1,2-Hydride Migration in Dialkyl α-Diazophosphonates Catalyzed by [Cu(MeCN)4]PF6: A Novel Approach to β-Amino (E)-Enylphosphonates

Article abstract of DOI:10.1055/s-0035-1560373

The regiospecific and stereoselective 1,2-migration reaction of dialkyl α-diazophosphonates for the synthesis of β-amino (E)-enylphosphonates is developed utilizing tetrakis(acetonitrile)copper(I) hexafluorophosphate [Cu(MeCN)₄PF₆] as the catalyst and N,N-dimethylformamide as an additive. A possible mechanism for the 1,2-migration reaction involving a metal carbene is presented. An investigation on the E/Z isomer selectivity of this process demonstrates that steric factors play an important role on the outcome. This process provides a straightforward access to β-amino (E)-enylphosphonates in moderate to good yields.

Full text of DOI:10.1055/s-0035-1560373

SYNTHESIS
0
0
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9
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7
8
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1
1
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7
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2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, 448–454
paper
448
H. Ge et al.
Paper
Synthesis
1,2-Hydride Migration in Dialkyl α-Diazophosphonates Catalyzed
by [Cu(MeCN)4]PF6: A Novel Approach to β-Amino (E)-Enylphos-
phonates
Haihong Gea
Shuang Liua
Yan Caia
Yuchao Suna
Zhiwei Miao*a,b
R1
R1
O
R1
O
O
R2
R2
R2
O
Cu(MeCN)4PF6 (5 mol%)
DMF (20 mol%)
N
O
P
OR3
N
N
H
+
OR3
OR3
P
OR3
CH2Cl2, 25 °C, 3 h
O
P
O
O
N2
H
O
R3O
OR3
E/Z ratio up to 97:3
overall yield = 54–94%
a State Key Laboratory of Elemento-Organic Chemistry,
Institute of Elemento-Organic Chemistry, Nankai University,
Weijin Road 94, Tianjin 300071, P. R. of China
miaozhiwei@nankai.edu.cn
b Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Weijin Road 94, Tianjin 300071, P. R.
of China
Received: 22.07.2015
Accepted after revision: 16.10.2015
Published online: 13.11.2015
tions.6 In 2013, we reported novel α-diazophosphonyl com-
pounds prepared from acids or a natural amino acid. The α-
diazophosphonates underwent C–H functionalization/O–H
insertion reactions with alcohols to afford β-alkoxy-substi-
tuted β-aminophosphonate derivatives (Scheme 1, eq. 1).7
As a natural extension of the α-diazophosphonate hydride
migration reaction, we have developed a stereoselective
tetrakis(acetonitrile)copper(I) hexafluorophosphate/iodine
[Cu(MeCN)4PF6/I2] catalyzed β,γ-dihydrogen shift reaction
for the synthesis of (Z)-β-alkenyl-substituted β-aminophos-
phonates (Scheme 1, eq. 2).8
DOI: 10.1055/s-0035-1560373; Art ID: ss-2015-h0450-op
Abstract The regiospecific and stereoselective 1,2-migration reaction
of dialkyl α-diazophosphonates for the synthesis of β-amino (E)-enyl-
phosphonates is developed utilizing tetrakis(acetonitrile)copper(I)
hexafluorophosphate [Cu(MeCN)4PF6] as the catalyst and N,N-dimethyl-
formamide as an additive. A possible mechanism for the 1,2-migration
reaction involving a metal carbene is presented. An investigation on the
E/Z isomer selectivity of this process demonstrates that steric factors
play an important role on the outcome. This process provides a
straightforward access to β-amino (E)-enylphosphonates in moderate to
good yields.
β-Aminophosphonates are the phosphorus analogues of
β-amino acids. As a result of their increased resistance to
enzymatic hydrolysis, phosphonates and other phosphonic
acid derivatives are often employed in medicinal chemistry
as isosteres of carboxylates9 and phosphates.10 β-Amino vi-
nylphosphonates can be regarded as isosteres of β-amino-
phosphonates, and significant efforts have been devoted to-
ward the development of efficient procedures for obtaining
these types of compounds, including methods that employ
C–C, C–N, and C–P bond formation.10 For example, Gevorgyan
and co-workers reported the synthesis of β-enaminophos-
phonates from the corresponding α-diazoethylphospho-
nates via an exclusive 1,2-aryl shift in the presence of silver
tetrafluoroborate AgBF4.10c Recently, we developed a regio-
specific and stereoselective 1,2-migration reaction for the
synthesis of β-amino (Z)-enylphosphonates catalyzed by
silver triflate (Scheme 1, eq. 3).11 In continuation of our in-
terest in the chemistry of aminophosphorus derivatives,12
we report herein the first example of the conversion of dial-
kyl α-diazophosphonates into β-amino (E)-enylphospho-
nates in a regiospecific and highly stereoselective manner
(Scheme 1, eq. 4).
