Synthesis of Lactams by Reductive Amination of Carbonyl Derivatives with ω-Amino Fatty Acids under Hydrosilylation Conditions

Article abstract of DOI:10.1002/ejoc.202100719

An efficient method for the preparation of lactams from ω-amino fatty acids under hydrosilylation is described. A variety of lactams such as pyrrolidinones, piperidinones and 2-azepanones were selectively synthesised in moderate to excellent yields (29 examples, up to 95 % isolated yields) with a good functional group tolerance. Notably, no metallic based catalyst was required to perform this transformation.

Full text of DOI:10.1002/ejoc.202100719

Communications
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Very Important Paper
Synthesis of Lactams by Reductive Amination of Carbonyl
Derivatives with ω-Amino Fatty Acids under Hydrosilylation
Conditions
Satawat Tongdee+,[a] Duo Wei+,[a] Jiajun Wu+,[a] Chakkrit Netkaew,[a] and Christophe Darcel*[a]
An efficient method for the preparation of lactams from ω-
amino fatty acids under hydrosilylation is described. A variety of
lactams such as pyrrolidinones, piperidinones and 2-azepa-
nones were selectively synthesised in moderate to excellent
yields (29 examples, up to 95% isolated yields) with a good
functional group tolerance. Notably, no metallic based catalyst
was required to perform this transformation.
Figure 1. Selected examples for lactams used in pharmaceuticals.
Amides, and more particularly lactams are crucial and versatile
intermediates building blocks in pharmaceutical chemistry,
polymer and synthetic organic chemistry.[1] Particularly pyrroli-
dinones, piperidinones and 2-azepanones are present in a large
class of natural products and biologically active molecules,
among the most sold drugs.[2] (Figure 1) Indeed, pyrrolidinones
are usually base motifs in the drug racetams such as
Levetiracetam, classically used for treatment of focal epilepsy in
adults, or Lenatidomide for the treatment of multiple myeloma.
Piperidinone motif is also widely met in pharmaceuticals like
Apixaban used to prevent venous thromboembolism. Drugs
based on caprolactam moiety are also popular as illustrated by
Benzepril used to treat high blood pressure and heart failure.
Thus, this topical context still prompts to prepare cyclic
amides in an efficient and simple way. Indeed, among the
numerous methodologies,[3] reductive ones were efficiently
developed.[4] Lactams can be obtained from the corresponding
cyclic imides by selective reduction with red-Al (sodium bis(2-
methoxyethoxy)aluminium hydride) or NaCNBH3,[5] hydrogena-
tion using ruthenium based catalysts,[6] TBAF or potassium
hydroxide catalysed hydrosilylation[7] or electrochemical
reduction.[8] Alternatively, N-substituted lactams produced from
keto-acids (e.g. levulinic acid) and primary amines under
reductive conditions were reported in both catalytic and
catalyst-free conditions such as hydrogenation,[9] hydrogen
transfer using formic acid[10] or hydrosilylation.[11] Similarly,
Al(OTf)3-catalysed hydrosilylation of keto-amides led to the
corresponding pyrrolidinones and piperidinones.[12] Noticeably,
the preparation of lactams can be also conducted starting from
amino alcohols.[13]
Recently, we have developed an iron-catalysed one-pot
preparation of N-substituted cyclic amines via reductive amina-
tion of carbonyl derivatives with ω-amino fatty acids under
hydrosilylation conditions.[14] During this study, we identified
that the first step of the synthesis leading to the lactams did
not require iron catalyst. Thus, we report an efficient and
selective one-pot preparation of N-substituted lactams (includ-
ing pyrrolidinones, piperidinones and 2-azepanones) via reduc-
tive amination of carbonyl derivatives with ω-amino fatty acids
by hydrosilylation (Scheme 1).
We began our initial optimization experiments based on the
previous results in which we have identified that the formation
of the piperidinone 3a can be obtained selectively starting
from 5-aminopentanoic acid 2 and benzaldehyde 1a by
°
reaction with 5 equiv. of phenylsilane at 100 C for 3 h in
toluene (Table 1, entry 1). When decreasing the quantity of
°
silane from 5 to 1 equiv., and the temperature from 100 C to
RT, we observed a huge decrease of activity and selectivity
(entries 2 and 3). We then studied the influence of the solvent.
