Trifluoroborane-catalyzed C-H functionalization/S-H insertion reaction: Construction of N,S-acetal quaternary centers

Article abstract of DOI:10.1055/s-0034-1380384

Abstract The trifluoroborane-catalyzed C-H functionalization/S-H insertion reaction of α-diazophosphonates with thiols has been developed. A plausible reaction mechanism has been proposed to understand the combined reaction. This process provides straightforward access to N,S-acetals containing quaternary centers in moderate to good yields and chemoselectivity.

Full text of DOI:10.1055/s-0034-1380384

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1669–1677
paper
1669
Y. Cai et al.
Paper
Synthesis
Trifluoroborane-Catalyzed C–H Functionalization/S–H Insertion
Reaction: Construction of N,S-Acetal Quaternary Centers
Yan Caia
Haihong Gea
Weize Suna
O
O
R1
R1
BF3·OEt2 (10 mol%)
O
P
O
P
OR2
N
R3
SH
H
+
N
OR2
OR2
CH2Cl2, 25 °C, 7.5 h
Zhiwei Miao*a,b
S
O
R3 H
OR2
O
N2
a State Key Laboratory of Elemento-Organic Chemistry,
Institute of Elemento-Organic Chemistry, Nankai University,
Tianjin 300071, P. R. of China
miaozhiwei@nankai.edu.cn
b Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin), Tianjin 300071, P. R. of China
Received: 31.10.2014
Accepted after revision: 19.02.2015
Published online: 25.03.2015
tions, including cyclopropanation, X–H (X = C, O, S, N, etc.),
insertion, and ylide formation.7d,8 The decomposition of α-
diazocarbonyl compounds catalyzed by metal complexes in
the presence of amines or alcohols is known to produce,
through insertion into the N–H and O–H bond, respectively,
the corresponding α-amino and α-hydroxy esters.9 Surpris-
ingly, however, the application of this methodology to S–H
bond insertion was investigated with less success, giving
modest yields of the corresponding α-phenylthio ester
along with a byproduct that can not be purified.10 The low
yields observed in S–H bond insertion reactions may be
partially attributed to the high coordination ability of the
sulfur atom to the transition metal which may destroy the
active of the catalyst. The relatively high stability of the sul-
fonium ylide intermediate also makes the free ylide more
favorable than the corresponding metal-complexed ylide.11
In contrast to α-diazocarbonyl compounds, α-diazo-
phosphonyl compounds have not been studied systemati-
cally in metal–carbene reactions.12 We have recently devel-
oped novel α-diazophosphonyl compounds prepared from
natural amino acid, which could afford β-alkoxy-substitut-
ed β-aminophosphonate derivatives through a combined
C–H functionalization/O–H insertion process [Scheme 1
(1)].13 We found that α-diazophosphonates could form a
metal–carbene complex, then the β-hydrogen on the phos-
phonate migrated to the carbene center to form a tertiary
carbocation intermediate; the O–H insertion process pro-
duces tertiary β-alkoxy-substituted β-aminophospho-
nates.13 The unique characteristics of the synthetic strategy
provided a good opportunity to develop a C–H functional-
ization/S–H insertion reaction for the synthesis of N,S-ace-
tal quaternary carbon containing β-aminophosphonates. β-
Aminophosphonates, the phosphorus analogues of β-amino
acids, have attracted attention because of their wide use as
enzyme inhibitors, agrochemicals, and pharmaceuticals.14
Continuing with our interest in the chemistry of amino-
DOI: 10.1055/s-0034-1380384; Art ID: ss-2014-h0666-op
Abstract The trifluoroborane-catalyzed C–H functionalization/S–H in-
sertion reaction of α-diazophosphonates with thiols has been devel-
oped. A plausible reaction mechanism has been proposed to under-
stand the combined reaction. This process provides straightforward
access to N,S-acetals containing quaternary centers in moderate to
good yields and chemoselectivity.
Key words α-diazophosphonate, C–H functionalization, S–H inser-
tion, N,S-acetal, combined reaction
The efficient construction of N,S-acetal quaternary car-
bon centers is an important challenge for organic chemists.1
N,S-Acetal quaternary centers are widely present in numer-
ous biologically active natural products and in a series of
pharmaceutically active compounds.2 Therefore, the devel-
opment of efficient synthetic methods to access these use-
ful N,S-acetal compounds is attractive for organic chem-
ists.1a,3
Among the various methods developed for the synthesis
of N,S-acetals,4 the addition of thiols to imines1e,5 stands out
as an efficient direct strategy. On the other hand, the ‘S’
atom in nucleophile-mediated synthetic reactions from the
corresponding diazo derivatives has been rarely investigat-
ed. In recent years, the groups of Moody and Zhou have
demonstrated the successful exploration of diazo com-
pounds in metal-catalyzed S–H insertion.6 However, the
carbenoid S–H bond insertion reaction leads to a series of
α-mercaptoester-containing tertiary centers.
α-Diazocarbonyl compounds have attracted great atten-
tion over the past decades due to their diverse reactivity.7
Diazocarbonyl compounds can be decomposed by transi-
tion-metal complexes to generate metal carbenes, which
can subsequently undergo diverse chemical transforma-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1669–1677

1670
Y. Cai et al.
Paper
Synthesis
previous work:
R
O
O
O
O
O
N
[Cu(MeCN)4]PF6, I2
CH2Cl2
N
O
+
+
N
(1)
(2)
P
OEt
HO
R
OEt
OEt
P
OEt
O
N2
OEt
O
P
O
OEt
O
this work:
O
R1
O
O
R1
P
O
P
OR2
R1
N
BF3·OEt2
CH2Cl2, 25 °C
O
P
R3 SH
OR2
+
N
+
N
OR2
S
O
N2
OR2
OR2
R3
OR2
O
O
O
Scheme 1 Previous and proposed work
phosphorus derivatives,15 in this communication, we report
the first example of the conversion of dialkyl α-diazophos-
phonates into β-alkylthio-substituted β-aminophospho-
nates with quaternary centers. In this transformation, we
employed boron trifluoride–diethyl ether complex as the
catalyst to decompose α-diazophosphonates in the pres-
ence of a thiol, which avoids the problem of the coordina-
tion of sulfur with the traditional employed transition-
metal catalysts [Scheme 1 (2)].
