Sulfonic acid-catalyzed autoxidative carbon-carbon coupling reaction under elevated partial pressure of oxygen

Article abstract of DOI:10.1002/adsc.201100563

An aerobic organocatalytic oxidative C-C bond formation reaction of benzylic C-H bonds with various C-nucleophiles is described. The coupling reaction proceeds by simply stirring the substrates under elevated partial pressure of oxygen in the presence of a sulfonic acid catalyst at room temperature. Elevation of the pressure enables the reaction of a broad scope of nucleophile substrates otherwise showing poor reactivity at ambient pressure. The benzylic C-H bonds of xanthene, acridanes, isochromane and related heterocycles could be functionalized with nucleophiles including ketones, 1,3-dicarbonyl compounds and aldehydes. Electron-rich arenes could be utilized as nucleophiles at elevated temperatures. The reactions are believed to proceed via autoxidation of the benzylic C-H bonds to the hydroperoxides and subsequent nucleophilic substitution catalyzed by sulfonic acids. Copyright

Full text of DOI:10.1002/adsc.201100563

FULL PAPERS
DOI: 10.1002/adsc.201100563
Sulfonic Acid-Catalyzed Autoxidative Carbon-Carbon Coupling
Reaction under Elevated Partial Pressure of Oxygen
ꢀron Pintꢁra,b and Martin Klussmanna,*
a
Max-Planck-Institut fꢂr Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mꢂlheim an der Ruhr, Germany
Fax : (+49)-208-306-2980; e-mail: klusi@mpi-muelheim.mpg.de
Present address: Institute of Organic Chemistry, University of Duisburg–Essen, Universitꢃtsstr. 7, 45117 Essen, Germany
b
Received: July 15, 2011; Revised: October 4, 2011; Published online: February 23, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100563.
À
Abstract: An aerobic organocatalytic oxidative C C ized with nucleophiles including ketones, 1,3-dicar-
bond formation reaction of benzylic C H bonds with bonyl compounds and aldehydes. Electron-rich
À
various C-nucleophiles is described. The coupling re- arenes could be utilized as nucleophiles at elevated
action proceeds by simply stirring the substrates temperatures. The reactions are believed to proceed
under elevated partial pressure of oxygen in the via autoxidation of the benzylic C H bonds to the
presence of a sulfonic acid catalyst at room tempera- hydroperoxides and subsequent nucleophilic substi-
ture. Elevation of the pressure enables the reaction tution catalyzed by sulfonic acids.
of a broad scope of nucleophile substrates otherwise
showing poor reactivity at ambient pressure. The Keywords: autoxidation; Brønsted acid catalysis; C
benzylic C H bonds of xanthene, acridanes, isochro- C coupling; C H activation; high-pressure chemis-
mane and related heterocycles could be functional- try; oxygen
À
À
À
À
Introduction
Recent work in this field revealed that simple transi-
tion metal salt catalysts and inexpensive peroxides
À
The classical synthetic methods of C C bond forma- can be used for the oxidative cross-coupling between
tion by substitution have the common drawback that different benzylic or allylic hydrocarbons,[3] amines[4]
prefunctionalized starting materials are required, or ethers[5] and various C H acidic compounds, for
À
À
while at the end of the operation undesired side prod- example. In addition, oxidative C C cross-coupling
ucts are formed from the leaving or activating groups. reactions utilizing elemental oxygen have been devel-
Both the synthesis of the reactive reagents as well as oped, catalyzed by Ru,[6] Fe[7] or Cu,[8] or by the com-
the proper disposal or recycling of the waste products bination of a redox-active transition metal and orga-
increase production costs, risk to human health and nocatalysts.[9] Catalyst recycling is possible, for exam-
environmental pollution. The concept of oxidative ple, by the use of Fe3O4 nanoparticles as heterogene-
À
coupling provides a straightforward alternative: a C
ous catalysts.[10]
In a previous communication, we reported that xan-
thene, acridanes as well as a tetrahydroisoquinoline
À
C bond formation at the expense of two C H bonds
with the aid of an oxidant (Scheme 1).[1]
To run these reactions under catalytic conditions can undergo a metal-free aerobic oxidative coupling
and with a low molecular weight and environmentally reaction with various ketones and a few 1,3-diketones,
benign oxidant is in line with the growing demand for malonic esters and b-keto esters.[11] Remarkably, this
sustainable technologies and green chemistry.[2] reaction does not require any redox-active catalyst or
harsh conditions but solely catalytic amounts of a
Brønsted acid and oxygen (Scheme 2).
We suggested the reaction to proceed via an autoxi-
dation–alkylation cascade via hydroperoxides and
thus termed it “autoxidative coupling”.[12] Here, we
report some initial experiments made during the dis-
covery of this reaction and an extension of the sub-
Scheme 1. Schematic representation of a catalytic aerobic
oxidative cross-coupling reaction.
Adv. Synth. Catal. 2012, 354, 701 – 711
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
701

ꢀron Pintꢁr and Martin Klussmann
FULL PAPERS
giving the best result with 83% (Table 1, entry 3).
