Transition-metal-free oxychlorination of alkenyl oximes:: In situ generated radicals with tert -butyl nitrite

Article abstract of DOI:10.1039/c6ob01374k

Oxychlorination of alkenyl oximes is harder compared to the analogous oxybromination or oxyiodination because of the difficulty associated with the formation of chlorine cations or radicals. A transition-metal-free oxychlorination of alkenyl oximes has be

Full text of DOI:10.1039/c6ob01374k

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Transition-metal-free oxychlorination of alkenyl oximes: in situ
generated radical with tert-butyl nitrite
Xiao-Wei Zhang, Zu-Feng Xiao, Mei-Mei Wang, Yan-Jun Zhuang and Yan-Biao Kang*
Received 00th January 20xx,
Accepted 00th January 20xx
Oxychlorination of alkenyl oximes is harder compared to the analogous oxybromination or oxyiodination because of the
difficulty associated to the formation of chlorine cations or radicals. A transition-metal-free oxychlorination of alkenyl
oximes has been developed, using t-BuONO as a dual oxidant and AlCl3 as chlorine source. This convenient and practical
method has been used to construct chloroisoxazolines in moderate to good yields, whereas N-chlorosuccinimide (NCS) failed
to promote this reaction.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Chloromethyl dihydroisoxazoles are useful synthons for
isoxazolidines, tetrahydropyrroles, and other synthetic
intermediates. Although it seems simple to approach chloromethyl
dihydroisoxazoles 2 directly from alkenyl oximes 1, surprisingly, this
straight forward synthetic method has been barely reported. Only
one example could be achieved via SciFinder, which was the
palladium-catalyzed oxychlorination of alkenyl oximes with 2 equiv
of CuCl2 as oxidant as well as Cl–source by Zhu et al. (Scheme 1, top).1
Albeit the oxidative cyclization of alkenyl oximes to induce oxygens,2
nitrogens,3 iodines,4 even carbons5 and other atoms6 to
dihydroisoxazoles have been well established, the oxychlorination of
1 is relatively difficult because of the uneasy generation of Cl–radical
or Cl–cation, compared to their iodine or bromine analogy. As a
transition metal-free process, despite N–bromosuccinimide (NBS)
gave high yield of oxybromination product of alkenyl oximes, N–
chlorosuccinimide (NCS) was not reactive at all (Scheme 1, middle).
A multiple step synthesis of chloromethyl dihydroisoxazole 2a has
been achieved on the basis of autoxidative nitrooxylation of alkenyl
oximes.7a Hence a straight forward strategy is needed to synthesis of
chloromethyl dihydroisoxazoles. On the basis of our previous work
on nitrite-mediated promoted synthetic methods7 as well as the self-
hydride transferring rearrangement of N-methyl isoxazolidines and
other reactions,8 dihydroisoxazoles are good precursors for
isoxazolidines. During the modification of the synthesis cis-
isoxazolidines, we explored a transition-metal-free oxychlorination
of alkenyl oximes via the strategy of radical cyclization-chlorination
with t-BuONO (TBN) and AlCl3. In this reaction, substoichiometric
palladium and transition metal oxidant such as CuCl2 have been
avoided.
Scheme 1. Strategy for oxychlorination of alkene oximes.
Results and discussion
Initially, we chose alkene oxime 1a as the substrate of the model
reaction to investigate reaction conditions. First, 1a was treated with
NCS, unfortunately, no conversion of 1a was observed (Table 1, entry
1). A new strategy was then applied by using the in situ generated
chlorine radical from Cl– and TBN. When hydric chloride (37% aq.)
was utilized, 2a was obtained in 52% yield. A series of other cheap
[Cl]-source such as LiCl, n-Bu4NCl, NH4Cl and AlCl3 were further
screened, however, trace or even no desired product was observed
except AlCl3 (entries 3–6), where AlCl3 gave the desired product 2a in
79% yield in the presence of 2 equiv of water. Water was add to this
reaction in consideration of the poor solubility of AlCl3 in CH3CN. To
Center of Advanced Nanocatalysis, Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026, China
* E-mail: ybkang@ustc.edu.cn
Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/x0xx00000x
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our surprise, the amount of water is important to this make sure if the reaction could be carried out undeVrienweAarrticnleeOuntlrinael
oxychlorination reaction (entries 6–9). The addition of 2 equiv of conditions in the presence of 1 equiv of NaODOAIc: 1a0n.1d0t3h9e/Cy6iOelBd01o3f724oK
water gave rise to the increase of yield to 80% from 48% (entries 6 kept almost unchanged. Thus the drawback of the acidic reaction
and 7). Switching the argon atmosphere to an open air atmosphere, media could be solved by the addition of base such as NaOAc.
the yield was nearly unchanged, suggesting that this reaction is not
air- or moisture-sensitive (entries 6 and 10). Since it is too humid in
summer in southern China, the reactions were still run under the
argon atmosphere. The yield increased to 88% when the amount of
AlCl3 lowered to 0.5 equivalent as THF was used as the solvent (entry
15). The reaction conditions in entry 15 was finally chosen as the
standard conditions for further investigation the reaction scope and
limitation. It’s worth noting that 2a was obtained in 83% yield with
acetic acid as solvent (entry 16), indicating that the carbocation
should not be involved because the carbocation should be trapped
by AcOH immediately.
