Palladacycle-catalyzed methylenecyclopropanation of bicyclic alkenes with propiolates

Article abstract of DOI:10.1021/jo402024v

An efficient way to access functionalized methylenecyclopropanes has been developed by palladacycle-catalyzed cyclopropanation of bicyclic alkenes with propiolates in high yields. The structure of the palladacycle was kept intact in the reaction, shown by ³¹P NMR spectrum studies. A rational mechanism has been proposed with a deuterium-labeled experiment. The usefulness of the functionalized methylenecyclopropanes has also been demonstrated.

Full text of DOI:10.1021/jo402024v

Article
pubs.acs.org/joc
Palladacycle-Catalyzed Methylenecyclopropanation of Bicyclic
Alkenes with Propiolates
Dong-Liang Mo,† Teng Yuan,† Chang-Hua Ding,*,† Li-Xin Dai,† and Xue-Long Hou*,†,‡
‡
†State Key Laboratory of Organometallic Chemistry, Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai, 200032, China
S
* Supporting Information
ABSTRACT: An efficient way to access functionalized methylenecyclopropanes has been developed by palladacycle-catalyzed
cyclopropanation of bicyclic alkenes with propiolates in high yields. The structure of the palladacycle was kept intact in the
reaction, shown by 31P NMR spectrum studies. A rational mechanism has been proposed with a deuterium-labeled experiment.
The usefulness of the functionalized methylenecyclopropanes has also been demonstrated.
high yields. The usefulness of the products is also
demonstrated.
INTRODUCTION
■
Methylene- and alkylidenecyclopropanes having a strained
three-membered carbocyclic ring and an exo-methylene moiety
are found in many natural-occurring and artificial biologically
active molecules.1 They have also served as highly versatile
synthons in organic synthesis and received intensive attention
from synthetic chemists over the past decade.2 To date, a
variety of methodologies for their synthesis have been reported,
such as elimination of cyclopropane derivatives,3 Wittig
olefinations,4 the addition of carbenes to allenes,5 the addition
of alkylidenecarbenes to olefins,6 and other cyclization
reactions.7 These procedures, however, suffer from a multistep
synthesis, harsh reaction conditions, lower yields, or limited
substrate scope. The preparation of alkylidenecyclopropanes
has also been realized by transition-metal-catalyzed reaction of
alkynes with alkenes. However, phenyl- and alkyl-substituted
alkynes were used in most cases.8 In the course of our research
on the development of palladacycles as the real transition metal
catalyst,9−11 we realized the selectivity switch in the reaction of
bicyclic alkenes with terminal alkynes, affording addition and
ring-opening products selectively using palladacycles with an
sp3 and sp2 C−Pd bond respectively.12 When terminal ynones
were the substrates, polysubstituted furans were obtained
regioselectively under palladacycle catalysis.13 Further research
showed that an alkylidenecyclopropane was produced if
propiolates were used to react with bicyclic alkenes. In this
paper, we report the reaction of bicyclic alkenes with
propiolates by using a phosphapalladacycle as the catalyst to
provide alkoxycarbonyl substituted alkylidenecyclopropanes in
RESULTS AND DISSCUSSION
■
The research was initiated by our findings in the mechanistic
studies on the reaction of bicyclic alkenes with ynones. In that
study, we found that the alkylidenecyclopropanes should be the
reaction intermediate, which was then transformed to furan
products (Scheme 1A). We reasoned that the latter rearrange-
ment may be attributed to the easy enolization of ketone. We
envisioned that alkylidenecyclopropanes should be afforded in
the presence of a palladacycle catalyst if we use a reactant that
does not enolize (Scheme 1B). Thus, the ethyl propiolate (2a)
(2.0 equiv) was reacted with 7-oxabenzonorbornadiene (1a) in
the presence of palladacycle P1 (2.5 mol %) as the catalyst in
1,2-dichloroethane (DCE) at 50 °C for 5 h. Indeed, expected
alkylidenecyclopropanes 3a was obtained in 51% yield, and its
structure was established by X-ray diffraction. The control
experiments with some common palladium species, such as
Pd(OAc)2, Pd(OAc)2/PPh3, Pd(OAc)2/(R)-BINAP,
Pd2(dba)3·CHCl3, Pd(CH3CN)2Cl2, and Pd(PPh3)2Cl2, re-
sulted in no reaction or low conversion (<10%), which revealed
the efficiency of a palladacycle in this reaction. A series of
palladacycles (Figure 1) were then examined under the
conditions shown in Table 1. Both the scaffold and donor
atom of palladacycles affected the reaction greatly. The reaction
Received: September 11, 2013
Published: October 15, 2013
© 2013 American Chemical Society
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Scheme 1. Reaction of Bicyclic Alkenes with Ynones or Propiolates Catalyzed by a Palladacycle
Figure 1. Palladacycles with different scaffolds and donor atoms.
group in palladacycle P5 was replaced with acetylacetonate, the
yield of 3a decreased dramatically to 38% (entry 6 vs 5). With
the palladacycle P5 in hand, the influence of solvents on the
reaction was evaluated. The reaction in toluene or CHCl3
afforded 3a in moderate yield (entries 9 and 10), while the yield
dropped sharply when tetrahydrofuran (THF), dimethoxy-
ethane (DME), or CH3CN was used as the solvent (entries
11−13 vs 5). The use of EtOH hampered the reaction; only
trace amount of product 3a was observed from 1H NMR (entry
14).