Also with b-keto esters as nucleophiles, the O2 partial
pressure has a high impact on reaction rate. Methyl
acetoacetate and ethyl acetoacetate react with 1 to a
useful extent only if a high pressure of diluted air is
applied. MsOH turned out to be a significantly better
catalyst than TfOH, giving the products 5 and 6 in
Scheme 2. Autoxidative coupling reaction.
strate scope by applying high partial pressure of 79% and 85% yield, respectively (Table 1, entries 4
oxygen.[13]
and 5). High pressure is also beneficial in the reaction
of diethyl malonate with xanthene. The use of TfOH
as catalyst gave higher yields of the 2-substituted mal-
onate 7 than with MsOH, but the conversion of 1 re-
mained below 50% even after an extended reaction
Results and Discussion
While the autoxidative coupling of xanthene (1) with time of 144 h (Table 1, entry 6). With the result that
ketones can be surprisingly fast, with full conversion high partial pressure of oxygen allows us to conduct
and very high yields under atmospheric pressure of the autoxidative coupling with otherwise nearly un-
oxygen or air (Scheme 2), extending the nucleophile reactive C-nucleophiles, we could now extend the
scope beyond ketones turned out to be rather diffi- product scope of this reaction.
cult. In contrast to our expectations, the more nucleo-
Aryl alkyl ketones have previously only given
philic b-keto esters and malonic acid esters hardly re- rather low yields at ambient pressure of oxygen,[11] so
acted under standard conditions. Since the reaction we tested these nucleophiles at the elevated oxygen
performance was not related to nucleophilicity, we partial pressure of 6 bar (Table 2). The raise in pres-
presumed that the oxidation step was the limiting sure had no significant effect; both with cyclic and
factor and that it depended on the nucleophile pres- acyclic aryl alkyl ketones only partial conversion of 1
ent. While the exact reason for this phenomenon is was achieved and moderate to low yields of the cross-
not yet clear, we decided to investigate reaction con- coupling products 8–13 were isolated, even after long
ditions that would enhance the autoxidation rate and reaction times of up to 200 h (Table 2, entries 1–6). In
thereby the yield of the desired products. To this end, the case of acetophenone derivatives, no higher con-
reactions at elevated partial pressure of oxygen version of 1 than 40% could be achieved, while the
seemed promising. We therefore performed a more reaction mixture was clean and the remaining xan-
systematic study of the role of O2 partial pressure on thene starting material was generally left unchanged
product formation. Xanthene was reacted with vari- (Table 2, entries 3–6). This still unclear phenomenon
ous C-nucleophiles and two sulfonic acid catalysts, has also been observed previously for acetophenone
methanesulfonic acid (MsOH) and triflic acid and acetone.[11]
(TfOH), under ambient pressure and at 6 bar partial
Various 1,3-diketones were used as nucleophiles in
pressure of oxygen, respectively (Table 1). Other the coupling with xanthene catalyzed by MsOH,
Brønsted acids were previously shown to be less ef- which gave higher yields than TfOH, as discussed
fective catalysts.[11] For reasons of safety, all experi- above. Cyclic 1,3-diketones (Table 3, entries 1, 3 and
ments under elevated pressure were performed in an 4) could be used as well as open-chain 1,3-diketones
autoclave charged with a 10/90 O2/N2 gas mixture and (Table 3, entries 2, 5 and 6) with moderate to good
not with elemental oxygen.
yields of the products 14–19. As had been seen with
Cyclic ketones react with 1 even under 1 bar O2 aryl alkyl ketones before, xanthene was not fully con-
partial pressure with both TfOH and MsOH to give verted, although the conversions were generally
the corresponding 1-(9’-xanthyl)-substituted ketones 2 higher. In the case of 1,3-cycloheptadione, the highest
and 3 with good yields (Table 1, entries 1 and 2). conversion was achieved with 95% after nearly four
While use of MsOH seems to result in a slightly days, giving 63% isolated yield of 17 (Table 3,
higher conversion and reaction rate, batches with entry 4). Interestingly, the autoxidative coupling of 1
TfOH as catalyst resulted in sometimes cleaner trans- with the sterically congested 2,2,6,6-tetramethylhep-
1
formations as judged by H NMR of the crude reac- tane-3,5-dione did not give the expected product, but
tion mixtures. In general, the differences are rather the b-keto ester 18 in 25% yield, arising from a spon-
marginal and unpredictable for simple ketones.
taneous Baeyer–Villiger oxidation (Table 3, entry 5).
In the case of 1,3-cyclohexanedione, the reaction This overoxidation is indicative of the formation of
under pure O2 atmosphere at ambient pressure was hydrogen peroxide as a by-product in the autoxidative
very slow and only small amounts of the product 4 coupling. While acetylacetone afforded the product
were detected by NMR spectroscopy. In contrast, the 19 with 33% yield (Table 3, entry 6), fluorinated ana-
reaction under 6 bar partial O2 pressure provided the logues 1,1,1-trifluoro- and 1,1,1,5,5,5-hexafluoroacetyl-
coupling product in good isolated yields with MsOH
ACHTUNGTRENaNGNU cetone only led to decomposition of the starting ma-
702
asc.wiley-vch.de
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 701 – 711

Sulfonic Acid-Catalyzed Autoxidative Carbon-Carbon Coupling Reaction
Table 1. Comparison of the autoxidative coupling of xanthene with different C-nucleophiles using two different oxygen par-
tial pressures and Brønsted acid catalysts, respectively.[a]
Entry
Nucleophile
Product
Yield[b] (0.1 MPa O2)
Yield[b] (6.0 MPa 10% O2)
TfOH
MsOH
TfOH
MsOH
1
2
3
4
51
67
50
4[c]
78
81
2
3
80
82
66
71
83
11[c]
4
5
5
6
7
1[c]
12[c]
26[c]
9[c]
49
38
39
79
12[c]
85
6
13[c]
11[c]
[a]
General conditions: xanthene (1.0 mmol), nucleophile (3.0 or 5.0 mmol), catalyst (0.05 mmol), O2 balloon or 60 bar of
10/90 O2/N2, room temperature, 64–144 h.
[b]
[c]
Isolated yield.
