Intramolecular ionic Diels-Alder reactions of α-acetylenic acetals

Article abstract of DOI:10.1021/jo048867t

The intramolecular ionic Diels-Alder reaction of α-acetylenic acetals as a precursor of the propargyl cation has been investigated in the presence of Lewis acids and in protic acids. The reaction of diene-tethered α-acetylenic acetals (1-2) with formic acid yielded the regioselective intramolecular ionic Diels-Alder reaction products, bicyclodienal (9) and bicyclodienone (11) derivatives, in good yields.

Full text of DOI:10.1021/jo048867t

SCHEME 1
Intramolecular Ionic Diels-Alder
Reactions of r-Acetylenic Acetals
Seung-Bo Shim, Yoon-Joo Ko, Byeong-Wook Yoo,
Chang-Keun Lim, and Jung-Hyu Shin*
School of Chemistry, Seoul National University,
Seoul 151-742, Korea
junghyu@snu.ac.kr
Received July 5, 2004
Abstract: The intramolecular ionic Diels-Alder reaction
of R-acetylenic acetals as a precursor of the propargyl cation
has been investigated in the presence of Lewis acids and in
protic acids. The reaction of diene-tethered R-acetylenic
acetals (1-2) with formic acid yielded the regioselective
intramolecular ionic Diels-Alder reaction products, bicy-
clodienal (9) and bicyclodienone (11) derivatives, in good
yields.
of R-acetylenic acetals as dienophiles has not previously
been reported. We report herein the intramolecular
Diels-Alder reaction of R-acetylenic acetals 1 and 2
under (1) Lewis and (2) protic acid catalysts.
The intramolecular Diels-Alder reaction1 is one of the
most powerful methods for the synthesis of many poly-
cyclic compounds, including natural products. However,
it is prerequisite that activating groups have to be built
into dienophiles to achieve the desired reactivity.2 Gas-
sman et al. demonstrated that both the inter- and
intramolecular ionic Diels-Alder reactions of allylic
alcohols and allylic ethers using protic acid proceed under
mild conditions give cycloadducts in high yields.3 For
example, the intermolecular ionic Diels-Alder reaction
of olefinic acetals is an excellent method for the synthesis
of corresponding cycloadducts bearing a protected car-
bonyl group without acrolein polymerization.4 Gassman
also reported that the protic acid-catalyzed intermolecu-
lar Diels-Alder reaction of cyclic acetals gives better
yields than that of acyclic acetals.4 Recently, Sammakia
reported that the chiral olefinic acetals derived from 2,4-
pentanediol undergo a Lewis acid promoted Diels-Alder
reaction, giving the corresponding cycloadducts in good
diastereoselectivity.5
The synthesis of diene-tethered R-acetylenic acetal 1
and 2 was accomplished from the coupling reaction of 7
or 8 with dienyl iodide 6,9 using the method reported by
Chong.10 The dienyl iodide 6 was prepared from aldehyde
311 through a sequence of propenyl additions, followed
by acetylation (4), elimination (5), and conversion of the
acetate to iodide 6 as depicted in Scheme 1.
When acetal 1 (Scheme 1) was treated with 0.1-1.0
equiv of alternative Lewis acids (BF3(OEt)2, AlCl3, SnCl4,
and TiCl4) in methylene chloride at -78 °C, only poly-
merized products were obtained. At the beginning, we
expected that the reaction might involve a Lewis acid
complex of oxonium ion (14, Scheme 2) from 1 as in the
case of olefinic acetal.5 Attempted use of Ti(O-iPr)4 in
methylene chloride at room temperature failed to pro-
mote any cycloaddition. Acetal 1 was recovered in 90%
yield. However, treatment of 1 with 1.0 equiv of TiCl2(O-
iPr)2 in methylene chloride at -78 °C yielded a novel
12
6-methyl-4-indancarbaldehyde 10 in 25% yield (entry 1).
