A diastereoselective intermodular heck reaction of 1,3-dioxepins

Article abstract of DOI:10.1021/ol702294u

A highly diastereoselective intermolecular Heck reaction of 1,3-dioxepins is reported. Substitution at both the 2- and 4-positions of the dioxepin directs the Pd coordination and subsequent olefin insertion to provide the trans-disubstituted adduct in goo

Full text of DOI:10.1021/ol702294u

ORGANIC
LETTERS
2007
Vol. 9, No. 24
5099-5102
A Diastereoselective Intermolecular
Heck Reaction of 1,3-Dioxepins
Christopher G. Nasveschuk, Jeffrey D. Frein, Nathan T. Jui, and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
roVis@lamar.colostate.edu
Received September 20, 2007
ABSTRACT
A highly diastereoselective intermolecular Heck reaction of 1,3-dioxepins is reported. Substitution at both the 2- and 4-positions of the dioxepin
directs the Pd coordination and subsequent olefin insertion to provide the trans-disubstituted adduct in good yield and high diastereoselectivity.
Chemoselective Heck reaction occurs at the dioxepin alkene in the presence of other olefinic functional groups. A labeling study has been
conducted which suggests that the reaction is under kinetic control.
The intramolecular Heck reaction has been extensively
investigated and has played a crucial role in the successful
synthesis of complex molecules.1,2 In stark contrast stands
the current state-of-the-art in the intermolecular Heck reaction
when using acceptors other than acyclic olefins. Perhaps most
illustrative of this issue is that only the simplest cyclic olefins
participate well in the asymmetric intermolecular Heck
reaction.3 A significant exception to this statement lies in
the asymmetric Heck reaction of dioxepins developed
independently by Shibasaki and Pfaltz.4,5 Only recently has
the diastereoselective intermolecular Heck reaction been
explored, where diastereoselectivity is induced by chelation
of an auxiliary.6,7 In the absence of the directing influence
of an auxiliary, the reaction should proceed through a pair
of competing transition states where the level of diastereo-
selection is dictated by sterics alone (Scheme 1).
Scheme 1
(1) See, for example: (a) Morphine: Hong, C. Y.; Kado, N.; Overman,
L. E. J. Am. Chem. Soc. 1993, 115, 11028-11029. (b) Gelsemine: Madin,
A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. J.
Am. Chem. Soc. 2005, 127, 18054-18065.
(2) For some excellent reviews of the Heck reaction, see: (a) Daves, G.
D., Jr.; Hallberg, A. Chem. ReV. 1989, 89, 1433-1445. (b) Meijere, A.;
Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379-2411. (c)
Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314-321. (d) Beletskaya,
I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009-3066. (e) Dounay,
A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945-2963.
There are few examples of this type of diastereoselective
Heck reaction. Larock and co-workers illustrated a diaste-
reoselective Heck reaction that provides trans-2,5-diaryltet-
rahydrofurans en route to platelet-activating factor antago-
nists.8 Takano has shown that a Heck reaction of a vinyl
halide on a 2-aryl-substituted dioxepin proceeds with high
diastereoselectivity en route to asarinin.9 More recently,
(3) (a) Ozawa, F.; Kubo, A.; Hayashi, T. J. Am. Chem. Soc. 1991, 113,
1417-1419. (b) Shibasaki, M.; Vogl, E. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New
York, 1999; Vol. 1, p 457.
(4) (a) Koga, Y.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett. 1994,
35, 1227-1230. (b) Loiseleur, O.; Meier, P.; Pfaltz, A. Angew. Chem., Int.
Ed. Engl. 1996, 35, 200-202.
(5) For a recent report of an asymmetric intermolecular oxidative Heck-
type reaction, see: Yoo, K. S.; Park, C. P.; Yoon, C. H.; Sakaguchi, S.;
O’Neill, J.; Jung, K. W. Org. Lett. 2007, 9, 3933-3935.
(6) (a) Buezo, N. D.; Alonso, I.; Carretero, J. C. J. Am. Chem. Soc. 1998,
120, 7129-7130. (b) de la Rosa, J. C.; Diaz, N.; Carretero, J. C. Tetrahedron
Lett. 2000, 41, 4107-4111. (c) Nilsson, P.; Larhed, M.; Hallberg, A. J.
Am. Chem. Soc. 2003, 125, 3430-3431.
(7) For a microreview on neighboring-group effects in the Heck reaction,
see: Oestreich, M. Eur. J. Org. Chem. 2005, 783-792.
10.1021/ol702294u CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/25/2007