Performing the reaction at RT in the presence of 1 equiv. of
[a] S. Tongdee,+ Dr. D. Wei,+ J. Wu,+ C. Netkaew, Prof. Dr. C. Darcel
Univ Rennes, CNRS, ISCR
(Institut des Sciences Chimiques de Rennes)
UMR 6226, F-35000, Rennes, France
E-mail: christophe.darcel@univ-rennes1.fr
https://iscr.univ-rennes1.fr/christophe-darcel
[+] These authors contributed equally to this work.
Scheme 1. Representative pathways for lactam synthesis under reductive
conditions.
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Table 1. Optimization of the reaction parameters.[a]
°
Entry
Silane [equiv.]
Solvent
T [ C]
Conv. [%]
Yield [%]
3a
4
5
1
2
3
4
5
6
7
8
PhSiH3 [5]
PhSiH3 [2]
PhSiH3 [1]
PhSiH3 [1]
PhSiH3 [1]
PhSiH3 [1]
PhSiH3 [1]
PhSiH3 [1]
PhSiH3 [1]
TMDS [1.5]
PMHS [3]
Et3SiH [3]
Ph2SiH2 [1.5]
(EtO)3SiH [3]
none
PhSiH3 [1]
PhSiH3 [1.5]
PhSiH3 [1.5]
PhSiH3 [2]
PhSiH3 [1.5]
Toluene
Toluene
Toluene
DMC
EtOAc
water
EtOH
t-amylOH
Neat
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
100[b]
50[c]
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
50
50
30
30
30
95
78
11
20
22
5
88
54
94
76
80
85
88
93
78
85
79
73
99
93
95
73
5
8
8
0
0
6
12
14
1
20
35
32
64
65
78
61
44
75
21
5
0
5
0
0
0
2
0
0
3
0
0
0
0
0
0
0
0
0
0
0
2
68
19
59
12
15
7
27
48
3
64
74
69
95
93
9
10
11
12
13
14
15
16
17
18
19
20
4
4
0
Neat
°
[a] General reaction conditions: 1a (0.1 mmol), 2 (0.1 mmol), hydrosilane, solvent (0.5 mL) at RT-100 C for 20 h under air atmosphere. The conversions and
yields were determined by 1H NMR spectroscopy; [b] 3 h; [c] 4 h.
phenylsilane, in dimethylcarbonate (DMC), ethyl acetate, or
water led to low conversions and selectivities (entries 4–6).
Using protic solvents such as ethanol or t-amylalcohol or
neat conditions permitted to increase the conversions, but with
a modest selectivity (entries 7–9). Afterwards, different hydro-
silanes were evaluated to study the selectivity of the reaction.
Using TMDS (1,1,3,3-tetramethyldisiloxane, 1.5 equiv.) and
PMHS (polymethylhydrosiloxane, 3 equiv.), good conversions
were obtained (up to 80%) but the imine 4 was detected as the
major product, with 12–15% of piperidinone 3a (entries 10 and
11). When using triethylsilane, diphenylsilane, or triethoxysilane,
similar results in terms of activity and selectivity were obtained
(entries 12–14). Noticeably, in the absence of hydrosilanes, small
amount of 3a was obtained (3%), the main product being the
imine 4 (75%, entry 15), highlighting the crucial importance of
hydrosilane in this transformation. Having identified phenyl-
silane as the best hydrosilane, its ratio was then studied. The
(N,N-dimethylamino)benzaldehyde led to the corresponding
pyrrolidinones 7b–7c in 83 and 42% yields, respectively.
Noticeably, starting from the hindered mesitaldehyde, the
corresponding product 7d was isolated in moderate yield
(67%). The transformation also tolerated halides (F, Cl, Br)
affording the derivatives 7e–7g in 82–89% yields.
Interestingly, benzodioxole, an important building block in
pharmaceuticals can be easily linked to pyrrolidinone core
leading to 7h in 89% yield.
It should be also underlined that pyrrolidinones bearing
reducible functional groups such as carboxylic ester (7i) nitro
(7j) and cyano (7k) could be synthesized in moderate isolated
yields (40–60%), exhibiting an interesting functional group
tolerance of this transformation. In addition, hetero-aromatic
aldehydes based on thiophene and pyrrole motifs were
selectively converted to 7l–7m in 55 and 69% yields,
respectively. Pyrrolidinone 7n bearing a ferrocenyl substituent
was also produced in 64% yield. Interestingly, starting from
cinnamaldehyde, the corresponding allylic pyrrolidinone 7o
was isolated in 40% yield, without observation of by-products
resulting from the hydrosilylation of the conjugated C=C bond.
