Simple Synthesis of γ-Spirolactams by Birch Reduction of Benzoic Acids

Article abstract of DOI:10.1002/ejoc.201601650

A convenient synthesis of γ-spirolactams in only two steps was developed. Birch reduction of benzoic acids and immediate alkylation with chloroacetonitrile afforded cyclohexadienes in high yields. The products could be isolated by crystallization on a large scale in analytically pure form. Subsequent hydrogenation with platinum(IV) oxide as the catalyst reduced the nitrile functionality and the double bonds in the same step with excellent stereoselectivity. The relative configurations were determined unequivocally by X-ray analyses. Direct cyclization of the intermediary formed amino acids afforded the desired γ-spirolactams in excellent overall yields. The procedure is characterized by few steps, cheap reagents, and can be performed on a large scale, interesting for industrial processes.

Full text of DOI:10.1002/ejoc.201601650

A Journal of
Accepted Article
Title: Simple Synthesis of γ-Spirolactams by Birch Reduction of
Benzoic Acids
Authors: Torsten Linker, Tobias Krüger, Alexandra Kelling, and Uwe
Schilde
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601650
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601650
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European Journal of Organic Chemistry
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COMMUNICATION
Simple Synthesis of γ-Spirolactams by Birch Reduction of
Benzoic Acids
Tobias Krüger, Alexandra Kelling, Uwe Schilde, and Torsten Linker*
Abstract: A convenient synthesis of γ-spirolactams in only two steps
is described. Birch reduction of benzoic acids and immediate
alkylation with chloroacetonitrile afford cyclohexadienes in high
yields. The products can be isolated by crystallization on a large
scale in analytically pure form. Subsequent hydrogenation with
platinum(IV) oxide as catalyst reduces the nitrile and the double
bonds in the same step and with excellent stereoselectivity. The
relative configurations have been determined unequivocally by X-ray
analyses. Direct cyclization of the intermediary formed amino acids
affords the desired γ-spirolactams in excellent overall yields. The
procedure is characterized by few steps, cheap reagents, and can
be performed on a large scale, interesting for industrial processes.
we describe the simple and convenient synthesis of γ-
spirolactams 1 (R = H, Me, n = 2) from commercially available
precursors in only two steps, which can be conducted on a large
[
11]
scale and might be applicable for industrial processes.
The Birch reduction of arenes is a powerful method for the
[
12]
preparation of 1,4-cyclohexadienes.
toluic acids represent inexpensive industrial starting
materials, they provide high yields, excellent regioselectivities,
Especially benzoic and
2
[
13]
[
14]
and allow the direct alkylation of the 1-position.
We applied
and arene
[
15]
such reactions for selective photooxygenations
[
16]
syntheses.
To obtain γ-spirolactams 1 by this strategy, a
nitrogen atom has to be introduced during the Birch reduction.
Chloroacetonitrile seems to be an especially attractive alkylating
[
17]
γ-Lactams are important organic heterocycles, which are found
reagent, since it is commercially available and much cheaper
[
1]
in nature and often exhibit interesting biological activities. They
than bromoacetonitrile. Interestingly, although many reports on
[
2]
[12,14]
are easily available and are applied in industry for large-scale
Birch reductions of benzoic acids exist in literature,
only one
[
3]
ring-opening polymerizations. Especially γ-spirolactams of the
general structure 1 (Figure 1) have attracted much attention as
example describes the reaction with chloroacetonitrile in
[
18a]
moderate yield,
more expensive iodoacetonitrile afforded
We therefore optimized the Birch reduction
[
4]
[18b]
potential medicinal agents and can be synthesized by various
only 58% yield.
[
5]
methods, but over many steps. Very recently, cyclohexane-
with benzoic acid (2a) as a model compound (Table 1).
based γ-spirolactams 1 (n = 2) have been described to bind to
[
a]
[
6]
Table 1. Birch reduction and alkylation of benzoic acids 2.
opioid receptors and as enzyme inhibitors in two patents.
CO H
2
CO H
2
NC
H
N
1. Li, solvent, –78 °C
R
R
2
. ClCH CN (equiv.)
2
O
R = alkyl, aryl, OH, NH2
2
3
n = 1, 2
[
b]
[c]
Entry
Acid
R
Solvent
Conc.
Equiv.
Conv.
