The oxidative acylnitroso hetero-diels-alder reaction catalyzed by dirhodium caprolactamate

Article abstract of DOI:10.1055/s-0031-1289786

An effective protocol is described for the generation and in situ Diels-Alder trapping of acylnitroso derivatives. In this procedure, the oxidation of hydroxamic acid is efficiently catalyzed by dirhodium(II) caprolactamate with tert-butyl hydroperoxide (

Full text of DOI:10.1055/s-0031-1289786

LETTER
▌1801
letter
The Oxidative Acylnitroso Hetero-Diels–Alder Reaction Catalyzed by Dirho-
dium Caprolactamate
Catalytic Oxidative Acylnitroso HDA Reaction
Xiarepati Tusun,a,b Chong-Dao Lu*a
a
Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, P. R. of China
b
Graduate University of the Chinese Academy of Sciences, Beijing 100049, P. R. of China
Fax +86(991)3838708; E-mail: clu@ms.xjb.ac.cn
Received: 07.04.2012; Accepted after revision: 09.05.2012
equivalent of TBHP in CH2Cl2 at room temperature. The
Abstract: An effective protocol is described for the generation and
HDA reaction proceeded smoothly to completion in 15
in situ Diels–Alder trapping of acylnitroso derivatives. In this pro-
minutes, providing the cycloadduct 4 in 87% isolated
yield (Scheme 1).
cedure, the oxidation of hydroxamic acid is efficiently catalyzed by
dirhodium(II) caprolactamate with tert-butyl hydroperoxide
(TBHP) in the presence of dienes at room temperature. Using this
approach we obtained a variety of hetero-Diels–Alder cycloadducts
in yields of up to 96% at 0.1 mol% catalyst loading.
Rh2(cap)4 (1.0 mol%)
t-BuOOH (1 equiv)
CH2Cl2, r.t.,15 min
OH
O
HN
N
Key words: catalysis, oxidation, acylnitroso, Diels–Alder reaction,
dirhodium(II)
+
O
O
t-BuO
t-BuO
1
2
3a
nitroso-
Diels–Alder
reaction
Since Kirby’s pioneering work was reported in 1973,1 the
hetero-Diels–Alder (HDA) reaction of acylnitroso com-
pounds has been recognized as a useful tool in direct 1,4-
functionalizations of conjugated dienes, and it provides
easy access to a number of nitrogen- and oxygen-contain-
ing natural products.2 Acylnitroso compounds are tradi-
tionally generated in situ by oxidizing hydroxamic acids
using oxidants such as periodates,3,4 due to the high reac-
tivity of acylnitroso species, these reactions are usually
conducted in the presence of trapping agents to ensure for-
mation of the desired products. In recent years, mild pro-
tocols have been developed in which these oxidations are
catalyzed by transition metals in conjunction with
TBHP,5–9 H2O2,10–13 and dioxygen.14,15 The combination
of ruthenium(II) complexes and tert-butyl hydroperoxide
(TBHP) has been reported to promote the oxidation of hy-
droxamic acids and subsequent HDA reactions, although
poor to moderate yields of 19–42% were obtained for
noncyclic dienes.6 Here, we report that dirhodium(II) cap-
rolactamate [Rh2(cap)4] exhibits similar oxidative reactiv-
ity toward hydroxamic acids when TBHP is the terminal
oxidant; this catalytic combination in the presence of di-
enes provides HDA cycloadducts in high efficiency under
mild reaction conditions. The present study provides the
first example of the Rh2(cap)4-catalyzed oxidation of hy-
droxamic acids and extends the potential utility of this im-
portant catalyst, which has already been used for efficient
catalytic oxidation of activated C–H bonds,16–22 phenols,
and anilines.23
N
O
Rh Rh
O
N
Rh2(cap)4
Boc
4a
87%
Scheme 1 Initial experimental results
Since the reaction proceeded quite fast, we investigated
the possibility of reducing the catalyst loading. Indeed, the
catalyst loading could be reduced to 0.1 mol% without ob-
vious loss of yield (Table 1), though excess TBHP was re-
quired (Table 1, entry 1, 2.0 equiv TBHP). When 4.0
equivalents of TBHP were used, hydroxamic acid 1 in
CH2Cl2 was completely consumed within two hours and
an even higher yield of 92% was obtained (Table 1, entry
2). Notably, less expensive T-HYDRO® (70 wt% TBHP
in water) is also a suitable terminal oxidant, however, in
this case a prolonged reaction time (38 h) is required for
complete conversion of 1 (Table 1, entry 3). Further in-
vestigations indicated that methanol is not a suitable sol-
vent for this reaction. In the presence of methanol (Table
1, entry 4), relatively small amount of 1 reacted and only
trace amounts of 4a were detected, even after a reaction
time of 24 hours, in addition, unwanted byproducts were
observed. Both TBHP and Rh2(cap)4 were essential, since
reactions lacking either one gave poor to moderate yields
(Table 1, entries 5 and 6). Moreover, attempts to replace
TBHP with hydrogen peroxide or Rh2(cap)4 with
Rh2(OAc)4 resulted in sluggish reactions with incomplete
conversion of hydroxamic acid 1 (Table 1, entries 7 and
8).
