Ligand design for Rh(iii)-catalyzed C-H activation: An unsymmetrical cyclopentadienyl group enables a regioselective synthesis of dihydroisoquinolones

Article abstract of DOI:10.1039/c4sc02590c

We report the regioselective synthesis of dihydroisoquinolones from aliphatic alkenes and O-pivaloyl benzhydroxamic acids mediated by a Rh(iii) precatalyst bearing sterically bulky substituents. While the prototypical Cp ligand provides product with low s

Full text of DOI:10.1039/c4sc02590c

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Ligand design for Rh(III)-catalyzed C–H activation:
an unsymmetrical cyclopentadienyl group enables
a regioselective synthesis of dihydroisoquinolones†
Cite this: Chem. Sci., 2015, 6, 254
*
Todd K. Hyster, Derek M. Dalton and Tomislav Rovis
We report the regioselective synthesis of dihydroisoquinolones from aliphatic alkenes and O-pivaloyl
benzhydroxamic acids mediated by a Rh(III) precatalyst bearing sterically bulky substituents. While the
prototypical Cp* ligand provides product with low selectivity, sterically bulky Cpt affords product with
excellent regioselectivity for a range of benzhydroxamic acids and alkenes. Crystallographic evidence
offers insight as to the source of the increased regioselectivity.
Received 25th August 2014
Accepted 22nd September 2014
DOI: 10.1039/c4sc02590c
www.rsc.org/chemicalscience
C–H activation mediated processes have provided a unique insertion was poorly selective with RhCp* (<3 : 1), RhCpt
retrosynthetic approach to access a variety of substituted complex was ineffective at providing synthetically useful levels
heterocycles.1 One tactic that has received increased attention is of selectivity. Furthermore, the Cpt ligand was only effective
the coupling of p-components with heteroatom containing with aryl substituted alkynes, presumably because of strong
molecules.2 A variety of transition metals are capable of steric interactions between the ligand and alkyne in the inser-
catalyzing this type of transformation, providing access to tion event.
dozens of heterocyclic motifs.1–3 A challenge for these methods
is controlling the regioselectivity of migratory insertion across
alkenes and alkynes aer the metallacycle forming C–H acti-
vation (eqn 1).
Steric and electronic effects are understood to control
migratory insertion of unsymmetrical alkynes in Rh(III)
catalyzed isoquinolone syntheses (eqn 1). When the substitu-
ents are electronically similar, the larger group resides b- to Rh
in the metallacycle to avoid unfavorable steric interactions
(selectivity is generally >10 : 1).4 When the substituents are
electronically different, the more electron-donating group
prefers being a- to rhodium in the metallacycle, presumably to
stabilize the electron poor metal.5,6 The type of C–H bond being
activated also plays an important role in the regioselectivity of
migratory insertion; aromatic substrates typically provide
synthetically useful regioselectivities when electronically
different alkynes are used (>10 : 1) but alkenyl C–H activation
leads to products with lower regioselectivities, presumably due
to minimal steric interactions during migratory insertion.7,8 We
found that sterically bulky di-tert-butylcyclopentadienyl ligand
(Cpt) enhances the regioselectivity of the alkyne migratory
insertion event in these cases, delivering regioselectivities
(>10 : 1) modestly above those achievable by Cp* ligated Rh
complexes (<6 : 1). However, when the alkyne migratory
Migratory insertion of alkenes to access heterocycles using
C–H activation chemistry is still relatively rare, with seminal
studies by Glorius and Fagnou reporting the synthesis of dihy-
droisoquinolones.9–11 Similar to alkynes, alkenyl electron-
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523,
USA. E-mail: rovis@lamar.colostate.edu
† Electronic supplementary information (ESI) available: Experimental procedures
and compound characterization. CCDC 1021286. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4sc02590c
254 | Chem. Sci., 2015, 6, 254–258
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donating groups favor the position adjacent to the metal in the amenable to this reaction. We were pleased to nd para-
metallacycle delivering high regioselectivity. In contrast to substituted benzhydroxamic acids are well tolerated (50–76%
alkynes, aliphatic alkenes afford product with poor regiose- yields) with both Cp* and Cpt ligands. Notably, the low regio-
lectivity (2 : 1) (eqn 2).5h,12 We hypothesized competing steric selectivity of <2.2 : 1 seen using [RhCp*Cl2]2 is dramatically
and electronic effects cause the low regioselectivity, with steric improved with [RhCptCl2]2 giving excellent regioselectivities of
effects favoring the formation of a 4-substituted product and >14 : 1 (Table 2, entries 1–4). Electron rich amides derived from
electronics favoring the formation of a 3-substituted product.13 gallic acid provide product in excellent yield and regioselectivity
As a temporary solution to this problem, our group and others (Table 2, entry 5). Finally, heterocyclic amides are both well
have employed tethering strategies to increase the regiose- tolerated under the reaction conditions and responsive to the
lectivity of the migratory insertion event (eqn 3).14,15 Of course, sterically bulky ligand, providing product with excellent regio-
regioselectivity controlled by the ligand on Rh would be the selectivity (Table 2, entries 6–7).
optimal solution to the selectivity problem (eqn 4).16 Conse-
meta-Substituents also provide exquisite levels of regiose-
quently, we focused our attention toward developing an inter- lectivity for alkene migratory insertion when Cpt is used
molecular variant of this reaction that would provide product (>15 : 1) (Table 3). Interestingly, when Cp* is used the C–H
with improved regioselectivity.
activation occurs exclusively at the 6-position; we suggest that
As a model system, we explored the impact ligands have on this selectivity is the result of steric interactions between the 2-
the coupling of O-pivaloyl-benzhydroxamic acid 1a with 1- substituent and metal complex during concerted metallation
decene 2a to provide dihydroisoquinolones 3a and 3a0. When deprotonation. Surprisingly, when Cpt is used, the regiose-
Cp* is used as a ligand, the desired products are isolated lectivity of the C–H activation actually decreases to afford a
in excellent yield but poor selectivity (2.4 : 1 3a : 3a0) (Table 1, mixture of 2- and 6-substituted products. While on the surface
entry 1).
the decrease of selectivity appears counterintuitive, it can be
To determine the effect that ligand electronics have on explained by the uneven distribution of steric bulk in the Cpt
product regioselectivity, we employed an electron decient 1- ligand, which we will comment on subsequently. Not only is this
triuoromethyl-2,3,4,5-tetramethylcyclopentadienyl
ligand decrease in selectivity mechanistically intriguing, it also offers
originally developed by Gassman (CpCF3
) and found that this
17
catalyst provides 3a and 3a0 products in good yield but without
an increase in selectivity (2.4 : 1) (Table 1, entry 2).18,19 Since
ligand electronics did not appear to affect product regiose-
lectivity, we tested an electron rich, sterically bulky di-phenyl-
tri-methyl Cp ligand (Cp‡) and were pleased to nd a remark-
able increase in selectivity from 2.4 : 1 to 12 : 1 (3a : 3a0).
Pleased by this improvement, we tested the sterically bulky di-
tert-butyl Cp ligand Cpt and were surprised to nd that RhCpt
provides the desired product in 91% yield with exquisite
regioselectivity (15 : 1) (Table 1, entry 4).
Table 2 Amide scopea
Entry
Starting material
Yieldb (%)
Cp*
Cpt
Having demonstrated that Cpt is able to substantially
increase the regioselectivity of alkene migratory insertion, we
explored the scope of O-pivaloyl benzyhydroxamic acids
1
2
3
4
X ¼ CF3 (1b)
X ¼ Cl (1c)
50
76
70
75
1.5 : 1
2.2 : 1
1.9 : 1
1.7 : 1
19 : 1
19 : 1
16 : 1
14 : 1
Table 1 Ligand optimizationa
X ¼ OMe (1d)
X ¼ Ph (1e)
5
6
95
1.9 : 1
15 : 1
Entry
Catalyst
Yield (%)
Regioselectivity
84
88
2.5 : 1
1.8 : 1
19 : 1
19 : 1
1
[RhCp*Cl2]2
[RhCpCF3Cl2]2
[RhCp‡Cl2]2
[RhCptCl2]2
90
85
82
92
2.4 : 1
2.4 : 1
12 : 1
15 : 1
2b
3c
4d
7
a
Reaction conditions: 1a (.2 mmol), 1-decene (.2 mmol),
precatalyst (1 mol%), CsOAc (200 mol%), MeOH (0.1 M). CpCF3
b
a
¼ 1-triuoromethyl-2-3,4,5-tetramethylcyclopentadienyl. Cp‡
¼
c
Reaction conditions: amide (.2 mmol), 1-decene (.2 mmol), precatalyst
(1 mol%), CsOAc (200 mol%), MeOH (0.1 M). b Isolated yield of reaction
using [RhCptCl2]2 as a precatalyst.
d
1,2-di-phenyl-3,4,5-trimethylcyclopentadienyl.
butylcyclopentadienyl.
Cpt
¼
1,3-di-t-
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Table 3 Influence of Cpt on C–H insertion selectivitya
Table 4 Impact of Cpt on alkene scopea
Entry
Alkene
Yieldb (%)
Cp*
Cpt
1c
2
85
68
1.6 : 1
1.6 : 1
5.1 : 1
9.4 : 1
3
4
5
70
95
85
1.3 : 1
2.3 : 1
1.6 : 1
5.5 : 1
14 : 1
8 : 1
6d
92
1.2 : 1
7.2 : 1
7
80
93
89
1.4 : 1
1 : 1
12 : 1
11 : 1
14 : 1
8e
9
2 : 1
a
Reaction conditions: amide (.2 mmol), 1-decene (.2 mmol), precatalyst
(1 mol%), CsOAc (200 mol%), MeOH (0.1 M). isolated yield of reaction
b
c
d
using [RhCptCl2]2 as a precatalyst. 67% yield. 80% yield. 85%
10
94
3 : 1
14 : 1
yield. e 79% yield.
a
Reaction conditions: 1a (.2 mmol), alkene (.2 mmol), precatalyst (1
b
mol%), CsOAc (200 mol%), MeOH (0.1 M). Isolated yield of reaction
using [RhCptCl2]2 as a precatalyst. Reaction conducted at 0 ꢀC.
c
d
e
an exciting opportunity to potentially reverse the regioselectivity
of C–H activation.
Products isolated as a 1 : 1 ratio of diastereomers. Product isolated
as a 2 : 1 ratio of diastereomers.
We next explored the alkene tolerance of the method. Allyl
benzene 2b furnishes a 1.6 : 1 ratio of dihydroisoquinolone with
RhCp* (Table 4, entry 1). When Cpt is employed, the regiose-
While it is desirable to achieve high regioselectivity for a single
regioisomer, it is even more attractive to use a ligand to access
alternate regioisomers. Currently, the only example of Rh(III)-
catalyzed synthesis of 4-substituted dihydroisoquinolones is with
potassium vinyltriuoroborates where electronics are believed to
control regioselectivity.20 We found that when vinylcyclohexane
was submitted to a reaction with [RhCp*Cl2]2 as the precatalyst,
ꢀ
lectivity increases to 4.5 : 1. Reducing the temperature to 0 C
further increases regioselectivity to 5.1 : 1. Placing an electron-
donating group on the aromatic ring increases the selectivity of
insertion (Table 4, entry 2). Aryl electron withdrawing substit-
uents do not, however, provide a change in regioselectivity
relative to phenyl (Table 4, entry 3). When the aromatic ring is
moved further from the alkene the regioselectivity observed
with Cpt increases and yields remain high (Table 4, entries 4
and 5). Ester and ketone functional groups are tolerated without
a detrimental impact on regioselectivity (Table 4, entry 6, 9, and
10). Unfortunately, alkenes bearing stereocenters are ineffective
at inducing diastereoselectivity with either ligand (Table 4,
entries 6 and 8). Vinyl cyclopropanes participate with good
levels of regioselectivity but poor diastereoselectivity (Table 4,
entry 8). Unprotected alcohols provide product in excellent yield
with no sign of oxidation (Table 4, entry 7).
Fig. 1 Impact of ligand on reaction of vinyl cyclohexane.
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the 3-substituted dihydroisoquinolone 4a was isolated in 90% and the alkene substituent affect both the alkene coordination
yield with 11 : 1 regioselectivity (Fig. 1). However, when the same and 1,2-insertion events.
