Ru-catalyzed rearrangement of N-methyl isoxazolidines to N-H 1,3-oxazinanes: A strategy of self-hydride transferring cleavage of N-O bonds

Article abstract of DOI:10.1021/ol500869p

A strategy of ruthenium-catalyzed self-hydride transferring cleavage of N-O bonds was designed and utilized in a cascade 1,3-dipolar cyclization of alkenes and N-methyl nitrones followed by an N-demethylative rearrangement, furnishing synthetically useful N-H 1,3-oxazinanes.

Full text of DOI:10.1021/ol500869p

Letter
pubs.acs.org/OrgLett
Ru-Catalyzed Rearrangement of N‑Methyl Isoxazolidines to N−H
1,3‑Oxazinanes: A Strategy of Self-Hydride Transferring Cleavage of
N−O Bonds
Chuan-Zhi Yao,† Zu-Feng Xiao,† Jie Liu, Xiao-Shan Ning, and Yan-Biao Kang*
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China
S
* Supporting Information
ABSTRACT: A strategy of ruthenium-catalyzed self-hydride transferring
cleavage of N−O bonds was designed and utilized in a cascade 1,3-dipolar
cyclization of alkenes and N-methyl nitrones followed by an N-demethylative
rearrangement, furnishing synthetically useful N−H 1,3-oxazinanes.
he dipolar cycloaddition of nitrones 1 with alkenes 2 has
Scheme 2. Conversion of cis-3a to cis-6a
T
already been well-established as a powerful method for the
construction of N-alkyl isoxazolidines1 3 which could be further
converted to the corresponding N-alkyl 1,3-aminoalcohols
through the reductive cleavage of N−O bonds, but the
subsequent removal of the N-alkyl group is difficult (Scheme
1). However, six-membered 1,3-oxazinanes2 6 are useful
cascade formation of 6a from 1a and styrene in the presence of
various precatalysts such as Pd(OAc)2, Co(OAc)2, BF3·Et2O,
AlCl3, Fe(OTf)2, RuCl3·xH2O, IrCl3·xH2O, RhCl3·xH2O,
RuCl2(PPh3)3, and [RuCl2(p-cymene)]2 (see Supporting
Information (SI) for details). Only [RuCl2(p-cymene)]2 and
RuCl2(PPh3)3 were found to be catalytically active for the
desired transformation (Table 1, entries 1, 14−16). Further
investigation revealed that K2CO3 and p-TsOH·H2O (PTSA)
facilitate higher conversions (Table 1, entries 1 and 7), as does
the presence of water (Table 1, entries 1 and 4). It is likely that
this is in part due to the increased solubility of inorganic salts in
toluene. In the absence of Ru or other additives (p-TsOH·
H2O−K2CO3−H2O) the reaction did not proceed (Table 1,
entries 6 and 7). [RuCl2(p-cymene)]2 alone has an inhibiting
effect on the first cycloaddition reaction because of
decomposition of nitrone to benzaldehyde (Table 1, entry 7).
Neither PTSA nor K2CO3 was found to catalyze the reaction
(Table 1, entries 8 and 9). Substituting PTSA and K2CO3 by
other carboxylic salts resulted in lower conversions (Table 1,
entries 10−11). Using other sulfonic acids such as CSA and
methanesulfonic acid also resulted in low conversions (Table 1,
entries 12−13). In most cases trans-3a was partially recovered.
The treatment of trans-3a under standard conditions gave rise
to partial decomposition of starting material instead of
formation of trans-6a. N-Ethyl and N-benzyl phenyl nitrones
were also tested, but only 24% and 2% conversions were
achieved (not shown in the table).
Scheme 1. Possible Routes from N-Methyl Isoxazolidines to
N−H 1,3-Oxazinanes
synthetic building blocks which can be readily converted to
N-alkyl- or N−H-functionalized 1,3-aminoalcohols in one step.
Thus, the transformation of isoxazolidines 3 to 1,3-oxazinanes 6
would be synthetically useful, but remains rare.3,4 The
development of a generally applicable transformation of
isoxazolidines 3 to N−H 1,3-oxazinanes 6 remains to be
established.
