Aluminum chloride-mediated acylation of methylenecyclobutanes. A facile synthetic protocol for the construction of substituted cyclopentenes

Article abstract of DOI:10.1021/ol8006502

(Chemical Equation Presented) Reactions of methylenecyclobutanes (MCBs) with acyl chlorides produce the corresponding substituted cyclopentene derivatives in moderate to high yields via ring enlargement in the presence of aluminum chloride under mild cond

Full text of DOI:10.1021/ol8006502

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2239-2242
Aluminum Chloride-Mediated Acylation
of Methylenecyclobutanes. A Facile
Synthetic Protocol for the Construction
of Substituted Cyclopentenes
Min Jiang and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai, China 200032
mshi@mail.sioc.ac.cn
Received March 20, 2008
ABSTRACT
Reactions of methylenecyclobutanes (MCBs) with acyl chlorides produce the corresponding substituted cyclopentene derivatives in moderate
to high yields via ring enlargement in the presence of aluminum chloride under mild conditions. A plausible mechanism has been proposed
on the basis of control and deuterium labeling experiments.
The Lewis acid promoted Friedel-Crafts reaction is a
powerful carbon-carbon bond-forming process in organic
chemistry.1 The acylation of an aromatic compound that
essentially results in the production of an aromatic ketone
by reacting an aromatic substrate with an acyl component is
the most common Friedel-Crafts reaction.2 During the last
decades, the chemistry on the acylation of cyclopropanes has
been explored with regard to the similarity between the
cyclopropane ring and the olefinic double bond.3 Recently,
Huang and co-workers reported that a variety of substituted
R,ꢀ-unsaturated ketone and benzofulvene derivatives were
readily prepared in good to excellent yields via the reaction
of methylenecyclopropanes (MCPs), a kind of highly strained
but readily accessible molecules, with various acyl chlorides
in the presence of aluminum chloride (Scheme 1).4 As for
Scheme 1. Acylation of Methylenecyclopropanes
(1) (a) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 3, Chapter 1.8, pp 293-339. (b) Meima, G. R.; Lee,
G. S.; Garces, J. M. In Friedel-Crafts Alkylation; Sheldon, R. A., Bekkum,
H., Eds.; Wiley-VCH: New York, 2001; pp 155-160.
these closely related analogues, methylenecyclobutanes
(MCBs), a class of moderately strained alkenes, it has been
known that they could be easily oxidized to the corresponding
cyclopentanone or cyclobutylmethanone derivatives in good
yields under mild reaction conditions.5 However, no report
on the AlCl3-catalyzed/mediated acylation of MCBs has been
disclosed thus far. Therefore, we attempted to examine the
reaction of MCBs 1 with a variety of acyl chlorides in the
(2) Gore, P. H. In Aromatic Ketone Synthesis in Friedel-Crafts and
Related Reactions; Olah, G. A., Ed.; John Wiley & Sons Inc.: London,
1964; Vol. III, Part 1, p 1.
(3) (a) Hart, H.; Curtis, O. E., Jr. J. Am. Chem. Soc. 1957, 79, 931–
934. (b) Hart, H.; Sandri, J. M. J. Am. Chem. Soc. 1959, 81, 320–326. (c)
Hart, H.; Levitt, G. J. Org. Chem. 1959, 24, 1261–1267. (d) Hart, H.;
Schlosberg, R. H. J. Am. Chem. Soc. 1966, 88, 5030–5033. (e) Hart, H.;
Schlosberg, R. H. J. Am. Chem. Soc. 1968, 90, 5189–5196.
10.1021/ol8006502 CCC: $40.75
Published on Web 05/02/2008
2008 American Chemical Society

