New metal-free one-pot synthesis of substituted allenes from enones

Article abstract of DOI:10.1021/ol802445p

(Chemical Equation Presented) A new metal-free, one-pot synthesis of substituted allenes from enones was discovered for the first time, in which a tertiary amine as a base was found to be an effective promoter in such novel transformations. The present synthetic protocol proceeded readily with high compatibility of sensitive functional groups, and it provides a new efficient way to access a series of synthetically important allenes without the use of metallic reagents or catalysts.

Full text of DOI:10.1021/ol802445p

ORGANIC
LETTERS
2008
Vol. 10, No. 24
5585-5588
New Metal-Free One-Pot Synthesis of
Substituted Allenes from Enones
Meng Tang, Chun-An Fan, Fu-Min Zhang, Yong-Qiang Tu,* Wen-Xue Zhang, and
Ai-Xia Wang
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry,
Lanzhou UniVersity, Lanzhou 730000, P. R. China
tuyq@lzu.edu.cn
Received October 23, 2008
ABSTRACT
A new metal-free, one-pot synthesis of substituted allenes from enones was discovered for the first time, in which a tertiary amine as a base
was found to be an effective promoter in such novel transformations. The present synthetic protocol proceeded readily with high compatibility
of sensitive functional groups, and it provides a new efficient way to access a series of synthetically important allenes without the use of
metallic reagents or catalysts.
Allenes are important molecules in modern organic chem-
istry, and their extraordinary chemical structure is found in
many bioactive natural products and pharmaceuticals.1 The
interesting reactivities of allenic structures have been widely
explored for selective functional group transformations, and
they have proven useful as versatile building blocks in
organic synthesis.2-4 Since the prediction of allenes by Van’t
Hoff in 1875,5a many efforts have been made to develop
various synthetic methods for the synthesis of this kind of
structurally unique molecule. The first documented synthesis
was disclosed by Burton and von Pechmann in 1887.5b
Throughout the past century, a variety of compounds
including functionalized alkynes, alkenes, and carbonyls have
been exploited in the synthesis of allenes.6 Most of the useful
synthetic methods have depended upon the use of the main
(1) Hoffman-Ro¨der, A.; Krause, N. Angew. Chem., Int. Ed. 2004, 43,
1196.
(2) (a) Allenes in Organic Synthesis; Schuster, H. F., Coppola, G. M.,
Ed.; John Wiley & Sons: New York, 1984. (b) The Chemistry of Ketenes,
Allenes, and Related Compounds Part 1; Patai, S., Ed.; John Wiley & Sons:
New York, 1980. (c) Modern Allene Chemistry; Krause, N., Hashmi,
A. S. K., Ed.; Wiley-VCH: Weinheim, 2004. (d) Cumulenes and Allenes
In Science of Synthesis: Houben-Weyl Methods of Molecular Transforma-
tions; Krause, N., Ed.; Georg Thieme Verlag: Stuttgart, Germany, 2008;
Vol. 44.
(4) (a) Ma, S. Pd-Catalyzed Two- or Three-Component Cyclization of
Functionalized Allenes. In Topics in Organometallic Chemistry; Tsuji, J.,
Ed.; Springer-Verlag: Heidelberg, 2005; pp 183-210. (b) Ma, S. Ald-
richimica Acta 2007, 40, 91.
(5) (a) Van’t Hoff, J. H. La Chimie dans l’Espace; Bazendijk, P. M.
(publisher): Rotterdam, 1875. (b) Burton, B. S.; Pechman, H. v. Ber. Dtsch.
Chem. Ges. 1887, 20, 145.
(3) For reviews, see: (a) Ma, S. Chem. ReV. 2005, 105, 2829. (b)
Brandsma, L.; Nedolya, N. A. Synthesis 2004, 735. (c) Sydnes, L. Chem.
ReV. 2003, 103, 1133. (d) Ma, S. Acc. Chem. Res. 2003, 36, 701. (e) Tius,
M. A. Acc. Chem. Res. 2003, 36, 284. (f) Wei, L.-L.; Xiong, H.; Hsung,
R. P. Acc. Chem. Res. 2003, 36, 773. (g) Bates, R.; Satcharoen, V. Chem.
Soc. ReV. 2002, 31, 12. (h) Ma, S. Carbopalladation of Allenes. In Handbook
of Organopalladium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.;
John Wiley & Sons: New York, 2002; pp 1491-1521. (i) Lu, X.; Zhang,
C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (j) Zimmer, R.; Dinesh, C. U.;
Nandanan, E.; Khan, F. A. Chem. ReV. 2000, 100, 3067. (k) Hashmi,
A. S. K. Angew. Chem., Int. Ed. 2000, 39, 3590. (l) Marshall, J. Chem.
ReV. 2000, 100, 3163. (m) Wang, K. K. Chem. ReV. 1996, 96, 207.
(6) For reviews, see: (a) Bruneau, C., Renaud, J.-L. Allenes and
Cumulenes. In ComprehensiVe Organic Functional Group Transformations
II; Katritzky, A. R., Taylor, R. J. K., Ed.; Elsevier: 2005; Vol. 1, pp
1019-1081. (b) Bruneau, C.; Dixneuf, P. H. Allenes and Cumulenes. In
ComprehensiVe Organic Functional Group Transformations I; Katritzky,
A. R., Meth-Cohn, O., Rees, C. W., Eds.; Elsevier: 1995; Vol. 1, pp
953-995. (c) Brummond, K. M.; DeForrest, J. E. Synthesis 2007, 795. (d)
Miesch, M. Synthesis 2004, 746. (e) Krause, N.; Hoffmann-Ro¨der, A.
Tetrahedron 2004, 60, 11671. (f) Hoffmann-Ro¨der, A.; Krause, N. Angew.
Chem., Int. Ed. 2002, 41, 2933. (g) Rossi, R.; Diversi, P. Synthesis 1973,
25. (h) Taylor, D. R. Chem. ReV. 1967, 67, 317.
10.1021/ol802445p CCC: $40.75
Published on Web 11/25/2008
2008 American Chemical Society