To further improve the reaction, the effect of additives was
investigated with palladacycle P5 as the catalyst and DCE as the
solvent (Table 2). We observed that the addition of a base,
such as NEt3 or Cs2CO3, shut down the reaction completely
while the starting material 1a was almost fully recovered
(entries 2 and 3). In contrast, the acid additive had great impact
on the reaction. A strong acid such as CF3COOH fully
inhibited the reaction (entry 4), while AcOH gave a lower yield
than that without any additive (entry 5 vs 1). Delightfully, the
addition of 50 mol % of benzoic acid led to an increased yield
of product 3a (entry 6 vs 1). We then examined the effect of
the quantity of benzoic acid on the reaction. These experiments
indicated the use of a catalytic amount of benzoic acid resulted
in a dramatic decrease of yield, while the use of a stoichiometric
amount of benzoic acid did not improve the reaction (entries 7
and 8 vs 6). Also, the substituents at the para-position of
benzoic acid have a great effect on the reaction (entries 9−12).
The presence of an electron withdrawing group diminished the
yield noticeably (entries 9 vs 6). In contrast, the introduction of
an electron donating group is beneficial for the reaction and the
best result was obtained when p-MeOC6H4COOH was used as
the additive, providing 3a in 84% yield (entry 12).
Table 1. Optimizations for Cyclopropanation of Bicyclic
Alkene 1a with Propiolate 2a
a
entry
solvent
palladacycle
3a, yield (%)
1
DCE
P1
P2
P3
P4
P5
P6
P7
P8
P5
P5
P5
P5
P5
P5
51
43
56
5
2
DCE
3
DCE
4
DCE
5
DCE
64
38
−
6
DCE
7
DCE
8
DCE
−
9
toluene
CHCl3
DME
THF
58
49
6
10
11
12
13
14
10
12
CH3CN
EtOH
b
Trace
a
Reaction conditions: 1a (28.8 mg, 0.2 mmol), 2a (40 μL, 0.4 mmol),
b
palladacycle (0.005 mmol), DCE (3.0 mL). Determined by 1H NMR.
usually proceeded smoothly by using P-containing palladacycles
P1−3 and P5−6 (entries 1−3 and entries 5−6) while no
reaction took place if N-containing palladacycles P7 and P8
were the catalysts (entries 7−8). Palladacycles P1−3 gave
product 3a in moderate yield (entries 1−3). In contrast, the
reaction became sluggish with palladacycle P4 although it has
the same scaffold as that of P3, perhaps due to its steric
hindrance (entry 4). Palladacycle P5 showed the highest
activity, affording 3a in 64% yield (entry 5). When the acetate
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3g−i). In addition, some other bicyclic alkenes, such as
dimethyl oxanorbornadiene-2,3-dicarboxylate and 7-azabenzo-
norbornadiene, could also be used in the reaction, providing
corresponding alkylidenecyclopropanes in good yields (3j−m).
It is worthwhile to note that no cyclopropanes were obtained
when norbornadiene derivates were used as the reactant;
instead, polycyclic products 3n and 3o were afforded in 71%
and 69% yield respectively.14 The examination of alkyne
substrates revealed that different alkyl and phenyl propiolates
reacted with oxa-bicyclicalkenes, providing the corresponding
alkylidenecyclopropanes in good yields (3a−e). Especially,
cyclopropanation product 3f was delivered in moderate yield
when tosylacetylene was the reagent. Propiolamide was also
applicable to the cyclopropanation reaction to give alkylidene-
cyclopropanes 3p in 81% yield. Further studies of substrate
scope revealed that the reaction is only applicable to terminal
propiolates. When methyl-2-butynoate was subjected to the
standard reaction conditions, no reaction occurred (not shown
in table).
To investigate the reaction mechanism, the reaction was
traced by a 31P NMR spectrum using palladacycle P2 as the
catalyst (Figure 2). The 31P NMR spectrum of palladacycle P2
shows the peak at δ 34.9 ppm (sample A), which disappeared,
and a new peak was observed at δ 30.6 ppm if 1.0 equiv of
methyl propiolate (2a) was added after 10 min (sample B).15
When bicyclic alkene 1a (1.0 equiv) was added into sample B,
the peak at δ 34.9 ppm appeared accompanied by two small
peaks at δ 25.0 and 24.6 ppm (Sample C). The peaks at δ 30.6,
Table 2. Evaluation of Additive for Palladacycle P5-
Catalyzed Cyclopropanation of Bicyclic Alkene 1a with
Propiolate 2a
a
entry
additive
equiv.
