Stereocontrolled synthesis of (E,Z)-dienals via tandem Rh(I)-catalyzed rearrangement of propargyl vinyl ethers

Article abstract of DOI:10.1021/ol4019985

A novel Rh(I)-catalyzed approach to functionalized (E,Z) dienals has been developed via tandem transformation where a stereoselective hydrogen transfer follows a propargyl Claisen rearrangement. Z-Stereochemistry of the first double bond suggests the involvement of a six-membered cyclic intermediate whereas the E-stereochemistry of the second double bond stems from the subsequent protodemetalation step giving an (E,Z)-dienal.

Full text of DOI:10.1021/ol4019985

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Stereocontrolled Synthesis of
(E,Z)‑Dienals via Tandem Rh(I)-Catalyzed
Rearrangement of Propargyl Vinyl Ethers
Dinesh V. Vidhani,* Marie E. Krafft, and Igor V. Alabugin*
Department of Chemistry & Biochemistry, Florida State University, Tallahassee,
Florida 32306, United States
alabugin@chem.fsu.edu
Received July 16, 2013
ABSTRACT
A novel Rh(I)-catalyzed approach to functionalized (E,Z) dienals has been developed via tandem transformation where a stereoselective hydrogen
transfer follows a propargyl Claisen rearrangement. Z-Stereochemistry of the first double bond suggests the involvement of a six-membered cyclic
intermediate whereas the E-stereochemistry of the second double bond stems from the subsequent protodemetalation step giving an (E,Z)-dienal.
Polyene motifs with (E,Z) stereochemistry are ubiqui-
tous in biologically active and naturally occurring sys-
tems1 and hence represent synthetically important targets
(Figure 1).2 Not only are synthetic routes to Z-alkenes
relatively limited,3 but such traditional approaches to un-
saturated conjugated Z-polyenes as Wittig and HornerÀ
WadsworthÀEmmons reactions cannot be used to directly
deliver unsaturated aldehydes.
(1) (a) McGarvey, B. D.; Attygalle, A. B.; Starratt, A. N.; Xiang, B.;
Schroeder, F. C.; Brandle, J. E.; Meinwald, J. Nat. Prod. 2003, 66, 1395.
(b) Robinson, C. Y.; Waterhous, D. V.; Muccio, D. D.; Brouillette, W. J.
Bioorg. Med. Chem. Lett. 1995, 5, 953. (c) Asfaw, N.; Storesund, H. J;
Skattebol, L.; Aasen A, J. Phytochemistry 1999, 52, 1491. (d) Hiraoka,
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2001, 65, 2749. (e) Matsumoto, H.; Asato, A. E.; Denny, M.; Baretz, B.;
Yen, Y.-P.; Tong, D.; Liu, R. S. H. Biochemistry 1980, 19, 4589.
(2) (a) Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1998.
(b) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (c) Sharpless,
K. B. Angew. Chem., Int. Ed. 2002, 41, 2024. (d) Chauvin, Y. Angew.
Chem., Int. Ed. 2006, 45, 3740. (e) Schrock, R. R. Angew. Chem., Int. Ed.
2006, 45, 374. (f) Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760.
(3) (a) Smith, A. B, III; Beauchamp, T. J.; LaMarche, M. J.;
Kaufman, M. D.; Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K.
J. Am. Chem. Soc. 2000, 122, 8654. (b) Dong, D.-J.; Li, H.-H.; Tian,
S.-K. J. Am. Chem. Soc. 2010, 132, 5018. (c) Still, W. C.; Gennari, C.
Tetrahedron Lett. 1983, 24, 4405. (d) Molander, G. A.; Dehmel, F.
J. Am. Chem. Soc. 2004, 126, 10313. (e) Huang, Z.; Negishi, E.-I. J. Am.
Chem. Soc. 2007, 129, 14788. (f) Belardi, J. K.; Micalizio, G. C. J. Am.
Chem. Soc. 2008, 130, 16870. (g) Lindlar, H.; Dubuis, R. Org. Synth.
1966, 46, 89. (h) Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S.
Synlett 2001, 430. (i) Kang, B.; Kim, D.-H.; Do, Y.; Chang, S. Org. Lett.
2003, 5, 3041. (j) Hansen, E. C.; Lee, D. Org. Lett. 2004, 6, 2035.
(k) Kang, B.; Lee, J. M.; Kwak, J.; Lee, Y. S.; Chang, S. J. Org. Chem.
2004, 69, 7661. (l) Sashuk, V.; Samojlowicz, C.; Szadkowska, A.; Grela,
K. Chem Commun. 2008, 2468. (m) Crowe, W. E.; Goldberg, D. R.
J. Am. Chem. Soc. 1995, 117, 5162.
Figure 1. Selected (E,Z) dienal natural products.
The metal-catalyzed cross-coupling of two sp2-hybridized
reactants requires activating functionalities (e.g., organo-
boranes or organostannanes) which may be toxic, expen-
sive, and/or deleterious for the overall atom efficiency.
Methods for the direct incorporation of the unsaturated
R,β carbonyl compounds with the Z-stereochemistry are
limited.4
r
10.1021/ol4019985
XXXX American Chemical Society

In this work, we disclose a tandem transformation of
propargyl vinyl ethers into dienals, where stereochemistry
at both double bonds in the product is defined simulta-
neously by the nature of a common cyclic intermediate
located at the Claisen rearrangement hypersurface con-
necting propargyl vinyl ethers with allene-aldehyde 1.
Trapping of such a cyclic structure via deprotonation
coupled with the Grob fragmentation should lead to the
conjugated dienals with E,Z-stereochemistry: the Z-geo-
metry at the R,β-alkene is defined by the syn-arrangement
of the endocyclic σ-bonds whereas the E-stereochemistry
at γ,δ-alkene stems from the syn-arrangement of the exo-
cyclic CÀR1 and CÀM bonds and proto-demetalation
with retention of configuration (Figure 2).
who found that the use of a multinuclear Au-catalyst
provides access to such a cyclic structure trappable by a
reaction with external nucleophiles (Figure 2).8
Because the equilibrium between the metalÀalkyne,
metalÀvinyl ether, and metalÀoxygen complexes should
strongly depend on the nature of metal, we scanned a
number of transition metal catalysts. Herein, we report that
stereoselective tandem isomerization of propargyl vinyl
ethers to (E,Z)-dienals can be achieved using Rh(I)-catalysis.
A screening of commonly used transition metals showed
that Au-based catalysts promote the Claisen rearrangement
step but only AuCl is efficient in moving the cascade further
(Table 1). However, the stereoselectivity of the final step
was, at best, modest. Pd-based catalysts were only successful
in promoting the first step. The hard Lewis acids such as
Cu(OTf)2, Zn(OTf)2, and Sc(OTf)3 were even less efficient.
On the other hand, [Rh(CO)2Cl]2 displayed remarkable
reactivity, effectively promoting both the allene formation
and its subsequent rearrangement into the desired (E,Z)-
dienal 2a (Table 1, entry 14). Donor phosphine ligands at the
Rh center eliminated the catalytic activity (entry 15).
Table 1. Catalyst Screeninga
Figure 2. “Two birds with one stone”: The proposed transforma-
tion of the six-membered intermediate in the metal-catalyzed
propargyl Claisen rearrangement into (E,Z)-dienals defines
stereochemistry in both double bonds of the product.
entry
catalyst
AuCl
1
2a
2b
b
1
2
À
28
9
72
17
3
AuCl3
72
93
100
100
12
100
8
3
Ph3PAuSbF6
[Au]SbF6
IPr-AuSbF6
PdCl2
4
4
À
À
À
À
3
À
À
À
À
À
À
À
À
À
À
2
Au(I)-catalyzed Claisen rearrangements of propargyl
and allenyl vinyl ethers were first reported by the groups
of Toste5 and Krafft,6 respectively. In a recent mechanistic
study of these two rearrangements,7 we found that although
the cyclic intermediate does not correspond to an energy
minimum at the DFT potential energy hypersurface
in the presence of the R3PAuSbF6-catalyst; the details of
5
6
7
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(PhCN)2Cl2
PtCl2
8
9
100
À
À
À
À
À
À
98
À
10
11
12
13
14
15
Cu(OTf)2
16
15
10
Zn(OTf)2
Au substrate interactions at this stage suggest that a slight
3 3 3
Sc(OTf)3
modification in the nature of the catalyst may be sufficient
for creating and trapping such a cyclic structure.8
b
[Rh(CO)2Cl]2
(PPh3)3RhCl
À
À
À
Although trapping via deprotonation has not been re-
ported so far and our initial attempts with weak bases such
as aniline led to deactivation of the Au-catalyst, we were
further encouraged by the results of Toste and co-workers
a Standard reaction conditions: 0.1 M Substrate in toluene-d8 at
50 °C in the presence of 10% metal catalyst for 24 h. Ratios determined
by proton NMR. b Complete conversion of substrate into 1 was observed,
followed by its full transformation into 2a and 2b.
(4) (a) Maynard, D. F.; Okamura, W. H. J. Org. Chem. 1995, 60,
1763. (b) Duhamel, L.; Guillemont, J.; Poirier, J.-M. Tetrahedron Lett.
1991, 32, 4495. (c) Cahard, D.; Duhamel, L.; Lecomte, S.; Poirier, J.-M.
Synlett 1998, 12, 1399. (d) Amos, R. A.; Katzenellenbogen, J. A. J. Org.
Chem. 1978, 43, 555.
(5) (a) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
(b) Mauleon, P.; Krinsky, J. L.; Toste, F. D. J. Am. Chem. Soc. 2009,
131, 4513.
Remarkably, [Rh(CO)2Cl]2 and AuCl provided cascade
products in high yields but with the opposite stereochem-
istry. Table 2 summarizes further optimization of the Rh-
catalyzed reactions. Coordinating solvents such as aceto-
nitrile form a strong complex with Rh(I) and deactivate
the catalyst.9 Rearrangement in the mildly coordinating
(6) Krafft, M. E.; Hallal, K. M.; Vidhani, D. V.; Cran, J. W. Org.
Biomol. Chem. 2011, 9, 7535.
(7) (a) Vidhani, D. V.; Cran, J. W.; Krafft, M. E.; Manoharan, M.;
Alabugin, I. V. J. Org. Chem. 2013, 78, 2059. (b) Vidhani, D. V.; Cran,
J. W.; Krafft, M. E.; Alabugin, I. V Org. Biomol. Chem. 2013, 11, 1624.
(8) Sherry, B. D.; Maus, L.; Laforteza, B. N.; Toste, F. D. J. Am.
Chem. Soc. 2006, 128, 8132.
(9) (a) Costa, M.; Della Pergola, R.; Fumagalli, A.; Laschi, F.; Losi,
S.; Macchi, P.; Sironi, A.; Zanello, P. Inorg. Chem. 2007, 46, 552.
(b) Fumagalli, A.; Martinengo, S.; Ciani, G.; Moret, M.; Sironi, A.
Inorg. Chem. 1992, 31, 2900.
B
Org. Lett., Vol. XX, No. XX, XXXX

CH2Cl2 was sluggish (10% dienal 2a and 35% allene-
aldehyde 1). The reaction in tetrahydrofuran gave 90%
allene-aldehyde 1 atrt and proceededslowly towardthe 3:1
mixture of the dienals at 50 °C.
Table 2. Optimization Studiesa
entry
solvent
temp
1
2a
2b
1
2
3
4
5
6
8
7
8
9
CD3CN
CD3CN
CD3NO2
THF-d8
THF-d8
CD2Cl2
toluene-d8
toluene-d8
C6D6
25
50
25
25
50
25
25
50
25
50
N.R
N.R
tracec
90
À
À
À
À
À
3
À
À
À
89
8
35
10
À
À
À
2
100
b
À
98
À
95
À
5
b
C6D6
À
95
a Standard reaction conditions: All reactions were performed at
0.1 M concentration in the presence of 10% [Rh(CO)2Cl]2. Relative
ratios were determined by proton NMR. b Complete conversion of enol
ether into 1 was observed that was subsequently fully converted into 2a
and 2b. c Significant decomposition of substrate was observed.
Figure 3. Products of Rh(I)-catalyzed rearrangements obtained
from their respective propargyl vinyl ethers. Percentages corre-
spond to the isolated yields. Values in parentheses show percent-
age of E,Z isomer determined by proton NMR. Reaction
conditions: 0.1 M solution of 0.1 mmol of propargyl vinyl ether
On the other hand, conversions in benzene and toluene
were clean and proceeded in high yield and remarkable E,
Z-selectivity for substrates with a broad range of aro-
matic substituents at the carbinol carbon (Figure 3). Both
donors and acceptors work well. Furthermore, other sp2-
substituents are also compatible with the cascade. For
example, a cyclohexenyl substituted substrate gavea dienal
product in 62% yield with excellent (E,Z)-stereoselectivity.
Furthermore, the cascade tolerates steric hindrance; even
with bulky substituents such as tert-butyl and mesityl, the
Claisen productsare quicklyformedat50°C and smoothly
converted to the dienals in ∼80% yield and excellent stereo-
selectivity upon further heating.
a
in toluene in the presence of 10% [Rh(CO)2Cl]2 at 50 °C.
Rearranges further into a mixture of products. b Requires 70 °C.
The current limitations of this process seem to be
associated with the possibility of further prototropic isom-
erizations. For substrates with an n-butyl group at the
carbinol carbon, the dienal yields decrease to ∼50% due to
formation of several nonidentified nonpolar byproducts.
In the presence of a secondary (cyclohexyl) substituent,
formation of Claisen product proceeded efficiently
(>90%) at 50 °C, but its subsequent rearrangement at
70 °C produced only a small amount of (E,Z) dienal
product together with unknown nonpolar products.
The cyclopropyl-substituted substrate was unreactive in
the presence of Rh(I) at 50 °C and decomposed at higher
temperatures.
Figure 4. Proposed catalytic cycle. Numbers in blue correspond
to the PCM-SCRF-M05-2X/LANL2DZ energies of the inter-
mediate species relative to the uncomplexed Rh(I)-dimer.
DFT calculations at the M05-2X/LANL2DZ level sug-
gest that the electron-rich vinyl ether dissociates the 16
electron Rh(I)-dimer to form a 16 electron Rh(I)-VE
complex which is expected to be the catalyst resting state
(Figure 4). The uncomplexed monomeric 14 electron pre-
catalyst, Rh(CO)2Cl, is unlikely to be persistent.10
Additional information regarding the mechanism of this
isomerization was provided by DFT calculations. They
revealed that the most stable complex produced via co-
ordination of Rh(I) with the vinyl ether is catalytically
(10) Pitcock, W. H., Jr.; Lord, R. L.; Baik, M.-H. J. Am. Chem. Soc.
2008, 130, 5821.
Org. Lett., Vol. XX, No. XX, XXXX
C

six-membered intermediate in the “cyclization-mediated
pathway” is often elusive and its presence and lifetime depend
on the intricate details of transition state complexation
with the catalyst. For example, we had shown in our earlier
work on Au-catalyzed rearrangement how coordination
of Au stabilizes the TS for the subsequent Grob-type frag-
mentation into the allene-aldehyde product to the extent
that the intermediate corresponds to a shallow inflection at
the potential energy surface.7 On the other hand, Siebert and
Tantillo found that a combination of transition-state com-
plexation with resonance stabilization converts a TS into a
cyclic intermediate in Pd-promoted Cope rearrangement.14
At the M05-2X/LANL2DZ level of theory, we did not
find an energy minimum corresponding to the six-membered
organorhodium intermediate in the parent system (Figure 5).
Further mechanistic exploration is needed to fully under-
stand the subtleties of this transformation since the (E,Z)-
stereochemistry of double bonds in the dienal is fully
consistent with the suggested transformation of the six-
membered intermediate in Figure 2. The stereochemistry
of the two double bonds in 2a and 2b was confirmed by
selective gradient-enhanced 1D NOESY (SELNOGP) and
comparison to the known proton NMRs of the (E,Z)
dienals 2a, 7, 8, 10, and 11.15
In summary, Rh-catalyzed Claisen rearrangement fol-
lowed by stereoselective hydrogen transfer converts pro-
pargyl vinyl ethers into the target (E,Z)-dienals in high
yields, excellent stereoselectivity, and with minimal waste.
The reaction tolerates steric hindrance and is compatible with
substituents of different electronic demand. This atom eco-
nomical method yields complex and stereochemically defined
dienals in only three steps from commercially available
aldehydes. Presently, we are exploring the mechanistic details
of the catalytic cycle.
Figure 5. CurtinÀHammett analysis of the three mechanisms.
Energies in toluene were calculated at the PCM-SCRF-M05-
2X/LANL2DZ level on the gas phase optimized geometries.
unproductive due to the high barrier (Figure 4, TS1:
41.2 kcal/mol). DFT computations performed at the M05-
2X level suggests that the less stable complexes formed via
coordination of Rh(I) with the alkyne or the oxygen re-
arrange via considerably lower barriers.11
Coordination of Rh(I) to the oxygen initiates the oxonia-
Claisen rearrangement which proceeds via a dissociative-
TS with a 23.4 kcal/mol barrier (Figure 5, TS2). Coordina-
tion of Rh(I) with the alkyne directs rearrangement via a
very low 9.7 kcal barrier (Figure 4, TS3). Even after the
CurtinÀHammett correction, the latter route offers
the lowest energy path for the Claisen rearrangement with
the barrier of 17.7 kcal/mol (Figure 5).12
Although the interception of the pericyclic pathway
is conceptually interesting and increasingly utilized
in the design of cascade organic transformations,13 the
Acknowledgment. Funding for this project was provided
by the MDS Research Foundation and NSF Grant CHE-
1152491 to I.A. We would also like to thank Dr. John Cran
(FSU) for helpful discussions, Dr. Steve Freitag (FSU) and
Dr. Banghao Chen (FSU) for assistance with 2D NMR
spectroscopy, and Dr. Umesh Goli (FSU) for acquiring
mass spectra.
ꢀ
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(12) For the stereoelectronic reasons for the endoselectivity in metal-
catalyzed reactions (“LUMO umpolung”), see: (a) Alabugin, I.; Gilmore,
K.; Manoharan, M. J. Am. Chem. Soc. 2011, 133, 12608. Reviews: (b)
Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513. (c) Peterson,
P. W.; Mohamed, R. K.; Alabugin, I. V. Eur. J. Org. Chem. 2013, 2013,
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Am. Chem. Soc. 2006, 128, 7436. (e) Byers, P. M.; Rashid, J. I.;
Mohamed, R. K.; Alabugin, I. V. Org. Lett. 2012, 14, 6032. (f) Hashmi,
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Supporting Information Available. Detailed experimen-
tal procedures; spectra and HRMS of all new com-
pounds; NOESY data for compounds 3a and 3b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Siebert, M. R.; Tantillo, D. J. J. Am. Chem. Soc. 2007, 129, 8686.
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(13) Selected precedents for the interception of pericyclic pathways:
Discovery of aborted pericyclic reactions: (a) Gilmore, K.; Manoharan,
M.; Wu, J.; Schleyer, P. v. R; Alabugin, I. V. J. Am. Chem. Soc. 2012,
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alkynes facilitating the design of such reactions, see: Alabugin, I. V.;
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The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX