Transition metal-free TEMPO-catalyzed oxidative cross-coupling of nitrones with alkynyl-grignard reagents

Article abstract of DOI:10.1002/adsc.201100327

An efficient mild one-pot protocol for the cross-coupling of nitrones and alkynyl-magnesium compounds using a catalytic amount of 2,2,6,6- tetramethylpiperidine-N-oxyl radical (TEMPO) as an environmentally benign organic oxidant and dioxygen as terminal o

Full text of DOI:10.1002/adsc.201100327

FULL PAPERS
DOI: 10.1002/adsc.201100327
Transition Metal-Free TEMPO-Catalyzed Oxidative Cross-
Coupling of Nitrones with Alkynyl-Grignard Reagents
Sandip Murarkaa and Armido Studera,*
a
Organisch-Chemisches Institut, Westfꢀlische Wilhelms-Universitꢀt, Corrensstrasse 40, 48149 Mꢁnster, Germany
Fax : (+49)-251-833-6523; phone: (+49)-251-833-3291; e-mail: studer@uni-muenster.de
Received: April 27, 2011; Revised: July 12, 2011; Published online: October 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100327.
Abstract: An efficient mild one-pot protocol for the tion metal on various N-tert-butylnitrones and alkyn-
cross-coupling of nitrones and alkynyl-magnesium yl-Grignard reagents. Moreover, the alkynylated ni-
compounds using a catalytic amount of 2,2,6,6-tetra- trone products are readily transformed to regioiso-
methylpiperidine-N-oxyl radical (TEMPO) as an en- merically pure 3,5-disubstituted isoxazoles.
vironmentally benign organic oxidant and dioxygen
as terminal oxidant is described. These coupling re- Keywords: cross-coupling; Grignard reagents; het-
actions can be performed without adding any transi- erocycles; one-pot process; organocatalysis; TEMPO
Introduction
successfully demonstrated an example of TEMPO-
mediated cross-coupling between aryl- and alkynyl-
Transition metal-catalyzed cross-coupling reactions Grignard reagents [Eq. (2)].[6b] Herein, we wish to
are among the most important and powerful tools report the first example of a transition metal-free oxi-
available to organic and organometallic chemists for dative cross-coupling reaction between nitrones and
[1]
À
C C bond formation. Among the many processes alkynyl-Grignard reagents using a catalytic amount of
developed, the Sonogashira reaction of terminal alk- TEMPO as an environmentally benign and commer-
ACHTUNGTRENNUNGynes with aryl or vinyl halides which allows the prepa- cially available oxidant and dioxygen as terminal oxi-
ration of compounds bearing an internal alkyne dant [Eq. (3)].
À
moiety can be highlighted as a cornerstone in this
C C bond formation via nucleophilic addition of
field.[2] Conjugated internal alkynes occur in numer- alkynyl metal compounds to unsaturated electrophiles
ous natural products, pharmaceuticals, and organic is a classical approach for alkynylation. The products
materials.[3] Recently, metal-mediated oxidative cross- obtained are amenable to further synthetic transfor-
coupling reactions of alkynyl metal reagents to syn- mations.[8] Nitrones are of paramount importance in
thesize various disubstituted alkynes have caught the
attention of many synthetic chemists. However, due
to the lack of solutions to overcome the undesired ho-
mocoupling process of the alkynyl metal species
under oxidative conditions, cross-coupling remains a
difficult task. Recently, there have been several at-
tempts to develop transition metal-free oxidative cou-
pling processes.[4–6] The transition metal-free oxidative
homocoupling of Grignard reagents has recently
gained attention.[5] As part of our program to develop
transition metal-free oxidative coupling processes in-
volving Grignard reagents, we reported on successful
homocoupling reactions of aryl-, alkenyl- and alkynyl-
Grignard reagents [Scheme 1, Eq. (1)][6a] by using
the
2,2,6,6-tetramethylpiperidine-N-oxyl
radical
Scheme 1. Oxidative coupling between Grignard reagents
(TEMPO)[7] as an oxidant. More recently, we have and TEMPO-catalyzed cross-coupling of 1 and 2.
