Studies on the ring-opening of bicyclic cyclopropanes activated by a carbonyl group

Article abstract of DOI:10.1016/j.tetlet.2013.01.053

Studies on the Friedel-Crafts reaction between carbonyl bicyclic cyclopropane and electronic-rich aromatic systems were conducted. Lewis acid and iminium cationic activation methods were examined. It was found that the cyclopropane ring-opening was highly dependent on the nature of the counter nucleophile as well as the activation method.

Full text of DOI:10.1016/j.tetlet.2013.01.053

Tetrahedron Letters 54 (2013) 1798–1801
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies on the ring-opening of bicyclic cyclopropanes activated by a
carbonyl group
⇑
Xiaojian Jiang, Zonghan Lim, Ying-Yeung Yeung
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Studies on the Friedel–Crafts reaction between carbonyl bicyclic cyclopropane and electronic-rich aro-
matic systems were conducted. Lewis acid and iminium cationic activation methods were examined. It
was found that the cyclopropane ring-opening was highly dependent on the nature of the counter nucle-
ophile as well as the activation method.
Received 2 December 2012
Revised 24 December 2012
Accepted 10 January 2013
Available online 25 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropane
Friedel–Crafts
Lewis acid
Selectivity
Mechanism
The cyclopropane is an important motif in organic synthesis.
Among the cyclopropane-related reactions,1,2 cyclopropane ring-
opening processes are frequently reported. The unique three-mem-
bered ring structure of cyclopropanes (both strain3 and electronic
features4) allows them to demonstrate activity similar to alkenes.
In order to enhance the reactivity of cyclopropanes, donor–accep-
tor or 1,3-dicarbonyl groups are commonly introduced.5,6 Although
good reactivity and selectivity can be achieved, these structural
requirements somewhat limit the scope and applicability.
Compared to the above-mentioned cyclopropane activation
methods, the use of mono-activated cyclopropane towards nucleo-
philic addition is rare. Herein, we report our recent progress on the
study of the Friedel–Crafts reaction using carbonyl bicyclic
cyclopropanes.
used as the Lewis acid to mediate the reaction. To our delight, com-
pound 2a, which corresponds to the type I product, was obtained in
52% yield (Table 1). The structure of 2a was confirmed unambigu-
ously by an X-ray crystallographic study7 (Fig. 1).
Substrate 1b was then subjected to the same conditions, but no
reaction was observed. Nonetheless, product 2b, which corre-
O
O
O
O
n
O
H
H
H
H
H
Me3SOI, NaH
DMSO
nR
1
H
Me
R
1a
1c
R = H, Me
1b
Our study was initiated by using cyclopropane 1 which could
readily be synthesized by cyclopropanation of the corresponding
unsaturated carbonyl-containing cycloalkenes (Scheme 1).
We reasoned that the ring strain due to the bicyclic system
might facilitate ring-opening in the presence of a single carbonyl
unit. It is noteworthy that for such bicyclic system, two bonds in
the cyclopropane moiety are ‘conjugated’ to the carbonyl group;
that is, both type I and type II products can potentially be obtained
through this cyclopropane ring-opening activity (Scheme 2).
Thus, 1a was subjected to the Friedel–Crafts reaction using
1,3,5-trimethoxybenzene as the nucleophile. Tin(IV) chloride was
Scheme 1. Synthesis of carbonyl bicyclic cyclopropane.
O
n
O
n
O
I
( )
II
( )
n
Nu
Nu
Nu
Product
Type II
Product
Type I
Scheme 2. Synthesis of carbonyl bicyclic cyclopropane.
⇑
Corresponding author. Tel.: +65 65167760; fax: +65 67791691.
E-mail address: chmyyy@nus.edu.sg (Y.-Y. Yeung).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.053

