Catalytic Coupling between Unactivated Aliphatic C-H Bonds and Alkynes via a Metal-Hydride Pathway

Article abstract of DOI:10.1021/jacs.7b02020

We report a Rh(I)-catalyzed site-selective coupling between ketone β-C(sp³)-H bonds and aliphatic alkynes using an in situ-installed directing group. Upon hydrogenation or hydration, various β-alkylation or β-aldol products of the ketones are obtained with broad functional group tolerance. Mechanistic investigations support the involvement of a Rh-H intermediate through oxidative addition of Rh(I) into the β-C-H bonds. Thus, to the best of our knowledge, this transformation represents the first example of catalytic couplings between unsaturated hydrocarbons and unactivated aliphatic C-H bonds via a metal-hydride pathway.

Full text of DOI:10.1021/jacs.7b02020

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Communication
Catalytic Coupling between Unactivated Aliphatic C-
H Bonds and Alkynes via a Metal-Hydride Pathway
Yan Xu, Michael C Young, and Guangbin Dong
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 07 Apr 2017
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Catalytic Coupling between Unactivated Aliphatic C−H Bonds
and Alkynes via a Metal−Hydride Pathway
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Yan Xu, †,‡ Michael C. Young‡ and Guangbin Dong*†,‡
†Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States
‡Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
Supporting Information Placeholder
Scheme 1. Transition metalꢀcatalyzed addition of C−H bonds
across alkenes/alkynes
ABSTRACT: We report a Rh(I)ꢀcatalyzed siteꢀselective couꢀ
pling between ketone β C(sp3)−H bonds and aliphatic alkynes
using an inꢀsituꢀinstalled directing group (DG). Upon
hydrogenation or hydration, various βꢀalkylation or βꢀaldol
products of the ketones are obtained with broad functional group
tolerance. Mechanistic investigations support the involvement of a
Rh−H intermediate through oxidative addition of Rh(I) into the β
C−H bonds. Thus, to the best of our knowledge, this
transformation represents the first example of catalytic couplings
between unsaturated hydrocarbons and unactivated aliphatic C−H
bonds via a metal−hydride pathway.
A. Overview
alkane
C–H bonds
M
X
M
-HX
H
H
R
M
M
M
R
CMD
approach
metal-hydride
approach
alkenes/
alkynes
TM
catalyst
H
R
H
M
M
R
R
+HX
R
R
R
insertion
products
B. Addition of
aliphatic C–H bonds across alkynes
unactivated
[Si]
Direct addition of unactivated C−H bonds across unsaturated
hydrocarbons, e.g. alkenes and alkynes, offers a byproductꢀfree
and redoxꢀneutral method to form carbon−carbon bonds.1 This
transformation can be possibly realized by two approaches
(Scheme 1A).2 In the first case, the C–H bond is cleaved through
a concerted metallationꢀdeprotonation (CMD) pathway,3 which is
followed by migratory insertion of the alkene or alkyne and then
protodemetallation to afford the coupling product (left cycle).
Alternatively, a metal−hydride species can be formed through
oxidative addition of a lowꢀvalent metal catalyst into a C–H
bond.4 Upon coordination of an unsaturate, the product is formed
via a sequence involving migratory insertion and reductive elimiꢀ
nation (right cycle). To date, addition of sp2 C–H bonds across
alkenes or alkynes has been extensively developed with both apꢀ
proaches,5 often resulting in complementary regioselectivity. In
contrast, much fewer examples are known for sp3 C–H bonds,6,7
of which the majority are at activated positions (benzylic,7aꢀc alꢀ
lylic,7d αꢀtoꢀheteroatoms7eꢀh or at activated methylenes7i). It was
not until recently that alkenylations of unactivated aliphatic C–H
bonds with alkynes were achieved with amide,8 amine9,10 and 2,6ꢀ
(tBu)2phenyl ether substrates,11 exclusively via a CMD pathway
(Scheme 1B). The direct coupling of unactivated aliphatic C–H
bonds with unsaturated hydrocarbons via a metal−hydride apꢀ
proach remained unknown.12 The challenge is threeꢀfold: 1) oxiꢀ
dative addition into unactivated sp3 C–H bonds is often signifiꢀ
cantly slower than sp2 C–H bonds;13 2) reductive elimination inꢀ
volving an alkyl moiety is generally difficult;14 and 3) lowꢀvalent
metals often catalyze oligomerization of unsaturated hydrocarꢀ
bons as a competitive reaction pathway.15 As part of our longꢀterm
interest in siteꢀselective C−H functionalization of ketones,16,17 we
herein describe the development of a Rhꢀcatalyzed ketone βꢀ
alkenylation method with aliphatic alkynes using an inꢀsituꢀ
installed directing group (DG) (Scheme 1C). Our mechanistic
study demonstrates that this C−H/alkyne coupling reaction proꢀ
ceeds through a metal−hydride reaction pathway.
O
H
DG
R1
R2
O
NH
DG
O
N
H
H
R
H
H
wl Rh(I)
You (Ni, 2015)
Maiti (Ni, 2015)
Minami &
Shi (Pd, 2016)
this work
Hiyama (Pd, 2016)
metal-hydride
approach
CMD approach
C. This work: ketone alkenylation via Rh-catalyzed sp3 C–H/alkyne coupling
O
H
H2/H+
O
DG
R
R2
N
H
DG NH2
Rh(I) cat.
R1
R
H
R
R2
-alkylation products
+
R1
O
H
R1
R2
C–H/alkyne coupling
HO
R1
R2
H+, H2O
R
-aldol products
D. Generation of metal–hydride species
DG
O
N
N
prior work
this work
N
Rh H
R
H
Rh
H
H
R
-functionalization
-functionalization
Our prior work involves introducing an enamine DG to generꢀ
ate a metal−hydride species at ketone α positions, which leads to
α−alkylation or alkenylation with olefins or alkynes (Scheme 1D,
left).16a,cꢀf To form a metal−hydride species at ketone β positions,
it was hypothesized that a properly selected imineꢀtype DG would
promote C−H oxidative addition through forming
a fiveꢀ
membered metallocycle.18,19 In addition, we envision that the
direct coupling of β C–H bonds with alkynes should introduce
one degree of unsaturation, which can serve as a convenient hanꢀ
dle to access other valuable derivatives, such as the βꢀalkylation
and βꢀaldol products (Scheme 1C).
Our study initiated with 2ꢀbutanone (1a) as a model substrate to
couple with 3ꢀhexyne (Table S1). We foresaw the advantage of
using an in situꢀgenerated hydrazone intermediate (i.e. 3a)20 that
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a
contains an additional coordinative motif. First, hydrazones
Run with 0.5 mmol 1a and 3.0 mmol 4a in 48h. All yields are
isolated yields. b 15 mol% [Rh]. c 72h. d 72h, 130 °C. e 2.5 ml 1,4ꢀ
dioxane, 20 equiv alkyne. The benzylic alkenylated product and
1
2
3
4
5
6
7
8
should exhibit enhanced stability over regular imines; and second,
the chelation effect would assist oxidative addition of Rh(I) into
the β C−H bond. After a survey of various DGs, metal precataꢀ
lysts, ligands and other reaction parameters, ultimately the desired
product (5a) was isolated in 74% yield using Rh(C2H4)2(acac)/(pꢀ
MeOC6H4)3P as the metal/ligand combination, hydrazine 2e to
form the optimal DG, and Li(acac) as the additive at 120 °C in
1,4ꢀdioxane. Unsurprisingly, the alkene migrated under the reacꢀ
tion conditions, leading to a mixture of γ,δꢀ and β,γꢀunsaturated
products.21 In general, the pyridineꢀderived hydrazone DGs are
more effective than the corresponding hydrazide or quinolineꢀ
derived DG (entries 2 and 3). A series of control experiments
were also conducted to understand the role of each reactant. No
product was observed in the absence of either the DG or the Rh
preꢀcatalyst (entries 7ꢀ8). The counter anion of the catalyst apꢀ
pears to be important, as replacing the Rh(C2H4)2(acac) with
[Rh(C2H4)2Cl]2 (without Li(acac)) provided the desired product in
a much lower yield (entry 9). (pꢀMeOC6H4)3P proved to be an
optimal ligand for this transformation, while using bidentate ligꢀ
ands generally gave no conversion of the starting material, and
other monoꢀdentate phosphines were less effective.22 A diminꢀ
ished yield was observed when less phosphine was used (entry
11). The excess phosphine ligand is likely beneficial for the cataꢀ
lyst dissociation from the product. The use of a lower catalyst
loading, e.g. 5 mol% Rh, still afforded 70% yield (entry 12). Fiꢀ
nally, the addition of Li(acac) improved the yield to some extent
(entry 13), while the addition of water reduced the reaction effiꢀ
ciency (entry 14).