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Adv. Synth. Catal. 2011, 353, 2708 – 2714

Transition Metal-Free TEMPO-Catalyzed Oxidative Cross-Coupling of Nitrones
organic synthesis, not only as 1,3-dipolar reagents in
cycloadditions or electrophiles toward organometallic
compounds, but also in a diverse array of other useful
reactions.[9] The reactivity of metal acetylides towards
C=N electrophiles has been intensively investigat-
ed.[10]
Results and Discussion
Recently, we have reported on zinc triflate-catalyzed
cross-dehydrogenative coupling (CDC) reactions be-
Scheme 3. Proposed TEMPO-catalyzed oxidative cross-cou-
pling between nitrones and alkynyl-Grignard reagents.
tween sp2
ACHTUNGTRENNUNG(C H) of nitrones 1 and spACHTUNGTRENN(UGN C H) of termi-
À
À
nal alkynes 4 in the presence of 3,3’,5,5’-tetra-tert-bu-
tyldiphenoquinone and dioxygen as oxidants for the
preparation of alkynylated nitrones 3 (Scheme 2).[11] practical points of view. Our planned cascade com-
This protocol turned out to be very efficient for the prises two consecutive one-pot processes involving
transformation of aliphatic nitrones; however, aro- nucleophilic addition of alkynyl-Grignards 2 to nitro-
matic nitrones did not react using Zn catalysis. In ad- nes 1 to form A, followed by TEMPO/O2-catalyzed
dition, although the organic oxidant was used in a oxidation to the cross-coupled a-alkynylated nitrones
substoichiometric amount in combination with O2 as 3 (Scheme 3).
co oxidant, we were not able to demonstrate the re-
We started our investigations by reacting N-Bn-ni-
generation of tert-butyldiphenoquinone using O2 trone 1 (R1 =i-Pr, R3 =Bn) with Mg-acetylide 2 (R2 =
during catalysis. We therefore continued our studies Ph, 1.1 equiv.) at room temperature in the presence of
by looking at other organic oxidants that are able to 2.2 equiv. of TEMPO as an oxidant. We found that re-
be in situ regenerated with O2 as a cheap terminal ox- action did not go to completion and oxidation
idant. In addition, to broaden the substrate scope, we stopped at low conversion (Table 1, entry 1). Inde-
decided to focus on more reactive alkynyl-Grignard pendent studies on TEMPO-mediated oxidation of
compounds which should also react with aromatic ni- hydroxylamine derivatives revealed that N-propargyl-
trones.
Surprisingly, we found that reactions of alkynyl-Mg
Table 1. Oxidative coupling of 1 and ClMg-phenylacetylide
under different conditions using a stoichiometric amount of
TEMPO as an oxidant.
reagents with nitrones leading to propargylic N-hy-
droxylamine derivatives are not well explored.[12]
Based on the fact that alkynyl-Mg derivatives react
only sluggishly with TEMPO,[6a] we envisioned to in
situ oxidize magnesiated propargylic N-hydroxyl-
ACHTUNGTRENNUNG
amine[13] intermediates of type A which should be
readily obtained by alkynyl-Mg addition to nitrones,
with TEMPO to the corresponding a-alkynylated ni-
trones 3, while avoiding the undesired homocoupling
of these alkynyl-Grignard reagents. The development
of efficient, versatile, one-pot, multistep protocols is
of great interest from economic, environmental and
Entry
R
Product
Time
Yield [%][a]
1
2
3
4
5
6
7
8
Bn
Bn
Bn
CHMePh
t-Bu
t-Bu
t-Bu
t-Bu
3a
3a
3a
3b
3c
3c
3c
3c
24 h
36[b,c]
85[c,d,e]
84[d,e]
81[e]
82[e]
70
45 min
45 min
40 min
30 min
2 h
24 h
24 h
<1[f]
5[e,f]
[a]
Isolated yield.
[b]
Oxidation did not go to completion and 3% of the unde-
sired regioisomer was isolated.
[c]
Alkynyl-Grignard was generated from corresponding ter-
minal alkyne using i-PrMgCl.LiCl.
