Copper-Catalyzed Oxidative Difunctionalization of Terminal Unactivated Alkenes

Article abstract of DOI:10.1021/acs.joc.8b00729

The copper(II)-promoted free-radical oxidative difunctionalization of terminal alkenes to access ketoazides by utilizing molecular oxygen has been reported. A series of styrene derivatives have been evaluated and were found to be compatible to give the desired difunctionalized products in moderate to good yields. The role of molecular oxygen both as an oxidant and oxygen atom source in this catalytic transformation has been unquestionably demonstrated by ¹⁸O-labeling studies and a radical mechanistic pathway involving the oxidative formation of azidyl radicals is also designed. This environment-friendly catalytic oxidative protocol can transform aldehyde to nitrile.

Full text of DOI:10.1021/acs.joc.8b00729

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Article
Copper catalyzed oxidative difunctionalization of terminal unactivated alkenes
Muhammad Ijaz Hussain, Yangyang Feng, Liangzhen Hu, Qingfu Deng, Xiaohui Zhang, and Yan Xiong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00729 • Publication Date (Web): 21 May 2018
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Copper catalyzed oxidative difunctionalization of terminal
unactivated alkenes
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Muhammad Ijaz Hussain,† Yangyang Feng,† Liangzhen Hu,† Qingfu Deng,† Xiaohui Zhang,† and
Yan Xiong†,‡,*
† School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331,
China
‡ State Key Laboratory of ElementoꢀOrganic Chemistry, Nankai University, Tianjin 300071,
China.
Email: xiong@cqu.edu.cn
Abstract
The copper(II)ꢀpromoted free radical oxidative difunctionalization of terminal alkenes to
access ketoazides by utilizing molecular oxygen has been reported. A series of styrene
derivatives have been evaluated and found to be compatible to give the desired difunctionalized
product in moderate to good yields. The role of molecular oxygen both as oxidant and oxygen
atom source in this catalytic transformation has been unquestionably demonstrated by 18O
labelling studies and a radical mechanistic pathway involving the oxidative formation of azidyl
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radicals is also designed. This environmentꢀfriendly catalytic oxidative protocol can transform
aldehyde to nitrile.
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Introduction
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Organic azides are the key structural motifs that have received a considerable attention due to
significant contribution in material science, natural products, and pharmaceuticals.1 They are
metabolically more active and wellꢀknown chemotherapeutic drugs that can be utilized as
prodrugs of primary amines.2 Azides are also distinctive moieties in various pharmacophores
such as azidocillin, azidothymidine (AZT), or the COXꢀ2 inhibitor and celecoxib derivative.3
Nevertheless, azidation of alkene is a viable option for the synthesis of productive organic azides
which are the irreplaceable origin of numerous azaꢀcontaining compounds such as amides,
amines imines, aziridines, and triazoles.4 Moreover, vicinal difunctionalization of olefinic double
bond including diazidation,5 azidocyanation,6 carboazidation,7 azidotrifluoromethylation,8
hydroxyꢀazidation,9 and ketoazidation,10 have been efficaciously used to contribute valuable
molecules. Thus, consequential efforts were made to develop new and highly effective
approaches in this field.
In 1995, Vankar et al. reported αꢀazidoketone from alkene upon its treatment with TMSN3 as
an azide source.11 This methodology, suffered from high uploading of metal salt (eqn 1, Scheme
1), impetus us to envision an environment friendly protocol from green chemistry point of view.
In 2013, catalytic azidation of silyl enol ether using a benziodoxoleꢀoriginated azide transfer
reagent has been demonstrated by Waser and coꢀworkers12 (eqn 2, Scheme 1). Nevertheless,
catalytic oxidative ketoazidation of unactivated alkenes using simple starting materials remains a
standing challenge. As of late, the progression of ecologically agreeable oxidation protocols
based on metal catalysts is highly fascinating. More specifically, the strategy involving metal
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catalysts liable for activating molecular oxygen is of ultimate interest.13 Therefore, as part of our
ongoing interest in oxidative catalysis and vicinal difunctionalization of alkenes,14 we reasoned
that an environmentally benign oxidative catalytic protocol for the ketoazidation of alkene is of
highly desired.
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Scheme 1
Approaches to synthesize ketoazide.
