Pyrrolidinone and piperidinone isocyanides from isocyano esters

Article abstract of DOI:10.1002/ejoc.201402572

The alkylation of isocyano esters with 1,2- and 1,3-dibromoalkanes affords bromo isocyanides. Under treatment with various amines the latter form new isocyano-substituted lactams, which can be further used in Passerini or Ugi reactions.

Full text of DOI:10.1002/ejoc.201402572

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402572
Pyrrolidinone and Piperidinone Isocyanides from Isocyano Esters
Madjid Ait Sidhoum,[a] Aurélie Dos Santos,[a] Laurent El Kaïm,*[a] and Laetitia Legras[a]
Keywords: Isocyanoacetates / Amines / Lactams / Nitrogen heterocycles / Multicomponent reactions
The alkylation of isocyano esters with 1,2- and 1,3-dibromo-
alkanes affords bromo isocyanides. Under treatment with
various amines the latter form new isocyano-substituted lact-
ams, which can be further used in Passerini or Ugi reactions.
Introduction
Recent interest in isocyanide-based multicomponent re-
actions (IMCRs) may be best explained by the efficiency
and the diversity offered by processes such as the Ugi,
Passerini, and Groebke–Bienaymé reactions.[1] If the avail-
ability of amines, aldehydes, and carboxylic acids as starting
partners is not a problem even for complex derivatives, the
isocyanide component remains problematic in terms of di-
versity, as very few derivatives are commercially available.
As a consequence, most IMCRs are based on a handful of
simple isocyanides [e.g., CyNC (Cy = cyclohexyl), tBuNC,
and isocyanoacetate derivatives], which limits the synthetic
potential of the multicomponent reaction (MCR) adducts.
Thus, simple and effective syntheses of complex isocyanides
are still needed. Conversions of isocyanides into more com-
plex ones usually involve acidic isocyanides such as tolu-
enesulfonyl methyl isocyanide (TosMiC) or ethyl iso-
cyanoacetate. Though the latter has been alkylated by sim-
ple alkyl halides,[2] its conversion into more complex iso-
cyanides such as heterocyclic derivatives is complicated by
potential intramolecular attack on the isocyano moiety
such as that observed in the Van Leusen and Schöllkopf
reactions.[3] In this context, the four-component dihydropy-
ridinone synthesis reported by Orru et al. is of interest
(Scheme 1a).[4] The heterocyclic isocyanides were formed
upon treatment of 1-azadienes with ethyl isocyanoacetate,
and they could further participate in various isocyanide-
based multicomponent reactions.[5] However, some con-
straints associated with the synthesis of the azadiene (use
of BuLi with a rather complex stepwise procedure at low
temperature) still limit the potential of this approach.
Herein, we wish to present alternative simple access to
cyclic isocyanides still with high diversity.
Scheme 1. Strategies towards new isocyano-substituted lactams.
Results and Discussion
Acidic isocyanides such as ethyl isocyanoacetate and
TosMiC have been alkylated with a variety of dihalogeno
compounds to form cyclized products through a double
alkylation process. These reactions represent interesting
access to cyclopropyl and cyclopentyl isocyanides, which
can be further hydrolyzed to amine and ketone derivatives
(Scheme 1b).[2a,6]
We envisioned that under controlled monoalkylation of
the isocyanoacetate, the resulting bromo isocyanides may
represent a powerful synthetic platform. Upon addition of
[a] DCSO-UMR 7652: CNRS-ENSTA-Ecole Polytechnique,
Laboratoire Chimie et Procédés, Ecole Nationale Supérieure de
Techniques Avancées,
828 Bd des Maréchauds, 91128 Palaiseau, France
E-mail: laurent.elkaim@ensta-paristech.fr
http://ucp.ensta-paristech.fr/sor.php
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402572.
