Synthesis of γ-Spirolactams by Birch Reduction of Arenes

Article abstract of DOI:10.1002/ejoc.202100056

A convenient method for the synthesis of γ-spirolactams in only three steps is described. Birch reduction of inexpensive and commercially available aromatic carboxylic acids in the presence of chloroacetonitrile affords nitriles in moderate to good yields. Suitable precursors are methyl-substituted benzoic acids, naphthoic, and anthroic acid. Subsequent catalytic hydrogenation proceeds smoothly with PtO₂ or Raney Ni as catalysts and lactams are isolated in excellent yields and stereoselectivities. Thus, up to 3 new stereogenic centers can be constructed as sole diastereomers from achiral benzoic acids. Furthermore, it is possible to control the degree of saturation at different pressures, affording products with 0, 1, or 2 double bonds. Overall, more than 15 new γ-spirolactams have been synthesized in analytically pure form.

Full text of DOI:10.1002/ejoc.202100056

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Synthesis of γ-Spirolactams by Birch Reduction of Arenes
Tobias Krüger[a] and Torsten Linker*[a]
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Dedicated to Professor Siegfried Hünig on the occasion of his 100th birthday.
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A convenient method for the synthesis of γ-spirolactams in only
three steps is described. Birch reduction of inexpensive and
commercially available aromatic carboxylic acids in the pres-
ence of chloroacetonitrile affords nitriles in moderate to good
yields. Suitable precursors are methyl-substituted benzoic acids,
naphthoic, and anthroic acid. Subsequent catalytic hydrogena-
tion proceeds smoothly with PtO2 or Raney Ni as catalysts and
lactams are isolated in excellent yields and stereoselectivities.
Thus, up to 3 new stereogenic centers can be constructed as
sole diastereomers from achiral benzoic acids. Furthermore, it is
possible to control the degree of saturation at different
pressures, affording products with 0, 1, or 2 double bonds.
Overall, more than 15 new γ-spirolactams have been synthe-
sized in analytically pure form.
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Introduction
The Birch reduction of arenes is an important synthetic trans-
formation in organic chemistry, providing an easy access to 1,4-
cyclohexadienes.[1,2] It has been applied for several total
syntheses of natural products.[3,4] Aromatic carboxylic acids are
especially attractive starting materials, since they afford high
yields and regioselectivities, and alkyl substituents can be
directly introduced in the reduction step.[5] The most practical
method for large-scale reactions is a solution of alkali metals in
liquid ammonia.[6] However, electrochemical[7] or very recent
photocatalytic reductions[8] have been developed as well.
Our group is working with 1,4-cyclohexadienes, derived
from Birch reductions, since more than twenty years. Initially,
we investigated their regio- and stereoselective oxidations with
singlet oxygen.[9,10] Later on, we developed a two-step sub-
stitution of aromatic carboxylic acids,[11] which was extended by
Studer for palladium-catalyzed functionalizations.[12] Very re-
cently, we described first Birch reductions in the presence of
chloroacetonitrile in a communication (Scheme 1a).[13]
Thus, benzoic or toluic acids (1a–d) reacted smoothly with
lithium in liquid ammonia and subsequent alkylation to nitriles
2, which were directly hydrogenated with PtO2 as catalyst.
Cyclization afforded γ-spirolactams 3 in only few steps and high
yields. Lactams are structural motifs of natural products[14] and
are potential medicinal agents.[15] Furthermore, their ability to
form hydrogen bridges has been applied in enantioselective
reactions.[16] On the other hand, the synthesis of spiro com-
pounds requires usually many steps,[17–19] in contrast, our
method offered an easy entry by Birch reduction.[13]
Scheme 1. Synthesis of γ-spirolactams 3–5 by Birch reduction of arenes 1
and subsequent catalytic hydrogenation.
saturated products 3 (Scheme 1a). Herein, we describe that the
sequence Birch reduction of aromatic carboxylic acids –
catalytic hydrogenation is a general method for the synthesis of
γ-spirolactams 3–5 (Scheme 1b). Birch reductions in the pres-
ence of chloroacetonitrile proceeded smoothly with various
dimethyl substituted benzoic acids (1e–g), naphthoic (1h), and
anthracene carboxylic acid (1i) for the first time. Furthermore,
now it was possible to obtain unsaturated products with 1 or 2
double bonds by optimization of the catalyst and reaction
conditions. Thus, we could synthesize more than 15 new γ-
spirolactams in only few steps and good yields.
However, in our communication we investigated only
simple benzoic or toluic acids (1a–d) and obtained completely
Results and Discussion
[a] T. Krüger, Prof. T. Linker
Although the Birch reduction is known since more than half a
century,[1,2] we published reactions in the presence of chloroace-
tonitrile, a commercially available and inexpensive reagent,[20]
for simple benzoic acids very recently.[13] Herein, we applied
such optimized reaction conditions with no co-solvent and high
Department of Chemistry
University of Potsdam
Karl-Liebknecht-Str. 24–25,14476 Potsdam/Golm, Germany
E-mail: linker@uni-potsdam.de
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concentrations for the regioisomeric dimethyl benzoic acids
(1e–g) for the first time (Table 1, entries 1–3).
ucts. However, all nitriles could be isolated in analytically pure
form and represent suitable precursors for new γ-spirolactams.
To obtain the desired γ-spirolactams 3, we had to reduce
the nitriles 2 and cyclize the corresponding amino acids. In our
previous communication with simple benzoic or toluic acids
(1a–d),[13] we found catalytic hydrogenations in the presence of
PtO2 suitable for the reduction of the nitrile group and all
double bonds in one step. Furthermore, cyclization to lactams
was achieved by simple heating in pyridine, without isolation of
the intermediate amino acids. Thus, we applied such reaction
conditions (method A) to the herein newly synthesized nitriles
2e–i (Table 2).
Indeed, regioisomeric dimethyl nitriles 2e–g afforded com-
pletely saturated γ-spirolactams 3e–g in very good overall
yields (Table 2, entries 1–3). Furthermore, two new stereogenic
centers were formed during the hydrogenation with excellent
selectivity. The isolation of only one diastereomer is in
accordance to our previous communication,[13] and can be
rationalized by coordination of the nitrile to PtO2. Thus, hydro-
gen must attack from the same face, and the methyl groups are
oriented cis to the carbonyl group (for detailed structures see
Figure 1).
The bicyclic nitrile 2h reacted smoothly as well and afforded
γ-spirolactam 3h in 94% yield (Table 2, entry 4). Only with
nitrile 2i, derived from 9-anthracenecarboxylic acid (1i), the
corresponding lactam 3i was isolated in slightly lower yield of
90% (Table 2, entry 5), due to decarboxylation, which was
described in similar catalytic hydrogenations as well.[23]
To retain the double bonds for future further functionaliza-
tions, we became interested in other reducing procedures and
optimized them with nitrile 2b derived from o-toluic acid
(Table 3). Catalytic hydrogenation with palladium on charcoal, a
common and cheap catalyst,[24] gave full conversion, but only
one double bond was reduced (entry 1). On the other hand,
rhodium on alumina, which has been applied for the synthesis
of lactams from nitriles,[25] gave no conversion (entry 2).
The reason for the slow reduction of the nitrile group might
be due to steric hindrance by the adjacent quaternary carbon
atom. Lithium aluminum hydride was not a suitable reagent,
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In contrast to benzoic acid (1a), such arenes are more
electron rich and react more slowly with lithium in ammonia.
