Ugi/xanthate cyclizations as a radical route to lactam scaffolds

Article abstract of DOI:10.1016/j.tetlet.2006.09.123

The combination of Ugi reaction and xanthate radical cyclization onto alkenes allows an easy access to various highly functionalized heterocycles. The addition of chloroacetic acid to primary amines, aldehydes and isocyanides in methanol followed by the t

Full text of DOI:10.1016/j.tetlet.2006.09.123

Tetrahedron Letters 47 (2006) 8259–8261
Ugi/xanthate cyclizations as a radical route to lactam scaffolds
a
b,
a
Laurent El Kaım,a,* Laurence Grimaud, Luis Demetrio Miranda and Emilie Vieu
*
¨
aLaboratoire Chimie et Proce´de´s, DCSO, UMR 7652, Ecole Nationale Supe´rieure de Techniques Avance´es,
32 Bd Victor, Paris 75015, France
bInstituto de Quimica, Universidad Nacional Autonoma de Mexico, Circuito Exterior, Ciudad Universitaria, Coyoacan,
Mexico DF 04510, Mexico
Received 4 July 2006; revised 13 September 2006; accepted 21 September 2006
Available online 10 October 2006
Abstract—The combination of Ugi reaction and xanthate radical cyclization onto alkenes allows an easy access to various highly
functionalized heterocycles. The addition of chloroacetic acid to primary amines, aldehydes and isocyanides in methanol followed
by the treatment with potassium ethyl xanthate, affords the xanthate Ugi adducts in good yields. These adducts were then submitted
to radical cyclization conditions with dilauroyl peroxide as initiator. The choice of an alkene function properly located on the amine
or the aldehyde permits the formation of 5- to 8-membered rings in moderate to good yields.
Ó 2006 Elsevier Ltd. All rights reserved.
The Ugi reaction is among the most efficient multicom-
ponent reactions available and has found wide applica-
tions in the synthesis of large arrays of complex
targets.1 In order to reach scaffolds of a higher structural
complexity and improved biological tolerance, the Ugi
reaction has very often been associated with further
synthetic conversions (known as post-condensation
reactions). Ugi couplings followed by cycloadditions,2
Heck reactions,3 cyclocondensations4 or RCM5 have
thus been developed to allow the formation of various
heterocyclic cores. On the other hand, radical cycliza-
tion reactions have emerged as a powerful tool for the
construction of heterocyclic systems.6 The development
of various tin free methods has further increased the
potential of these processes. Over the last decade, Zard
et al. have demonstrated the efficiency of xanthate chem-
istry for the formation of C–C bonds in both intra and
intermolecular fashions.7 To the best of our knowledge,
the use of radical cyclizations on Ugi adducts has not yet
been documented yet.
The use of four components in Ugi reactions offers mul-
tiple solutions for the introduction of an alkene moiety
prone to xanthate transfer cyclization. Indeed, xan-
thate-Ugi adducts can be readily prepared by the use
of a-chlorocarboxylic acid as the acidic component in
the Ugi reaction followed by the nucleophilic displace-
ment of chlorine with potassium O-ethyl xanthate.
When isovaleraldehyde, allylamine, chloroacetic acid
and t-butylisocyanide were mixed in methanol, the Ugi
adduct was obtained after several hours at room temper-
ature. Next, the addition of potassium O-ethyl xanthate
(1.1 equiv) furnished the Ugi-xanthate adduct 1a in a
good yield after 1 h at room temperature. Heating 1a
under radical cyclization conditions (reflux in 0.3 M
1,2-dichloroethane with 15 mol % dilauroyl peroxide)
gave the expected lactam 2a, as a 1:1 mixture of separa-
ble diastereoisomers in a 70% isolated yield (Scheme 1).
Various aldehydes and isocyanides behaved similarly
with allylamine and chloroacetic acid to give the corre-
sponding Ugi-xanthate adducts 1b,c which underwent
5-exo-trig cyclizations to furnish pyrrolidinones 2b,c,
in good yields (Scheme 1). Related pyrrolidinone struc-
tures have shown interesting biological activities in the
treatment of conditions such as epilepsy.8
Interested by both radical and isocyanide chemistry, we
thus contemplated the formation of complex structures
by the coupling of radical xanthate cyclizations and
Ugi condensations.
*
Corresponding authors. Tel.: +33145525537; fax: +33145528322
(L.E.K.); tel.: +525556224440; fax: +525556162217 (L.D.M.);
e-mail addresses: laurent.elkaim@ensta.fr; lmiranda@servidor.
unam.mx
The degeneracy of radical additions to xanthates allows
successful reactions even with slow radical processes,
which are poorly compatible with tin hydride chemistry.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.123

