Consecutive C-H functionalization reactions of arenes: Synthesis of carbo- and heteropolycyclic skeletons

Article abstract of DOI:10.1002/anie.200902989

Doubling the bet: Two C-H bonds become functionalized upon exposure of co-aryl propargylic tosylates to Sc(OTf)₃ (see scheme). The reaction involves a new domino process that can tolerate both electron-withdrawing and -donating substituents on the arene unit. Different carbo- and heterocyclic frameworks can be assembled by using this approach to formally conquer the hydroarylation process.

Full text of DOI:10.1002/anie.200902989

Angewandte
Chemie
DOI: 10.1002/anie.200902989
Heterocycles
À
Consecutive C H Functionalization Reactions of Arenes: Synthesis of
Carbo- and Heteropolycyclic Skeletons**
Samuel Suꢀrez-Pantiga, David Palomas, Eduardo Rubio, and Josꢁ M. Gonzꢀlez*
The use of domino reactions allows a rapid elaboration of
molecular complexity from simple precursors.[1] Benzofused
rings are often assembled by using intramolecular Friedel–
Crafts processes,[2] and advances in alkyne hydroarylation
reactions have contributed to expand the field.[3] As for the
mechanism, these carbocyclizations are typically assumed to
be electrophilic aromatic substitution reactions and require
electron-rich arenes to occur.[4,5] The involvement of electron-
poor arenes in hydroarylation reactions of alkynes has little
precedent,[6–10] and it involves other mechanistic pathways
(Scheme 1). Thus, Chernyak and Gevorgyan prepared fluo-
renes by palladium-catalyzed 5-exo-dig hydroarylation of
acetates that takes place through isomerization and subse-
quent allene arylation.[7,8]
Herein, we report a catalytic polycyclization reaction of
tethered w-aryl propargyl esters that is compatible with
arenes substituted by electron-withdrawing groups
(Scheme 2).[11] Its utility to access carbo- and heterocyclic
scaffolds is also documented.[12]
Scheme 2. New domino reaction of w-aryl alkyne derivatives.
Ts =4-toluenesulfonyl
Initially, we investigated the reactivity of propargylic
esters towards gold catalysts.[13] Our research group has
recently reported the catalytic assembly of cyclopent-2-
enimines by [4+1] cyclization of propargyl tosylates and N-
tosyl imines.[14] The reaction comprises an isomerization to a
2-tosyloxi-1,3-diene through two selective 1,2-migrations.[15]
On this basis, we reasoned that it might be possible to
catalytically generate a class of dienes that could subsequently
give rise to new arylation strategies. Readily available aryl
propargyl ethers, N-tosyl-amines, or even 4-phenyl-1-butyne
were elaborated into precursors by the reaction with alde-
hydes and subsequent esterification. Based on our past
experience, pivalaldehyde was chosen and added to N-
propargyl-N-tosylaniline to eventually afford appropriate
model compounds upon esterification.[16] These esters were
reactive towards different metal precatalysts like Lewis and
Brønsted acids. Pivaloate and acetate derivatives failed to
give cyclization: either the starting material or the Meyer–
Schuster rearranged enone were isolated.[17] Nevertheless, the
bis(tosylate) 1a gave 2a, which contains a cyclopenta[de]qui-
Scheme 1. Arene–alkyne cyclizations of electron-poor arene units.
EWG=electron-withdrawing group.
ortho-alkynyl biaryls through o-palladation, insertion, and
protiodemetalation steps.[6] Nolan and co-workers reported a
gold(I)-catalyzed synthesis of indenes from aryl propargyl
[*] S. Suꢀrez-Pantiga, D. Palomas, Dr. E. Rubio, Prof. Dr. J. M. Gonzꢀlez
Departamento de Quꢁmica Orgꢀnica e Inorgꢀnica and Instituto
Universitario de Quꢁmica Organometꢀlica “Enrique Moles”-Unidad
Asociada al C.S.I.C.—Universidad de Oviedo
C/Juliꢀn Claverꢁa 8, 33006 Oviedo (Spain)
Fax: (+34)985-103-450
E-mail: jmgd@uniovi.es
À
noline core and arises from a double C H functionalization of
the arene and a selective 1,2-alkyl-migration (Scheme 3).
Initial trials showed that heating the reaction mixture at
about 608C was required for the cyclization to occur and that
1,2-dichloroethane (DCE) was an appropriate solvent. Sev-
eral catalytic systems were assayed in this polar, low
coordinating solvent—the use of toluene or acetonitrile
severely slowed down or inhibit the process depending on
the catalytic system—and the results are outlined in Table 1.