Table 1. Optimization of the conditions
entrya
1
2
3
4
5
6
7
8
[Cl] (equiv)b
NCS
HCl (2, 37%)
LiCl (1.5)
t-BuONO (equiv)
H2O (equiv)b
2a (%)c
0
52
trace
trace
trace
80
48
59
54
79
84
46
75
20
88
83
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.5
1.0
0.25
1.5
1.5
–
–
2
2
2
2
–
5
10
2
2
2
2
2
2
2
NH4Cl (1.5)
nBu4NCl (1.5)
AlCl3 (1.2)
AlCl3 (1.2)
AlCl3 (1.2)
AlCl3 (1.2)
AlCl3 (1.2)
AlCl3 (0.5)
AlCl3 (0.5)
AlCl3 (0.5)
AlCl3 (0.5)
AlCl3 (0.5)
AlCl3 (0.5)
9
10d
11
12e
13e
14e
15e
16f
Scheme 2. Reaction scope. Conditions: 1 (0.25 mmol), AlCl3 (0.125 mmol), H2O (0.5
mmol), THF (2 mL), t-BuONO (0.375 mmol), RT, 20 min, argon. Isolated yield.
The oxybromination and oxyiodination have been investigated
with randomly selected substrates (Scheme 3). Using CBr4 as the
bromine source, the oxybromination products 3a to 3e were
obtained in generally high yields. CBr4 is reactive to generate Br-
radical, whereas 2a could not be obtained from CCl4. The
oxyiodination products 4a and 4b were also afforded in 88% and 66%
yields, respectively.
a Reaction conditions: 1a (0.25 mmol), t-BuONO (1.5 equiv), CH3CN (2 mL), argon,
b
c
d
room temperature. [Cl] (0.5–1.5 equiv), H2O (0–10 equiv). Isolated yields.
Under air. e Using THF as solvent instead of CH3CN. f Using AcOH as solvent instead
of CH3CN.
Various substrates were subjected to the standard conditions,
affording desired oxychlorination products 2a–2q in generally
moderate to good yields (Scheme 2). For example, products 2a–2i
bearing various substituted phenyl groups, regardless difference in
electronic properties and substitution patterns, were obtained in
good to high yields in 20 minutes at room temperature. Besides
phenyl groups, naphthyl and heteroaryl substituted products 2j, 2k
and 2l were also achieved in good yields. Multiple substituted 4,5-
dihydroisoxazoles 2m and 2n could also be obtained in 83% and 62%
yields, respectively. This reaction also worked well for the alkenyl
oxime 1q with an internal C=C bond and afforded the trans-product
2q in 55% yield. Only trace amount of cis-isomer of 2q could be
observed in the 1H NMR spectrum of the crude product. The
configuration of 2q was assigned by comparison of the 1H NMR
Scheme 3. Oxybromination and oxyiodination.
9
spectrum with that of literature.1, Aliphatic substrates with
protecting groups such as TBDPS and 4-phthalimidyl were also
tolerable in the standard condition (2o and 2p). Despite TBDPS group
is sensitive to acidic conditions, it still survived in this reaction. To
This synthetically practical oxychlorination reaction has been
evaluated by the synthesis of pyrrolidine (Scheme 4). Isoxazoline 2a
was transformed to isoxazolidine 5 through methylation and
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reduction with the selectivity of 6.3/1 (cis/trans). The major cis- radical. Alternatively, HNO2 and/or NO2 generatVeidew Afrotircmle Ontlhinee
compound 5 was smoothly converted to pyrrolidin-3-ol 6 in 86% yield. hydrolysis of TBN under acidic conditionsDcOoI:u1l0d.1a0l3s9o/Ca6cOtBa0s137th4Ke
oxidant, however, the generation of key intermediate A needs 1
equiv of t-BuO-radical, whereas it could not be generated by such
way. Therefore, NO or its dimer should act as the oxidant.
Scheme 4. Synthesis of pyrrolidin-3-ol. (a) Me3OBF4, CH3NO2, RT, 5 h; then NaBH4,
EtOH, –30 oC, 3 h. (b) Zn, CH3CO2H, H2O, 50 oC, 4 h.
To explore the reaction mechanism, control experiments were
designed and carried out (Scheme 5). The oxychlorination reaction
were completely shut down when 3 equiv of TEMPO was added to
the standard conditions, affording the TEMPO-adduct 7 in 72% yield
Scheme 6. Relationship between yield and the amount of t-BuONO.
(eqn 1), whereas 2a or 7 could not be obtained without t-BuONO.
Hence t-BuONO plays the role of radical initiator. Compound 1r was
subjected to the standard conditions to give the ring opening product
2r in 38% yield (eqn 2). When AlCl3 and H2O were replaced by 1.5
equiv of HCl 37%, aq.), 2a was isolated in 52% yield (eqn 3),
suggesting that low concentration of HCl generated by the hydrolysis
A plausible mechanism for this reaction is demonstrated in
Scheme 7. First, t-BuONO oxidizes oxime 1 to intermediate A, with
the generation of NO and tert-butanol. Oxime radical A experiences
a 5-exo-trig cyclization and generated the intermediate B which
bearing an unstable carbon radical. Simultaneously, nitric oxide
oxidizes Cl-anion to chlorine radical. Considering only 1.5 equiv of
t-BuONO has been used for the oxychlorination and 1 equiv of
of the AlCl3 could be the active Cl-source for this reaction. The
chlorine radical trapping experiment was carried out.10 The reaction
t-BuONO was consumed to oxidize compound
1 into oxime
was carried out in the presence of trapping reagent 8,11 trapping
product 9 was isolated in 39% yield (eqn 4). On the basis of above
experimental evidence, it was assumed that this reaction should pass
through a radical pathway, where t-BuONO works as dual role of a
radical initiator and an oxidant.
radical, we believe that nitric oxide may directly play the role of
oxidant. Finally, intermediate B combined with chlorine radical to
afford product 2. Alternatively, intermediate B might be oxidized to
carbocation C which spontaneously traps chlorine anion to form
product 2. Considering the difficulty of oxidizing a primary carbon
radical to carbocation under such conditions as well as the evidence
of Cl-radical (Scheme 5, eqn 4), the radical pathway is preferred. The
carbocation pathway should be ruled out because the reaction run
in AcOH gave 83% of 2a without AcOH trapping product (Table 1,
entry 16).
Scheme 7. Proposed reaction mechanism.
Conclusions
In conclusion, a highly efficient radical oxychlorination of alkenyl
oximes with t-BuONO and AlCl3 has been developed. Various
chloroisoxazolines bearing aryl, heteroary, and alkyl groups could be
obtained in moderate to high yields, avoiding using toxic radical
initiator or transition-metal reagents such as palladium and copper
reagents. This convenient and practical method has been used to
construct chloroisoxazolines, which could be further elaborated to
useful hydroxyl pyrrolidine. The control experiments suggested the
radical nature of this reaction, and a plausible reaction mechanism
was proposed accordingly. The oxybromination and oxyiodination
could also be achieved.
Scheme 5. Control experiments.
To verify NO or t-BuONO is the oxidant to convert Cl-anion to Cl-
radical, the relationship between the yield of 2a and the amount of
t-BuONO was examined. The yield of 2a was found to be dependent
on the amount of t-BuONO (Scheme 6). The hypothesis that t-BuONO
rather than NO works as the oxidant for the generation of Cl-radical
is not supported by these results because that at least 2 equiv of t-
BuONO should be necessary, one equiv for oxidative generation of
nitroxyl radical and another equiv for oxidation of chlorine anion to
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2h was obtained from 1h according to the general procedure A as
Experimental section
General procedure A for oxychlorination
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DOI: 10.1039/C6OB01374K
1
a white solid (45.7 mg, 87%); H NMR (400 MHz, CDCl3) δ 7.57 (d, J =
8.0 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 5.00-4.93 (m, 1 H), 3.71 (dd, J =
11.2, 4.4 Hz, 1 H), 3.56 (dd, J = 11.2, 7.6 Hz, 1 H), 3.49 (dd, J = 16.8,
10.4 Hz, 1 H), 3.33 (dd, J = 16.8, 6.4 Hz, 1 H), 2.38 (S, 3 H). 13C NMR
(100 MHz, CDCl3) δ 156.4, 141.0, 129.8, 127.1, 126.5, 79.9, 45.1, 39.0,
21.8. HRMS (ESI) calcd for C11H13NOCl [M+H]+ 210.0686, found
210.0683.
