Multistep organocatalysis for the asymmetric synthesis of multisubstituted aldehydes from allylic alcohols

Article abstract of DOI:10.1002/ejoc.201200863

The combination of a copper complex and a chiral amine organocatalyst induces the formation of multifunctionalized aldehydes from aromatic and aliphatic allylic alcohols. Reactions occur with excellent levels of enantioselectivity, under environmentally benign conditions, and without involving stoichiometric amounts of chemical oxidants for the oxidation of the allylic alcohols or rigorous reaction conditions for transition-metal catalysis.

Full text of DOI:10.1002/ejoc.201200863

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200863
Multistep Organocatalysis for the Asymmetric Synthesis of Multisubstituted
Aldehydes from Allylic Alcohols
Xuan-Huong Ho,[a] Hyun-Ji Oh,[a] and Hye-Young Jang*[a]
Keywords: Organocatalysis / Enamines / Copper / Michael addition / Aldehydes
The combination of a copper complex and a chiral amine or- environmentally benign conditions, and without involving
ganocatalyst induces the formation of multifunctionalized al-
dehydes from aromatic and aliphatic allylic alcohols. Reac-
tions occur with excellent levels of enantioselectivity, under
stoichiometric amounts of chemical oxidants for the oxidation
of the allylic alcohols or rigorous reaction conditions for tran-
sition-metal catalysis.
thetic methods in which selective bond formations and
multifunctional group transformations occur in the same
vessel.[6]
Introduction
Transition-metal catalysis, organocatalysis, and bio-
catalysis have attracted much attention in the field of or-
ganic synthesis because their reactions can provide highly
complex molecules as well as good chemo-, regio-, and ster-
eoselectivity, thus allowing organic synthesis to be applied
in the fine chemical, pharmaceutical, and other industries.
In recent years, dual catalytic systems, which combine dif-
ferent catalytic species among transition-metal complexes,
organic catalysts, and biocatalysts, have been reported for
multifunctionalization and multistep, one-pot reactions.[1]
In particular, transition-metal catalysis combined with en-
amine/iminium organocatalysis has often been employed to
induce nonconventional functionalization of aldehydes/
ketones in a stereoselective manner. By adding stoichiomet-
ric or catalytic loadings of transition-metal complexes, the
enamine intermediates formed from chiral amine catalysts
and carbonyl compounds can undergo a single-electron oxi-
dation process, leading to the formation of enamine radicals
that promote singly occupied molecular orbital (SOMO)
catalysis.[2] Rather than oxidizing enamines, transition-
metal complexes activate electrophiles, which then react
with enamine intermediates to afford unconventional cou-
pling products with high levels of stereoselectivity.[3–5] In
addition to the above-mentioned reactions where the metal
catalyst and organocatalyst are added simultaneously, the
sequential addition of transition-metal complexes and or-
ganocatalysts induces a new type of dual catalytic reaction.
Such tandem reactions involving sequential addition of
metal and enamine catalysts have been intensively studied
to provide efficient, step-economical, and practical syn-
Although a number of multicatalytic reactions using
both organocatalysts and transition-metal catalysts have
been implemented and their powerful advantages illus-
trated, one of the limitations of dual metal–organocatalytic
reactions is that the rigorous reaction conditions require an
inert atmosphere and purified solvents to maintain the tran-
sition-metal catalyst reactivity. Therefore, a new combina-
tion of metal catalyst and organocatalyst that promotes se-
lective multifunctionalization under aerobic conditions was
considered. As an aerobic metal-catalyzed reaction, copper-
catalyzed oxidation (step 1) is conducted under aerobic con-
ditions and with unpurified solvent systems, where no haz-
ardous and toxic oxidants or anhydrous reaction setups are
required.[7–10] The aerobic oxidation products formed from
allylic alcohols were subjected to organocatalyzed Michael
addition conditions (iminium catalysis, step 2).[11–13] By
combining aerobic oxidation of allylic alcohols and organo-
catalyzed Michael addition, large amounts of solvents and
silica gel to purify the resulting aldehydes are not required,
and storage of the relatively unstable aldehydes is avoided.