To test this hypothesis, we selected the reaction be-
tween diethyl α-diazophosphonate 1a13 and ethanethiol
(2a) as a model reaction for the optimization of the reaction
conditions in the presence of catalyst in dichloromethane at
25 °C; the results are summarized in Table 1. The results re-
Table 1 Optimization of the Reaction Conditionsa
O
O
O
O
catalyst (10 mol%)
N
O
N
N
EtSH
+
+
H
O
P
OEt
solvent, r.t., 7.5 h
EtS
P
OEt
2a
O
OEt
O
P
N2
O
OEt
EtO
OEt
1a
3a
4a
Entry
Catalyst
Solvent
Ratiob (3a/4a)
Overall yieldc (%)
e
1d
2d
3
Cu(MeCN)4PF4
AgOTf
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
–
–
e
–
–
TfOH
67:33
12:88
48:52
84:16
–
50
23
41
69
4
H3PO4
5
ClSO3H
6
BF3·OEt2
AcOH
e
7
–
e
8
ClCH2CO2H
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
–
–
9
44:56
58:42
81:19
60:40
49
51
51
45
10
11
12
toluene
ClCH2CH2Cl
DMF
a Reaction conditions: α-diazophosphonate 1a (0.28 mmol, 1 equiv), ethanethiol (2a, 1.4 mmol, 5 equiv), catalyst (10 mol%), solvent (4 mL), 25 °C, 7.5 h (addi-
tion: 1.5 h, after addition: 6 h).
b The product ratio was determined by 31P NMR of the crude product.
c Overall yield of the mixture of 3a and 4a after silica gel chromatography.
d 5 mol% catalyst was used.
e No reaction.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1669–1677

1671
Y. Cai et al.
Paper
Synthesis
vealed
that
transition-metal
catalysts
such
as
higher yield (69% combined yield) compared to the other
catalysts, it was used in further investigations. Screening
solvents showed that tetrahydrofuran, toluene, 1,2-dichlo-
roethane, and N,N-dimethylformamide provided 3a in low-
er yields (entries 9–12). Therefore, the tentatively opti-
mized reaction conditions were determined to use di-
chloromethane as the solvent.
With the optimized conditions in hand, we next investi-
gated the substrate scope of the S–H bond insertion reac-
tion. The insertion reactions of various substituted thiols
2a–g and different dialkyl α-diazophosphonates 1a–l,
which derived from different natural amino acids, were
conducted under the optimized reaction conditions (Table
2). α-Diazophosphonates 1a–f with different substituents
in the β-position, such as methyl, isopropyl, isobutyl, ben-
zyl, (1,3-dioxoisoindolin-2-yl)propyl, and 4-acetoxybenzyl
groups, afforded good level yields and chemoselectivity for
the S–H bond insertion reaction with ethanethiol (2a) and
[Cu(MeCN)4]PF6 and silver(I) triflate did not decompose 1a
in the presence of 2a due to strong coordination of sulfur to
the metal catalyst (entries 1 and 2). Therefore, we turn our
attention to Brønsted acids that could also decompose di-
azo compounds.16
Encouraged by this initial result, we continued to opti-
mize the reaction conditions. From Table 1, it is clear that
the diazo decomposition could be effected under various
reaction conditions and that the ratio of the two products
3a and 4a depends on the catalyst employed. Screening
several catalysts revealed that phosphoric acid, chlorosul-
fonic acid, and boron trifluoride–diethyl ether complex
were able to promote this reaction (entries 4–6).
It is worthwhile noting that when acetic acid and chlo-
roacetic acid were employed in this reaction, no reaction
occurred and the starting material 1a was recovered (en-
tries 7 and 8). Since boron trifluoride–diethyl ether gave a
Table 2 Scope of the Reactiona
O
O
O
R1
R1
R1
BF3·OEt2 (10 mol%)
O
P
OR2
O
P
N
N
R3 SH
2
N
+
+
OR2
OR2
CH2Cl2, 25 °C, 7.5 h
S
OR2
OR2
O
O
P
N2
R3
O
OR2
O
1
3
4
Entry
Phosphonate Thiol
R1
R2
R3
Product
Ratiob
(3/4)
Overall yieldc Isolatedyield
(%) of 3 + 4 (%) of 3
1
2
1a
1b
1c
1d
1e
1f
2a
2a
2a
2a
2b
2b
2b
2b
2c
2d
2e
2f
Me
Et
Et
3a/4a
3b/4b
3c/4c
3d/4d
3e/4e
3f/4f
84:16
77:23
75:25
77:23
85:15
77:23
25:75
88:12
87:13
90:10
86:14
84:16
68:32
81:19
83:17
82:18
75:25
64:36
69:31
69
68
70
62
72
60
70
82
67
77
64
67
45
72
49
55
71
59
62
55
51
52
44
41
43
19
65
52
60
49
52
29
55
39
43
46
40
48
i-Pr
Et
Et
3
i-Bu
Et
Et
4
Bn
Et
Et
5
(CH2)4NPhth
Et
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-FC6H4
4-MeOC6H4
2-MeC6H4
i-Pr
6
4-AcOC6H4
Et
7
1g
1a
1a
1a
1a
1a
1a
1h
1i
(CH2)2SMe
Me
Et
3g/4g
3h/4a
3i/4a
3j/4a
3k/4a
3l/4a
3m/4a
3n/4h
3o/4i
3p/4j
3q/4k
3r/4l
8
Et
9
Me
Et
10
11
12
13
14
15
16
17
18
19
Me
Et
Me
Et
Me
Et
2g
2a
2a
2a
2b
2a
2a
Me
Et
t-Bu
Me
Me
i-Pr
Bu
Me
i-Pr
Bu
Et
Me
Et
1j
Me
Et
1k
1l
Bn
4-MeC6H4
Et
Bn
1m
Bn
Et
3s/4m
a Reaction conditions: α-diazophosphonate 1 (0.28 mmol), 2 (1.4 mmol), BF3·OEt2 (10 mol%), CH2Cl2 (4 mL), 25 °C, 7.5 h (addition: 1.5 h; after addition: 6 h).
b The product ratio was determined by 31P NMR of the crude product.
c Overall yield of the mixture of 3 and 4 after silica gel chromatography; 3 and 4 were separated by additional chromatography.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1669–1677

1672
Y. Cai et al.
Paper
Synthesis
4-methylbenzenethiol (2b) (entries 1–6). The R1 group of
the diazo compounds influences both reactivity and che-
moselectivity in the S–H bond insertion reaction. When di-
ethyl α-diazophosphonate 1g was used, which is derived
from methionine, with 4-methylbenzenethiol (2b) the β-
elimination product of the carbenoid 4g predominated (en-
try 7).
Substituted benzenethiols were also examined in the S–
H bond insertion reaction. All the tested benzenethiols un-
derwent the insertion reaction smoothly and the corre-
sponding insertion products were obtained in good yields.
The electronic effect of the benzenethiol substituent on the
chemoselectivity was negligible. The reactions of 4-fluoro-
benzenethiol (2c) and 4-methoxybenzenethiol (2d) gave a
similar product ratio for S–H insertion/β-elimination (en-
tries 9 and 10). Substitution at the ortho position of ben-
zenethiol, using 2-methylbenzenethiol (2e) resulted in a
lower 64% combined yield of 3k and 4, indicating the exis-
tence of a negative steric effect on the benzenethiol sub-
strate (entry 11). In addition to benzenethiols, aliphatic thi-
ols were also examined in the S–H bond insertion reaction
with carbenoids derived from diethyl α-diazophosphonate
1a. Sterically hindered thiols 2f,g underwent the S–H inser-
tion reaction affording the insertion products 3l,m in mod-
erate yields (entries 12 and 13).
