A facile preparation of exo-cyclic conjugated dienes fused to lactams or lactones via intramolecular coupling of acetylenes and their behavior in Diels-Alder reactions.

Article abstract of DOI:10.1021/ol0065221

[reaction: see text] Treatment of bis-acetylenic amides or esters 3 with (eta(2)-propene)Ti(O-i-Pr)(2) generates functionalized titanacyclopentadienes which, upon hydrolytic workup, give exo, exo-cyclic conjugated dienes 4 in good yields. Some regio- and stereochemical aspects of their Diels-Alder reaction with dienophiles are also disclosed.

Full text of DOI:10.1021/ol0065221

ORGANIC
LETTERS
2000
Vol. 2, No. 22
3481-3484
A Facile Preparation of exo-Cyclic
Conjugated Dienes Fused to Lactams or
Lactones via Intramolecular Coupling of
Acetylenes and Their Behavior in
Diels−Alder Reactions
Hirokazu Urabe, Ryota Nakajima, and Fumie Sato*
Department of Biomolecular Engineering, Graduate School of Bioscience and
Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku,
Yokohama, Kanagawa 226-8501, Japan
fsato@bio.titech.ac.jp
Received August 30, 2000
ABSTRACT
Treatment of bis-acetylenic amides or esters 3 with (η2-propene)Ti(O-i-Pr)2 generates functionalized titanacyclopentadienes which, upon hydrolytic
workup, give exo,exo-cyclic conjugated dienes 4 in good yields. Some regio- and stereochemical aspects of their Diels−Alder reaction with
dienophiles are also disclosed.
exo-Cyclic conjugated dienes 2 shown in eq 1 are useful
intermediates in organic synthesis. Particularly, the charac-
teristic structure of a diene fixed in a cisoid conformation is
prone to undergo Diels-Alder and related reactions to enable
convenient preparation of polycyclic compounds.1 A recent
and straightforward method to prepare dienes of type 2 is
the transition metal-mediated cyclization of diynes 1 as
formulated in eq 1.2-4 Considering the synthetic flexibility,
(1) (a) Desimoni, G.; Tacconi, G.; Barco, A.; Pollini, G. P. Natural
Products Synthesis through Pericyclic Reactions; American Chemical
Society: Washington, D.C., 1983. (b) Fringuelli, F.; Taticchi, A. Dienes in
the Diels-Alder Reaction; Wiley: New York, 1990. (c) Carruthers, W.
Cycloaddition Reactions in Organic Synthesis; Pergamon Press: Oxford,
1990. (d) Oppolzer, W. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 315-
512. (e) Weinreb, S. M. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 401-
449. (f) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, pp 513-550. (g)
Waldmann, H. Synthesis 1994, 535-551.
(2) For review on group 4 metal-mediated diyne cyclization, see:
Buchwald, S. L.; Nielsen, R. B. Chem. ReV. 1988, 88, 1047-1058. Negishi,
E. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 5, pp 1163-1184. Broene, R. D.;
Buchwald, S. L. Science 1993, 261, 1696-1701. Negishi, E.; Takahashi,
T. Acc. Chem. Res. 1994, 27, 124-130. Maier, M. In Organic Synthesis
Highlights II; Waldmann, H., Ed.; VCH: Weinheim, 1995; pp 99-113.
Ohff, A.; Pulst, S.; Lefeber, C.; Peulecke, N.; Arndt, P.; Burlakov, V. V.;
Rosenthal, U. Synlett 1996, 111-118. Negishi, E.; Takahashi, T. Bull. Chem.
Soc. Jpn. 1998, 71, 755-769.
we envisaged that the functionalized congener 4 having a
carbonyl group would be a versatile compound as well.
However, the method of eq 1 so far appears inapplicable to
the synthesis of functionalized dienes 4 from 32,3,5 due
probably to the lack of compatibility of the carbonyl group.6
We recently reported that the intermolecular coupling of
functionalized acetylenes with titanium(II) alkoxide nicely
10.1021/ol0065221 CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/04/2000