Yield determined by 1H NMR with n-heptadecane as internal standard.
terials to a complex mixture without any observation and 2), while the use of plain b-keto esters gave
of oxidative alkylation. better yields with regards to the conversion of xan-
Among the investigated nucleophiles, b-keto esters thene (Table 4, entries 3–6). Bulky substituents like
excel with high conversions and selectivities (Table 4). isopropyl (Table 4, entry 5) or isobutyl (Table 4,
Although xanthene is again not fully consumed after entry 6) at the ester moiety or at the C-terminus do
a reaction time of three days, more than 70% of con- not suppress the reaction significantly either.
version is achieved in all cases and yields of the prod-
In addition, we investigated the feasibility of the
ucts 20–25 range from 47 to 85%. The use of b-keto oxidative a-alkylation of aliphatic aldehydes with xan-
1,5-diesters gave good conversions but only moderate thene (Table 5).[13] A comparison of some solvents re-
yields of around 50% for 20 and 21 (Table 4, entries 1 vealed that the highest reaction rate, full conversion
Adv. Synth. Catal. 2012, 354, 701 – 711
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
703

ꢀron Pintꢁr and Martin Klussmann
FULL PAPERS
Table 2. The reaction of xanthene with different aryl alkyl ketones.[a]
Entry
1
Ketone
Product
Conversion [%][b]
51
Yield [%][c]
48
8
2
3
4
5
9
62
32
38
62
32
36
10
11
12
13
27
33
25
32
6
[a]
Conditions: xanthene (1.0 mmol), nucleophile (5.0 mmol), TfOH (0.07 mmol), CH2Cl2 (0.00–1.00 mL), 6.0 MPa 10/90
O2/N2, room temperature, 200 h.
[b]
Conversion determined by GC measurement referred to n-heptadecane internal standard.[c] Isolated yield. Xant=9-
xanthyl.
of 1 and comparably clean transformations could be longer chain-lengths of the aldehyde, 9-xanthone for-
achieved if ethyl acetate was used as solvent. Analysis mation is suppressed and the yield of the carboxylic
of the reaction mixture by thin layer chromatography acid coupling products increases (Table 5, entries 2–
indicated the formation of three products. In addition 4). Propionaldehyde gave 28% yield of the carboxylic
to the undesired xanthone 27, which was formed to a acid 26b (Table 5, entry 2), while with pentanal, 44%
significant extent (15–31%), a-(9-xanthyl)carboxylic was achieved (Table 5, entry 3). The branched 3-meth-
acids 26b–d were obtained as major products in yields ylbutyraldehyde excelled with its high selectivity for
ranging from 28% to 78%. Analysis of the third the corresponding acid 26d under the same reaction
(most non-polar) product fraction by mass spectrome- conditions, which was isolated in 78% yield (Table 5,
try and NMR indicated the a-(9-xanthyl)aldehydes, entry 4).
along with their aldol-condensation homologues. Un-
The overoxidation of the primarily formed a-(9-
fortunately, separation and characterization of these xanthyl)aldehydes to the carboxylic acids 26b–d must
compounds proved to be difficult by manual prepara- be effected rather by the hydrogen peroxide generat-
À
tive chromatography. Accordingly, we isolated the ed as waste product in the C C coupling step than by
carboxylic acids as major products.
elemental oxygen. A direct oxygen-mediated oxida-
In the case of acetaldehyde, even slow and cautious tion of aliphatic aldehydes requires transition metal
addition of TfOH catalyst to the pre-cooled (À308C) catalysts,[14] photoactivation[15] or elevated tempera-
solution of the starting materials led to an immediate tures,[16] while H2O2 readily oxidizes aldehydes to the
and fierce aldol condensation reaction as indicated by corresponding acids in the presence of acid catalyst,[17]
intensive warming and GC-MS measurement. Treat- conditions very similar to the ones used in the present
ment of this solution with 10% oxygen under study.
10.0 MPa pressure resulted in a complex reaction mix-
We also examined the oxidative coupling of xan-
ture and incomplete conversion of 1. Neither the ex- thene with electron-rich aromatic compounds. 1,3,5-
pected acid 26a nor the corresponding aldehyde could Trimethoxybenzene gave no reaction with 1 at ambi-
be detected or isolated, the only characterizable prod- ent pressure or at elevated pressure at room tempera-
uct formed was xanthone 27 (Table 5, entry 1). With ture. Heating to 708C under 10 bar of oxygen partial
704
asc.wiley-vch.de
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 701 – 711

Sulfonic Acid-Catalyzed Autoxidative Carbon-Carbon Coupling Reaction
Table 3. The reaction of xanthene with different 1,3-diketones.[a]
Entry
1
Diketone
Product[b]
Time [h]
128
Conversion [%][c]
48
Yield [%][d]
47
14
15
16
2
3
96
88
77
79
66
76
4
5
17
88
95
63
18
19
88
48
72
56
25
33
6
[a]
Conditions: xanthene (1.0 mmol), nucleophile (3.0 mmol), MsOH (0.07 mmol), CH2Cl2 (1.00-2.00 mL), 6.0 MPa 10/90
O2/N2, room temperature.
Major tautomeric form in CDCl3 or DMSO-d6 is shown.
Conversion determined by GC measurement referred to n-heptadecane internal standard.
Isolated yield. Xant=9-xanthyl.
[b]
[c]
[d]
pressure led to full conversion within 24 h if TfOH
was used as catalyst, while the conversion of 1 re-
mained below 20% if MsOH was used instead. The
desired product 28 could be isolated with 80% yield.
With 1,3-dimethoxybenzene, higher temperature
(908C) and longer reaction time (3 days) were needed
to obtain full conversion of 1. The o,p-isomer 29 was
isolated in 65% yield as the major product, accompa-
nied by a small amount (ca. 3%) of the o,o-product,
which could not be isolated pure enough. With ani-
sole, full conversion of 1 could be achieved at 1008C
after four days, but the chemoselectivity dropped
drastically, and the isomeric products 30a and 30b
gave only low yields of 27% and 4%, respectively
(Scheme 3).
