Ene-carbonyl reductive coupling for the synthesis of 3,3-disubstituted phthalide, 3-hydroxyisoindolin-1-one and 3-hydroxyoxindole derivatives

Article abstract of DOI:10.1002/adsc.201300973

An efficient method for the synthesis of three classes of heterocyclic derivatives such as 3,3-disubstituted phthalides, 3-hydroxyisoindolin-1-ones and 3-hydroxyoxindoles, is reported. In the presence of the simple reductive system, zinc (Zn)/ammonia (NH₃) [or zinc-copper (Zn-Cu)/ammonia], a wide range of alkenes including acrylates, acrylonitrile, acrylamide and vinyl sulfoxide underwent reductive coupling with methyl 2-acylbenzoates and subsequent lactonization to provide 3,3-disubstituted phthalides in good to high yields at ambient temperature. In a similar manner, 3-hydroxyisoindolin-1-one and 3-hydroxyoxindole derivatives could also be easily prepared by direct reductive coupling of phthalimides and N-substituted isatins with activated alkenes, respectively. Application of this methodology towards the synthesis of 1-naphthol derivatives on a gram scale is also depicted. Furthermore, the intramolecular phthalimides-ene reductive coupling afforded the respective cyclization products with high diastereoselectivity.

Full text of DOI:10.1002/adsc.201300973

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DOI: 10.1002/adsc.201300973
Ene-Carbonyl Reductive Coupling for the Synthesis of
3,3-Disubstituted Phthalide, 3-Hydroxyisoindolin-1-one and
3-Hydroxyoxindole Derivatives
Chien-Hung Yeh,a Yi-Chuen Lin,a Subramaniyan Mannathan,a Kevin Hung,a
and Chien-Hong Chenga,*
a
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
E-mail: chcheng@mx.nthu.edu.tw
Received: November 3, 2013; Published online: March 3, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300973.
Abstract: An efficient method for the synthesis of easily prepared by direct reductive coupling of
three classes of heterocyclic derivatives such as 3,3- phthalimides and N-substituted isatins with activated
disubstituted phthalides, 3-hydroxyisoindolin-1-ones alkenes, respectively. Application of this methodolo-
and 3-hydroxyoxindoles, is reported. In the presence gy towards the synthesis of 1-naphthol derivatives on
of the simple reductive system, zinc (Zn)/ammonia a gram scale is also depicted. Furthermore, the intra-
(NH3) [or zinc-copper (Zn-Cu)/ammonia], a wide molecular phthalimides–ene reductive coupling af-
range of alkenes including acrylates, acrylonitrile, ac- forded the respective cyclization products with high
rylamide and vinyl sulfoxide underwent reductive diastereoselectivity.
coupling with methyl 2-acylbenzoates and subse-
quent lactonization to provide 3,3-disubstituted
phthalides in good to high yields at ambient temper- Keywords: ammonia; 3,3-disubstituted phthalides; 3-
ature. In a similar manner, 3-hydroxyisoindolin-1- hydroxyisoindolin-1-ones; 3-hydroxyoxindoles; re-
one and 3-hydroxyoxindole derivatives could also be ductive coupling; zinc; zinc-copper
Introduction
For the synthesis of 3-hydroxyisoindolin-1-ones[8]
and 3-hydroxyoxindoles,[9,10] several strategies have
Phthalides (isobenzofuranones), a class of heterocy- been reported. However, the reductive coupling of
cles with the framework of a five-membered lactone phthalimides with activated alkenes to afford 3-hy-
adjacent to a benzene ring, occur in an abundance of droxyisoindolin-1-one derivatives is only scarcely
biologically active compounds which are useful for mentioned in literature, with examples such as the
the treatment of several diseases.[1] There is an array intra- and intermolecular reductive coupling of
of methods developed in the past few years for the phthalACTHUNTGRNEUNGimides with activated alkenes via an electrore-
synthesis of 3-substituted phthalides.[2] Nevertheless, ductive method[11] or samarium(II) iodide (SmI2)
the synthesis of 3,3-disubstituted phthalides is only re- chemistry.[12] Moreover, to the best of our knowledge,
ported in a few contributions, for example, by the rho- the synthesis of 3,3-disubstituted phthalides and 3-hy-
dium-catalyzed sequential [2+2+2] cycloaddition droxyoxindole derivatives via ene-carbonyl reductive
with transesterification,[3a] the allylic alkylation of coupling has never been reported.
