Intramolecular carbonyl nitroso ene reaction catalyzed by iron(III) chloride/hydrogen peroxide as an efficient tool for direct allylic amination

Article abstract of DOI:10.1002/adsc.201100632

A mild, simple oxidation protocol employing iron(III) chloride as a catalyst and hydrogen peroxide as a stoichiometric oxidant was found to be compatible with an intramolecular carbonyl nitroso ene reaction and allowed us to efficiently convert hydroxamic acids into a diverse range of 1,2- and 1,3-amino alcohol derivatives in a single operation. Copyright

Full text of DOI:10.1002/adsc.201100632

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DOI: 10.1002/adsc.201100632
Intramolecular Carbonyl Nitroso Ene Reaction Catalyzed by
Iron(III) Chloride/Hydrogen Peroxide as an Efficient Tool for
N
Direct Allylic Amination
Duncan Atkinson,a Mikhail A. Kabeshov,b Mark Edgar,a and Andrei V. Malkova,*
a
Department of Chemistry, Loughborough University, Loughborough, LE11 3TU, U.K.
Fax : (+44)-1509-22-3925; e-mail: a.malkov@lboro.ac.uk
Current address: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, U.K.
b
Received: August 8, 2011; Published online: December 8, 2011
th
ˇ
´
Dedicated to Professor Pavel Kocovsky on the occasion of his 60 birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100632.
Abstract: A mild, simple oxidation protocol em-
ploying iron(III) chloride as a catalyst and hydro-
The nitroso ene reaction is another type of allylic
G
amination that can give rise to similar products with-
out using noble metal catalysts.[6] An intramolecular
variant of the carbonyl nitroso ene reaction was re-
ported by Kirby[7] more than two decades ago but
since then it has remained unexplored (Scheme 2, 4!
5!6!7). Due to the instability of nitroso compounds
5, they were prepared in situ by low temperature per-
gen peroxide as a stoichiometric oxidant was found
to be compatible with an intramolecular carbonyl
nitroso ene reaction and allowed us to efficiently
convert hydroxamic acids into a diverse range of
1,2- and 1,3-amino alcohol derivatives in a single
operation.
AHCTUNGTREGUNiNN odate oxidation of the corresponding hydroxamic
Keywords: amination; amino alcohols; cyclization;
ene reaction; oxidation
acids 4 and intercepted with cyclopentadiene to form
adducts 6, which then, after isolation, were thermally
converted into 7, presumably through the transition
state A. This method represents a complementary al-
ternative to the Pd- and Rh-catalyzed aminations:
ꢀ
here the new C N bond is formed with a concomitant
Amino alcohols, particularly 1,2- and 1,3-derivatives, allylic shift of the double bond. However, the synthet-
are commonly featured in many pharmaceuticals and ic potential of this method is limited by the need to
natural products, and they also find wide use as syn- isolate the Diels–Alder adducts. Herein, we report on
thetic building blocks.[1] In recent years, synthetic the development of a catalytic oxidation protocol to
strategies towards these structural motifs employing effect cyclization of hydroxamic acids 4 into 7 in a
ꢀ
C H functionalization as a key bond-forming event single step. While this manuscript was in preparation,
are increasingly gaining momentum.[2]
a similar single-pot intramolecular acyl nitroso reac-
Intramolecular allylic amination (1!2, Scheme 1) tion was reported by Read de Alanis.[8]
can be accomplished in the presence of Pd(II)[3,4] and
Rh(II)[5] catalysts, however, in the latter case allylic
ꢀ
C H insertion of nitrenes competes with aziridina-
tion, furnishing a mixture of the respective products 2
and 3 (Scheme 1).
Scheme 1. Transition metal-catalyzed intramolecular amina-
tion.
Scheme 2. Intramolecular carbonyl nitroso ene reaction.
Adv. Synth. Catal. 2011, 353, 3347 – 3351
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Duncan Atkinson et al.
