Catalytic Annulation of Diethyl Methylenecyclopropane-1,1-dicarboxylate with 1,1-Dicyanoalkenes

Article abstract of DOI:10.1021/acs.orglett.7b01023

The catalytic annulation of methylenecyclopropane 1 with 1,1-dicyanoalkenes 2 using a Mg-Sn catalytic system was developed. Selective formation of cyclopentylidenemalonates 3 and spiro[2,3]hexane-1,1-dicarboxylates 4 was accomplished via the choice of a proper solvent and an effective catalytic system.

Full text of DOI:10.1021/acs.orglett.7b01023

Letter
pubs.acs.org/OrgLett
Catalytic Annulation of Diethyl Methylenecyclopropane-1,1-
dicarboxylate with 1,1-Dicyanoalkenes
Itaru Suzuki, Shinji Tsunoi, and Ikuya Shibata*
Research Center for Environmental Preservation, Osaka University, 2-4 Yamadaoka, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: The catalytic annulation of methylenecyclopro-
pane 1 with 1,1-dicyanoalkenes 2 using a Mg−Sn catalytic
system was developed. Selective formation of cyclopentylide-
nemalonates 3 and spiro[2,3]hexane-1,1-dicarboxylates 4 was
accomplished via the choice of a proper solvent and an
effective catalytic system.
ethylenecyclopropanes (MCPs) can undergo a variety of
reactions facilitated by the release of the intramolecular
dienolate A, which then reacted with the isocyanate. Intra-
M
molecular alkylation of the resultant adduct finally produced a
methylene γ-lactam, thus indicating that the initial addition of
the isocyanate occurred at the α-position of dienolate A. On the
basis of these results, herein we present the catalytic reaction of
MCP 1a with dicyanoalkenes 2, in which magnesium and tin
systems combine as effective catalysts. In particular, regiose-
lectivity control of cyclopentylidenemalonates 3 and spiro-
[2,3]hexane-1,1-dicarboxylates 4 was accomplished via the
proper choice of catalyst and solvent (Scheme 2).
strain of the small ring and its exocyclic CC bond.1 The
main-group metal and Lewis acid (LA) catalysts activate MCPs,
leading to cleavage of the distal bond.2 Thus, MCPs react not
only at the α-position but also at the γ-position to give a variety
of cyclic products.2d We have established the [3 + 2]-
annulation of simple cyclopropanes with isocyanates (Scheme
1, eq 1).3 We previously reported the formation of an ate
Scheme 1. Catalytic Annulation of Cyclopropanes with
Isocyanates
Scheme 2. Catalytic Annulation of Methylenecyclopropanes
with 1,1-Dicyanoalkenes
Initially, we performed the catalytic annulation of methyl-
enecyclopropane-1,1-dicarboxylate ester 1a with 1,1-dicyanoal-
kene 2a at 40 °C using THF as solvent (Table 1). In the
absence of catalyst, the reaction did not proceed (Table 1, entry
1). There was no reaction when 0.1 equiv of Bu2SnI2 was used
as the catalyst (Table 1, entry 2). On the other hand, the use of
MgBr2 was shown to promote the reaction of methylenecyclo-
prane 1a and dicyanoalkene 2 (Table 1, entry 3), affording a
mixture of cyclopentylidenemalonate 3a and adduct 4a in 81%
overall yield. MgI2 as the catalyst afforded 3a predominantly
(Table 1, entry 4). Using a system that combined Bu2SnI2 with
MgI2 gave 3a with the highest level of selectivity (80:2; Table 1,
entry 5). In the initial stage, the byproduct 4a seemed to be a [2
complex, MgBr+[Bu2SnBrI2]−, that serves as the active catalyst
in the Bu2SnI2−MgBr2 catalytic system. A characteristic of the
tin ate complex is its hybrid makeup, wherein both an acidic
magnesium cation and a nucleophilic Sn−I bond are parts of
the same molecule.4 Although a similar catalytic principle has
been reported for MgI2,5 the hybrid characteristic of the tin
catalyst confers a higher level of activity. The accessibility of a
variety of cyclopropanes is another positive factor for the tin
catalyst. We have already applied the tin catalytic system to the
reaction of methylenecyclopropane 1a with an isocyanate, and
4-methylene-γ-butyrolactam was obtained as a product
(Scheme 1, eq 2).3 The ring opening of 1a afforded tin
Received: April 5, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01023
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
entries 6, 8, 10, 12, 14, 16, and 18 vs 7, 9, 11, 13, 15, 17, and
19).