[**] Financial support for this work is acknowledged (grant
nos. CTQ2007-61048 and IB08-088). S.S.-P. and D.P. thank the
MICINN for predoctoral FPU fellowships. We also thank Dr. ꢂngel
L. Suꢀrez-Sobrino for his helpful assistance with the X-ray analysis.
We are grateful to the referees for their kind and helpful suggestions
to improve the manuscript, particularly for the labeling experiments.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902989.
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Table 2: Sc(OTf)3-catalyzed reaction of w-aryl propargyl tosylates 1.[a]
Entry Alkyne
Product
t [min] Yield [%][b]
Scheme 3. Carbocyclization of 1a into 2a (see Table 1 for the reaction
conditions).
1
2
1b, X=O
1c, X=CH2
2b, X=O
2c, X=CH2
40
30
60
66[c]
For the catalytic system, satisfactory results were obtained
[18]
[19]
when using gold(I) from IPrAuCl/AgBF4
or Sc(OTf)3
(Table 1, entries 3 and 7), while PtII, AuIII, and several
Brønsted acids were ineffective (Table 1, entries 9, 6, and
10–15, respectively).
3
4
1d, X=NTs
1e, X=CH2
2d, X=NTs
2e, X=CH2
40
5
61
80
Table 1: Screening for catalytic activity (see Scheme 3).[a]
5
1 f
2 f
180
92[d]
Entry
Catalyst
t [h]
Yield of 2a [%][b]
(5 mol%)
1
2
3
4
5
6
7
8
[Au(PPh3)]NTf2
[Au(PPh3)]Cl/AgBF4
Ia/AgBF4
Ib
II/AgBF4
III
24
22
24
24
24
24
21
24
14
27
20
24
24
24
24
–
6
1g
3g
60
54[e]
28
64
–
21
–
67
20
–
–
–
–
–
[a] 0.1m in DCE, at 608C, Sc(OTf)3 (5 mol%). [b] Yield of isolated
product after purification by column chromatography. [c] The alternative
gold(I)-catalyzed reaction gave 2c in 60% yield after isolation (IPrAuCl/
AgBF4 (5 mol%), 30 min, 608C, DCE). [d] Reaction carried out at room
temperature. [e] In C6H5Cl at 1208C.
Sc(OTf)3
[c]
Ga(OTf)3
[c]
9
PtCl2
10
11
12
13
14
15
HOTs[d]
HOTf[e]
HOTf[f]
HOTf[g]
reaction took place selectively with migration of either a
methyl group, a primary alkyl chain with concomitant ring-
expansion, a phenyl ring, or hydrogen. For the latter case, the
subsequent cyclization was not observed and the conjugate
diene 3g was isolated (Table 2, entry 6).[20] This cyclization
gives access to partially saturated skeletons as either hetero-
cycles (quinoline derivatives 2a, 2d, 2 f, and 3g; Table 2,
entries 3, 5, and 6), chromene 2b (Table 2, entry 1), or pure
carbocycles (acenaphthylene 2c or fluoranthene 2e; Table 2,
entries 2 and 4). Next, the influence of the arene substituent
[f]
HNTf2
–
–
none
[a] 1a (0.2 mmol) was dissolved in anhydrous DCE (2 mL) under an
argon atmosphere, the catalyst was added, and the mixture heated at
608C. [b] Yield of isolated product after purification by column
chromatography. [c] 7.5 mol% of catalyst was added. [d] 5 and
10 mol% of catalyst were tested. [e] 5 mol% of catalyst was added
resulting in the decomposition of 1a. [f] 1 mol% of catalyst was added
resulting in the recovery of most of 1a. [g] 2 mol% of catalyst was added
resulting in the partial recovery (77%) of 1a. Tf=trifluoromethanesul-
fonyl.
À
was tested (Table 3). This C H functionalization works for an
array of arenes featuring different substitution patterns.
Remarkably, strong electron-withdrawing groups are nicely
tolerated (see 2k and 2m; Table 3, entries 4 and 6). In fact,
these results help to expand the scope of the metal-catalyzed
arene–alkyne cyclization process.
Also, 2p was prepared in 75% yield on a 10 mmol scale
from the parent alcohol. Compound 2p was tosylated and
then taken to the cyclization step without further purification,
thereby showing the convenience of this transformation. The
catalyst load was reduced to 2 mol% and an efficient
cyclization was still obtained (Scheme 4).