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Table 1. Optimization of the intramolecular nitroso ene cyclization.[a]
Entry
Catalyst (mol%)
Cu(OTf)2, (2)
Oxidant
Solvent, T [oC]
Yield[b] 9a [%]
Yield[b] 9b [%]
1
2
3
4
5
6
7
8
G
H2O2
THF, r.t.
THF, r.t.
THF, 60
MeOH, 60
MeOH, r.t.
MeOH, 60
i-PrOH, 100
i-PrOH, r.t.
70
69
0[c]
0[c]
0[c]
45]
10
Cu(OTf)2, (2)
Cu(OTf)2, (2)
MoO5A(HMPA)·py (2)
R
t-BuOOH
H2O2[d]
H2O2
H2O2[d]
H2O2[d]
H2O2
N
n/a
n/a
60
n/a
n/a
30
U
FeCl3 (4)
FeCl3 (4)
FeCl3 (4)
FeCl3 (25)
56,e]
64[f]
n/a
–
[a]
The reactions were carried out on a 0.5-mmol scale with 1.2 equiv. of oxidant for 18 h, unless stated otherwise.
Isolated yield.
Not formed, starting material decomposed.
6 equiv. of oxidant were used.
E/Z 4:1.
E/Z 6:1.
[b]
[c]
[d]
[e]
[f]
In the past, the procedures for the oxidation of hy- (4 mol%) and 50% aqueous H2O2 (1.2 equiv.) in
droxamic acids were tailored for cycloaddition of ni- MeOH at room temperature. The less reactive 8b
troso derivatives to dienes (e.g., 5!6, Scheme 2).[9] under these conditions gave only 10% of 9b (Table 1,
The ene reaction is substantially slower than cycload- entry 5), however raising the temperature to 608C
dition. Strong oxidants employed in the cycloaddition produced the desired 9b in 56% yield as a 4:1 E/Z
methods at prolonged exposures appear to destroy mixture (Table 1, entry 6). Interestingly, a further in-
both the carbonyl nitroso intermediates and the ene crease of the reaction temperature to 1008C (the sol-
adducts and therefore, for the successful ene reaction, vent was changed to i-PrOH) improved the E/Z ratio
milder oxidation protocols are required. Following of 9b to 6:1 (yield 64%, Table 1, entry 7).
earlier reports on a single-pot intermolecular carbonyl
Oxidation of the hydroxamic acids to the respective
nitroso ene reaction, which usually requires excess nitroso intermediates is likely to be carried out by the
alkene,[10] we set out to investigate a more challenging metal. The role of the stoichiometric oxidant is to re-
intramolecular variant with an inherent 1:1 stoichiom- generate the catalytically active metal species, as with-
etry. Preliminary experiments were carried out em- out the oxidant no catalytic turnover was observed
ploying model substrates 8a and 8b derived from (E)- (Table 1, entry 8). It is worth noting that the catalytic
crotyl alcohol and (E)-2-hexenol (Table 1). Cycliza- system based on FeACHTNUTRGNEUNG(III)/H2O2, known to promote ep-
tion of hydroxamic acid 8a (R=Me) proceeded oxidation of alkenes,[12] under the reaction conditions
smoothly in the presence of catalytic Cu(II) triflate employed here did not produce epoxides.
(2 mol%) and 50% aqueous H2O2 (1.2 equiv.) to fur-
The apparent difference in reactivity of 8a and 8b
nish the respective product 9a in 70% yield (Table 1, prompted us to have a closer look at the steric factors
entry 1). For hexenyl derivative 8b (R=n-Pr), the influencing removal of the allylic hydrogen
same Cu(II) system proved inefficient resulting in de- (Scheme 3). In the set of substrates 8a–d, the reactivi-
composition of the starting material. Changing the ty drops dramatically in the order Me>n-Pr>Bn>i-
stoichiometric oxidant to t-BuOOH essentially repro- Pr, where 9c was isolated in just 10%, whereas 9d was
duced the results obtained with H2O2 (Table 1, not formed at all,[13] which reflects increase of the
ꢀ
entry 2); raising the reaction temperature to 608C steric congestion around the allylic C H bond. Even
was not helpful (Table 1, entry 3). A brief screening formation of the thermodynamically stable fragments,
of catalytic systems[11] revealed that MoO
CHTUNGTREN(NUNG HMPA)Py such as styrene (9c) or trisubstituted alkene (9d), was
5A
(2 mol%) with 6 equiv. of H2O2 at 608C did show not able to offset this trend.
