Functionalization of Csp3-H bond-Sc(OTf)3-catalyzed domino 1,5-hydride shift/cyclization/Friedel-Crafts acylation reaction of benzylidene Meldrum's acids

Article abstract of DOI:10.1016/j.tetlet.2009.06.007

Under Sc(OTf)₃ catalysis, benzylidene Meldrum's acids bearing a tethered p-methoxyphenethyl group were observed to undergo a [1,5]-hydride shift/cyclization at room temperature, representing a mild Csp³-H bond functionalization. The resulting spiro Meldrum's acid intermediates then underwent intramolecular Friedel-Crafts acylation, completing the one-pot, domino reaction. The reported protocol generates the 6-6-5-6 tetracyclic core of tetrahydrobenzo[b]fluoren-11-ones.

Full text of DOI:10.1016/j.tetlet.2009.06.007

Tetrahedron Letters 50 (2009) 4706–4709
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Tetrahedron Letters
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Functionalization of Csp3–H bond—Sc(OTf)3-catalyzed domino 1,5-hydride
shift/cyclization/Friedel–Crafts acylation reaction of benzylidene
Meldrum’s acids
*
Stuart J. Mahoney, David T. Moon , Jon Hollinger, Eric Fillion
Department of Chemistry, University of Waterloo, Waterloo, Ontario, Canada N2L 3G1
a r t i c l e i n f o
a b s t r a c t
Article history:
Under Sc(OTf)3 catalysis, benzylidene Meldrum’s acids bearing a tethered p-methoxyphenethyl group
were observed to undergo a [1,5]-hydride shift/cyclization at room temperature, representing a mild
Csp3–H bond functionalization. The resulting spiro Meldrum’s acid intermediates then underwent intra-
molecular Friedel–Crafts acylation, completing the one-pot, domino reaction. The reported protocol gen-
erates the 6-6-5-6 tetracyclic core of tetrahydrobenzo[b]fluoren-11-ones.
Received 14 April 2009
Revised 22 May 2009
Accepted 1 June 2009
Available online 6 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
A renewed interest in the tert-amino effect and related [1,5]-hy-
dride shift/cyclization reactions has been apparent in the recent lit-
erature as an efficient method of functionalizing Csp3–H bonds.1,2
This methodology has advanced from harsh thermal conditions
and excess Lewis or Brønsted acids3 to mild,4 catalytic protocols.5,6
In addition, progress has been made toward catalytic enantioselec-
tive variants7 as well as finding applications in key disconnections
of total syntheses.8
Examples of the tert-amino effect performing a [1,5]-hydride
shift/cyclization onto Meldrum’s acid derivatives have been re-
ported in the literature under thermal conditions albeit in moder-
ate yields.9 Our group has had success employing alkylidene
Meldrum’s acids as conjugate addition acceptors10 and has also
exploited Meldrum’s acid derivatives as powerful acylating
agents,11 both under catalytic Lewis acidic conditions.
to successfully effect the desired reaction sequence as shown in
Table 1. The best result came from conducting the reaction with
Sc(OTf)3 (10 mol %), which provided tetracycle 3a in 48% yield.
The use of toluene as solvent proved to be superior to nitrometh-
ane (entry 8), which had been optimal for previous Friedel–Crafts
acylations with Meldrum’s acids.11
As the yield for the domino process was still low, the focus then
turned to studying the initial 1,5-hydride shift/cyclization step in
more detail. It was postulated that the high temperature was
decomposing benzylidene 1a before complete conversion to 2a
could occur. Indeed, we were pleased to find that by performing
the reaction at room temperature spirocyclic intermediate 2a
could be isolated in 90% yield (Table 2, entry 1).14,15 The scope of
the [1,5]-hydride shift/cyclization reaction was then investigated
under these optimized conditions (Table 2). The p-NMe2 group
was also found to promote the reaction under catalytic conditions
at 70 °C (Table 2, entry 2). Further exploration of substrates bearing
As depicted in Scheme 1, we envisaged that a catalytic protocol
analogous to the
a,b-unsaturated acceptors reported (aldehydes,
ketones and malonates) could be developed to promote a benzylic
[1,5]-hydride shift/cyclization onto highly electrophilic12 benzyli-
dene Meldrum’s acids 1 to afford spirocycles 2, which would un-
dergo intramolecular Friedel–Crafts acylation and generate
complex tetracycles 3.
We began our investigation by subjecting benzylidene Mel-
drum’s acid 1a13 to a range of Brønsted and Lewis acids, having
reasoned that the activating p-OMe group should be suitable for
providing both stabilization for the developing carbocation during
O
O
O
O
O
catalyst
O
O
O
X
X
1
2
the hydride shift while being sufficiently
subsequent FC acylation. Gratifyingly, several catalysts were found
p-nucleophilic for the
O
X
* Corresponding author. Tel.: +1 519 888 4567x32470; fax: +1 519 746 0435.
E-mail address: efillion@uwaterloo.ca (E. Fillion).
3
Present address: Dalton Medicinal Chemistry Partners, Toronto, Ontario, Canada
M3J 2S3.
Scheme 1. General strategy.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.007

S. J. Mahoney et al. / Tetrahedron Letters 50 (2009) 4706–4709
4707
Table 1
Table 2
Initial exploration of the domino sequence
Scope of the Sc(OTf)3-catalyzed [1,5]-hydride transfer/cyclization at room
temperature
O
O
Entry
Substrate
Product (isolated yield) catalyst
loading (mol %)/time (h)
O
catalyst
O
O
PhMe
70 °C, 24 h
OMe
O
O
O
O
O
1a
3a
O
O
OMe
O
1
Entry
Catalyst
Loading (mol %)
Yield (%)
2a (90%)
OMe
20/12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
—
AlCl3
PdCl2
TiCl4
—
NR
NR
NR
NRa
NR
37
1a
20
20
20
20
20
10
10
20
20
10
30
100
20
20
OMe
Al(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
TMSOTf
Mg(NTf2)2
Sc(NTf2)2
BF3ÁOEt2
BF3ÁOEt2
TFA
O
O
O
O
O
O
48
O
O
22b
NR
NR
17
2
3
4
5
2b (63%)a
20/20
NMe2
1b
45
39
NR
19
NMe2
TfOH
O
O
O
a
MeO
O
O
Reaction performed at 50 °C.
Nitromethane used as solvent.
O
O
b
O
MeO
2c (99%)
20/15
OMe
a p-OMe revealed that substitution on the bridging aromatic moi-
ety was tolerated in forming 2c (entry 3) and an anticipated rate
acceleration was observed in forming the all-carbon quaternary
centre of 2d (entry 4), which would proceed through a more stabi-
lized tertiary carbocation. The 3,4,5-trimethoxy analogue 1e was
found to preferentially undergo a competing Friedel–Crafts alkyl-
ation, in addition to a reductive cleavage of Meldrum’s acid moiety
enroute to forming tricycle 4e (entry 5) as the major product.16
Furthermore, benzylidene malonate 1f (Table 2, entry 6) also
proved successful but needed an elevated reaction temperature
(100 °C) as compared to the other entries owing to the superior
electrophilicily of benzylidene Meldrum’s acids.
Dialkoxy models 1g and 1h were found to undergo both path-
ways without an apparent bias (Scheme 2). Under optimized con-
dition, the reaction of 1g was sluggish, providing a 1.0:0.34:0.29
ratio of 1g:2g:4g after 45 h as determined by the analysis of the
1H NMR of the crude reaction mixture. Compounds 2g and 4g were
isolated in modest yields. Similar results were obtained with 1h,
which led to a mixture of 1h:2h:4h in a 1:0.56:0.67 ratio.