[d]
[e]
[f]
7% of the undesired regioisomer was isolated.
2 equiv. of H2O were added after the addition reaction.
Reaction was carried out using dioxygen as oxidant in
the absence of TEMPO.
Scheme 2. CDC between various nitrones and terminal al-
kynes.
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Table 2. Oxidative coupling of 1 and 2 using stoichiometric
amount of TEMPO as oxidant.
ic hydroxylamines are oxidized far faster as compared
to the corresponding Mg derivatives. Indeed, addition
of 2 equiv. of H2O after initial adduct formation,
which is completed in less than 5 min for aliphatic ni-
trones, showed a striking rate acceleration for the oxi-
dation process. Oxidation was completed within
45 min providing nitrone 3a in a very good yield
(84%, entry 3). However, the formation of small
amounts of the other possible regioisomer arising
from oxidation at the benzylic position was observed
in this reaction (7%). Generation of Mg-acetylide 2
(R2 =Ph) via deprotonation of phenylacetylene either
with i-PrMgCl.LiCl[14] or i-PrMgCl was found to be
equally effective (Table 1, compare entries 2 and 3).
Formation of the regioisomeric nitrone was fully sup-
pressed by replacing the N-Bn group in the nitrone
by an N-phenethyl substituent and 3b was isolated in
81% yield (entry 4). Also the t-Bu congener, where
the regioselectivity problem during oxidation does
not occur, worked well: the cross-coupling product 3c
was isolated in 82% yield (entry 5). In contrast to the
N-Bn-nitrone case, for the N-t-Bu-nitrone adduct A
(R1 =i-Pr, R2 =Ph, R3 =t-Bu) the oxidation process
went to completion without the aid of water albeit at
the expense of a longer reaction time and a slightly
lower yield (entry 6). All following experiments were
therefore performed with N-t-Bu-substituted nitrones
applying the “H2O”-protocol. Importantly, no oxida-
Entry R1
R2
No Time Yield
[min] [%][a]
AHCTUNGTRENNUNG
1
2
3
4
Me2CH
3-Me-C6H4
4-MeO-C6H4
4-CF3-C6H4
6-MeO-2-naph-
thyl
3d 20
3e 10
3f 50
3g 15
86
68
77
80
Me2CH
Me2CH
Me2CH
5
6
7
8
Me2CH
Me2CH
Me2CH
Me2CH
Me2CH
c-C6H11
n-Bu
Ph
4-MeO-
C6H4
1-cyclohex-1-enyl 3h 10
89
80
76
75
79
80
82
65
55
n-Pr
3i 15
3j 10
3k 10
3l 15
3m 10
3n 10
3o 60
3p 55
c-C6H11
Me3Si
9
PhCH2OCH2
10
11
12
13
Ph
Ph
Ph
Ph
[a]
Isolated yield.
tion was observed in the absence of TEMPO and give 3k and 3l (entries 8 and 9). The nitrone compo-
water using dioxygen as an oxidant (entry 7). Only nent was also systematically varied using phenylalkyn-
5% cross-coupling product 3c was isolated in the ab- yl-MgX as reaction partner. Aliphatic nitrones de-
sence of TEMPO using the “H2O”-protocol under rived from cyclic and acyclic aldehydes both worked
otherwise identical conditions (entry 8). The TEMPO efficiently to provide the corresponding cross cou-
source did not influence reaction outcome (sublimed, pling products 3m and 3n (entries 10 and 11). Impor-
non-sublimed, different providers, see Supporting In- tantly, less reactive aromatic nitrones were also suita-
formation).
ble substrates for our oxidative cross-coupling reac-
We next studied the substrate scope by reacting tion (entries 12 and 13).