Noticeably, when the reaction was performed with an alkanal
such as 3-phenylpropanal under similar conditions, the corre-
sponding 1-(3-phenylpropyl)pyrrolidin-2-one (7u) was obtained
with only 10% isolated yield.
°
use of 2 equiv. of PhSiH3 in ethanol at 30 C permitted to obtain
piperidinone 3a in 95% yield, with trace amount of imine 4.
Similarly, under neat conditions, 3a was obtained specifically in
93% yield (entries 16–20).
With our optimized conditions in hand, we then explored
the substrate scope for the reductive amination of carbonyl
derivatives with ω-amino fatty acids into N-substituted lactams
(Table 2 and Table 3). First, the reaction of 4-aminobutanoic
acid 6 with several aldehydes was examined. Benzaldehyde was
smoothly converted into the corresponding N-substituted
pyrrolidinone 7a in 95% isolated yield. Using substituted
benzaldehyde by donating groups such as p-anisaldehyde or p-
The reaction of 4-aminobutanoic acid was also evaluated
with ketones. Noticeably, cyclohexanone and cycloheptanone
reacted nicely leading to the corresponding N-cyclohexyl and
N-cycloheptylpyrrolidinones 7p and 7q with 63 and 74% yields,
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Table 2. Scope of the synthesis of pyrrolidinones by reductive amination
of carbonyl derivatives with 4-aminobutanoic acid.[a]
Table 3. Scope of the synthesis of piperidinones 3 and 2-azepanones 9 by
reductive amination of carbonyl derivatives with 5-aminopentanoic acid
and 6-aminohexanoic acid, respectively.[a]
[a] General reaction conditions: 1 (0.6 mmol), 2 or 8 (0.5 mmol), PhSiH3
°
(2 equiv.) and ethanol (0.5 mL), 40 C, 18 h. Isolated yields of 3 or 9 are
shown; [b] Reaction for 24 h; [c] Reaction for 48 h.
acid moiety. Importantly, this transformation seems to be
specific to ω-amino fatty acid derivatives. Indeed, the reaction
of methyl 4-aminobutyric ester with benzaldehyde under similar
conditions did not lead to the expected pyrrolidinones, but
only to the corresponding imine. In order to have experimental
evidences of the pathway of this sequential transformation, we
performed the reaction of benzaldehyde with n-butylamine in
[a] General reaction conditions:
1 (0.6 mmol), 6 (0.5 mmol), PhSiH3
°
(2 equiv.) and ethanol (0.5 mL), 40 C, 18 h; Isolated yields of 7 are shown;
[b] Reaction for 18 h in methanol, 69% NMR-yield, in ethanol, 60% NMR
yield, in isopropanol, 56% NMR yield. [c] Reaction for 24 h. [d] Reaction at
°
°
ethanol at 40 C for 18 h (Table 4). In the absence of silane, only
80 C.
the condensation took place generating selectively the corre-
sponding imine 10 (entry 1). In the presence of 2 equiv. of
phenylsilane, 10 was still the main product with only trace
amount of 11, and 12, resulting from the reductive amination
and the double reductive amination of benzaldehyde, respec-
tively (entry 2). By addition of 1 equiv. of carboxylic acid such as
acetic acid, even if aldimine 10 was still obtained as the major
compound, a significant amount of the derivatives resulting
from reductive amination of benzaldehyde 11 and 12 were
detected (70:21:9 ratio) (entry 3). Using a stronger acid such as
respectively. Similarly, starting from 4-phenylbutan-2-one, 7r
was isolated in 68%. By contrast, when conducting the reaction
with acetophenone and 1-indanone, the corresponding pyrroli-
dinones 7s and 7t were obtained in poor yields (22 and 10%,
respectively).
Next, this reductive amination was extended to 5-amino-
pentanoic acid 2 in order to synthesize the corresponding
piperidinones 3 (Table 3).
In the selected examples represented in Table 3, p-methoxy-
and p-chloro- substituted benzaldehydes led to the correspond-
ing piperidinones 3b and 3c, in 62 and 65% yields, respectively.