2i was obtained from 1i according to the general procedure A as a
white solid mp 146-147 oC (46.2 mg, 84%); 1H NMR (400 MHz, CDCl3)
δ 7.78 (d, J = 8.4 Hz, 2 H), 7.70 (d, J = 8.4 Hz, 2 H), 5.11-5.03 (m, 1 H),
3.73 (dd, J = 11.6, 4.4 Hz, 1 H), 3.63 (dd, J = 11.6, 6.8 Hz, 1 H), 3.50
(dd, J = 16.8, 10.8 Hz, 1 H), 3.35 (dd, J = 17.2, 6.8 Hz, 1 H). 13C NMR
(100 MHz, CDCl3) δ 155.3, 133.6, 132.9, 127.5, 118.6, 114.0, 80.9,
45.1, 38.1. HRMS (ESI) calcd for C11H10NOCl [M+H]+ 221.0482, found
221.0486.
AlCl3 (0.5 equiv) was weighed directly into a Schlenk tube and dried
under high vacuum for 5 min, then the solution of oxime 1 (0.25
mmol) in THF (2 ml), t-BuONO (1.5 equiv) and water (2 equiv) were
added sequentially under argon atmosphere. The reaction mixture
was stirred at room temperature for 20 min, then the mixture was
concentrated under reduced pressure and the residue was purified
by silica gel column chromatography (EA/PE) to give the product.
2a was obtained from 1a according to the general procedure A as
a white solid, (43.3 mg, 88%); 1H NMR (400 MHz, CDCl3) δ 7.69-7.66
(m, 2 H), 7.45-7.38 (m, 3 H), 5.02-4.94 (m, 1 H), 3.71 (dd, J = 11.2, 4.4
Hz, 1 H), 3.58 (dd, J = 11.2, 7.2 Hz, 1 H), 3.49 (dd, J = 16.8, 10.4 Hz, 1
H), 3.33 (dd, J = 16.8, 6.4 Hz, 1 H).1
2b was obtained from 1b according to the general procedure A as
a brown solid mp 106-108 oC (70.4 mg, 80%); H NMR (400 MHz,
1
2j was obtained from 1j according to the general procedure A as a
CDCl3) δ 7.55 (d, J = 1.6 Hz, 2 H), 7.41 (t, J = 1.6 Hz, 1 H), 5.09-5.01 (m,
1 H), 3.72 (dd, J = 11.6, 4.4 Hz, 1 H), 3.60 (dd, J = 11.6, 7.2 Hz, 1 H),
3.45 (dd, J = 16.8, 10.4 Hz, 1 H), 3.30 (dd, J = 17.2, 6.8 Hz, 1 H). 13C
NMR (100 MHz, CDCl3) δ 154.6, 135.9, 132.3, 130.4, 125.4, 80.7, 45.0,
38.3. HRMS (ESI) calcd for C10H9NOCl3 [M+H]+ 263.9750, found
263.9752.
2c was obtained from 1c according to the general procedure A as
a white solid mp 122-123 oC (48.8 mg, 74%); 1H NMR (400 MHz,
CDCl3) δ 7.75-7.74 (m, 2 H), 7.72-7.71 (m, 1 H), 5.08-5.00 (m, 1 H),
3.72 (dd, J = 11.6, 4.0 Hz, 1 H), 3.60 (dd, J = 11.6, 7.2 Hz, 1 H), 3.44
(dd, J = 16.8, 10.4 Hz, 1 H), 3.29 (dd, J = 17.2, 6.8 Hz, 1 H). 13C NMR
(100 MHz, CDCl3) δ 154.4, 135.9, 132.8, 128.7, 123.7, 80.7, 45.0, 38.3.
HRMS (ESI) calcd for C10H9NOClBr2 [M+H]+ 351.8739, found
351.8736.
2d was obtained from 1d according to the general procedure A as
a colourless crystal (45.7 mg, 86%); 1H NMR (400 MHz, CDCl3) δ 7.70-
7.64 (m, 2 H), 7.14-7.07 (m, 2 H), 5.04-4.96 (m, 1 H), 3.72 (dd, J = 11.2,
4.4 Hz, 1 H), 3.58 (dd, J = 11.6, 7.6 Hz, 1 H), 3.49 (dd, J = 17.2, 10.8 Hz,
1 H), 3.33 (dd, J = 17.2, 6.4 Hz, 1 H). 19F NMR (376 MHz, CDCl3) δ -
109.4.1
1
white solid mp 84-86 oC (43.5 mg, 71%); H NMR (400 MHz, CDCl3) δ
7.99-7.91 (m, 2 H), 7.87-7.84 (m, 3 H), 7.56-7.50 (m, 2 H), 5.09-5.01
(m, 1 H), 3.76 (dd, J = 11.2, 4.4 Hz, 1 H), 3.66-3.58 (m, 2 H), 3.47 (dd,
J = 16.8, 6.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ 156.6, 134.4, 133.3,
128.9, 128.7, 128.2, 127.6, 127.5, 127.1, 126.9, 123.8, 80.3, 45.2,
38.9. HRMS (ESI) calcd for C14H13NOCl [M+H]+ 246.0686, found
246.0686.