various N-t-Bu-nitrones 1 (R1 =i-Pr, R3 =t-Bu) with
We then envisioned to run our cross-coupling reac-
various alkynyl-Grignard reagents 2 under the opti- tion catalytic in TEMPO using dioxygen as terminal
mized conditions (Table 2). All Mg-acetylides 2 were oxidant. To this end, we reacted 1 (R1 =i-Pr, R3 =t-
generated from the corresponding terminal alkynes Bu) with 2 (R2 =Ph) in presence of 10 mol% of
via deprotonation with i-PrMgCl and the oxidation TEMPO and dioxygen (1 atm, balloon) at room tem-
process which took 10 to 60 min was followed by thin perature. Pleasingly, the desired cross coupling prod-
layer chromatography. Arylalkynyl-Grignard reagents uct 3c was formed in very good yield (82%) by stir-
bearing electron-donating as well as electron-with- ring the reaction mixture for 24 h (Table 3, entry 1).
drawing substituents at the aryl moiety reacted with Lowering the TEMPO loading to 5 mol% led to a re-
the isopropyl nitrone 1 (R1 =i-Pr, R3 =t-Bu) to give duced yield of 3c (63%) along with 14% of unreacted
the cross-coupling products 3d–f in high yields N-hydroxylamine intermediate (entry 2). In order to
(Table 2, entries 1–3). The (6-methoxy-2-naphthyl)- show the broad scope of the catalytic variant, a series
ACHTUNGTRENNUNGalkynyl-Mg compound delivered the corresponding of structurally and electronically diverse alkynyl-
internal alkyne 3g in a good yield (entry 4). We found Grignard reagents 2 were reacted with several N-t-
that magnesiated enynes are good substrates as shown Bu-nitrones 1. Several aliphatic alkynes including
by the successful preparation of 3h (89%, entry 5). magnesiated enynes (entries 4, 9, 12 and 15), less re-
Less reactive alkylalkynyl-Grignard reagents were active alkylalkynyl-Grignard reagents (entries 5, 11
equally efficient to afford 3i, j (entries 6, 7) and the and 13),
a silyl-protected alkynyl-Mg derivative
benzyloxymethyl- and silyl-protected alkynyl-Mg de- (entry 7) and aromatic nitrones (entries 12–15) were
rivatives underwent high-yielding cross-couplings to successfully transformed to the corresponding cross-
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Transition Metal-Free TEMPO-Catalyzed Oxidative Cross-Coupling of Nitrones
Table 3. Oxidative coupling of 1 and 2 using catalytic
amount of TEMPO and dioxygen as terminal oxidant.
Entry R1
R2
3
Yield [%][a]
1
Me2CH
Ph
Ph
3c
3c
82
63
84
2[b]
3
Me2CH
Me2CH
Me2CH
Me2CH
Me2CH
Me2CH
c-C6H11
c-C6H11
n-Bu
6-MeO-2-naphthyl 3g
1-cyclohex-1-enyl
n-Pr
c-C6H11
Me3Si
Ph
1-cyclohex-1-enyl
Ph
4
5
6
7
8
9
10
11
12
13
14
15
3h 82
3i
3j
3k 75
3m 78
3q 80
3n 78
3r
3s
3t
78
79
Scheme 5. Proposed mechanism for oxidative coupling be-
tween nitrones 1 and alkynyl-Grignard reagents 2.
n-Bu
Ph
Ph
n-Pr
80
62
60
1-cyclohex-1-enyl
n-Pr
4-Me-C6H4 Ph
4-Me-C6H4 1-cyclohex-1-enyl
3u 42
3v 48
than direct e-transfer from A. Moreover, we assume
that e-transfer from the hydroxylamine B and subse-
quent deprotonation to C is not occurring since the si-
lyloxyamine 5, which likely has a similar reduction
potential as its hydroxylamine of type B, was not oxi-
dized under the reaction conditions. a-H bearing ni-
[a]
[b]
Isolated yield.