MBH (Morita–Baylis–Hillman) carbonates with 3-
As a matter of fact, 3,3-disubstituted phthalide, 3-
phthalides,[3b] the addition of ortho-lithium or hydroxyisoindolin-1-one, 3-hydroxyoxindole and re-
Grignard reagents to ketones or carbon dioxide,[4] the lated structures appear in abundant bioactive mole-
Pd-catalyzed oxyalkynylation reaction of olefins with cules, for instance, sinaspirolide,[13] ansasirolide,[13] shi-
hypervalent iodine reagents,[5] the solid-state photore- hunine,[14] citalopram,[15] talopram,[15]corollosporine,[16]
action of N,N-disubstituted 2-benzoylbenzamides[6] chilenine,[17]
fumadensine,[18]
NU8165,[19]
SM-
and the lanthanide-promoted annulation of dihalides 130686,[20] arundaphine[21] and welwitindolinone C[22]
with keto esters.[7]
(Figure 1). Thus, the development of a new synthetic
strategy to afford these skeletons is in high demand.
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Chien-Hung Yeh et al.
Figure 1. Representative 3,3-disubstituted phthalides, 3-hydroxyisoindolin-1-ones, 3-hydroxyoxindoles and related structures.
Herein, we report a new synthetic method based on tional screenings of reaction stoichiometry and sol-
[23]
Zn/NH3 (or Zn-Cu/NH3) mediated ene-carbonyl re- vent species, a quantitative yield was achieved by in-
ductive coupling, which provides an efficient and creasing the loading of alkene and Zn to 1.0 mmol
practical route to access 3,3-disubstituted phthalide, 3- (Table 1, entry 8). Interestingly, Zn-Cu/NH3 as the re-
hydroxyisoindolin-1-one and 3-hydroxyoxindole skel- ductive system was also found to be effective afford-
etons in a highly regio- and chemoselective manner. ing 3aa in similar 98% yield (Table 1, entries 15 and
It is worth noting that all of the reactions were per- 16) and no product was obtained in the absence of
formed under ambient conditions.
H2O (Table 1, entry 17). Moreover, when NH3 was re-
placed by various amine species, such as primary
amines (n-butylamine and benzene-1,2-diamine), sec-
ondary amine (diphenylamine) and ammonia salts
(ammonium acetate and ammonium carbonate), only
Results and Discussion
During the course of an initial investigation, we the recovery of starting material 1a or 3-
tested the reaction of methyl 2-benzoylbenzoate (1a) phenylphthalide (1a’) was observed (Table 1, en-
AHCTUNGTRENNUNG
(0.20 mmol) with acrylonitrile (2a) (0.60 mmol) in the tries 18–22). This reveals that gaseous ammonia
presence of Zn (0.60 mmol)/saturated aqueous [NH3(g)] plays a central role for activation of the Zn-
NH4OH solution (0.20 mmol) as the reductive system ketyl radical to effect the ene-carbonyl reductive cou-
and CH3CN (1.20 mL) as the solvent. When the reac- pling.[23]
tion was carried out at ambient temperature, no ex-
Having the optimized reaction conditions in hand,
pected product 3aa was found. (Table 1, entry 2). At we subsequently explored the scope of the alkenes
1008C, the reaction did not afford any reductive cou- (Table 2). When methyl acrylate (2b) and ethyl acry-
pling product, instead 3-phenylphthalide 1a’ was ob- late (2c) were used as ene-species, both 3,3-disubsti-
served as a result of the reduction of 1a (Table 1, tuted phthalides (3ab and 3ac) were obtained in high
entry 3). We then switched to several different reduc- yields (Table 2). However, when tert-butyl acrylate
tive coupling systems, SmI2/HMPA, Ni
CoI2A(dppe)/Zn, but only the recovery of starting ma- and 41% yields of the desired products 3ad and 3ae
terial 1a was obtained (Table 1, entries 4–6).
