Tandem cycloaddition reactions of allenyl diazo compounds forming triquinanes via trimethylenemethane diyls

Article abstract of DOI:10.1021/ja207591e

A tandem reaction strategy for forming triquinanes from linear allenyl diazo compounds through an intramolecular 1,3-dipolar cycloaddition reaction of an allenyl diazo group that generates a trimethylenemethane (TMM) diyl followed by an intramolecular [2

Full text of DOI:10.1021/ja207591e

COMMUNICATION
pubs.acs.org/JACS
Tandem Cycloaddition Reactions of Allenyl Diazo Compounds
Forming Triquinanes via Trimethylenemethane Diyls
Taek Kang, Won-Yeob Kim, Yeokwon Yoon, Byung Gyu Kim, and Hee-Yoon Lee*
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
S Supporting Information
b
Scheme 1. Generation of Methylcyclopentene TMM Dyl 1
ABSTRACT: A tandem reaction strategy for forming
triquinanes from linear allenyl diazo compounds through
an intramolecular 1,3-dipolar cycloaddition reaction of an
allenyl diazo group that generates a trimethylenemethane
(TMM) diyl followed by an intramolecular [2 + 3] TMM
diyl cycloaddition reaction has been developed. The new
tandem cycloaddition reaction is readily applicable to the
synthesis of complex molecules with high versatility and
efficiency.
he concept of the ideal synthesis has been an important goal
T
of organic synthesis.1 Toward this goal, various aspects of
economy of the synthesis have become the measures of the
efficiency of synthetic routes to complex targets.1b These objec-
tives are also in accord with the principles of green chemistry.2
Multistep reactions in one synthetic operation3 are known as
tandem, domino, and cascade reactions. They satisfy the objec-
tives of ideal synthesis and the principles of green chemistry. The
reactions not only construct complex structures in a single
operation but also eliminate isolation and purification steps of
the intermediates.
accessed through a 1,3-dipolar cycloaddition reaction between a
diazo compound and an allene, and we designed a tandem
cycloaddition reaction strategy for obtaining triquinane struc-
tures from substrates containing olefin, allene, and diazo func-
tional groups (Scheme 2). Herein we report an efficient tandem
cycloaddition reaction strategy for the formation of triquinanes
via TMM diyls.
The tandem cycloaddition reaction strategy could produce
linearly fused as well as angularly fused triquinanes by altering the
substitution pattern on the allene functionality. The diazo group
of I or IV would undergo an intramolecular cycloaddition
reaction with the allene to form II or V, respectively. Tetrahy-
drocyclopentapyrazole II or V would lose N2 to generate TMM
diyl III or VI, which would undergo another [2 + 3] cycloaddi-
tion reaction to produce the triquinane structure.6b
The designed tandem cycloaddition reaction strategy was first
executed with linear substrate 5a (Table 1). When 5a in toluene
solution was heated at 110 °C,12 exceptionally clean conversion
was observed. The desired linearly fused triquinane 6a was
obtained in 83% yield (Table 1, entry 1). Though the reaction
is believed to follow the tandem cycloaddition reaction sequence
shown in Scheme 2, no intermediate was observed. A similar
reaction of allenyl azide was also reported to proceed through the
corresponding triazole intermediate to produce tetrahydropen-
tapyrrole, but the intermediate was not observed. It was calcu-
lated that the loss of N2 from the triazole intermediate is an
exothermic process.13 Indirect evidence for the formation of the
intermediate II was obtained when substrates with different
Cycloaddition reactions have played a role in the development
of tandem reactions. They rapidly increase architectural com-
plexity and frequently occur with control of stereo- and regio-
selectivity. While trimethylenemethane (TMM)-mediated cyclo-
addition reactions have played a major role in cyclopentanoid
synthesis,4 they have not been used in the context of a tandem
cycloaddition reaction. A synthetically viable TMM diyl was first
observed by Koebrich in 1969.5 The identity and properties of
the TMM diyl were thoroughly studied by Berson from the late
1970s through the early 1980s.6 On the basis of his studies, TMM
diyl was successfully applied to the [2 + 3] cycloaddition reaction
by Little.7 The scope of the TMM diyl chemistry was also
extended to the formation of six-, seven-, and eight-membered
rings through various radical pathways.8
We recently reported a tandem reaction strategy for obtaining
triquinanes from alkylidene carbenes via TMM diyls.9 This
tandem reaction strategy expanded the scope of TMM-mediated
[2 + 3] cycloaddition reactions to the synthesis of angularly fused
triquinanes.10 TMM diyl (1) can be generated from methylene-
2,3-diazabicyclo[2.2.1]hept-2-ene (2), bicyclo[3.2.1]hex-1-ene
(3), or tetrahydrocyclopentapyrazole (4) (Scheme 1).11 While
all of these precursors to 1 were extensively studied, tetrahydro-
cyclopentapyrazole 4 was studied less than the other precursors,
presumably because of the difficulty of preparing 4. We envi-
sioned that the tetrahydrocyclopentapyrazole structure could be
Received: August 11, 2011
Published: October 17, 2011
r
2011 American Chemical Society
18050
dx.doi.org/10.1021/ja207591e J. Am. Chem. Soc. 2011, 133, 18050–18053
|

Journal of the American Chemical Society
COMMUNICATION
Scheme 2. Tandem Reaction Sequence of Allenyl Diazo
Compounds To Give Triquinanes
Table 1. Tandem Reaction of Linear Substrates To Give
Linearly Fused Triquinanes
lengths of the tether between the aziridinyl imine and allene
functionalities were subjected to the same reaction conditions
(Scheme 3). When substrate 7a bearing a two-carbon tether was
subjected to the reaction conditions, cyclopropylpyrazole 8a was
obtained without further rearrangement.14 The substrate with a
four-carbon tether, 7b, produced cyclopentapyrazole 8b instead
of anticipated cyclohexapyrazole compound. Selectivity for five-
membered ring formation from the intramolecular cycloaddition
reaction was in accord with the outcomes of other cycloaddition
reactions of allenes.15 In both cases, the first cycloaddition
reaction products with pyrazole rings were isolated. These results
support the existence of intermediate II in the tandem cycloaddi-
tion reaction pathway leading to the triquinane product.
a Isolated yields. b Obtained as 7:1 mixture with the syn-cis isomer.
Scheme 3. Effect of the Tether Length in the DiazoÀAllene
Cycloaddition Reaction
Table 1 shows that the new tandem reaction protocol is quite
versatile and efficient in comparison with previous synthetic meth-
ods using the TMM diyl cycloaddition reaction.7,9 The reaction
tolerates various substitution patterns, as the trisubstituted allenes 5c
and 5e produced the corresponding linearly fused triquinanes 6c and
6e in good yield. The formation of 6e is noteworthy since the
product contains consecutive quaternary carbon centers at the ring
junction, which poses high steric congestion. The relative stereo-
chemistry of the products was confirmed through correlation
spectroscopy (COSY) and nuclear Overhauser effect (NOE)
experiments for all the products and comparison of the spectroscopic
data of 6c with previously reported ones.16
Given the wide applicability and high efficiency of the tandem
reaction strategy for the synthesis of linearly fused triquinanes,
the synthetic strategy was also applied to the synthesis of angu-
larly fused triquinanes. Though the alkylidene carbene-mediated
TMM diyl [2 + 3] cycloaddition showed limited efficiency for the
formation of angularly fused triquinanes in our previous report,10
it appeared that the low efficiency of the tandem reaction was
not due to the strain energy associated with the TMM diyl
18051
dx.doi.org/10.1021/ja207591e |J. Am. Chem. Soc. 2011, 133, 18050–18053

Journal of the American Chemical Society
COMMUNICATION
Table 2. Tandem Reaction of Linear Substrates To Give
Angularly Fused Triquinanes
Scheme 4. Representative Synthetic Pathways Leading to the
Substrates
When the sterically demanding substrate 9d was subjected to
the tandem cycloaddition reaction conditions after formation of
the aziridinyl imine, angularly fused triquinane 10d was obtained
with a significant amount of byproducts (Table 2, entry 5). The
main byproducts appeared to be the products of the unexpected
intermolecular cycloaddition reaction between the TMM diyl
intermediate and styrene, the latter being generated from the
aziridinyl imine during the formation of the diazo group. To
eliminate the side reaction, the aziridinyl imine was replaced by
the sodium salt of tosylhydrazone as the precursor for the diazo
functional group.18 When 9a was subjected to reaction condi-
tions B (Table 2, entry 2), the reaction produced angularly fused
triquinane 10a almost quantitatively. The reaction time was
substantially shorter than for conditions A, which implies that
the rate determining step of the tandem reaction is formation of
the diazo group. When the new procedure was applied to
substrate 9d, the tandem reaction proceeded smoothly to
produce angularly fused triquinane 10d in good yield without
the formation of byproducts (Table 2, entry 6).
a Conditions A: 2-phenylaziridin-1-amine, CH2Cl2, toluene, 110 °C, 12 h.
Conditions B: NH2NHTs/MeOH, NaH/toluene, 110 °C, 4 h. b Isolated
yields. c Xylene, 160 °C, 12 h.
cycloaddition reaction. Thus, it was hoped that the current
tandem cycloaddition route could produce angularly fused
triquinanes efficiently. When aldehyde 9a was subjected to the
tandem cycloaddition reaction sequence after aziridinyl imine
formation, angularly fused triquinane 10a was obtained in 93%
yield (Table 2, entry 1), which is a dramatic improvement over
the yield of the alkylidene carbene-mediated TMM diyl cycload-
dition reaction.10 The diazo intermediate could also be generated
from the corresponding ketone 9b, though the reaction was
slower than that of 9a. A higher temperature was required in
order to form the diazo group with a rate comparable to that for
formation of the diazo functionality from aldehyde imines. This
result expands the substrate scope and flexibility of the process.
The substituent on the allenyl group can be exchanged with the
substituent at the diazo group for the same product. As demon-
strated in the previous report, the cycloaddition reaction can be
stereoselective. The substrate with the substituent on the tether,
9c, produced angularly fused triquinane 10c stereoselectively.17
Substrates for the tandem cycloaddition reaction can be readily
prepared in straightforward manners (Scheme 4). Typically,
substrates for the linear triquinanes were prepared from 11
through cuprate addition to form allene 13 via alkynol 12.
Substrates for the angular triquinanes were prepared from allenyl
intermediate 15 obtained from activated 1,4-butynediol.
In conclusion, we have developed a tandem cycloaddition
route to triquinanes from linear substrates via a cycloaddition
18052
dx.doi.org/10.1021/ja207591e |J. Am. Chem. Soc. 2011, 133, 18050–18053

