Metal-free ring expansions of methylenecyclopropanes through nitrene equivalent

Article abstract of DOI:10.1002/ejoc.201100629

An interesting nitrene equivalent mediated metal-free ring expansion of methylenecyclopropanes was developed in the presence of iodosobenzene diacetate (PIDA) and 3-amino-2-ethyl-4(3H)-quinazolinone under mild conditions. A variety of cyclobutylidene hydr

Full text of DOI:10.1002/ejoc.201100629

FULL PAPER
DOI: 10.1002/ejoc.201100629
Metal-Free Ring Expansions of Methylenecyclopropanes Through Nitrene
Equivalent
Di-Han Zhang,[a] Yin Wei,[a] and Min Shi*[a]
Keywords: Small ring systems / Rearrangement / Ring expansion / Nitrenes
An interesting nitrene equivalent mediated metal-free ring
expansion of methylenecyclopropanes was developed in the
presence of iodosobenzene diacetate (PIDA) and 3-amino-2-
ethyl-4(3H)-quinazolinone under mild conditions. A variety
of cyclobutylidene hydrazine derivatives were obtained in
moderate to excellent yields as separable (Z)/(E) isomeric
mixtures.
Introduction
Results and Discussion
Initial studies using diphenylmethylenecyclopropane (1a,
0.2 mmol) as the substrate were aimed at determining the
reaction outcome and the subsequent optimization of the
reaction conditions. The results of these experiments are
summarized in Table 1. Using Q-NH2 (2.0 equiv.) as a reac-
tant and K2CO3 (4.0 equiv.) as a base in the presence of
PhI(OAc)2 (2.2 equiv.) in dichloromethane (DCM) at room
The introduction of highly strained small ring systems as
molecular building blocks has attracted much attention in
organic synthesis, because the relief of ring strain can pro-
vide a potent thermodynamic driving force.[1] Due to their
inherent ring strain, interesting preparative aspects and ap-
plications specific to these ring compounds have been sig-
nificantly developed recently. Among the rapid formations
of molecular complexity induced by highly strained small
ring systems, ring expansions are extremely interesting. In
this aspect, transition-metal-catalyzed ring expansion re-
arrangements of methylenecyclopropanes (MCPs)[2] to cy-
clobutene derivatives and cyclobutanone derivatives as well
as other large ring systems have been widely reported,[3,4]
whereas only a few examples of the ring expansions of
MCPs in the absence of a metal complex have been ex-
plored.[5] For example, in 2006, Yu and co-workers reported
a nitrene equivalent mediated ring expansion of MCPs and
methylenecyclobutanes (MCBs) in the presence of N-ami-
nophthalimide and iodosobenzene diacetate [PhI(OAc)2].[6]
After that, we also reported the stereoselective additions of
2,4-dinitrophenylsulfenamide to MCPs in the presence of
PhI(OAc)2 (PIDA) to give the corresponding ring-enlarge-
ment products in good yields under mild conditions.[7] In
this paper, we wish to report one more interesting example
on the ring expansions of MCPs to give the corresponding
cyclobutylidene hydrazine derivatives in good yields with
(Z) configuration as the major products by using 3-amino-
2-ethyl-4(3H)-quinazolinone (Q-NH2) as the reactant in the
presence of PhI(OAc)2 under mild conditions.
Table 1. Optimization of the reaction conditions.[a]
Entry
Base
x/y/z
Solvent
Yield [%][b]
2a
3a
1
2
3
4
5
6
K2CO3
Na2CO3
Li2CO3
Cs2CO3
2.0:2.2:4.0
2.0:2.2:4.0
2.0:2.2:4.0
2.0:2.2:4.0
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
69
74
56
60
65
73
65
59
63
74
63
66
22
26
22
24
12
27
28
35
30
23
9
NaHCO3 2.0:2.2:4.0
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
1.5:1.7:2.0
1.2:1.4:2.0
1.5:1.7:2.0
1.5:1.7:2.0
1.5:1.7:2.0
1.5:1.7:2.0
1.5:1.7:2.0
7
8[c]
9
10
11
12
DCE
Et2O
CH3CN
[a] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, China
Fax: +86-21-64166128
8
[a] All reactions were carried out with 1a (0.2 mmol), Q-NH2
(x equiv.), PhI(OAc)2 (y equiv.), and base (z equiv.) in the solvent
(2.0 mL), unless otherwise specified. [b] Isolated yield, 2a and 3a
are separable. [c] The oxidant is PhI(OPiv)2 (1.7 equiv.).