Key words diazo compounds, α-diazophosphonates, 1,2-hydride mi-
gration, tetrakis(acetonitrile)copper(I) hexafluorophosphate, β-amino
(E)-enylphosphonates
Cyclopropanation, insertion of X–H (X = C, O, S, N, etc.),1
and ylide formation2 are frequently encountered in the
transition-metal-complex-catalyzed decomposition of α-
diazocarbonyl compounds.3 In addition to these typical
transformations, there are several other types of reactions
in diazo carbonyl chemistry. 1,2-Migration is one of the
fundamental reactions in transition-metal-catalyzed reac-
tions of α-diazocarbonyl compounds.4 Among these 1,2-mi-
gration reactions, 1,2-hydride migration is generally pre-
dominant. In some cases, 1,2-hydride migrations find use-
ful applications in organic synthesis. For example, Taber
and co-workers have shown that 1,2-hydride migration
promoted by rhodium(II) trifluoroacetate dimer provides
an efficient route to (Z)-α,β-unsaturated esters in good
yields.5
α-Diazocarbonyl compounds have attracted significant
attention due to their diverse reactivity. In contrast to α-di-
azocarbonyl compounds, α-diazophosphonyl compounds
have not been studied systematically in metal carbene reac-
α-Diazophosphonyl compound 1a,7 derived from an
amino acid, was the first substrate studied in order to ex-
amine the effect of different catalysts on the migration re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 448–454

449
H. Ge et al.
Paper
Synthesis
previous work:
O
R
O
O
Cu(MeCN)4PF6, I2
CH2Cl2
O
O
N
(1)
(2)
N
N
O
HO
R
P
OEt
P
N2
R1
O
O
OEt
P
OEt
OEt
O
EtO OEt
O
O
R1
O
R2
R2
O
OR3
OR3
Cu(MeCN)4PF6, I2
CH2Cl2
O
P
OR3
β,γ-dihydrogen shift product
Z isomer only
N
N
OR3
P
N2
R1
O
O
O
R1
R2
O
R2
AgOTf, NaBARF
MTBE
O
P
OR3
N
O
N
OR3
(3)
H
O
N2
P
O
OR3
R3O
this work:
R1
O
R2
R1
O
N
O
R2
O
Cu(MeCN)4PF6, DMF
CH2Cl2
O
P
OR3
N
O
regiospecific and
highly stereoselective
(4)
OR3
P
OR3
N2
OR3
H
Scheme 1 Previous and current work on the synthesis of β-aminophosphonates
action. The results are summarized in Table 1. A variety of
Lewis acids such as CuOTf, Rh2(OAc)4, Hg(OTf)2, AgOTf,
Cu(MeCN)4PF6, and so on, have been reported to catalyze
the decomposition of diazocarbonyl compounds.13 Our
studies revealed that CuOTf and Rh2(OAc)4 could only de-
compose 1a in low yields to afford products 2a and 3a with
poor stereoselectivities (Table 1, entries 1 and 2). Hg(OTf)2
did not decompose 1a at all and the starting material was
recovered (Table 1, entry 3). AgOTf promoted the reaction
smoothly to afford mainly (Z)-α,β-unsaturated phospho-
nate 3a in high yield (Table 1, entry 4). To our delight
Cu(MeCN)4PF6 catalyzed the decomposition of 1a with ex-
cellent stereoselectivity (E/Z = 93:7) (Table 1, entry 5), but
in low yield. This result encouraged us to choose
Cu(MeCN)4PF6 as the catalyst for further optimization of the
reaction conditions. To improve the reactivity and stereose-
lectivity, the effects of different additives and solvents were
investigated.
Initially, different additives were evaluated in order to
study the stereoselectivity of this transformation.1k,m,14 As
shown in Table 1, both the efficiency and stereoselectivity
of this reaction was affected dramatically by the additive. In
the presence of Cu(MeCN)4PF6 as the catalyst (5 mol%) and
phenylacetylene (20 mol%) as the additive in dichlorometh-
ane, the reaction proceeded with an increased E/Z ratio of
92:8 and a yield of 61% (Table 1, entry 6). After screening
N,N-dimethylformamide as an additive (E/Z = 94:6, yield:
63%), it was found that benzamide, acetamide and acetoni-
trile did not give superior results in terms of reactivity and
stereoselectivity (Table 1, entries 7–10).
With Cu(MeCN)4PF6 as the best catalyst combined with
N,N-dimethylformamide as additive (Table 1, entry 7), we
next carried out the reaction in different solvents. Among
the various solvents tested, diethyl ether, toluene, tetrahy-
drofuran and acetone afforded lower yields of the expected
products 2a and 3a with moderate stereoselectivities (Table
1, entries 11–14). The most suitable solvent was found to be
dichloromethane and diethyl (E)-[2-(1,3-dioxoisoindolin-2-
yl)prop-1-en-1-yl]phosphonate (2a) was obtained in good
yield and high stereoselectivity (Table 1, entry 7). Further
optimization of the reaction conditions revealed that a de-
crease in the loading of the Cu(MeCN)4PF6 catalyst to 3
mol% and N,N-dimethylformamide to 10 mol% led to a de-
crease in the yield and stereoselectivity (Table 1, entry 15).
A similar result was obtained when the reaction was per-
formed in dichloromethane with an increased catalyst load-
ing (Table 1, entry 16). Thus, the optimum reaction condi-
tions for this transformation were as follows: α-diazophos-
phonate 1a (0.28 mmol), Cu(MeCN)4PF6 (5 mol%) as the
catalyst N,N-dimethylformamide (20 mol%) as the additive,
dichloromethane (4 mL) as the solvent, and room tempera-
ture conditions. The two stereoisomers 2a and 3a could be
separated by column chromatography.
Based on the above optimization efforts, we next inves-
tigated the substrate scope of this reaction (Table 2). The
impact of different substituent groups on the β-position of
the dialkyl α-diazophosphonates 1 was evaluated. The reac-
tions of α-diazophosphonates 1a–e, with different substitu-
ents on the β-position (methyl, isopropyl, isobutyl, benzyl,
and 2-propylisoindoline-1,3-dione), afforded moderate
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 448–454

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H. Ge et al.
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Synthesis
(1b) to high yields (1a,c–e) of the β-amino-α,β-unsaturated
phosphonates 2a–e in favor of the E isomer (Table 2, entries
1–5).