We began our studies by examining the reaction of hy-
droxamic acid 1 and 1.2 equivalents of 1,3-cyclohexadi-
ene 3 in the presence of 1 mol% Rh2(cap)4 and 1.0
SYNLETT 2012, 23, 1801–1804
Advanced online publication: 29.06.2012
DOI: 10.1055/s-0031-1289786; Art ID: ST-2012-W0309-L
© Georg Thieme Verlag Stuttgart · New York
Using the optimized reaction conditions of 0.1 mol%
Rh2(cap)4, 4.0 equivalents of TBHP, 1.0 equivalents of
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1802
X. Tusun, C.-D. Lu
LETTER
Table 1 Optimization and Control Experiments (1 + 3a → 4a)a
tends to abstract a proton from substrates and subsequent-
ly initiate transformations.21 It is therefore possible that
the reaction described here proceeds via H-atom abstrac-
tion from the hydroxamic acid mediated by the tert-butyl-
peroxy radical, producing the acyl nitroxyl radical.35 This
radical is further oxidized to the acylnitroso compound by
an oxidative species such as the tert-butylperoxy radical
or Rh25+ species, which is a one-electron oxidation prod-
uct derived from Rh2(cap)4. Another possibility that can-
not be ruled out is that the acylnitroso compound is
furnished through dismutation of the acyl nitroxyl radi-
cal.36 Further studies are needed to elucidate the detailed
mechanism of this reaction.
Entry Catalyst
(0.1 mol%)
Oxidant
Temp
(°C)
Time
(h)
Yield
(%)b
1c
2
Rh2(cap)4
TBHP
TBHP
T-HYDRO
TBHP
none
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
20
2
84
92
92
Rh2(cap)4
Rh2(cap)4
Rh2(cap)4
Rh2(cap)4
none
3
38
24
24
56
78
24
4d
5
–
e
14
61
50
37
6
TBHP
H2O2
7
Rh2(cap)4
Rh2(OAc)4
Table 2 Hetero-Diels–Alder Trapping of Acylnitroso by Dienes
8
TBHP
r.t.
Rh2(cap)4 (0.1 mol%)
t-BuOOH (4 equiv)
a Reactions were performed using 1 (1.0 equiv), 3 (1.2 equiv), catalyst
(0.1 mol%), and oxidant (4.0 equiv) in CH2Cl2 (0.2 M/[substrate]) un-
less otherwise noted.
diene(s) (3)
CH2Cl2, r.t.
cycloadduct(s)
1
2
b Isolated yields after silica gel chromatography.
c Conditions: 2.0 equiv of TBHP were used.
d MeOH was used as solvent.
4
Entry Diene (3)
Time (h) Product (4)
Yield (%)a
e A complex mixture with low conversion was obtained.
O
hydroxamic acid, and 1.2 equivalents of diene in CH2Cl2
at room temperature, we investigated the scope of the re-
action with different 1,3-dienes. The dienes were those
commonly used to test the scope of the nitroso-Diels–
Alder (NDA) reaction (Table 2). Cyclic dienes 3a–c were
good NDA-trapping substrates and gave the correspond-
ing cycloadducts 4a–c in excellent yields (Table 2, entries
1–3), while 1,3-cyclooctadiene (3d), 9,10-dimethylan-
thracene (3e), and acyclic dienes (3f–i) generally gave
moderate yields (Table 2, entries 4–9).24,25 The yields ob-
tained by our Rh2(cap)4-catalyzed oxidative protocol are
generally higher than that using ruthenium(II) complex-
es.5–9 Exposing the densely functionalized cyclic diene 3j
to the reaction conditions resulted in a complex mixture,
while adding 2.0 equivalents NaHCO3 to the reaction in
order to avoid the hydrolysis of the silyl ether made the
NDA cycloaddition feasible and furnished the desired
product 4j in 47% yield with complete regio- and dia-
steroselectivity.26 Desilylation of 4j mediated by HF and
subsequent β-elimination of the amino group afforded the
O-nitroso aldol product 5 of the β-keto-γ,δ-unsaturated es-
ter 6,27 the precursor of diene 3j (Scheme 2).