reaction was catalyzed by [RhCptCl2]2 the opposite isomer 4b was
Based on the X-ray crystal structure and regioselectivity data,
isolated in 75% yield and 10 : 1 (4b : 4a) regioselectivity. Given we propose the following model for regioselectivity of the 1,2-
this unexpected discovery, we were interested in gleaning insight migratory insertion of alkenes, where steric contributions from
into how Cpt inuences regioselectivity of alkene migratory the t-butyl groups inuence both alkene coordination and
insertion. A competition experiment between vinyl cyclohexane insertion events to give high selectivity. With small alkyl
2m and 1-decene 2a run to 10% conversion favored the formation alkenes, we propose that steric interactions from one t-butyl of
1
of dihydroisoquinolone 3a in >19 : 1 ratio as determined by H Cpt disfavor alkene coordination (I) and subsequent insertion to
NMR. This experiment suggests that enhanced steric interactions give the b-substituted product 3a0 (Fig. 3). Coordination of the
between the substrate and ligand slow the rate of migratory alkene with the steric bulk oriented away from the t-butyl group
insertion.
nds minimized steric interactions during coordination (II).
To investigate the steric differences between the RhCp* and Subsequent migratory insertion from II places the alkyl
RhCpt systems X-ray analysis was conducted on a 5-membered substituent a to Rh in the transition state, which we propose is
RhCpt metallacycle. While we were unable to obtain a 5- able to stabilize a buildup of partial positive charge, making the
membered rhodacycle from our system, Jones and coworkers a-substituted product 3a both sterically and electronically
previously characterized 5-membered rhodacycle 5a from N- favored with Cpt. In the case of the Cp* ligand with small alkyl
benzylidenemethanamine and [RhCp*Cl2]2.21 We found that a alkenes, neither steric nor electronic interactions dominate so
similar metallacycle 5b derived from [RhCptCl2]2 could be low selectivity is observed.
obtained in crystalline form under identical conditions and was
evaluated by single crystal X-ray diffraction.
However if the size of the alkene substituent is signicantly
increased, as in the case of vinyl cyclohexane, then Cpt favors
A comparison of the bond lengths and angles reveals several the opposite regioisomer. While certainly a puzzling result, we
notable differences between our Cpt rhodacycle and the Cp* propose that the selectivity can be explained by Cpt rotation
rhodacycle reported by Jones (Fig. 2). The Rh–Cp centroid such that the t-butyl groups both occupy the space above the
distance in 5b is 0.011 A longer than 5a which is either the result metallacycle. Cpt rotation gears the O-piv toward the alkene
˚
of increased steric interactions, or an artifact of Cpt being a less coordination site disfavoring alkene coordination to this side
electron-donating ligand. While there are subtle differences in (IV) favoring the a-substituted product 3a. At the same time,
many bond lengths and angles, the most striking difference is alkene coordination (III) with the cyclohexyl opposite the O-piv
the angle C3–Rh–Cl, which is 98.03ꢀ in 5b while only 90.09ꢀ in minimizes steric interactions enabling insertion of the large
5a. The angle increase is likely the result of steric interactions alkene and preferential formation of b-substituted product 3a0.
caused by the tert-butyl moiety being situated directly over the While not conclusive, the observation that cyclohexyl alkene
Rh–Cl bond. As alkene exchange presumably occurs with Cl, we reacts signicantly slower than n-octyl alkene suggests that
suggest that steric interactions between the t-butyl of the ligand migratory insertion of the cyclohexyl alkene proceeds through a
higher energy and potentially highly ordered transition state,
such as Cpt rotation.
Fig. 2 X-Ray analysis.
Fig. 3 Rationale for selectivity.
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8 For additional examples of alkenyl Rh(III)-catalyzed C–H
activation to synthesize heterocycles; see: (a) G. Song,
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Conclusions
In conclusion, we found that sterically bulky di-tert-butyl
cyclopentadienyl ligand (Cpt) is effective at increasing regiose-
lectivity of alkene migratory insertion in the synthesis of dihy-
droisoquinolones by Rh(III) C–H activation catalysis. In contrast
to previous cases where Cp* delivers modest levels of regiose-
lectivity of migratory insertion (with alkynes), Cpt renders
previously non-selective reactions (with alkenes) highly regio-
selective. Furthermore, ligand control (Cp* vs. Cpt) enables the
highly selective synthesis of two regioisomeric products with
vinylcyclohexanes. Finally, crystallographic evidence lends
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¨
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a
possible explanation of the enhanced
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a
chiral
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Acknowledgements
We thank the NIGMS for generous support of this research
(GM80442). T.R thanks Johnson Matthey for a generous loan of
Rh salts. D.M.D. thanks the NIH Ruth Kirschstein predoctoral
fellowship for funding.
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