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M. A. Sidhoum, A. Dos Santos, L. El Kaïm, L. Legras
SHORT COMMUNICATION
primary amines, the latter should form intermediate iso- was isolated in 68% yield under the addition of tryptamine
cyano amines, which could further cyclize either onto the (2 equiv.) to 3c.
isocyanide moiety or onto the ester function (Scheme 1c,
path a or b). Though both paths represent interesting access
to heterocyclic scaffolds, the formation of isocyano-substi-
tuted lactams under a rather simple procedure would be
more challenging owing to their interest as starting materi-
als for multicomponent reactions.
To demonstrate the concept, ethyl isocyano(phenyl)acet-
ate 1a was selected because of its higher acidity and lower
risk of dialkylation compared to that of unsubstituted iso-
cyanoacetates. Compound 1 was alkylated by using an ex-
cess amount of 1,2-dibromoethane (2a) in acetonitrile un-
der basic conditions to form isocyanide 3a in 76% yield
(Scheme 2). Upon heating the latter at reflux with (2-meth-
Scheme 3. Lactam isocyanides from 1b.
oxyethyl)amine (4a, 4 equiv.) in methanol, we were de-
To assess the potential of these isocyanides in isocyanide-
lighted to observe the formation of the expected lactam 5a based multicomponent reactions, several Passerini reactions
in a moderate 35% yield. The use of more polar solvents were tested with bulkier lactams 5a–d, and the results are
allowed the yield to be increased, and the optimized condi- displayed in Table 1 (Entries 1–8). As observed for the iso-
tions were obtained by working in DMSO with the amine cyanodihydropyridinones of Orru et al.,[5a] all lactams dis-
(3 equiv.) acting as both a base and a nucleophile. Pyrrol- played good reactivity and formed amides 6a–h in high
idinone 5a was then obtained in 64% yield. (p-Chloro- yields. However, the reaction was poorly diastereoselective,
benzyl)amine (4b) could be used instead of 4a to form 5b as shown by the 1:1 mixture of diastereomers obtained after
in a comparable 61% yield. The synthetic method is highly treating 5c with isobutyraldehyde and phenylacetic acid. All
versatile, as other dialkylating agents may be used as ef- other examples were thus performed with formaldehyde.
ficiently to form five- and six-membered-ring lactams. In- The behavior of these isocyano-substituted lactams in Ugi
deed, 1a may be equally alkylated with 1,3-dibromopropane reactions was next examined. Surprisingly, all attempts to
to form bromo derivative 3b in 73% yield. The cyclization couple lactams derived from ethyl isocyano(phenyl)acetate
of the latter under treatment with 4a and 4b in DMSO led 1 (i.e., 5a–d) failed to give any Ugi adduct. Despite the us-
to new isocyanopiperidinones 5c and 5d with higher effi- ual higher efficiency of the latter reaction, classical coupling
ciency compared to that of related isocyanide 3a.
conditions in molar methanol at room temperature left iso-
We next examined the reactivity of the less acidic ethyl 2- cyanides 5a and 5c unreacted [trials with (2-methoxyethyl)-
isocyanopropionate (1b) towards dibromo-1,3-propane. The amine, formaldehyde, or isobutyraldehyde and phenylacetic
formation of the related bromo isocyanide required a longer acid or acetic acid] and forcing the coupling under micro-
reaction time (12 h) and was more efficient if performed in wave conditions led to intractable mixtures. However, less
DMF in the presence of a catalytic amount of sodium iod- bulky methyl-substituted lactams obtained from ethyl 2-iso-
ide (Scheme 3). As previously observed, the addition of cyanopropionate (1b) could be successfully used in Ugi re-
various amines afforded isocyanopiperidinones in good to actions (Table 1, Entries 9–12). Again, there was no control
moderate yields. Most noteworthy was the formation of of the diastereoselectivity if an aldehyde other than formal-
complex piperidone derivatives such as indole 5g, which dehyde was used in the coupling (Table 1, Entry 12).
Scheme 2. New lactam isocyanides from 1a. DIPEA = N,N-diisopropylethylamine.