To assess the effects of the substrates on the product se-
lectivity, we set out to study reactions of a series of dialkyl
α-diazophosphonates 1j–n under the optimized catalytic
conditions. The size of the R3 group on the α-diazophos-
phonate had no significant influence on the ability of the
substrate to participate in the migration process. When the
bulk of the R3 group was increased from methyl to butyl,
the E/Z isomeric products 2 and 3 were obtained in moder-
ate to good yields (Table 2, entries 10–14).
A possible mechanism for the reaction is shown in
Scheme 2.15 The α-diazophosphonate 1 initially forms a
metal–carbene complex A with Cu(MeCN)4PF6 and N,N-di-
methylformamide. The metal carbene is a resonance hybrid
of a formal metal carbene A and a metal-stabilized carboca-
tion B, which together describe the reactivity of the inter-
mediate. It has been suggested that in this metal–carbene
intermediate, the carbon attached to the metal has a partial
positive charge.16 The E/Z stereoselectivity of the β-amino-
α,β-unsaturated phosphonates implies that conformational
factors may play a role in the migration process. For the mi-
gration to occur, it is necessary that the migrating bond
It was found that the E/Z isomer selectivity of products
2 and 3 was influenced by the size of the R1 and R2 groups
on the α-diazophosphonates 1. With increasing bulk of the
R1 group, the E/Z ratios of 2 and 3 ranged from 94:6 to
67:33 with moderate yields being obtained (Table 2, entries
1–5). In cases where the substituents on the β-position of
the dialkyl α-diazophosphonates 1 were methylsulfanyl-
ethyl (1f) or 4-acetylphenyl (1g) groups, the reactions did
not proceed, probably due to the fact that the sulfur atom
and acetate group might coordinate with copper(I) and hin-
der the reaction (Table 2, entries 6 and 7). Furthermore, the
α-diazophosphonyl compounds 1h and 1i, derived from the
unnatural amino acids 2-aminobutanoic acid and 2-amino-
2-phenylacetic acid, respectively, also underwent the de-
sired transformation to give the corresponding products in
moderate stereoselectivities (Table 2, entries 8 and 9).
Table 1 Optimization of the Reaction Conditionsa
O
O
O
catalyst (5 mol%)
additive (20 mol%)
O
O
N
N
N
H
O
+
P
OEt
solvent, r.t., 3 h
P
OEt
O
H
O
P
N2
O
OEt
OEt
EtO
OEt
1a
2a
3a
Entry
Catalyst
Solvent
Additive
E/Z ratio (2a:3a)b
Yield (%)c
1
2
CuOTf
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
–
–
–
–
–
37:63
77:23
–
11
15
NR
84
38
61
63
63
36
51
52
41
35
53
53
55
Rh2(OAc)4
Hg(OTf)2
AgOTf
3
4
27:73
93:7
5
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
Cu(MeCN)4PF6
6
phenylacetylene
DMF
92:8
7
94:6
8
PhCONH2
MeCONH2
MeCN
64:36
75:25
95:5
9
10
11
12
13
14
15d
16e
DMF
86:14
67:33
88:12
80:20
95:5
toluene
THF
DMF
DMF
acetone
CH2Cl2
CH2Cl2
DMF
DMF
DMF
94:6
a Unless otherwise noted, all the reactions were carried out using α-diazophosphonate 1a (0.28 mmol, 1 equiv), solvent (2 mL), catalyst (5 mol%), additive (20
mol% in 2 mL of solvent), 25 °C, 3 h (before addition: 1.5 h; after addition: 1.5 h).
b The product ratio was determined by 31P NMR spectroscopy of the crude product.
c Overall yield of the mixture of 2a and 3a after silica gel chromatography. NR = no reaction.
d Cu(MeCN)4PF6 (3 mol%) and DMF (10 mol%) were used.
e Cu(MeCN)4PF6 (10 mol%) and DMF (40 mol%) were used.
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Synthesis
Table 2 Scope of the Reactiona
R1
R1
O
O
R1
O
N
O
R2
R2
O
R2
Cu(MeCN)4PF6 (5 mol%)
DMF (20 mol%)
N
N
+
H
O
P
OR3
P
OR3
OR3
OR3
O
CH2Cl2, r.t.
P
O
O
H
N2
R3O
OR3
1
2
3
Entry
Substrate
R1
R2
R3
Et
E/Z ratio (2/3)b
Yield (%)c
1
2
1a
1b
1c
1d
1e
1f
H
H
94:6
67:33
80:20
78:22
80:20
–
63
76
54
75
80
–
Me
i-Pr
Ph
Me
H
Et
3
Et
4
H
Et
5
(CH2)3NPhth
H
Et
6
CH2SMe
H
Et
7
1g
1h
1i
p-AcOC6H4
H
Et
–
–
8
Me
Ph
H
H
Et
85:15
75:25
97:3
82:18
96:4
86:14
86:14
56
80
84
94
81
60
73
9
Et
10
11
12
13
14
1j
H
H
H
H
H
Me
i-Pr
n-Bu
i-Pr
n-Bu
1k
1l
H
H
1m
1n
Ph
Ph
a Reaction conditions: α-diazophosphonate 1 (0.28 mmol), CH2Cl2 (2 mL), Cu(MeCN)4PF6 (5 mol%), DMF (20 mol% in 2 mL of CH2Cl2), 25 °C, 3 h (before addition:
1.5 h; after addition: 1.5 h).
b The product ratio was determined by 31P NMR spectroscopy of the crude product and the configuration of 2 was assigned as E from the 1H–1H NOESY spec-
trum.
c Overall yield of the mixture of 2 and 3 after silica gel chromatography.
needs to be parallel to the p orbital of the carbene carbon in
the transition states.17 Thus, the β-hydrogen migration is
proposed to occur via transition state B′ with trans elimina-
tion of the copper catalyst leading to the observed E-isomer.