some activity providing 9b in 45% yield (Table 1,
Next, we investigated diastereoselectivity of the ni-
entry 4). However, the best results were obtained troso ene cyclization. To circumvent the issues of re-
with Fe
ACHTUNGTRENNUNG(III) as a catalyst. Crotyl derivative 8a was activity, secondary crotyl analogues 10a–d were select-
readily cyclized into 9a in the presence of FeCl3·6H2O ed (Scheme 4). By employing the reaction conditions
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Adv. Synth. Catal. 2011, 353, 3347 – 3351

Intramolecular Carbonyl Nitroso Ene Reaction Catalyzed by IronACTHNUTRGNEUG(N III) Chloride/Hydrogen Peroxide
important factor affecting the cyclization, as 14, a Z-
isomer of 8a, failed to give any product. Formation of
the 6-membered ring required more forcing condi-
tions than the 5-membered counterpart. At room
temperature, cyclization of hydroxamic acid 15 into
16 took 72 h (58% yield), but at 1008C it was com-
plete overnight (yield 60%, Table 2, entry 3). Cycliza-
tion of the more substituted derivatives 17, 19 and 21
required elevated temperature and was accomplished
in good yields (Table 2, entries 4–6). Importantly, in
contrast to the high sensitivity of the cyclization to
Scheme 3. Steric effects in the intramolecular carbonyl ni-
troso ene cyclization.
ꢀ
the surroundings of the allylic C H bond, steric fac-
tors do not play any significant role in the formation
ꢀ
of C N bond, which is manifested by a facile forma-
developed for 8a (4 mol% FeCl3·6H2O and 1.2 equiv. tion of spiro derivative 20 and a highly substituted ox-
H2O2 in i-PrOH at room temperature), cyclization azolidinone 22 (Table 2, entries 5 and 6, respectively).
proceeded uneventfully to furnish mixtures of syn and Furthermore, 22 was obtained in high diastereoselec-
anti products 11a–d. Rather surprisingly, a 2:1 syn/anti tivity (dr>25:1).
mixture was formed regardless of the steric size of the
Preliminary DFT calculations[14] suggest a pericyclic
substituent. Relative configurations of the stereoiso- 6-membered transition state D (Scheme 5) as a possi-
1
mers were established by analysis of their H NMR ble key point of the reaction mechanism.[15,16] We
spectra (for details, see Supporting Information). Var- have also identified formation of aziridine N-oxide C,
iation of solvents (CH2Cl2, CHCl3, THF, toluene) and however the extent of its contribution to the overall
catalyst [CuACHTUNGTRENNUNG(OTf)2, ligand free and as a complex with reaction mechanism is not clear at the moment. At
phenanthroline] had no effect on the syn/anti ratio. the same time, we were unable to find a polarized bir-
However, the diastereoselectivity was improved by adical intermediate that played an important role in
lowering the reaction temperature. The reactivity of the case of aryl and alkyl nitroso compounds.[16] Ab-
hydroxamic acids 10 proved to be sufficient to attain sence of biradical species is indirectly supported by
good conversion at ꢀ208C in 72 h. Thus, in the case the different reactivities of E-8a and Z-14, since oth-
of 11d diastereoselectivity increased to 5:1 (yield erwise they would converge to the same biradical in-
51%). It is worth noting that the diastereoisomers are termediate due to a rapid rotation about single bonds.
readily separable by chromatography.