To assess the effects of the substrate on product selec-
tivity, we studied the reactions of a series of dialkyl α-di-
azophosphonates 1h–m catalyzed by boron trifluoride–di-
ethyl ether. The results show that the size of the R2 group in
the α-diazophosphonate 1 has almost no influence on reac-
tivity in the S–H insertion reaction (entries 14–19). The
structure of 3f was confirmed by single crystal X-ray dif-
fraction (Figure 1).17
We postulate the following mechanism for the forma-
tion of product 3 and 4 (Scheme 2). Diazo compounds are
ambiphilic reagents.7f From the resonance structures 1 and
A of the α-diazophosphonate it is apparent that the carbon
to which the diazo group is attached has a partial negative
charge and thus is nucleophilic. Therefore the electron-
O
O
R1
O
R1
O
N
N
P
OR2
OR2
S
P
OR2
R3
O
OR2
N2
O
3
1
BF3·OEt2
R3
S
O
O
R1
H
R1
O
N
N
BF3·OEt2
–
P
OR2
OR2
OR2
O
P
N+
O
OR2
O
D
N
1,3-hydrogen migration
A
BF3·OEt2
N2
O
O
R1
R1
O
O
+
R3 SH
N
N
+
P(OR2)2
P(OR2)2
H
H
2
– BF3·OEt2
–BF3·OEt2
O
O
B
C
O
R1
P
N
OR2
OR2
O
O
4
Scheme 2 Plausible reaction mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1669–1677

1673
Y. Cai et al.
Paper
Synthesis
O
N
O
BF3·OEt2 (10 mol%)
O
H
O
N
+
EtSH
CH2Cl2, r.t., 7.5 h
P
OEt
EtS
2a
O
P
EtO
4a
Scheme 3 Control experiment determined by 1H NMR
O
OEt
OEt
3a
generated in situ from α-diazophosphonates to produce
N,S-acetals containing quaternary centers in good yields
with moderate to good chemoselectivity (up to 90:10). A
plausible reaction mechanism has been proposed to ex-
plain the combined C–H functionalization/S–H insertion
reaction. Further research studies for asymmetric synthesis
of this reaction are currently underway in our laboratory.
All reactions and manipulations were performed using standard
Schlenk techniques. Solvents were dried and distilled prior to use ac-
cording to the standard methods. Unless otherwise indicated, all ma-
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). N2 gas (99.999%) was purchased from Boc Gas Inc.
1H, 13C, and 31P NMR spectra were recorded in CDCl3 at Bruker 400
MHz spectrometers, TMS served as internal standard (δ = 0) for 1H
NMR and 13C NMR, H3PO4 served as internal standard (δ = 0) for 31P
NMR. The crystal structure was determined on a Bruker SMART 1000
CCD diffractometer. Mass spectra were recorded on a LCQ advantage
spectrometer with ESI resource. HRMS were recorded on APEXII and
ZAB-HS spectrometer. Melting points were determined on a T-4 melt-
ing point apparatus (uncorrected). Optical rotations were recorded on
a Perkin Elmer 241 polarimeter.
Figure 1 X-ray crystal structure of 3f
deficient boron trifluoride–diethyl ether could attack the
diazo carbon and decomposed the α-diazophosphonate
along with extrusion of nitrogen. Then the β-hydrogen on
the phosphonate migrated to the carbene center to form
the intermediate B. Formation of sulfonium ylide D can be
envisaged by the nucleophilic addition of thiol 2 onto elec-
trophilic resonance complex C. 1,3-Hydrogen migration in
the resultant sulfonium ylide D would furnish the sulfide 3
along with the reactive boron trifluoride species to com-
plete the catalytic cycle. On the other hand, ylide C may also
be transformed into byproduct 4 through loss of boron tri-
fluoride–diethyl ether and β-hydrogen migration before the
attack of the thiol.
In order to explore the mechanism of this reaction,
compound 4a18 was treated with ethanethiol (2a) under the
standard reaction conditions. The 1H NMR result did not de-
tect the desired product 3a in the mixture (Scheme 3). The
result clearly ruled out the possibility of initial formation of
compound 4 followed by thia-Michael addition to give com-
pound 3.
Dialkyl α-diazophosphonates were synthesized by methods reported
in a previous publication.13 Spectroscopic data (1H, 13C, and 31P NMR,
HRMS) for 4a–f,h–m are identical to those reported.18 Data for 4g are
given in the Supporting Information.
Dialkyl 2-(Alkylthio)-2-(1,3-dioxoisoindolin-2-yl)alkylphospho-
nates 3 and Dialkyl 2-(1,3-dioxoisoindolin-2-yl)alk-1-enylphos-
phonates 4; General Procedure
BF3·OEt2 (3.6 μL, 0.028 mmol) and thiol (1.4 mmol) dissolved in anhyd
CH2Cl2 (2 mL) was injected to an oven-dried Schlenk tube under N2.
Dialkyl α-diazophosphonate 1 (0.28 mmol) was diluted with anhyd
CH2Cl2 (2 mL) and was drawn into a gastight syringe. It was then add-
ed to the mixture dropwise over a period of 1.5 h with the help of a
syringe pump. When the addition was complete, the mixture was
stirred for a further 6 h at 25 °C. The solvent was then removed under
reduced pressure and the crude residue was purified by chromatogra-
phy (silica gel, CH2Cl2–EtOAc, 15:1) to afford the corresponding prod-
ucts 3 and 4; 3 and 4 were separated by additional chromatography.
In conclusion, we have demonstrated the extension of
our methodology to a novel boron trifluoride–diethyl ether
catalyzed combined C–H functionalization/S–H insertion
reaction of α-diazophosphonates with thiols. A broad range
of thiols underwent the insertion reaction with carbenoids
Diethyl 2-(1,3-Dioxoisoindolin-2-yl)-2-(ethylthio)propylphospho-
nate (3a)
Colorless oil; yield: 0.060 g (55%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1669–1677

1674
Y. Cai et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.80–7.82 (m, 2 H, Ph), 7.69–7.71 (m, 2
H, Ph), 3.93–4.07 (m, 5 H, 2 OCH2, CH2P), 2.72–2.80 (m, 1 H, SCH2),
2.55–2.68 (m, 1 H, SCH2), 2.41 (s, 3 H, CH3), 2.15–2.26 (m, 1 H, CH2P),
1.18 (dd, J = 15.6, 7.4 Hz, 6 H, 2 CH3), 1.11 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 168.64, 134.07, 131.65, 123.06, 65.24,
61.77, 61.71, 36.58 (d, J = 135.2 Hz, C–P), 27.92, 23.90, 16.24, 16.12,
13.72.
Diethyl 2,6-Bis(1,3-dioxoisoindolin-2-yl)-2-(p-tolylthio)hexyl-
phosphonate (3e)
Colorless oil; yield: 0.048 g (41%).
1H NMR (400 MHz, CDCl3): δ = 7.93–7.99 (m, 2 H, Ph), 7.80–7.87 (m, 4
H, Ph), 7.75–7.80 (m, 2 H, Ph), 7.25 (d, J = 7.8 Hz, 2 H, Ph), 7.05 (d, J =
7.8 Hz, 2 H, Ph), 4.03–4.14 (m, 4 H, 2 OCH2), 3.82–3.94 (m, 3 H, CH2P,
CH2), 2.90 (dd, J = 18.9, 8.3 Hz, 1 H, CH2P), 2.53–2.72 (m, 2 H, CH2),
2.35 (s, 3 H, CH3), 1.95–2.04 (m, 1 H, CH2), 1.74–1.91 (m, 3 H, CH2),
1.27 (t, J = 7.1 Hz, 3 H, CH3), 1.21 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 168.40, 168.35, 140.03, 136.67,
133.99, 133.88, 132.22, 131.44, 129.79, 127.08, 123.18, 122.98, 73.53,
61.75, 38.23, 34.72, 31.15 (d, J = 136.9 Hz, C–P), 28.60, 22.23, 21.26,
16.21.
