A conjunctive carboiodination: Indenes by a double carbopalladation- reductive elimination domino process

Article abstract of DOI:10.1002/anie.201204716

Something gained, nothing lost: A Pd⁰-catalyzed domino intermolecular/intramolecular process terminated by carbohalogenation is reported. In this reaction, two new C-C bonds, one new C-I bond and one five-membered ring are formed in a single step, and all of the atoms in the starting materials are incorporated into the product (see scheme). Copyright

Full text of DOI:10.1002/anie.201204716

Angewandte
Chemie
DOI: 10.1002/anie.201204716
Carbohalogenation
A Conjunctive Carboiodination: Indenes by a Double
Carbopalladation–Reductive Elimination Domino Process**
Xiaodong Jia, David A. Petrone, and Mark Lautens*
2
We recently developed a novel Pd0-catalyzed carbon–halogen
bond forming reaction based on reversible oxidative addition.
This reaction was highlighted in various intra- and intermo-
lecular processes.[1] These formal carboiodinations were
facilitated by the carbon–iodine reductive elimination pro-
ceeding through alkene carbopalladation (Scheme 1). Tong
hybridized C Br bonds, the analogous sp -hybridized C I
bond formation was unsuccessful.
À
À
This prompted us to design a 2-iodo-a-methyl styrene
substrate, which in the presence of an alkyne, would allow us
to test the feasibility of an intermolecular–intramolecular
domino reaction (Scheme 1, path b).[3,4] If compatible, we
could still harness the reactivity of the vinyl PdII intermediate
as means to access a new class of carboiodination products.
Herein, we report the development of a palladium-
catalyzed domino intermolecular alkyne insertion/intramo-
À
lecular alkene insertion terminated by a C I reductive
elimination. This methodology allows access to racemic
polysubstituted indenes through the formation of two new
carbon–carbon bonds and one new carbon–iodine bond.
We initially chose 1a and 2a to optimize the reaction
conditions, and to test the effect of using different ligands
(Scheme 2). At 1008C in toluene, the carboiodinated indene
product 3a could be isolated in 96% yield when 5 mol%
[Pd(Q-Phos)2] was used. Only 8% of 3a was obtained when
P(o-tol)3 was used as the ligand, and PCy3 gave no detectable
product.
Scheme 1. Intramolecular and intermolecular carboiodination.
et al. also described interesting variants of this concept
towards the synthesis of substituted bicyclic[2a] and hetero-
cyclic[2b] frameworks. Our observed reactivity is strictly
dependent on a bulky P-ligand, such as Q-Phos being present
during catalysis. Since all previous reports highlight the
formation of sp3 carbon–iodine bonds, we hoped to extend the
scope of this transformation to the synthesis of vinyl iodides
using this ligand class. We attempted an intermolecular
carboiodination reaction between an aryl iodide and an
internal alkyne, but failed to isolate any of the desired product
(Scheme 1, path a). Despite previous accounts of this ligandꢀs
unique ability to induce reductive elimination to form sp2-
Scheme 2. Optimization of the reaction conditions.
The optimized reaction conditions were then applied to
various alkynes to explore the scope of this transformation
(Table 1). Symmetrical diaryl alkynes gave excellent yields of
the desired indenes (entries 1–8). When dialkyl alkynes were
used, the yields were generally lower, which may be a result of
the presence of b-hydrogens in the vinyl PdII intermediate
(entries 9 and 10). We also attempted the reactions of 1a and
various terminal alkynes, but no reaction was observed, and
the starting materials remained unchanged. Dibromo alkyne
2g gave only 32% yield, which could be increased to 57% by
the addition of 1 equivalent of Et3N (entry 7). The effect of
added amine base remains unclear, but may be related to the
regeneration of the active Pd0 species.[6] No reaction occurred
[*] Dr. X.-D. Jia, D. A. Petrone, Prof. Dr. M. Lautens
Davenport Laboratories, Department of Chemistry
University of Toronto
80 St. George Street, Toronto, ON, M5S 3H6 (Canada)
E-mail: mlautens@chem.utoronto.ca
[**] This research was supported by the Natural Sciences and Engi-
neering Research Council of Canada (NSERC), the Merck Frosst
Centre for Therapeutic Research, and the University of Toronto. X.J.
thanks Northwest Normal University (China) for research support
at the University of Toronto. We thank Dr. Alan Lough (University of
Toronto) for the X-ray structure of 5. We thank Johnson Matthey for
the donation of palladium catalysts.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204716.