Results and Discussion
The initial investigation was intended to set an optimized condition. Styrene was chosen as
the model substrate for copper catalyzed oxidative difunctionalization with azide to inspect a
variety of parameters and the results are summarized in Table 1. In the presence of 10 mol%
Cu(OTf)2, the reaction of styrene (1a, 0.5 mmol) and TMSN3 (4 equiv) in 4 mL of MeCN was
performed for 12 hours in the presence of molecular oxygen. To our delight, 47% yield of the
desired ketoazide was obtained (Table 1, entry 1). All polar and nonꢀpolar solvents such as
toluene, DCM, and DMSO except MeCN were found ineffective to proceed the reaction (Table
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1, entries 2ꢀ4). Changing the catalysts from organometallic copper salts to inorganic copper salts
led to inferior results except for CuSO4 that responded well to give envisioned product 2a and
side product 3a (Table 1, entries 5ꢀ9). As Cu(OTf)2 proceeded the transformation selectively,
while CuSO4 salt gave a high yield. Therefore, we decided to optimize both of them (for more
detail see the Supporting Information). The reaction under argon was not effective that the subtle
condition resulting in oxidant is important (Table 1, entry 10). In aerobic reaction condition,
along with the desired product, a noticeable yield of aldehyde was also observed (Table 1, entry
11). Molecular oxygen which is a green and costꢀeffective oxidant plays a vital role in selective
conversion, makes this oxidative practice environmentꢀfriendly. However, attempt to utilize
another azide source such as NaN3 was not effective (Table 1, entry 12). The same salt of zinc
metal was failed to precede the product (Table 1, entry 13). Moreover, the amount of solvent,
catalyst, and azide source was optimized; as a result, 4.5 equivalent of TMSN3, 15 mol% of
Cu(OTf)2 and 4 mL of MeCN were found to be the best amount for this transformation (entries
14ꢀ19). Next, we studied the effect of time and temperature, the best outcome was observed at
room temperature for 18 hours, and while either lowering or raising of both time and temperature
was found the lower yield (Table 1, entries 20ꢀ22). To further improve the yield of desired
product different additives were also investigated (see Table S3 in the Supporting Information).
Thus, the optimized reaction conditions were TMSN3 (4.5 equivalent), and Cu(OTf)2 (15
mol %), in CH3CN at room temperature under a molecular oxygen atmosphere for 18 hours.
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Table 1
Optimization of reaction conditions.a
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Entry
Solvent
N3 source
(eq)
Catalyst
(10 mol %)
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(CH3CN)4·PF6
Cu(acac)2
CuSO4
Yield b (%),
ratio (2a:3a)c
47 (47 : 0)
0
1
2
MeCN
Toluene
DCM
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
NaN3
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3
0
4
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
0
5
22 (12 : 10)
26 (14 : 12)
86 (72 : 14)
15(15 : traces)
0
6
7
8
CuBr2
9
CuCN
10d
11e
12
13
14f
15g
16h
17i
18j
19k
20l
21m
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Zn(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
traces
71 (46 : 25)
traces
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
TMSN3
0
60 (60 : 0)
43 (43 : 0)
52 (52 : 0)
54 (54 : 0)
55 (55 : 0)
73(47 : 0)
80 (80 : 0)
15 (15 : 0)
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22n
MeCN
TMSN3
Cu(OTf)2
11 (11 : 0)
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a Conditions: 1a (0.5 mmol), N3 source (4 equivalent), and Catalyst (10 mol %) in solvent (4 mL)
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utilizing air as oxidant at rt for 12 h. Yield determined by HꢀNMR using mesitylene as an
internal standard. c 1HꢀNMR yield ratio of ketoazidation and aldehyde product. Rection under
d
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argon. e aerobic reaction. f 4.5 equivalent of TMSN3. g Used 3 equivalent of TMSN3. h Used 3 mL
of MeCN. i Used 5 mL of MeCN . j 5 mol% of the catalyst. k15 mol% of the catalyst. l Reaction
for 18 h. m at 50 °C for 18 h. n at 0 °C for 18.