3a, yield (%)
1
−
NEt3
−
64
b
2
0.5
0.5
0.5
0.5
0.5
0.05
1.0
0.5
0.5
0.5
0.5
N.o.
b
3
Cs2CO3
N.o.
b
4
CF3COOH
N.o.
5
AcOH
57
77
60
73
53
74
81
84
6
PhCOOH
7
PhCOOH
8
PhCOOH
9
p-NO2C6H4COOH
p-BrC6H4COOH
p-MeC6H4COOH
p-MeOC6H4COOH
10
11
12
a
Reaction conditions: 1a (28.8 mg, 0.2 mmol), 2a (40 μL, 0.4 mmol),
b
P5 (0.005 mmol), DCE (3.0 mL). N.o. = Not observed.
Under the optimized conditions, the substrate scope of the
reaction was evaluated (Table 3). Various oxabicyclic alkenes
with a methoxy group and Br atom as the substituent were
suitable substrates to afford products 3 in high yields (3a and
a
Table 3. Substrate Scope for Palladacycle P5-Catalyzed Cyclopropanation of Bicyclic Alkenes with Propiolates
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), P5 (0.005 mmol), p-MeOC6H4COOH (15.2 mg, 0.1 mmol), DCE (3.0 mL).
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Figure 2. 31P NMR spectrum studies of the reaction (sample A: 31P NMR of palladacycle P2 in DCE; sample B: 31P NMR was detected when 2a
(1.0 equiv) was added to A after 10 min; sample C: 31P NMR was detected when 1a (1.0 equiv) was added to B after 1 h; sample D: 31P NMR was
detected after 5 h when 1a was consumed by TLC).
25.0, and 24.6 ppm disappeared completely, and only the peak
of palladacycle P2 was found at δ 35.0 ppm after 5 h (Sample
D). Product 3a was separated by column chromatography in
56% yield from sample D. These results showed that the
palladacycles served as a real transition metal catalyst in the
reaction, which was supported further by mass spectra (ESI)
study. It was found that palladacycle P2 gave a peak at m/z
409.0 (sample A), which could also be obtained when the
reaction completed (sample D).16
Scheme 2. A Plausible Mechanism for the Palladacycle-
Catalyzed Cyclopropanation of Bicyclic Alkenes with
Propiolates
A further clue concerning the reaction mechanism comes
from deuterium labeling experiments. It demonstrated that
product 3a partially deuterium-labeled at the exo-vinyl carbon
was afforded by the reaction using either a deuterium-labeled
terminal alkyne or deuterium-labeled acid as an additive (eqs 1
and 2).
lecular protonolysis to release product 3 and the palladacycle
catalyst. The acid additive may accelerate this protonolysis step.
The usefulness of the alkoxycarbonyl substituted alkylidene-
cyclopropane product 3 was also investigated. The reaction of
alkylidenecyclopropanes 3a with 4.0 equiv of CuBr2 under 85
°C produced dibromide 4 in 53% yield,17 and its structure was
determined by X-ray diffraction (Scheme 3, eq 3). Furthermore,
when 3a was treated with nitrone in toluene at 100 °C, [3 + 2]
cycloaddition products isoxazolidine 5a and 5b were obtained
Based upon the above evidence and the literature,8h,10a
a
plausible mechanism was proposed (Scheme 2). The reaction
of a palladacycle with propiolate 2 produces alkynylpalladium-
(II) A, which adds to the oxabicyclic alkene to form
intermediate B. Intermediate B goes through an intramolecular
insertion to form intermediate C, which undergoes intermo-
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129 (62), 115 (46), 77(10); IR (KBr, neat): 3052, 3003, 2971, 2907,
1756, 1706, 1459, 1373, 1191, 746, 665 cm−1; HRMS (EI) m/z for
C15H14O3: Calcd 242.0943; Found 242.0959.
Scheme 3. Transformation of Product 3a
1
3b. 39.6 mg, yield 87%. White solid. Mp: 106−108 °C; H NMR
(300 MHz, CDCl3): δ 1.98 (d, J = 7.2 Hz, 1H), 2.23 (d, J = 7.2 Hz,
1H), 3.78 (s, 3H), 5.52 (s, 1H), 5.62 (s, 1H), 6.20 (s, 1H), 7.19−7.21
(m, 2H), 7.37−7.38 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 26.0,
28.5, 51.5, 80.1, 80.2, 111.7, 119.6, 119.7, 126.5, 126.6, 146.3, 146.4,
151.2, 165.9; MS (EI) m/z (rel): 228 (M+, 6), 199 (16), 185 (12), 168
(76), 155 (25), 141 (100), 128 (34), 115 (52), 77 (8); IR (KBr, neat):
3045, 3013, 2949, 2841, 1755, 1694, 1458, 1434, 1288, 1040, 757, 669
cm−1; HRMS (EI) m/z for C14H12O3: Calcd 228.0786; Found
228.0784.