Correia and co-workers described a diastereoselective Heck
reaction of substituted pyrrolines with arenediazonium salts
as an approach to aryl kainoids.10
that contains active catalyst, during which there is a color
change from orange to red-brown.15,16
The halide scope of the reaction was evaluated. Iodoben-
zene is a competent coupling partner, while the reaction is
sluggish when bromobenzene is used (85% vs 32% after 24
h). Phenyl triflate does not participate under these conditions.
The scope of the desymmetrizing Heck reaction of 1,3-
dioxepins with respect to substitution at the acetal position
is broad. Simple alkyl, and electron-rich and -deficient
aromatic substitution is well tolerated (entries 1, 2, 6, and 8,
Table 2). The stereochemistry of the Heck adducts was
determined to be trans by NOE experiments and single-
crystal X-ray diffraction analysis of 8. Pendant and strained
cyclopropane and cyclobutane substituents remain intact
under the reaction conditions (entries 3-5, 7, and 9).
Chemoselectivity for the dioxepin olefin is exclusive in the
presence of other potentially reactive E-olefins (entries 10
and 11). Unprotected alcohols are also tolerated and exhibit
no deleterious effects on the reaction (entry 5). The coupling
partner scope is also quite broad, where electron-rich aryl,17
1,2-disubstituted, 1,1-disubstituted, and trisubstituted18 alk-
enyl iodides provide dioxepin products with good diaste-
reoselectivity and respectable yields19 (entries 6-9).
Dioxepins that contain a preexisting stereocenter at the
4-position are also competent olefins for the Heck reaction
(Table 3). Electron-rich, -neutral, and -deficient aromatics
all couple in excellent diastereoselectivity and good yield to
provide the trans-dioxepin products (entries 1-3). Interest-
ingly, when the size of the substituent at the dioxepin
4-position reaches a steric threshold, the reverse olefin
insertion becomes competitive (entries 5 and 6) and in the
extreme is the major product (entry 7).
We became interested in a diastereoselective Heck reaction
of 1,3-dioxepins as a route to polysubstituted substrates
which would undergo stereoselective [1,3]-rearrangements
to afford tetrahydrofurans, an approach that we have already
documented.11 In order to maximize efficiency, we required
the reaction to use equimolar amounts of the aryl halide and
olefin, a condition not commonly found in asymmetric
intermolecular Heck reactions.12 Herein we report the scope
of the diastereoselective intermolecular Heck reaction using
1,3-dioxepins as substrates.
Initial experiments revealed that the diastereoselectivity
is dependent on concentration (entries 1 and 2, Table 1).
Table 1. Reaction Optimization
dr
entry
1
conditions
(trans:cis)
PPh3, K2CO3, n-Bu4NCl
0.1 M MeCN/H2O (9:1), 50 °C
PPh3, K2CO3, n-Bu4NCl
1 M MeCN/H2O (9:1), 50 °C
1 equiv i-Pr2NEt, BnEt3NCl
DMF, 80 °C
33:67
2
3
4
85:15
95:5
3 equiv i-Pr2NEt, BnEt3NCl
DMF, 80 °C
>95:5b
a Reactions were preformed with 5-8 mol % of Pd(OAc)2. b The minor
In order to rationalize the stereochemistry of the products,
we considered thermodynamic versus kinetic selectivity. It
has been established that alkenes can “walk” under a variety
of Heck conditions by Pd-H-mediated isomerization to the
more thermodynamically favored position.20 To evaluate this