When aqueous NH4OH was replaced with NH3
ACHTUNGRTEN(NNUG cod)2/Zn and (2d) and acrylamide (2e) were employed, only 26%
CHTUNGTRENNUNG
were observed.
To our delight, the product yields of 3ad and 3ae
(1 atm, balloon pressure) and H2O (0.4 mmol), we were greatly improved by replacing zinc dust with the
were pleased to find that the desired product 3aa was Zn-Cu couple and using DMF as solvent (Scheme 1).
obtained in 67% yield (Table 1, entry 7). After addi- In addition, the reductive couplings of 1a with
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Ene-Carbonyl Reductive Coupling for the Synthesis
Table 1. Optimization studies for the synthesis of 3,3-disubstituted phthalides.[a]
Entry
Additive
Solvent
Temp.
[8C]
Yield of
Yield of
3aa[a] [%]
1a’[a] [%]
1
NH4Cl (0.20 mmol)
NH4OH (0.20 mmol)
NH4OH (0.20 mmol)
SmI2 (1.00 mmol), HMPA (1.60 mmol), t-BuOH (0.60 mmol)
CH3CN
CH3CN
CH3CN
THF
CH3CN
CH3CN
CH3CN
CH3CN
THF
r.t.
r.t.
100
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
99
55
2[b]
3[b]
4[b,c]
5
RSM
0
RSM
RSM
RSM
Co
Ni(cod)2 (5 mol%), ZnCl2 (0.60 mmol)
NH3 (1 atm)
NH3 A(1 atm)
A
6
ACHTUNGTRENNUNG
7
67
28
0
2
0
0
38
36
23
0
0
10
8[d]
9
R
99[e]
37
NH3 (1 atm)
NH3 (1 atm)
NH3 (1 atm)
NH3 (1 atm)
NH3 (1 atm)
NH3 (1 atm)
10
11
12
13
14
15[f]
16[f]
17[b]
18
19
20
21
22
methanol
ethanol
ether
15
21
31
trace
trace
98[e]
98[e]
0
DCM
toluene
CH3CN
DMF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
NH
NH
3 A
3 A(1 atm)
NH3 (1 atm)
n-butylamine (0.20 mmol)
benzene-1,2-diamine (0.20mmol)
diphenylamine (0.20 mmol)
NH4OAc (0.20 mmol)
RSM
RSM
RSM
0
0
46
42
ACHTUNGTRENNUNG(NH4)2CO3 (0.20 mmol)
[a]
All the yields mentioned above are NMR yields using mesitylene as the internal standard.
No water was added.
[b]
[c]
[d]
[e]
[f]
The reaction was carried out according to a previously reported procedure.[24]
Zn dust (1.0 mmol) and 2a (1.0 mmol) were used.
Isolated yield.
Zn dust was replaced with Zn-Cu. HMPA=hexamethylphosphoramide. RSM=recovery of starting material.
a broad range of ene species, N-methylacrylamide 7.0 mmol, 1.7 g) with methyl acrylate (2b) affording
(2f), phenyl vinyl sulfoxide (2g), methyl crotonate 3ab (1.8 g) in 88% isolated yield.
(2h) and a-methylene-g-butyrolactone (2i), using Zn-
As illustrated in Table 3, the scope of the reaction
Cu/NH3 were also investigated. All of them provided was successfully extended to various methyl 2-acyl-
the desired phthalides in moderate yields. Especially, benzoate derivatives (1). With the Zn-Cu/NH3 (or
b-substituted acrylate 2h afforded 3ah with high dia- Zn/NH3) reductive system, a wide range of 3,3-disub-
stereoselectivity. Other ene species, such as cinna- stituted phthalide derivatives was prepared in good to
mates and methacrylates gave the desired products in moderate yields. The results demonstrated that the R2
low yields.
