Nickel-catalyzed direct addition of diorganozinc reagents to phthalimides: Selective formation of gamma-hydroxylactams

Article abstract of DOI:10.1055/s-0033-1339890

The nickel-catalyzed addition of diorganozinc reagents to phthalimides proceeds with excellent selectivity to provide 3-substituted-3- hydroxyisoindolin-1-one products. These 3-hydroxy-γ-lactams are produced cleanly in high yield with numerous examples of imide substitution and a broad range of diorganozinc reagents that are prepared and utilized without purification. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339890

LETTER
▌2567
lNettierckel-Catalyzed Direct Addition of Diorganozinc Reagents to Phthalimides:
Selective Formation of Gamma-Hydroxylactams
Nickel-Catalyzed Addition of Diorganozinc Reagents to Phthalimides
Joseph M. Dennis, Catherine M. Calyore, Jessica S. Sjoholm, J. Patrick Lutz, Joseph J. Gair, Jeffrey B. Johnson*
Hope College Department of Chemistry, 35 East 12th St., Holland, MI 49423, USA
Fax +1(616)3957118; E-mail: jjohnson@hope.edu
Received: 26.06.2013; Accepted after revision: 04.09.2013
N-phenyl-3-hydroxyisoindolin-1-one (2; Scheme 1). Due
Abstract: The nickel-catalyzed addition of diorganozinc reagents
to the previously mentioned observation of this skeleton
to phthalimides proceeds with excellent selectivity to provide 3-sub-
in natural products and other bioactive molecules, we pur-
sued the optimization and full exploration of this reactiv-
stituted-3-hydroxyisoindolin-1-one products. These 3-hydroxy-γ-
lactams are produced cleanly in high yield with numerous examples
of imide substitution and a broad range of diorganozinc reagents ity. Herein, we present the development of a nickel-
that are prepared and utilized without purification.
catalyzed methodology for the cNickel-Catalyzed Addi-
tion of Diorganozinc Reagents to Phthalimidesoupling of
phthalimides with diorganozinc reagents that leads to se-
lective mono-addition of the organometallic with a broad
range of imide and nucleophile substitution for the selec-
tive preparation of 3-substituted 3-hydroxyisoindolin-1-
ones.
Key words: imide, catalysis, lactams, organometallic reagents,
nickel
The development of transition-metal-catalyzed coupling
methodologies has a continual influence on the evolution
of synthetic organic chemistry.1 In addition to the devel-
opment of previously unknown transformations and cou-
plings, transition-metal catalysis can provide greater
control over known reactions through the use of less
forceful reaction conditions, ultimately allowing the use
of a broader range of substrates. For example, the reaction
of strongly nucleophilic organometallic reagents, such as
Grignards2 and organolithiums,3 with imides is well prec-
edented. These reactions, however, are often plagued by
uncontrolled multiple nucleophile additions to generate
complex mixtures of products. The controlled addition of
a single alkyl or aryl nucleophile would offer a clear route
to the formation of 3-substituted 3-hydroxyisoindolin-1-
ones, a structural motif found in numerous natural
products4 and bioactive compounds,5 including chlorthal-
idone, which is a diuretic utilized to treat hypertension.6
Access to these 3-hydroxy-γ-lactams has been achieved
through a number of procedures,7,8 including recent routes
utilizing alkynyl benzoic acids9 or rhodium-catalyzed
oxidative acylation,10 but these methods generally fail to
demonstrate broad substrate scope for nitrogen, back-
bone, and/or 3-carbon substitution.
O
O
O
[Ni]
(stoich)
[Ni]
(cat.)
