Cycloaddition reactions of trimethylenemethane diyls generated from alkynyl iodonium salts

Article abstract of DOI:10.1016/j.tetlet.2008.07.092

Intramolecular [2+3] cycloaddition reaction of trimethylenemethane diyls that were generated successfully from the reaction of malonate anions containing diene units with propynyl iodonium salts via alkylidene carbene intermediates produced linearly fused

Full text of DOI:10.1016/j.tetlet.2008.07.092

Tetrahedron Letters 49 (2008) 5693–5696
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Tetrahedron Letters
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Cycloaddition reactions of trimethylenemethane diyls generated
from alkynyl iodonium salts
*
Hee-Yoon Lee , Yeokwon Yoon, Yeon-Hee Lim, Yonghan Lee
School of Molecular Science (BK21) and Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular [2+3] cycloaddition reaction of trimethylenemethane diyls that were generated success-
fully from the reaction of malonate anions containing diene units with propynyl iodonium salts via alkyl-
idene carbene intermediates produced linearly fused triquinanes.
Received 16 June 2008
Revised 15 July 2008
Accepted 17 July 2008
Available online 22 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Alkylidene carbene
Trimethylenemethane
Diyl
Triquinane
Cycloaddition reactions are powerful tools for the synthesis of
complex target molelcules as they provide quick entries into
complex structures with good control of regiochemistry and
stereochemistry.1 [2+3] Cycloaddition reactions of trimethyle-
nemethanes (TMMs), either as TMM diyls or as TMM zwiterionic
precursors, have been used for efficient construction of cyclopen-
tane ring system.2 TMM diyls could be generated from diazenes
or alkylidene carbenes,3 and TMM diyls generated from diazenes
have been applied to organic synthesis.4 Recently, we reported
an application of alkylidene carbene routes to TMM diyls as a
new synthetic methodology for the construction of linearly fused
triquinanes through cycloaddition reaction of TMM diyls generated
from acyclic linear starting materials (Scheme 1).5
pounds from linear precursors was deemed plausible. However,
our initial attempt failed to provide TMM diyl derived cycloaddi-
tion reaction products as reaction of propynyl iodonium salt with
various nitrogen nucleophiles produced azabicyclo[3.1.0]hexane
5 instead of generating the TMM diyl (Scheme 2).7
The reason for failure to form TMM diyls was believed that the
nitrogen atom in the intermediate 50 altered the stability and reac-
tivity of methylenecyclopropane intermediates.8 This explanation
was supported by the formation of TMM diyls from the reaction
of propynyl iodonium salt with the anion of allyl Meldrum’s acid
as evidenced by the formation of diyl dimers.9 The dimer formation
indicated that the formation of TMM diyls from alkynyl iodonium
salts was feasible, and guided us to explore the development of a
convergent synthetic route to triquinane compounds from alkynyl
iodonium salts and proper carbon nucleophiles.
Herein, we report the synthesis of linearly fused triquinanes
from alkynyl iodonium salts with proper carbon nucleophiles. Pro-
pynyl iodonium salt was selected for the alkylidene carbene pre-
cursor to avoid competing reactions like C–H insertion reaction
or rearrangement reaction after the formation of alkylidene carb-
enes.10 Mono-substituted malonate ester derivatives, 6, were
selected as the counter part of propynyl iodonium salt for the for-
mation of alkylidene carbene intermediates. When the anion of
malonate derivative 6a, that was prepared from allylated diethyl
malonate, 1,4-dibromo-2-butene, and diethyl malonate through
sequential alkylation reactions, was reacted with propynyl iodoni-
um salt at room temperature, one major product and a minor prod-
uct were obtained in good yield. The reaction proceeded through
anticipated addition of malonate anion to propynyl iodonium salt
to generate alkylidene carbene. The subsequent intramolecular
We were also interested in the formation of TMM diyls from
alkylidene carbenes generated from alkynyl iodonium salts6 since
convergent route or multi-component route to polycyclic com-
Ph
Ph
H
H
H
110 oC
O
O
O
N
Ph
N
OH
1
2
Scheme 1. TMM diyl from epoxyaziridinyl imine and cycloaddition reaction.
* Corresponding author. Tel.: +82 42 869 2835; fax: +82 42 869 8370.
E-mail address: leehy@kaist.ac.kr (H.-Y. Lee).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.092