2
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Pyrrolidinone and Piperidinone Isocyanides from Isocyano Esters
697 cm–1. HRMS: calcd. for C12H12BrNO2 281.0051; found
281.0059.
Table 1. Passerini and Ugi reactions of isocyanides 5a–d.
Methyl 5-Bromo-2-isocyano-2-methylpentanoate (3c): 1,3-Dibromo-
propane (0.457 mL, 4.5 mmol, 3.0 equiv.), cesium carbonate
(538 mg, 1.65 mmol, 1.1 equiv.), and sodium iodide (23 mg,
0.15 mmol, 10 mol-%) were added to a solution of methyl 2-iso-
cyanopropanoate (0.75 m in dry DMF, 170 mg, 1.5 mmol). The re-
sulting mixture was stirred under argon at 40 °C for 26 h. Fil-
tration, removal of the solvent under reduced pressure, and purifi-
cation (flash chromatography on silica gel: petroleum ether/diethyl
ether, 9:1) afforded 3c as a yellow-green oil. Yield: 64% (225 mg).
=
0.5 (petroleum ether/diethyl ether, 70:30). 1H NMR
Entry R1NC
R2
R3
R4
Adduct
Rf
(% yield)
(400 MHz, CDCl3): δ = 3.84 (s, 3 H), 3.43 (t, J = 5.1 Hz, 2 H),
2.16–2.07 (m, 2 H), 1.99–1.83 (m, 2 H), 1.66 (s, 3 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 169.8, 159.4, 63.3, 53.8, 38.4, 32.3,
1
2
3
4
5
6
7
8
9
5a
5a
5b
5b
5c
5c
5c
5d
5e
5h
5h
5e
ClCH2
PhCH2
ClCH2
PhCH2
C6H11CH2
PhCH2
ClCH2
PhCH2
CH3
H
H
H
H
H
CHMe2
H
H
–
–
–
–
–
–
–
–
allyl
6a (89)
6b (81)
6c (77)
6d (73)
6e (74)
6f (84)[a]
6g (86)
6h (74)
7a (71)
7b (64)
7c (54)
7d (69)[a]
27.5, 26.4 ppm. IR (ν): ν = 2136, 1747, 1541, 1456, 1248, 1165,
˜
˜
1116, 979 cm–1. HRMS: calcd. for C8H12BrNO2 233.0051; found
234.0049.
3-Isocyano-1-(2-methoxyethyl)-3-phenylpyrrolidin-2-one (5a): (2-
Methoxyethyl)amine (4a, 3.0 equiv.) was added to a solution of 3a
(0.5 m in DMSO, 3.5 mmol) under an inert gas. The mixture was
heated at 80 °C for 7 h. Extraction with water and dichloromethane
followed by purification by flash chromatography on silica gel (pe-
troleum ether/ethyl acetate, 80:20, 70:30, and then 60:40) afforded
5a as a yellow oil. Yield: 64% (547 mg). 1H NMR (400 MHz,
CDCl3): δ = 7.40–7.34 (m, 3 H, H-ar), 7.33–7.22 (m, 2 H, H-ar),
3.66–3.58 (m, 2 H, 5-H, 3-H), 3.54–3.50 (m, 2 H, 2-H), 3.49–3.39
(m, 2 H, 3-H, 5-H), 3.29 (s, 3 H, 1-H), 2.73–2.64 (m, 1 H, 4-H),
2.59–2.50 (m, 1 H, 4-H) ppm. 13C NMR (100.6 MHz, CDCl3): δ =
168.2 (C-7), 159.1 (C-8), 136.1 (C-9), 129.1, 128.9, 125.2 (C-ar),
70.3 (C-2), 67.5 (C-6), 58.8 (C-1), 44.8 (C-3), 43.8 (C-5), 37.3 (C-
H
H
H
10
11
12
CH3
tBu
CH3
allyl
MeO(CH2)2
allyl
4-ClC6H4
[a] Obtained as a 1:1 mixture of diastereomers.