Furthermore, chloro-acetonitrile is CH acidic, resulting in
protonated 1,4-cyclohexadienes 6 as side-products, which is
especially a problem for sterically hindered substrates. Thus,
2,3- and 2,6-dimethylbenzoic acids (1e and 1f) afforded the
desired nitriles 2e and 2f in only 65 and 64% yield (Table 1,
entries 1 and 2). However, separation of the side-products 6e
and 6f was possible by column chromatography, and all
compounds could be isolated in analytically pure form. On the
other hand, the sterically less hindered 3,5-dimethylbenzoic
acid (1g) afforded only very small amounts of protonation 6g,
and the main product 2g was isolated in good yield (entry 3).
After the successful Birch reductions of dimethylbenzoic
acids (1e–g), we became interested in reactions of bi- and
tricyclic aromatic carboxylic acids in the presence of chloroace-
tonitrile. Thus, 1-naphthoic acid (1h) reacted smoothly and
afforded nitrile 2h in excellent yield (Table 1, entry 4). On the
other hand, 9-anthracenecarboxylic acid (1i) gave a complex
mixture under the same reaction conditions (entry 5). Besides
protonation 6i and small amounts of the desired nitrile 2i,
alkylation products at the 10-position were formed as well.
Although a reductive alkylation of 9-anthracenecarboxylic acid
(1i) was hitherto unknown,[2] this behavior is in accordance to
Birch reductions of anthracene and its corresponding esters.[21,22]
Therefore, we altered the reaction conditions and added tert-
butanol prior to chloroacetonitrile to the Birch reduction
(Table 1, entry 6). Indeed, now the formation of the 10-alkyl
product was suppressed completely. Although this procedure
afforded a somehow larger amount of side-product 6i due to
protonation by the alcohol, the desired nitrile 2i was now easily
separated by column chromatography and isolated in analyti-
cally pure form.
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In summary, we applied the Birch reduction in the presence
of chloroacetonitrile to various methyl-substituted benzoic
acids, naphthoic and anthroic acid for the first time. For
sterically hindered substrates protonation afforded side-prod-
Table 1. Birch reduction of carboxylic acids 1.[a]
Table 2. Catalytic hydrogenation of nitriles 2 with PtO2 and subsequent
cyclization to γ-spirolactams 3.[a]
Entry
Acid
R
2 [%][b]
6 [%][b]
Entry
Nitrile
R
3 [%][b]
1
2
3
4
5
6
1e
1f
1g
1h
1i
2,3-dimethyl
2,6-dimethyl
3,5-dimethyl
1-naphthalene
9-anthracene
9-anthracene[d]
65
64
86
92
28
45
33
34
<5
<5
45[c]
45
1
2
3
4
5
2e
2f
2g
2h
2i
2,3-dimethyl
2,6-dimethyl
3,5-dimethyl
1-naphthalene
9-anthracene
92
92
94
94
90
1i
[a] Reactions were performed on a 20 mmol scale. For procedure and
conditions, see the Experimental Section. [b] Yield of analytically pure
product, isolated by column chromatography. [c] Alkylation at 10-position
as side-product. [d] Addition of tert-butanol (3.0 mL) prior to chloroace-
tonitrile.
[a] Reactions were performed on a 2 mmol scale. For procedure and
conditions, see the Experimental Section. For detailed structures see
Figure 1. [b] Yield of analytically pure product, isolated by column
chromatography.
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for the synthesis of lactams previously.[26] Indeed, now the
unsaturated γ-spirolactam 4b could be isolated for the first
time. However, the yield was only 28%, due to low conversion
and formation of side-product 5b (entry 4).
1
2
3
4
Finally, best conditions were found by catalytic hydro-
genation with Raney nickel as catalyst.[27] Thus, reaction of nitrile
2b under 1 bar hydrogen pressure proceeded smoothly and
gave full conversion after 3 d. Subsequent cyclization in the
presence of pyridine afforded γ-spirolactam 4b in 92% yield in
analytically pure form (entry 5, method B). Only a small amount
of side-product 5b was formed, which was easily separated by
column chromatography. We repeated the hydrogenations at
various pressures (entries 6–8), to increase the amount of this γ-
spirolactam 5b. Indeed, at 50 bar this compound with only one
double bond was isolated as main product in analytically pure
form in 94% yield (entry 8, method C). Thus, we could control
the degree of saturation in γ-spirolactams 4b and 5b by simple
variation of the hydrogen pressure.
To demonstrate the generality of such Raney nickel
reductions, we applied methods B and C to various other
nitriles 2a–h[13] (Figure 1). Indeed, method B afforded com-
pletely unsaturated γ-spirolactams 4a–h in all cases in high
yields. Method C gave very good yields with nitriles 2b, 2c, and
2e, because they differ in their substitution pattern. In all cases,
the sterically less hindered double bond was reduced selec-
tively. Unsubstituted nitrile 2a afforded a mixture of lactams,
but the partly hydrogenated product 5a could be isolated by
column chromatography in 56% yield. Overall, together with
the catalytic hydrogenations in the presence of PtO2 (meth-
od A), we obtained a library of 18 new γ-spirolactams 3–5 in
high yields (Figure 1).
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6
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Figure 1. Library of γ-spirolactams 3–5, obtained by catalytic hydrogena-
tions. Reactions were performed on a 2 mmol scale; method A: PtO2, 1 bar
H2, 3 d; method B: Raney nickel, 1 bar H2, 4 h; method C: Raney nickel, 50 bar
H2, 3 d. Yield of analytically pure product, isolated by column chromatog-
raphy. [a] Formation of 34% of diene 4a as side-product, separated by
column chromatography.
Table 3. Optimization of the reduction of nitrile 2b and subsequent
cyclization to γ-spirolactams 4b or 5.[a]
Conclusion
In summary, we have demonstrated that Birch reduction of
aromatic carboxylic acids in the presence of chloroacetonitrile
and subsequent catalytic hydrogenation is a general and
convenient method for the synthesis of γ-spirolactams. Various
regioisomeric dimethyl benzoic, naphthoic, and anthroic acids
have been used as starting materials for the first time, and
nitrile carboxylic acids were isolated in moderate to good yields.
Hydrogenation in the presence of PtO2 as catalyst (method A)
affords completely saturated lactams in high yields in analyti-
cally pure form. Furthermore, the reactions proceed with
excellent stereoselectivities and up to 3 new stereogenic
centers can be constructed. Catalytic hydrogenations with
Raney nickel give γ-spirolactams with 2 double bonds at 1 bar
(method B) and with 1 double bond at 50 bar (method C). Thus,
it is possible to control the degree of saturation by simple
variation of the hydrogen pressure. Additionally, the double
bonds might be used for further functionalizations. Overall, we
synthesized more than 15 new γ-spirolactams from inexpensive
aromatic carboxylic acids in only few steps and good yields.
Entry
Reagent/Catalyst
H2 (bar)
4b [%][b]
75[c]
5b [%][b]
1
2
3
4
5
6
7
8
Pd/C
Rh/Al2O3
LiAlH4
NaBH4/CoCl2
Raney Ni
Raney Ni
Raney Ni
Raney Ni
1
1
–
–
–
–
–
10
5
12
48
94
[d]
–
70[e]
28[e]
92
1
10
30
50
83
38
3
[a] Reactions were performed on a 2 mmol scale. For procedure and
conditions, see the Experimental Section. For detailed structures see
Figure 1. [b] Yield of analytically pure product, isolated by column
chromatography. [c] Only reduction of one double bond. [d] No
conversion. [e] Only reduction of the carboxylic acid group. [f] Only 40%
conversion.
because the acid was directly reduced to the corresponding
alcohol (entry 3). To overcome this problem, we investigated
NaBH4 in the presence of CoCl2 next, which has been applied
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124.2 (d), 129.1 (s), 173.0 (s). IR (KBr): v=3071, 2275, 1733, 1225,
Experimental Section
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782, 702 cmÀ 1. Anal. Calcd for C11H13NO2 (191.23): C, 69.09; H, 6.85;
N, 7.33. Found: C, 69.37; H, 7.19; N, 7.40.
General Information. Melting points were determined by using a
Mel-Temp from Electrothermal. TLC was performed using TLC Silica
gel 60 F254 aluminum sheets from Merck. 1H NMR and 13C NMR
spectra were measured by using a Bruker NEO 500 (500 MHz,
125 MHz) or a Bruker Avance 600 (600 MHz, 150 MHz) NMR
spectrometer. Signals were assigned by two-dimensional methods
(HSQC). The IR spectra were recorded in KBr pellets by using a
Nicolet Avatar 370 FT-IR spectrometer from Thermo Electron
Corporation. Elemental analysis was performed on a Vario EL III
elemental analyzer. HRMS spectra were measured at a GC-MS Trace
DSX II spectrometer. All starting materials were used as purchased
without further purification. Raney nickel was activated according
to the procedure of Nishimura.[27]
2,6-Dimethylcyclohexa-2,5-diene-1-carboxylic acid (6f). Following
the general procedure, the title compound was obtained as a white
solid as side-product (1.03 g, 34%). Rf =0.75 (dichloromethane/
methanol/AcOH=9:0.9:0.1). Mp=105–106 C. 1H NMR (600 MHz,
°
CDCl3): δ=1.77 (s, 6H), 2.64 (dm, J=22.6 Hz, 1H), 2.78 (dm, J=
22.6 Hz, 1H), 3.46 (tm, J=6.2 Hz 1H), 5.67–5.68 (m, 2H), 11.72 (br,
1H). 13C{1H} NMR (150 MHz, CDCl3): δ=21.9 (q), 27.6 (t), 52.2 (d),
122.5 (d), 128.4 (s), 179.5 (s). IR (KBr): v=2879, 1706, 1294, 964,
777 cmÀ 1. Anal. Calcd for C9H12O2 (152.19): C, 71.03; H, 7.95. Found:
C, 71.00; H, 7.94.
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1-(Cyanomethyl)-3,5-dimethylcyclohexa-2,5-diene-1-carboxylic
acid (2g). Following the general procedure, the title compound
was obtained as a white solid (3.30 g, 86%). Rf =0.40 (dichloro-
General Procedure for Birch Reductions. Arene carboxylic acid 1
(20 mmol) was introduced into a three-necked flask (250 mL),
equipped with a dry-ice condenser and cooled to – 78 C by a dry-
ice acetone bath. Ammonia (100 mL) was condensed into the
three-necked flask, and lithium (275 mg, 40 mmol) was added in
methane/methanol/AcOH=9:0.9:0.1). Mp=115–116 C. 1H NMR
°
°
(600 MHz, CDCl3): δ=1.80 (s, 6H), 2.54 (dm, J=22.4 Hz, 1H), 2.59
(dm, J=22.4 Hz, 1H), 2.68 (s, 2H), 5.40 (d, J=0.5 Hz, 2H), 10.58 (br,
1H). 13C{1H} NMR (150 MHz, CDCl3): δ=22.9 (q), 28.3 (t), 35.9 (t), 48.4
(s), 117.1 (s), 117.9 (d), 137.5 (s), 178.7 (s). IR (KBr): v=3184, 2268,
1723, 1205, 926, 815, 687 cmÀ 1. Anal. Calcd for C11H13NO2 (191.23):
C, 69.09; H, 6.85; N, 7.33. Found: C, 68.85; H, 6.93; N, 7.39.
°
small pieces to the solution at – 78 C, until it remained blue. For
anthroic acid 1i 200 mL of ammonia was used, due to solubility
problems. For this acid, tert.-butanol (3.0 mL) was added after
lithium as well, to suppress formation of 10-alkylation. After stirring
°
for 1 h at – 78 C, chloroacetonitrile (2.5 mL, 40 mmol) was added
1-(Cyanomethyl)-1,4-dihydronaphthalene-1-carboxylic acid (2h).
Following the general procedure, the title compound was obtained
as a white solid (3.92 g, 92%). Rf =0.60 (dichloromethane/meth-
via syringe within 2 min and the ammonia was 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
1
°
anol/AcOH=9:0.9:0.1). Mp=117–118 C. H NMR (500 MHz, CDCl3):
with dichloromethane (3×50 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 purified by column chromatography (hexanes/MeÀ O-tBu 1:1
+0.5%AcOH) to obtain the nitriles 2 and side-products 6 in
analytically pure form. The syntheses and analytical data of nitriles
2a–d have been reported previously.[13]
δ=3.01 (d, J=16.7 Hz, 1H), 3.09 (d, J=16.7 Hz, 1H), 3.54 (ddd, J=
22.2, 3.6, 2.2 Hz, 1H), 3.61 (ddd, J=22.2, 3.6, 2.2 Hz, 1H), 5.91 (dt, J=
10.1, 2.2 Hz, 1H), 6.38 (dt, J=10.1, 3.6 Hz, 1H), 7.25–7.35 (m, 4H),
11.00 (br, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ=29.2 (t), 29.6 (t),
48.8 (s), 117.0 (s), 124.0 (d), 126.1 (d), 127.3 (d), 128.5 (d), 129.4 (d),
129.8 (d), 131.8 (s), 133.9 (s), 178.1 (s). IR (KBr): v=3133, 3075, 2278,
1733, 1227, 741 cmÀ 1. Anal. Calcd for C13H11NO2 (213.24): C, 73.22; H,
5.20; N, 6.57. Found: C, 73.15; H, 5.49; N, 6.59.
1-(Cyanomethyl)-2,3-dimethylcyclohexa-2,5-diene-1-carboxylic
acid (2e). Following the general procedure, the title compound
was obtained as a white solid (2.49 g, 65%). Rf =0.31 (dichloro-
9-(Cyanomethyl)-9,10-dihydroanthracene-9-carboxylic acid (2i).
Following the general procedure, the title compound was obtained
as a white solid (2.35 g, 45%). Rf =0.15 (MeOtBu/hexane/AcOH=
methane/methanol/AcOH=9:0.9:0.1). Mp=147–148 C. 1H NMR
°
(600 MHz, CDCl3): δ=1.67 (s, 3H), 1.76 (s, 3H), 2.67–2.83 (m, 2H),
2.79 (d, J=17.0 Hz, 1H), 2.84 (d, J=17.0 Hz, 1H), 5.60 (dt, J=9.9,
2.1 Hz, 1H), 6.13 (dt, J=9.9, 3.5 Hz, 1H), 10.65 (br, 1H). 13C{1H} NMR
(150 MHz, CDCl3): δ=14.4 (q), 19.2 (q), 25.9 (t), 33.0 (t), 51.1 (s),
117.1 (s), 120.3 (s), 124.0 (d), 130.0 (d), 131.3 (s), 178.4 (s). IR (KBr):
v=3135, 2274, 1728, 1220, 729 cmÀ 1. Anal. Calcd for C11H13NO2
(191.23): C, 69.09; H, 6.85; N, 7.33. Found: C, 68.89; H, 6.76; N, 7.21.
