Selective transition-metal-free vicinal cis-dihydroxylation of saturated hydrocarbons

Article abstract of DOI:10.1039/C6SC03055F

A transition-metal-free cis-dihydroxylation of saturated hydrocarbons under ambient reaction conditions has been developed. The described approach allows a direct and selective synthesis of vicinal diols. The new reaction thereby proceeds via radical iodination and a sequence of oxidation steps. A broad scope of one-pot dual C(sp³)-H bond functionalization for the selective synthesis of vicinal syn-diols was demonstrated.

Full text of DOI:10.1039/C6SC03055F

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EDGE ARTICLE
Selective Transition-Metal-Free Vicinal cis-Dihydroxylation of
Saturated Hydrocarbons
Luis Beringa,b and A. P. Antonchicka,b
Received 00th January 20xx,
Accepted 00th January 20xx
Transition-metal-free cis-dihydroxylation of saturated hydrocarbons under ambient reaction conditions has been
developed. The described approach allows direct and selective synthesis of vicinal diols. The new reaction proceeds
thereby via radical iodination and a sequence of oxidation steps. A broad scope of one-pot dual C(sp3)-H bond
DOI: 10.1039/x0xx00000x
www.rsc.org/
functionalization
for
the
selective
synthesis
of
vicinal
syn-diols
was
demonstrated.
functionalization, practical methods enabling the direct vicinal
dihydroxylation of hydrocarbons are not known. Herein we
report the first selective vicinal cis-dihydroxylation of
saturated hydrocarbons (Scheme 1C). The developed method
allows synthesis of cis-diols under transition-metal-free and
ambient reaction conditions.
Introduction
C-H bond functionalization of aliphatic hydrocarbons
represents a longstanding goal in organic chemistry.1 Selective
functionalization of the chemical inert and ubiquitous C(sp3)-H
bond is a great challenge. Participation of hydrocarbons in
chemical reactions often requires high temperatures at the
expense of controllability and economy of product formation.2
Besides aliphatic C-H bond halogenation, alkylation,
aminations, dehydrogenation and borylation, direct C-H bond
hydroxylation gained significant interest.3 Alcohols and polyols
are important synthetic precursors, structural motifs in natural
products and bioactive molecules and employed in numerous
of industrial processes.4 To date a variety of metal-based,
cytochrome P450 inspired and metal-free methods for the
hydroxylation of unactivated C-H bonds exist.5 Since 1983,
Barton and co-workers pioneered the iron-mediated oxidation
of alkanes under mild conditions (GIF chemistry) and more
recently White et al. developed an iron-based catalyst that
efficiently oxidizes one equivalent of cyclohexane to the
corresponding ketone (Scheme 1A).6 In the absence of metal-
catalyst, oxidation of hydrocarbons was realized using oxidants
in the presence of strong acids or dimethyldioxirane and
analogues (Scheme 1B).7 Overoxidation, dehydration and low
selectivity are common outcomes of the described methods.
1,2-Diols have high importance in organic synthesis and found
wide application. State of art methods for diol synthesis are
predominately based on dihydroxylation of alkenes in a metal-
catalyzed or metal–free manner.8 Despite the progress
towards efficient and selective aliphatic C-H bond mono-
Scheme 1 Direct C(sp3)-H bond oxidation of alkanes
Results and discussion
In 2002 Barluenga and co-workers reported the metal-free
functionalization of cyclohexane
diacetate (PIDA), I2 and tBuOH (Scheme 2).9 The reaction
proceeds via the formation of iodocyclohexane ( ), further
oxidation and trans-addition of acetylhypoiodide (AcOI) to give
2-iodohexyl acetate ( ). Critical for the transformation is the
(1) using phenyliodine
2
4
generation of an alkene intermediate through elimination of
AcOI. The same course of reaction was proposed by Sudalai et
al.10 Nevertheless, high excess of alkane (200 equiv) and
elevated temperatures were required in both cases to achieve
products. In the course of our studies exploring radical
reactions and the functionalization of simple alkanes mediated
by hypervalent iodine(III) reagents, we considered the
transient formation of iodoalkanes and further oxidation in a
a.Max-Planck-Institut für molekulare Physiologie
Abteilung Chemische Biologie
Otto-Hahn-Straße 11, 44227 Dortmund (Germany).
b.Technische Universität Dortmund
Otto-Hahn-Straße 4a, 44227 Dortmund (Germany).
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 1 Optimization of reaction conditionsa
View Article Online
DOI: 10.1039/C6SC03055F
Entry
Oxidant
ArI or ArI(III) Solvent Yieldb (%)
d.r.c
(equiv)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17d
18e
19f
AcO2H (16.5)
AcO2H (16.5)
AcO2H (16.5)
AcO2H (16.5)
AcO2H (16.5)
AcO2H (16.5)
H2O2 (16.5)
TBHP (16.5)
mCPBA (16.5)
Na2S2O8 (16.5)
AcO2H (12.5)
AcO2H (12.5)
AcO2H (12.5)
AcO2H (12.5)
AcO2H (12.5)
AcO2H (12.5)
AcO2H (12.5)
AcO2H (12.5)
AcO2H (12.5)
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIFA
DIBA
4-MeC6H4I
4-FC6H4I
2-MeC6H4I
IBA
4-MeC6H4I
4-MeC6H4I
4-MeC6H4I
AcOH
HCO2H
HFIP
CH3CN
CH2Cl2
w/o
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
72
32
18
16
20
5.3:1
7:1
1.5:1
1.5:1
1.5:1
4.3:1
-
-
-
-
5:1
5:1
6:1
6.3:1
5:1
10:1
6.5:1
6:1
n.c.
Scheme 2 Proposal for the vicinal-dihydroxylation
cascade reaction fashion as a promising approach for the
synthesis of diols from saturated hydrocarbons.11 During our
primary screening we found, that beside known hypervalent
iodine based methods, the PIDA-I2-NaN3 system enabled
radical iodination.9,10,12 Furthermore, we hypothesized that by
combining radical iodination with an excess of oxidant, such as
peracetic acid, epoxidation of the generated alkene would take
place and subsequent ring opening would lead to the
formation of trans-2-hydroxycyclohexyl acetate. However,
during extensive screening we found, that trans-addition of
AcOI cannot be bypassed, but an additional oxidation step of
17
n.d.
n.d.
n.d.
traces
53
97
99
79
53
8
99
86
8
2-iodocyclohexyl acetate (4) is possible to accomplish (Scheme
2). Formation of mono-acetylated diol
5 proceeds in this case
via oxidative nucleophilic substitution of iodine.13 We were
pleased to find, that iodination and the sequence of oxidations
could be performed as a one-pot reaction. Through hydrolysis
a
Reaction conditions: 1. ArI or ArI(III) (0.6 mmol, 1 equiv), oxidant (see table),
cyclohexane (12.5 equiv), I2 (0.8 equiv), NaN3 (2.5 equiv), AcOH (0.1 M), rt, 24 h;
of the crude product cis-cyclohexane-1,2-diol (6) was obtained
b
2. LiOH (2 equiv), MeOH (0.2 M), rt. Yields are given for isolated products after
column chromatography. Calculated based on ArI or ArI(III). c Diastereomeric ratio
in 72% yield with a relative diastereoselectivity of 5.3:1 (Table
1, entry 1). The systematic optimization was started by
screening different solvents, but no improvement was found
(Table 1, entry 2-6 and see the supporting information). Usage
of AcOH was convenient, since AcO2H is a solution in AcOH.
Among all tested oxidants solely the use of peracetic acid
(d.r.) according to 1H-NMR. 8.5 equiv, 6.25 equiv or 1 equiv of cyclohexane.
d
e
f
Abbreviations: n.d. = not detected, w/o = without, HFIP = hexafluoroisopropanol,
PIFA
methylbiphenyl, IBA = 2-iodobenzoic acid, n.c. = not calculated.
= phenyliodine bis(trifluoroacetate), DIBA = 2,2’-diiodo-4,4’,6,6’-tetra-
one of the lowest loadings in direct hydroxylation of simple
alkanes reported. Obtained diol
yielded product
6 and an optimum was found when using 12.5
6 is a valuable precursor for
equiv of oxidant (Table 1, entry 7-10 and see the supporting
information). KI and NIS were examined as alternative iodine
sources, but yielded only traces of product (see the supporting
information). Significant improvements were achieved during
the screening of aryl iodides (Table 1, entry 11-16 and see the
the production of adipic acid which is one of the most
important chemical intermediates in industry.14 Having the
optimized conditions in hand, we started to explore the scope
of this novel method for the transition-metal-free
dihydroxylation alkanes by testing cyclic, linear and branched
saturated hydrocarbons at higher scale (Table 2). Gratifyingly,
by varying the ring size to 5, 7 and 8 carbons the desired
products were obtained in good to moderate yields.
supporting information). 4-Iodotoluene yielded diol
6 in 99%
yield with respect to the aryl iodide and slightly improved the
diastereoselectivity (up to 6.5:1). Further screening of
additives revealed the substoichiometric use of iodine to be
most advantageous (see the supporting information). High
atom efficiency is a typical feature of iodination via radical
activation.9,12 In contrast, increased loading of I2 lowered
product formation. We assume that unwanted radical
scavenging disturbed the propagation of the reaction. Next,
different azides were tested, but the initially used 2.5 equiv of
NaN3 yielded the highest product formation (see the
supporting information). Finally, we stressed our novel system
by reducing the amounts of alkane as far as possible.
Unchanged product formation was still observed when 8.5
equiv of cyclohexane were added to the reaction (Table 1,
entry 17-19 and see the supporting information).
Nevertheless, the application of 8.5 equiv of cyclohexane is
Comparable to cyclohexane-1,2-diol (
diol ( ) was formed in 86% yield and with a d.r. of 6.3:1.
6), cis-cyclopentane-1,2-
8
Significant improvement of diastereoselectivity was observed
with increasing ring size of the hydrocarbons. Only trace
amounts of the trans-diastereomer of diol 10 were detected
and cyclooctane
Interestingly, the reaction conditions developed by Barluenga
and co-workers were used to convert cycloheptane ( ) into 2-
iodo-1-methylcyclohexyl acetate, while our developed reaction
conditions smoothly formed the desired diol without ring
contraction.9,12 Furthermore, the results suggest that the
relative stereochemistry is influenced by the neighboring
group effect of the acetate group during the oxidative
displacement of iodine.13c We assume that this effect becomes
(11) yielded exclusively the cis-isomer.
9
2 | J. Name., 2012, 00, 1-3
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Table 2 Scope of the vicinal dual C(sp3)-H bond hydroxylation of various saturated hydrocarbonsa
View Article Online
DOI: 10.1039/C6SC03055F
Entry
1
Substrate
Productsb
r.r.c
Yieldd (%)
-
-
-
-
99
2
3
4
86
85
37
5e-g
21 : 1: 7
18.5 : 1 : 5
> 20 : 1
90 (68h)
91 (73i)
86
6e-g
7e-g
8e, g
9e, g
10e-g
11e-g
6.5 : 1.5 : 1
5.5 : 2 : 1
7.7 : 1
68
73
55
8 : 1
20
a Reaction conditions: 1. Alkane (8.5 equiv), 4-MeC6H4I (0.3 mmol, 1 equiv), I2 (0.8 equiv), NaN3 (2.5 equiv) and AcO2H (12.5 equiv) in AcOH (0.1 M), rt, 24 h; 2. LiOH (2
equiv), MeOH (0.1 M), rt. b Diastereomeric ratio (d.r.) according to 1H-NMR. Major isomer is shown. c Regioisomeric ratio (r.r.) according to 1H-NMR. d Yields are given
e
f
g
for isolated products. Calculated based on 4-MeC6H4I. Scaled to 0.9 mmol of 4-MeC6H4I. 3.5 equiv of NaN3. BzCl (2.5 equiv) and DMAP (5 mol%) in DCM/Py
(0.45 M). h Yield of isolated regioisomers 14a and 14b. i Yield of isolated regioisomers 16a and 16b.
less dominant with increasing ring size. Next, tertiary (3°) yields and excellent regioselectivity (Table 2, entry 7). The
carbon containing alkanes were tested. Although iodination dihydroxylation of linear alkanes was realized in good yields as
predominantly occurred on the 3° position, minor well (Table 2, entry 8 and 9). Benzoylation of 2° hydroxyl
functionalization of secondary (2°) positions occurred as well. groups was applied to facilitate handling of volatile
Straightforward benzoylation of diols allowed the isolation of compounds. Major products were identified as result of the
14a
,
b
and 16a
,
b
in good yields (Table 2, entry 5, 6) and iodination of 2° carbon position and further transformation to
and 22a . Although oxidation predominantly
revealed, that functionalization of the 3° position proceeded give 20a
,
b
, b
with a high regioselectivity. A remarkable improvement occurred at 2° carbon atoms, minor product formation as a
regarding the selectivity of the radical iodination was observed result of 1° C-H bond iodination or elimination to a terminal
when using 1,4-dimethylcyclohexane (17). Offering two 3° double bond was observed (20c and 22c). Finally, branched
carbon atoms for iodination reduced the probability for alkanes containing 3° carbon atoms were tested in the
functionalization of the 2° C-H position and only traces of reaction. 3-Methylpentane (23) yielded products 24 in 55%
product 18b were formed, while 18a was isolated in good yield and demonstrated regioselectivity in a comparable
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manner to the previous examples. Elimination of oxidized
iodine to the thermodynamically more stable double bond had
View Article Online
DOI: 10.1039/C6SC03055F
a
strong influence on the distribution of regioisomers.
Interestingly, due to steric hindrance, product 26 revealed an
opposite ratio of regioisomer formation, since dihydroxylation
of a terminal double bond took preferentially place. Although
in the absence of 3° positions C-H functionalization via
iodination resulted in the formation of regioisomers, it should
be noted that among all possible oxidation products
exclusively vicinal oxidation was observed and moreover
overoxidation to ketones was not detected. Attempts to use
aliphatic ethers, esters or carboxylic acids remained
unsuccessful under the developed conditions.
Having established the scope of the vicinal dihydroxylation
using saturated hydrocarbons, the reaction mechanism was
studied. By omitting the aryl iodide, iodine or sodium azide no
product formation took place. The application of
iodocyclohexane instead of cyclohexane smoothly yielded the
expected product which was isolated in 98% yield (see
supporting information). Additionally, we were able to study
the reaction profile by means of GC-MS. Monitoring of
a
Scheme 4 Dihydroxylation of iodoalkanes. Reaction conditions: Iodoalkane
(1 equbiv, 0.5 mmol), 4-MeC6H4I (0.6 equiv), AcO2H (7.5 equiv) in cAcOH (0.3 M), rt,
24 h; Ac2O (3 equiv), DMAP (5 mol%) in DCM/Py (0.45 M); LiOH (2 equiv),
MeOH (0.1 M), rt
The use of azide radicals allows a dramatically reduced loading
of alkanes and enables iodination at ambient temperature,
which makes the formation of iodoalkanes more efficient. The
formation of IN3 as intermediate10 was excluded, since
formation of 1-azido-2-iodocyclohexane or 2-azidocyclohexyl
acetate was not observed under the developed reaction
conditions. In control experiments iodocyclohexane (
converted to product under the developed reaction
conditions (see the supporting information). Next,
iodocyclohexane ( ) is oxidized and reductive elimination of
AcOI leads to cyclohexene ( ). Subsequent trans-addition of
AcOI to cyclohexene ( ) provides . Further oxidation of by
peracetic acid and nucleophilic substitution gives product 5 13c
important intermediates
2 and 4 and product 5 formation was
2) was
possible (see the supporting information and Scheme 3). A
significant kinetic deuterium isotope effect was observed (KIE
= 7.4), when using d12-cyclohexane and 1 (see the supporting
information). Consequently, the abstraction of hydrogen from
cyclohexane is the rate-limiting step. A proposed reaction
mechanism is outlined in Scheme 3. Initially 4-iodotoluene is
oxidized by peracetic acid in the presence of acetic acid. Ligand
5
2
3
3
4
4
.
The stereochemical outcome can be reasoned through a
competition between an Woodward- and Prévost-type
reaction.13c,15 The Woodward-type reaction was favoured for
cyclic alkanes. It is important to note that under the developed
reaction conditions epoxidation of cyclohexene by peracetic
exchange with NaN3 leads to intermediate
thermolysis at ambient temperature to give an azide radical
) and an iodine centred radical ( is scavenged by
).11a
iodine whereupon AcOI and 4-iodotoluene are formed. The
azide radical reacts with providing a cyclohexyl radical. This
A, which undergoes
(B
C
C
1
acid (
selective formation of trans-cyclohexane-1,2-diol after
hydrolysis upon oxidation of cyclohexene ( ) with peracetic
3) does not occur. A control experiment revealed the
transformation is the rate limiting step of the developed
cascade reaction. In the following step, the cyclohexyl radical is
trapped by iodine or AcOI to provide iodocyclohexane (2). The
principal difference to the reaction conditions developed by
Barluenga and co-workers9 is based on the application of
sodium azide instead of tBuOH.
3
acid (see the supporting information). This founding highlights
the importance of AcOI which is formed in situ.
The application of C-H bond functionalization for the selective
derivatization of complex molecules gained great interest and
offers unique advantages in terms of efficiency and atom
economy.16 However, the required excess of starting material
in this protocol negotiates those advantages. Based on the
results obtained during the studies on the reaction
mechanism, we visioned that the use of iodoalkanes offers the
opportunity to selectively introduce vicinal diols into more
complex substrates by mimicking the developed reaction
conditions. In this process radical iodination is excluded and
the iodine atom in alkyl iodide plays the role of a traceless
directing group for metal-free dihydroxylation. According to
our proposal, ester 27 yielded the dioxygenated product 28 in
good yields using 1 equiv of starting material (Scheme 4).
Furthermore, the functionalization of complex molecules was
tackled by using cholestane derivative 29. The dihydroxylated
products were isolated with good cis selectivity after
hydrolysis in 40% yield (Scheme 4). It is notable that 29
Scheme 3 Plausible reaction mechanism
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5
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contains 7 weak tertiary C-H bonds, which were untouched
under the applied reaction conditions. It must be noted, that
common reaction routes include multiple reaction steps and
the use of expensive and toxic osmium catalyst or are
mediated by metal reagents.17
A. Periana, D. J. Taube, S. Gamble, H. Taube,ViTew. ASratictloehO,nliHne.
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Conclusions
We have developed the first efficient and scalable method for
the
transition-metal-free
double
C(sp3)-H
bond
functionalization of saturated hydrocarbons. Cyclic, linear and
branched alkanes were converted selectively to vicinal diols
under ambient reaction conditions. Furthermore, we
demonstrated for the first time the use of the iodine atom of
alkyl iodides as traceless directing group for metal-free
dihydroxylation. Our discovery is grounded on an
unprecedented cascade reaction.
6
7
8
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Full synthetic characterization, general experimental
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Acknowledgements
We gratefully acknowledge Prof. Dr. H. Waldmann for his
generous support. This work was supported by the Fonds der
Chemischen Industrie e.V (FCI Fellowship to L. Bering).
Notes and references
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