substituent attached to the keto moiety of 1 including
As a control experiment, the Zn-Cu couple was re- 4-fluorophenyl (1b), 4-chlorophenyl (1c), 4-methoxy-
placed with Cu powder and as a result, only recovery phenyl (1d), 2-furan (1h), 3-benzo[b]thiophene (1i), or
of the starting material was obtained. It is noteworthy 3-pyridyl (1j) is well tolerated. Conversely, 2-pyridyl
that for the reactions of 1a with 2d–h, 3-phenylphtha- (1k) afforded 3ka only in 17% yield. It is important
lide was observed as the major product under Zn/ to mention that the reductive debromination product
NH3 as reductive system. To verify the preparative 3aa was observed when the R2 moiety is 4-bromo-
utility of the present methodology, we scaled up the phenyl. Interestingly, the reaction of methyl 9-oxo-
model reaction of methyl 2-benzoylbenzoate (1a; fluorene-1-carboxylate (1l) with 2b gave only the re-
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Table 2. Zn/NH3 (Zn-Cu/NH3) mediated reductive coupling
of methyl 2-benzoylbenzoate 1a and activated alkenes 2.[a,b]
Table 3. Results of Zn-Cu/NH3 mediated reductive coupling
of methyl 2-acylbenzoate derivatives and activated alk-
AHCTUNGTRENNUNG
enes.[a,b]
[a]
All reactions were carried out under an ammonia atmos-
phere using
1
(0.20 mmol),
2
(1.00 mmol), H2O
(0.40 mmol) and Zn (1.00 mmol) in CH3CN (1.2 mL) at
room temperature for 20 h.
Yields are of isolated products.
Zn-Cu as reducing agent and DMF as solvent.
The diastereomeric ratio was determined by 1H or
13C NMR spectroscopy.
[b]
[c]
[d]
ductive coupling product 3lb in excellent yield
[Scheme 2, Eq. (1)]. Pleasingly, methyl ortho-[(me-
thoxycarbonyl)carbonyl]benzoate (1m) also reacted
with 2c to afford disubstituted phthalide 3mc in 36%
yield [Scheme 2, Eq. (2)].
[a]
All reactions were carried out under ammonia atmos-
phere using 1a (0.20 mmol),
2 (1.00 mmol), H2O
(0.40 mmol) and Zn-Cu (1.00 mmol) in DMF (1.2 mL) at
room temperature for 20 h.
Yields are of isolated products.
[b]
[c]
Zn instead of Zn-Cu and CH3CN instead of DMF as sol-
vent.
The diastereomeric ratio was determined by 1H NMR
spectroscopy.
[d]
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Ene-Carbonyl Reductive Coupling for the Synthesis
Scheme 1. Optimization studies for the reductive coupling of methyl 2-benzoylbenzoate (1a) with acrylamide (2e).
Scheme 2. Reductive couplings of 1l with 2b, 1m with 2c and 1a with 4.
When the ene species was switched to methyl pro- yield upon replacing CH3CN with tetrahydrofuran
piolate (4), the reductive coupling followed by reduc- (THF) as solvent (Table 4, entry 2). After extensive
tion of the olefin occurred to give 3ab in 76% yield studies, improved yields were obtained by increased
[Scheme 2, Eq. (3)]. The control experiment showed loading of Zn to 1.0 mmol and switching the solvent
that no yne-carbonyl reductive coupling product was system to dichloromethane (DCM) (Table 4,
observed when we reduced the reaction time or the entry 11).
zinc loading.
Having established the optimized reaction condi-
Due to the fact that phthalimides are effective tions, we subsequently explored reactions of different
single electron transfer acceptors,[11,12] we envisioned substituted phthalimides with acrylonitrile (2a). When
that the reductive coupling of carbonyl substrates of R1 was a methyl (5b), benzyl (5c), para-fluorophenyl
phthalimide with activated alkenes could also be (5d), para-methoxyphenyl (5e), 1-phenylethyl (5f) or
achieved by a Zn-NH3 reductive system; under ketyl (1R)-1-(4-methoxyphenyl)ethyl group (5j), the desired
radical initiation conditions. Thus, we examined the products were isolated in good to moderate yields
reaction of N-phenylphthalimide (5a) and acryloni- (82–51%, Table 5). Subsequently, the reductive cou-
trile (2a) under Zn-NH3 conditions (Table 4, entry 1). plings of phthalimides with a broad range of ene spe-
The starting material was fully converted in a short cies [methyl acrylate (2b), acrylamide (2e), N-methyl-
period, but we observed only a complicated hetero-in- acrylamide (2f) methyl vinyl ketone (2j) and vinyl
termolecular coupling mixture. Fortunately, 3- sulfone (2k)] were investigated, all of them provided
hydroxyACHTUNGTRENNUNGisoindolin-1-one 6aa was obtained in 35% the desired 3-hydroxyisoindolin-1-one derivatives
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Table 4. Optimization studies for the synthesis of 3-hydroxy-
ACHTUNGTRENNUNG
isoindolin-1-one.[a]
Entry
Zn [mmol]
Time [h]
Solvent
Yield [%][b]
Scheme 3. Intramolecular reductive coupling reactions of N-
substituted phthalimides.