5694
H.-Y. Lee et al. / Tetrahedron Letters 49 (2008) 5693–5696
Ph
Ph
IPh OTf
Ph
Ts
Ts
N
N
+
N
Ts
E
E
E
E
E
E
3
4
5'
E=COOEt
5
Scheme 2. Rearrangement of methylenecyclopropane.
E
H
E
H
E
E
H
+
4
+
E
E
E
H
H
E
E
E
E
E
4
: 1
6a
7a
8a
E= COOEt
E
E
E
E
E
E
E
E
E
E
E
E
Scheme 3. Triquinanes from alkynyl iodonium salt.
cyclopropanation, contrary to the previously observed results from
nitrogen nucleophile 3, produced TMM diyl intermediate that
underwent [2+3] cycloaddition reaction to produce 7a in 42% yield
as the major product along with a minor product 8a in 11% yield
(Scheme 3).11
The structures of the major and minor products were deduced
from the NMR spectroscopic data, and relative stereochemistry
was assigned unambiguously through the NOE experiment
(Scheme 4). The major product had cis-anti triquinane structure,
and the minor product had cis–syn triquinane structure. The cur-
rent result of formation of the minor product with cis–syn stereo-
chemistry, and the ratio of the major product and the minor
product are similar to the result of symmetrical TMM cycloaddition
reaction.12
This result was somewhat unexpected since our previous
reports of [2+3] cycloaddition reaction of unsymmetric TMM diyls
produced only the cis-anti isomers as the isolated products and no
other isomers were identified in a significant amount. The different
selectivity might be attributed to the conformational difference in
the transition state due to different substitution patterns of TMM
diyls that could provide subtle difference in steric and electronic
environment.
The relative stereochemistry of 7a and 8a indicated that both
isomeric products were formed from the same conformation, and
only difference was the connecting points. Comparison of four pos-
sible transition states for the cyclization could explain, at least in
part, the stereoselectivity of the cyclization reaction. Transition
states C and D are clearly disfavored due to the interaction
between axially oriented hydrogen of the tether and the methyl
group. This is why we did not observe products derived from tran-
sition state C or D in this Letter or in the previous reports. In the
previous reports where there were no malonate unit attached to
TMM diyls, the transition state B appeared disfavored due to inter-
action of vinylic hydrogen with cyclopentene ring, and only the
products derived from the transition state A were observed.
In the current reaction, the transition state A shows the steric
interaction between vinylic hydrogens and one ester unit of the
malonate part. This interaction might have diminished the clear
preference of the transition state A during the cycloaddition reac-
tion, and the reaction produced a mixture of 7a and 8a though the
transition state A is favored. This explanation was supported by the
selectivity obtained from the substrates with Meldrum’s acid in-
stead of malonate unit.
When the reaction was applied to various substrates, the selec-
tivity of the reaction was similar in all cases (Table 1).
Among the results in the Table 1, entries 3–5 are noteworthy
since the acidic nature of the allylic protons of the substrates
prevented the formation of alkylidene carbenes under strong basic
conditions in the previous report.13 The results of entries 3, 4, and 5
showed that high acidity of the malonate protons of the substrates
allowed the formation of the desired products though in low yield.
The current protocol would be applicable to wide variety of sub-
strates as it offers milder reaction conditions than previous reports.
Since Meldrum’s acid anion was known to be more stable and the
better nucleophile for alkynyl iodonium salts than malonate
7.2%
H
8.2%
5.2%
CH3
E
H
H
H
H
H
H
H
E
E
E
E
E
E
E
H
7a
8a
Scheme 4. N.O.E. experiments of 7a and 8a.