Ph
N
N
Ph
N
Ph
H
Et2Zn
Et2Zn
HO
O
1
2
previous work
this work
Scheme 1
In the presence of 10 mol% Ni(COD)2 (COD = 1,5-cy-
clooctadiene) and 11 mol% PPh3 in THF at 55 °C, dieth-
ylzinc cleanly adds to N-phenylphthalimide, providing the
direct addition product 2 in 81% isolated yield. In the pro-
cess of reaching these optimized conditions, numerous ex-
periments were performed to ascertain the role of the
various components of this transformation (Table 1). In
the absence of nickel, under otherwise standard condi-
tions, no product was observed (entry 2). A number of li-
gands provide the product in low yields, while also
generating the decarbonylation product (entries 3–5).12 In
contrast, the use of Ph3P provided the 3-hydroxyisoindo-
lin-1-one exclusively with high yield. The use of bench-
stable Ni(acac)2 (acac = acetylacetonate) as the catalyst
required a slight excess of diethylzinc in order to generate
the proposed Ni(0) active catalyst, but provided the de-
sired product in a nearly identical yield to that obtained
with Ni(COD)2 (entry 6). In optimizing reaction condi-
tions, alternative solvents, nucleophiles, and temperatures
were also explored.
In previous work, our group reported the nickel-mediated
decarbonylative coupling of diorganozinc reagents and
phthalimides to generate ortho-substituted benzamides
(Scheme 1).11 While tolerant of a wide variety of function-
ality on both the diorganozinc and phthalimide reagents,
this methodology is significantly limited by the lack of
catalyst turnover. In the process of exploring potential cat-
alytic conditions for this decarbonylative transformation,
we observed the nickel-catalyzed direct addition of dieth-
ylzinc to N-phenylphthalimide (1) to selectively generate
With the development of the optimized conditions, our ef-
forts turned toward exploration of the substrate scope. A
series of N-substituted phthalimides was prepared and
tested for reactivity (Table 2). Aromatic substrates con-
taining a variety of substituents were found to be compat-
ible with the reaction conditions, providing good to
excellent yields. The reaction was tolerant of a significant
SYNLETT 2013, 24, 2567–2570
Advanced online publication: 16.10.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339890; Art ID: ST-2013-S0592-L
© Georg Thieme Verlag Stuttgart · New York

2568
J. M. Dennis et al.
LETTER
Table 1 Optimization of the Nickel-Catalyzed Direct Addition
Table 2 Scope of the Reaction with Respect to N-Phthalimide Sub-
stitutiona
O
O
Ni(COD)2 (10 mol%)
Ph3P (11 mol%)
O
O
Ni(COD)2 (10 mol%)
Ph3P (11 mol%)
N
Ph
N Ph
Et2Zn (1.1 equiv)
THF, Ar, 55 °C
N
R
N R
Et2Zn (1.1 equiv)
THF, Ar, 55 °C
O
HO
1
2
O
HO
Entry
Conditions (deviation from standard)a
Yield of 2 (%)
Entry
R
Product
Yield (%)
1
2
3
4
5
6
7
8
9
none
81
0
1
2
3
4
5
6
7
8
Ph
2
3
4
5
6
7
8
9
81
82
78
93
81
68
86
66b
no Ni source
3-MeC6H4
4-MeC6H4
4-EtC6H4
4-i-PrC6H4
3,5-(F3C)2C6H3
4-EtO2CC6H4
4-ClC6H4
no ligand
<5
<5
12
80
65
8
ligand = bipy
ligand = pyridine
metal = Ni(acac)2, Et2Zn (1.5 equiv)
1,4-dioxane at 95 °C
EtZnBr instead of Et2Zn
25 °C
a Standard conditions: Imide (0.5 mmol), Ni(COD)2 (10 mol%), Ph3P
(11 mol%), Et2Zn (0.55 mmol), 55 °C, THF, Ar atmosphere.
b Yield by GC/MS analysis. Separation from the elimination product
generated by dehydration proved difficult and led to significantly re-
duced isolated yield.
40
a Standard conditions: 1 (0.5 mmol), Ni(COD)2 (10 mol%), Ph3P (11
mol%), Et2Zn (0.55 mmol), 55 °C, THF, Ar atmosphere.
range of functional groups, including those that are not
compatible with more reactive organometallic species,
such as aryl esters and N-aryl halides (entries 7 and 8).
