Guided desaturation of unactivated aliphatics

Article abstract of DOI:10.1038/nchem.1385

The excision of hydrogen from an aliphatic carbon chain to produce an isolated olefin (desaturation) without overoxidation is one of the most impressive and powerful biosynthetic transformations for which there are no simple and mild laboratory substitutes. The versatility of olefins and the range of reactions they undergo are unsurpassed in functional group space. Thus, the conversion of a relatively inert aliphatic system into its unsaturated counterpart could open new possibilities in retrosynthesis. In this article, the invention of a directing group to achieve such a transformation under mild, operationally simple, metal-free conditions is outlined. This 'portable desaturase' (Tz o °Cl) is a bench-stable, commercial entity (Aldrich, catalogue number L510092) that is facile to install on alcohol and amine functionalities to ultimately effect remote desaturation, while leaving behind a synthetically useful tosyl group.

Full text of DOI:10.1038/nchem.1385

ARTICLES
PUBLISHED ONLINE: 8 JULY 2012 | DOI: 10.1038/NCHEM.1385
Guided desaturation of unactivated aliphatics
Ana-Florina Voica, Abraham Mendoza†, Will R. Gutekunst†, Jorge Otero Fraga and Phil S. Baran
*
The excision of hydrogen from an aliphatic carbon chain to produce an isolated olefin (desaturation) without overoxidation
is one of the most impressive and powerful biosynthetic transformations for which there are no simple and mild laboratory
substitutes. The versatility of olefins and the range of reactions they undergo are unsurpassed in functional group space.
Thus, the conversion of a relatively inert aliphatic system into its unsaturated counterpart could open new possibilities in
retrosynthesis. In this article, the invention of a directing group to achieve such a transformation under mild, operationally
simple, metal-free conditions is outlined. This ‘portable desaturase’ (TzoCl) is a bench-stable, commercial entity (Aldrich,
catalogue number L510092) that is facile to install on alcohol and amine functionalities to ultimately effect remote
desaturation, while leaving behind a synthetically useful tosyl group.
f all the functional groups in organic chemical space, the conditions to provide a tertiary alkyl bromide (14 ꢀ 15) and (3)
olefin must be regarded as one of the most privileged base-mediated elimination (tetramethylpiperidine (TMP), 80 8C)
from the vantage point of utility in synthesis. As a result, (15 ꢀ 16) to give the desired olefin. In stunning contrast, nature
O
methods for olefin synthesis and functionalization have been devel-
oped extensively and applied in both academic and industrial
sectors. Most olefin-forming reactions rely on pre-oxidized starting
materials and fall into four main categories: functionalization of
ketones or aldehydes (aldol condensation, Wittig olefination and
more), modification of other alkenes (olefin metathesis, metal-
catalysed coupling reactions and others), reductive transformations
of alkynes (stereoselective reduction, reductive coupling, among
others) or synthesis by elimination reactions (from alcohols,
halides and so on)1. A less-explored strategy for olefin synthesis is
the direct desaturation of the parent alkane. Within this category,
the dehydrogenation of activated aliphatics (which leads to
enones, dienes, styrenes and others), generally a more facile
process, is utilized broadly and continues to be investigated2. In
contrast, the efficient oxidation of unactivated alkanes directly to
give alkenes remains an unmet challenge and approaches to this
problem rarely surface in methodological studies3. Select examples
of reported strategies for alkane dehydrogenation are shown in
Fig. 1. Among these, Breslow’s ground-breaking work awakened
the community to the strategic value of a remote desaturation reac-
tion and provided extensive studies on steroid frameworks4–6. In
general, these approaches employ high-energy radicals (Fig. 1a,b)4,7
or transition metals (Fig. 1c,d)8–13 to overcome the high kinetic
stability of the C–H bond. Although these pioneering studies clari-
fied the difficulties in achieving such a transformation (regiocontrol,
product isolation, functional-group tolerance), most of the methods
lack the generality and practicality required for wide use in complex
systems. Important limitations include the use of inconvenient
starting materials (for example, peroxides), poor substrate scope,
overoxidation of the resulting olefin, large substrate excesses or
harsh reaction conditions. Therefore, the invention of a broadly
applicable, mild protocol to achieve regio- and chemoselective desa-
turation of unactivated aliphatics remains highly desirable.
a O-centred radical abstraction/oxidation–Cekovic, Beckwith, Kochi
FeSO4
OH
OH
OH
Cu(OAc)2
O
+
Me
Me
AcOH/H2O
Me
Me
Me
1
2 (60%)
3 (10%)
b Photochemical transfer hydrogenation–Breslow
R
R
Me
Me
OH
Me
Me
hν
H
O
O
PhH (0.001 M)
55%
O
O
O
H
Me
Me
4
5
R =
Me
c Oxidative addition/β-H elimination–Brookhart, Crabtree, Goldman, Bergman
cat. 8
cat. NaOtBu
O
O
6
7
9
(tBu)2P
Ir
Cl
8
P(tBu)2
200 °C
TON = 1,600
H
tBu
tBu
Me
10
d
Cyclometallation/β-Helimination–for Pd: Yu, Catellani, Boudoin;for Pt: Sames
O
O
Me
Me
Me
Me
10 mol% Pd(OAc)2
Benzoquinone
N
N
NH
NH
DMSO/AcOH
120 °C, 12 h
30%
11
12
O
O
Ph
Ph
Our interest in a direct desaturation reaction was sparked during Figure 1 | Pioneering studies for alkane desaturation. a, Protocol for
the synthesis of the eudesmane terpenes using a cyclase–oxidase dehydrogenation employing peroxide-derived oxyl radicals7. b, Breslow’s
synthetic strategy (Fig. 2a)14. To achieve the formal dehydrogenation pioneering study of a remote dehydrogenation4–6. c, Application of Ir-based
catalysts towards the desaturation of cyclic alkanes3,8,9; TON ¼ turnover
of substrate 13 to give 16, three individual steps were required,
numbers. d, Example of a Pd-catalysed guided desaturation reaction10–13
cat. ¼ catalytic, DMSO ¼ dimethyl sulfoxide.
.
which involved (1) N-bromination with acetyl hypobromite
(13 ꢀ 14), (2) homolysis–recombination under photochemical
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA; †These authors contributed
equally to this work. e-mail: pbaran@scripps.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1385
ARTICLES
a
b
c
A formal desaturation via C–H oxidation: application in total synthesis
Me
Me
Me
O
Me
O
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
AcOBr
hν
TMP
HO
O
HO
O
HO
HO
H
Br
O
O
O
O
NH
NBr
NH
NH
F3C
F3C
F3C
F3C
13
14
15
16
One postulated mechanism for enzymatic desaturation
R
O
R
O
R
O
R
O
Desaturase
enzyme
(Δ9)
[–e–]
[–H+]
9
H
Me
Me
Me
Me
17
18
19
20
Guided desaturation: design of a ‘portable’ desaturase
Me
Me
Me
H
Et2N
Me
Me
Me
N
N
[+H+]
[+e–]
TzºCl
XH
X
X
N
SO2
SO2
N
NEt2
A (X = O, NH)
B
C
SO2Cl
TzºCl (21)
H-transfer
Me
Me
Portable desaturase
Commercially available from Aldrich,
catalogue number L510092
• Bench stable
H
Me
H
Me
H
Me
[–e–]
[–H+]
X
X
X
SO2
SO2
SO2
• Easily prepared (>100 g)
• Facile installation
F
E
D
Figure 2 | Design of a directing group for desaturation. a, Example of a strategic formal desaturation in the total synthesis of eudesmane terpenes.
b, Proposed mechanism for the enzymatic desaturation in nature. c, Description of the concept behind the guided desaturation reaction with a
portable desaturase.
is able to use desaturase enzymes to achieve direct, selective and are stable to basic, reductive and alkylating conditions, even in
controlled oxidations of aliphatic carbon chains with remarkable complex settings33,34. To append an aryl triazene to alcohols and
precision. One striking example is shown in Fig. 2b for the biosyn- amines, a functionalized aryl sulfonyl chloride was deemed
thesis of fatty acids15,16. This overall process is believed to occur appropriate and led to a triazene sulfonyl chloride (o-tosyl triazene
through a number of discrete steps including (1) C-9 specific chloride, TzoCl, 21) as our portable desaturase of interest. The pro-
alkane hydrogen abstraction, (2) single-electron oxidation of the posed set of events for the guided desaturation is outlined in Fig. 2c.
resulting alkyl radical to a carbocation and (3) stereoselective loss After installing the directing group onto the desired substrate to give
of a proton to provide olefin 20. Inspired by this approach to B, treatment with acid in the presence of a single-electron reductant
olefin synthesis, an analogous laboratory process was pursued. would provide an aryl radical C via an aryl diazonium intermediate.
