Metal-free intramolecular carbonyl-olefin metathesis of ortho-prenylaryl ketones

Article abstract of DOI:10.1055/s-0030-1260320

On treatment with boron trifluoride etherate as a Lewis acid, acetophenone and benzophenone derivatives bearing a prenyl (or a related) side chain in ortho-position were shown to undergo intramolecular carbonyl-olefin metathesis, in the absence of any tra

Full text of DOI:10.1055/s-0030-1260320

LETTER
2487
Metal-Free Intramolecular Carbonyl–Olefin Metathesis of ortho-Prenylaryl
Ketones
Metal-Free
C
arbon
r
yl–Olef
n
in Metathesis
e
of ortho-Prenyla
S
r
yl Ketones oicke, Nikolay Slavov, Jörg-Martin Neudörfl, Hans-Günther Schmalz*
Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Köln, Germany
Fax +49(221)4703064; E-mail: schmalz@uni-koeln.de
Received 10 August 2011
Dedicated to Prof. S. Blechert on the occasion of his 65th birthday
tively, was only achieved in the presence of stoichiomet-
Abstract: On treatment with boron trifluoride etherate as a Lewis
acid, acetophenone and benzophenone derivatives bearing a prenyl
(or a related) side chain in ortho-position were shown to undergo in-
tramolecular carbonyl–olefin metathesis, in the absence of any tran-
sition-metal catalyst. The cationic cyclization process is supposed
to proceed via an oxetane intermediate, which fragments to give the
cyclization product (indene or 1,2-dihydronaphthalene) and a ke-
tone (acetone) as a stoichiometric by-product. Several substrates
were shown to afford the metathesis products with up to 93% yield.
ric amounts of Mo-, W- or Ti-alkylidenes.6
Against this background we considered our recent discov-
ery of an efficient ‘metal-free’ carbonyl–olefin ring-
closing metathesis of sufficient importance to justify
some further investigation. In the course of the total syn-
thesis of the marine natural product pestalone7 we had
treated the ortho-prenylated benzophenone derivative 4a
with BF3·SMe2 in the attempt to achieve selective depro-
tection (de-O-methylation).8 To our surprise, a cyclized
side-product was formed in 20% yield and identified by
X-ray crystallography as the arylindene 5a (Scheme 2).
Key words: olefin metathesis, cyclization, Lewis acids, carbenium
ions, oxetanes, natural products
During the last decades, ring-closing olefin metathesis
(RCM) has evolved into one of the most powerful meth-
ods of C–C bond formation in organic chemistry
(Scheme 1).1 Parallel to the development of various effec-
tive catalysts (transition-metal carbene complexes)2 a
large number of applications of RCM both in academic
and in industrial synthesis have been reported.1,3 The ele-
gance of the methodology is also reflected by the prodi-
Cl
Cl
MeO
MeO
Cl
Cl
O
Table 1
OMe
R
OMe
R
MeO
OMe
MeO
OMe
gious
mechanism
involving
metalacyclobutane
5a (R = CHO)
5b (R = Br)
4a (R = CHO)
4b (R = Br)
intermediates formed by reversible [2+2] cycloaddition.4
Scheme 2 Lewis acid promoted cyclization of the pestalone deriva-
tives 4a and 4b
diene
+
+
A:
B:
By varying the reaction conditions (Lewis acid, solvent,
and reaction time) we succeeded to optimize the forma-
tion of 5a to 84% (Table 1, entry 3). With a related sub-
strate, i.e. the brominated compound 4b, we initially
observed mainly decomposition under similar conditions.
However, when we switched to BF3·OEt2 (as an even
more common reagent) we obtained the metathesis prod-
uct 5b in 93% yield after aqueous workup and purification
(Table 1, entry 6). The structure of 5b was also confirmed
by X-ray crystal structure analysis (Figure 1).9
1
2
RCM
O
O
carbonyl–
olefin
3
2
Scheme 1 Ring-closing metathesis (RCM) starting either from a
diolefin (diene metathesis; A) or from an unsaturated carbonyl com-
pound (carbonyl–olefin metathesis; B)
While diene metathesis (Scheme 1; A) represents the
common pattern to prepare cyclic olefins (2) through
RCM, only a few examples for intramolecular carbonyl–
olefin metathesis (Scheme 1, B) have been described. Fol-
lowing early work in the Grubbs laboratory,5 the synthesis
of cycloalkenes from olefinic ketones and esters, respec-
Interestingly, the unexpected and facile formation of the
indene derivatives 5a and 5b represents a rare and by far
the most efficient example of a metal-free carbonyl–olefin
metathesis reaction.10
We were thus curious whether this type of transformation
is unique for the highly substituted benzophenone sub-
strates of type 4 or if it would also be observed for ortho-
prenylaryl ketones and related substrates of type 6 in gen-
eral. According to our mechanistic proposal7 (Scheme 3)
the BF3-promoted process starts with a Prins-type (exo-
SYNLETT 2011, No. 17, pp 2487–2490
x
x
.x
x
.2
0
1
1
Advanced online publication: 19.09.2011
DOI: 10.1055/s-0030-1260320; Art ID: B14911ST
© Georg Thieme Verlag Stuttgart · New York