1c
OMe
O
O
O
O
O
O
O
O
Me
Me
2d (21%)
20/1
OMe
1d
OMe
O
O
MeO
OMe
OMe
O
O
OMe
OMe
4e (22%)
40/43
1e
OMe
At this point the domino sequence was revisited having opti-
mized the initial [1,5]-hydride shift/cyclization. It was found to
be advantageous to sequentially stir the benzylidene Meldrum’s
acid at room temperature in the presence of Sc(OTf)3, allowing
for complete formation of the intermediate, before increasing
the reaction temperature to 100 °C for the Friedel–Crafts acyla-
tion as depicted in Table 3. These tuned conditions furnished
3a in 78% yield (entry 1) compared to the 48% yield in the pre-
liminary investigation (Table 1, entry 7).17,18 Despite the ability
of 1c to cleanly convert to the intermediate in high yield (Table
2, entry 3) only a moderate yield for the domino reaction was
obtained (Table 3, entry 2); however, we were pleased to form
tetracycle 3d bearing the sterically congested all-carbon quater-
nary centre in good yield (entry 3) suggesting the poor yield in
Table 2, entry 4 may have been attributed to product instability.
Applying these conditions to the dialkoxy substrates 1g and 1h
furnished the desired products 3g and 3h, respectively, in
respectable yield in accord with their ability to convert to the
O
O
O
OMe
OMe
MeO
OMe
O
6
2f (99%)b
20/4.5
1f
Reaction performed at 70 °C.
OMe
OMe
a
b
Reaction performed at 100 °C.
spiro-intermediate, and considering the formation of three new
bonds: a C–H and two C–C bonds.
In summary, a tandem one-pot formation of tetrahydrobenzo
[b]fluoren-11-ones from benzylidene Meldrum’s acids under Lewis
acid catalysis, via [1,5]-hydride shift/cyclization/Friedel–Crafts
acylation was described.

4708
S. J. Mahoney et al. / Tetrahedron Letters 50 (2009) 4706–4709
the Government of Canada (NSERC CGS-M), the Ontario Govern-
ment (OGS) and the University of Waterloo for scholarships.
O
O
O
O
O
O
OMe
OMe
O
O
Supplementary data
Sc(OTf)3
2g (16%)
(40 mol %)
+
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.007.
OMe
OMe
PhMe, rt, 45 h
1g
OMe
References and notes
OMe
1. Selected examples of the tert-amino effect: (a) Nijhuis, W. H. N.; Verboom, W.;
El-Fadl, A. A.; Van Hummel, G. J.; Reinhoudt, D. N. J. Org. Chem. 1989, 54, 209–
216; (b) Verboom, W.; van Dijk, B. G.; Reinhoudt, D. N. Tetrahedron Lett. 1983,
24, 3923–3926; (c) Meth-Cohn, O.; Suschitzky, H. Adv. Heterocycl. Chem. 1972,
14, 211–278.
2. For reviews, see: (a) Mátyus, P.; Éliás, O.; Tapolcsányi, P.; Polonka-Bálint, A.;
Halász-Dajka, B. Synthesis 2006, 2625–2639; (b) Quintela, J. M. Recent Res.
Devel. Org. Chem. 2003, 7, 259–278.
4g (12%)
O
O
O
O
O
O
O
O
O
O
Sc(OTf)3
(40 mol %)
2h (15%)
3. (a) Noguchi, M.; Yamada, H.; Sunagawa, T. J. Chem. Soc., Perkin Trans. 1 1998,
3327–3329; (b) Atkinson, R. S.; Green, R. H. J. Chem. Soc., Perkin Trans. 1 1974,
394–401.
+
PhMe, rt, 45 h
O
4. Barluenga, J.; Fañanás, M.-M.; Aznar, F.; Valdés, C. Angew. Chem., Int. Ed. 2008,
47, 6594–6597.
1h
O
O
5. For a paper highlighting the significance, see: Tobisu, M.; Chatani, N. Angew.
Chem., Int. Ed. 2006, 45, 1683–1684.