f
g
the diꢀalkenylated product were observed in <5% yield. Use the
preꢀcondensed substrate. h no HCl was added in the hydrogenation
i
step. In step 2, the hydrolysis was conducted before the hydroꢀ
genation. brsm = based on recovered starting material. rr: regioiꢀ
somer ratio.
The scope of the ketoneꢀalkyne coupling was then explored
(Scheme 2). Both linear and cyclic ketones can couple with aliꢀ
phatic internal alkynes efficiently.23 Simple treatment of the
alkenylation products with Pd/C and H2, followed by addition of
aqueous HCl afforded the corresponding βꢀalkylated ketones in
one pot. When unsymmetrical ketones were employed as the subꢀ
strates, alkenylation occurred predominately at the primary C–H
bonds. However, in the absence of β methyl groups, the benzylic
methylenes can also be activated (6j). A range of functional
groups were compatible, including aryl chlorides (6p), free alcoꢀ
hols (6l, 6m), ethers (6n, 6w), amides (6k), nitriles (6n) and esters
(6x). While bulky pinacolone gave a low conversion (6o),24 αꢀ
branches (6e, 6h, 6i) were well tolerated. In addition, various
symmetrical and unsymmetrical aliphatic alkynes can be used as
coupling partners (6q-v), including a protected homopropargyl
alcohol moiety (6s) that is often used as a synthetic handle. Note
that when a heavier alkyne (e.g. 5ꢀdecyne) was employed, the
alkyne loading can be reduced to 3 equiv without significantly
affecting the yield (6r). Excellent regioselectivity was achieved
when the two substituents of alkynes are differentiated by size
(6u, 6v), favoring C–C bond formation at the less hindered side of
the alkynes.
9
10
11
12
13
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Scheme 2. Substrate scope with various ketones and alkynesa
O
H
DG-NH2 (2e) (1.0 equiv)
2 mol% TsOH, 4h, then
10 mol% Rh(C2H4)2(acac)
30 mol% (p-MeOC6H4)3P
Scheme 3. Synthesis of β-aldol adducts through the Rhꢀ
R1
Me
DG
catalyzed C–H alkenylation/hydration sequencea
R2 R3
1aꢀw
O
H
N
H
Pd/C, H2
R1
R5
R1
R5
+
R2 R3
25 mol% Li(acac), 4Å M.S.