Having the optimal reaction conditions in hand, we next evaluated the scope of this reaction
and the results are summarized in Table 2. The reaction of TMSN3 and variety of styrene
derivatives gave the desired product 2. The oxidative catalytic system was compatible with
halide, ester, ether, and alkyl group at the paraꢀ position. The presence of electron poor
substituents on styrene (2b-f) offered the desired product in good yields 56ꢀ79%. Electronꢀ
donating groups (2g-i) responded to this protocol to give moderate to good yields. The
compounds having electron rich groups with no resonance effect, only inductive effect, for
example, methyl and tꢀbutyl paraꢀsubstituted styrene (2h-i) usually improves the ketoazidation
outcome while the methoxy group (2g) on the same position inhibits the transformation due to
the robust resonance influence which showed that this oxidative catalytic transformation depends
upon on the electronic properties. Meanwhile, styrenes having substituents metaꢀ and orthoꢀ
position (1j-n) were also investigated under standard reaction conditions and found the desired
products in moderate to good yields. The lower response of orthoꢀsubstituted styrene to this
protocol showed a prominent role of the steric parameter. An even more significant desired
product was observed for disubstituted styrenes (2o-p). To extend further the generality of this
oxidative catalytic methodology, we also investigated various vinylic substituted styrenes. Alkyl
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and nitrile functional failed to deliver the desired product but phenyl substitution gave the
corresponding product only 45% which indicate that this protocol is specific for terminal alkenes
(2q-s). Furthermore, the scope of reaction with respect to fused ring system was also considered.
To our delight, this oxidative catalytic protocol was capable to transform the vinyl naphthalene
(2t) to the required product in good yield. On the other hand, no oxidative difunctionalization
was observed in case of aliphatic as well as heterocyclic olefins (see Figure S1 in the Supporting
Information).
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Table 2
Scope of ketoazidation of alkenes.a
2b,
2e,
2a,
2c,
4d,
2f,
80% (77%)
79% (75%)
62% (58%)
66% (60%)
56% (52%)
60% (57%)
2g,
2h,
2i,
2j,
2k,
2l,
30% (27%)
76% (73%)
70% (68%)
77% (73%)
60% (55%)
58% (51%)
2n,
2r,
2m,
2o,
2p,
2q,
52% (50%)
41% (35%)
58% (75%)
75% (70%)
traces
0%
2s,
2t,
45% (40%)
58% (53%)
a Conditions: 1a (0.5 mmol) TMSN3 (4.5 equivalent) and catalyst (15 mol %) in solvent (4 mL)
1
at rt for 18 h and yield determined by HꢀNMR using mesitylene as an internal standard while
isolated yield is in parenthesis.
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The substrate 1u underwent oxidative cleavage to 3a and 3u (eqn 4, scheme 2), while α,αꢀ
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diarylallylic alcohols substrate 1v was degraded to benzophenone15 in 52% yield (eqn 5, scheme
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Scheme 2 Oxidative cleavage of olefins.
The optimized reaction condition for method B was TMSN3 (4 equiv), and CuSO4 (10
mol %), in 4 mL of CH3CN at room temperature in an aerobic condition (see the supplementary
data). The scope of this methodology is depicted in graph 1. Both electron donating and electron
withdrawing derivatives of styrene responded well to give the respective ketoazides along with
oxidative cleaved benzaldehyde products in noticeable yield. The overall yields of reactions were
excellent.
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.
Graph 1 Scope of ketoazidation of alkenes utilizing method B.
As mentioned above, we envisioned an environment friendly protocol for difunctionalization
of the alkene. Interestingly, this protocol function well to transform aldehyde to nitrile function
(5a-b) in good yield (eqn 6ꢀ7 scheme 3).16 To evaluate further, benzaldehyde found ineffective to
this oxidative protocol (eqn 8, scheme 3) while phenyl acetaldehyde responded to system and
gave the nitrile product in 33% (eqn 9, scheme 3).
O
Cu(OTf)2 (15 mol%)
CN
CN
CH3CN (4 mL)
H
H
TMSN3
(4.5 eq)
(6)
(7)
+
O2, r.t., 18 h
O
O
5a, 75%
O
1w
1x
Cu(OTf)2 (15 mol%)
CH3CN (4 mL)
TMSN3
(4.5 eq)
+
+
O2, r.t., 18 h
5b, 68%
Cu(OTf)2 (15 mol%)
CH3CN (4 mL)
CN
O
TMSN3
(4.5 eq)
(8)
(9)
O2, r.t., 18 h
5c, 0%
3a
3y
Cu(OTf)2 (15 mol%)
CH3CN (4 mL)
H
CN
TMSN3
(4.5 eq)
+
O
O2, r.t., 18 h
5d,
33%
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Scheme 3 Approaches to synthesize nitrile from the aldehyde.
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8
To certify this assumption and acquire straightforward proof, chemical trapping of radicals
was performed by using wellꢀknown radicalꢀtrapping reagents TEMPO (2,2,6,6ꢀtetramethylꢀ1ꢀ
piperidinyloxy). Chemical trapping was carried out under standardized reaction conditions and
the desired difunctionalized product was achieved in 8% yield (eqn 11, scheme 4). This
observation was consistent with the hypothesis that the reaction likely involved freeꢀradical
intermediates and proceeded via a singleꢀelectronꢀtransfer (SET) process triggered by copperꢀII
oxidation. As reaction under argon, in the absence of oxidant, was incapable to transform alkenes
to give the difunctionalized ketoazide that declares a prominent role of molecular oxygen both as
oxidant and source of an oxygen atom (eqn 10, scheme 4). To further investigate the source of
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oxygen atom oxygen isotopic labelling using H2 O reactions were performed, both in the
presence and absence of molecular oxygen (eqn 12, scheme 4) and in either case no
ketoazidation was observed through gas chromatography mass spectrometry (GCꢀMS) analysis.
Scheme 4 Control experiments.
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On the basis of above experimental results, a plausible mechanistic pathway for the
difunctionalization of alkene is outlined to interpret the observed reactivates in Figure 1.
Oxidation of the azide anion by copper catalyst would proceed to the corresponding radical.
Plausibly, the addition of the ultimate radical to the styrene would yield the less hindered
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benzylic radical
A, which later trapped by molecular oxygen to produce peroxy radical B as
an intermediate on exposure to molecular oxygen that might undergo to ketoazide by two
pathways.10d,17 In pathway I, the radical intermediate
is formed from the intermediate B
C
by the abstraction of a nearby hydrogen
produce intermediate that ultimately yield ketoazide. To complete the catalytic cycle,
hydroxy radical reoxidized the copperꢀI back to copperꢀII. Whereas, in case of pathway II,
copperꢀI is oxidized into copperꢀII by peroxy radical intermediate to form an intermediate
that subsequently, oxidizes TMSN3 to generate azido radical and intermediate , which
, subsequently undergoes 1,2ꢀhydride shift to
D
B
E
F
finally, transformed to ketoazides.
Figure 1 Plausible mechanism of the reaction.
Conclusion
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In conclusion, we have reported a simple, mild and environment friendly, copper
catalyzed oxidative protocol for the difunctionalization of alkene via a radical pathway. A
wide variety of functional groups have been evaluated and found to be compatible to give
the desired difunctionalized products in moderate to good yields. This catalytic oxidative
protocol was capable to transform terminal aldehyde to nitrile. Research on the synthetic
utility of this oxidative protocol and more mechanistic details are presently being pursued in
our laboratories.
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Experimental Section
1
General information: The H and 13C NMR spectra were recorded in CDCl3 solution at 500
o
1
(125) MHz spectrometer at 20ꢀ25 C. H NMR spectra were reported in parts per million using
TMS (δ = 0.00 ppm) as an internal standard. 13C NMR spectra were reported in parts per million
using solvent CDCl3 (δ = 77.2 ppm) as an internal standard. Highꢀresolution mass spectra
(HRMS) electrospray ionization (ESI) was carried out on a UPLCꢀQꢀToF MS spectrometer. All
reagents were purchased from commercial suppliers and used as received. All experiments were
conducted in the atmosphere. Column chromatography and thinꢀlayer chromatography (TLC)
which was used to monitor the reactions were performed on silica gel. 1e, 1g, 1j, and 1m, were
prepared following the reported procedure.
General protocol for the preparation of alkene. 18
Step 1: 36 g of PPh3 and 100 mL of toluene (dried) were added into a 500 mL round bottom
flask, which produced a clean solution. Then 11 mL of CH3I was added into the above clean
solution at 0°C drop wisely. Then a condenser was put on the round bottom flask and the
solution was heated to reflux for 4 hr, which would produce white solid. The white solid was
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filtered and dried under the vacuum, which was used directly without further purification
(100% yield, white solid).
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Step 2: Triphenylphosphine methyliodide salt (2.5 g, 6.2 mmol) prepared in step 1 was
added into 30 mL dried Et2O, which resulted in a cloudy solution and KOtBu (1.57 g, 14
mmol) was added into the round bottom flask at 0°C, the color of which changed from white
into yellow immediately. The mixture remained stirring for 4 hr. Then 0.7 g (4.63 mmol) of
3ꢀnitrobenzaldehyde was added into the round bottom flask and kept reacting for 10 hr at
room temperature. After TLC analysis showed all the aldehyde was consumed completely,
the reaction was terminated and filtrated, washed by Et2O. Organic solvent was removed on
the rotaꢀvapor and the residue was purified by flash column chromatography (pure hexane) to
get the desired olefin product, which was confirmed by 1HꢀNMR (60% unoptimized yield).
