Metal-free three-component oxyazidation of alkenes with trimethylsilyl azide and N-hydroxyphthalimide

Article abstract of DOI:10.1021/jo502327r

A novel and facile oxyazidation of alkenes under metal-free and mild conditions has been reported. A remarkable feature of the developed procedure is consecutive construction of C-O and C-N bonds in one step. The process allows quick and selective assembly of alkyl azide from readily available starting materials, where N-hydroxyphthalimide was used as an oxygen-radical precursor and TMSN₃ as the N₃ source. A range of aromatic alkenes bearing synthetically useful functional groups was tolerated.

Full text of DOI:10.1021/jo502327r

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Article
Metal-free Three-Component Oxyazidation of Alkenes
with Trimethylsilyl Azide and N-Hydroxyphthalimide
Xiao-Feng Xia, Zhen Gu, Wentao Liu, Haijun Wang, Yongmei Xia, Haiyan Gao, Xiang Liu, and Yong-Min Liang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 09 Dec 2014
Downloaded from http://pubs.acs.org on December 9, 2014
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Metalꢀfree ThreeꢀComponent Oxyazidation of Alkenes with
Trimethylsilyl Azide and NꢀHydroxyphthalimide
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Xiao-Feng Xia,*† Zhen Gu,† Wentao Liu,† Haijun Wang† Yongmei Xia,† Haiyan Gao,†
Xiang Liu,† Yong-Min Liang‡
†
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of
Chemical and Material Engineering, Jiangnan University, Wuxi, Jiangsu, 214122, China.
‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000,
China.
Eꢀmail: xiaxf@jiangnan.edu.cn
A novel and facile oxyazidation of alkenes under metalꢀfree and mild conditions has been reported. A
remarkable feature of the developed procedure is consecutive construction of CꢀO and CꢀN bonds in one step.
The process allows quick and selective assembly of alkyl azide from readily available starting materials,
where Nꢀhydroxyphthalimide was used as an oxygenꢀradical precursor and TMSN3 as the N3 source. A
range of aromatic alkenes bearing synthetically useful functional groups were tolerated.
INTRODUCTION
Nitrogenꢀcontaining compounds occupy a significant position in natural products, material science, and
pharmaceuticals, which has inspired the search for more milder and efficient CꢀN bondꢀforming reactions.1
As highly important nitrogenꢀcontaining compounds, organic azides gained great attention and have been
recognized as efficient synthetic intermediates, which can be easily transformed into amines under reductive
conditions.2 The traditional methods for most organic azides syntheses are based on the transformation of
alkyl halides via a SN2 reaction. Recently, chemists found that using azidyl radicals in the functionalization
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of alkenes can directly realize various straightforward transformations for the construction of substituted
organic azides.3 For example, in the past decade, several groups have reported some methods of azidyl
radical addition to alkenes followed by formation of CꢀX (X= O, Se, N, I, F, CN) bonds using TMSN3, NaN3
or IN3 as the N3 source (Scheme 1, equation 1).4 However, to the best of our knowledge, these procedures are
not well developed, and up to now straightforward and efficient approaches for organic azide syntheses by
the addition of the oxygen radical to alkenes followed CꢀN bonds formation have been rarely reported. In
addition, direct azidation of alkene under metalꢀfree oxidation conditions was also developed.4a,5 For
instance, in 2013, the Antonchick5a group has independently reported a novel azidation method for the
construction of azide oxindoles from alkene compounds using PhI(OCOCF3)2 as oxidant (Scheme 1,
equation 2). Herein, we report a metalꢀfree functionalization of alkenes by the addition of oxygen radicals
followed by trapping with an azidyl source at room temperature to give synthetically useful
2ꢀazidoꢀ2ꢀphenylethoxyꢀisoindolinone compounds, which could provide a broad range of possibilities for
further derivatization (Scheme 1, equation 3).
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Scheme 1. Azidation of alkenes.
RESULTS/DISCUSSION
It was revealed that Nꢀhydroxyphthalimide (NHPI) can generate the phthalimide Nꢀoxyl (PINO) radical,
which is an active catalytic species to realize CꢀH bond functionalization.6 Recently, PINO was also utilized
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as a stoichiometric reactant in organic synthesis to construct the CꢀO bond.7 We envisaged that PINO can be
also utilized as a stoichiometric reactant for radical addition, and the results are reported herein. Our
investigation began with the reaction of styrene 1a, TMSN3, and Nꢀhydroxyphthalimide using 20 mmol%
CuCl as catalyst and PhI(OAc)2 as oxidant, and the target product 4a was obtained in 57% yield at ambient
temperature (see Table 1, entry 1). In order to increase the yield, several copper catalysts were evaluated,
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.
.
including CuCl, CuBr, CuI, Cu(OTf)2, CuBr2, Cu(OAc)2, and CuCl2 2H2O, wherein CuCl2 2H2O displayed
high catalytic activity (see Table S1, entry 18). When 4Å MS was added into the reaction system, the yield
was increased. To our delight, in the absence of copper catalyst, 4a was still formed (Table 1, entry 4), which
meant that the copper catalyst did not play a decisive role in the reaction. When 2.0 equiv. PhI(OAc)2 was
used, the yield increased to 70% similar to previous results (entry 2 vs entry 5). PhI(OCOCF3)2 (2.0 equiv.)
gave a lower yield (entry 6). When NaN3 was used as the nitrogen source instead of TMSN3, a very low
yield was obtained (entry 7). Meanwhile, screening of solvents revealed that DCE was the best for the
reaction under metalꢀfree conditions (entries 8ꢀ12). Control experiment showed that only a little product was
detected by GC in the reaction in the absence of oxidant (PhI(OAc)2).