Conformation B′′ is likely to be disfavored because of steric
hindrance between the phosphonate and phthalimide
groups. The additive, N,N-dimethylformamide, used in the
reaction may stabilize the transition-metal-catalyst com-
plex and serves to increase the overall yield.
In conclusion, we have developed a new and convenient
synthesis of β-amino (E)-enylphosphonates from amino
acid derived dialkylphosphonates with good control over
the regio- and stereochemistry. An investigation of the fac-
tors influencing the E/Z isomer selectivity revealed that ste-
ric factors play an important role in affecting the stereo-
chemical outcome of this carbene reaction. Efforts are un-
derway to further develop this novel synthetic process in
our laboratory.
terials were obtained from commercial sources, and used as pur-
chased without dehydration. Flash column chromatography was per-
formed on silica gel (particle size 10–40 μm, Ocean Chemical Factory
of Qingdao, China). Nitrogen gas (99.999%) was purchased from Boc
Gas Inc. 1H NMR, 13C NMR and 31P NMR spectra were recorded in
CDCl3 using a Bruker 400 MHz spectrometer. TMS served as the inter-
nal standard (δ = 0) for 1H NMR and 13C NMR, and H3PO4 was em-
ployed as the internal standard (δ = 0) for 31P NMR. Mass spectrome-
try (ESI) was performed using an LCQ advantage spectrometer.
β-Amino (E/Z)-Enylphosphonates 2 and 3; General Procedure
Cu(MeCN)4PF6 (0.014 mmol) and DMF (0.056 mmol), in an oven-dried
Schlenk tube, were dissolved in CH2Cl2 (2 mL) under an N2 atm, and
the resulting solution was stirred for 10 min at 25 °C. Dialkyl α-diazo-
phosphonate 1 (0.28 mmol) was diluted with CH2Cl2 (2 mL) and, using
a gastight syringe with the aid of a syringe pump, was transferred
dropwise to the reaction mixture over a period of 1.5 h. After the ad-
dition was complete, the mixture was stirred for another 1.5 h at
25 °C. The solvent was then removed under reduced pressure and the
crude residue was purified by silica gel chromatography (CH2Cl2–
EtOAc, 15:1) to afford the corresponding products 2 and 3.
Diethyl (E)-[2-(1,3-Dioxoisoindolin-2-yl)prop-1-en-1-yl]phospho-
nate (2a)
All reactions and manipulations were performed using standard
Schlenk line techniques. Solvents were dried and distilled prior to use
according to standard methods.18 Unless otherwise indicated, all ma-
Yield: 0.057 g (63%); light yellow oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 448–454

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H. Ge et al.
Paper
Synthesis
O
N
O
O
R1
H
R1
R2
O
R2
H
N
P
OR3
OR3
O
P
O
or
R3O
OR3
2
3
R1
R2
R1
R2
DMF
O
P
OR3
OR3
CuLn
OR3
OR3
PhthN
PhthN
DMF
or
P
CuLn
O
R1
R2
N2
DMF
steric hindrance
or
O
P
OR3
OR3
R2
O
P
R2
CuLn
OR3
OR3
R1
PhthN
R1
O
OR3
PhthN
P
CuLn
DMF
PhthN
OR3
H
1
H
B''
B'
Cu(MeCN)4PF6
(CuLn)
DMF
R1
R2
R1
R2
O
P
O
OR3
OR3
OR3
P
PhthN
PhthN
DMF
OR3
H
CuLn
CuLn
DMF
B
A
Scheme 2 Conformations leading to β-hydrogen migration
1H NMR (400 MHz, CDCl3): δ = 8.08–7.85 (m, 2 H, Ph), 7.85–7.71 (m, 2
H, Ph), 5.78 (dd, J = 10.7, 0.5 Hz, 1 H, CH), 4.44–3.97 (m, 4 H,
2 × OCH2), 2.53 (d, J = 2.7 Hz, 3 H, CH3), 1.38 (t, J = 7.1 Hz, 6 H,
2 × CH3).
13C NMR (101 MHz, CDCl3): δ = 166.13 (C=O), 146.76 (d, J = 19.5 Hz,
C–N), 134.67, 131.47, 123.86 (Ph), 115.20 (d, J = 188.6 Hz, C–P), 62.01
(d, J = 5.4 Hz, OCH2), 18.89 (d, J = 3.8 Hz, CH3), 16.33 (d, J = 6.6 Hz,
CH3).
Diethyl (E)-[2-(1,3-Dioxoisoindolin-2-yl)-4-methylpent-1-en-1-
yl]phosphonate (2c)
Yield: 0.055 g (54%); light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.93–7.90 (m, 2 H, Ph), 7.82–7.79 (m, 2
H, Ph), 5.72 (d, J = 10.2 Hz, 1 H, CH), 4.25–4.13 (m, 4 H, 2 × OCH2), 3.09
(dd, J = 7.3, 2.4 Hz, 2 H, CH2), 1.70–1.59 (m, 1 H, CH), 1.40 (t, J = 7.1 Hz,
6 H, 2 × CH3), 0.95 (d, J = 6.6 Hz, 6 H, 2 × CH3).
13C NMR (101 MHz, CDCl3): δ = 166.38 (C=O), 150.22 (d, J = 20.1 Hz,
C–N), 134.64, 131.36, 123.89 (Ph), 116.78 (d, J = 188.9 Hz, C–P), 61.95
(d, J = 5.2 Hz, OCH2), 38.98 (d, J = 3.0 Hz, CH2), 26.93 (CH), 22.19 (CH3),
16.36 (d, J = 6.5 Hz, CH3).
31P NMR (162 MHz, CDCl3): δ = 15.47 (s).
ESI-MS: m/z = 324.1 [M + H]+.