4.9:4.9:0.2). Mp=203–204 C. 1H NMR (500 MHz, DMSO): δ=3.38
°
(s, 2H), 4.13 (d, J=20.1 Hz, 1H), 4.25 (d, J=20.1 Hz, 1H), 7.32–7.42
(m, 8H), 13.29 (br, 1H). 13C{1H} NMR (125 MHz, DMSO): δ=28.9 (t),
33.4 (t), 53.0 (s), 118.4 (s), 126.7 (d), 126.8 (d), 127.7 (d), 128.3 (d),
134.7 (s), 134.9 (s), 173.9 (s). IR (KBr): v=3667, 2982, 2903, 2279,
1727, 1401, 1232, 1049, 714 cmÀ 1. Anal. Calcd for C17H13NO2
(263.29): C, 77.55; H, 4.98; N, 5.32. Found: C, 77.46; H, 4.94; N, 5.25.
2,3-Dimethylcyclohexa-2,5-diene-1-carboxylic acid (6e). Following
the general procedure, the title compound was obtained as a white
solid as side-product (1.01 g, 33%). Rf =0.71 (dichloromethane/
10-(Cyanomethyl)-9,10-dihydroanthracene-9-carboxylic acid (10-
2i). Following the general procedure, the title compound was
obtained as a white solid as side-product (2.35 g, 45%). Rf =0.45
methanol/AcOH=9:0.9:0.1). Mp=86–87 C. 1H NMR (600 MHz,
°
(MeOtBu/hexane/AcOH=4.9:4.9:0.2). Mp=190–191 C. 1H NMR
°
CDCl3): δ=1.71 (s, 3H), 1.72 (s, 3H), 2.58 (dm, J=22.2 Hz, 1H), 2.73
(dm, J=22.2 Hz, 1H), 3.62–3.66 (m, 1H), 5.74 (dm, J=9.9 Hz, 1H),
5.91 (dm, J=9.9 Hz, 1H), 11.47 (br, 1H). 13C{1H} NMR (150 MHz,
CDCl3): δ=17.5 (q), 18.9 (q), 32.8 (t), 49.1 (d), 120.5 (s), 122.2 (d),
127.5 (s), 127.9 (d), 179.9 (s). IR (KBr): v=2871, 1699, 1288, 1227,
890, 779, 682 cmÀ 1. Anal. Calcd for C9H12O2 (152.19): C, 71.03; H,
7.95. Found: C, 71.06; H, 8.01.
(500 MHz, DMSO): δ=2.98 (d, J=7.9 Hz, 2H), 4.43 (t, J=7.9 Hz, 1H),
5.11 (s, 1H), 7.34 (ddd, J=7.3, 7.1, 1.4 Hz, 2H), 7.36 (ddd, J=7.3, 7.1,
1.5 Hz, 2H), 7.46 (dd, J=7.1, 1.5 Hz, 2H), 7.51 (dd, J=7.1, 1.4 Hz, 2H),
12.93 (br, 1H). 13C{1H} NMR (125 MHz, DMSO): δ=27.6 (t), 40.9 (d),
51.0 (d), 119.2 (s), 127.3 (d), 127.5 (d), 128.8 (d), 129.1 (d), 133.9 (s),
136.5 (s), 173.8 (s). IR (KBr): v=3249, 2988, 2901, 1694, 1486, 1450,
1194, 765, 654 cmÀ 1. Anal. Calcd for C17H13NO2 (263.29): C, 77.55; H,
4.98; N, 5.32. Found: C, 77.40; H, 4.90; N, 5.30.
1-(Cyanomethyl)-2,6-dimethylcyclohexa-2,5-diene-1-carboxylic
acid (2f). Following the general procedure, the title compound was
obtained as a white solid (2.46 g, 64%). Rf =0.61 (dichloromethane/
9,10-Dihydroanthracene-9-carboxylic acid (4i). Following the
general procedure with addition of tert.-butanol, the title com-
pound was obtained as a white solid as side-product (2.02 g, 45%).
methanol/AcOH=9:0.9:0.1). Mp=215–216 C. 1H NMR (600 MHz,
°
CDCl3): δ=1.64 (s, 6H), 2.62 (dm, J=23.1 Hz, 1H), 2.69 (dm, J=
23.1 Hz, 1H), 3.03 (s, 2H), 5.77 (s, 2H), 13.03 (br, 1H). 13C{1H} NMR
(150 MHz, CDCl3): δ=18.8 (q), 22.3 (t), 26.9 (t), 52.6 (s), 118.0 (s),
Rf =0.51 0.15 (MeOtBu/hexane/AcOH=4.9:4.9:0.2). Mp=207–
1
°
208 C. H NMR (500 MHz, DMSO): δ=3.92 (d, J=18.1 Hz, 1H), 4.13
(d, J=18.1 Hz, 1H), 5.00 (s, 1H), 7.25 (dd, J=7.4, 6.8 Hz, 2H), 7.29
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(ddd, J=7.4, 6.8, 1.7 Hz, 2H), 7.37 (d, J=6.8 Hz, 2H), 7.42 (dd, J=6.8,
raphy (EtOAc) to obtain the γ-spirolactams 3 in analytically pure
form.
1
2
3
4
5
6
7
8
9
1.7 Hz, 2H), 12.54 (br, 1H). 13C{1H} NMR (125 MHz, DMSO): δ=35.0
(t), 52.3 (d), 126.2 (d), 127.1 (d), 127.8 (d), 128.3 (d), 134.6 (s), 136.5
(s), 172.7 (s). IR (KBr): v=3031, 2901, 1698, 1216, 713 cmÀ 1. Anal.
Calcd for C15H12O2 (224.26): C, 80.34; H, 5.39. Found: C, 80.15; H,
5.23.
cis-6,7-Dimethyl-2-azaspiro[4.5]decan-1-one (3e). Following the
general procedure, the title compound was obtained as a white
solid (335 mg, 92%). Rf =0.31 (EtOAc). Mp=129–130 C. 1H NMR
°
(500 MHz, CDCl3): δ =0.83 (d, J=6.9 Hz, 3H), 0.89 (d, J=7.1 Hz, 3H),
1.10–1.30 (m, 4H), 1.55–1.64 (m, 2H), 1.73–1.80 (m, 1H), 1.81–1.88
(m, 2H), 2.24 (ddd, J=12.7, 6.7, 1.7 Hz, 1H), 3.19 (tm, J=9.7 Hz, 1H),
3.27 (td, J=9.7, 6.7 Hz, 1H), 7.27 (br, 1H). 13C{1H} NMR (125 MHz,
CDCl3): δ=8.4 (q), 20.2 (q), 22.6 (t), 27.6 (t), 27.9 (t), 31.7 (d), 34.0 (t),
36.5 (d), 38.8 (t), 47.9 (s), 182.6 (s). IR (KBr): v=3667, 3193, 2982,
2917, 1684, 1075, 789 cmÀ 1. Anal. Calcd for C11H19NO (181.28): C,
72.88; H, 10.56; N, 7.73. Found: C, 73.51; H, 10.56; N, 7.61.
