Iron(III)-catalyzed tandem sequential methanol oxidation/aldol coupling

Article abstract of DOI:10.1002/adsc.200505163

Iron(III)-catalyzed methanol oxidations have been performed using hydrogen peroxide as oxidant. Formaldehyde is formed in situ and reacts subsequently with activated ketones to give α-hydroxymethyl carbonyl compounds in good yields. As side reactions iron

Full text of DOI:10.1002/adsc.200505163

FULL PAPERS
DOI: 10.1002/adsc.200505163
Iron(III)-Catalyzed Tandem Sequential Methanol
Oxidation/Aldol Coupling
Vincent Lecomte, Carsten Bolm*
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule Aachen, Landoltweg 1, 52074 Aachen,
Germany
Fax: (þ49)-241-809-2391, e-mail: carsten.bolm@oc.rwth-aachen.de
Received: April 19, 2005; Accepted: July 16, 2005
Abstract: Iron(III)-catalyzedmethanol oxaidtions
reactions iron-catalyzed a-hydroxylations have been
have been performed using hydrogen peroxide as ox- observed.
idant. Formaldehyde is formed in situ andreacts sub-
sequently with activatedketones to give a-hydroxy- Keywords: aldol reaction; catalysis; hydrogen perox-
methyl carbonyl compounds in good yields. As side ide; iron; methanol oxidation
Introduction
Results and Discussion
Formaldehyde is an important C1 electrophile in organic For the development of an iron-catalyzed tandem se-
synthesis,[1] andthe aldol coupling remains one of the
most potent carbon-carbon bondforming reactions.
Aldol products (and especially hydroxymethyl deriva- ing materials as well as test reactions andconditions had
quential process involving a methanol oxidation fol-
lowedby a C C bondformation, all reagents andstart-
[2]
À
tives) have extensively been usedfor the synthesis of im-
to be carefully selected. For the second catalytic step the
aldol reaction appeared particularly attractive due to its
portant biologically active compounds,[3] andin order to
avoid the use of formaldehyde or its derivatives, new synthetic relevance. Furthermore, to the best of our
procedures are continuously being developed.[4]
knowledge, the challenging catalytic oxidation of meth-
Investigating the use of iron complexes in organic syn- anol to formaldehyde[13] has never been combinedwith
thesis,[5] our group has recently described an efficient an aldol process, making the investigation on such tan-
asymmetric sulfide oxidation and an oxidative hydrocar- dem sequential catalysis scientifically interesting.
bon functionalization.[6] Iron catalysts andhydrogen
Since some iron(III) salts are water-tolerant Lewis
peroxide are attractive for these purposes, since both acids, which have already been used in Mukaiyama-
are environmentally andeconomically friendly. Thus
we focusedour attention on the use of iron andhydro-
type aldol reactions,[14] and considering the findings by
Schwarz, who showedthat iron(III) couldefficiently co-
gen peroxide in the field of alcohol oxidation. Par- ordinate to 1,3-diketo compounds,[15] we began our stud-
ticularly, the conversion of methanol into formaldehyde ies by mixing 3.5 mol % of Fe(acac)3, 1.5 equivalents of
andits subsequent reaction in a carbon-carbon bond
forming process was regarded as challenge.
H2O2 and1 equivalent of ethyl 2-cyclopentanonecar-
boxylate (1a) in methanol as shown in Scheme 1. Two
Catalytic alcohol oxidation has been widely developed major reactions resulted, and to our delight one of
mainly with dioxygen,[7] or hydrogen peroxide as oxi- them was the methanol oxidation/aldol coupling tan-
dants.[8] Since Fentonꢀs work,[9] however, iron has re- dem reaction affording aldol product 2a in 23% yield.
mained rather underexploited in the field of alcohol oxida- In addition, a-hydroxylated ketone 3a andopen-chain
tion. Apart from Fe(III)/tert-butyl hydroperoxide, Fe(III) product 4 were isolatedin 25% yieldandtrace
nitrate, some iron-porphyrin andiron-non-heme sys-
amounts,[16] respectively. No reaction was observedin
tems,[10] only the combination of FeBr3 andH O2 has the absence of Fe(acac)3 or when dioxygen (1 atm)
2
been used for selective oxidation of secondary alcohols.[11] was usedas oxidant.
[17]
Here, we present our first results concerning the use of
These initial results promptedus to investigate the re-
the commercially available Fe(acac)3 as a catalyst for a action in more detail and to determine, which factors in-
tandem sequential methanol oxidation/aldol coupling fluencedits outcome. Interestingly, the presence of a
reaction[12] to afforda range of activatedketones, fur-
sub-stoichiometric amount of an aldehyde favored the
nishing a-(hydroxymethyl)ketones in good yields.
aldol product formation. The ratio of products 2a versus
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Fe(III)-Catalyzed Tandem Sequential Methanol Oxidation/Aldol Coupling
FULL PAPERS
yield), suggesting that the acacÀ ligandplays a decisive
role during the course of the reaction. When dioxygen
was usedas oxidant the starting material was quantita-
tively recovered.
The formation of formaldehyde during the course of
the reaction was assessedandconfirmedby the Nash
test.[18] In this case, the catalysis was performedin the ab-
sence of b-keto ester 1a, andthe analysis was done after
precipitation of the iron salts by pentane.
Scheme 1. Iron-catalyzedconversion of 1a in the presence of
methanol andH O2.
2
For a first evaluation of the substrate scope, both proc-
À
esses (oxidation and C C bondformation) were decou-
pledandthe transformations were studiedin a two
steps-one pot version. Thus first methanol was oxidized
using a catalytic amount of Fe(acac)3 andhydrogen per-
oxide as oxidant (with or without benzaldehyde as co-
catalyst), andthen, in a separate step, various carbonyl
compounds were added to the resulting mixture con-
taining the preformed formaldehyde. As test substrates,
b-carbonyl esters 1a–1c, b-diketone 1d, and2-(2-pyri-
dinyl)-cyclohexanone (1e) were chosen.
Table 1. Effect of aldehydes in iron-catalyzed oxidation reac-
tions of b-keto ester 1a.
[a]
Entry RCHO
mol % of RCHO Yield[%]
2a
3a
1[b]
2[b]
3
Ph-
Ph-
Ph-
100
20
20
20
20
20
20
20
20
52
53
73
73
65
73
76
8
20
14
25
25
28
27
22
18
31
4
p-Me-C6H4-
p-MeO-C6H4-
p-Cl-C6H4-
o-Br-C6H4-
i-Bu-
5[c]
6
7
8
9
t-Bu-
46
[a]
After column chromatography.
Reaction performedin air.
At the endof the reaction 65% of the aldehyde was recov-
ered.
[b]
[c]
In Table 2 the results of this screening are summar-
ized. In most cases, the yield of 2 was higher when the
catalysis was performedin the presence of benzalde-
3a was thus used as an indicator for the two oxidation re- hyde (20 mol %; method B). Apparently, a-carboxycy-
actions and the results, using different aldehydes, are cloalkanones 1a and 1b were goodsubstrates giving un-
presentedin Table 1.
der these modified conditions the corresponding a-hy-
Thus, by performing the iron catalysis in the presence droxymethylated compounds 2a and 2b in 97 and63%,
of 1 equivalent of benzaldehyde (in air) the yield of 2a respectively (Table 2, entries 1 and2). 2-Pyridinyl-sub-
was increasedto 52% (Table 1, entry 1). Under argon
stituted 1e also reactedwell, but the yieldof 2e was
and with only 20 mol % of this aldehyde, 2a was even ob- only moderate (44% in the absence of benzaldehyde;
tained in 73% yield (entry 3). No aldol product stem- entry 5). Diketone 1d provedto be unsuitable as sub-
ming from benzaldehyde was formed. The reaction strate (entry 4), and b-keto ester 1c gave the correspond-
was slightly dependent on the substitution pattern of ing a-hydroxymethylated product 2c only as a minor
the benzaldehyde, electron-withdrawing groups on the product. With the latter starting material diketo diester
aromatic ring being better for the product formation 6 was predominantly formed (in up to 65% yield).