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Method A: General procedure for synthesis of 2
In schlenk line with a magnetic stirring bar and Cu(OTf)2 (0.027 g, 0.15 mmol) were placed
in a two neck round bottom flask at room temperature and air was exchanged with argon
three times for 5ꢀ10 min. After that styrene (0.5 mmol) and TMSN3 (0.296 mL, 4.5 mmol)
were successively in the excess of argon. The reaction mixture was subjected to oxygen
balloon and stirred for 18 h. Subsequently, a saturated aqueous solution of sodium thiosulfate
(Na2S2O3) was added, and the mixture was diluted with water and extracted with
dichloromethane. The combined organic phases were dried over magnesium sulfate. and
concentrated in vacuo. The residue was chromatographed on a silica gel column to get
ketoazidation 2 and results are summerized in Table 2.
Method B: General procedure for synthesis of 2 and 3
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The styrene (0.5 mmol) was dissolved in 4 mL of CH3CN in the reaction tube. TMSN3
(0.263 mL, 4.0 mmol) and CuSO4 (0.008 g, 0.10 mmol) were added consecutively. The
reaction mixture was stirred at room temperature for 9 hours. Subsequently, A saturated
aqueous solution of sodium thiosulfate (Na2S2O3) was added, and the mixture was diluted
with water and extracted with dichloromethane. The combined organic phases were dried
over magnesium sulfate. and concentrated in vacuo. The residue was chromatographed on a
silica gel column to give ketoazidation 2 and 3 and results are depicited in the graph 1.
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1H- and 13C-NMR analytical data
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4-cyanostyrene (1e)19 Brown liquid, 257 mg, 43% yield. H NMR (500 MHz, CDCl3): δ
7.61 (2H, d, J = 8.0 Hz, ArH), 7.48 (2H, d, J = 8.0 Hz, ArH), 6.73 (1H, dd, J = 17.5, 11 Hz,
CH), 5.88 (1H, d, J = 17.5 Hz, CH), 5.45 (1H, d, J = 11 Hz, CH).
4-methoxysyrene (1g)20 colorless liquid, 280 mg, 45% yield. 1H NMR (500 MHz, CDCl3): δ
7.33 (2H, d, J = 8.5 Hz, ArH), 6.84 (2H, d, J = 8.5 Hz, ArH), 6.65 (1H, dd, J = 17.5, 10.5 Hz,
CH), 5.60 (1H, d, J = 17.5 Hz, CH), 5.11 (1H, d, J = 11.0 Hz, CH), 3.78 (3H, s, CH3).
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3-vinyl styrene (1j)21 colorless liquid, 362 mg, 60% yield. H NMR (500 MHz, CDCl3): δ
7.43 (1H, s, ArH), 7.31ꢀ7.28 (3H, m, ArH), 6.72 (2H, dd, J = 17.5, 11.0 Hz, ArH), 5.77 (2H,
d, J = 17.5 Hz, ArH), 5.26 (3H, d, J = 11.0 Hz, ArH).
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3-nitro styrene (1m)20 Brown liquid, 366 mg, 53% yield. H NMR (500 MHz, CDCl3): δ
8.26 (1H, t, J = 2 Hz, ArH), 8.12ꢀ8.09 (1H, m, ArH), 7.71 (1H, d, J = 8.0, Hz, ArH), 7.50
(1H, t, J = 8 Hz, ArH), 6.77 (1H, dd, J = 17.5, 10.5 Hz, CH ) 5.90 (1H, d, J = 18 Hz, CH),
5.45 (1H, d, J = 11 Hz, CH).
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2-Azido-1-phenylethanone (2a)22 Yellow oil, 60 mg, 77% yield. H NMR (500 MHz,
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CDCl3): δ 7.91 (2H, d, J = 7.5 Hz, ArH), 7.63 (1H, t, J = 7.5 Hz, ArH), 7.50 (2H, t, J = 8 Hz,
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ArH), 4.57 (2H, s, CH2); C NMR (125 MHz, CDCl3): δ 193.4, 134.6, 134.3 129.2, 128.1,
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55.1.
2-Azido-1-(4-fluorophenyl)ethanone (2b)23 White solid, 67.2 mg, 75% yield. 1H NMR (500
MHz, CDCl3): δ 7.97ꢀ7.93 (2H, m, ArH), 7.18 (2H, t, J = 8.5 Hz, ArH), 4.55 (2H, s, CH2).
2-Azido-1-(4-chlorophenyl)ethanone (2c)23 White solid, 59.5 mg, 58% yield. 1H NMR (500
MHz, CDCl3): δ 7.85 (2H, d, J = 8.5 Hz, ArH), 7.48 (2H, d, J = 9.0 Hz, ArH), 4.54 (2H, s,
CH2).
