Facile Hydrogenolysis of C(sp3)–C(sp3) σ Bonds

Article abstract of DOI:10.1002/adsc.201600535

The modification of benzylic quaternary, tertiary, and secondary carbon centers through palladium-catalyzed hydrogenolysis of C(sp³)–C(sp³) σ bonds is presented. When benzyl Meldrum's acid derivatives bearing quaternary benzylic centers are treated under mild hydrogenolysis conditions – palladium on carbon and atmospheric pressure of hydrogen – aromatics substituted with tertiary benzylic centers and Meldrum's acid are obtained with good to excellent yield. Analogously, substrates containing tertiary or secondary benzylic centers yield aromatics substituted with secondary benzylic centers or toluene derivatives, respectively. Furthermore, this strategy is used for the high yielding synthesis of diarylmethanes. The scope of the reductive dealkylation reaction is explored and the limitations with respect to steric and electronic factors are determined. A mechanistic analysis of the reaction is described that consisted of deuterium labelling experiments and hydrogenolysis of enantioenriched derivatives. The investigation shows that the C(sp³)–C(sp³) σ bond-cleaving events occur through a hybrid S_N1/S_N2 mechanism, in which the palladium center displaces a carbon-based leaving group, namely Meldrum's acid, with inversion of configuration, followed by reductive elimination of palladium to furnish a C?H bond. (Figure presented.).

Full text of DOI:10.1002/adsc.201600535

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DOI: 10.1002/adsc.201600535
Facile Hydrogenolysis of C(sp3)–C(sp3) s Bonds
Eric Fillion,a,* Eric Beaton,a Yen Nguyen,a Ashraf Wilsily,a Ganna Bondarenko,a
and Jꢀrꢁme Jacqa
a
Department of Chemistry, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada
Fax : (+1)-519-746-0435; phone (+1)-519-888-4567; e-mail: efillion@uwaterloo.ca
Received: May 19, 2016; Revised: July 12, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600535.
Abstract: The modification of benzylic quaternary, to steric and electronic factors are determined. A
tertiary, and secondary carbon centers through palla- mechanistic analysis of the reaction is described that
dium-catalyzed hydrogenolysis of C(sp3)–C(sp3) consisted of deuterium labelling experiments and hy-
s bonds is presented. When benzyl Meldrumꢂs acid drogenolysis of enantioenriched derivatives. The in-
derivatives bearing quaternary benzylic centers are vestigation shows that the C(sp3)–C(sp3) s bond-
treated under mild hydrogenolysis conditions – palla- cleaving events occur through a hybrid SN1/SN2
dium on carbon and atmospheric pressure of hydro- mechanism, in which the palladium center displaces
gen – aromatics substituted with tertiary benzylic a carbon-based leaving group, namely Meldrumꢂs
centers and Meldrumꢂs acid are obtained with good acid, with inversion of configuration, followed by re-
À
to excellent yield. Analogously, substrates containing ductive elimination of palladium to furnish a C H
tertiary or secondary benzylic centers yield aromatics bond.
substituted with secondary benzylic centers or tolu-
ene derivatives, respectively. Furthermore, this strat-
egy is used for the high yielding synthesis of diaryl- Keywords: diarylmethane; hydrogenolysis; Mel-
methanes. The scope of the reductive dealkylation drumꢂs acid; quaternary centers; reductive dealkyla-
reaction is explored and the limitations with respect tion
Introduction
methyl Meldrumꢂs acid as carbon-based leaving
groups, which transform quaternary and tertiary ben-
The functionalization or interconversion of sp3-hy- zylic C(sp )–C(sp ) bonds into C(sp ) X bonds (X=
bridized carbon centers by substitution reactions in- C, H, N).[7] Liꢂs group described a related FeCl3-cata-
volving cleavage of C(sp3)–C(sp3) s bonds remains lyzed substitution at sp3-hybridized tertiary stabilized
relatively unexplored.[1,2] In this regard, there is (primarily dibenzylic) carbon centers using p-nucleo-
a growing interest in using Meldrumꢂs acid, malonates philes, where 1,3-diphenylpropane-1,3-dione acted as
and other cyclic and acyclic 1,3-dicarbonyl compounds a leaving group.[8]
3
3
3
À
as carbon-based leaving groups in substitutions and
Prior to our 2009 report on the hydrogenolysis of
benzyl Meldrumꢂs acids, all examples of C–C s bond
related transformations.[3]
Tsuji–Trost substitutions and related isomerizations hydrogenolysis reported in the literature required
with 1,3-dicarbonyls as carbon-based leaving groups forcing conditions, including high temperature,[9] in-
À
under palladium or nickel catalysis have been report- volve C C bonds in strained rings such as cyclopro-
ed.[4] Kotora and co-workers pioneered transition pane,[10] benzocyclobutanes,[11] [2.2]paracyclophane,[12]
metal-catalyzed deallylation of malonate derivatives or in activated cyclohexadienones[13] and cyclohexene-
through an alkene hydrometallation/b-carbon elimina- diones,[14] for which scission is driven by aromatiza-
tion strategy.[5] Our group documented the hydroge- tion. We showed that exposure of benzyl Meldrumꢂs
nolysis of benzyl Meldumꢂs acids bearing an all- acids to palladium on carbon under atmospheric pres-
carbon benzylic quaternary center under mild reac- sure of hydrogen induced reductive cleavage of
tions conditions to form aromatics bearing a tertiary C(sp3)–C(sp3) s bonds to release Meldrumꢂs acid and
benzylic stereocenter and Meldrumꢂs acid.[6] Subse- the aromatic product (Scheme 1). We described both
quently, we reported Lewis acid-promoted substitu- the reactivity of benzyl Meldrumꢂs acid derivatives
tion reactions employing Meldrumꢂs acid and 5- bearing benzylic all carbon quaternary centers in hy-
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Results
Effect of the Aryl Group Substitution Pattern
The C(sp3)–C(sp3) s bond hydrogenolysis reaction
was first explored by studying the effect of substitu-
tion on the aryl group in substrates 1, containing an
all-carbon benzylic quaternary center (Table 1).[15] Hy-
Scheme 1. General hydrogenolysis strategy.
drogenolysis reactions and the efficacy of Meldrumꢂs drogenolysis of 1a and of 1b using H2 (1 atm), Pd/C
acid as a carbon-based leaving group. These observa- (15 mol% Pd) in MeOH at room temperature result-
tions provided an opportunity to tackle the synthetic ed in excellent conversions and good isolated yields
challenge of converting benzylic sp3-hybridized all (entries 1 and 2).[16] Substitution by an alkoxy group
carbon quaternary centers to methines via cleavage/ produced different results depending on the position
substitution of C–C s bonds. One of the distinct ad- of the ether functionality (entries 3–5). The hydroge-
vantages of this synthetic method over the use of clas- nolysis of para 1c and ortho 1e derivatives led to iso-
sical leaving groups is that Meldrumꢂs acid can be re- propylbenzenes 2c and 2e with good conversions and
covered and recycled in the preparation of the benzyl yields. On the contrary, the hydrogenolysis of meta-
Meldrumꢂs acid derivatives.