1
3c. 69.8 mg, yield 88%. White solid. Mp: 116−118 °C; H NMR
in 24% and 59% yield respectively (Scheme 3, eq 4).18
Isoxazolidines have been demonstrated as valuable building
blocks which were readily converted to γ-amino alcohols, β-
amino acids, and β-lactams in recent decades.19
(400 MHz, CDCl3): δ 1.29 (d, J = 4.4 Hz, 3H), 1.31 (d, J = 4.4 Hz,
3H), 1.96 (d, J = 7.2 Hz, 1H), 2.21 (d, J = 7.2 Hz, 1H), 5.06−5.15 (m,
1H), 5.51 (s, 1H), 5.59 (s, 1H), 6.16 (s, 1H), 7.19−7.21 (m, 2H),
7.35−7.39 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 21.9, 25.8, 28.4,
67.5, 80.0, 80.1, 112.5, 119.6, 119.7, 126.5, 126.6, 146.4, 146.5, 150.5,
165.0; MS (ESI) m/z (rel): 257.4 (M+H)+; IR (KBr, neat): 2986,
1752, 1706, 1461, 1369, 1190, 1110, 746 cm−1; HRMS(ESI) m/z for
C16H17O3 (M+H)+: Calcd 257.1178; Found 257.1174.
CONCLUSION
■
In summary, we have developed a simple and efficient method
for preparing functionalized methylenecyclopropanes via cyclo-
propanation of bicyclic alkenes with propiolates catalyzed by a
phosphapalladacycle. The mechanism investigations demon-
strate that the palladacycle was the real transition metal catalyst
in the reaction. The usefulness of the products is also
demonstrated. Further investigations on the applications of
the protocol as well as the palladacycles in organic synthesis are
in progress.
3d. 49.3 mg, yield 85%. Yellow oil; 1H NMR (400 MHz, CDCl3): δ
2.06 (d, J = 7.2 Hz, 1H), 2.30 (d, J = 7.2 Hz, 1H), 5.57 (s, 1H), 5.64
(s, 1H), 6.38 (s, 1H), 7.15−7.23 (m, 5H), 7.35−7.42 (m, 4H); 13C
NMR (100 MHz, CDCl3): δ 26.6, 28.9, 80.3, 80.4, 111.5, 119.7, 119.8,
121.7, 125.7, 126.6, 126.7, 129.4, 146.3, 146.4, 150.8, 153.6, 163.8; MS
(ESI) m/z (rel): 313 (M+Na)+; IR (KBr, neat): 3056, 1721, 1593,
1492, 1458, 1197, 1144, 883, 759, 668 cm−1; HRMS (ESI) m/z for
C19H14NaO3 (M+Na)+: Calcd 313.0841; Found 313.0836.
3e. 37.6 mg, yield 74%. Colorless oil; 1H NMR (400 MHz, CDCl3):
δ 1.98 (d, J = 7.2 Hz, 1H), 2.23 (d, J = 7.2 Hz, 1H), 4.68 (d, J = 4.8
Hz, 2H), 5.25 (d, J = 10.4 Hz, 1H), 5.35 (d, J = 17.2 Hz, 1H), 5.51 (s,
1H), 5.60 (s, 1H), 5.94−6.03 (m, 1H), 6.21 (s, 1H), 7.19−7.20 (m,
2H), 7.36−7.37 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 26.1, 28.5,
64.9, 80.1, 80.2, 111.8, 117.9, 119.6, 119.7, 126.5, 126.6, 132.3, 146.3,
146.4, 151.5, 165.0; MS (EI) m/z (rel): 254 (M+, 0.5), 213 (6), 185
(93), 169 (24), 157 (58), 141 (100), 129 (66), 115 (56), 77 (7); IR
(KBr, neat): 3051, 3001, 1712, 1647, 1458, 1370, 1171, 881, 759, 668
cm−1; HRMS (EI) m/z for C16H14O3: Calcd 254.0943; Found
254.0948.
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed under an
atmosphere of either dry argon or nitrogen using oven-dried glassware.
Solvents were treated using standard procedures and were distilled
under an atmosphere of nitrogen before use. Commercially available
reagents were used without further purification. H and 13C NMR
1
spectra were recorded on an NMR instrument operated at 300, 400
MHz respectively. Chemical shifts are reported in ppm from
tetramethylsilane with the solvent resonance as the internal standard
(CDCl3: δ 7.26 ppm). Data are reported as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br =
broad, m = multiplet or unresolved), coupling constants (Hz), and
integration. 13C NMR spectra were recorded on an NMR instrument
operated at 75, 100 MHz respectively with complete proton
decoupling. Chemical shifts are reported in ppm from tetramethylsi-
lane with the solvent resonance as the internal standard (CDCl3: δ
77.0 ppm). IR spectra were recorded from thin films of pure samples.
MS and HRMS were measured in EI or ESI mode, and the mass
analyzer of the HRMS was TOF. Flash column chromatography was
performed on silica gel (300−400 mesh). The palladacycles P1,20
P2,21 P3, P4,22 P5,11b P6,13 P7,11a and P823 were prepared according
to literature methods, and their spectral data matched literature values.
General Procedure for Cyclopropanation of Oxabicyclic
Alkenes with Propiolates Catalyzed by Palladacycle P5. In a
Schlenk tube, palladacycle P5 (2.5 mol %), oxabicyclic alkenes 1 (0.2
mmol), and p-MeOC6H4COOH (15.2 mg, 0.1 mmol) were dissolved
in DCE (3 mL) under argon. Terminal alkyne 2 (0.4 mmol) was
added slowly to the mixture. Then, the mixture was stirred at 50 °C
until the substrate 1 disappeared (monitored by TLC). The solvent
was removed, and the residue was purified by flash chromatography on
silica gel using PE/EtOAc (10/1−5/1) as the eluent to give product 3.
3a. 40.6 mg, yield 84%. White solid. Mp: 60−62 °C; 1H NMR (300
MHz, CDCl3): δ 1.31 (t, J = 6.9 Hz, 3H), 1.97 (d, J = 6.9 Hz, 1H),
2.21 (d, J = 6.9 Hz, 1H), 4.20 (q, J = 6.9 Hz, 2H), 5.52 (s, 1H), 5.61
(s, 1H), 6.19 (s, 1H), 7.18−7.21 (m, 2H), 7.35−7.37 (m, 2H); 13C
NMR (75 MHz, CDCl3): δ 14.3, 25.9, 28.4, 60.2, 80.0, 80.1, 112.1,
119.6, 119.7, 126.5, 126.59, 146.3, 146.4, 150.9, 165.5; MS (EI) m/z
(rel): 242 (M+, 2), 213 (18), 185 (59), 168 (48), 157 (45), 141 (100),
1
3f. 27.2 mg, yield 42%. Yellow solid. Mp: 135−136 °C; H NMR
(300 MHz, CDCl3): δ 2.06 (d, J = 7.2 Hz, 1H), 2.37 (d, J = 7.2 Hz,
1H), 2.43 (s, 3H), 5.51 (s, 1H), 5.53 (s, 1H), 6.67 (s, 1H), 7.19−7.22
(m, 2H), 7.33−7.36 (m, 4H), 7.80 (d, J = 8.1 Hz, 2H); 13C NMR (75
MHz, CDCl3): δ 21.6, 26.3, 28.6, 80.2, 80.3, 119.8, 119.9, 121.5, 126.7,
126.8, 127.7, 129.8, 138.1, 144.3, 145.9, 146.0, 148.0; MS (ESI) m/z
(rel): 325.1 (M+H)+; IR (KBr, neat): 3047, 3003, 1745, 1598, 1458,
1341, 1289, 1140, 1083, 756, 675 cm−1; HRMS (ESI) m/z for
C19H17O3S (M+H)+: Calcd 325.0898; Found 325.0892.
1
3g. 51.3 mg, yield 85%. White solid. Mp: 121−123 °C; H NMR
(300 MHz, CDCl3): δ 1.31 (t, J = 6.6 Hz, 3H), 2.02 (d, J = 6.9 Hz,
1H), 2.26 (d, J = 6.9 Hz, 1H), 3.82 (s, 6H), 4.23 (q, J = 6.6 Hz, 2H),
5.69 (s, 1H), 5.79 (s, 1H), 6.16 (s, 1H), 6.69 (s, 2H); 13C NMR (75
MHz, CDCl3): δ 14.3, 25.5, 28.1, 56.0, 56.1, 60.2, 78.3, 78.4, 111.5,
111.6, 111.8, 135.5, 147.3, 147.4, 150.9, 165.5; MS (EI) m/z (rel): 302
(M+, 69), 274 (40), 259 (43), 245 (53), 228 (42), 215 (100), 199
(58), 171 (54), 115 (69), 77 (30); IR (KBr, neat): 3009, 2841, 1755,
1702, 1500, 1458, 1262, 1082, 807, 712 cm−1; HRMS (EI) m/z for
C17H18O5: Calcd 302.1154; Found 302.1146.