A copper catalyst used for alcohol oxidation promotes the
highly stereoselective oxyamination of β-substituted alde-
hydes through the involvement of enamine intermediates
(step 3).[2c,2j,2n–2s,3,14] Notably, our multicatalytic system in-
volving Cu complexes and chiral secondary amines fur-
nishes a three-step reaction (oxidation/iminium/enamine
catalysis) in a single-pot with high levels of stereoselectivity
under environmentally benign and step-economical condi-
tions.[15]
[a] Energy Systems Research, Ajou University,
Suwon 443-749, Korea
Fax: +82-31-219-1615
E-mail: hyjang2@ajou.ac.kr
Results and Discussion
Homepage: http://ajou.ac.kr/~hyjang2
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200863.
Initially, a two-step tandem sequence comprising Cu-
catalyzed oxidation and chiral amine catalyzed Michael ad-
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X.-H. Ho, H.-J. Oh, H.-Y. Jang
SHORT COMMUNICATION
dition was conducted (Table 1). For aerobic oxidation of and high enantioselectivities. 2-Naphthyl- and 2-furyl-sub-
allylic alcohols, a previously reported CuI-TEMPO com- stituted allylic alcohols 5a and 6a were converted into de-
plex was utilized under an oxygen atmosphere.[8] Upon ex- sired products 5b and 6b in 64 and 74% yield with of 96
posure of cinnamyl alcohol (1a) to a solution of CuCl and 93%ee, respectively. Cyclopropyl-substituted allylic
(10 mol-%) and TEMPO (10 mol-%) under 1 atm of oxy- alcohol 7a afforded Michael addition product 7b in 55%
gen, the complete oxidation of 1a occurred in less than 1 h yield with 80%ee. By performing tandem oxidation/imin-
to form cinnamaldehyde (α,β-unsaturated aldehyde). The ium catalytic reactions, the isolation and purification pro-
chiral amine catalyst, (S)-2-[diphenyl(trimethylsilyloxy)- cesses of the oxidation products were omitted, allowing vol-
methyl]pyrrolidine (10 mol-%), and diethyl malonate atile α,β-unsaturated aldehydes to participate in the asym-
(3 equiv.) were then added to the Cu-catalyzed oxidation metric iminium catalysis, as shown in entry 7 (Table 2).
reaction solution. Without any additive, β-substituted alde-
Table 2. Examples of tandem oxidation/Michael addition of allylic
hyde 1b was formed in 39% yield with 80%ee. To improve
the yield and enantioselectivity, various acid and base addi-
tives were tested. Brønsted bases were expected to depro-
tonate malonate and improve the nucleophilicity of malon-
ate nucleophiles.[13f] Depending on the countercation of the
inorganic base, the yield was increased to 66% and the
enantioselectivity to 89% (Table 1, entries 2–4). Because the
addition of acid additives promotes iminium ion formation
from cinnamyl aldehyde and chiral diphenylprolinol silyl
ether, a few carboxylic acids were added to gauge the in-
crease in yield and enantioselectivity.[13i] In the presence of
carboxylic acids (30 mol-%), the enantioselectivity dramati-
cally increased to ee values higher than 95% (Table 1, en-
tries 5–7). Among the acid additives, benzoic acid showed
the highest yield (71%). Furthermore, with even lower load-
ings of benzoic acid (10 mol-%), the yield of 1b was im-
proved to 85% and good enantioselectivity was maintained
(95%ee; Table 1, entry 8).
alcohols.[a]
Table 1. Optimization of tandem oxidation/Michael addition of 1a.
[a] A mixture of aldehyde (0.25 mmol), CuCl (10 mol-%), and
TEMPO (10 mol-%) in DMF was stirred under 1 atm of oxygen
for
1 h.
(S)-2-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine
(10 mol-%), benzoic acid (indicated mol-%), and diethyl malonate
(3 equiv.) were then added to the Cu-catalyzed oxidation reaction
solution until starting materials are consumed completely.
[b] PhCO2H (10 mol-%). [c] PhCO2H (50 mol-%).