1
2
92
N
Boc
3a
4a
4b
4c
O
N
2
14
6
92
96
Boc
3b
O
N
3
Boc
3c
O
4
24
24
68
61
N
Boc
3d
4d
O
N
Boc
HN
5
Boc
O
O
O
Boc
HF (aq),
THF
O
CO2Et
CO2Et
N
TBSO
CO2Et
79%
3e
1) NaH,
4e
4f
TBSCl
2) oxidative
4j
5
6
Ph
Ph
Ph
nitroso HDA
O
N
Scheme 2 Desilylation–β-elimination cascade
6
14
68
Boc
Ph
3f
It has been well documented that the tert-butylperoxy rad-
ical can be generated from TBHP in the presence of dirho-
dium caprolactamate and that the tert-butylperoxy radical
Synlett 2012, 23, 1801–1804
© Georg Thieme Verlag Stuttgart · New York

LETTER
Catalytic Oxidative Acylnitroso HDA Reaction
1803
Table 2 Hetero-Diels–Alder Trapping of Acylnitroso by Dienes
(continued)
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Rh2(cap)4 (0.1 mol%)
t-BuOOH (4 equiv)
References
diene(s) (3)
CH2Cl2, r.t.
cycloadduct(s)
1
2
(1) Kirby, G. W.; Sweeny, J. G. J. Chem. Soc., Chem. Commun.
1973, 704.
(2) For a recent review, see: Bodnar, B. S.; Miller, M. J. Angew.
Chem. Int. Ed. 2011, 50, 5630.
4
Entry Diene (3)
Time (h) Product (4)
Yield (%)a
(3) Kirby, G. W. Chem. Soc. Rev. 1977, 6, 1.
(4) Gowenlock, B. G.; Richter-Addo, G. B. Chem. Rev. 2004,
104, 3315.
O
N
Boc
(5) Flower, K. R.; Lightfoot, A. P.; Wan, H.; Whiting, A. Chem.
Commun. 2001, 1812.
(6) Flower, K. R.; Lightfoot, A. P.; Wan, H.; Whiting, A.
J. Chem. Soc., Perkin Trans. 1 2002, 2058.
(7) Chow, C. P.; Shea, K. J. J. Am. Chem. Soc. 2005, 127, 3678.
(8) Howard, J. A. K.; Ilyashenko, G.; Sparks, H.; Whiting, A.
Dalton Trans. 2007, 2108.
(9) Howard, J. A. K.; Ilyashenko, G.; Sparkes, H. A.; Whiting,
A.; Wright, A. R. Adv. Synth. Catal. 2008, 350, 869.
(10) Iwasa, S.; Tajima, K.; Tsushima, S.; Nishiyama, H.
Tetrahedron Lett. 2001, 42, 5897.
4g
7
12
65b
3g
O
N
Boc
Boc
4g′
O
N
8
10
57
(11) Iwasa, S.; Fakhruddin, A.; Tsukamoto, Y.; Kameyama, M.;
Nishiyama, H. Tetrahedron Lett. 2002, 43, 6159.
(12) Adamo, M. F. A.; Bruschi, S. J. Org. Chem. 2007, 72, 2666.
(13) Atkinson, D.; Kabeshov, M. A.; Edgar, M.; Malkov, A. V.
Adv. Synth. Catal. 2011, 353, 3347.
3h
4h
O
N
Boc
(14) Chaiyaveij, D.; Cleary, L.; Batsanov, A. S.; Marder, T. B.;
Shea, K. J.; Whiting, A. Org. Lett. 2011, 13, 3442.
(15) Frazier, C. P.; Engelking, J. R.; Read de Alaniz, J. J. Am.
Chem. Soc. 2011, 133, 10430.
4i
9
8
81c
(16) For oxidation of tertiary amines, see: Catino, A. J.; Nichols,
J. M.; Nettles, B. J.; Doyle, M. P. J. Am. Chem. Soc. 2006,
128, 5648.