2488
A. Soicke et al.
LETTER
strates. These compounds were prepared by Suzuki
coupling12 of 2-acetylphenyl boronic acid (11) with the al-
lylic bromides 12a–c (Scheme 4).
Table 1 Variation of Reaction Conditions for the Cyclization of 4a
and 4b, According to Scheme 2a
Entry Starting Reagent
material (equiv)
Time
(min)
Solventb Product
(%)c
As another substrate of type 6, which carries a homopre-
nyl side chain and would thus give rise to a six-membered
metathesis product, we prepared the acetophenone deriv-
ative 16 as shown in Scheme 5. Starting from 1-tetralone
(14), addition of methylmagnesium iodide and subsequent
acidic dehydration13 gave the dihydronaphthalene 15 in
high yield. Ozonolysis of the double bond then afforded
the keto aldehyde (after workup with dimethyl sulfide)14
which was finally transformed into the homoprenyl ace-
tophenone 16 by Wittig reaction.
1
2
3
4
5
6
4a
4a
4a
4a
4b
4b
BF3·SMe2 (1.7)
BF3·SMe2 (6.0)
BF3·SMe2 (1.7)
AlCl3 (1.7)
120
75d
45
A
A
B
B
B
B
5a (20)
5a (50)
5a (84)
5a (36)
5b (<5)
5b (93)
45
BF3·SMe2 (1.7)
BF3·OEt2 (2.5)
45
45
a Reaction conditions: starting material (1 equiv), 0.05 M in solvent,
Br
R1
0 °C.
b Solvent A: CH2Cl2–SMe2 (1:2); solvent B: CH2Cl2.
c Isolated yield.
R2
12a–c
d Reaction was performed at –30 °C.
cat. Pd2(dba)2
O
O
R1
K2CO3, toluene
B(OH)2
R2
11
a: R1 = R2 = Me
13a (78%)
13b (59%)
13c (56%)
b: R1 = Me; R2 = H
c: R1 = homoprenyl; R2 = Me
Scheme 4 Preparation of compounds 13a–c through Suzuki cou-
pling
O
a,b
c,d
O
Figure 1 Structure of 5b in the crystalline state9
14
15
16
Scheme 5 Synthesis of substrate 16. Reagents and conditions: (a)
MeMgI, EtO2, r.t., 1 h; (b) HCl (3 N), r.t., 1 h, 98% over 2 steps; (c)
O3, MeOH, –78 °C, 4 h, then Me2S, r.t., 24 h, 35%; (d) n-BuLi,
i-PrPPh3I, THF, –78 °C, 2 h, then r.t., 16 h, 30%.
trig) cyclization of 6 to form a tertiary carbenium ion 8,
which isomerizes to the benzylic cation 10 via an oxetane
intermediate 9. At the end, the product 7 is liberated to-
gether with acetone in an entropically favored fragmenta-
tion step.11
With the substrates 13a–c and 16 in our hands, the stage
was set to study their tendency to undergo Lewis acid pro-
moted ring-closing metathesis (Scheme 6).
R
R
BF3
BF3⋅OEt2
O
O
n
n
BF3⋅OEt2
R1
7
6
n
(Table 2)
n
R2
– acetone
13a–c (n = 1)
16 (n = 2)
17 (n = 1)
18 (n = 2)
BF3
BF3
BF3
R
R
R
O
O
O
Scheme 6 BF3-induced RCM of substrates of type 13 and 16
n
n
n
We were pleased to find that the envisioned transforma-
tions indeed took place, most smoothly with the prenyl-
and homoprenyl-substituted substrates. Under optimized
conditions (1.5 equiv of BF3·OEt2, CH2Cl2, –40 °C, 60
min) the prenyl acetophenone 13a afforded the methylin-
dene 17 in a rather clean and high-yielding reaction
(Table 2, entry 1).15 Similarly, the homoprenyl-substitut-
8
9
10
Scheme 3 Proposed mechanism for the BF3-promoted metathesis
cyclization of substrates of type 6
To probe the generality of the reaction we decided to em-
ploy ortho-prenyl acetophenone (13a) and its analogues
with a crotyl (13b) or a geranyl side chain (13c) as sub-
Synlett 2011, No. 17, 2487–2490 © Thieme Stuttgart · New York