31P NMR (162 MHz, CDCl3): δ = 24.22.
HRMS (ESI): m/z [M + Na]+ calcd for C17H24NO5PS: 408.1005; found:
408.1007.
Diethyl 2-(1,3-Dioxoisoindolin-2-yl)-2-(ethylthio)-3-methylbutyl-
phosphonate (3b)
31P NMR (162 MHz, CDCl3): δ = 24.17.
HRMS (ESI): m/z [M + Na]+ calcd for C33H35N2O7PS: 657.1795; found:
Colorless oil; yield: 0.056 g (51%).
1H NMR (400 MHz, CDCl3): δ = 7.77–7.83 (m, 2 H, Ph), 7.66–7.71 (m, 2
H, Ph), 3.97–4.09 (m, 4 H, 2 OCH2), 3.62–3.72 (m, 1 H, CH), 3.25 (dd, J =
20.7, 15.6 Hz, 1 H, CH2P), 2.90–3.00 (m, 1 H, SCH2), 2.74–2.87 (m, 2 H,
SCH2, CH2P), 1.14–1.23 (m, 15 H, 5 CH3).
657.1797.
4-[3-(Diethoxyphosphoryl)-2-(1,3-dioxoisoindolin-2-yl)-2-(p-tol-
ylthio)propyl]phenyl Acetate (3f)
13C NMR (101 MHz, CDCl3): δ = 169.10, 133.91, 131.74, 122.96, 62.04,
61.78, 61.72, 33.99, 31.14 (d, J = 139.1 Hz, C–P), 25.80, 19.05, 18.26,
16.24, 16.18, 13.31.
31P NMR (162 MHz, CDCl3): δ = 25.15.
HRMS (ESI): m/z [M + Na]+ calcd for C19H28NO5PS: 436.1318; found:
White solid; yield: 0.052 g (43%); mp 165–168 °C.
1H NMR (400 MHz, CDCl3): δ = 7.73–7.79 (m, 4 H, Ph), 7.69–7.73 (m, 2
H, Ph), 7.29 (d, J = 6.5 Hz, 2 H, Ph), 7.06 (d, J = 8.2 Hz, 2 H, Ph), 6.96 (d,
J = 8.2 Hz, 2 H, Ph), 4.37 (d, J = 14.4 Hz, 1 H, CH2), 4.20 (d, J = 14.4 Hz, 1
H, CH2), 4.05–4.15 (m, 2 H, OCH2), 3.93–4.04 (m, 2 H, OCH2), 3.39 (dd,
J = 18.4, 16.1 Hz, 1 H, CH2P), 2.67 (dd, J = 19.8, 15.7 Hz, 1 H, CH2P), 2.31
(s, 3 H, CH3), 2.24 (s, 3 H, CH3), 1.27 (t, J = 7.1 Hz, 3 H, CH3), 1.14 (t, J =
7.1 Hz, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 169.43, 168.32, 149.79, 139.91,
136.69, 134.07, 133.67, 133.18, 131.32, 129.76, 127.50, 122.90,
120.98, 73.03, 62.08, 61.65, 40.09, 32.28 (d, J = 138.1 Hz, C–P), 21.18,
16.32, 16.13.
436.1320.
Diethyl 2-(1,3-Dioxoisoindolin-2-yl)-2-(ethylthio)-4-methylpen-
tylphosphonate (3c)
Colorless oil; yield: 0.057 g (52%).
1H NMR (400 MHz, CDCl3): δ = 7.80–7.84 (m, 2 H, Ph), 7.70–7.74 (m, 2
H, Ph), 4.00–4.13 (m, 4 H, 2 OCH2), 3.49 (dd, J = 18.6, 15.9 Hz, 1 H,
CH2P), 3.02 (dd, J = 20.2, 15.8 Hz, 1 H, CH2P), 2.71–2.86 (m, 2 H, SCH2),
2.59–2.69 (m, 2 H, CH2), 1.95–2.06 (m, 1 H, CH), 1.27 (t, J = 7.0 Hz, 3 H,
CH3), 1.22 (t, J = 7.0 Hz, 3 H, CH3), 1.17 (t, J = 7.5 Hz, 3 H, CH3), 1.11 (d,
J = 6.6 Hz, 3 H, CH3), 1.04 (d, J = 6.6 Hz, 3 H, CH3).
31P NMR (162 MHz, CDCl3): δ = 24.52.
HRMS (ESI): m/z [M + Na]+ calcd for C30H32NO7PS: 604.1529; found:
604.1525.
13C NMR (101 MHz, CDCl3): δ = 168.81, 134.09, 131.46, 123.05, 70.87,
61.82, 61.64, 42.69, 32.62 (d, J = 141.4 Hz, C–P), 25.14, 24.51, 24.17,
23.81, 16.35, 16.27, 12.94.
31P NMR (162 MHz, CDCl3): δ = 24.55.
HRMS (ESI): m/z [M + Na]+ calcd for C20H30NO5PS: 450.1475; found:
Diethyl 2-(1,3-Dioxoisoindolin-2-yl)-4-(methylthio)-2-(p-tolyl-
thio)butylphosphonate (3g)
Colorless oil; yield: 0.023 g (19%).
1H NMR (400 MHz, CDCl3): δ = 7.75–7.79 (m, 2 H, Ph), 7.68–7.72 (m, 2
H, Ph), 7.22 (d, J = 8.0 Hz, 2 H, Ph), 6.99 (d, J = 8.0 Hz, 2 H, Ph), 3.95–
4.09 (m, 4 H, 2 OCH2), 3.79–3.90 (m, 1 H, CH2P), 2.81–3.15 (m, 4 H, 2
CH2), 2.45 (dd, J = 19.6, 15.7 Hz, 1 H, CH2P), 2.27 (s, 3 H, CH3), 2.16 (s, 3
H, CH3), 1.22 (t, J = 7.1 Hz, 3 H, CH3), 1.12 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 168.30, 140.28, 136.83, 134.10,
131.34, 129.87, 126.69, 123.04, 72.83, 61.92, 61.86, 35.28, 31.19 (d, J =
136.8 Hz, C–P), 28.94, 21.29, 16.29, 16.16, 15.47.
450.1472.
Diethyl 2-(1,3-Dioxoisoindolin-2-yl)-2-(ethylthio)-3-phenylpro-
pylphosphonate (3d)
Colorless oil; yield: 0.048 g (44%).
1H NMR (400 MHz, CDCl3): δ = 7.78–7.82 (m, 2 H, Ph), 7.68–7.73 (m, 2
H, Ph), 7.45–7.50 (m, 2 H, Ph), 7.21–7.26 (m, 3 H, Ph), 4.25 (d, J = 14.1
Hz, 1 H, CH2), 4.04–4.14 (m, 3 H, CH2, OCH2), 3.93–4.03 (m, 2 H,
OCH2), 3.26 (dd, J = 18.4, 15.9 Hz, 1 H, CH2P), 2.60–2.80 (m, 3 H, CH2P,
SCH2), 1.26 (t, J = 7.1 Hz, 3 H, CH3), 1.17 (t, J = 7.5 Hz, 3 H, CH3), 1.13 (t,
J = 7.1 Hz, 3 H, CH3).