Using the optimized conditions from Table 1, a series of
During the tandem oxidation/Michael addition of 1a, the
substrates were tested with malonates (Table 2). The chiral product of tandem oxidation/iminium/enamine catalysis,
amine catalyzed addition of dimethyl malonate to the oxid- compound 1c, was observed in low yield (Ͻ5%). Presum-
ized cinnamyl alcohol afforded desired Michael addition ably, TEMPO, which was used as a ligand to the copper
product 2b in 43% yield with 94%ee (Table 2, entry 2). ion during oxidation, was added to the α-position of 1b to
Next, a variety of allylic alcohols were exposed to the reac- give 1c.[16] Upon diethyl malonate addition to the iminium
tion conditions in the presence of diethyl malonate (Table 2, intermediate derived from the chiral diphenylprolinol silyl
entries 3–7). Halogen-substituted cinnamyl alcohols 3a and ether and an α,β-unsaturated aldehyde, the enamine inter-
4a participated in the reaction and provided good yields mediate was formed and reacted with the copper-coordi-
2
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Organocatalysis for the Asymmetric Synthesis of Aldehydes
nated TEMPO complex.[2c,2o,3a,3c] To improve the yield of excellent enantioselectivity (Table 4). To perform the three-
the tandem oxidation/Michael addition/α-oxyamination, step reaction, the allylic alcohols were subjected to a solu-
2 equiv. of TEMPO was added in the presence of adaman-
tine-1-carboxylic acid (30 mol-%) to give single dia-
Table 4. Examples of tandem oxidation/Michael addition/oxyamin-
stereomer 1c in 21% yield with 99%ee (Table 3, entry 1).[17]
ation of allylic alcohols.[a]
Next, different amounts of carboxylic acid were applied; 1c
was formed in 45% yield with 96%ee with the use of
10 mol-% of the acid (Table 3, entry 4). Instead of sequen-
tial addition, a three-step, one-pot reaction was attempted;
product 1c was obtained in 33% yield with 95%ee (Table 3,
entry 6). The low yield of 1c stems from incomplete oxyam-
ination of Michael addition product 1b.
Table 3. Tandem oxidation/Michael addition/α-oxyamination of 1a.
[a] AdamCO2H = Adamantane-1-carboxylic acid. [b] Reaction
time = 48 h. [c] One-pot reaction.
[a] A mixture of the aldehyde (0.25 mmol), CuCl (10 mol-%),
and TEMPO (10 mol-%) in DMF was stirred under 1 atm of
oxygen for 1 h. (S)-2-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine
(10 mol-%), adamantane-1-carboxylic acid (30 mol-%), diethyl ma-
lonate (3 equiv.), and TEMPO (2 equiv.) were then added to the
Cu-catalyzed oxidation reaction solution until the starting materi-
A series of aromatic- and aliphatic-substituted allylic
alcohols were tested with diethyl malonate; the tandem oxi-
dation/malonate addition/TEMPO addition products were
obtained as single diastereomers in moderate yields with als were consumed completely.
Scheme 1. Catalytic cycle for the tandem oxidation/iminium catalysis and the tandem oxidation/iminium/enamine catalysis.
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X.-H. Ho, H.-J. Oh, H.-Y. Jang
SHORT COMMUNICATION
(10 mol-%), and TEMPO (10 mol-%) was stirred under 1 atm of
oxygen for 1 h. (S)-2-[Diphenyl(trimethylsilyloxy)methyl]pyrrolid-
ine (10 mol-%), adamantane-1-carboxylic acid (30 mol-%), diethyl
malonate (3 equiv.), and TEMPO (2 equiv.) were then added to the
Cu-catalyzed oxidation reaction solution until the α,β-unsaturated
aldehyde was consumed completely.
tion containing CuCl, TEMPO, and oxygen. Subsequent
addition of chiral diphenylprolinol silyl ether, TEMPO, ma-
lonate, and adamantane-1-carboxylic acid to the Cu-cata-
lyzed oxidation reaction mixture afforded the desired α,β-
substituted products. Compared to the two-step reaction re-
sults in Table 2, most allylic alcohols were converted into
the tandem reaction products with improved enantio-
selectivity. In particular, cyclopropyl-substituted aldehyde
7a was transformed into 7c with 91%ee (Table 4, entry 4),
whereas tandem oxidation/malonate addition product 7b
showed an 80%ee. In addition to 7a, crotyl alcohol (8a)
was subjected to the reaction conditions to give 8c in lower
Supporting Information (see footnote on the first page of this arti-
cle): General information and reaction procedure, product charac-
1
terization, copies of the H NMR and 13C NMR spectra.
Acknowledgments
yield and selectivity (21% yield, 88%ee; Table 4, entry 5) This study was supported by the Korea Research Foundation (No.
2011-0030745 and 2011-0005996). The authors thank Korean Basic
Science Institute (Deagu) for mass spectra.
than 7a.
A
plausible reaction mechanism is illustrated in
Scheme 1. Step 1 is the simple aerobic oxidation of the all-
ylic alcohol. The oxidized compound enters into the imin-
ium catalytic cycle to form iminium intermediate I. As pro-
posed for previous iminium-catalyzed Michael addition re-
actions,[11–13] the chirality is installed simultaneously with
the addition of diethyl malonate. Without the addition of
TEMPO, 1b is generated after hydrolysis of II. With cop-
per-assisted TEMPO addition, enamine intermediate II fur-
ther reacts with the copper–TEMPO complex to afford
three-step tandem reaction product 1c.
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Conclusions
We have presented multicatalytic reactions that are com-
posed of oxidation, iminium catalysis, and enamine cataly-
sis. By controlling the amount of TEMPO, allylic alcohols
were converted into β-substituted aldehydes and α,β-substi-
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selectivity. In particular, by combining Cu-catalyzed aerobic
oxidation with organocatalysis, the substrate scope of α,β-
unsaturated aldehydes was expanded to low-molecular-
weight aliphatic alcohols as well as aromatic alcohols.
Furthermore, merging iminium/enamine catalysis provides
a highly stereoselective protocol for the formation of α,β-
substituted aldehydes as a single diastereomer with remark-
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organocatalytic reactions such as iminium-catalyzed malon-
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Experimental Section
Representative Procedure for the Oxidation/Michael Addition Reac-
tion: A mixture of aldehyde (0.25 mmol), CuCl (10 mol-%), and
TEMPO (10 mol-%) in DMF was stirred under 1 atm of oxygen
for
1 h.
(S)-2-[Diphenyl(trimethylsilyloxy)methyl]pyrrolidine
(10 mol-%), benzoic acid (indicated mol-%), and diethyl malonate
(3 equiv.) were then added to the Cu-catalyzed oxidation reaction
solution until the α,β-unsaturated aldehyde was consumed com-
pletely.
Representative Procedure for the Oxidation/Michael Addition/Oxy-
amination Reaction: A mixture of aldehyde (0.25 mmol), CuCl
4
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[15] Recently, our group published a paper regarding the photo-
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[10] For the domino oxidation/iminium catalysis using 10 equiv. of
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[17] The relative stereochemistry of 1c was confirmed by comparing
1
the H NMR spectroscopic data in ref.[15]
Received: June 29, 2012
Published Online: ᭿
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5

Job/Unit: O20863
/KAP1
Date: 04-09-12 15:21:31
Pages: 6
X.-H. Ho, H.-J. Oh, H.-Y. Jang
SHORT COMMUNICATION
Multistep Organocatalysis
X.-H. Ho, H.-J. Oh, H.-Y. Jang* ..... 1–6
Multistep Organocatalysis for the Asym-
metric Synthesis of Multisubstituted Alde-
hydes from Allylic Alcohols
Keywords: Organocatalysis / Enamines /
Copper / Michael addition / Aldehydes
A tandem aerobic oxidation/Michael ad-
dition/oxyamination reaction by using all-
ylic alcohols was attempted in the presence
of Cu-TEMPO and a chiral secondary
amine catalyst. The reaction sequence pro-
vides α,β-substituted aldehydes in good
yield with excellent stereoselectivity.
6
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