O
O
Ni(COD)2 (10 mol%)
Ph3P (11 mol%)
To date the reactivity has been limited to relatively elec-
tron-deficient aryl-substituted phthalimides.13 N-Alkyl or
N-aryl species containing electron-releasing functional-
ity, such as N-benzyl or N-4-methoxyphenyl
phthalimides, provide little or no product when subjected
to standard reaction conditions; the starting imides, or the
corresponding amide acid generated from hydrolysis dur-
ing workup, are recovered. Likewise, imides with saturat-
ed backbones, such as 2,3-dimethylsuccinimide, failed to
react under the standard conditions.
N
Ar
N
Ar
Ph2Zn (1.3 equiv)
THF, Ar, 55 °C
Ph
O
HO
10
Ar =
11
Nu source:
CO2Et
Ph2Zn (commercial): 84%
PhBr, n-BuLi, ZnCl2: 82%
Scheme 2 Use of commercial diphenylzinc versus that prepared and
utilized without purification
With the successful demonstration of nucleophiles pre-
pared in situ, a broad range of diorganozinc reagents was
explored as coupling partners (Table 3). Steric aspects of
the nucleophiles appear to have a modest effect, because
the coupling proceeds efficiently with ortho-, meta-, and
para-substituted aryl nucleophiles with only minor influ-
ence on the yield (entries 1–6). The functional group tol-
erance includes typical ether, thioether and
trifluoromethyl moieties, but also extends to more exotic
nucleophiles, such as aryl fluoride and bromide (entries
11 and 13). The bromide is formed via the diarylzinc re-
agent prepared from 1-bromo-4-iodobenzene. An alkyl
ester nucleophile, utilized without purification following
generation from zinc chloride and (1-ethoxycyclopro-
poxy)trimethylsilane,14 also readily adds to imide 1 with
excellent conversion, but isolation is complicated by the
propensity of the product to undergo dehydration to gen-
erate a mixture of alkenes.
In addition to elaboration of the phthalimide substituents,
the scope of diorganozinc reagents was also explored.
Commercially available reagents worked smoothly, but
the availability of commercial diorganozinc reagents is
quite limited. It was therefore paramount that the reaction
proceeds efficiently with nucleophiles prepared and uti-
lized with minimum purification. To address this require-
ment, a solution of diphenylzinc, prepared through
lithium–halogen exchange of bromobenzene and subse-
quent reaction with ZnCl2, was utilized as the nucleophilic
reagent under Ni(COD)2/Ph3P catalysis. By utilizing im-
ide 10 under otherwise standard reaction conditions, the
desired product of this reaction was obtained in 82% yield
compared to 84% yield obtained with commercially avail-
able Ph2Zn (Scheme 2). It should be emphasized that the
diorganozinc reagents were utilized as prepared as a solu-
tion in THF, suggesting no deleterious effects of residual
organics and salts formed during nucleophile preparation.
As illustrated by the optimization studies, this reaction is
extremely sensitive to the electronic nature of both the
Synlett 2013, 24, 2567–2570
© Georg Thieme Verlag Stuttgart · New York

LETTER
Nickel-Catalyzed Addition of Diorganozinc Reagents to Phthalimides
2569
O
Table 3 Scope of the Reaction with Prepared Diorganozinc Nucleo-
O
O
philesa
Ph
N
ZnR
N
Ph
N
Ph
O
O
Ni(COD)2 (10 mol%)
Ph3P (10 mol%)
R
R
RZnO
D
O
N
Ph
N
Ph
[Ni]
O
C
R2Zn (1.3 equiv)
THF, Ar, 55 °C
R
O
HO
O
N
O
O
O
O
Entry
R
Product
Yield (%)
Ph
Ph
N
Ph
N
ZnR
[Ni]
1
2
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-MeSC6H4
4-t-BuC6H4
2-naphthyl
4-F3CC6H4
4-FC6H4
12
13
14
15
16
17
18
19
20
21
22
23
24
82
81
65
76
78
60
85
80
33
76
75
85
56b
R
[Ni]
[Ni]
R
RZnO
E
B
A
R2Zn
3
Scheme 3 Proposed mechanism
4
5
ate this catalytic cycle and the influence of electronic ef-
fects on the proposed divergence of paths.