X. Jiang et al. / Tetrahedron Letters 54 (2013) 1798–1801
1799
Table 1
Cyclopropane ring-opening reaction with 1,3,5-trimethoxybenzene promoted by SnCl4
OMe
O
SnCl4
24 h
H
+
2
n
R
MeO
OMe
1
Entrya
Substrate
Solvent
CH2Cl2
Temp (°C)
Product
Isolated yield (%)
O
H
O
OMe
2a
OMe
1
25
52
H
MeO
1a
O
H
2
3
CH2Cl2
25
60
No reaction
H
1b
O
O
H
OMe
MeO
PhCl
2b
45
63
H
OMe
O
1b
O
H
OMe
4
4
CH2Cl2
25
60
2c
Me
1c
O
Me
OMe
MeO
Me
PhCl
No reaction
H
1d
a
Reactions were carried out with cyclopropane 1 (1.0 mmol), 1,3,5-trimethoxybenzene (1.1 mmol) and SnCl4 (1.0 mmol) in solvent (2 mL).
sponds to type II nucleophilic attack, was obtained in 45% yield
when the reaction was conducted in chlorobenzene at 60 °C.8 Com-
pared to 1a, there is no type I product in the ring-opening reaction
of 1b. A possible explanation is that type I ring-opening of 1b in-
volves the formation of a highly ring strain seven-membered ring
system, which is energetically unfavourable (Table 1).
When using 1c as the substrate, interestingly, 2c was isolated in
63% yield and neither the type I nor the type II product was de-
tected. We rationalize that this result can be explained by the path-
way depicted in Scheme 3 which involves the formation of
a,b-
unsaturated ketone 3 from 1c promoted by SnCl4.9 We have also
examined cyclopropane 1d, but no reaction was observed and
the starting material was recovered quantitatively.
The structures and stereochemistry of products 2b and 2c were
established by crystallographic analysis of the benzoate derivatives
4 and 5, which could readily be synthesized from 2b and 2c
through
a reduction-esterification sequence (Scheme 4 and
Fig. 2).7 Interestingly, adducts 2 and their derivatives 4 and 5
resemble the structures of several biologically active compounds.10
We also examined an alternative activation mode, which in-
volves an iminium cation derived from pyrrolidine (Table 2).11
When using anthrone as the nucleophile, both 1a and 1b gave rise
to the type II ring-opening products 6a and 6b which were isolated
in 78% and 56% yields, respectively. However, there was no reac-
tion when using 1,3,5-trimethoxybenzene as the nucleophile.12
Figure 1. X-ray structure (ORTEP) of 2a.

1800
X. Jiang et al. / Tetrahedron Letters 54 (2013) 1798–1801
Cl3Sn
O
OMe
HCl
Cl3Sn
path a
O
O
O
O
O
-SnCl4
-HCl
Me
O
H
SnCl4
OMe
MeO
OMe
isomerization
H
H
H
SnCl4
path a
Cl
path b
Cl3Sn
Me
1c
Me
path b
HCl
H
Me
Me
Me
MeO
OMe
-HCl
Cl
-SnCl4
3
2c
Me
Scheme 3. Plausible mechanisms for the synthesis of 2c.
O
This suggests that the reaction is highly dependent on both the
nature of the nucleophile as well as the mode of activation.
In summary, we have reported the use of carbonyl bicyclic
cyclopropane in Friedel–Crafts reactions. The type of cyclopropane
ring-opening appears to be highly dependent on various factors.
Further investigations on the mechanism and applications are
underway.
O
O
OMe
MeO
1. NaBH4, THF
OMe
MeO
O2N
2. O2N(C6H4)COCl
92%
OMe
OMe
2b
4
O
O
O
Acknowledgements
OMe
1. NaBH4, THF
2. O2N(C6H4)COCl
83%
OMe
NO2
We thank the National University of Singapore for financial sup-
port (Grant No. 143-000-509-112) and the scholarship to X. Jiang
(NUS Research Scholarship).
Me
OMe
Me
OMe
MeO
MeO
5
2c
Scheme 4. Synthesis of derivatives 4 and 5.
Figure 2. X-ray structures (ORTEP) of 4 and 5.