Table 1. Selected List of Screening for the Optimized Conditions.a
Entry
1a : 2 : 3
1:2:1.2
2:2:1
Catalyst (%)
20% CuCl
Oxidant
Solvent
DCE
Yield[%]b
57%
1
2
3
4
5
6
1.2 eq. PhI(OAc)2
.
10% CuCl2 2H2O
1.2 eq. PhI(OAc)2 DCE+4Å MS
1.2 eq. PhI(OAc)2 DCE+4Å MS
1.2 eq. PhI(OAc)2 DCE+4Å MS
2.0 eq. PhI(OAc)2 DCE+4Å MS
73%
.
2:2:1
5% CuCl2 2H2O
52%
2:2:1
—
—
—
47%
2:3:1
70%
2:3:1
2.0 eq.
DCE+4Å MS
64%
PhI(OCOCF3)2
7c
8
2:3:1
2:3:1
—
—
2.0 eq. PhI(OAc)2 DCE+4Å MS
20%
40%
2.0 eq. PhI(OAc)2
2.0 eq. PhI(OAc)2
CH3CN+4Å
MS
9
2:3:1
—
DCM+4Å
MS
30%
10
11
2:3:1
2:3:1
—
—
2.0 eq. PhI(OAc)2 THF+4Å MS
20%
45%
2.0 eq. PhI(OAc)2
2.0 eq. PhI(OAc)2
—
toluene+4Å
MS
12
13
2:3:1
2:3:1
—
—
actone+4Å
MS
56%
<5%
DCE+4Å MS
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a Conditions: 3 (0.3 mmol), 1a (equiv.), azide (equiv.) in solvent (2.0 mL), at room temperature,
in air, 12h. b Yields of isolated product after chromatography on silica gel. c 2 equiv. NaN3 was
used instead of TMSN3.
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Using the optimized conditions (Table 1, entry 21), the scope of the transformation was investigated. As
shown in scheme 2, a great variety of substituted styrenes were converted to the corresponding alkyl azides
in good to moderate yields. Several useful functional groups were tolerated, including fluoro, chloro, bromo,
iodo, nitro, ester, ether and alkyl substituents, at the different positions of styrenes. An electronꢀwithdrawing
substituent favored product formation, whereas an electronꢀdonating group gave slightly lower yields. When
4ꢀvinylphenyl acetate was employed, poor regioselectivity was observed (4h, regioisomeric ratio = 5:2).
Naphthalenes bearing vinyl groups at position 2 afforded the desired products in 51% (4i) yield. αꢀMethyl
styrene gave the corresponding product 4m in moderate yield; (E)ꢀβꢀmethyl styrene was also compatible,
and provided a mixture of diastereoisomers 4o (dr = 66:34). Dihydronaphthalene can also participate in the
reaction, but gave a low yield (4p). (E)ꢀ1,2ꢀDiphenylethene gave a mixture of diastereoisomers 4q (dr =
53:47). Several nonꢀstyrenes also reacted. For example, norbornylene can deliver the target product, and
only the major isomer was separated in spite of a low yield (4r).When cyclohexene was employed as a
substrate, cyclohexenylꢀPINO (4s) was selectively obtained in good yield. A possible mechanism for the
formation of cyclohexenylꢀPINO product (4s) was proposed (Scheme 3). The imidazole analogue of styrene
gave the expected 4t in moderate yield, while allyl phenyl ether gave a mixture of products with no apparent
regioselectivity (r.r. = 1:1, 4u).
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N3
N3
N3
PINO
PINO
PINO
5
6
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8
O
70%
,
4c
44%,
4b
57%,
72%,
N3
N3
N3
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PINO
PINO
PINO
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Cl
F
Br
4f
52%,
4e
4d
78%,
N3
N3
N3
PINO
PINO
PINO
O
O
O2N
4i
51%,
4h,
56%,
r.r. = 5:2
4g
91%,
N3
N3
N3
PINO
PINO
PINO
Cl
O
Br
4l
72%,
70%, 4k
4j
60%,
N3
N3
N3
PINO
PINO
PINO
PINO
I
4n
70%, 4o, dr = 66:34
50%,
4m
55%,
N3
N3
PINO
Ph
PINO
H
H
N3
Ph
30%
4q
,
dr>98:2
72%, , dr= 53:47
4p
40%, , dr>98:2
N3
N3
N
O
PINO
N
PINO
4s
PINO
4u
30%, , r.r. = 1:1
69%,
4t
60%,
Scheme 2. Scope of metalꢀfree oxyazidation of alkenes. Reaction conditions: alkene (0.6 mmol, 2.0 equiv.),
TMSN3 (0.9 mmol, 3.0 equiv.), 3 (0.3 mmol), PhI(OAc)2 (0.6 mmol, 2.0 equiv.), DCE (3.0 mL), 4Å M.S.,12 h, in
air, at room temperature. r.r.= regioisomeric ratio (major : minor). PINO = phthalimide Nꢀoxyl.
Scheme 3. The mechanism for the formation of 4s.
As mentioned above, azido compounds are very useful synthetic intermediates and building blocks in
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organic synthesis. Hence, the azido products were further utilized in other transformations. In the presence of
PPh3 and water, 2ꢀ(2ꢀazidoꢀ2ꢀphenylethoxy)ꢀisoindolineꢀ1,3ꢀdione (4a) was efficiently reduced to the
corresponding amine product 5a in 40% yield at room temperature.4b The product 4a can also undergo the
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classical click reaction in the presence of CuSO4 5H2O (10 mmol%) and Cu powder (4.0 equiv.) at room
temperature to afford the corresponding triazole 6a in 40% yield (Scheme 4). 3j
Scheme 4. Further synthetic transformations
In order to gain insight into the mechanism, some control experiments were carried out (Scheme 5). In the
absence of TMSN3 the dioxygenation product 7a was obtained in 68% yield, which was consistent with a
mechanism involving the PINO radical intermediate. The structure of the product 7a was further confirmed
by Xꢀray crystallography (see the Supporting Information).8 The product 7a can be transformed into
1ꢀphenylethaneꢀ1,2ꢀdiol 8a in moderate yield by cleavage of the NꢀO bond with Mo(CO)6 (Scheme 5ꢀa). To
gain further understanding about the reaction mechanism, inhibition experiments were conducted. When 2.0
equiv. of TEMPO (2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy) or BHT (2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol) was
added into the reaction system, the desired transformation was found to be completely inhibited, providing
further evidence that a radical addition mechanism was involved in this transformation (Scheme 5ꢀb and c).
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Scheme 5. Mechanistic experiments
According to the above experimental results and related published research studies7c,9, a possible
mechanism is outlined in Scheme 6. First, NHPI is oxidized to give the oxygenꢀcentred radical PINO. PINO
then quickly reacts with styrene to give radical A, which can be further oxidized to cation B in the presence
of PhI(OAc)2. Last, cation B was attacked by -N3 to give the azido product.
Scheme 6. Proposed Mechanism
In conclusion, we have developed an efficient metalꢀfree oxyazidation of activated and unactivated
alkenes for the synthesis of alkyl azides that holds great potential for the subsequent transformation of the
azido unit. A radical addition process is involved in this transformation with the formation of CꢀO and CꢀN
bonds. Further investigations on the scope and synthetic application of these reactions are ongoing in our
group.
EXPERIMENTAL SECTION
1
General Remarks: Column chromatography was carried out on silica gel. Unless noted H NMR spectra
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were recorded on 400 MHz in CDCl3 and dꢀDMSO, 13C NMR spectra were recorded on 100 MHz in CDCl3
and dꢀDMSO. IR spectra were recorded on an FTꢀIR spectrometer and only major peaks are reported in cmꢀ1.
Melting points were determined on a microscopic apparatus and were uncorrected. All new products were
further characterized by HRMS (high resolution mass spectra), high resolution mass spectrometry (HRMS)
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spectra was obtained on a micrOTOFꢀQ instrument equipped with an ESI source; copies of their H NMR
and 13C NMR spectra are provided. Commercially available reagents 1, 2, 3 and solvents were used without
further purification.
Typical procedure for the synthesis of products 4
To a solution of Nꢀhydroxyphthalimide (3, 0.3 mmol, 48.9 mg) in DCE (3.0 mL) was added styrene (1, 0.6
mmol), TMSN3 (2, 0.9 mmol), PhI(OAc)2 (193.2 mg, 2.0 equiv.) and 4Å MS (40 mg). The reaction mixture
was then stirred for 12 h at room temperature in air. After the reaction, the resulting mixture was quenched
with water and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried
over Na2SO4 and concentrated. Purification of the crude product by flash column chromatography afforded
the product 4 (petroleum ether/ethyl acetate as eluent (6:1)).
Characterization data of compounds 4
o
1
2ꢀ(2ꢀazidoꢀ2ꢀphenylethoxy)isoindolineꢀ1,3ꢀdione (4a, 70%, 64.7mg), M.P.=66ꢀ68 C, white solid, H NMR
(400 MHz, CDCl3): 7.68ꢀ7.76 (m, 4 H), 7.51ꢀ7.52 (m, 2 H), 7.36ꢀ7.37 (m, 3 H), 5.50ꢀ5.53 (m, 1 H),
3.89ꢀ3.94 (dd, 1 H, J = 12.0 Hz, 8.0 Hz), 3.59ꢀ3.63 (dd, 1 H, J = 12.0 Hz, 4.0 Hz); 13C NMR (100 MHz,
CDCl3): 163.3, 135.8, 134.9, 134.4, 134.1, 129.0, 128.5, 127.8, 123.4, 87.5, 54.1; IR (cmꢀ1): 3064, 3035,
2935, 2105, 1789, 1736, 1668, 1459, 1370, 1187, 1126, 1077, 1019, 976, 877, 761, 701; HRMS (ESI) m/z:
calcd for C16H12N4NaO3: M+Na = 331.0807; found: 331.0814.
2ꢀ(2ꢀazidoꢀ2ꢀpꢀtolylethoxy)isoindolineꢀ1,3ꢀdione (4b, 57%, 55.1mg), M.P.=64ꢀ65 C, white solid, 1H NMR
o
(400 MHz, CDCl3): 7.73ꢀ7.75 (m, 2 H), 7.67ꢀ7.69 (m, 2 H), 7.38ꢀ7.40 (m, 2 H), 7.16ꢀ7.18 (m, 2 H),
5.47ꢀ5.50 (dd, 1 H, J = 8.0 Hz, 4.0 Hz), 3.88ꢀ3.93 (dd, 1 H, J = 12.0 Hz, 8.0 Hz), 3.56ꢀ3.61 (dd, 1 H, J =
14.0 Hz, 6.0 Hz), 2.32 (s, 3 H); 13C NMR (100 MHz, CDCl3): 163.5, 139.7, 134.5, 132.0, 128.8, 127.9, 123.5,
87.4, 54.2, 21.3; IR (cmꢀ1): 2926, 2103, 1735, 1368, 975, 876, 814, 702; HRMS (ESI) m/z: calcd for
C17H14N4NaO3: M+Na = 345.0964; found: 345.0958.
