Construction of a tetracyclic butterfly-like scaffold: Palladium-catalyzed heck/arylation cascade

Article abstract of DOI:10.1002/chem.200903029

Controlled carbopalladation: Only slight changes in the starting material (see scheme) resulted in rather different compounds in palladium-catalyzed domino reactions. A novel tetracyclic butterfly-like scaffold was constructed in a one-pot reaction via the Pd-catalyzed 5-exo-trig carbopalladation and arylation cascade in high yield.

Full text of DOI:10.1002/chem.200903029

COMMUNICATION
DOI: 10.1002/chem.200903029
Construction of a Tetracyclic Butterfly-Like Scaffold:
Palladium-Catalyzed Heck/Arylation Cascade
Ko Hoon Kim, Hyun Seung Lee, Sung Hwan Kim, Se Hee Kim, and Jae Nyoung Kim*[a]
Palladium-catalyzed domino reactions coupled with care-
fully designed substrates allow for rapid establishment of
Transcriptase Inhibitors) including nevirapine;[6] derivatives
of this class could be developed as a new candidate for the
treatment of HIV-1 (Scheme 1).
complex molecules.[1–3] In particular, tandem carbon carbon
À
bond formations through a palladium-catalyzed Heck/aryla-
tion cascade are important in that complex molecules can
be directly constructed in a single operation.[3a–e] Inter- or
intra-Heck reactions are the origin of a variety of domino
reactions in which the key common feature is the formation,
after the carbopalladation step, of a s-alkylpalladium(II) in-
termediate lacking a suitable b-hydrogen syn with respect to
the palladium center.[2,3] The s-alkylpalladium(II) intermedi-
ate undergoes various cascade processes such as another
[3f,h]
Heck reaction,[3g] alkyl C H activation,
and aryl C H ac-
À
À
tivation.[3a–e] As an example of intramolecular Heck/aryla-
tion cascade, Grigg and co-workers reported that an aryl
Scheme 1. Synthetic rationale of tetracyclic indenoACTHNUTRGNE[NUG 2,1-a]indane.
À
halide bearing a carbon carbon multiple bond and an addi-
tional aryl group undergoes a bis-cyclization when treated
with a palladium(0) catalyst.[3b] Although tremendous efforts
have been invested in the Pd-catalyzed domino reactions,
there remains limited overlap between two key transforma-
tions, intramolecular Heck reaction and arylation.[3a–e]
In this context, we prepared g-hydroxy ester 1a by the
indium-mediated Barbier reaction of 2-bromobenzaldehyde
with the bromide of Baylis–Hillman adduct[7] in 90%.[4,8]
The syn-isomer of 1a was formed exclusively as reported.[4,8]
With compound 1a, we examined a Pd-catalyzed cyclization
reaction under various conditions as shown in Scheme 2.
When we used Na2CO3 or Cs2CO3 as a base, g-hydroxybute-
nolide 2 was isolated as the major product (56–58%), as in
our previous paper.[4]
Recently, we reported the synthesis of g-hydroxybuteno-
lides from g-hydroxy ester which was prepared from the
Baylis–Hillman adducts via an indium-mediated Barbier re-
action.[4] We established that this g-hydroxy ester could be
used as an excellent substrate for the construction of
indenoACHTUNGTRENNUNG
[2,1-a]indane scaffold[5] when the aryl moiety has an
ortho-Br substituent via the Pd0-catalyzed Heck (carbopalla-
Fortunately we isolated three interesting compounds 3a,
À
dation)/aryl C H activation cascade (Scheme 1). We also
4, and 5a using PdACTHUNGTERN(NUG OAc)2/PPh3/HCOONa in DMF. The
plausible mechanisms for the formation of these compounds
imagined that the conformation of indeno
A
À
fold would resemble the butterfly-like conformation which
is essential to many NNRTIs (Non-Nucleosides Reverse
are shown in Scheme 2. An oxidative addition of C Br
bond to Pd0 and 5-exo-carbopalladation afforded one
common intermediate 6, which underwent three different
À
pathways. Compound 3a was formed via the aryl C H acti-
[a] K. H. Kim, H. S. Lee, S. H. Kim, S. H. Kim, Prof. J. N. Kim
Department of Chemistry and Institute of Basic Science
Chonnam National University, Gwangju 500-757 (Republic of Korea)
Fax : (+62)530-3389
vation cascade, compound 4 via the reductive quenching,
and compound 5a via d-carbon elimination/decarboxylation
cascade as in our previous paper.[9] The yield of 3a was un-
satisfactory although 5-exo-carbopalladation was the major
cyclization mode.[10] In addition, separation of 3a and 4 was
somewhat tedious (see Supporting Information).