substituted derivative 1d was sluggish and gave
In this manuscript, further investigations have <10% conversion after 24 h. Fluoro-substituted
broadened the substrate scope and have brought addi- benzyl Meldrumꢂs acids 1f and 1g were inert towards
tional insight into the hydrogenolysis mechanism. Ini- the hydrogenolysis reaction at room temperature (en-
tially, the exploration of the scope focused on varying tries 6 and 7). The study has exposed the electronic
substitution on the aromatic group with different demands of the reaction, where the substrates con-
alkyl and alkoxy groups at each of the ortho-, meta- taining 4-fluorophenyl (1f), 3-fluoro-4-methoxyphenyl
and para-positions. Furthermore, the effects of differ-
ing alkyl group substitution both on the benzylic
center and on the Meldrumꢂs acid 5-position were ex-
amined, including substrates with dibenzylic centers.
Table 1. Scope of the hydrogenolysis reaction – varying sub-
stitution on the aryl group.
Competition experiments were performed with diben-
zyl Meldrumꢂs acid derivatives, and reactions where
two different benzyl Meldrumꢂs acid derivatives were
present were conducted to determine the relative
ease of cleaving the benzylic C–C s bond for different
benzyl groups, an alkene example was studied to ex-
Entry Ar
Conversion [%][a] Yield [%]
amine hydrogenolysis versus hydrogenation, and addi-
tive experiments were performed to probe the ability
of different aromatics to compete with the substrate
to adsorb to the catalyst surface. Finally, the mecha-
nism of the reaction was studied with deuterium la-
belling experiments involving enantioenriched benzyl
Meldrumꢂs acid derivatives with quaternary benzylic
stereocenters. Compilation of the information that
was gathered in the various experiments has allowed
us to propose a hybrid SN1/SN2 mechanism, where the
metal center behaves as a nucleophile and displaces
the carbon-based leaving group with inversion of con-
figuration at the benzylic center. In addition, follow-
ing cleavage of the benzylic C–C s bond, a subsequent
1
C6H5 (1a)
>95
>95
>95
<10
>95
<5
80 (2a)[b]
80 (2b)
78 (2c)
2
4-PhC6H4 (1b)
3
4
5
6
4-(H17C8O)C6H4 (1c)
3-(H17C8O)C6H4 (1d)
2-(H17C8O)C6H4 (1e)
4-FC6H4 (1f)
ND (2d)
90 (2e)[c]
ND (2f)
ND (2g)
ND (2h)
NR (2i)
ND (2j)
90 (2k)
7
3-F-4-(MeO)C6H3 (1g) <5
8
9
4-t-BuC6H4 (1h)
3-t-BuC6H4 (1i)
4-i-PrC6H4 (1j)
4-n-BuC6H4 (1k)
3-EtC6H4 (1l)
2-EtC6H4 (1m)
4-(t-BuCH2)C6H4 (1n) >95
4-i-BuC6H4 (1o)
4-(t-BuO)C6H4 (1p)
4-(i-PrO)C6H4 (1q)
<5
NR
10
>95
>95
>95
10
11
12
13
14
15
16
17
64 (2l)[d]
83 (2m)
81 (2n)
À
Pd-catalyzed exchange of the benzylic C H bonds
>95
>95
>95
72 (2o)
70 (2p)[d]
82 (2q)
occurs. It was established that the exchange of benzyl-
À
ic C H bonds at enantiomerically pure tertiary ste-
reocenters in the presence of Pd/C, MeOH and H2
proceeds with retention of configuration.
[a]
The % conversion was determined from the ratio of
1
product to starting material by analysis of the H NMR
spectrum of the crude reaction mixture.
Yield of Meldrumꢂs acid.
Reaction time was 48 h using 20 mol% Pd.
Reaction time was 48 h.
[b]
[c]
[d]
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(1g), and 3-octyloxyphenyl (1d) exhibited poor reac- good conversions and isolated yields (entries 3, 5, and
tivity. Following the investigation of the reaction elec- 6). Increasing the catalyst loading to 50% enabled 1i
tronics, several alkyl-substituted derivatives (1h–o) to react completely and 2i was isolated with 80%
were studied. Substrates bearing linear alkyl groups yield. Similarly, an increased catalyst loading enabled
(ethyl or n-butyl) resulted in >95% conversion while 1g to achieve 84% conversion and a 60% yield of 2g
the introduction of a-branched alkyl groups (isopro- was obtained. A 96 h reaction time was necessary to
pyl or tert-butyl) led to poor reactivity regardless of completely react 1j and obtain a 91% yield. Unfortu-
the position of the group (entries 8–15).[17] Further nately, compounds 1d and 1f still resulted in less than
studies revealed that b-branched alkyl groups (isobu- 50% conversion (entries 1 and 2). Thus, some of the
tyl or neopentyl) also exhibited high reactivity and substrates that were problematic under the standard
conversions >95% were obtained (entries 14 and 15). conditions due to sterics of the substituted aromatic
The analogous branched alkoxy groups (isopropoxide ring reacted cleanly under optimized conditions but
or tert-butoxide) gave similar results (entries 16 and substrates bearing 3-octyloxyphenyl (1d), 4-fluoro-
17). Therefore, having a tertiary or quaternary center phenyl (1f), and 3-fluoro-4-methoxyphenyl (1g) gave
directly attached to the aromatic ring, in addition to poor results. Thus, an increased importance of the
the all-carbon quaternary center bearing the Mel- electronic effects of the reaction over the steric de-
drumꢂs acid moiety, is detrimental to the hydrogenoly- mands has been demonstrated.
sis reaction. On the other hand, substrates with linear
Of note, in EtOAc at 658C, electron-rich 1c gave
or b-branched alkyl chains attached to the aromatic a 1:1 mixture of aromatic compound 2c and its analo-
ring were shown to be reactive in the reductive deal- gous hydrogenated derivative 2c’, which were isolated
kylation reaction.
in 33% and 39% yields, respectively (Scheme 2). The
Next, in order to develop a general hydrogenolysis over-reduction was found to favour cis-2c’ in the ratio
protocol, conditions had to be found that would allow 2:1 as determined by analysis of the crude reaction
1
the reaction of substrates bearing a-branched chains. mixture by H NMR. This transformation is usually
From 1h, increasing the temperature to 658C led to difficult owing to the high stability of aromatic com-
decomposition of the substrate – probably due to the pounds and the numerous previous reports have all
known reaction of MeOH with Meldrumꢂs acid deriv- required harsh conditions or expensive catalysts with
atives.[18] This prompted the use of non-nucleophilic a high loading.[19]
EtOAc, a common solvent for hydrogenolysis or hy-
The hydrogenation of 2c to 2c’ was successfully per-
drogenation reactions. In EtOAc at 658C, 20 mol% formed under similar reaction conditions, suggesting
Pd led to >95% conversion after 48 h, and product that hydrogenation follows hydrogenolysis of the C–C
2h was isolated in 76% yield (Table 2, entry 4). The s bond (Scheme 3). However, for the reaction to pro-
new conditions were applied to the various Mel- ceed to completion and to isolate 2c’ in 86% yield,
drumꢂs acid derivatives that did not react at room a stoichiometric amount of palladium catalyst was re-
temperature in MeOH (Table 2). With some addition- quired.
al optimization, substrates 1g, 1i, and 1j resulted in
Addition of 2 equivalents of Meldrumꢂs acid pre-
vented over-reduction and resulted in a clean hydro-
genolysis reaction of 1c, providing an 82% yield of 2c
(Scheme 4). This is similar to the results obtained in
Table 2. Reductive dealkylation at 658C in EtOAc.
En- Ar
try
Time Conversion Yield
[h]
[%][a]
[%]
1
2
3
4
5
6
3-(C8H17O)C6H4 (1d)
4-FC6H4 (1f)
3-F-4-(MeO)C6H3 (1g) 24
4-t-BuC6H4 (1h)
3-t-BuC6H4 (1i)
4-i-PrC6H4 (1j)
48
18
38
42
84
>95
>95
>95
ND (2d)
ND (2f)
60 (2g)[b]
76 (2h)
48
24
96
80 (2i)[b]
91 (2j)
[a]
The % conversion was determined from the ratio of
product to starting material by analysis of the H NMR
1
spectrum of the crude reaction mixture.
50 mol% Pd.
[b]
Scheme 2. Formation of over-reduced products.
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Table 3. Effect of the benzylic alkyl substituents.
Scheme 3. Hydrogenation of 2c.
Entry R; R’
Conversion [%][a] Yield [%]
1
2
3
4
5
Me; Me (1c)
>95
>95
>95
>95
78 (2c)
86 (2r)
90 (2s)
Me; Et (1r)
Me; n-Bu (1s)
(CH2)5 (1t)
82 (2t)
Me; i-Pr (1u)
20, >95
ND, 70 (2u)[b]
Scheme 4. Over-reduction suppression with Meldrumꢂs acid
as additive.
[a]
The % conversion was determined from the ratio of
product to starting material by analysis of the H NMR
1
spectrum of the crude reaction mixture.
100 mol% Pd.
MeOH at room temperature (Table 1, entry 3). It is
postulated that Meldrumꢂs acid competitively binds to
the catalyst versus product 2c, hampering further hy-
drogenation to 2c’.
[b]
Table 4. Effect of substitution at the benzylic position and 5-
position of Meldrumꢀs acid moiety.
Effect of the Benzylic Carbon Substitution Pattern
After looking at the role of the aromatic moiety, we
then turned our attention to studying the influence of
the substitution at the benzylic position of the sub-
strates. Above, it has been shown that gem-dimethyl-
benzyl Meldrumꢂs acids react smoothly with H2 in the
presence of a catalytic amount of Pd/C (Table 1). An
array of substrates containing all-carbon quaternary
benzylic centers substituted with different alkyl
groups were subjected to the hydrogenolysis condi-
tions at room temperature (Table 3).
Good conversions and yields were obtained by re-
placing one of the methyl groups with a linear alkyl
chain (ethyl and n-butyl) (Table 3, entries 2 and 3).
Cyclohexane derivative 1t furnished product 2t in
80% yield (entry 4); however, substitution of one
methyl by an a-branching alkyl group, namely isopro-
pyl, resulted in a considerable decrease in reactivity
(entry 5). Conversion >95% could be achieved by
using a stoichiometric amount of the palladium cata-
lyst.
En- Conditions[a] R; R’
try
Conversion Yield
[%][b]
[%]
1
2
3
4
5
6
7
8
A
B
A
B
A
B
A
B
Me; H (3a)
Me; H (3a)
H; H (3b)
H; H (3b)
Me; Me (3c) 47
Me; Me (3c) >95
8
ND (4a)
12 (4a)[c]
ND (4b)
10 (4b)[c]
ND (4a)
94 (4a)
18
14
20
H; Me (3d)
H; Me (3d)
62
55 (4b)
>95
80 (4b)
[a]
[b]
[c]
Conditions A: H2 (1 atm), 10 wt% Pd/C (15 mol% Pd),
MeOH, room temperature, 24 h. Conditions B: H2
(1 atm), 10 wt% Pd/C (15 mol% Pd), EtOAc, 658C, 24 h.
The % conversion was determined from the ratio of
product to starting material by analysis of the H NMR
spectrum of the crude reaction mixture.
1
Decomposition of the starting material (~30%) was ob-
served as determined by analysis of the crude H NMR
Hydrogenolysis of Benzyl Meldrumꢀs Acids with
Mono- or Unsubstituted Benzylic Centers
1
spectrum.
Unexpectedly, the hydrogenolysis of benzyl Mel-
drumꢂs acids with mono- or unsubstituted benzylic
centers (3a and 3b) was sluggish under both sets of pounds 3c and 3d resulted in an enhancement of reac-
conditions (Table 4, entries 1–4). Alkylation of the C- tivity in the hydrogenolysis process (Table 4, en-
5 position of the Meldrumꢂs acid moiety to form com- tries 5–8); >95% conversion and good isolated yields
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Table 5. Competition experiments with dibenzyl Meldrumꢂs
acid derivatives.
were obtained when the reaction was performed at
658C in EtOAc.
Catalyst Inhibition by Hydrogenolysis Product
The enhanced adsorption of the product on the cata-
lystꢂs surface versus the starting material could ex-
plain some of the limited conversions previously ob-
served. Therefore, the influence of excess toluene and
hydrogenolysis product 2c on the reaction starting
from 1c was studied (Scheme 5). According to the ex-
Entry X/X’
Ratio 3/3’[a] Yield [%][b]
1
2
3
4
5
6
7
8
9
4-(H17C8O)/H (5a)
4-n-Bu/H (5b)
2-(MeO)/H (5c)
4-(MeO)/4-Me (5d)
4-(MeO)/4-n-Bu (5e)
4-n-Bu/4-t-Bu (5f)
4-(MeO)/4-(H17C8O) (5g) 39/61
4-(MeO)/2-(MeO) (5h)
4-(H17C8O)/4-F (5i)
>99/1
>99/1
>99/1
87/13
76/24
1/>99
65 (3b)
57 (3e)
85 (3f)
Scheme 5. Inhibition of the reductive dealkylation reaction
by the product.
46/6 (3g/3h)
44 (3g/3e)[c]
34 (3i)
71 (3g/3b)[d]
62 (3g/3f)[e]
78 (3j)[f]
periments, the product of the reaction decreases the
rate of hydrogenolysis, and resulted in lower conver-
sion over a 24-hour period, which is commonly ob-
served in Pd/C-catalyzed reactions.[17b,c] Only a slight
difference was observed between toluene and 2c.
50/50
1/>99
[a]
1
Determined by analysis of the H NMR spectrum of the
crude reaction mixture.
Conversion in all cases was >95%.
Mixture of 3g and 3e.
Mixture of 3g and 3b.
[b]
[c]
[d]
[e]
[f]
Competition Experiments and Relative Rate of
Cleavage of Benzylic Groups
Mixture of 3g and 3f.
50 mol% Pd
Competition experiments were performed to obtain
insights into the steric and electronic requirements of electron-donating methoxy and alkoxy groups gave
C(sp3)–C(sp3) s bond cleavage. Dibenzyl Meldrumꢂs a mixture of products where cleavage of the benzyl
acid derivatives 5, which contain two benzylic C–C group bearing the methoxy substituent was slightly
s bonds that could potentially be cleaved, were pre- favoured (entry 7). In addition, it was found that elec-
pared and submitted to reductive dealkylation condi- tron-donating groups substituted at either the ortho
tions. As shown in Table 5, the lack of benzylic alkyl or para position are equivalent with respect to hydro-
substituents requires this type of substrate to be react- genolysis of the benzylic bond as a 50:50 mixture was
ed at 658C in EtOAc. Since the final product of the obtained for substrate 5h (entry 8). As depicted in
reaction is not alkylated at the 5-position of Mel- entry 9, the electron-rich benzyl group is cleaved
drumꢂs acid, it was anticipated to be inert under the faster than the one substituted with fluorine.
reaction conditions.
Additional information on the relative rates of hy-
Hydrogenolysis of an unsubstituted benzyl group drogenolysis was obtained from competition experi-
occurred selectively versus a benzyl group substituted ments between substrates 1a, 1c, and 1k. The sub-
with either an electron-donating alkoxy or electron- strates were reacted in a 1:1 ratio, under standard re-
neutral alkyl group at either the para or ortho posi- action conditions, and disappearance of the starting
tion (entries 1–3). Reaction of substrates 5d and 5e material was determined after 2 h (Table 6). As previ-
showed that hydrogenolysis of the alkyl-substituted ously observed (Table 5), the C6H5C(CH3)2 moiety in
arene (methyl and n-butyl) occurs more rapidly than 1a
was
cleaved
faster
than
the
4-
with the methoxy-substituted aromatic (entries 4 and (H17C8O)C6H5C(CH3)2 moiety in 1c and the 4-n-
5). Hydrogenolysis of substrate 5f showed that hydro- BuC6H5C(CH3)2 moiety in 1k (entries 1 and 2), sug-
genolysis favours linear alkyl substituents over a- gesting an optimal interaction of the phenyl ring with
branched alkyl groups (entry 6). Competition between the palladium catalyst. Of note, when determining the
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Table 6. Competition experiments.
Table 7. Hydrogenolysis of spiro substrate 6.
En- Substrates Ar/Ar’
try
Conversion
[%][a]
En-
try
Conditions
Yield
7a [%]
Yield
7b [%]
1
2
3
C6H5 (1a)/4-(H17C8O)C6H4 (1c)
C6H5 (1a)/4-n-BuC6H4 (1k)
4-(H17C8O)C6H4 (1c)/4-n-BuC6H4 (1k) 44/21 (2c/2k)
25/13(2a/2c)
35/9 (2a/2k)
1
2
3
15 mol% Pd, MeOH, r.t.
30 mol% Pd, MeOH, r.t.
15 mol% Pd, EtOAc, 658C
13
18
54
77
69
ND
[a]
1
Determined by analysis of the H NMR spectrum of the
crude reaction mixture.
hydrogenolysis rates of Meldrumꢂs acid 1c versus 1k,
the trend was reversed when comparing with sub- the hydrogenolysis process. At low temperature, hy-
strates 5d and 5e, and alkoxy-bearing substrate 1c re- drogenolysis of the C(sp3)–C(sp3) s bond occurs faster
acted at a faster rate (entry 3).
resulting in significant ring opening prior to alkene re-
The lower conversion observed in entries 1 and 2 duction. The proposed acyclic alkene intermediate
1
might be rationalized by a better affinity of substrate was not detected in the crude H NMR spectra. When
1a and product 2a for the catalyst surface, preventing the temperature is increased, the olefin hydrogenation
the other substrates from reacting. However, the rate becomes favoured, which forms cyclohexane 7a,
of hydrogenolysis of 1a is fairly slow due to the ab- which does not react further; thus, low yields of 7b
sence of electron-donating groups to stabilize the are obtained. As illustrated in Scheme 6, treatment of
transition state. When 1a and 2a are not present, the 7a with either set of conditions did not result in signif-
other substrates can efficiently interact with the cata- icant hydrogenolysis after 24 h. For comparison, 5-
lyst, resulting in faster reaction and higher conver- allyl-5-benzyl Meldrumꢂs acid yielded exclusively 5-
sion.
The scope of the reaction was also investigated
propyl Meldrumꢂs acid.
with spiro Meldrumꢂs acid derivative 6, which con-
tains a cyclic alkene (Table 7). Under standard condi-
tions (entry 1), the starting material 6 was fully con-
verted to a mixture of 7a and 7b.[20] Cyclohexane de-
rivative 7a results from hydrogenation of the olefin
and was isolated with only 13% yield while compound
7b, resulting from both hydrogenation and hydroge-
nolysis processes, was obtained in 77% yield. On in-
creasing the catalyst loading from 15 mol% to 7a.
30 mol% of Pd similar results were obtained
(entry 2). Surprisingly, using high temperature condi-
Scheme 6. Reductive dealkylation of spiro Meldrumꢂs acid
tions in EtOAc resulted in selective hydrogenation of Diarylmethane Synthesis
the alkene and cyclohexane 7a was isolated with 54%
yield and only traces of 7b were observed.
Diarylmethane compounds are an important subunit
These results could be explained by the sluggish re- in a number of biologically active molecules.[21] Differ-
activity of 7a towards hydrogenolysis. In Meldrumꢂs ent synthetic pathways to these compounds are
acid 6, the C(sp3)–C(sp3) s bond is both benzylic and known which usually involve cross-coupling method-
allylic, while in Meldrumꢂs acid 7a the C(sp3)–C(sp3) ology using organoboron,[22] organostannane,[23] orga-
s bond is only benzylic, with a decreased reactivity in nozinc,[24] or other reagents.[25] Reduction of diarylme-
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Table 8. Synthesis of diarylmethanes.
Table 9. Hydrogenolysis of enantioenriched all-carbon qua-
ternary centers with inversion of configuration.
Entry
Ar/Ar’
Yield [%][a]
1
2
3
4
5
6
7
8
4-(MeO)C6H4/4-(MeO)C6H5 (8a)
2-(MeO)C6H4/C6H5 (8b)
3-(MeO)C6H4/C6H5 (8c)
4-t-BuC6H4/C6H5 (8d)
4-t-BuC6H4/4-t-BuC6H4 (8e)
3-(MeO)C6H4/3-(MeO)C6H4 (8f)
4-(MeO)C6H4/4-FC6H4 (8g)
4-FC6H4/C6H5 (8h)
96 (9a)
98 (9b)
95 (9c)
96 (9d)
99 (9e)
93 (9f)
81 (9g)
81 (9h)
En-
try
X; er
er
[%] Inversion[a]
([%] Yield)[b]
[a]
Conversion >95% in all cases as determined by analysis
of the H NMR spectrum of the crude reaction mixtures.
1
1
2
3
4
5
C8H17O (1r); 98.5 (R):1.5 (S)
MeO (1v); 98.5(R):1.5 (S)
Ph (1w); 98 (R):2 (S)
4 (R); 96 (S)
97 (93) (2r)[c]
5.5 (R); 94.5 (S)
96 (72) (2v)[d]
9.5 (R): 90.5 (S)
92 (51) (2w)
thanols is also frequently employed.[26] As previously
discussed, the hydrogenolysis reaction is sluggish for
enolizable benzyl Meldrumꢂs acid derivatives with ter-
tiary benzylic centers but it was postulated that the
presence of two aryl groups could promote the reac-
tion resulting in the formation of diarylmethane prod-
ucts. In Table 8, it is shown that the reaction proceeds
in excellent yield for a variety of electron-rich and
electron-poor substrates and for substrates with steri-
cally demanding aryl substituents. Most examples, in-
cluding the seemingly problematic 4,4’-di-tert-butyl
and 3,3’-dimethoxy substrates 8e and 8f, respectively,
proceeded in excellent yield.
4-MeO (10a); 86 (S):14 (R)
6-MeO (10b); 99 (S):1 (R)
21 (S); 79 (R)
93 (49) (11a)[e,f]
9 (S): 91 (R)
92 (62) (11b)[g]
[a]
Inversion of er.
Isolated yield. Conversion >95% unless stated otherwise
[b]
(as determined from the ratio of product to starting ma-
1
terial by analysis of the H NMR spectrum of the crude
reaction mixture).
Using 30 mol% Pd.
Using EtOAc, 658C.
Using 50 mol% Pd.
90% conversion.
[c]
[d]
[e]
[f]
Mechanistic Studies: Hydrogenolysis of
Enantioenriched All-Carbon Quaternary Centers
[g]
65% conversion.
In order to rationalize the results presented above, we
embarked on an investigation of the reaction mecha- Deuterium Labelling Experiments
nism, initially by evaluating the stereochemical integ-
rity of the reaction. Enantioenriched Meldrumꢂs acid It was postulated that either the hydride of a palladi-
derivatives 1 and 10 previously reported by our group um hydride species would directly displace Meldrumꢂs
were subjected to hydrogenolysis (Table 9).[27] It was acid, or that the Pd center of a palladium hydride spe-
shown that the reductive dealkylation reaction pro- cies would perform the displacement followed by re-
ceeds with near complete inversion of configuration, ductive elimination. The observed inversion of config-
with a level of inversion of 92–97%. The absolute ste- uration suggested at first an SN2-like displacement of
reochemistry of benzyl derivatives 2 was determined Meldrumꢂs acid. Therefore, to gather more knowledge
by comparison with the known compound (S)-2v. The about the substitution mechanism and the nature of
absolute stereochemistry of (R)-11 was established by the nucleophilic species involved, several deuterium
synthesis of (R)-1-ethyl-6-methoxyindane (11b) from labelling experiments were performed (Table 10). The
a modified literature procedure.[28]
hydrogenolysis reactions of 1c and 1e were performed
using different combinations of D2 or H2 and CD3OD
or CH3OH. When excess gas is used (balloon), incom-
plete deuterium incorporation at the a-position was
observed in the mixed cases using either H2/CD3OD
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Table 10. Labelling studies.
flask) and the solvent was found to be the major con-
tributor to the benzylic hydrogen of the product.
When CD3OD was used with either H2 or D2, high
deuterium incorporations were observed; however,
negligible deuterium incorporation was measured
when CH3OH was used with D2 (entries 7–12). These
results indicate that the exchange is an equilibrium
process where the most abundant hydrogen source is
incorporated to the benzylic position. When the gas is
limited, the solvent is more abundant and dominates,
but when excess gas is used, it competes with the sol-
vent for incorporation. Unfortunately, the 2-alkoxy
derivative did not react completely (45–53% conver-
sion) and modest isolated yields (37–41%) of the deu-
terated product were obtained. This is surprising, as
previous experiments have shown negligible reactivity
difference between 2- and 4-substituted derivatives,
when the substituent is the same (Table 1, entry 3
versus entry 5 and Table 5, entry 8). Also, deuterium
incorporation was observed at the b-positions (Dꢂ and
D’’) when CD3OD was used as the solvent (entries 7,
9, 10, and 12). Of note is that DeKreuk and co-work-
ers did observe b-hydrogen exchange when reacting
2-phenyl-2-propanol with D2 (1 atm), and Pd/C, in
AcOD at 308C, to yield cumene.[17b,c]
Entry Gas/Solvent
1
2
a-D-Incorporation [%][a,b]
Excess gas (balloon)
1
2
3
4
5
6
H2/CD3OD
D2/CH3OH
D2/CD3OD
H2/CD3OD
D2/CH3OH
D2/CD3OD
1c 2c 52
1c 2c 32
1c 2c >95
1e 2e 17[c]
1e 2e 45[c]
1e 2e 94[c]
2 Equivalents of gas (sealed flask) D-Incorporation [%][a,b]
a-position
(D)
b-position
(D’+D’’)[d]
7
8
9
10
11
12
H2/CD3OD
D2/CH3OH
D2/CD3OD
H2/CD3OD
D2/CH3OH
D2/CD3OD
1c
1c
1c
1e
1e
1e
2c
2c
2c
2e
2e
2e
90 (85)
2 (77)
27
0
>95 (54)
75 (41)[e]
3 (38)[f]
17
7
0
>95 (37)[ g]
15
The existence of an exchange reaction in our
system was further confirmed using the regioisomeric
hydrogenolysis products 2c, 2d and 2e (Table 11).
Using 2 equivalents of H2 with CD3OD in a sealed
tube, product d-2c was obtained with 84% deuterium
incorporation at the benzylic position and a similar
result was obtained for substrate 2d (entries 1 and 2);
however, the deuterium incorporation for the 2-
alkoxy compound 2e is minimal (less than 5%) after
24 h.[30] Deuterium incorporation was also observed at
the b-position (entries 1 and 2). Incorporation at the
[a]
[b]
[c]
[d]
[e]
[f]
1
At the benzylic position (determined by H NMR).
Isolated yields (%) provided in parentheses.
20 mol% Pd.
1
Determined by H and 2H NMR.
45% conversion.
53% conversion.
[g]
46% conversion. % conversion determined from the
ratio of product to starting material by analysis of the
1H NMR spectrum of the crude reaction mixture.
or D2/CH3OH (entries 1/2, 4/5); however, near com- b-position was unexpected considering that typically
plete deuterium incorporation was achieved for D2/ forcing conditions are required to affect this type of
CD3OD (entries 3 and 6). The percentage of deuteri- transformation.[29] The difference of reactivity ob-
um incorporation at the benzylic position was difficult served (a-incorporation) for 2e might be due to elec-
to reproduce and this was attributed to difficulties in
controlling the amount of hydrogen available to the
Table 11. Hydrogen–deuterium exchange studies.
reaction (balloon size, refilling). The incomplete deu-
terium incorporation and inconsistent results in the
mixed cases can be explained by a benzylic hydrogen
exchange process that has been described by Sajiki
and co-workers.[29] They report an efficient methodol-
À
À
ogy for converting a benzylic C H bond to a C D
bond using conditions similar to our standard hydro-
genolysis protocol. Using a limited quantity of H2
(sealed flask) and catalytic Pd/C, hydrogen from the
benzylic C–H can selectively be exchanged with deu-
terium from the solvent. This exchange obfuscates the
analysis because, regardless of the source of the origi-
nal hydride, it can be exchanged with the solvent. The
deuterium labelling experiments were repeated using
a limited quantity of gas (2 equivalents in a sealed
Entry
X
D-Incorporation [%][a,b]
a-position b-position [ppm]
dbenzylic
1
2
3
4-C8H17O (2c) 84 (78) (d-2c) 18
2.86
2.86
3.33
3-C8H17O (2d) 74 (72) (d-2d)
2-C8H17O (2e) 2 (98) (d-2e)
2
0
[a]
1
Determined by H and 2H NMR.
[b]
Isolated yields (%) provided in parentheses.
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tronic effects resulting from conformational restric-
tions of the isopropyl group, where the molecule pre-
fers to have the isopropyl group oriented with the hy-
drogen pointed towards the ortho substituent to mini-
mize steric interactions. Electrostatic repulsion be-
tween the oxygen lone pairs and the C–H s bond
electrons causes polarization of the bonds, which is re-
flected by the significant downfield shift observed for
1
the benzylic proton in the H NMR spectrum.
The influence of the acidic proton of Meldrumꢂs
acid was then studied. In order to minimize the ef-
fects of the benzylic hydrogen exchange reaction,
ortho-substituted 1e was labelled with deuterium at
the Meldrumꢂs acid 5-position to form d-1e. The deu-
terium-labelled substrate was then subjected to the
same conditions (sealed tube) and the results were
similar to those obtained with (non-deuterated) com-
pound 1e (Table 12). Once again, the solvent was the
dominant deuterium source where 84% D-incorpora-
Scheme 7. H–H and H–D exchange with retention of config-
uration.
tion was obtained when CD3OD was used with H2 zylic position is stereospecific. To the best of our
and 93% D-incorporation was found, when CD3OD knowledge, this is the first example of C–H to C–D
was used with D2. However, when CH3OH was used exchange in which an all-carbon stereocenter is ste-
with D2, only 1% D-incorporation was achieved. reospecifically labelled.[31] This supports that the in-
Thus, the influence of the acidic Meldrumꢂs acid version of configuration observed in the hydrogenoly-
proton is negligible with respect to deuterium incor- sis reaction is solely due to the C–C s bond cleaving
poration. Once again, deuterium incorporation was process. Of note, a 10% D-incorporation at the b-po-
observed at the b-position (entries 1 and 3).
sitions was also observed.
The existence of an exchange reaction at the ben-
zylic center required the stereochemical integrity of
the final product of the hydrogenolysis reaction to be Discussion
verified. The enantioenriched benzyl compound (S)-
2r was employed in two exchange (H–H or H–D) re- From the numerous parameters of the reaction that
actions under the standard conditions with excess H2 were studied, different information and guidelines
or D2 (Scheme 7). Compounds (S)-2r and d-(S)-2r were extracted. First of all, the nature (substitution
were obtained with retention of configuration, dem- pattern) of the aromatic ring has a strong influence
onstrating that the H–D exchange reaction at the ben- on the reaction, where a subtle combination of steric
and electronic factors is at play. Competition experi-
ments underlined the importance of an optimal coor-
dination to the metal surface.[32] On the other hand,
the importance of the electronic effects also appears
in this study: the reactivity is enhanced by the pres-
ence of electron-donating groups, either alkyl or
alkoxy group, at the ortho or para position with a fine
balance of sterics and electronics, and is retarded by
electron-withdrawing groups. This is consistent with
an electron-deficient transition state, with positive
charge development at the benzylic carbon, which
seems to corresponds to either an SN1 reaction mech-
anism, or an SN2 mechanism, in which the bond-form-
ing and bond-breaking events are asynchronous; the
Table 12. Deuterium labelling experiments.
Entry
Gas
Solvent
D-Incorporation [%][a,b]
a-position
b-position
1
2
3
H2
D2
D2
CD3OD
CH3OH
CD3OD
84 (46)[c]
1 (36)[d]
8
0
24
>95 (37)[e]
À
C C bond would be at least partially broken before
[a]
1
Determined by H and 2H NMR.
Isolated yields [%] provided in parentheses.
Conversion 55%.
the nucleophile attacks the benzylic cation. A modifi-
cation of the reaction conditions revealed that using
EtOAc as the solvent and increasing the temperature
to 658C allows the reaction to be performed on sub-
strates with less labile benzyl groups. In some cases,
an augmentation of the catalyst loading is also neces-
[b]
[c]
[d]
[e]
Conversion 56%.
Conversion 41%. % conversion determined from the
ratio of product to starting material in the crude
1H NMR spectrum.
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sary. For electron-rich benzyl groups, the modified
Next, the scope of the hydrogenolysis reaction was
conditions were found to produce a cyclohexane broadened by the efficient and very clean synthesis of
product by hydrogenation of the benzene ring. Thus diarylmethanes. The high reactivity of diarylmethyl
the standard conditions are preferred in these cases. Meldrumꢂs acids can be first explained by a stronger
Alternatively, Meldrumꢂs acid can be added to the re- adsorption of the substrate to the catalyst, regardless
action since it was shown to prevent over-reduction.
of the substitution pattern, and second by electronic
Second, the study of the benzylic alkyl group substi- contributions from both aromatic rings stabilizing the
tution revealed a strong and somewhat peculiar influ- carbocationic character of an asynchronous SN2 mech-
ence on the reaction. For substrates with quaternary anism, or simply promoting an SN1 pathway. Similar
benzylic centers bearing two alkyl groups, secondary observations were made for spiro substrate 6, bearing
alkyl groups (isopropyl) were shown to hinder the re- an allylic/benzylic all-carbon quaternary center. How-
action likely the result of poor adsorption of the sub- ever, following hydrogenation, compound 7a likely
strate onto the catalyst surface, while primary alkyl has a conformation that disfavours binding to the cat-
groups (ethyl, n-butyl, indanyl) and methyl groups al- alyst, or geometrical constraints hampering the C–C
lowed complete hydrogenolysis reactions. Again, s bond cleavage.
these observations are consistent with a highly elec-
Finally, the research was directed towards obtaining
tron-deficient transition state, with positive charge de- mechanistic insights. First, near complete inversion of
velopment at the electrophilic carbon center, support- configuration is observed for the hydrogenolysis of
ing an SN1-like mechanism. The SN1-like mechanism enantioenriched substrates, in addition to a positive
is further supported by the fact that the hydrogenoly- influence of electron-donating substituents on the aro-
sis reaction proceeds sluggishly and low conversions matic ring, and increased substitution at the benzylic
are achieved for substrates containing a secondary or position. After confirming that the inversion of con-
tertiary benzylic center.
figuration observed in the hydrogenolysis reaction
À
Removal of the enolizable proton via alkylation of occurs only due to the C C bond cleavage event, it
the Meldrumꢂs acid C-5 position greatly improved the was proposed that the incomplete inversion observed
reactivity. This difference in reactivity between enoliz- in the initial investigations of enantioenriched deriva-
able and non-enolizable structures is difficult to ra- tives might be related to some of the observed deute-
tionalize, as the difference in acidity between Mel- rium incorporation at the homobenzylic positions.
drumꢂs acid (pKa =7.32 in DMSO) and 5-methyl Mel- From the labelling experiments, the hydrogen in the
drumꢂs acid (pKa =7.42 in DMSO) is minimal and reaction comes from the gas while a secondary pro-
does not explain the large rate and reactivity differ- cess exchanges the benzylic hydrogen of the product
ence.[33] On the other hand, it is postulated that 5- with the solvent. Carreira and co-workers have stud-
methyl Meldrumꢂs acid bearing a sterically demanding ied an analogous reaction involving hydrogenolysis of
all-carbon quaternary center increases the ground- benzylic nitro groups.[35] In their studies, they found
state energy of the substrate, consequently facilitating that the resulting benzylic hydrogen comes solely
its departure in the substitution process.[34] X-Ray from the solvent. They propose that palladium displa-
analysis shows only an insignificant difference in the ces the nitro group to form a benzylic palladium spe-
À
length of the breakable C C bonds (Table 13). Fur- cies that is then protonated by the solvent before un-
thermore, no atypical conformations for the Mel- dergoing reductive elimination to furnish the product.
drumꢂs acids (chair conformation for Meldrumꢂs acids In our system, deuterium incorporation at the b-posi-
3m and 3n, and boat conformation for 1x, 3k, and 3l) tion is a distinct feature, which could occur by hydro-
were observed.
genation of an alkene resulting from b-hydride elimi-
nation of a benzylic palladium intermediate. The ob-
served deuterium incorporation at the b-position re-
veals the nature of the nucleophilic species; palladium
displaces Meldrumꢂs acid to form a benzylic palladi-
um species that is configurationally stable. This claim
is reinforced by the fact that 1e leads to 2e under D2
(2 equiv) in CD3OD with high levels of incorporation
at the a- and b-positions (Table 10, entry 12, and
Table 12, entry 3). However, 2e is inert under the
same reaction conditions, and no significant D-incor-
poration is observed (Table 11, entry 3).
Table 13. X-Ray analysis of Meldrumꢂs acid derivatives.
Entry
R
R’
R’’
C-5–C-11 bond length [ꢄ]
1
2
3
4
5
Me Me H (1x)
1.565
1.541
1.562
H
H
H
H
H
H (3k)
H (3l)
Me (3m) 1.566
Me (3n) 1.568
Compiling these results allows the following mecha-
nism to be proposed (Scheme 8). The first step is
a hybrid SN1/SN2 displacement of Meldrumꢂs acid by
a nucleophilic palladium hydride species, as revealed
Me
H
Me
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Scheme 8. Proposed hydrogenolysis mechanism.
by the carbocationic character of the transition state. SN2 displacement. This hybrid mechanism relates with
It is suggested that this displacement is assisted by co- the wide array of substrates discussed above.
ordination of Meldrumꢂs acid via the carbonyl group
From the palladium-bound benzylic product, reduc-
to the palladium(II) surface upon adsorption of H2 by tive elimination to form the inverted product occurs
the catalyst. The complexation to the Lewis acidic rapidly but a small amount of b-hydride elimination
catalyst further activates the leaving group and helps occurs, destroying the stereogenic center. The result-
À
in the C C bond breaking events that proceed ing alkene is hydrogenated to a racemic mixture of
through a polar transition state, explaining the facile products. This mechanism explains the loss of enan-
displacement at an all-carbon quaternary center in tiomeric excess observed in the hydrogenolysis of
comparison to less substituted carbon centers. In an enantioenriched compounds and deuterium incorpo-
SN2-like mechanism, the bond-forming and bond- ration at the homobenzylic position.[36] Additional C–
À
breaking events would be asynchronous; the C C H/C–D exchange at the a- and b-positions occurs sub-
bond would be at least partially broken before the nu- sequently to the hydrogenolysis, without affecting the
cleophile attacks the benzylic cation. In an SN1 mech- enantioselectivity of the product.
