Orthogonally protected 1,2-diols from electron-rich alkenes using metal-free olefin syn-dihydroxylation

Article abstract of DOI:10.1021/acs.orglett.6b02959

A new method for the stereoselective metal-free syn-dihydroxylation of electron-rich olefins is reported, involving reaction with TEMPO/IBX in trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP) and the addition of a suitable nucleophile. Orthogonally

Full text of DOI:10.1021/acs.orglett.6b02959

Letter
pubs.acs.org/OrgLett
Orthogonally Protected 1,2-Diols from Electron-Rich Alkenes Using
Metal-Free Olefin syn-Dihydroxylation
Ignacio Colomer, Rosimeire Coura Barcelos, Kirsten E. Christensen, and Timothy J. Donohoe*
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, U.K.
S
* Supporting Information
ABSTRACT: A new method for the stereoselective metal-free syn-
dihydroxylation of electron-rich olefins is reported, involving reaction
with TEMPO/IBX in trifluoroethanol (TFE) or hexafluoroisopropanol
(HFIP) and the addition of a suitable nucleophile. Orthogonally protected
syn 1,2-diols were obtained with high levels of diastereocontrol, and these
products were selectively deprotected and selectively functionalized into
synthetically useful compounds.
lefin dihydroxylation is one of the most powerful tools in
organic chemistry. The functionalization of vicinal carbons
via double C−O bond formation can be achieved in a single step,
and established dihydroxylation methods give high levels of
stereospecificity.1 In particular, OsO4 has been used extensively
in organic synthesis for the syn dihydroxylation of olefins,
although its toxic nature is well recognized.
Scheme 1. Metal-Free Dihydroxylation Using Hypervalent
Iodine and TEMPO in Fluorinated Solvents
O
The development of new methods to overcome the use of
toxic reagents is of great interest, and many groups have been
devoted to finding new metal-free dihydroxylation procedures.2
Peroxides,3 hydroxamic acids4 and hypervalent iodine reagents5
used in stoichiometric amounts give good yields of syn-
dioxygenation products, with modest to good diastereocontrol.
Chiral hypervalent iodine reagents have also been used in
diacetoxylation6 and lactonization reactions.7 In addition, the use
of substochiometric amounts of hypervalent iodine reagents has
been developed recently.8 Alternatively the use of stable
persistent radicals such as nitroxyl radicals, in particular
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO), has allowed
a breakthrough in this area.9 Although great advances have been
made in the functionalization of olefins using TEMPO, with an
emphasis on stereoselective intermolecular aminooxygenation,10
azidooxygenation,11 oxyarylation,12 and trifluorooxygenation,13
the dioxygenation reaction itself remains underexplored.14
Following our recent research on the stereoselective synthesis
of cyclobutanes II via oxidation of styrenes to a radical cation I,
we became intrigued with the idea of trapping this radical cation
intermediate (Scheme 1).15 The use of TEMPO has led to the
discovery of a new metal-free dihydroxylation process with the
incorporation of both TEMPO and an external nucleophile (or
the solvent in its absence).
Changing to trifluoroethanol (TFE) gave no product with any of
the hypervalent iodine reagents used (Table 1, entries 4−6).16
Increasing the oxidant loading, using 20 mol % of IBX in HFIP,
improved the yield up to 85% with high syn stereocontrol (Table
1, entry 7). Interestingly, the use of an acidic nonfluorinated
solvent, such as AcOH, gave the analogous product 3a, but with
much lower diastereocontrol (Table 1, entry 8). In sharp contrast
when using a polar protic but nonacidic solvent, such as EtOH,
no product was observed. Finally, some control experiments
were carried out without using any hypervalent iodine additive.
While the use of TFE gave no reaction (Table 1, entry 10, in
agreement with entries 4−6), surprisingly the reaction in HFIP
or AcOH allowed isolation of the corresponding product 2a/3a
(Table 1, entries 11 and 12), in low yield (compare entries 11 vs 7
and 12 vs 8). It is also noteworthy that much better
diastereocontrol is again observed with HFIP than with AcOH.
Finally taking advantage of the lack of reactivity in TFE
(compared to HFIP) using a 1:1 mixture of TFE/AcOH gave 3a
We began using trans-anethole 1a as a model alkene under
previously optimized conditions for the synthesis of cyclobutanes
(10 mol % of PIDA in hexafluoroisopropanol (HFIP) at rt), with
the addition of 1.2 equiv of TEMPO as a radical trapping agent
(Table 1, entry 1). The protected diol 2a was obtained in 37%
yield as a single syn diastereoisomer. Using hypervalent
iodine(V) gave better results, with IBX as the most promising,
affording 2a in 66−76% yield (Table 1, entries 2 and 3).
Received: September 30, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02959
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Letter
influence the conformation and reactivity of a cationic
intermediate.22 At this point we cannot comment on the role
that ion pairing plays in controlling the cation reactivity, and this
factor may well differ between the two solvent regimes. Control
experiments which involved resubjecting mixtures or single
diastereoisomers of 3a to the reaction conditions in HFIP or
AcOH solvent led to no change in product composition, thus
ruling out equilibration at the benzylic center.
Table 1. Optimization of the Dioxygenation of 1a
entry
solvent
HFIP
oxidant
yield of 2 or 3 (%)
dr
Next, we decided to explore the reaction scope for both the
addition of HFIP leading to products 2 (Scheme 3) and the
1
2
3
10 mol % PIDA
10 mol % DMP
10 mol % IBX
10 mol % PIDA
10 mol % DMP
10 mol % IBX
20 mol % IBX
20 mol % IBX
20 mol % IBX
−
2a (37)
2a (66)
2a (76)
0
≥95:5
≥95:5
≥95:5
−
HFIP
HFIP
TFE
Scheme 3. Scope of the Metal-Free Dioxygenation with
Hexafluoroisopropanol Incorporation
a
4
a
5
a
TFE
0
−
−
6
TFE
0
7
HFIP
AcOH
EtOH
TFE
2a (85)
3a (70)
0
≥95:5
60:40
−
8
9
10
0
−
b
11
b
HFIP
AcOH
TFE/AcOH
−
−
2a (45)
3a (42)
3a (93)
≥95:5
60:40
≥95:5
12
13
20 mol % IBX
a
Traces of the corresponding cyclobutane were observed; however,
b
almost all starting material was recovered. 50% of starting material
was recovered.
in 93% yield and with high diastereocontrol (Table 1, entry 13 vs
8).
Based on the above experiments our mechanistic proposal is
shown in Scheme 2. Observing a strong background reaction in
incorporation of AcOH to give orthogonally protected 1,2-diols
3 (Scheme 4). The scope for the dioxygenation of alkenes via
HFIP addition was explored using styrenes with different
electron-rich aromatic rings; therefore, starting from E-asarone
(Ar = 2,4,5-trimethoxyphenyl) or from the 3,4-dimethoxy
derivative, products 2b and 2c were obtained. The incorporation
of an ortho-Br substituent in the aromatic ring is tolerated,
without diminishing the reactivity (2d) (Scheme 3). Moreover,
substituents on the allylic position, such as ethyl, i-Pr, or
cyclopropyl, were all compatible (2e−g) (Scheme 3). When (Z)-
1f styrene was used under these conditions, the same syn
diastereoisomer 2f was observed; this stereoconvergence is
supporting evidence for the proposed mechanistic pathway
proceding via a free cation (see Scheme 2). Note that the
regiochemistry and syn relative stereochemistry was proven
based on an X-ray crystal structure of 2c,23 and the remaining
products in Scheme 3 were assigned by analogy.
We then focused our efforts on studying the scope of
carboxylic acid incorporation because of the easy and selective
deprotection protocols that exist. We also decided to concentrate
on 1,2-disubstituted alkenes in order to study the diastereocon-
trol of the process. Keeping the p-methoxyphenyl ring (PMP)
constant we first investigated the compatibility of the allylic
substitution. Aliphatic linear (3b), branched (3c) (Scheme 4), or
alicyclic (3d) substitution resulted in good yields of the
corresponding TEMPO/acetate products (Scheme 4). Further-
more, different functional groups such as protected alcohol (3e)
(Scheme 4), halide (3f) (Scheme 4), or ester (3g) (Scheme 4)
were examined, all with very good results. For all of the examples
above only the syn diastereoisomer was observed by NMR
spectroscopy. However, when an alkene substrate containing a
carboxylic acid was tested, δ-lactone 3h derived from intra-
molecular attack was obtained in excellent yield. In this case the
anti-isomer was formed selectively; this change in stereo-
Scheme 2. Proposed Reaction Pathway
the absence of a hypervalent iodine reagent (Table 1, entries 11−
12), and being aware of the ability of TEMPO to dispropor-
tionate in acidic solvents,17 we propose the generation of
hydroxylamine III and oxoamonium cation IV.18 Electron-rich
olefin 1a may react with oxoamonium cation IV to form benzylic
cation intermediate V,19 which will then be trapped by a
nucleophile (either an external carboxylic acid or HFIP).20 The
beneficial role of IBX in this reaction may then be to generate
oxoamonium cation IV in situ, therefore improving the yield.21
The stereochemical outcome of the cation trapping can be
rationalized using intermediate V, with the external nucleophile
approaching antiperiplanar to the R1 group, in a conformation
that minimizes allylic strain, thus rendering a net syn
dihydroxylation. At this point we do not rule out the possibility
of the OTEMP nitrogen atom in the intermediate cation playing
a role in directing the nucleophile. The high levels of
diastereocontrol displayed when using fluorinated solvents may
be related to their larger dielectric constant (ε = 26 for TFE and ε
= 18 for HFIP) compared to AcOH (ε = 6.2), which may
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remain electron-rich for the reaction to proceed. In Scheme 4, the
syn relative stereochemistry was proven using the X-ray crystal
structure of 3a,23 and the remaining compounds were assigned
by analogy or by correlation of derivatives to compounds that are
known in the literature, vide infra.
Scheme 4. Scope of the Metal-Free Dioxygenation with
Carboxylic Acid Incorporation
Finally in order to demonstrate the utility of this new method
we addressed the selective deprotection of both hydroxy groups.
First, treating acetates 3a−d with K2CO3 in MeOH gave
monoprotected alcohols 4a−d in excellent yields (Scheme 5a).
Scheme 5. Functionalization of the OTEMP Adducts
chemistry is due to the intramolecular nature of the nucleophile
and supports our mechanistic proposal (see attack of a
nucleophile from within the R1 group in V, Scheme 2).24
Different carboxylic acid nucleophiles can be used; thus allyl
TMS substrate in combination with propionic acid gives 3i with
good results. Alternatively adding an aromatic acid or pivalic acid
offers the possibility of accessing syn 1,2-diols 3j and 3k with
diverse protecting groups.
Moving to the aromatic ring we examined electron-rich
examples such as E-asarone (3l) (Scheme 4), 2-methyl (3m)
(Scheme 4), or 3-methyl (3o) derivatives (Scheme 4) as well as
those bearing other substituents, for example 2-fluoro (3n)
(Scheme 4). The aryl olefin is not limited to p-methoxy styrenes,
and the method also works with less electron-donating
substituents, for example 3,4-dimethyl (3p) or naphthalene
substituents (3q) (Scheme 4); however, in these cases the yield
and diastereocontrol are compromised. Moreover, a representa-
tive group of terminal styrenes 3r−t (Scheme 4) and a diene 3u
(Scheme 4) were tested with the latter example showing
regioselectivity in favor of oxidation of the terminal olefin.
Although the reaction scope is quite broad, the olefin must
In order to deprotect the OTEMP functionality, hexafluor-
oisopropyl ether 2a and esters 3a and 3j were subjected to
reductive cleavage under standard conditions using Zn/AcOH to
form alcohols 5a−c in very good yields (Scheme 5a). Note that
when acetate 3a was used alcohol 5c was obtained together with
the acetate migration product (not shown, see Supporting
Information (SI)). Fully deprotected syn 1,2-diols 6a−d were
prepared by reaction of a monodeprotected product under the
complementary set of conditions (see 4a−d → 6a−d via N−O
bond cleavage and 5c → 6a by acetate cleavage).
The spectroscopic data for syn 1,2-diols 6a/6c were in
agreement with those previously reported in the literature, and
the 1H/13C NMR spectroscopic data of diols 6b and 6d matched
those of authentic syn diols made by OsO4 catalyzed
dihydroxylation of the corresponding E-alkene (see Supporting
Information). In addition, ketones 7a−b were obtained by
oxidative cleavage of the N−O bond with m-CPBA from 2e or 3a
C
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(Scheme 5a).25 The deprotection of lactone 3h under reductive
conditions resulted in the formation of transesterified product 8
in good yield, and the NMR data for this anti-compound
matched those in the literature (Scheme 5b). Alternatively the
electron-rich aromatic PMP ring can be oxidized to a carboxylic
acid using catalytic RuCl3,26 forming orthogonally protected α,β-
dihydroxy acids 9. Deprotection of 2d via reductive N−O bond
cleavage and subsequent Pd catalyzed intramolecular O-arylation
furnished dihydrobenzofuran 10 (Scheme 5d). Furthermore,
NOE experiments on 10 supported its cis-stereochemistry and
therefore the syn stereochemistry of 2d.
A new method for the syn-selective metal-free dioxygenation of
electron-rich olefins in fluorinated solvents has been presented;
the procedure involves a proposed reaction with an in situ
generated oxoammonium cation, followed by the addition of a
suitable nucleophile.
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(15) (a) Colomer, I.; Coura Barcelos, R.; Donohoe, T. J. Angew. Chem.,
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(16) We have not observed oxidation of the fluorinated solvent,
although TFE can be oxidized by oxoammonium salts or DMP:
(a) Linderman, R. J.; Graves, D. M. Tetrahedron Lett. 1987, 28, 4259−
4262. (b) Ignatowska, J.; Shyshkov, O.; Zipplies, T.; Hintzer, K.;
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02959.
■
S
Roschenthaler, G.-V. J. Fluorine Chem. 2012, 141, 35−40.
̈
(17) (a) de Nooy, A. E. J.; Besemer, A. C.; van Bekkum, H. Tetrahedron
1995, 51, 8023−8032. (b) Ma, Z.; Bobbitt, J. M. J. Org. Chem. 1991, 56,
6110−6114.
Full experimental details, copies of spectral data (PDF)
Crystallographic data (CIF)
(18) (a) Kelly, C. B.; Lambert, K. M.; Mercadante, M. A.; Ovian, J. M.;
Bailey, W. F.; Leadbeater, N. E. Angew. Chem., Int. Ed. 2015, 54, 4241−
4245. (b) Kelly, C. B.; Mercadante, M. A.; Wiles, R. J.; Leadbeater, N. E.
Org. Lett. 2013, 15, 2222−2225.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: timothy.donohoe@chem.ox.ac.uk.
ORCID
(19) For a similar discrete benzylic carbocation, see: Mohan, R. S.;
Whalen, D. L. J. Org. Chem. 1993, 58, 2663−2269.
(20) See: (a) Pradhan, P. P.; Bobbitt, J. M.; Bailey, W. F. Org. Lett.
2006, 8, 5485−5487. We are aware of little precedent for the reaction of
oxoammonium cations with electron-rich olefins: (b) Takata, T.;
Tsujino, Y.; Nakanishi, S.; Nakamura, K.; Yoshida, E.; Endo, T. Chem.
Lett. 1999, 28, 937−938.
Ignacio Colomer: 0000-0001-5542-7034
Timothy J. Donohoe: 0000-0001-7088-6626
Notes
The authors declare no competing financial interest.
(21) We propose that IBX (Iodine-V) can oxidize TEMPO-H to
oxoamonioum cation IV generating a hypervalent iodine(III) species
that could engage in a second TEMPO-H oxidation process, therefore
requiring only 20 mol % of IBX for the best efficiency. The ability of
hypervalent iodine(III) to oxidize TEMPO-H to its oxoamonium cation
is well established: De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.;
Piancatelli, G. J. Org. Chem. 1997, 62, 6974−6977.
ACKNOWLEDGMENTS
■
We thank the European Union and the European Commission
for financial support (IC): the research leading to these results
has received funding from the People Programme (Marie Curie
Actions) of the European Union’s Seventh Framework
Programme (FP7/2007-2013). R.C.B. thanks FAPESP (Award
No. 2014/16516-9) for funding. We thank W. Akhtar and Dr. A.
L. Thompson (University of Oxford) for assistance with the
single crystal X-ray diffraction studies.
́ ́
(22) For reviews of HFIP, see: (a) Begue, J.-P.; Bonnet-Delpon, D.;
Crousse, B. Synlett 2004, 18−29. (b) Shuklov, I. A.; Dubrovina, N. V.;
Borner, A. Synthesis 2007, 2007, 2925−2943.
̈
(23) Low temperature single crystal X-ray diffraction data were
collected using a (Rigaku) Oxford Diffraction SuperNova diffractom-
eter: (a) Cosier, J.; Glazer, A. M. J. Appl. Crystallogr. 1986, 19, 105−107.
Raw frame data were reduced using CrysAlisPro, and the structures were
solved using ‘Superflip’ before refinement with CRYSTALS as per the SI
(CIF). (b) Palatinus, L.; Chapuis, G. J. Appl. Crystallogr. 2007, 40, 786−
790. (c) Parois, P.; Cooper, R. I.; Thompson, A. L. Chem. Cent. J. 2015,
9, 30. (d) Cooper, R. I.; Thompson, A. L.; Watkin, D. J.J. Appl.
Crystallogr. 2010, 43, 1100−1107. Full refinement details are given in
the Supporting Information (CIF). Crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre (CCDC
1498189−90) and can be obtained via www.ccdc.cam.ac.uk/data_
request/cif.10.1107/S0021889810025598
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Org. Lett. XXXX, XXX, XXX−XXX