3 (%)
R
n
1
[d]
1
2
3
4
5
6
7
2a
2a
2a
2a
2b
2c
2d
H
H
H
H
NH /THF
3
0.1 M
0.1 M
0.5 M
0.5 M
0.5 M
0.5 M
0.5 M
3.0
3.0
3.0
1.6
1.6
1.6
1.6
80%
90%
76
Figure 1. Examples of γ-spirolactams 1.
NH
NH
NH
NH
NH
NH
3
3
3
3
3
3
86
>97%
>97%
>97%
>97%
>97%
97
96
Despite the great biological and medicinal interest, no
efficient syntheses, even for the unsubstituted γ-spirolactam 1a
[e]
o-Me
m-Me
p-Me
85
(
R = H, n = 2), exist in literature. A classical procedure starts
[
7]
from trimethylsilyl azide and cyclic anhydrides, more recently
97
the α-deprotonation of cyclohexane carboxylates and alkylation
[
f]
[
6, 8]
92
with bromoacetonitrile has been applied.
spirolactams 1 (R ≠ H, n = 2) have been obtained by oxidative
Functionalized γ-
[
a] Reactions were performed on a 0.1 mol scale. For procedures and
[
9]
cyclizations of phenols or, very recently, by construction of the
conditions, see Experimental Section and Supporting Information. [b]
Equivalents of chloroacetonitrile added. [c] Yield of analytically pure products,
[
10]
cyclohexane ring by a radical tandem reaction.
However, all
[
18]
isolated by crystallization. [d] Similar to literature on a 15 mmol scale. [e]
The corres-ponding 2,5-cyclohexadiene carboxylic acid was isolated in 10%
as side-product. [f] 55:45 mixture of diastereomers, separated by column
chromato-graphy.
methods require expensive starting materials and reagents,
many steps and often proceed in only moderate yields. Herein,
[*]
T. Krüger, A. Kelling, apl. Prof. U. Schilde, Prof. T. Linker
Department of Chemistry, University of Potsdam
Karl-Liebknecht-Str. 24-25
All reactions were performed with 0.1 mol of the benzoic acid
2, to demonstrate the applicability of the method on large scales.
However, the cyclohexadiene 3a was isolated in only 76% with
THF as co-solvent (entry 1), because of incomplete conversion,
14476 Potsdam (Germany)
E-mail: linker@uni-potsdam.de; http://www.chem.uni-
potsdam.de/groups/ochome
[
18]
in accordance to literature on a smaller scale. We therefore
dissolved the acid in sole liquid ammonia, a procedure, which
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201601650
COMMUNICATION
was effective in our previous studies.
[
15, 16]
Indeed, the yield of 3a
[a]
Table 2. Catalytic hydrogenations of cyclohexadienes 3.
was increased to 86% (entry 2). A further improvement was the
higher concentration of 0.5 M, which gave full conversion (entry
H
CN
N
CN
3
). Under such conditions, even the amount of chloroacetonitrile
could be reduced to 1.6 equiv., still affording the cyclohexadiene
a in excellent yield (entry 4). This method was employed as
general procedure for the toluic acids 2b–d as well
CO H
CO H
2
2
O
H , cat., pressure
2
3
+
R
R
R
MeOH, 20 °C
(
Experimental Section and Supporting Information).
3
1
4
The o-Me substituted acid 2b gave the cyclohexadiene 3b in
somewhat lower 85% yield (entry 5), since the α-protonated 2,5-
cyclohexadiene carboxylic acid was isolated as side-product.
This can be explained by steric hindrance with the methyl group
during attack of chloroacetonitrile and protonation after work-up.
On the other hand, the toluic acids 2c and 2d afforded the
alkylated products 3c and 3d again in excellent yields (entries 6,
Entry
Acid
R
Scale
Catalyst
Pressure
1 (%)
4 (%)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3a
3b
3c
H
H
2 mmol
2 mmol
2 mmol
2 mmol
2 mmol
2 mmol
20 mmol
20 mmol
20 mmol
20 mmol
Pd/C
Pd/C
1 atm
50 bar
1 atm
50 bar
1 atm
1 atm
1 atm
1 atm
1 atm
1 atm
< 5
< 5
< 5
10
98
97
H
Pd(OH)
Pd(OH)2
Rh/Al
PtO2
PtO
PtO2
2
96
7
). The p-Me derivative 3d was obtained as
a
55:45
H
87
diastereomeric mixture, since two new stereogenic centers are
generated far away from each other during the Birch reduction.
However, the two diastereomers could be separated by column
chromatography and were isolated in analytically pure form. The
relative configurations could not be established by NOESY
measurements, since the stereocenters are too far away.