Diethyl (E)-[2-(1,3-Dioxoisoindolin-2-yl)-3-methylbut-1-en-1-
yl]phosphonate (2b)
31P NMR (162 MHz, CDCl3): δ = 15.05 (s).
ESI-MS: m/z = 753.0 [2 M + Na]+.
Yield: 0.075 g (76%); light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.85–7.81 (m, 2 H, Ph), 7.73–7.69 (m, 2
H, Ph), 5.49 (d, J = 11.2 Hz, 1 H, CH), 4.24–4.03 (m, 4 H, 2 × OCH2),
3.81–3.69 (m, 1 H, CH), 1.31 (t, J = 7.1 Hz, 6 H, 2 × CH3), 1.06 (d, J = 6.9
Hz, 6 H, 2 × CH3).
13C NMR (101 MHz, CDCl3): δ = 166.17 (C=O), 155.51 (d, J = 20.0 Hz,
C–N), 133.38, 130.74, 122.74 (Ph), 119.17 (d, J = 183.4 Hz, C–P), 61.12
(d, J = 5.2 Hz, OCH2), 31.65 (d, J = 2.3 Hz, CH), 19.62 (CH3), 15.31 (d,
J = 6.5 Hz, CH3).
Diethyl (E)-[2-(1,3-Dioxoisoindolin-2-yl)-3-phenylprop-1-en-1-
yl]phosphonate (2d)
Yield: 0.084 g (75%); light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.84–7.75 (m, 2 H, Ph), 7.74–7.67 (m, 2
H, Ph), 7.23–7.05 (m, 5 H, Ph), 5.82 (d, J = 10.2 Hz, 1 H, CH), 4.53 (d,
J = 2.2 Hz, 2 H, CH2), 4.27–4.18 (m, 4 H, 2 × OCH2), 1.40 (t, J = 7.1 Hz, 6
H, 2 × CH3).
13C NMR (101 MHz, CDCl3): δ = 166.18 (C=O), 148.48 (d, J = 19.8 Hz,
C–N), 136.25, 131.08, 128.81, 128.46, 126.73, 123.76, 116.89 (Ph),
116.89 (d, J = 188.6 Hz, C–P), 62.19 (d, J = 5.5 Hz, OCH2), 36.46 (d,
J = 3.7 Hz, CH2), 16.37 (d, J = 6.6 Hz, CH3).
31P NMR (162 MHz, CDCl3): δ = 13.14 (s).
ESI-MS: m/z = 352.1 [M + H]+.
31P NMR (162 MHz, CDCl3): δ = 14.86 (s).
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ESI-MS: m/z = 821.3 [2 M + Na]+.
Diisopropyl (E)-[2-(1,3-Dioxoisoindolin-2-yl)prop-1-en-1-yl]phos-
phonate (2k)
Diethyl (E)-[2,6-Bis(1,3-dioxoisoindolin-2-yl)hex-1-en-1-yl]phos-
Yield: 0.092 g (94%); light yellow oil.
phonate (2e)
1H NMR (400 MHz, CDCl3): δ = 7.88–7.84 (m, 2 H, Ph), 7.78–7.74 (m, 2
H, Ph), 5.75 (d, J = 10.4 Hz, 1 H, CH), 4.92–4.48 (m, 2 H, 2 × OCH), 2.49
(s, 3 H, CH3), 1.35 (d, J = 5.7 Hz, 12 H, 4 × CH3).
13C NMR (101 MHz, CDCl3): δ = 166.16 (C=O), 145.80 (d, J = 19.4 Hz,
C–N), 134.61, 131.47, 123.77 (Ph), 117.15 (d, J = 188.4 Hz, C–P), 70.78
(d, J = 5.4 Hz, OCH), 24.05 (d, J = 4.2 Hz, CH3), 23.86 (d, J = 4.4 Hz, CH3),
18.81 (d, J = 3.7 Hz, CH3).
Yield: 0.114 g (80%); light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.80–7.76 (m, 2 H, Ph), 7.72–7.69 (m, 2
H, Ph), 7.68–7.65 (m, 2 H, Ph), 7.61–7.58 (m, 2 H, Ph), 5.62 (d, J = 10.6
Hz, 1 H, CH), 4.16–4.03 (m, 4 H, 2 × OCH2), 3.55 (t, J = 7.0 Hz, 2 H, CH2),
3.05 (t, J = 6.7 Hz, 2 H, CH2), 1.71–1.61 (m, 2 H, CH2), 1.43–1.33 (m, 2
H, CH2), 1.29 (t, J = 7.0 Hz, 6 H, 2 × CH3).
13C NMR (101 MHz, CDCl3): δ = 168.23 (C=O), 166.35 (C=O), 150.26 (d,
J = 20.0 Hz, C–N), 134.58, 133.76, 132.08, 131.39, 123.86, 123.09 (Ph),
116.89 (d, J = 188.3 Hz, C–P), 62.12 (d, J = 5.5 Hz, OCH2), 37.52 (CH2),
30.51 (d, J = 3.6 Hz, CH2), 27.94 (CH2), 24.60 (d, J = 1.3 Hz, CH2), 16.32
(d, J = 6.5 Hz, CH3).
31P NMR (162 MHz, CDCl3): δ = 14.70 (s).
ESI-MS: m/z = 533.4 [M + Na]+.
31P NMR (162 MHz, CDCl3): δ = 12.97 (s).
ESI-MS: m/z = 374.2 [M + Na]+.
