Carbon-based leaving group in substitution reactions: Functionalization of sp3-hybridized quaternary and tertiary benzylic carbon centers

Article abstract of DOI:10.1021/ol301442z

Lewis acid promoted substitution reactions employing Meldrum's acid and 5-methyl Meldrum's acid as carbon-based leaving groups are described which transform unstrained quaternary and tertiary benzylic C_sp ³-C_sp³ bonds into C_sp³-X bonds (X = C, H, N). Importantly, this reaction has a broad scope in terms of both suitable substrates and nucleophiles with good to excellent yields obtained (typically >90%).

Full text of DOI:10.1021/ol301442z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Carbon-Based Leaving Group in
Substitution Reactions: Functionalization
of sp3-Hybridized Quaternary and Tertiary
Benzylic Carbon Centers
Stuart J. Mahoney, Tiantong Lou, Ganna Bondarenko, and Eric Fillion*
Department of Chemistry, University of Waterloo, Waterloo, Ontario, N2L 3G1,
Canada
efillion@uwaterloo.ca
Received May 25, 2012
ABSTRACT
Lewis acid promoted substitution reactions employing Meldrum’s acid and 5-methyl Meldrum’s acid as carbon-based leaving groups are
described which transform unstrained quaternary and tertiary benzylic Csp3ꢀCsp3 bonds into Csp3ꢀX bonds (X = C, H, N). Importantly, this reaction
has a broad scope in terms of both suitable substrates and nucleophiles with good to excellent yields obtained (typically >90%).
The direct modification/functionalization of sp3-hybri-
dized carbon centers through cleavage of unstrained CꢀC
σ-bonds remains a challenging transformation in organic
synthesis.1ꢀ5 In 2009 our group discovered two such
reactions in which Meldrum’s acid functions as a highly
effective and convenient leaving group in the Pd-catalyzed
hydrogenolysis of quaternary benzyl Meldrum’s acids,6
replacing an unstrained benzylic Csp3ꢀCsp3 σ-bond with a
Csp3ꢀH bond with inversion of configuration (Scheme 1)
and additionally with tertiary benzylic Meldrum’s acids
in the presence of Sc(OTf)3 and a nucleophile.7 Subse-
quently, Li’s group described a related FeCl3-catalyzed
substitution at sp3-hybridized tertiary stabilized (primarily
diaryl) carbon centers, with π-nucleophiles, in which 1,3-
diphenylpropane-1,3-dione acted as a leaving group.8
We postulated that substitution of Meldrum’s acid
derivatives at sp3-hybridized benzylic carbon centers with
carbon- and heteroatom-based nucleophiles, via CꢀC
σ-bond cleaving/CꢀX (X = C, N, H) σ-bond forming
reactions, would allow for benzylic functionalization.
(1) For selected general reviews on CꢀC σ-bond scission, see: (a)
Ruhland, K. Eur. J. Org. Chem. 2012, 2683. (b) Murakami, M.;
Matsuda, T. Chem. Commun. 2011, 47, 1100. (c) Park, Y. J.; Park,
J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41, 222. (d) Jun, C.-H. Chem.
Soc. Rev. 2004, 33, 610. (e) Rybtchinski, D.; Milstein, D. Angew. Chem.,
Int. Ed. 1999, 38, 870. (f) Murakami, M.; Yoshihiko, I. In Topics in
Organometallic Chemistry; Murai, S., Ed.; Springer-Verlag: Berlin, 1999;
Vol. 3, p 97.
(2) For a review on advances in leaving groups, see: Lepore, S. D.;
Mondal, D. Tetrahedron 2007, 63, 5103.
(3) TsujiꢀTrost substitutions and related isomerizations with 1,3-
diketone, malonate, cyclopentadienyl, and Meldrum’s acid as carbon-
based leaving groups under palladium or nickel catalysis have been
reported; for selected examples, see: (a) Fisher, E. L.; Lambert, T. H.
Org. Lett. 2009, 11, 4108. (b) Trost, B. M.; Simas, A. B. C.; Plietker, B.;
(4) For an isolated example of a nickel catalyzed substitution em-
ploying Meldrum’s acid as a leaving group, see: Sumida, Y.; Yorimitsu,
H.; Oshima, K. Org. Lett. 2010, 12, 2254.