However, we obtained single crystals of the pure isomers, and
the structures of cis-3d and trans-3d were assigned
unequivocally by X-ray analyses (Figure 2 and Supporting
H
2
O
3
< 5
< 5
< 5
< 5
< 5
< 5
< 5
[
b]
H
98
98
[
b]
H
2
[
b,c]
o-Me
m-Me
p-Me
96
97
[
b,c]
PtO
PtO
2
2
[
b]
1
1
0
1
cis-
3d
96
97
[
19]
Information).
[
b]
trans-
p-Me
20 mmol
PtO
2
1 atm
< 5
3
d
[
a] For procedures and conditions, see Experimental Section and Supporting
Information. [b] Yield of analytically pure products, isolated after heating in
pyridine by crystallization. [c] Formation of only one diastereomer.
To optimize the conditions, we initially conducted reactions
on a 2 mmol scale (entries 1–6). Hydrogenation of cyclo-
hexadiene 3a with 10% palladium on carbon, a common and
[
20a]
cheap catalyst,
the double bonds were reduced, and nitrile 4a was isolated in
8% yield (entry 1). We repeated the reaction at 50 bar (entry 2),
gave indeed full conversion. However, only
cis-3d
trans-3d
9
but again the nitrile group was intact. This is surprising, since
amines have been obtained by the same catalyst even at 1
Figure 2. Molecular structures of cyclohexadienes cis-3d and trans-3d.
[
21]
atm. We therefore investigated palladium hydroxide on carbon
Pearlman´s catalyst) next (entries 3, 4), which is more active
(
In summary, the Birch reduction of benzoic acids 2 and
immediate alkylation with chloroacetonitrile proceeds smoothly
in one step. The reactions can be performed on large scales and
the yields of cyclohexadienes 3 are good to excellent. The
products are conveniently isolated by crystallization and are
obtained in analytically pure form. Thus, in terms of costs and
efficiency, this procedure is advantageous over the known LDA
deprotonations of cyclohexane carboxylates and subsequent
[22]
and has been used for the reduction of nitriles as well.
However, although some lactam 1a could be detected in the
NMR of the crude product at 50 bar, the nitrile 4a was still the
main product. Rhodium on alumina is another catalyst for the
reduction of nitriles, which was even applied in the synthesis of
[23]
lactams. However, under the slightly basic reaction conditions
a migration of the double bond was observed at 1 atm of
hydrogen gas and neither lactam 1a nor nitrile 4a could be
isolated (entry 5). The reason for the slow reduction of the nitrile
group in acid 3a might be steric hindrance with the adjacent
quaternary carbon atom.
[
6, 8]
alkylations with bromoacetonitrile.
To obtain the desired γ-spirolactams 1, the nitrile group had
to be reduced to the amine in the next step. Many procedures
[
20]
are known for this transformation,
functional groups (nitrile, carboxylic acid, double bond) have to
be taken into account. Thus, reaction with LiAlH is not suitable,
however the different
Finally, we found optimal conditions with platinum(IV) oxide,
which is more expensive but more efficient than the other
catalysts and has often been applied for the reduction of
4
since the carboxylic acid would be reduced to the corresponding
alcohol. Furthermore, for large scale or industrial applications, a
catalytic hydrogenation would be advantageous. Therefore, we
[24]
nitriles. Indeed, even at 1 atm of hydrogen gas, full conversion
was achieved after 48 h and no nitrile group and no double bond
could be detected in the NMR of the crude product.
Lactamization directly proceeded under the reaction conditions,
investigated different catalysts with nitrile 3a as
a model
compound (Table 2).
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European Journal of Organic Chemistry
10.1002/ejoc.201601650
COMMUNICATION
but some free amino acid was still present. To complete the Experimental Section
cyclization, the crude product was simply heated for 8 h in
pyridine, and thus the γ-spirolactam 1a was isolated in 98% after
one crystallization (entry 6). After the successful optimization of
the hydrogenation conditions, we repeated the reaction with 20
mmol of cyclohexadiene 3a and only 50 mg (1 mol%) of
platinum(IV) oxide, to demonstrate the applicability of the method
on larger scales. Indeed, the yield of lactam 1a was still
excellent (entry 7) and the product was isolated in analytical
pure form. Therefore, this method was employed as general
procedure for the cyclohexadienes 3b–d as well (Table 2,
Experimental Section, and Supporting Information).