presence of AlCl3. In this paper, we wish to present a novel
ring enlargement of MCBs in the AlCl3-mediated reactions
with acyl chlorides to produce the corresponding cyclopen-
tene derivatives in good yields.
Initial examinations using diphenylmethylenecyclobutane
1a (1.0 or 3.0 equiv) as the substrate to react with acetyl
chloride 2a (1.0-1.5 equiv) in the presence of AlCl3
(1.0-1.5 equiv) in dichloromethane were aimed at determin-
ing the optimal conditions, and the results of these experi-
ments are summarized in Table 1. 1-(2,3-Diphenylcyclopent-
2a and AlCl3 as well as 2.0 equiv of 1a and 1.0 equiv of 2a
and AlCl3 were employed, respectively (Table 1, entries 7
and 8). The examination of the solvent effects indicated that
DCE is the best one for this transformation (Table 1, entries
9-11). On the other hand, using other Lewis acids such as
FeCl3, ZnCl2, TiCl4, SnCl4, or HgCl2 instead of AlCl3 did
not give satisfactory results (Table 1, entries 12-16). Only
32% of 3a was produced when ZnCl2 was utilized as a Lewis
acid under the standard conditions (Table 1, entry 13).
Therefore, the best conditions are to carry out the reaction
in DCE at 50 °C using 2.0 equiv of 1a and 1.0 equiv of 2a
and AlCl3.
With these optimal conditions in hand, we next carried
out this novel acylation using a variety of starting materials
1 and acyl chlorides 2 as shown in Table 2. As for
Table 1. Optimization of the Reaction Conditions
Table 2. Scope and Limitations on the Acylation of MCBs
Catalyzed by AlCl3
entry MClx 1a/2a/MClx solvent T (°C) yieldb (%) of 3a
1
2
3
4
5
6
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
FeCl3
ZnCl2
TiCl4
SnCl2
HgCl2
1/1/1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
DCE
DCE
Et2O
THF
MeCN
DCE
DCE
DCE
DCE
rt
rt
rt
0
32
27
17
trace
51
60
70
72
NR
NR
NR
trace
32
NR
NR
NR
1/1.1/1.1
1/1.5/1.5
1/1/1
3/1/1
3/1/1
3/1/1
2/1/1
2/1/1
2/1/1
2/1/1
rt
yieldb
(%) of 3
40
50
50
30
50
50
50
50
50
50
50
entrya
MCBs (R1/R2)
1a (C6H5/C6H5)
1a
1a
1b (p-MeC6H4/p-MeC6H4) 2a (Me)
1b
1c (p-ClC6H4/p-ClC6H4)
1c
1c
1c
1d (p-FC6H4/p-FC6H4)
1d
1e (p-BrC6H4/p-BrC6H4) 2f (p-BrC6H4)
1f (m,p-Me2C6H3/C6H5)
1g (p-ClC6H4/C6H5)
1h (Bu/Bu)
2 (R3)
7
8a
9
1
2
3
4
5
6
7
8
2b (Et)
3b, 70
3c, 64
3d, 71
3e, 77
3f, 77
3g, 67
3h, 68
3i, 53
2c (C6H5)
2d (C6H5CH2)
10
11
12
13
14
15
16
2/1/1
2/1/1
2/1/1
2/1/1
2b (Et)
2a (Me)
2b (Et)
2e (p-NO2C6H4)
2f (p-BrC6H4)
2a (Me)
2/1/1
DCE
9
3j, 61
3k, 68
3l, 67
a Reaction conditions: 1a (0.6 mmol), MClx (0.3 mmol), MeCOCl (0.3
mmol), solvent (2.0 mL). The reactions were carried out at various
temperatures. b Isolated yields.
10
11
12
13
14
15
16
2b (Et)
3m, 51
3n, 73c
3o, 65d
3p, -e
2a (Me)
2a (Me)
2a (Me)
2-enyl)ethanone 3a was obtained in 32% yield at room
temperature (20 °C) within 1 h via a ring enlargement when
equal molar amounts of 1a, 2a, and AlCl3 were employed
(Table 1, entry 1). Increasing the employed amounts of 2a
and AlCl3 as well as decreasing the reaction temperature did
not improve the yields of 3a under otherwise identical
conditions (Table 1, entries 2, 3 and 4). When the employed
amounts of 2a and AlCl3 were reduced to 1/3 equiv of 1a,
3a was formed in 51% yield at room temperature (Table 1,
entry 5). Further examination of the reaction conditions
revealed that increasing the reaction temperature to 40 °C
afforded 3a in 60% yield in 1,2-dichloroethane (DCE) when
3.0 equiv of 1a and 1.0 equiv of 2a and AlCl3 were employed
(Table 1, entry 6). Moreover, at 50 °C, 3a was obtained in
70% and 72% yields when 3.0 equiv of 1a and 1.0 equiv of
1a
2g (p-BrC6H4SO2Cl) 3q, -e
a Reaction conditions: 1 (0.6 mmol), AlCl3 (0.3 mmol), R3COCl (0.3
mmol), DCE (2.0 mL). The reactions were carried out at 50 °C. b Isolated
yields. c Isomeric mixtures (1:1) based on GLC. d Isomeric mixtures (1:2)
based on H NMR spectrum. e No reaction.
1
symmetrical MCBs 1a-e, the reactions proceeded smoothly
with various aliphatic or aromatic acyl chlorides 2 to afford
the corresponding cyclopentenes 3b-m in 51-77% yields
(Table 2, entries 1-12). The substituents on the aromatic
ring of MCBs 1 and acyl chlorides did not have significant
influence on this reaction outcomes. However, as for unsym-
metrical aromatic MCBs 1f and 1g, the corresponding
products 3n and 3o were obtained as isomeric mixtures in
good yields (Table 2, entries 13 and 14). It should be noted
that using aliphatic MCB 1h, in which both R1 and R2 are
alkyl groups, as the substrate or using sulfonyl chloride such
as p-BrC6H4SO2Cl as acylation reagent under the standard
conditions, no reactions occurred (Table 2, entries 15 and 16).
Under these optimal conditions, we further investigated
the acylation of a variety of unsymmetrical MCBs 1i-k
(4) Huang, X.; Yang, Y.-W. Org. Lett. 2007, 9, 1667–1670.
(5) (a) Graham, S. H.; William, A. J. S. J. Chem. Soc. 1959, 4066–
4072. (b) Farcasiu, D.; Schleyer, P. V. R.; Ledlie, D. J. Org. Chem. 1973,
38, 3455–3459. (c) Graham, S. H.; William, A. J. S. J. Chem. Soc. C 1966,
655–660. (d) Fitjer, L.; Kanschik, A.; Majewski, M. Tetrahedron Lett. 1988,
29, 5525–5528. (e) Shen, Y. M.; Wang, B.; Shi, Y. Angew. Chem., Int. Ed.
2006, 45, 1429–1432. (f) Jiang, M.; Liu, L.-P.; Shi, M. Tetrahedron 2007,
63, 9599–9604.
2240
Org. Lett., Vol. 10, No. 11, 2008