31P NMR (162 MHz, CDCl3): δ = 23.82.
HRMS (ESI): m/z [M + Na]+ calcd for C24H30NO5PS2: 530.1195; found:
530.1192.
Diethyl 2-(1,3-Dioxoisoindolin-2-yl)-2-(p-tolylthio)propylphos-
phonate (3h)
13C NMR (101 MHz, CDCl3): δ = 168.62, 135.76, 134.19, 131.75,
131.40, 127.93, 127.04, 123.14, 70.72, 62.01, 61.62, 39.77, 31.97 (d, J =
140.4 Hz, C–P), 24.11, 16.37, 16.16, 12.99.
Colorless oil; yield: 0.082 g (65%).
1H NMR (400 MHz, CDCl3): δ = 7.78–7.83 (m, 2 H, Ph), 7.70–7.74 (m, 2
H, Ph), 7.26 (d, J = 8.0 Hz, 2 H, Ph), 7.04 (d, J = 8.0 Hz, 2 H, Ph), 3.92–
4.11 (m, 5 H, 2 OCH2, CH2P), 2.31 (s, 3 H, CH3), 2.21–2.29 (m, 4 H, CH2P,
CH3), 1.20 (t, J = 7.1 Hz, 3 H, CH3), 1.11 (t, J = 7.1 Hz, 3 H, CH3).
31P NMR (162 MHz, CDCl3): δ = 24.47.
HRMS (ESI): m/z [M + Na]+ calcd for C23H28NO5PS: 484.1318; found:
484.1323.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1669–1677

1675
Y. Cai et al.
Paper
Synthesis
13C NMR (101 MHz, CDCl3): δ = 168.23, 140.16, 137.12, 134.05,
131.59, 129.79, 127.23, 123.05, 67.76, 61.75, 36.51 (d, J = 134.8 Hz, C–
P), 27.96, 21.31, 16.25, 16.14.
13C NMR (101 MHz, CDCl3): δ = 168.59, 134.04, 131.73, 123.07, 65.59,
61.71, 37.07 (d, J = 134.2 Hz, C–P), 34.55, 28.02, 24.90, 24.41, 16.24,
16.10.
31P NMR (162 MHz, CDCl3): δ = 24.36.
31P NMR (162 MHz, CDCl3): δ = 24.11.
HRMS (ESI): m/z [M + Na]+ calcd for C22H26NO5PS: 470.1162; found:
HRMS (ESI): m/z [M + Na]+ calcd for C18H26NO5PS: 422.1162; found:
470.1164.
422.1164.
Diethyl 2-(1,3-Dioxoisoindolin-2-yl)-2-[(4-fluorophenyl)thio]pro-
pylphosphonate (3i)
Diethyl 2-(tert-Butylthio)-2-(1,3-dioxoisoindolin-2-yl)propyl-
phosphonate (3m)
Colorless oil; yield: 0.067 g (52%).
Colorless oil; yield: 0.034 g (29%).
1H NMR (400 MHz, CDCl3): δ = 7.73–7.81 (m, 2 H, Ph), 7.66–7.71 (m, 2
H, Ph), 7.28–7.36 (m, 2 H, Ph), 6.89 (t, J = 8.5 Hz, 2 H, Ph), 3.90–4.06
(m, 5 H, 2 OCH2, CH2P), 2.17–2.29 (m, 4 H, CH3, CH2P), 1.16 (t, J = 7.1
Hz, 3 H, CH3), 1.08 (t, J = 7.1 Hz, 3 H, CH3).
1H NMR (400 MHz, CDCl3): δ = 7.80–7.84 (m, 2 H, Ph), 7.67–7.73 (m, 2
H, Ph), 3.82–4.07 (m, 5 H, 2 OCH2, CH2P), 2.55 (s, 3 H, CH3), 2.20 (dd,
J = 19.9, 15.3 Hz, 1 H, CH2P), 1.36 (s, 9 H, 3 CH3), 1.18 (t, J = 7.1 Hz, 3 H,
CH3), 1.08 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 168.14, 139.23, 139.14, 134.15,
131.47, 123.09, 116.30, 116.09, 67.89, 61.78, 36.52 (d, J = 135.5 Hz, C–
P), 28.00, 16.24, 16.13.
31P NMR (162 MHz, CDCl3): δ = 24.04.
HRMS (ESI): m/z [M + Na]+ calcd for C21H23FNO5PS: 474.0911; found:
13C NMR (101 MHz, CDCl3): δ = 168.60, 134.01, 131.81, 123.06, 67.06,
61.70, 47.62, 37.60 (d, J = 133.8 Hz, C–P), 32.11, 29.78, 16.23, 16.07.
31P NMR (162 MHz, CDCl3): δ = 24.00.
HRMS (ESI): m/z [M + Na]+ calcd for C19H28NO5PS: 436.1318; found:
436.1320.
474.0912.
Dimethyl 2-(1,3-Dioxoisoindolin-2-yl)-2-(ethylthio)propylphos-
phonate (3n)
Diethyl 2-(1,3-Dioxoisoindolin-2-yl)-2-[(4-methoxyphe-
nyl)thio]propylphosphonate (3j)
Colorless oil; yield: 0.061 g (55%).
Colorless oil; yield: 0.079 g (60%).
1H NMR (400 MHz, CDCl3): δ = 7.74–7.95 (m, 2 H, Ph), 7.57–7.74 (m, 2
H, Ph), 3.97 (t, J = 16.5 Hz, 1 H, CH2P), 3.63 (d, J = 11.0 Hz, 3 H, OCH3),
3.60 (d, J = 11.0 Hz, 3 H, OCH3), 2.67–2.81 (m, 1 H, SCH2), 2.55–2.66
(m, 1 H, SCH2), 2.37 (s, 3 H, CH3), 2.22 (dd, J = 20.1, 15.5 Hz, 1 H, CH2P),
1.15 (t, J = 7.5 Hz, 3 H, CH3).
1H NMR (400 MHz, CDCl3): δ = 7.75–7.82 (m, 2 H, Ph), 7.67–7.72 (m, 2
H, Ph), 7.28 (d, J = 8.7 Hz, 2 H, Ph), 6.73 (d, J = 8.7 Hz, 2 H, Ph), 3.94–
4.09 (m, 5 H, 2 OCH2, CH2P), 3.75 (s, 3 H, OCH3), 2.17–2.31 (m, 4 H,
CH3, CH2P), 1.18 (t, J = 7.1 Hz, 3 H, CH3), 1.10 (t, J = 7.1 Hz, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 168.22, 161.05, 138.73, 134.05,
131.57, 123.02, 114.48, 67.80, 61.73, 55.28, 36.36 (d, J = 134.7 Hz, C–
P), 27.89, 16.25, 16.14.
31P NMR (162 MHz, CDCl3): δ = 24.42.
HRMS (ESI): m/z [M + Na]+ calcd for C22H26NO6PS: 486.1111; found:
13C NMR (101 MHz, CDCl3): δ = 168.71, 134.09, 131.62, 123.11, 65.13,
52.60, 52.26, 35.83 (d, J = 135.4 Hz, C–P), 27.97, 23.95, 13.72.
31P NMR (162 MHz, CDCl3): δ = 26.93.
HRMS (ESI): m/z [M + Na]+ calcd for C15H20NO5PS: 380.0692; found:
380.0691.