1
3h. 49.1 mg, yield 81%. White solid. Mp: 119−122 °C; H NMR
(300 MHz, CDCl3): δ 1.31 (t, J = 6.9 Hz, 3H), 1.96 (d, J = 7.2 Hz,
1H), 2.20 (d, J = 7.2 Hz, 1H), 3.89 (s, 6H), 4.20 (q, J = 6.9 Hz, 2H),
5.48 (s, 1H), 5.78 (s, 1H), 6.15 (s, 1H), 7.00 (d, J = 5.1 Hz, 2H); 13C
NMR (75 MHz, CDCl3): δ 14.3, 26.3, 28.8, 56.3, 60.2, 80.5, 80.6,
104.7, 104.8, 111.6, 139.0, 139.1, 147.5, 147.6, 150.9, 165.6; MS (ESI)
m/z (rel): 303 (M+H)+; IR (KBr, neat): 2937, 2834, 1707, 1500,
1462, 1204, 1078, 847, 667 cm−1; HRMS (ESI) m/z for C17H18NaO5
(M+Na)+: Calcd 325.1052; Found 325.1052.
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1
3i. 59.7 mg, yield 75%. Yellow solid. Mp: 158−160 °C; H NMR
(400 MHz, CDCl3): δ 1.31 (t, J = 6.8 Hz, 3H), 1.98 (d, J = 6.8 Hz,
1H), 2.22 (d, J = 6.4 Hz, 1H), 4.21 (q, J = 6.8 Hz, 2H), 5.45 (s, 1H),
5.53 (s, 1H), 6.19 (s, 1H), 7.61 (d, J = 6.8 Hz, 2H); 13C NMR (75
MHz, CDCl3): 14.3, 25.3, 27.8, 60.4, 79.5, 79.6, 113.0, 122.4, 122.5,
125.1, 125.2, 147.3, 147.4, 148.9, 165.2; MS (EI) m/z (rel): 398 (M+,
4), 372 (19), 356 (15), 299 (25), 262 (8), 207 (17), 167 (4), 139
(100), 69 (15); IR (KBr, neat): 2986, 2851, 1697, 1183, 831, 675
cm−1; HRMS (EI) m/z for C15H12Br2O3: Calcd 397.9153; Found
397.9155.
1623, 1422, 880, 754, 670 cm−1; HRMS (ESI) m/z for C13H12NO2 (M
+H)+: Calcd 214.0863; Found 214.0896.
Reaction of 3a with CuBr2. The Synthesis of Product 4. In a
Schlenk tube with a condenser, substrate 3a (48 mg, 0.2 mmol) and
CuBr2 (176 mg, 0.8 mmol) were dissolved in the mixed solvent of
CH3CN (4 mL) and H2O (1 mL) under argon. Then, the mixture was
stirred at 85 °C for about 10 h. The solvent was removed, and the
residue was purified by flash chromatography on silica gel using PE/
EtOAc (10/1−5/1) as the eluent to give product 4 as a white solid;
yield 53%. Mp: 166−167 °C; 1H NMR (300 MHz, CDCl3): δ 1.20 (t,
J = 1.5 Hz, 3H), 4.09−4.13 (m, 2H), 4.52 (s, 1H), 5.44 (s, 1H), 5.46
(s, 1H), 5.85 (s, 1H), 5.89 (s, 1H), 7.30−7.31 (m, 4H); 13C NMR (75
MHz, CDCl3): δ 13.9, 40.6, 46.6, 60.7, 82.6, 83.0, 121.4, 121.8, 126.6,
129.0, 129.2, 140.0, 140.4, 149.7, 163.8; MS (ESI) m/z (rel): 422.9 (M
+Na)+; IR (KBr, neat): 2981, 2966, 2936, 2854, 1714, 1647, 1464,
1254, 1212, 1178, 1045, 736, 679 cm−1; HRMS (ESI) m/z for
C15H14Br2O3Na (M+Na)+: Calcd 422.9207; Found 422.9186.
Reaction of 3a with Nitrone. The Synthesis of Products 5a
and 5b. In a Schlenk tube, (Z)-N-benzylidenemethanamine oxide
(308 mg, 2.28 mmol) was added to a solution of compound 3a (415
mg, 1.71 mmol) in toluene (4 mL), and the reaction mixture was
stirred for 40 h at 100 °C. Evaporation of the solvent under reduced
pressure and purification of the crude product by chromatography on
silica gel (ethyl acetate/petroleum ether = 1/8) afforded product 5a
(158 mg, 24%) and product 5b (379.6 mg, 59%).
3j. 37.5 mg, yield 61%. Colorless oil; 1H NMR (400 MHz, CDCl3):
δ 1.30 (t, J = 7.2 Hz, 3H), 2.27 (d, J = 6.8 Hz, 1H), 2.51 (d, J = 6.8 Hz,
1H), 3.85 (s, 6H), 4.20 (q, J = 7.2 Hz, 2H), 5.41 (s, 1H), 5.49 (s, 1H),
6.14 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 14.1, 26.0, 28.5, 52.3,
60.3, 82.0, 82.1, 111.9, 146.6, 147.0, 149.8, 162.4, 162.5, 165.1; MS
(EI) m/z (rel): 308 (M+, 1), 248 (9), 220 (18), 203 (57), 191 (12),
176 (100), 161 (13), 153 (18), 96 (27), 79 (42); IR (KBr, neat):
2985, 2957, 2906, 1717, 1630, 1438, 1263, 1185, 733, 692 cm−1;
HRMS (EI) m/z for C15H16O7: Calcd 308.0896; Found 308.0898.