H.-Y. Lee et al. / Tetrahedron Letters 49 (2008) 5693–5696
5695
E
E
E
E
E
H
E
E
H
E
H
E
H
E
E
E
H
H
H
E
E
E
E
8a
7a
B
A
E
=COOEt
E
E
E
E
E
H
E
E
H
H
E
E
H
E
H
E
E
H
H
E
E
E
E
C
D
not f ound
not found
Scheme 5. Transition states of the cycloaddition reaction.
Table 1
Cycloaddition reaction of TMM diyls16
R
H
R
R
E
H
H
4
E
E
+
E
A
A
A
E
E
H
H
6
7
8
E=COOEt
Entry
Substrate
A
R
Product (yield) (%)
1
2
3
4
5
6a
6b
6c
6d
6e
C(COOEt)2
C(COOEt)2
O
O
H
Ph
H
Ph
H
7a (42)
7b (43)
7c (16)
7d (17)
7e (23)
8a (11)
8b (12)a
8c (4)
8d (4)
8e (8)
Figure 1. X-ray crystal structure of compound 10c.
NTs
a
These products were isolated as an inseparable mixture.
The reaction was extended to other substrates and showed the
better or similar efficiency for the production of the major prod-
ucts, and no other minor isomers were identified in significant
amounts (Table 2).
For the substrates with acidic functional groups (entries 3 and
4), the reaction proceeded much better than the corresponding
substrates with malonate unit, and for other substrates the reac-
tion yielded similar result.
anion,14 we tested the substrates with anions of Meldrum’s acid
derivatives corresponding to the substrate 6c for the better result.
As anticipated, the Meldrum’s acid anion produced the desired
compound in better yield as 42% of 10c. This result clearly showed
that Meldrum’s acid containing substrate 9c generated the desired
anion better than the malonate analog 6c. Contrary to the malon-
ate analog 6c, the minor stereo-isomer was not detected in isolable
amount (Scheme 6).
In summary, we have demonstrated that a mild synthetic route
to linearly fused triquinane compounds from malonate anions and
The better selectivity from the reaction of 9c than 6c could well
be due to cyclic structure of Meldrum’s acid that reduces steric hin-
drance of the transition state A as shown in Scheme 5.
The structure of 10c was confirmed through X-ray crystallogra-
phy as it showed the cis-anti triquinane structure (Figure 1).15
These data supported the assignment of structures 7 and 8 from
the cycloaddition reaction.
Table 2
Cycloaddition reaction of TMM diyls16
R
R
H
H
O
O
O
4
O
O
A
A
H
O
O
O
9
O
H
10
O
O
H
O
Entry
Substrate
A
R
Product (yield) (%)
4
+
O
1
2
3
4
5
9a
9b
9c
9d
9e
C(COOEt)2
C(COOEt)2
O
O
H
Ph
H
Ph
H
10a (31)
10b (29)
10c (42)
10d (43)
10e (46)
O
O
O
O
H
O
42%
9c
10c
Me2C
Scheme 6. Meldrum’s acid route to TMM diyl.