The high relative energy of TS D (25 kcalmolꢀ1) may
The scope of the reaction was investigated with the explain the observed relatively slow rate of cycliza-
aid of hydroxamic acids 12, 14, 15, 17, 19 and 21 rep- tion. In the presence of CuCl2, the activation energy
resenting diverse substitution patterns (Table 2). of H-transfer was found to be 10 kcalmolꢀ1 lower
Prenyl derivative 12 with a relatively electron-rich (15 kcalmolꢀ1 vs. 25 kcalmolꢀ1). This suggests that in
double bond proved to be one of the most reactive our catalytic system transition metal species may play
substrates. The reaction was complete in less than 3 h the dual role of both oxidant and Lewis acid.
with both FeACHTUNGTRENNUNG(III) and Cu(II) catalysts furnishing the
respective oxazolidinone 13 in good yields (Table 2,
entry 1). E-Geometry of the alkene appears to be an
Scheme 4. Diastereoselectivity in the intramolecular carbonyl nitroso ene reaction.
Adv. Synth. Catal. 2011, 353, 3347 – 3351
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Duncan Atkinson et al.
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Table 2. Scope of the intramolecular nitroso ene cycliz-
Experimental Section
ACHTUNGTRENNUNG
ation.[a]
General Method for Cyclization of Hydroxamic Acids
with Methyl Hydrogen Abstraction (9a, 11a–d)
Entry Substrate
1
T [oC] Product
Yield[b] [%]
60 (83)[d]
50% aqueous H2O2 (0.041 mL, 0.6 mmol) was added to a
mixture of the hydroxamic acid (0.5 mmol) and FeCl3·6H2O
(5.4 mg, 4 mol%), in i-PrOH (4 mL), at 08C. The reaction
mixture was brought to room temperature and left for 18 h.
The mixture was then diluted with 1M HCl (20 mL) and ex-
tracted with ethyl acetate (3ꢁ30 mL). The combined organic
fractions were evaporated at reduced pressure and the crude
product was purified by chromatography on a column of
silica gel with a mixture of petroleum ether (40–60) and
AcOEt (2:1!1:1).
r.t.[c]
2
3
100[e]
100[g]
0[f]
60 (58)[h]
General Procedure for Cyclization of Hydroxamic
Acids with Methylene Hydrogen Abstraction (9b, 9c,
18, 20, 22)
FeCl3·6H2O (5.4 mg, 4 mol%) was added to the appropriate
hydroxycarbamate (0.5 mmol) in i-PrOH (6 mL), and, after
the addition of 50% H2O2 (0.20 mL, 3 mmol), heated at
1008C in a sealed vessel for 18 h. The mixture was then di-
luted with 1M HCl (20 mL) and extracted with ethyl acetate
(3ꢁ30 mL). The combined organic layers were evaporated
at reduced pressure and the crude product was purified by
chromatography on a column of silica gel with a mixture of
petroleum ether (40–60) and AcOEt (2:1!1:2).
4
5
100[e]
60
100[e]
100[e]
65
6
90[i]
Acknowledgements
[a]
We thank Loughborough University for a studentship to
D. A.
The reactions were carried out on a 0.5-mmol scale with
FeCl3 (4 mol%) and 50% aqueous H2O2, in i-PrOH for
18 h at the temperature indicated.
Isolated yield.
1.2 equiv. of oxidant were used.
[b]
[c]
[d]
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Yield in parenthesis is for the reaction catalyzed by
CuACHTUNGTRENNUNG(OTf)2 (2 mol%).
6 equiv. of oxidant were used.
Not formed, starting material decomposed.
3 equiv. of oxidant were used.
Yield in parenthesis is for the reaction at room tempera-
ture (72 h).
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Scheme 5. Possible mechanism for the intramolecular nitroso ene cyclization.
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Adv. Synth. Catal. 2011, 353, 3347 – 3351

Intramolecular Carbonyl Nitroso Ene Reaction Catalyzed by IronACTHNUTRGNEUG(N III) Chloride/Hydrogen Peroxide
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