group metal reagents and/or transition metal catalysts.3c,6e,f
Recently, however, we discovered a new, metal-free, one-
pot synthesis of multisubstituted allenes that commence from
enones7 (Scheme 1). To the best of our knowledge, the
procedure used was as follows: a solution of 1a (1.0 equiv)
and TsNHNH2 (1.1 equiv) in analytically pure EtOH was
stirred at room temperature until 1a disappeared. Molecular
sieves (4 Å) and a base (2.0 equiv) were subsequently added,
and the mixture was heated at reflux for the indicated time.
During the initial optimization of this novel allenic synthesis
(Table 1), it was found that the type of base, as well as the
Scheme 1. One-Pot Synthesis of Allenes from Enones
Table 1. Base-Promoted Allenic Synthesis from Enone 1aa
present method constitutes the first example of an allenic
synthesis that exploits in situ generated R,ꢀ-unsaturated
tosylhydrazones8-11 under mild Lewis basic conditions.10
Moreover, this metal-free synthetic protocol proceeds readily
with regioselective double bond migration and delivers
various trisubstituted and 1,1-disubstituted allenes under
conditions that are compatible with many functional groups.
Herein we will present our preliminary results on this
chemistry.
entry
base
NEt3
time (h)b
yield (%)c
1
20
20
45
12
70
20
45
8
83
56
52
56
26
41
37
0e
2d
3
NEt3
iPr2NEt
DABCO
pyridine
NHEt2
NHiPr2
NaOMe
NaOH
4
5
6
7
8
9
10
12
20
0e
Our initial study was performed with enone 1a as a model
Na2CO3
tracee
substrate in the presence of TsNHNH2.12 The typical
a Typical procedure: a mixture of 1a (100.0 mg, 0.5 mmol) and
TsNHNH2 (102.0 mg, 5.5 × 10-1 mmol) in EtOH (2 mL) was stirred at
room temperature until 1a disappeared, and then EtOH (2 mL), 4 Å
molecular sieves (0.5 g), and base (1.0 mmol) were added sequentially.
The resulting mixture was heated to reflux for the indicated time. b Refluxing
time. c Isolated yield. d Without use of 4 Å MS. e For entries 8-10, 4-ethyl-
5-(3-phenylpropyl)-pyrazole was isolated in 90, 92, and 67% yield,
respectively.9,13
(7) Enolates prepared from enones through 1,4-addition can be converted
into allenes. For reference, see: Brummond, K. M.; Dingess, E. A.; Kent,
J. L. J. Org. Chem. 1996, 61, 6096.
(8) For the reductive rearrangement of R,ꢀ-unsaturated tosylhydrazones
to alkene through 1,3-transposition, see: (a) Qi, W.; Mclntosh, M. C. Org.
Lett. 2008, 10, 357. (b) Silvestri, M. G.; Bednarski, P. J.; Kho, E. J. Org.
Chem. 1985, 50, 2798. (c) Kabalka, G. W.; Summer, S. T. J. Org. Chem.
1981, 46, 1217. (d) Hutchins, R. O.; Natale, N. R. J. Org. Chem. 1978, 43,
2299. (e) Kabalka, G. W.; Yang, D. T. C.; Baker, J. D., Jr. J. Org. Chem.
1976, 41, 574. (f) Hutchins, R. O.; Kacher, M.; Rua, L. J. Org. Chem.
1975, 40, 923. (g) Hutchins, R. O.; Milewski, C. A.; Maryanoff, B. E. J. Am.
Chem. Soc. 1973, 95, 3662. For a review, see: (h) Ripoll, J.-L.; Valle´e, Y.
use of 4 Å molecular sieves, played a key role in the current
transformation. Of the bases screened, NEt3 proved to be
the most effective for this reaction (83% yield, entry 1). Of
special significance was the fact that a lower yield of product
(56%) was obtained in the absence of 4 Å molecular sieves
(entry 2). Among other tertiary amines examined, Hu¨nig’s
base (entry 3) and DABCO (entry 4) gave moderate yields
of the desired allene 3a, while only a very low yield (26%)
was obtained using pyridine as a base (entry 5). Compared
with acyclic tertiary amines (entries 1-3), the use of cyclic
DABCO reduced the reaction time to 12 h, but it always led
to a much lower yield of product (56%). Further investiga-
tions with other bases (entries 6 and 7) revealed that
secondary organic amines were far less effective, the
expected product 3a being delivered in around 40% yield.
By the way of contrast, employing inorganic Brønsted bases
(e.g., NaOH, NaOMe, and Na2CO3) led to isolation of a
totally different product: 4-ethyl-5-(3-phenylpropyl)-pyrazole
(entries 8-10),9,13 which was consistent with previous
reports on the thermal decomposition of R,ꢀ-unsaturated
tosylhydrazone sodium salts.9
Synthesis 1993, 659
.
(9) R,ꢀ-Unsaturated tosylhydrazones have been used in the synthesis
of pyrazoles for a long time. For the related references, see: (a) Aggarwal,
V. K.; Alonso, E.; Bae, I.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Patel,
M.; Porcelloni, M.; Richardson, J.; Stenson, R. A.; Studley, J. R.; Vasse,
J.-L.; Winn, C. L. J. Am. Chem. Soc. 2003, 125, 10926. (b) Doyle, M. P.;
Yan, M. J. Org. Chem. 2002, 67, 602. (c) Sharp, J. T.; Findlay, R. H.;
Thorogood, P. B. J. Chem. Soc., Perkin Trans. 1 1975, 102. (d) Closs,
G. L.; Bo¨ll, W. A. Angew. Chem., Int. Ed. Engl. 1963, 2, 399. (e) Closs,
G. L.; Closs, L. E.; Bo¨ll, W. A. J. Am. Chem. Soc. 1963, 85, 3796
.
(10) Johnson et al. have reported the formation of allene and other
products from R,ꢀ-unsaturated tosylhydrazone via radical carbene intermedi-
ate. For references, see: (a) Klett, M. W.; Johnson, R. P. J. Am. Chem. Soc.
1985, 107, 3963. (b) Stierman, T. J.; Johnson, R. P. J. Am. Chem. Soc.
1985, 107, 3971. (c) Price, J. D.; Johnson, R. P. J. Am. Chem. Soc. 1985,
107, 2187. (d) Stierman, T. J.; Johnson, R. P. J. Am. Chem. Soc. 1983,
105, 2492
.
(11) For other representative examples on the synthetic application of
R,ꢀ-unsaturated tosylhydrazones, see: (a) Baptistella, L. H. B.; Aleixo, A. M.
Synth. Commun. 2002, 32, 2937. (b) Sato, T.; Homma, I. Bull. Chem. Soc.
Jpn. 1971, 44, 1885. (c) Duerr, H. Chem. Ber. 1970, 103, 369. (d) Dauben,
W. G.; Lorber, M. E.; Vitmeyer, N. D.; Shapiro, R. H.; Duncan, J. H.;
Tomer, K. J. Am. Chem. Soc. 1968, 90, 4762
.
(12) Substituted benzenesulfonyl hydrazine has been used in allene
synthesis from propargylic alcohols and their derivatives. For references,
see: (a) Movassaghi, M.; Ahmad, O. K. J. Org. Chem. 2007, 72, 1838. (b)
Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492. (c) Danheiser,
R. L.; Carini, D. J.; Fink, D. M.; Basak, A. Tetrahedron 1983, 39, 935. (d)
Kabalka, G. W.; Newton, R. J., Jr.; Chandler, J. H.; Yang, D. T. C. J. Chem.
Soc., Chem. Commun. 1978, 726.
Intrigued by the above data, the generality and scope of
this reaction were investigated under the optimized condi-
tions. As shown in Table 2, various unsaturated ketones of
(13) For details on its analytical data, see page 13 in Supporting
Information.
5586
Org. Lett., Vol. 10, No. 24, 2008