6
7
As outlined in Scheme 4, the product 3-hydroxyisoindo-
lin-1-ones can be further diversified through a variety of
reactions. Treatment with sodium cyanoborohydride
leads to 3-alkyl-1-isoindolinones 25,3 whereas treatment
of the same species with sodium borohydride in alcoholic
solvents generates 3-alkoxy esters 26.3,15 Treatment of the
3-hydroxyisoindolin-1-ones with acid results in the dehy-
dration product, generating a cis/trans mixture of the cor-
responding alkenes 27. Finally, treatment of the products
with lithium aluminum hydride results in reduction of the
substrate to the corresponding 1-substituted isoindole 28.
These examples demonstrate the versatility of the substi-
tuted γ-lactams and illustrate the potential utility of the
newly developed methodology.
8
9
10
11
12
13
3,5-(F3C)2C6H3
4-BrC6H4
a Standard conditions: 1 (0.5 mmol), Ni(COD)2 (10 mol%), Ph3P
(11 mol%), Ar2Zn (0.68 mmol), 55 °C, THF, Ar atmosphere.
b Yield by GC/MS analysis.
phthalimide substituents and the ligand. This sensitivity is
similar to that observed in our previous decarbonylation
methodology, and in conjunction with the lack of multiple
addition products, suggests a shared mechanistic path-
way. As such, it is proposed that the reaction proceeds via
a nickel metalacycle rather than through direct nucleo-
philic attack (Scheme 3). Oxidative addition of the nick-
el(0) catalyst into the imide provides nickel(II)
metalacycle A. This metalacycle can subsequently under-
go decarbonylation as it does under catalysis with bipy,
ultimately leading to the catalytically dormant nickel(0)-
carbonyl species, or react with the diorganozinc reagent
through transmetallation. Under catalysis with Ph3P, the
latter pathway dominates, presumably due to destabiliza-
tion of the nickel-carbonyl intermediate through the use of
the more π-accepting phosphine ligand. Zinc amide spe-
cies B then undergoes subsequent reductive elimination to
form amide salt C. Free ketoacid has not been observed
under any reaction conditions, leading to the assumption
that intermediate C undergoes rapid intramolecular cycli-
zation to generate lactam D prior to the acidic workup,
which results in formation of the 3-hydroxy-γ-lactam. It is
also possible that intermediate B undergoes cyclization to
form E prior to reductive elimination, although this seems
less likely due to the relative electrophilicity of metal acyl
complex B and ketone C. Studies are underway to evalu-
O
O
NaBH4
MeOH
NaCNBH3
acid
N
Ph
N
Ph
O
MeO
26
25
N
Ph
HO
O
LiAlH4
H2SO4 (cat.)
N
Ph
N
Ph
28
27
Scheme 4 Elaboration of 3-substituted-3-hydroxyisoindolin-1-ones
In summary, the coupling of N-substituted phthalimides
with diorganozinc reagents has been demonstrated by uti-
lizing nickel(0) catalysis.16 Diorganozinc reagents gener-
ated from aryl bromides and used without purification can
be utilized to generate a broad range of substituted 3-hy-
droxyisoindolin-1-ones in good to excellent yield. Efforts
to understand the mechanistic interconnection of this
methodology with decarbonylative cross-coupling are on-
going.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2567–2570

2570
J. M. Dennis et al.
LETTER
(14) Zhang, Y.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 15964.
(15) Base, such as NaBH4 or NaOMe, is required for the
formation of 26. No reaction was observed in the absence of
base under otherwise identical reaction conditions.
(16) Direct Addition of Et2Zn to Phthalimides; Typical
Procedure: Ph3P (13.1 mg, 0.055 mmol) and N-
Acknowledgment
Acknowledgment is made to the Donors of the American Chemical
Society Petroleum Research Fund (50347-UNI1), as well as the Ca-
mille and Henry Dreyfus Foundation and the Research Corporation
(7833) for partial support of this research. We thank the Towsley
Foundation and the NSF (CHE-1148719) for financial support.
Grants from the NSF for the purchase of NMR spectrometers
(CHE-0922623) and GC/MS instrumentation (CHE-0952768) are
also gratefully acknowledged.
phenylphthalimide (111.6 mg, 0.50 mmol) were combined
with a stirbar in an oven-dried 25 mL round-bottomed flask.
The flask was transferred into an inert atmosphere glove
box, where Ni(COD)2 (14.0 mg, 0.051 mmol) was added.
The flask was sealed with a septum and removed from the
glove box, whereupon THF (2 mL) was added, followed by
Et2Zn (56.5 μL, 0.55 mmol, 1.1 equiv). The solution was
then brought up to temperature in a 55 °C oil bath and stirred
for 16 h. Upon completion of the reaction, the mixture was
cooled to r.t., the septum was removed and Et2O (15 mL)
was added. The addition of 2 M aq HCl (15 mL) quenched
the reaction, which was then extracted with Et2O
(3 × 15 mL). The combined organic layers were washed
with brine (15 mL), dried over MgSO4, and concentrated
under reduced pressure. The resulting yellow oil was
purified by column chromatography (hexane–EtOAc, 4:1) to
provide 2 (81% yield).
Direct Addition with Diorganozinc Reagents Generated
In Situ; Typical Method: 1-Bromo-4-tert-butylbenzene
(230 μL, 1.33 mmol) was added to an oven-dried 10-mL
round-bottomed flask, sealed with a septum, evacuated and
refilled with Ar (×3) and dissolved in THF (2 mL). The
reaction mixture was cooled to –78 °C, nBuLi (2.5 M in
hexanes, 536 μL, 1.34 mmol) was added dropwise and the
mixture was stirred at –78 °C for 1 h. In a separate flask,
ZnCl2 (92.1 mg, 0.68 mmol) was dried by heating under
vacuum and then dissolved in THF (1 mL). This solution
was then added to the solution of ArLi, still at –78 °C. The
reaction was removed from the cold bath and allowed to
warm to r.t. while stirring for 30 min.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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References and Notes
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In a separate 25 mL round-bottomed flask, N-
phenylphthalimide (112 mg, 0.50 mmol) and Ph3P (14.2 mg,
0.054 mmol) were combined and transferred into an inert
atmosphere glove box, where Ni(COD)2 (14.1 mg, 0.051
mmol) was added. This flask was sealed with a septum and
removed from the glove box, whereupon THF (2 mL) was
added, followed by the Ar2Zn solution. The solution was
then brought up to 55 °C in an oil bath and stirred for 16 h.
Upon completion of the reaction, the mixture was cooled to
r.t., the septum was removed and Et2O (15 mL) was added.
The addition of 2 M aq HCl (15 mL) quenched the reaction,
which was then extracted with Et2O (3 × 15 mL). The
combined organic layers were washed with brine (15 mL),
dried over MgSO4 and concentrated under reduced pressure.
The resulting residue was purified by column
(12) Due to the strength of the nickel–carbonyl bond,
decarbonylation leads to deactivation of the catalyst and
results in low yields of the desired products.
(13) It should be noted that with the use of electron-deficient
heteroatom-containing N-substituted imides, such as
N-(2-pyridyl)phthalimide, uncatalyzed addition of
diorganozinc nucleophiles was observed.
chromatography (hexane–EtOAc, 9:1) to provide 19 as a
white solid (80% yield).
Synlett 2013, 24, 2567–2570
© Georg Thieme Verlag Stuttgart · New York

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