X. Jiang et al. / Tetrahedron Letters 54 (2013) 1798–1801
1801
Table 2
3. (a) Bagutski, V.; de Meijere, A. Adv. Synth. Catal. 2007, 349, 1247–1255; (b) de
Meijere, A.; Redlich, S.; Frank, D.; Magull, J.; Hofmeister, A.; Menzel, H.; König,
B.; Svoboda, J. Angew. Chem., Int. Ed. 2007, 46, 4574.
Cyclopropane ring-opening reaction promoted by an iminium cationa
4. (a) de Meijere, A. Angew. Chem., Int. Ed. 1979, 18, 809; (b) Wiberg, K. B. In
Introduction, Houben–Weyl Methods of Organic Chemistry; de Meijere, A., Ed.;
Thieme: Stuttgart, 1997; Vol. E17a, p 1ff.
H
N
O
5. (a) Sapeta, K.; Kerr, M. A. Org. Lett. 2009, 11, 2081–2084; (b) Carson, C. A.; Kerr,
M. A. Org. Lett. 2009, 11, 777–779; (c) Perreault, C.; Goudreau, S. R.; Zimmer, L.
E.; Charette, A. B. Org. Lett. 2008, 10, 689–692; (d) Tanaka, M.; Ubukata, M.;
Matsuo, T.; Yasue, K.; Matsumoto, K.; Kajimoto, Y.; Ogo, T.; Inaba, T. Org. Lett.
2007, 9, 3331–3334; (e) Bowman, R. K.; Johnson, J. S. Org. Lett. 2006, 8, 573–
576; (f) Moustafa, M. M.; Pagenkopf, B. L. Org. Lett. 2010, 12, 3168–3171; (g)
Lifchits, O.; Charette, A. B. Org. Lett. 2008, 10, 2809–2812; (h) Lebold, T. P.;
Leduc, A. B.; Kerr, M. A. Org. Lett. 2009, 11, 3770–3772; (i) Grover, H. K.; Lebold,
T. P.; Kerr, M. A. Org. Lett. 2011, 13, 220–223; (j) Korotkov, V. S.; Larionov, O. V.;
Hofmeister, A.; Magua, J. J. Org. Chem. 2007, 72, 7504–7510; (k) Lifchits, O.;
Alberrico, D.; Zakharian, I.; Charette, A. B. J. Org. Chem. 2008, 73, 6838–6840; (l)
Emmett, M. R.; Grover, H. K.; Kerr, M. A. J. Org. Chem. 2012, 77, 6634–6637; (m)
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Liu, X.-Y.; Liang, Y.-M. Chem. Asian J. 2012, 7, 1538–1541.
6. In many cases, an additional activator, such as a Lewis acid was used. For
related references, see: (a) Han, Z.; Uehira, S.; Tsuritani, T.; Shinokubo, H.;
Oshima, K. Tetrahedron 2001, 57, 987; (b) Alper, P. B.; Meyers, C.; Lerchner, A.;
Siegel, D. R.; Carreira, E. M. Angew. Chem., Int. Ed. 1999, 38, 3186; (c) Smith, A.
B.; Searborough, R. M. Tetrahedron Lett. 1978, 19, 1649; (d) Ogoshi, H.; Setsane,
J.-I.; Yoshida, Z.-I. Organomet. Chem. 1980, 185, 95; (e) Ogoshi, H.; Kikuchi, Y.;
Yamaguchi, T.; Toi, H.; Aoyama, Y. Organometallics 1987, 6, 2175; (f) Ru, H.; Wu,
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H
6
+
nucleophile
4 A MS
toluene
n
H
1
reflux, 16 h
Substrate
Nucleophile
Product
Isolated yield (%)
O
H
O
OH
78
H
1a
6a
O
O
O
H
O
OH
56
H
1b
6b
O
H
OMe
No reaction
MeO
OMe
H
1a
a
Reactions were carried out with cyclopropane
(2.5 mmol) and 4 Å molecular sieves (200 mg) in toluene (2.0 mL) at reflux.
1
(1.0 mmol), pyrrolidine
7. CCDC-912261, CCDC-912262 and CCDC-912260 contain the supplementary
crystallographic data for compounds 2a, 4 and 5, respectively, which are
available free of charge via www.ccdc.cam.ac.uk.
References and notes
8. Representative procedure: To a solution of 1b (110 mg, 1.0 mmol) and 1,3,5-
trimethoxybenzene (185 mg, 1.1 mmol) in PhCl (2 mL) was added SnCl4
(0.1 mL, 1.0 mmol, 1 M in CH2Cl2) at 25 °C under nitrogen atmosphere. The
reaction mixture was heated to 60 °C and stirred for 24 h. The resultant
mixture was diluted with water (4 mL) and the aqueous layer was extracted
with EtOAc (3 Â 10 mL). The organic layers were combined, dried over Na2SO4,
and concentrated under reduced pressure. The resulting crude product was
purified by flash column chromatography on silica gel (EtOAc/Hexanes, 1:5) to
yield 2b as a colourless oil (45% yield). 1H NMR (CDCl3, 500 MHz): 6.11 (s, 2H),
3.76 (s, 9H), 2.64–2.52 (m, 2H), 2.33–2.24 (m, 3H), 2.12–1.93 (m, 3H), 1.83–
1.80 (m, 1H), 1.43–1.37 (m, 1H); 13C NMR (CDCl3, 125 MHz): d 212.9, 159.5,
159.0, 108.8, 90.4, 55.4, 48.1, 41.5, 39.4, 31.3, 29.3, 25.5; MS(ESI) for C16H22O4
[M+H]+: 279.1.
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12. We also performed the reaction using anthrone as the nucleophile and SnCl4 as
the Lewis acid promoter. However, no reaction was observed for both 1a and
1b.