Conclusions
We prepared a new family of bromo isocyanides through
alkylation of isocyano esters with dibromoalkanes. Beside
the isocyanide function, these derivatives possess two elec-
trophilic centers that may be activated under the addition
of primary amines. Piperidinone and pyrrolidinone isocyan-
4) ppm. IR: ν = 2928, 1711, 1496, 1449, 1281, 700 cm–1. HRMS:
˜
calcd. for C14H16N2O2 244.1212; found 244.1211.
2-[1-(2-Methoxyethyl)-2-oxo-3-phenylpyrrolidin-3-ylamino]-2-oxo-
ethyl 2-Chloroacetate (6a): Formaldehyde (40% in H2O, 1.0 equiv.)
ides were obtained through
a sequential alkylation/
amidification process. The resulting lactams represent inter- and chloroacetic acid (1.0 equiv.) were successively added to a solu-
tion of 5a (1 m in CH2Cl2, 1 mmol) under an inert gas. The mixture
was stirred at room temperature for 18 h, and it was then concen-
trated in vacuo. The crude product was purified by flash
chromatography on silica gel to afford 6a as a brown oil. Yield:
89 % (328 mg). 1H NMR (400 MHz, CDCl3): δ = 7.42 (d, J =
esting scaffolds for multicomponent reactions, as shown by
their successful use in Passerini and Ugi couplings. We are
exploring further the potential of the intermediate bromo
isocyanides as well as the use of catalysts to improve the
poor diastereoselectivity observed in the Passerini and Ugi
coupling reactions of aldehydes.
7.6 Hz, 2 H, H-ar), 7.32–7.21 (m, 4 H, H-ar, N-H), 4.62 (d, JAB
=
15.4 Hz, 1 H, 10-H), 4.56 (d, JAB = 15.4 Hz, 1 H, 10-H), 4.10 (s, 2
H, 12-H), 3.66–6.57 (m, 1 H, 3-H), 3.51–3.29 (m, 5 H, 2-H, 4-H,
3-H), 3.23 (s, 3 H, 1-H), 3.02–2.93 (m, 1 H, 5-H), 2.72–2.62 (m, 1
H, 5-H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 172.6 (C-7),
166.2 (C-11), 165.6 (C-9), 139.2 (C-8), 128.9, 128.4, 125.9 (C-ar),
70.2 (C-2), 63.8 (C-10), 63.7 (C-6), 59.1 (C-1), 45.6 (C-4), 43.3 (C-
Experimental Section
Methyl 4-Bromo-2-isocyano-2-phenylbutanoate (3a): Cs2CO3
(1.0 equiv.) and 1,2-dibromoethane (3.0 equiv.) were successively
added to a solution of methyl 2-isocyano-2-phenylacetate (1a, 0.5 m
in CH3CN; 10 mmol) under an inert gas. The resulting mixture was
heated at reflux for 4 h. After the addition of water and extraction
with CH2Cl2, the combined organic fraction was dried with
MgSO4, and the solvents were removed under reduced pressure.
The residue was purified by flash chromatography on silica gel (pe-
troleum ether/diethyl ether, 9:1 then 8:2) to provide 3a as a yellow
3), 40.5 (C-12), 33.5 (C-5) ppm. IR: ν = 2936, 1750, 1675, 1521,
˜
1442, 1173, 700 cm–1. HRMS: calcd. for C17H21ClN2O5 368.1139;
found 368.1153.
N-Allyl-N-{2-[1-(2-methoxyethyl)-3-methyl-2-oxopiperidin-3-yl-
amino]-2-oxoethyl}acetamide (7a): Formaldehyde (37% in H2O,
0.039 mL, 0.52 mmol, 1.1 equiv.), allylamine (0.032 mL,
0.43 mmol), and acetic acid (0.025 mL, 0.43 mmol) were success-
1
oil. Yield: 76% (2150 mg). H NMR (400 MHz, CDCl3): δ = 7.58
ively added to a solution of 5e (1 m in methanol, 85 mg,
(d, J = 7.3 Hz, 2 H, H-ar), 7.52–7.43 (m, 3 H, H-ar), 3.85 (s, 3 H, 0.43 mmol). The resulting mixture was stirred at room temperature
1-H), 3.46 (t, J = 10.6 Hz, 1 H, 6-H), 3.32 (t, J = 10.6 Hz, 1 H, 6- for 24 h. Then, it was concentrated under reduced pressure and
H), 3.00 (t, J = 12.8 Hz, 1 H, 5-H), 2.79 (t, J = 12.8 Hz, 1 H, 5-H) purified by flash chromatography on silica gel (dichloromethane/
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 167.3 (C-2), 162.6 (C-
4), 133.8 (C-7), 129.5, 129.3, 124.8 (C-ar), 70.2 (C-3), 54.3 (C-1),
ethyl acetate, 90:10; then dichloromethane/methanol, 98:02, 95:05)
to afford 7a as a mixture of rotamers (yellow oil, ratio: 75:25).
Yield: 71% (99 mg). Rf = 0.39 (dichloromethane/methanol, 95:05).
42.5 (C-5), 25.1 (C-6) ppm. IR: ν = 2950, 1743, 1503, 1559, 1148,
˜
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M. A. Sidhoum, A. Dos Santos, L. El Kaïm, L. Legras
SHORT COMMUNICATION
1H NMR (400 MHz, CDCl3): δ = 6.81 (s, 1 H), 6.56 (s, 1 H), 5.80–
5.68 (m, 1 H), 5.27–5.08 (m, 2 H), 4.03–3.98 (m, 2 H), 3.98–3.94
(m, 2 H), 3.90 (s, 2 H), 3.82 (s, 2 H), 3.55–3.39 (m, 5 H), 3.35–3.29
(m, 1 H), 3.30 (s, 3 H), 2.31–2.16 (m, 2 H), 2.13 (s, 3 H), 2.16 (s, 3
H), 1.91–1.71 (m, 2 H), 1.46 (s, 3 H), 1.44 (s, 3 H) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 172.0, 171.9, 171.7, 171.5, 168.4, 167.8,
132.8, 132.1, 118.7, 117.4, 70.9, 59.0, 56.6, 56.3, 52.3, 51.8, 50.2,
49.7, 49.6, 48.3, 48.2, 33.0, 32.9, 25.2, 21.9, 21.3, 20.4, 20.3 ppm.
boken, NJ, 2005, vol. 65, pp. 1–140; j) A. Dömling, K. Wang,
W. Wa n g , Chem. Rev. 2012, 112, 3083–3135.
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1580–1592; b) A. M. van Leusen, R. J. Bouma, O. Possel, Tet-
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[3] a) U. Schöllkopf, R. Schröder, E. Blume, Justus Liebigs Ann.
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IR (thin film): ν = 2927, 1626, 1419, 1205, 1113 cm–1. HRMS:
˜
calcd. for C16H27N3O4 325.2002; found 325.2003.
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5i, 6a–h, and 7a–7d.
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Acknowledgments
We thank Dr. Laurence Grimaud for helpful discussions, the Ecole
Nationale Supérieure de Techniques Avancées (ENSTA) for finan-
cial support, and the Ministry of Higher Education and Scientific
Research of Algeria for a scholarship.
[5] a) M. Paravidino, R. Scheffelaar, R. F. Schmitz, F. J. J.
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Received: May 13, 2014
Published Online: ᭿
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Pyrrolidinone and Piperidinone Isocyanides from Isocyano Esters
Multicomponent Reactions
M. A. Sidhoum, A. Dos Santos,
L. El Kaïm,* L. Legras ..................... 1–5
Pyrrolidinone and Piperidinone Isocyan-
ides from Isocyano Esters
A new family of isocyano-substituted lact-
ams is created from isocyano esters through
an alkylation/amidification process. Their
use in Passerini and Ugi reactions is ex-
plored.
Keywords: Isocyanoacetates
Lactams / Nitrogen heterocycles / Multi-
component reactions
/ Amines /
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