LETTER
Metal-Free Carbonyl–Olefin Metathesis of ortho-Prenylaryl Ketones
2489
Table 2 BF3-Induced Metathesis Cyclization of Substrates 13a–c
and 16 According to Scheme 6a
References and Notes
(1) For selected reviews, see: (a) Ivin, F. J. Olefin Metathesis;
Academic Press: London, 1983. (b) Schmalz, H.-G. Angew.
Chem. Int. Ed. 1995, 34, 1833. (c) Grubbs, R. H.; Miller,
S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (d) Grubbs,
R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (e) Schuster,
M.; Blechert, S. Angew. Chem. Int. Ed. 1997, 36, 2036.
(f) Schrock, R. R. Tetrahedron 1999, 55, 8141.
Entry
Substrate
13a
Product
17
Yield (%)b
1
2
3
4
87
13b
17
tracesc
38
13c
17
(g) Fürstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012.
(h) Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed.
2003, 42, 4592. (i) Deiters, A.; Martin, S. F. Chem. Rev.
2004, 104, 2199.
16
18
75
a Reaction conditions: 8a–8c and 12 (1 equiv), 0.05 M solution in
CH2Cl2, BF3×OEt2 (1.5 equiv), –40 °C, 1 h.
b Isolated yield.
(2) (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34,
18. (b) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1
1998, 371. (c) Dragutan, I.; Dragutan, V.; Filip, P.
ARKIVOC 2005, (x), 105. (d) Wengrovius, H. J.; Sancho, J.;
Schrock, R. R. J. Am. Chem. Soc. 1981, 103, 3932.
(e) Grubbs, R. H. Handbook of Metathesis; Wiley-VCH:
Weinheim, .
c Detected by GC–MS.
ed substrate 16 smoothly gave rise to the dihydronaphtha-
lene 18 (entry 4).
(3) (a) Astruc, D. New J. Chem. 2005, 29, 42. (b) Basset, J.-M.;
While the ortho-geranyl acetophenone 13c could also be
successfully cyclized to give 17 (entry 3), the metal-free
RCM reaction did not occur with ortho-crotyl acetophe-
none (13b) as a substrate. Only traces of the RCM product
17 could be detected by GC–MS in this case besides unre-
acted starting material. This result can be understood in
terms of the proposed mechanism (compare Scheme 3). A
second alkyl substituent at the distal position of the olefin
6 seems to be required to sufficiently stabilize the initially
formed carbocation of type 8 (formation of a tertiary car-
benium ion).
Leconte, M. Chemtech 1980, 10, 762.
(4) (a) Herrison, J.-L.; Chauvin, Y. Makromol. Chem. 1970,
141, 161. (b) Katz, T. J.; McGinnis, J. J. Am. Chem. Soc.
1977, 99, 1903. (c) Leconte, M.; Basset, J. M.; Quignard, F.;
Larroche, C. Mechanistic Aspects of the Olefin Metathesis
Reaction, in Reactions of Coordinated Ligands, Vol. 1;
Braterman, P. S., Ed.; Plenum: New York, 1986, 371.
(5) (a) Pine, S. H.; Zahler, R.; Evans, D. A.; Grubbs, R. H. J. Am.
Chem. Soc. 1980, 102, 3270. (b) For a review, see: Grubbs,
R. H.; Pine, S. H. Comprehensive Organic Synthesis, Vol. 5;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, 1115.
(6) (a) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115,
3800. (b) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C.
F. J. Am. Chem. Soc. 1996, 118, 1565. (c) Nicolaou, K. C.;
Postema, M. H. D.; Yue, E. W.; Nadin, A. J. Am. Chem. Soc.
1996, 118, 10335. (d) Majumder, U.; Rainier, J. D.
Tetrahedron Lett. 2005, 46, 7209. (e) Iyer, K.; Rainier, J. D.
J. Am. Chem. Soc. 2007, 129, 12604.
(7) Slavov, N.; Cvengros, J.; Neudörfl, J.-M.; Schmalz, H.-G.
Angew. Chem. Int. Ed. 2010, 49, 7588.
(8) Konieczny, M. T.; Maciejewski, G.; Konieczny, W.
Synthesis 2005, 1575.
To further support the proposed mechanism, we per-
formed an experiment (cyclization of 13a to 17) where we
trapped the expected by-product (acetone) by the addition
of ortho-nitrobenzaldehyde under basic conditions
(NaOH).16 The formation of indigo (as indicated by the
occurrence of a deep blue insoluble solid) clearly proved
the generation of acetone in accordance to the suggested
mechanism.
In conclusion, we have shown that the Lewis acid mediat-
ed ‘metal-free’ carbonyl–olefin ring-closing metathesis17
reflects a rather general reactivity option of ortho-prenyl-
aryl ketones, i.e. a frequently occurring substructure in
natural product chemistry. The surprisingly facile trans-
formation is supposed to proceed (like the transition-
metal-catalyzed olefin metathesis) via a four-membered-
ring intermediate.
(9) For a summary of data see: Cambridge Crystallographic
Data Centre; Deposit Number: CCDC-836866.
(10) (a) Jackson, A. C.; Goldman, B. E.; Snider, B. B. J. Org.
Chem. 1984, 49, 3988. For Lewis acid induced carbonyl–
alkyne metathesis reactions (related to enyne metathesis),
see, for instance: (b) Curini, M.; Epifano, F.; Maltese, F.;
Rosati, O. Synlett 2003, 552. (c) Rhee, J. U.; Krische, M. J.
Org. Lett. 2005, 7, 2493. (d) Jin, T.; Yamamoto, Y. Org.
Lett. 2007, 9, 5259. (e) Bera, K.; Sarkar, S.; Biswas, S.;
Maiti, S.; Jana, U. J. Org. Chem. 2011, 76, 3539.
(11) For the Lewis acid induced fragmentation of oxetanes
prepared by Paterno–Büchi cycloaddition, see: Carless, H.
J.; Trivedi, H. S. J. Chem. Soc., Chem. Commun. 1979, 382.
(12) Gerbino, D. C.; Mandolesi, S. D.; Podesta, J. C.; Schmalz,
H.-G. Eur. J. Org. Chem. 2009, 3964.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(13) Silva, L. F.; Siqueira, F. A.; Pedrozo, E. C.; Vieira, F. Y. M.;
Doriguetto, A. C. Org. Lett. 2007, 9, 1433.
This work was supported by the University of Cologne and the
Fonds der Chemischen Industrie.
(14) Enders, D.; Niemeier, O. Synlett 2004, 2111.
(15) It proved to be important to quench the reaction mixture by
addition of aq NaHCO3 prior to extractive workup.
Otherwise significant amounts of a by-product (a dimer of
17 as indicated by GC–MS) were formed probably through
a proton-mediated process.
Synlett 2011, No. 17, 2487–2490 © Thieme Stuttgart · New York

