Modular Assembly of Spirocarbocyclic Scaffolds through Pd0-Catalyzed Intermolecular Dearomatizing [2+2+1] Annulation of Bromonaphthols with Aryl Iodides and Alkynes

Article abstract of DOI:10.1002/anie.201612127

A novel palladium(0)-catalyzed dearomatizing [2+2+1] spiroannulation of 1-bromo-2-naphthols with aryl iodides and alkynes was developed for the rapid assembly of spiro[indene-1,1′-naphthalen]-2′-ones. This three-component cascade reaction was realized thr

Full text of DOI:10.1002/anie.201612127

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International Edition: DOI: 10.1002/anie.201612127
German Edition: DOI: 10.1002/ange.201612127
À
C H Activation
Modular Assembly of Spirocarbocyclic Scaffolds through Pd0-
Catalyzed Intermolecular Dearomatizing [2+2+1] Annulation of
Bromonaphthols with Aryl Iodides and Alkynes
Zhijun Zuo+, Hui Wang+, Liangxin Fan, Jingjing Liu, Yaoyu Wang, and Xinjun Luan*
Abstract: A novel palladium(0)-catalyzed dearomatizing
[2+2+1] spiroannulation of 1-bromo-2-naphthols with aryl
iodides and alkynes was developed for the rapid assembly of
spiro[indene-1,1’-naphthalen]-2’-ones. This three-component
cascade reaction was realized through consecutive Catellani-
catalyzed two-component dearomative cyclization[14] allowed
the direct use of phenol diazonium salts, halophenols,
halonaphthalenes, naphthols, and N-aryl ureas as one-
carbon synthons to react with two equivalents of alkynes,
thereby leading to various spirocarbocylces. Meanwhile, the
pursuit of Pd0-catalyzed dearomative spirocyclizations of
indole derivatives with a second reactant has also seen
significant progress.[15] Despite these elegant achievements on
two-component processes, the discovery of related annula-
tions with three distinct starting materials to assemble
complex spirocyclic frameworks still remains a formidable
challenge.[16] Herein we disclose a Pd0-catalyzed dearomatiz-
ing [2+2+1] spiroannulation of readily available bromonaph-
thols with aryl iodides and alkynes for the one-step
direct assembly of spiro[indene-1,1’-naphthalen]-2’-ones
(Scheme 1).
À
type C H activation, unsymmetrical biaryl coupling, alkyne
migratory insertion, and arene dearomatization. The potential
utility of our method is illustrated by the one-step construction
of the polycyclic skeletons of dalesconols A and B from
alkyne-tethered aryl iodides and 1-bromo-2-naphthol.
S
pirocyclic frameworks are commonly occurring structural
motifs in many bioactive compounds[1] and have been used as
core building blocks for a wide range of functional materials[2]
and chiral ligands.[3] Transition-metal-catalyzed dearomatiza-
tion of aromatic systems, which offers unusual strategic
disconnections, have proven to be a powerful tool for
accessing a variety of challenging but synthetically valuable
spirocyclic molecules.[4] Pioneering examples of transition-
metal-catalyzed dearomative spirocyclizations were realized
by the groups of Hamada,[5] You,[6] Buchwald,[7] and Feringa[8]
through an intramolecular design by using tethered phe-
nol,[5,6b,7a] naphthol,[5,6f–g,7a,8] indole,[5b,6a,c] or pyrrole[6d–e] deriv-
atives to avoid the unwanted heteroatom alkylation/arylation
or Friedel–Crafts-type reaction pathway. However, further
advancement of this intramolecular strategy for building
other diversified spirocylces has been dramatically limited, in
part due to the need for high-cost substrates that often require
multistep synthesis. In this context, substantial efforts have
been focused on the development of more atom- and step-
economical intermolecular processes. Very recently, we,[9] and
the groups of Gulꢀas and MascareÇas,[10] Lam,[11] and You[12]
have independently demonstrated RuII- and RhIII-catalyzed
dearomatizing [3+2] spiroannulations of phenol-derived biar-
Scheme 1. Three-component dearomatizing [2+2+1] spiroannulation.
NBE=norbonene.
This work stems from palladium/norbornene (NBE)
chemistry, which was originally discovered by Catellani
et al.[17] Seminal works[18] by Catellani and Lautens revealed
that a myriad of biaryl-containing carbocyclic and hetero-
cyclic compounds (III) could be obtained through palladium-
catalyzed ortho-arylation of an aryl iodide (I) with a bifunc-
tional aromatic reagent (II) followed by intramolecular ring
closure with NBE as a transient mediator (Scheme 2). These
À
À
yls with alkynes through a C H bond activation approach.
processes are initiated by NBE-assisted C H palladation to
Soon afterwards, a non-oxidative version was enabled by Pd0
catalysis.[13] Moreover, the potent strategy of palladium-
form five-membered palladacycle A, which then reacts with
haloarene II to generate biarylpalladium species B. Subse-
quent elimination of NBE through b-carbon elimination then
occurs to give the key intermediate C. In connection with our
[*] Z. Zuo,[+] H. Wang,[+] L. Fan, J. Liu, Prof. Dr. Y. Wang, Prof. Dr. X. Luan
Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of the Ministry of Education, College of Chemistry &
Materials Science, Northwest University, Xi’an, 710127 (China)
E-mail: xluan@nwu.edu.cn
À
persistent interest in the development of cooperative C H
activation/dearomatization reactions,[9,14d] we wondered
whether the in situ formed intermediate C could be inter-
cepted with alkyne IV through a dearomative pathway to
produce spirocyclic compound V (path a). However, addi-
tional challenges arise from the fact that: 1) the utilization of
aromatic motif II, which is prone to undergo dearomatization,
dramatically increases the risk for the direct cyclization of
intermediate B to provide NBE-containing spirocarbocylce
VI (path b),[16,19] and 2) the two-component annulation of two
Prof. Dr. X. Luan
State Key Laboratory of Elemento-organic Chemistry
Nankai University, Tianjin, 300071 (China)
[+] These authors contributed equally to this work.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201612127.
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Table 1: Optimization of the reaction conditions.
Entry [Pd]
Ligand
Base
Solvent Yield [%][a]
4a 5a 6a 7a[b]
1
2
3
4
5
6
7
8
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
K2CO3 DMF
K3PO4 DMF
Cs2CO3 DMF
0
0
0
2
7
0
6
0
0
2
4
3
0
2
1
3
0
0
0
–
32
–
36
22
25
18
2
25
13
46
20
30
22
12
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
11 24
46 27
Cs2CO3 MeCN 21 15
Cs2CO3 DME
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
33 11
18
35 34
23 13
32 22
41 2
39 30
41 20
5
[Pd(allyl)Cl]2 PPh3
Scheme 2. Reaction design for the palladium/norbornene catalysis.
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DPPP[c]
9
DPPF[c]
BINAP[c]
TFP
10
11
12
13
14
15
16
17
equivalents of I with alkyne V might form phenathrene
product VII (path c).[20] Therefore, the key for the envisioned
reaction is to find suitable conditions to effectively prevent
the unwanted side reactions.
PCy3
P(o-Tol)3
XPhos
t-BuXPhos Cs2CO3 DMF
JohnPhos Cs2CO3 DMF
DavePhos Cs2CO3 DMF
DavePhos Cs2CO3 DMF
DavePhos Cs2CO3 DMF
DavePhos Cs2CO3 DMF
9
7
60 16
10
16
8
3
–
To address the aforementioned challenge, we commenced
our studies with 1-bromo-2-naphthol (2a), which possesses
a higher potential to undergo dearomatization,[8,21] as the
bifunctional reactant II for the designed three-component
reaction (Table 1). At the outset, a reaction mixture of 1a, 2a,
and 3a in DMF was heated at 1008C in the presence of
5.0 mol% Pd(OAc)2, 12.0 mol% PPh3, 1.0 equivalent of
NBE, and 2.0 equivalent of K2CO3, but neither the dearoma-
tizing products (V and VI) nor dibenzofuran (III)[22] were
observed under these typical Catellani-reaction conditions,[23]
and only side product 7a[20] was obtained through the
annulation of 1a with 3a (entry 1). Upon optimization on
the base, the envisioned 4a[13a] was indeed obtained, albeit
with low yields (entries 2–3). Despite this encouraging out-
come with the use of Cs2CO3, the desired transformation
suffered from the concomitant generation of byproducts 5a,
6a,[14a,b] and 7a. Other common solvents and palladium
precursors for Catellani-type reactions were tested, but none
of them showed a positive effect (entries 4–7). Further results
revealed that various phosphine ligands were effective, and
the troublesome issue of the formation of unwanted 5a and
7a could be addressed (entries 8–17). When BINAP was
employed, product 4a was isolated in 41% yield, with only
2% of the NBE-containing byproduct 5a (entry 10). This
observation indicated that the evolution from intermediate B
to C through b-carbon elimination could be facilitated with
the more rigid ligand. However, the use of bisphosphine
ligands did not inhibit the formation of 7a (entries 8–10), thus
implying that the cross-coupling of 1a with 2a was not
rendered fast enough to suppress the unwanted homo-
coupling of 1a. Although several monophosphine ligands
failed to improve the reaction (entries 11–13), Buchwald-type
ligands gave a dramatic enhancement in both reactivity and
48
79
84
–
–
–
9
8
2
17
–
18[d] Pd(OAc)2
19[e] Pd(OAc)2
20[f] Pd(OAc)2
–
31
–
[a] Yield of isolated product. [b] Yield was based on the amount of 2a.
[c] 6.0 mol%. [d] 3a was not added. [e] 1a was not added. [f] 2a was not
added. DMF=N,N-dimethylformamide, DME=dimethyl ether,
DPPP=1,3-bis(diphenylphosphino)propane, DPPF=1,1’-bis(diphenyl-
phosphino)ferrocene, BINAP=2,2’-Bis(diphenylphosphino)-1,1’-
binaphthyl.
selectivity (entries 14–17). As a result, the electron-rich
DavePhos, which has been employed by the Liu group for
À
the selective ortho C H trifluoroethylation of aryl iodies
under Pd/NBE catalysis,[24] turned out to be the optimal
ligand, affording 4a in 84% yield, with negligible amounts of
byproducts 5a–7a (entry 17). Finally, three control reactions
were conducted with different combinations of two of the
three substrates, and the expected products 5a, 6a, and 7a
were isolated in 17%, 32%, and 31% yield, respectively
(entries 18–20). Therefore, the successful execution of the
title reaction was realized by avoiding at least three com-
petitive side reactions.
With the optimized conditions established, the scope with
respect to the aryl iodides was first examined. The results
indicated that various functional groups are tolerated, and the
reactions of aryl iodides 1b–p with 2a and 3a underwent the
envisioned [2+2+1] spiroannulations efficiently to deliver the
dearomatized products 4b–p in 46–82% yields (Table 2). For
example, functionalization of the 3- and 4-positions of 1a with
methyl (1b,e), chloro (1c), nitro (1d), or ester (1 f) groups was
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Table 2: Scope with respect to the aryl iodides.
Table 3: Scope with respect to the 1-bromo-2-naphthols.
7-positions of bromonaphthols could be substituted with
electron-donating groups (EDGs) such as a methoxy group
(2d,l,p), or electron-withdrawing groups (EWGs) such as
chloro (2e,n), formyl (2 f), and ester (2g,m) groups. The
electron-rich 1-bromo-2-naphthols generally showed better
performance for the title transformation. The potentially
labile aryl chloride remained intact in the process, and the
structure of 4m’ was confirmed by X-ray crystallography.[25]
A
TMS-substituted substrate (2c) was found to be compatible as
well. It is noteworthy that heterocyclic 5-bromoquinolin-6-ol
(2q) behaved quite well in the dearomatizing [2+2+1]
spiroannulation with 1a and 3a, leading to the anticipated
compound 4p’ in 60% yield. However, it should be men-
tioned that o-bromophenols were not applicable under the
current reaction conditions.
Having examined the reaction scope of aryl iodides and
bromonaphthols, we eventually turned our focus to evaluating
the performance of alkynes (Table 4). Overall, a broad range
of symmetrical alkynes containing various aromatic groups
were tolerated in the three-component [2+2+1] annulation
[a] Reactions were conducted in DME at 1208C.
well tolerated. The methyl substituent could be varied with
a bulkier ethyl or isopropyl group to afford compounds 4g–h
in good yields (78% and 79%). Moreover, a high yield (76%)
of 4i was obtained with naphthalene-derived substrate (1i).
When the methyl group of 1a was substituted with other
substituents, such as methoxy (1j), methoxymethoxy (1k),
trifluoromethoxy (1l), fluoro (1m), chloro (1n), trifluoro-
methyl (1o), or 2-thienyl (1p) groups, the corresponding
reactions had to be run in DME at a higher temperature
(1208C), which gave spirocyclic molecules 4j–p in 46–68%
yields. Notably, this method features the direct use of three
commercially available substrates, thereby avoiding multistep
substrate preparation and enabling the synthesis of many
highly functionalized spirocylic compounds that were
extremely difficult or inaccessible by the prior method with
halogenated biaryls and alkynes.[13a] In sharp contrast to the
Table 4: Scope with respect to the alkynes.
previously reported two-component reactions that rely on
[9–12]
À
a highly regioselective C H functionalization approach,
this new process served as a reliable complementary strategy
for exclusive formation of the opposite regioisomer.
Next, we continued to explore the generality of this new
three-component reaction by using a variety of functionalized
1-bromo-2-naphthols (2b–q) to react with 1a and 3a, and the
experimental data are shown in Table 3. Gratifyingly, the
corresponding reactions proceeded smoothly to give the
desired spirocyclic products 4a’-p’ in 54–89% yields. Besides
aliphatic (2b,k) and aromatic (2h–j,o) groups, the 3-, 6-, and
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reaction, affording products 4a’’–g’’ in 67%-83% yields.