Table 1. Reaction of 1a with Alkenes 2 To Give
Cyclopentylidenemalonates 3
a
We had already established that the characteristic feature of
the tin halide ate complex MgX+[Bu2SnBrX2]− is its hybrid
makeup. MgX+ acts as a Lewis acid to activate the dicarboxylate
moiety to accelerate the ring opening of simple cyclopropanes
(Scheme 4).3 Simultaneously, a prolonged Sn−I bond that
b
entry
2, R
2a, Ph
cat.
3, yield (%)
4, yield (%)
1
2
−
3a, tr
4a, tr
4a, tr
4a, 34
4a, 12
4a, 2
Scheme 4. Ring Opening of MCPs
Bu2SnI2
3a, tr
3
MgBr2
3a, 47
3a, 83
3a, 80
3b, 93
3a, 78
3c, 68
3c, 73
3d, 61
3d, 76
3e, 72
3e, 90
3f, 55
3f, 57
3g, 61
3g, 74
3h, 82
3h, 67
4
MgI2
5
Bu2SnI2−MgI2
MgI2
6
2b, p-ClC6H4
2c, p-BrC6H4
2d, p-FC6H4
2e, p-NO2C6H4
2f, p-MeOC6H4
2g, p-MeC6H4
2h, Np
4b, tr
4b, 4
4c, tr
4c, tr
4d, 3
4d, 4
4e, tr
4e, tr
4f, 20
4f, 20
4g, tr
4g, 17
4h, 7
4h, 8
7
Bu2SnI2−MgI2
MgI2
8
9
Bu2SnI2−MgI2
MgI2
10
11
12
13
14
15
16
17
18
19
Bu2SnI2−MgI2
MgI2
Bu2SnI2−MgI2
MgI2
occupies the axial position in the trigonal-bipyramidal tin
structure10 attacks the cyclopropane in an effective manner.
When the tin complex was reacted with an equimolar amount
of simple cyclopropane 1b at rt for 24 h, a ring-opened adduct,
iodoethyl malonate, was formed in 45% yield, whereas the use
of only Bu2SnI2 or MgI2 afforded lower yields (<10%) (Scheme
4, eq 1). In contrast, when an equimolar catalyst was reacted
with methylenecycloproprane 1a at 0 °C for 15 min, even the
sole use of MgBr2 was sufficient to initiate ring opening
(Scheme 4, eq 2). As a result of its highly strained structure,
methylenecycloproprane 1a displayed a higher reactivity in the
catalytic annulation when only a magnesium salt was used
(Table 1, entries 3, 4, 6, 8, 10, 12, 14, 16, and 18).
Bu2SnI2−MgI2
MgI2
Bu2SnI2−MgI2
MgI2
Bu2SnI2−MgI2
a
Conditions: 1a (0.75 mmol), 2a (0.5 mmol), cat. (0.05 mmol), THF
b
(1 mL), 25 °C, 24 h. tr = trace.
+ 3]-adduct derived from the addition of the α-carbon of tin
dienolate A, similar to that of isocyanate (Scheme 1, eq 2).3
However, there are no vinyl protons in the 1H NMR spectrum,
and two sets of methylene protons and a set of methine protons
were observed. The byproduct 4a proved to be a spirocarbo-
cycle structure. The products, cyclopentylidenemalonate 3a and
spiro[2,3]hexane-1,1-dicarboxylate 4a, were formally classified
as a distal-bond-cleaved [3 + 2]-annulation product and a ring-
untouched [2 + 2]-cycloaddition product, respectively.
There is a possibility of rearrangement from spirocarbocycle
4 to the stable adduct 3. Thus, heating of 4a in the presence of
the catalyst afforded 3a, albeit in a low yield (19%). The
reaction proceeded via ring opening of the cyclopropane
moiety, as shown in Scheme 5. However, when spirocarbocycle
For the synthesis of cyclopentylidenemalonate 3, a plausible
reaction path is shown in Scheme 3. Initially, the metal iodide
Scheme 5. Rearrangement of 4a to 3a
Scheme 3. Formation of Cyclopentylidenemalonates 3
catalyst attacks 1a at C3 to give metal dienolate A.6 In a
subsequent step, the dienolate adds to the alkene at the γ-
carbon, giving metal keteneimine B. In the last stage, the
intramolecular alkylation to alkyl iodide affords cyclopentyli-
denemalonate 3 and regenerates the catalyst. Thus, the reaction
involves the catalytic employment of metal dienolate A.7−9
Table 1 also shows the results of the reaction of 1a with
various 1,1-dicyanoalkenes 2 under the optimized conditions
(Table 1, entries 6−19). By the reactions with various 1,1-
dicyanoalkenes 2 bearing functionalized aromatic substituents,
the corresponding cyclopentylidenemalonates 3 were obtained
with high selectivity. The levels of catalytic activity for both
MgI2 and Bu2SnI2−MgI2 were comparable in all cases (Table 1,
4a was treated under the conditions shown in Table 1 (40 °C),
no rearrangement occurred. Hence, cyclopentylidenemalonate
3a was formed directly rather than by rearrangement of 4a.