5696
H.-Y. Lee et al. / Tetrahedron Letters 49 (2008) 5693–5696
11. Reaction condition and spectral data of 7a and 8a, reaction condition: To a stirred
solution of 6a (78 mg, 0.189 mmol) in THF (18 mL) was added KHMDS (454
propynyl iodonium salts and the stereoselectivity of [2+3] cycload-
dition reaction of TMM diyls with olefins are sensitive to the struc-
ture of the substrates. The compatibility of the current synthetic
methodology with relatively acidic functional groups widened
the scope of substrates, and could be applicable to the preparation
of various complex structures.
lL
of 0.5 M solution in toluene, 0.227 mmol) at 0 °C. After being stirred for 30 min,
the reaction mixture was allowed to warm to room temperature and a solution
of 1-propynyl(phenyl)iodonium triflate17 (97 mg, 0.246 mmol) in THF (18 mL)
was added for 40 min via cannula. The reaction mixture was stirred for 4 h. The
resulting product was quenched with saturated NH4Cl solution (10 mL) and
extracted with EtOAc (5 mL ꢀ 3). The organic layers were combined and dried
over MgSO4. The filtrate was concentrated in vacuo, and the residue was
purified by flash column chromatography on silica gel (EtOAc/Benzene = 1:30)
to yield 36 mg (0.08 mmol, 42%) of 7a and 9 mg (0.02 mmol, 11%) of 8a,
spectral data, Compound 7a: 1H NMR (400 MHz, CDCl3): d 4.20–4.11 (8H, m),
3.19 (1H, m), 3.03–2.96 (1H, m), 2.94–2.85 (1H, m), 2.82–2.77 (1H, dd, J = 12.6,
7.0 Hz), 2.66–2.60 (1H, ddd, J = 13.0, 8.8, 2.2 Hz), 2.50–2.44 (1H, ddd, J = 12.9,
8.1, 2.1 Hz), 1.84–1.75 (2H, m), 1.74–1.73 (3H, d, J = 2.4 Hz), 1.70–1.67 (1H, m),
1.62–1.57 (1H, m), 1.25–1.18 (13H, m).; 13C NMR (100 MHz, CDCl3): d 171.7,
171.4, 171.2, 170.7, 155.1, 125.0, 73.4, 62.5, 61.3, 61.3, 61.1, 61.0, 47.0, 45.2,
40.6, 40.3, 39.5, 38.8, 36.7, 14.1, 14.1, 14.0, 14.0, 12.2.; 8a: 1H NMR (400 MHz,
CDCl3): d 5.07 (1H, d, J = 1.5 Hz), 4.20–4.10 (8H, m), 3.39–3.35 (1H, ddd,
J = 16.4, 4.0, 1.5 Hz), 3.10–2.97 (2H, m), 2.86–2.81 (1H, ddd, J = 16.4, 3.1,
1.5 Hz), 2.61–2.56 (1H, ddd, J = 12.8, 8.0, 1.5 Hz), 2.53–2.48 (1H, ddd, J = 13.2,
8.0, 1.5 Hz), 2.00–1.95 (1H, dd, J = 12.9, 9.0 Hz), 1.95–1.90 (1H, dd, J = 13.1,
8.5 Hz), 1.72–1.71 (2H, d, J = 7.8 Hz), 1.26–1.17 (12H, m), 1.08 (3H, s).; 13C NMR
(100 MHz, CDCl3): d 172.1, 171.2, 170.9, 170.7, 158.5, 113.4, 67.2, 64.4, 64.0,
61.3, 61.2, 61.0, 60.9, 46.4, 43.2, 40.7, 39.7, 39.3, 38.0, 22.4, 14.1, 14.1, 14.1,
14.1.
Acknowledgments
We acknowledge financial support from KOSEF through the
center of molecular design & synthesis. We are grateful to Profes-
sor Kimoon Kim at POSTECH for X-ray crystallographic data collec-
tion for structure 10c.
References and notes
1. (a) Cycloaddition Reactions in Organic Synthesis; Kobayashi, S., Jorgensen, K. A.,
Eds.; Wiley-VCH Verlag GmbH: Weinheim, 2001; (b) Nicolaou, K. C.; Snyder, S.
A.; Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668–
1698; (c) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Pergamon:
Oxford, UK, 1990.
2. (a) Yamago, S.; Nakamura, E. In Organic Reactions; Overman, L. E., Ed.; John
Wiley & Sons: New York, 2002; Vol. 61, pp 1–217; (b) Little, R. D. Transition
Metal Mediated Cycloadditions. In Comprehensive Organic Reactions; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 239–270; (c)
Chan, D. M. T. Transition Metal Mediated Cycloadditions. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 5, pp 271–314.
12. Little, R. D. Chem. Rev. 1996, 96, 93–114.
13. Lee, H.-Y.; Kim, W.-Y.; Lee, S. Tetrahedron Lett. 2007, 48, 1407–1410.
14. Ochiai, M.; Ito, T.; Takaoka, Y.; Masaki, Y.; Kunishima, M.; Tani, S.; Nagao, Y. J.
Chem. Soc., Chem. Commun. 1990, 118–119.
15. Crystal data for 10c:
C
16H20O5, FW = 292.32, monoclinic, a = 6.1734(3) Å,
= 90°, b = 90.484(2)°, = 90°, V =
b = 19.5389(9) Å, c = 12.2444(6) Å,
a
c
1476.88(12) A3, Z = 4, R = 0.1221, spectral data of 10c: 1H NMR (400 MHz,
CDCl3): d 3.94–3.87 (2H, m), 3.57–3.47 (3H, m), 3.15–3.08 (2H, m), 2.61–2.56
(1H, dd, J = 12.6, 7.6 Hz), 2.16–2.11 (1H, dd, J = 12.6, 7.4 Hz), 1.80–1.75 (1H, dd,
J = 12.4, 7.6 Hz), 1.73 (3H, s), 1.71 (3H, s), 1.57–1.56 (3H, d, J = 2.4 Hz), 1.51–
1.43 (1H, m).; 13C NMR (100 MHz, CDCl3): d 170.2, 169.2, 156.4, 125.4, 104.8,
75.2, 73.1, 69.1, 48.7, 48.6, 42.3, 41.1, 36.4, 29.7, 28.2, 11.4.
3. Berson, J. A. Acc. Chem. Res. 1978, 11, 446–453.
4. Allan, A. K.; Law Carroll, G.; Little, R. D. Eur. J. Org. Chem. 1998, 1–12.
5. Lee, H.-Y.; Kim, Y. J. Am. Chem. Soc. 2003, 125, 10156–10157.
6. (a) Ochiai, M.; Kunishima, M.; Nagao, Y.; Fuji, K.; Shiro, M.; Fujita, E. J. Am.
Chem. Soc. 1986, 108, 8281–8283; (b) Stang, P. J. Angew. Chem., Int. Ed. 1992, 31,
274–285.
16. Reaction conditions for the cyclization are the same as the reaction condition
of 6a in Ref. 11 and all the isolated products showed satisfactory spectroscopic
data and purity.
17. Bachi, M. D.; Bar-Ner, N.; Crittell, C. M.; Stang, P. J.; Williamson, B. L. J. Org.
Chem. 1991, 56, 3912.
7. Lee, H.-Y.; Lee, Y.-H. Synlett 2001, 1656–1658.
8. Feldman, K. S.; Mareska, D. A. Tetrahedron Lett. 1998, 39, 4781–4784.
9. Lee, H.-Y.; Kim, Y.; Lee, Y.-H.; Kim, B. G. Tetrahedron Lett. 2001, 7431–7434.
10. The competing reaction between C–H insertion and intramolecular
cyclopropanation reaction produced insertion reaction as the major product
and did not show any cyclopropanation derived product
Ph
IPh
O
O
+
O
O
O
O
O
70%
O
O
OBn
.