2k was obtained from 1k according to the general procedure A as
a colourless oil (41.8 mg, 83%); 1H NMR (400 MHz, CDCl3) δ 7.43-7.41
(m, 1 H), 7.25-7.23 (m, 1 H), 7.09-7.06 (m, 1 H), 5.03-4.95 (m, 1 H),
3.72 (dd, J = 11.2, 4.0 Hz, 1 H), 3.58 (dd, J = 11.2, 7.6 Hz, 1 H), 3.52
(dd, J = 12.8, 6.4 Hz, 1 H), 3.37 (dd, J = 16.8, 6.0 Hz, 1 H).1
2l was obtained from 1l according to the general procedure A as a
white solid mp 68-69 oC (30.2 mg, 65%); 1H NMR (400 MHz, CDCl3) δ
7.53 (d, J = 1.6 Hz, 1 H), 6.75 (d, J = 3.6 Hz, 1 H), 6.50 (q, J = 1.6 Hz, 1
H), 4.99-4.91 (m, 1 H), 3.70 (dd, J = 11.6, 4.4 Hz, 1 H), 3.55 (dd, J =
11.2, 7.2 Hz, 1 H), 3.46 (dd, J = 16.8, 10.4 Hz, 1 H), 3.31 (dd, J = 16.8,
6.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ 148.7, 144.9, 144.7, 112.6,
112.1, 79.8, 44.8, 38.8. HRMS (ESI) calcd for C8H9NO2Cl [M+H]+
186.0322, found 186.0322.
2e was obtained from 1e according to the general procedure A as
a white solid mp 153-154 oC (55.5 mg, 92%); 1H NMR (400 MHz,
CDCl3) δ 8.30-8.26 (m, 2 H), 7.87-7.83 (m, 2 H), 5.14-5.07 (m, 1 H), ),
3.75 (dd, J = 11.2, 4.0 Hz, 1 H), 3.65 (dd, J = 11.2, 7.2 Hz, 1 H), 3.54
(dd, J = 16.8, 10.8 Hz, 1 H), 3.39 (dd, J = 17.2, 6.8 Hz, 1 H). 13C NMR
(100 MHz, CDCl3) δ 155.0, 149.0, 135.4, 127.9, 124.4, 81.0, 45.0, 38.2.
HRMS (ESI) calcd for C10H10N2O3Cl [M+H]+ 241.0380, found 241.0378.
2f was obtained from 1f according to the general procedure A as a
colourless crystal (35.3 mg, 63%); 1H NMR (400 MHz, CDCl3) δ 7.64-
7.59 (m, 2 H), 6.95-6.90 (m, 2 H), 4.99-4.91 (m, 1 H), 3.71 (dd, J = 11.2,
4.4 Hz, 1 H), 3.56 (dd, J = 11.2, 7.6 Hz, 1 H), 3.48 (dd, J = 16.8, 10.4 Hz,
1 H), 3.32 (dd, J = 16.8, 6.4 Hz, 1 H).1
2g was obtained from 1g according to the general procedure A as
a white solid mp 65-66 oC (56.2 mg, 85%); 1H NMR (400 MHz, CDCl3)
δ 7.80 (d, J = 8.4 Hz, 2 H), 7.68 (d, J = 8.4 Hz, 2 H), 5.10-5.02 (m, 1 H),
3.74 (dd, J = 11.2, 4.0 Hz, 1 H), 3.62 (dd, J = 11.2, 7.2 Hz, 1 H), 3.52
(dd, J = 17.2, 10.8 Hz, 1 H), 3.37 (dd, J = 16.8, 6.4 Hz, 1 H). 13C NMR
(100 MHz, CDCl3) δ 155.5, 132.8, 132.6, 132.2, 127.4, 126.1 (q, J = 3.8
Hz), 125.4, 122.6, 80.7, 45.1, 38.5. 19F NMR (376 MHz, CDCl3) δ -62.9.
HRMS (ESI) calcd for C11H10NOClF3 [M+H]+ 246.0403, found 246.0404.
2m was obtained from 1m according to the general procedure A
as a white solid (43.3 mg, 83%);1H NMR (400 MHz, CDCl3) δ 7.68-7.65
(m, 2 H), 7.42-7.40 (m, 3 H), 3.65-3.51 (m, 3 H), 3.13-3.08 (m, 1 H),
1.62 (s, 3 H).1
2n was obtained from 1n according to the general procedure A as
a white solid mp 61-62 oC (370. mg, 62%); 1H NMR (400 MHz, CDCl3)
δ 7.34-7.26 (m, 2 H), 7.25-7.15 (m, 2 H), 4.45 (t, J = 6.4 Hz, 1 H), 3.83
(dd, J = 11.6, 6.4 Hz, 1 H), 3.73 (dd, J = 11.6, 7.2 Hz, 1 H), 2.36 (s, 3 H),
1.34 (s, 3 H), 1.21 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ 165.4, 138.1,
131.2, 129.7, 129.3, 128.2, 125.8, 88.5, 54.2, 41.3, 25.7, 20.6, 18.8.