2490
A. Soicke et al.
LETTER
(16) (a) Poe, S. L.; Cummings, M. A.; Haaf, M. P.; McQuade,
D. T. Angew. Chem. Int. Ed. 2006, 45, 1544. (b) Baeyer,
A.; Drewsen, V. Ber. 1882, 15, 2856.
pressure. The residue was purified by chromatography on
silica(cyclohexane) to provide 3-methyl-1H-indene (17; 150
mg, 1.15 mmol, 87%) as a colorless oil; Rf 0.65 (pentane).
1H NMR (300 MHz, CDCl3): d = 2.18 (dd, 3 H), 3.33 (m, 2
H), 6.21 (d, 1 H) 7.20 (dt, 1 H), 7.33 (q, 2 H), 7.46 (d, 1 H).
13C NMR (75 MHz, CDCl3): = 13.0, 37.6, 118.8, 123.6,
124.4, 126.0, 128.7, 139.9, 144.3, 146.1. IR-ATR:(film) =
3013 (w), 2931 (w), 1681 (m), 1460 (m), 1433 (m), 1379
(m), 1015 (m), 1001 (m), 943 (m), 760 (s), 717 (s) cm–1.
HRMS (EI, 70 eV): m/z calcd for C10H10: 130.0782; found:
130.079.
(17) General Procedure for BF3·Et2O-Induced Ring-Closing
Metathesis: In an argon-flushed Schlenk tube ortho-prenyl
acetophenone (13a; 250 mg, 1.32 mmol) dissolved in anhyd
CH2Cl2 (26 mL) was cooled to –40 °C. Dropwise addition of
BF3·OEt2 (0.25 mL, 1.98 mmol) afforded a yellow solution,
which was stirred for 1 h at –40 °C. After addition of sat. aq
NaHCO3 (20 mL) at 0 °C the mixture was extracted with
CH2Cl2 (3 × 40 mL). The combined organic layers were
dried (MgSO4), filtered and concentrated under reduced
Synlett 2011, No. 17, 2487–2490 © Thieme Stuttgart · New York

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