than electron-donating substituents (Table 1, entries 6
and7 versus 4 and5, respectively). No clear trendwas
Presumably, the formation of 6 is relatedto the pres-
ence of the two enolizable a hydrogens in 1c, which leads
foundfor the a-hydroxylation reaction to give 3a, which to water elimination of 2c followedby Michael-type ad-
seemed to be independent of the type of aromatic alde- dition to the resulting a,b-unsaturatedketo ester 5 to
hyde. The use of aliphatic aldehydes gave unsatisfying give 6 (Scheme 2).[19]
results in the formation of 2a (entries 8 and9), andagain,
the a-hydroxylation remained almost unchanged. With ble 2, entry 1) under these stepwise conditions indicates
FeCl3 ·6 H2O as catalyst only 3a was formed(35% that the conversion of methanol to formaldehyde (with
The excellent yieldof 2a in the conversion of 1a (Ta-
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FULL PAPERS
Table 2. Iron-catalyzedconversions of 1a–e to give products
2a–e and 6.
pothesized. In order to test the intermediacy of such ox-
idizing agent, various reactions of 1a in the presence of
Fe(acac)3 andperacids were performed. The results
are shown in Table 3.
Apparently, compared to the standard conditions the
ratio between 2a and 3a decreased, when m-CPBA was
usedas oxidant (Table 3, entries 1 and2). Thus, less a-
hydroxymethylated product 2a was formed, whereas
the amount of hydroxylated ketone 3a increased(or re-
mainedconstant). In the presence of a carboxylate (en-
try 3), more methanol was oxidized, leading to an in-
creased amount of aldol product 2a.
Entry
Ketone
Product
Yields [%][a]
[b]
[b]
MethodA
MethodB
1
2
3
1a
1b
1c
2a
2b
2c
6
2d
2e
78
39
28
65
traces
44
97
63
22
61
traces
41
From all of these data we conclude that 2a and 3a are
formedin concurrent processes andthat the ratio be-
tween the two pathways is influencedby the presence
of the added benzaldehyde, which acts as catalyst for
the oxidation of methanol by hydrogen peroxide. With
or without benzaldehyde the activated ketone (here
1a) is directly oxidized (by hydrogen peroxide or air, if
present) to give a-hydroxylated 3a. In a parallel process
methanol is converted into formaldehyde, which under-
goes a subsequent aldol reaction with 1a affording 2a. In
the presence of benzaldehyde the methanol oxidation
becomes fast(er) andtherefore the amount of aldol
product 2a increases. When the process is performed
in two steps (compare data in Table 2) all hydrogen per-
oxide is first consumed by the oxidation of methanol,
and the subsequently added ketone 1a reacts rapidly
with the in situ formed formaldehyde in the aldol-type
4
5
1d
1e
[a]
After column chromatography.
Method A: no aldehyde was added; method B: addition of
20 mol % of PhCHO.
[b]
À
C C bondformation. Since at that stage no oxidant is
present anymore, the amount of a-hydroxylated prod-
uct 3a is low. The activating effect of benzaldehyde pre-
sumably stems from its conversion into the correspond-
ing (per)carboxylic acidby activatedhydrogen perox-
ide,[20] which is even known to proceedin the presence
Scheme 2. Iron-catalyzedconversion of 1c in the presence of
H2O2 andmethanol.
respect to hydrogen peroxide) is essentially quantita- of FeCl3 in acetonitrile.[21] Alternatively, a-hydroxy hy-
tive. The limiting step appears to be the aldol reaction, droperoxides arising from a pre-activation of the alde-
which is substrate-dependent.
