Tertiary amine-triggered cascade SN2/cycloaddition: An efficient construction of complex azaheterocycles under mild conditions

Article abstract of DOI:10.1021/ol302329b

In this paper, an amine-triggered cascade S_N2/cycloaddtion sequence between 2-(acetoxymethyl)buta-2,3-dienoate 1 and various π-system functionalized tosylamides 3 has been reported, which provides a facile method for stereoselective construction of structurally diverse azaheterocycles.

Full text of DOI:10.1021/ol302329b

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Tertiary Amine-Triggered Cascade
SN2/Cycloaddition: An Efficient
Construction of Complex
Azaheterocycles under Mild Conditions
Jian Hu, Bing Tian, Xinyan Wu, and Xiaofeng Tong*
Key Laboratory for Advanced Materials and Institute of Fine Chemicals,
East China University of Science and Technology, Meilong Road No. 130,
Shanghai, 200237, P.R. China
tongxf@ecust.edu.cn
Received August 20, 2012
ABSTRACT
In this paper, an amine-triggered cascade SN2/cycloaddtion sequence between 2-(acetoxymethyl)buta-2,3-dienoate 1 and various π-system
functionalized tosylamides 3 has been reported, which provides a facile method for stereoselective construction of structurally diverse
azaheterocycles.
The development of new reactions that increase mole-
cular complexity in an economical1 and green2 fashion is a
paramount goal of modern chemical synthesis. Cascade
reactions represent one of the most efficient techniques for
this goal, which combine multiple transformations in one
pot, thereby eliminating the need for separate workup and
isolation steps.3 In the majority of cases, the functionality
produced from the first step renders the subsequent step
possible, which can allow for a rapid increase in molecular
complexity. Herein, we report a new cascade reaction
under mild conditions for facile construction of complex
azaheterocycles from readily available starting materials 1
and 3 (Scheme 1).
In our laboratory, we are interested in exploring alleno-
ate 1, which can be readily converted into intermediate A
with the interaction of a phosphine catalyst (Scheme 1).4
We have demonstrated that A is a potential biselectrophile
for (4 þ n) annulations with various 1,n-bisnucleophiles.
Surprisingly, a formal SN2-substituted product 2 was
isolated in 76% yield when N-butyl-tosylamide was tested
(Scheme 1). This result led us topropose thatthe remaining
allenic moiety in 2 might offer an additional chance to
(1) (a) Wender, P. A.; Miller, B. L. Nature 2009, 460, 197. (b) Wender,
P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008,
41, 40. (c) Trost, B. M. Science 1991, 254, 1471. (d) Trost, B. M. Angew.
Chem., Int. Ed. 1995, 34, 259.
(2) (a) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and
Practice; Oxford University: New York, 1998. (b) Hjeresen, D. L.; Schutt, D.
L; Boese, J. M. J. Chem. Educ. 2000, 77, 1543. (c) Ryan, M. A.;
Tinnesand, M., Eds. Introduction to Green Chemistry; American Chemi-
cal Society: Washington, DC, 2002.
(3) For selected reviews, see: (a) Tietze, L. F.; Brasche, G.; Gericke,
K. M. Domino Reactions in Organic Chemistry; Wiley-VCH: Weinheim,
2006. (b) Ho, T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(c) Tietze, L. F. Chem. Rev. 1996, 96, 115. (d) Nicolaou, K. C.; Chen, J. S.
Chem. Soc. Rev. 2009, 38, 2993.
(4) (a) Zhang, Q.; Yang, L.; Tong, X. J. Am. Chem. Soc. 2010, 132,
2550. (b) Li, C.; Zhang, Q.; Tong, X. Chem. Commun. 2010, 46, 7828.
(c) Li, K.; Hu, J.; Tong, X. Chem. Commun. 2012, 48, 2900.
r
10.1021/ol302329b
XXXX American Chemical Society