(5) For other approaches to the cleavage of unstrainedCꢀC σ-bonds,
see: (a) He, C.; Guo, S.; Huang, L.; Lei, A. J. Am. Chem. Soc. 2010, 132,
ꢀ
8273. (b) Najera, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2009, 48,
ꢁ
2452. (c) Necas, D.; Kotora, M. Org. Lett. 2008, 10, 5261. (d) Tobisu,
M.; Chatani, N. Chem. Soc. Rev. 2008, 37, 300. (e) Gooßen, L. J.;
Rodrıguez, N.; Gooßen, K. Angew. Chem., Int. Ed. 2008, 47, 3100. (f)
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Necas, D.; Drabina, P.; Sedlak, M.; Kotora, M. Tetrahedron. Lett. 2007,
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48, 4539. (g) Tursky, M.; Necas, D.; Drabina, P.; Sedlak, M.; Kotora, M.
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Organometallics 2006, 25, 901. (h) Necas, D.; Tursky, M.; Tislerova, I;
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Kotora, M. New J. Chem. 2006, 30, 671. (i) Necas, D.; Tursky, M.;
Kotora, M. J. Am. Chem. Soc. 2004, 126, 10222. (j) Zhang, N.; Vozzolo,
J. J. Org. Chem. 2002, 67, 1703. (k) Jun, C.-H.; Lee, H.; Lim, S.-G. J. Am.
Chem. Soc. 2001, 123, 751. (l) Chatani, N.; Ie, Y.; Kakiuchi, F.; Murai, S.
J. Am. Chem. Soc. 1999, 121, 8645. (m) Jun, C.-H.; Lee, H. J. Am. Chem.
Soc. 1999, 121, 880.
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Jakel, C.; Xie, J. Chem.;Eur. J. 2005, 11, 7075. (c) Vicart, N.; Gore, J.;
Cazes, B. Tetrahedron 1998, 54, 11063. (d) Bricout, H.; Carpentier, J.-F.;
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Mortreux, A. Tetrahedron Lett. 1997, 38, 1053. (e) Vicart, N.; Gore, J.;
Cazes, B. Synlett 1996, 850. (f) Nilsson, Y. I. M.; Andersson, P. G.;
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€
r
10.1021/ol301442z
XXXX American Chemical Society

Herein, we report a Lewis acid promoted modification/
functionalization of sp3-hybridized quaternary and ter-
tiary benzylic carbon centers through displacement of
carbon-based leaving groups, namely Meldrum’s acid
and 5-methyl Meldrum’s acid (Scheme 1).
Table 1. Methyl Substitution at Quaternary Centers
The substitution reaction was shown to be general
with an array of substrate substitutions and nucleophiles,
under mild conditions, and proceeding in good to excellent
yields.
entry
X
R; R0
yielda (%)
The ability to substitute Meldrum’s acid at quaternary all-
carbon sp3-hybridized centers with a methyl group was first
explored. Trimethylaluminum was chosen for its combined
Lewis aciditiy and nucleophilic properties upon complexa-
tion with a Lewis base.9 A wide array of readily available
benzyl Meldrum’s acids 1 effectively reacted with Me3Al to
yield 2 in excellent yields at room temperature. As depicted in
Table 1, the process was general as electronics and sterics did
not affect the efficiency of the substitution reaction. Both
mesomerically and inductively donating groups, electron
neutral groups as well as mildly electron withdrawing groups,
afforded the desired product with excellent isolated yields.
1
2
3
4
5
6
7
8
H
RꢀR0 = (CH2)5 (1a)
R = R0 = Me (1b)
R = R0 = Me (1c)
R = R0 = Me (1d)
RꢀR0 = (CH2)5 (1e)
RꢀR0 = (CH2)5 (1f)
R = R0 = Me (1g)
R = R0 = Me (1h)
RꢀR0 = (CH2)5 (1i)
R = R0 = Me (1j)
R = R0 = Me (1k)
R = R0 = Me (1l)
R = R0 = Me (1m)
RꢀR0 = (CH2)5 (1n)
quant (2a)
96 (2b)
93 (2c)
95 (2d)
quant (2e)
95 (2f)
91 (2g)
94 (2h)
96 (2i)
98 (2j)
97 (2k)
89 (2l)
quant (2m)
98 (2n)
4-t-Bu
4-(MeO)
4-(C8H17O)
4-Cl
4-F
2-Et
2-(C8H17O)
2-F
3- t-Bu
9
10
11
12b
13
14
3-(C6H13
)
3-(C8H17O)
3-TMS
3-F
a In all cases, conversion was >95%. b Reaction time was 5 h.
Scheme 1. General Strategy
furnished 2s in 84% yield (Figure 1). Substitution was also
realized with TMSCN, yielding 2t in quantitative yield.