Journal of the American Chemical Society
COMMUNICATION
reaction of TMM diyls generated from the 1,3-dipoar cycloaddi-
tion reaction of allenyl diazo compounds. The current tandem
reaction shows versatility, efficiency, and wide applicability to
complex natural product synthesis, as the tricyclic compounds
can be obtained from linear substrates with various substitution
patterns.
(18) Kaufman, G. M.; Smith, J. A.; Vander Stouw, G. G.; Shechter, H.
J. Am. Chem. Soc. 1965, 87, 935–937.
’ ASSOCIATED CONTENT
S
Supporting Information. Synthetic schemes for the sub-
b
strates, experimental details, and spectral data (including COSY
and NOE spectra) for the cycloaddition reaction products. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
leehy@kaist.ac.kr
’ ACKNOWLEDGMENT
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(NRF) funded by the Ministry of Education, Science and
Technology (KRF-2008-314-C00198).
’ REFERENCES
(1) (a) Gaich, T.; Baran, P. S. J. Org. Chem. 2010, 75, 4657–4673. (b)
Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev. 2009,
38, 3010–3021. (c) Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind.
1997, 765–769.
(2) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University Press: New York, 2000.
(3) (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(b) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, Germany, 2006. (c) Nicolaou, K. C.;
Edmonds, D. J.; Bulger., P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–
7186.
(4) Yamago, S.; Nakamura, E. Org. React. 2002, 61, 1–217.
(5) Koebrich, G.; Heinemann, H. Chem. Commun. 1969, 493–494.
(6) (a) Berson, J. A. In Diradicals; Borden, W. T., Ed.; Wiley: New
York, 1982; pp 151À194. (b) Lazzara, M. G.; Harrison, J. J.; Rule, M.;
Hilinski, E. F.; Berson, J. A. J. Am. Chem. Soc. 1982, 104, 2233–2243.
(7) (a) Little, R. D. Chem. Rev. 1996, 96, 93–114. (b) Little, R. D.;
Ott, M. M. Stud. Nat. Prod. Chem. 2000, 22, 195–243.
(8) Allan, A. K.; Caroll, G. L.; Little, R. D. Eur. J. Org. Chem.
1998, 1–12.
(9) Lee, H. Y.; Kim, Y. J. Am. Chem. Soc. 2003, 125, 10156–10157.
(10) Lee, H. Y.; Jung, Y.; Yoon, Y.; Kim, B. G. Org. Lett. 2010,
12, 2672–2674.
(11) Cichra, D. A.; Duncan, C. D.; Berson, J. A. J. Am. Chem. Soc.
1980, 102, 6527–6533.
(12) Schultz, A. G.; Puig, S. J. Org. Chem. 1985, 50, 915–916.
(13) Feldman, K. S.; Iyer, M. R.; Lopez, C. S.; Faza, O. N. J. Org.
Chem. 2008, 73, 5090–5099.
(14) Lahti, P. M.; Berson, J. A. J. Am. Chem. Soc. 1981, 103,
7011–7012.
(15) (a) Lee, H. Y.; Sohn, J. H.; Kim, H. Y. Tetrahedron Lett. 2001,
42, 1695–1698. (b) Zhang, X.; Ko, R. Y. Y.; Li, S.; Miao, R.; Chiu, P.
Synlett 2006, 1197–1200.
(16) Lee, H. Y.; Kim, W. Y.; Lee, S. Tetrahedron Lett. 2007, 48,
1407–1410.
(17) Yoon, Y. K.; Kang, T.; Lee, H. Y. Chem.—Asian J. 2011, 6,
646–651.
18053
dx.doi.org/10.1021/ja207591e |J. Am. Chem. Soc. 2011, 133, 18050–18053