Rh(I)-catalyzed ring-opening of hetaryne-furan diels-alder adducts: Rapid access to stereochemically defined heterocyclic scaffolds

Article abstract of DOI:10.1021/ol200057j

Probing the nucleophilic ring-opening of various bicyclic [2.2.1] hetaryne-furan Diels-Alder adducts revealed that efficient reactivity could be observed with heteroatom nucleophiles by using a cationic Rh(I) complex in combination with a chiral Josiphos-

Full text of DOI:10.1021/ol200057j

ORGANIC
LETTERS
2011
Vol. 13, No. 6
1370–1373
Rh(I)-Catalyzed Ring-Opening of
Hetaryne-Furan Diels-Alder Adducts:
Rapid Access to Stereochemically Defined
Heterocyclic Scaffolds
Trung D. Nguyen, Robert Webster, and Mark Lautens*
Department of Chemistry, University of Toronto, Toronto, Ontario, Canada, M5S 3H6
mlautens@chem.utoronto.ca
Received January 8, 2011
ABSTRACT
Probing the nucleophilic ring-opening of various bicyclic [2.2.1] hetaryne-furan Diels-Alder adducts revealed that efficient reactivity could be
observed with heteroatom nucleophiles by using a cationic Rh(I) complex in combination with a chiral Josiphos-type phosphine ligand.
Remarkably, this catalyst system was not impeeded by the incorporation of a heteroatom into the substrate. Racemic materials afforded separable
mixtures of enantioenriched regioisomers, indicating that strong reagent control is operative.
In the context of modern organic synthesis, benzyne and
other arynes are generally considered classic well-studied
reactiveintermediates.1 Arynesare highlyreactivepartners
in cycloadditions, and consequently Diels-Alder reac-
tions are commonly used as both traps for the detection
of arynes and useful synthetic tools for the construction of
polycyclic scaffolds. Reacting arynes with furan affords
[2.2.1] benzo-fused oxabicyclic alkenes that have served as
highly useful building blocks through transition metal
catalyzed asymmetric ring-opening reactions.2 A number
of heterocyclic variants of arynes and their corresponding
hetaryne-furan Diels-Alder adducts are known (Figure 1),3
but until now the behavior of such heterocyclic systems in
transition metal catalyzed ring-opening reactions had not
been explored.
Figure 1. Examples of hetaryne-furan Diels-Alder adducts.
(1) For recent reviews on arynes, see: (a) Pelissier, H.; Santelli, M.
Tetrahedron 2003, 59, 701. (b) Wenk, H.; Winkler, M.; Sander, W.
Angew. Chem., Int. Ed. 2003, 42, 502. (c) Dyke, A.; Hester, A.; Lloyd-
Jones, G. Synthesis 2006, 24, 4093. (d) Pena, D.; Perez, D.; Guitian, E.
Heterocycles 2007, 74, 89. (e) Sanz, R. Org. Prep. Proceed. Int. 2008,
40, 215.
A number of challenges are associated with the incor-
poration of a heteroatom into the oxabicyclic substrate:
the potential for catalyst poisoning is introduced, and
substrate electronics may be strongly affected.4
~
ꢀ
ꢀ
(2) Ni catalysis: (a) Lautens, M.; Chiu, P.; Ma, S.; Rovis, T. J. Am.
Chem. Soc. 1995, 117, 532. (b) Lautens, M.; Ma, S.; Chiu, P. J. Am.
Chem. Soc. 1997, 119, 6478. bPd catalysis:(c) Lautens, M.; Hiebert, S.
J. Am. Chem. Soc. 2004, 126, 1437. (d) Li, L.; Rayabarapu, D.; Nandi,
M.; Cheng, C. Org. Lett. 2003, 5, 1621. (e) Ogura, T.; Yoshida, K.;
Yanagisawa, A.; Imamoto, T. Org. Lett. 2009, 11, 2245. nCu catalysis:(f)
(3) 2,3-Pyridyne: (a) Walters, M.; Shay, J. Synth. Commun. 1997, 27,
3573. 3,4-Pyridyne:(b) Tsukazaki, M.; Snieckus, V. Heterocycles 1992,
33, 533. Thiophyne:(c) Ye, X.; Li, W.; Wong, H. J. Am. Chem. Soc. 1996,
118, 2511. 5,6-Indolyne:(d) Buszek, K.; Luo, D.; Kondrashov, M.;
Brown, N.; VanderVelde, D. Org. Lett. 2007, 9, 4135.
(4) Our previous work indicates that substrate electronics can have a
profound effect on reactivity and selectivity: (a) Lautens, M.; Schmid,
G. A.; Chau, A. J. Org. Chem. 2002, 67, 8043. (b) Lautens, M.; Fagnou,
K. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5455.
ꢀ
Arrayas, R.; Cabrera, S.; Carretero, J. Org. Lett. 2003, 5, 1333. (g)
Millet, R.; Gremaud, L.; Bernardez, T.; Palais, L.; Alexakis, A. Synthesis
2009, 2101. Ir catalysis:(h) Yang, D.; Hu, P.; Long, Y.; Wu, Y.; Zeng,
H.; Wang, H.; Zuo, X. Beilstein J. Org. Chem. 2009, 5, 53. Rh catalysis:
(i) Lautens, M.; Fagnou, K.; Hiebert, S. Acc. Chem. Res. 2003, 36, 48 and
references cited therein.
r
10.1021/ol200057j
Published on Web 02/24/2011
2011 American Chemical Society