E-mail: mshi@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100629.
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Eur. J. Org. Chem. 2011, 4940–4944

Metal-Free Ring Expansions of MCPs Through Nitrene Equivalent
temperature (20 °C), we found that ring expansion products When R1 or R2 is an alkyl group such as Me or when R1
2a and 3a (the geometric isomer of 2a) were obtained in 69 and R2 is a substituted cyclohexyl group, the corresponding
and 22% yield, respectively (Table 1, Entry 1). Other bases major products 2 were obtained in 23–31% yield along with
such as Na2CO3, Li2CO3, Cs2CO3, and NaHCO3 were also a trace amount of 3 (Table 2, Entries 10–12). Using MCB
examined, and we found that Na2CO3 afforded a better re- 1p as the substrate, no reaction occurred under the opti-
sult and that the total yield of 2a and 3a could be improved mized conditions (Table 2, Entry 13). Using other simple
to Ͼ99% along with a ratio of 2.85:1 (Table 1, Entries 2– olefins as substrates, no reactions occurred either. The
5). Then, the employed amounts of Q-NH2, PhI(OAc)2, and product structures of 2b–2m and 3b–3j were determined by
Na2CO3 were carefully examined, and it was found that 2a NMR spectroscopy, MS, and HRMS (see the Supporting
and 3a could be obtained in 73 and 27% yield, respectively, Information for details). In all cases, (Z)/(E) isomeric mix-
in the presence of Q-NH2 (1.5 equiv.), PhI(OAc)2 tures were separable by silica gel column chromatography.
(1.7 equiv.), and Na2CO3 (2.0 equiv.) in DCM (Table 1, En-
tries 6 and 7). Using PhI(OPiv)2 as an oxidant afforded 2a
Table 2. Nitrene equivalent mediated ring expansions of various
MCPs 1 under the optimized conditions.[a]
and 3a in 59 and 35% yield, respectively, under identical
conditions (Table 1, Entry 8). Further examination of the
solvent effects revealed that DCM was the solvent of choice,
and other organic solvents such as tetrahydrofuran (THF),
1,2-dichloroethane (DCE), Et2O, and CH3CN also facili-
tated the formation of 2a and 3a, but the reactions were
not as good as those performed in DCM (Table 1, En-
tries 9–12). The structure of compound 2a was confirmed
by X-ray diffraction (Figure 1).[8]
Figure 1. ORTEP drawing of 2a.
[a] All reactions were carried out with 1 (0.2 mmol), Q-NH2
(1.5 equiv.), PhI(OAc)2 (1.7 equiv.), and Na2CO3 (2.0 equiv.) in
DCM (2.0 mL) at r.t. for 2–3 h. [b] Isolated yield, 2 and 3 are sepa-
rable.