2-Azido-1-(4-bromophenyl)ethanone (2d)24 Off white solid, 71.7 mg, 60% yield. H NMR
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(500 MHz, CDCl3): δ 7.78 (2H, d, J = 8.5 Hz, ArH), 7.65 (2H, d, J = 8.5 Hz, ArH), 4.53 (2H,
s, CH2); 13C NMR (125 MHz, CDCl3): δ 192.5, 133.2, 132.5, 129.6, 129.5, 55.0.
2-Azido-1-(4-cyanophenyl)ethanone (2e)25 Light yellow solid, 48.4 mg, 52% yield.1H
NMR (500 MHz, CDCl3): δ 8.02 (2H, d, J = 8.5 Hz, ArH), 7.82 (2H, d, J = 8.5 Hz, ArH),
4.58 (2H, s, CH2).
2-Azido-1-(4-acetoxyphenyl)ethanone (2f)10d White solid,62.4 mg, 57% yield. H NMR
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(500 MHz, CDCl3): δ 7.94 (2H, d, J = 8.5 Hz, ArH), 7.24 (2H, d, J = 8.5 Hz, ArH), 4.54 (2H,
s, CH2), 2.33 (3H, s, CH3).
2-Azido-1-(4-methoxyphenyl)ethanone (2g)10d,23,26 White solid, 25.8 mg, 27% yield. H
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NMR (500 MHz, CDCl3): δ 7.89 (2H, d, J = 8.5 Hz, ArH), 6.96 (2H, d, J = 8.5 Hz, ArH),
4.51 (2H, s, CH2), 3.88 (3H, s, OCH3).
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2-Azido-1-(4-methylphenyl)ethanone (2h)26 Off white solid, 63.9 mg, 73% yield.1H NMR
(500 MHz, CDCl3): δ 7.80 (2H, d, J = 8.0 Hz, ArH), 7.29 (2H, d, J = 8.0 Hz, ArH), 4.53 (2H,
s, CH2), 2.43 (3H, s, CH3).
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2-Azido-1-(4-(tert-butyl)phenyl)ethanone (2i)24 White solid, 73.8 mg, 68% yield. H NMR
(500 MHz, CDCl3): δ 7.84 (2H, d, J = 8.5 Hz, ArH); 7.50 (2H, d, J = 8.5 Hz, ArH), 4.53 (2H,
s, CH2), 1.34 (9H, s, CH3).
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2-Azido-1-(3-chlorophenyl)ethanone (2k).27 Brown solid, 53.6 mg, 55% yield. H NMR
(500 MHz, CDCl3): δ 7.89 (1H, t, J = 1.5 Hz, ArH), 7.78 (1H, d, J = 8 Hz, ArH), 7.60 (1H,
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dd, J = 8.0, 1.0 Hz, ArH), 7.46 (1H, t, J =8 Hz, ArH), 4.54 (2H, s, CH2); C NMR (125
MHz, CDCl3): δ 192.3, 136.1, 135.6, 134.2, 130.5, 128.3, 126.2, 55.1.
2-Azido-1-(3-bromophenyl)ethanone (2l).28 Light yellow solid, 61.2 mg, 51% yield. H
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NMR (500 MHz, CDCl3): δ 8.03 (1H, s, ArH), 7.78 (1H, d, J = 4 Hz, ArH), 7.74 (1H, s,
ArH), 7.39 (1H, s, ArH), 4.55 (2H, s, CH2).
2-Azido-1-(3-nitrophenyl)ethanone (2m).29 Yellow crystals, 51.5 mg, 50% yield. 1H NMR
(500 MHz, CDCl3): δ 8.73 (1H, s, ArH), 8.49 (1H, d, J = 7.5 Hz, ArH ), 8.29 (1H, d, J = 7.5 Hz,
ArH ), 7.78 (1H, t, J = 8 Hz, ArH ), 4.69 (2H, s, CH2). 13C NMR (125 MHz, CDCl3): δ 191.7,
148.6, 135.6, 133.7, 130.5, 128.4, 122.9, 55.2.
2-Azido-1-(2-bromophenyl)ethanone (2n).29 Pale yellow solid, 41.8 mg, 35% yield. H
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NMR (500 MHz, CDCl3): δ 7.64 (1H, d, J = 7.5 Hz, ArH). 7.46ꢀ7.40 (1H, m, ArH), 7.37
(1H, td, J = 7.5, 2 Hz, ArH), 4.48 (2H, s, CH2).
