Modular Functionalization of Arenes in a Triply Selective Sequence: Rapid C(sp2) and C(sp3) Coupling of C?Br, C?OTf, and C?Cl Bonds Enabled by a Single Palladium(I) Dimer

Article abstract of DOI:10.1002/anie.201808386

Full control over multiple competing coupling sites would enable straightforward access to densely functionalized compound libraries. Historically, the site selection in Pd⁰-catalyzed functionalizations of poly(pseudo)halogenated arenes has been unpredictable, being dependent on the employed catalyst, the reaction conditions, and the substrate itself. Building on our previous report of C?Br-selective functionalization in the presence of C?OTf and C?Cl bonds, we herein complete the sequence and demonstrate the first general arylations and alkylations of C?OTf bonds (in <10 min), followed by functionalization of the C?Cl site (in <25 min), at room temperature using the same air- and moisture-stable Pd^I dimer. This allowed the realization of the first general and triply selective sequential C?C coupling (in 2D and 3D space) of C?Br followed by C?OTf and then C?Cl bonds.

Full text of DOI:10.1002/anie.201808386

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
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Accepted Article
Title: Modular Functionalization of Arenes in a Triply Selective
Sequence: Rapid Csp2 and Csp3 Coupling of C-Br, C-OTf & C-Cl
enabled by a Single Pd(I) dimer
Authors: Sinead T Keaveney, Gourab Kundu, and Franziska
Schoenebeck
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808386
Angew. Chem. 10.1002/ange.201808386
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10.1002/anie.201808386
Angewandte Chemie International Edition
DOI: 10.1002/anie.201??
Chemoselectivity
Modular Functionalization of Arenes in a Triply Selective Sequence:
Rapid Csp2 and Csp3 Coupling of C-Br, C-OTf & C-Cl enabled by a
Single Pd(I) dimer
Sinead T. Keaveney, Gourab Kundu and Franziska Schoenebeck*
Abstract: The full control over multiple competing coupling sites
would enable straightforward access to densely functionalized
compound libraries. Historically, the site-selection in Pd(0)
catalyzed functionalizations of poly(pseudo)halogenated arenes
has been unpredictable, being dependent on the employed catalyst,
conditions and the substrate itself. Building on our previous report
of Br-selective functionalization in the presence of C-OTf and C-
Cl, we herein complete the sequence and demonstrate the first
general arylations and alkylations of C-OTf (in <10 min), followed
by the C-Cl site (in <25 min) at room temperature using the same
air-and moisture stable Pd(I) dimer. This allowed the realization of
the first general and triply selective, sequential C-C coupling (in
2D and 3D space) of C-Br, then C-OTf, then C-Cl.
couplings.[6] We therefore focused our attention on alternative
oxidation states that bear potential for bimetallic synergy and
alternative mechanisms.[7] In this context, our group recently reported
an a priori predictable and rapid Csp2-Csp2 and Csp2-Csp3 coupling of
aromatic C-Br bonds in the presence of C-OTf and C-Cl under open-
flask conditions using the air-stable Pd(I) dimer 1 (Figure 1).[8] With
selective C-Br functionalization realized, the next challenge towards
modular functionalization lies in the selective manipulation of the C-
OTf and C-Cl sites in a rapid and general manner. We herein present
a solution to this challenge.
 Goal: Rapid & Fully Selective Functionalization
Library
of diversely & densely
functionalized arenes
Requirement:
predictable, general & practical
Polyfunctionalized arenes are ubiquitous building blocks in
pharmaceuticals, materials and natural products.[1] To meet the ever-
increasing demands for diverse compound libraries and the exploration
of chemical space in a two- and three-dimensional fashion, highly
modular, streamlined and diversifiable approaches in the assembly of
densely functionalized arenes are desired.[2] Ideally, these features are
paired with the potential for automation to realize high-throughput
operations. In this context, owing to the relative mildness and
functional group tolerance, site-selective and sequential Pd-catalyzed
cross-coupling of polyhalogenated arenes is a highly desired
technology.[3] However, while the approximate reactivity order of C-I
> C-Br ≈ C-OTf > C-Cl is frequently quoted,[3] the actual site-
selectivity of Pd(0)-catalyzed cross-coupling reactions is the result of a
complex interplay of the ligand/catalyst, the reaction conditions
(additive, solvent) and most importantly, the steric and electronic bias
of the substrate itself.[4] As such, identified coupling conditions for a
given substrate frequently fail if slight structural or electronic
modifications are introduced (vide infra). However, to access libraries
of compounds in a programmable fashion, a general, a priori
predictable and fully selective technology will be required. Ideally,
this is paired with practical features, such as rapid speed, robustness
(e.g. air-tolerance) and broadness for maximal diversity (Csp2 & Csp3
coupling partners). In this context, Pd(0)-based cross-coupling[5]
frequently suffers from oxygen sensitivity, extended reaction times
(hours), substrate specificity in site-selectivity, and additional
mechanistic challenges, such as β-hydride elimination in Csp2-Csp3
 Challenges in Pd-catalyzed selective C-OTf vs. C-Cl functionalization:
.