took place to afford functionalized dienes.7 As an intramo-
lecular cyclization of diynes connected by an amide or an
ester linkage such as 3 has not yet been investigated, we
were interested in the viability of this mode of cyclization.
Herein the preliminary results as well as the regio- and
stereoselective Diels-Alder reaction of the resultant dienes
of type 4 will be disclosed.
Table 1. Preparation of exo-Cyclic Conjugated Dienes Fused
to Lactams or Lactones
The starting materials 3 (X ) NR) were prepared by
standard methods involving acylation of propargylamines
with a propiolic chloride as exemplified for 5 in Scheme 1.7
Scheme 1. Preparation and Cyclization of Amide-Tethered
Diyne 5
The cyclization was carried out by the treatment of the diyne
with (η2-propene)Ti(O-i-Pr)2 (6) prepared in situ from Ti-
(O-i-Pr)4 and i-PrMgCl.8 Hydrolytic workup of the reaction
mixture afforded the desired diene 8 having exclusively the
(3) For the preparation of dienes via diyne cyclization mediated by
transition metals other than group 4, see: Trost, B. M.; Krische, M. J. Synlett
1998, 1-16. Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem.
ReV. 1996, 96, 635-662. Lautens, M.; Klute, W.; Tam, W. Chem. ReV.
1996, 96, 49-92. Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34,
259-281. Tamao, K.; Kobayashi, K.; Ito, Y. Synlett 1992, 539-546. Trost,
B. M. Acc. Chem. Res. 1990, 23, 34-42.
(4) A preparation of polycyclic compounds based on the cyclization of
diyne 1 with a group 4 metalocene reagent followed by Diels-Alder reaction
was reported; see: Nugent, W. A.; Calabrese, J. C. J. Am. Chem. Soc. 1984,
106, 6422-6424.
(5) Formation of functionalized rhodacycles similar to 7 in Scheme 1 is
known, but its conversion to diene upon hydrolysis is not clear. Mu¨ller, E.
Synthesis 1974, 761-774.
(6) Some attempts to promote the cyclization of similar functionalized
enynes were unsuccessful. An enyne tethered by an ester analogous to 14
in Table 1 failed in the titanocene-mediated cyclization. Zhao, Z.; Ding,
Y.; Zhao, G. J. Org. Chem. 1998, 63, 9285-9291. Berk, S. C.; Grossman,
R. B.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 8593-8601.
Palladium-catalyzed arylative cyclization of an enyne tethered by amide
afforded a product similar to 17 only in a low yield. Xie, X.; Lu, X.
Tetrahedron Lett. 1999, 40, 8415-8418. See also: Lu, X.; Zhu, G.; Wang,
Z. Synlett 1998, 115-121.
Z,Z configuration (by NOE study of 1H NMR spectroscopy)
in good yield. Alternatively, deuteriolysis gave the bis-
deuterated product 8-d2, confirming the presence of func-
(7) Hamada, T.; Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 1999,
121, 7342-7344.
3482
Org. Lett., Vol. 2, No. 22, 2000

tionalized titanacyclopentadiene 7 before the workup. A
variety of N-hetereocyclic dienes were prepared by this
method, the results of which are summarized in entries 1-6
of Table 1. The reaction proceeded in good yield to give
relatively strained five-membered lactams having two exo-
methylene substituents. A bulky substituent close to the
reaction center in substrate 12 (entry 5) did not retard the
cyclization at all. Even when the regiochemistry of the
cyclization (entry 2) is not in accord with the intrinsic
preference observed in the intermolecular coupling reac-
tion,7,9 the desired product 16 was successfully obtained. Bis-
acetylenic esters 14 and 15, prepared from the corresponding
propargyl alcohols and the propiolic chloride, afforded exo-
cyclic conjugated dienes 21 and 22 fused to butyrolactone
as well (entries 7 and 8). The lower yields recorded for these
lactones as compared to the aforementioned lactams are most
likely attributable to the ester cleavage by the elimination
reaction as shown in eq 2 or, possibly, by the nucleophilic
attack of the Grignard reagent or 6 to the carbonyl group. In
fact, the released propargyl alcohol was detected in 12-
25% yield in these cases.
through NOE correlation of their protons (for example, 24
in Figure 1). The carbonyl group conjugated to the diene
Figure 1. Values in % refer to selected NOE enhancements.
moiety apparently contributed to the regioselective reaction
with the above unsymmetrical dienophiles. Besides the
regioselectivity, diene 8 showed very high stereoselectivity,
endo preference, in the reaction with N-phenylmaleimide to
give a single adduct, 25 (eq 4). More importantly, a
With the desired dienes 4 (eq 1) in hand, we proceeded to
the next stage to see their behavior in Diels-Alder reaction.
The reaction of diene 8, having equal substituents (Me3Si)
at both terminal carbons, with ethyl propiolate or an alkynone
provided an answer to the regiochemical issue (eq 3). The
proximate substituent (i-Pr) to the reacting center in 12
showed efficient chiral induction to form again an almost
single adduct, 26, out of the four possible stereoisomers. The
structures of 25 and 26 were verified by 1H NMR spectros-
(9) In an intermolecular cyclization where no positional bias exists, a
nonsilylated propiolic amide 29 was incorporated into the diene 30
exclusively with its amide group being placed at the terminal position of
the diene system, which is not the case in 16 of entry 2, Table 1.
diene exhibited good regiochemical control with ethyl
propiolate, which was further improved by acetylenic ketone
to be 93:7. In both cases, the major adduct 23 or 24 has two
acyl groups in the para-position,10 which was established
(10) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: London, 1976; pp 132-136.
(11) Juaristi, E.; Leo´n-Romo, J. L.; Reyes, A.; Escalante, J. Tetrahe-
dron: Asymmetry 1999, 10, 2441-2495. Bloch, R. Chem. ReV. 1998, 98,
1407-1438. Enders, D.; Reinhold: U. Tetrahedron: Asymmetry 1997, 8,
1895-1946.
(8) Sato, F.; Urabe, H.; Okamoto, S. Pure Appl. Chem. 1999, 71, 1511-
1519. Sato, F.; Urabe, H.; Okamoto, S. Synlett 2000, 753-775. Sato, F.;
Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100, 2835-2886.
Org. Lett., Vol. 2, No. 22, 2000
3483