After having screened several nucleophiles, we
turned our attention to other “electrophiles” besides
xanthene. Preliminary experiments had shown that N-
unsubstituted acridanes 35 undergo a slow oxidation
Scheme 3. Reaction conditons: xanthene (1.0 mmol), arene
(3.0 mmol), TfOH (0.05 mmol), CH2Cl2 (0.40 mL), 10.0 MPa
to the corresponding acridines under the above men- 10/90 O2/N2 (at 298 K).
Adv. Synth. Catal. 2012, 354, 701 – 711
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
705

ꢀron Pintꢁr and Martin Klussmann
FULL PAPERS
Table 4. The reaction of xanthene with different b-keto esters.[a]
Entry
1
b-Keto ester
Product
Conversion [%][b]
95
Yield [%][c]
55
20
21
22
23
24
25
2
3
4
5
74
83
88
72
81
47
81
85
54
69
6
[a]
Conditions: xanthene (1.0 mmol), nucleophile (5.0 mmol), MsOH (0.07 mmol), CH2Cl2 (0.40 mL), 6.0 MPa 10/90 O2/N2,
room temperature, 72 h.
Conversion determined by GC measurement referred to n-heptadecane internal standard.
Isolated yield. Xant=9-xanthyl.
[b]
[c]
À
tioned reaction conditions, but no C C coupling wanted to explore the cross-coupling between acri-
occurs. Therefore, N-Cbz-protected acridanes 36a–g danes bearing additional subsituents and other nucle-
were investigated as substrates. The parent compound ophiles to access a broader range of products. We pre-
36a had been successfully used in the autoxidative pared the acridanes 36a–g as starting material in four
coupling with cyclopentanone before.[11] We now steps, starting from 2-chlorobenzoic acid 31 and sub-
Table 5. The reaction of xanthene with different aliphatic aldehydes.[a]
Entry
R
Conversion [%][b]
Product
Yield of 26 [%][c]
Yield of 27 [%][c]
1
2
3
4
H
74
98
99
99
26a
26b
26c
26d
0
18
31
20
15
Me
n-Pr
i-Pr
28
44
78
[a]
Conditions: xanthene (1.0 mmol), aldehyde (5.0 mmol), TfOH (0.05 mmol), EtOAc (0.40 mL), 10.0 MPa 10/90 O2/N2,
room temperature, 48 h.
Conversion determined by GC measurement referred to n-heptadecane internal standard.
Isolated yield.
[b]
[c]
706
asc.wiley-vch.de
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 701 – 711

Sulfonic Acid-Catalyzed Autoxidative Carbon-Carbon Coupling Reaction
acid or with polyphosphoric acid formed in situ. The
use of the latter was necessary for methoxy-substitut-
ed anthranilic acid 33d, as sulfuric acid gave almost
complete demethylation to 34h. Filtration of the pre-
cipitated free bases 34a–f and 34i turned out to be
À
more difficult than in the case of their HSO4 or
À
H2PO4 salts, therefore a repetitive centrifugation-de-
cantation procedure was necessary for their proper
isolation. The acridones 34 were then smoothly con-
verted to acridanes 35 using borane reduction. Cbz-
protection with Cbz-Cl and n-BuLi as base furnished
the acridane starting materials 36a–f. The hydroxy-ac-
ridone 34h was converted analogously to the doubly
Cbz-protected acridane 36g. With these starting mate-
rials in hand, we first tested the reaction with acetone
as nucleophile under different conditions (Table 6,
also see the Supporting Information for more details).
MsOH was found to be the most effective catalyst for
the coupling reaction, whereas TfOH often gave irre-
producible results and complex mixtures of products.
By varying the catalyst loading of MsOH, the highest
yield to conversion ratio was observed with 3 or
5 mol% of catalyst. At higher catalyst loadings, the
formation of the undesired acridone side product was
slightly suppressed but without further increasing the
Scheme 4. Synthesis of acridane derivatives as substrates for
the autoxidative coupling. Reagents and conditions: i) Cu,
Cu2O, K2CO3, methoxyethanol, 1408C, 5 h; ii) conc. H2SO4,
1008C, 4 h; iii) P2O5, 85% H3PO4, 1008C, 3 h; iv) BH3·THF,
THF, reflux, 90 min; v) n-BuLi, THF, 08C, Cbz-Cl.
stituted anilines 32a–g, based on reported procedures yield of the desired product. The autoxidative cou-
(Scheme 4).[18]
pling did not take place in the absence of MsOH. As
The Cu/Cu2O-catalyzed Ullmann heterocoupling in had been seen with xanthene, acetone turned out to
refluxing 2-methoxyethanol worked well with unsub- be a rather poor coupling partner, providing com-
stituted aniline 32a as well as with derivatives 32b–f pound 37a with a maximum isolated yield of 32% and
bearing electron-withdrawing or electron-donating incomplete conversion of the acridane (Table 6,
substituents in the 4-position. The corresponding N- entry 1). No further improvement of the reaction was
arylanthranilic acids 33a–f were converted to acri- achieved, although no experiments at elevated tem-
dones 34a–f by treatment with concentrated sulfuric peratures were performed. However, if phenylacetone
Table 6. Autoxidative coupling of N-Cbz protected acridanes with acetone and phenylacetone.[a]
Entry
Acridane
R1
R2
Conversion [%][b]
Product
Yield [%][c]
dr[d]
1
2
3
4
5
6
7
8
36a
36a
36b
36c
36d
36e
36f
36g
H
H
Et
Bu
OMe
F
Cl
OCbz
H
60
99
99
99
94
95
99
80
37a
38a
38b
38c
38d
38e
38f
38g
32
98
86
83
84
82
85
75
–
–
Ph
Ph
Ph
Ph
Ph
Ph
Ph
52:48
52:48
55:45
54:46
59:41
58:42
[a]
Conditions: N-Cbz acridane (1.0 mmol), acetone (10.0 mmol) or phenylacetone (5.0 mmol), MsOH (0.05 mmol), CH2Cl2
(0.0–0.4 mL), 10.0MPa 10/90 O2/N2, room temperature, 72 h.[b] Conversion determined by GC measurement referred to n-
1
heptadecane internal standard.[c] Isolated yield.[d] Diastereomeric ratio determined by H NMR.