.
.
Unpredictable
No generality in arylation
No alkylation (challenge:
β-H elimination)
.
.
Reaction times (hours)
Air-sensitive
Solved in 2017
(our previous work)
Unsolved
Problem
This Work:

C-OTf selective
Very fast



Air-tolerant
High functional group
tolerance


Rapid C-Cl coupling
Aryl & alkyl introduced
Figure 1. Challenges (top) in site-selective couplings and this work (bottom)
While there are isolated reports of Pd(0)-catalyzed C-OTf arylations
in the presence of C-Cl, the corresponding alkylation appears
essentially unexplored, and there has been no demonstration of
tolerance to diverse functionality, nor generality in terms of
steric/electronic bias on the substrate or coupling partner.[9] As such,
we initially set out to explore the potential of generality of existing
methodology, and investigated a Pd(OAc)2/PCy3 catalyzed Suzuki
coupling protocol previously identified to give selective arylation of
4-chlorophenyl triflate at room temperature.[4g] We found that while
the previously reported 4-chlorophenyl triflate provided excellent C-
OTf coupling with 2-tolyl boronic acid (90%, as reported
previously[4g]), an alternative substitution pattern was much less
efficient, resulting in much lower conversion to the product (<10%,
see SI, Table S1). Even when maintaining a 1,4-substitution pattern of
the Cl and OTf groups, much lower conversions were observed when
varying the substrate structure, and the reaction also appeared
intolerant to different boronic acid coupling partners, with a significant
drop in conversion when moving from 2-tolyl (90%) to 4-methoxy
(26%) or alternative boronic acids. Overall, these data suggest that re-
optimization would be needed for alternative targets; there is no
[]
Dr. S. T. Keaveney, Mr G. Kundu, Prof. Dr. F. Schoenebeck
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, 52074 Aachen, Germany
E-mail: franziska.schoenebeck@rwth-aachen.de
Homepage: http://www.schoenebeck.oc.rwth-aachen.de/
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxx.
1
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10.1002/anie.201808386
Angewandte Chemie International Edition
generality. As such, we set out to explore the possibility of Pd(I)
catalyzed selective functionalization of C-OTf over C-Cl.
aldehyde (6) groups were well tolerated. Moreover, not just arylation
(using both heterocyclic and non-heterocyclic aromatics, 19-21), but
also the more challenging alkylation could be achieved selectively at
C-OTf (over C-Cl) in an equally rapid (10 minutes) and efficient
manner open to air. Pleasingly we were able to selectively couple both
primary (14-16) and secondary (17, 18, 22, 23) alkyl groups in high
yields; of particular note is the successful incorporation of the
challenging branched secondary alkyl group (23), which are especially
prone to isomerization. To the best of our knowledge, this is the first
general site-selective alkylation of C-OTf in the presence of C-Cl.
Lastly, a number of different substrate and R-ZnCl combinations
were examined, highlighting that this technique can be used to
generate structurally diverse compound libraries (24-43). For example,
ortho and meta substituted chloroaryl triflates are shown to undergo
successful alkylation, with both primary and secondary alkyl groups
(24-30) and many of these compounds have not been reported
previously (for example, 33-42).
To explore the scalability of this methodology, we performed the C-
OTf selective coupling with 1 g of starting material; pleasingly, 78%
yield of the product 10 was isolated (Table 1). It should also be noted
that while NMP was a very effective solvent, alternative polar solvents
proved to be equally effective.[12] As an example, for 4-chlorophenyl
triflate exclusive C-OTf selectivity and high yields of the product 2
were obtained in DMI (90%), DMPU (76%) and DMAc (92%).
