A chemo- And regioselective Pd(0)-catalyzed three-component spiroannulation

Article abstract of DOI:10.1039/d0cc07389j

A chemo- and regioselective Pd(0)-catalyzed spiroannulation has been successfully developed. The key feature of this method is the use of readily available 1,2-dihaloarenes, alkynes and 2-naphthols for the rapid assembly of spirocarbocyclic molecules. Mechanistic studies revealed that this domino reaction proceeded through a cascade of oxidative addition to Pd(0), alkyne migratory insertion, and 2-naphthol-facilitated dearomatizing [4+1] spiroannulation.

Full text of DOI:10.1039/d0cc07389j

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DOI: 10.1039/D0CC07389J
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A Chemo- and Regioselective Pd(0)-Catalyzed Three-Component
Spiroannulation
Received 00th January 20xx,
Accepted 00th January 20xx
Jiaoyu Wu, Lu Bai,* Lingbo Han, Jingjing Liu, and Xinjun Luan*
DOI: 10.1039/x0xx00000x
A chemo- and regioselective Pd(0)-catalyzed spiroannulation has
been successfully developed. The key feature of this method is the
use of readily available 1,2-dihaloarenes, alkynes and 2-naphthols
for the rapid assembly of spirocarbocyclic molecules. Mechanistic
studies revealed that this domino reaction proceeded through a
cascade of oxidative addition to Pd(0), alkyne migratory insertion,
and 2-naphthol-facilitated dearomatizing [4+1] spiroannulation.
Spirocyclic architectures containing an all-carbon quaternary
center are the structural cores for a large number of functional
molecules that exhibit remarkable biological or photophysical
properties.1-2 As a result, the development of new and efficient
methodologies for their rapid assemblies has evoked growing
interest to synthetic chemists.3 In the past decade, transition
metal-catalyzed dearomatization of phenolic derivatives has
emerged as a useful approach for making spirocarbocycles.4 It
is notable that most of pioneering examples were achieved by
intramolecular design,5-6 while synthetic efficiency was largely
eroded by the fact that a rather complex substrate, being
often obtained by multi-step syntheses, could only lead to a
single spirocyclic product. From the viewpoints of atom- and
step-economy, it is highly desirable to develop intermolecular
protocols for the rapid assembly of diversified spirocycles by
employing different types of simple starting materials.
Scheme 1. Development of Three-component Dearomatizing
[2+2+1] Spiroannulations.
[2+2+1] spiroannulations of 2-naphthols (or halophenols) with
two equivalent of alkynes were developed by Pd(II)- and Pd(0)-
catalysis, respectively.11 By contrast, only a single example of
three-component reaction, which is [2+2+1] spiroannulation of
ortho-substituted aryl iodide, 1-bromo-2-naphthol and alkyne,
was rendered by using Pd(0)/norbornene cooperative catalysis
(Scheme 1a).12 In this context, we herein disclose a new three-
component reaction, which uses diverse dihaloarenes, alkynes
and 2-naphthols for the rapid assembly of a wider spectrum of
spirocarbocycles,13 by simpler Pd(0)-catalysis (Scheme 1b).
Inspired by the studies of Pd(0)-catalyzed reactions with 1,2-
dihaloarenes,14 we tested the feasibility of making spirocycles
Clearly, one major challenge for promoting intermolecular
processes via the involvement of phenol dearomatization is to
control the chemoselectivity by avoiding conventional reaction
pathways.7 Therefore, two-component reactions, which might
cause fewer byproducts, have been first studied. In 2013, we
reported an unprecedented example of Ru(II)-catalyzed [3+2]
spiroannulation of phenol-based biaryls with alkynes by using
a C-H activation/dearomatization strategy.8 Later on, it was
found that such transformation could be promoted by Rh(III)-
and Pd(II)-catalysis.9-10 To further simplify the phenolic partner,
with 1-bromo-2-iodobenzene (1a), 1,2-diphenylethyne (2a
)
and 2-naphthol (3a) (Table 1). Gratifyingly, it was found that an
attractive [2+2+1] spiroannulation took place efficiently to give
product 4a in 90% yield with a combination of Pd(OAc)2 (5.0
mol%), dppp (6.0 mol%), and K3PO4 (2.0 equiv.) in 1,4-dioxane
at 130 C for 16 h (entry 1). Control experiments revealed that
other palladium sources like Pd2(dba)3 and [Pd(allyl)Cl]2 didn’t
show comparable results as Pd(OAc)2 (entries 2-3). Further
studies by replacing the ligand with PPh3, dppe and dppb led
to decrement for the reaction efficiency (entries 4-6). Notably,
the reaction was also able to proceed under simple ligand-free
conditions, giving 4a in 82% yield (entry 7). Moreover, attempt
with other bases couldn’t improve the reaction, and the use of
Cs2CO3 or Na3PO4 shut down the process (entries 9-10). In
addition, solvent screening showed that DMF and THF were
applicable (entries 11-12), but not better than 1,4-dioxane, for
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the titled [2+2+1] spiroannulation. Thereby, the reaction scope efficient for dihaloarenes bearing an electron-doVnieawtiAnrtgiclegOronluinpe
DOI: 10.1039/D0CC07389J
was surveyed under both conditions A and B at the same time.