O
4h (19%)
6. (a) McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2009, 131, 402–403; (b) Zhang,
C.; Murarka, S.; Seidel, D. J. Org. Chem. 2009, 74, 419–422; (c) Pastine, S. J.;
McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2005, 127, 12180–12181; (d)
Pastine, S. J.; Sames, D. Org. Lett. 2005, 7, 5429–5431.
Scheme 2. Cyclization of substrates 1g and 1h.
7. Murarka, S.; Zhang, C.; Konieczynska, M. D.; Seidel, D. Org. Lett. 2009, 11, 129–
132.
8. Ruble, J. C.; Hurd, A. R.; Johnson, T. A.; Sherry, D. A.; Barbachyn, M. R.; Toogood,
P. L.; Bundy, G. L.; Graber, D. R.; Kamilar, G. M. J. Am. Chem. Soc. 2009, 131,
3991–3997.
Table 3
Scope of the domino reaction
9. (a) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.; Pipko, S. E.; Tolmachev,
A. A. Synth. Commun. 2008, 38, 3032–3043; (b) D’yachenko, E. V.; Glukhareva, T.
V.; Nikolaenko, E. F.; Tkachev, A. V.; Morzherin, Y. Y. Russ. Chem. Bull. Int. Ed.
2004, 53, 1240–1247.
10. (a) Wilsily, A.; Lou, T.; Fillion, E. Synthesis 2009, 2066–2072; (b) Dumas, A. M.;
Fillion, E. Org. Lett. 2009, 11, 1919–1922; (c) Wilsily, A.; Fillion, E. Org. Lett.
2008, 10, 2801–2804; (d) Fillion, E.; Carret, S.; Mercier, L. G.; Trépanier, V. É.
Org. Lett. 2008, 10, 437–440; (e) Fillion, E.; Wilsily, A.; Liao, E-T. Tetrahedron:
Asymmetry 2006, 17, 2957–2959; (f) Fillion, E.; Wilsily, A. J. Am. Chem. Soc.
2006, 128, 2774–2775.
11. (a) Fillion, E.; Dumas, A. M. J. Org. Chem. 2008, 73, 2920–2923; (b) Fillion, E.;
Dumas, A. M.; Hogg, S. A. J. Org. Chem. 2006, 71, 9899–9902; (c) Fillion, E.;
Dumas, A. M.; Kuropatwa, B. A.; Malhotra, N. R.; Sitler, T. C. J. Org. Chem. 2006,
71, 409–412; (d) Fillion, E.; Fishlock, D.; Wilsily, A.; Goll, J. M. J. Org. Chem.
2005, 70, 1316–1327; (e) Fillion, E.; Fishlock, D. Org. Lett. 2003, 5, 4653–4656.
12. Kaumanns, O.; Mayr, H. J. Org. Chem. 2008, 73, 2738–2745.
13. Benzylidene 1a was prepared via two routes. See Supplementary data for
details.