The former two catalysts were further tested with 1b,
which is an oxygen-tethered compound. Although the scan-
dium-catalyzed cyclization took place and furnished the
related dihydrocyclopenta[de]-2H-chromene derivative 2b
(Table 2, entry 1), a complex mixture was obtained for gold
catalysis and no evidence for the presence of 2b was
observed. For carbon-based 1c, the outcomes were similar
for the two catalytic systems in terms of both yield and
reaction time, which was much shorter than for the related
heteroatom-containing precursors (Table 2, entry 2). Thus,
Sc(OTf)3 was used to test the scope of the process with respect
to the nature of the migrating group (R1 in Scheme 2, see
Table 2) and the arene (R in Scheme 2, see Table 3). The
A tentative mechanistic proposal to account for the
observed results is outlined in Scheme 5. Activation of the
alkyne upon coordination to the electrophilic metal[19,21]
launches a tosylate migration with a concomitant 1,2-shift of
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Table 3: Cyclization of 1 to 2: arene substitution tolerance.[a]
Entry
Alkyne
Product
t [h]
Yield [%][b]
À
Scheme 4. C H functionalization of w-aryl-substituted propargylic
alcohol derivatives: tosylation and double arylation reactions.
1
2
3
4
1h, R=F
1i, R=I
1j, R=Me
1k, R=CN
2h, R=F
2i, R=I
2j, R=Me
2k, R=CN
40
32
22
24
62[c]
54[d]
68[e]
60
on gold. The evolution of this intermediate was studied under
different reaction conditions. So, addition of catalytic
amounts of Sc(OTf)3 or IPrAuCl/AgBF4 to 3h led to the
formation of only trace amounts of 2h. However, when pure
3h was exposed to TsOH (1 equiv) in DCE at 608C for
15 hours, a clean, fast, and efficient conversion into 2h took
place. As the formation of 3 gives rise to a stoichiometric
amount of TsOH, the second cyclization event could reason-
ably be promoted by the Brønsted acid formed as the reaction
progresses.[25] A central role for the tosylate group in the
evolution of A to C is supported by the absence of 2 from (5,6-
dimethyl-hepta-3,5-dienyl)benzene 5[26] upon exposure to
Sc(OTf)3.[27]
5
6
1l, R=Ph
1m, R=NO2
2l, R=Ph
2m, R=NO2
5
35
77
56[g]
[f]
7
8
1n, R=Ph
1o, R=Br
2n, R=Ph
2o, R=Br
24
5
70
91
Moreover, reactions of [D1]-1p (deuterated at the prop-
argylic position), [D1]-1n (deuterated at the active ortho-
position), or [D2]-1n (deuterium at both the active ortho and
propargylic positions) revealed exclusive incorporation of
deuterium at C8-position for the carbocycle 2p and the C3-
position for the heterocycle 2n. In both cases, the label resides
only at the methylene unit built from the sp carbon atom in
the parent alkyne 1. Finally, a cross-over experiment between
[D2]-1n and 1c again shows the formation of deuterated 2c,
with incorporation of deuterium only at the new methylene
carbon unit arising from the starting alkyne carbon atom.[16]
The scope of this cyclization was expanded to accomplish
the functionalization of two linked arene units. So, when 1r
was subjected to the Sc(OTf)3-catalyzed cyclization then
compound 6, which has the structure of a 5,6-dihydro-
naphtho[3,2,1-de]chromene, was isolated in 76% yield
(Scheme 6). Also, the formation of 6 implies major differ-
ences at the final steps. After the Lewis acid catalyzed
9
1p
1q
2p
2q
0.1
87
36
10
21
[a] 0.1m in DCE, at 608C, Sc(OTf)3 (5 mol%). [b] Yield of isolated
product after purification by column chromatography. [c] Alternatively,
IPrAuCl/AgBF4 (5 mol%), at 808C in DCE for 44 h gives 2h (27% yield).
[d] Gold(I)-catalyzed reaction (IPrAuCl/AgBF4 (5 mol%), at 608C in
DCE). [e] 2j was isolated in 70% yield from the gold(I) process.
[f] Structure of 2m was confirmed by X-ray analysis.[28] [g] 1m (21%) and
p-NO2C6H4OH (14%) recovered.
R1 that is followed by loss of a proton and a
subsequent protiodemetalation to furnish the diene
A.[14,22] Next, electrophilic activation of the conju-
gated diene[23] yields a stabilized carbocation B that
enters the first electrophilic aromatic substitution
event. The resulting cycloisomerization process
would render the conversion of 1 into C, which
could then further evolve under the reaction con-
ditions. As a function of the nature of the R1 and R
substituents, C would either simply suffer TsOH
loss to afford 3[24] or keep advancing through a
cationic intermediate D to afford 2. The following
facts provide support for some aspects of this
mechanistic proposal.
Thus, a minor amount of 3h was isolated from
the reaction of 1h with the catalytic system based
Scheme 5. Proposed working-model for the evolution of 1 into 2.
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[7] N. Marion, S. Dꢀez-Gonzꢁlez, P. de Frꢂmont, A. R. Noble, S. P.