1
2
0.6
0.6
1.0
0.6
0.6
0.6
0.6
0.6
0.6
0.6
1.0
1.0
0.6
1
CH3CN
THF
THF
ND
35
30
low
low
70
20
20
16
16
16
1
1
1
2
1
3[c]
4[d]
5
ether
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
6[d]
7[d]
8[d,e]
9[f]
51
RSM
RSM
50
10[d]
11[d]
12[h]
13[e,i]
86 (75)[g]
trace
ND
24
6
[a]
Reaction conditions: 5a (0.20 mmol), 2a (0.60 mmol),
H2O (0.40 mmol) and Zn dust (0.60–1.00 mmol) in sol-
vent (1.5 mL) under an NH3 atmosphere.
All the yields mentioned above were NMR yields using
mesitylene as internal standard.
[b]
[c]
[d]
2a (1.0 mmol) was used.
NH3 was bubbled into the reaction flask with ice bath
Figure 2. X-ray crystal structures of compound 6k.
cooling.
[e]
[f]
[g]
[h]
[i]
No H2O was added.
In the absence of NH3(g)
Isolated yield.
NH3(g) was replaced with NH4Cl.
NH3(g) was replaced with BF3·THF (RSM=recovery of
starting material; ND=no desired product).
.
this, we first applied the standard reaction conditions
(as described in Table 5) to phthalimide 5k. Although
the 5k only gave low conversion, we were glad to ob-
serve the expected product 6k (Figure 2) with high
diastereoselectivity. Subsequently, fully conversion
was enabled by increasing the loading of H2O to
(82–22% yields), despite the fact that some products 6.0 equiv. Next, we tested the intramolecular coupling
were obtained in unsatisfactory yields. The yields of phthalimides with an a,b-unsaturated ketone motif
were significantly improved by simply replacing zinc (5l) and the reaction was also found to be successful
dust with Zn-Cu couple; such as 6da, 6ea and 6ab. by using this set of reaction conditions.
However, no expected product was observed when
Isatins bear an electron-withdrawing carbonyl
we tested methyl crotonate (2h) or a-methylene-g-bu- group and thus could be a suitable skeleton for the
tyrolactone (2i) as ene species. To identify the prepa- Zn-NH3 reductive coupling reaction. Thus, we tested
rative utility of the present methodology, we chose to the reaction of NH-isatin (1H-indole-2,3-dione) with
scale up the model reaction of N-benzylphthalimide acrylonitrile (2a) under the standard reaction condi-
(5c; 6.0 mmol, 1.4 g) with acrylonitrile (2a). This af- tions. The initial study revealed that NH-isatin was
forded 6ca (1.3 g) in 72% isolated yield.
fully consumed within several minutes, but no expect-
Following the previously reported intramolecular ed product was observed. Next, an attempt was con-
coupling of phthalimides with a,b-unsaturated esters ducted by modifying NH-isatin into N-Boc-isatin,
by an electroreductive system[11] or SmI2 chemistry,[12] however, the result was unsuccessful because no inter-
we envisaged that these Zn-NH3 conditions could pro- molecular coupling product was generated. Delighted-
vide an opportunity to achieve the intramolecular re- ly, when N-methylisatin (7a) was employed, the 3-hy-
ductive coupling reaction (Scheme 3). To examine droxyoxindole derivative 8aa was afforded in a 76%
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Table 5. Results of zinc mediated reductive coupling of phthalimides and activated alk-
ACHTUNGTRENNUNG
enes.[a,b]
[a]
All reactions were carried out under an ammonia atmosphere using 5 (0.20 mmol), 2
(0.60 mmol), H2O (0.40 mmol) and Zn (1.00 mmol) in CH2Cl2 (1.5 mL).
