Efficient access to 3-substituted-γ-hydroxylactams: The uncatalyzed addition of diorganozinc reagents to cyclic imides with heterocyclic substitution

Article abstract of DOI:10.1016/j.tetlet.2014.01.130

A range of 3-substituted-γ-hydroxylactams have been prepared via the uncatalyzed addition of organozinc nucleophiles to cyclic imides. This reactivity is primarily limited to imides containing heterocyclic N-substitution, but proceeds efficiently with a variety of diorganozinc reagents, including those prepared and utilized without purification, as well as organozinc halides. It is hypothesized that the presence of a Lewis basic directing group is required for optimum reactivity.

Full text of DOI:10.1016/j.tetlet.2014.01.130

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient access to 3-substituted-c-hydroxylactams:
the uncatalyzed addition of diorganozinc reagents to cyclic
imides with heterocyclic substitution
⇑
Kimberly S. DeGlopper, Joseph M. Dennis, Jeffrey B. Johnson
Department of Chemistry, Hope College, 35 East 12th St, Holland, MI 49423, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A range of 3-substituted-c-hydroxylactams have been prepared via the uncatalyzed addition of organo-
Received 17 January 2014
Revised 23 January 2014
Accepted 28 January 2014
Available online xxxx
zinc nucleophiles to cyclic imides. This reactivity is primarily limited to imides containing heterocyclic N-
substitution, but proceeds efficiently with a variety of diorganozinc reagents, including those prepared
and utilized without purification, as well as organozinc halides. It is hypothesized that the presence of
a Lewis basic directing group is required for optimum reactivity.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Imides
Organozinc reagents
Nucleophilic addition
Directing groups
Introduction
Access to these hydroxy-lactams can be achieved through tradi-
tional nucleophilic addition utilizing Grignard or lithium reagents,
The use of Lewis basic functionality to direct reactivity has long
been utilized to control the formation of complex organic species.1
Recent studies have repeatedly demonstrated the significance of
these groups on transition metal catalysis,2 particularly within
the realm of inert bond activation, such as that occurring with C–
H3 and C–C bonds.4 The presence of a directing group can be uti-
lized to control stereochemistry, enhance regioselectivity, or even
promote reactions that fail to proceed in the absence of such a
group. In the course of exploring the substrate scope for our re-
cently reported methodology utilizing nickel species to catalyze
the addition of diorganozinc reagents to phthalimides,5 we ob-
served that substrates containing heteroaromatic directing groups
within phthalimide nitrogen substitution undergo reaction in the
absence of nickel. Herein we present our efforts to optimize the
substrate-directed, selective mono-addition of diorganozinc nucle-
ophiles to N-substituted imide moieties while examining the scope
of amenable substituents that promote the uncatalyzed addition.
The addition of nucleophilic aryl reagents to phthalimides pro-
but these reactions are often fraught with uncontrolled multiple
additions that lead to complex product mixtures.9 Several more re-
cently developed methods, including rhodium-catalyzed oxidative
acylation10 and the utilization of alkynyl benzoic acids,11 work well
for simple structures but generally fail to demonstrate broad sub-
strate scope, notably for inclusion of heteroatoms within the nitro-
gen substituent.12
Results and discussion
In a recent publication, we reported the use of nickel catalysis to
achieve the selective mono-addition of diorganozinc reagents to
O
Et2Zn (1.1 equiv)
N
no reaction
THF, 55 °C
O
vides ready access to substituted 3-hydroxy-
c
-lactams, a structural
O
O
N
motif observed in numerous biologically active molecules,6,7
including chlorthalidone, a diuretic utilized to treat hypertension.8
Et2Zn (1.1 equiv)
THF, 55 °C
N
N
N
2
Et
HO
O
1
⇑
Corresponding author. Tel.: +1 616 395 7083; fax: +1 616 395 7118.
E-mail address: jjohnson@hope.edu (J.B. Johnson).
Scheme 1. Uncatalyzed addition of diorganozinc reagents to imides containing
heterocyclic substitution.
http://dx.doi.org/10.1016/j.tetlet.2014.01.130
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: DeGlopper, K. S.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.01.130