Given the inherent difficulty of controlling an intermolecular desa- This inherently high-energy radical would abstract a proximal
turation17,18, as in the case of enzymes, a directing group19 (portable hydrogen atom to generate a lower energy alkyl radical D that
desaturase) that could be appended to commonly encountered would be oxidized to a carbocation E and finally terminated to
alcohol and amine functional groups to guide20 dehydrogenation give the desired alkene F. Additionally, if a suitable metal salt
of unactivated alkanes was designed. In this article, the development could participate in both the reduction and oxidation steps, a
of a portable desaturase is presented together with a protocol for redox cycle could be envisioned to allow for catalysis. The final
desaturation that requires no added metal salts, proceeds under design element involves the directing group transforming into a
mild reaction conditions and, most importantly, avoids overoxida- simple tosylate or tosylamine at the end of the reaction, functional
tion of the olefin product.
groups commonly employed in modern organic synthesis.
Three basic criteria were taken into account when designing the
portable desaturase: (1) reactivity—the employment of a highly Results and discussion
reactive species capable of controlled H-abstraction; (2) practical- TzoCl (21) was prepared in two steps from commercial 2-bromo-5-
ity—short, scalable synthesis and stability; (3) ease of installation methylaniline (see Supplementary Information). Gram quantities of
and versatility of the resulting functionality. For the reactivity cri- this directing group can be obtained and stored indefinitely at
terion, aryl radicals were identified as highly reactive, very short- ambient temperature without notable decomposition. After attach-
lived intermediates (rate of H-abstraction by aryl radicals is of the ing the directing group to the pilot substrate, 2-cyclopentylethanol,
order of 106 M21 s21 (ref. 21)), but are employed rarely in C–H under straightforward reaction conditions (dimethylaminopyridine,
functionalization reactions22,23 because of difficulties associated dichloromethane, room temperature, 90% yield) to give 22, studies
with their efficient generation and promiscuous reactivity24–26. An towards alkane desaturation began (Table 1).
underutilized tactic to generate aryl radicals is the reductive
When considering metal catalysts for the desired desaturation
dissociation of aryl triazenes27 in the presence of acid and catalytic reaction, copper salts were the obvious starting point because of
metal salts28–30. Traditionally used as protecting groups for their ability to promote the reductive dissociation of triazenes
anilines31 and linkers in solid-phase synthesis32, aryl triazenes can (Sandmeyer chemistry)31,35 and to rapidly oxidize alkyl radicals
be prepared in high yields from the corresponding anilines and into carbocations36. Indeed, preliminary screening demonstrated
2
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1385
ARTICLES
the ability of catalytic copper(II) bromide in the presence of
trifluoroacetic acid (TFA) to provide the desired olefin 23 in 20%
yield when acetonitrile was used as solvent (Table 1, entry 1);
however, this product was accompanied by the inseparable
reduction (24) and Sandmeyer (25) by-products. Importantly,
though, under these reaction conditions by-products that resulted
from olefin overoxidation were not observed. Switching from aceto-
nitrile to nitromethane was key to suppressing 24 (Table 1, entry 2),
a by-product that seemingly arises by H-abstraction from the
solvent24. During further investigations of the reaction, 2,2,6,6-tetra-
methylpiperidin-1-oxyl (TEMPO, 1 equiv.) was added in an attempt
to trap a radical intermediate or to inhibit the reaction altogether,
but surprisingly it resulted in a transformation with higher yield
(Table 1, entry 3). Intrigued by this result, a control experiment
was performed in the absence of copper salts (Table 1, entry 4) to
reveal that TEMPO alone could facilitate the desaturation in a
slightly better yield and without the Sandmeyer by-product 25.