possibility, 3,3,6,6-2H4-dioxepin 23 was synthesized. If the
trans-dioxepin is produced by thermodynamic selectivity
(isomerization/epimerization by Pd-H or Pd-D), there
should be 2H enrichment at the 5-position and 1H enrichment
at the 7-position of the dioxepin. If kinetic selectivity
predominates, then no 5-2H or 7-1H enrichment should be
observed. Exposure of 23 to the optimized modified Jeffery
1
diastereomer was not observed by H NMR.
We hypothesized that a more organic-soluble base would
serve to increase the rate of X-Pd-H decomposition, thus
suppressing the undesired Pd-H-mediated epimerization of
the desired trans-diastereomer. The reaction, when conducted
using our optimized modified Jeffery conditions,13,14 provides
the desired dioxepin in excellent yield and selectivity (entry
3). The concentration of base also plays a role under the
optimized conditions, although the effect is not as pro-
nounced (95:5 vs >95:5, entries 3 and 4). It is worthy of
note that, in both of the described Heck conditions, an
induction period of 10 min is critical in obtaining a solution
(15) This observation is consistent with the formation of Pd nanoparticles
and/or colloids which have been implicated in the Heck reaction and other
Pd-catalyzed reactions: (a) Consorti, C. S.; Zanini, M. L.; Leal, S.; Ebeling,
G.; Dupont, J. Org. Lett. 2003, 5, 983-986. (b) de Vries, A. H. M.; Mulders,
J. M. C. A.; Mommers, J. H. M.; Henderickx, H. J. W.; de Vries, J. G.
Org. Lett. 2003, 5, 3285-3288. (c) Consorti, C. S.; Flores, F. R.; Dupont,
J. J. Am. Chem. Soc. 2005, 127, 12054-12065.
(16) For procedures and discussion about how to determine the “true”
catalyst, see: (a) Lin, Y.; Finke, R. G. Inorg. Chem. 1994, 33, 4891-
4910. (b) Widegren, J. A.; Finke, R. G. J. Mol. Catal. A: Chem. 2003,
198, 317-341. (c) O¨ zkar, S.; Finke, R. G. J. Am. Chem. Soc. 2002, 124,
5796-5810.
(17) Electron-deficient aryl iodides, which undergo more facile oxidative
addition, also participate; under unoptimized conditions (entry 2, Table 1),
p-CF3C6H4I provides the dioxepin in 48% yield with 88:12 dr.
(18) Fourteen percent of another inseparable olefin isomer is produced.
(19) Vinyl iodide is invariably consumed; ∼20% unreacted dioxepin may
be reisolated.
(8) Larock, R. C.; Gong, W. H. J. Org. Chem. 1990, 55, 407-408.
(9) Takano, S.; Samizu, K.; Ogasawara, K. Synlett 1993, 785-787.
(10) da Silva, K. P.; Godoi, M. N.; Correia, C. R. D. Org. Lett. 2007, 9,
2815-2818.
(11) (a) Nasveschuk, C. G.; Jui, N. T.; Rovis, T. Chem. Commun. 2006,
29, 3119-3121. (b) Nasveschuk, C. G.; Rovis, T. J. Org. Chem. 2007, in
press.
(12) See ref 4.
(13) (a) Jeffery, T. Tetrahedron 1996, 52, 10113-10130. For examples
of modified Jeffery’s conditions in the Heck reaction, see: (b) Reference
9. (c) Ogasawara also reported a singular example: Samizu, K.; Ogasawara,
K. Chem. Lett. 1995, 543-544. A useful resource for conditions commonly
used in Heck reactions: (d) Heck, R. F. Org. React. 1982, 27, 345-390.
(14) We optimized these conditions to be as follows: 1.05 equiv of ArI,
1 equiv of dioxepin, 8 mol % of Pd(OAc)2, 2 equiv of BnEt3NCl, 3 equiv
of i-Pr2NEt, 0.4 M in DMF (with respect to the alkene) at 80 °C.
(20) See ref 2.
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Org. Lett., Vol. 9, No. 24, 2007