Here we report our efforts toward the development of a
reaction cascade from N-methyl nitrones to N−H 1,3-
oxazinanes through novel Ru-catalyzed5 self-hydride trans-
ferring cleavage of N−O bonds.
cis-Isoxazolidine 3a (R1 = R2 = Ph) was initially tested with
[RuCl2(p-cymene)]2 as the catalyst to probe the possibility of
N−O cleavage followed by a C−H oxidative cleavage N-
demethylation reaction. It was found that cis-3a was stereo-
specifically converted to the desired cis-6a in quantitative
conversion (Scheme 2).
The reversibility of the cycloaddition reaction between
nitrone and styrene was also investigated to probe whether
Since cis-isoxazolidine cis-3a could be prepared as the major
product in situ by the 1,3-dipolar cycloaddition reaction of
nitrone 1a (R1 = Ph) and styrene at 110 °C, we investigated the
Received: March 24, 2014
Published: April 15, 2014
© 2014 American Chemical Society
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Letter
Table 1. Investigation of the Reaction Conditions
Scheme 4. Effect of Additives
t-3a/c-3a/6a, conv
b
entry
cat.
additives
(%)
a
c
1
[Ru]
[Ru]
[Ru]
[Ru]
[Ru]
−
K2CO3/PTSA/H2O
PTSA/H2O
5/0/60
2
14/12/4
24/15/41
27/18/39
4/3/49
3
K2CO3/H2O
K2CO3/PTSA
K2CO3/PTSA/4 Å MS
K2CO3/PTSA/H2O
−
4
5
6
20/84/0
investigated. First, various nitrones were subjected to standard
conditions with styrene, resulting in acceptable yields of the cis-
isomer (Table 2, entries 1−8). Naphthyl and 2-furyl nitrones
d
7
[Ru]
24/38/2
8
−
−
[Ru]
PTSA
40/50/0
20/83/0
21/10/21
20/22/23
9
K2CO3/H2O
HCO2Na
a
10
11
Table 2. Scope of the Reaction
[Ru]
K2CO3/H2O/2,4,6-
Me3C6H2CO2H
e
12
[Ru]
[Ru]
K2CO3/H2O/CSA
20/40/9
25/50/17
13/0/35
19/84/0
15/79/0
13
14
15
16
K2CO3/H2O/MeSO3H
RuCl2(PPh3)3 K2CO3/PTSA/H2O
b
entry
R1, 1
R2, 2
Ph, 2a
6
yield (%)
68
RhCl3·xH2O
IrCl3·xH2O
K2CO3/PTSA/H2O
K2CO3/PTSA/H2O
1
Ph, 1a
Ph, 1a
6a
6a
6b
6c
6d
6e
6f
c
a
2
Ph, 2a
82
Standard conditions: 0.5 mmol of 1a, 2.0 mmol of styrene, 2.5 mol %
[RuCl2(p-cymene)]2 [Ru], 15 mol % p-TsOH·H2O (PTSA), 1.0 mmol
of H2O, 0.5 mmol of K2CO3, 2.0 mL of toluene, 110 °C, 24 h.
3
1-Naph, 1b
Ph, 2a
60
60
60
60
61
71
77
63
68
68
69
61
62
62
62
67
66
58
54
4
2-Furyl, 1c
Ph, 2a
b
Conversions of trans-3a, cis-3a, and 6a were determined by 1H NMR
5
3-ClC6H4, 1d
2-BrC6H4, 1e
4-CF3C6H4, 1f
3,4-(Cl)2C6H3, 1g
3,4-(Cl)2C6H3, 1g
3,4-(Cl)2C6H3, 1g
3,4-(Cl)2C6H3, 1g
3,4-(Cl)2C6H3, 1g
3,4-(Cl)2C6H3, 1g
3,4-(Cl)2C6H3, 1g
3,4-(Cl)2C6H3, 1g
3,4-(Cl)2C6H3, 1g
Ph, 1a
Ph, 2a
(400 MHz) using CH3NO2 and tBuOMe as internal standards.