Methyl ester reducible functional group was also tolerated
affording 3d in 51% yield. 6-Aminohexanoic acid 8 was then
evaluated to prepare 2-azepanones 9 as shown in Table 3. Thus,
benzaldehyde, p-anisaldehyde and p-chlorobenzaldehyde fur-
nished 9a–9c in moderate yields (35–43%). Methyl 4-formyl-
benzoate can be also transformed to the corresponding 2-
azepanone 9d in 48% without alteration of the ester moiety.
Interestingly, this transformation resulted from (i) the imine
formation by condensation of amine with carbonyl derivatives,
(ii) following by its reduction and finally an amidation of the
Table 4. Experimental evidences for the mechanism pathway.[a]
Entry PhSiH3 [equiv.] Additive [equiv.] Conv. [%] ratio [%]
10
11 12
1
2
3
4
PhSiH3 [0]
PhSiH3 [2]
PhSiH3 [2]
PhSiH3 [2]
–
–
95
>99
94
100
93
70
0
0
3
21
0
3
9
CH3CO2H [1]
TFA [1]
>99
82 18
[a] General reaction conditions: 1a (0.5 mmol), n-butylamine (0.5 mmol),
°
PhSiH3 (0-2 equiv.) and ethanol (0.5 mL), 40 C, 18 h. GC-yields.
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TFA[15] led to 11 and 12 in a 82:18 ratio (entry 4). These results
clearly demonstrated that Brönsted acids such as carboxylic
acids were helpful for the transformation of imines to lactams
in the presence of hydrosilanes, via the reduction of the imines
by hydrosilylation.[16,17]
In summary, this contribution described a simple reductive
procedure for the easy preparation of N-substituted lactams
(including pyrrolidinones, piperidinones and 2-azepanones)
starting from ω-amino fatty acids and a variety of carbonyl
derivatives, via reductive amination performed under hydro-
silylation conditions. The reaction proceeds with a nice func-
tional group tolerance as reducible groups such as carboxylic
ester, nitro, cyano and C=C bond were well tolerated. Interest-
ingly, this transformation involving a hydrosilylation step did
not need an external catalyst, the acid moiety playing the role
of internal activator during the reaction.
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Experimental Section
Typical procedure for catalytic reductive amination of carbonyl
derivatives with ω-amino fatty acids leading to lactams. In a
20 mL Schlenk tube under air, ω-amino fatty acids 2, 6 or 8
(0.5 mmol), carbonyl derivatives 1 (0.6 mmol), PhSiH3 (123.4 μL,
°
2 equiv.) and ethanol (0.5 mL) were stirred at 40 C for 18 h. After
cooling to room temperature, the reaction mixture was dried under
reduced pressure, and then the crude mixture was distilled using a
bulb-to-bulb distillation apparatus. The distilled residue was then
subjected to column chromatography (silica gel; ethyl acetate as
the eluent) to afford the desired product.
Acknowledgements
[12] J. Qi, C. Sun, Y. Tian, X. Wang, G. Li, Q. Xiao, D. Yin, Org. Lett. 2014, 16,
We thank the Université de Rennes 1, the Centre National de la
Recherche Scientifique (CNRS) and the FR Increase. S.T. and C.N.
thank the Fondation Rennes1 for a fellowship. J. W. thanks the
Chinese Scolarship Council for a PhD fellowship. We also thank
Jérôme Ollivier for assistance for HR-MS analysis.
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: ω-Amino fatty acids · Hydrosilylation · Lactam ·
Metal catalyst Free · Reductive Amination
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Manuscript received: June 18, 2021
Revised manuscript received: July 16, 2021
Accepted manuscript online: July 21, 2021
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COMMUNICATIONS
S. Tongdee, Dr. D. Wei, J. Wu, C.
Netkaew, Prof. Dr. C. Darcel*
1 – 5
Synthesis of Lactams by Reductive
Amination of Carbonyl Derivatives
with ω-Amino Fatty Acids under
Hydrosilylation Conditions
An unprecedented efficient method
for the reductive amination of
carbonyl derivatives with ω-amino
fatty acids under hydrosilylation con-
ditions was developed leading to the
corresponding lactams. A variety of
pyrrolidinones, piperidinones, 2-aze-
panones were prepared in up to 95%
isolated yields (29 examples).