Furthermore, although many unsymmetrical hetary-
ne-furan Diels-Alder cycloadducts can be easily prepared
as racemates, no method for their synthesis in enantiomeri-
cally pure form currently exists in the literature. We did not
see this as a major limitation however, since we previously
demonstrated that racemic unsymmetrical oxabenzonor-
bornenes can be ring-opened with a chiral catalyst to give
a regiodivergent resolution,5 wherein each enantiomer of
the substrate reacts in parallel to afford a mixture of
enantioenriched regioisomers.6
Bu-Josiphos that previously demonstrated an excellent
reactivity profile in our earlier work also failed to give any
conversion (Table 1, entry 6).7 We were pleased to discover
however that employing the [Rh(cod)2OTf] catalyst with
t-Bu-Josiphos in the absence of any additive gave efficient
ring-opening, yielding methanolysis products 6a and 6b that
were separable by flash chromatography, each in >99% ee
(Table 1, entry 8).
Table 2. Effect of Nitrogen Position
Table 1. Initial Screen of Catalyst Conditions
yield [%]
(% ee)a
entry
catalyst
ligand additive
6a
6b
1b
2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
Rh(cod)2OTf
Rh(cod)2OTf
Rh(cod)2OTf
Rh(cod)2OTf
Rh(cod)2OTf
none
dppf
dppf
none
dppf
1
none
none
NH4Cl
none
none
TBAI
n.r.
n.r.
n.r.
n.r.
n.r.
n.r.
3c
4
d
d
-
n.r.
-
5
n.r.
n.r.
n.r.
6e
7f
8g
n.r.
1
NH4BF4 n.r.
none
1
29 (>99) 34 (>99)
a Yield determined following column chromatography, % ee in par-
entheses determined by chiral HPLC. b Reaction performed using 2,2,2-
TFE as the solvent. c NH4Cl (1 equiv) was added to the catalyst prior to
the addition of substrate. d Complete decomposition to an intractable
mixture was observed. e TBAI (20 mol %) was added to the catalyst prior
to the addition of substrate. f NH4BF4 (1 equiv) was added to the catalyst
prior to the addition of substrate. g Reaction performed at 60 °C.
a Yield determined following column chromatography, % ee in
parentheses determined by chiral HPLC. b Isolated as an inseparable
mixture of regioisomers (ratio determined by 1H NMR).
We then examined the ring-opening of oxabicycle 2 with
nitrogen nucleophiles (Table 2, entries 2-4). The products
were obtained in good combined yield as near 1:1 mixtures
of separable regioisomers. In general, ring-opening of ox-
abicycle 2 with amines proceeded to give one regioisomer
(product type a) in moderate ee (60-75%) and the other
regioisomer (product type b) as virtually a single enantiomer
(>99% ee).8 In contrast, the ring-opening of 1,4-dihydro-
epoxyisoquinoline 3 was also investigated and found to
proceed with high efficiency to give both regioisomeric
dihydroisoquinoline products in excellent ee (Table 2, en-
tries 5-8).
We initiated our study by attempting the Rh(I)-catalyzed
methanolysis of 1,4-dihydroepoxyquinoline 2 (Table 1). It
was found to be recalcitrant toward most standard Rh-
catalyzed ring-opening conditions, failing to react using
[Rh(cod)Cl]2 with or without dppf or protic additives
(Table 1, entries 1-3). Changing to ligand-free conditions
with the cationic species [Rh(cod)2OTf] consumed the sub-
strate 2, but this proved too reactive and led only to decom-
position (Table 1, entry 4). Using a Rh-I species (generated
in situ from [Rh(cod)2OTf] and TBAI) in combination with t-
The intricacy of substrate electronics was further probed
by examining the reactivity of substituted 1,4-dihydro-
epoxyquinolines 14 and 15 (Table 3).9 Ethoxy-substituted
oxabicycle 14 reacted efficiently, giving regioisomeric pairs
of products in good yield (Table 3, entries 1-4). A strong
€
(5) (a) Webster, R.; Boing, C.; Lautens, M. J. Am. Chem. Soc. 2009,
131, 444. (b) Webster, R.; Boyer, A.; Fleming, M.; Lautens, M. Org.
Lett. 2010, 12, 5418.
(6) For reviews on regiodivergent/parallel kinetic resolutions, see:
Kumar, R. R.; Kagan, H. B. Adv. Synth. Catal. 2010, 352, 231. Dehli,
J. R.; Gotor, V. Chem. Soc. Rev. 2002, 31, 365. For selected reports, see:
Wu, B.; Parquette, J. R.; RajanBabu, T. V. Science 2009, 326, 1662.
Jana, C. K.; Studer, A. Angew. Chem., Int. Ed. 2007, 46, 6542. Gansauer,
A.; Fan, C. A.; Keller, F.; Keil, J. J. Am. Chem. Soc. 2007, 129, 3484.
(7) (a) Lautens, M.; Fagnou, K. J. Am. Chem. Soc. 2001, 123, 7170.
(b) Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed. 2002, 41, 26.
(8) This difference in enantioselectivity is likely because oxabicycle 2
possesses a strong inherent substrate reactivity bias, leading to the
erosion of the ee for one product; however this cannot be verified since
we have not successfully ring-opened oxabicycle 2 using an achiral
catalyst in order to observe the substrate’s inherent mode of reactivity
(see ref 5a for a more thorough discussion).
€
€
Gansauer, A.; Fan, C. A.; Keller, F.; Karbaum, P. Chem.;Eur. J. 2007,
13, 8084. Pineschi, M.; Del Moro, F.; Crotti, P.; Di Bussolo, V.;
Macchia, F. J. Org. Chem. 2004, 69, 2099. Tanaka, K.; Fu, G. C. J.
Am. Chem. Soc. 2003, 125, 8078. Chen, Y. G.; Deng, L. J. Am. Chem.
Soc. 2001, 123, 11302. Vedejs, E.; Chen, X. H. J. Am. Chem. Soc. 1997,
119, 2584. Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Ruppar, D. A.;
Martin, S. F.; Spaller, M. R.; Liras, S. J. Am. Chem. Soc. 1995, 117,
11021. Bolm, C.; Schlingloff, G. J. Chem. Soc., Chem. Commun. 1995,
1247.
(9) Prepared according to literature procedures. For ethoxy-substi-
tuted oxabicycle 14, see: (a) Connon, S.; Hegarty, A. J. Chem. Soc.,
Perkin Trans. 1 2000, 1245. For chloro-substituted oxabicycle 15, see:(b)
ꢀ
Guitian, E. Eur. J. Org. Chem. 2001, 4543.
Org. Lett., Vol. 13, No. 6, 2011
1371