Our previous work had indicated that solvent polarity can impact the
nature of the active species, and hence the preference of C-OTf vs C-
Cl functionalization.[4d] We reasoned that in the presence of
coordinating additives, ‘Pd-ate’ complexes could be generated via
dynamic ligand exchanges from Pd(0) in the polar media, which would
preferentially react with C-OTf. While our current data suggest that
Pd(I) is not reactive directly with C-Cl and C-OTf, due to high
activation barriers, we envisioned that the dinuclear entity could act as
a
precursor to a defined bisligated ‘ate’ complex via rapid
activation.[7a,10]
Consequently, we investigated the effectiveness of a number of
polar solvents at facilitating chemoselective Negishi cross-coupling at
C-OTf with the air-stable Pd(I) dimer 1. To our delight, the use of N-
methyl-2-pyrrolidinone (NMP) led to completely selective C-OTf over
C-Cl functionalization in less than 10 minutes at room temperature.
Notably, no efforts were made to avoid oxygen; the reaction was run
in an open flask.[11] These newly found data were very promising, as
the coupling is more rapid and robust than any previous protocol.
We next explored whether the protocol is general and applicable for
a wide range of substrates (Table 1). To our delight, we were able to
perform selective arylation, regardless of whether the C-Cl and C-OTf
were positioned ortho (3, 12), meta (3, 9) or para (2, 7-8, 12), or
whether additional steric hindrance or functionality was present (5, 6).
Heterocycles (7, 8, 13), nitrile (9), nitro (10), fluoro (11), keto (5) and
Table 1. Scope of Pd(I) dimer 1 enabled chemoselective C-OTf (over C-Cl) Negishi coupling in NMP.
Conditions: Substrate (0.4 mmol), Pd(I) dimer 1 (0.01 mmol), R-ZnCl (0.6 mmol) in NMP, reaction mixture stirred for 10 minutes in a flask open to air. aR-ZnCl (0.46
mmol) was used. bReaction performed on larger scale (1 g, 3.27 mmol).
2
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10.1002/anie.201808386
Angewandte Chemie International Edition
Table 3. Sequential double-functionalization of bis(pseudo)halogenated arenes
Having achieved chemoselective C-OTf over C-Cl functionalization
through a general, rapid and air-tolerant procedure, we next sought to
develop facile C-Cl functionalization using the Pd(I) dimer 1, to
eventually allow functionalization at all three sites using the same
catalyst. The use of ArCl electrophiles in cross-coupling reactions is
generally more difficult, sometimes requiring high temperatures (up to
100 °C) and/or extended reaction times (up to 72 hours).[4g,13]
Encouraged by the high reactivities seen with 1, we slowly added
phenyl ZnCl (over 15 min) to a mixture of 1 and 2-chloro nitrobenzene
in NMP at r.t., and allowed the mixture to react for an additional 10
min. Pleasingly, we observed efficient C-Cl coupling and isolated 44
(Table 2) in 89% yield.
Table 2. Scope of Pd(I)-catalyzed C-Cl coupling.
Conditions Substrate (0.4 mmol), Pd(I) dimer 1 (0.01 mmol), R1-ZnCl (0.4-0.8 mmol,
see SI for details). aC-Cl coupling done at 80 °C. bReaction mixture filtered through
silica prior to C-Cl functionalization.
For b) (C-OTf then C-Cl functionalization) efficient coupling was
also achieved in one-pot, using NMP as solvent throughout. Finally,
for coupling sequence c) (C-Br then C-Cl) a procedure analogous to a)
was applied (although under argon and over 25 min. to facilitate C-Cl
coupling). Overall, the desired bis-functionalized products were
obtained in good yields, with the introduction of both aryl and alkyl
groups being demonstrated.
Conditions: Chloroarene (0.4 mmol) and Pd(I) dimer 1 (0.01 mmol) under Ar, R-
ZnCl (0.8 mmol) added slowly over 15 minutes, then mixture stirred for 10 minutes.
Reaction done at: a80 °C, b50 °C. cContains 15% linear isomer.
With all combinations allowing selective and sequential
functionalizations, we next studied the functionalization of all three
sites (Table 4). We achieved the C-Br, followed by C-OTf
functionalization in a total of 15 minutes in one-pot open to air (as
described above) and subsequently purified the resulting chloro arene
intermediate. The C-Cl functionalization step was then performed in
NMP under argon. This sequence allowed the tri-substituted product
to be synthesized in high overall yields in a total reaction time of only
40 minutes, using the air stable Pd(I) dimer 1 for all three
functionalization steps.
We next tested the C-Cl coupling more widely, assessing electron-
rich and -poor arenes, and examining sp2 and sp3 C-C bond formations;
pleasingly, in each case high yields of the desired products were
obtained after only 25 minutes under argon (Table 2). While Negishi
cross-coupling protocols utilizing aryl-Cl have been reported,[14] our
method is a more rapid, general and operationally simple alternative;
for example, with Pd(0) catalysis products 48 and 58 were previously
obtained in 50% and 92%, respectively, after 2 hours at 100 °C.[14d] In
contrast, these compounds were obtained in 93% and 95% yield after
only 25 minutes at room temperature with our protocol.
With the ability to functionalize all three sites in a general fashion
using a single catalyst and the defined reactivity sequence of Br > OTf
> Cl established, we next explored the sequential functionalization of
a) Br then OTf, b) OTf then Cl, or c) Br then Cl. These sequences were
performed in one-pot at room temperature, with a total reaction time
of 15 - 35 minutes (Table 3). For a), the cross coupling partner was
added to a solution of bromoaryl triflate and Pd(I) dimer 1 in THF.
After 5 min, NMP was added to the same pot (producing 1:1
THF/NMP) and R2-ZnCl was added, yielding the bisfunctionalized
arene in excellent yields in a total reaction time of 15 minutes at r.t.
3
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10.1002/anie.201808386
Angewandte Chemie International Edition
Table 4. Sequential triple-functionalization of tris(pseudo)halogenated arenes
S. G. Ballmer, E. P. Gillis, S. Fujii, M. J. Schmidt, A. M. E. Palazzolo,
J. W. Lehmann, G. F. Morehouse, M. D. Burke, Science 2015, 347, 1221
[3] For reviews, see: a) J. Almond-Thynne, D. C. Blakemore, D. C. Pryde,
A. C. Spivey, Chem. Sci. 2017, 8, 40; b) I. Fairlamb, Chem. Soc. Rev.
2007, 36, 1036; c) S. Schröter, C. Stock, T. Bach, Tetrahedron 2005, 61,
2245
[4] a) F. Proutiere, E. Lyngvi, M. Aufiero, I. A. Sanhueza, F. Schoenebeck,
Organometallics 2014, 33, 6879; b) T. D. Tran et al. ChemMedChem
2014, 9, 1378; c) Z. Hassan, M. Hussain, A. Villinger, P. Langer,
Tetrahedron 2012, 68, 6305; d) F. Proutiere, F. Schoenebeck, Angew.
Chem. Int. Ed. 2011, 50, 8192; e) J. B. J. Milbank, D. C. Pryde, T. D.
Tran, WO2011004276, 2011; f) G. Espino, A. Kurbangalieva, J. M.
Brown, Chem. Commun. 2007, 1742; g) A. F. Littke, C. Y. Dai, G. C.
Fu, J. Am. Chem. Soc. 2000, 122, 4020; h) T. Kamikawa, T. Hayashi,
Tetrahedron Lett. 1997, 38, 7087
[5] For recent reviews on Pd catalyzed cross-coupling reactions see: a) P.
Ruiz-Castillo, S. L. Buchwald, Chem. Rev. 2016, 116, 12564; b) C. C. C.
Johansson Seechurn, M. O. Kitching, T. J. Colacot, V. Snieckus, Angew.
Chem. Int. Ed. 2012, 51, 5062.
[6] For examples of recent developments that avoid β-H elimination
(without site-selectivity), see: a) B. Atwater, N. Chandrasoma, D.
Mitchell, M. J. Rodriguez, M. Pompeo, R. D. J. Froese, M. G. Organ,
Angew. Chem. Int. Ed. 2015, 54, 9502; b) Y. Yang, K. Niedermann, C.
Han, S. L. Buchwald, Org. Lett. 2014, 16, 4638; c) M. Giannerini, M.
Fañanás-Mastral, B. L. Feringa, Nat. Chem. 2013, 5, 667.
Conditions: Substrate (0.4 mmol), Pd(I) dimer 1 (0.01 mmol), R1-ZnCl (0.44-0.8
mmol, see SI for details) aThe chloro-aryl-triflate was isolated prior to C-OTf
functionalization.
