Intermolecular transition metal-catalyzed [4 + 2 + 2] cycloaddition reactions: A new approach to the construction of eight-membered rings

Article abstract of DOI:10.1021/ja026351q

Transition metal-catalyzed cycloaddition reactions represent powerful methods for the construction of complex polycyclic systems. We have developed a new intermolecular metal-catalyzed [4 + 2 + 2] cycloaddition of heteroatom-tethered enyne derivatives wit

Full text of DOI:10.1021/ja026351q

Published on Web 06/29/2002
Intermolecular Transition Metal-Catalyzed [4 + 2 + 2] Cycloaddition
Reactions: A New Approach to the Construction of Eight-Membered Rings
P. Andrew Evans,* John E. Robinson, Erich W. Baum, and Aleem N. Fazal
Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405
Received March 28, 2002
Scheme 1
Transition metal-catalyzed cycloaddition reactions represent
powerful methods for the construction of complex polycyclic
systems.1 The intermolecular [4 + 4] cycloisomerization is
representative of this class of transformations, in which acyclic
dienes undergo formal cycloaddition reactions to furnish the
corresponding eight-membered rings.2,3 A significant limitation with
this process is the poor selectivity often obtained in heterocyclo-
additions employing stereoelectronically different 1,3-butadiene
derivatives. Although this limitation can be circumvented through
intramolecularity4 or related intermolecular variants, the direct
carbocyclization of a tethered enyne with a 1,3-diene has not been
described and would nonetheless provide a valuable addition to
this family of cycloaddition reactions.5 Herein, we now describe
the first metal-catalyzed intermolecular [4 + 2 + 2] cycloaddition
of the heteroatom-tethered enyne derivatives 1 with 1,3-butadiene
for the construction of the bicyclic eight-membered heterocycles 2
(eq 1).
Table 1. Development of the Rhodium-Catalyzed [4 + 2 + 2]
Cycloaddition Reaction
entry
additivea,b
ratio of 2a: 3ac
yield of 2a (%)d,e
yield of 3a (%)f
1
2
3
4
5
none
AgOTf
AgBF4
AgPF6
AgSbF6
1:8
28:1
11:1
2:1
7 (0)
85 (4)
74 (0)
49 (2)
2 (6)
57
3
7
27
89
The mechanistic hypothesis, outlined in Scheme 1 describes the
basis of the new carbocyclization reaction. We anticipated that the
tethered enyne i should coordinate the metal leading to the formation
of the metallacycle iii, which upon addition of 1,3-butadiene should
promote migratory insertion followed by a reductive elimination
to afford the [4 + 2 + 2] cycloaddition adduct v. The adVantage
of this approach is the ability to significantly increase the molecular
complexity of the cycloadduct through the introduction of additional
ring(s) and stereogenic centers. Moreover, given the significant
stereoelectronic difference between the enyne and diene compo-
nents, it should be possible to suppress the formation of the
homocycloaddition and/or oligomerization.6
Preliminary studies tested the feasibility of this hypothesis, as
outlined in Table 1. Treatment of the enyne 1a with Wilkinson’s
catalyst (Rh(PPh3)3Cl) under an atmosphere of 1,3-butadiene in
refluxing toluene, furnished a trace amount of 2a (entry 1), owing
to the propensity for the enyne 1a to undergo homocycloaddition
to afford 3a (ds g 19:1). Gratifyingly, the silVer triflate modified
rhodium catalyst, furnished the desired cycloaddition adduct 2a in
85% yield (entry 2). The ability to alter selectivity in this manner
prompted additional studies to explore the effect of various silver
salts on the cycloaddition (entries 2-5). Interestingly, a rather
intriguing trend in selectivity emerged from this study. In the
extreme case, the hexafluoroantimonate counterion completely
1:44
a All reactions were carried out on a 0.5 mmol reaction scale using 10
mol % of Wilkinson’s catalyst [Rh(PPh3)3Cl] in refluxing toluene under
an atmosphere of 1,3-butadiene. b The rhodium catalyst was modified with
20 mol % of the silver salt as indicated. c Ratios of hetero- and homo-
cycloaddition products were determined by capillary GLC and HPLC on
aliquots of the crude reaction mixture. d GLC yields. e Yields in parentheses
are for cyclooctadiene (by GLC). f HPLC yields.
reverses the selectivity for heterocycloaddition in the presence of
1,3-butadiene, to afford the homodimer 3a in 89% yield. The origin
of this selectivity was attributed to the propensity for these catalysts
to promote oligomerization of 1,3-butadiene, thereby reducing its
effective concentration. Analysis of the crude reaction mixture
confirmed this hypothesis, in which the silver triflate modified
catalyst furnished the least amount of oligomer, and thus explained
the origin of the excellent selectivity for the heterocycloaddition
(entry 2).
Table 2 outlines the examination of the influence of various
heteroatom tethers and alkyne substitution on the rhodium-catalyzed
[4 + 2 + 2] cycloaddition.7 This study demonstrated that nitrogen,
sulfur, and oxygen containing tethered enynes furnish the corre-
sponding cycloadducts in excellent yield and with analogous
selectivity. The cycloaddition is tolerant of both substituted and
unsubstituted alkynes, producing only trace amounts of the enyne
* To whom correspondence should be addressed. E-mail: paevans@
indiana.edu.
9
8782
J. AM. CHEM. SOC. 2002, 124, 8782-8783
10.1021/ja026351q CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
Table 2. Scope of the Intermolecular Rhodium-Catalyzed [4 + 2
+ 2] Cycloaddition Reaction (eq 1)a
lent selectivity can be obtained for either the homo- or hetero-
cycloaddition adducts through the judicious choice of metal
counterion. The development of the tandem rhodium-catalyzed
allylic substitution [4 + 2 + 2] cycloaddition provides a convenient
three-component coupling that circumvents the prior formation of
the enyne derivative. Finally, the introduction of a stereogenic center
at C-2 leads to a diastereoselective cycloaddition, which provides
a powerful new method for the construction of bicyclic octanoid
ring systems applicable to target-directed synthesis.
entry
X
R
ratio of 2: 3b
yield of 2 (%)c
1
2
3
4
5
6
7
8
9
TsN
“
“
SO2
“
“
O
“
“
H
Me
Ph
H
Me
Ph
H
a
b
c
d
e
f
g
h
i
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
g19:1
91
91
87
79
73
87
71
81
92
Me
Ph
Acknowledgment. We sincerely thank the National Institutes
of Health (GM58877) for generous financial support. We also thank
Johnson and Johnson for a Focused GiVing Award, Pfizer Phar-
maceuticals for the CreatiVity in Organic Chemistry Award, and
Novartis Pharmaceuticals for an Academic AchieVement Award. The
Camille and Henry Dreyfus Foundation is thanked for a Camille
Dreyfus Teacher-Scholar Award (P.A.E.), and the Organic Chem-
istry Division of the American Chemical Society (2001-2002) for
a Graduate Fellowship (J.E.R.), sponsored by Eli Lilly.
a All reactions were carried out on a 0.5 mmol reaction scale using 10
mol % of Wilkinson’s catalyst [Rh(PPh3)3Cl], modified with 20 mol %
AgOTf, in refluxing toluene under an atmosphere of 1,3-butadiene. b Ratios
1
of hetero- and homocycloadducts were determined by 400 MHz H NMR
with the exception of 2a/3a (26:1 by crude GLC/HPLC). c Isolated yields.
cycloisomerization and alkene isomerization products. Moreover,
the sulfone tethers provide a new class of substrates for carbocy-
clization reactions that utilize tethered enynes.
Supporting Information Available: Spectral data for 2a-i, 3a,
and 6 (PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
We envisioned that the development of a tandem three-
component allylic amination/cycloaddition would highlight the
synthetic utility of this new carbocyclization reaction (eq 2).8
Treatment of the lithium salt of N-tosylpropargylamine 4 with allyl
carbonate in the presence of Wilkinson’s catalyst, modified with
silver triflate, at room temperature furnished the enyne 1a. The
reaction mixture was then heated at reflux for ca. 12 h under an
atmosphere of 1,3-butadiene, to afford the cycloaddition adducts
2a/3a in 87% yield, as a g19:1 mixture favoring the hetero-
cycloaddition adduct 2a.9
References
(1) (a) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996,
96, 635. (b) Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002, 102,
813.
(2) For recent reviews, on metal-mediated cyclooctanoid construction, see:
(a) Sieburth, S. McN.; Cunard, N. T. Tetrahedron 1996, 52, 6251. (b)
Mehta, G.; Singh, V. Chem. ReV. 1999, 99, 881. (c) Yet, L. Chem. ReV.
2000, 100, 2963.
