New method for the synthesis of lactones via nickel-catalyzed isocyanides insertion

Article abstract of DOI:10.1080/00397911.2013.771402

A novel nickel catalyst for the reaction of tert-butyl isocyanide insertion was discovered. In this approach, 1,2-bis(diphenylphosphino)ethane (L3) serves as an efficient ligand, thereby allowing the preparation of lactones from (o-bromophenyl)phenylethanone derivatives. It is noteworthy that this is the first example of nickel acting as a metal catalyst in the reactions of tert-butyl isocyanide insertion. The significance of this methodology may draw many chemists attention in the field of isocyanide-incorporating reactions. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.771402

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New Method for the Synthesis of
Lactones via Nickel-Catalyzed
Isocyanides Insertion
Xiang-Dong Fei a , Ting Tang a , Zhi-Yuan Ge a & Yong-Ming Zhu a
a College of Pharmaceutical Sciences, Soochow University , Suzhou ,
China
Published online: 05 Sep 2013.
To cite this article: Xiang-Dong Fei , Ting Tang , Zhi-Yuan Ge & Yong-Ming Zhu (2013) New Method for
the Synthesis of Lactones via Nickel-Catalyzed Isocyanides Insertion, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 43:24, 3262-3271
To link to this article: http://dx.doi.org/10.1080/00397911.2013.771402
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Synthetic Communications1, 43: 3262–3271, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.771402
NEW METHOD FOR THE SYNTHESIS OF LACTONES
VIA NICKEL-CATALYZED ISOCYANIDES INSERTION
Xiang-Dong Fei, Ting Tang, Zhi-Yuan Ge, and
Yong-Ming Zhu
College of Pharmaceutical Sciences, Soochow University, Suzhou, China
GRAPHICAL ABSTRACT
Abstract A novel nickel catalyst for the reaction of tert-butyl isocyanide insertion was
discovered. In this approach, 1,2-bis(diphenylphosphino)ethane (L3) serves as an efficient
ligand, thereby allowing the preparation of lactones from (o-bromophenyl)phenylethanone
derivatives. It is noteworthy that this is the first example of nickel acting as a metal catalyst
in the reactions of tert-butyl isocyanide insertion. The significance of this methodology may
draw many chemists’ attention in the field of isocyanide-incorporating reactions.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Acid hydrolysis; isocoumarins; isocyanides; nickel catalyst; phthalides
INTRODUCTION
Because of their multifunctional character, (o-bromophenyl)ethanone deriva-
tives are useful synthetic intermediates for the preparation of heterocycles.[1–9]
Several articles[1–3] reported examples of benzofurans syntheses via intramolecular reac-
tions using 2-(o-bromophenyl)-1-ethanone as starting material. Besides, it is not surpris-
ing that a number of transition-metal-catalyzed processes have been and are still being
Received December 16, 2012.
Address correspondence to Yong-Ming Zhu, College of Pharmaceutical Sciences, Soochow
University, Suzhou 215123, China. E-mail: zhuyongming@suda.edu.cn
3262

NICKEL-CATALYZED ISOCYANIDE INSERTION
3263
Scheme 1. Transition-metal–catalyzed reactions of tert-butyl isocyanide insertion.
described.[4–8] Recently, we have reported on the use of (o-bromophenyl)ethanones as
starting materials with tert-butyl isocyanide for the synthesis of substituted lactones
(Scheme 1),[9] which is a core structure of various natural products[10,11] and designed
pharmaceutical molecules.[12–15] Since the pioneering work of Ugi,[16–18] isocyanides
have long proved themselves to be irreplaceable building blocks in modern organic
chemistry. To date, reactions of isocyanide insertion including two-component reac-
tions[19–22] and multicomponent reactions (MCRs)[23–26] have become increasingly
important. Most of the reactions via tert-butyl isocyanide insertion were all catalyzed
by palladium or were metal free. In a continuation of our interest in lactone syntheses
using isocyanides, we are making efforts to explore more novel and efficient synthetic
methods. According to Scheme 1,[9] although Pd(OAc)2 has proved to be a good metal
catalyst, black Pd0 could be generated, which made the reaction tube difficult clean.
Thus, we considered nickel as a kind of inexpensive transition metal that has character-
istics similar to palladium. The idea that nickel might be a good catalyst for this kind of
insertion reaction prompted us to investigate the methodology. Thus, we used model
substrate 1aa in our previous work to test different transition-metal catalysts. To our
delight, NiCl2=1,2-bis(diphenylphosphino)ethane (DPPE) proved to be an efficient
and clean catalyst system. Herein we report a novel approach to the preparation of iso-
coumarins and phthalides based on the nickel-catalyzed cyclization and hydrochloric
acid hydrolysis.
DISCUSSION
Initially, we examined the intermolecular reaction of 2-(o-bromophenyl)-1-
phenylethanone 1aa and tert-butyl isocyanide as the model substrates to screen
the reaction conditions, and the results are depicted in Table 1. Reaction of 1aa with
tert-butyl isocyanide was tested in dimethylformamide (DMF) at 135 ꢀC in the pres-
ence of NiCl2 (5 mol%) and PPh3 (10 mol%), which was found to be effective (entry
1, Table 1). Product (Z)-(1H)-3-phenyl-N-tert-butylisochromen-1-imine 2aa was
obtained in 68% yield after 12 h. Then, several phosphorus ligands were tested to find
an optimal one, which had the best catalytic activity for the reaction (entries 2–6).
The expected product 2aa was formed in 89% yield when L3 (DPPE) was employed
as the ligand (entry 3). A diminished yield was obtained when Cs2CO3 was used as