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L. E. Kaı¨m et al. / Tetrahedron Letters 47 (2006) 8259–8261
R1
COOH
1) MeOH (1M)
rt, 16 h
H2N
COOH
1) MeOH (1M)
S
O
R1
O
Cl
Cl
N
R2
rt, 16 h
H2N
R1
+
∗
NC
R2
EtO
S
N
S
O
H
2) EtOC(S)SK
rt, 1 h
O
R1
2) EtOC(S)SK
rt, 1 h
H
O
CHO
N
∗
NC
EtO
S
N
1a: R1=
1b: R1=p-MeOPh, R2=
1c: R1=p-MeOPh, R2=p-ClBn, 70%
i
-Bu, R2=
t
-Bu, 63%
-Bu, 72%
H
t
1e: R1=3,4-(MeO)2Ph:90%
1,2-dichloroethane
DLP 15 mol %
reflux, 3h
1f: R1=OMe
72%
1,2-dichloroethane
OEt
DLP 30 mol %
reflux, 5h
S
S
2a: R1=
2b: R1=p-MeOPh, R2=
2c: R1=p-MeOPh, R2=p-ClBn,60% (1:1)
i
-Bu, R2=
t
-Bu, 70% (1:1)
-Bu, 63% (1:1)
∗
R1
S
O
EtO
R1
t
O
O
N
R2
∗
N
S
N
N
H
N
∗
H
N
H
R1
∗
O
∗
Bu3SnH 1.1 eq
1,2-dichloroethane
(0.3 M), reflux, 2 h
3e: R1=3,4-(MeO)2Ph:75%
Scheme 1.
O
O
2e: R1=3,4-(MeO)2Ph:38%
2f: R1=OMe
40%
We thus turned our attention to the formation of lac-
tams of higher ring size. Six-membered ring compounds
could be obtained by a similar Ugi coupling with homo-
allyl amines. Overkleeft et al. reported a convenient for-
mation of homoallyl Ugi adducts using a Staudinger/
aza-Wittig tandem process.9 We applied their procedure
in a one-pot formation of Ugi xanthate adduct 1d
directly from 1-bromobutene in a 50% overall isolated
yield. Thus, after azide formation in DMSO, MeOH
was added to perform the aza-Wittig reaction followed
by the Ugi coupling. For the latter transformation,
2-xanthyl acetic acid was used directly in place of
chloroacetic acid, making the process shorter and
demonstrating the compatibility of the xanthate moiety
with the Ugi coupling conditions. Next, 1d was trans-
formed efficiently into the piperidinone 2d via a 6-exo
radical cyclization in a 64% isolated yield (Scheme 2).
Scheme 3.
nide and homoveratrylamine to form 1e in a high yield
(Scheme 3). When xanthate 1e was submitted to the rad-
ical cyclization with 30 mol % of dilauroyl peroxide, we
were pleased to observe the formation of lactam 2e as a
single diastereoisomer via an 8-endo-trig cyclization. The
absence of any 7-exo cyclization product was compatible
with the selectivity reported on related systems.10 The
structure of xanthate 2e was further confirmed by the
reduction to 3e with Bu3SnH (Scheme 3).11
In conclusion, we have disclosed a new multicomponent
two-step procedure to form lactams using an Ugi
reaction, followed by a radical cyclization. This strategy
further demonstrates the interest of the xanthate
radical process for the fast assembly of complex cyclic
structures with high diversity. We will report further
investigations on the coupling of radical chemistry with
Ugi reactions in due course.
For the construction of 8-membered ring lactams, we
chose to introduce the alkene moiety through the alde-
hyde component. Commercial 2,2-dimethyl-4-pentenal
was thus coupled with chloroacetic acid, t-butylisocya-
1. NaN3, DMSO (2 M)
60 °C, 1 d
References and notes
N
Br
2. MeOH (1 M), PPh3,
Ph
1. For recent reviews, see: (a) Banfi, L.; Riv, R. Org. React.
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CyNC
EtO
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60 °C, 15 h
S
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∗
S
64%
dr 1:1
O
N
O
Ph
1,2-dichloroethane
∗
EtO
S
N
O
∗
DLP 30 mol %
reflux, 3 h
NH
Cy
O
´
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NH
Cy
2d
1d
Scheme 2.