With these optimal conditions in hand, we next exam-
ined a variety of MCPs 1 in this reaction, and the results
are shown in Table 2. For MCPs having electron-donating
groups on the benzene ring, such as Me and MeO groups,
On the other hand, in the case of MCPs 1n and 1o, in
products 2 and 3 could be obtained in good to high total which R1 is an aromatic group and R2 is a hydrogen atom,
yields (Table 2, Entries 1 & 2 and 4 & 5). Only in the case the reactions proceeded smoothly to give different addition
of unsymmetrical diarylmethylenecyclopropane 1d was the products under the standard conditions (Scheme 1). As for
corresponding desired product 2d formed in 52% yield with MCP 1n with a MeO group at the ortho position of the
a trace amount of product 3d (Table 2, Entry 3). As for benzene ring, alcohol derivative 4n was mainly obtained in
MCPs with electron-withdrawing groups, such as F, Cl, and 52% yield. If the MeO group was introduced at the para
Br atoms on the benzene ring, all of the reactions proceeded position of the benzene ring, MCP 1o gave ring expansion
smoothly to afford the corresponding ring expansion prod- product 3o in 15% yield along with the formation of adduct
ucts 2 and 3 in good total yields (Table 2, Entries 6–9). 5o in 45% yield.
Eur. J. Org. Chem. 2011, 4940–4944
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D.-H. Zhang, Y. Wei, M. Shi
FULL PAPER
Scheme 3. Nitrene equivalent mediated ring expansions of MCP 1a
in the presence of TEMPO.
On the basis of the above results, a plausible mechanism
for the ring expansion of MCPs with Q-NH2 mediated by
iodosobenzene diacetate is tentatively outlined in Scheme 4.
Similar to the reaction mechanism proposed by Yu,[6] Q-
NH2 is first oxidized with PhI(OAc)2 to afford active ni-
trene equivalent C.[9] Then, intermediate C reacts with
MCP to give the ring expansion rearrangement product via
either aziridine intermediate D (path a) or ionic intermedi-
ate E (path b).
Scheme 1. Addition reactions of MCPs 1n and 1o under the stan-
dard conditions.
As shown in Scheme 2, in the presence of AgBF4,
Yb(OTf)3 or TfOH (5 mol-%), we found that 2a [(Z) config-
uration] could be transformed into 3a [(E) configuration] in
DCE at room temperature over 6 h in 95–99% yield. This
transformation of the (Z) isomer into the (E) isomer pre-
sumably proceeded through protonated intermediate A to
intermediate B via the rotation around the single bond.
Using AgBF4 or Yb(OTf)3 as the catalyst, a trace amount
of Brønsted acid (proton source) derived from the decom-
position of the catalyst by ambient moisture exists in the
reaction system, which can also cause such isomerization.
Scheme 4. A plausible reaction mechanism for the formation of 2
and 3.
As shown in Scheme 5, when R1 is an aromatic group (2-
MeOC6H4 or 4-MeOC6H4) and R2 is a hydrogen atom, the
reaction of these MCPs with intermediate C generates ad-
dition product F, perhaps due to the lower steric hindrance
of MCPs 1n and 1o compared to that of other MCPs shown
in Table 2. If the MeO group is introduced at the ortho posi-
tion of the benzene ring, corresponding adduct F undergoes
hydrolysis to give the corresponding alcohol derivative 4n,
presumably owing to steric repulsion between the 2-MeO
group at the aromatic ring and the OAc group.
Scheme 2. Transformation of 2a (Z configuration) into 3a (E con-
figuration).
Scheme 5. A plausible reaction mechanism for the formation of 4n
and 5o.
To further understand this interesting ring enlargement
reaction, one control experiment using 2,2,6,6-tetramethyl-
1-piperidinyloxy (TEMPO) as the radical inhibitor was per-
formed under the standard conditions (Scheme 3). We con-
firmed that the reaction under these optimized conditions
was unaffected by the addition of the radical inhibitor, ren-
Conclusions
In summary, we have reported an interesting nitrene
dering unlikely the intervention of a radical or biradical equivalent mediated metal-free ring expansion of methyl-
pathway.
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enecyclopropanes with 3-amino-2-ethyl-4(3H)-quinazol-
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Metal-Free Ring Expansions of MCPs Through Nitrene Equivalent
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inone (Q-NH2) in the presence of iodosobenzene diacetate
under mild conditions. A variety of cyclobutylidene hydraz-
ine derivatives were obtained in moderate to excellent yields
as separable (Z)/(E) isomeric mixtures. Efforts are under-
way to further elucidate the reaction mechanism and the
scope and limitations of this reaction in the laboratory.