1,4-dioxane, 120 °C, N2
R2 R3
N
NH
R4
5aꢀx
then 1M HCl
benzene
90 °C
R4
R4
R5
NH2
2e
6aꢀx
4aꢀk
0.5 mmol scale
A. Scope of the ketones
O
H
Me
Me
O
O
H
O
H
Et
O
H
Et
Et
nPr
Et
Et
H
Et
Me
Et
Et
6e
[step 1] 67%b
[step 2] 99%
Et
H
Et
6a
6b
6c
6d
Me
Me
[step 1] 74%
[step 2] 85%
[step 1] 70%
[step 2] 96%
[step 1] 63%
[step 2] 92%
[step 1] 50%
[step 2] 97%
O
Me
Me
O
H
O
H
Et
Me
Me
Et
O
H
Me
Et
Et
Et
O
Me Et
Me
Et
Me
6f
6g
6h
6i
6j
H
Et
[step 1] 85%, 3:1 mono:di [step 1] 60% [step 1] 68%, 1:1 mono:dic
[step 1] 50%d
[step 2] 97%
[step 1] 56%d,e
[step 2] 85%
[step 2] 91%
[step 2] 80%
[step 2] 96%
O
H
O
H
O
H
OH
O
H
Et
NC
Et
Et
2
Et
Et
Me
Et
Et
6m
[step 1] 51%c
Et
O
6l
6k
6n
O
N
[step 1] 60%c
[step 2] 90%h
HO
[step 1] 60%d
[step 1] 42%
[step 2] 91%
Me
[step 2] 93%
[step 2] 60%
O
H
DG
Me
DG
Me
N
H
N
H
O
H
Et
[step 2]
Me
Me
Et
6p
Cl
Me
Et
+
H
Me Me
Me Me
90%
Me Me
Et
Me
Me
5oa
5ob
6o
5oa:5ob = 1:5
[step 1] 47%f
[step 2] 85%h,i
[step 1] 15% (79% brsm)g
O
O
B. Scope of the alkynesg
Me
OSi(iPr)3
Me
H
H
O
H
O
H
O
H
a
b
c
d
nPr
Me
nBu
Me
Me
Me
Me
All yields are isolated yields. 72h. from > 20:1 rr. 15
Me
nPr
Me
6u
[step 1] 63%c
>20:1 rr
nBu
e
Me
mol% [Rh].
The benzylic alkenylated product and the diꢀ
Me
6r
6s
6t
6q
[step 1] 60%
53% w/ 3 equiv alkynes
[step 2] 95%
[step 1] 70%, 1.1:1 rr
[step 2] 77%h, i
[step 1] 58%
[step 2] 88%
[step 1] 60%
[step 2] 80%
alkenylated product were observed in <5% yield.
[step 2] 87%
While the initial alkenylation products contain olefin isomers,
the olefins generally share the same tertiary carbon at the γꢀ
position. Thus, a Markovnikov hydration is expected to yield a γꢀ
O
H
O
H
O
H
OMe
OAc
Me
Me
Me
Me
6v
OMe
OAc
6w
6x
[step 1] 50%, >20:1 rr
[step 2] 90%
[step 1] 54%c
[step 1] 45% (0.2 mmol)
[step 2] 85%h, i
ketol, formally a
after simply treating the alkenylation products in aqueous H2SO4
βꢀaldol adduct, as a unified product. Indeed,
[step 2] 85%
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o
at 0 C for 1h, the hydration products (in equilibrium between γꢀ
ketol and hemiketal forms) were readily obtained in moderate to
good yields, and gratifyingly, the DG was removed at the same
time (Scheme 3). Interestingly, when 2ꢀmethylcyclohexanone was
used as the substrate, the final hydration product underwent simꢀ
ultaneous cyclization and dehydration to afford dihydrofuran 7fb.
was successfully isolated and characterized, which is likely driven
by forming a stronger Ir–H bond (Scheme 4C). While this specific
Ir complex was found catalytically inactive, this result nevertheꢀ
less demonstrates the feasibility of oxidative addition of a lowꢀ
valent groupꢀ9 metal into unactivated β C–H bonds with this speꢀ
cific hydrazone type of DG. Finally, the observed regioselectivity
for insertion of unsymmetrical alkynes (6u, 6v and 7e) is conꢀ
sistent with a hydrideꢀmigratory insertion pathway instead of an
alkylꢀmigratory insertion pathway.26 Altogether, our mechanistic
investigations strongly support a metal−hydride reaction pathway.