groups in this region. Hydroxyls (entries 2 and 3), a bulky
enone (entry 4), a conjugated diene (entry 5), silyl groups
(entries 7, 11, and 13), and the azide group (entry 10) all
remain unaffected. The reaction of 1d (entry 4) is especially
noteworthy since this reaction shows an interesting regiose-
lective hydrazonation of one of two enone moieties, in which
the less bulky ketone reacted preferentially with 1.1 equiv
of TsNHNH2. Moreover, from the results in Table 2, it can
be seen that the substituents R1 and R2 in 1 have little
influence on this reaction, demonstrating its generality.
However, the substituent R3 could apparently affect the
transformation. In comparison with 1h of entry 8 (R3 ) H),
the reaction of 1l (R3 ) Me, entry 12) proceeded quite
slowly, with around 60% conversion after 4 days. With 1m
as substrate (entry 13), a similar result was obtained. It
demonstrates that the bulk of substitute R3 has unfavorable
influence on this transformation. Attempts to access 1,3-
disubstituted and tetrasubstituted allenes by using enone 1
(R1 ) phenylpropyl, R2 ) H, R3 ) H) and 2-benzyl-4-
methyl-1-penten-3-one did not give positive results at this
stage, possibly due to the undesired competitive 1,4-addition
of TsNHNH2 to enones.14
Table 2. Synthesis of Allenes from Various Enonesa
To address this unusual NEt3-promoted allenic synthesis,
a plausible reaction pathway has been proposed in Scheme
2 although the detailed mechanism remains unclear at this
Scheme 2
.
Proposed Pathway in NEt3-Promoted Allenic
Synthesis
stage. With in situ formation of the hydrazone 2 from 1 and
TsNHNH2,15 the nucleophilic addition of NEt3 as an organic
Lewis base onto R,ꢀ-unsaturated tosylhydrazone 2 and loss
of the p-toluenesulfinic acid anion is thought to yield the
diazene cationic intermediate 4.16 Then, a base-induced 1,4-
elimination took place, resulting in the formation of the
diazenyl diene intermediate 5. Under reflux conditions, an
intramolecular 1,5-hydrogen reductive rearrangement, with
the double bond migration from C1,2 to C2,3, gives the
desired allene 3 by the release of N2.8 From this proposed
mechanism, various experimental observations can be un-
a For experimental procedure, see Supporting Information. b Refluxing
d
time. c Isolated yield. About 1:1 dr measured by 13C NMR. e TBDPS )
t-butyldiphenylsilyl. f Z:E ) > 99:<1. g 59% yield was obtained on the
basis of the recovered hydrazone. h Z:E ) 56:44. i 54% yield was obtained
on the basis of the recovered hydrazone.
(14) Magnus, P.; Roe, M. B. Tetrahedron Lett. 1995, 36, 5479.
(15) When the isolated hydrazone 2a in Table 1 was separately subjected
to the reaction system (4 Å molecular sieves, 2.0 equiv of NEt3, EtOH,
reflux), the desired allene 3a could also be obtained in around 80% yield.
This fact clearly demonstrates that hydrazone 2 is involved in the current
allenic synthesis.
general structure 1 were subjected to this reaction, and a
series of trisubstituted and 1,1-disubstituted allenes 3 were
obtained in generally good yield. Remarkably, our reaction
conditions show good compatibility with different functional
Org. Lett., Vol. 10, No. 24, 2008
5587

derstood. For example, when using inorganic Brønsted bases
(entries 8-10, in Table 1), the deprotonation of the NHTs
moiety in 2 of Scheme 2 preferentially took place, giving
an R,ꢀ-unsaturated tosylhydrazone sodium salt, which quickly
underwent elimination-cyclization to furnish the pyrazole.9
This reactivity was clearly differentiated from the nucleo-
philicity observed using organic amines as Lewis bases
(entries 1-7, in Table 1) toward the unsaturated tosylhy-
drazones 2 in Scheme 2. Additionally, the unfavorable steric
hindrance during the nucleophilic addition of NEt3 to 2 in
Scheme 2 might be one of the reasons for the low conver-
sions and yields, when R3 was methyl, not hydrogen (entries
12 and 13, Table 2).
allenes from enones has been discovered, and a series of
allenes with sensitive functional groups have been synthe-
sized in good yield. Further investigations into the detailed
mechanism and toward developing an asymmetric variation
are currently underway in our laboratory.
Acknowledgment. We thank the NSFC (Nos. 20621091,
20672048, and 20732002) and the Chang Jiang Scholars
Program for financial support.
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, a new metal-free, one-pot protocol for the
synthesis of various trisubstituted and 1,1-disubstituted
(16) Ito, K.; Maruyama, J. Chem. Pharm. Bull. 1983, 31, 3014.
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