copy as shown in Figure 1. It is interesting to note that the
N-phenethyl group in 13 (eq 5),11 the chiral carbon of which
is the fifth atom from the reacting center, still showed
appreciable chiral induction (better than 2:1) to give two
separable stereoisomers 27 and 28. This nontrivial remote
chiral induction should be attributable to the flat and rigid
shape of diene 13.
These dienes proved to be versatile substrates for the Diels-
Alder reaction with electron-deficient acetylenes or olefins
to give heteropolycyclic compounds in a regio- and stereo-
selective manner.13,14
Acknowledgment. We thank the Ministry of Education,
Science, Sports and Culture (Japan) for financial support.
OL0065221
(12) Representative procedure for the preparation of 8: To a stirred
solution of bis-acetylenic amide 5 (40 mg, 0.117 mmol) and Ti(O-i-Pr)4
(0.052 mL, 0.176 mmol) in 3 mL of Et2O was added a 1.35 M solution of
i-PrMgCl in ether (0.260 mL, 0.351 mmol) at -78 °C under argon to give
a yellow homogeneous solution. The solution was warmed to -30 °C over
60 min, during which period its color turned brown. After stirring at -30
°C for an additional 4 h, the reaction was terminated by the addition of 1
N HCl, and the organic products were extracted with ether. The combined
organic layers were washed with an aqueous solution of NaHCO3, dried
over MgSO4, and concentrated in vacuo to give a crude oil, which was
chromatographed on silica gel (hexanes-ether) to afford the title compound
(32 mg, 80%) as an oil.
(13) The nitrogen heterocycles obtained herein will be useful intermedi-
ates for the synthesis of both pyrrolidine and isoindoline derivatives. Cordell,
G. A., Saxton, J. E., Shamma, M., Smith, G. F., Eds. Dictionary of Alkaloids;
Chapman and Hall: London, 1989. Glasby, J. S., Ed. Encyclopedia of the
Alkaloids; Plenum Press: New York, 1975.
(14) For further elaboration based on the silylated diene and allylsilane
moieties in the products, see: Luh, T.-Y.; Wong, K.-T. Synthesis 1993,
349-370. Weber, W. P. In Silicon Reagents for Organic Synthesis; Springer-
Verlag: Berlin, 1983. Colvin, E. W. In Silicon in Organic Synthesis;
Butterworth: London, 1981. Fleming, I.; Dunogue´s, J.; Smithers, R. In
Organic Reactions; Kende, A. S., Ed.; Wiley: New York, 1989; Vol. 37,
pp 57-575. Fleming, I.; Barbero, A.; Walter, D. Chem. ReV. 1997, 97,
2063-2192.
In conclusion, titanium-mediated intramolecular cycliza-
tion of an amide- or ester-tethered diyne afforded exo-cyclic
dienes incorporated in lactams or lactones in good yields.12
3484
Org. Lett., Vol. 2, No. 22, 2000