Isolated yields.
5c (6.0 mmol), 2a (30.0 mmol), H2O (12.0 mmol) and Zn (30.0 mmol) in CH2Cl2
(45.0 mL) were used.
Zn-Cu instead of Zn.
Zn (0.60 mmol) was used.
H2O (1.2 mmol) was used.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
Zn-Cu conditions achieved the same yield as with Zn dust conditions.
1
The diastereomeric ratio was determined by H NMR spectroscopy.
isolated yield under the standard conditions (Table 6). corresponding products in moderate to good yields.
The N-methyl group of 7a was then replaced with dif- Similarly, methoxy-substituted isatin (7f) also worked
ferent substituents (phenyl 7b and benzyl 7c) and sub- well, furnishing 8fa in good yield. Furthermore, in
sequent screening with a variety of ene species under analogy to the ene-phthalimide reductive coupling,
Zn-NH3 reductive conditions afforded all of the de- the Zn-Cu couple also has a directly beneficial influ-
sired products in 84-42% yields without further opti- ence on the ene-isatin reductive coupling and the
mization of the procedure (Table 6). The scope of the result is well documented. To demonstrate the gram-
reaction was also tested with various substituted isa- scale preparation of a 3-hydroxyoxindole derivative,
tins 7d–g. For instance, fluoro-, and chloro-substituted we chose the reaction of isatin 7h (1.5 g, 6.0 mmol)
isatins (7e, 7g, 7h) were well tolerated to afford the
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Table 6. Results of zinc mediated reductive coupling of N-substituted isatins and activated
alkenes.[a,b]
[a]
All reactions were carried out under an ammonia atmosphere using 7 (0.20 mmol), 2
(0.60 mmol), H2O (0.40 mmol) and Zn (1.00 mmol) in CH2Cl2 (1.5 mL).
Isolated yields.
7c (6.0 mmol), 2a (18.0 mmol), H2O (12.0 mmol) and Zn (30.0 mmol) in CH2Cl2
[b]
[c]
(45.0 mL) were used.
Zn-Cu instead of Zn.
Zn-Cu conditions achieved the same yield as with Zn dust conditions.
[d]
[e]
with acrylonitrile 2a. Gratifyingly, the reaction afford- on a gram scale (Scheme 4). We believe that a series
ed 8ha (1.4 g) in 73% isolated yield.
of 1-naphthol derivatives can be prepared through the
To show the synthetic utility of this methodology, sequential manipulation. Also, we revealed the exten-
we treated 3,3-disubstituted phthalide 3ab with sion of this methodology to the synthesis of 3-
sodium hydride in toluene at reflux (Dieckmann con- hydroxy
ACHTUNGTRENiNUNG soindolin-1-one 6ja’ by oxidative cleavage of
densation), which furnished 1-naphthol[25] derivative 9 the N-a-methyl-4-methoxybenzyl group of 6ja via
Scheme 4. Dieckmann condensation to afford a 1-naphthol
derivative.
Scheme 5. Oxidative removal of the N-a-methyl-4-methoxy-
benzyl group.
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Ene-Carbonyl Reductive Coupling for the Synthesis
Scheme 6. A plausible mechanistic pathway for the formation of 3,3-disubstituted phthalide.
strate followed by further reduction gives a five-mem-
bered zincacycle II. Final protonation and in situ lac-
tonization affords the 3,3-disubstituted phthalide
3.[23,27] Similarly, for the ene-phthalimide and ene-N-
substituted isatin reductive couplings it is proposed
that Zn-NH3 initiates a single electron transfer to
a phthalimide or an N-substituted isatin to form a Zn-
ketyl radical III or III’ (Scheme 7). Addition of this
radical to the alkene substrate followed by further re-
duction gives a five-membered zincacycle IV or IV’,
while final protonation affords 3-hydroxyisoindolin-1-
one and 3-hydroxyoxindole.