General procedure for Birch reductions: Benzoic acid 2 (100 mmol)
was introduced into a three-necked flask (500 mL) equipped with a dry-
ice condenser and cooled to – 78 °C by a dry-ice acetone bath. Ammonia
(
200 mL) was condensed into the three-necked flask, and lithium (1.39 g,
00 mmol) was added in small pieces to the solution at – 78 °C, until it
remained blue. After stirring for 1 h at – 78 °C, chloroacetonitrile (10.0 mL,
60 mmol) was added via syringe within 2 min and the ammonia was
2
1
allowed to evaporate overnight at RT. The solid residue was dissolved in
water (70 mL), cooled to 0 °C, acidified with 6 M HCl to pH 2 and
extracted with dichloromethane (3 x 50 mL). The combined organic
layers were dried over sodium sulfate, filtered over a small pad of silica
gel, and the solvent was removed in vacuo. The crude products were
crystallized from n-hexane to obtain the cyclohexadienes 3 in analytically
pure form (Supporting Information).
In all hydrogenations, the double bonds and nitrile groups
were reduced in the same step, and the desired cyclohexane-
based γ-spirolactams 1 were obtained in very high yields (entries
7
–11). Interestingly, starting from the o- and m-isomers 2b and
c a new stereogenic center is formed during the hydrogenation
General procedure for catalytic hydrogenations: Cyclohexadiene 3
(20 mmol) was dissolved in methanol (300 mL) at RT and platinum(IV)
oxide (50 mg, 1 mol%) and 37% HCl (1.5 mL) was added. The solution
was purged with hydrogen gas for 5 min, equipped with a balloon filled
with hydrogen gas and hydrogenated under stirring for 48 h. The solution
was filtered through a pad of Celite, washed with methanol (2 x 50 mL),
and the solvent was removed in vacuo. The residue was dissolved in
pyridine (500 mL) and heated for 8 h under reflux. The pyridine was
removed in vacuo and the residue was dissolved in dichloromethane
2
with excellent selectivity. Thus, we could only isolate a single
diastereomer for both reactions (entries 8, 9). The relative
configurations were assigned unequivocally by X-ray analyses.
Since 1b and 1c crystallize in the centrosymmetric space group
P2
1
/c, the packing contains both enantiomers, only one of each
[
25]
is shown (Figure 3 and Supporting Information).
(
200 mL), extracted with 1 N HCl (100 mL), dried over sodium sulfate,
and concentrated in vacuo. The solid γ-spirolactams 1 crystallized from n-
hexane in analytically pure form (Supporting Information).
Acknowledgements
We thank the University of Potsdam for generous financial
support.
1
b
1c
Figure 3. Molecular structures of γ-spirolactams 1b and 1c.
Keywords: diastereoselectivity • hydrogenation • lactams •
reduction • synthetic methods
The methyl groups are oriented cis to the carbonyl groups
and thus the hydrogenation occurs from the opposite face. We
explain this high selectivity by a coordination of the nitrile, which
has to be reduced as well, to the metal surface during the
hydrogenation, in accordance to other heterogenic reactions of
[1]
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Activity (Ed.: T. Janecki), Wiley-VCH, Weinheim, 2013.
[
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[
26]
this functional group.
Finally, since the p-isomers cis-2d and
trans-2d have been separated after the Birch reduction, we
obtained the corresponding diasteromerically pure γ-
spirolactams cis-1d and trans-1d as well (entries 10, 11).
[
5]
Reviews: a) R. Pradhan, M. Patra, A. K. Behera, B. K. Mishra, R. K.
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Zhang, J. Org. Chem. 2016, 81, 5362–5369.
In conclusion, we developed an easy entry to cyclohexane-
based γ-spirolactams in only two steps from benzoic acids. The
method is characterized by commercially available inexpensive
precursors. Birch reduction in the presence of chloroacetonitrile
on a large scale afforded cyclohexadienes in good to excellent
yields, isolated by simple crystallization. Subsequent
hydrogenation with platinum(IV) oxide as catalyst proceeded
smoothly, and the nitrile group and double bonds were reduced
in the same step with excellent stereoselectivities. After
cyclization, the γ-spirolactams were isolated in very high yields
by crystallization in analytically pure form. The relative
configurations have been established unequivocally by four X-
ray structures. Since various benzoic acids are commercially
available, the method might be applied for the synthesis of other
substituted γ-spirolactams, which are potential medicinal agents.