HRMS (ESI) calcd for C13H17NOCl [M+H]+ 238.0999, found 238.0995.
2o was obtained from 1o according to the general procedure A as
a white solid mp 75-77 oC (64.2 mg, 58%); 1H NMR (400 MHz, CDCl3)
δ 7.67-7.64 (m, 4 H), 7.45-7.36 (m, 6 H), 4.20 (dd, J = 7.6, 6.0 Hz, 1 H),
3.75 (t, J = 6.0 Hz, 2 H), 3.70 (dd, J = 11.6, 6.0 Hz, 1 H), 3.60 (dd, J =
11.6, 7.6 Hz, 1 H), 2.32-2.28 (m, 2 H), 1.94-1.87 (m, 2 H), 1.26 (s, 3 H),
1.12 (s, 3 H), 1.06 (s, 9 H). 13C NMR (100 MHz, CDCl3) δ 166.7, 135.9,
134.1, 130.0, 128.0, 87.8, 63.3, 52.2, 41.3, 29.2, 27.2, 25.2, 21.3, 19.6,
18.4. HRMS (ESI) calcd for C25H34NO2NaSiCl [M+Na]+ 466.1945, found
466.1945.
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2p was obtained from 1p according to the general procedure A as
3o was obtained from 1o according to the general procedure B as
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a white solid mp 157-159 oC (55.1 mg, 69%); H NMR (400 MHz, a colorless oil (99.7 mg, 82% yield). 1H NMR (D4O00I: 1M0.H10z,39C/DCC6lO3)Bδ0173.7647K-
CDCl3) δ 7.85-7.82 (m, 2 H), 7.73-7.70 (m, 2 H), 4.23 (t, J = 7.0 Hz, 1 7.64 (m, 4 H), 7.45-7.36 (m, 6 H), 4.27 (dd, J = 7.6, 6.0 Hz, 1 H), 3.75
H), 4.00 (t, J = 7.4 Hz, 2 H), 3.70 (dd, J = 11.6, 6.4 Hz, 1 H), 3.60 (dd, J (t, J = 6.0 Hz, 2 H), 3.53 (dd, J = 10.4, 6.0 Hz, 1 H), 3.42 (dd, J = 10.8,
= 11.6, 7.4 Hz, 1 H), 2.58 (t, J = 7.4 Hz, 2 H), 1.31 (s, 3 H), 1.16 (s, 3 H). 7.6 Hz, 1 H), 2.30 (dd, J = 9.2, 7.2 Hz, 2 H), 1.94-1.87 (m, 2 H), 1.27 (s,
13C NMR (100 MHz, CDCl3) δ 168.5, 163.7, 134.4, 132.3, 123.7, 87.8, 3 H), 1.11 (s, 3 H), 1.06 (s, 9 H). 13C NMR (100 MHz, CDCl3) δ 166.8,
52.1, 41.1, 35.1, 25.1, 23.8, 18.4. HRMS (ESI) calcd for 135.9, 134.1, 130.0, 128.0, 87.7, 63.3, 52.3, 29.2, 28.3, 27.2, 25.3,
1
C16H17N2O3NaCl [M+Na]+ 343.0825, found 345.0828.
21.4, 19.6, 18.4. HRMS (ESI) calcd for C25H35NO2SiBr [M+H]+
2q was obtained from 1q according to the general procedure A as 488.1615, found 488.1620.
a white solid mp 92-94 oC (32.3 mg, 55%); 1H NMR (600 MHz, CDCl3)
δ 7.70-7.67 (m, 2 H), 7.44-7.40 (m, 3 H), 4.58 (dd, J = 7.2, 3.0 Hz, 1 H,
H7a), 4.55 (q, J = 3.6 Hz, 1 H, H7), 3.59 (ddd, J = 10.2, 7.2, 7.2, Hz, 1
H, H3a), 2.08-1.98 (m, 3 H), 1.82-1.76 (m, 1 H), 1.54-1.50 (m, 1 H),
1.39-1.33 (m, 1 H). 13C NMR (100 MHz, CDCl3) δ 164.1, 130.7, 129.2,
128.8, 127.4, 84.1, 55.1, 43.0, 29.5, 25.9, 17.3. HRMS (ESI) calcd for
C13H15NOCl [M+H]+ 236.0842, found 236.0841.