The role of benzaldehyde remained unclear at this more soluble they couldact as ligands for iron, andcon-
stage, andits conversion into perbenzoic acidthrough sequently, several catalytically active species might exist
hyde by the hydrogen peroxide may be involved. Being
iron-catalyzed reaction with hydrogen peroxide was hy- in solution. Their identification and pH-dependent for-
Table 3. Dependence of the ratio between 2a and 3a on the oxidizing system.
Entry
Oxidizing system
Yield [%]
2a
3a
1
2
3
m-CPBA (1.5 equivs.)
26
18
46
40
21
25
m-CPBA (20 mol %)þH2O2 (1.5 equivs.)
p-MeOC6H4COONa (20 mol %)þH2O2 (1.5 equivs.)
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Fe(III)-Catalyzed Tandem Sequential Methanol Oxidation/Aldol Coupling
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Table 4. Solvent effect in the a-hydroxylation of 1a and 1b.[a]
Entry
Ketone
Solvent
Yield[%]
1
2
3
4
5
1a
1a
1a
1a
1b
MeOH
i-PrOH
t-BuOH
CH2Cl2
i-PrOH
23 (2a)
25 (3a)
43 (3a)
47 (3a)
9 (3a)
–
–
–
–
47 (3b)
[a]
Reaction conditions: 1a or 1b (1 mmol), Fe(acac)3
(0.1 mmol), H2O2 (1.5 mmol) in solvent (2.5 mL) at rt
for 24 h.
Scheme 3. Iron-catalyzedMannich-type reaction starting
from methanol.
mation are currently under investigation. From the cur-
rent data it is difficult to propose clearly defined inter-
mediates, but the results presented in Table 3 suggest
that upon addition of an aldehyde a species such as a car-
boxylate is involved in the catalytic cycle. Under stand-
ardconditions, the presence of radicals cannot be ex-
cluded, and additional studies shall reveal, which step
of the reaction sequence is most prone to involve such
intermediates.
Scheme 4. Mechanism for the deacylation of 2a upon treat-
ment with base.
Another interesting aspect relates to the formation of
the a-hydroxylated products 3. Their metal-catalyzed
formation with dioxygen as the oxidant is well known.[22] nich-type product 8a. Instead, the open-chain acrylic es-
To the best of our knowledge, however, the use of dilut- ter 9 was quantitatively obtained.
ed aqueous hydrogen peroxide (30%) activated by an
iron complex has never been reported.[23] We therefore aldol product 2a,[26] which proceeded intramolecularly
briefly examinedthis reaction as well andstudiedthe in- via 10 with the amine acting as base. This hypothesis
fluence of the solvent first. The results are shown in Ta- was confirmedin a control experiment starting from
The formation of 9 was attributedto a deacylation of
ble 4.
2a, which afforded 9 upon treatment with diethylamine
In all solvents the formation of the corresponding a- (Scheme 4).
hydroxylated products 3a and 3b starting from b-keto es-
ters 1a or 1b, respectively, was observed(Table 4). The
yields of 3a rangedfrom 9–43% with isopropyl alcohol
being the best solvent. Only in the catalysis performedin
methanol (starting from 1a) was an aldol product
formed.
All other attempts with diethylamine 7a were unsuc-
cessful, but, finally, Mannich product 8b was obtained
using the aniline hydrochloride 7b andisolatedin 22%
yield(not optimized).
Since the iron-catalyzed oxidative formaldehyde for- Conclusion
mation from methanol proceeded so well, we decided
to extendthis chemistry andto investigate a Mannich-
For the first time, a tandem sequential methanol oxida-
type reaction. Due to their synthetic relevance such met- tion/aldol coupling reaction catalyzed by a simple iron
al-catalyzedazo-aldolization processes between imines
andsilylenol ethers have already been studiedin great
(III) complex is described. The reaction utilizes 30%
aqueous hydrogen peroxide as oxidant and avoids the
detail,[24,25] but, as far as we know, no example of a cata- use of formaldehyde or surrogates in the preparation
lyzed tandem sequential methanol oxidation/Mannich the industrially interesting b-keto a-hydroxymethylat-
reaction has even been reported. Scheme 3 shows our edcarbonyl compounds. In the presence of a substoi-
approach. For having a high concentration of formalde- chiometric amount of an aldehyde the reaction rate is
hyde, the reaction was performed in a sequential mode increased. Under optimized conditions the products
(compare with the two steps-one pot version described are formed(at room temperature) in moderate to excel-
above). Thus, methanol was first oxidized with hydrogen lent yield. Furthermore, an iron-catalyzed a-hydroxyla-
peroxide under iron catalysis, and subsequently the tion of keto esters has also been disclosed. Although at
amine (in the form of its HCl salt) followedby the ke-
the present stage the yields in this reaction are only
tone (here 1a) were added to the formaldehyde-contain- moderate, the transformation itself is interesting, and
ing reaction mixture. With diethylamine (Et2NH·HCl; these results servedalready as starting point for further
7a) as amine, a new product was formed within a few mi- investigations, which are currently ongoing in our labo-
nutes, but unfortunately it was not the expectedMan-
ratories.
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Experimental Section
References and Notes
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aldehyde; b) for a recent example for an asymmetric a-
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Materials
Ketones 1a–d as well as the aldehydes were purchased
from commercial suppliers andusedwithout further pu-
rification. 2-(2-Pyridinyl)cyclohexanone (1e) was pre-
paredaccording to ref. [27] The solvents were distilled pri-
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conducted under argon unless otherwise specified.
Products 2a,[28] 3a,[22a] 2b,[3e] 2c,[29] 6,[19] 7b,[30] 9,[26] were
in accordance to published data, 2e was fully character-
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Representative Procedure for the Tandem Sequential
Methanol Oxidation/Aldol Coupling
In a Schlenk tube equippedwith a magnetic stirring bar
under argon, a solution of Fe(acac)3 (35.3 mg, 0.1 mmol)
and benzaldehyde (20 mL, 0.2 mmol) in methanol
(2.5 mL) was treated hydrogen peroxide (170 mL,
1.5 mmol) at room temperature. The tube was capped,
andthe solution was stirredfor 40 min (small exother-
mic effect). Then, ketone 1e (175 mg, 1.0 mmol) was
added, and the resulting solution was stirred for 3 h.
The mixture was then hydrolyzed with a saturated aque-
ous solution of NaHCO3 (10 mL), andthe organic phase
was extractedwith CH 2Cl2 (3Â5 mL). The organic frac-
tions were collected, dried over Na2SO4, andthe solvent
was evaporatedunder reducedpressure. The crude
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1
yield: 84 mg (41%); H NMR: d¼1.42–2.04 (m, 5H),
2.31–2.60 (m, 3H), 3.69 (d, CH2-O, J¼11.6 Hz), 3.81
(d, CH2-O, J¼11.6 Hz), 7.12–7.20 [m, CH(Py)], 7.64
[dt, CH(Py), J¼1.7, 7.7 Hz], 8.53 [m, CH(Py)]; 13C
NMR: d¼20.31, 26.89, 32.31, 39.89 (4 CH2), 60.93 (C-
2), 67.91 (C-OH), 120.74, 121.09, 135.83, 148.37,
¼
158.90, 213.68 (C O); MS (EI, 70 eV): m/z (%)¼205
[Mþ, 13] , 190 (31), 175 [(MÀCH2O)þ, 100], 160 (27),
146 (63), 131 (37), 118 (41), 105 (49), 77 (17), 51 (10);
IR (CHCl3): n¼3453, 3058, 2937, 2865, 1708, 1633,
1589, 784, 751, 550 cmÀ1; anal. calcd. for C12H15NO2
(205.06): C 70.22, H 7.37, N 6.82; found: C 70.04, H
7.70, N 6.42.
Acknowledgements
We are grateful to the Fonds der Chemischen Industrie and the
Deutsche Forschungsgemeinschaft (DFG) within the Schwer-
punktprogramm 1118 for financial support.
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Fe(III)-Catalyzed Tandem Sequential Methanol Oxidation/Aldol Coupling
FULL PAPERS
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