Hydrogenolysis of unstrained carbon-carbon σ bonds: Stereoselective entry into benzylic tertiary centers

Article abstract of DOI:10.1021/ja9076815

(Chemical Equation Presented) The modification of sp³-hybridized carbon centers through Pd-catalyzed reductive cleavage of unstrained carbon-carbon @ bonds is described. From the hydrogenolysis of benzyl Meldrum's acids bearing an all-carbon be

Full text of DOI:10.1021/ja9076815

Published on Web 10/07/2009
Hydrogenolysis of Unstrained Carbon-Carbon σ Bonds: Stereoselective
Entry into Benzylic Tertiary Centers
Ashraf Wilsily, Yen Nguyen, and Eric Fillion*
Department of Chemistry, UniVersity of Waterloo, Waterloo, Ontario, Canada N2L 3G1
Received September 9, 2009; E-mail: efillion@uwaterloo.ca
The functionalization or modification of sp3-hybridized carbon
centers by cleavage of unstrained carbon-carbon σ bonds remains
unexplored to date.1 Although hydrogenolysis of C-Z bonds (Z
) N, O, S, halogen) is common, hydrogenolysis of C-C bonds
under mild reaction conditions is unprecedented.2 All examples of
C-C bond hydrogenolysis reported in the literature necessitate
either high temperature/pressure conditions3 or involve C-C bonds
in strained rings, such as cyclopropanes and cyclobutanes, or in
activated cyclohexadienones,4 for which scission is driven by
aromatization.5
hampered the reactivity and led to modest levels of conversion to
2i. However, when run under stoichiometric conditions, hydro-
genolysis of 1i furnished 2i in good yield (entry 9). Secondary
benzylic Meldrum’s acid 1j was inert toward hydrogenolysis (entry
10), but the analogous diaryl 1k was fully converted to 2k, which
was isolated in 96% yield (entry 11).
Table 1. Scope of the C-C Hydrogenolysis in Benzyl Meldrum’s
Acids
In the course of preparing a series of benzyl Meldrum’s acid
derivatives,6,7 we discovered that their exposure to Pd/C in the
presence of H2 induced reductive C-C σ-bond scission to release
the corresponding aromatics 2 and Meldrum’s acid (3) (Scheme
1). This observation provided an opportunity to tackle the synthetic
challenge of modifying sp3-hybridized carbon centers via cleavage
of C-C σ bonds. Moreover, we have reported a number of protocols
(including enantioselective strategies) for the facile preparation of
benzyl Meldrum’s acid derivatives 1 bearing an all-carbon benzylic
quaternary stereocenter via conjugate addition of organometallic
reagents to 5-(1-arylalkylidene) Meldrum’s acids.8 Herein, we
document a catalytic hydrogenolysis of C-C bonds in benzyl
Meldrum’s acid derivatives 1 to access tertiary benzylic stereo-
centers 2 and Meldrum’s acid in good to excellent yields and
conversions (Scheme 1). Additionally, some mechanistic aspects
of the transformation are discussed.
entry
X
R; R′
conv. (%)
yield (%)
76 (2a)
71 (2b)
1
2
3
4
5
6
7
8
9
4-(OC8H17) R ) R′ ) Me (1a)
>95
>95
>95
9
4-Ph
H
R ) R′ ) Me (1b)
R ) R′ ) Me (1c)
a
80 (2c)
3-(OC8H17) R ) R′ ) Me (1d)
2-(OC8H17) R ) R′ ) Me (1e)
4-(OC8H17) RsR′ ) (CH2)5 (1f)
4-(OC8H17) R ) Me; R′ ) Et (1g)
4-(OC8H17) R ) Me; R′ ) n-Bu (1h)
4-(OC8H17) R ) Me; R′ ) i-Pr (1i)
N/A (2d)
65 (71) (2e)
81 (2f)
86 (2g)
90 (2h)
b
b
80 (92)
91
>95
>95
c
c
20 (>95) N/A (70) (2i)
10 4-(OC8H17) R ) H; R′ ) Me (1j)
11 4-(OMe) R ) H; R′ ) 4-MeOC6H4 (1k) >95
<5
N/A (2j)
96 (2k)
a Yield for the isolation of Meldrum’s acid, as product 2c was too
volatile. b The conversion and yield in parentheses were obtained using
20 mol % Pd. c The conversion and yield in parentheses were obtained
using 100 mol % Pd.
Scheme 1
The hydrogenolysis mechanism was investigated first through
labeling studies. Subjecting 1a to 10% Pd/C (15 mol % Pd) and
CD3OD under a hydrogen atmosphere afforded 52% deuterium
incorporation at the benzylic position of 2a (Scheme 2a). Performing
the reaction under D2 with undeuterated methanol provided 32%
deuterium incorporation at the benzylic position of 2a (Scheme 2b).
The hydrogenolysis was then performed under deuterium gas with
deuterated methanol, which led to full deuterium incorporation at
the benzylic position (Scheme 2c). In all three experiments, <5%
deuterium incorporation was observed at the methyl position of
the isopropyl group.