6
Ph, 2a
c
d
Styrene was recovered in 80% yield. 23% PhCHO and 71% styrene
were observed. CSA refers to (+)-Camphor-10-sulfonic acid.
7
Ph, 2a
e
8
Ph, 2a
6g
6h
6i
9
4-MeC6H4, 2b
4-ClC6H4, 2c
2-ClC6H4, 2d
3-ClC6H4, 2e
4-tBuC6H4, 2f
4-BrC6H4, 2g
2-BrC6H4, 2h
styryl, 2i
trans-3a could isomerize to cis-3a, which contributed to higher
yields of 1,3-oxazinane adducts. The starting materials were
recovered, in both the presence and absence of p-Me-styrene
(Scheme 3). This suggests that the 1,3-dipolar cycloaddition
10
11
12
13
14
15
16
17
18
19
20
21
22
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
6t
Scheme 3. Probing the cis/trans Isomerization of 3a
4-MeC6H4, 2b
4-MeC6H4, 2b
4-MeC6H4, 2b
4-tBuC6H4, 2f
C6H13, 2j
4-CF3C6H4, 1f
2-BrC6H4, 1e
2-BrC6H4, 1e
Ph, 1a
c
C5H11, 1h
Ph, 2a
6u
80
reaction of nitrone 3a with styrene is not reversible for either
the cis- or trans-isomers of product 3a. Since the isomerizations
of cis- and trans-isoxazolidines were not observed and only cis-
3a could be converted to cis-6a (Scheme 2), the conversions to
the desired N−H 1,3-oxazinanes are likely dependent on the
cis/trans ratios of the isoxazolidine intermediates.
a
Using standard conditions: 0.5 mmol of 1a, 2.0 mmol of styrene, 2.5
mol % [RuCl2(p-cymene)]2, 15 mol % p-TsOH·H2O, 1.0 mmol of
H2O, 0.5 mmol of K2CO3, 2.0 mL of toluene, 110 °C, 24 h (see SI for
details). Isolated yields. Isolated cis-3 was used.
b
c
The [3 + 2] cycloaddition between 1a and styrene without a
catalyst or additives produced cis- and trans-3a in a 1.5:1 ratio
(Scheme 4). Surprisingly, the cis/trans ratio increased to 4:1
when K2CO3 and H2O were added. A modified one-pot two-
step version of this Ru-catalyzed cascade reaction between 1a
and styrene was performed using K2CO3 and H2O as additives
for the first [3 + 2] cycloaddition step, resulting in an overall
75% yield of cis-6a. This yield is higher than that of the one-pot
reaction reported in Table 1 entry 1, suggesting that the two-
step cascade process improves the cis/trans-selectivity, resulting
in a higher yield of the target 1,3-oxazinane product.
gave the corresponding products 6b and 6c in 60% yield each.
The reaction was found to tolerate chloro-substitution of both
the styrene and nitrone resulting in products 6i−k, which could
be isolated in moderate yields from 63% to 68%. 4-
Methylstyrene afforded the product 6h with the highest
isolated yield (77%) (Table 2, entry 9). trans-1-Phenyl-1,3-
butadiene gave the corresponding product 6o in 62% yield.
Phenyl, 4-CF3-phenyl, and 2-Br-phenyl nitrones could be
reacted with 4-methylstyrene under standard conditions to give
the corresponding 1,3-oxazinanes 6p−r in 62%, 67%, and 66%
yields, respectively (Table 2, entries 17−19). The styrenes
bearing 4-methyl and 4-tert-butyl groups were treated with 2-
Under standard conditions, the sensitivity of the reaction to
both functionalized nitrone and styrene starting materials was
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bromophenyl nitrone to give the corresponding products 6r
and 6s in 66% and 58% yields, respectively.
Scheme 7. Proposed Mechanism
For the aliphatic alkene, 1-octene, the reaction with phenyl
nitrone produced the corresponding cycloproduct 6t in 54%
yield (Table 2, entry 21). The nitrones bearing 2-aliphatic
chains were not stable in the presence of K2CO3−H2O under
standard conditions, thus the two-step strategy was utilized. For
example, the cycloadduct 6u bearing an n-pentyl group was
obtained in 80% yield using this method.