3i
O
N
Boc
(17) For oxidation of secondary amines, see: Choi, H.; Doyle,
M. P. Chem. Commun. 2007, 745.
(18) For benzylic oxidation, see: Catino, A. J.; Nichols, J. M.;
Choi, H.; Gottipamula, S.; Doyle, M. P. Org. Lett. 2005, 7,
5167.
(19) For allylic oxidation, see: Catino, A. J.; Forslund, R. E.;
Doyle, M. P. J. Am. Chem. Soc. 2004, 126, 13622; and ref.
21 and 22 below.
4i′
OTBS
O
Boc
CO2Et
CO2Et
N
TBSO
10d
14
47
4j
3j
a Isolated yields after silica gel chromatography.
(20) Choi, H.; Doyle, M. P. Org. Lett. 2007, 9, 5349.
(21) McLaughlin, E. C.; Choi, H.; Wang, K.; Chiou, G.; Doyle,
M. P. J. Org. Chem. 2009, 74, 730.
(22) For propargylic oxidation, see: McLaughlin, E. C.; Doyle,
M. P. J. Org. Chem. 2008, 73, 4317.
b Obtained as a 1:1 mixture of inseparable regioisomers.
c Obtained as a 2:1 mixture of inseparable regioisomers.
d Conditions: 2.0 equiv of NaHCO3 were used.
(23) For oxidation of phenol and aniline, see: Ratnikov, M. O.;
Farkas, L. E.; McLaughlin, E. C.; Chiou, G.; Choi, H.; El-
Khalafy, S. H.; Doyle, M. P. J. Org. Chem. 2011, 76, 2585.
(24) General Procedure for the Oxidative Acylnitroso
Hetero-Diels–Alder Reaction Catalyzed by Dirhodium
Caprolactamate
In summary, dirhodium caprolactamate in the presence of
TBHP is effective at catalyzing the oxidation of hy-
droxamic acid to the acylnitroso derivative at catalyst
loadings as low as 0.1 mol% under mild reaction condi-
tions. The generated acylnitroso derivative is trapped in
situ by dienes, providing a variety of hetero-Diels–Alder
cycloadducts. The catalytic reaction reported here serves
as the first example for the dirhodium(II)-catalyzed oxida-
tion of hydroxamic acid derivatives and significantly ex-
tends the utility of this unique catalyst.
A 0.0020 M solution of Rh2(cap)4·2MeCN in CH2Cl2 (0.25
mL, 0.0005 mmol, 0.1 mol%) and diene 3 (0.6 mmol, 1.2
equiv) were sequentially added to a solution of BocNHOH
(66.6 mg, 0.5 mmol) in CH2Cl2 (2.5 mL). Then TBHP (5–6
M solution in decane; 2 mmol, 4 equiv) was added dropwise
to the resulting mixture. The reaction mixture was stirred at
r.t. and monitored by TLC. Reaction completion was
confirmed by the disappearance of the starting material. The
solvent was removed by evaporation to give the crude
product, which was purified by silica gel chromatography to
afford the desired products. Analysis of the cycloadducts
4a–e and 4g–i gave results identical to those previously
reported.6,28–33
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (20972182 and 21172251), the ‘Western Light’ pro-
gram (XBBS200820) and the Chinese Academy of Sciences.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1801–1804

1804
X. Tusun, C.-D. Lu
LETTER
(25) tert-Butyl 3,6-diphenyl-3,6-dihydro-2H-1,2-oxazine-2-
carboxylate (4f)
m/z calcd for C21H37NO6SiNa [M + Na]+: 450.2288; found:
450.2284.
The general procedure described above was followed
using BocNHOH (66.6 mg, 0.5 mmol), 1,4-diphenyl-1,3-
butadiene (123.8 mg, 0.6 mmol), Rh2(cap)4·2MeCN (0.0005
mmol), and TBHP (5–6 M solution in decane, 2 mmol). The
reaction mixture was stirred for 12 h and purified by silica
gel chromatography using PE–EtOAc (5:1) as eluent to give
cycloadduct 4f (114 mg, 68%) as a colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 7.30–7.55 (m, 10 H), 6.11–6.17 (m,
2 H), 5.59 (br, 2 H), 1.52 (s, 9 H). 13C NMR (400 MHz,
CDCl3): δ = 154.4, 139.4, 137.3, 129.1, 128.8, 128.6, 128.4,
127.94, 127.88, 127.86, 126.6, 81.6, 79.2, 52.3, 28.5. ESI-
HRMS: m/z calcd for C21H23NO3 [M + H]+: 338.1756;
found: 338.1756.