Further insights into the mechanism were obtained by investigat-
ing the hydrogenolysis of enantioenriched benzyl Meldrum’s acids.
As depicted in Table 2, Meldrum’s acids (R)-1g, (R)-1l, and (R)-
1m reacted with virtually complete inversion of configuration
(92-97%) at the benzylic center to yield products (S)-2g, (S)-2l,
and (S)-2m, respectively. The absolute stereochemistry of the
products was determined by correlation with the known compound
(S)-2l.9
When 2,2-dimethyl-5-(2-(4-(octyloxy)phenyl)propan-2-yl)-1,3-
dioxane-4,6-dione (1a) was subjected to 10% Pd/C (15 mol % Pd)
and MeOH at room temperature (rt) under an atmosphere of
hydrogen for 24 h, 97% conversion to Meldrum’s acid and 2a was
observed, and 2a was isolated in 76% yield (Table 1, entry 1). In
the absence of H2 or Pd/C, the hydrogenolysis reaction did not
proceed. Similar results were obtained with Meldrum’s acid
derivatives 1b and 1c (entries 2 and 3). Important electronic factors
were at play, as illustrated by the facile hydrogenolysis of the para
and ortho analogues 1a and 1e in comparison with the meta-
substituted compound 1d (entries 1, 4, and 5). 2,2-Benzyl Mel-
drum’s acid 1f afforded cyclohexyl-substituted aromatic 2f in 91%
conversion and 81% yield (entry 6). Replacing one of the methyl
groups at the all-carbon quaternary benzylic center with larger
primary groups such as Et or n-Bu did not affect the reaction, and
2g and 2h were obtained in excellent conversions and 86 and 90%
yields, respectively (entries 7 and 8). Substitution with an i-Pr group
Nearly complete inversion of configuration in the hydrogenolysis
of enantioenriched all-carbon quaternary centers strongly suggests
that the reductive C-C σ-bond scission reaction proceeds through
9
15606 J. AM. CHEM. SOC. 2009, 131, 15606–15607
10.1021/ja9076815 CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
In summary, we have described the modification of sp3-
hybridized carbon centers through Pd-catalyzed reductive cleavage
of unstrained C-C σ bonds. The hydrogenolysis of benzyl
Meldrum’s acids bearing an all-carbon benzylic quaternary center
furnished Meldrum’s acid and aromatics substituted with a tertiary
benzylic stereocenter in good to excellent yields. Mechanistic studies
showed that the reductive cleavage of enantioenriched benzylic
quaternary centers proceeds with inversion of configuration, sup-
porting a “loose” SN2 pathway. We are currently exploring the scope
of this transformation with respect to other benzyl Meldrum acids
and studying the mechanism thoroughly.
Scheme 2. Labeling Studies
Acknowledgment. This work was supported by the Natural
Sciences and Engineering Research Council of Canada (NSERC),
the Government of Ontario (Early Researcher Award to E.F.), the
Canadian Foundation for Innovation, the Ontario Innovation Trust,
and the University of Waterloo. A.W. is indebted to NSERC for
CGS-M and CGS-D scholarships.
Table 2. Hydrogenolysis of Enantioenriched All-Carbon
Quaternary Centers with Inversion of Configuration
Supporting Information Available: Experimental procedures and
NMR spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
er of 1 (R/S) er of 2 (S/R) inv (%)a
yield (%)
References
entry
X
1
2
3
4-(OC8H17) [(R)-1g] 98.5:1.5
96:4
94.5:5.5
90.5:9.5
97
96
92
93 [(S)-2g]
72 [(S)-2l]
51 [(S)-2m]
(1) For reviews of C-C bond activation, see: (a) Nec¸as, D.; Kotora, M. Curr.
Org. Chem. 2007, 11, 1566. (b) Jun, C.-H. Chem. Soc. ReV. 2004, 33, 610.
For relevant modifications of sp2-hybridized carbon centers initiated by
C(sp2)-C(sp) or C(sp2)-C(sp2) σ-bond scission, see: (c) Dreis, A. M.;
Douglas, C. J. J. Am. Chem. Soc. 2009, 131, 412. (d) Watson, M. P.;
Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 12594. (e) Nakao, Y.; Ebata,
S.; Yada, A.; Hiyama, T.; Ikawa, M.; Ogoshi, S. J. Am. Chem. Soc. 2008,
130, 12874.
(2) King, A. O.; Larsen, R. D. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York,
2002; Vol. 1, pp 995-1050.
4-(OMe) [(R)-1l]
Ph [(R)-1m]
98.5:1.5
98:2
a Inversion of er.
an SN2 mechanism. Furthermore, an electron-withdrawing group
retarded the hydrogenolysis (Table 1, entry 4), and its rate was
strongly dependent upon the size of the benzylic substituent (Table
1, entry 9). The lack of reactivity of 1d and 1j and the high
conversion and yield obtained with 1k illustrate the “loose” nature
of the SN2 mechanism,10 in which a significant development of
positive charge occurs in the transition state.