1
2ꢀ(2ꢀazidoꢀ2ꢀ(4ꢀmethoxyphenyl)ethoxy)isoindolineꢀ1,3ꢀdione (4c, 44%, 44.6mg), oil, H NMR (400 MHz,
CDCl3): 7.68ꢀ7.76 (m, 4 H), 7.42ꢀ7.44 (m, 2 H), 6.87ꢀ6.89 (m, 2 H), 5.46ꢀ5.49 (m, 1 H), 3.89ꢀ3.94 (dd, 1 H,
J = 12.0 Hz, 8.0 Hz), 3.79 (s, 3 H), 3.57ꢀ3.62 (dd, 1 H, J = 16.0 Hz, 4.0 Hz); 13C NMR (100 MHz, CDCl3):
163.4, 160.6, 134.4, 129.4, 128.6, 126.8, 123.4, 113.9, 87.0, 55.1, 53.9; IR (cmꢀ1): 2936, 2106, 1735, 1611,
1514, 1369, 1252, 1026, 975, 703; HRMS (ESI) m/z: calcd for C17H14N4NaO4: M+Na = 361.0913; found:
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361.0907.
2ꢀ(2ꢀazidoꢀ2ꢀ(4ꢀbromophenyl)ethoxy)isoindolineꢀ1,3ꢀdione (4d, 78%, 90.3mg), M.P.=91ꢀ92oC, pale yellow
solid, 1H NMR (400 MHz, CDCl3): 7.69ꢀ7.77 (m, 4 H), 7.49ꢀ7.51 (m, 2 H), 7.41ꢀ7.43 (m, 2 H), 5.45ꢀ5.48 (m,
1 H), 3.85ꢀ3.90 (dd, 1 H, J = 14.0 Hz, 4.0 Hz), 3.58ꢀ3.62 (dd, 1 H, J = 12.0 Hz, 4.0 Hz); 13C NMR (100 MHz,
CDCl3): 163.3, 134.5, 132.1, 131.7, 129.5, 129.4, 128.5, 123.5, 86.8, 53.9; IR (cmꢀ1): 2930, 2105, 1735,
1369, 1285, 1073, 1013, 975, 790, 702; HRMS (ESI) m/z: calcd for C16H11N4NaBrO3: M+Na = 408.9912;
found: 408.9907.
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2ꢀ(2ꢀazidoꢀ2ꢀ(4ꢀchlorophenyl)ethoxy)isoindolineꢀ1,3ꢀdione (4e, 72%, 73.9mg), M.P.= 93ꢀ94 oC, pale yellow
solid, 1H NMR (400 MHz, CDCl3): 7.76ꢀ7.78 (m, 2 H), 7.70ꢀ7.72 (m, 2 H), 7.45ꢀ7.49 (m, 2 H), 7.34ꢀ7.37 (m,
2 H), 5.47ꢀ5.50 (m, 1 H), 3.85ꢀ3.91 (dd, 1 H, J = 16.0 Hz, 8.0 Hz), 3.58ꢀ3.62 (dd, 1 H, J = 12.0 Hz, 4.0 Hz);
13C NMR (100 MHz, CDCl3): 163.3, 134.5, 129.2, 128.8, 128.6, 123.5, 86.8, 53.9; IR (cmꢀ1): 2931, 2105,
1736, 1671, 1368, 828, 702; HRMS (ESI) m/z: calcd for C16H11N4NaClO3: M+Na = 365.0417; found:
365.0412.
2ꢀ(2ꢀazidoꢀ2ꢀ(4ꢀfluorophenyl)ethoxy)isoindolineꢀ1,3ꢀdione (4f, 52%, 50.9mg), M.P.=69ꢀ70oC, pale yellow
solid, 1H NMR (400 MHz, CDCl3): 7.76ꢀ7.78 (m, 2 H), 7.70ꢀ7.72 (m, 2 H), 7.50ꢀ7.52 (m, 2 H), 7.04ꢀ7.10 (m,
2 H), 5.47ꢀ5.50 (dd, 1 H, J = 8.0 Hz, 4.0 Hz), 3.87ꢀ3.92 (dd, 1 H, J = 14.0 Hz, 6.0 Hz), 3.58ꢀ3.63 (dd, 1 H, J
= 14.0 Hz, 6.0 Hz); 13C NMR (100 MHz, CDCl3): 163.4, 134.5, 129.9, 129.8, 128.6, 123.5, 115.7, 115.5,
86.8, 54.0; IR (cmꢀ1): 2934, 2105, 1736, 1512, 836, 702; HRMS (ESI) m/z: calcd for C16H11N4NaFO3: M+Na
= 349.0713; found: 349.0707.
2ꢀ(2ꢀazidoꢀ2ꢀ(4ꢀnitrophenyl)ethoxy)isoindolineꢀ1,3ꢀdione (4g, 91%, 96.4mg), M.P.=87ꢀ88oC, pale yellow
solid, 1H NMR (400 MHz, CDCl3): 8.24ꢀ8.26 (m, 2 H), 7.73ꢀ7.80 (m, 6 H), 5.56ꢀ5.59 (dd, 1 H, J = 4.0 Hz,
4.0 Hz), 3.88ꢀ3.93 (dd, 1 H, J = 14.0 Hz, 6.0 Hz), 3.67ꢀ3.72 (dd, 1 H, J = 14.0 Hz, 6.0 Hz); 13C NMR (100
MHz, CDCl3): 163.3, 148.5, 142.2, 134.8, 128.7, 123.7, 86.6, 53.9; IR (cmꢀ1): 2931, 2107, 1736, 1522, 1348,
853, 702; HRMS (ESI) m/z: calcd for C16H11N5NaO5: M+Na = 376.0658; found: 376.0652.