where R1 is an aromatic group and R2 is a proton, and found
these reactions also proceeded smoothly to give the corre-
sponding cyclopentenes 3r-y in 72-87% yields as a single
isomer whether they have electron-poor or electron-rich
aromatic ring (Table 3, entries 1-8). Their structures were
Scheme 2
.
Reaction of MCB 1l with Acetyl Chloride in the
Presence of AlCl3
Table 3. Scope and Limitations on the Acylation of MCBs
Catalyzed by AlCl3
and 68% yield, respectively under the standard conditions.
These results suggest that compound 4 itself is not affected
by Lewis acid, but could undergo rearrangement to produce
3 in the coexistence of Lewis acid and acyl chloride.
entrya
MCBs (R1)
R3
yield (%)b of 3
1
2
3
4
5
6
7
8
1i (p-ClC6H4)
2a (Me)
2b (Et)
2a (Me)
2b (Et)
2e (p-BrC6H4)
2e (Me2CH)
2a (Me)
3r, 85
3s, 87
3t, 82
3u, 84
3v, 82
3w,72
3x, 80
3y, 75
1i
1j (p-BrC6H4)
1j
1j
1j
Scheme 3. Control Experiments
1k (p-MeC6H4)
1k
2c (C6H5)
a Reaction conditions: 1 (0.6 mmol), AlCl3 (0.3 mmol), R3COCl (0.3
mmol), DCE (2.0 mL). The reactions were carried out at 50 °C. b Isolated
yields.
determined by spectroscopic data, HRMS and microanalyses
(see the Supporting Information). Furthermore, the X-ray
crystal structure of 3v was determined and its CIF data are
presented in the Supporting Information (Figure 1).6
The cyclobutane ring is essential in this transformation
because if using diphenylmethylenecyclopentane 5a and
diphenylmethylenecyclohexane 5b as the substrates under
the standard conditions, the corresponding Friedel-Crafts
products 6a and 6b were obtained in 54% and 67% yields,
respectively (Scheme 4).
Scheme 4. Acylation of 5a (0.6 mmol) and 5b (0.6 mmol) with
Acetyl Chloride (0.3 mmol) in the Presence of AlCl3
Figure 1. ORTEP drawing of 3v.
Furthermore, when using MCB 1l in which R1 is an
aromatic group and R2 is a methyl group as the substrate,
we found that 3-cyclobut-1-enyl-3-methylbutan-2-one de-
rivative 4 was formed in 68% yield along with 3z in 15%
yield within 0.5 h under the standard conditions. However,
when the reaction time was prolonged to 2 h, traces of 4
were obtained and the yield of 3z increased to 73%,
indicating that 4 might be the intermediate in this reaction
(Scheme 2). As the control experiments shown in Scheme
3, we also confirmed that 4 remained unchanged by treatment
with AlCl3 (1.0 equiv) in DCE at 50 °C after 2 h in the
absence of acetyl chloride 2a and adding 1.0 equiv of acyl
chloride 2a or 2b into the mixture afforded 3z in 84% yield
To confirm the mechanism of this acylation reaction, we
performed deuterium labeling studies with deuterated me-
thylenecyclobutane 7 (Scheme 5). Under the standard condi-
tions, reaction of 7 (D > 99%) with acetyl chloride afforded
the product mixtures of 8 in 83% yield with 18% and 81%
D content at C1 position, respectively based on the corre-
sponding H NMR spectroscopic data, suggesting that the
acylation occurred at two different places (see the Supporting
Information).
1
A plausible mechanism for the formation of cyclopentene
derivatives 3 is outlined in Scheme 6 based on the above
Org. Lett., Vol. 10, No. 11, 2008
2241