E-mail: kimjn@chonnam.ac.kr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903029.
Chem. Eur. J. 2010, 16, 2375 – 2380
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2375

clic acetate 3a-OAc (33%) and naphthalene 11a (49%).
The d-carbon elimination/decarboxylation product 5a-OAc
was not observed at all, and dihydronaphthalene was con-
verted to 11a completely. Although the exo/endo selectivity
(33:49) was similar to that of the condition A (32:37), the
amount of tetracyclic acetate 3a-OAc was increased to
33%. As a next, temperature dependence on the exo/endo
ratio was examined and the results are summarized in
Table 1. At lower temperature or at the early stage of the
reaction dihydronaphthalene 10a-OAc was isolated (en-
tries 1 and 3); however, the exo/endo ratio hardly changed.
Table 1. Temperature effect in the Pd-catalyzed reaction of 1a-OAc.[a]
Entry Conditions
3a-OAc [%] 10a-OAc [%] 11a [%] Ratio[b]
1
2
3
4
808C, 36 h
1108C, 2 h
1108C, 40 min 37
1508C, 2 h 35
28
33
5
0
46
0
45
49
8
0.36
0.40
0.41
0.52
Scheme 2. Pd-catalyzed cascade reaction of 1a. a) Pd
PPh3 (10 mol%), Na2CO3 (1.5 equiv), DMF, 808C, 4 h. b) Pd
(5 mol%), PPh3 (10 mol%), Cs2CO3 (1.5 equiv), DMF, 1008C, 2 h. c) Pd-
(OAc)2 (10 mol%), PPh3 (20 mol%), HCOONa (1.0 equiv), DMF,
1108C, 3 h.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
32
[a] PdACTHUNGTRNEUNG(OAc)2 (10 mol%), PPh3 (20 mol%), Cs2CO3 (2.0 equiv), DMF.
[b] Ratio means the proportion of product(s) formed via exo-carbopalla-
dation.
ACHTUNGTRENNUNG
Thus, we decided to protect the hydroxyl group of 1a as
an acetate to obtain compound 1a-OAc (90%) in order to
avoid unwanted lactonization and examine the Pd-catalyzed
reactions more freely under different reaction conditions. At
first, we examined the reaction of 1a-OAc under the influ-
ence of HCOONa/DMF (condition A in Scheme 3) and ob-
The stereochemistry between OAc and a b-hydrogen
atom in 10a-OAc is cis, and a base-mediated E2 elimination
mechanism has to be ruled out.[11] However, the elimination
of AcOH from 10a-OAc to 11a was completed within 1 h at
1108C in the presence of both a palladium catalyst and
Cs2CO3, as shown in Table 2 (entry 1). The reaction showed
Table 2. Aromatization of 10-OAc to 11a by syn-elimination of AcOH.
