Palladium-Catalyzed Spirocyclization through C?H Activation and Regioselective Alkyne Insertion

Article abstract of DOI:10.1002/anie.201706325

A Pd-catalyzed spirocyclization involving a sequential carbopalladation, intramolecular C?H activation, and a highly regioselective alkyne insertion to afford spirooxindoles and spirodihydrobenzofurans has been achieved. The spirocyclic products were generated in good to excellent yields with complete regiocontrol in a readily scalable procedure.

Full text of DOI:10.1002/anie.201706325

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Accepted Article
Title: Pd-Catalyzed Spirocyclization via C-H Activation and
Regioselective Alkyne Insertion
Authors: Hyung Yoon, Martin Rolz, Felicitas Landau, and Mark Lautens
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706325
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10.1002/anie.201706325
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Pd-Catalyzed Spirocyclization via C–H Activation and
Regioselective Alkyne Insertion
Hyung Yoon, Martin Rölz, Felicitas Landau, and Mark Lautens*[a]
Dedication ((optional))
Abstract: A Pd-catalyzed spirocyclization involving a sequential
carbopalladation, intramolecular C–H activation and highly
generating spirooxindoles and spirodihydrobenzofurans in good
to excellent yields under high regiocontrol.
a
regioselective alkyne insertion to afford spirooxindoles and
spirodihydrobenzofurans has been achieved. The spirocyclic
products were generated in good to excellent yields with complete
regiocontrol in a readily scalable procedure.
The use of C–H functionalization to enable the synthesis of
novel scaffolds has become commonplace in modern organic
chemistry and results in the improvement of both step- and atom-
economy.[1] The vast majority of progress made in this field has
relied on the use of a preinstalled directing group which greatly
improve selectivity and reactivity.[2-4] The functionalization of C–H
bonds in an intramolecular fashion, wherein oxidative addition to
a carbon–halogen bond situates the metal centre in a favourable
position to interact with a chosen C–H bond.[5] Despite the
remarkable progress made in this field, selective functionalization
remains a challenge. In this regard, the application of C–H
functionalization in a domino process has extended the versatility
and applicability of the reaction as it enables the metal centre to
interact with remote bonds that may otherwise be unreactive.[6-10]
Employing this approach, we present a novel Pd-catalyzed
spirocyclization reaction.
Scheme 1. Pd-catalyzed spirocyclization via C–H activation and insertion of π-
system.
We began our study by synthesizing the proposed
spirooxindole based on the reaction conditions outlined by
Malinkova (Scheme 2).[16] Subjecting 1a’ to these reaction
conditions gave 3a in 14% yield and trace amounts of 3a’. The
spirocyclic structure of 3a was confirmed by spectroscopic
analysis and single crystal X-ray crystallography.[17] Encouraged
by this initial result, the reaction conditions were optimized to yield
3a in 79% yield and >20:1 ratio of regioisomers (rr) while
minimizing the formation of side products.[18]
Recently, our group and the García-López group have
employed C–H functionalization in a domino process to generate
spirocycles via carbopalladation, C–H activation, and migratory
insertion or direct reductive elimination sequence.[11-14]
Unfortunately, diastereo- and regioselective migratory insertion
into the palladacycle involving highly reactive intermediates have
proven to be challenging. In 2014, Garg and co-workers[15] have
experimentally and computationally reported that unsymmetrical
and electronically biased arynes show excellent regioselective
addition reactions whereas in our study,[12,13] these arynes
undergo the migratory insertion in poor regiocontrol (Scheme 1,
A). Following this work, the García-López group reported the
spirocyclization involving α-diazocarbonyl compounds albeit in
modest diastereoselectivity (Scheme 1, B).[14] As a solution to
circumvent the lack of selectivity observed in the described
reactions, we sought to investigate less reactive π-systems
(Scheme 1, C). Herein, we showcase the Pd-catalyzed
spirocyclization via the insertion of unsymmetrical alkynes
Scheme 2. Initial result and optimized conditions.
[a]
H. Yoon, M. Rölz, F. Landau, Prof. Dr. M. Lautens
Department of Chemistry, Davenport Chemical Laboratories
University of Toronto
80 St. George Street, Toronto, Ontario M5S 3H6 (Canada)
E-mail: mlautens@chem.utoronto.ca
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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With the optimized conditions in hand, the generality of the
methodology was explored (Scheme 3). Unless stated otherwise,
all spirocycles were generated in >20:1 rr. On gram scale, 3a was
synthesized in 74% yield, however, a longer reaction time was
necessary for the full consumption of 1a. Fluorinated acrylamide
1b provided 3b in 74% yield. Electron-rich substituents were
tolerated and gave 3c and 3d in moderate yields (61% and 62%
yield respectively). Other nitrogen protecting groups such as –Bn
and –MOM were tolerated in the cyclization (3e and 3f, 73% and
76% yield respectively). Substitution by a pyridinylbromide did not
impede the generation of 3g. Electron-rich substituents on the
pendant aromatic ring aided in the cyclization forming 3h in 88%
yield. A tethered thiophene group participated in the C–H
Internal alkynes other than ethyl phenylpropiolate were also
investigated (Scheme 4). The insertion of ethyl 2-butynoate
provided 3k in 85% yield. Substitution of the ester to a non-
enolizable ketone generated 3l in 79% yield. Indole derived
alkyne 2d was incorporated to give 3m in excellent yield (90%
yield) while the Weinreb amide 2e required higher temperature to
generate 3n (120 ºC, 78% yield). Phenylpropionitrile reacted in
good yield albeit with slightly lower regioselectivity (3o, 84% yield,
9:1 rr). The diaryl alkyne 2g underwent the regioselective insertion
at elevated temperatures to give 3p in 63% yield. The connectivity
was confirmed by spectroscopic analysis and X-ray
crystallography.[17] The 4-trifluoromethyl-2-pyridine bearing
alkyne 2h gave 3q in 68% yield at elevated temperature.[19] Less
activated internal alkynes did not participate in the reaction.[20]
activation forming 3i in moderate yield.
Ph
EtO2C
Br
Pd(PPh3)4 (10 mol%)
Cs2CO3 (1.5 equiv)
R2
O
Ph
R1
R2
N
R5
PhMe, 100 °C
0.1 M, 24 h
EtO2C
R1
O
N
R5
1a - 1h
1 equiv
2a
2.0 equiv
3a - 3i
>20:1 rr
Ph
Ph
Ph
EtO2C
EtO2C
EtO2C
R
O
O
O
N
O
N
N
O
Me
Me
, 74% yield (
R = OMe, 61% yield (3c)
Me
3a
3a
R
F
3b
3d
79% yield (
)
X-ray
=
)
62% yield ( )
74% yielda,b
Ph
Ph
Ph
N
Ph
EtO2C
OMe
EtO2C
EtO2C
EtO2C
S
O
O
O
O
N
N
R
N
N
Me
88% yieldb
Me
3g
Me
3i
3h
(
)
R
R
Bn
3e
=
=
, 73% yield (
, 76% yield (
)
3f
)
67% yield (
)
56% yield (
)
MOM
Scheme 3. Pd-catalyzed spirocyclization forming spirooxindoles. Reaction
scope with varied acrylamides. 0.2 mmol scale. All yields refer to isolated
proucts. rr values determined by 1H NMR analysis of the crude reaction mixture.
[a] Reaction run on 3.16 mmol scale. [b] Reaction run for 48 h.
Scheme 5. Pd-catalyzed spirocyclization forming spirooxindoles. Reaction
scope with varied internal alkynes. 0.2 mmol scale. All yields refer to isolated
products. rr values determined by 1H NMR analysis of the crude reaction mixture.
Surprisingly, functionalization of the pendant aromatic ring
with electron-poor substituents interfered in the generation of the
desired spirooxindole (Scheme 4). Intrigued by this result,
palladacycle 3j’ was independently synthesized (Scheme 4, A).
The subsequent reaction with the model alkyne led to full
consumption of 3j’ however, no desired spirooxindole 3j was
formed. This suggests that the insertion of the alkyne is kinetically
disfavoured with respect to the decomposition of 3j’.
Following
the
success
making
spirooxindoles,
spirodihydrobenzofurans were also targeted (Scheme 5). Using
the aryliodide 4a, 5 mol% of Pd(PPh3)4, and slight excess of
Cs2CO3 and alkyne 2a, 5a was generated in 88% yield and 20:1
rr.[17] On gram-scale, 5a was isolated in 94% yield with identical
regioselectivity. Sterically encumbered aryliodide 4b reacted in
good yield (83% yield). In the presence of a second halogen, the
cyclization generated 5c in 88% yield. The spirocyclic structure
was confirmed by spectroscopic analysis and x-ray
crystallography.[17] Electron-rich substituents on the aryliodide
and pendant aromatic ring cyclized in good to excellent yields (5d
and 5f, 75% and 92% yield respectively). Electron-poor
substituents on the aryliodide or tethered aromatic ring required
longer reaction times and gave moderate yields (5e and 5g, 66%
and 55% yield respectively). N-tosyl spiroindoline was cyclized in
good yield (5h, 83% yield).
Scheme 4. Stepwise Pd-catalyzed spirocyclization. All reactions run on 0.2
mmol scale. Yield refers to isolated proucts.
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10.1002/anie.201706325
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COMMUNICATION
In analogy to the benzyne insertion spirocyclization, the
mechanism is thought to proceed via a similar sequence (Scheme
7). Acrylamide 1a undergoes oxidative addition followed by a 5-
exo trig carbopalladation forming the alkylpalladium(II)
intermediate B. The generation of B places the Pd center in close
proximity to the pendant aromatic ring to generate the spirocyclic
palladacycle C via C–H activation. A regioselective migratory
insertion of the activated alkyne predominantly generates
palladacycle D and trace amounts of E.[22] Lastly, reductive
elimination releases 3a and 3a’ and regenerates the catalyst.
3a + 3a'
1a
Pd0
O
Ph
CO2Et
EtO2C
PdII
Ph
N
PdII Me
PdII
A
O
O
N
N
Me
D
Me
E
Scheme 6. Pd-catalyzed spirocyclization forming spirodihydrobenzofurans.
Reaction scope with varied aryliodides. 0.2 mmol scale. All yields refer to
isolated products. rr values determined by 1H NMR analysis of the crude
reaction mixture. [a] Reaction run on 2.97 mmol scale. [b] Reaction run for 24 h.
PdII
N
PdII
O
EtO2C
Me
O
B
Ph
N
Me
C
Cs2CO3
CsBr,
CsHCO3
Alkynes 2b - 2h were also probed for the synthesis of
spirodihydrobenzofurans (Scheme 6). Ethyl 2-butynoate
generated 5i in 83% yield. The phenyl ketone substituted alkyne
2c inserted to form 5j in good yield (84% yield). Spirocycles 5k
and 5l were successfully synthesized in excellent yield via the
insertion of alkynes 2d and 2e respectively. Unlike the selectivity
observed with the spirooxindole, nitrile bearing spirocycle 5m was
generated in >20:1 rr. Diaryl alkyne 2e participated in the reaction
to give 5n in 83% yield. The 5-trifluoromethyl-2-pyridine bearing
alkyne also provided the desired spirocycle but required an
extended reaction time.[21]
Scheme 8. Postulated mechanism for the spirocyclization.
Palladacycle C, which was synthesized previously in our
group,[12] reacted with ethyl phenylpropiolate to afford 3a in 75%
yield and >20:1 rr (Scheme 8). This result suggests that this
complex is a likely intermediate in the catalytic cycle and the
consistent regioselectivity observed further supports to the
proposed mechanism.
Ph
PPh3
EtO2C
Ph3P Pd
Ph
EtO2C
(2 equiv)
O
O
PhMe, 100 °C, 24 h
N
N
Me
C
Me
75% NMR yield (3a)
>20:1 rr
Scheme 9. Stoichiometric experiment forming the spirooxindole via the
preformed palladacycle. 0.1 mmol scale. Yield was determined by 1H NMR
spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.
In conclusion, we have developed
a
Pd-catalyzed
spirocyclization via C–H activation and alkyne insertion forming
spirooxindoles and spirodihydrobenzofurans. Various functional
groups were tolerated and the products were synthesized in good
to excellent yields and excellent rr (>20:1). Analagous to the
previous work incorporating arynes, the transformation is thought
to proceed through the generation of the spirocyclic palladacycle
followed by a highly regioselective insertion of the alkyne. We are
currently working on expanding the scope of the reaction and the
application of this transformation. We are currently carrying out a
comprehensive study on the mechanism of this class of reactions.
Scheme 7. Pd-catalyzed spirocyclization forming spirodihydrobenzofurans.
Reaction scope with varied internal alkynes. 0.2 mmol scale. All yields refer to
isolated products. rr values determined by 1H NMR analysis of the crude
reaction mixture. [a] Reaction run for 24 h.
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[7]
a) J. Ye, M. Lautens, Nat. Chem. 2015, 7, 863. b) M. Sickert, H.
Weinstabl, B. Peters, X. Hou, M. Lautens, Angew. Chem. Int. Ed. 2014,
53, 5147.
Acknowledgements ((optional))
We thank the University of Toronto, Alphora Research, Inc., and
the Natural Sciences and Engineering Research Council
(NSERC) for financial support. H.Y. thanks the Ontario Graduate
Scholarship program for funding. We thank Dr. I. Franzoni, Dr. M.
Wegmann and Y.J. Jang (University of Toronto) for insightful
discussion during the project. We thank Dr. D. A. Petrone (ETH
Zürich) for proofreading the manuscript. We thank Professor J.-A.
García López (Universidad de Murcia) for correspondence on
related work and sharing unpublished results. We thank Dr. Alan
Lough (University of Toronto) for single-crystal X-ray analysis of
3a, 3o, and 4c. We thank Dr. Darcy Burns, Dr. Sergiy Nokhrin,
and Dr. Jack Sheng (University of Toronto) for their assistance in
the variable temperature NMR studies of 3l, 3m, 4k, and 4l.
[8]
[9]
For a comprehensive review and references therein, see: V. P. Mehta,
J.-A. García-López, ChemCatChem. 2017, 9, 1149.
For recent selected examples, see: a) O. René, D. Lapointe, K. Fagnou,
Org. Lett. 2009, 11, 4560. b) Z. Lu, C. Hu, J. Guo, J. Li, Y. Cui, Y. Jia,
Org. Lett. 2010, 12, 480. c) T. Piou, A. Bunescu, Q. Wang, L. Neuville, J.
Zhu, Angew. Chem. Int. Ed. 2013, 52, 12385. d) M. Wang,; X. Zhang, Y.-
X. Zhuang, Y.-H. Xu, T.-P. Loh, J. Am. Chem. Soc. 2015, 137, 1341. e)
W. Kong, Q. Wang, J. Zhu, J. Am. Chem. Soc. 2015, 137, 16028. f) U.
K. Sharma, N. Sharma, Y. Kumar, B. K. Singh, E. V. Van der Eycken,
Chem. Eur. J. 2016, 22, 481. g) X.-X. Wu, W.-L. Chen, Y. Shen, S. Chen,
P.-F. Xu, Y.-M. Liang, Org. Lett. 2016, 18, 1784. h) Z.-Y. Gu, C.-G. Liu,
S.-Y. Wang, S.-J. Ji, Org. Lett. 2016, 18, 2379. i) T. Yao, D. He, Org. Lett.
2017, 19, 842.
[10] For selected examples, see: a) R. Grigg, P. Fretwell, C. Meerholtz, V.
Sridharan, Tetrahedron 1994, 50, 359. b) R. T. Ruck, M. A. Hoffman, M.
M. Kim, M. Shevlin, W. V. Kandur, I. W. Davies, Angew. Chem. Int. Ed.
2008, 47, 4711. c) G. Satyanarayana, C. Maichle-Mossmer, M. E. Maier,
Chem. Commun. 2009, 1571. d) T. Piou, L. Neuville, J. Zhu, Org. Lett.
2012, 14, 3760. e) T. Piou, L. Neuville, J. Zhu, Angew. Chem. Int. Ed.
2012, 51, 11561. f) H. Zheng, Y. Zhu, Y. Shi, Angew. Chem Int. Ed. 2014,
53, 11280.
Keywords: Alkynes • C–H Activation • Palladium •
Regioselectivity • Spiro compounds
[1]
For selected reviews and references therein, see: a) D. Alberico, M. E.
Scott, M. Lautens, Chem. Rev. 2007, 107, 174. b) C. Liu, J. Yuan, M.
Gao, S. Tang, W. Li, R. Shi, A. Lei, Chem. Rev. 2015, 115, 12138. c) J.
F. Hartwig, J. Am. Chem. Soc. 2016, 138, 2. d) N. Della Ca’, M. Fontana,
E. Motti, M. Catellani, Acc. Chem. Res. 2016, 49, 1389.
[11] J. Ye, Z. Shi, T. Sperger, Y. Yasukawa, C. Kingston, F. Schoenebeck, M.
Lautens, Nat. Chem. 2017, 9, 361.
[12] H. Yoon, A. Lossouarn, F. Landau, M. Lautens, Org. Lett. 2016, 18, 6324.
[13] M. Pérez-Gómez, J.-A. García-López, Angew. Chem. Int. Ed. 2016, 55,
14389.
[2]
For selected reviews and references therein, see: a) X. Chen, K. M.
Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094. b)
T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147. c) R. Giri, S.
Thapa, A. Kafle, Adv. Synth. Catal. 2014, 356, 1395. d) Z. Chen, B. Wang,
J. Zhang, W. Yu, Z. Liu, Y. Zhang, Org. Chem. Front. 2015, 2, 1107. e)
T. Gensch, M. N. Hopkinson, F. Glorius, J. Wencel-Delord, Chem. Soc.
Rev. 2016, 45, 2900.
[14] M. Pérez-Gómez, S. Hernández-Ponte, D. Bautista, J.-A. García-López,
Chem. Commun. 2017, 53, 2842.
[15] J. M. Medina, J. L. Mackey, N. K. Garg, K. N. Houk, J. Am. Chem. Soc.
2014, 136, 15798.
[16] J. L. Portscheller, H. C. Malinakova, Org. Lett. 2002, 4, 3679.
[17]
CCDC 1557699 (3a), 1557701 (3p) and 1557700 (5c) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Center.
[3]
[4]
For selected reviews and references therein, see: a) F. Shi, R. C. Larock,
in Remote C–H Activation via Through-Space Palladium and Rhodium
Migrations for C–H Activation (Ed J.-Q. Yu and Z. Shi), Springer,
Heidelberg, 2010, pp. 123-164. b) R. Sharma, K. Thakur, R. Kumar, I.
Kumar, U. Sharma, Catalysis Reviews, 2015, 57, 345.
[18] Refer to the SI for deoptimization table for spirooxindoles and
spirodihydrobenzofurans.
For selected examples, see: a) D. Leow, G. Li, T.-S. Mei, J.-Q. Yu, Nature,
2012, 486, 518. b) R.-Y. Tang, G. Li, J.-Q. Yu, Nature. 2014, 507, 215.
c) X.-C. Wang, W. Gong, L.-Z. Fang, R.-Y. Zhu, S. Li, K. M. Engle, J.-Q.
Yu, Nature. 2015, 519, 334. d) J. J. Topzewski, P. J. Cabrera, N. I. Saper,
M S. Sanford, Nature, 2016. 531, 220. e) Z. Zhang, K. Tanaka, J.-Q. Yu,
Nature. 2017, 543, 538.
[19] Increasing the reaction temperature to 120 ºC led to the 1,4-Pd shift and
C–H activation sequence to generate the side product in higher
quantities. Reference: A. Bunescu, T. Piou, Q. Wang, J. Zhu, Org. Lett.
2015, 17, 334.
[20] The internal unactivated alkynes probed were diphenylacetylene, hex-3-
yne, and 1,4-dimethoxybut-2-yne. Unfortunately, dimethyl but-2-
ynedioate also did not insert.
[5]
For selected reviews and references therein, see: a) R. Giri, B.-F. Shi, K.
M. Engle, N. Maugel, J.-Q. Yu, Chem. Soc. Rev. 2009, 38, 3242. b) O.
Baudoin, Chem. Soc. Rev. 2011, 40, 4902. c) Y. Park, Y. Kim, S. Chang,
Chem. Rev. 2016, DOI: 10.1021/acs.chemrev.6b00644. d) C. G. Newton,
S.-G. Wang, C. C. Oliveira, N. Cramer, Chem. Rev. 2017, DOI:
10.1021/acs.chemrev.6b00692. e) O. Baudoin, Acc. Chem. Res. 2017,
50, 1114.
[21] The benzofused cyclobutane byproduct was observed when reacting the
5-trifluoromethyl-2-pyridine bearing alkyne. Reference: J. Ye, Z. Shi, T.
Sperger, Y. Yasukawa, C. Kingston, F. Schoenebeck, M. Lautens, Nat.
Chem. 2017, 9, 361.
[22] There are 4 possible regioisomers after the insertion of the alkyne
however, the
2 most plausible isomers are shown. All 4 possible
[6]
G. C. Tsui, M. Lautens, in C–H Activation Reactions in Domino
Processes, in Domino Reactions: Concepts for Efficient Organic
Synthesis (Ed L. F. Tietze), Wiley-VCH, Weinheim, 2014, pp. 67-103 and
references therein.
regioisomers are shown in the supporting information.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Hyung Yoon, Martin Rölz, Felicitas
Landau, Mark Lautens*
Page No. – Page No.
Pd-Catalyzed Spirocyclization via C–
H Activation and Regioselective
Alkyne Insertion
C–H activate and insert: A Pd-catalyzed cascade reaction involving a sequential
carbopalladation, intramolecular C–H activation and a highly regioselective alkyne
insertion generates a variety of spirooxindoles and spirodihydrobenzofurans. The
spirocycles are generated in good to excellent yield and >20:1 ratio of regioisomers.
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