2
K. S. DeGlopper et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 1
Table 3
Scope of imide substituents for the uncatalyzed direct addition of diethylzinca
Use of 3,4-dimethylmaleimide backbonea
O
O
N
O
O
N
Et2Zn (1.1 equiv)
THF, 55 °C
Nucleophile
N
N
R
N
N
R
THF, 55 °C
R
Et
O
O
HO
HO
16
Entry
R
Product
Yield (%)
Entry
R
Source
Product
Yield (%)
1
2
3
4
5
6
7
2-Pyridyl
6-Methyl-2-pyridyl
3-Pyridyl
4-Pyridyl
2-Thiazolyl
N(CH3)2
2
3
4
5
6
7
8
83
78
82
<5
71
35
<5
1
2
3
4
5
Et
Ph
Et2Zn
17
18
19
20
20
84
91
74
95
81
Ph2Zn
Ar2Znb
Ar2Znb
ArZnClc
3,5-(CF3)2-C6H3
4-OMe-C6H4
4-OMe-C6H4
a
OCH3
Standard conditions: Imide (0.5 mmol), nucleophile (0.55 mmol), THF (2 mL),
55 °C under an argon or nitrogen atmosphere.
a
Standard conditions: Imide (0.5 mmol), Et2Zn (0.55 mmol), THF (2 mL), 55 °C,
b
Diorganozinc reagent generated from aryl bromide, nBuLi, and ZnCl2 and used
argon or nitrogen atmosphere.
without purification.
c
Organozinc halide generated from aryl bromide, nBuLi, and ZnCl2 and used
without purification.
O
O
N
O
Beyond coordination effects, electronics may play a role, as the
heteroaromatic substrates are all significantly electron deficient.
To probe this possibility, a series of phthalimides with electron
deficient N-aryl substituents were prepared and tested under the
standard reaction conditions. None of these substrates, which in-
cluded 3,5-bis(trifluoromethyl)-, pentafluoro-, and 4-nitro-phenyl
moieties, reacted with diethylzinc. These results suggest that the
coordination event is required for the uncatalyzed reaction.
Beyond heteroaromatic substituents, N-(dimethylamino)
phthalimide also undergoes reaction with diethylzinc, albeit in
only 35% yield (Table 1, entry 6). Notably, the analogous N-meth-
oxy phthalimide (Table 1, entry 7) does not show similar behavior,
even at extended reaction times. Similarly, amine-substituted
phthalimide 9 and N-(2-methoxyphenyl)phthalimide (Scheme 2),
each of which contains potential directing functionality, also fails
to react under the standard conditions.
With the scope of amenable heteroatom substituents in hand,
several other nucleophiles were examined for reactivity, using N-
(2-pyridyl)phthalimide (10) and N-2-thiazolyl-phthalimide (11)
as the test substrates. The reaction proceeds remarkably efficiently
using commercially available diphenylzinc, producing desired
hydroxy-lactams 12 and 13 in 95% and 94% yield, respectively
(Table 2). As with our previous work, the reaction also proceeds
efficiently with diorganozinc reagents generated from the corre-
sponding aryl bromide via lithium–halogen exchange and reaction
N
N
O
O
9
CH3
Scheme 2. A sample of substrates that fail to undergo direct addition.
phthalimides. In the course of performing control experiments, it
was observed that while the vast majority of N-substituted phthal-
imides require a nickel catalyst to react with diorganozinc re-
agents, N-(2-pyridyl)-phthalimide (1) undergoes alkylation in the
absence of a transition metal catalyst (Scheme 1). At 55 °C in THF
under an inert atmosphere over 16 h, diethylzinc is added to 1 to
generate hydroxy-lactam 2 in 83% yield following workup and
purification.13
To examine the influence of the heteroaromatic substituent, a
series of additional imides were prepared and subjected to similar
reaction conditions. Substrates containing 2- and 3-pyridines and
2-thiazolyl react smoothly, each producing the desired hydroxy-
lactam in good to excellent yields (Table 1). To our surprise, the
4-pyridyl phthalimide failed to undergo reaction, yielding unre-
acted starting materials even after extended reaction times, lead-
ing to the conclusion that the observed reactivity is due, at least
in part, to the relative proximity of heteroatoms on the N-substitu-
ent and the coordination of the diorganozinc reagents during the
course of the reaction.
Table 2
Scope of nucleophiles amenable to direct addition to heterocycle-substituted imidesa
O
O
Nucleophile
THF, 55 °C
N
Ar
N Ar
R
O
HO
N
N
Ar =
, 10 Ar =
11
,
S
Entry
Substrate
R
Nucleophile/source
Product
Yield (%)
1
2
3
4
5
6
7
10 (Ar = 2-pyridyl)
11 (Ar = 2-thioazolyl)
Ph
Ph
Ph2Zn, commercial
Ph2Zn, commercial
12
13
14
14
15
15
12
95
94
90
72
77
56
>5
10
10
10
10
10
4-OCH3C6H4
4-OCH3C6H4
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
Ph
Ar2Zn, from ArBr, BuLi, ZnCl2
ArZnCl, from ArBr, BuLi, ZnCl2
Ar2Zn, from ArBr, BuLi, ZnCl2
ArZnCl, from ArBr, BuLi, ZnCl2
PhB(OH)2, commercial
a
Standard conditions: Imide (0.5 mmol), nucleophile (0.55 mmol), THF (2 mL), 55 °C, argon or nitrogen atmosphere.
Please cite this article in press as: DeGlopper, K. S.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.01.130

K. S. DeGlopper et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
O
H
Towsley Foundation, and the NSF (CHE-1148719) for financial
support of this research. Grants from the NSF for the purchase of
NMR spectrometers (CHE-0922623) and GC/MS instrumentation
(CHE-0952768) are also gratefully acknowledged.
O
H
N
N
O
H
H
Et2Zn (1.1 equiv)
THF, 55 °C
Et
H
H
Et
O
N
HO
O
O
21
Supplementary data
N
N
H
Et
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.01.
130. These data include MOL files and InChiKeys of the most
important compounds described in this article.
Scheme 3. Product mixture obtained from imides with saturated backbones.
with ZnCl2 as demonstrated with both electron rich and electronic
deficient species (Table 2, entries 3 and 5). Notably, these nucleo-
philes can be prepared and utilized without purification with no
significant effect upon the reaction yield. In a similar fashion,
organozinc halides also efficiently produce the desired hydroxy-
lactam products, albeit in slightly reduced yield (entries 4 and 6).
Notably, boronic acids fail to react under the standard reaction
conditions (entry 7).
In contrast to our recent nickel-catalyzed coupling of phthali-
mides and diorganozinc reagents,5,14 this reaction also proceeds
with other cyclic imides. While the use of maleimides was compli-
cated by competing conjugate addition, the use of N-(2-pyridyl)-
3,4-dimethyl maleimide (16)15 led to the desired products with a
range of nucleophiles, including diorganozinc and organozinc ha-
lides (Table 3), in very good yields. The use of imides with satu-
rated backbones, however, such as imide 21 in Scheme 3,
generates a mixture of alkene products, presumably formed via de-
sired diorganozinc addition followed by elimination.
References and notes
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In summary, we have observed the substrate-specific
uncatalyzed addition of diorganozinc reagents to cyclic imides.
Nucleophilic addition occurs very efficiently with heteroaro-
matic-containing substrates, presumably via the coordination of
the diorganozinc reagent. This work uncovers the importance of
directing groups in simple reactivity, and presents an efficient
and selective production of 3-substituted-c-hydroxylactams
containing appended heterocyclic moieties.
13. See the Supplementary material for all experimental details.
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Acknowledgment is made to the Donors of the American
Chemical Society Petroleum Research Fund (50347-UNI1), the
Please cite this article in press as: DeGlopper, K. S.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.01.130