Entry
Substrate
Catalyst loading
(mol %)/time at rt
(h)/time at 100 °C (h)
Product (yield)
O
1
1a
20/12/1.5
20/15/2
10/5/1
OMe
3a (78%)
O
MeO
2
3
4
5
1c
1d
1g
1h
OMe
3c (55%)
O
Route A:
O
OMe
OMe
1) CBr4, PPh3, CH2Cl2 (0 °C)
Me
3d (61%)
H
2) n-BuLi, THF (-78 °C)
O
O
then NH4Cl (-78 °C to rt)
(90% over 2 steps)
MeO
MeO
40/36/3
40/36/3.5
1) 2-bromobenzaldehyde
CuI, NEt3, PdCl2(PPh3)2
50 °C (80%)
Meldrum's acid
pyrrolidinium
O
3g (52%)
acetate (10 mol %)
H
H
OMe
1a
2) H2 (1 atm), Pd/C
EtOAc, rt (99%)
PhH, rt (83%)
OMe
O
Route B:
3h (41%)
O
O
O
1) NaH, DMF
rt to 60 °C (67%)
+
OMe
2) H2 (1 atm), Pd/C
EtOAc, rt (quant)
PPh3Br
MeO
Acknowledgements
O
This work was supported by the Government of Ontario (Early
Researcher Award to E.F.), the Merck Frosst Centre for Therapeutic
Research, the Natural Sciences and Engineering Research Council of
Canada (NSERC), the Canadian Foundation for Innovation, the On-
tario Innovation Trust and the University of Waterloo. S.J.M. thanks
1) LiAlH4, THF, 0 °C (95%)
OMe
1a
2) PCC, CH2Cl2, 0 °C (76%)
3) Meldrum's acid
pyrrolidinium acetate (10 mol %)
OMe
PhH, rt (83%)

S. J. Mahoney et al. / Tetrahedron Letters 50 (2009) 4706–4709
4709
14. Gd(OTf)3 was unable to promote the reaction under the optimized conditions
or when performed in MeCN, in contrast to the rate enhancement over Sc(OTf)3
exhibited in a related study, see Ref. 7.
17. General procedure for domino reaction: Reaction carried out as in [1,5]-hydride
shift/cyclization procedure and once [1,5]-hydride shift/cyclization is completed
as indicated by 1H NMR (aliquots were withdrawn), the reaction vessel was
immersed in a pre-heated 100 °C oil bath and stirred until full conversion had
occurred as monitored by TLC. Caution: There is a slight pressure build-up
since acetone and CO2 are produced as byproducts. The reaction mixture was
then diluted with CH2Cl2 and washed with H2O (2Â), brine (1Â), dried with
MgSO4, filtered and concentrated by rotary evaporation. The resulting crude
mixture was purified by flash chromatography (silica gel and hexanes/EtOAc)
18. Subjection of 2a to Sc(OTf)3 (20 mol %) at 100 °C for 1.5 h furnished 3a in 60%
yield.
15. General procedure for [1,5]-hydride shift/cyclization: In a glove box, benzylidene
Meldrum’s acid (generally 0.25 mmol), Sc(OTf)3 (heated at 180 °C under high
vacuum, 0.5 mm Hg for 2 h and stored in glove box) and toluene (distilled over
CaH2 then degassed, 0.1 M) were added to a glass vial equipped with a magnetic
stir bar. The vial was then capped with a septum and stirred at the appropriate
temperature; reaction progress was monitored by 1H NMR. Products can be
isolated either by diluting with CH2Cl2 and washing with H2O (2Â), brine (1Â),
drying over MgSO4, filtering, and concentrating by rotary evaporation. The
resulting crude mixture was purified by flash chromatography (silica gel and
hexanes/EtOAc).
16. A 1.0:0.72:0.43 ratio of 1e:4e:5e was obtained as determined by analysis of the
1H NMR of the crude mixture. When 1e was subjected to Sc(OTf)3 (40 mol %) at
70 °C for 15.5 h, the reaction went to completion and tricyclic compounds 4e
and 5e were isolated in 26% and 21% yields, respectively. The formation of 4e
and 5e suggests that in the presence of Sc(OTf)3, Meldrum’s acid is eliminated
following the intramolecular Friedel–Crafts alkylation to form a stabilized
dibenzylic carbocation, which is subsequently reduced by a hydride to provide
4e, or trapped by acetone to furnish 5e. The source of hydride remains to be
identified. Acetone is likely formed by the decomposition of Meldrum’s acid.
Such reduction process of benzylic Meldrum’s acid is unprecedented.
O
O
Sc(OTf)3
Sc(OTf)3
OMe
O
1e
OMe
O
- Meldrum's acid
OMe
MeO
MeO
OMe
OMe
H-
MeO
OMe
4e (26%)
O
OMe
OMe
OH
OMe
5e (21%)