General procedure C for oxyiodination
CHl3 (2.0 equiv) was weighed directly into a Schlenk tube and dried
under vacuum for 5 min, then the solution of oxime 1 (0.25 mmol) in
THF (2 mL), t-BuONO (1.5 equiv) were added sequentially under
argon atmosphere. After stirring at RT for 20 min, the mixture was
concentrated under reduced pressure and purified by silica gel
column chromatography (EA/PE) to give the product.
4a was obtained from 1a according to the general procedure C as
a white solid (63.2 mg, 88%); 1H NMR (400 MHz, CDCl3) δ 7.66-7.63
(m, 2 H), 7.42-7.36 (m, 3 H), 4.91-4.83 (m, 1 H), 3.47 (dd, J = 16.8,
11.2 Hz, 1 H), 3.38 (dd, J = 10.0, 4.0 Hz, 1 H), 3.22 (dd, J = 10.0, 8.8 Hz,
1 H), 3.18 (dd, J = 16.8, 6.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ
156.1, 130.6, 129.3, 129.0, 127.0, 80.6, 41.2, 8.0.12
2r was obtained from 1r according to the general procedure A as
a colourless oil (23.7 mg, 38%); 1H NMR (400 MHz, CDCl3) δ 4.61 (s, 2
H), 4.21 (dd, J = 7.2, 6.0 Hz, 1 H), 3.70 (dd, J = 11.2, 6.0 Hz, 1 H), 3.62-
3.57 (m, 3 H), 3.35 (s, 3 H), 2.31-2.26 (m, 2 H), 1.99-1.92 (m, 2 H), 1.28
(s, 3 H), 1.14 (s, 3 H). 13C NMR (100 MHz, CDCl3) δ 166.5, 96.8, 87.8,
67.2, 55.6, 52.2, 41.2, 26.3, 25.2, 21.7, 18.4. HRMS (ESI) calcd for
C11H20NO3NaCl [M+Na]+ 272.1029, found 272.1023.
4j was obtained from 1j according to the general procedure C as a
light yellow solid mp 101-103 oC (55.6 mg, 66%). 1H NMR (400 MHz,
General procedure B for oxybromination
CBr4 (1.5 equiv) was weighed directly into a Schlenk tube and dried CDCl3) δ 7.96-7.83 (m, 5 H), 7.56-7.50 (m, 2 H), 5.09- 5.01 (m, 1 H),
under vacuum for 5 min, then the solution of oxime 1 (0.25 mmol) in 3.66-3.58 (m, 2 H), 3.48-3.41 (m, 2 H). 13C NMR (100 MHz, CDCl3) δ
THF (2 mL), t-BuONO (1.5 equiv) were added sequentially under 156.3, 134.4, 133.2, 128.9, 128.7, 128.2, 127.6, 127.4, 127.1, 126.9,
argon atmosphere. After stirring at RT for 20 min, the mixture was 123.7, 80.9, 41.2, 8.0. HRMS (ESI) calcd for C14H13NOI [M+H]+
concentrated under reduced pressure and purified by silica gel 338.0036, found 338.0038.
column chromatography (EA/PE) to give the product.
Synthesis of 6. To a solution of 2a (0.4 mmol) in nitromethane (3
3a was obtained from 1a according to the general procedure B as mL) was added trimethyloxonium tetrafluoroborate (2 equiv). The
a light yellow solid (54.8 mg, 91%); 1H NMR (400 MHz, CDCl3) δ 7.68- mixture was stirred at room temperature for 5 h and concentrated in
7.66 (m, 2 H), 7.42-7.39 (m, 3 H), 5.03-4.95 (m, 1 H), 3.57 (dd, J = 10.4, vacuo. The crude tetrafluoroborate product was dissolved in ethanol
4.4 Hz, 1 H), 3.51 (dd, J = 17.2, 10.8 Hz, 1 H), 3.41 (dd, J = 10.8, 8.4 Hz, (4 mL) and stirred at -30 ˚C, while sodium borohydride (10 equiv) was
1 H), 3.32 (dd, J = 17.2, 6.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3) δ added portionwise. The mixture was stirred at this temperature for
156.3, 130.6, 129.3, 129.0, 127.0, 79.9, 39.8, 33.5.1
3 h before saturated ammonium chloride solution was added to
3h was obtained from 1h according to the general procedure B as quench the reaction. Then, the mixture was extracted with ethyl
1
a white solid (60.3 mg, 95% yield). H NMR (400 MHz, CDCl3) δ 7.56 acetate and the combined organic layers were washed with water
(d, J = 8.0 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 5.01-4.93 (m, 1 H), 3.57 and brine, dried with MgSO4, filtered, and concentrated in vacuo. The
(dd, J = 10.4, 4.4 Hz, 1 H), 3.49 (dd, J = 17.2, 10.4 Hz, 1 H), 3.40 (dd, J crude material was purified by flash column chromatography (PE/EA
= 10.4, 8.4 Hz, 1 H), 3.30 (dd, J = 17.2, 6.4 Hz, 1 H), 2.38 (S, 3 H). 13C = 30:1) and gave compound 5, 66.1 mg, 78% yield with 6.3:1 cis-
NMR (100 MHz, CDCl3) δ 156.4, 141.0, 129.8, 127.0, 126.4, 79.8, 40.0, selectivity. White solid mp 59-60 oC. 1H NMR (400 MHz, CDCl3) δ 7.36-
33.5, 21.7.1
7.28 (m, 5 H), 4.42-4.34 (m, 1 H), 3.82 (dd, J = 10.8, 6.8 Hz, 1 H), 3.57
3j was obtained from 1j according to the general procedure B as a (dd, J = 10.8, 6.8 Hz, 2 H), 2.91-2.83 (m, 1 H), 2.58 (s, 3 H), 2.19-2.12
white solid mp 94 oC (65.8 mg, 91% yield). 1H NMR (400 MHz, CDCl3) (m, 1 H). 13C NMR (100 MHz, CDCl3) δ 138.8, 129.1, 128.4, 127.9, 76.7,
δ 7.96 (dd, J = 8.8, 1.6 Hz, 1 H), 7.91-7.90 (m, 1 H), 7.87-7.83 (m, 3 H), 73.8, 47.1, 44.5, 43.4. HRMS (ESI) calcd for C11H15NOCl [M+H]+
7.56-7.50 (m, 2 H), 5.09-5.01 (m, 1 H), 3.66-3.58 (m, 2 H), 3.48-3.41 212.0842, found 212.0840.
(m, 2 H). 13C NMR (100 MHz, CDCl3) δ 156.5, 134.4, 133.2, 128.9,
The cis-product 5 (0.2 mmol) and activated zinc powder (10 equiv)
128.7, 128.2, 127.6, 127.5, 127.1, 126.9, 123.8, 80.2, 39.8, 33.6. were weighed directly into a flask before acetic acid (2 mL) and water
HRMS (ESI) calcd for C14H13NOBr [M+H]+ 290.0175, found (2 mL) were added. The reaction was stirred at 50 ˚C for 4 h, then
290.0180.
neutralized by NaOH solution, filtrated, and the mixture was
3k was obtained from 1k according to the general procedure B as extracted with DCM and the combined organic layers were washed
1
a light yellow oil (54.6 mg, 89% yield). H NMR (400 MHz, CDCl3) δ with water and brine, dried with MgSO4, filtered, and concentrated
7.42-7.39 (m, 1 H), 7.23-7.21 (m, 1 H), 7.09-7.05 (m, 1 H), 5.04-4.95 in vacuo. The crude material was purified by flash column
(m, 1 H), 3.59-3.48 (m, 2 H), 3.40 (dd, J = 10.4, 8.4 Hz, 1 H), 3.37-3.29 chromatography (DCM/MeOH = 50:1), and gave 38.2 mg of 6 with a
(m, 2 H). 13C NMR (100 MHz, CDCl3) δ 152.2, 131.7, 129.2, 129.0, yield of 86%. Colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.33-7.30 (m,
127.7, 80.2, 40.7, 33.4.1
4 H), 7.29-7.23 (m, 1 H), 4.56-4.51 (m, 1 H), 3.65 (dd, J = 10.0, 6.4 Hz,
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
1 H), 3.44 (dd, J = 9.6, 7.2 Hz, 1 H), 2.42 (br s, 1 H), 2.32 (dd, J = 10.0,
5.2 Hz, 1 H), 2.19 (s, 3 H), 2.13-2.04 (m, 2 H). 13C NMR (0 MHz, CDCl3)
δ 142.1, 128.8, 127.9, 127.7, 69.9, 69.8, 66.0, 46.2, 40.5. HRMS (ESI)
calcd for C11H16NO [M+H]+ 178.1232, found 178.1234.
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DOI: 10.1039/C6OB01374K
Acknowledgements
We thank the National Natural Science Foundation of China
(NSFC 21404096, U1463202), the Fundamental Research Funds
for the Central Universities of China (WK2060190026,
WK3430000001), Anhui Provincial Natural Science Foundation
(1608085MB24) for financial support.
10. Hydric chloride is a medium strong acid, which will result in the
decomposition of oxime substrate. A low concentration of HCl is
generated by the hydrolysis of AlCl3 in the present of water, which
is much milder.
Notes and references
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1
9. 600M H-NMR spectrum of 2q shows that Hc is pseudo-quartet
with a small J-value (3.56 Hz). If Hc is at the axial position (trans
to oxygen), the diaxial Ja-c should be larger than 7.2 Hz (below).
The trans-configuration could be explained by the model below.
6 | J. Name., 2012, 00, 1-3
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