In conclusion, we have demonstrated an a priori predictable and
operationally simple sequence to alkylate and arylate aromatic C-OTf
sites in the presence of C-Cl within 15 minutes at r.t. under air,
regardless of the electronic or steric bias imposed by the substrate. Key
to the success of this strategy was the use of an air- and moisture stable
Pd(I) dimer along with NMP (or DMPU, DMI or DMAc) as solvent.
The same solvent/catalyst combination also allowed for subsequent C-
Cl functionalization (in 2D and 3D space) at r.t. in 25 minutes. Overall,
the newly developed technology enabled full control over all three
coupling sites in the order C-Br > C-OTf > C-Cl, with triply selective
and sequential functionalization having been demonstrated in only 40
min, using the same Pd(I) dimer. Given the generality, robustness, rapid
speed and full control, we anticipate widespread applications of this
methodology, including the implementation in automated approaches
to rapidly access molecular complexity in a programmable fashion.
[7] For our mechanistic work on the feasibility of dinuclear metal catalysis,
see: a) M. Aufiero, T. Scattolin, F. Proutiere, F. Schoenebeck,
Organometallics 2015, 34, 5191; b) G. Yin, I. Kalvet, F. Schoenebeck,
Angew. Chem. Int. Ed. 2015, 54, 6809; c) I. Kalvet, K. J. Bonney, F.
Schoenebeck, J. Org. Chem. 2014, 79, 12041; d) K. J. Bonney, F.
Proutiere, F. Schoenebeck, Chem. Sci. 2013, 4, 4434
[8] a) I. Kalvet, G. Magnin, F. Schoenebeck, Angew. Chem. Int. Ed. 2017,
56, 1581; b) I. Kalvet, T. Sperger, T. Scattolin, G. Magnin, F.
Schoenebeck, Angew. Chem. Int. Ed. 2017, 56, 7078
[9] Alkylation of C-OTf in the presence of C-Cl has been achieved with
three substrates under Pd-catalysis: a) S. Dupuy, K.-F. Zhang, A.-S.
Goutierre, O. Baudoin, Angew. Chem. Int. Ed. 2016, 55, 14793 (with β-
H elimination /isomerization occurring); and b) E. G. Corley, K. Conrad,
J. A. Murry, C. Savarin, J. Holko, G. Boice, J. Org. Chem. 2004, 69,
5120 (using a Cu co-catalyst). For examples of selective arylation, see:
c) Z. Hassan, S. Al-Shidhani, A. Al-Ghafri, A. Al-Harrasi, J. Hussain, R.
Csuk, Tetrahedron Lett. 2015, 56, 7141; d) C. Zhou, Q. Liu, Y. Li, R.
Zhang, X. Fu, C. Duan, J. Org. Chem. 2012, 77, 10468; e) S. Ishikawa,
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Satoko, U. Takahiro, S. Ai, T. Asami, K. Yusuke, E. Koichi, B. Utpal,
K. Takanori, K. Atsushi, M. Yasunari, S. Hironao, Chem. Eur. J. 2007,
13, 5937
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[11] Due to the moisture-sensitivity of organometallic reagents, use safety
precautions when using an open flask.
We thank the RWTH Aachen University and the European Research
Council (ERC-637993) for funding.
Keywords: homogeneous catalysis • chemoselectivity • Pd(I) dimer •
sequential • C-C coupling
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[1] a) Transition Metal-Catalyzed Couplings in Process Chemistry: Case
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Wiley, 2013; b) New Trends in Cross-Coupling: Theory and
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[2] For examples of iterative cross-coupling through selective
transmetalation, see: a) C. M. Crudden, C. Ziebenhaus, J. P. G. Rygus,
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4
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10.1002/anie.201808386
Angewandte Chemie International Edition
Layout 2:
Chemoselectivity
Predictable Sequence C-Br > C-OTf > C-Cl
S. T. Keaveney, G. Kundu, F.
Schoenebeck* __________ Page – Page
Modular Functionalization of Arenes in
a Triply Selective Sequence: Rapid
Csp2 and Csp3 Coupling of C-Br, C-OTf
& C-Cl enabled by a Single Pd(I) dimer
Triply selective, sequential and very rapid Csp2 and Csp3 couplings at room
temperature are demonstrated using the same air- and moisture stable Pd(I)
dimer, allowing full control over all coupling sites.
5
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