The Selective Cross-Coupling of Secondary Alkyl Zinc Reagents to Five-Membered-Ring Heterocycles Using Pd-PEPPSI-IHeptCl

Article abstract of DOI:10.1002/anie.201503941

The ability to cross-couple secondary alkyl centers is fraught with a number of problems, including difficult reductive elimination, which often leads to β-hydride elimination. Whereas catalysts have been reported that provide decent selectivity for the expected (non-rearranged) cross-coupled product with aryl or heteroaryl oxidative-addition partners, none have shown reliable selectivity with five-membered-ring heterocycles. In this report, a new, rationally designed catalyst, Pd-PEPPSI-IHept^Cl, is demonstrated to be effective in selective cross-coupling reactions with secondary alkyl reagents across an impressive variety of furans, thiophenes, and benzo-fused derivatives (e.g., indoles, benzofurans), in most instances producing clean products with minimal, if any, migratory insertion for the first time. A wide variety of five-membered-ring heterocycles were successfully cross-coupled to secondary alkyl zinc reagents with the new precatalyst Pd-PEPPSI-IHept^Cl, which features a bulky N-heterocyclic carbene ligand. This catalyst suppresses migratory-insertion (rearrangement) pathways, and the desired products are thus formed with high selectivity.

Full text of DOI:10.1002/anie.201503941

.
Angewandte
Communications
International Edition: DOI: 10.1002/anie.201503941
German Edition: DOI: 10.1002/ange.201503941
Cross-Coupling
The Selective Cross-Coupling of Secondary Alkyl Zinc
Reagents to Five-Membered-Ring Heterocycles Using
Pd-PEPPSI-IHeptCl**
Bruce Atwater, Nalin Chandrasoma, David Mitchell, Michael J. Rodriguez,
Matthew Pompeo, Robert D. J. Froese, and Michael G. Organ*
Angewandte
Chemie
9502
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 9502 –9506

Angewandte
Chemie
Abstract: The ability to cross-couple secondary alkyl centers is
fraught with a number of problems, including difficult
reductive elimination, which often leads to b-hydride elimi-
nation. Whereas catalysts have been reported that provide
decent selectivity for the expected (non-rearranged) cross-
coupled product with aryl or heteroaryl oxidative-addition
partners, none have shown reliable selectivity with five-
membered-ring heterocycles. In this report, a new, rationally
designed catalyst, Pd-PEPPSI-IHeptCl, is demonstrated to be
effective in selective cross-coupling reactions with secondary
alkyl reagents across an impressive variety of furans, thio-
phenes, and benzo-fused derivatives (e.g., indoles, benzofur-
ans), in most instances producing clean products with minimal,
if any, migratory insertion for the first time.
Figure 1. Desired reductive elimination (RE) and migratory insertion
(MI) pathways for the Pd-mediated cross-coupling of a secondary alkyl
zinc reagent to aromatic heterocycles. Ar=five- or six-membered
heteroaromatic compound, R1 and R2 =alkyl groups.
W
ithin the last five years, interest in the development of
2
3
À
methods for the construction of C(sp ) C(sp ) bonds has been
growing rapidly.[1] Many companies in the pharmaceutical
sector have initiated programs to incorporate aromatic and
heteroaromatic molecules that are decorated with branched
alkyl chains (i.e., the carbon bound to the aromatic ring is
secondary) into their medicinal-compound collections.[2] This
move is to compensate, in part, for the relatively low success
rates of polyaromatic, “flat” compounds (e.g., biaryls) as
clinical candidates.[2] Branched, alkyl-substituted heterocycles
are also being aggressively pursued in the development of
new OLEDs (organic light-emitting diodes) for the visual-
display, screen, and lighting industries.[3] Therefore, the
high interest in five-membered-ring heteroaromatic com-
pounds in a number of sectors,[2,3] we were encouraged to
attempt to couple 3-pentylzinc bromide (11) with a small
selection of such compounds (10; Scheme 1) using our most
2
3
À
construction of C(sp ) C(sp ) bonds has become a heavily
pursued area of synthetic chemistry to support the discovery,
investigation, and manufacturing of these societally important
compounds that collectively are worth tens of billions of
dollars annually.[4]
One of the areas that is pursued most aggressively for
Scheme 1. Cross-coupling of 3-pentylzinc bromide (11) to various five-
membered-ring heterocycles. See Figure 2 for the structure of the
PEPPSI precatalyst.
2
3
À
C(sp ) C(sp ) bond formation is palladium-catalyzed cross-
coupling (see Figure 1 for general mechanistic considerati-
ons).[4a,b,g,5] Being a late transition metal, Pd is highly tolerant
of reactive functional groups, such as esters, nitriles, and even
alcohols, amines, and carboxylic acids.[6] This makes Pd
catalysis particularly desirable because it can be used to
assemble complex, densely functionalized targets in a highly
convergent fashion. Recently, we have made advances in Pd-
selective catalyst to date,[5a] Pd-PEPPSI-IPentCl (9,[7] see
Figure 2; PEPPSI = pyridine-enhanced precatalyst prepara-
tion, stabilization, and initiation). Unfortunately, despite all
attempts with 9, isomerization by migratory insertion (MI)
extensively led to nearly exclusive formation of the isomeric
product(s) (i.e., B and C) rather than the desired one (A)
from direct reductive elimination (RE; see Figure 1 for key
mechanistic interpretation). Poor selectivity was observed
independent of whether oxidative addition occurred at the C2
(12) or C3 position (13 or 14) of the five-membered ring.
2
3
À
catalyzed C(sp ) C(sp ) couplings involving six-membered-
ring aromatic and heteroaromatic compounds.[5] Owing to the
[*] Dr. B. Atwater, Dr. N. Chandrasoma, M. Pompeo, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, Ontario, M3J1P3 (Canada)
E-mail: organ@yorku.ca
Dr. D. Mitchell, Dr. M. J. Rodriguez
Lilly Research Laboratories
Indianapolis, IN 46285 (USA)
Dr. R. D. J. Froese
The Dow Chemical Company
Midland, MI 48674 (USA)
[**] This work was supported by NSERC Canada in the form of a CRD
grant and by the Eli Lilly Research Award Program (LRAP).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503941.
Figure 2. Pd-PEPPSI precatalysts used in this study.
Angew. Chem. Int. Ed. 2015, 54, 9502 –9506
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
9503

.
Angewandte
Communications
Table 1: Comparison of several PEPPSI precatalysts for the cross-
coupling of a variety of five-membered-ring heterocycles (10) and
2-propylzinc bromide (19).
As 11 could be coupled with six-membered heteroaro-
matic compounds with complete selectivity using 9,[5a] it
would appear that the five- and six-membered-ring congeners
are strikingly different in their reactivity, the former being
much more difficult to cross-couple with any level of
selectivity. This encouraged us to carry out a thorough
sweep of the literature, and strikingly, we found that there
are no reported scope studies for the general and selective
coupling of secondary alkyl fragments to five-membered-ring
heterocycles, including 5,6-fused systems where the site of
oxidative addition is in the five-membered ring (i.e., at the C2
or C3 position of e.g., indole, benzofuran).[8] Given the high
importance of such compounds, the dearth of published
results speaks to the difficulty of this coupling. Herein, we
disclose the first comprehensive report on the Pd-catalyzed
cross-coupling of secondary alkyl organometallics to produce
these highly prized products.
Normal (N) to rearranged (R) product ratio[a]
Given the surprising, but consistent poor preliminary
results in Scheme 1 with the heterocyclic oxidative-addition
partners, the first and easiest structural feature to investigate
was the impact of bond angles, and thus possible size (steric)
effects that are due to changes in the bond angles in the five-
versus the six-membered ring. One might argue that with the
smaller bond angles in the five-membered ring, there is
a reduced steric footprint/influence in the transition state for
b-hydride elimination (BHE), which we have demonstrated
to be the key to mitigate migratory insertion (MI).[5a] When
we submitted the indenyl analogue to the same transforma-
tion, the reaction proceeded well, cleanly providing the
desired, non-rearranged isomer (15A). Given the direct
physical comparison between the aromatic compounds lead-
ing to 13A or 14A with 15A, it is difficult to implicate
reduced steric effects into the rationale for the poor
selectivity. The fact that MI is the primary reaction path
taken whether the coupling is occurring at the C2 or
C3 position of the five-membered ring also makes it challeng-
ing on first glance to implicate electronic or coordination
effects. Concurrently, we investigated the electronic features
of these heterocycles by computational studies, and the
corresponding finding will be discussed below.
Moving forward, we hypothesized that if the ligandꢀs bulk
was brought further into the coordination sphere of Pd, we
could make up for any lost steric impact of the five-membered
ring. Furthermore, this might also override any unfavorable
electronic features that the five-membered heterocycles
impart on the critical steps of RE and BHE.[5a] To this end,
two catalysts, Pd-PEPPSI-IHept[9] (17) and Pd-PEPPSI-
IHeptCl (18;[10] Figure 2), were applied to this cross-coupling
along with 9 and its analogue Pd-PEPPSI-IPent (16),[5b, 11]
which is not chlorinated in the NHC core (Table 1).
2-Propylzinc bromide (19), while a seemingly simple sub-
strate, is actually the most challenging secondary organome-
tallic reagent to cross-couple selectively owing to the max-
imum number of hydrides that enable BHE, and thus MI, to
occur.
Product
IPent (16)
IPentCl (9)
IHept (17)
IHeptCl (18)
1
2
3
4
5
6
7
8
20
21
22
23
24
25
26
27
1:9.4
1:1
2.7:1
1:3
1:9
1:18
1:6
5.5:1
24:1
20.7:1
5:1
3:1
1:1
1:1.5
3:1
9:1
1.1:1
1:3
1:8
9:1
only N
only N
only N
6:1
2:1
23:1
7.2:1
trace
only N
n.r.
1:2[b]
1.3:1[c]
[a] Unless otherwise indicated, reactions proceeded to the coupled
products will full conversion. [b] Reaction proceeded to 22% conversion.
[c] Reaction proceeded to 17% conversion.
chlorinated analogues were much more selective. In the case
of IHeptCl (18), the branched product was always formed as
the major one, and in many cases, N was the only isomer
produced. Coupling at the C3 position in the five-membered
ring (entries 1–4) is noticeably more selective than at the
C2 position (entries 5–8) for all heteroaromatic compounds
studied. Whereas it could be argued that steric effects
influence the selectivity with N-substituted indoles (e.g.,
27), this would seem less likely for benzothiophene and
benzofuran substrates. Certainly, the physical presence of the
fused benzene ring is more noticeable at the C3 position, but
the same trend is observed in its absence (see Table 2). A
substrate survey revealed that this trend of greater intrinsic
selectivity at the C3 than at the C2 position was also observed
with simple five-membered heterocycles. With 2-propylzinc
bromide, methyl 2-thiophenecarboxylate reacted with high
selectivity at the C3 position (31), whereas no selectivity was
observed at the C2 position (30). With a 4-piperidenylzinc
derivative, both furan (29) and thiophene (32) electrophiles
coupled with no visible MI, providing the desired products in
excellent yield. Again, methylindole could be coupled with
complete selectivity at the C2 position (34), whereas some
interesting diheteroatom-containing structures reacted with
2-propyl- (33 and 36) and 3-pentylzinc bromide (35) with
good to excellent selectivity. Collectively, these results suggest
that there is a pronounced electronic effect that differentiates
the C2 and C3 positions, assuming for now that there is no
coordination to Pd.
When considering the data in Table 1, a number of trends
become apparent. In most cases, IPent (16) and IHept (17)
actually led to greater amounts of the MI product (i.e., R)
than of the desired branched product (i.e., N), whereas their
9504 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 9502 –9506

Angewandte
Chemie
Table 2: Cross-coupling of various five-membered heterocycles with
secondary alkyl zinc bromides using the Pd-PEPPSI-IHeptCl (18)
catalyst.[a]
Figure 3. Experimental selectivity [ln(normal/rearranged)] versus the
computed DDE° values, which are the TS energy differences in
kcalmolÀ1 [TS(4$6a)ÀTS(4$5)] at a) the C2 position and b) the
*
C3 position for substrates 20–27. &: IPent, O heterocycle; : IPent,
Cl
~
&
*
:
S heterocycle; : IPent, N heterocycle; : IPent , O heterocycle;
Cl
Cl
~
IPent , S heterocycle; : IPent , N heterocycle.
catalyst. Independently, the calculations are very predictive
for both positions. Steric hindrance plays a much greater role
in the b-hydride elimination TS [TS(4$6a)] than in the
reductive-elimination TS [TS(4$5)]; therefore, increasing
the steric bulk on the NHC (from IPent to IHept) and/or
adding chloride substituents in the backbone, which push the
large substituents towards the active site (i.e., in IPentCl and
IHeptCl),[5] leads to enhanced selectivity.
In summary, two new, rather bulky Pd NHC catalysts, Pd-
PEPPSI-IHept (17) and Pd-PEPPSI-IHeptCl (18),[10] have
been reported, and their use in the selective cross-coupling of
secondary alkyl zinc reagents to five-membered-ring hetero-
cycles has been investigated. The selectivities that were
achieved with Pd-PEPPSI-IHeptCl (18) in this study,[10] both at
the C2 and C3 positions of various heteroaromatic com-
pounds, are without precedent. This catalyst provides a power-
ful approach in the pursuit of complex new compounds for the
discovery and manufacture of new therapeutics and novel
materials, including OLEDS.
[a] The ratios below the product numbers are the N/R ratios, which were
determined by H NMR spectroscopy of the product mixture both prior
1
to and following purification. The yield of isolated product after column
chromatography on silica gel is given in parentheses. [b] The reaction
was performed at 508C; the fraction of the minor, rearranged isomer
contained some of the 1- and 2-pentyl isomers. Boc=tert-butyloxycar-
bonyl.
In an effort to understand the normal (N) to rearranged
(R) selectivity, a series of calculations were carried out on
compounds 20–27. Whereas the coupling of 4 (see Figure 1)
leading to the normal product (5) accesses only one irrever-
sible transition state, the formation of the rearranged product
requires accessing two b-hydride-elimination transition states
[TS(4$6a) and TS(6b$7)] and the reductive-elimination
transition state [TS(7$8)] that leads from the linear alkyl
species (7) to the rearranged product (8). Previous work[5]
demonstrated that the first b-hydride elimination TS is the
key one for formation of the rearranged product (R) as it is an
irreversible step, and once accessed, the subsequent barriers
are lower. Those computations[5] also demonstrated a good
predictive ability for to the experimental N/R selectivities by
computing the transition-state energy differences (DDE° =
E{TS(4$6a)}ÀE{TS(4$5)}). The convention implies that
a positive value for DDE° gives a higher TS for the b-hydride
elimination and thus favors the normal product (5) whereas
a negative DDE° value suggests the formation of greater
amounts of the rearranged product (8). Calculations were
performed on the Pd-PEPPSI-IPent and Pd-PEPPSI-IPentCl
catalysts,[12] and the experimental selectivities and the com-
puted data were compared for substrates substituted at the C2
(Figure 3a) and the C3 position (Figure 3b; for more details,
see the Supporting Information).[13]
Keywords: alkyl zinc reagents · cross-coupling ·
N-heterocyclic carbenes · palladium · transition-metal catalysis
How to cite: Angew. Chem. Int. Ed. 2015, 54, 9502–9506
Angew. Chem. 2015, 127, 9638–9642
[1] a) R. J. Lundgren, M. Stradiotto, Chem. Eur. J. 2012, 18, 9758 –
9769; b) R. Jana, T. P. Pathak, M. S. Sigman, Chem. Rev. 2011,
111, 1417 – 1492.
[2] a) F. Lovering, MedChemComm 2013, 4, 515 – 519; b) S. Danda-
pani, L. A. Marcaurelle, Curr. Opin. Chem. Biol. 2010, 14, 362 –
370; c) F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009,
52, 6752 – 6756.
[3] S. Xu, E. H. Kim, A. Wei, E.-i. Negishi, Sci. Technol. Adv. Mater.
2014, 15, 044201, and references cited therein.
[4] For recent advances in the cross-coupling of secondary alkyl
nucleophiles, see: a) L. Li, S. Zhao, A. Joshi-Pangu, M. Diane,
M. R. Biscoe, J. Am. Chem. Soc. 2014, 136, 14027 – 14030; b) Y.
Yang, K. Niedermann, C. Han, S. L. Buchwald, Org. Lett. 2014,
16, 4638 – 4641; c) L. Li, C.-Y. Wang, R. Huang, M. R. Biscoe,
Nat. Chem. 2013, 5, 607 – 612; d) J. T. Binder, C. J. Cordier, G. C.
Fu, J. Am. Chem. Soc. 2012, 134, 17003 – 17006; e) M. C. Perry,
A. N. Gillett, T. C. Law, Tetrahedron Lett. 2012, 53, 4436 – 4439;
f) A. Joshi-Pangu, M. Ganesh, M. R. Biscoe, Org. Lett. 2011, 13,
1218 – 1221; g) C. Duplais, A. Krasovskiy, B. H. Lipshutz,
Organometallics 2011, 30, 6090 – 6097; h) C. Han, S. L. Buch-
wald, J. Am. Chem. Soc. 2009, 131, 7532 – 7533.