486.1113.
Diisopropyl 2-(1,3-Dioxoisoindolin-2-yl)-2-(ethylthio)propylphos-
phonate (3o)
Diethyl 2-(1,3-Dioxoisoindolin-2-yl)-2-(o-tolylthio)propylphos-
phonate (3k)
Colorless oil; yield: 0.042 g (39%).
Colorless oil; yield: 0.062 g (49%).
1H NMR (400 MHz, CDCl3): δ = 7.81–7.87 (m, 2 H, Ph), 7.70–7.76 (m, 2
H, Ph), 4.57–4.72 (m, 2 H, 2 OCH), 3.89–4.03 (m, 1 H, CH2P), 2.72–2.88
(m, 1 H, SCH2), 2.58–2.69 (m, 1 H, SCH2), 2.44 (s, 3 H, CH3), 2.16 (dd,
J = 20.3, 15.3 Hz, 1 H, CH2P), 1.25–1.32 (m, 3 H, CH3), 1.21–1.25 (m, 6
H, 2 CH3), 1.13–1.19 (m, 6 H, 2 CH3).
13C NMR (101 MHz, CDCl3): δ = 168.69, 134.02, 131.78, 123.04, 70.37,
65.42, 37.80 (d, J = 136.1 Hz, C–P), 27.98, 24.04, 23.96, 23.88, 23.76,
13.77.
1H NMR (400 MHz, CDCl3): δ = 7.78–7.85 (m, 2 H, Ph), 7.69–7.75 (m, 2
H, Ph), 7.22–7.32 (m, 3 H, Ph), 6.96–7.04 (m, 1 H, Ph), 3.94–4.17 (m, 5
H, 2 OCH2, CH2P), 2.45 (s, 3 H, CH3), 2.32 (dd, J = 20.1, 15.4 Hz, 1 H,
CH2P), 2.22 (s, 3 H, CH3), 1.20 (t, J = 7.1 Hz, 3 H, CH3), 1.11 (t, J = 7.1 Hz,
3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 168.28, 143.89, 138.23, 134.10,
131.64, 130.75, 130.42, 130.07, 126.28, 123.09, 68.48, 61.79, 61.72,
37.06 (d, J = 134.2 Hz, C–P), 27.64, 21.34, 16.26, 16.13.
31P NMR (162 MHz, CDCl3): δ = 22.35.
HRMS (ESI): m/z [M + Na]+ calcd for C19H28NO5PS: 436.1318; found:
31P NMR (162 MHz, CDCl3): δ = 24.18.
HRMS (ESI): m/z [M + Na]+ calcd for C22H26NO5PS: 470.1162; found:
436.1320.
470.1165.
Dibutyl 2-(1,3-Dioxoisoindolin-2-yl)-2-(ethylthio)propylphospho-
nate (3p)
Diethyl 2-(1,3-Dioxoisoindolin-2-yl)-2-(isopropylthio)propylphos-
phonate (3l)
Colorless oil; yield: 0.046 g (43%).
Colorless oil; yield: 0.059 g (52%).
1H NMR (400 MHz, CDCl3): δ = 7.78–7.85 (m, 2 H, Ph), 7.66–7.75 (m, 2
H, Ph), 3.88–4.05 (m, 5 H, 2 OCH2, CH2P), 2.69–2.84 (m, 1 H, SCH2),
2.56–2.68 (m, 1 H, SCH2), 2.41 (s, 3 H, CH3), 2.14–2.28 (m, 1 H, CH2P),
1H NMR (400 MHz, CDCl3): δ = 7.77–7.82 (m, 2 H, Ph), 7.65–7.70 (m, 2
H, Ph), 3.82–4.04 (m, 5 H, 2 OCH2, CH2P), 3.18–3.32 (m, 1 H, CH), 2.43
(s, 3 H, CH3), 2.17 (dd, J = 19.9, 15.4 Hz, 1 H, CH2P), 1.22 (d, J = 6.9 Hz, 3
H, CH3), 1.11–1.19 (m, 6 H, 2 CH3), 1.07 (t, J = 7.0 Hz, 3 H, CH3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1669–1677

1676
Y. Cai et al.
Paper
Synthesis
1.46–1.54 (m, 2 H, CH2), 1.37–1.45 (m, 2 H, CH2), 1.23–1.33 (m, 4 H, 2
CH2), 1.17 (t, J = 7.5 Hz, 3 H, CH3), 0.86 (t, J = 7.4 Hz, 3 H, CH3), 0.81 (t,
J = 7.4 Hz, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 168.66, 134.05, 131.70, 123.09, 65.50,
65.29, 36.48 (d, J = 135.1 Hz, C–P), 32.39, 27.99, 23.93, 18.68, 13.74,
13.57.
31P NMR (162 MHz, CDCl3): δ = 24.57.
HRMS (ESI): m/z [M + Na]+ calcd for C27H36NO5PS: 540.1944; found:
540.1950.
Acknowledgment
31P NMR (162 MHz, CDCl3): δ = 24.35.
We thank the National Natural Science Foundation of China
(21072102), the Committee of Science and Technology of Tianjin
(11JCYBJC04200) and State Key Laboratory of Elemento-Organic
Chemistry in Nankai University for financial support.
HRMS (ESI): m/z [M + Na]+ calcd for C21H32NO5PS: 464.1631; found:
464.1636.
Dimethyl 2-(1,3-Dioxoisoindolin-2-yl)-3-phenyl-2-(p-tolyl-
thio)propylphosphonate (3q)
Supporting Information
Colorless oil; yield: 0.056 g (46%).
1H NMR (400 MHz, CDCl3): δ = 7.73–7.78 (m, 2 H, Ph), 7.67–7.71 (m, 4
H, Ph), 7.27–7.36 (m, 5 H, Ph), 6.95 (d, J = 7.9 Hz, 2 H, Ph), 4.35 (d, J =
14.3 Hz, 1 H, CH2), 4.20 (d, J = 14.3 Hz, 1 H, CH2), 4.09–4.17 (m, 2 H,
OCH2), 3.99–4.07 (m, 2 H, OCH2), 3.37 (dd, J = 18.4, 15.9 Hz, 1 H,
CH2P), 2.79 (dd, J = 20.0, 15.7 Hz, 1 H, CH2P), 2.23 (s, 3 H, CH3), 1.29 (t,
J = 7.1 Hz, 3 H, CH3), 1.18 (t, J = 7.1 Hz, 3 H, CH3).
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380384.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
References
13C NMR (101 MHz, CDCl3): δ = 168.36, 139.81, 136.68, 136.10,
134.06, 132.04, 131.30, 129.72, 127.98, 127.64, 127.02, 122.88, 73.10,
62.05, 61.64, 40.61, 32.62 (d, J = 138.9 Hz, C–P), 21.18, 16.34, 16.19.
31P NMR (162 MHz, CDCl3): δ = 24.69.
HRMS (ESI): m/z [M + Na]+ calcd for C28H30NO5PS: 546.1475; found:
(1) For selected recent examples, see: (a) DeLorbe, J. E.; Jabri, S. Y.;
Mennen, S. M.; Overman, L. E.; Zhang, F.-L. J. Am. Chem. Soc.