Dibutyl (E)-[2-(1,3-Dioxoisoindolin-2-yl)prop-1-en-1-yl]phospho-
nate (2l)
Yield: 0.086 g (81%); light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.93–7.87 (m, 2 H, Ph), 7.82–7.77 (m, 2
H, Ph), 5.78 (d, J = 10.5 Hz, 1 H, CH), 4.10 (q, J = 6.7 Hz, 4 H, 2 × OCH2),
2.53 (d, J = 2.7 Hz, 3 H, CH3), 1.86–1.63 (m, 4 H, 2 × CH2), 1.55–1.35
(m, 4 H, 2 × CH2), 0.95 (t, J = 7.4 Hz, 6 H, 2 × CH3).
Diethyl (E)-[2-(1,3-Dioxoisoindolin-2-yl)but-1-en-1-yl]phospho-
nate (2h)
Yield: 0.053 g (56%); light yellow oil.
13C NMR (101 MHz, CDCl3): δ = 166.10 (C=O), 146.65 (d, J = 19.8 Hz,
C–N), 134.65, 131.45, 123.83 (Ph), 115.09 (d, J = 188.8 Hz, C–P), 65.67
(d, J = 5.5 Hz, OCH2), 32.42 (d, J = 6.6 Hz, CH2), 18.90 (d, J = 3.6 Hz,
CH3), 18.78 (CH2), 13.62 (CH3).
31P NMR (162 MHz, CDCl3): δ = 15.65 (s).
ESI-MS: m/z = 402.2 [M + Na]+.
1H NMR (400 MHz, CDCl3): δ = 7.98–7.83 (m, 2 H, Ph), 7.82–7.73 (m, 2
H, Ph), 5.63 (d, J = 10.8 Hz, 1 H, CH), 4.22–4.09 (m, 4 H, 2 × OCH2), 3.08
(dd, J = 13.9, 6.4 Hz, 2 H, CH2), 1.35 (t, J = 7.0 Hz, 6 H, 2 × CH3), 0.99 (t,
J = 7.4 Hz, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 166.45 (C=O), 152.01 (d, J = 17.4 Hz,
C–N), 134.66, 131.39, 123.88 (Ph), 115.72 (d, J = 187.7 Hz, C–P), 62.03
(d, J = 5.2 Hz, OCH2), 29.71 (CH2), 24.54 (d, J = 3.6 Hz, CH3), 16.34 (d,
J = 6.6 Hz, CH3).
Diisopropyl (E)-[2-(1,3-Dioxoisoindolin-2-yl)-3-phenylprop-1-en-
1-yl]phosphonate (2m)
31P NMR (162 MHz, CDCl3): δ = 14.96 (s).
ESI-MS: m/z = 338.2 [M + H]+.
Yield: 0.072 g (60%); light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.86–7.74 (m, 2 H, Ph), 7.72–7.66 (m, 2
H, Ph), 7.23–7.06 (m, 5 H, Ph), 5.81 (d, J = 9.9 Hz, 1 H, CH), 4.87–4.74
(m, 2 H, 2 × OCH), 4.54 (d, J = 2.1 Hz, 2 H, CH2), 1.40 (d, J = 6.2 Hz, 12
H, 4 × CH3).
Diethyl (E)-[2-(1,3-Dioxoisoindolin-2-yl)-2-phenylvinyl]phospho-
nate (2i)
Yield: 0.086 g (80%); colorless oil.
13C NMR (101 MHz, CDCl3): δ = 166.28 (C=O), 147.52 (d, J = 19.7 Hz,
C–N), 136.48, 134.47, 131.14, 128.88, 128.41, 126.66, 123.72 (Ph),
118.69 (d, J = 188.8 Hz, C–P), 71.08 (d, J = 5.5 Hz, OCH), 36.35 (d,
J = 3.6 Hz, CH2), 24.13 (d, J = 4.3 Hz, CH3), 24.00 (d, J = 4.6 Hz, CH3).
31P NMR (162 MHz, CDCl3): δ = 12.44 (s).
ESI-MS: m/z = 450.2 [M + Na]+.
1H NMR (400 MHz, CDCl3): δ = 7.94–7.90 (m, 2 H, Ph), 7.83–7.79 (m, 2
H, Ph), 7.61–7.57 (m, 2 H, Ph), 7.45–7.39 (m, 3 H, Ph), 6.04 (d, J = 9.7
Hz, 1 H, CH), 4.06–3.93 (m, 4 H, 2 × OCH2), 1.18 (t, J = 7.1 Hz, 6 H,
2 × CH3).
13C NMR (101 MHz, CDCl3): δ = 166.07 (C=O), 145.58 (d, J = 16.4 Hz,
C–N), 134.72, 131.53, 130.05, 128.68, 128.13, 124.04 (Ph), 117.24 (d,
J = 190.5 Hz, C–P), 62.13 (d, J = 6.0 Hz, OCH2), 16.08 (d, J = 6.7 Hz, CH3).
Dibutyl (E)-[2-(1,3-Dioxoisoindolin-2-yl)-3-phenylprop-1-en-1-
yl]phosphonate (2n)
31P NMR (162 MHz, CDCl3): δ = 13.54 (s).
ESI-MS: m/z = 408.2 [M + Na]+.
Yield: 0.093 g (73%); light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.82–7.76 (m, 2 H, Ph), 7.73–7.68 (m, 2
H, Ph), 7.25–7.06 (m, 5 H, Ph), 5.83 (d, J = 10.2 Hz, 1 H, CH), 4.54 (d,
J = 1.6 Hz, 2 H, CH2), 4.16 (q, J = 6.7 Hz, 4 H, 2 × OCH2), 1.80–1.68 (m, 4
H, 2 × CH2), 1.51–1.42 (m, 4 H, 2 × CH2), 0.96 (t, J = 7.4 Hz, 6 H,
2 × CH3).
13C NMR (101 MHz, CDCl3): δ = 166.18 (C=O), 148.40 (d, J = 19.6 Hz,
C–N), 136.28, 134.53, 131.07, 128.81, 128.45, 126.72, 123.77 (Ph),
116.79 (d, J = 189.3 Hz, C–P), 65.90 (d, J = 6.1 Hz, OCH2), 36.47 (d,
J = 3.6 Hz, CH2), 32.46 (d, J = 6.7 Hz, CH2), 18.81 (CH2), 13.65 (CH3).
Dimethyl (E)-[2-(1,3-Dioxoisoindolin-2-yl)prop-1-en-1-yl]phos-
phonate (2j)
Yield: 0.069 g (84%); light yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.91–7.86 (m, 2 H, Ph), 7.81–7.76 (m, 2
H, Ph), 5.73 (d, J = 10.8 Hz, 1 H, CH), 3.79 (d, J = 11.3 Hz, 6 H,
2 × OCH3), 2.51 (d, J = 2.7 Hz, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 165.02 (C=O), 146.60 (d, J = 19.7 Hz,
C–N), 133.72, 130.37, 122.87 (Ph), 112.32 (d, J = 190.1 Hz, C–P), 51.43
(d, J = 5.5 Hz, OCH3), 17.90 (d, J = 3.9 Hz, CH3).
31P NMR (162 MHz, CDCl3): δ = 15.03 (s).
ESI-MS: m/z = 478.4 [M + Na]+.
31P NMR (162 MHz, CDCl3): δ = 18.56 (s).
ESI-MS: m/z = 318.4 [M + Na]+.
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Acknowledgment
Org. Lett. 2001, 3, 2989. (f) DeAngelis, A.; Dmitrenko, O.; Fox, J.
M. J. Am. Chem. Soc. 2011, 134, 11035. (g) Qin, C. M.; Davies, H.
M. L. J. Am. Chem. Soc. 2013, 135, 14516. (h) Dudones, J. D.;
Sampson, P. Tetrahedron 2000, 56, 9555. (i) Otte, M.; Kuijpers, P.
F.; Troeppner, O.; Ivanović-Burmazović, I.; Reek, J. N. H.; De
Bruin, B. Chem. Eur. J. 2013, 19, 10170.
We thank the National Natural Science Foundation of China
(21072102), the Committee of Science and Technology of Tianjin
(15JCYBJC20700) and the State Key Laboratory of Elemento-Organic
Chemistry in Nankai University for financial support.
(5) (a) Taber, D. F.; Hennessy, M. J.; Louey, J. P. J. Org. Chem. 1992,
57, 436. (b) Taber, D. F.; Herr, R. J.; Pack, S. K.; Geremia, J. M.
J. Org. Chem. 1996, 61, 2908.
Supporting Information
(6) (a) Zhu, S. F.; Chen, W. Q.; Zhang, Q. Q.; Mao, H. X.; Zhou, Q. L.
Synlett 2011, 919. (b) Zhou, C. Y.; Wang, J. C.; Wei, J. H.; Xu, Z. J.;
Guo, Z.; Low, K. H.; Che, C. M. Angew. Chem. Int. Ed. 2012, 51,
11376. (c) Briones, J. F.; Davies, H. M. L. Org. Lett. 2011, 13, 3984.
(d) Lindsay, V. N. G.; Fiset, D.; Gritsch, P. J.; Azzi, S.; Charette, A.
B. J. Am. Chem. Soc. 2013, 135, 1463. (e) Davies, H. M. L.; Lee, G.
H. Org. Lett. 2004, 6, 2117. (f) Zhang, H.; Wen, X. J.; Gan, L. H.;
Peng, Y. G. Org. Lett. 2012, 14, 2126. (g) Hashimoto, T.; Maruoka,
K. J. Am. Chem. Soc. 2007, 129, 10054.
(7) Cai, Y.; Lu, Y. C.; Yu, C. B.; Lyu, H. R.; Miao, Z. W. Org. Biomol.
Chem. 2013, 11, 5491.
(8) Cai, Y.; Lyu, H. R.; Yu, C. B.; Miao, Z. W. Adv. Synth. Catal. 2014,
356, 596.
(9) See the following reviews: (a) Palacios, F.; Alonso, C.; de los
Santos, J. M. Chem. Rev. 2005, 105, 899. (b) Palacios, F.; Alonso,
C.; de los Santos, J. M. In Enantioselective Synthesis of β-Amino
Acids, 2nd ed.; Juaristi, E.; Soloshonok, V. A., Eds.; Wiley-VCH:
New York, 2005, 277–317.
(10) (a) Palacios, F.; Ochoa de Retana, A. M.; Pascual, S.; Oyarzabal, J.
J. Org. Chem. 2004, 69, 8767. (b) Panarina, A. E.; Dogadina, A. V.;
Zakharov, V. I.; Ionin, B. I. Tetrahedron Lett. 2001, 42, 4365.
(c) Gulevich, A. V.; Helan, V.; Wink, D. J.; Gevorgyan, V. Org. Lett.
2013, 15, 956.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560373.
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References
(1) For selected examples on carbenoid C–H insertion, see:
(a) Doyle, M. P.; Ratnikov, M.; Liu, Y. Org. Biomol. Chem. 2011, 9,
4007. (b) DeAngelis, A.; Shurtleff, V. W.; Dmitrenko, O.; Fox, J.
M. J. Am. Chem. Soc. 2011, 133, 1650. (c) Wolckenhauser, S. A.;
Devlin, A. S.; Du Bois, J. Org. Lett. 2007, 9, 4363. (d) Davies, H. M.
L. Angew. Chem. Int. Ed. 2006, 45, 6422. (e) Davies, H. M. L.;
Townsend, R. J. J. Org. Chem. 2001, 66, 6595. For selected exam-
ples of carbenoid O–H insertions, see: (f) Zhu, S. F.; Song, X. G.;
Li, Y.; Cai, Y.; Zhou, Q. L. J. Am. Chem. Soc. 2010, 132, 16374.