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[9] L. Cui, G. Zhang, Y. Peng, L. Zhang, Org. Lett. 2009, 11, 1225 –
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[10] A. Saito, S. Oda, H. Fukaya, Y. Hanzawa, J. Org. Chem. 2009, 74,
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[11] Metal-catalyzed intramolecular cyclizations of aryl-substituted
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Scheme 6. Mechanistic interpretation for the formation of 6.
isomerization and the initial cyclization has occurred, the
À
resulting diene could cyclize through C H functionalization
of the second arene nucleus: a process that could be likely
catalyzed by the liberated Brønsted acid. Eventually, a retro-
ene reaction would aromatize the ring at the time that the
À
noticed C C bond breaking occurs to liberate propene.
Overall, the reactions reported here open up new
perspectives for advancing the topic of hydroarylation of
unsaturated systems. These intramolecular domino reactions
of propargyl tosylates and arenes with catalytic Sc(OTf)3
provide smooth access to a variety of carbo- and hetero-
polycyclic frameworks. The process is tolerant of strong
electron-withdrawing groups on the arene unit. Also, a
comparison of the scandium- and gold-catalyzed reactions
gives interesting insights for the challenges related to the
activation of unsaturated systems.
[14] S. Suꢁrez-Pantiga, E. Rubio, C. ꢄlvarez-Rffla, J. M. Gonzꢁlez,
Org. Lett. 2009, 11, 13 – 16.
[15] Review: B. Crone, S. F. Kirsch, Chem. Eur. J. 2008, 14, 3514 –
3522.
Received: June 3, 2009
Revised: August 7, 2009
Published online: September 11, 2009
[16] For experimental details and characterization data for com-
pounds 1–6, as well as labeling experiments, see the Supporting
Information.
[17] R. S. Ramꢃn, N. Marion, S. P. Nolan, Tetrahedron 2009, 65,
1767 – 1773.
Keywords: carbocycles · heterocycles · hydroarylation ·
Lewis acids · propargylic esters
.
[18] a) P. de Fremont, N. M. Scott, E. D. Stevens, S. P. Nolan,
Organometallics 2005, 24, 2411 – 2418; b) N. Marion, R. S.
Ramꢃn, S. P. Nolan, J. Am. Chem. Soc. 2009, 131, 448 – 449.
[19] For reviews on the use of Sc(OTf)3 in organic synthesis, see: a) S.
Kobayashi, Eur. J. Org. Chem. 1999, 15 – 27; b) S. Kobayashi in
Lewis Acids in Organic Synthesis, Vol. 2 (Ed.: H. Yamamoto),
Wiley-VCH, Weinheim, 2000, pp. 883 – 910; seminal work on
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1737.
[20] Under these reaction conditions the reaction did not go to
completion. Products 1g (9%) and N-tosylaniline (12%) were
isolated by column chromatography. Longer reaction times
caused decomposition. The use of microwave radiation did not
result in any major improvement.
[21] For a review on carbophilic activation by p-acids, see: A.
Fürstner, P. W. Davies, Angew. Chem. 2007, 119, 3478 – 3519;
Angew. Chem. Int. Ed. 2007, 46, 3410 – 3449.
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[22] The [4+1] cyclization described in reference [14] can be accessed
using a catalytic amount of Sc(OTf)3, although giving a lower
yield than for gold-catalysis and is also accompanied by other
side products. See the Supporting Information.
[23] Sc(OTf)3-induced Friedel–Crafts cyclization of 1,3-bis-exocyclic
dienes leading to 4a-methyltetrahydrofluorenes: T. Lomberget,
E. Bentz, D. Bouyssi, G. Balme, Org. Lett. 2003, 5, 2055 – 2057.
[24] See for instance the conversion of 1g into 3g. Also, minor
amounts of 3h were isolated from the gold-catalyzed reaction of
1h.
upon heating for 24 h in DCE, the reaction gives the corre-
sponding diene 3a (25%), which arises from a single cyclization
rather the double cyclization product 2a. For the use of TTBP in
metal-catalyzed reactions, see: T. Schwier, A. W. Sromek,
D. M. L. Yap, D. Chernyak, V. Gevorgyan, J. Am. Chem. Soc.
2007, 129, 9868 – 9878.
[26] 5 was prepared by a cross-coupling reaction, see the Supporting
Information.
[27] After heating at 608C for 40 min only compound 5 was present in
the reaction mixture. By extending the reaction time to 1 h it
allowed the identification of significant amounts of unchanged 5,
although some decomposition was evident by TLC. This trend
was still noticed when heating lasted foe 3 or 7 h. After 24 h, only
trace amounts of 5 were present, and a complex mixture was
formed without any evidence for the formation of a type-2
product.
[28] CCDC 734150 (2m) 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.
[25] The inhibition of the conversion of 1a into 2a upon exposure to
catalytic amounts of Sc(OTf)3 in the presence of 2,4,6-tri-tert-
butylpyrimidine (TTBP) supports this hypothesis. In this case,
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