Reduction with Pd/C. Nitrile 2b (355 mg, 2.0 mmol) was dissolved
in methanol (30 mL) at RT and palladium on charcoal (25 mg,
1 mol%) was added. The solution was purged with hydrogen gas
for 5 min, equipped with a balloon filled with hydrogen gas and
hydrogenated under stirring at 1 bar for 2 h. The solution was
filtered through a pad of Celite, washed with methanol (2×30 mL)
and the solvent was removed in vacuo. The crude product showed
in the NMR that the nitrile was intact but the unsubstituted double
bond was hydrogenated besides small amount of hydrogenation of
both double bonds. Purification by column chromatography
(hexanes/MeÀ O-tBu 1:1+0.5% AcOH) afforded the partly hydro-
genated product as colorless oil (270 mg, 75%).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
cis-6,10-Dimethyl-2-azaspiro[4.5]decan-1-one (3f). Following the
general procedure, but the pressure was adjusted to 50 bar, the
title compound was obtained as a white solid (333 mg, 92%). Rf =
1
°
0.27 (EtOAc). Mp=163–164 C. H NMR (500 MHz, CDCl3): δ=0.90
(d, J=6.7 Hz, 6H), 1.23 (qt, J=13.2, 3.5 Hz, 1H), 1.30–1.38 (m, 4H),
1.67 (dm, J=13.2 Hz, 1H), 1.78 (qd, J=13.2, 3.5 Hz, 2H), 1.98 (t, J=
7.7 Hz, 2H), 3.20 (t, J=7.7 Hz, 2H), 6.77 (br, 1H). 13C{1H} NMR
(125 MHz, CDCl3): δ=17.2 (q), 26.1 (t), 30.9 (t), 33.2 (t), 40.1 (t), 41.2
(d), 50.2 (s), 179.6 (s). IR (KBr): v=3667, 2968, 2906, 1672, 1387,
1278, 1057, 794 cmÀ 1. Anal. Calcd for C11H19NO (181.28): C, 72.88; H,
10.56; N, 7.73. Found: C, 72.94; H, 10.58; N, 7.70.
1-(Cyanomethyl)-2-methylcyclohex-2-ene-1-carboxylic acid. Rf =
0.45 (dichloromethane/methanol/AcOH=9:0.9:0.1). 1H NMR
(500 MHz, CDCl3): δ=1.60–1.73 (m, 1H), 1.72 (td, J=1.9, 1.5 Hz, 3H),
1.84 (ddtd, J=13.9, 9.6, 6.6, 3.1 Hz, 1H), 1.69 (ddd, J=13.6, 9.6,
3.1 Hz, 1H), 2.08–2.03 (m, 2H), 2.19 (ddd, J=13.6, 8.0, 3.1 Hz, 1H),
2.71(d, J=16.9 Hz,1H), 2.86 (d, J=16.9 Hz,1H), 5.81 (dqd, J=4.0, 1.5,
0.7 Hz, 1H), 10.18 (br, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ=18.5
(q), 19.8 (t), 24.9 (t), 25.1 (t), 32.4 (t), 48.2 (s), 117.6 (s), 129.5 (d),
129.7 (s), 178.9 (s). IR (film): v=3207, 2932, 2867, 1698, 1446, 1219,
1174, 934, 807, 712 cmÀ 1. HRMS (ESI-TOF) m/z: [M]+ Calcd for
C10H13NO2 179.0946; Found: 179.0935.
cis-7,9-Dimethyl-2-azaspiro[4.5]decan-1-one (3g). Following the
general procedure, the title compound was obtained as a white
solid (340 mg, 94%). Rf =0.20 (EtOAc). Mp=140–141 C. 1H NMR
°
(600 MHz, CDCl3): δ=0.59 (dt, J=12.8, 11.9 Hz, 1H), 0.87 (d, J=
6.7 Hz, 6H), 1.18 (dd, J=13.2, 12.4 Hz, 2H), 1.40 (dtd, J=13.2, 3.0,
2.0 Hz, 2H), 1.47 (ddqdd, J=12.4, 11.9, 6.7, 3.6, 3.0 Hz, 1H), 1.62 (dtt,
J=12.8, 3.6, 2.0 Hz, 1H), 1.95 (t, J=7.0 Hz, 2H), 3.27 (t, J=7.0 Hz,
2H), 7.26 (br, 1H). 13C{1H} NMR (150 MHz, CDCl3): δ=22.6 (q), 28.8
(d), 32.3 (t), 39.3 (t), 40.3 (t), 43.3 (t), 45.3 (s), 183.6 (s). IR (KBr): v=
3195, 2948, 2907, 1698, 1304, 809, 583 cmÀ 1. Anal. Calcd for
C11H19NO (181.28): C, 72.88; H, 10.56; N, 7.73. Found: C, 72.87; H,
10.68; N, 7.72.
Reduction with LiAlH4. Nitrile 2b (355 mg, 2.0 mmol) was dissolved
in dry diethyl ether (20 mL) and lithium aluminum hydride (38 mg,
1.0 mmol) was added slowly. The mixture was stirred for 16 h under
nitrogen atmosphere, filtered through a pad of Celite, washed with
methanol (3×50 mL) and the solvent was removed in vacuo. The
crude product showed in the NMR that the nitrile was intact but
the acid group was reduced to the alcohol. Purification by column
chromatography (dichloromethane/EtOAc=5:1) afforded the alco-
hol as colorless oil (230 mg, 70%).
3,4-Dihydro-2H-spiro[naphthalene-1,3’-pyrrolidin]-2’-one
(3h).
Following the general procedure, the title compound was obtained
°
1-(Cyanomethyl)-1-(hydroxymethyl)-2-methylcyclohex-2,5diene.
as a white solid (380 mg, 94%). Rf =0.24 (EtOAc). Mp=172–173 C.
1
Rf =0.41 (dichloromethane/EtOAc=5:1). H NMR (500 MHz, CDCl3):
1H NMR (500 MHz, CDCl3): δ=1.76 (dddddd, J=21.0, 13.3, 5.5, 4.1,
2.3 Hz, 1H), 1.87–1.91 (m, 1H), 2.01–2.08 (m, 2H), 2.25–2.34 (m, 2H),
2.81 (d, J=16.6, 4.1 Hz, 1H), 2.89 (ddd, J=16.6, 11.4, 5.5 Hz, 1H),
3.37–3.44 (m, 2H), 7.07–7.20 (m, 4H), 8.04 (br, 1H). 13C{1H} NMR
(125 MHz, CDCl3): δ=19.8 (t), 29.5 (t), 31.4 (t), 38.7 (t), 39.4 (t), 48.9
(s), 126.5 (d), 126.6 (d), 127.7 (d), 129.2 (d), 137.2 (s), 138.8 (s), 183.2
(s). IR (KBr): v=3204, 3086, 2863, 1680, 1284, 732 cmÀ 1. Anal. Calcd
for C13H15NO (201.27): C, 77.58; H, 7.51; N, 6.96. Found: C, 77.69; H,
7.76; N, 6.95.
δ=1.73 (q, J=1.7 Hz, 3H), 2.14 (br, 1H), 2.39 (d, J=16.7 Hz,1H), 2.49
(d, J=16.7 Hz,1H), 2.65 (ddqd, J=23.2, 3.4, 2.1, 1.7, 1.6 Hz,1H), 2.75
(ddqd, J=23.2, 3.4, 2.1, 1.7, 1.6 Hz,1H), 3.41 (d, J=10.7 Hz,1H), 3.58
(d, J=10.7 Hz,1H), 5.48 (dt, J=10.0, 2.1 Hz, 1H), 5.79 (qq, J=1.7,
1.6 Hz,1H), 6.08 (dtd, J=10.0, 3.4, 1.6 Hz, 1H). 13C{1H} NMR (125 MHz,
CDCl3): δ=18.4 (q), 24.8 (t), 27.3 (t), 43.8 (s), 67.1 (t), 117.6 (s), 126.4
(d), 127.2 (d), 129.8 (d), 130.3 (s). IR (film): v=3423, 2922, 2875,
2250, 1714, 1421, 1016, 739 cmÀ 1. 182.1545. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C10H14NO 164.1075; Found: 164.1075.
10H-spiro[anthracene-9,3’-pyrrolidin]-2’-one (3i). Following the
General Procedure for the Catalytic Hydrogenation with PtO2
(method A). Nitrile 2 (2.0 mmol) was dissolved in methanol (30 mL)
at RT and platinum(IV) oxide (5.0 mg, 1 mol%) and 37% HCl
(0.2 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 at 1 bar for 3d. The solution was
filtered through a pad of Celite, washed with methanol (2×30 mL)
and the solvent was removed in vacuo. Diastereoselectivities were
determined from the NMR of the crude products. The residue was
dissolved in pyridine (50 mL) and heated for 8 h under reflux. The
pyridine was removed in vacuo and the residue was dissolved in
dichloromethane (50 mL), extracted with 1 NHCl (30 mL), the
organic phase was dried over sodium sulfate, and concentrated in
vacuo. The crude products were purified by column chromatog-
general procedure, the title compound was obtained as a white
solid (450 mg, 90%). Rf =0.37 (EtOAc). Mp=255–256 C. 1H NMR
°
(500 MHz, DMSO): δ=2.29 (t, J=6.6 Hz, 2H), 3.29 (t, J=6.6 Hz, 2H),
4.04 (s, 2H), 7.22–7.26 (m, 6H), 7.35–7.37 (m, 2H), 8.44 (br, 1H). 13C
{1H} NMR (125 MHz, DMSO): δ=35.2 (t), 38.6 (t), 38.7 (t), 54.1 (s),
126.2 (d), 126.8 (d), 126.9 (d), 128.1 (d), 136.4 (s), 139.6 (s), 178.1 (s).
IR (KBr): v=3218, 3061, 2859, 1655, 1485, 1277, 746 cmÀ 1. Anal.
Calcd for C17H15NO (249.31): C, 81.90; H, 6.06; N, 5.62. Found: C,
81.83; H, 6.01; N, 5.67.
General Procedure for the Catalytic Hydrogenation with Raney
Nickel (method B and C). Nitrile 2 (2.0 mmol) was dissolved in
methanol/water 1:1 (30 mL) at RT and activated Raney nickel
(6.0 mg, 10 mol%)[27] was added. The solution was purged with
hydrogen gas for 5 min, equipped with a balloon filled with
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hydrogen gas and hydrogenated under stirring at 1 bar for 4 h
trans-8-Methyl-2-azaspiro[4.5]deca-6,9-dien-1-one (trans-4d). Fol-
lowing the general procedure (method B), the title compound was
obtained as white solid (300 mg, 92%). Rf =0.24 (EtOAc). Mp=159–
1
2
3
4
5
6
7
8
9
(method B). To obtain partly unsaturated γ-spirolactams 5, hydro-
genation was performed in an autoclave at 50 bar for 3d
(method C). The solution was filtered through a pad of Celite,
washed with methanol (2×30 mL) (caution! The Raney nickel
should not become completely dry, because it might catch fire) and
the solvent was removed in vacuo. The residue was dissolved in
pyridine (50 mL) and heated for 8 h under reflux. The pyridine was
removed in vacuo and the residue was dissolved in dichloro-
methane (50 mL), extracted with 1 NHCl (30 mL), the organic phase
was dried over sodium sulfate, and concentrated in vacuo. The
crude products were purified by column chromatography (EtOAc)
to obtain the γ-spirolactams 4 and 5 in analytically pure form.
1
°
160 C. H NMR (500 MHz, CDCl3): δ =1.06 (d, J=7.3 Hz, 3H), 2.06 (t,
J=6.8 Hz, 2H), 2.85–2.90 (m, 1H), 3.35 (t, J=6.8 Hz, 2H), 5.52 (dd,
J=10.1, 1.9 Hz, 2H), 5.83 (dd, J=10.1, 3.1 Hz, 2H), 7.95 (br, 1H). 13C
{1H} NMR (125 MHz, CDCl3): δ=21.7 (q), 30.3 (d), 36.9 (t), 39.2 (t),
47.0 (s), 125.1 (d), 132.9 (d), 179.9 (s). IR (KBr): v=3666, 3188, 2961,
2893, 1676, 1271, 798, 735, 680 cmÀ 1. Anal. Calcd for C10H13NO
(163.22): C, 73.59; H, 8.03; N, 8.58. Found: C, 73.49; H, 8.06; N, 8.56.
6,7-Dimethyl-2-azaspiro[4.5]deca-6,9-dien-1-one (4e). Following
the general procedure (method B), the title compound was
obtained as white solid (335 mg, 95%). Rf =0.31 (EtOAc). Mp=78–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
1
°
79 C. H NMR (500 MHz, CDCl3): δ =1.64 (s, 3H), 1.67 (s, 3H), 1.91
(ddd, J=13.3, 8.2, 3.7 Hz, 2H), 2.32 (ddd, J=13.3, 9.3, 7.7 Hz, 2H),
2.58 (ddd, J=22.7, 3.4, 0.7 Hz, 1H), 2.70 (ddd, J=22.7, 3.4, 0.7 Hz,
1H), 3.31 (ddd, J=9.8, 9.3, 3.7 Hz, 1H), 3.38 (ddd, J=9.8, 8.2, 7.6 Hz,
1H), 5.58 (dt, J=10.0, 0.7 Hz, 1H), 5.82 (dt, J=10.0, 3.4 Hz, 1H), 7.92
(br, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ=14.4 (q), 19.2 (q), 32.9 (t),
34.2 (t), 39.7 (t), 51.3 (s), 123.8 (s), 125.4 (d), 127.2 (d), 128.0 (s),
180.7 (s). IR (KBr): v=3667, 2980, 2902, 1678, 1385, 1257, 1057, 890,
695 cmÀ 1. Anal. Calcd for C11H15NO (177.25): C, 74.54; H, 8.53; N,
7.90. Found: C, 74.33; H, 8.72; N, 7.91.
Products from method B
Azaspiro[4.5]deca-6,9-dien-1-one (4a). Following the general
procedure (method B), the title compound was obtained as white
solid (280 mg, 94%). Rf =0.13 (EtOAc). Mp=144–145 C. 1H NMR
°
(500 MHz, CDCl3): δ=2.09 (t, J=6.8 Hz, 2H), 2.65 (dtt, J=23.2, 3.3,
2.0 Hz, 1H), 2.80 (dtt, J=23.2, 3.3, 2.0 Hz, 1H), 3.36 (td, J=6.8,
0.8 Hz, 2H), 5.57 (dt, J=10.3, 2.0 Hz, 2H), 5.94 (dt, J=10.3, 3.3 Hz,
2H), 7.84 (br, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ=26.1 (t), 37.0 (t),
39.2 (t), 46.8 (s), 126.3 (d), 126.6 (d), 180.1 (s). IR (KBr): v=3177,
2887, 1678, 1270, 810, 708, 674 cmÀ 1. Anal. Calcd for C9H11NO
(149.19): C, 72.45; H, 7.43; N, 9.39. Found: C, 72.41; H, 7.40; N, 9.35.
6,10-Dimethyl-2-azaspiro[4.5]deca-6,9-dien-1-one (4f). Following
the general procedure (method B), the title compound was
obtained as white solid (325 mg, 92%). Rf =0.24 (EtOAc). Mp=149–
1
6-Methyl-2-azaspiro[4.5]deca-6,9-dien-1-one (4b). Following the
°
150 C. H NMR (600 MHz, CDCl3): δ =1.66 (s, 6H), 2.13 (t, J=7.3 Hz,
general procedure (method B), the title compound was obtained as
2H), 2.56 (d, J=23.0 Hz, 1H), 2.66 (d, J=23.0 Hz, 1H), 3.32 (t, J=
7.3 Hz, 2H), 5.55 (s, 2H), 8.26 (br, 1H). 13C{1H} NMR (150 MHz, CDCl3):
δ=19.1 (q), 27.1 (t), 31.5 (t), 40.6 (t), 52.7 (s), 122.0 (d), 132.1 (s),
179.6 (s). IR (KBr): v=3193, 3087, 2978, 2880, 1690, 1289, 781,
625 cmÀ 1. Anal. Calcd for C11H15NO (177.25): C, 74.54; H, 8.53; N,
7.90. Found: C, 74.49; H, 8.55; N, 7.89.
white solid (300 mg, 92%). Rf =0.15 (EtOAc). Mp=121–122 C. 1H
°
NMR (500 MHz, CDCl3): δ =1.65 (q, J=1.8 Hz, 3H), 1.90 (ddd, J=
13.3, 8.5, 4.8 Hz, 1H), 2.28 (ddd, J=13.3, 8.9, 6.3 Hz, 1H), 3.27 (dddd,
J=9.9, 8.9, 4.8, 0.9 Hz, 1H), 3.35 (dddd, J=9.9, 8.5, 6.3, 0.7 Hz, 1H),
2.58 (dttq, J=23.1, 3.4, 2.0, 1.8 Hz, 1H), 2.71 (dttq, J=23.1, 3.4, 2.0,
1.8 Hz, 1H), 5.51 (dt, J=9.9, 2.0 Hz, 1H), 5.61 (ddq, J=3.4, 2.0,
1.8 Hz, 1H), 5.82 (dddd, J=9.9, 3.4, 2.0, 1.5 Hz, 1H), 8.31 (br, 1H). 13C
{1H} NMR (125 MHz, CDCl3): δ=19.2 (q), 26.7 (t), 33.8 (t), 39.8 (t),
49.7 (s), 123.0 (d), 125.3 (d), 127.0 (d), 131.3 (s), 179.9 (s). IR (KBr): v=
3198, 2958, 2873, 1685, 1276, 801, 713 cmÀ 1. Anal. Calcd for
C10H13NO (163.22): C, 73.59; H, 8.03; N, 8.58. Found: C, 73.35; H, 8.22;
N, 8.45.
7,9-Dimethyl-2-azaspiro[4.5]deca-6,9-dien-1-one (4g). Following
the general procedure (method B), the title compound was
obtained as white solid (330 mg, 93%). Rf =0.19 (EtOAc). Mp=132–
1
°
133 C. H NMR (500 MHz, CDCl3): δ =1.73 (s, 6H), 2.02 (t, J=6.8 Hz,
2H), 2.43 (dm, J=22.1 Hz, 1H), 2.61 (dm, J=22.1 Hz, 1H), 3.32 (dd,
J=7.2, 6.8 Hz, 2H), 5.28 (s, 2H), 7.78 (br, 1H). 13C{1H} NMR (125 MHz,
CDCl3): δ=23.1 (q), 35.9 (t), 37.1 (t), 39.3 (t), 49.1 (s), 120.8 (d), 134.1
(s), 181.0 (s). IR (KBr): v=3197, 3086, 2863, 1685, 1275, 927, 785,
592 cmÀ 1. Anal. Calcd for C11H15NO (177.25): C, 74.54; H, 8.53; N,
7.90. Found: C, 74.42; H, 8.49; N, 7.82.
7-Methyl-2-azaspiro[4.5]deca-6,9-dien-1-one (4c). Following the
general procedure (method B), the title compound was obtained as
1
°
white solid (310 mg, 95%). Rf =0.16 (EtOAc). Mp=98–99 C. H NMR
(500 MHz, CDCl3): δ =1.69 (d, J=1.7 Hz, 3H), 2.01 (ddd, J=7.0, 6.6,
1.5 Hz, 2H), 2.49 (dddd, J=24.6, 3.4, 2.1, 1.5 Hz, 1H), 2.68 (dddd, J=
24.6, 4.2, 3.4, 1.5 Hz, 1H), 3.31 (ddd, J=7.0, 6.6, 1.8 Hz, 2H), 5.25 (qt,
J=1.7, 1.5 Hz, 1H), 5.52 (ddd, J=9.9, 4.2, 2.1 Hz, 1H), 5.89 (dt, J=
9.9, 3.4 Hz, 1H), 8.12 (br, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ=23.2
(q), 30.8 (t), 36.8 (t), 39.2 (t), 47.9 (s), 120.8 (d), 126.0 (d), 126.4 (d),
133.9 (s), 180.6 (s). IR (KBr): v=3204, 2959, 2864, 1686, 1273, 712,
692 cmÀ 1. Anal. Calcd for C10H13NO (163.22): C, 73.59; H, 8.03; N,
8.58. Found: C, 73.58; H, 8.31; N, 8.29.
4H-Spiro[naphthalene-1,3’-pyrrolidin]-2’-one (4h). Following the
general procedure (method B), the title compound was obtained as
white solid (365 mg, 92%). Rf =0.40 (EtOAc). Mp=154–155 C. 1H
°
NMR (500 MHz, CDCl3): δ =2.34 (ddd, J=13.3, 7.3, 5.7 Hz, 1H), 2.50
(ddd, J=13.3, 8.0, 6.7 Hz, 1H), 3.44 (ddd, J=21.9, 3.6, 2.2 Hz, 1H),
3.47–3.52 (m, 2H), 3.55 (ddd, J=21.9, 3.6, 2.2 Hz, 1H), 5.82 (dt, J=
10.0, 2.2 Hz, 1H), 6.14 (dt, J=10.0, 3.6 Hz, 1H), 7.16–7.26 (m, 4H),
7.89 (br, 1H). 13C{1H} NMR (125 MHz, CDCl3): δ=29.8 (t), 38.9 (t), 39.8
(t), 49.6 (s), 126.3 (d), 126.5 (d), 126.9 (d), 127.0 (d), 127.7 (d), 128.7
(d), 134.3 (s), 136.9 (s), 180.8 (s). IR (KBr): v=3191, 3078, 2873, 1679,
1278, 736 cmÀ 1. Anal. Calcd for C13H13NO (199.25): C, 78.36; H, 6.58;
N, 7.03. Found: C, 78.40; H, 6.45; N, 6.90.
cis-8-Methyl-2-azaspiro[4.5]deca-6,9-dien-1-one (cis-4d). Follow-
ing the general procedure (method B), the title compound was
obtained as white solid (300 mg, 92%). Rf =0.25 (EtOAc). Mp=127–
1
°
128 C. H NMR (600 MHz, CDCl3): δ =1.17 (d, J=7.3 Hz, 3H), 2.11 (t,
J=6.8 Hz, 2H), 2.75 (qtt, J=7.3, 3.4, 1.9 Hz, 1H), 3.39 (t, J=6.8 Hz,
2H), 5.55 (dd, J=10.1, 1.9 Hz, 2H), 5.89 (dd, J=10.1, 3.4 Hz, 2H), 7.18
(br, 1H). 13C{1H} NMR (150 MHz, CDCl3): δ=22.6 (q), 30.8 (d), 37.0 (t),
39.1 (t), 47.0 (s), 125.2 (d), 132.9 (d), 179.5 (s). IR (KBr): v=3667,
3188, 2959, 2893, 1677, 1271, 1069, 1036, 797, 732, 684 cmÀ 1. Anal.
Calcd for C10H13NO (163.22): C, 73.59; H, 8.03; N, 8.58. Found: C,
73.38; H, 8.15; N, 8.42.
Products from method C
2-Azaspiro[4.5]dec-6-en-1-one (5a). Following the general proce-
dure (method C), the title compound was obtained as white solid
1
°
(170 mg, 56%). Rf =0.27 (EtOAc). Mp=93–94 C. H NMR (600 MHz,
CDCl3): δ =1.49–1.56 (m, 1H), 1.60 (ddd, J=13.1, 6.7, 3.1 Hz, 1H),
1.82–2.12 (m, 6H), 3.31 (ddd, J=8.0, 5.5, 1.0 Hz, 2H), 5.48 (ddt, J=
10.0, 2.2, 1.0 Hz, 1H), 5.92 (ddd, J=10.0, 4.3, 3.2 Hz, 1H), 7.41 (br,
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Full Papers
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1H). 13C{1H} NMR (150 MHz, CDCl3): δ=19.3 (t), 24.7 (t), 30.3 (t), 35.7
(t), 39.2 (t), 45.1 (s), 128.6 (d), 130.4 (d), 182.7 (s). IR (KBr): v=3195,
2902, 1675, 1284, 798, 710, 671 cmÀ 1. Anal. Calcd for C9H13NO
(151.21): C, 71.49; H, 8.67; N, 9.26. Found: C, 71.52; H, 8.48; N, 9.34.
Keywords: Arenes · Birch reduction · Hydrogenation · Lactams ·
Synthetic methods
1
2
3
4
5
6
7
8
9
6-Methyl-2-azaspiro[4.5]dec-6-en-1-one (5b). Following the gen-
eral procedure (method C), the title compound was obtained as
1
°
white solid (310 mg, 94%). Rf =0.21 (EtOAc). Mp=92–93 C. H NMR
(600 MHz, CDCl3): δ =1.40–1.48 (m, 1H), 1.64 (s, 3H), 1.64–1.68 (m,
1H), 1.74–1.80 (m, 2H), 1.89–1.96 (m, 2H), 2.03–2.09 (m, 1H), 2.17–
2.26 (m, 1H), 3.28–3.335 (m, 2H), 5.61 (s, 1H), 7.52 (br, 1H). 13C{1H}
NMR (150 MHz, CDCl3): δ=19.0 (t), 19.3 (q), 25.2 (t), 31.6 (t), 32.6 (t),
39.5 (t), 48.6 (s), 126.6 (d), 133.3 (s), 182.4 (s). IR (KBr): v=3206,
2923, 1683, 1285, 802, 641 cmÀ 1. Anal. Calcd for C10H15NO (165.23):
C, 72.69; H, 9.15; N, 8.48. Found: C, 72.50; H, 9.27; N, 8.42.
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7-Methyl-2-azaspiro[4.5]dec-6-en-1-one (5c). Following the gener-
al procedure (method C), the title compound was obtained as white
solid (300 mg, 91%). Rf =0.22 (EtOAc). Mp=106–107 C. 1H NMR
°
(600 MHz, CDCl3): δ =1.52–1.58 (m, 2H), 1.69 (dt, J=1.5, 0.7 Hz, 3H),
1.78 (ddt, J=13.0, 9.8, 0.7 Hz, 1H), 1.85–1.93 (m, 2H), 1.97 (ddd, J=
12.7, 6.7, 4.5 Hz, 1H), 1.96–2.05 (m, 1H), 2.04 (dt, J=12.7, 7.8 Hz, 1H),
3.30 (dddd, J=7.8, 6.7, 3.3, 1.1 Hz, 2H), 5.22 (ddq, J=2.7, 1.7, 1.5 Hz,
1H), 6.98 (br, 1H). 13C{1H} NMR (150 MHz, CDCl3): 13C{1H} NMR
(125 MHz, CDCl3): δ=19.8 (t), 24.2 (q), 29.7 (t), 30.0 (t), 35.9 (t), 39.2
(t), 45.4 (s), 122.9 (d), 137.8 (s), 183.0 (s). IR (KBr): v=3267, 2962,
2926, 2903, 1659, 1275, 1066, 728 cmÀ 1. Anal. Calcd for C10H15NO
(165.23): C, 72.69; H, 9.15; N, 8.48. Found: C, 72.87; H, 9.29; N, 8.48.
[13] T. Krüger, A. Kelling, U. Schilde, T. Linker, Eur. J. Org. Chem. 2017, 2017,
1074–1077.
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5342.
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1549.
6,7-Dimethyl-2-azaspiro[4.5]dec-6-en-1-one (5e). Following the
general procedure (method C), the title compound was obtained as
white solid (330 mg, 92%). Rf =0.27 (EtOAc). Mp=99–100 C. 1H
°
NMR (500 MHz, CDCl3): δ =1.43–1.52 (m, 1H), 1.59 (s, 3H), 1.62 (s,
3H), 1.63–1.70 (m, 3H), 1.83–1.93 (m, 2H), 2.01–2.19 (m, 2H), 3.31
(dd, J=9.0, 5.0 Hz, 2H), 7.28 (br, 1H). 13C{1H} NMR (125 MHz, CDCl3):
δ=14.9 (q), 19.6 (t), 20.0 (q), 31.4 (t), 31.7 (t), 32.4 (t), 39.5 (t), 49.9
(s), 125.4 (s), 131.3 (s), 183.2 (s). IR (KBr): v=3204, 2904, 2826, 1674,
1445, 1381, 1282, 1065, 793 cmÀ 1. Anal. Calcd for C11H17NO (179.26):
C, 73.70; H, 9.56; N, 7.81. Found: C, 73.49; H, 9.46; N, 7.55.
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Acknowledgements
We thank the University of Potsdam for financial support.
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Conflict of Interest
Manuscript received: January 19, 2021
Accepted manuscript online: January 21, 2021
The authors declare no conflict of interest.
Eur. J. Org. Chem. 2021, 1585–1591
www.eurjoc.org
1591
© 2021 Wiley-VCH GmbH