3264
X. D. FEI ET AL.
Table 1. Condition optimizations of 1aa with tert-butyl isocyanidea
Entry
Catalyst
NiCl2
NiCl2
Ligand
Base
Solvent
Yieldb (%)
1
2
L1
L2
L3
L4
L5
L6
L3
L3
L3
L3
L3
L3
—
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Toluene
Dioxane
DMF
DMF
DMF
68
54
89
16
28
23
19
82
0c
3
NiCl2
NiCl2
4
5
NiCl2
NiCl2
6
7
NiCl2
NiCl2
8
9
NiCl2
NiCl2
10
11
12
13
5c
Ni(OAc)2
Ni(acac)2
NiCl2 ꢁ DPPE
46d
80d
53d
aReaction conditions: All reactions were performed with 1aa (0.5 mmol), tert-butyl isocyanide
(0.75 mmol), NiCl2 (2.5 mol%), ligand (5 mol%), and base (1.0 mmol) in 3.0 mL of anhydrous solvent at
135 ꢀC for 12 h. L1, triphenylphosphine; L2, 1,10-bis(diphenylphosphino)ferrocene; L3, 1,2-bis(diphenyl-
phosphino)ethane; L4, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; L5, bis[(2-diphenylphosphino)-
phenyl]ether; L6, (R)-2,20-bis(diphenylphosphino)-1,10-binaphthyl.
bIsolated yield.
cReaction at 110 ꢀC.
dReaction time for 24 h.
the base (entry 7). When the solvent was switched to dimethylsulfoxide (DMSO),
toluene, or dioxane, the yield of 2aa decreased (entries 8–10). Other Ni catalysts such
as Ni(OAc)2, Ni(acac)2, and NiCl2 ꢁ DPPE were also tested, and we obtained lower
yields and longer reaction time (entries 11–13). On the basis of these considerations,
our catalytic system was set as NiCl2 (5 mol%) and DPPE (10 mol%) in DMF using
K2CO3 (2 equiv) as a base. Then, acid hydrolysis of 2aa could form 3-phenylisocou-
marin 3aa in good yield.
With the optimized reaction conditions established, the scope of the reaction
was investigated. Substituents R3, including aryl (Table 2, entries 1–9), heteroaryl
(Table 2, entries 10–12), and alkyl (Table 2, entries 13 and 14), which were present
in substrates 1aa–1an, were well tolerated. 2-(2-Bromophenyl)-1-phenylethanones
with methyl, methoxyl, fluoro, and sensitive functional groupss such as chloro and
strong electron-withdrawing groups such as trifluoromethyl all gave the correspond-
ing substituted isocoumarins in good to excellent yields (Table 2, entries 2–9). Sub-
strates with electron-deficient aromatics afforded greater yields than electron-rich
ones. Note that good yields were obtained when R3 was a heteroaryl group including
pyridyl, furyl, or thiophenyl (Table 2, entries 10–12). Aliphatic groups such as cyclo-

NICKEL-CATALYZED ISOCYANIDE INSERTION
3265
Table 2. Synthesis of isocoumarins from substrates with isocyanides
Entry
Substrate
Product
Yielda (%)
1
1aa[27]
1ab[27]
1ac[27]
3aa
3ab
3ac
86
2
3
77
79
4
1ad[27]
3ad
87
5
6
7
1ae[27]
1af[27]
1ag[27]
3ae
3af
3ag
89
86
91
(Continued )

3266
X. D. FEI ET AL.
Table 2. Continued
Entry
Substrate
Product
Yielda (%)
8
9
1ah[27]
3ah
3ai
61
1ai[27]
88
10
1aj[28]
3aj
68b
11
12
1ak[29]
3ak
3al
55b
1al[29]
52b
13
14
1 am[27]
3 am
3an
68b
1an[27]
66b
15
16
1ao[30]
3ao
3ap
86
1ap[31]
59b
(Continued )