electronic effect appears to be operative, since one of the
two regioisomers (product type a) was produced in only
modest ee (58-89%), while the other (product type b) was
universally formed in very high ee (>99%). Conversly,
chloro-substituted oxabicycle 15 exhibited excellent ee for
each regioisomeric product, and good yields were main-
tained for both regioisomers (Table 3, entries 5-8).
Scheme 1. Regiodivergent Ring-Opening of a Quinolyne-
Furan Diels-Alder Adduct
Table 3. Effect of Aryl Substitution
Scheme 2. Regiodivergent Ring-Opening of an Indoly-
ne-Furan Diels-Alder Adduct
a Yield determined following column chromatography, % ee in
parentheses determined by chiral HPLC. b Absolute configuration
established using X-ray analysis.
Our success prompted us to investigate more complex
heterocycle-fused [2.2.1] oxabicyclic systems. We were
drawn to quinoline-fused oxabicycles, such as 24
(Scheme 1), that were conveniently accessible in high yield
using a protocol developed by Knochel and co-workers.10
Subjecting quinoline-fused oxabicycle 24 to the cationic
Rh-OTf/t-Bu-Josiphos catalyst system resulted in nucleo-
philic ring-opening with both diisopropylamine and piper-
idine to give separable regiosiomeric products with
exceptional enantioselectivity (>95% ee).
Indolynes have recently garnered significant interest
from the synthetic community and have been the subject
of several theoretical studies.11 We found that indoly-
ne-furan cycloadduct 27 reacted smoothly under our
optimized conditions to furnish good combined yields of
ring-opened regiosomers in excellent ee (Scheme 2).
A proposed catalytic cycle that corroborates our pre-
vious work in this area is depicted below (Scheme 3).12 The
key event in the cycle is the enantioselective ionization of
the substrate IIa/IIb C-O bond by the cationic active
catalyst I to give an activated complex IIIa/IIIb repre-
sented as a Rh-σ-enyl species. Protonation of the active
complex IIIa/IIIb by the nucleophile is believed to precede
nucleophilic addition13 to give IVa/IVb that is subse-
quently intercepted by the resulting anionic nucleophile
(10) Sapountzis, I.; Lin, W.; Fischer, M.; Knochel, P. Angew. Chem.,
Int. Ed. 2004, 43, 4364.
(11) (a) Buszek, K.; Brown, N.; Luo, D. Org. Lett. 2009, 11, 201. (b)
Bronner, S.; Bahnck, K.; Garg, N. Org. Lett. 2009, 11, 1007. (c) Tian, X.;
Huters, A.; Douglas, C.; Garg, N. Org. Lett. 2009, 11, 2349. (d) Brown,
N.; Luo, D.; Decapo, J.; Buszek, K. Tetrahedron Lett. 2009, 50, 7113. (e)
Cheong, P.; Paton, R.; Bronner, S.; G-Yoon, J.; Garg, N.; Houk, K.
J. Am. Chem. Soc. 2009, 132, 1267. (f) Garr, A.; Luo, D.; Brown, N.;
Cramer, C.; Buszek, K.; VanderVelde, D. Org. Lett. 2010, 12, 96.
(12) Fleming, M. J.; Lautens, M. In Catalyzed Carbon-Heteroatom
Bond Formation; Yudin, A. K., Ed.; John Wiley & Sons Ltd.: Chichester,
2010.
(13) This is based on the following observations: the reaction rate
increases with decreasing nucleophile pKa; no productive reaction is
observed using anionic nucleophiles; protic additives generally acceler-
ate the reaction.
1372
Org. Lett., Vol. 13, No. 6, 2011

in an SN20 fashion to deliver the product and regenerate the
active catalyst.
enantiomerically pure form over a short sequence of steps.
The products of this chemistry are mostly novel heterocyclic
analogues of a bioactive class of compounds (2-amino-
tetralins),14 making this methodology geared toward diver-
sity-oriented synthesis and potentially very useful for med-
icinal chemists. Studies directed at the synthesis of
enantiomerically pure hetaryne-furan Diels-Alder ad-
ducts to better exploit the utility of this method are ongoing
in our laboratories and will be reported in due course.
Scheme 3. Proposed Catalytic Cycle
Acknowledgment. This research was supported by the
Natural Sciences and Engineering Research Council of
Canada (NSERC), the Merck Frosst Centre for Ther-
apeutic Research, and the University of Toronto. We
thank Solvias AG for the generous donation of chiral
ligands.
Supporting Information Available. Experimental pro-
cedures, characterization data for new compounds, addi-
tional data tables. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) (a) Koe, B.; Weissman, A.; Welch, W.; Browne, R. J. Pharmacol.
Exp. Ther. 1983, 226, 686. (b) Freeman, J.; Michalson, E.; D’andrea, S.;
Baczynskyj, L.; Von Voigtlander, P.; Lahti, R.; Smith, M.; Lawson, C.;
Scahill, T.; Mizsak, S.; Szmuszkovicz, J. J. Med. Chem. 1991, 34, 1891.
(c) Zhang, Y.; Tropsha, A.; McPhail, A.; Lee, K. J. Med. Chem. 1994, 37,
1460. (d) Necas, M.; Dostal, J.; Kejnovska, I.; Vorlickova, M.; Slavik, J.
J. Mol. Struct. 2005, 734, 1.
In summary, the regiodivergent nucleophilic ring-open-
ing of various racemic hetaryne-furan Diels-Alder ad-
ducts was achieved using a chiral cationic Rh(I) catalyst.
A number of polycyclic heterocycles were prepared in
Org. Lett., Vol. 13, No. 6, 2011
1373