Trying to get an insight into the ene-carbonyl re-
ductive coupling reaction, some control experiments
were devised by testing hydroxylactam 5c’ and 7a’
with 2a under Zn-NH3 conditions, respectively
(Scheme 8). In the standard reaction timescale, we
Scheme 7. A possible key intermidiate for the formation of
3-hydroxyisoindolin-1-one and 3-hydroxyoxindole.
ceric
ammonium
nitrate
(CAN)
oxidation could not observe the expected product [Scheme 8,
Eqs. (1) and (2)]. However, by extending the reaction
(Scheme 5).[26]
A possible mechanism for the ene-carbonyl reduc- time to 22 h, 8aa was obtained in 34% NMR yield via
tive coupling is outlined in Scheme 6. It is proposed a slowly proceeding 1,4-addition of 7a’ with 2a under
that Zn-Cu/NH3 (or Zn/NH3) initiates a single elec- basic conditions [Scheme 8, Eq. (3)].[10h] These obser-
tron transfer to a carbonyl group to form a Zn-ketyl vations implicate, in the presence of Zn-NH3, that the
diradical I. Addition of this radical to the alkene sub- phthalimides and N-substituted isatins form the ketyl
radical components as key intermediates in-situ, then
react with activated alkenes to furnish the expected
product rather than proceeding through intermediate
7a’.
Conclusions
In summary, we have established an effective Zn-NH3
(or Zn-Cu/NH3) reductive cross-coupling protocol to
generate a series of 3,3-disubstituted phthalides, 3-hy-
droxyisoindolin-1-ones and 3-hydroxyoxindole deriva-
tives. From a synthetic point of view, this approach is
attractive due to the use of cheap and readily avail-
able materials in a reaction with an easily manageable
and a simple modular procedure. It is worth mention-
ing that the 3,3-disubstituted phthalide products syn-
Scheme 8. Control studies.
thesized in this manner have a broad scope and can
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Chien-Hung Yeh et al.
EtOAc/hexane as eluent gave the 3-hydroxyisoindolin-1-one
6.
be extended for the synthesis of 1-naphthol deriva-
tives via the Dieckmann condensation. Furthermore,
it discloses a straightforward route to access a series
of biologically activated molecules and there is prom-
ise in developing intramolecular reductive coupling
procedures to afford biologically useful motifs with
high diastereoselectivity.
Typical Procedure for Synthesis of 3-Hydroxy-
oxindole Derivatives
A glass tube equipped with magnetic stir bar was charged
with zinc dust (or zinc-copper couple) (1.00 mmol,
5.0 equiv.), N-substituted isatin 7 (0.20 mmol, 1.0 equiv.), ac-
tivated alkene 2 (0.60 mmol, 3.0 equiv.), H2O (0.40 mmol,
2.0 equiv.) and dry dichloromethane (1.50 mL) and was then
sealed with a rubber septum. NH3(g) was bubbled into the re-
action flask cooled with an ice bath for 0.5 min, then the re-
action was allowed to warm to room temperature with con-
tinued stirring for 0.5–5.0 h. The resulting mixture was dilut-
ed with EtOAc, filtered through Celite and the filtrate was
then concentrated. Separation on a silica gel column using
EtOAc/hexane as eluent gave the 3-hydroxyoxindole 8.
Experimental Section
Typical Procedure for Synthesis of 3,3-Disubstituted
Phthalide Derivatives
A glass tube equipped with magnetic stir bar was charged
with zinc-copper couple (or zinc dust) (1.00 mmol,
5.0 equiv.), methyl 2-benzoylbenzoate
1
(0.20 mmol,
1.0 equiv.), activated alkene 2 (1.00 mmol, 5.0 equiv.), H2O
(0.40 mmol, 2.0 equiv.) and dry dimethylformamide (or ace-
tonitrile) (1.20 mL) and was then sealed with a rubber
septum. The solution was saturated with NH3(g) from a bal-
loon by slow bubbling for 5 min and was stirred at room
temperature for 20 h (note: NH3 should only be handled in
a chemical fume hood.). The resulting mixture was diluted
with EtOAc, filtered through Celite and the filtrate was
then concentrated. Separation on a silica gel column using
hexane/EtOAc as eluent gave 3,3-disubstituted phthalide 3.