Reaction of 2 containing a cyclic acetal moiety with
TiCl2(O-iPr)2 at room temperature over 2 h gave 10 in a
lower yield of 10% (entry 2).
On the basis of these reports, we envisioned that
acetylenic acetals seemed to be powerful dienophiles
provided that they were activated into propargyl cations.
Although there are known examples of the intermolecular
Diels-Alder reaction of propargyl cations generated from
propargyl halides,6 1,1-diphenyl-2-propyn-l-ol,7 and tri-
ethyl orthopropiolate8 as dienophiles, to the best of our
knowledge, the intramolecular ionic Diels-Alder reaction
Gassman established that catalysis by a strong protic
acid, such as trifluoromethanesulfonic acid (TfOH), is
generally preferred in the intermolecular ionic Diels-
Alder reaction of acrolein acetals and substituted prop-
argyl alcohol.4,7 Treatment of acetal 1 with 0.1 equiv of
(1) For reviews on the intramolecular Diels-Alder reaction, see: (a)
Roush, W. R. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds; Pergamon: Oxford, UK, 1991; Vol. 5, Chapter 4.4,
pp 513-550. (b) Fallis, A. G. Acc. Chem. Res. 1999, 32, 464.
(2) (a) House, H. O.; Cronin, T. H. J. Org. Chem. 1965, 30, 1061. (b)
Roush, W. R. J. Am. Chem. Soc. 1978, 100, 3599. (c) Roush, W. R.;
Peseckis, S. M. J. Am. Chem. Soc. 1981, 103, 6696. (d) Shea, K. J.;
Gilman, J. W. Tetrahedron Lett. 1983, 24, 657.
(6) Mayr, H.; Halberstadt, I. K. Angew. Chem., Int. Ed. Engl. 1980,
19, 814.
(7) Gassman, P. G.; Singleton, D. A. Tetrahedron Lett. 1987, 28,
5969.
(8) Gassman, P. G.; Chavan, S. P. Tetrahedron Lett. 1988, 29, 3407.
(9) Cramer, C. J.; Harmata, M.; Rashatasakhon, P. J. Org. Chem.
2001, 66, 5641.
(10) Chong, J. M.; Wong, S. Tetrahedron Lett. 1986, 27, 5445.
(11) Stowell, J. C. J. Org. Chem. 1970, 35, 244.
(12) (a) Mikami, K.; Terada, M.; Nakai, T. J. Am. Chem. Soc. 1990,
112, 3949. (b) Kumareswaran, R.; Vankar, P. S.; Reddy, M. V. R.; Pitre,
S. V.; Roy, R.; Vankar, Y. D. Tetrahedron 1999, 55, 1099. (c) Aso, M.;
Ojida, A.; Yang, G.; Cha, O.-J.; Osawa, E.; Kanematsu, K. J. Org.
Chem. 1993, 58, 3960.
(3) (a) Gassman, P. G.; Singleton, D. A. J. Am. Chem. Soc. 1984,
106, 7993. (b) Gassman, P. G.; Singleton, D. A. J. Org. Chem. 1986,
51, 3075.
(4) Gassman, P. G.; Singleton, D. A.; Wilwerding, J. J.; Chavan, S.
P. J. Am. Chem. Soc. 1987, 109, 2182.
(5) Sammakia, T.; Berliner, M. A. J. Org. Chem. 1994, 59, 6890.
10.1021/jo048867t CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/14/2004
8154
J. Org. Chem. 2004, 69, 8154-8156

TABLE 1. Intramolecular Diels-Alder Reactions of Acetals 1 and 2
yielda (%)
temp
(°C)
time
(h)
entry
acetal
acid and solvent
9
10
11
1
2
3
4
5
6
7
8
1
2
1
1
1
2
1
2
1.0 equiv of TiCl2(O-iPr)2 in CH2Cl2
1.0 equiv of TiCl2(O-iPr)2 in CH2Cl2
0.5 equiv of TfOH in CH2Cl2
0.1% v/v HCOOH in CHCl3
10% v/v HCOOH in CHCl3
-78
0.5
2
0.5
48
24
46
0.5
0.5
25
10
tb
95
47
33
-78 to rt
-78 to rt
tb
tb
50
rt
rt
rt
rt
21
23
17
27
86
82
10% v/v HCOOH in CHCl3
10% v/v HCOOH in pentane
10% v/v HCOOH in pentane
a Isolated yields. b Trace amount.