When no additives were employed and the reaction was run only
with acid (Table 1, entry 5), trace amounts of the desired product
were observed, accompanied by mostly nonspecific decomposition.
In the absence of acid, no reaction took place and the starting
material was recovered intact (Table 1, entry 6).
These exciting metal-free desaturation conditions prompted
further optimization of the reaction with respect to acid, tempera-
ture, concentration and nitroxide radical. Using three equivalents
of TFA as the acid, the temperature can be lowered to 60 8C and
the reaction time shortened to 1.5 hours to consume the starting
material fully and to give the desired olefin 23, along with minor
amounts of 24, in 68% isolated yield (Table 1, entry 7). When the
stronger trifluoromethanesulfonic acid (TfOH, 2 equiv.) was
employed, the reaction proceeded efficiently at room temperature
over three hours to give 23 in 54% yield (Table 1, entry 8).
Increasing the reaction concentration to 0.05 M reduced the yield
Table1 | Development of a method for guided desaturation.
Me
Me
Me
N
N
NEt2
R
SO2
SO2
SO2
Conditions*
O
O
O
CH3NO2 (0.025 M)
1.5–3 h
H
24 R = H
25 R = Br
23
22
Entry Copper
source
Additive
(equiv.)
Acid
(equiv.) (8C)
Te mp erat ure Yield%
(ratio
23:24:25)†
1
CuBr2
–
–
TFA (2) 80
TFA (2) 80
34 (20:13:1)‡
(5 mol%)
2
3
CuBr2
(5 mol%)
CuBr2
31 (5:1:2)
TEMPO (1) TFA (2) 80
TEMPO (1) TFA (2) 80
40 (6:1:1)
(5 mol%)
4
5
6
7
8
–
–
–
–
–
50 (4.5:1:0)
12 (20:1:0)
NR
–
TFA (3) 80
80
TEMPO (1)
TEMPO (1) TFA (3) 60
TEMPO (1) TfOH (2) r.t.
–
68 (10:1:0)§
54
(20:1:0) (45ꢁ)
15 (20:1:0)
24 (20:1:0)
9
10
–
–
AZADO (1) TFA (3) 60
Ad2NO† (1) TFA (3) 60
Me
Me
Me
Me
Ad2NO• =
=
=
AZADO
TEMPO
N
O
N
O
N
O
*Conditions: reactions run on 0.025 mmol of 22 in CH3NO2. †Yields and ratios are based on 1H-NMR
integration relative to an internal standard (1,3,5-trimethoxybenzene). ‡Reaction run in CH3CN
(0.025 M). §Isolated yield. ꢁReaction run at 0.05 M. r.t. ¼ room temperature.
Table 2 | Substrate scope for the guided desaturation reaction.
Et2N
H
N
• 20 examples
• No metal required
TFA (3 equiv.), 60 °C, 1.5 h
H
Me
N
Me
-or-
• Predictable dehydrogenation site
• No overoxidation observed
• Good functional group tolerance
• No strong oxidants required
H
TfOH (2 equiv.), r.t., 3 h
X
X
S
S
TEMPO (1 equiv.)
CH3NO2
O2
O2
X = NH, O
X = NH, O
OTs Me
Me
OTs
Me
Ts
Ts
Me
HN
Me
Me Me
Me HN
Me
Me
:
Me
Me
Me
26 (44%)*
30 (55%)*
35a
35b
OTs
(60%, 35a:35b = 10:1)†
Me
33 (92%)*
OTs
Me
(74%, >1 g scale)
[X-ray]
OTs
Me
Ph
Me
27 (36%)*
NHTs
CO2Me
NHTs
CO2tBu
37 (40%)*
31 (69%, E:Z=1:1)*
Me
Me
36 (47%)*
OTs
Me
Me
OTs
Me
Me
23 (68%)*,‡
28 (41%)*
OTs
NHTs
Me
NHTs
NHTs
Me
OTs
CO2Me
38 (51%)*,§
[X-ray]
Me
Me
34 (59%)†
39 (50%)†
29 (32%)*
32 (51%)*,‡
*General procedure A: substrate (0.100 mmol), TEMPO (1 equiv.), TFA (3 equiv.), CH3NO2 (0.025 M), 60 8C, 1.5 h (isolated yield). †General procedure B: substrate (0.100 mmol), TEMPO (1 equiv.), TfOH
(2 equiv.), CH3NO2 (0.025 M), r.t., 3 h (isolated yield). ‡Isolated yield of a mixture of olefin products and reduction by-product (10:1). §Isolated yield of a mixture of olefin product and reduction
by-product (7:1); see the Supplementary Information for details.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1385
ARTICLES
to 45%. Finally, other nitroxide radical species were tested with the
hope to increase the reaction efficiency, but both the less hindered 2-
azaadamantane N-oxyl (AZADO)37 and the more hindered 1,1-dia-
damantyl nitroxide (Ad2NO)38 were inferior to the cheaper, com-
mercially available TEMPO (Table 1, entries 9 and 10). Thus,
with two sets of conditions in hand (Table 1, entries 7 and 8), the
substrate scope of the newly developed desaturation reaction
system was explored.
a
Desaturation of eudesmane derivative 40
Me
Me
TEMPO (1 equiv.)
TFA (3 equiv.)
Me
Me
Me
Me
Me
Me
Me
:
Me
CH3NO2
60 ºC, 1.5 h
TsO
TsO
41b
TzoO
40
H
H
41a
(46%, 41a:41b = 2:1)
[X-ray]
b Desaturation of dihydroabietylamine derivative 42
iPr
iPr
+
iPr
Ts
As shown in Table 2, a variety of primary and secondary alcohols
are viable substrates for the guided dehydrogenation reaction,
and give moderate-to-good yields of olefinic products. In these
systems, the desaturation reaction takes place most efficiently
when a tertiary carbon centre is in a 1,3-relationship to the function-
ality that carries the portable desaturase and this selectivity implies a
1,7-H-abstraction by the intermediate aryl radical. Such a process is
described only briefly in the literature23,39, and aryl radicals usually
Me
N
Me
TEMPO (1 equiv.)
TfOH (2 equiv.)
CH3NO2
4 ºC, 3 h
H
H
H
Me
Me
NHTzo
Me
NHTs
Me
[X-ray]
[X-ray]
Me
43 (30%)
44 (16%)
42
c
Desaturation of 18-β-glycyrrhetinic acid derivative 45
TzºO
Me
TsO
prefer the 1,5- or 1,6-H-abstraction mode of reactivity22,25,40
.
H
When simple aliphatic secondary alcohols were employed in the
guided desaturation (26–29), good selectivity for tertiary alkyl
positions was detected and the desired alkenes were obtained as
the only isolable oxidized products in moderate yields. For these
substrates, the reaction proceeded best when TFA was used as the
acid, whereas TfOH generally led to decomposition. On a substrate
designed to test for oxidation at a tertiary alkyl site versus a benzylic
site, the desaturation reaction provided the olefin product 27 (36%
yield) and no styrene derivatives were observed. These data do not
rule out the possibility of H-abstraction at the benzylic position,
but such potential products may be unstable under the reaction
conditions (vide infra). Furthermore, because the portable desatur-
ase favours H-abstraction at the proximal tertiary alkyl positions,
site-selective oxidation can be performed (for example, 28) and
functional groups, such as olefins, are also tolerated in the reaction
(for example, 29). An ideal substrate for the guided desaturation is
menthol, which cleanly gives isopulegol tosylate 33 in 92% yield in
an efficient desaturation process accommodated by the more rigid
molecular organization of the substrate.
Aliphatic primary alcohols are also suitable substrates for the
guided desaturation reaction. Alkenol tosylates 30 and 31 were
obtained in good yield as mixtures of olefin isomers because of
uncontrolled elimination from the corresponding tertiary alkyl
cations. Cyclic substrates behave well under the desaturation con-
ditions, to give products such as 23 and 32 in good yields (68%
and 51%, respectively). These substrates reiterate a limitation of the
method, the formation of small amounts of reduction product (for
example, 24) that are difficult to separate from the desired alkene.
When applied to alcohol-derived substrates, the desaturation
reaction provided only homoallylic tosylates and no allylic tosylates
were isolated. However, given the modest yields obtained in certain
cases (for example, 26–29), it is probable that allylic tosylates are gen-
erated (by elimination of the alkyl cation towards the tosylate group),
but simply decompose during the reaction. In support of this possi-
bility, tosic acid is always observed as a by-product in the crude reac-
tion mixture of the alcohol-derived substrates. Additionally, this
mode of elimination is operative in the case of the allylic tosylamine
35b, the nitrogen analogue of 26. Therefore, substrates that lead to
allylic tosylates (for example, alcohols in a 1,2-relationship to a ter-
tiary centre) are not well suited to this method.
TEMPO (1 equiv.)
TFA (3 equiv.)
Me Me
Me
Me Me
Me
CH3NO2
60 ºC, 3 h
Me
Me
HO
HO
Me Me
Me Me
45
46 (47%)*
d Desaturation of tetrapeptide 47
Me NHTzº
NHTs
H
O
O
Me
Me
TEMPO (2 equiv.)
TFA (4 equiv.)
HN
HN
Me
HN
HN
Me
CH3NO2
60 ºC, 3 h
O
O
O
H2N
O
H
H
N
Me
N
Me
H2N
O
Me
O
Me
Ph
Ph
48 (35%)
47
Figure 3 | Applications of the guided desaturation reaction on complex
substrates. a, Desaturation of a sesquiterpene derivative to a mixture of
alkene regioisomers. b, Example of an interrupted desaturation reaction and
methylene dehydrogenation. c, Application of the desaturation reaction
towards diene synthesis in a complex setting. d, Synthesis of a tetrapeptide
incorporating a dehydroleucine amino-acid residue. *Yield based on a mixture
of product and reduction by-product (10:1); see Supplementary Information.
and amino esters are desaturated selectively to provide valuable
dehydroaminoesters (36–38) in useful yields.
To explore this methodology in more complex settings, sub-
strates derived from natural products were synthesized and tested
under the reaction conditions. As such, the dihydrojunenol deriva-
tive 40 was identified as a desirable substrate for the desaturation
reaction. Although similar in substructure with the simpler
menthol, 40 contains two equidistant, but sterically different, ter-
tiary sites available for oxidation. Using the procedure in Fig. 3a,
the desaturation reaction generated a 2:1 mixture of inseparable
regioisomers in 46% yield. This result suggests that H-abstraction
with an aryl radical is indifferent to the steric environment
around the C–H bond as long as a favourable geometry for abstrac-
tion is possible41,42
The dehydroabietyl amine derivative 42 poses an interesting
.
In addition to primary and secondary alcohols, aliphatic amines challenge for selective C–H functionalization, given two reactive
are also competent substrates for the guided desaturation reaction, benzylic sites, a hindered tertiary ring junction and an otherwise
and lead to either homoallylic (34–37) or allylic tosylamines (38 unfunctionalized decalin system. Treatment of 42 with TEMPO
and 39). It was found that for amine-derived substrates, TfOH (1 equiv.) in the presence of TfOH (2 equiv.) at a temperature as
performs slightly better in the desaturation reaction compared to low as 4 8C gave two oxidation products (Fig. 3b). The major
TFA. Indeed, menthylamine behaves well to give 34 in 59% yield, product was the rearranged and cyclized sulfonamide 43 (30%
and 35 is obtained in 60% yield as a 10:1 mixture of homoallylic yield), which arises by an interrupted desaturation process. It
(major) and allylic (minor) tosylamines. Furthermore, allylic tosyl- appears that on formation of the tertiary carbocation, a Wagner–
amines, such as 39, can be prepared selectively in good yield (50%) Meerwein rearrangement occurs to provide the more stabilized
4
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ARTICLES
a 1,7-abstraction event
d Preliminary result of a TEMPO-catalysed desaturation reaction
D
Me
Me
O
S
Me
Me
TEMPO (1 equiv.)
O
O
O
S
TEMPO (0.25 equiv.)
TFA (3 equiv.)
TFA (3 equiv.)
D
OTzº
50a
H
OTzº
Me
CH3NO2
60 °C, 1.5 h
34%*
CH3NO2
60 °C, 3 h
51%†
OTs
49
D
O
Me
Me
S
57
33
(50a:50b = 8:1)
O
50b
b In situ trapping of the aryl radical intermediate
e Proposed reaction mechanism for the guided desaturation reaction
O
O
TEMPO (1 equiv.)
OTzº Me
Me
Me
Me
TFA (3 equiv.)
O
Me
CH3NO2
60 °C, 1.5 h
47%†
Me
Me
H
51
54
N
N
TFA N2
Et2N
SO2
SO2
SO2
O
O
O
TFA (2 equiv.)
–NHEt2•TFA
O
O
O
O
S
H
H
S
H
O
Me
22
58
59
O
Me
Me
Me
Me
Me
H
52
53
H
H
Me
O
Me
O
Me
TEMPO+
TEMPO
c TEMPO-promoted desaturation from a diazonium intermediate
tBuONO (1.5 equiv.)
CH3NO2, 0 °C, 10 min
then TEMPO, r.t., 3 h
O
O
S
H
H
H
O
SO2
OSO2Ph
SO2
SO2
H
O
H2N
55
56
–H+
Entry
TEMPO (equiv.)
Yield (%)*
23
61
60
1
2
3
1
0.1
0
44
31
<5‡
Figure 4 | Mechanistic investigations and proposed reaction mechanism. a, Deuterium-labelling study to support a 1,7-abstraction event during
desaturation. b, Indirect evidence for the in situ formation of an intermediate aryl radical. c, Example of a desaturation reaction starting from an aniline
derivative. d, Initial result that supports a catalytic cycle in TEMPO. e, Proposed sequence of events for the guided desaturation reaction. *Yields
1
†
‡
are based on H-NMR integration relative to an internal standard (1,3,5-trimethoxybenzene). Isolated yield. The reaction resulted in mostly
nonspecific decomposition.
benzylic cation, which is then trapped intramolecularly by the goal was to confirm, through deuterium labelling, the H-abstraction
tosylamine moiety. The minor product 44 (16% yield) can be event that productively leads to the olefin product (Fig. 4a). Thus,
accounted for by initial abstraction from an unactivated methylene when deuterium was incorporated at the tertiary alkyl site in 49,
C–H bond and subsequent termination to the disubstituted olefin. deuterium transfer was, indeed, observed in the desaturated
Thus, the guided desaturation affords oxidation products at sites product 50, but the reaction was less efficient (34% yield for 50a,
other than the more reactive benzylic positions that would be versus 68% for 23, see Table 1) and a new minor product was
targeted in intermolecular oxidation processes.
observed that is tentatively assigned to the olefin isomer 50b.
To demonstrate the ability to generate dienes in complex settings, Presumably the stronger deuterium–carbon bond diverts the aryl
the triterpene derivative 45, which contains a trisubstituted olefin radical towards the normally less-reactive methylene C–H bond.
and a free secondary alcohol, was subjected to the reaction
The second goal was to provide evidence for the formation of
conditions (Fig. 3c). As a result, 46 was obtained in 47% yield as the aryl radical intermediate from the triazene precursor (Fig. 4b).
the major product of the reaction after allylic 1,8-H-abstraction, Thus, when 51 was subjected to the reaction conditions, both
oxidation and elimination to the most stable diene system. The cyclization and desaturation took place to give 54 in 47% yield.
secondary alcohol remains untouched under these conditions This result is consistent with the intermediate aryl radical adding
and the sensitive diene functionality is contained safely in the across the alkyne to produce a reactive vinyl radical, 52, which
final product43.
performs a favourable 1,5-H-abstraction to generate the tertiary
Following the successful desaturation of aminoesters (36–38, alkyl radical 53, which is further oxidized and terminated to give
Table 2), this protocol was tested further on a more complex an olefin.
tetrapeptide. When 47 was subjected to the reaction conditions,
Third, to clarify the role of TEMPO in the reaction, aniline
the desaturated product 48 was isolated in 35% yield without substrate 55 was prepared and converted into the corresponding
racemization of any of the four chiral centres (Fig. 3d). diazonium salt, a presumed intermediate in the reaction (Fig. 4c).
Additionally, the portable desaturase allows for site-selective When TEMPO (1 equiv.) was added at room temperature, the
oxidation on substrates such as 47 that are distinguished by dehydrogenation event took place and olefin 56 was isolated in
strong chelating ability, multiple sites available for oxidation and 44% yield (Fig. 4c, entry 1). When the TEMPO loading was
reactive functional groups.
lowered to 0.1 equiv. (Fig. 4c, entry 2), the reaction provided the
Preliminary experiments to clarify both the mechanism of the product in only a slightly lower yield (31%, TON ¼ 3); the
reaction and the role of TEMPO are shown in Fig. 4. The first absence of TEMPO led to nonspecific decomposition of the starting
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1385
ARTICLES
10. Giri, R., Maugel, N., Foxman, B. M. & Yu, J-Q. Dehydrogenation of inert alkyl
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support a catalytic cycle, but it is inefficient under the current reac-
tion conditions. Importantly, these transformations proceed under
acid-free conditions, which implies that TFA is not required in
the oxidation events, but merely to liberate the diazonium salt
from the starting triazene.
´
11. Baudoin, O., Herrbach, A. & Gueritte, F. The palladium-catalyzed C–H
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Based on our experimental results and literature precedent, the
proposed reaction mechanism for the TEMPO-mediated desatura-
tion reaction is presented in Fig. 4e. First, TFA converts triazene
22 into the diazonium TFA salt 58. TEMPO then promotes its
reductive decomposition to the aryl radical 59, an event concomi-
tant with the generation of N2 and the oxidation of TEMPO to
TEMPOþ (ref. 44). Once formed, 59 undergoes H-abstraction to
generate an alkyl radical intermediate 60, which is oxidized to the
corresponding carbocation 61 by the TEMPOþ previously formed
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in the overall process45. Remarkably, no aryl- or alkyl-TEMPO
recombination adducts are observed. Finally, based on the proposed
mechanism, the reaction should be catalytic in TEMPO and prelimi-
nary results show that this is true (Fig. 4c, TON ¼ 3; Fig. 4d, TON ¼
2), but it suffers from low efficiency. Further experiments are
currently underway to explore this possibility fully.
In conclusion, a new chemical moiety, TzoCl (21), has been
designed to mimic processes observed in nature and leads to desa-
turated aliphatics. The chemistry performed by this directing group
is centred on the high reactivity of an aryl radical masked as an aryl
triazene. This application expands the chemistry of the aryl radical,
as it exploits this reactive intermediate as a useful tool for C–H
functionalization. The desaturation reaction described herein is
applicable on simple substrates derived from saturated alcohols
and amines, to give olefin products in a predictable fashion
without any overoxidation. Some of the drawbacks of this method
are the modest product yields, the formation of minor amounts of
inseparable reduction products and the occasional difficulties in
purification. Nonetheless, the guided desaturation reaction can be
applied successfully in complex settings, as it shows very good
functional group tolerance and leads to useful oxidized products.
Additionally, the intriguing reaction mechanism suggests that
TEMPO can act as a single-electron shuttle, which provides
impetus to investigate further a truly catalytic version of this
transformation. Studies to expand the scope of this transformation
and apply it in two-phase terpene total synthesis are forthcoming.
Received 1 February 2012; accepted 18 May 2012;
published online 8 July 2012
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Acknowledgements
We thank D-H. Huang and L. Pasternack for NMR spectroscopic assistance, A. Rheingold
and C. Moore for X-ray crystallographic analysis, M. Wasa for assistance with chiral high
performance liquid chromatography and L. Leman for assistance with the peptide
synthesis. Financial support for this work was provided by the National Institute of General
Medical Sciences, National Institute of Health (GM-097444), Spanish Ministry of
Education and Science (MEC)–Fulbright Program (postdoctoral fellowship for A.M.),
National Science Foundation (predoctoral fellowship for W.R.G.), the Spanish MEC
(predoctoral grant for J.O.F.) and Bristol-Myers Squibb (unrestricted research support).
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Author contributions
A-F.V. and P.S.B. conceived the original concept for the desaturation reaction, A-F.V., A.M.,
W.R.G. and J.O.F. conducted the experimental work and analysed the results, A-F.V.,
W.R.G., A.M. and P.S.B. co-wrote the manuscript.
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Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at www.nature.com/
reprints. Correspondence and requests for materials should be addressed to P.S.B.
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