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MHz, CDCl3): 8.29ꢀ8.31 (m, 0.4 H), 8.21ꢀ8.23 (m, 0.4 H), 7.90ꢀ7.95 (m, 0.5 H), 7.82ꢀ7.86 (m, 0.5 H),
7.74ꢀ7.76 (m, 2 H), 7.68ꢀ7.70 (m, 2 H), 7.54ꢀ7.56 (m, 2 H), 7.11ꢀ7.14 (m, 2 H), 6.12ꢀ6.16 (m, 0.4 H),
5.52ꢀ5.55 (m, 1.0 H), 4.28ꢀ4.34 (m, 0.4 H), 3.86ꢀ3.90 (m, 1.0 H), 3.77ꢀ3.80 (m, 0.4 H), 3.58ꢀ3.62 (m, 1.0 H),
2.29 (s, 1.2 H), 2.28 (s, 3 H); 13C NMR (100 MHz, CDCl3): 169.0, 168.9, 163.3, 159.1, 157.2, 151.5, 151.0,
135.8, 134.4, 134.1, 132.5, 127.9, 123.4, 122.1, 121.7, 86.8, 58.8, 54.1, 50.5, 20.9; IR (cmꢀ1): 2932, 2106,
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1738, 1665, 1509, 1370, 1199, 976, 911, 702; HRMS (ESI) m/z: calcd for C18H14N4NaO5: M+Na = 389.0862;
found: 389.0856.
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2ꢀ(2ꢀazidoꢀ2ꢀ(naphthaleneꢀ2ꢀyl)ethoxy)isoindolineꢀ1,3ꢀdione (4i, 51%, 54.8mg), oil, H NMR (400 MHz,
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CDCl3): 7.93 (s, 1 H), 7.85ꢀ7.87 (m, 1 H), 7.78ꢀ7.83 (m, 2 H), 7.66ꢀ7.69 (m, 3 H), 7.59ꢀ7.61 (m, 2 H),
7.43ꢀ7.45 (m, 2 H), 5.68ꢀ5.71 (m, 1 H), 3.96ꢀ4.02 (dd, 1 H, J = 16.0 Hz, 8.0 Hz), 3.64ꢀ3.68 (dd, 1 H, J = 12.0
Hz, 4.0 Hz); 13C NMR (100 MHz, CDCl3): 163.4, 134.3, 133.7, 132.7, 132.4, 128.5, 128.1, 127.8, 127.7,
126.7, 126.4, 124.5, 123.4, 87.6, 54.1; IR (cmꢀ1): 3058, 2930, 2103, 1734, 1368, 1186, 1126, 975, 751, 702;
HRMS (ESI) m/z: calcd for C20H14N4NaO3: M+Na = 381.0964; found: 381.0958.
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2ꢀ(2ꢀazidoꢀ2ꢀ(3ꢀmethoxyphenyl)ethoxy)isoindolineꢀ1,3ꢀdione (4j, 60%, 60.8mg), oil, H NMR (400 MHz,
CDCl3): 7.68ꢀ7.76 (m, 4 H), 7.24ꢀ7.28 (m, 1 H), 7.14ꢀ7.15 (m, 1 H), 7.04ꢀ7.06 (m, 1 H), 6.87ꢀ6.90 (m, 1 H),
5.51ꢀ5.54 (m, 1 H), 3.86ꢀ3.91 (dd, 1 H, J = 12.0 Hz, 8.0 Hz), 3.83 (s, 3 H), 3.57ꢀ3.61 (dd, 1 H, J = 12.0 Hz,
4.0 Hz); 13C NMR (100 MHz, CDCl3): 163.3, 159.6, 136.5, 134.4, 129.5, 128.7, 123.4, 119.9, 115.6, 112.7,
87.4, 55.2, 54.3; IR (cmꢀ1): 2940, 2104, 1735, 1602, 1368, 1268, 876, 787, 702; HRMS (ESI) m/z: calcd for
C17H14N4NaO4: M+Na = 361.0913; found: 361.0907.
2ꢀ(2ꢀazidoꢀ2ꢀ(3ꢀbromophenyl)ethoxy)isoindolineꢀ1,3ꢀdione (4k, 70%, 81.1mg), M.P.=65ꢀ66oC, pale yellow
solid, 1H NMR (400 MHz, CDCl3): 7.77ꢀ7.79 (m, 2 H), 7.71ꢀ7.73 (m, 2 H), 7.67 (s, 1 H), 7.48ꢀ7.52 (m, 2 H),
7.25ꢀ7.29 (m, 1 H), 5.42ꢀ5.45 (dd, 1 H, J = 8.0 Hz, 4.0 Hz), 3.85ꢀ3.90 (dd, 1 H, J = 14.0 Hz, 6.0 Hz),
3.59ꢀ3.63 (dd, 1 H, J = 16.0 Hz, 4.0 Hz); 13C NMR (100 MHz, CDCl3): 163.3, 137.4, 134.5, 130.1, 128.6,
126.3, 123.6, 122.5, 86.8, 54.1; IR (cmꢀ1): 3065, 2928, 2104, 1737, 1470, 1369, 1188, 1125, 976, 877, 787,
701; HRMS (ESI) m/z: calcd for C16H11N4NaBrO3: M+Na = 408.9912; found: 408.9907.
2ꢀ(2ꢀazidoꢀ2ꢀ(2ꢀchlorophenyl)ethoxy)isoindolineꢀ1,3ꢀdione (4l, 72%, 73.9mg), M.P.=60ꢀ61oC, pale yellow
solid, 1H NMR (400 MHz, CDCl3): 7.97ꢀ7.99 (m, 1 H), 7.77ꢀ7.79 (m, 2 H), 7.70ꢀ7.73 (m, 2 H), 7.37ꢀ7.41 (m,
1 H), 7.29ꢀ7.33 (m, 2 H), 6.04ꢀ6.06 (m, 1 H), 3.80ꢀ3.85 (dd, 1 H, J = 14.0 Hz, 6.0 Hz), 3.66ꢀ3.70 (m, 1 H);
13C NMR (100 MHz, CDCl3): 163.2, 134.5, 132.9, 132.8, 130.3, 127.1, 123.5, 84.1, 53.4; IR (cmꢀ1): 2928,
2105, 1738, 1367, 975, 876, 759, 702; HRMS (ESI) m/z: calcd for C16H11N4NaClO3: M+Na = 365.0417;
found: 365.0412.