R2 is a H atom or a methyl group, intermediate H (compound
4 in Scheme 2) is probably first formed via intermediate B
(path b). Intermediate H (R2 ) Me or H) can afford
intermediate C via intermediates I and B through intramo-
lecular rearrangements to furnish the corresponding product
3. In the mean time, intermediate H (R2 ) H, not Me) can
also produce intermediate K from intermediate J in the
presence of AlCl3. Aryl transfer gives intermediate L which
is also a phenonium ion intermediate.8 Then, the correspond-
ing product 3 is produced similarly via intermediates M, N,
and O successively. When both R1 and R2 are aromatic
groups, the reaction exclusively proceeds through path a,
presumably due to that the two sterically bulky aromatic
groups block out the acylation at C1 position. When R1 is
an aromatic group and R2 is a H atom, the rearrangement
can proceed mainly through path b and partially through path
a to afford the corresponding product 3 which are consistent
with the deuterium labeling experiment shown in Scheme
4. When R1 is an aromatic group and R2 is a methyl group,
intermediate H is fairly stable, which can be isolated from
the reaction mixtures. Moreover, a control experiment using
intermediate C as the substrate indeed afforded the corre-
sponding product 3 in moderate yield under the standard
reaction conditions, indicating that intermediate C should
be the reaction intermediate (Supporting Information).
In summary, we have developed an efficient acylation
reaction of methylenecyclobutanes using AlCl3 as a Lewis
acid to produce cyclopentene derivatives 3 in moderate to
good yields via ring enlargement with easily available
reagents under mild conditions. These functionalized cyclo-
pentenes are a common structural motif found in many
natural products and bioactive compounds. A plausible
mechanism has been proposed on the basis of control and
deuterium labeling experiments. Clarification of the reaction
mechanism and further application of this transformation are
in progress.
Scheme 5. Deuterium Labeling Experiment
deuterium labeling and control experiments. The in situ
generated acyl cation in the presence of AlCl3 reacts with
MCB 1 to produce intermediate A, which eliminates an
allylic proton to give intermediate B.7 When both R1 and R2
are aromatic groups, intermediate C is produced via inter-
mediate B in the presence of AlCl3 and subsequently gives
intermediate D (path a). Ring enlargement of cyclobutane
affords intermediate E along with the fromation of interme-
diate F which is a phenonium ion intermediate.8 Aryl transfer
through intermediate F furnishes intermediate G, which
produces the corresponding product 3 via the elimination of
AlCl3. On the other hand, when R1 is an aromatic group and
Scheme 6. Proposed Reaction Mechanism
Acknowledgment. We thank the Shanghai Municipal
CommitteeofScienceandTechnology(04JC14083,06XD14005)
and the National Natural Science Foundation of China for
financial support (20472096, 20672127, and 20732008).
Supporting Information Available: Detailed description
of experimental procedures, full characterization of new
compounds shown in Tables 1–3, X-ray crystal analysis data
of 3v. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL8006502
(6) The crystal data of 3v have been deposited in CCDC with no. 671857.
Empirical formula: C18H14Br2O; formula weight: 406.11; crystal color, habit:
colorless, prismatic; crystal dimensions: 0.431 × 0.365 × 0.227 mm; crystal
system: monoclinic; lattice type: primitive; lattice parameters: a ) 11.323(2)
Å, b ) 31.150(6) Å, c ) 13.860(3) Å, R ) 90°, ꢀ ) 96.603(3)°, γ ) 90°,
V ) 4856.2(16) Å3; space group: P2(1)/c; Z ) 12; Dcalc ) 1.666 g/cm3;
F000 ) 2400; diffractometer: Rigaku AFC7R; residuals: R; Rw: 0.0413,
0.0613.
(7) (a) The examples for the similar allylic addition reaction: Chou, P. K.;
Dahlke, G. D.; Kass, S. R. J. Am. Chem. Soc. 1993, 115, 315–324. (b)
Glasovac, Z.; Eckert, M. M.; Dacres, J. E.; Kass, S. R. J. Chem. Soc., Perkin
Trans. 2 2002, 410–415.
(8) (a) Selected papers on the aryl transfer through phenonium ion:
Jackson, E. L.; Pastiut, L. J. Am. Chem. Soc. 1928, 50, 2249–2260. (b)
Cram, D. J. J. Am. Chem. Soc. 1949, 71, 3863–3870. (c) Cram, D. J. J. Am.
Chem. Soc. 1952, 74, 2129–2137.
2242
Org. Lett., Vol. 10, No. 11, 2008