3k. 38.2 mg, yield 65%. Colorless oil; 1H NMR (400 MHz, CDCl3):
δ 2.28 (d, J = 7.2 Hz, 1H), 2.52 (d, J = 7.2 Hz, 1H), 3.77 (s, 3H), 3.85
(s, 6H), 5.42 (s, 1H), 5.50 (s, 1H), 6.15 (s, 1H); 13C NMR (100 MHz,
CDCl3): δ 26.1, 28.5, 51.5, 52.3, 82.0, 82.1, 111.5, 146.6, 147.0, 150.1,
162.4, 162.5, 165.5; MS (ESI) m/z (rel): 317.0 (M+Na)+; IR (KBr,
neat): 2961, 1738, 1719, 1704, 1440, 1238, 1132, 856, 696 cm−1;
HRMS (ESI) m/z for C14H14NaO7 (M+Na)+: Calcd 317.0637; Found
317.0636.
5a. Yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.17 (t, J = 7.2 Hz,
3H), 1.69 (d, J = 8.0 Hz, 1H), 1.85 (d, J = 8.0 Hz, 1H), 2.59 (s, 3H),
3.61 (d, J = 8.8 Hz, 1H), 3.71 (d, J = 8.8 Hz, 1H), 4.08−4.19 (m, 2H),
5.24 (s, 1H), 5.27 (s, 1H), 7.14−7.17 (m, 2H), 7.29−7.44 (m, 7H);
13C NMR (100 MHz, CDCl3): δ 14.1, 28.0, 30.2, 42.8, 59.1, 60.6, 77.2,
3l. 51.0 mg, yield 74%. Colorless oil; 1H NMR (400 MHz, CDCl3):
δ 1.29 (d, J = 5.2 Hz,6H), 2.27 (d, J = 7.2 Hz, 1H), 2.50 (d, J = 7.2 Hz,
1H), 3.85 (s, 6H), 5.05−5.11 (m, 1H), 5.41 (s, 1H), 5.48 (s, 1H), 6.11
(s, 1H); 13C NMR (100 MHz, CDCl3): δ 21.8, 25.9, 28.5, 52.2, 52.3,
67.7, 82.0, 82.1, 112.3, 146.6, 147.0, 149.5, 162.5, 162.6, 164.6; MS
(ESI) m/z (rel): 345 (M+Na)+; IR (KBr, neat): 2983, 2956, 2849,
1740, 1712, 1629, 1438, 1266, 1110, 896, 691 cm−1; HRMS (ESI) m/z
for C16H18NaO7 (M+Na)+: Calcd 345.0950; Found 345.0949.
3m. 44.4 mg, yield 68%. Yellow oil; 1H NMR (400 MHz, CDCl3): δ
1.32 (s, 9H), 1.96 (d, J = 7.2 Hz, 1H), 2.17 (d, J = 7.2 Hz, 1H), 3.79
(s, 3H), 5.46 (s, 1H), 5.49(s, 1H), 6.23 (s, 1H), 7.15−7.17 (m, 2H),
7.35−7.36 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 27.0, 27.9, 29.6,
51.5, 61.8, 62.2, 80.2, 114.3, 119.9, 120.2, 120.4, 126.2, 126.3, 146.0,
146.2, 152.8, 165.7; MS (ESI) m/z (rel): 350.1 (M+Na)+; IR (KBr,
neat): 3033, 2979, 2952, 1753, 1706, 1390, 1369, 1174, 913, 732, 669
cm−1; HRMS (ESI) m/z for C19H21NNaO4 (M+Na)+: Calcd
350.1368; Found 350.1364.
77.5, 78.9, 119.2, 119.7, 126.1, 126.2, 127.7, 128.4, 128.7, 145.9, 146.3,
172.1; MS (EI) m/z (rel): 377 (M+, 3), 205 (44), 160 (45), 144 (77),
132 (100), 118 (63); IR (KBr, neat): 2959, 1731, 1175, 980, 754, 698
cm−1; HRMS (ESI) m/z for C23H24NO4 (M+H)+: Calcd 378.1705;
Found 378.1706.