Experimental Section
General Procedure for Metal-Free Ring Expansions of MCPs under
the Standard Reaction Conditions: Under ambient atmosphere,
MCP
1 (0.2 mmol, 1.0 equiv.), Q-NH2 (1.5 equiv.), Na2CO3
(2.0 equiv.), and DCM (2.0 mL) were added into an Schlenk tube.
The reaction was initiated by addition of PIDA (1.7 equiv.). Then,
the reaction mixture was stirred at room temperature until the reac-
tion was complete. The solvent was removed under reduced pres-
sure, and the residue was purified by flash column chromatography
(SiO2) to give corresponding products 2 and 3 in moderate to good
yields.
Compound 2a: Yield: 59 mg, 73%. White solid. M.p. 183–185 °C.
IR (neat): ν = 3062, 3025, 2992, 1676, 1596, 1471, 1367, 1112, 909,
˜
1
767, 688 cm–1. H NMR (400 MHz, CDCl3, TMS): δ = 1.12 (t, J
= 7.2 Hz, 3 H, CH3), 2.35 (q, J = 7.2 Hz, 2 H, CH2), 2.66 (t, J =
8.0 Hz, 2 H, CH2), 3.29 (t, J = 8.0 Hz, 2 H, CH2), 7.05–7.09 (m, 6
H, Ar), 7.19 (br. s, 4 H, Ar), 7.31 (t, J = 8.0 Hz, 1 H, Ar), 7.42 (d,
J = 8.0 Hz, 1 H, Ar), 7.60 (t, J = 8.0 Hz, 1 H, Ar), 8.10 (d, J =
8.0 Hz, 1 H, Ar) ppm. 13C NMR (100 MHz, CDCl3, TMS): δ =
10.0, 27.4, 27.6, 33.3, 71.1, 121.0, 125.6, 126.5, 126.7, 127.0, 128.1,
128.2, 133.4, 146.7, 154.9, 158.1, 181.2 ppm. MS (ESI): m/z = 394
[M + H]+. HRMS (ESI): calcd. for C26H24N3O [M + H]+ 394.1914;
found 394.1929.
Compound 3a: Yield: 22 mg, 27%. White solid. M.p. 181–183 °C.
IR (neat): ν = 3051, 3020, 2932, 1675, 1591, 1468, 1364, 1140, 905,
˜
1
750, 691 cm–1. H NMR (400 MHz, CDCl3, TMS): δ = 1.13 (t, J
= 7.6 Hz, 3 H, CH3), 2.67 (q, J = 7.6 Hz, 2 H, CH2), 2.84–2.87 (m,
2 H, CH2), 2.90–2.93 (m, 2 H, CH2), 7.24–7.28 (m, 2 H, Ar), 7.37
(t, J = 7.6 Hz, 4 H, Ar), 7.43–7.47 (m, 1 H, Ar), 7.59 (d, J = 7.6 Hz,
4 H, Ar), 7.67–7.75 (m, 2 H, Ar), 8.28 (d, J = 7.6 Hz, 1 H, Ar) ppm.
13C NMR (100 MHz, CDCl3, TMS): δ = 10.9, 28.2, 29.0, 32.8,
65.3, 121.2, 126.3, 127.0, 127.1, 127.2, 128.6, 134.0, 143.4, 147.0,
156.9, 186.2 ppm. MS (ESI): m/z = 416 [M + Na]+. HRMS (ESI):
calcd. for C26H23N3NaO [M + Na]+ 416.1733; found 416.1736.
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Acknowledgments
We thank the Shanghai Municipal Committee of Science and Tech-
nology (08dj1400100-2), National Basic Research Program of
China (973)-2009CB825300, and the National Natural Science
Foundation of China for financial support (21072206, 20472096,
20872162, 20672127, 20821002, and 20732008).
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FULL PAPER
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