The reaction could be scaled up to 1 g each of 1g and styrene
to give 2 g of the corresponding product 6g in 67% yield. The
loading of the Ru-catalyst could be lowered down to 0.5 mol %
(Scheme 5).
Scheme 5. Gram-Scale Reaction
The molecular structure of 6m was determined by an X-ray
crystal structure analysis (CCDC 989484) (Figure 1).
Configurations of 6a−u were corroborated by the resemblance
of NMR analysis.
Scheme 8. Deuterium-Labelling Experiments
Figure 1. Molecular structure of 6m, determined by X-ray diffraction
(50% probability ellipsoids) (CH2Cl2−AcOEt).
catalyst is regenerated after the proton transfer. When N-CD3
cis-3a-D3 (>99% D) was treated under standard conditions, cis-
6a-D (>99% D) was obtained. The kinetic isotope effect (kH/
kD = 1) indicates that C−H cleavage step is not the rate-
limiting step, which indicates pathway (c) might not be
involved in this reaction (Scheme 8). Thus, both pathways (a)
and (b) seem reasonable.
Since 1,3-oxazinanes are useful bioactive compounds and
synthetic intermediates,6 we aimed to use them to prepare syn-
1,3-aminoalcohols (Scheme 6). cis-1,3-Oxazinane 6g was
Scheme 6. Transform 6g to 4g
In conclusion, we have developed a Ru-catalyzed cascade [3
+ 2]-cyclization and rearrangement to N−H 1,3-oxazinanes
using the strategy of self-hydride transferring cleavage of N−O
bonds. This novel protocol provides a facile access to
synthetically useful N-H 1,3-oxazinanes which could not be
otherwise synthesized via the conventional dipolar cyclo-
addition of readily available inexpensive N-methyl nitrones.
This strategy demonstrates good tolerance to a range of
functional groups. Even the N-substitution was limited on the
methyl group, but in further transformations the corresponding
methylene group (N−CH2−O) will be removed, which makes
the strategy more “atom-economic”.8 The detailed mechanistic
study, the asymmetric version, and the synthetic applications of
this reaction are underway in our laboratory.
treated with NH2OH·HCl in wet methanol,4a,7 and the
corresponding N−H syn-1,3-aminoalcohol 4g was isolated in
94% yield. Thus, N−H 1,3-aminoalcohols could be obtained in
excellent yields in a single step.
The proposed reaction mechanism is demonstrated in
Scheme 7. Geometric effects and the steric hindrance have a
dramatic influence on this reaction that neither trans-3a nor N-
ethyl or N-benzyl cis-3 could be well converted. To understand
the mechanism, deuterium labeling experiments were done and
demonstrated in Scheme 8 (for the details of D-labeling
experiments, see SI). Probably only cis-3a might coordinate to
catalytically active species A to form complex B which is
transferred to final product 6a through the single-electron-
transfer (SET) pathway (a), the N−O oxidative insertion
pathway (b), or the C−H cleavage hydride transferring N−O
cleavage pathway (c), all via the key intermediate E. The Ru-
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and spectroscopic data for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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Organic Letters
Letter
Demeunynck, M.; Carrez, D.; Croisy, A.; Lansiaux, A.; Bailly, C.;
Colson, P. J. Med. Chem. 2003, 46, 967. (d) Fixler, N.; Demeunynck,
M.; Duflos, A.; Lhomme, J. Heterocycles 1998, 48, 755.
AUTHOR INFORMATION
■
Corresponding Author
(7) A slightly lower yield was achieved with HCl in wet MeOH.
(8) As the corresponding form of a methylene leaving group, HCHO
is smaller than PhCHO or another aldehyde.
*E-mail: ybkang@ustc.edu.cn.
Author Contributions
†C.-Z.Y and Z.-F.X. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank The Fundamental Research Funds for the Central
Universities (WK2060190022, WK2060190026). We are grate-
ful to Prof. Xiao-Yi Yi of the Central South Univ. China for
assistance with X-ray crystallographic analysis and Dr. S. C. E.
Stieber of CaRLa of Universitat Heidelberg for linguistic
̈
polishing of the manuscript.
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