Entry Conditions
10a-OAc [%] 11a [%]
1
Pd
(OAc)2 (10 mol%), PPh3 (20 mol%)
0
91
Cs2CO3 (1.0 equiv), DMF, 1108C, 1 h
Cs2CO3 (1.0 equiv), DMF, 1108C, 1 h
Cs2CO3 (1.0 equiv), DMF, 1108C, 12 h
DMF, reflux, 24 h
2
3
4
64
0
4
30
88
86
Scheme 3. Pd-catalyzed reaction of 1a-OAc. a) Pd
PPh3 (20 mol%), HCOONa (2.0 equiv), DMF, 1108C, 3 h. b) Pd
(10 mol%), PPh3 (20 mol%), Cs2CO3 (2.0 equiv), DMF, 1108C, 2 h.
ACHTUNGTRENNUNG
sluggish reactivity without a palladium catalyst under the
same conditions (entry 2) and a long time was required for
the completion (entry 3). Without a base, elimination re-
quired 24 h for completion even at the refluxing tempera-
ture of DMF (entry 4). The results indicate that the combi-
nation of a base and a palladium catalyst has a significant
beneficial effect for the syn-elimination of AcOH. We also
proposed the possibility for the involvement of a p-benzyl-
palladium complex;[12] however, it was not clear whether a
mechanism involving the formation of p-benzylpalladium
complex and a subsequent syn b-H elimination process oc-
curred or not. For the effect of a base, deprotonation of the
acetyl hydrogen make the energy of dihydronaphthalene
high and subsequently make the elimination more facile as
in the anionic oxy-Cope rearrangement;[13] however, the
reason is also not clear at this moment.[14]
AHCTUNGTRENNUNG
tained four compounds 3a-OAc (15%), 5a-OAc (17%),
10a-OAc (34%), and 11a (3%). The formations of 3a-OAc
and 5a-OAc were the results of a 5-exo-carbopalladation,
while dihydronaphthalene 10a-OAc and naphthalene 11a
were formed via the 6-endo carbopalladation. Interestingly,
the results of 1a and 1a-OAc were quite different under the
same conditions involving the use of HCOONa (compare
Schemes 2 and 3). In the reaction of alcohol 1a, 5-exo-car-
bopalladation occurred exclusively to produce 3a, 4, and 5a
as the major products (Scheme 2), while the reaction of 1a-
OAc showed severe competition between 5-exo (32%, 3a-
OAc/5a-OAc) and 6-endo (37%, 10a-OAc/11a) carbopalla-
dations (Scheme 3). The reaction of 1a-OAc under the influ-
ence of Cs2CO3 (condition B in Scheme 3) produced tetracy-
Although marginal success was obtained with 1a-OAc,
the yield of tetracyclic compound 3a-OAc (33%) was still
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Palladium-Catalyzed Heck/Arylation Cascade
COMMUNICATION
unsatisfactory (Scheme 3 and entry 2 in Table 1). The com-
petition between 5-exo/6-endo carbopalladations could be
controlled by the change of either the conformation of start-
ing materials or reaction conditions.[2c,10] We reasoned out
that 5-exo mode could be increased if we increase steric hin-
drance around the hydroxyl group. Thus, we decided to ex-
amine the exo/endo selectivity with three representative
compounds, ethyl ester 1b-OAc, benzoate 1a-OBz, and silyl
derivative 1a-OTBS, with the expectation that the change of
the size of the substituents could alter the conformation of
the substrates and will affect on the ratio of exo/endo carbo-
palladations. The results carried out under Cs2CO3 condi-
tions are shown in Table 3 (entries 1–3). The reaction of
ethyl ester (entry 1) and benzoate (entry 2) did not alter the
ratio (0.41–0.53). However, tetracyclic compound 3a-OTBS
was isolated in 89% when we used 1a-OTBS (entry 3)
along with methylene indane 5a-OTBS (3%). The two
products 3a-OTBS and 5a-OTBS are the results of 5-exo
carbopalladation. Although trace amounts of naphthalene
and the corresponding dihydronaphthalene were observed
on TLC (<5%) we could not isolate them in appreciable
amounts. Based on the combined yields of 3a-OTBS and
5a-OTBS, the exo/endo selectivity reached 0.92, at last.
Other three OTBS derivatives 1c-OTBS, 1d-OTBS, and 1e-
OTBS (entries 4–6) showed the same reasonable exo/endo
selectivity (>0.91) to produce tetracyclic compounds as the
major products (86–88%).
As a next experiment, we examined the reactions of four
1 f derivatives which were prepared from the Baylis–Hill-
man adduct of acrylonitrile as shown in Scheme 4. During
the In-mediated Barbier reaction, b-hydroxy nitrile 1 f was
formed as a syn/anti mixture (1:2). After separation of syn
and anti isomers in pure forms, protection of the alcohol
group to their acetates and TBS derivatives in high yields,
and we examined the Pd-catalyzed reactions under the opti-
mized conditions. However, the results were quite different.
Irrespective of the protecting groups (OAc/OTBS) and the
nature of conformations (syn/anti), naphthalene 11c was ob-
tained as the major compound in 81–88% yields. The results
stated that 6-endo carbopalladation was the principle path-
way and this might be presumably due to the small size of
the nitrile group compared to the ester group in the previ-
ous cases. As described above,
a slight modification of starting
material affects much on the
Table 3. Pd-catalyzed domino reaction of various substrates.[a]
Ratio[b]
0.53
carbopalladation mode as fol-
lows: 1a-OAc (competition be-
tween 5-exo/6-endo), 1a-OTBS
(exclusively 5-exo), and 1 f-OAc
and 1 f-OTBS (exclusively 6-
endo).
Entry
Substrate
t [h]
Products [%]
1
2
Thus, we turned our attention
to g-keto ester 12, as shown in
Scheme 5. If we oxidize 1a with
PCC to the corresponding
ketone 12, the conformation
could be much different with
that of 1a due to the change of
angle around g-carbon from tet-
rahedral sp3 to trigonal sp2. If 6-
endo carbopalladation is the
preferred pathway we will
obtain naphthol derivative 14,
while the 5-exo mode would
provide tetracyclic ketone de-
rivative 13. The reaction of 12
in DMF at 1208C in the pres-
2
3
1
1
1
0.41
3
>0.92[e]
>0.93[e]
>0.92[e]
4[c]
ence of PdACHTUNGTRNEUNG(OAc)2/PPh3/Cs2CO3
5
unfortunately showed the for-
mation of intractable complex
mixture. When we ran the reac-
tion of 12 in DMF using Et3N
as a base at 1208C (Scheme 5),
three interesting compounds
were isolated: naphthol 14
(24%), cyclopropane derivative
15 (47%), and indenone 16
(10%). In the reaction of 12,
6[d]
1
>0.91[e]
[a] PdACHTUNGTRENNUNG(OAc)2 (10 mol%), PPh3 (20 mol%), Cs2CO3 (2.0 equiv), DMF, 1108C. [b] Ratio means the proportion
of product(s) formed via exo-carbopalladation. [c] Ar is p-tolyl. [d] Ar is 4-chlorophenyl. [e] Trace amounts
(<5%) of the corresponding naphthalene and dihydronaphthalene were observed on TLC.
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J. N. Kim et al.
Scheme 4. Preparation of 1 f-OAc and 1 f-OTBS and their Pd-catalyzed
reactions. a) Ac2O (1.5 equiv), pyridine (2.0 equiv), DMAP (0.1 equiv),
CH2Cl2, RT, 60 min. b) TBSCl (2.0 equiv), imidazole (3.0 equiv), DMF,
RT, 3 days.
Scheme 6. Pd-catalyzed domino reaction of 17. a) Et3N (1.0 equiv), DMF,
RT, 3 h. b) PdACTHNUGTRNEUNG(OAc)2 (10 mol%), PPh3 (20 mol%), Et3N (2.0 equiv),
DMF, 1208C, 2 h.
in a syn relationship, while indenone 16 when COOMe and
palladium are syn.