(g) Zhu, S. F.; Cha, Y.; Mao, H. X.; Xie, J. H.; Zhou, Q. L. Nat. Chem.
2010, 2, 546. (h) Zhu, S. F.; Chen, C.; Cai, Y.; Zhou, Q. L. Angew.
Chem. Int. Ed. 2008, 47, 932. (i) Chen, C.; Zhu, S. F.; Liu, B.; Wang,
L. X.; Zhou, Q. L. J. Am. Chem. Soc. 2007, 129, 12616. (j) Maier, T.
C.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 4594. For selected exam-
ples of carbenoid N–H insertions, see: (k) Zhu, S. F.; Xu, B.;
Wang, G. P.; Zhou, Q. L. J. Am. Chem. Soc. 2012, 134, 436. (l) Hou,
Z. R.; Wang, J.; He, P.; Wang, J.; Qin, B.; Liu, X. H.; Lin, L. L.; Feng,
X. M. Angew. Chem. Int. Ed. 2010, 49, 4763. (m) Liu, B.; Zhu, S. F.;
Zhang, W.; Chen, C.; Zhou, Q. L. J. Am. Chem. Soc. 2007, 129,
5834. (n) Moody, C. J. Angew. Chem. Int. Ed. 2007, 49, 9148. For
selected examples of carbenoid Si–H insertions, see: (o) Zhang,
Y. Z.; Zhu, S. F.; Wang, L. X.; Zhou, Q. L. Angew. Chem. Int. Ed.
2008, 47, 8496. For selected examples of carbenoid S–H inser-
tions, see: (p) Zhang, Y. Z.; Zhu, S. F.; Cai, Y.; Mao, H. X.; Zhou, Q.
L. Chem. Commun. 2009, 5362.
(11) Cai, Y.; Ge, H. H.; Yu, C. B.; Sun, W. Z.; Zhan, J. C.; Miao, Z. W. RSC
Adv. 2014, 4, 21492.
(12) (a) Kong, S. S.; Fan, W. D.; Wu, G. P.; Miao, Z. W. Angew. Chem.
Int. Ed. 2012, 51, 8864. (b) Fang, Z. J.; Yang, H. H.; Miao, Z. W.;
Chen, R. Y. Helv. Chim. Acta 2011, 94, 1586. (c) Wang, Y. D.;
Wang, Y. Y.; Yu, J. P.; Miao, Z. W.; Chen, R. Y. Chem. Eur. J. 2009,
15, 9290. (d) Wang, Y. D.; Wang, F.; Wang, Y. Y.; Miao, Z. W.;
Chen, R. Y. Adv. Synth. Catal. 2008, 350, 2339.
(13) For selected examples, see: (a) Cao, Z. Y.; Zhou, F.; Yu, Y. H.;
Zhou, J. Org. Lett. 2013, 15, 42. (b) Wang, J.; Boyarskikh, V.;
Rainier, J. D. Org. Lett. 2011, 13, 700. (c) Li, J.; Liao, S. H.; Xiong,
H.; Zhou, Y. Y.; Sun, X. L.; Zhang, Y.; Zhou, X. G.; Tang, Y. Angew.
Chem. Int. Ed. 2012, 51, 8838. (d) Song, X. G.; Zhu, S. F.; Xie, X. L.;
Zhou, Q. L. Angew. Chem. Int. Ed. 2013, 52, 2555.
(14) Bachmann, S.; Fielenbach, D.; Jørgensen, K. A. Org. Biomol. Chem.
2004, 2, 3044.
(15) Taber, D. F.; You, K. K.; Rheingold, A. L. J. Am. Chem. Soc. 1996,
118, 547.
(16) Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.;
Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993,
115, 958.
(17) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry, 3rd ed.; Harper Collins Publishers: New York, 1987.
(18) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals, 3rd ed.; Pergamon: Oxford, 1988.
(2) For selected recent examples, see: (a) Li, Z. J.; Parr, B. T.; Davies,
H. M. L. J. Am. Chem. Soc. 2012, 134, 10942. (b) Xu, X. F.; Hu, W.
H.; Zavalij, P. Y.; Doyle, M. P. Angew. Chem. Int. Ed. 2011, 50,
11152. (c) Li, Z. J.; Davies, H. M. L. J. Am. Chem. Soc. 2010, 132,
396. (d) DeAngelis, A.; Taylor, M. T.; Fox, J. M. J. Am. Chem. Soc.
2009, 131, 1101. (e) Huang, H. X.; Guo, X.; Hu, W. H. Angew.
Chem. Int. Ed. 2007, 46, 1337.
(3) For reviews, see: (a) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou,
L.; Ye, T. Chem. Rev. 2010, 110, 704. (b) Padwa, A. Chem. Soc. Rev.
2009, 38, 3072. (c) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds:
From Cyclopropanes to Ylides; Wiley-Interscience: New York,
1998, 433–436.
(4) (a) Zhou, L.; Liu, Y. Z.; Zhang, Y.; Wang, J. B. Chem. Commun.
2011, 47, 3622. (b) Xu, F.; Zhang, S. W.; Wu, X. N.; Liu, Y.; Shi, W.
F.; Wang, J. B. Org. Lett. 2006, 8, 3207. (c) Xiao, F. P.; Wang, J. B.
J. Org. Chem. 2006, 71, 5789. (d) Xu, F.; Shi, W. F.; Wang, J. B.
J. Org. Chem. 2005, 70, 4191. (e) Jiang, N.; Qu, Z. H.; Wang, J. B.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 448–454