Ambient synthesis of dienals via triazole-gold and amine catalysis relay

Article abstract of DOI:10.1021/ol503393a

A highly efficient synthesis of substituted conjugated dienals was developed through a triazole-gold (TA-Au)-catalyzed propargyl vinyl ether rearrangement followed by an amine catalyzed allene-aldehyde tautomerization. Various substituted vinylogous aldehydes were prepared in one pot with good to excellent yields (up to 95%) under mild conditions with high atom economy.

Full text of DOI:10.1021/ol503393a

Letter
pubs.acs.org/OrgLett
Ambient Synthesis of Dienals via Triazole−Gold and Amine Catalysis
Relay
Stephen E. Motika, Qiaoyi Wang, Xiaohan Ye, and Xiaodong Shi*
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506, United States
S
* Supporting Information
ABSTRACT: A highly efficient synthesis of substituted
conjugated dienals was developed through a triazole−gold
(TA−Au)-catalyzed propargyl vinyl ether rearrangement
followed by an amine catalyzed allene−aldehyde tautomeriza-
tion. Various substituted vinylogous aldehydes were prepared
in one pot with good to excellent yields (up to 95%) under
mild conditions with high atom economy.
inylogous aldehydes represent unique and interesting
building blocks in organic synthesis.1 The rich reactivity
often requiring multiple subsequent steps and harsh con-
ditions.4 In these cases, substrate scope and low atom economy
(large amount of byproduct waste generated) are also
problematic and synthetically unappealing. Thus, new methods
toward dienal synthesis with high efficiency (less steps, high
atom economy) are desirable. Herein, we divulge a new strategy
to expedite the synthesis of substituted 1,3-dienals from readily
available starting materials. This process is initiated by
chemoselective triazole gold catalysis and leads to a highly
efficient amine tautomerization relay (good to excellent yields
and atom economy) under extremely mild conditions.
With interest in developing new syntheses of 1,3-dienals, our
attention initially turned towards the metal-catalyzed propargyl
vinyl ether 1 rearrangement.5 As shown in Scheme 1B,
compound 1 may undergo metal-catalyzed rearrangement to
form allene 2. Alabugin and co-workers recently reported that
[Rh(CO)2Cl]2 could promote the isomerization of 1, giving
dienal 3 through the proposed vinyl-Rh intermediates, though
high catalyst loading (10%) and elevated reaction temperature
(50 °C) were required.6
V
inherited through diene−aldehyde conjugation provides a
synthetic scaffold for a host of transformations. Interesting
reactions have been developed using this rather unique
synthon, including recent efforts toward asymmetric organo-
catalysis using trienamine activation.2,3 However, despite great
synthetic versatility, the utilization of diene−aldehydes is far
from paradigmatic in complex molecule construction, largely
due to the challenges associated with the preparation of these
starting materials. As shown in Scheme 1A, typical syntheses of
conjugated dienals are achieved through Wittig condensation,
Scheme 1. Diene Aldehyde: Important but Hard To Prepare
This transformation was interesting as it offered a new
approach to prepare dienals with high efficiency, though the
high catalyst loading greatly reduces the viability of applying
this method as a practical synthesis. The screening of reaction
conditions also revealed an interesting catalyst reactivity
dilemma for this transformation. With gold catalysts, good
reactivity was observed for both alkyne and allene activation.
Thus, even low catalyst loading (usually <1%) and mild
conditions (rt) would effectively promote the initial rearrange-
ment. However, no dienal 3 was observed due to the existing
side reactions associated with gold-catalyzed allene activation.
For example, Nolan and co-workers reported indene formation
through phenyl addition to the [IPrAu]+ activated allene.7
Received: November 22, 2014
Published: January 7, 2015
© 2015 American Chemical Society
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Allene−aldehyde cyclization catalyzed by gold−oxonium
complex [(PPh3Au)3O]+ has also been reported by Toste and
co-workers.8 In contrast, the [Rh] catalyst could transfer vinyl
ether 1 to dienal 3, which was likely associated with lower
reactivity of the vinylrhodium toward protodemetalation and
lower π-acidity for subsequent allene activation (compared with
[Au]). Therefore, high catalyst loading and harsh reaction
conditions seem inevitable in these systems.