(27) Desilylation–β-Elimination Product 5
To a solution of cycloadduct 4j (51.0 mg, 0.12 mmol) in
THF (2.0 mL) was added aq HF (40 wt%) (20 μL), and the
resulting mixture was vigorously stirred for 90 min at r.t.
The reaction was quenched with sat. aq NaHCO3 and treated
by usual workup. Purification by silica gel chromatography
using PE–EtOAc (5:1) as eluent to give the product 5 as a
colorless oil (29.7 mg, 79%). 1H NMR (400 MHz, CDCl3):
δ = 7.64 (s, 1 H), 6.99–7.03 (m, 1 H), 6.13 (dd, J = 1.6, 10.0
Hz, 1 H), 4.22–4.30 (m, 2 H), 2.54–2.69 (m, 2 H), 2.37–2.45
(m, 1 H), 1.46 (s, 9 H), 1.28 (t, J = 6.8 Hz, 3 H), 1.28 (d, J =
6.8 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 193.8, 166.0,
156.3, 151.2, 129.2, 91.2, 82.2, 62.1, 35.8, 33.2, 28.3, 15.7,
14.3. ESI-HRMS: m/z calcd for C15H23NO6Na [M + Na]+:
336.1423; found: 336.1415.
(26) 3-tert-Butyl-4-ethyl-5-(tert-butyldimethylsilyloxy)-8-
methyl-2-oxa-3-azabicyclo[2.2.2]oct-5-ene-3,4-
dicarboxylate (4j)
(28) Jekins, N. E.; Ware, R. W. Jr.; Atkinson, R. N.; King, S. B.
Synth. Commun. 2000, 30, 947.
(29) Zhang, D.; Sueling, C.; Miller, M. J. J. Org. Chem. 1998, 63,
885.
(30) Hall, A.; Bailey, P. D.; Rees, D. C.; Rosair, G. M.;
Wightman, R. H. J. Chem. Soc., Perkin Trans. 1 2000, 329.
(31) Tolman, V.; Hanus, J.; Sedmera, P. Collect. Czech. Chem.
Commun. 1999, 64, 696.
(32) Defoin, A.; Joubert, M.; Heuchel, J.-M.; Strehler, C.;
Streich, J. Synthesis 2000, 1719.
(33) Cowart, M.; Bennett, M. J.; Kervin, J. F. Jr. J. Org. Chem.
1999, 64, 2240.
(34) Yamomoto, K.; Hentemann, M. F.; Allen, J. G.;
Danishefsky, S. J. Chem.–Eur. J. 2003, 9, 3242.
(35) Lub, J.; de Boer, Th. J. Recl. Trav. Chim. Pays-Bas 1984,
103, 328.
To a solution of BocNHOH (146.5 mg, 1.1 mmol) in CH2Cl2
(2.5 mL) were sequentially added Rh2(cap)4·2MeCN (0.8
mg, 0.0011 mmol), followed by NaHCO3 (184.4 mg, 2.2
mmol) and then diene 3j34 (390.7 mg, 1.32 mmol). The
resulting solution was stirred for 10 min, after which TBHP
(5–6 M solution in decane, 4.4 mmol) was added dropwise.
The reaction mixture was stirred at r.t. for 14 h, solvent was
removed by evaporation, and the residue was purified by
silica gel chromatography using PE–EtOAc (10:1) as eluent
to give cycloadduct 4j (221 mg, 47%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 5.38 (d, J = 6.8 Hz, 1 H),
4.69–4.72 (m, 1 H), 4.19–4.28 (m, 2 H), 2.55–2.58 (m, 1 H),
2.26–2.28 (m, 1 H), 1.47 (s, 9 H), 1.33 (t, J = 6.8 Hz, 3 H),
1.07 (d, J = 6.8 Hz, 3 H), 1.01–1.05 (m, 1 H), 0.91 (s, 9 H),
0.20 (s, 3 H), 0.18 (s, 3 H). 13C NMR (100 MHz, CDCl3):
δ = 167.4, 158.7, 150.2, 101.8, 84.4, 81.9, 61.6, 51.8, 34.3,
32.2, 28.4, 25.5, 20.4, 18.1, 14.2, –4.6, –4.8. ESI-HRMS:
(36) Samuni, A.; Goldstein, S. J. Phys. Chem. A 2011, 115, 3022;
and references cited therein.
Synlett 2012, 23, 1801–1804
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.