anism, following the elimination of Meldrumꢂs acid,
the cationic intermediate would remain bound to the
surface of the catalyst, preventing racemization, and Conclusions
the nucleophilic palladium hydride would then attack
the cationic intermediate opposite to the face origi- In conclusion, we have presented a facile Pd/C-cata-
nally bound to Meldrumꢂs acid. Thus, the most accu- lyzed hydrogenolysis of C(sp3)–C(sp3)
s
bonds,
rate and representative mechanism is a hybrid SN1/ a formal substitution of the carbon-based leaving
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tario for OGS scholarship. Dr. Jalil Assoud (Meldrumꢀs acids
3k, and 3l), University of Waterloo, and Dr. Alan Lough
(Meldrumꢀs acid 1x, 3m, and 3n), University of Toronto, are
gratefully acknowledged for X-ray structure determinations.
group Meldrumꢂs acid, with inversion of configuration
at the stereogenic carbon center, by a hydride. In this
transformation, the palladium center behaves as a nu-
cleophile, and the substitution mechanism exhibiting
both SN1 and SN2 features, with carbocationic charac-
ter in the transition state.
The reaction was shown to be general and allows References
the synthesis of tertiary and secondary centers and
[1] For recent reviews on C–C s bond activation, see: a) F.
toluene derivatives as well as diarylmethanes, al-
though the crucial electronic and steric requirements
were thoroughly outlined. We also demonstrated the
stereospecificity of the Pd/C-catalyzed benzylic hydro-
gen exchange, which occurs with retention of configu-
ration.
Chen, T. Wang, N. Jiao, Chem. Rev. 2014, 114, 8613–
8661; b) A. Dermenci, J. W. Coe, G. Dong, Org. Chem.
Front. 2014, 1, 567–581; c) K. Ruhland, Eur. J. Org.
Chem. 2012, 2683–2706. For relevant modification of
sp2-hybridized carbon center initiated by C(sp2)–C(sp)
or C(sp2)–C(sp2) s bond scission, see: d) T. Patra, S.
Agasti, A. Modak, D. Maiti, Chem. Commun. 2013, 49,
8362–8364; e) A. M. Dreis, C. J. Douglas, J. Am. Chem.
Soc. 2009, 131, 412–413; f) M. P. Watson, E. N. Jacob-
sen, J. Am. Chem. Soc. 2008, 130, 12594–12595; g) Y.
Nakao, S. Ebata, A. Yada, T. Hiyama, M. Ikawa, S.
Ogoshi, J. Am. Chem. Soc. 2008, 130, 12874–12875. For
Experimental Section
Typical Procedure for Hydrogenolysis of Benzyl
Meldrumꢀs Acids with Substrate 1k
À
reviews on C C bond activation, see: h) D. NeÅas, M.
To a resealable Schlenk tube was added 5-[2-(4-butylphe-
nyl)propan-2-yl]-2,2-dimethyl-1,3-dioxane-4,6-dione
Kotora, Curr. Org. Chem. 2007, 11, 1566–1591; i) T.
Satoh, M. Miura, Top. Organomet. Chem. 2005, 1–20;
j) C.-H. Jun, Chem. Soc. Rev. 2004, 33, 610–618; k) B.
Rybtchinski, D. Milstein, Angew. Chem. 1999, 111,
918–932; Angew. Chem. Int. Ed. 1999, 38, 870–883;
l) M. Murakami, Y. Ito, Top. Organomet. Chem. 1999,
3, 97–129; m) R. H. Crabtree, Chem. Rev. 1985, 85,
245–269.
(102 mg, 0.320 mmol) (1k) and 10% Pd/C (51 mg,
0.048 mmol, 15 mol% Pd). MeOH (3.2 mL) was added to
the Schlenk tube through a septum via a syringe. The sus-
pension was degassed with vacuum and then refilled with H2
gas (3ꢅ) with the help of a balloon. The tube was sealed
and the suspension was stirred at room temperature for
24 h. The mixture was filtered through a pad of celite, rins-
ing with CH2Cl2. The solvent was removed under reduced
pressure at 08C due to the volatility of the product. Purifica-
tion by flash column chromatography, eluting with 100%
pentane afforded compound 2k as a colorless oil; yield:
[2] L. Di, S. Yao, M. Li, G. Wu, W. Dai, G. Wang, L. Li, N.
Guan, ACS Catal. 2015, 5, 7199–7207.
[3] For other carbon-based leaving groups: cyclopentadien-
yl anion as leaving group in allylic substitution reac-
tions, see: a) E. L. Fisher, T. H. Lambert, Org. Lett.
2009, 11, 4108–4110. Crabtree and co-workers reported
a similar reaction involving (5,5-dialkycyclopentadie-
1
51 mg (90%). H NMR (CDCl3, 300 MHz): d=7.17–7.09 (m,
4H), 2.89 (septet, J=6.9 Hz, 1H), 2.59 (t, J=7.6 Hz, 2H),
1.6–1.55 (m, 2H), 1.39 (sextet, J=7.6 Hz, 2H), 1.25 (d, J=
6.9 Hz, 6H), 0.94 (t, J=7.3 Hz, 3H); 13C NMR (CDCl3,
75 MHz): d=146.0 (C), 140.2 (C), 128.3 (CH), 126.2 (CH),
35.2 (CH2), 33.7 (CH2), 33.6 (CH), 24.1 (CH3), 22.4 (CH2),
13.9 (CH3); GC/MS: m/z=176.1 (LR-MS), calcd. for C13H20
(M+): 176.2.
CCDC 1484398 (1x), CCDC 1484399 (3m), CCDC
1484400 (3n), CCDC 1484401 (3k), and CCDC 1484402 (3l)
contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
À
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This work was supported by the Natural Sciences and Engi-
neering Research Council of Canada (NSERC), the Govern-
ment of Ontario (Early Researcher Award to E.F.), the Cana-
dian Foundation for Innovation Trust (New Opportunities),
and the University of Waterloo. A.W. is indebted to NSERC
for CGS-M and CGS-D scholarships. E.B. is indebted to
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Adv. Synth. Catal. 0000, 000, 0 – 0
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FULL PAPERS
14 Facile Hydrogenolysis of C(sp3)–C(sp3) s Bonds
Adv. Synth. Catal. 2016, 358, 1 – 14
Eric Fillion,* Eric Beaton, Yen Nguyen, Ashraf Wilsily,
Ganna Bondarenko, Jꢀrꢁme Jacq
Adv. Synth. Catal. 0000, 000, 0 – 0
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ÞÞ
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