SCHEME 2
of 12 obtained were in good agreement with those
previously reported.14
The mechanistic steps involved in these intramolecular
ionic Diels-Alder reactions are of particular interest to
us. We anticipated that protonation of acetal 1 by a Lewis
acid or protic acid would give reactive intermediates, such
as Lewis acid complexes of oxonium ion 14, propargyl
cation 15, and allenyl cation 16,6,15 which might readily
undergo cyclization into cycloadducts (Scheme 2).
The cyclization of the C8-C9 with the C1-C4 portion
of 15 to bicyclodienal 9 followed by slow aromatization16
will give 10. Alternatively, the cyclicization of C9-C10
with the diene moiety of 16 will afford bicyclodienenone
11. However, the ratios of adduct 9 to adduct 11 resulting
from treatment of acetals 1 and 2 with formic acid were
strongly dependent on the reaction conditions as shown
in Table 1.
To establish the detailed mechanistic pathways in-
volved in the formation of 9, 10, and 11 outlined in
Scheme 2, we performed NMR studies. Treatment of
acetal 1 with formic acid in CDCl3 (1:10 v/v) at 25 °C for
10 min provided a 71:21 mixture of compounds 1 and 1317
(Scheme 2) when determined by 1H NMR analysis.18 After
a reaction of 2 h, 1 was converted into a mixture of 13
(23%), 9 (43%), 10 (1%), and 11 (10%) with a 77%
combined yield (1H NMR analysis). Furthermore, when
the reaction mixture was allowed to stand for 5 h, most
of acetal 1 and propargyl aldehyde 13 were consumed.
After a reaction of 111 h, the slow aromatization of 9 was
completed to give indancarbaldehyde 10 quantitatively.
We presume that this intramolecular ionic Diels-Alder
reaction proceeds via Pathway A or Pathway B to give
cycloadducts 9 and 11 (Scheme 2). The above results
strongly suggest that one of the key steps in the protic
acid-promoted Diels-Alder reaction of acetal 1 is the
formation of the propargyl aldehyde 13, which is cyclized
TfOH, however, gave only trace amounts of Diels-Alder
cycloadducts (entry 3). In contrast, when the reaction was
subjected to acetic acid, acetal 1 remained unreacted.
After screening a variety of protic acids, formic acid
was our choice for cyclization of acetals 1 and 2. Reaction
of acetal 1 with 0.1% v/v formic acid in chloroform at 50
°C for 48 h afforded 10 in 95% yield as the sole product
(entry 4). Similar treatment of acetal 1 with 10% v/v
formic acid in chloroform at room temperature for 24 h
gave a mixture of 9 (21%), 10 (41%), and 11 (17%) (entry
5). Treatment of acetal 2 with 10% v/v formic acid in
chloroform gave similar results to acetal 1 (entry 6).
Interestingly, the use of 10% v/v formic acid in pentane
(i.e., two-phase system) rapidly gave 11 in good yields
(entries 7 and 8). The structure of each of the novel
compounds 9, 10, and 11 was assigned on the basis of
extensive spectral studies.13 Furthermore, the structure
of 11 was confirmed by oxidation to the known 6-methyl-
1-tetralone 12 (Scheme 2). The 1H and 13C NMR spectra
(14) Das, J.; Valenta, Z.; Ngooi, T. K. Can. J. Chem. 1991, 6, 474.
(15) Mayr, H.; Baeuml, E. Tetrahedron. Lett. 1983, 24, 357.