Table 2. Scope of Symmetric 1,3-Dioxepins
Table 3. Scope of 4-Substituted 1,3-Dioxepins
differentiation of the dioxepin olefin carbons. A comparison
of the 13C chemical shifts of these atoms reveals that as steric
bulk of the substituent is increased the parts per million
difference decreases (14a, 17a, 21a, Scheme 2). This is
presumably a reflection of a different ground state conforma-
tion of the dioxepin resulting from an increased steric demand
Scheme 2
2
conditions showed no H enrichment at the 5-position and
no 1H incorporation at the 7-position (eq 1).21 When
combined, these data suggest that the high levels of diaste-
reoselection obtained under the optimized conditions are a
result of kinetic selectivity and not epimerization by a long-
lived Pd-H.
A potential rationale to explain the regioselectivity of Heck
reactions on 4-substituted substrates may lie in a ground state
Org. Lett., Vol. 9, No. 24, 2007
5101

of the cyclohexyl and tert-butyl groups relative to n-pentyl.
This difference may also manifest itself in an electronic
manner, effectively polarizing the double bond. Whatever
the underlying principle involved, this effect correlates well
with the experimental results: as the steric bulk of the
substituent is increased, regioselectivity decreases.
tions, the all cis-2,4,5-trisubstituted dioxepin was formed in
good yield and excellent diastereoselectivity (eq 2).24 This
stereochemical outcome is not easily rationalized.
The relative stereochemistry may be rationalized by our
proposed stereochemical model (Scheme 3). With 2-substi-
In related work, we have used the vinyl acetals obtained
from these reactions in a stereoselective Lewis acid mediated
ring contraction to form tri- and tetrasubstituted tetrahydro-
furans.11 We also note that simple acidic hydrolysis4a of
compounds such as 17 leads to trans-disubstituted lactols
and lactol ethers in good yield with preservation of stereo-
chemistry (eq 3).
Scheme 3
In summary, we have developed a general and highly
trans-diastereoselective intermolecular Heck reaction of 1,3-
dioxepins. Substitution at the 2- and 4-positions of 1,3-
dioxepins leads to the trans-dioxepin product. Labeling
studies suggest that the selectivity is kinetic in origin and
not a result of an initial unselective olefin insertion followed
by an epimerization event. The overall synthetic sequence
provides an efficient and modular approach to the versatile
1,3-dioxepin framework.
tuted dioxepins, coordination of the large Pd-alkyl species,
whether a nanoparticle or monometallic-based, to the olefin
occurs trans to the dioxepin substituent for steric reasons.22
With 4-substituted dioxepins, olefin coordination cis to the
allylic alkyl substituent is disfavored, a situation observed
in many similar organometallic reactions involving allylically
substituted olefins.23
We next directed our attention toward determining the
combined effect of substitution at the 2- and 4-positions of
the dioxepin. Surprisingly, we found that when cis-2,4-
disubstituted dioxepin 25 was subjected to optimized condi-
Acknowledgment. We thank Eli Lilly, Boehringer In-
gelheim, and Johnson & Johnson for support. T.R. is a fellow
of the Alfred P. Sloan Foundation and thanks the Monfort
Family Foundation for a Monfort Professorship.
(21) Crossover experiments between 1 and 23, and 1 and 24 using
optimized modified Jeffery conditions also did not show any 2H enrichment
at the 5-position and no 1H enrichment at the 7-position in the dioxepin
product.
(22) Coordination of the Pd to the acetal oxygens is also a possibility;
this type of interaction has been invoked to explain the stereochemical
outcome of Fe-catalyzed [4 + 4] ene reactions of 1,3-dioxepins. See:
Takacs, J. M.; Anderson, L. G.; Newsome, P. W. J. Am. Chem. Soc. 1987,
109, 2542-2544.
(23) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307-1370.
Supporting Information Available: Experimental pro-
cedures and characterization data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL702294U
(24) Relative stereochemistry was determined by NOE experiments. See
Supporting Information for details.
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Org. Lett., Vol. 9, No. 24, 2007