TBS-derivative 3a-OTBS was converted to alcohol 3a in
high yield (92%) with TBAF while 3a-OAc was converted
to 3a by selective hydrolysis with K2CO3 in MeOH as
shown in Scheme 7. We reasoned out that the epimer of 3a
could be synthesized by oxidation of the alcohol in 3a to
ketone 13 and reduction with NaBH4. Actually, oxidation of
3a with PCC afforded ketone 13 in 87%. Reduction of 13
with NaBH4 produced the epimer, epi-3a, as the major
product (92%) and 3a was formed in trace amounts (2%).
The convex face of the ketone 13 is roomy more than the
concave face for the attack of a hydride. The coupling con-
stant JH10ÀOH was 10.8 Hz and JH9bÀH10 was 8.1 Hz for the epi-
3a. The coupling constant JH10ÀOH was 10.8 Hz and JH9bÀH10
was 0 Hz for the original alcohol 3a. This means that the
two protons of 3a at the positions of 9b and 10 are in an or-
thogonal position. Compound 3a was a sticky oil, so that
the structure of 3a-OTBS was confirmed by its crystal struc-
ture.[18] The compound 3a-OTBS has a butterfly-like confor-
mation as expected, and the angle between two wings was
Scheme 5. Pd-catalyzed domino reaction of 12.
however, we observed a rapid isomerization of the double
bond to form compound 17. Actually compound 12 disap-
peared completely within 5 min under the reaction condi-
tions. Thus we prepared 17 from 12 (Et3N, CH3CN, RT, 3 h,
87%) and carried out the reaction under the same condi-
tions. Single compound 17 (E isomer) was obtained presum-
ably due to repulsive steric and electronic effects between 2-
bromobenzoyl and methyl ester groups. As expected the re-
action of 17 showed the same results, that is, the formation
of 14 (26%), 15 (45%), and 16 (11%) as shown in
Scheme 6. The common arylpalladium intermediate 18 can
[15]
À
undergo three different pathways. Allylic C H activation,
reductive elimination of Pd0, and double-bond isomerization
could produce naphthalene 14 (path a). 5-endo-trig Carbo-
3
palladation[16] followed by sp C H activation produced cy-
À
clopropane 15 (path b).[3f,h] As reported,[3f,9a] d-carbon elimi-
nation/decarboxylation afforded indenone 16 (path c). Two
diastereomeric intermediates 20 and 21 could be formed
during the 5-endo-carbopalladation of 18 via the corre-
sponding oxo-p-allylpalladium complex 22.[17] Cyclopropane
15 was formed when the methyl and palladium moiety are
Scheme 7. Synthesis of the epimer of 3a. a) TBAF (2.0 equiv), THF, RT,
1 h (92%). b) K2CO3 (1.5 equiv), MeOH, RT, 4 h (87%). c) PCC
(2.0 equiv), DCM, RT, 4 h (87%). d) NaBH4 (1.5 equiv), MeOH, 08C,
1 h (92%).
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Palladium-Catalyzed Heck/Arylation Cascade
COMMUNICATION
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In summary, we developed an efficient synthetic approach
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of novel indenoACHTUNGTRENNUNG[2,1-a]indane scaffold starting from the
Baylis–Hillman adduct via the combination of two key reac-
tions: In-mediated Barbier reaction and Pd-catalyzed 5-exo-
carbopalladation/arylation cascade in a reasonably regiose-
lective manner (exo/endo >0.91). The Pd-catalyzed cascade
reactions of compounds 1a–f are highly dependent upon the
protecting group of alcohol moiety as well as EWG of the
Baylis–Hillman adduct, especially in their 5-exo versus 6-
endo carbopalladation stage. In addition, the reaction condi-
tions, especially the base, affect the reaction. Further deriva-
tization of this butterfly-like indenoACTHNUTRGNEU[GN 2,1-a]indanes and evalu-
ation of their biological activities are actively under prog-
ress.