In the C-C bond scission process, the Meldrum’s acid moiety
is directly displaced either by a palladium hydride or Pd(0) to yield
a benzylic organopalladium intermediate that undergoes protonation
by MeOH. The latter mechanism was proposed Carreira and co-
workers11 in the hydrogenolysis of secondary benzylic nitro groups
under similar conditions, on the basis of the observation that the
hydrogen atom incorporated into the product originated strictly from
the solvent.
In our labeling study, the hydrogen/deuterium incorporation
originated from both the solvent and the gas. These observations
seem to indicate that nucleophilic attack, either by palladium hydride
or by Pd(0), is slower than isotopic dilution, which occurs through
exchange on the Pd surface between the reactive palladium species
and the acidic proton of the solvent (Scheme 2a,b). The modest
level of deuterium incorporation may also be the result of both
pathways, operating simultaneously.
The slight erosion of the enantiomeric ratio during the reaction
can occur as a result of a competitive SN112 or alkene formation,
either by Meldrum’s acid or palladium ꢀ-hydride elimination
followed by olefin hydrogenation (Table 2).13 This is supported
by the <5% incorporation of deuterium at the methyl position of
the isopropyl group (Scheme 2a-c).
(3) (a) Grubmu¨ller, P.; Maier, W. F.; Schleyer, P. v. R.; McKervey, M. A.;
Rooney, J. J. Chem. Ber. 1980, 113, 1989. (b) Maier, W. F.; Grubmu¨ller,
P.; Thies, I.; Stein, P. M.; McKervey, M. A.; Schleyer, P. v. R. Angew.
Chem., Int. Ed. Engl. 1979, 18, 939. (c) Grubmu¨ller, P.; Schleyer, P. v. R.;
McKervey, M. A. Tetrahedron Lett. 1979, 20, 181.
(4) (a) Miller, B.; Lewis, L. J. Org. Chem. 1974, 39, 2605. (b) Carson, J. F.
J. Am. Chem. Soc. 1951, 73, 1850.
(5) For cyclopentadienyl anion as the leaving group in allylic substitution
reactions, see: Fisher, E. L.; Lambert, T. H. Org. Lett. 2009, 11, 4108.
(6) Fillion, E.; Wilsily, A.; Fishlock, D. J. Org. Chem. 2009, 74, 1259.
(7) The hydrogenolysis of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione,
forming a 98:2 mixture of 5-ethyl Meldrum’s acid and 5,5-dimethyl
Meldrum’s acid, has been reported. See: Gro¨ger, C.; Musso, H.; Robnagel,
I. Chem. Ber. 1980, 113, 3621.
(8) (a) Wilsily, A.; Lou, T.; Fillion, E. Synthesis 2009, 2066. (b) Dumas, A. M.;
Fillion, E. Org. Lett. 2009, 11, 1919. (c) Wilsily, A.; Fillion, E. Org. Lett.
2008, 10, 2801. (d) Fillion, E.; Wilsily, A.; Liao, E-T. Tetrahedron:
Asymmetry 2006, 17, 2957. (e) Fillion, E.; Wilsily, A. J. Am. Chem. Soc.
2006, 128, 2774.
(9) Pfaltz, A.; Blankenstein, J.; Hilgraf, R.; Ho¨rmann, E.; McIntyre, S.; Menges,
F.; Scho¨nleber, M.; Smidt, S.; Wu¨stenberg, B.; Zimmermann, N. AdV. Synth.
Catal. 2003, 345, 33.
(10) For discussions of SN1-SN2 mechanisms, see: (a) Phan, T. B.; Nolte, C.;
Kobayashi, S.; Ofial, A. R.; Mayr, H. J. Am. Chem. Soc. 2009, 131, 11392.
(b) Vitullo, V. P.; Grabowski, J.; Sridharan, S. J. Am. Chem. Soc. 1980,
102, 6463. (c) Ko, E. C. F.; Parker, A. J. J. Am. Chem. Soc. 1968, 90,
6447.
(11) Fessard, T. C.; Motoyoshi, H.; Carreira, E. M. Angew. Chem., Int. Ed. 2007,
46, 2078.
(12) (a) Kieboom, A. P. G.; van Rantwijk, F. Hydrogenation and Hydrogenolysis
in Synthetic Organic Chemistry; Delft University Press: Delft, The
Netherlands, 1977; pp 87-155. (b) An “SN1-type” mechanism has been
proposed for hydrogenolysis of tertiary benzyl alcohols. See: Kieboom,
A. P. G.; de Kreuk, J. F.; van Bekkum, H. J. Catal. 1971, 20, 58.
(13) Thakar, N.; Polder, N. F.; Djanashvili, K.; van Bekkum, H.; Kapteijn, F.;
Moulijn, J. A. J. Catal. 2007, 246, 344.
JA9076815
9
J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009 15607