Gram-Scale Synthesis of 3-Hydroxyisoindolin-1-one
Derivative 6ca
A 100-mL round-bottom flask equipped with magnetic stir
bar was charged with methyl N-benzylphthalimide 5c (1.4 g,
6.0 mmol, 1.0 equiv.), zinc dust (2.0 g, 30.0 mmol, 5.0 equiv.),
acrylonitrile 2a (2.0 mL, 30.0 mmol, 5.0 equiv.), H2O
(0.2 mL, 12.0 mmol, 2.0 equiv.) and freshly distilled dichloro-
methane (45 mL) were then added and the flask was closed
with a rubber septum. A long needle was connected to am-
monia gas cylinder via a tygon tubing and then was pierced
through the septum. The solution was saturated with NH3(g)
by slow bubbling for 5 min and stirred at room temperature
for 8 h. Then an needle (23G) was pierced through septum
for the relaxation of excess NH3(g) and the reaction was
quenched with saturated aqueous NH4Cl (25 mL). Following
extraction with dichloromethane (3ꢁ15 mL), the combined
organic layer was dried over MgSO4, filtered through Celite
and concentrated. Separation on a column of silica gel using
EtOAc/hexane as eluent gave 6ca as a yellow solid; yield:
1.3 g (72%).
Gram-Scale Synthesis of 3,3-Disubstituted Phthalide
Derivatives (3ab)
A 100-mL round-bottom flask equipped with a magnetic stir
bar was charged with methyl 2-benzoylbenzoate 1a (1.7 g,
7.00 mmol, 1.0 equiv.), zinc dust (2.3 g, 35.0 mmol,
5.0 equiv.), methyl acrylate 2b (3.0 g, 35.0 mmol, 5.0 equiv.),
H2O (0.3 g, 14.0 mmol, 2.0 equiv.) and freshly distilled aceto-
nitrile (35 mL) were then added and the flask was closed
with a rubber septum. A long needle was connected to the
ammonia gas cylinder via a tygon tubing and then was
pierced through the septum. The solution was saturated with
NH3(g) by slow bubbling for 20 min and stirred at room tem-
perature for 30 h. The reaction was quenched with saturated
aqueous NH4Cl (25 mL), then extracted with EtOAc (3ꢁ
Gram-Scale Synthesis of 3-Hydroxyisoindolin-1-one
15 mL). The combined organic layer was dried over MgSO4, Derivative 8ha
filtered through Celite and concentrated. Separation on
a column of silica gel using hexane/EtOAc as eluent gave
3ab as a colorless oil; yield: 1.8 g (88%).
Prepared in a similar manner to the gram-scale synthesis of
3-hydroxyisoindolin-1-one derivative 6ca, using isatin 7h
(1.5 g, 6.0 mmol, 1.0 equiv.), zinc dust (2.0 g, 30.0 mmol,
5.0 equiv.), acrylonitrile 2a (1.2 mL, 18.0 mmol, 3.0 equiv.),
H2O (0.2 mL, 12.0 mmol, 2.0 equiv.), dry dichloromethane
(45.0 mL) and NH3(g). The reaction was completed in 1 h
and the 3-hydroxyisoindolin-1-one derivative 8ha was ob-
tained; yield: 1.4 g (73%).
Typical Procedure for Synthesis of 3-Hydroxyiso-
indolin-1-one Derivatives
A glass tube equipped with magnetic stir bar was charged
with zinc dust (or zinc-copper couple) (1.00 mmol,
5.0 equiv.), phthalimide 5 (0.20 mmol, 1.0 equiv.), activated
alkene
2
(0.60 mmol, 3.0 equiv.), H2O (0.40 mmol,
X-Ray Crystallography
2.0 equiv.) and dry dichloromethane (1.50 mL) and was then
sealed with a rubber septum. NH3(g) was bubbled into the re-
action flask cooled with an ice bath for 0.5 min, then the re-
action was allowed to warm to room temperature with con-
tinued stirring 1.0–8.0 h. The resulting mixture was diluted
with EtOAc, filtered through Celite and the filtrate was
then concentrated. Separation on a silica gel column using
CCDC 955498 (3be), CCDC 955499 (3db), CCDC 957413
(3mc), CCDC 967403 (6k; Figure 2), CCDC 967404 (6l) and
CCDC 969282 (8ab) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
840
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FULL PAPERS
Ene-Carbonyl Reductive Coupling for the Synthesis
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