2011, 133, 6549. (b) DeLorbe, J. E.; Horne, D.; Jove, R.; Mennen,
S. M.; Nam, S.; Zhang, F.-L.; Overman, L. E. J. Am. Chem. Soc.
2013, 135, 4117. (c) Jabri, S. Y.; Overman, L. E. J. Am. Chem. Soc.
2013, 135, 4231. (d) Kim, J.; Ashenhurst, J. A.; Movassaghi, M.
Science (Washington, D.C.) 2009, 324, 238. (e) Wang, H. Y.;
Zhang, J. X.; Cao, D. D.; Zhao, G. ACS Catal. 2013, 3, 2218.
(2) (a) Bull, S. D.; Davies, S. G.; Parkin, R. M.; Sancho, F. S. J. Chem.
Soc., Perkin Trans. 1 1998, 2313. (b) Ding, G.; Jiang, L.; Guo, L.;
Chen, X.; Zhang, H.; Che, Y. J. Nat. Prod. 2008, 71, 1861.
(c) Kamei, H.; Oka, M.; Hamagishi, Y.; Tomita, K.; Komishi, M.;
Oki, T. J. Antibiot. 1990, 43, 1018. (d) Huang, R.; Zhou, X.; Xu, T.;
Yang, X.; Liu, Y. Chem. Biodiv. 2010, 7, 2809. (e) Cornacchia, C.;
Cacciatore, I.; Baldassarre, L.; Mollica, A.; Feliciani, F.; Pinnen, F.
Mini-Rev. Med. Chem. 2012, 12, 2. (f) Borthwick, A. D. Chem. Rev.
2012, 112, 3641.
(3) For selected epidithiodiketopiperazine total syntheses, see ref.
1a and: (a) Williams, R. M.; Rastetter, W. H. J. Org. Chem. 1980,
45, 2625. (b) Wu, Z.; Williams, L. J.; Danishefsky, S. J. Angew.
Chem. Int. Ed. 2000, 39, 3866. (c) Boyer, N.; Movassaghi, M.
Chem. Sci. 2012, 3, 1798. (d) Iwasa, E.; Hamashima, Y.; Fujishiro,
S.; Higuchi, E.; Ito, A.; Yoshida, M.; Sodeoka, M. J. Am. Chem. Soc.
2010, 132, 4078. (e) Kim, J.; Movassaghi, M. J. Am. Chem. Soc.
2010, 132, 14376. (f) Fukuyama, T.; Nakatsuka, S.; Kishi, Y. Tet-
rahedron 1981, 37, 2045. (g) Fukuyama, T.; Kishi, Y. J. Am. Chem.
Soc. 1976, 98, 6723.
(4) For selected examples, see: (a) Katritzky, A. R.; Szajda, M.;
Bayyuk, S. Synthesis 1986, 804. (b) Kurz, T.; Widyan, K.;
Elgemeie, G. H. Phosphorus, Sulfur Silicon Relat. Elem. 2006, 181,
299. (c) Kita, Y.; Shibata, N.; Kawano, N.; Yoshida, N.;
Matsumoto, K.; Takebe, Y. J. Chem. Soc., Perkin Trans. 1 1996,
2321.
(5) For selected recent examples, see: (a) Ingle, G. K.; Mormino, M.
G.; Wojtas, L.; Antilla, J. C. Org. Lett. 2011, 13, 4822. (b) Fang, X.;
Li, Q.-H.; Tao, H.-Y.; Wang, C.-J. Adv. Synth. Catal. 2013, 355, 327.
(c) Luo, Z.-B.; Hou, X.-L.; Dai, L.-X. Tetrahedron: Asymmetry
2007, 18, 443. (d) Cao, Y. M.; Zhang, F. T.; Shen, F. F.; Wang, R.
Chem. Eur. J. 2013, 19, 9476.
546.1477.
Diisopropyl 2-(1,3-Dioxoisoindolin-2-yl)-2-(ethylthio)-3-phenyl-
propylphosphonate (3r)
Colorless oil; yield: 0.042 g (40%).
1H NMR (400 MHz, CDCl3): δ = 7.77–7.85 (m, 2 H, Ph), 7.67–7.73 (m, 2
H, Ph), 7.52 (d, J = 6.5 Hz, 2 H, Ph), 7.21–7.29 (m, 3 H, Ph), 4.54–4.77
(m, 2 H, 2 OCH), 4.29 (d, J = 14.1 Hz, 1 H, CH2), 4.12 (d, J = 14.1 Hz, 1 H,
CH2), 3.23 (dd, J = 18.9, 15.9 Hz, 1 H, CH2P), 2.71–2.83 (m, 1 H, SCH2),
2.59–2.68 (m, 1 H, SCH2), 2.53 (dd, J = 20.1, 15.6 Hz, 1 H, CH2P), 1.22–
1.29 (m, 6 H, 2 CH3), 1.12–1.19 (m, 6 H, 2 CH3), 1.06 (d, J = 6.2 Hz, 3 H,
CH3).
13C NMR (101 MHz, CDCl3): δ = 168.61, 135.93, 134.12, 131.97,
131.54, 127.80, 126.97, 123.10, 70.94, 70.73, 70.25, 39.56, 32.96 (d, J =
139.8 Hz, C–P), 24.10, 23.92, 23.72, 12.99.
31P NMR (162 MHz, CDCl3): δ = 22.53.
HRMS (ESI): m/z [M + Na]+ calcd for C25H32NO5PS: 512.1631; found:
512.1635.
Dibutyl 2-(1,3-Dioxoisoindolin-2-yl)-2-(ethylthio)-3-phenylpro-
pylphosphonate (3s)
Colorless oil; yield: 0.051 g (48%).
1H NMR (400 MHz, CDCl3): δ = 7.77–7.82 (m, 2 H, Ph), 7.67–7.72 (m, 2
H, Ph), 7.46 (d, J = 6.1 Hz, 2 H, Ph), 7.20–7.27 (m, 3 H, Ph), 4.25 (d, J =
14.1 Hz, 1 H, CH2), 4.10 (d, J = 14.1 Hz, 1 H, CH2), 3.96–4.05 (m, 2 H,
OCH2), 3.87–3.95 (m, 2 H, OCH2), 3.26 (dd, J = 18.5, 15.9 Hz, 1 H,
CH2P), 2.59–2.82 (m, 3 H, SCH2, CH2P), 1.51–1.63 (m, 2 H, CH2), 1.39–
1.48 (m, 2 H, CH2), 1.30–1.37 (m, 2 H, CH2), 1.22–1.29 (m, 2 H, CH2),
1.17 (t, J = 7.5 Hz, 3 H, CH3), 0.88 (t, J = 7.4 Hz, 3 H, CH3), 0.81 (t, J = 7.4
Hz, 3 H, CH3).
13C NMR (101 MHz, CDCl3): δ = 168.60, 135.78, 134.17, 131.76,
131.40, 127.91, 127.03, 123.14, 70.74, 65.76, 65.40, 39.73, 32.53,
32.40, 31.76 (d, J = 116.0 Hz, C–P), 24.13, 18.77, 18.68, 13.60, 13.00.
(6) (a) Bartrun, H. E.; Blakemore, D. C.; Moody, C. J.; Hayes, C. J. Tet-
rahedron 2013, 69, 2276. (b) Xu, B.; Zhu, S. F.; Zhang, Z. C.; Yu, Z.