Recently, our group has developed 1,2,3-triazole−gold
complexes (TA−Au) as a new class of gold catalysts in
promoting alkyne activation.9 The interesting new reactivity of
this catalyst is evidenced through the observation of true
chemoselectivity (activating alkyne over allene), allowing direct
access to allene aldehyde 2 in excellent isolated yields.10 With
this information, we postulated that TA−Au catalysts might
offer a new opportunity to achieve dienal 3 if a compatible
tautomerization condition could be identified. Surely, this new
strategy will be more practical with the employment of much
more reactive yet chemoselective gold catalysts. To explore the
necessary tautomerization step, we prepared allene−aldehyde
2a and administered various isomerization conditions initially.
The reaction conditions are summarized in Figure 1A.
isomerization occurred even upon rotary evaporation (after
column). To explore this reaction, we first characterized all four
isomers using comprehensive NOE analysis (see the Support-
ing Information). With the structures of the four isomers
identified, we monitored the isomerization process using H
NMR.
1
As shown in Figure 1B, monitoring the reaction by NMR
indicated the complete conversion of 2a within 40 min at room
temperature. Kinetic isomers 3ac and 3ad (cis-double bonds at
γ/δ positions) were formed initially, similar to the allene
iodination reaction we reported previously.11 These two kinetic
isomers further isomerized into the thermodynamic isomers
3aa and 3ab (trans-double bonds at γ/δ positions) over time
(30 h), eventually reaching thermodynamic equilibrium with
3aa:3ab at a 2:1 ratio (overall >95% yields).12 This result
clearly demonstrated the feasibility of amine catalyzed allene−
aldehyde tautomerization for the synthesis of substituted
dienals as proposed.13 Moreover, the illustration of the reaction
kinetic profile provides valuable mechanistic insight for
achieving various dienal isomers selectively. With this crucial
mechanistic insight on the tautomerization step, we focused our
attention on the catalytic relay with vinyl ether 1 as the starting
materials.14 Again, the key concern is whether gold catalysts
work in this one-pot process given the allene-aldehyde
intermediate and the other competing side reactions described
earlier. To test this hypothesis, we charged various gold
catalysts (5%) to 1 in DCM with the presence of 20% L-proline.
The results are summarized in Figure 2.
Figure 2. TA−Au-promoted catalysis relay. Reaction conditions: 1a
(0.5 mmol), Au catalyst (5 mol %), L-proline (20 mol %) in
dichloromethane (0.4 M). Determined by 1H NMR using 1,3,5-
trimethoxybenzene as an internal standard. Other gold catalysts, such
as JohnPhosAuCl/AgOTf and XphosAuCl/AgOTf, were also screened
in one-pot conditions, giving less than 15% yield of desired product.
No desired allene intermediate was observed with 10% TfOH.
Figure 1. Allene−aldehyde 2a tautomerization. General reaction
conditions: 2a (0.5 mmol), L-proline (20 mol %) in solvent (0.4 M).
Yield was determined by H NMR using 1,3,5-trimethoxybenzene as
1
an internal standard.
With PPh3AuCl/AgOTf as catalyst, 1a was completely
consumed within 2 h. However, very little dienal 3a was
obtained (<10%). Significant amounts of decomposition were
observed as well as the 1,3-rearrangement described in Toste’s
previous report.15 Switching the gold catalyst to silver-free
PPh3AuNTf2 gave slower reaction kinetics, which suggested the
coordination of amine significantly decreased gold catalyst
reactivity. The combination of gold−oxonium catalysts and
proline gave no reaction at all after 24 h, once again
demonstrating a competitive binding of the secondary amine
toward gold cation. In the case of TA−Au, lower reactivity was
observed in the presence of amine catalysts (55% conversion of
1a after 2 h). However, the reaction was very clean with dienal
3a being observed as the only product (90% brsm yield,
As shown in Figure 1A, treating 2a with TfOH in MeOH
gave a trace amount of the desired dienal. Extending the
reaction time caused significant decomposition of 2a. Similar
results were observed with strong base (50% KO-t-Bu).
Fortunately, reacting 2a with catalytic proline (20%) gave
rapid allene isomerization even at room temperature (100%
conversion in 40 min), forming the desired dienal 3a in nearly
quantitive yield (>95%, combined all isomers).
With the presence of two conjugated double bonds, one
practical issue involved the formation of different isomers.
Although Alabugin and co-workers reported excellent double-
bond selectivity (only formed 3aa and 3ab with >20:1 ratio),
we found it was hard to isolate pure stereoisomers since
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3aa:3ab = 2:1). Considering that TA−Au could selectively
promote the reaction to the allene intermediate, we tested the
reaction in a one-pot, two-step fashion: (A) treating 1a with
TA−Au only and monitoring the reaction by TLC and (B)
adding proline into the reaction when 1a was all consumed.
With this revised procedure, 3a was formed in nearly quantitive
yield (>95%).
Since allene 2a was formed during the reaction, good kinetic
selectivity can be observed during the tautomerization step. For
example, quenching the dienal reaction mixtures 3a with
NaBH4 gave the isomer 4ac and 4aa (dienol products) as the
two major products with 65% and 15% isolated yields
correspondingly. Notably, the conjugated dienals 3 can undergo
rapid isomerization upon column chromatography. Thus, to
isolate pure isomers, reduction of the carbonyl is necessary.
With this optimal catalytic relay condition in hand, we explored
the reaction substrate scope.
Electron-donating and electron-withdrawing groups on both R1
and R2 positions do not influence the overall reactivity.
Notably, some special substituted groups, such as cyclopropyl
(4m) and TMS (4q), could be easily incorporated into the R2
position. Finally, terminal alkyne also worked well in this
transformation, giving the simple dienal in good overall yield
(4rb). The broad functional group tolerability highlighted the
great advantage of this new method over other literature-
reported approaches in preparing substituted dienals.
The stereoselectivity (Z/E isomers of double bond) is still an
important factor for this reaction. As mentioned above, during
our investigation, isomerization to thermodynamically stable
isomers (or mixtures) occurred even during chromatography
and rotary evaporation. Thus, stereoselectivity for the double
bond at the 5−6 positions can be easily achieved through
isomerization. By simply extending reaction time (12 h), 5,6-
trans double-bond products (a and b) were obtained in all
applicable cases, as shown in Figure 3. With substituted groups
at the C-4 position (from terminal alkyne R2 group), the ratio
between isomer a and b will be greatly influenced depending on
the size of the R2 group. As shown in Figure 4A, while R2 = n-
As shown in Figure 3, this reaction tolerates a wide substrate
scope, giving the desired dienals (diene alcohols) in excellent
Figure 4. TMS as removable conformational control group.
Bu gave a modest a:b ratio (2:1), both t-Bu and TMS greatly
improved the stereoselectivity, giving a:b >10:1. Notably, the
tolerance for TMS-substituted alkynes provides excellent
conformational control (12:1 ratio). Removal of the TMS
group gave the all trans−trans dienal as the only isomer
observed. Thus, with this removable TMS group, both double-
bond conformers a and b could be achieved with high
selectivity.
In conclusion, we report the application of gold catalysis and
amine catalysis relay as a new approach to achieve the synthesis
of substituted, conjugated-dienals with high efficiency. The
chemoselective TA−Au catalyst was identified as the optimal
choice while other gold catalyst gave poor to modest yields.
The wide substrate tolerance, mild reaction conditions, and
high efficiency (1% loading) hold promise for future one-pot
designs using readily available propargylvinyl ethers as starting
materials.
Figure 3. Reaction scope. General reaction conditions: 1 (0.5 mmol),
TA−Au catalyst (1 mol %) in dichloromethane (0.4 M) at rt, followed
by L-proline (20 mol %). The reaction was then diluted with 2 mL of
MeOH and quenched by NaBH4 (0.5 mmol). Isolated yields are
shown.
yields (combining all isomers) in almost all cases. The NaBH4
quench at the early stage of isomerization helped to trap the
major kinetic isomers, allowing isolation in good yield for most
of the cases. Various substituent groups are tolerated at the R1
position, including alkyl (such as 4k, 4l), aryl (such as 4a−4j),
and heterocycles (such as 4n, 4o). Similarly, aryl and alkyl
groups are both suitable for terminal-alkyne R2 position.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and NMR data. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Akhmedov, N. G.; Petersen, J. L.; Shi, X. Angew. Chem., Int. Ed. 2014,
53, 4657. (e) Wang, D.; Cai, R.; Sharma, S.; Jirak, J.; Thummanapelli,
S. K.; Akhmedov, N. G.; Zhang, H.; Liu, X.; Petersen, J. L.; Shi, X. J.
Am. Chem. Soc. 2012, 134, 9012. (f) Wang, Q.; Aparaj, S.; Akhmedov,
N. G.; Petersen, J. L.; Shi, X. Org. Lett. 2012, 14, 1334. (g) Wang, D.;
Zhang, Y.; Harris, A.; Gautam, L. N. S.; Shi, X. Adv. Synth. Catal. 2011,
353, 2584. (h) Wang, D.; Zhang, Y.; Cai, R.; Shi, X. Beilstein J. Org.
Chem. 2011, 7, 1014. (i) Chen, Y.; Yan, W.; Akhmedov, N.; Shi, X.
Org. Lett. 2010, 12, 344.
(10) (a) Duan, H.; Sengupta, S.; Petersen, J. L.; Akhmedov, N.; Shi,
X. J. Am. Chem. Soc. 2009, 131, 12100. (b) Wang, D.; Gautam, L. N.
S.; Bollinger, C.; Harris, A.; Li, M.; Shi, X. Org. Lett. 2011, 13, 2618.
(11) Wang, D.; Ye, X.; Shi, X. Org. Lett. 2010, 12, 2088.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xiaodong.shi@mail.wvu.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the NSF (CHE-1362057, CHE-1228336) and NSFC
(21228204) for financial support.
■
REFERENCES
■
(12) Changing the proline catalyst loading to 10% gave higher ratios
of 3aa:3ab (>12:1, 93%) after 20 h.
(1) For selected examples, see: (a) Dell’Amico, L.; Albrecht, L.;
Naicker, T.; Poulsen, P. H.; Jorgensen, K. A. J. Am. Chem. Soc. 2013,
135, 8063. (b) Delpech, B. In Advances in Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Academic Press: New York, 2014; Vol. 111, p 1.
(c) Janardanan, D.; Sunoj, R. B. Org. Biomol. Chem. 2011, 9, 1642.
(d) Popovsky, V. A.; Stepanov, A. V.; Grigorieva, N. Y. Russ. Chem.
Bull. 2012, 61, 1616. (e) Sakaguchi, T.; Okuno, Y.; Tsutsumi, Y.;
Tsuchikawa, H.; Katsumura, S. Org. Lett. 2011, 13, 4292. (f) Vidhani,
D. V.; Krafft, M. E.; Alabugin, I. V. Org. Lett. 2013, 15, 4462.
(g) Zhang, P.; Morken, J. P. J. Am. Chem. Soc. 2009, 131, 12550.
(2) For selected examples, see: (a) Albrecht, L.; Acosta, F. C.; Fraile,
A.; Albrecht, A.; Christensen, J.; Jorgensen, K. A. Angew. Chem., Int. Ed.
2012, 51, 9088. (b) Albrecht, L.; Gomez, C. V.; Jacobsen, C. B.;
Jorgensen, K. A. Org. Lett. 2013, 15, 3010. (c) Jiang, H.; Cruz, D. C.;
Li, Y.; Lauridsen, V. H.; Jorgensen, K. A. J. Am. Chem. Soc. 2013, 135,
5200. (d) Jurberg, I. D.; Chatterjee, I.; Tannert, R.; Melchiorre, P.
Chem. Commun. 2013, 49, 4869. (e) Kumar, I.; Ramaraju, P.; Mir, N.
A. Org. Biomol. Chem. 2013, 11, 709. (f) Li, X.; Lin, M.-H.; Han, Y.;
Wang, F.; Cheng, J.-P. Org. Lett. 2014, 16, 114. (g) Liu, J.-X.; Zhou,
Q.-Q.; Deng, J.-G.; Chen, Y.-C. Org. Biomol. Chem. 2013, 11, 8175.
(h) Ma, C.; Gu, J.; Teng, B.; Zhou, Q.-Q.; Li, R.; Chen, Y.-C. Org. Lett.
2013, 15, 6206. (i) Prieto, L.; Talavera, G.; Uria, U.; Reyes, E.; Vicario,
J. L.; Carrillo, L. Chem.Eur. J. 2014, 20, 2145. (j) Zhang, S.-J.;
Zhang, J.; Zhou, Q.-Q.; Dong, L.; Chen, Y.-C. Org. Lett. 2013, 15, 968.
(k) Zhu, K.; Huang, H.; Wu, W.; Wei, Y.; Ye, J. Chem. Commun. 2013,
49, 2157.
(13) For selected examples of amino catalysis, see: (a) Jurberg, I. D.;
Chatterjee, I.; Tannert, R.; Melchiorre, P. Chem. Commun. 2013, 49,
4869. (b) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.;
Bertelsen, S.; Jorgensen, K. A. Chem. Commun. 2011, 47, 632.
(c) Marigo, M.; Melchiorre, P. Chemcatchem. 2010, 2, 621. (d) List, B.
Angew. Chem., Int. Ed. 2010, 49, 1730. (e) Melchiorre, P. Angew.
Chem., Int. Ed. 2009, 48, 1360. (f) Melchiorre, P.; Marigo, M.; Carlone,
A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
(14) For selected examples of combining gold and organocatalysis,
see: (a) Hack, D.; Loh, C. C. J.; Hartmann, J. M.; Raabe, G.; Enders,
D. Chem.Eur. J. 2014, 20, 3917. (b) Barber, D. M.; Duris, A.;
Thompson, A. L.; Sanganee, H. J.; Dixon, D. J. ACS Catal. 2014, 4,
634. (c) Loh, C. C. J.; Enders, D. Chem.Eur. J. 2012, 18, 10212.
(d) Chiarucci, M.; di Lillo, M.; Romaniello, A.; Cozzi, P. G.; Cera, G.;
Bandini, M. Chem. Sci. 2012, 3, 2859. (e) Loh, C. C. J.; Badorrek, J.;
Raabe, G.; Enders, D. Chem.Eur. J. 2011, 17, 13409. (f) Hashmi, A.
S. K.; Hubbert, C. Angew. Chem., Int. Ed. 2010, 49, 1010. (g) Zhong,
C.; Shi, X. Eur. J. Org. Chem. 2010, 2999.
(15) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978.
(3) For the selected review of organocatalysis, see: (a) Loh, C. C. J.;
Enders, D. Chem.Eur. J. 2012, 18, 10212. (b) Hirano, K.; Piel, I.;
Glorius, F. Chem. Lett. 2011, 40, 786. (c) Kampen, D.; Reisinger, C.
M.; List, B. Top. Curr. Chem. 2010, 291, 395. (d) Bertelsen, S.;
Jorgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178. (e) Dondoni, A.;
Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (f) Yu, X.; Wang, W.
Org. Biomol. Chem. 2008, 6, 2037. (g) Enders, D.; Niemeier, O.;
Henseler, A. Chem. Rev. 2007, 107, 5606. (h) Seayad, J.; List, B. Org.
Biomol. Chem. 2005, 3, 719.
(4) (a) Bellassoued, M.; Salemkour, M. Tetrahedron 1996, 52, 4507.
(b) Zhang, P.; Morken, J. P. J. Am. Chem. Soc. 2009, 131, 12550.
(c) Kann, N.; Rein, T.; Aakermark, B.; Helquist, P. J. Org. Chem. 1990,
55, 5312.
(5) For an example of gold-catalyzed synthesis of unsaturated
carbonyl compounds, see: Hashmi, A. S. K.; Graf, K.; Ackermann, M.;
Rominger, F. ChemCatChem 2013, 5, 1200.
(6) Vindhani, D. V.; Krafft, M. E.; Alabugin, I. V. Org. Lett. 2013, 15,
4462. With [Rh(CO)2Cl]2 as catalyst, 10% loading and 50 °C are
required. [Rh] activates both alkyne and allene.
(7) (a) Marion, N.; Díez-Gonzalez, S.; Fremont, P.; Noble, A. R.;
Nolan, S. P. Angew. Chem., Int. Ed. 2006, 45, 3647. (b) Marion, N.;
Carlqvist, P.; Gealageas, R.; Fremont, P.; Maseras, F.; Nolan, S. P.
Chem.Eur. J. 2007, 13, 6437.
(8) Sherry, B. D.; Maus, L.; Laforteza, B. N.; Toste, F. D. J. Am.
Chem. Soc. 2006, 128, 8132.
(9) (a) Xi, Y.; Wang, Q.; Su, Y.; Li, M.; Shi, X. Chem. Commun. 2014,
50, 2158. (b) Xi, Y.; Wang, D.; Ye, X.; Akhmedov, N. G.; Petersen, J.
L.; Shi, X. Org. Lett. 2014, 16, 306. (c) Wang, Q.; Motika, S. E.;
Akhmedov, N. G.; Petersen, J. L.; Shi, X. Angew. Chem., Int. Ed. 2014,
53, 5418. (d) Xi, Y.; Dong, B.; McClain, E. J.; Wang, Q.; Gregg, T. L.;
293
DOI: 10.1021/ol503393a
Org. Lett. 2015, 17, 290−293