP//BP86-
D3-BJ/def2-SVP level of theory. The optimized geometries are
shown.
results in the intermediate IX. Reductive elimination of Pd(II)
intermediate (IX) generated the fused cyclopentane rings 9a via
the regeneration of Pd(0). The compound 9a undergoes Pd-
initiated oxidation of alcohol (9a) to ketone (9) as final product.
We have successfully elucidated the palladium catalyzed
cascade cyclization in halogenated diene system for the
formation of structurally discriminated unusual scaffolds. The
variation of temperature in the reaction affected the mode of
cyclization leading to the competitive predominance for fused
cyclopentane-cyclopropane rings or aromatic analogue.
Interestingly, the structural difference in substrate led to the
variation in mode of termination ensuring the liberation of fused
bicyclopentane rings as product under Pd-catalyzed reaction
conditions. The formation of cyclopropane fused cyclopentane,
was further justified using density functional theory based
calculations.
O
Ph
9
OH
9
a
Ph
PdPPh3
PPh3
Pd(II)
Ph
OH
8
Reductive
Elimination
Oxidative Addition
Ph3P
Pd
Ph3P Br
Pd
ACKNOWLEDGMENT
Ph
We would like to thank Department of Science and
Technology, New Delhi, India and Council of Scientific and
Industrial Research, New Delhi, India for the financial support.
DYR thanks the University Grants Commission (UGC) for the
fellowship.
OH VII
Ph
IX
OH
Ph3P
H
Br
C
-
Pd
H
A
cti
v
a
tio
n
Ph
OH
VIII

4
Tetrahedron
Notes and references
8. Meyer, F. E.; Parsons, P. J.; Meijere, A. J. Org.
Chem. 1991,56, 6488.
1
.
(a) Yamamoto, Y. Chem. Soc. Rev., 2014, 43, 1575;
b) Wu, X. F.; Neumann, H.; Beller, M. Chem. Soc.
(
9. Ray, D.; Ray, J. K. Org. Lett., 2007, 9, 191.
Rev., 2011, 40, 4986.; (c) Nicolaou, K. C.; Bulger, P.
G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442;
1
0. Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B:
Condens. Matter Mater. Phys., 1988, 37, 785.
(d) Nandi, S.; Singha, R.; Samanta, S.; Ray, J. K.
Tetrahedron Lett. , 2012, 53, 2659; (e) Singha, R.;
Roy, S.; Nandi, S.; Ray, P.; Ray, J. K. Tetrahedron
Lett. 2013, 54, 657; (f) Nandi, S.; Singha, R.; Ray, J.
K. Tetrahedron, 2015, 71, 669; (g) Ghosh, M.; Ray,
J.K. Tetrahedron 2017,73, 3731.
11. Grimme, S.; Ehrlich, S.; Goerigk, L. J. Comput.
Chem., 2011, 32, 1456.
1
1
1
1
2. Dieter, K. M.; Stewart, J. J. P. J. Mol. Struct., 1988,
63, 143.
1
3. Schaefer, H. Horn; Ahlrichs, R. J. Chem. Phys.,
992, 97, 2571.
2
3
4
.
.
.
Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew.
Chem. Int. Ed. 2005, 44, 4442.
1
4. (a) Becke, A. D. Phys. Rev. A., 1988, 38, 3098. (a)
Perdew, J. P. Phys. Rev. B., 1986, 34, 7406.
Wang, G. –Z.; Shang, R.; Cheng, W. –M.; Fu, Y. J.
Am. Chem. Soc. 2017, 139, 18307−18312.
5. TURBOMOLE V6.5, a development of University
of Karlsruhe and Forschungzentrum Karlsruhe
GmbH, 19892007, TURBOMOLE GmbH since
X. Dong, Y. Han, F. Yan, Q. Liu, P. Wang, K. Chen,
Y. Li, Z. Zhao, Y. Dong and H. Liu, Org. Lett., 2016,
1
8, 3774–3777.
2
007.
5
.
(a) Zhang, Y.; Negishi, E. I. J. Am. Chem. Soc. 1989,
1
6. Ahlrichs, R.; Br, M.; Hser, M.; Horn, H.; Khmel, C.
1
11, 3454. (b) Grigg, R.; Dorrity, M. J.; Malone, J.
Chem. Phys. Lett., 1989, 162, 165.
F.; Sridharan, V.; Sukirthalingam, S. Tetrahedron
Lett. 1990, 31, 1343. (c) Wu, G.; Lamaty, F.;
Negiehi, E. I. J. Org. Chem. 1989, 54, 2507; (d)
Trost, B. M.; Lee, D. C. J. Am. Chem. Soc. 1988,
1
10, 7255; (e) Karstens, W. F. J.; Stol, M.; Rutjes, F.
Supplementary Material
P. J. T.; Kooijman, H.; Spek A. L.; Hiemstra, H. J.
Organomet. Chem. 2001, 624, 244; (f) Paul, S.;
Samanta, S.; Ray, J. K. Tetrahedron Lett. 2010, 51,
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
5
604; (g) Samanta, S.; Mohapatra, H.; Jana, R.; Ray,
J. K. Tetrahedron Lett. 2008, 49, 7153.
6
7
.
.
Nakano, S.; Inoue, N.; Hamada, Y.; Nemoto, T. Org.
Lett. 2015, 17, 2622.
(a) Grigg, R.; Sridharan, V. Tetrahedron Lett. 1992,
3
3, 7965; (b) Grigg, R.; Redpath, J.; Sridharan, V.;
Click here to remove instruction text...
Wilson, D. Tetrahedron Lett. 1994, 35, 7661; (c)
Zhang, Y.; Negeshi, E. I. J. Am. Chem. Soc. 1989,
1
11, 3454.


Various mode of cyclization
Formation of structurally differing fused
cyclopenta(e)none

The discrimination in the fate of palladium
intermediates formed in situ undergoing
heck cyclization preferentially arises out of
the difference in reaction temperature as
well as substrate architecture.

Sequential heck reaction of 1-Bromo-5-
methyl-1-aryl-hexa-1,5-dien-3-ol
derivatives followed by oxidation or
2
termination via sp C-H activation in
aromatic ring led to the formation of fused
cyclopentanes.
Highlights

The mechanism for the formation of
cyclopentanone fused with cyclopropane

An unprecedented Pd-catalyzed
intramolecular Heck cyclization

5
ring system is supported by density
functional theory based calculations.