Experimental Section
[4] K. H. Kim, H. S. Lee, S. H. Kim, K. Y. Lee, J.-E. Lee, J. N. Kim,
Bull. Korean Chem. Soc. 2009, 30, 1012–1020.
[5] For the natural products having indenoACHTNUTGRNEUNG[2,1-a]indane skeleton includ-
Typical procedure for the synthesis of 3a-OTBS: A solution of 1a-OTBS
(150 mg, 0.3 mmol), PdACHTUNGTRENNUNG(OAc)2 (7 mg, 10 mol%), PPh3 (17 mg, 20 mol%),
and Cs2CO3 (205 mg, 0.6 mmol) in DMF (2 mL) was stirred at 1108C for
1 h under nitrogen atmosphere. The reaction mixture was allowed to cool
to room temperature, quenched with water (10 mL), and extracted with
diethyl ether (3ꢁ30 mL). The combined organic layers were washed with
dilute HCl solution, brine, dried over MgSO4, and concentrated under
vacuum. The residue was purified by column chromatographic purifica-
tion process (hexanes/Et2O 20:1) to afford compounds 3a-OTBS
(111 mg, 89%) as a white solid and 5a-OTBS (3 mg, 3%) as colorless oil.
ing pallidol, see: a) S. A. Snyder, S. P. Breazzano, A. G. Ross, Y. Lin,
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Biochem. Biophys. Res. Commun. 2009, 379, 283–287.
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M. R. Yadav, R. Giridhar, Bioorg. Med. Chem. 2009, 17, 5744–5762,
and references therein.
[7] For the general review on the chemical transformations of the
Baylis–Hillman adducts, see: a) S. Gowrisankar, H. S. Lee, S. H.
Kim, K. Y. Lee, J. N. Kim, Tetrahedron 2009, 65, 8769–8780; b) D.
Basavaiah, A. J. Rao, T. Satyanarayana, Chem. Rev. 2003, 103, 811–
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2008, 2897–2912.
Typical procedure for the synthesis of 3a: To a stirred solution of com-
pound 3a-OTBS (150 mg, 0.8 mmol) in THF (2 mL) at room temperature
was added TBAF solution (1m, 1.6 mL, 1.6 mmol) in THF. The reaction
mixture was stirred at room temperature for 1 h. The reaction mixture
was poured into water (10 mL) and extracted with diethyl ether (3ꢁ
30 mL). The combined organic layers were washed with brine, dried over
MgSO4, and concentrated under vacuum. The residue was purified by
column chromatographic purification process (hexanes/EtOAc 5:1) to
afford compound 3a as colorless oil (98 mg, 92%).
Acknowledgements
This work was supported by National Research Foundation of Korea
Grant funded by the Korean Government (2009-0070633). J.N.K. wishes
to thank Professor Shim Sung Lee and Mr. Sunhong Park at Gyeongsang
National University for their analyses of X-ray crystal structure.
[8] For the syn-selective synthesis of starting materials, see: a) L. A. Pa-
quette, J. Mendez-Andino, Tetrahedron Lett. 1999, 40, 4301–4304;
b) A. S.-Y. Lee, Y.-T. Chang, S.-H. Wang, S.-F. Chu, Tetrahedron
Lett. 2002, 43, 8489–8492; c) G. W. Kabalka, B. Venkataiah, C.
Chen, Tetrahedron Lett. 2006, 47, 4187–4189; d) S. H. Yu, M. J. Fer-
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12808–12809.
À
Keywords: carbopalladation · C H activation · domino
reactions · Heck reaction · palladium
[9] For d-carbon elimination/decarboxylation in a similar system, see:
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[18] CCDC-749251 (3a-OTBS) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
À
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Received: November 3, 2009
Published online: January 27, 2010
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Chem. Eur. J. 2010, 16, 2375 – 2380