π-Nucleophiles 2-methylfuran and 2-methylthiophene
were also effective in the substitution reaction, with complete
regioselectivity for the 5-position. Reacting 2-(trimethyl-
siloxy)furan and 1c led to a 9:1 mixture of regioisomeric
butenolides in an 84% combined yield. Furthermore, the
azide functionality was also introduced at the benzylic posi-
tion via the use of azidotrimethylsilane.
Having established the substrate scope of the methyla-
tion of benzyl Meldrum’s acids, we proceeded to explore
the range of nucleophiles compatible with this system.
After optimization studies,10 it was found that a com-
bination of Lewis acid, AlCl3, and an external nucleo-
phile furnished substitution products in good yield
under mild reaction conditions (Figure 1).11 From 1c,
the relatively weak nucleophile allyltrimethylsilane and
methallyltrimethylsilane led to 2o and 2p, respectively,
in excellent yields. Allenyl and propargyl compounds
2q and 2r were formed from 1c and propargylTMS and
allenylSnBu3, respectively.
The generality of the substitution reaction was further
established by investigating the reactivity of tertiary
The same net result of our hydrogenolysis protocol6 was
achieved by the reaction of 1c with i-Bu3Al, which
(7) Meldrum’s acid was reductively cleaved and displaced by acetone
(C-alkylation); see: Mahoney, S. J.; Moon, D. T.; Hollinger, J.; Fillion,
E. Tetrahedron Lett. 2009, 50, 4706.
(8) Li, H.; Li, W.; Liu, W.; He, Z.; Li, Z. Angew. Chem., Int. Ed. 2011,
50, 2975.
(9) Related strategies of activation/methylation to afford tert-alkyl-
substituted aromatics have been demonstrated from tertiary benzylic
alcohols and chlorides; for an example, see: Hartsel, J. A.; Craft, D. T.;
Chen, Q.-H.; Ma, M.; Carlier, P. R. J. Org. Chem. 2012, 77, 3127 and
references cited therein.
(10) Alternative Lewis acids surveyed in optimization studies were
found to deliver inferior yields to AlCl3 with the main side reactions
being elimination and indane formation.
(11) In the absence of added nucleophile, from 1c, the following
indane was formed in 80% yield, where Ar = (4-MeO)C6H4.
Figure 1. Scope of the nucleophile. In all cases, conversion was
a
b
c
>95%. Nucleophile employed: allylTMS; methallylTMS; pro-
pargylTMS; dallenylSnBu3; ei-Bu3Al (in the absence of AlCl3);
fTMSCN; g2-methylfuran; h2-methylthiophene; i2-(trimethylsiloxy)-
j
furan; 77% of butenolide 2w plus 7% of minor regioisomer 2x
isolated as individual components; kTMSN3.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Substitutions at Tertiary Benzylic Centers
Figure 2. Leaving group comparison in allyl substitutions.
entry
1a
Ar; Ar0; R
Cond
A
Nu
Me
yield (%)
Ar = Ar0 = C6H5;
R = H (3a)
N/A (4a)
the methylation reaction (Table 2, entry 11, gas evolu-
tion also observed), and the allylation proceeded slug-
gishly (Table 2, entry 12). Remarkably, the methylated
analogue 3g enabled the methyl and allyl substitutions to
proceed in excellent yields (Table 2, entries 13 and 14). The
utility of this methodology was further demonstrated by
applying the methylation conditions to the synthesis of the
potent inhibitor of tubulin polymerization 4k (Table 2,
entry 15).13
A direct comparison to alternative leaving groups was
performed with substrates bearing the challenging qua-
ternary benzylic center motif under our optimized allyla-
tion conditions (Figure 2). In analyzing the allyl sub-
stitutions of 1o, 5aꢀd, Meldrum’s acid as a leaving group
was found to be superior to 1,3-diphenylpropane-1,3-dione,
acetate, chloride, and hydroxide,14 as 1o furnished 2z in
highest yield.15
2a
3
(3a)
B
A
allyl
Me
50 (4b)
92 (4a)
Ar = Ar0 = C6H5;
R = Me (3b)
4
5
(3b)
B
A
allyl
Me
93 (4b)
Ar = Ar0 = 4-(MeO)C6H4;
quant (4c)
R = H (3c)
6
7a
(3c)
B
A
allyl
Me
94 (4d)
95 (4e)
Ar = 4-(MeO)C6H4;
Ar0 = C6H5; R = H (3d)
(3d)
8
9a
B
A
allyl
Me
96 (4f)
87 (4g)
Ar = 4-(MeO)C6H4;
Ar0 = 4-ClC6H4; R = H (3e)
(3e)
10a
11
B
A
allyl
Me
91 (4h)
Ar = Ar0 = 4-ClC6H4;
N/A (4i)
R = H (3f)
12a
13
(3f)
B
A
allyl
Me
42 (4j)
96 (4i)
Ar = Ar0 = 4-ClC6H4;
R = Me (3g)
In conclusion, we have described unprecedented sub-
stitution reactions through CꢀC σ-bond cleaving/CꢀX
(X = C, N, H) σ-bond forming reactions that allow
for direct modification of sp3-hybridized tertiary and
quaternary carbon centers with good to excellent
yields. Notably, a wide range of electronics and sub-
stitutions are tolerated on the substrate and a large
collection of nucleophiles can be added using this
system. Current efforts are directed at broadening
the use of Meldrum’s acid derivatives as convenient
leaving groups.