5b. White solid. Mp 160−162 °C; 1H NMR (400 MHz, CDCl3): δ
0.76 (t, J = 7.2 Hz, 3H), 1.57 (d, J = 8.0 Hz, 1H), 1.94 (d, J = 8.0 Hz,
1H), 2.66 (s, 3H), 3.52−3.57 (m, 1H), 3.66−3.71 (m, 1H), 3.88 (d, J
= 7.6 Hz, 1H), 4.11 (d, J = 8.4 Hz, 1H), 5.19 (s, 1H), 5.29 (s, 1H),
7.13−7.17 (m, 2H), 7.29−7.34 (m, 5H), 7.37−7.39 (m, 2H); 13C
NMR (100 MHz, CDCl3): δ 13.4, 27.3, 30.1, 43.5, 55.5, 60.1, 75.8,
77.2, 77.8, 119.2, 119.6, 126.1, 126.2, 127.9, 128.1, 135.5, 145.8, 146.0,
169.9; IR (KBr, neat): 2961, 1738, 1173, 848, 700, 672 cm−1; HRMS
(ESI) m/z for C23H24NO4 (M+H)+: Calcd 378.1705; Found
378.1705.
3n. 27.0 mg, yield 71%. Colorless oil; 1H NMR (300 MHz, CDCl3):
δ 1.22 (t, J = 7.2 Hz, 3H), 1.68−1.73 (m, 2H), 1.78 (m, 1H), 1.85−
1.88 (m, 1H), 1.93−1.98 (m, 1H), 2.21−2.25 (m, 1H), 2.27−2.31 (m,
1H), 3.01−3.06 (m, 1H), 4.08 (dd, J = 11.4, 7.2 Hz, 2H), 5.77 (s, 1H);
13C NMR (75 MHz, CDCl3): δ 14.3, 26.1, 27.1, 28.3, 29.2, 31.0, 31.4,
32.9, 59.2, 109.9, 164.6, 167.2; MS (EI) m/z (rel): 190 (M+, 18), 161
(6), 145 (14), 117 (94), 86 (65), 84 (100), 47 (55); IR (KBr, neat):
3059, 3039, 2927, 2858, 1709, 1643, 1447, 1383, 1211, 1145, 1041,
862, 740, 617 cm−1; HRMS (EI) m/z for C12H14O2: Calcd 190.0994;
Found 190.0992.
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectra of compounds 3a−3p, 4, and 5, and X-ray analysis data
of 3a and 4 in cif format. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
3o. 42.2 mg, yield 69%. Colorless oil; 1H NMR (400 MHz, CDCl3):
δ 1.26 (t, J = 7.2 Hz, 3H), 1.76 (d, J = 13.6 Hz, 1H), 2.25−2.29 (m,
1H), 2.35−2.37 (m, 1H), 2.51−2.53 (m, 1H), 2.65−2.68 (m, 1H),
3.71 (s, 3H), 3.73 (s, 3H), 3.77−3.78 (m, 1H), 4.14 (q, J = 7.2 Hz,
2H), 5.88 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 14.2, 24.9, 37.2,
38.4, 38.5, 40.7, 41.4, 43.5, 52.0, 52.1, 59.9, 113.3, 155.4, 166.3, 169.5;
MS (EI) m/z (rel): 306 (M+, 13), 291 (1), 275 (6), 246 (7), 201 (10),
115 (20), 43 (100); IR (KBr, neat): 2985, 2955, 1733, 1654, 1440,
1216, 1151, 1035 cm−1; HRMS (EI) m/z for C16H18O6: Calcd
306.1103; Found 306.1100.
■
Corresponding Authors
*E-mail: xlhou@sioc.ac.cn.
*E-mail: dingch@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the Major Basic
Research Development Program (2011CB808700), National
Natural Science Foundation of China (21032007, 21272251,
21121062), Chinese Academy of Sciences, the Technology
Commission of Shanghai Municipality, and the Croucher
Foundation of Hong Kong.
1
3p. 34.5 mg, yield 81%. White solid. Mp: 188−191 °C; H NMR
[400 MHz, (CD3)2SO]: δ 1.94 (d, J = 7.2 Hz, 1H), 2.19 (d, J = 7.2 Hz,
1H), 5.53 (s, 1H), 5.57 (s, 1H), 6.09 (s, 1H), 7.05 (brs, 1H),7.16−7.19
(m, 2H), 7.25 (brs, 1H), 7.39−7.43 (m, 2H); 13C NMR [100 MHz,
(CD3)2SO]: δ 24.8, 27.6, 79.5, 79.7, 115.5, 120.1, 120.2, 126.5, 126.6,
145.4, 147.2, 147.3, 166.7; IR (KBr, neat): 3339, 3158, 1760, 1665,
11475
dx.doi.org/10.1021/jo402024v | J. Org. Chem. 2013, 78, 11470−11476

The Journal of Organic Chemistry
Article
(13) Ge, G.-C.; Mo, D.-L.; Ding, C.-H.; Dai, L.-X.; Hou, X.-L. Org.
Lett. 2012, 14, 5756.
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