One outlier aside, an excellent fit is indicated in Figure 3a,
and the data again fit acceptably well in Figure 3b. The solid
data points in both plots reside in the upper right part of the
graphs, indicating that better selectivity was achieved with the
Pd-PEPPSI-IPentCl (9) than with the Pd-PEPPSI-IPent (16)
Angew. Chem. Int. Ed. 2015, 54, 9502 –9506
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
9505

.
Angewandte
Communications
[5] a) M. Pompeo, N. Hadei, R. D. J. Froese, M. G. Organ, Angew.
Chem. Int. Ed. 2012, 51, 11354 – 11357; Angew. Chem. 2012, 124,
11516 – 11519; b) S. C¸ alimsiz, M. G. Organ, Chem. Commun.
2011, 47, 5181 – 5183.
[6] a) T. Bresser, G. Monzon, M. Mosrin, P. Knochel, Org. Process
Res. Dev. 2010, 14, 1299 – 1303; b) Z. Dong, G. Manolikakes, J.
Li, P. Knochel, Synthesis 2009, 681 – 686; c) A. Metzger, M. A.
Schade, P. Knochel, Org. Lett. 2008, 10, 1107 – 1110.
[10] The Pd-PEPPSI-IPentCl (9), Pd-PEPPSI-IHept (17), and Pd-
PEPPSI-IPentCl (18) precatalysts are commercially available
through Total Synthesis Ltd (http://www.totalsynthesis.ca).
[11] For the introduction and other uses of Pd-PEPPSI-IPent, see:
a) K. H. Hoi, S. C¸ alimsiz, R. D. J. Froese, A. C. Hopkinson,
M. G. Organ, Chem. Eur. J. 2012, 18, 145 – 151; b) M. Sayah,
M. G. Organ, Chem. Eur. J. 2011, 17, 11719 – 11722; c) K. H. Hoi,
S. C¸ alimsiz, R. D. J. Froese, A. C. Hopkinson, M. G. Organ,
Chem. Eur. J. 2011, 17, 3086 – 3090; d) C. Valente, M. E.
Belowich, N. Hadei, M. G. Organ, Eur. J. Org. Chem. 2010, 23,
4343 – 4354; e) S. C¸ alimsiz, M. Sayah, D. Mallik, M. G. Organ,
Angew. Chem. Int. Ed. 2010, 49, 2014 – 2017; Angew. Chem. 2010,
122, 2058 – 2061; f) M. Dowlut, D. Mallik, M. G. Organ, Chem.
Eur. J. 2010, 16, 4279 – 4283; g) M. G. Organ, S. C¸ alimsiz, M.
Sayah, K. H. Hoi, A. J. Lough, Angew. Chem. Int. Ed. 2009, 48,
2383 – 2387; Angew. Chem. 2009, 121, 2419 – 2423.
[7] For the introduction and other uses of the Pd-PEPPSI-IPentCl
catalyst, see: a) M. Pompeo, J. L. Farmer, R. D. J. Froese, M. G.
Organ, Angew. Chem. Int. Ed. 2014, 53, 3223 – 3226; Angew.
Chem. 2014, 126, 3287 – 3290; b) M. Sayah, M. G. Organ, Chem.
Eur. J. 2013, 19, 16196 – 16199; c) K. H. Hoi, J. A. Coggan, M. G.
Organ, Chem. Eur. J. 2013, 19, 843 – 845; d) C. Valente, S.
C¸ alimsiz, K. H. Hoi, D. Mallik, M. Sayah, M. Organ, Angew.
Chem. Int. Ed. 2012, 51, 3314 – 3332; Angew. Chem. 2012, 124,
3370 – 3388.
[12] The conformations of the 3-pentyl chains are computationally
problematic, therefore, only the conformation of the X-ray
structure was used.
[8] For papers containing one or two examples with five-membered
heterocycles as substrates, see Ref. [4b, c, and f].
[13] Calculations used the B3LYP/6-31*/LANL2TZ(F) method.
Additional information is available in the Supporting Informa-
tion.
[9] a) Pd-PEPPSI-IHept was first prepared in 2008 and disclosed at
the 238th American Chemical Society National Meeting, August
16, 2009: “The Role of Bulkiness in Promoting Pd-NHC-
Catalysed Cross-Couplings: A Synergy Between Experiment,
Spectroscopy, and Theory”, ORGN-400; see also: b) M. Sayah,
Ph. D. Thesis, York University, 2013.
Received: April 30, 2015
Published online: June 25, 2015
9506 www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 9502 –9506