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This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201601650
COMMUNICATION
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0.0990 (I > 2σ(I)). For details of data collection and structure solution
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1
[
2 r
19] Crystal data for cyclohexadiene cis-3d: C10H11NO , M = 177.20 g·mol ,
3
crystal dimensions 0.80 x 0.42 x 0.37 mm , orthorhombic, space group
P2 , a = 6.4796(3), b = 8.3314(4), c = 17.9741(12) Å, V = 970.32(9)
1 1 1
2 2
3
-1
-1
Å , Z = 4, ρcalcd = 1.213 g·cm ; µ(MoK
T = 210 K; 2Θmax 64.02°, 24523 reflections measured, 3188 unique
int = 0.0373), R = 0.0365, wR = 0.0939 (I > 2σ(I)). For details of data
collection and structure solution and refinement, see Supporting
Information. CCDC 1520843 contains the supplementary
crystallographic data for this paper.
Crystal data for cyclohexadiene trans-3d: C10
α
) = 0.085 mm (λ = 0.71073 Å),
=
(
R
H
11NO
3
2 r
, M = 177.20
-
1
g·mol , crystal dimensions 0.75 x 0.2 x 0.1 mm , monoclinic, space
group P2
1
,
a
=
8.3740(5),
b
=
6.6076(3),
c = 8.4923(5) Å, β =
3
-1
9
0
7.164(5)°, V = 466.23(4) Å , Z = 2, ρcalcd = 1.262 g·cm ; µ(MoK
α
) =
-
1
.089 mm (λ = 0.71073 Å), T = 210 K; 2Θmax
=
49.95°, 9388
reflections measured, 1636 unique (Rint = 0.0227), R = 0.0269, wR =
.0730 (I > 2σ(I)). For details of data collection and structure solution
0
and refinement, see Supporting Information. CCDC 1520844 contains
the supplementary crystallographic data for this paper.
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Ohno, H. Tanaka, M. Komatsu, Y. Ohshiro, Synlett 1991, 919–920; c)
C.-B. Xue, W. F. DeGrado, Tetrahedron Lett. 1995, 36, 55–58; d) C.-B.
Xue, W. F. DeGrado, J. Org. Chem. 1995, 60, 946–952.
-
1
[
25] Crystal data for γ-spirolactam 1b: C10
H
17NO, M
r
= 167.25 g·mol ,
3
crystal dimensions 1.2 x 0.93 x 0.70 mm , monoclinic, space group
P2
1
/c, a = 6.7020(5), b = 14.1782(10), c = 9.8528(8) Å, β = 94.745(7)°,
3
-1
-1
V = 933.03(12) Å , Z = 4, ρcalcd = 1.191 g·cm ; µ(MoKα) = 0.076 mm (λ
=
0.71073 Å), T = 210 K; 2Θmax
= 50.00°, 5729 reflections measured,
1
604 unique (Rint = 0.0571), R = 0.0424, wR = 0.1052 (I > 2σ(I)). For
details of data collection and structure solution and refinement, see
Supporting Information. CCDC 1520845 contains the supplementary
crystallographic data for this paper.
-
1
Crystal data for γ-spirolactam 1c:
C
10
H
17NO,
3
M
r
=
167.25 g·mol ,
crystal dimensions 1.0 x 0.62 x 0.30 mm , monoclinic, space group
P2
1
/c,
a = 15.9612(11), b = 5.9713(4), c = 10.4042(9) Å, β =
3
-1
1
0
08.201(6)°, V = 942.00(13) Å , Z = 4, ρcalcd = 1.179 g·cm ; µ(MoKα) =
-
1
.075 mm (λ = 0.71073 Å), T = 210 K; 2Θmax
=
49.98°, 5721
reflections measured, 1641 unique (Rint = 0.0429), R = 0.0372, wR =
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European Journal of Organic Chemistry
10.1002/ejoc.201601650
COMMUNICATION
COMMUNICATION
T. Krüger, A. Kelling, U. Schilde, T.
Linker*
Page No. – Page No.
Simple Synthesis of γ-Spirolactams
by Birch Reduction of Benzoic Acids
Reduction + Reduction: This simple sequence allows the synthesis of γ-spiro-
lactams 3 from commercially available benzoic acids 1 via cyclohexadienes 2 in
only 2 steps. The method is characterized by cheap reagents, good to high yields,
and excellent diastereoselectivities, and the products can be isolated by
crystallization on a large scale.
This article is protected by copyright. All rights reserved.