L. E. Kaı¨m et al. / Tetrahedron Letters 47 (2006) 8259–8261
8261
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11. Typical procedure for 1f: 2,2-dimethyl-4-pentenal (272 lL,
2.0 mmol), 2-methoxyethylamine (174 lL, 2.0 mmol),
chloroacetic acid (189 mg, 2.0 mmol) and t-butyl isocya-
nide (226 lL, 2.0 mmol) were mixed in methanol (2 mL) at
room temperature for 16 h. When the starting material
was totally consumed, potassium O-ethyl xanthate was
added and the resultant mixture was stirred at room
temperature for 1 h. Extraction and purification by flash
column chromatography (silica gel; petroleum ether–
diethyl ether, 30:70) furnished 1f as a white solid (72%
yield).
A solution of this Ugi adduct 1f (242 mg,
0.56 mmol) was then refluxed in 1,2-dichloroethane
(1 mL) for 15 min under argon. Dilauroyl peroxide
(DLP) was then added (10%) to the refluxing solution,
followed by additional portions (5% every 90 min). When
the starting material had been totally consumed (after
addition of 30% of DLP), the crude mixture was cooled
to room temperature, concentrated under reduced pres-
sure and purified by flash column chromatography (silica
gel; petroleum ether–ethyl acetate, 60:40) to afford 2f as a
yellow oil (40% yield). Rf: 0.3 (60:40 petroleum ether/
ethyl acetate).1H NMR (CDCl3, 400 MHz) d 7.45 (br s,
1H), 4.68 (q, 2H, J = 7.1 Hz), 4.42 (dt, 1H, J = 14.3,
2.2 Hz), 4.06 (td, 1H, J = 10.6, 2.2 Hz), 3.80–3.73 (m,
1H), 3.48 (s, 1H), 3.40 (s, 3H), 3.41–3.39 (m, 1H), 3.01–
2.98 (m, 1H), 2.98–2.96 (m, 1H), 2.97–2.93 (m, 1H), 2.45
(ddd, 1H, J = 18.1, 12.9, 5.4 Hz), 2.20 (ddd, 1H,
J = 12.9, 5.4, 2.6 Hz), 1.78 (tdd, 1H, J = 12.9, 5.4,
2.6 Hz), 1.56 (d, 1H, J = 15.4 Hz), 1.44 (t, 3H,
J = 7.1 Hz), 1.31 (s, 9H), 1.25 (s, 3H), 1.14 (s, 3H).13C
NMR (CDCl3, 100.6 MHz) d 213.6, 174.9, 170.2, 72.5,
71.9, 70.0, 59.3, 54.4, 51.2, 43.6, 42.3, 41.2, 34.4, 32.0,
31.0, 28.9, 28.3, 14.2. MS (ID, ICP NH3) m/z 433
(M+H+). HRMS calcd for C20H36N2O4S2: 432.2116,
found: 432.2123.