Adv. Synth. Catal. 2012, 354, 701 – 711
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
707

ꢀron Pintꢁr and Martin Klussmann
FULL PAPERS
posed after isolation by column chromatography. By
using preparative TLC for isolation of the products,
1H NMR spectra of compounds 39 were of sufficient
quality to confirm their structure. However, a com-
plete decay of the products was observed within a few
hours, accompanied by the emergence of the corre-
sponding acridones 40 (Scheme 5).
Expanding the substrate scope to other benzylic
substrates beyond xanthene and acridanes represents
another challenge. Previous studies showed that relat-
ed substrates like fluorene or diarylmethanes are un-
reactive under our reaction conditions. We next
turned our attention to isochromane (41), encouraged
by the report of its autoxidation to 1-hydroperoxyiso-
chromane 43 and bis(1-isochromanyl) peroxide 44.[19]
Pure isochromane was reported to undergo autoxida-
tion to peroxides to the extent of ca. 50% within four
weeks. In order to enhance the rate of autoxidation,
Scheme 5. Autoxidative coupling of acridanes with 1,3-cyclo-
hexanedione and to the unstable products 40.
was used as nucleophile instead of acetone, almost neat isochromane was vigorously stirred in an auto-
full conversion of the acridanes 36a–g was achieved clave pressurized with 10/90 O2/N2 gas mixture at
to give the products 38a–g with good isolated yields 5.0 MPa and room temperature. This procedure did
1
up to 98% in the case of 38a (Table 6, entry 2). The indeed accelerate the autoxidation: H NMR analysis
nature of the substituents on the acridane did not of the crude reaction mixture showed the formation
have a significant effect on the product yields of the hydroperoxide 43 (22%), peroxide 44 (50%,
(Table 6, entries 3–8). The diastereoselectivities were dr=58:42) and lactone 45 (11%), accompanied by
rather low in the range of 1:1 to 3:2.
some unreacted isochromane (17%) after 48 h
We also tested acridanes with 1,3-cyclohexadione as (Table 7, entry 1). If isochromane was stirred under
nucleophile, which had given high yields with xan- high pressure of oxygen in a 1:1 mixture with acetyl-
thene (Table 1). Under similar reaction conditions,
ACHTUNGTRENaNUGN cetone, a potential nucleophile, the degree of autoxi-
the acridanes 36a–d and 36g gave clean and almost dation was reduced but still amounted to a combined
full conversion, as judged by GC and TLC analysis. peroxide yield of 41% at a conversion of ca. 67%
Unfortunately, the corresponding products 39 decom- (Table 7, entry 2).
Table 7. Product distribution of isochromane autoxidation and autoxidative coupling under different conditions.[a]
Entry
42 (equiv.)
[acid]
Time [h]
41 [%][b]
43 [%][b]
44 [%][b]
45 [%][b]
46 [%][b]
1
2
3
4
5
6
7
8
0
1
1
1
1
1
1
1
1
1
1
1
5
–
–
48
42
18
45
45
45
45
45
45
42
42
42
72
17
33
37
28
49
20
45
38
56
44
45
72
31
22
24
0
0
3
31
1
0
0
0
50
17
16
16
41
31
42
3
1
11
9
0
0
11
3
11
12
2
7
3
11
7
8
–
0
20
29
0
MsOH (5 mol%)
MsOH (5 mol%)
TFA (5 mol%)
NBu4HSO4 (5 mol%)
HNO3 (5 mol%)
H2SO4 (5 mol%)
TfOH (5 mol%)
TfOH (1 mol%)
TfOH (2 mol%)
TfOH (10 mol%)
TfOH (5 mol%)
0
2
34
25
26
26
15
35
9
10
11
12
13
0
0
0
8
4
15
[a]
General conditions: isochromane, acetylacetone, catalyst, 10/90 O2/N2 atmosphere at 5.0 MPa, room temperature, neat.
Determined by H NMR measurement of the crude reaction mixture, refering to n-heptadecane as internal standard.
[b]
1
708
asc.wiley-vch.de
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 701 – 711

Sulfonic Acid-Catalyzed Autoxidative Carbon-Carbon Coupling Reaction
In accordance with our proposed mechanism and
the results discussed above, Brønsted acid catalysis
should enable the nucleophilic substitution of the per-
oxide group. We thus treated a 1:1 mixture of neat
isochromane, acetylacetone and 5 mol% MsOH
under the same conditions for 18 h. As expected, the
coupling product 3-(1-isochromanyl)acetylacetone 46
was formed, although in a rather low yield of 20%.
Conversion of isochromane was incomplete and the
only side products that could be detected were iso-
chromanone and the peroxide 44 (Table 7, entry 3).
Extending the reaction time to 45 h resulted in an in-
creased conversion of isochromane and a yield of the
coupling product of 29%, while the amounts of the
side products were unchanged (Table 7, entry 4). Ap-
Scheme 6. Autoxidative coupling reactions of cyclic ethers.
Yields according to H NMR, yields in parentheses: based
on remaining starting material.
parently, MsOH can catalyze the nucleophilic substi-
tution of the hydroperoxide 43 by acetylacetone, but
not of the peroxide 44. We thus screened for an alter-
native Brønsted acid catalyst that would enable the
1
conversion of both peroxides to the desired product 6.0 MPa of 10/90 O2/N2 atmosphere, the amount of
in order to enhance the yield. lactone side product formed is significantly lower
The weaker acids trifluoroacetic acid (TFA) and than in the case of isochromane. The substituted
NBu4HSO4 gave none of the coupling product 46 but product 48 could be isolated with 31% yield or 60%
mainly peroxides 43 and 44 (Table 7, entries 5 and 6). based on unreacted starting material.
Nitric acid gave traces of coupling product only and
the peroxide 44 as the major product (Table 7,
In contrast, phthalane 49 did not react with acetyl-
ACHTUNGTRENaNGNU cetone under similar conditions, but the reaction
entry 7). Sulfuric acid gave almost full conversion of with acetone led to full conversion of 49 after 6 days.
both peroxides and the desired product 46 was After work-up by preparative column chromatogra-
formed with a relatively high yield of 34% (Table 7, phy, only 7% of acetone derivative 50 and 38% of lac-
entry 8). Under the same conditions, triflic acid cata- tone 51 could be isolated, which indicates the forma-
lyzed the product formation with a slightly lower tion of intractable materials to a substantial extent.
yield of 25% and basically full conversion of all per- Interestingly, in 50 both benzylic carbon atoms are
oxides, but with a larger amount of starting material oxidized compared to the starting material 49. When
left over (Table 7, entry 9). This improved product se- a mixture of 51 and acetone was treated under the
lectivity led us to explore the use of TfOH in more same conditions, no further reaction occurred. Thus,
detail. At lower catalysts loadings of 1 and 2 mol%, the formation of 50 proceeds via initial oxidative cou-
conversion of isochromane was slightly increased but pling followed by oxygenation to the lactone. Appa-
more 44 was left over and the yields of 23 were basi- rently, the yield is low due to the tendency towards
cally unchanged (Table 7, entries 10 and 11). At a lactone formation and other oxidative decomposition
higher loading of 10 mol%, conversion of isochro- pathways.
mane and yield of 46 was reduced (Table 7, entry 12).
Based on previous mechanistic investigations[11] and
The yield of the desired product could be further in- the results with isochromane discussed above, we be-
creased to 35% by increasing the amount of acetyl- lieve that the oxidative cross-coupling reaction pro-
ACHTUNGTRENNUNGacetone to 5 equivalents (Table 7, entry 13). In spite ceeds via peroxide intermediates like 43 or 44. A
of extensive studies, no further improvement of the Brønsted acid-catalyzed substitution of the peroxide
À
reaction could be achieved. In agreement with our group by carbon nucleophiles can then give rise to C
previous studies,[11] the addition of transition metal
salts did not increase the yields, indicating that the
process does not require metal catalysis but runs or-
ganocatalytically (see Supporting Information).
Finally, the isochromane derivative dibenzo-
ACHTUNGTRENNUNG
[b,d]pyran (47)[20] and the benzylic ether phthalane
(49) were subjected to autoxidative coupling condi-
tions (Scheme 6). Pyran 47 also represents a constitu-
tional isomer to xanthene 1 and showed similar chem-
ical behavior with acetylacetone. Although conversion
of 47 is rather low after 72 h of treatment under Scheme 7. Proposed reaction mechanism.
Adv. Synth. Catal. 2012, 354, 701 – 711
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
709

ꢀron Pintꢁr and Martin Klussmann
FULL PAPERS
C bond formation (Scheme 7). Strong acids like sul- Experimental Section
fonic acids represent the optimal catalysts for the sub-
Unless otherwise indicated, all reagents and solvents were
stitution, while weaker acids do not facilitate the reac-
tion or do so only to a lesser extent. The observed
Bayer–Villiger rearrangement leading to xanthyl-b-
keto ester 18 and the formation of carboxylic acids
26b–e from the corresponding aldehydes is a further
support for the release of hydrogen peroxide as by-
product of substitution reactions with peroxides. Ac-
purchased from commercial distributors and used as re-
ceived. Solvents used for preparative liquid chromatography
were of technical grade and used after distillation in a
rotary evaporator. Oxidative coupling reactions were moni-
tored by GC analysis on an Agilent Technologies 6890N
Network GC System equipped with a MN Optimaꢅ
5
Accent capillary column (0.32 mmꢆ30 mꢆ0.25 mm) and
flame ionization detector using n-heptadecane as internal
standard. 1H NMR spectra were recorded at 500 MHz,
13C NMR spectra were recorded at 125 MHz and chemical
shifts are reported relative to TMS and are referenced to
the solvent residual peaks. Isolation of the compounds by
preparative column chromatography was performed on
Merck Silica Gel 60 (40–63 mm).
À
cordingly, we term this C H functionalization via au-
toxidation an “autoxidative coupling”.
The observed high intrinsic oxidizability of xan-
thene and acridane derivatives is in good accordance
À
with the low benzylic C H bond dissociation energy
values of xanthene derivatives,[21] but it does not ex-
plain why our preliminary studies revealed very low
reactivity of similar compounds like diarylmethane
derivatives. This and the exact role of the nucleophile
compound on the initiating autoxidation step remain
the subject of ongoing mechanistic studies.
Representative Procedure
Acridane (36a) (0.315 g, 1.00 mmol), phenylacetone (661 mL,
5.00 mmol), n-heptadecane (31 mL, 0.10 mmol; optional as
internal standard) and methanesulfonic acid (3.25 mL,
0.05 mmol) were charged in a glass vial (d=15 mmꢆh=
45 mm) containing a magnetic stirring bar. The open vial
containing the reaction solution was placed in a stainless
steel autoclave (nominal volume 36 mL), sealed and pressur-
ized with a gas mixture containing 10% O2 in N2 up to
10.0 MPa. Magnetic stirring (750 minÀ1) of the reaction mix-
ture at 20–258C was continued for 72 h, then conversion was
Conclusions
In summary, we have developed an aerobic cross-cou-
pling method that only requires a simple sulfonic acid
À
catalyst and oxygen. Benzylic C H bonds in xan-
1
thene, acridane and isochromane derivatives can be
functionalized with a broad variety of nucleophilic
carbonyl compounds as well as with electron-rich
arenes. While no or very little conversion with these
nucleophiles is achieved at ambient pressure of
oxygen, elevated partial pressures of oxygen up to
10 bar result in moderate to good yields of the desired
coupling products. Under these reaction conditions,
the nucleophile scope of the autoxidative coupling re-
action has become significantly extended. This
method could provide access to compounds with ap-
plications as materials or pharmaceuticals; for exam-
ple, xanthenes and acridanes are known as pharma-
ceutically active compounds and natural products and
they are used as dyes or molecular switches.[22] Efforts
towards the extension of the substrate scope beyond
the reported “electrophiles”, that is, benzylic methyl-
ene groups in heterocycles, are underway in our labo-
ratory.
determined by H NMR measurement of the crude reaction
mixture. Isolation of 38a was accomplished by preparative
column chromatography on silica (60 g, d=25 mmꢆh=
260 mm) using a gradient of toluene in ethyl acetate from
100:0 to 90:10.
Safety Note: Oxidative reactions at high pressure should
always be performed under an inert gas containing no more
than 10% oxygen for reasons of safety, as most flammable
organic compounds have a limiting oxygen concentration
above 10%.
Acknowledgements
The authors thank Prof. Benjamin List for financial support
and helpful discussions and Esther Bçß and Tim Hillring-
haus for help in preparing the Supporting Information.
The reaction is believed to proceed via peroxides References
and thus relies on the intrinsic sensitivity of the “pro-
[1] a) M. Klussmann, D. Sureshkumar, Synthesis 2011,
electrophilic” substrates towards autoxidation. Under
increased partial pressures of oxygen or at elevated
temperatures, the generation of benzylic hydroperox-
ides is facilitated to a synthetically useful rate, which
can be converted to the desired products by reaction
with carbon nucleophiles under acid catalysis in situ.
The simplicity and resource-efficiency of this cross-
coupling method could serve as a model towards the
development of other green reactions.
353–369; b) C. S. Yeung, V. M. Dong, Chem. Rev. 2011,
111, 1215–1292; c) C. J. Scheuermann, Chem. Asian J.
2010, 5, 436–451; d) C.-J. Li, Acc. Chem. Res. 2009, 42,
335–344.
[2] P. Anastas, N. Eghbali, Chem. Soc. Rev. 2010, 39, 301–
312.
[3] a) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2006, 128, 56–57;
b) Z. Li, L. Cao, C.-J. Li, Angew. Chem. 2007, 119,
6625–6627; Angew. Chem. Int. Ed. 2007, 46, 6505–6507.
710
asc.wiley-vch.de
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 701 – 711

Sulfonic Acid-Catalyzed Autoxidative Carbon-Carbon Coupling Reaction
[4] a) S.-I. Murahashi, N. Komiya, H. Terai, Angew. Chem.
2005, 117, 7091–7093; Angew. Chem. Int. Ed. 2005, 44,
6931–6933; b) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2005,
127, 6968–6969; c) Z. Li, D. S. Bohle, C.-J. Li, Proc.
Natl. Acad. Sci. USA 2006, 103, 8928–8933; d) Z. Li,
P. D. MacLeod, C.-J. Li, Tetrahedron: Asymmetry 2006,
17, 590–597; e) A. Sud, D. Sureshkumar, M. Kluss-
mann, Chem. Commun. 2009, 3169–3171; f) W. Han,
A. R. Ofial, Chem. Commun. 2009, 6023–6025; g) P.
Liu, C.-Y. Zhou, S. Xiang, C.-M. Che, Chem. Commun.
2010, 46, 2739–2741; h) J. Xie, Z.-Z. Huang, Angew.
Chem. 2010, 122, 10379–10383; Angew. Chem. Int. Ed.
2010, 49, 10181–10185.
[5] Z. Li, R. Yu, H. Li, Angew. Chem. 2008, 120, 7607–
7610; Angew. Chem. Int. Ed. 2008, 47, 7497–7500.
[6] a) S.-I. Murahashi, N. Komiya, H. Terai, T. Nakae, J.
Am. Chem. Soc. 2003, 125, 15312–15313; b) A. Yu, Z.
Gu, D. Chen, W. He, P. Tan, J. Xiang, Catal. Commun.
2009, 11, 162–166.
[16] A. M. C. F. Castelijns, J. M. Hogeweg, S. P. J. M. Van
Nispen, Netherlands Patent PCT/NL1995/000358, 1996.
[17] a) K. Sato, M. Hyodo, J. Takagi, M. Aoki, R. Noyori,
Tetrahedron Lett. 2000, 41, 1439–1442; b) K. Bahrami,
M. M. Khodaei, S. Kamali, Chin. J. Chem. 2008, 26,
1119–1121.
[18] a) R. M. Acheson, R. G. Bolton, J. Chem. Soc. Perkin
Trans. 1 1975, 650–653; b) Z. Szulc, J. Młochowski, J.
Palus, J. Prakt. Chem. 1988, 330, 1023–1029; c) B. L.
Mylari, T. J. Carty, P. F. Moore, W. J. Zembrowski, J.
Med. Chem. 1990, 33, 2019–2024; d) G. Krishnegowda,
P. Thimmaiah, R. Hegde, C. Dass, P. J. Houghton, K. N.
Thimmaiah, Bioorg. Med. Chem. 2002, 10, 2367–2380;
e) X. Mei, A. T. August, C. Wolf, J. Org. Chem. 2006,
71, 142–149; f) A. Boumendjel, S. Macalou, A. Ahmed-
Belkacem, M. Blanc, A. Di Pietro, Bioorg. Med. Chem.
2007, 15, 2892–2897; g) V. S. Gopinath, P. Thimmaiah,
K. N. Thimmaiah, Bioorg. Med. Chem. 2008, 16, 474–
487; h) Y. C. Mayur, Zaheeruddin, G. J. Peters, C.
Lemos, I. Kathmann, V. V. S. R. Prasad, Arch. Pharm.
2009, 342, 640–650; i) P. Singh, J. Kaur, P. Kaur, S.
Kaur, Bioorg. Med. Chem. 2009, 17, 2423–2427; j) N.
Desbois, A. Szollosi, A. Maisonial, V. Weber, E.
Moreau, J.-C. Teulade, O. Chavignon, Y. Blache, J. M.
Chezal, Tetrahedron Lett. 2009, 50, 6894–6896.
[7] S. Murata, K. Teramoto, M. Miura, M. Nomura, Bull.
Chem. Soc. Jpn. 1993, 66, 1297–1298.
[8] a) O. Baslꢁ, C.-J. Li, Green Chem. 2007, 9, 1047–1050;
b) Y. Shen, M. Li, S. Wang, T. Zhan, Z. Tan, C.-C. Guo,
Chem. Commun. 2009, 953–955; c) D. Sureshkumar, A.
Sud, M. Klussmann, Synlett 2009, 1558–1561; d) O.
Baslꢁ, N. Borduas, P. Dubois, J. M. Chapuzet, T.-H.
Chan, J. Lessard, C.-J. Li, Chem. Eur. J. 2010, 16, 8162–
8166; e) L. Huang, T. Niu, J. Wu, Y. Zhang, J. Org.
Chem. 2011, 76, 1759–1766.
[9] a) W.-J. Yoo, C. A. Correia, Y. Zhang, C.-J. Li, Synlett
2009, 138–142; b) C. A. Correia, C.-J. Li, Tetrahedron
Lett. 2010, 51, 1172–1175.
[10] T. Zeng, G. Song, A. Moores, C.-J. Li, Synlett 2010,
2002–2008.
[19] a) S. Siegel, S. Coburn, J. Am. Chem. Soc. 1951, 73,
5494–5495; b) A. Rieche, E. Schmitz, Chem. Ber. 1957,
90, 1082–1093.
[20] Prepared based on a reported method: P. S. Dewar,
A. R. Forrester, R. H. Thomson, J. Chem. Soc. C 1971,
3950–3959.
[21] X. Zhang, F. G. Bordwell, J. Org. Chem. 1992, 57,
4163–4168.
[22] a) X. Huang, T. Zhang, J. Org. Chem. 2010, 75, 506–
509; b) W. Tang, H. Hioki, K. Harada, M. Kubo, Y. Fu-
kuyama, J. Nat. Prod. 2007, 70, 2010–2013; c) M. S. T.
GonÅalves, Chem. Rev. 2009, 109, 190–212; d) B. L. Fer-
inga, J. Org. Chem. 2007, 72, 6635–6652; e) T. Troxler,
K. Hurth, H. Mattes, M. Prashad, P. Schoeffter, D. Lan-
genegger, A. Enz, D. Hoyer, Bioorg. Med. Chem. Lett.
2009, 19, 1305–1309; f) K. Chibale, M. Visser, D. van
Schalkwyk, P. J. Smith, A. Saravanamuthu, A. H. Fair-
lamb, Tetrahedron 2003, 59, 2289–2296; g) R. Pellic-
ciari, G. Costantino, M. Marinozzi, A. Macchiarulo, L.
Amori, P. Josef Flor, F. Gasparini, R. Kuhn, S. Urwyler,
Bioorg. Med. Chem. Lett. 2001, 11, 3179–3182; h) M.
Nꢇgrꢈdi, Product Class 2: Benzopyrylium Salts, in: Sci-
ence of Synthesis, Vol. 14, (Ed.: E. J. Thomas), Georg
Thieme Verlag, Stuttgart, New York, 2003, pp 201–273;
i) R. H. Prager, C. M. Williams, Product Class 9: Acri-
dines, in: Science of Synthesis, Vol. 15, (Ed.: D. S.
Black), Georg Thieme Verlag, Stuttgart, New York,
2004, pp. 987–1028.
[11] ꢀ. Pintꢁr, A. Sud, D. Sureshkumar, M. Klussmann,
Angew. Chem. 2010, 122, 5124–5128; Angew. Chem.
Int. Ed. 2010, 49, 5004–5007.
[12] For other recent autoxidative coupling methods, see:
a) M. Brasse, J. A. Ellman, R. G. Bergman, Chem.
Commun. 2011, 47, 5019–5021; b) Y.-C. Wong, M.-T.
Hsieh, P. K. Amancha, C.-L. Chin, C.-F. Liao, C.-W.
Kuo, K.-S. Shia, Org. Lett. 2011, 13, 896–899.
[13] During the preparation of this manuscript, an asym-
metric variant of our autoxidative coupling was report-
ed, using aldehydes as nucleophiles: B. Zhang, S.-K.
Xiang, L. H. Zhang, Y. Cui, N. Jiao, Org. Lett. 2011, 13,
5212–5215.
[14] a) M. Lim, C. M. Yoon, G. An, H. Rhee, Tetrahedron
Lett. 2007, 48, 3835–3839; b) M. Tada, S. Muratsugu, M.
Kinoshita, T. Sasaki, Y. Iwasawa, J. Am. Chem. Soc.
2010, 132, 713–724.
[15] M. Hajimohammadi, N. Safari, H. Mofakham, A. Shaa-
bani, Tetrahedron Lett. 2010, 51, 4061–4065.
Adv. Synth. Catal. 2012, 354, 701 – 711
ꢄ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
711