Palladium-Catalyzed Intermolecular [4+1] Spiroannulation by C(sp3)?H Activation and Naphthol Dearomatization

Article abstract of DOI:10.1002/anie.201813202

A novel palladium-catalyzed [4+1] spiroannulation was developed by using a C(sp³)?H activation/naphthol dearomatization approach. This bimolecular domino reaction of two aryl halides was realized through a sequence of cyclometallation-facilitat

Full text of DOI:10.1002/anie.201813202

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Accepted Article
Title: Palladium-Catalyzed Intermolecular [4+1] Spiroannulation via
C(sp3)–H Activation and Naphthol Dearomatization
Authors: Bojun Tan, Lu Bai, Pin Ding, Jingjing Liu, Yaoyu Wang, and
Xinjun Luan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201813202
Angew. Chem. 10.1002/ange.201813202
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10.1002/anie.201813202
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Palladium-Catalyzed Intermolecular [4+1] Spiroannulation via
C(sp3)–H Activation and Naphthol Dearomatization
Bojun Tan,† Lu Bai,† Pin Ding, Jingjing Liu, Yaoyu Wang, Xinjun Luan*
Abstract: A novel palladium-catalyzed [4+1] spiroannulation was
developed by using a C(sp3)–H activation/naphthol dearomatization
approach. This bimolecular domino reaction of two aryl halides was
realized through a sequence of cyclometallation-facilitated C(sp3)–H
activation, biaryl cross-coupling, and naphthol dearomatization, thus
rendering the rapid assembly of a new class of spirocyclic molecules
in good yields with broad functional group tolerance. Preliminary
mechanistic studies indicated that C-H cleavage is likely involved in
the rate-determining step, and the five-membered palladacycle was
identified as the key intermediate for the intermolecular coupling.
palladacycles (Aa-Ac) from an aryl iodide via C-H cleavage, and
subsequent homo- or cross-couplings with another aryl halide
(Ara-Arc or Ar'X) to generate biaryl-containing species (Ba-Bc) for
further elaboration (Scheme 2).[6-8] Noteworthy, Pd/norbornene
(NBE) catalysis, namely the Catellani reaction, has proven to be
a powerful approach for the rapid assembly of a large number of
biaryl-embraced molecules through the bisfunctionalization of
aryl iodides, by taking advantage of the unique reactivity of aryl-
NBE-PdII intermediate Aa (Scheme 2a).[6] Very recently, Lautens
first illustrated that palladacycle Ab, which was formed through
intramolecular Heck-cyclization/C(sp2)–H activation, was able to
couple with aryl iodides to furnish a variety of polycyclic products
(Scheme 2b).[7,9] In contrast, catalytically bimolecular coupling of
aryl halides facilitated by palladacycle Ac has been dramatically
limited, although a number of elegant intra- and intermolecular
processes have been realized on the basis of cyclopalladation of
2-tert-butyl aryl halides through C(sp3)–H cleavage.[10] To our
knowledge, all the known examples were disclosed in the seminal
report by Dyker,[8] which are one homo-coupling with 2-iodo-tert-
butylbenzene and three cross-couplings with electron-rich aryl
bromides, affording ortho-arylated benzocyclobutenes in acceptable
yields (Scheme 2c). In connection with our persistent interest in
the development of transition-metal-catalyzed dearomatization
reactions,[3,11] we postulated that using bromophenol derivatives,
which possess great potential to serve as one carbon synthons
via biaryl cross-coupling[12] and subsequent dearomatization,[3d]
to react with in situ generated palladacycle Ac would lead to an
unique [4+1] spiroannulation. The main issue for such a process
is if -alkyl-PdII species Bc could preferentially undergo alkylative
dearomatization, rather than giving rise to benzocyclobutene via
C(sp2)–H alkylation. Here, we present our efforts on this subject.
Transition-metal-catalyzed dearomatization is of great interest
since it allows to convert readily available aromatic feedstocks
into partially saturated three-dimensional architectures.[1] From a
synthetic standpoint, a cooperative strategy by combining C–H
activation[2] together with arene dearomatization represents a
rather economical approach to streamline chemical synthesis by
enabling the use of simpler starting materials and offering novel
synthetic disconnections. Consequently, several metal-catalyzed
transformations within this category were recently developed by
us[3] and others[4] through the incorporation of C(sp2)–H bond
activation, affording a plethora of novel molecular frameworks. In
sharp contrast, the development of such processes involving the
functionalization of alkane C(sp3)–H bond, which is lack of direct
interaction from the metal center,[5] is still a daunting challenge.
In this context, we wish to report an unprecedented example of
palladium-catalyzed [4+1] spiroannulation through a C(sp3)–H
activation/naphthol dearomatization domino process (Scheme 1).
Scheme 1. C(sp3)–H Activation/arene dearomatization reaction (this work).
The key to success of this proposal is the involvement of an
electron-rich palladacyclic intermediate A for enabling the cross-
coupling of two electrophilic aryl halide components. In fact, this
reaction design was inspired by the tremendous achievements
in the area of catalytic generation of C(sp2)–PdII–C(sp3)-involved
[*]
B. Tan,[†] L. Bai,[†] P. Ding, J. Liu, 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
Prof. Dr. X. Luan
State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin, 300071 (China)
Scheme 2. Catalytic processes involving electron-rich palladacycles.
[†]
These authors contributed equally to this work.
Stimulated by the aforementioned challenges, we initiated
the studies by investigating the reaction of 1a with 2a (Table 1).
Supporting information for this article is given via a link at the end
of the document.
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10.1002/anie.201813202
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Table 2. Scope with respect to aryl iodides.
Gratifyingly, the anticipated [4+1] spiroannulation was realized
by a catalytic system consisting of Pd(OAc)2, PPh3, CsOPiv, and
Cs2CO3 in DMF at 130 C, affording product 3a in 34% yield
(entry 1). Its structure was confirmed by X-ray crystallography.[13]
Further studies revealed that the ligands had a critical impact on
both reactivity and selectivity (entries 2-8). Use of more electron-
rich monophosphines led to the formation of 3a in higher yields
(entries 2-3), but the efficiency was eroded by the concomitant
generation of 4a through homo-coupling of 1a.[8] Bisphosphine
ligands were applicable for this process, but no superior results
were given (entries 6-8). Overall, electron-deficient P(p-F-C6H4)3
turned out to be the better ligand (entry 5). Moreover, attempts
by using other palladium sources and bases didn’t improve the
reaction (entries 9-13). Much to our delight, the use of organic
phosphoric acids, which were identified as the enhancement
additives for Pd-catalyzed C(sp3)–H alkylation processes,[14] was
able to greatly promote the reaction (entries 14-15). Replacing
CsOPiv with (BnO)2PO2H, the yield of 3a was increased to 83%.
Additionally, it should be noted that the run with bromo-substrate
1a' proceeded properly to give 3a in 53% yield (entry 16).
Table 1. Optimization of the reaction conditions.
Yield(%)[a]
Entry
[Pd]
Ligand
Base
Additive
3a 4a
34
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PPh3
PCy3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
5
50 18
42 21
P(p-Anisyl)3
P(o-Tol)3
P(p-F-C6H4)3 Cs2CO3
BINAP
DPPM
DPPE
P(p-F-C6H4)3 Cs2CO3
P(p-F-C6H4)3 Cs2CO3
23
63
2
4
Cs2CO3
Cs2CO3
Cs2CO3
49 11
31
29
3
5
27 15
Pd2(dba)3
9
31
0
0
9
2
[Pd(allyl)Cl]2 P(p-F-C6H4)3 Cs2CO3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
P(p-F-C6H4)3 Na2CO3
P(p-F-C6H4)3 K2CO3
P(p-F-C6H4)3 Cs2CO3
P(p-F-C6H4)3 Cs2CO3
P(p-F-C6H4)3 Cs2CO3
CsOPiv
12 10
Notably, strong-coordinating free amine didn’t hamper the [4+1]
spiroannulation, albeit in lower yield of 3l. More interestingly, the
reaction with a sterically hindered substrate 1q gave rise to 3e in
47% yield, while the anticipated 3q was nearly not formed. This
abnormal phenomenon, which presumably arises from palladium
migration through palladacycle A and followed by activating the
C(sp2)−H bond ortho to the tert-butyl group, is quite similar to the
previous studies.[10c-d,f-g] Replacing the methyl group of 1q with a
fluoro substituent (1r) allowed the generation of envisioned 3r in
43% yield, along with the formation of 24% of migration product
3r'. The large reaction difference between 1q and 1r indicated
that palladium migration was mainly affected by steric hindrance.
To suppress the formation of such an “abnormal” regioisomer by
preventing the C(sp2)−H activation step, substrate 1s containing
an additional tert-butyl group was synthesized. As expected, the
C(sp3)−H/C(sp2)−H bonds activation/naphthol dearomatization
process was completely shut down, and structurally congested
3s was obtained as the only product through an extremely
challenging step of tetra-ortho-substituted biaryl cross-coupling.
BINA-PO2H
(BnO)2PO2H
(BnO)2PO2H
72
83
53
0
0
0
16[b] Pd(OAc)2
[a] Isolated yields. [b] 1a was replaced by 1-bromo-2-(tert-butyl)benzene (1a').
BINA-PO2H = 1,1ʹ-Binaphthyl-2,2ʹ-diyl hydrogenphosphate.
With the optimized reaction conditions in hand, the substrate
scope was first explored by reacting an important number of aryl
iodides (1a-w) with 2a, and the results proved that this coupling
partner could be varied on both the aromatic ring and the alkyl
moiety, thus providing a new class of spirocyclic molecules (3a-
w) in 31-88% yields (Table 2). With regards to the aryl ring, it
can be substituted on its different positions with a wide spectrum
of functional groups including electron-donating or electron-
neutral methoxy (3b), benzyloxy (3c), phenylthio (3d), methyl
(3e,j,q,s), trimethylsilyl (3f), acetyl amino (3k) and free amino (3l)
groups, and electron-withdrawing phenyl (3g), acetyl (3h), chloro
(3i), fluoro (3m,r,r'), formyl (3n), ester (3o) and nitro (3p) groups.
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In comparison to these results, it is notable that the use of
substrates (1b-i) bearing a meta-substituent to the tert-butyl
group all delivered the anticipated products, with the palladium-
migration induced regioisomers being not observed or formed at
neglectable amounts. Finally, it should be mentioned that alkyl
moieties (1j,t-w) other than tert-butyl group were also tolerable,
with the targeted C(sp3)−H bond functionalization all occurred at
the methyl group, affording the desired products 3j and 3t-w in
51-85% yields with 1:1 to 3.7:1 diastereomeric ratios.
Next, we continued to survey the reaction scope with respect
to the 1-bromo-2-naphthols for the [4+1] spiroannulation process
(Table 3). Satisfactorily, the reactions of 2b-k with 1b proceeded
smoothly to give their corresponding products 3a'-j' in 44-81%
yields. Notably, the naphthalene ring could be substituted with
electron-donating groups such as methoxy (3a'-b') and benzyloxy
(3c') groups, methyl (3d'), trimethylsilyl (3e'), phenyl (3f') and 2-
thienyl (3g') groups, and electron-withdrawing groups such as
ester (3h') and chloro (3i') groups. Notably, heterocyclic 5-
bromoquinolin-6-ol (2k) was also tolerated, providing the desired
product 3j' in 72% yield. In particularly, it is remarkable that 4-
bromonaphthalen-1-ol (2l) could undergo [4+1] spiroannulation
with 1b under the identical reaction conditions, leading to the
formation of compound 3k' with a different spirocyclic skeleton,
which was unambiguously elucidated by X-ray crystallography.[13]
less approachable for the palladium center. Much to our delight,
under similar reaction conditions, an interesting spiroannulation
between 2-iodoanisole 5a and 2a took place to give compound
6a[13] in 19% yield (Scheme 3a). Accordingly, such process was
realized through homo-coupling of aryl iodide 5a and followed by
subsequent cross-coupling with aryl bromide 2a, via a sequence
of C(sp3)–H activation, biaryl homo-coupling, C(sp2)–H activation,
biaryl cross-coupling, and naphthol dearomatization. Noteworthy,
the use of 5b, which contains an adjacent substituent to the
methoxy group, allowed the direct bimolecular annulation with
2a to afford anticipated 6b[13] in 33% yield. It needs to mention
that the limited efficiency of these two reactions was caused by
several rather competitive homo-couplings of 2-iodoanisoles.[15]
Table 3. Scope with respect to 1-bromo-2-naphthols.
Scheme 3. Preliminary studies based on C-H activation of methoxy group.
To gain insights into the reaction mechanism, several control
experiments were carried out (Scheme 4). An intramolecular
competition reaction with dimethylated [D3]-1u, bearing one fully
deuterated methyl group, demonstrated kinetic isotope effects
for the formation of both two diastereomers (3ua and 3ub)[13]
(kH/kD = 5.8 & 5.7; Scheme 3a), suggesting that primary methyl
C(sp3)−H bond cleavage was most likely involved in the rate-
determining step. Next, reacting the palladacyle 1aA, which was
prepared by Cámpora’s method,[16] with an equal molar amounts
of BINAP[17] and 2a, gave rise to 3a in 46% yield (Scheme 3b),
thus giving strong evidence for supporting an electron-rich
palladacycle-involved mechanism for the titled transformation.
Inspired by Dyker’s earlier reports on the Pd(0)-catalyzed
homo-coupling of 2-iodoanisoles through C-H bond activation of
methoxy group,[15] we speculated that the simple 2-iodoanisoles
might be able to serve as a four-atom synthon for the titled [4+1]
spiroannulation. Compared to the above studies with 2-iodo-tert-
butylbenzenes, the use of 2-iodoanisoles would be more difficult
for the C-H activation step, since the swinging methoxy group is
Scheme 4. Mechanistic studies.
In conclusion, we have developed an unprecedented Pd(0)-
catalyzed [4+1] spiroannulation reaction, wherein two distinct
aryl halides were used to construct novel spirocyclic scaffolds
through a C(sp3)−H activation/naphthol dearomatization cascade.
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Acknowledgements
We thank the National Science Foundation of China (21672169),
the Key Science and Technology Innovation Team of Shaanxi
Province (2017KCT-37) and the Key Laboratory Project of Xi'an
(201805058ZD9CG42) for financial support.
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Keywords: C-H activation • dearomatization • palladacycle •
domino reaction • palladium
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10.1002/anie.201813202
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
B. Tan, L. Bai, P. Ding, J. Liu, Y. Wang,
X. Luan*
Page No. – Page No.
Palladium-Catalyzed
Intermolecular
[4+1] Spiroannulation via C(sp3)–H
Activation
Dearomatization
and
Naphthol
An unprecedented palladium-catalyzed [4+1] spiroannulation of two types of aryl
halides has been developed for the rapid construction of a new class of spirocyclic
frameworks. This intermolecular domino process was realized through a sequence
of C(sp3)-H cleavage, unsymmetrical biaryl coupling, and naphthol dearomatization.
This article is protected by copyright. All rights reserved.