(4b,c,f), while it was necessary to involve the dppp ligand for
Table 1. Optimization of the reaction conditionsa
reactions with electron-deficient dihaloarenes to obtain good
yields for the desired products (4e
Table 3. Scope of alkynes
,g-l).
Entry Variation from the standard conditions Yield (%)b
1c
2
3
4
5
None
90
0
Pd2(dba)3 instead of Pd(OAc)2
[Pd(allyl)Cl]2 instead of Pd(OAc)2
PPh3 instead of dppp
26
62
69
77
82
45
0
0
54
61
dppe instead of dppp
dppb instead of dppp
6
7d
8
without dppp
K2CO3 instead of K3PO4
Cs2CO3 instead of K3PO4
Na3PO4 instead of K3PO4
DMF instead of 1,4-dioxane
THF instead of 1,4-dioxane
9
10
11
12
a0.3 mmol 1a, 0.3 mmol 2a, 0.2 mmol 3a, 5.0 mol% [Pd] and
6.0 mol% L were used. bIsolated yield. cMethod A. dMethod B.
Table 2. Scope of 1-bromo-2-iodobenzenes
Next, we turned our attention to the scope of alkynes
2 and
the experimental data are shown in Table 3. Overall, a broad
range of symmetrical alkynes, bearing various aromatic,
heterocyclic and aliphatic groups, underwent the titled [2+2+1]
spiroannulations with 1a and 3a quite efficiently, affording the
desired products 4a'-m' in high yields. Although there was no
clear trend by using different conditions, these two methods
could give complementary results for certain alkynes. To unveil
the potential on controlling alkyne migratory insertion, some
unsymmetrical alkynes were tested. As expected, products
4n'-p' could be obtained in good yields, but regioselectivities
were rather low. When an alkyl/vinyl mixed alkyne was used,
product 4q' was formed as single regioisomer, with method B
giving a higher yield. To our delight, the reaction with aryl/silyl
mixed alkynes could also lead to products 4r'-s' as single
regioisomer,15 and alkynes were installed in a steric-controlled
fashion that silyl group is close to the spirocyclic center, which
is consistent with literature precedents.16
Having examined the scope of 1-bromo-2-iodobenzenes and
alkynes, we investigated the tolerance of functional groups on
the 2-naphthol. As shown in Table 4, a variety of substituents
First, we explored the scope of 1-bromo-2-iodobenzenes (1)
(Table 2). Gratifyingly, by reacting 1b-m with 2a and 3a, a
number of spirocyclic products 4b-m could be prepared in
good yields (up to 88%) with exclusive regioselectivities (>19:1
rr for all the cases). Various substituents on the phenyl ring
including electron-donating methoxy (4a''
,l'',n'') and silyl (4b''-
c'') groups, and electron-withdrawing groups such as phenyl
(4d''), 2-thienyl (4e''), chloro (4f''
,o''), bromo (4g'',m''), formyl
were well tolerated, including electron-donating methoxy (4b
and methyl (4c) groups, and electron-withdrawing groups such
as a fluoro (4d ), ester (4e ), chloro (4h), trifluoromethoxy
4i), acetyl (4j) and cyano (4l) group. Noteworthy, all the
,f)
(4h''), acetyl (4i''), ester (4j'') and cyano (4k'') groups could be
introduced on the 3-, 6- and 7-positions of naphthyl ring. The
ligand-free method B was generally applicable, but dppp was
occasionally required for getting better reaction performance.
It is notable that chloro-group was well tolerated under ligand-
free conditions, affording the desired 4f'' and 4o'' in 82% and
75% yield, respectively. More strikingly, substrates bearing a
more reactive bromo-group, which might serve as a useful
,g,
m
,k
(
reactions led to a single product, which was strictly controlled
by the two halides in a site-specific manner. This statement
was strongly supported by single-crystal X-ray crystallographic
studies on 4e and 4k 15
Overall, methods A and B were both
.
2 | J. Name., 2012, 00, 1-3
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handle for further derivatization,13c behaved smoothly to give This outcome implied: i) alkyne
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2
reacted more preferentially
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products 4g'' and 4m'' in high yields. In addition, it should be than naphthol
mentioned that heterocyclic quinolin-6-ol could participate generated from
well in the [2+2+1] spiroannulation to provide 4p'' in 40% yield. producing Pd(0)-catalyst and formally reduced products
3
towards the aryl-Pd(II) sDpOecI:i1e0s.1t0h3a9t/Dw0aCsC0in73s8i9tuJ
1
; ii) naphthol
3
should be the reductant for
and
. Next, 3a was mixed with Pd(OAc)2, leading to dinaphthol 8
5
Table 4. Scope of 2-naphthols
7
in 18% yield and expected active Pd(0)-species (Scheme 2c).17
Remarkably, when 1aIII was combined with 2a and 3h, the
titled [2+2+1] spiroannulation proceeded to give 4g'' in 22%
yield (Scheme 2d). Moreover, the reaction with 1o, which
contains one more bromo-group in comparison to 1aIII, took
place to afford 4n in 37% yield (Scheme 2e). These results
indicated that aryl chloride reacted smoothly in the presence
of a generally more active bromo-functionality being involved
at different partners. Presumably, such a unique reactivity was
possibly enabled by intramolecularly directed activation of
CCl bond to accelerate its oxidative addition.
Inspired by the tolerance of additional bromo-substituent
on the naphthyl ring, we tested more 1,2-dihalobenzenes for
this transformation. As shown in Table 5, 1,2-diidobenzene 1aI
and 1,2-dibromobenzene 1aII were well suited for the titled
[2+2+1] spiroannulation, giving rise to the desired 4a in similar
yields by these two methods (entries 1-2). To our surprise, 1-
chloro-2-iodobenzene 1aIII and 1-chloro-2-bromobenzene 1aIV
,
bearing a far less reactive chloro-group, were found to be
applicable as well, providing product 4a in acceptable yields
(entries 3-4). Notably, 1,2-dichlorobenzene 1aV was unreactive
(entry 5), which indicated that such a domino process couldn’t
be triggered by the oxidative addition to aryl chloride to Pd(0).
Table 5. Scope of 1,2-Dihalobenzenes
Yield(%) of 4a
Entry
1aI-V
X
X'
A | B
Scheme 2. Mechanistic studies
1
2
3
4
5
1aI
I
Br
I
Br
Cl
I
74% | 78%
43% | 44%
58% | 47%
40% | 8%
0% | 0%
1aII
1aIII
1aIV
1aV
Br
Cl
Cl
Cl
Based on the above results and prior reports,8-12 a plausible
reaction pathway for the formation of product
4 is shown in
Scheme 3. First, active Pd(0)-catalyst is generated by reduction
of Pd(OAc)2 with naphthol 3a. Afterwards, oxidative addition
occurs at the more active iodo-site of 1-bromo-2-iodobenzene
To shed light on the reaction mechanism, a series of control
experiments were performed (Scheme 2). When compound 1n
was reacted with 2a and 3a under both the two conditions, 1:1
mixtures of products 4b and 4f were obtained (Scheme 2a),
indicating that the methoxyl group of 1n didn’t affect its initial
(1) to give arylpalladium species I. At this stage, two reaction
modes might be considered: a) coordination and migratory
insertion of alkyne 2a provides intermediate II; b) electrophilic
palladation of 3a takes place to generate II'. According to the
oxidative addition of C
to controlling the regiochemistry. So it is believed that the
excellent regiochemistry for 1-bromo-2-iodobenzenes (1b-m
I bond to Pd(0) and couldn’t contribute
regiochemistry for 1, the first mode is reasonable while the
second one could be excluded. Subsequently, intermediate II
undergoes electrophilic palladation with naphthol 3a, followed
)
was just controlled by the position of two halides. Thereby, the
reaction should be triggered from aryl iodide, and proceed via
by tautomerization and reductive elimination to deliver V. At
the same time, active Pd(0)-catalyst is regenerated. Next, it is
assumed that the hydroxyl group would direct Pd(0)-species to
facilitate regioselective oxidative addition of aryl halide V. The
intermediate VI then undergoes dearomative ring-contraction
migratory insertion of alkyne
and 3a led to dehalogenated products 5-7, which were not
found in the standard reaction with 1a 2a and 3a (Scheme 2b).
2. Notably, a control run with 1a
,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Chemistry; Astruc, D., Ed.; Wiley-VCH, Weinheim, Germany,
to give spirocyclic VII. Finally, reductive elimination takes place
View Article Online
2002; p 539.
to form product
isolated, control runs with analogue
10 were able to give dearomative spiroannulation product
4
. Although plausible intermediate
and its Cl-counterpart
in
V was not
2
For two recent examples, see: (a) Z. ZDhOoIu: ,10S..10X3ie9/,DX0.CCCh0e7n38,9YJ.
Tu, J. Xiang, J. Wang, Z. He, Z. Zeng and B. Z. Tang, J. Am.
Chem. Soc., 2019, 141, 9803; (b) R. P. Kaiser, D. Nečas, T.
Cadart, R. Gyepes, I. Císařová, J. Mosinger, L. Pospíšil and M.
Kotora, Angew. Chem. Int. Ed., 2019, 58, 17169.
For reviews, see: (a) V. A. D’yakonov, O. A. Trapeznikova, A.
Meijere, U. M. Dzhemilev, Chem. Rev., 2014, 114, 5775; (b)
A. Ding, M. Meazza, H. Guo, J. W. Yang and R. Rios, Chem.
Soc. Rev., 2018, 47, 5946.
9
5
reasonable yields (Scheme 4). These results clearly supported
the above proposed reaction pathway. In addition, based on
3
4
the behavior of electron-deficient substrates (1e
the methods A and B, it is believed that dppp should be more
helpful for promoting the reductive elimination from VII to
thus enhancing the yield of corresponding products (4e g-k).
,g-k) by using
4
,
,
For reviews, see: (a) C. Zhuo, W. Zhang, and S. You, Angew.
Chem. Int. Ed., 2012, 51, 12662; (b) C. Zhuo, C. Zheng and S.
You, Acc. Chem. Res., 2014, 47, 2558; (c) T. Nemoto and Y.
Hamada, Synlett, 2016, 27, 2301; (d) W. Wu, L. Zhang and S.
You, Chem. Soc. Rev., 2016, 45, 1570; (e) W. Sun, G. Li, L.
Hong and R. Wang, Org. Biomol. Chem., 2016, 14, 2164; (f)
C. Zheng and S. You, Chem., 2016,
For pioneering examples, see: (a) T. Nemoto, Y. Ishige, M.
Yoshida, Y. Kohno and Y. Hamada, Org. Lett., 2010, 12
1, 830.
5
6
,
5020; (b) S. Rousseaux, J. García-Fortanet, M. A. Del Aguila
Sanchez and S. L. Buchwald, J. Am. Chem. Soc., 2011, 133,
9282; (c) Q. Wu, W. Liu, C. Zhuo, Z. Rong, K. Ye and S. You,
Angew. Chem. Int. Ed., 2011, 50, 4455.
For examples, see: (a) A. Rudolph, P. H. Bos, A. Meetsma, A.
Minnaard and B. L. Feringa, Angew. Chem., Int. Ed., 2011,
50, 5834; (b) T. Nemoto, Z. Zhao, T. Yokosaka, Y. Suzuki, R.
Wu and Y. Hamada, Angew. Chem. Int. Ed., 2013, 52, 2217;
(c) M. J. James, J. D. Cuthbertson, P. O’Brien, R. J. K. Taylor
and W. P. Unsworth, Angew. Chem. Int. Ed., 2015, 54, 1; (d)
R. Xu, P. Yang and S. You, Chem. Commun., 2017, 53, 7553.
For examples, see: (a) Y. Suzuki, T. Nemoto, K. Kakugawa, A.
Hamajima, Y. Hamada, Org. Lett., 2012, 14, 2350; (b) Q. Xu,
L. Dai and S. You, Org. Lett., 2012, 14, 2579.
7
Scheme 3. Proposed mechanism
8
9
J. Nan, Z. Zuo, L. Luo, L. Bai, H. Zheng, Y. Yuan, J. Liu, X.
Luan and Y. Wang, J. Am. Chem. Soc., 2013, 135, 17306.
(a) A. Seoane, N. Casanova, N. Quiñones, J. L. ascare as
and M. Gulías, J. Am. Chem. Soc., 2014, 136, 7607; (b) S.
Kujawa, D. Best, D. J. Burns, H. W. Lam, Chem. Eur. J., 2014,
20, 8599; (c) J. Zheng, S. Wang, C. Zheng and S. You, J. Am.
Chem. Soc., 2015, 137, 4880.
Scheme 4. Control experiments with 9 and 10.
10 L. Han, H. Wang and X. Luan, Org. Chem. Front., 2018, 5,
In summary, we have developed a novel Pd(0)-catalyzed
dearomative [2+2+1] spiroannulation reaction, which offers an
unprecedented pathway for the rapid assembly of spirocyclic
molecules from three rather simple chemical feedstocks in an
intermolecular manner. Remarkably, the regiochemistry of this
domino transformation, with respect to both 1,2-dihaloarene
and alkyne coupling partners, could be selectively controlled
by the precise variation of their structures.
2453.
11 (a) S. Gu, L. Luo, J. Liu, L. Bai, H. Zheng, Y. Wang and X. Luan,
Org. Lett., 2014, 16, 6132; (b) L. Bai, Y. Yuan, J. Liu, J. Wu, L.
Han, H. Wang, Y. Wang and X. Luan, Angew. Chem. Int. Ed.,
2016, 55, 6946.
12 Z. Zuo, H. Wang, L. Fan, J. Liu, Y. Wang and X. Luan, Angew.
Chem. Int. Ed., 2017, 56, 2767.
13 For applications of spirocarbocycles, see: (a) G. B. Jones, Y.
Lin, Z. Xiao, L. Kappen and I. H. Goldberg, Bioorg. Med.
Chem., 2007, 15, 784; (b) Y. Zhang, H. Ge, W. Zhao, H. Dong,
Q. Xu, S. Li, J. Li, J. Zhang, Y. Song and R. Tan, Angew. Chem.
Int. Ed., 2008, 47, 5823; (c) H. Wang, Y. Liu, W. Hu, W. Xu, P.
Wang, Y. Wang and Luan, X. Org. Electron., 2018, 61, 376.
14 (a) J. Barluenga, A. Jiménez-Aquino, F. Aznar and C. Valdés,
J. Am. Chem. Soc., 2009, 131, 4031; (b) T. Liu, C. Xing and Q.
Hu, Angew. Chem. Int. Ed., 2010, 49, 2909.
This work was supported by NSFC (21925108, 21901203),
Key Laboratory of Xi'an (201805058ZD9CG42) and Education
Department of Shaanxi Province (18JS108, 20JK0934).
Conflicts of interest
There are no conflicts to declare.
15 CCDC 1978474 (4e), 1978473 (4k) and 1978475 (4s'
)
contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystal-lographic Data Centre.
Notes and references
16 For an early example, see: R. C. Larock, E. K. Yum, M. J.
Doty and K. K. C. Sham, J. Org. Chem., 1995, 60, 3270.
1
(a) J. A. Marshall, S. F. Brady and N. H. Andersen, The
Chemistry of Spiro[4.5]decane Sesquiterpenes. In
Fortschritte der Chemie Organischer Naturstoffe; Springer-
Verlag: New York, 1974; (b) S. Quideau, In Modern Arene
17 No related dinaphthols were formed, when 3b
,
3c and 3o
were respectively mixed with Pd(OAc)2 under the same
conditions. So the formation of corresponding 4a''
4n'' couldn’t be enabled by the ligand-free method B.
,
4b'' and
4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC07389J
A novel Pd(0)-catalyzed three-component [2+2+1] dearomatizing reaction for the highly chemo-
and regio-selective assembly of spirocarbocycles is described.