When dichloromethane instead of THF was used as the
solvent, a dramatic change in the product (3a/4a = 11%/72%)
was observed in the reaction of 1a with 2a catalyzed by
Bu2SnI2−MgI2 (Table 2, entry 1). Thus, the major product was
4a.
Scheme 6 summarizes the mechanism for the syntheses of
the two different types of products, 3a and 4a. Both products
are derived from the same intermediate, keteneimine B,
B
DOI: 10.1021/acs.orglett.7b01023
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Organic Letters
Letter
generated by the addition of the γ-carbon of dienolate A. The
product is determined in the cyclization step. As solvents, the
difference between dichloromethane and THF can be explained
by their coordinating ability. THF, a coordinating solvent,
aligns with Mg2+ and prevents the activation of the Michael
acceptor moiety in B, and the intramolecular alkylation then
proceeds to give 3 (route a). With dichloromethane, the
effective activation of the Michael acceptor in B induces an
intramolecular conjugate addition (route b). The resultant
intermediate C causes a subsequent alkylation and gives
spirocarbocycles 4, which thereby regenerates the catalyst.
For the selective synthesis of spirocarbocycle 4a, it is
important to suppress the intramolecular alkylation (route a) in
intermediate B. Accordingly, the halogen moiety in B was
changed from an alkyl iodide either to alkyl bromide or
chloride, both of which are less reactive than iodide. With the
sole use of MgX2, the reaction seemed to proceed by the same
protocol as that with the tin ate complex. In fact, compared
with MgI2, using MgBr2 and MgCl2 catalysts afforded
spirocarbocycle 4a predominantly (Table 2, entries 2−4). It
is noteworthy that the five-coordinate tin gave results that were
superior to the sole use of MgX2. Thus, when either the
Bu2SnBr2−MgBr2 or the Bu2SnCl2−MgCl2 system was used as
a catalyst, spirocarbocycle 4a was obtained selectively, as
expected (Table 2, entries 5 and 6). Among the catalytic
systems examined, Bu2SnCl2−MgCl2 was the best choice to
afford the selective formation of 4a. Thus, the five-coordinate
tin was the preferred conjugate addition prior to alkylation.11
Synthetic and natural spirocarbocycles have attracted the
attention of organic chemists because of their unique
multidimensional structural features and numerous possible
reactions whereby they undergo a carbon−carbon bond
cleavage.12 Among them, spiro[2,3]hexanes are rare structures.
To date, there are few examples of the synthesis of
spiro[2,3]hexanes wherein transition metal catalysts are
necessary.13,14 Table 3 summarizes the results of the reaction
Table 2. Reaction of 1a with Alkene 2a To Give
Spirocarbocycle 4a
a
b
entry
cat.
3a, yield (%)
4a, yield (%)
1
2
3
4
5
6
Bu2SnI2−MgI2
MgI2
11
28
6
72
58
76
68
80
99
MgBr2
MgCl2
tr
Bu2SnBr2−MgBr2
Bu2SnCl2−MgCl2
tr
tr
a
Conditions: 1a (0.75 mmol), 2a (0.5 mmol), cat. (0.05 mmol),
b
CH2Cl2 (1 mL), 25 °C, 24 h. tr = trace.
Scheme 6. Catalytic Cycle for the Formation of 3 and 4
a
Table 3. Reaction of 1a with Alkenes 2 To Give Spirocarbocycles 4
b
entry
2, R
2a, Ph
cat.
