Oxidative rearrangement of malondialdehyde: Substrate scope and mechanistic insights

Article abstract of DOI:10.1039/c4ra11237g

A novel oxidative rearrangement of malondialdehyde was described. Under the effect of H₂O₂, malondialdehyde smoothly transferred to carboxylic acid with C-C bond cleavage in good to excellent yields. Mechanistic studies showed that this reaction proceeded via the formation of a 1,2-dioxolane intermediate, followed by concert C-C, O-O, C-H bond cleavage and a hydride shift.

Full text of DOI:10.1039/c4ra11237g

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Oxidative rearrangement of malondialdehyde:
substrate scope and mechanistic insights†
Cite this: RSC Adv., 2014, 4, 53397
a
b
c
c
a
a
Xin Yu, Zheng Liu, Zilei Xia, Zhigao Shen, Xixian Pan, Hui Zhang*
b
and Weiqing Xie*
Received 26th September 2014
Accepted 16th October 2014
DOI: 10.1039/c4ra11237g
www.rsc.org/advances
A novel oxidative rearrangement of malondialdehyde was described. trapped by intramolecular Michael addition to furnish 1,2,4-
5
Under the effect of H
2
O
2
, malondialdehyde smoothly transferred to trioxane when a Michael acceptor is present. Bloodworth and
carboxylic acid with C–C bond cleavage in good to excellent yields. co-workers developed cyclo-oxymercuration of Criegee inter-
Mechanistic studies showed that this reaction proceeded via the mediate with tethered alkene followed by reductive demercu-
6
formation of a 1,2-dioxolane intermediate, followed by concert C–C, ration to prepare 1,2,4-trioxane.
O–O, C–H bond cleavage and a hydride shift.
On the other hand, the removal of functional groups via C–C
bond cleavage reactions plays a prominent role in organic
7
synthesis. Since the rst report of the decarbonylation of alde-
Baeyer–Villiger oxidation is one of the most important trans-
hydes mediated by stoichiometric amounts of Wilkinson's
formations of ketones and aldehydes, which is widely employed
8a
catalyst by Tsuji and Ohno in 1965, other reports described the
1
in organic synthesis. This reaction provides a regioselective
ꢀ
catalytic decarbonylation of aldehydes at 200 C with Wilkin-
and stereospecic insertion of an oxygen atom to a C–C bond to
8b,8c
son's catalyst or other rhodium-based catalysts.
Still other
produce an ester or lactone (Fig. 1). A two-step mechanism has
8a–8j
8k
8l
transition metal-based catalysts including Rh,
Ru, Ir and
2
been proposed based on mechanistic studies: (1) formation of
8m–8s
Pd
proved effective for the catalytic decarbonylation of
Criegee intermediate II via addition of a peroxide to a carbonyl;
aldehydes. Mechanistic studies showed that migratory extrusion
(2) stereospecic skeletal rearrangement of a Criegee interme-
8j
of CO from metal acyl adduct is the rate-limiting step. Although
diate to lactone or ester III, which constitutes the rate-
determining step. As the second step suffers from a relatively
higher free energy barrier, the Criegee intermediate II could be
intercepted by other reaction pathways before it undergoes
skeletal rearrangement. In this regard, interrupted Baeyer–Vil-
liger oxidation for formation of 1,2,4-trioxane through cycliza-
the direct extrusion of carbonyl group with C–C bond cleavage
proved useful in total synthesis, these decarbonylation
9
3–6
tion of Criegee intermediate is well documented.
For
example, Criegee intermediate with appendage hydroxyl could
3
transfer to 1,2,4-trioxane via intramolecular acetalization. This
reaction has been widely employed in synthesis of natural
product (e.g. artemisinin) and pharmaceutical molecules with
4
antimalarial activity. Criegee intermediate could also be
a
Department of Chemistry, School of Science & Instrumental Analysis and Research
Center, Shanghai University, Shanghai 200444, China. E-mail: yehao7171@163.com
b
State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China. E-mail:
xiewq@sioc.ac.cn
c
State Key Laboratory of Natural Medicines, Center of Drug Discovery, China
Pharmaceutical University, Nanjing 210009, China
†
Electronic supplementary information (ESI) available: General experimental
procedures, mechanical studies and spectroscopic date for the all compounds.
See DOI: 10.1039/c4ra11237g
Fig. 1 Pathway of Baeyer–Villiger oxidation and interrupted Baeyer–
Villiger oxidations.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 53397–53401 | 53397

View Article Online
RSC Advances
Communication
procedures suffered from catalyst availability and cost, harsh (Table 1, entry 2 and 5) presumably due to the competitive self-
reaction condition and sometimes, the need for CO scavengers. catalyzed effect of resulting carboxylic acids. In contrast, addi-
Herein, we discovered a novel oxidative decarbonylation of tion of strong Brønsted acids (e.g. HCl, TfOH, Tf NH) gave
2
malondialdehyde mediated by H O that avoided disadvantages inferior results owing to lability of malondialdehyde to strong
2
2
of metal catalyzed decarbonylation reactions. The mechanistic acid. Gratifyingly, camphorsulfonic acid provided optimal
studies also supported a tandem acetalization–fragmentation result, rendering the reaction completed in 1 h. In sharp
1
pathway of Criegee intermediate.
Serendipitously, we found that treatment of malondialde- using H
hyde 1a with H using phosphoric acid as catalyst led to yields were obtained even aer extending reaction time
contrast, Lewis acids, which facilitate Baeyer–Villiger oxidation
2 2
O as oxidant, slowed down the reaction and reduced
2 2
O
carboxylic acid 2a as the sole product (Table 1, entry 3). This (Table 1, entry 11 to 14). Other reaction condition optimization
result was quite unexpected as both aldehydes were oxidized to was also performed. For example, solvent screenings showed
carboxylic acids along with C–C bond cleavage under mild that ethyl acetate afforded best isolated yields than any other
reaction condition (vide infra). Recognizing that this reaction solvents (Table 1, entry 16, 17 and ESI†). Comparable result
provided quite novel reaction scenario for interrupting Baeyer– could be obtained by reducing catalyst loading to 5 mol%
Villiger oxidation, we embarked on the reaction condition (Table 1, entry 18). It should also be pointed out that the reac-
optimization for this reaction. To our interest, malondialde- tion is not sensitive to oxygen and moisture, and the reaction
hyde 1a smoothly transferred to carboxylic acid 2a in 82% yield could be performed in open ask without rigorous exclusion of
in 5 h even in the absence of any catalyst (Table 1, entry 1). This water.
could be ascribed to be the self-catalyzed effect of the resulting
Aer establishing the optimal reaction condition, various
carboxylic acids (vide infra). Although phosphoric acid was a malondialdehydes were prepared and subjected to the standard
good promoter for this reaction, employing chiral phosphoric reaction conditions to test the substrate scope of this reaction.
acid did not lead to any noticeable enantioselectivity (Table 1, To our delight, most of malondialdehydes smoothly underwent
entry 4). Subsequently, various Brønsted acids were screened to oxidative decarbonylation reaction, leading to carboxylic acid in

nd a suitable catalyst for this reaction (Table 1, entry 2–10). good to excellent yields in 1 h (Scheme 1). The reaction was
Carboxylic acids displayed no obvious accelerating effect found to be somewhat sensitive to steric hindrance and lower
yields were obtained for those hindrance-encumbering malon-
dialdehydes (Scheme 1, 2h, 2j and 2l). The reaction conditions
were found to be compatible with various protecting groups.
Besides the acid-tolerated protecting groups (Scheme 1, TBDPS
of 2a and Bn of 2c), acid-labile protection group was also found
to be intact under the reaction conditions (Scheme 1, Tr of 2d).
Table 1 Reaction condition optimization for oxidative decarbon-
ylation of malondialdehyde 1a
a
2-Phenyl-malondialdehydes bearing various electron-rich or
b
Entry
Catalyst (equiv.)
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
—
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
CHCl
EA
3
3
3
3
3
3
3
3
3
3
3
3
3
3
5
12
2
2
5
2
2
2
2
82(80)
62
PhCOOH (0.1)
[(C
8H-R-TRIP (0.1)
CF COOH (0.1)
4-CH (C )SO
HCl (0.1)
HBF (0.1)
TfOH (0.1)
6
H
5
)O]
2
PO
2
H (0.1)
86
65
c
3
72
79
60
82
55
91
56
54
NR
72
97
75
86
3
6
H
4
3
H (0.1)
4
10
11
12
13
14
15
16
17
18
dl-CSA (0.1)
Ag(OTf)
1
12
12
12
6
1
1
Zn(OTf)
FeCl
Cu(OTf)
dl-CSA (0.1)
dl-CSA (0.1)
dl-CSA (0.1)
2
3
2
MeOH
Acetone
EA
2
1
dl-CSA (0.05)
97(93)
a
2 2
Reaction conditions: malondialdehyde 1a (0.2 mmol) with H O (0.24
mmol) was carried out in the presence of catalytic acid (0.02 mmol) in
b
solvent (2 mL) at rt. NMR yields by using 1,4-dimethoxybenzene as Scheme
1
Substrate variation of oxidative decarbonylation of
c
internal standard. Isolated yields are shown in parentheses. 0% ee.
malondialdehyde.
53398 | RSC Adv., 2014, 4, 53397–53401
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
1
electron-withdrawing groups were smoothly converted to phe- reaction progress was monitored by using H NMR spectroscopy
nylacetic acids in excellent yields (Scheme 1, 2m–2q). Easily in CDCl (see ESI†). The diagram clearly showed that addition of
3
oxidable functionalities such as alkene, alkyne could also catalytic CSA obviously accelerated the reaction and a self-
survive under the reaction conditions (Scheme 1, 2i–2k, 2t and catalytic effect of resulting carboxylic acids was also observed
1
13
2
u). Additionally, this reaction was also easily scaled up and in the absence of catalyst. Analysis of H and C NMR spectra of
carboxylic acid 2b, 2s and 2t could be efficiently prepared in reaction mixture also revealed the formation of formic acid in
gram scale by following the standard procedure. 50% yield, implying that both aldehydes were oxidized to
Although H mediated C–C bond cleavage of 1,3-dicar- carboxylic acids under the oxidative decarbonylation condition
2 2
O
bonyl compounds has been sporadically reported, mechanistic (Scheme 2, eqn (1)). To determine the source of a-proton of the
pathways of those reactions have not been fully studied to resulting carboxylic acid, deuterated malondialdehyde 1e-d was
10
date. To gain insights into the reaction mechanism, the also prepared and subjected to the standard reaction conditions
Scheme 2, eqn (2)). Interestingly, carboxylic acid 2e-d was
(
obtained with completely deuterated on the a-position as
1
judged by H NNR spectrum, indicating that one of the alde-
hyde protons shied to the a-position during the course of
oxidative decarbonylation reaction via a concert reaction
pathway.
To further elucidate the reaction pathway of the oxidative
decarbonylation reaction, DFT calculations at the level of
B3LYP/6-31g(d) in the gas phase were also performed by the
11
Gaussian 09 programme. As depicted in Fig. 2, the calculation
showed that unlike Baeyer–Villiger oxidation, the formation of
Criegee intermediate I1 turned out to be the rate-limiting step of
this reaction as transition state T1 suffered the largest free
Scheme
reaction.
2 Mechanistic studies of the oxidative decarbonylation
À1
2
energy barrier (19.5 kcal mmol ). Once the Criegee
À1
Fig. 2 Reaction coordinate of the oxidative decarbonylation reaction. Gibbs free energies (enthalpies) are in kcal mol
.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 53397–53401 | 53399

View Article Online
RSC Advances
Communication
Acknowledgements
We are grateful for nancial support from the National Natural
Science Foundation of China (grand no. 21202187, 21372239).
Notes and references
1
2
For reviews see: (a) G. R. Krow, Comprehensive Organic
Synthesis, Oxford, 1991, vol. 7, p. 671; (b) G. R. Krow, Org.
React., 1993, 43, 251; (c) G. Strukul, Angew. Chem., Int. Ed.,
1998, 37, 1198; (d) M. Renz and B. Meunier, Eur. J. Org.
Scheme 3 Proposed mechanism for the oxidative decarbonylation of
malondialdehyde.
Chem., 1999, 4, 737; (e) G.-J. ten Brink, I. W. C. E. Arends
and R. A. Sheldon, Chem. Rev., 2004, 104, 4105.
For mechanistic studies of Baeyer–Villiger oxidation, see: (a)
S. L. Friess and A. H. Soloway, J. Am. Chem. Soc., 1951, 73,
intermediate I1 formed, it quickly cyclized to 1,2-dioxolane I2
instead of formation of hydroxyaldehyde through Baeyer–Vil-
liger transition state T-BV, as calculation showed that T2 (7.1
3968; (b) M. F. Hawthorne and W. D. Emmons, J. Am.
Chem. Soc., 1958, 80, 6398; (c) Y. Ogata and Y. Sawaki, J.
Org. Chem., 1969, 34, 3985; (d) B. W. Palmer and A. Fry, J.
Am. Chem. Soc., 1970, 92, 2580; (e) Y. Ogata and Y. Sawaki,
J. Am. Chem. Soc., 1972, 94, 4189; (f) M. A. Winnik and
V. Stoute, Can. J. Chem., 1973, 51, 2788; (g) M. A. Winnik,
V. Stoute and P. Fitzgerald, J. Am. Chem. Soc., 1974, 96,
1977; (h) Y. Itoh, M. Yamanaka and K. Mikami, J. Org.
Chem., 2013, 78, 146.
For selected examples, see: (a) B. Kerr and K. J. McCullough,
J. Chem. Soc., Chem. Commun., 1985, 9, 590; (b) C. Singh,
Tetrahedron Lett., 1990, 31, 6901; (c) P. M. O'Neill, M. Pugh,
J. Davies, S. A. Ward and B. K. Park, Tetrahedron Lett.,
À1
À1
kcal mol for cis-isomer and 6.3 kcal mol for trans-isomer)
suffered much lower free energy barrier than that of Baeyer–
À1
Villiger transition state T-BV (19.5 kcal mol ). Once relatively
stable intermediate I2 formed, fragmentation of I2 to carboxylic
acids naturally took place as free energy barrier was 12.6 kcal
À1
À1
mol
for cis-isomer and 15.8 kcal mol
for trans-isomer
respectively, which could be easily overcome at room tempera-
3
ture. This could also explain why no signal of I2 was observed on
1
H NMR spectrum of crude reaction mixture at room tempera-
ture (see ESI†). It's also found by calculation that the frag-
mentation step was a concert process and transition state T3
underwent C–C, O–O and C–H bond cleavage with concurrent
shi of hydride, which was antiperiplanar to the departure of
formic acid (see ESI†).
2
001, 42, 4569; (d) C. Singh, S. Pandey, G. Saxena,
N. Srivastava and M. Sharma, J. Org. Chem., 2006, 71, 9057;
e) S. Erhardt, S. A. Macgregor, K. J. McCullough, K. Savill
(
and B. J. Taylor, Org. Lett., 2007, 9, 5569; (f) M. Ravi,
D. Anand, R. Maurya, P. Chauhan, N. K. Naikade,
S. K. Shukl and P. P. Yadav, Synlett, 2013, 24, 0173; (g)
J. F. B. Hall, R. A. Bourne, X. Han, J. H. Earley, M. Poliakoff
and M. W. George, Green Chem., 2013, 15, 177.
For reviews on artemisinin and its analogues, see the
following: (a) D. L. Klayman, Science, 1985, 228, 1049; (b)
Y. Tang, Y. Dong and J. L. Vennerstrom, Med. Res. Rev.,
Based on the mechanistic studies and DFT calculations, we
proposed a plausible mechanism for this novel interrupted
Baeyer–Villiger oxidation (Scheme 3). Malondialdehyde 1 reac-
ted with hydroperoxide to give Criegee intermediate I1 catalyzed
by Brønsted acid. Rather than proceeding to the Baeyer–Villiger
reaction pathway, Criegee intermediate I1 spontaneously
underwent intramolecular acetalization between peroxide and
the other aldehyde to deliver 1,2-dioxolane I2 with the aid of
acid. Eventually, acid catalyzed fragmentation of 1,2-dioxolane
I2 with concurrent cleavage of C–C, O–O and C–H bond and
antiperiplanar shi of hydride led to carboxylic acid 2 and for-
mic acid.
4
2004, 24, 425; (c) C. W. Jefford, Drug Discovery Today, 2007,
12, 487; (d) K. M. Muraleedharan and M. A. Avery, Drug
Discovery Today, 2009, 14, 793; (e) D. Chaturvedi,
A. P. S. P. Goswami, N. C. Barua and P. G. Rao, Chem. Soc.
Rev., 2010, 39, 435.
5
(a) C. W. Jefford, D. Jaggi, S. Kohmoto, J. Boukouvalas and
G. Bernardinelli, Helv. Chim. Acta, 1984, 67, 2254; (b)
C. W. Jefford, D. Jaggi, J. Boukouvalas and S. Kohmoto, J.
Am. Chem. Soc., 1983, 105, 6497; (c) C. W. Jefford,
S. Kohmoto, J. Boukouvalas and U. Burger, J. Am. Chem.
Conclusions
In summary, oxidative decarbonylation of malondialdehyde was
efficiently achieved in good to excellent yields simply using
H
2
O
2
as oxidant. Deuterium experiment and DFT calculations
Soc.,
1983,
105,
6498;
(d)
D.
M.
Rubush,
showed that capture of Criegee intermediate via intramolecular
acetalization with appendage aldehyde followed by concert C–C,
O–O and C–H bond cleavage with concurrent migration of
hydride was the reaction pathway. Currently, other type of
interrupted Baeyer–Villiger oxidation based on tandem acetali-
zation–fragmentation reaction of Criegee intermediate is
actively explored in our laboratory.
M. A. R. B. J. Morges, D. H. Thamm and T. Rovis, J. Am.
Chem. Soc., 2012, 134, 13554.
6 (a) A. J. Bloodworth and A. Shah, J. Chem. Soc., Chem.
Commun., 1991, 947; (b) J. E. Anderson, A. J. Bloodworth,
J. Cai, A. G. Davies and N. A. Tallant, J. Chem. Soc., Chem.
Commun., 1992, 1689; (c) J. Cai and A. G. Davies, J. Chem.
Soc., Perkin Trans. 1, 1992, 3383; (d) A. J. Bloodworth and
53400 | RSC Adv., 2014, 4, 53397–53401
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
N. A. Tallant, J. Chem. Soc., Chem. Commun., 1992, 428; (e)
J. E. Anderson, A. J. Bloodworth and A. Shah, J. Chem. Soc.,
Perkin Trans. 2, 1993, 1927; (f) A. J. Bloodworth and
K. A. Johnson, Tetrahedron Lett., 1994, 35, 8057; (g)
A. J. Bloodworth, T. Hagen, K. A. Johnson, I. LeNoir and
C. Moussy, Tetrahedron Lett., 1997, 38, 635.
(o) J. Tsuji and K. Ohno, J. Am. Chem. Soc., 1968, 90, 94; (p)
J. W. Wilt and W. W. Pawlikowski, J. Org. Chem., 1975, 40,
3641; (q) S. Matsubara, Y. Yokota and K. Oshima, Org. Lett.,
2004, 6, 2071; (r) D. Ferri, C. Mondelli, F. Krumeich and
A. Baiker, J. Phys. Chem. B, 2006, 110, 22982; (s) A. Modak,
A. Deb, T. Patra, S. Rana, S. Maity and D. Maiti, Chem.
Commun., 2012, 48, 4253.
9 For recent applications in total synthesis, see: (a) T. Kato,
M. Hoshikawa, Y. Yaguchi, K. Izumi, Y. Uotsu and
K. Sakai, Tetrahedron, 2002, 58, 9213; (b) R. K. Boeckman,
J. Zhang and M. R. Reeder, Org. Lett., 2002, 4, 3891; (c)
S. M. Allin, S. L. James, M. R. J. Elsegood and W. P. Martin,
J. Org. Chem., 2002, 67, 9464; (d) M. G. Banwell,
M. J. Coster, A. J. Edwards, O. P. Karunaratne, J. A. Smith,
L. L. Welling and A. L. Willis, Aust. J. Chem., 2003, 56, 585;
(e) G. S. Weatherhead, G. A. Cortez, R. R. Schrock and
A. H. Hoveyda, Proc. Natl. Acad. Sci. U. S. A., 2004, 101,
5805; (f) J. P. Malerich, T. J. Maimone, G. I. Elliott and
D. Trauner, J. Am. Chem. Soc., 2005, 127, 6276; (g)
M. Harmata and S. Wacharasindhu, Org. Lett., 2005, 7,
2563; (h) A. Padwa and H. Zhang, J. Org. Chem., 2007, 72,
2570; (i) H. Ueda, A. Takada and H. Tokuyama, Tetrahedron
Lett., 2013, 54, 7115.
7
8
(a) J. F. Hartwig, Organotransition Metal Chemistry, from
Bonding to Catalysis, University Science Books, New York,
2010; (b) J. Tsuji, Organopalladium Chemistry for Organic
Synthesis, Wiley, New York, 2002, vol. 2, p. 2648.
For Rh catalyzed reactions see: (a) J. Tsuji and K. Ohno,
Tetrahedron Lett., 1965, 6, 3969; (b) K. Ohno and J. Tsuji, J.
Am. Chem. Soc., 1968, 90, 99; (c) D. H. Doughty and
L. H. Pignolet, J. Am. Chem. Soc., 1978, 100, 7083; (d)
M. D. Meyer and L. I. Kruse, J. Org. Chem., 1984, 49, 3195;
(
2
e) T. Shibata, N. Toshida and K. J. Takagi, Org. Chem.,
002, 67, 7446; (f) R. K. Boeckman, J. Zhang and
M. R. Reeder, Org. Lett., 2002, 4, 3891; (g) T. Morimoto,
K. Fuji, K. Tsutsumi and K. Kakiuchi, J. Am. Chem. Soc.,
2002, 124, 3806; (h) G. S. Weatherhead, G. A. Cortez,
R. R. Schrock and A. H. Hoveyda, Proc. Natl. Acad. Sci. U. S.
A., 2004, 101, 5805; (i) M. Kreis, A. Palmelund, L. Bunch
and R. Madsen, Adv. Synth. Catal., 2006, 348, 2148; (j)
P. Fristrup, M. Kreis, A. Palmelund, P. O. Norrby and 10 (a) C. Mannich, Chem. Ber., 1941, 74, 1007; (b) L. Ruzicka,
R. Madsen, J. Am. Chem. Soc., 2008, 130, 5206; For Ru
catalyzed reactions, see: ; (k) G. Domazetis, B. Tarpey,
D. Dolphin and B. R. James, J. Chem. Soc., Chem. Commun.,
Ed. Rey and A. C. Muhr, Helv. Chim. Acta, 1944, 27, 472; (c)
J. R. Billeter and K. Mieseher, Helv. Chim. Acta, 1946, 29,
859; (d) J. Eichenberger, Helv. Chim. Acta, 1948, 31, 1663;
(e) G. B. Payne, J. Org. Chem., 1959, 24, 1830; (f)
G. B. Payne, J. Org. Chem., 1961, 26, 4793; (g) W. Cocker
and D. H. Grayson, J. Chem. Soc., Perkin Trans. 1, 1975, 1347.
1980, 939; For Ir catalyzed reactions, see: ; (l) T. Iwai,
T. Fujihara and Y. Tsuji, Chem. Commun., 2008, 6215; For
Pd catalyzed reactions, see: ; (m) J. O. Hawthorne and
M. H. Wilt, J. Org. Chem., 1960, 25, 2215; (n) J. Tsuji, 11 For detailed information of DFT calculation, see ESI.†
K. Ohno and T. Kajimoto, Tetrahedron Lett., 1965, 6, 4565;
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 53397–53401 | 53401