(3) For examples of metal-catalyzed [4 + 4] cycloaddition reactions, see:
(a) Co: Lautens, M.; Tam, W.; Lautens, J. C.; Edwards, L. G.; Crudden,
C. M.; Smith, A. C. J. Am. Chem. Soc. 1995, 117, 6863. (b) Fe: Baldenius,
K.-U.; tom Dieck, H.; Ko¨nig, W. A.; Icheln, D.; Runge, T. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 305. (c) Ni: Brun, P.; Tenaglia, A.; Waegell, B.
Tetrahedron Lett. 1983, 24, 385. (d) Ru: Itoh, K.; Masuda, K.; Fukahori,
T.; Nakano, K.; Aoki, K.; Nagashima, H. Organometallics 1994, 13, 1020
and references therein.
(4) Wender, P. A.; Ihle, N. C. J. Am. Chem. Soc. 1986, 108, 4678.
(5) For examples of other metal-catalyzed cycloaddition reactions leading to
eight-membered rings, see: (a) [6 + 2]: Wender, P. A.; Correa, A. G.;
Sato, Y.; Sun, R. J. Am. Chem. Soc. 2000, 122, 7815. (b) [5 + 2 + 1]:
Wender, P. A.; Gamber, G. G.; Hubbard, R. D.; Zhang, L. J. Am. Chem.
Soc. 2002, 124, 2876.
(6) The rhodium-catalyzed cycloisomerization of 1,3-butadiene is known to
favor oligomerization rather than the formation of cyclooctadiene, see:
Bosch, M.; Brookhart, M. S.; Ilg, K.; Werner, H. Angew Chem., Int. Ed.
2000, 39, 2304.
(7) Although the carbocyclization proceeds with heteroatom tethers, the carbon
tethered derivatives lead to mixtures, in which enyne cycloisomerization
was the major adduct. For a rhodium-catalyzed version, see: Cao, P.;
Wang, B.; Zhang, X. J. Am. Chem. Soc. 2000, 122, 6490.
(8) For a related tandem rhodium-catalyzed allylic alkylation/Pauson-Khand
annulation, see: Evans, P. A.; Robinson, J. E. J. Am. Chem. Soc. 2001,
123, 4609.
(9) RepresentatiVe Experimental Procedure: Wilkinson’s catalyst (46.1 mg,
10 mol %) was weighed into an oven-dried sealed tube and dissolved in
anhydrous toluene (2.0 mL). Silver triflate (26.1 mg, 0.1 mmol) was then
added in one portion, and the reaction vessel evacuated and reevacuated
with argon (three times), then stirred at room temperature for ca. 20 min.
Lithium hexamethyldisilyl azide (89.2 mg, 0.53 mmol) was added in a
single portion from a tared vial to a stirred solution of p-toluenesulfonyl
propargylic amine (114 mg, 0.55 mmol) in anhydrous toluene (2.0 mL)
at room temperature, and stirred for ca. 10 min under an atmosphere of
argon. The anion was then transferred Via Teflon cannula to the preformed
catalyst solution, rinsing with toluene (2 × 0.5 mL). Allyl carbonate (58.7
mg, 0.50 mmol) was then added in one portion Via a tared 100-µL syringe.
The sealed tube was then charged with 1,3-butadiene, and the reaction
was allowed to stir at room temperature ca. 2 h, then placed in 110 °C oil
bath, and heated at reflux for ca. 12 h. The reaction mixture was
concentrated in vacuo and purified by flash chromatography (gradient
elution 10-20% ethyl acetate/hexanes) to furnish the azabicycle 2a (132
mg, 87%) as a white crystalline solid.
Encouraged by the results in Table 2, we decided to examine
the diastereoselective intermolecular rhodium-catalyzed [4 + 2 +
2] cycloaddition using a C-2 substituted derivative to direct the
carbocyclization. Preliminary attempts revealed that although the
cycloaddition was feasible, the reaction required reduced concentra-
tion to suppress unwanted side reactions. Treatment of the enyne
5 under the optimized reaction conditions (0.0625M), furnished the
azabicycles 6 in 91% yield, as a g19:1 mixture of diastereoisomers
(eq 3). The stereochemistry was confirmed with the aid of an NOE
experiment, which established the syn relationship of the protons
at C-2/C-3.
In conclusion, we have developed a new intermolecular metal-
catalyzed [4 + 2 + 2] cycloaddition of heteroatom-tethered enyne
derivatives with 1,3-butadiene. This study demonstrates that excel-
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