1
2
3
4
5
6
7
8
Regarding the reaction mechanism, the key question is whether
the C−H activation occurs through a metal−hydride pathway or a
CMD pathway. To address this question, first, the deuteriumꢀ
labeling experiments were carried out with a βꢀd9ꢀpinacolone
derivative (Scheme 4A). A tertiary alkyl ketone substrate was
specifically chosen to avoid potential H/D scrambling between the
α and β positions through a βꢀH elimination and reꢀinsertion
pathway. If the reaction follows a metal−hydride pathway, the
deuterium at the original β position should be transferred to the δ
position of the product (the vinyl hydrogen in major product
5ob).7g However, in the case of a CMD pathway, the reaction
should end with a protodemetalation step, thus it is expected that
significant deuterium erosion at the δ position would occur in the
presence of external proton sources.9 Our experiments showed
that complete deuterium incorporation was found at the vinyl
position of product 5ob with either acetylacetone (100 mol%) or
MeOH (800 mol%). In addition, almost no deuterium loss was
found at either the unreacted methyl groups or the recycled startꢀ
ing material. All of these observations support a metal−hydride
pathway and disfavor a CMD pathway.25 Second, as a control
experiment, when nonꢀdeuterated substrate 3o was subjected to
the reaction with excess d4ꢀmethanol, nearly no deuterium incorꢀ
poration was observed at either the β or vinyl position of the
products or the recycled starting material (Scheme 4B). This reꢀ
sult further ruled out a CMD pathway.
9
Scheme 5. Proposed catalytic cycle
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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60
Accordingly, a plausible catalytic cycle is proposed (Scheme
5). First, upon hydrazone formation (step A), coordination with
Rh(I) through chelation with the DG facilitates oxidative addition
into the βꢀC(sp3)–H bond to generate a Rh(III)−hydride species
(step C). The hydride intermediate then undergoes alkyne migraꢀ
tory insertion (step D), sp2ꢀsp3 reductive elimination (step E), and
ligand exchange with a new substrate (step B) to yield the
alkenylation product and resume the catalytic cycle. Further olefin
migration of the product may take place, which can also be cataꢀ
lyzed by Rh (step F).21 Efforts toward enabling use of catalytic
DGs as well as coupling with alkenes are ongoing.
Scheme 4. Preliminary mechanistic studies
> 99% D
> 99% D
A.
DG
DG
N
D
N
D
D
D
D D
> 99% D
Me
Me
H3C
H3C
DG
D3C CD3
D3C CD3
N
Me
Me
CD3
H3C
> 99% D
> 99% D
D3C CD3
ca. 1: 4.5
"standard conditions"
ASSOCIATED CONTENT
12-13% yield
d9ꢀ3o
d9ꢀ5oa
d9ꢀ5ob
without M.S.
(1.0 equiv)
> 99% D
+ 100 mol% H(acac)
or
DG
N
Me
+
Supporting Information Experimental procedures; specꢀ
tral data. This material is available free of charge via the Internet
at http://pubs.acs.org.
+ 800 mol% MeOH
CD3
Et
Et
H3C
D3C CD3
H(acac): pentane-2,4-dione
N
NH
4a
(6.0 equiv)
d9ꢀ3o
DG =
75% recovered
95% H
AUTHOR INFORMATION
> 99% H
> 99% H
B.
DG
DG
N
H
N
H
Corresponding Author
H
H
H H
Me
Me
H3C
H3C
DG
gbdong@uchicago.edu
H3C CH3
H3C CH3
N
Me
Me
80% H
CH3
80% H
H3C
> 99% H
> 99% H
5ob
Me
H3C CH3
Notes
ca. 1: 4.5
13% yield
"standard conditions"
3o
5oa
without M.S. & Li(acac)
The authors declare no competing financial interests.
(1.0 equiv)
> 99% H
+ 500 mol% d4ꢀmethanol
DG
N
+
ACKNOWLEDGMENT
CH3
Et
Et
H3C
N
NH
4a
(6.0 equiv)
H3C CH3
3o
75% recovered
DG =
We thank the Frasch Foundation and NSF (CAREER: CHEꢀ
1254935) for funding. G.D. is a Searle Scholar and Sloan Fellow.
C.
REFERENCES
N
N
[Ir(coe)2Cl]2
HN
Cl
IrIII
HN
C6D6
70ºC, 4 h
N
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H
N
H
Me
Me
Me Me
Me
Me
3oa
8
Xꢀray structure
Attempts to capture the Rh–H intermediate via NMR experiꢀ
ments were unfruitful; however, the corresponding Ir–H complex
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4
5
6
7
8
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(3) Lapointe D.; Fagnou, K. Chem. Lett. 2010, 39, 1118.
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(g)
Zhang, F.ꢀL.; Hong, K.;
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