3, yield (%)
4, yield (%)
1
2
Bu2SnCl2−MgCl2
MgCl2
3a, tr
3a, tr
3b, tr
3b, tr
3c, tr
3c, tr
3d, tr
3d, tr
3e, tr
3e, tr
3f, tr
3f, 31
3g, tr
3g, tr
3h, tr
3h, tr
4a, 99
4a, 68
4b, 95
4b, tr
3
2b, p-ClC6H4
2c, p-BrC6H4
2d, p-FC6H4
2e, p-NO2C6H4
2f, p-MeOC6H4
2g, p-MeC6H4
2h, Np
Bu2SnCl2−MgCl2
MgCl2
4
5
Bu2SnCl2−MgCl2
MgCl2
4c, 98
4c, 30
4d, 96
4d, tr
4e, 99
4e, 40
6
7
Bu2SnCl2−MgCl2
MgCl2
8
9
Bu2SnCl2−MgCl2
MgCl2
10
11
12
13
14
15
16
c
Bu2SnBr2−MgBr2
MgBr2
4f, 55
c
4f, 33
Bu2SnCl2−MgCl2
MgCl2
4g, 96
4g, 8
Bu2SnCl2−MgCl2
MgCl2
4h, 97
4h, 46
a
b
c
Conditions: 1a 0.75 mmol, 2 0.5 mmol, cat. 0.05 mmol, CH2Cl2 1 mL, 25 °C, 24 h. tr = trace. The bromide catalyst gave a superior yield
compared with the chloride catalyst.
C
DOI: 10.1021/acs.orglett.7b01023
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Organic Letters
Letter
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using various aromatic 1,1-dicyanoalkenes 2. For the formation
of 4, Bu2SnX2−MgX2 was a superior catalyst to MgX2 alone in
all cases (compare entries 1, 3, 5, 7, 9, 11, 13, and 15 vs entries
2, 4, 6, 8, 10, 12, 14, and 16). For the selective formation of 4,
three factors were important: the use of the noncoordinative
solvent CH2Cl2, a metal chloride catalyst, and five-coordinate
tin. Spiro[2,3]hexane-1,1-dicarboxylates 4 could be isolated in
1
diastereomerically pure form, as shown by the H and 13C
NMR spectra. For spirocarbocycle 4d with a p-bromophenyl
substituent, X-ray crystal analysis was successful.15 The aryl and
the carbon substituted for by dicarboxylates occupied the less-
hindered cis positions in the wing-shaped cyclobutane ring.
In conclusion, we have developed a catalytic conversion of
methylenecyclopropanes. The Mg−Sn catalytic system is an
effective catalyst. Regioselectivity control is accomplished via
the choice of a proper solvent and catalytic system. In
particular, the synthesis of the rare spiro[2,3]hexane structure
4 is noted.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01023.
Experimental procedures and spectral data (PDF)
X-ray data for compound 4c (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*shibata@epc.osaka-u.ac.jp
ORCID
(8) (a) Shibata, I.; Suwa, T.; Ryu, K.; Baba, A. J. Org. Chem. 2001, 66,
8690−8692. (b) Shibata, I.; Tsunoi, S.; Sakabe, K.; Miyamoto, S.;
Kato, H.; Nakajima, H.; Yasuda, M.; Baba, A. Chem. - Eur. J. 2010, 16,
13335−13338.
Ikuya Shibata: 0000-0002-9619-4019
Notes
The authors declare no competing financial interest.
(9) Tsunoi, S.; Seo, Y.; Takano, Y.; Suzuki, I.; Shibata, I. Org. Biomol.
Chem. 2016, 14, 1707−1714.
ACKNOWLEDGMENTS
■
(10) For five-coordinate tin, see: (a) Davis, A. G. Organotin
Chemistry; VCH: New York, 1997; pp 18−24. (b) Harrison, P. G.
Chemistry of Tin; Blackie: London, 1989; pp 71−89. (c) Holecek, J.;
Nadvornik, M.; Handlir, K.; Lycka, A. J. Organomet. Chem. 1983, 241,
177−184. (d) Nadvornik, M.; Holecek, J.; Handlir, K.; Lycka, A. J.
Organomet. Chem. 1984, 275, 43−51.
We are grateful for financial support from The Naito
Foundation. We also thank Mr. Sho Yamashita and the
Instrumental Analysis Center, Faculty of Engineering, Osaka
University, for assistance with collecting the spectral data.
(11) Yasuda and Baba reported that five-coordinate tin increases the
HOMO level of the tin enolate and promotes conjugate addition
effectively. See: Yasuda, M.; Chiba, K.; Ohigashi, N.; Katoh, Y.; Baba,
A. J. Am. Chem. Soc. 2003, 125, 7291−7300.
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DOI: 10.1021/acs.orglett.7b01023
Org. Lett. XXXX, XXX, XXX−XXX