NICKEL-CATALYZED ISOCYANIDE INSERTION
3267
Table 2. Continued
Entry
17
Substrate
Product
Yielda (%)
1aq[27]
3aq
66
aIsolated yield.
bReaction time for 24 h.
hexyl and tert-butyl were also tolerated (Table 2, entries 13 and 14). In addition,
substrates including disubstituents R2 and R3, such as 1ao and 1ap, also afforded
3ao and 3ap in moderate yields, respectively (Table 2, entries 15 and 16).
Furthermore, 1-(o-bromophenyl)-2-phenylethanones 1ba–1bi were also investi-
gated, and the results are summarized. This method was successfully applied to
Table 3. Synthesis of phthalides from substrates with isocyanides
Entry
Substrate
Product
Yielda(%)
1
1ba[27]
3ba
3bb
87
2
3
1bb[27]
78
1bc[27]
3bc
80
(Continued )

3268
X. D. FEI ET AL.
Table 3. Continued
Entry
Substrate
Product
Yielda(%)
4
5
1bd[27]
3bd
3be
86
1be[27]
84
59
58
6
7
1bf[27]
3bf
1bg[27]
3bg
8
9
1bh[27]
3bh
3bi
67
1bi[27]
48b
aIsolated yield.
bReaction time for 24 h.
synthesize various phthalides. As illustrated in Table 3, substrates containing
electron-donating and electron-withdrawing groups could be used and provided
the corresponding products in moderate to good yields (Table 3, entries 1–8). Note
that substrate with aliphatic group such as 1-(o-bromophenyl)undecan-1-one also
gave product 3bi in moderate yield (Table 3, entry 9).
A plausible mechanism of this reaction is outlined in Scheme 2. Oxidative
addition[32–34] of 1aa to Ni0 leads to form complex A, followed by tert-butyl isocya-
nide insertion to form B. NickelII in complex B, which coordinates to the oxygen

NICKEL-CATALYZED ISOCYANIDE INSERTION
3269
Scheme 2. Plausible mechanism of nickel-catalyzed cyclization reaction.
atom of hydroxyl group,[35] promotes the form of C. Reductive elimination[32–34] of
C leads to the intermediate 2aa with the regeneration of Ni0 species.
In summary, we have developed novel and efficient NiCl2-catalyzed reactions
for the synthesis of isocoumarins and phthalides from easily accessible substrates
and tert-butyl isocyanide. The mechanism was investigated, and a key intermediate
was isolated and characterized. The advantage that electron-deficient substrates
showed greater reactivity than electron-rich ones was found to be contrary to the
Pd catalyst system. This approach provides one of the easiest pathways for accessing
this class of valuable compounds.
EXPERIMENTAL
General Procedure for the Synthesis of Lactones 3
A sealed tube was charged with a magnetic stir bar, and 1 (0.5 mmol), tert-butyl
isocyanide (0.75 mmol), NiCl2 (2.5 mol%), DPPE (5 mmol%), K2CO3 (1.0 mmol,
138 mg), and anhydrous dimethylformamide (DMF, 3 mL) were added at the same
time. The tube was purged with nitrogen gas and stirred at 135 ꢀC for 12 h. After
reaction completion, the mixture was filtered through a short plug of celite, and
DMF was removed by vacuum. The combined filtrates were refluxed in tetrahydro-
furan (THF, 15 mL) and HCl (1 M, 3 mL) for 2 h. Then, the mixture was extracted
with EtOAc, dried (Na2SO4), and evaporated. The residue was purified on a silica-gel
column using petroleum ether = EtOAc as the eluent to give the pure target products 3.
3-Phenyl-1H-isochromen-1-one (3aa)[9]
White solid, 80–82 ꢀC. 1H NMR (400 MHz, CDCl3) d 8.30 (d, J ¼ 8.1 Hz, 1H),
7.87 (d, J ¼ 7.8 Hz, 2H), 7.71 (t, J ¼ 7.6 Hz, 1H), 7.52–7.41 (m, 5H), 6.94 (s, 1H). 13
C
NMR (75 MHz, CDCl3) d 162.3, 153.6, 137.5, 134.9, 131.9, 129.9, 129.6, 128.8,
128.1, 125.9, 125.2, 120.5, 101.8.

3270
X. D. FEI ET AL.
SUPPORTING INFORMATION
1
Full experimental details and H and 13C NMR spectra can be found via the
Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support by PAPD (a project funded
by the Priority Academic Program Development of Jiangsu Higher Education
Institutions) and National Nature Science Foundation of China (No. 21172162).
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