Diaryl alkynes substituted with methyl (3b), methoxy (3c),
fluoro (3d), chloro (3e), trifluoromethyl (3 f), or ester (3g)
groups were well accommodated. Additionally, the alkyne 3h,
which bears a heterocyclic 2-thienyl group, efficiently under-
went the [2+2+1] annulation with 1a and 2a, leading to 4g’’
in 83% yield. To our delight, dialkylacetylenes (3i,j), which
were not tolerated in the Pd/NBE-catalyzed [2+2+2] annu-
lation of aryl iodides with alkynes for the synthesis of
phenanthrenes,[20] were found to be suitable for this new
process, providing the desired products 4h’’ and 4i’’ in high
yields (85% and 81%), without the potential allenic byprod-
uct being formed through b-hydride elimination. Moreover,
the catalytic run with alkyl/aryl mixed alkynes 3k proceeded
smoothly to give product 4j’’ in 68% yields but with poor
regioselectivity (1.8:1 rr). In contrast, the reaction with
unsymmetrical alkyne 3l led to the formation of 4k’’ as
a single regioisomer, with 3l being installed in such a manner
that the alkene group is close to the spirocyclic carbon center,
and its structure was confirmed by X-ray crystallography.[25]
In order to further demonstrate the practicality of this
three-component domino process, a scale-up experiment
(4.0 mmol) was carried out under the standard reaction
conditions. As depicted in Scheme 3, gram-scale preparation
of product 4a (1.2 g) was successfully achieved in 74% yield.
using 10.0 mol% of Pd(OAc)2, 20.0 mol% of P(o-Tol)3,
1.0 equivalent of NBE, and 2.0 equivalents of Cs2CO3,
affording the desired products 9a–e in 52–68% yields. The
structure of 9a was unambiguously assigned by X-ray
crystallography.[25] Remarkably, the main polycyclic skeleton
of dalesconols A and B could be rapidly assembled from two
readily available starting materials in a single step through the
À
formation of three C C bonds. Moreover, the pendant phenyl
group could be substituted with different functional groups,
offering a great opportunity to furnish the final ring for the
whole skeleton of these two molecules.
In summary, we have developed an unprecedented Pd0-
catalyzed NBE-mediated dearomatizing [2+2+1] spiroannu-
lation of bromonaphthols with aryl iodides and alkynes, which
provides a variety of spirocyclic molecules in good yields.
With NBE as a transient mediator, this three-component
À
domino process is likely realized through a sequence of C H
activation, biaryl coupling, alkyne migratory insertion, and
naphthol dearomatization. Notably, this method represents
a rare example of transition-metal-catalyzed processes for the
rapid assembly of spirocarbocycles in an intermolecular
fashion starting from three very simple substrates. Efforts to
expand the reaction scope and detailed mechanistic studies
are underway.
Acknowledgements
This work was supported by the NSFC (21672169, 61605158),
the “1000 Youth Talents Plan”, Education Department of
Shaanxi Province (12JS113, 16JK1790), and the Northwest
University for generous financial support (YZZ15004).
Scheme 3. Gram-scale preparation of 4a.
Conflict of interest
To highlight the potential utility of this new synthetic
method, preliminary studies were performed to construct the
structural cores of the immunosuppressive polyketides dales-
conols A and B[1a] by using alkyne-tethered aryl iodides 8a–
e to react with 2a (Scheme 4). After further optimization, the
two-component reactions, which were heated in DMF at
1308C for 10 hours, showed excellent performance when
The authors declare no conflict of interest.
À
Keywords: C H activation · dearomatization ·
homogeneous catalysis · palladium · spiroannulation
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4
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dium precursor.
[9] a) J. Nan, Z. Zuo, L. Luo, L. Bai, H. Zheng, Y. Yuan, J. Liu, X.
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[25] CCDC 1521363 (4m’), 1521366 (4k’’) and 1521365 (9a) contain
the supplementary crystallographic data for this paper. These
data are provided free of charge from The Cambridge
Crystallographic Data Centre.
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Manuscript received: December 14, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
À
C H Activation
Z. Zuo, H. Wang, L. Fan, J. Liu, Y. Wang,
X. Luan*
&&& — &&&
Modular Assembly of Spirocarbocyclic
Scaffolds through Pd0-Catalyzed
Intermolecular Dearomatizing [2+2+1]
Annulation of Bromonaphthols with Aryl
Iodides and Alkynes
Spiro staircase: A novel palladium(0)-
catalyzed dearomatizing [2+2+1] spi-
roannulation of 1-bromo-2-naphthols
with aryl iodides and alkynes was devel-
oped for the rapid assembly of spiro[in-
dene-1,1’-naphthalen]-2’-ones. This three-
component cascade reaction was realized
À
through consecutive Catellani-type C H
activation, unsymmetrical biaryl cou-
pling, alkyne migratory insertion, and
arene dearomatization steps.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!