only the terminal CꢀC double bond of allene participated in
[2 þ 2] cycloaddition (eq 1).7 Further optimization of the
conditions disclosed that DABCO is a better catalyst for this
cascade reaction, enabling 4a to be obtained in 99% yield
under otherwise identical conditions (eq 1).8 It is worth
noting that the corresponding SN2-substituted compound
was not observed at all, strongly implying that the subse-
quent [2 þ 2] cycloaddition might be a fast step.
Scheme 1. Design Plan for Cascade Reaction
develop a cascade reaction when tosylamide 3, bearing a
proper functionalized group (FG), was instead employed
(Scheme 1). Indeed, the chemistry of allenes has been
recognized as an integral part of modern synthetic
methods.5 The higher reactivity of this type of cumulated
system, compared to that of alkenes and alkynes, offers
unique opportunities for the invention of new reactions. In
thiscontext, thermallyand photochemicallyinducedallene
cycloadditions have been well developed for the prepara-
tion of natural and non-natural products of interest.6 With
these considerations in mind, we thus envisioned that
π-system functionalized tosylamide 3might be able to initiate
a cascade reaction: catalytic SN2-type substitution follo-
wed by intramolecular cycloaddition of an allenoate and a
π-system (Scheme 1).
This amine-triggered SN2/[2 þ 2] cycloaddition sequen-
tial reaction can be extended to alkyne-functionalized
substrate 3b. Indeed, the DABCO-catalyzed reaction of 1
and 3b occurs smoothly to afford bicyclo[4.2.0]octa-1,6-
diene 4b in 58% yield (eq 2).7
The success of [2 þ 2] cycloaddition inspired us to
explore the possibility of a DielsꢀAlder reaction with the
use of diene-functionalized tosylamide as the substrate. Some-
what surprisingly, [2 þ 2] cycloaddition products 4c and 4d
were still isolated in yields of 69% and 99%, respectively,
when compounds 3c and 3d were employed (eq 3).
Scheme 2. Synthesis of Compounds 5dꢀg via a Two-Step
Procedure
We initially employed tosylamide 3a to verify the pos-
tulation outlined in Scheme 1. The reaction of 1 and 3a,
with the use of PPh3 (20 mol %) asthe catalyst and Cs2CO3
(1.3 equiv) as the base in toluene solvent at 50 °C, delivered
the desired bicyclo[4.2.0]oct-1-ene 4a in 76% yield, in which
(5) For books, see: (a) Schuster, H. F.; Coppola, G. M. Allenes in
Organic Synthesis; Wiley: New York, 1984. (b) Landor, S. R. The Chem-
istry of the Allenes; Academic: London, 1982. (c) Krause, N.; Hashmi,
A. S. K. Modern Allene Chemistry; Wiley-VCH: Weinheim, 2004. For
selected reviews, see: (d) Ma, S. Chem. Rev. 2005, 105, 2829. (e) Bandini,
M. Chem. Soc. Rev. 2011, 40, 1358. (f) Aubert, C.; Fensterbank, L.;
Garcia, P.; Malacria, M.; Simonneau, A. Chem. Rev. 2011, 111, 1954.
(6) For selected reviews, see: (a) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Chem. Soc. Rev. 2010, 39, 783. (b) Dolbier, W. R., Jr.
Acc. Chem. Res. 1991, 24, 63. (c) Back, T. G.; Clary, K. N.; Gao, D.
Chem. Rev. 2010, 110, 4498. (d) Yu, S.; Ma, S. Angew. Chem., Int. Ed.
2012, 51, 3074.
(7) For representive intramolecular [2 þ 2] cycloaddtion of allene
under thermal conditions, see: (a) Padwa, A.; Meske, M.; Murphree,
S. S.; Watterson, S. H.; Ni, Z. J. Am. Chem. Soc. 1995, 117, 7071. (b)
Hansen, T. V.; Skattebøl, L.; Stenstrøm, Y. Tetrahedron 2003, 59, 3461.
(c) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Redondo, M. C.; Torres,
M. R. Chem.;Eur. J. 2006, 12, 1539. (d) Ohno, H.; Mizutani, T.;
Kadoh, Y.; Aso, A.; Miyamura, K.; Fujii, N.; Tanaka, T. J. Org. Chem.
2007, 72, 4378. (e) Mukai, C.; Hara, Y.; Miyashita, Y.; Inagaki, F.
J. Org. Chem. 2007, 72, 4454. (f) Jiang, X.; Ma, S. Tetrahedron 2007, 63,
7589. (g) Oh, C. H.; Gupta, A. K.; Park, D. I.; Kim, N. Chem. Commun.
2005, 5670.
Interestingly, 4d was found to undergo a rearrangement
reaction in refluxing toluene, offering 5d in 58% isolated
yield as a single isomer (Scheme 2). It should be noted that
the overall yield of 5d would dramatically drop to 21%
when the rearrangement step was directly conducted by
heating just after the completion of SN2/[2 þ 2] cycloaddi-
tion. Probably, the presence of DABCO and salts might
impose some negative effects on the subsequent rearrange-
ment. This two-step procedure is also applicable to sub-
strates 3eꢀf, offering the rearrangement products 5eꢀf in
moderate overall yields (Scheme 2). However, 4c was
(8) Without the catalyst, the reaction was sluggish and the yield of 4a
was 7% even when the reaction time was elongated to 48 h.
B
Org. Lett., Vol. XX, No. XX, XXXX

Figure 1. X-ray crystal structures of 5e. Thermal ellipsoids are
set at 50% probability.
Figure 2. X-ray crystal structure of 7c (left) and transition state
for [4 þ 2] cycloaddition (right). Thermal ellipsoids are set at
50% probability.
recovered in 91% yield even upon exposure to refluxing
toluene for 24 h.
The relative stereochemistry of 5e was unambiguously
determined by single crystal X-ray diffraction analysis
(Figure 1). The stereochemistry of other compounds was
Scheme 4. Scope of Cascade SN2/[4 þ 2] Cycloadditiona
Scheme 3. Proposal for the Diradical-Involved Rearrangement
1
tentatively assigned by comparing the H NMR spectra
with those of 5e.
The chemical outcome of this rearrangement can be
explained by the proposed mechanism shown in Scheme 3
(with 4d as the substrate). Compound 4d might be able to
undergo thermally induced selective homocleavage of the
a-bond of cyclobutane to produce diradical intermediate B
which is believed to coexist with its resonant C.9 For inter-
mediate C, the phenyl group and cyclohexane moiety should
be in opposite directions in order to minimize their steric
hindrances. As a result, product 5d with a trans-configuration
would be formed after recombination of the two radicals.
While the anticipated DielsꢀAlder reaction was not
observed in the cases of diene-functionalized tosylamides
3cꢀg, we next wanted to extend the chemistry to the
a Reaction conditions: 1 (0.24 mmol), 6(0.2mmol), DABCO(20mol%),
Cs2CO3 (1.3 equiv), toluene (2.0 mL), 3 h, under Ar. All yields reported are
those of isolated products.
furan-functionalized analogue considering that furan has
been proven to be an excellent diene in DielsꢀAlder
reactions.10 Fortunately, tosylamide 6a was found to react
well with 1 under the optimized conditions, offering oxa-
tricycle 7a in almost quantitative yield (Scheme 4, entry 1).
In contrast to [2 þ 2] cycloaddition, the internal CꢀC
double bond of allene participated in the [4 þ 2] cycloaddi-
tion process selectively. Introduction of a methyl group
into the 5-position of furan had no negative effect on the
(9) (a) Jung, M. E.; Nishimura, N.; Novack, A. R. J. Am. Chem. Soc.
2005, 127, 11206. (b) Jung, M. E.; Nishimura, N. J. Am. Chem. Soc.
1999, 121, 3529. (c) Dolbier, W. R., Jr.; Mancini, G. J. Tetrahedron Lett.
1975, 16, 2141. (d) Dolbier, W. R., Jr.; Piedrahita, C. A.; Al-Sader, B. H.
Tetrahedron Lett. 1979, 20, 2957. (e) Jung, M. E.; Murakami, M. Org.
Lett. 2007, 9, 461.
(10) For selected reviews, see: (a) Schindler, C. S.; Carreira, E. M.
Chem. Soc. Rev. 2009, 38, 3222. (b) Takao, K.-i.; Munakata, R.;
Tadano, K.-i. Chem. Rev. 2005, 105, 4779. (c) Brieger, G.; Bennett,
J. N. Chem. Rev. 1980, 80, 63.
Org. Lett., Vol. XX, No. XX, XXXX
C

reaction, and the corresponding product 7b was obtained in
95% yield (Scheme 4, entry 2). In this case, three quaternary
stereocenters were successfully established. Substrate 6c,
with a tethered phenyl group, gave 7c in 96% yield with a
6:1 diastereoselectivity (Scheme 4, entry 3). However, redu-
cing the reaction temperature to 25 °C significantly im-
proved the diastereoselectivity, rendering 7c as a single
isomer. The [4 þ 2] cycloaddition could smoothly occur at
a lower temperature likely due to the ThorpeꢀIngold
effect11 imposed by the tethered phenyl group. As a result,
7c with 87% ee was obtained in 98% yield when 6c with
85% ee was reacted at 25 °C. Similarly, the reaction of the
substrate with an alkyl group at tether, such as 6d, 6e, and6f,
afforded the corresponding products as a single isomer in
high yields (Scheme 4, entries 4ꢀ6). The structure of 7c was
unambiguously established by X-ray analysis, which clearly
disclosed that the subsequent DielsꢀAlder reaction pro-
ceeded in an endo-fashion (Figure 2).12 The reaction of
substrate 6g with an extended carbon tether was found to
be worse, offering 7g only in 31% yield (Scheme 4, entry 7).
example, the endocyclic olefin of 7a can be selectively
epoxidated using common m-CPBA epoxidation condi-
tions while the exo-one is untouched, providing epoxide
product 8 in 70% isolated yield (eq 5).13
In summary, we have developed an efficient SN2/
cycloaddtion cascade reaction of allenoate 1 with various
π-system functionalized tosylamides in the presence of a
catalytic amount of DABCO, which provides a facile
access to important classes of azaheterocycles. The reac-
tion features readily available starting materials and mild
reaction conditions. More importantly, this cascade reac-
tion increases molecular complexity by forming three
σ-bonds and up to three rings, as well as quaternary
centers. Additional investigations of the synthetic trans-
formation are currently underway in our laboratory.
Acknowledgment. The financial support from NSFC
(No. 21002025), the Fundamental Research Funds for
the Central Universities, Shanghai Rising-Star Program
(11QA1401700), and Specialized Research Fund for the
Doctoral Program of Higher Education (20100074120014)
is highly appreciated.
Interestingly, anthracene-functionalized tosylamide 6h
also proceeded under these conditions, producing com-
pound 7h in 97% yield (eq 4).
The products of the cascade reaction possess olefins,
which might be available for further transformations. For
Supporting Information Available. Experimental pro-
cedures and copies of NMR spectra for all new products
and X-ray crystallographic data for 5e and 7c (CIF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) For reviews, see: (a) Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105,
1735. (b) Sammes, P. G.; Weller, D. J. Synthesis 1995, 1205. (c) Galli, C.;
Mandolini, L. Eur. J. Org. Chem. 2000, 3117. (d) Bunz, U. H. F. Top.
Curr. Chem. 1999, 201, 131.
(12) (a) Ismail, Z. M.; Hoffmann, H. M. R. J. Org. Chem. 1981, 46,
3549. (b) Lohse, A. G.; Hsung, R. P. Org. Lett. 2009, 11, 3430.
(c) Henderson, J. R.; Chesterman, J. P.; Parvez, M.; Keay, B. A. J.
Org. Chem. 2010, 75, 988 and references therein.
(13) The bridged Ha is a singlet, indicating that the corresponding
JH ‑H value is really small. Thus, the relative stereochemistry between Ha and
a
b
Hb could be assigned to be syn.
The authors declare no competing financial interest.
D
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