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2ꢀ(2ꢀazidoꢀ2ꢀphenylpropoxy)isoindolineꢀ1,3ꢀdione (4m, 55%, 53.1mg), oil, H NMR (400 MHz, CDCl3):
7.82ꢀ7.84 (m, 2 H), 7.74ꢀ7.77 (m, 2 H), 7.69ꢀ7.71 (m, 2 H), 7.37ꢀ7.42 (m, 3 H), 3.86ꢀ3.94 (m, 2 H), 1.82 (s,
3 H); 13C NMR (100 MHz, CDCl3): 165.1, 139.3, 134.6, 128.6, 128.2, 126.5, 123.5, 89.6, 58.6, 21.7; IR
(cmꢀ1): 3061, 2934, 2104, 1736, 1187, 1115, 972, 767, 702; HRMS (ESI) m/z: calcd for C17H14N4NaO3:
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M+Na = 345.0964; found: 345.0958.
2ꢀ(2ꢀazidoꢀ2ꢀ(4ꢀiodophenyl)propoxy)isoindolineꢀ1,3ꢀdione (4n, 50%, 67.2mg), oil, 1H NMR (400 MHz,
CDCl3): 7.82ꢀ7.85 (m, 2 H), 7.73ꢀ7.77 (m, 4 H), 7.42ꢀ7.44 (m, 2 H), 3.84 (dd, J = 12.0 Hz, 32.0 Hz, 2 H),
1.75 (s, 3 H); 13C NMR (100 MHz, CDCl3): 165.0, 139.3, 137.3, 134.7, 128.9, 128.5, 123.6, 94.8, 89.2, 58.3,
21.7; IR (cmꢀ1): 2984, 2105, 1791, 1736, 1368, 1310, 1077, 927, 876, 705; HRMS (ESI) m/z: calcd for
C17H13N4NaIO3: M+Na = 470.9930; found: 470.9925.
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2ꢀ(1ꢀazidoꢀ1ꢀphenylpropanꢀ2ꢀyloxy)isoindolineꢀ1,3ꢀdione (4o, 70%, 67.6mg), dr=66:34, 1H NMR (400 MHz,
CDCl3): 7.70ꢀ7.72 (m, 2 H), 7.66ꢀ7.69 (m, 2 H), 7.52ꢀ7.54 (m, 1.3 H), 7.46ꢀ7.48 (m, 0.8 H), 7.34ꢀ7.39 (m, 3
H), 5.28ꢀ5.31 (dd, 1 H, J = 8.0 Hz, 4.0 Hz), 4.01ꢀ4.08 (m, 1 H), 1.43 (d, 2 H, J = 4.0 Hz), 1.10 (d, 1 H, J =
8.0 Hz); 13C NMR (100 MHz, CDCl3): 163.3, 134.3, 128.7, 128.4, 128.1, 123.3, 91.6, 90.6, 59.8, 59.5, 16.3,
15.9; IR (cmꢀ1): 2932, 2107, 1736, 1668, 1374, 983, 876, 701; HRMS (ESI) m/z: calcd for C17H14N4NaO3:
M+Na = 345.0964; found: 345.0958.
2ꢀ(1ꢀazidoꢀ1,2,3,4ꢀtetrahydronaphthalenꢀ2ꢀyloxy)isoindolineꢀ1,3ꢀdione (4p, 40%, 40.1mg), dr>98:2
M.P.=104ꢀ105 oC, white solid, 1H NMR (400 MHz, CDCl3): 7.85ꢀ7.87 (m, 2 H), 7.75ꢀ7.80 (m, 3 H),
7.25ꢀ7.32 (m, 2 H), 7.16ꢀ7.18 (m, 1 H), 5.07ꢀ5.08 (d, J = 3.6 Hz, 1 H), 4.36ꢀ4.37 (m, 1 H), 2.91ꢀ2.96 (m, 2
H), 2.55ꢀ2.59 (m, 1 H), 2.10ꢀ2.16 (m, 1 H); 13C NMR (100 MHz, CDCl3): 163.9, 137.3, 134.6, 132.1, 129.5,
126.5, 123.6, 84.2, 58.5, 24.6, 22.9; IR (cmꢀ1): 2932, 2099, 1734, 1370, 1258, 974, 876, 775, 752, 702;
HRMS (ESI) m/z: calcd for C18H14N4NaO3: M+Na = 357.0964; found: 357.0958.
2ꢀ(2ꢀazidoꢀ1,2ꢀdiphenylethoxy)isoindolineꢀ1,3ꢀdione (4q, 72%, 82.9mg), M.P.=111ꢀ113oC, white solid,
dr=53:47, 1H NMR (400 MHz, CDCl3): 7.57ꢀ7.59 (m, 2 H), 7.53ꢀ7.55 (m, 2 H), 7.47ꢀ7.50 (m, 1 H),
7.19ꢀ7.39 (m, 5 H), 7.04ꢀ7.09 (m, 4 H), 5.57ꢀ5.60 (m, 1 H), 5.10ꢀ5.12 (m, 0.45 H), 4.99ꢀ5.01 (m, 0.51 H);
13C NMR (100 MHz, CDCl3): 163.0, 134.1, 128.4, 127.7, 123.1, 123.0, 91.1, 89.5, 68.6, 67.6; IR (cmꢀ1):
2927, 2105, 1735, 979, 876, 760, 701; HRMS (ESI) m/z: calcd for C22H16N4NaO3: M+Na = 407.1120; found:
407.1115.
2ꢀ(3ꢀazidobicyclo[2.2.1]heptanꢀ2ꢀyloxy)isoindolineꢀ1,3ꢀdione (4r, 30%, 26.8mg, major stereoisomer), M.P.