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2-Azido-1-(1,2-diphenyl)ethanone (2s).30 White solid, 47.4 mg, 40% yield. H NMR (500
MHz, CDCl3): δ 7.88 (2H, d, J = 7.5 Hz, ArH), 7.51 (1H, t, J = 7.5 Hz, ArH), 7.42ꢀ7.35 (7H,
m, ArH), 5.72 (1H, s, CH).
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2-Azido-1-(naphthalen-2-yl)ethanone (2u).24 White solid, 56 mg, 53% yield. 1H NMR (500
MHz, CDCl3): δ 8.39(1H, s, ArH), 7.97ꢀ7.87 (4H, m, ArH), 7.64 (2H, t, J = 8 Hz, ArH), 7.58
(1H, t, J = 8.0 Hz, ArH), 4.70 (2H, s, CH2).
Benzaldehyde (3a).31 Yellow oil, 10.6 mg, 20% yield. 1H NMR (500 MHz, CDCl3): δ 10.01
(1H s, CHO), 7.87 (2H, dd, J = 7.5, 1.5 Hz, ArH), 7.64ꢀ7.60 (1H, m, ArH) 7.52 (2H, t, J =
8.0 Hz, ArH).
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4-cyanobenzaldehyde (3e).32 Off white solid, 11.8 mg, 18% yield. H NMR (500 MHz,
CDCl3): δ 10.10 (1H s, CHO), 8.00 (2H, d, J = 23.5 Hz, ArH), 7.86 (2H, d, J = 8.5 Hz, ArH).
4-acetoxybenzaldehyde (3f)33 White solid, 22.2 mg, 27% yield. 1H NMR (500 MHz, CDCl3): δ
9.99 (1H s, CHO), 7.92 (2H, d, J = 8.5 Hz, ArH), 7.28 (2H, d, J = 8.0 Hz, ArH), 2.33 (3H, s,
CH3).
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4-methoxybenzaldehyde (3g).31b White solid, 14.9 mg, 22% yield. H NMR (500 MHz,
CDCl3): δ 9.89 (1H s, CHO), 7.85 (2H, d, J = 8.5 Hz, ArH), 7.01 (2H, d, J = 9.0 Hz, ArH),
3.90 (3H, s, CH3).
4-ter. butylbenzaldehyde (3i).34 White solid, 14.6 mg, 18% yield.1H NMR (500 MHz,
CDCl3): δ 9.98 (1H s, CHO), 7.82 (2H, d, J = 8.5 Hz, ArH), 7.55 (2H, d, J = 8.0 Hz, ArH),
1.35 (9H, s, CH3).
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3-nitrobenzaldehyde (3m).31c Off white solid, 17.4 mg, 23% yield. H NMR (500 MHz,
CDCl3): δ 10.14 (1H s, CHO), 8.73 (1H, s, ArH), 8.50 (1H, dd, J = 8.0, 1.0 Hz, ArH), 8.25
(1H, d, J = 7.5 Hz, CH9), 7.79 (1H, t, J = 8.0 Hz, ArH).
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Benzophenone (4a).31a White solid, 45.5 mg, 50% yield. 1H NMR (500 MHz, CDCl3): δ 7.8
(2H m, CH), 7.58 (4H, t, J = 7.5 Hz, ArH), 7.48 (4H, t, J = 7.5 Hz, ArH).
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3-(2-Methoxyphenyl)-acrylonitrile (5a).35 Brown liquid, 55.7 mg, 70% yield. H NMR
(500 MHz, CDCl3): δ 7.62 (1H, d, J = 16.5 Hz, CH), 7.41ꢀ7.36 (2H, m, ArH), 6.97 (2H, t, J =
7.5 Hz, ArH), 6.93 (2H, t, d = 8.0 Hz, ArH), 6.05 (1H, d, J = 16.5 Hz, ArH), 3.89 (3H, s,
CH3). 13C NMR (125 MHz, CDCl3): δ 158.4, 146.6, 132.5, 129.1, 122.7, 121.0, 119.2, 111.5,
97.10, 55.7.
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phenylacrylonitrile (5b).31a Brown liquid, 41.9 mg, 65% yield. H NMR (500 MHz,
CDCl3): δ 7.45ꢀ7.25 (6H, m, ArH), 5.88 (1H, d, J = 17 Hz, CH).