Reaction conducted with 5 mol% of TEMPO.
coupling products in good yields using a catalytic troxides are well known to undergo disproportiona-
amount of TEMPO for oxidation.
tion leading to nitrones and hydroxylamines.[7a,15]
In order to get a clearer picture on the mechanism Therefore, as the final step we suggest the dispropor-
of the oxidation step we ran an additional control ex- tionation of two nitroxides C to give the nitrone 3
periment. Based on the observation that water addi- and hydroxylamine B which further reacts with
tion is beneficial, we assumed that the magnesiated TEMPO via H-transfer to C. Regeneration of
hydroxylamine A is oxidized at a lower rate as com- TEMPO from TEMPOH with O2 is well known to be
pared to the corresponding hydroxylamine. Therefore, efficient under basic conditions.[7a]
the H-atom might be involved at the initial stage of
Finally, the potential of the alkynylated nitrone
the process. We prepared silyloxyamine 5 and subject- products for follow-up chemistry was documented by
ed it to the TEMPO oxidation. In fact, no reaction transforming them into regioisomerically pure 3,5-di-
was observed indicating that H-transfer from the hy-
droxylamine might be the initial step in the oxidation portant class of five-membered nitrogen heterocycles
(Scheme 4). that are prevalent in a number of biologically impor-
substituted isoxazoles.[11] Isoxazoles belong to an im-
ACHTUNGTRENNUNG
Our suggested mechanism is depicted in Scheme 5. tant compounds.[16] The [3 +2]cycloaddition of al-
The Grignard reagent first adds to the nitrone to give kynes with nitrile oxides shows some drawbacks,
adduct A. This metallated hydroxylamine can directly namely a competing dimerization of the nitrile oxides,
be oxidized by TEMPO via electron transfer to give low yields and sometimes lack of regioselectivity.[17]
nitroxide C. Since addition of water accelerates the After extensive screening as discussed in our recent
oxidation, we currently believe that nitroxide forma- communication[11] we found that treatment of 3c with
tion via the hydroxylamine B by H-transfer is faster BCl3 (30 mol%) in dichloroethane at 908C provided
7a in a good yield (71%, Scheme 6). We have also de-
veloped a two-step protocol for the conversion of 3c
to regioisomerically pure 7a by first reacting 3c with
TiCl4 in CH2Cl2 (sealed tube at 508C for 24 h) to the
corresponding oxime 6a followed by gold-catalyzed
cycloisomerization to 7a.[18] The two-step protocol was
also successfully applied to the preparation of isoxa-
zoles 7b–h. Good to excellent yields were obtained
for these transformations (60–90%).
Scheme 4. Attempted oxidation of silylated derivative 5
using 2.2 equivalent of TEMPO as an oxidant.
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Sandip Murarka and Armido Studer
FULL PAPERS
brated relative to solvent residual proton and carbon chemi-
cal shift: CHCl3 (d=7.26 for 1H NMR and d=77.00 for
13C NMR). TLC was performed using Merck silica gel 60 F-
254 plates, detection of compounds with UV light or dipping
into a solution of KMnO4 (1.5 g in 400 mL H2O, 5 g
NaHCO3), followed by heating. Flash column chromatogra-
phy (FC) was performed using Merck or Fluka silica gel 60
(40–63 mm) applying a pressure of about 0.4 bar. Mass spec-
tra were recorded on a Finnigan MAT 4200S, a Bruker Dal-
tonics Micro Tof, a Waters-Micromass Quatro LCZ (ESI);
peaks are given in m/z (% of basis peak).
General Procedure I: Generation of Alkynyl-
Grignard Reagents (2)
i-PrMgCl in THF (1.90M, 0.32 mL, 0.60 mmol, 1.21 equiv.)
was added dropwise to the corresponding alkyne
(0.55 mmol, 1.1 equiv.) in dry THF (1.5 mL) at 08C. The re-
sulting reaction mixture was stirred at room temperature for
1 h. This alkynyl-Grignard reagent was immediately used for
the cross coupling reaction.
General Procedure II: Cross-Coupling Reaction
between Nitrones 1 and Alkynyl-Grignard Reagents 2
using Stoichiometric Amounts of TEMPO as Oxidant
Scheme 6. Transformation of alkynylnitrones 3 to 3,5-disub-
stituted isoxazoles 7.