= 75ꢀ76 oC, white solid, 1H NMR (400 MHz, CDCl3): 7.84ꢀ7.86 (m, 2 H), 7.75ꢀ7.77 (m, 2 H), 4.39ꢀ4.40 (t, 3J
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= 2.0 Hz, 1 H), 3.73ꢀ3.75 (t, J = 2.4 Hz, 1 H), 2.70 (m, 1 H), 2.33ꢀ2.35 (m, 1 H), 2.09ꢀ2.15 (m, 1 H),
1.71ꢀ1.76 (m, 1 H), 1.64ꢀ1.67 (m, 1 H), 1.38ꢀ1.56 (m, 3 H); 13C NMR (100 MHz, CDCl3): 163.7, 134.6,
128.8, 123.6, 95.0, 68.5, 42.1, 40.1, 34.7, 26.3, 19.7; IR (cmꢀ1): 2962, 2096, 1736, 1372, 1019, 786, 703;
HRMS (ESI) m/z: calcd for C15H14N4NaO3: M+Na = 321.0964; found: 321.0958.
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2ꢀ(cyclohexꢀ2ꢀenyloxy)isoindolineꢀ1,3ꢀdione (4s, 69%, 50.3mg), m.p.= 62ꢀ63 oC, white solid, 1H NMR (400
MHz, CDCl3): 7.83ꢀ7.85 (m, 2 H), 7.74ꢀ7.77 (m, 2 H), 6.07ꢀ6.10 (m, 1 H), 5.92ꢀ5.95 (m, 1 H), 4.75ꢀ4.76 (m,
1 H), 2.12ꢀ2.20 (m, 1 H), 1.99ꢀ2.05 (m, 3 H), 1.79ꢀ1.87 (m, 1 H), 1.61ꢀ1.64 (m, 1 H); 13C NMR (100 MHz,
CDCl3): 164.2, 134.9, 134.3, 128.9, 123.8, 123.4, 80.8, 27.2, 25.1, 18.1; IR (cmꢀ1): 2938, 2099, 1734, 1650,
1540, 1518, 790, 702;
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2ꢀ(2ꢀazidoꢀ2ꢀ(1Hꢀimidazolꢀ1ꢀyl)ethoxy)isoindolineꢀ1,3ꢀdione (4t, 60%, 53.6mg), M.P.=142ꢀ143oC, white
solid, 1H NMR (400 MHz, dꢀDMSO): 8.63 (s, 1 H), 8.46ꢀ8.53 (m, 1 H), 8.08ꢀ8.16 (m, 3 H), 7.95ꢀ7.97 (m, 1
H), 7.62 (s, 1 H), 6.57ꢀ6.60 (m, 1 H), 4.66ꢀ4.71 (m, 1 H), 4.50ꢀ4.55 (m, 1 H); 13C NMR (100 MHz,
dꢀDMSO): 168.7, 167.4, 166.7, 137.6, 134.0, 131.8, 129.9, 128.4, 123.6, 118.0, 87.3, 50.9, 21.2; IR (cmꢀ1):
3442, 2113, 1675, 1650, 1026, 1003, 824, 764; HRMS (ESI) m/z: calcd for C13H11N6O3: M+H = 299.0893;
found: 299.0887.
2ꢀ(2ꢀazidoꢀ3ꢀphenoxypropoxy)isoindolineꢀ1,3ꢀdione (4u, 30%, 30.4mg), r.r.=1:1, 1H NMR (400 MHz,
CDCl3): 7.71ꢀ7.84 (m, 4 H), 7.23ꢀ7.28 (m, 3 H), 7.02 (m, 1 H), 6.85ꢀ6.88 (m, 0.6 H), 6.73ꢀ6.77 (m, 0.4 H),
6.20ꢀ6.21 (m, 0.9 H), 5.67ꢀ5.72 (m, 0.5 H), 5.51ꢀ5.53 (m, 0.6 H), 4.96ꢀ4.98 (m, 0.3 H), 4.70ꢀ4.72 (m, 0.3 H);
13C NMR (100 MHz, CDCl3): 163.6, 156.5, 150.5, 146.9, 134.4, 134.2, 129.6, 129.4, 128.8, 123.4, 122.5,
117.4, 117.0, 116.2, 114.5, 105.3, 104.3, 103.7, 84.6, 74.8, 70.1, 50.5; IR (cmꢀ1): 2935, 2106, 1734, 1493,
1224, 968, 878, 757, 700; HRMS (ESI) m/z: calcd for C17H14N4O4Na: M+Na = 361.0913; found: 361.0907.
Synthetic transformation of product 4a to 5a and 6a.
The reaction of 2ꢀ(2ꢀazidoꢀ2ꢀphenylethoxy)isoindolineꢀ1,3ꢀdione 4a (308 mg, 1.0 mmol) and PPh3(786 mg,
3.0 mmol) were placed in a Schlenk tube under air, followed by the addition of THF (2.0 mL) and water (2.0
mL). The reaction was conducted at room temperature for 12h. After that, 5.0 mL water was added and the
reaction was extracted by ethyl acetate twice (10 mL each time). The crude product was purified by flash
column chromatography on silica gel (eluent: petroleum ether / ethyl acetate = 3: 1) to afford the product 5a
(112.8 mg, solid).
2ꢀ(2ꢀaminoꢀ2ꢀphenylethoxy)isoindolineꢀ1,3ꢀdione (5a, 40%, 112.8 mg), M.P.=113ꢀ114 oC, pale yellow solid,
1H NMR (400 MHz, CDCl3): 7.79ꢀ7.80 (m, 2 H), 7.67ꢀ7.68 (m, 2 H), 7.28ꢀ7.40 (m, 5 H), 5.19 (s, 2 H, NH2),
4.91ꢀ4.94 (dd, 1 H, J = 4.0 Hz, 4.0 Hz), 4.06ꢀ4.09 (dd, 1 H, J = 4.0 Hz, 4.0 Hz), 3.80ꢀ3.85 (dd, 1 H, J = 16.0
Hz, 4.0 Hz); 13C NMR (100 MHz, CDCl3): 167.9, 138.3, 133.7, 131.7, 126.7, 123.0, 83.2, 41.6; IR (cmꢀ1):
3473, 3061, 3033, 2940, 1772, 1711, 1424, 1393, 1370, 1188, 1063, 1025, 923, 759, 716; HRMS (ESI) m/z:
calcd for C16H15N2O3: M+H = 283.1083; found: 283.1097.
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The reaction of 2ꢀ(2ꢀazidoꢀ2ꢀphenylethoxy)isoindolineꢀ1,3ꢀdione 4a (308 mg, 1.0 mmol), ethynylbenzene
(122.4 mg, 1.2 mmol), CuSO4·5H2O (25.0 mg, 0.1 mmol) and Cu powder (256 mg, 4.0 mmol) were placed
in a flameꢀdried Schlenk tube under air, followed by the addition of DMSO (4.0 mL).The reaction was
conducted at room temperature for 6 h in dark place. After that, 5.0 mL water was added and the reaction
was extracted by ethyl acetate. The crude product was purified by flash column chromatography on silica gel
(eluent: petroleum ether / ethyl acetate = 1: 1) to afford the product 6a (164 mg, solid).
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2ꢀ(2ꢀphenylꢀ2ꢀ(4ꢀphenylꢀ1Hꢀ1,2,3ꢀtriazolꢀ1ꢀyl)ethoxy)isoindolineꢀ1,3ꢀdione (6a, 40%, 164mg), M.P.=
193ꢀ194 oC, pale yellow solid , 1H NMR (400 MHz, CDCl3): 8.13 (s, 1 H), 7.83ꢀ7.84 (m, 2 H), 7.66ꢀ7.71 (m,
4 H), 7.47ꢀ7.49 (m, 2 H), 7.39ꢀ7.43 (m, 3 H), 7.36ꢀ7.37 (m, 3 H), 5.79ꢀ5.82 (m, 1 H), 5.02ꢀ5.07 (m, 1 H),
4.86ꢀ4.90 (m, 1 H); 13C NMR (100 MHz, CDCl3): 163.3, 147.7, 134.6, 134.1, 130.0, 128.8, 128.7, 128.5,
127.7, 125.7, 123.6, 121.1, 86.8, 53.6; IR (cmꢀ1): 2926, 1734, 1540, 1516, 763, 699; HRMS (ESI) m/z: calcd
for C24H18N4O3Na: M+Na = 433.1277; found: 433.1271.
Typical procedure for the synthesis of product 7a
The reaction of NꢀHydroxyphthalimide (3, 0.4 mmol, 65.2 mg) in DCE (3.0 mL) was added styrene (1, 0.2
mmol, 20.8 mg), PhI(OAc)2 (128.8 mg, 0.4 mmol) and 4Å MS (40 mg). The reaction mixture was then
stirred for 12 h at room temperature in air. The resulting mixture was quenched with water and extracted
twice with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and
concentrated. Purification of the crude product by flash column chromatography afforded the product 7a
(petroleum ether/ethyl acetate as eluent (3:1), 68%, 58.2 mg).
Compound 7a, M.P.=180ꢀ181oC, white solid, 1H NMR (400 MHz, CDCl3): 7.66ꢀ7.79 (m, 8 H), 7.55ꢀ7.58 (m,
2 H), 7.34ꢀ7.36 (m, 3 H), 5.85ꢀ5.87 (m, 1 H), 4.91ꢀ4.95 (m, 1 H), 4.54ꢀ4.58 (m, 1 H); 13C NMR (100 MHz,
CDCl3): 163.3, 162.9, 134.4, 134.2, 128.6, 128.0, 123.4, 123.3, 85.6, 79.2; IR (cmꢀ1): 2924, 1788, 1733,
1653, 1540, 1462, 1394, 1375, 1187, 1131, 1076, 1021, 972, 878, 700; HRMS (ESI) m/z: calcd for
C24H16N2O6Na: M+Na = 451.0906; found: 451.0901.
Typical procedure for the synthesis of compound 8a
A mixture of 7a (58.2 mg, 0.136 mmol), Mo(CO)6 (71.8 mg, 0.272 mmol), Et3N (206 mg, 2.04mmol) in
MeCNꢀH2O (15:1, 3 mL) was stirred at 80oC for 18h. Afterwards, the mixture was concentrated, and the
1
residue purified by chromatography on silica (ethyl acetate/hexane= 1:1) to give 8a (12.2 mg, 65%).
H
NMR (400 M HZ, CDCl3): 7.24ꢀ7.28 (m, 5 H), 4.72ꢀ4.75 (dd, J = 8.0, 4.0 Hz, 1 H), 4.06 (s, 2 H), 3.55ꢀ3.67
(m, 2 H); 13C NMR (100 MHz, CDCl3): 140.5, 128.4, 127.8, 126.0, 74.6, 67.9; the spectral data were
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identical to the values of the previous reports: commercially available ꢀCAS#16355ꢀ00ꢀ3.
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Supporting Information Available: Representative experimental procedures, Xꢀray crystallographic data of
7
8
1
7a, and H NMR and 13C NMR spectra of all compounds are available free of charge via the Internet at
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http://pubs.acs.org.
Acknowledgment. We thank the National Science Foundation of China NSF 21402066, the Fundamental
Research Funds for the Central Universities (JUSRP11419) and Natural Science Foundation of Jiangsu
Province (BK20140139) for financial support. Financial support from MOE&SAFEA for the 111 project
(B13025) is also gratefully acknowledged.
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