(16) (a) Vanderzande, D. J.; Kiekens, E. G.; Martens, H. J.; Hoor-
naert, G. J. J. Org. Chem. 1986, 51, 1019. (b) Shakespeare, W. C.;
Johnson, R. P. J. Am. Chem. Soc. 1990, 112, 8578.
(17) Compound 13 was readily separated by column chromatography
and characterized by NMR analysis. See the Supporting Information.
(18) See the Supporting Information for the quantification of cyclized
products during the course of acetal 1 reaction in 1:10 (v/v) HCOOH/
CDCl3 at 25 °C.
(13) The coupling pattern of the 1H signal in the 1, 4-cyclohexadiene
moiety of 11 was investigated by decoupling experiments. Irradiation
of the H-4 and H-10 resulted in a long-range coupling between H-4
and H-1. In addition, the analysis of the HMBC correlation confirmed
the unambiguous structure of 11. The IR spectrum showed the
presence of a carbonyl carbon with a strong CdO stretch at 1693 cm-1
.
J. Org. Chem, Vol. 69, No. 23, 2004 8155

SCHEME 3
completely consumed within 3 min and bicyclodienenone
11 was observed as a major product (65% yield) with
concomitant formation of several unknown products. The
acid-catalyzed dehydration20 of â-hydroxy ketones gener-
ally needs a stronger acid, a higher reaction temperature,
and a longer time. However, we failed to observe the
expected â-hydroxy ketone 19 in our reaction conditions.
On the basis of this NMR study, the mechanism involving
an oxete intermediate seems to be more suited to explain
our results.
In conclusion, we have demonstrated that diene-
tethered R-acetylenic acetals 1 and 2 undergo Lewis acid-
catalyzed cyclization, giving indancarbaldehyde 10. In
addition, the intramolecular Diels-Alder reactions of 1
and 2 in the presence of formic acid gave bicyclodienal
9, indancarbaldehyde 10, and bicyclodienone 11 in good
yields, respectively. The yields and distribution of prod-
ucts in the cyclization reaction were strongly dependent
upon the reaction conditions.
into bicyclodienal 9 and bicyclodienone 11 via cation
species 14-16 (Scheme 2).
We also propose the mechanism for the formation of
11 depicted in Scheme 3 to explain our experimental
results. Vinyl cation 17 is generated from the cyclization
of propargyl cation 15 or allenyl cation 16 (Scheme 2).
Rearrangement of vinyl cation 17 through two different
mechanistic pathways might lead to the formation of 11
(Scheme 3). One mechanism involves an enol intermedi-
ate 18, which undergoes tautomerization to give â-hy-
droxy ketone 19, the dehydration of which produces 11,
while the other involves oxete intermediate19 20 affording
11. When the reaction of acetal 1 with formic acid-d2 in
D2O (2:1 v/v) at 25 °C was monitored by 1H NMR, 1 was
Acknowledgment. Support of this work by the
Brain Korea 21 project is greatly appreciated.
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO048867T
(20) (a) Noyce, D. S.; Reed, W. L. J. Am. Chem. Soc. 1958, 80, 5539.
(b) Boyer, F.-D.; Descoins, C. L.; Thanh, G. V.; Descoins, C.; Prange´,
T.; Ducrot. P.-H. Eur. J. Org. Chem. 2003, 1172. (c) Kozikowski, A. P.;
Li, C.-S. J. Org. Chem. 1987, 52, 3541. (d) Meyer. W. L.; Brannon, M.
J.; Merritt, A.; Seebach, D. Tetrahedron. Lett. 1986, 27, 1449.
(19) This oxete mechanism is similar to that postulated by Harding
for acid-catalyzed intramolecular cyclization of 5-cyclodecynone. See:
(a) Harding, C. E.; Stanford, G. R. J. Org. Chem. 1989, 54, 3054. (b)
Harding, C. E.; King, S. L. J. Org. Chem. 1992, 57, 883.
8156 J. Org. Chem., Vol. 69, No. 23, 2004