The nitrone (0.50 mmol, 1 equiv.) was dissolved in THF
(1.5 mL) and added to the flask containing a solution of al-
kynyl-Grignard reagent 2 prepared according to GP I and
the resulting reaction mixture was stirred for 5 min (aliphat-
ic nitrone) to 40 min (aromatic nitrone) at room tempera-
ture, followed by the addition of distilled water (18 mL,
1.0 mmol, 2.0 equiv.). TEMPO (173 mg, 1.1 mmol,
2.2 equiv.) was then added and the resulting reaction mix-
ture was stirred at room temperature for 5 to 60 min. After
completion, the reaction was quenched by adding saturated
aqueous NH4Cl (10 mL) solution and then methy tert-butyl
ether (MTBE) (10 mL) was added. The aqueous layer was
extracted with MTBE (2ꢃ10 mL); the combined organic
layers were washed with saturated brine (10 mL), dried over
MgSO4, filtered and concentrated under vacuum. Crude
product was purified by flash column chromatography on
silica gel by using a 25:75 mixture of MTBE/pentane as an
eluent to provide analytically pure product 3.
Conclusions
In conclusion, we have described a highly efficient
transition metal-free cross-coupling reaction between
nitrones and alkynyl-Grignard reagents by using envi-
ronmentally friendly TEMPO as a mild organic oxi-
dant. Cross-coupling can be conducted using catalytic
amounts of TEMPO in combination with O2 as termi-
nal oxidant. These coupling reactions work well on
various aliphatic and aromatic nitrones with alkynyl-
Grignard reagents. Moreover, products of type 3 are
readily transformed to isoxazoles.[11] Reactions are
very easy to perform and products are obtained with
high yields. To the best of our knowledge, this is the
first report on TEMPO/O2-catalyzed oxidation of N-
hydroxylamines to the corresponding nitrones.
General Procedure III: Cross-Coupling Reaction
between Nitrones 1 and Alkynyl-Grignard Reagents 2
using Catalytic Amounts of TEMPO and Dioxygen as
Terminal Oxidant
Experimental Section
The nitrone (0.50 mmol, 1 equiv.) was dissolved in THF
(1.5 mL) and added to the flask containing a solution of al-
kynyl-Grignard reagent 2 prepared according to GP I and
the resulting reaction mixture was stirred for 5 min (aliphat-
ic nitrone) to 40 min (aromatic nitrone) at room tempera-
ture, followed by the addition of distilled water (18 mL,
1.0 mmol, 2.0 equiv.). TEMPO (7.85 mg, 0.05 mmol,
0.1 equiv.) was then added and the flask was connected with
an oxygen balloon (~1 atm) and the resulting solution was
stirred at room temperature for 24 h. After completion, the
reaction was quenched by adding saturated aqueous NH4Cl
(10 mL) solution and then MTBE (10 mL) was added. The
All reactions involving air- or moisture-sensitive reagents or
intermediates were carried out in heat gun-dried glassware
under an argon atmosphere using standard Schlenk tech-
niques. THF was freshly distilled from Na under argon. All
other solvents and reagents were purified according to stan-
dard procedures or were used as received from Aldrich,
Fluka, Acros or Lancaster. The nitrones 1[1] were synthe-
sized according to known procedures. 1H NMR and
13C NMR spectra were recorded on a DPX 300 at 300 K. All
resonances are reported relative to TMS. Spectra were cali-
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Transition Metal-Free TEMPO-Catalyzed Oxidative Cross-Coupling of Nitrones
aqueous layer was extracted with MTBE (2ꢃ10 mL); the
combined organic layers were washed with saturated brine
(10 mL), dried over MgSO4, filtered and concentrated under
vacuum. The crude product was purified by flash column
chromatography on silica gel by using a 25:75 mixture of
MTBE/pentane as an eluent to provide analytically pure
product 3.
2008, 47, 8727; d) S. Kirchberg, T. Vogler, A. Studer,
Synlett 2008, 18, 2841; e) T. Vogler, A. Studer, Adv.
Synth. Catal. 2008, 350, 1963; f) S. Kirchberg, R. Frçh-
lich, A. Studer, Angew. Chem. 2009, 121, 4299; Angew.
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lich, A. Studer, Angew. Chem. 2010, 122, 7029; Angew.
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Acknowledgements
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We thank the SFB 858 for supporting our work (stipend to
SM).
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