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Table 1: Scope of alkynes.[a]
from PdII insertion to the more electron-rich carbon atom.
When 1-phenyl-1-propyne 2l was used in this reaction, the
product ratio was increased to 4.82:1. However, by-product 5
was isolated in 39% yield in the presence of N-methyldicy-
clohexyl amine base. Cyclopropane 5 is presumed to be
derived from intermediate neopentyl PdII species D (see
Scheme 5) undergoing intermolecular cyclization and subse-
Entry Product
Yield Entry Product
[%]
Yield
[%]
À
quent b-hydride elimination, instead of C I reductive elim-
ination (Scheme 3b).[6,7,9] Further studies concerning the
improvement of regioselectivity are ongoing in our laboratory
and will be reported in due course.
1
96
93
6
7
92
Iodinated styrene derivatives 1 bearing additional func-
tionality were also investigated. Generally, the reactions
proceeded smoothly to furnish the desired indenes in good
yields (Table 2). 2-Iodo-5-bromo a-methyl styrene was well
2
3
57[b]
Table 2: Scope of 2-iodo-a-methyl styrene.[a]
94
87
8
9
84
Entry Product
Yield Entry Product
[%]
Yield
[%]
4
5
67[c]
1
75[b]
3
4
89
N.R.[d] 10
68[c]
2
88
N.R.
[a] Reaction conditions: Substrate 1 (0.1 mmol), alkyne 2 (0.12 mmol),
[Pd(Q-Phos)2] (5 mol%), 0.2m in toluene, 1008C for 16 h. [b] Reaction ran
in the presence of 1 equiv of Et3N. [c] 3 Equiv of alkynes were used. [d] No
reaction.
[a] Reaction conditions: Substrate 1 (0.1 mmol), alkyne 2a (0.12 mmol),
[Pd(Q-Phos)2] (5 mol%), 0.2m in toluene, 1008C for 16 h. [b] Reaction
ran in the presence of 1 equiv of Et3N.
when bulky alkynes were used, presumably due to steric
reasons (entry 5). When electronically polarized alkyne 2k
was used, a 1.85:1 ratio of regioisomers was observed
(Scheme 3a). Interestingly, the major isomer was derived
tolerated in this reaction when 1 equivalent of Et3N was
added highlighting the concept of reversible oxidative addi-
tion at remote sites (entry 1).[1a] Electron-rich aryl iodide 1l
was converted to the corresponding indene in 88% yield
Scheme 3. Preliminary regioselectivity results.
2
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(entry 2). Alkene 1d was used to test olefin steric effects, and
appeared to have no effect on reaction efficiency (entry 3).
However, iodinated 1,1-diaryl alkene does not react under the
standard conditions, presumably due to increased steric
effects preventing efficient carbopalladation (entry 4).
We extended this methodology to include reaction with
strained, bicyclic norbornene (Scheme 4), in which the
palladium intermediate cannot undergo syn-b-hydride elim-
Experimental Section
To a 0.5–2 mL biotage microwave vial equipped with a magnetic stir
bar was added the compounds 1 (24.4 mg, 0.1 mmol) and 2 (21.4 mg,
0.12 mmol). The vial was purged with argon for 5 min, after which
[Pd(Q-Phos)2] (7.6 mg, 5 mol%) and toluene (0.5 mL) were added.
The vial was capped and immersed to an oil bath pre-heated to 1008C.
After stirring for 16 h, the vial was cooled and the solution was
filtered over a pad of silica gel eluting with Et2O. The products were
purified by flash chromatography using hexanes or 1% Et2O/hexane
as eluent.
Received: June 15, 2012
Revised: July 11, 2012
Published online: && &&, &&&&
Keywords: carbohalogenation · domino reaction ·
.
double carbopalladation · indenes
Scheme 4. Reaction with norbornene.
[1] a) S. G. Newman, M. Lautens, J. Am. Chem. Soc. 2010, 132,
11416 – 11417; b) S. G. Newman, M. Lautens, J. Am. Chem. Soc.
2011, 133, 1778 – 1780; c) S. G. Newman, J. K. Howell, N.
Nicolaus, M. Lautens, J. Am. Chem. Soc. 2011, 133, 14916 –
14919.
ination.[1b] Reoptimization of the reaction conditions showed
[Pd(PtBu3)2] to be the best catalyst.[8] Styrene 1a gave 65% of
tetracycle 4a as a 1.1:1 mixture of diastereomers.
A possible mechanism is proposed to rationalize the
product formation (Scheme 5). Substrate binding first
occurs[10] to generate Pd0 complex A. This then undergoes
a reversible oxidative addition which generates PdII inter-
mediate B. Intermolecular alkyne insertion occurs to produce
C, which can undergo cyclic alkene carbopalladation to form
D. The indene product is formed once intermediate D
[2] For other carboiodination reactions, see: a) H. Liu, C. Chen, L.
Wang, X. Tong, Org. Lett. 2011, 13, 5072 – 5075; b) H. Liu, C. Li,
D. Qiu, X. Tong, J. Am. Chem. Soc. 2011, 133, 6187 – 6193.
[3] For recent examples of palladium-catalyzed intermolecular
domino reactions involving alkynes, see: a) C. Wang, S. Rakshit,
F. Glorius, J. Am. Chem. Soc. 2010, 132, 14006 – 14008; b) F.
Zhou, M. Yang, X. Lu, Org. Lett. 2009, 11, 1405 – 1408; c) S. T.
Heller, S. Natarajan, Org. Lett. 2007, 9, 4947 – 4950; d) C.-G.
Dong, P. Yeung, Hu, Q. -S, Org. Lett. 2007, 9, 363 – 366; e) T.
Konno, J. Chae, T. Miyabe, T. Ishihara, J. Org. Chem. 2005, 70,
10172 – 10174; f) T. Gerfaud, L. Neuville, J. Zhu, Angew. Chem.
2009, 121, 580 – 585; Angew. Chem. Int. Ed. 2009, 48, 572 – 577;
g) for a review on this subject, see: G. Zeni, R. C. Larock, Chem.
Rev. 2006, 106, 4644 – 4680, and references therein; h) K. C.
Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. 2005, 117,
4516 – 4563; Angew. Chem. Int. Ed. 2005, 44, 4442 – 4489.
[4] a) J.-C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan, Chem.
Rev. 2005, 105, 1001 – 1020; b) P. J. Parsons, C. S. Penkett, A. J.
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A. Heumann, Tetrahedron 2000, 56, 5959 – 5989.
À
undergoes C I reductive elimination.
In summary, we have developed an efficient palladium-
catalyzed domino carboiodination process between iodoaryl
alkenes and internal alkynes en route to substituted indenes.
In addition, norbornene participates in this reaction, afford-
ing the corresponding polycyclic indene in synthetically useful
yield. We are currently focusing on expanding the scope of
this transformation and further exploring its use in construc-
tion of complex molecular architectures. Mechanistic and
computational studies concerning this type of transformation
are also underway in our laboratory.
[5] For a review concerning the Tollman angle of phosphine
lingands, see: C. A. Tolman, Chem. Rev. 1997, 97, 313 – 348.
[6] I. D. Hills, G. C. Fu, J. Am. Chem. Soc. 2004, 126, 13178 – 13179.
[7] For a review of cyclic carbopalladations, see: E. Negishi, C.
Copꢁret, S. Ma, S. Y. Liou, L. Fang, Chem. Rev. 1996, 96, 365 –
393.
[8] Our previous results also show that [Pd(PtBu3)2] is more efficient
than [Pd(Q-Phos)2] in the intermolecular reaction with norbor-
nene. See Ref. [1b] for details.
[9] CCDC 885982 (5) contains the supplementary crystallographic
data for this paper. This data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[10] The mechanism of Pd0-catalyzed carbohalogenation of alkenes
was investigated by computation, see: Y. Lan, P. Liu, S. G.
Newman, M. Lautens, K. N. Houk, Chem. Sci. 2012, 3, 1987 –
1995.
Scheme 5. Proposed mechanism.
Angew. Chem. Int. Ed. 2012, 51, 1 – 4
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Angewandte
Communications
Communications
Carbohalogenation
Something gained, nothing lost: A Pd0-
catalyzed domino intermolecular/intra-
molecular process terminated by carbo-
halogenation is reported. In this reaction,
X.-D. Jia, D. A. Petrone,
M. Lautens*
&&&& — &&&&
À
À
two new C C bonds, one new C I bond
and one five membered ring are formed
in a single step, and all of the atoms in the
starting materials are incorporated into
the product (see scheme).
A Conjunctive Carboiodination: Indenes
by a Double Carbopalladation–Reductive
Elimination Domino Process
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 4
These are not the final page numbers!