X.; Ma, Y.; Zhou, Q. L. Chem. Sci. 2014, 5, 1442.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1669–1677

1677
Y. Cai et al.
Paper
Synthesis
(7) For recent reviews, see: (a) Xiao, Q.; Zhang, Y.; Wang, J. B. Acc.
Chem. Res. 2013, 46, 236. (b) Zhao, X.; Zhang, Y.; Wang, J. B.
Chem. Commun. 2012, 48, 10162. (c) Davies, H. M. L.; Morton, D.
Chem. Soc. Rev. 2011, 40, 1857. (d) Doyle, M. P.; Ratnikov, M.;
Liu, Y. Org. Biomol. Chem. 2011, 9, 4007. (e) Doyle, M. P.; Duffy,
R.; Ratnikov, M.; Zhou, L.; Ye, T. Chem. Rev. 2010, 110, 704.
(f) Zhang, Y.; Wang, J. B. Chem. Commun. 2009, 5350. (g) Padwa,
A. Chem. Soc. Rev. 2009, 38, 3072. (h) Davies, H. M. L.; Denton, J.
R. Chem. Soc. Rev. 2009, 38, 3061. (i) Zhang, Z. H.; Wang, J. B. Tet-
rahedron 2008, 64, 6577. (j) Davies, H. M. L.; Hedley, S. J. Chem.
Soc. Rev. 2007, 36, 1109. (k) Davies, H. M. L.; Bechwith, R. E. J.
Chem. Rev. 2003, 103, 2861. (l) Mckervey, M. A.; Doyle, M. P.;
McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds: From Cyclopropanes to Ylide;
Wiley: New York, 1998, 433–436. (m) Miller, D. J. D.; Moody, J.
Tetrahedron 1995, 51, 10811.
(8) For elected examples on carbenoid C–H insertion, see ref. 7d
and: (a) DeAnglis, A.; Shurtleff, V. W.; Dmitrenko, O.; Fox, J. M.
J. Am. Chem. Soc. 2011, 133, 1650. (b) Wolckenhauser, S. A.;
Devlin, A. S.; Du Bios, J. Org. Lett. 2007, 9, 4363. (c) Davies, H. M.
L. Angew. Chem. Int. Ed. 2006, 45, 6422. (d) Davies, H. M. L.;
Townsend, R. J. J. Org. Chem. 2001, 66, 6595. For selected exam-
ples on carbenoid O–H insertion, see: (e) Zhu, S. F.; Song, X. G.;
Li, Y.; Cai, Y.; Zhou, Q. L. J. Am. Chem. Soc. 2010, 132, 16374.
(f) Zhu, S. F.; Cha, Y.; Mao, H. X.; Xie, J. H.; Zhou, Q. L. Nat. Chem.
2010, 2, 546. (g) Zhu, S. F.; Chen, C.; Cai, Y.; Zhou, Q. L. Angew.
Chem. Int. Ed. 2008, 47, 932. (h) Chen, C.; Zhu, S. F.; Liu, B.;
Wang, L. X.; Zhou, Q. L. J. Am. Chem. Soc. 2007, 129, 12616.
(i) Maier, T. C.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 4594. For
selected examples on carbenoid N–H insertion, see: (j) Zhu, S.
F.; Xu, B.; Wang, G. P.; Zhou, Q. L. J. Am. Chem. Soc. 2012, 134,
436. (k) 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. (l) Liu,
B.; Zhu, S. F.; Zhang, W.; Chen, C.; Zhou, Q. L. J. Am. Chem. Soc.
2007, 129, 5834. (m) Moody, C. J. Angew. Chem. Int. Ed. 2007, 46,
9148. For selected examples on carbenoid Si–H insertion, see:
(n) Zhang, Y. Z.; Zhu, S. F.; Wang, L. X.; Zhou, Q. L. Angew. Chem.
Int. Ed. 2008, 47, 8496.
Moody, C. J. Tetrahedron Lett. 1994, 35, 5949. (f) Landais, Y.;
Planchenault, D. Synlett 1995, 1191. (g) Cox, G. G.; Moody, C. J.;
Austin, D. J.; Padwa, A. Tetrahedron 1993, 49, 5109.
(10) (a) Moyer, M. P.; Feldman, P. L.; Rapoport, H. J. Org. Chem. 1985,
50, 5223. (b) Brunner, H.; Wutz, K.; Doyle, M. P. Monatsh. Chem.
1990, 121, 755. (c) Bulugahapitiya, P.; Landais, Y.; Parra-
Rapado, L.; Planchenault, D.; Weber, V. J. Org. Chem. 1997, 62,
1630.
(11) Zhang, Y. Z.; Zhu, S. F.; Cai, Y.; Mao, H. X.; Zhou, Q. L. Chem.
Commun. 2009, 5362.
(12) (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) Wang, J.; Boyarshikh, V.;
Rainier, J. D. Org. Lett. 2011, 13, 700. (f) Davies, H. M. L.; Lee, G.
H. Org. Lett. 2004, 6, 2117. (g) Zhang, H.; Wen, X. J.; Gan, L. H.;
Peng, Y. G. Org. Lett. 2012, 14, 2126. (h) Hashimoto, T.; Maruoka,
K. J. Am. Chem. Soc. 2007, 129, 10054.
(13) Cai, Y.; Lu, Y. C.; Yu, C. B.; Lyu, H. R.; Miao, Z. W. Org. Biomol.
Chem. 2013, 11, 5491.
(14) For recent reviews see the following: (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; Juaristi, E.; Soloshonok, V. A., Eds.; Wiley: New
York, 2005, 2nd ed. 277–317.
(15) (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. (e) Cai, Y.; Lyu, H.
R.; Yu, C. B.; Miao, Z. W. Adv. Synth. Catal. 2014, 356, 596.
(16) (a) Jiang, N.; Ma, Z. H.; Qu, Z. H.; Xing, X. Y.; Xie, L. F.; Wang, J. B.
J. Org. Chem. 2003, 68, 893. (b) Xiao, F. P.; Zhang, Z. H.; Zhang, J.;
Wang, J. B. Tetrahedron Lett. 2005, 46, 8873.
(17) See the supporting information for details on the crystal struc-
ture of 3f. Crystallographic data for the structural analysis of
compound 3f has been deposited at the Cambridge Crystallo-
graphic Data Centre as No. CCDC 969832. These data can be
obtained free of charge by contacting The Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK;
fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk.
(18) Cai, Y.; Ge, H. H.; Yu, C. B.; Sun, W. Z.; Zhan, J. C.; Miao, Z. W. RSC
Adv. 2014, 4, 21492.
(9) For metallo-carbene insertion into N–H bonds, see:
(a) Paulissen, R.; Hayez, E.; Hubert, A. J.; Teyssié, P. Tetrahedron
Lett. 1974, 15, 607. (b) Nicoud, J.-F.; Kagan, H. Tetrahedron Lett.
1971, 12, 2065. For metallo-carbene insertion into O–H bonds,
see: (c) Cox, G. G.; Miller, D. J.; Moody, C. J.; Sie, E.-R. H. B.;
Kulagowski, J. J. Tetrahedron 1994, 50, 3195. (d) Haigh, D. Tetra-
hedron 1994, 50, 3177. (e) Aller, E.; Cox, G. G.; Miller, D. J.;
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1669–1677