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phenylacetonitrile (5d).36 Colourles liquid, 17.6 mg, 30% yield. H NMR (500 MHz,
CDCl3): δ 7.38ꢀ7.35 (2H, m, ArH), 7.32 (3H, t, J = 5 Hz, ArH), 3.73 (2H, s, CH2).
1H- and 13C-NMR Spectra for new compounds
2-Azido-1-(3-vinylphenyl)ethanone (2j): white solid, 68.3 mg, 73% yield, mp = 40ꢀ42 °C
1H NMR (500 MHz, CDCl3): δ 7.90 (1H, s, ArH), 7.74 (1H, d, J = 8.0 Hz, ArH), 7.64 (1H, d,
J = 8.0 Hz, ArH), 7.44 (1H, t, J = 8.0 Hz, ArH), 6.74 (1H, dd, J = 17.5, 11.0 Hz, ArH), 5.83
(1H, d, J = 17.5 Hz, ArH), 5.36 (1H, d, J = 10.5 Hz, ArH), 4.55 (2H, s, CH2); 13C NMR (125
MHz, CDCl3): δ 193.3, 138.5, 135.7, 134.8, 131.6, 129.2, 127.1, 125.7, 115.9, 55.0. HRMS
(m/z) calculated for C10H9N3ONa+ : 210.0643, found: 210.0636.
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2-Azido-1-(5-bromo-2-fluorophenyl)ethanone (2o): Yellow crystals, 70.7 mg, 55% yield,
mp = 62ꢀ64.2 °C. 1H NMR (500 MHz, CDCl3): δ 8.23(1H, d, J = 8.5 Hz, ArH ), 7.80 (1H, td,
J = 7.5, 0.5 Hz, ArH ), 7.71ꢀ7.68 (1H, m, ArH ), 7.43 (1H, dd, J = 7.5, 1 Hz, ArH ), 4.32 (2H,
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s, CH2); C NMR (125 MHz, CDCl3): δ 190.5 (1C, d, J = 5.37 Hz, CO), 161.3 (1C, d, J =
253.37 Hz, ArC), 138.6 (1C, d, J = 9.12 Hz, ArC), 133.6 (1H, d, J = 3.12 Hz, ArC), 124.2
(1C, d, J = 15.75 Hz, ArC), 118.8 (1H, d, J = 25.25 Hz, ArC), 118.1 (1C, d, J = 3.0 Hz, ArC),
58.8 (1C, d, J = 12.6 Hz, CH2). HRMS (m/z) calculated for C8H5BrFN3ONa+ : 279.9498,
found: 279.9486.
2-Azido-1-(3-bromo-4-fluorophenyl)ethanone (2p): White solid. 89.9 mg, 70% yield mp
= 71.2ꢀ73.8 °C. 1H NMR (500 MHz, CDCl3): δ 8.14 (1H, dd, J = 6.5, 2 Hz, ArH), 7.89ꢀ7.86
(1H, m, ArH), 7.25 (1H, t, J = 8.5 Hz, ArH), 4.56 (2H, s, CH2).13C NMR (125 MHz,
CDCl3): δ 190.9 (1C, s, CO), 162.6 (1C, d, J = 255.62 Hz, ArC), 134.0 (1C, d, J = 1.5 Hz,
ArC), 131.9 (1C, d, J = 3.62 Hz, ArC), 129.3 (1C, d, J = 8.62 Hz, ArC), 117.2 (1C, d, J =
22.87 Hz, ArC), 110.3 (1C, d, J = 21.62 Hz, ArC), 54.8 (1C, s, CH2). HRMS (m/z)
calculated for C8H5BrFN3ONa+ : 279.9498, found: 279.9484.
Supporting Information.
Experimental procedures, and 1H NMR and 13C NMR Spectra for compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgments
We gratefully acknowledge funding from the National Natural Science Foundation of
China (no. 21372265).
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AzidoꢀReductase in Human Liver Microsomes: Activation by Ethacrynic Acid, Dipyridamole,
and Indomethacin and Inhibition by Human Immunodeficiency Virus Protease Inhibitors.
Antimicrob. Agents Chemother. 1998, 42, 1654ꢀ1658; (c) Koudriakova, T.; Manouilov, K. K.;
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Schinazi, R. F.; Chu, C. K. In Vitro and in Vivo Evaluation of 6ꢀAzidoꢀ2',3'ꢀdideoxyꢀ2'ꢀfluoroꢀβꢀ
Dꢀarabinofuranosylpurine and N6ꢀMethylꢀ2',3'ꢀdideoxyꢀ2'ꢀfluoroꢀβꢀDꢀarabinofuranosyladenine
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