14
15
(3g)
B
A
allyl
Me
94 (4j)
Ar = 2-naphthyl;
Ar0 = 3,4,5-(OMe)3Ph;
Ar0 = 3,4,5-(OMe)3C6H2;
R = Me (3h)
99 (4k)
a Reaction was performed in (CH2Cl)2 at 50 °C.
benzhydryl Meldrum’s acids 3. Relative to quaternary
benzyl Meldrum’s acids 1, benzhydryl Meldrum’s acids 3
were shown to be sensitive to the electronics of the rings.12
To our surprise, substitution product 4a was not formed
when 3a was reacted with Me3Al (Table 2, entry 1).
Instead, vigorous gas evolution was observed and starting
material recovered, suggesting a competing deprotonation
of the Meldrum’s acid moiety with formation of methane.
Similarly, the optimized conditions for allylation furnished
compound 4b in only modest yield (Table 2, entry 2).
Gratifyingly, methylation of the 5-position of Meldrum’s
acid remedied this limitation. Substitution product 4a was
formed in 92% yield when 3b was treated with Me3Al
(Table 2, entry 3). The allylation of 3b also proceeded in
highyield (Table 2, entry 4). Facile reactions were observed
with electron-rich substrates 3c, 3d, and 3e which
efficiently afforded the desired methylation and al-
lylation products for both AlCl3 and Me3Al systems
(Table 2, entries 5ꢀ10). Substrate 3f bearing strong
inductively withdrawing substituents was inert toward
Acknowledgment. This work was supported by the
Natural Sciences and Engineering Research Council of
Canada (NSERC), the Government of Ontario (ERA to
E.F.), the Canadian Foundation for Innovation (CFI), the
Ontario Innovation Trust (OIT), and the University of
Waterloo. T.L. is indebted to NSERC for a USRA scholar-
ship. S.J.M. is indebted to NSERC and the University of
Waterloo for graduate scholarships. Dr. Ashraf Wilsily,
ꢀ
(13) (a) Messaoudi, S.; Hamze, A.; Provot, O.; Treguier, B.; De
Losada, J. R.; Bignon, J.; Liu, J.-M.; Wdzieczak-Bakala, J.; Thoret,
S.; Dubois, J.; Brion, J.-D.; Alami, M. Chem. Med. Chem. 2011, 6, 488.
(b) Alami, M.; Messaoudi, S.; Hamze, A.; Provot, O.; Brion, J.-D.; Liu,
J.-M.; Bignon, J.; Bakala, J. Patent WO/2009/147217 A1, Dec 10, 2009.
For a recent synthesis, see: (c) Taylor, B. L. H.; Swift, E. C.; Waetzig, J. D.;
Jarvo, E. R. J. Am. Chem. Soc. 2011, 133, 389.
(14) For a review of direct substitutions on stabilized alcohols, see:
Emer, E.; Sinisi, R.; Capdevila, M. G.; Petruzziello, D.; De Vincentiis,
F.; Cozzi, P. G. Eur. J. Org. Chem. 2011, 647–666.
(15) For 5aꢀd, the lower yields of 2z reflected competing pathways:
(12) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
Org. Lett., Vol. XX, No. XX, XXXX
elimination and indane formation.
C

California Institute of Technology, is thanked for pre-
liminary experiments. Yen Nguyen, Toronto Research
Supporting Information Available. Experimental pro-
cedures and NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
ꢀ ^
Chemicals, and Dr. Jerome Jacq, UCB Pharma France,
are acknowledged for kindly sharing benzylidene
Meldrum’s acids.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX