One-pot oxidation/isomerization of Z-allylic alcohols with oxygen as stoichiometric oxidant

Article abstract of DOI:10.1021/ol302420k

A method for generating (E)-α,β-unsaturated aldehydes from Z-allylic alcohols or E/Z-mixtures is described. The one-pot procedure involves a Cu-catalyzed oxidation followed by an organocatalytic Z/E-isomerization with N,N-dimethylaminopyridine (DMAP).

Full text of DOI:10.1021/ol302420k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
One-Pot Oxidation/Isomerization
of Z‑Allylic Alcohols with Oxygen
as Stoichiometric Oxidant
€
Daniel Konning, Wolf Hiller, and Mathias Christmann*
Faculty of Chemistry, TU Dortmund University, Otto-Hahn-Str. 6, D-44227 Dortmund,
Germany
mathias.christmann@tu-dortmund.de
Received August 31, 2012
ABSTRACT
A method for generating (E)-R,β-unsaturated aldehydes from Z-allylic alcohols or E/Z-mixtures is described. The one-pot procedure involves a Cu-
catalyzed oxidation followed by an organocatalytic Z/E-isomerization with N,N-dimethylaminopyridine (DMAP).
The finite availability of fossil resources urges chemists to
rethink some fundamental elements of synthesis planning.1
Strategies for designing more eco-efficient and cost-effective
chemical transformations are overlapping with the agendas
of “green chemistry” and “sustainable chemistry”.2 Thus,
the avoidance of isolating and purifying intermediates
and the joining of successive reaction steps into one-pot
processes3 are highly desirable. Many synthetic routes pro-
ceed via nonstorable aldehyde intermediates that are gener-
ated shortly before use. Telescoping the oxidation step with
follow-up reactions obviates the requirement for isolating
the aldehyde and provides cost savings in solvent usage and
reaction vessel time. The main obstacle for merging reactions
with an initial oxidation step4 is overcoming the often harsh
reaction conditions along with stoichiometric byproducts.
While organocatalytic reactions with preceding MnO2 oxi-
dation have been reported,5 it is desirable to reduce the
amount of oxidant. Rueping et al. recently reported an
oxidative iminium-activated cascade using tetra-n-propyl-
ammonium perrhuthenate (TPAP) as the catalyst and
N-methylmorpholine-N-oxide (NMO) as the oxidant.6
Further improvements could be achieved with O2 (or aero-
bic oxygen) as well as H2O2. Both oxidants generate H2O as
the sole byproduct that is usually tolerated by the subsequent
organocatalytic transformations.
Herein, we report our efforts in cascading an oxidation
with an organocatalytic isomerization step that emerged
from the preparation of a series differently protected E-4-
hydroxybut-2-enal (E-1) derivatives for a total synthesis
campaign. Published routes involve cross-metathesis of
double protected Z-but-2-ene-1,4-diols with acrolein7
or E-selective half-reduction of but-2-yne-1,4-diol with
RedAl or LiAlH4 followed by monoprotection.8
(1) Sheldon, R. A. Catal. Today 2011, 167, 3.
(2) (a) Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39, 301. (b)
Sheldon, R. A.; Arends, I.; Hanefeld, U. in Green Chemistry and
Catalysis; Wiley-VCH: Weinheim, Germany, 2007. (c) Sheldon, R. A.
Chem. Commun. 2008, 3352.
For economic reasons and safety concerns we decided
against large-scale metal hydride reductions but opted for
(3) (a) Vaxelaire, C.; Winter, P.; Christmann, M. Angew. Chem., Int.
Ed. 2011, 50, 3605. (b) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2011, 50, 8492.
(4) Taylor, R. J. K.; Reid, M.; Foot, J.; Raw, S. A. Acc. Chem. Res.
2005, 38, 851.
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(6) (a) Rueping, M.; Sunden, H.; Sugiono, E. Chem.;Eur. J. 2012,
18, 3649. (b) Rueping, M.; Dufour, J.; Maji, M. S. Chem. Commun. 2012,
48, 3406.
(7) (a) Hansen, E. C.; Lee, D. Org. Lett. 2004, 6, 2035. (b) Skucas, E.;
Zbieg, J. R.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 5054. (c)
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(5) For example, see: Maki, B. E.; Chan, A.; Phillips, E. M.; Scheidt,
K. A. Tetrahedron 2009, 65, 3102.
r
10.1021/ol302420k
XXXX American Chemical Society

the oxidation of monoprotected Z-but-2-ene-1,4-diols9
(Z-2) followed by an Z/E-isomerization. In the literature,
oxidations of Z-2 have been described with virtually any
known oxidant.10 Interestingly, only pyridine-based oxi-
dations (PCC,11 ParikhÀDoering12) result in concomitant
Z/E-isomerization. We speculated that pyridine is the
responsible isomerization catalyst. Indeed, treatment of
Z-1 with pyridine (1 equiv)13 results in a clean isomeriza-
tion to afford E-1 within 15 min. At this time, we took
notice of an efficient aerobic CuI(bpy)-TEMPO oxidation
of primary alcohols reported by Stahl.14 His efficient
protocol is based on pioneering work by Semmelhack,15
catalysts that would be expected to survive the oxidation
conditions. Interestingly, Stahl uses N-methylimidazole
(NMI), an aromatic amine base additive that could act as
the isomerization catalyst. Figure 1 depicts the catalytic
activity of pyridine, NMI, and other nitrogen-based cata-
lysts (0.25 M Z-2b in MeCN-d3, R = Ac, 1 mol % catalyst).
Pyridine was the slowest of all tested amines and led to just
4% conversion in the observed time window (185 min).
NMI was significantly faster (11% conversion) but still
not a useful catalyst. In 1985, Keck19 reported N,N-
dimethylaminopyridine (DMAP)20 as the catalyst for the
isomerization of R,β-unsaturated thioesters, and Evans21
ꢀ 16
Marko, Sheldon,17 and Koskinen.18 As monoprotected
Z-but-2-ene-1,4-diol was one of the most reactive sub-
strates in Stahl’s screening, we used his optimized condi-
tions and added pyridine (1 equiv) after completion of the
oxidation (Scheme 1). Aldehyde E-1 was isolated in 87%
yield. Although this one-pot procedure already solves the
initial problem, we were not satisfied with the efficiency
of the isomerization.
Scheme 1. One-Pot OxidationÀIsomerization of Z-2a Using
Stahl’s Conditions and a Stoichiometric Amount of Pyridine
A plausible mechanism involves a reversible 1,4-addi-
tion of pyridine and is related to the MoritaÀBaylisÀ
Hillman (MBH) and the RauhutÀCurrier (RC) reactions.
Therefore, we tested a series of successful MBH and RC
Figure 1. Conversion of Z-1b vs time plots of the Z/E-isomer-
ization with different aromatic amines as catalyst.
(8) (a) Organ, M. G.; Cooper, J. T.; Rogers, L. R.; Soleymanzadeh,
F.; Payl, F. J. Org. Chem. 2000, 65, 7959. (b) Crimmins, M. T.; DeBaillie,
A. C. J. Am. Chem. Soc. 2006, 128, 4936.
(9) E-But-2-ene-1,4-diol is significantly more expensive.
(10) (a) Swern: Uenishi, J.; Motoyama, M.; Kimura, Y.; Yonemitsu,
O. Heterocycles 1998, 47, 439. (b) PCC: Roush, W. R.; Reilly, M. L.;
Koyama, K.; Brown, B. B. J. Org. Chem. 1997, 62, 8708. (c) PDC:
Crilley, M. M. L.; Golding, B. T.; Pierpoint, C. J. Chem. Soc., Perkin
Trans. 1 1988, 2061. (d) TPAP/NMO: Zhang, P.; Morken, J. P. J. Am.
Chem. Soc. 2009, 131, 12550.
used a similar isomerization in the total synthesis of
lepicidine. Apart from these two examples, there has been
no systematic investigation of pyridine/DMAP-catalyzed
isomerizations. In our test reaction, DMAP was a very
active catalyst resulting in complete conversion. Using
Mayr’s nucleophilicity parameter N as a guide,22 we tested
more nucleophilic analogs of DMAP (N = 15 in MeCN).
The recently reported Bn-Super-DMAP23 (N = 18)
(11) Ramachandran, P. V.; Burghardt, T. E.; Reddy, M. V. R. J. Org.
Chem. 2005, 70, 2329.
(12) Boone, M. A.; McDonald, F. E.; Lichter, J.; Lutz, S.; Cao, R.;
Hardcastle, K. I. Org. Lett. 2009, 11, 851.
(13) It is possible to use substoichiometric amounts of pyridine at the
(17) (a) Dijksman, A.; Arends, I. W. C. E.; Sheldon, R. A. Chem.
ꢀ
Commun. 1999, 1591. (b) Dijksman, A.; Marino-Gonzalez, A.; Mirata i
Payeras, A.; Arends, I. W. C. E.; Sheldon, R. A. J. Am. Chem. Soc. 2001,
123, 6826. (c) Sheldon, R. A.; Arends, I. W. C. E.; Ten Brink, G.-J.;
Dijksman, A. Acc. Chem. Res. 2002, 35, 774. (d) Dijksman, A.; Arends, I.
W. C. E.; Sheldon, R. A. Org. Biomol. Chem. 2003, 1, 3232. (e) Gamez,
P.; Arends, I. W. C. E.; Reedijk, J.; Sheldon, R. A. Chem. Commun. 2003,
2414. (f) Gamez, P.; Arends, I. W. C. E.; Sheldon, R. A.; Reedijk, J. Adv.
Synth. Catal. 2004, 346, 805.
(18) Kumpulainen, E. T. T.; Koskinen, A. M. P. Chem.;Eur. J.
2009, 15, 10901.
(19) Keck, G. E.; Boden, E. P.; Mabury, S. A. J. Org. Chem. 1985, 50,
709.
cost of extended reaction times.
(14) (a) Hoover, J. M.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133,
16901. (b) Hoover, J. M.; Steves, J. E.; Stahl, S. S. Nat. Protoc. 2012, 7,
1162. (c) For an alternative organocatalytic oxidation, see: Shibuya, M.;
Osada, Y.; Sasano, Y.; Tomizawa, M.; Iwabuchi, Y. J. Am. Chem. Soc.
2011, 133, 6497.
ꢀ
(15) (a) Semmelhack, M. F.; Schmid, C. R.; Cortes, D. A.; Chou,
C. S. J. Am. Chem. Soc. 1984, 106, 3374. (b) Semmelhack, M. F.; Schmid,
ꢀ
C. R.; Cortes, D. A. Tetrahedron Lett. 1986, 27, 1119.
ꢀ
(16) (a) Marko, I. E.; Giles, P. R.; Tsukazaki, M.; Brown, S. M.;
ꢀ
Urch, C. J. Science 1996, 274, 2044. (b) Marko, I. E.; Gautier, A.;
€
(20) Steglich, W.; Hofle, G. Tetrahedron Lett. 1970, 54, 4727.
ꢀ
Chelle-Regnaut, I.; Giles, P. R.; Tsukazaki, M.; Urch, C. J.; Brown,
ꢀ
(21) Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.
(22) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66.
(23) (a) De Rycke, N.; Berionni, G.; Couty, F.; Mayr, H.; Goumont,
R.; David, O. R. P. Org. Lett. 2011, 13, 530. (b) For a review, see: De
Rycke, N.; Couty, F.; David, O. R. P. Chem.;Eur. J. 2011, 17, 12852.
S. M. J. Org. Chem. 1998, 63, 7576. (c) Marko, I. E.; Gautier, A.;
Mutonkole, J.-L.; Dumeunier, R.; Ates, A.; Urch, C. J.; Brown, S. M.
ꢀ
J. Organomet. Chem. 2001, 624, 344. (d) Marko, I. E.; Gautier, A.;
Dumeunier, R.; Doda, K.; Philippart, F.; Brown, S. M.; Urch, C. J.
Angew. Chem., Int. Ed. 2004, 43, 1588.
B
Org. Lett., Vol. XX, No. XX, XXXX

showed a remarkable increase in the reaction rates, and the
well-established MBH-catalyst DABCO (N = 19) was
even faster. The most effective candidate of our screening
was 9-azajulolidine,24 an exceptional acylation catalyst25
that was recently used in aza-MBH reactions.26
Table 1. One-Pot OxidationÀIsomerization of Monoprotected
Z-But-2-ene-1,4-diols (Z-2)
Despite the good correlation between reaction rates and
nucleophilicity parameters, we are not convinced that the
addition of the catalyst is the rate-limiting step. Studies of
Houk and Krenske27 on 1,4-additions of thiols to vinyl-
ketones suggest that Z-alkenones react faster than the
corresponding E-diastereomers. If the principle of the
microscopic reversibility is applicable, the elimination to
the thermodynamically more stable E-isomer should be
rate-limiting, thereby making the nucleofugic properties of
the catalyst the dominating factor. In summary, DMAP is
a good and affordable catalyst possessing sufficient activ-
ity. If a lower catalyst loading is desired or less reactive
substrates are used, 9-azajulolidine is an excellent choice.
After investigating the second step of the combined
oxidationÀisomerization, we tried to optimize the one-
pot procedure (Table 1). Employing an oxygen balloon
allowed a lower catalyst loading to be used, which mini-
mized inferences inthe subsequent transformation asbeing
more important than the use of air as oxidant. At this
point, we wondered whether DMAP could act as an
aromatic base in the oxidation step. Replacing NMI by
DMAP not only was possible but also resulted in an
accelerated oxidation (entries 1 and 2). Together with
changing the ligand to the more electron-rich diMeObpy,17f
it was now possible to carry out the one-pot oxida-
tionÀisomerization with 1 mol % CuI/TEMPO/diMeObpy
and 2 mol % DMAP. Gratifyingly, the positive effects of
DMAP and diMeObpy appear to be synergistic (entries
1À4). The oxidation has been used in a preparative28 setting
up to 0.1 mol scale. Alternative protecting groups did not
affect the rate of the oxidation step but showed a marked
influence on the isomerization rate (entries 5À8).
entry
2, R
t [h]
ligand
bpy
base
E/Za
[%]b
1c
2c
3c
4c
5d
6d
7d
8c
2b, Ac
1.5
1.5
1.5
1.5
1.25
3.5
5
NMI
7:93
99:1
15:85
99:1
99:1
99:1
99:1
99:1
20
58
78
89
86
96
86
95
2b, Ac
bpy
DMAP
NMI
2b, Ac
diMeObpy
diMeObpy
diMeObpy
diMeObpy
diMeObpy
diMeObpy
2b, Ac
DMAP
DMAP
DMAP
DMAP
DMAP
2a, TBS
2c, Bn
2d, PMB
2e, THP
2.5
a Determined by NMR spectroscopy. b Isolated yield. c 1 mmol scale.
d 10 mmol scale.
Table 2. Substrate Scope for Oxidation of Allylic Alcohols
With optimized conditions for the oxidation of Z-2 in
hand, we investigated the scope of this one-pot process for
other allylic alcohols. Our method is well-suited for sub-
strates where the E-isomer is less available or, more
importantly, where the allylic alcohol is an E/Z-mixture.
In such a case, the E/Z-ratio can be driven into the
thermodynamic equilibrium without the need for chroma-
tographic separation of the allylic alcohol. As shown in
(24) Held, I.; Xu, S.; Zipse, H. Synthesis 2007, 1185 and references
therein.
(25) Heinrich, M. R.; Klisa, H. S.; Mayr, H.; Steglich, W.; Zipse, H.
Angew. Chem., Int. Ed. 2003, 42, 4826.
(26) Lindner, C.; Tandon, R.; Liu, Y.; Maryasin, B.; Zipse, H. Org.
Biomol. Chem. 2012, 10, 3210.
(27) Krenske, E. H.; Petter, R. C.; Zhu, Z.; Houk, K. N. J. Org.
Chem. 2011, 76, 5074.
(28)
a Isolated yield. b 9-Azajulolidine was used instead of DMAP. c After
completion of the oxidation, 9-azajulolidine (5 mol %) was added and
the reaction mixture was heated to 95 °C. d 1 mmol scale. e 10 mmol scale.
The products were purified by distillation. f c = 0.5 M.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 2, allylic alcohol 329 was obtained as a 2:1 Z/E
isomeric mixture by a Wittig olefination/Dibal-H reduc-
tion sequence from TBS-protected lactaldehyde. The oxi-
dationÀisomerization of 3 to aldehyde 4 reveals that an
alkyl substitution in the 4-position slows down the rate of
the isomerization (entry 1). Replacing DMAP with 9-aza-
julolidine (entry 2) led to a significant acceleration of the
reaction. Similarly, removal of the 4-silyloxy group re-
sultedinalowerisomerization rateandnecessitatedthe use
of 9-azajulolidine (entry 3). In the bidirectional elongation
of a dialdehyde, an olefination with an E/Z-selectivity of
95:5 accumulates to an EE/EZ-ratio of 90:10, rendering a
separation of the minor isomer necessary. Taking advan-
tage of our stereoconvergent oxidation, even starting from
an EE/EZ-ratio of 1:99 of the bisallylic alcohol 7 (entry 4)
results in a 99:1 EE/EZ-ratio of the dialdehyde 8, an
important building blockin the synthesisofpheromones.30
The isomerization of 2-Me-substituted R,β-unsaturated
aldehydes such as 931 proved to be very challenging
(entry 5). Upon completion of the oxidation, only heating
to reflux resulted in a complete isomerization to give
aldehyde 10. The oxidation of allylic alcohols Z-11 and
E-11 under standard conditions showed comparable oxi-
dation rates with a slow Z/E-isomerization (cf. entries 6
and 7). The low catalyst loading of 1 mol % (CuI/ligand/
TEMPO) makes our protocol attractive even without
accompanying isomerization. The oxidation of the allylic
alcohol 13 is one step in our total synthesis of ripostatin
B.32 The desired aldehyde 14 could be obtained cleanly in
89% yield (entry 8).
Scheme 2. One-Pot Oxidation/DielsÀAlder Reaction
catalyzed isomerization could be coupled with the catalytic
oxidation in a one-pot fashion. As a model reaction, we
selected an organocatalytic intramolecular DielsÀAlder
reaction33 first described by Koskinen34 and MacMillan35
that has been used in our group in total syntheses of
UCS1025A36 and amaminol B.37 Scheme 2 shows the
DielsÀAlder stepin the synthesisof the keydecalin subunit
16 of UCS1025A from trienol 15. To test the compatibility
of the DielsÀAlder reaction with the oxidation conditions,38
we carried out both steps separately (with isolation of the
aldehyde) and as a one-pot procedure. In both cases, very
similar yields and selectivities were observed. On this basis,
we are optimistic that other organocatalytic processes could
be successfully coupled with Cu-catalyzed oxidations.
We have developed a stereoconvergent one-pot oxidationÀ
isomerization of allylic alcohols with oxygen as the oxidant
and DMAP as the organocatalyst. Our optimized condi-
tions, with or without isomerization, constitute an efficient
protocol (1 mol % CuI/TEMPO/diMeObpy and 2 mol %
DMAP) that should allow for telescoping with other orga-
nocatalytic transformations39 and further displace tradi-
tional superstoichiometric oxidants such as MnO2.
At this point, we explored whether other organocatalytic
reactions of R,β-unsaturated aldehydes than the DMAP-
(29) Chin, Y.-J.; Wang, S.-Y.; Loh, T.-P. Org. Lett. 2009, 11, 3674.
€
(30) de Figueiredo, R. M.; Berner, R.; Julis, J.; Liu, T.; Turp, D.;
Acknowledgment. We thank the Mercator Research
Center Ruhr (MERCUR) for financial support. We also
thank Dr. Olivier David (University of Versailles) for a gift
of Bn-Super-DMAP and helpful discussions and Prof.
Hendrik Zipse and Prof. Herbert Mayr (both University
of Munich) for helpful discussions.
Christmann, M. J. Org. Chem. 2007, 72, 640.
(31) Mortensen, M. S.; Osbourn, J. M.; O’Doherty, G. A. Org. Lett.
2007, 9, 3105.
(32) Winter, P.; Hiller, W.; Christmann, M. Angew. Chem., Int. Ed.
2012, 51, 3396.
(33) Merino, P.; Marques-Lopez, E.; Tejero, T.; Herrera, R. P.
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Synthesis 2010, 1.
€ €
(34) (a) Selkala, S. A.; Koskinen, A. M. P. Eur. J. Org. Chem. 2005,
1620. (b) Kumpulainen, E. T. T.; Koskinen, A. M. P.; Rissanen, K. Org.
Lett. 2007, 9, 5043.
(35) Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 11616.
(36) (a) Lambert, T. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2006,
128, 426. (b) de Figueiredo, R. M.; Voith, M.; Frohlich, R.; Christmann,
Supporting Information Available. Experimental proce-
dure and compound characterization. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
€
€
M. Synlett 2007, 391. (c) de Figueiredo, R. M.; Frohlich, R.; Christmann,
M. Angew. Chem., Int. Ed. 2007, 46, 2883.
(39) After submission of our manuscript, an aerobic oxidation-
initiated organocatalytic multistep transformation of allylic alcohols
was reported using 10 mol% CuI/TEMPO as a catalyst: Ho, X.-H.; Oh,
H.-J.; Jang, H.-Y. Eur. J. Org. Chem. 2012DOI: 10.1002/ejoc.201200863.
(37) Jacobs, W. C.; Christmann, M. Synlett 2008, 247.
(38) The idea to couple a Cu-based oxidation and an organocatalytic
DielsÀAlder reaction marked the starting point of Koskinen’s detailed
oxidation studies (cf. ref 18 and Kumpulainen, E. T. T. Dissertation,
University of Aalto, 2010, pp 89À90).
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX