Palladium-catalyzed oxidative synthesis of highly functionalized ortholactones

Article abstract of DOI:10.1002/chem.201500862

A palladium-catalyzed oxidative reaction is reported which converts dihydropyrans to their corresponding ortholactone. The products are formed in good to excellent yields with a very high level of chemoselectivity and functional group tolerance. Mechanist

Full text of DOI:10.1002/chem.201500862

DOI: 10.1002/chem.201500862
Communication
&
Synthetic Methods
Palladium-Catalyzed Oxidative Synthesis of Highly Functionalized
Ortholactones
Kate L. Baddeley, Qun Cao, Mark J. Muldoon,* and Matthew J. Cook*[a]
[Eq. (2)].[11] This method used CuCl2 as co-catalyst in an atmos-
Abstract: A palladium-catalyzed oxidative reaction is re-
phere of pure oxygen and provided, in most cases, high yield
ported which converts dihydropyrans to their correspond-
and regioselectivity. We hypothesized that we could build
ing ortholactone. The products are formed in good to ex-
upon Sigman’s work to render the oxidative ortholactone for-
cellent yields with a very high level of chemoselectivity
mation catalytic and use atmospheric air rather than pure
and functional group tolerance. Mechanistic studies con-
oxygen as the terminal oxidant. Herein, we report the first cat-
firm that the reaction proceeds by a Wacker-type mecha-
alytic ortholactone formation using atmospheric air as the ter-
nism.
minal oxidant [Eq. (3)].
Ortholactones are a class of cyclic orthoester which have great
potential for synthetic utility. These compounds can act as
electrophiles, following Lewis or protic acid activation, allowing
for substitution of either one[1] or both of the alcohol leaving
groups.[2] A major obstacle to their greater use in synthesis is
their formation which generally requires harsh conditions
which are not tolerant of a wide range of functionality. These
include strongly alkylative conditions such as Meerwein’s salt,[3]
Lewis acidic conditions analogous to a Noyori ketalization,[4]
the substitution of anomeric gem-dihalides[5] or by cycloaddi-
tion reactions, which only provides specific substitution pat-
terns.[6] Spirocyclic ortholactones can also be formed through
the condensation of diols with lactones under acid catalysis[7]
or from an addition–elimination strategy using anomeric vinyl
sulfides.[8] Although there are many methods available, most
require strongly alkylative, acidic or basic conditions that do
not tolerate sensitive functionality.
We began examining the possibility of rendering the ortho-
lactonization catalytic using air as the terminal oxidant
(Table 1). We used an in situ prepared PdII/(À)-sparteine cata-
lyst, similar to the preformed complex used by Sigman, in a re-
actor with 40 bar of compressed air. Gratifyingly, this provided
excellent reactivity with high yields being obtained. Neverthe-
less, due to the supply problems with sparteine[12] and the
issues surrounding the use of pressurized reactors, we began
examining more accessible methods. A screen of ligands found
that many diamine ligands including both pyridine and basic
amine based groups performed well with N,N,N’,N’-tetramethyl
cyclohexyldiamine (L2), providing the highest yields. We were
able to lower the palladium loading to 4 mol% and maintain
reactivity, however, at lower catalyst loadings the reaction pro-
ceeds at a much slower rate leading to reduced yields. The
issue of pressurized vessels could be addressed by performing
the reaction in an open vessel (a condenser fitted with
a drying tube). This allowed for a continuous resupplying of
the oxygen levels thus maintaining a constant reaction and
preventing the formation of palladium black and provided
complete conversion and 85% isolated yield of the ortholac-
Holzapfel reported an alternative approach whereby ortho-
lactones could be derived from glycals via an oxidative
Wacker-type reaction [Eq. (1)].[9] This method provided very
high yields, however, one equivalent of a palladium complex
was required and all attempts to render this reaction catalytic
through the addition of exogenous oxidants failed. Since this
report there have been significant advances in PdII-catalyzed
oxidation catalysis.[10] One advance has been the use of ligands
which lead to the formation of PdII complexes that exhibit im-
proved catalytic turnover and high selectivity towards the de-
sired product. A good example of relevant work in this area, is
Sigman’s oxidation of styrenes in the presence of alcohols to
form ketals using a preformed Pd[(À)-sparteine]Cl2 as catalyst
[a] K. L. Baddeley, Q. Cao, Dr. M. J. Muldoon, Dr. M. J. Cook
School of Chemistry and Chemical Engineering
Queen’s University Belfast, Belfast, BT9 5AG (UK)
E-mail: m.j.muldoon@qub.ac.uk
m.cook@qub.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500862.
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Table 1. Optimization studies.
Table 2. Substrate scope.
Entry
1
Product
Entry
6
Product
Entry
Pd source ([mol%])
Ligand
P [bar]
Yield [%][a,b]
1
2
3
4
5
6
7
8
[PdCl2(MeCN)2] (8)
[PdCl2(MeCN)2] (8)
[PdCl2(MeCN)2] (8)
[PdCl2(MeCN)2] (8)
[PdCl2(MeCN)2] (8)
[PdCl2(MeCN)2] (8)
PdCl2 (8)
Pd(OAc)2 (4)
Pd(OAc)2 (2)
Pd(OAc)2 (4)
Pd(OAc)2 (4)
(À)-sparteine
40
40
40
40
40
40
40
40
40
10
1
1 (O2)[d]
86 (81)
69
93 (60)
100 (75)
83
93 (60)
69
95 (76)
57
BiPy
L1
L2
L3
L4
L2
L2
L2
L2
L2
L2
2a, 85%
2b, 69%
2c, 65%
2d, 54%
2e, 29%
2 f, 60%
2g, 45%
2h, 54%
2i, 68%
2
3
4
5
7
8
9
9
10
11[c]
12
55
98 (85)
98 (84)
Pd(OAc)2 (4)
1
[a] Yields determined by H NMR analysis of the crude using PhCHO as an
internal standard (following completion of the reaction). [b] Values in pa-
rentheses indicate isolated yields of pure 2a. [c] Reaction conducted in
a flask open to the atmosphere at 408C. [d] Performed using a balloon of
pure oxygen.
tone 2a. This was also comparable to when the reaction was
run under an atmosphere of pure oxygen which provided simi-
lar levels of conversion and isolated yields.[13]
With the optimized conditions in hand (Table 1, entry 11), we
began examining the scope of the reaction (Table 2). The or-
tholactonization was effective for other carbohydrate-derived
dihydropyrans including the glucal tribenzoate 2b, alongside
the galactal 2c and rhamanal 2d albeit in slightly reduced
yields. When the C-5 substituent was removed, as in xylal 2e,
the yield was much reduced due to product decomposition.
The reaction was also tolerant of amides 2 f, free alcohols 2h
and ketals 2i highlighting the very mild conditions.
For less substituted dihydropyran substrates the isolated
yields were much lower due to the decomposition of the prod-
uct prior to the complete consumption of the starting material.
We were able to identify and isolate the major decomposition
product with lactone 4 being produced in high yields. The or-
tholactone 2j could be produced and isolated if the reaction
was performed under a high pressure of air and this was ob-
served performing a ring opening to form ester 3 which then
Scheme 1. Othrolactone decomposition pathway.
5 was promoted through prolonged exposure of the ortholac-
tone 2k to silica gel, thus expelling methanol and forming 5.
Due to the instability of some of the dimethoxy ortholac-
tones, we began examining the use of alternative alcohols
which may provide enhanced stability. We discovered that the
reaction of 1a is very sensitive to sterics. When ethanol is used
as solvent, the reaction proceeds much slower and using iso-
propanol no reaction is observed with quantitative recovery of
starting material. The reaction is much more facile when diols
are used and excellent yields are obtained when 2,2-dimethyl-
propan-1,3-diol is used to form spirocyclic product 11 a
(Table 3). It was necessary to perform the reaction with the ad-
underwent
a lactonization and elimination to form 4
(Scheme 1). This process is so facile that silica gel and even the
residual acid in untreated CDCl3 will promote this pathway.
The presence of an unprotected alcohol group was also in-
vestigated with C-6 hydroxy substituent 1k (Scheme 2). In this
case, the alcohol does not appear to effect the ortholactone
formation with 2k being formed and isolated; however, the re-
action also contained bicyclic ortholactone 5. The formation of
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Table 4. 1,3-Diol substrate scope.
Scheme 2. Bicyclic ortholactone formation.
Table 3. Alcohol scope.
Entry
1
Product
Entry
7
Product
11 a, 92%
11 b, 80%
11 l, 90%
11 c, 70%
11 d, 98%
11 e, 52%
11 k, 52%
11 m, 80%
11 n, 88%
11 j, 72%
11 o, 75%
11 p, 47%
Entry
1
Product
Entry
4
Product
2
3
4
5
6
8
6a, 30%
9a,[a] 70%, 1:1:1:1 d.r.
9
2
3
5
6
7a, no reaction
10a,[a] 80%
10
11
12
8a, 53%
11 a,[a] 92%
[a] Reaction performed in DMF using 10 equivalents of diol.
dition of solvent as the diol is a solid, and this also allowed us
to lower the stoichiometry of alcohol to 10 equivalents.
We examined the scope of the reaction using 2,2-dimethyl-
propan-1,3-diol as the alcohol donor. We found that these re-
actions gave superior yields compared to the methoxy cases
due to the enhanced stability of the ortholactone functional
groups tolerated, and with little sign of decomposition. The re-
action is tolerant of differently protected glucal derivatives
11 a,b,l, alongside other carbohydrate series including galactal
11 c, rhamanal 11 d and xylal 11 e (Table 4). Free alcohols were
tolerated at the C-3, C-4 and C-6 positions 11 k,m,n with no ox-
idation observed or side reactions occurring. Non-carbohydrate
derived dihydropyrans were also excellent substrates, provid-
ing iso-butyl 11 j and 2-bromophenyl 11 o ortholactones in
high yields. We were also able to demonstrate this method on
a five-membered substrate with furan ortholactone 11 p being
produced.
value of 1.80 which is consistent with proton transfer being
rate limiting. In the case of the 2,2-dimethylpropan-1,3-diol
conditions, high yields and deuterium transfer were observed
with 14 being produced in 90% yield with 97% D incorpora-
tion. Again, facial selectivity was observed albeit lower than
the methanol case (71:29 d.r.). To our surprise, when the kinetic
isotope effect was measured a kH/kD value of 0.84 was ob-
tained thus indicating a change in mechanism in comparison
with the formation of 13, and suggesting a change in geome-
try from sp2 to sp3 occurs during the rate-limiting step. When
the reaction was performed in [D4]methanol, no deuterium
was incorporated at the C-2 position of 15.
To probe the mechanism of the two sets of conditions, deu-
terium labeling studies were performed.[14] Using C-1 deuterat-
ed glycal 12 the reaction was performed firstly with methanol
as the alcohol donor. This provided the corresponding ortho-
lactone 13 with 93% deuterium incorporation at the C-2 posi-
tion [Eq. (4)]. Interestingly, the deuterium transfer occurred
with facial selectivity to provide 13 in a 83:17 d.r. We also per-
formed a kinetic isotope effect study and measured a kH/kD
With our mechanistic data in hand we can propose a mecha-
nism which accounts for all the observations and data
(Scheme 3).[15]
The electron-rich dihydropyran 12 undergoes trans-oxypalla-
dation to form acetal complex II. b-Hydride elimination pro-
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Communication
In conclusion, we have developed robust and high yielding
methods for the formation of highly functionalized 2-deoxyor-
tholactones. These reactions are performed under neutral con-
ditions from readily available substrates using atmospheric air
as the terminal oxidant. In particular, the spirocyclic derivatives
are the most effective due to their stability relative to the di-
methoxy variant. We have discovered some interesting side re-
actions to form bicyclic systems and highlighted the major de-
composition pathway. Finally, our mechanistic studies have elu-
cidated the pathways involved, including the difference in
rate-limiting step for the two sets of conditions developed.
The use of these compounds in synthesis is currently being in-
vestigated.
Acknowledgements
We gratefully acknowledge the Engineering and Physical Scien-
ces Research Council (EPSRC DTA Award) for a studentship
(K.L.B.).
Keywords: aerobic oxidation · ortholactone · palladium ·
synthetic methods · Wacker-type reaction
[1] a) L. R. Takaoka, A. J. Buckmelter, T. E. La Cruz, S. D. Rychnovsky, J. Am.
Chem. Soc. 2005, 127, 528; b) T. E. La Cruz, S. D. Rychnovsky, J. Org.
Chem. 2007, 72, 2602.
[2] a) A. Mekhalfia, I. E. Markꢁ, H. Adams, Tetrahedron Lett. 1991, 32, 4783;
b) I. E. Markꢁ, A. Mekhalfia, D. J. Bayston, H. Adams, J. Org. Chem. 1992,
57, 2211; c) I. E. Markꢁ, D. Bayston, Tetrahedron Lett. 1993, 34, 6595;
d) I. E. Markꢁ, M. Bailey, F. Murphy, J. P. Declercq, B. Tinant, J. Feneau-
Dupont, A. Krief, W. Dumont, Synlett 1995, 123; e) C. M. Yu, J. Y. Lee, B.
So, J. Hong, Angew. Chem. Int. Ed. 2002, 41, 161; Angew. Chem. 2002,
114, 169.
[3] a) P. Deslongchamps, R. Chenevert, R. J. Taillefer, C. Moreau, J. K. Saun-
ders, Can. J. Chem. 1975, 53, 1601; b) P. Deslongchamps, J. Lessard, Y.
Nadeau, Can. J. Chem. 1985, 63, 2485.
[4] A. G. M. Barrett, H. B. Broughton, S. V. Attwood, A. A. L. Gunatilaka, J.
Org. Chem. 1986, 51, 495.
[5] a) J. P. Praly, L. Brard, G. Descotes, Tetrahedron Lett. 1988, 29, 2651;
b) J. P. Praly, Z. El Kharraf, P. J. Corringer, L. Brard, G. Descotes, Tetrahe-
dron 1990, 46, 65.
[6] a) R. R. Schmidt, B. Beitzke, Synthesis 1982, 750; b) S. Yamago, E. Nak-
mura, J. Org. Chem. 1990, 55, 5553; c) M. Uyanik, T. Yasui, K. Ishihara, Tet-
rahedron 2010, 66, 5841, and references therein.
Scheme 3. Proposed mechanism.
vides a ketene acetal with the palladium–deuteride complex
coordinated to one face. This can exist either as a cationic
complex III or via the decomplexation of one of the amine li-
gands IV.[16] Deprotonation of the palladium complex leads to
palladium(0) complex V and oxocarbenium ion 16 which is
trapped by a second equivalent of alcohol to form ortholac-
tone 13 and 14. The coordination–deprotonation event leads
to the facial selectivity of the deuterium transfer. The diaste-
reomeric ratio in 13/14 can be obtained either from the facial
selectivity of the initial oxypalladation or via a decomplexation
pathway. V is then oxidized back to PdII using the CuCl2 and air
to regenerate the original catalyst I. When methanol is used as
the nucleophile, b-hydride elimination appears rate limiting
whereas the inverse secondary effect when dimethylpropane
diol is used, suggests oxypalladation is rate limiting, presume-
ably due to the much more sterically demanding nucleophile.
[7] a) H. Ohtake, T. Iimori, S. Ikegami, Tetrahedron Lett. 1997, 38, 3413; b) H.
Ohtake, S. Ikegami, Org. Lett. 2000, 2, 457; c) H. Ohtake, N. Ichiba, S. Ike-
gami, J. Org. Chem. 2000, 65, 8171.
[8] T. E. La Cruz, S. D. Rychnovsky, Synlett 2004, 2013.
[9] C. W. Holzapfel, G. J. Englebrecht, G. H. Verdoorn, Heterocycles 1989, 28,
433.
[10] Reviews: a) S. S. Stahl, Angew. Chem. Int. Ed. 2004, 43, 3400; Angew.
Chem. 2004, 116, 3480; b) K. M. Gligorich, M. S. Sigman, Chem. Commun.
2009, 3854; c) E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocornola,
Chem. Rev. 2007, 107, 5318; d) R. I. McDonald, G. Liu, S. S. Stahl, Chem.
Rev. 2011, 111, 2981.
[11] A. M. Balija, K. J. Stowers, M. J. Schultz, M. S. Sigman, Org. Lett. 2006, 8,
1121.
[12] In recent years (À)-sparteine has not been widely available commercial-
ly. This shortage has led to researchers preparing surrogates: J. D. Firth,
P. O’Brien, L. Ferris, Org. Biomol. Chem. 2014, 12, 9357.
[13] Ortholactone products are sensitive to silica gel chromatography lead-
ing to reduced isolated yields compared to those measured by NMR
spectroscopy.
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[14] For reviews and discussion of kinetic isotope measurements in catalytic
reactions, see: a) M. Gꢁmez-Gallego, M. A. Sierra, Chem. Rev. 2011, 111,
4857; b) E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51,
3066; Angew. Chem. 2012, 124, 3120.
[16] A. Gogoll, J. ꢃrnebro, H. Grennberg, J. E. Bꢂckvall, J. Am. Chem. Soc.
1994, 116, 3631.
[15] For reviews of Wacker-type reaction mechanisms, see: a) J. A. Keith,
P. M. Henry, Angew. Chem. Int. Ed. 2009, 48, 9038; Angew. Chem. 2009,
Received: March 3, 2015
ˇ
´
121, 9200; b) P. Kocovsky, J. E. Bꢂckvall, Chem. Eur. J. 2015, 21, 36.
Published online on && &&, 0000
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Communication
COMMUNICATION
A breath of fresh air: A palladium-cata-
lyzed oxidative reaction is reported
which converts dihydropyrans to their
corresponding ortholactone. The prod-
ucts are formed in good to excellent
yields with a very high level of chemo-
selectivity and functional group toler-
ance (see scheme). Mechanistic studies
confirm that the reaction proceeds by
a Wacker-type mechanism.
&
Synthetic Methods
K. L. Baddeley, Q. Cao, M. J. Muldoon,*
M. J. Cook*
&& – &&
Palladium-Catalyzed Oxidative
Synthesis of Highly Functionalized
Ortholactones
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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