Efficient synthesis of azaspirodienones by microwave-assisted radical spirocyclization of xanthate-containing ugi adducts

Article abstract of DOI:10.1055/s-0029-1218700

The sequential use of an Ugi reaction and radical spirocyclization under microwave irradiation conditions is described. The process provides rapid access to spirodienone lactams. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1218700

PAPER
1285
Efficient Synthesis of Azaspirodienones by Microwave-Assisted Radical
Spirocyclization of Xanthate-Containing Ugi Adducts
Synthesis of
A
zas
o
pirodienone
c
s
from
U
gi
í
A
dduc
o
ts Gámez-Montaño,*a Tannya Ibarra-Rivera,a Laurent El Kaïm,b Luis D. Mirandac
a
b
c
Departamento de Química, Universidad de Guanajuato, Noria Alta S/N, 36050 Guanajuato, Gto., Mexico
Fax +52(473)73200068168; E-mail: rociogm@quijote.ugto.mx
Laboratoire Chimie et Procédés, DCSO, UMR 7652, and Ecole Nationale Supérieure de Techniques Avancées, 32 Bd Victor,
75015 Paris, France
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán, 04510 México,
D. F., Mexico
Received 22 August 2009; revised 4 January 2010
thate-based (cf. Zard et al.4) tin free-radical spirolactam-
ization, involving the transformation of a benzenoid ring
into a dienone system, was recently developed in our lab-
oratory.5 On the basis of this report, the utilization of a p-
methoxybenzylamine derivative as the amine component
in the Ugi reaction was expected to provide rapid access
to substituted spirolactams, whose biological activity and
complex structure make them an important synthetic tar-
get (Scheme 1).6 The results of this endeavor are de-
scribed herein. In a related nonradical approach, a one-pot
entry to the synthesis of azaspirodienones by using a se-
quential combination of an Ugi reaction and a Michael cy-
clization was recently described by Santra and Andreana.7
Abstract: The sequential use of an Ugi reaction and radical spiro-
cyclization under microwave irradiation conditions is described.
The process provides rapid access to spirodienone lactams.
Key words: Ugi reaction, cyclizations, spiro compounds, lactams,
microwave reactions
In medicinal chemistry, the screening of small-molecule
libraries is of great importance in drug discovery. In this
regard, an important goal in organic synthesis continues to
be the development of efficient synthetic technologies
that provide rapid access to libraries of molecules with
broad structural diversity. Success in establishing an effi-
cient combination of different reactions can lead to the as-
sembly of libraries of small molecules (e.g., combinatorial
chemistry). The selection of efficient consecutive pro-
cesses does, indeed, merit consideration as a viable alter-
native means to create libraries of molecules bearing a
variety of functional groups and having broad structural
diversity.
Initially, the Ugi reaction was performed at room temper-
ature in methanol, by using approximately equimolar
amounts of the four components,1 but the reactions were
slow (10–20 h) under these conditions. When a catalytic
amount of indium(III) chloride was added, the reactions
were completed within a few hours. When the Ugi reac-
tion was completed, the potassium salt of xanthic acid was
added to the reaction mixture to generate the Ugi xanthate
adducts, usually in excellent yields (Table 1).
We recently demonstrated that the sequential combination
of an Ugi reaction with a free-radical cyclization leads to
the efficient construction of different heterocyclic scaf-
folds.1 Given that multicomponent reaction processes per-
mit the rapid, convergent, and often efficient generation of
small molecules,2 and that radical processes have enor-
mous utility in carbon–carbon bond-formation reactions,3
we chose to study the possibility of the combination of
these two reaction types. In this context, an efficient xan-
With these materials in hand, we studied the spirocycliza-
tion reaction. The reported conditions involve the portion-
wise addition of lauroyl peroxide (DLP) over 12 hours to
a boiling dichloroethane solution containing the Ugi xan-
thate adducts 1.5 These reactions were examined under
microwave irradiation conditions to reduce the reaction
time. Microwave-accelerated radical polymerization reac-
O
R1 NH
R1
O
R4
R3
N
R1NC
R2
R4
H
O
N
n
O
n NH2
N
MeOH, InCl3
MeO
DLP
R3
R2
n
R3
R2
Xth
then KSC(S)OEt
O
O
Cl
H
R4
HO
OMe
O
Xth = SC(S)OEt
n = 1,2
1
2
Scheme 1
SYNTHESIS 2010, No. 8, pp 1285–1290
x
x
.
x
x
.2
0
1
0
Advanced online publication: 12.03.2010
DOI: 10.1055/s-0029-1218700; Art ID: M04909SS
© Georg Thieme Verlag Stuttgart · New York

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R. Gámez-Montaño et al.
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Table 1 Synthesis of Substituted Spirolactams 2
Entry
R1
R2
R3
R4
n
Adduct
Yield
(%)b
Spirodienone
Yield
(%)b
1a
2c
1
2
2,6-Me2C6H3
2,6-Me2C6H3
2,6-Me2C6H3
t-Bu
H
H
Et
1
1
1
1
1
1
2
2
2
2
1a
1b
1c
1d
1e
1f
90
98
93
95
93
97
98
85
97
97
2a
2b
2c
2d
2e
2f
82
90
63
85
65
93
82
70
93
25
H
H
i-Pr
3
H
H
4-ClC6H4
i-Pr
4
H
H
5
t-Bu
OMe
H
H
i-Pr
6
t-Bu
OMe
H
i-Pr
7
t-Bu
H
i-Pr
1g
1h
1i
2g
2h
2i
8
t-Bu
H
OMe
H
i-Pr
9
2,6-Me2C6H3
2,6-Me2C6H3
H
i-Pr
10
OMe
H
i-Pr
1j
2j
a Reaction conditions for the synthesis of the Ugi xanthate adducts 1: amine, aldehyde, isocyanide, ClCH2CO2H, then KSC(S)OEt, InCl3 (10
mmol%), MeOH (1 M), r.t.
b Isolated yield.
c Reaction conditions for the synthesis of the spirodienones 2: Ugi xanthate adduct 1, DLP (1.5 equiv, in 5 portions), toluene (0.1 M), 250 W,
100 °C, 25 min.
tions are now well documented,8 but the use of this meth-
odology in free-radical-based organic synthesis is less
known.9 Thus, the microwave-assisted radical spirocy-
HN
N
O
clizations were performed in a monomodal open-vessel
system.10 The lauroyl peroxide (1.5 equiv) was added por-
tionwise (0.3 equiv/5 min) to a microwave-irradiated (250
W, 100 °C) solution of the Ugi xanthate adduct in toluene,
over a 25-minute period. Under these conditions, the
product yields were similar to those obtained by the con-
ventional method, but the reaction times were consider-
ably shortened. Notable is that the portionwise addition of
lauroyl peroxide (1.5 equiv) over 25 minutes to a solution
of 1a in toluene at 100 °C under conventional heating re-
sulted in incomplete consumption of the starting material.
A possible explanation is that the initiator fragmentation
process and/or the radical propagation pathways are likely
to be more efficient under microwave irradiation condi-
tions.
MeO
MeO
α
DLP
β
1j
O
3
α
β
NH
O
O
HN
O
MeO
MeO
N
N
R2
O
5
MeO
4
DLP
Ref. 5
The data in Table 1 show that functionalized five- and six-
membered spirodienone lactams were obtained in good
yields from both aliphatic and aromatic aldehydes in all
cases but one. The dimethoxy-substituted Ugi adduct 1j
(entry 10) gave a mixture of the expected spirodienone 2j
(25% yield) and benzazepine 6 (45% yield) (Scheme 2)
under conventional and microwave irradiation conditions.
Compound 6 may arise by an initial ipso attack
(Scheme 2, path a) and rearrangement of the spiro inter-
mediate 4 to form a seven-membered radical precursor 5,
or by direct cyclization to this radical (Scheme 2, path b),
or by a combination of both mechanisms. However, this is
only a hypothesis at this point, because there is no exper-
imental evidence for this intermediate.
2j
HN
O
MeO
MeO
N
6
O
Scheme 2 Proposed mechanism for the formation of 2j and 6
In closing, an efficient protocol for the preparation of sub-
stituted five- and six-membered spirolactams, by use of a
sequential combination of an Ugi reaction and a micro-
wave-assisted radical spirocyclization, was developed.
Synthesis 2010, No. 8, 1285–1290 © Thieme Stuttgart · New York

PAPER
Synthesis of Azaspirodienones from Ugi Adducts
1287
13C NMR (75 MHz, CDCl3): d = 13.8, 13.9, 18.6, 19.9, 30.9, 40.0,
55.3, 70.8, 114.4, 127.1, 127.8, 128.1, 128.8, 133.8, 135.1, 159.2,
168.9, 169.4, 213.6.
HRMS–FAB: m/z [M + H]+ calcd for C26H34N2O4S2: 503.2038;
found: 503.2036.
This protocol represents a very useful method for the con-
struction of libraries of azaspirodienones.
All reactions were performed in anhydrous solvents under an argon
atmosphere. General starting materials and solvents such as MeOH
and toluene are commercially available and were acquired from
Sigma Aldrich and used without further purification. The micro-
wave-assisted radical spirocyclizations were performed by using a
CEM Discover Synthesis™ Unit (CEM Corp., Matthews, NC) in a
monomodal open-vessel system. Reaction progress was monitored
by TLC on precoated Merck silica gel Kieselgel 60 F254 plates; the
spots were visualized under UV light (254 nm). Flash chromatogra-
phy was conducted on silica gel (230–400 mesh). Melting points
were determined on a Fisher-Jones instrument. The IR spectra were
S-(N-{(4-Chlorophenyl)[N-(2,6-dimethylphenyl)carbam-
oyl]methyl}-N-(4-methoxybenzyl)carbamoyl)methyl O-Ethyl
Dithiocarbonate (1c)
White solid; mp 146–148 °C; Rf = 0.3 (hexanes–EtOAc, 7:3).
IR (CHCl3): 1659, 1513 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.37 (t, J = 7.5 Hz, 3 H), 2.16 (s,
6 H), 3.76 (s, 3 H), 3.97 (d, J = 16.2 Hz, 1 H), 4.04 (d, J = 16.2 Hz,
1 H), 4.60 (q, J = 7.5 Hz, 2 H), 4.67 (d, J = 18.1 Hz, 2 H), 4.85 (d,
J = 18.1 Hz, 2 H), 6.01 (br s, 1 H), 6.78 (d, J = 8.6 Hz, 2 H), 7.01–
7.10 (m, 5 H), 7.28 (d, J = 8.0 Hz, 2 H), 7.46 (d, J = 8.0 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.0, 18.6, 39.9, 50.5, 55.3, 63.5,
70.6, 114.0, 127.4, 127.9, 128.2, 129.0, 131.2, 133.0, 133.2, 134.9,
135.4, 159.0, 167.3, 168.2, 213.9.
1
measured on a NICOLET FT-55X spectrophotometer. H and 13C
NMR spectra of samples in CDCl3 were recorded on Varian Gemini
200, Varian Unity 300, and Bruker Avance 400 spectrometers.
TMS was used as an internal reference. HRMS was carried out on a
JEOL SX-102 instrument.
Ugi Reaction; General Procedure
HRMS–FAB: m/z [M + H]+ calcd for C29H31ClN2O4S2: 571.1492;
found: 571.1501.
A soln of the appropriate aldehyde (1.0 mmol), the appropriate
amine (1.0 mmol), and InCl3 (0.1 mmol) in anhyd MeOH (1 mL)
was stirred for 1 h at r.t. Chloroacetic acid (1.0 mmol) was then add-
ed and the mixture was stirred for 15 min. The appropriate isocya-
nide (1.0 mmol) was then added and the reaction mixture was stirred
for 2–4 h at r.t. until the reaction was completed (according to TLC).
Then KSC(S)OEt (1.2 mmol) was added, and the mixture was
stirred for 3 h. The mixture was filtered and the solvent was evapo-
rated. The resulting residue was dissolved in EtOAc (5 mL). The or-
ganic layer was washed with distilled H2O (3 × 7 mL), dried
(Na2SO4), and concentrated in vacuo. The resulting yellowish solid
was purified by column chromatography (silica gel, hexanes–
EtOAc).
S-{N-[1-(N-tert-Butylcarbamoyl)-2-methylpropyl]-N-(4-meth-
oxybenzyl)carbamoyl}methyl O-Ethyl Dithiocarbonate (1d)
White solid; mp 108–109 °C; Rf = 0.3 (hexanes–EtOAc, 8:2).
IR (CHCl3): 1663, 1633 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.86 (d, J = 6.6 Hz, 3 H), 1.00 (d,
J = 6.6 Hz, 3 H), 1.32 (s, 9 H), 1.42 (t, J = 8.0 Hz, 3 H), 2.33–2.40
(m, 1 H), 3.62 (d, J = 16.0 Hz, 1 H), 3.78 (s, 3 H), 4.10 (d, J = 16.0
Hz, 1 H), 4.32 (d, J = 11.0 Hz, 1 H), 4.62 (q, J = 8.0 Hz, 2 H), 4.68
(d, J = 16.8 Hz, 1 H), 4.93 (d, J = 16.8 Hz, 1 H), 6.28 (br s, 1 H),
6.82 (d, J = 8.8 Hz, 2 H), 7.15 (d, J = 8.8 Hz, 2 H),
S-(N-{1-[N-(2,6-Dimethylphenyl)carbamoyl]propyl}-N-(4-
methoxybenzyl)carbamoyl)methyl O-Ethyl Dithiocarbonate
(1a)
Yellow oil; Rf = 0.3 (hexanes–EtOAc, 8:2).
IR (film): 1650, 1589 cm–1.
13C NMR (75 MHz, CDCl3): d = 13.9, 19.3, 19.8, 27.6, 28.8, 40.4,
51.5, 55.5, 70.7, 114.3, 128.1, 129.3, 159.1, 169.2, 169.4, 213.9.
HRMS–FAB: m/z [M + H]+ calcd for C22H34N2O4S2: 455.2038;
found: 455.2043.
1H NMR (200 MHz, CDCl3): d = 0.96 (t, J = 7.0 Hz, 3 H), 1.37 (t,
J = 7.0 Hz, 3 H), 1.85–1.90 (m, 1 H), 2.01–2.20 (m, 1 H), 2.16 (s, 6
H), 3.79 (s, 3 H), 4.05 (d, J = 16.0 Hz, 1 H), 4.10 (d, J = 16.0 Hz, 1
H), 4.61 (q, J = 7.0 Hz, 2 H), 4.77 (s, 2 H), 4.85–4.91 (m, 1 H), 6.92
(d, J = 8.8 Hz, 2 H), 7.06 (m, 3 H), 7.25 (d, J = 8.8 Hz, 2 H), 7.91
(br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 11.0, 13.6, 18.5, 21.9, 39.8, 49.4,
55.2, 61.7, 70.7, 114.3, 127.1, 127.6, 128.1, 128.6, 133.6, 135.0,
159.1, 168.5, 169.3, 213.4.
S-{N-[1-(N-tert-Butylcarbamoyl)-2-methylpropyl]-N-(3,4-
dimethoxybenzyl)carbamoyl}methyl O-Ethyl Dithiocarbonate
(1e)
Yellow oil; Rf = 0.4 (hexanes–EtOAc, 7:3).
IR (CHCl3): 1633, 1520 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.89 (d, J = 6.3 Hz, 3 H), 0.97 (d,
J = 6.3 Hz, 3 H), 1.31 (s, 9 H), 1.38 (t, J = 7.2 Hz, 3 H), 2.35–2.47
(m, 1 H), 3.78 (d, J = 16.0 Hz, 1 H), 3.85 (s, 3 H), 3.87 (s, 3 H), 4.08
(d, J = 16.0 Hz, 1 H), 4.28 (d, J = 10.5 Hz, 1 H), 4.62 (q, J = 7.2 Hz,
2 H), 4.69 (d, J = 16.8 Hz, 1 H), 4.90 (d, J = 16.8 Hz, 1 H), 6.27 (br
s, 1 H), 6.78–6.81 (m, 3 H).
HRMS–FAB: m/z [M + H]+ calcd for C25H32N2O4S2: 489.1882;
found: 489.1877.
13C NMR (75 MHz, CDCl3): d = 13.7, 19.3, 19.6, 27.6, 28.6, 40.3,
51.3, 55.9, 56.0, 70.6, 110.3, 111.2, 118.9, 129.5, 148.4, 149.3,
169.1, 169.2, 213.8.
HRMS–FAB: m/z [M + H]+ calcd for C23H37N2O5S2: 485.2144;
found: 485.2146.
S-(N-{1-[N-(2,6-Dimethylphenyl)carbamoyl]-2-methylpropyl}-
N-(4-methoxybenzyl)carbamoyl)methyl O-Ethyl Dithiocarbon-
ate (1b)
White solid; mp 139–140 °C; Rf = 0.3 (hexanes–EtOAc, 7:3).
IR (CHCl3): 1640, 1513 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.89 (d, J = 6.4 Hz, 3 H,), 1.10 (d,
J = 6.4 Hz, 3 H), 1.40 (t, J = 7.0 Hz 3 H), 2.16 (s, 6 H), 2.62–2.75
(m, 1 H), 3.78 (s, 4 H), 3.97 (d, J = 16.0 Hz, 1 H), 4.23 (d, J = 16.0
Hz, 1 H), 4.63 (q, J = 7.2 Hz, 2 H), 4.73–4.75 (m, 2 H), 6.86 (d,
J = 8.6 Hz, 2 H), 7.06 (m, 3 H), 7.26 (d, J = 8.6 Hz, 2 H), 8.18 (br
s, 1 H).
S-{N-[1-(N-tert-Butylcarbamoyl)-2-methylpropyl]-N-(2,4-
dimethoxybenzyl)carbamoyl}methyl O-Ethyl Dithiocarbonate
(1f)
Yellow oil; Rf = 0.37 (hexanes–EtOAc, 7:3).
IR (CHCl3): 1642, 1622 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.80 (d, J = 6.6 Hz, 3 H), 0.92 (d,
J = 6.6 Hz, 3 H), 1.28 (s, 9 H), 1.39 (t, J = 7.2 Hz, 3 H), 2.41–2.53
(m, 1 H), 3.78 (s, 3 H), 3.81 (s, 3 H), 3.98 (d, J = 15.6 Hz, 1 H),
Synthesis 2010, No. 8, 1285–1290 © Thieme Stuttgart · New York

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R. Gámez-Montaño et al.
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4.01–4.17 (m, 1 H), 4.21 (d, J = 15.6 Hz, 1 H), 4.59 (d, J = 17.0 Hz,
1 H), 4.61 (q, 2 H, J = 7.2 Hz), 4.72 (d, J = 17.0 Hz, 1 H), 6.41–6.43
(m, 2 H), 7.0 (d, J = 8.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.7, 19.0, 19.7, 27.3, 28.6, 39.8,
51.0, 55.2, 55.3, 70.4, 98.4, 103.9, 116.9, 128.9, 157.8, 160.5,
168.9, 169.3, 213.7.
Microwave-Assisted Radical Spirocyclization; General Proce-
dure
A deaerated soln of the appropriate Ugi xanthate adduct (1 mmol)
in anhyd toluene (5 mL) was microwave-irradiated (250 W) at 100
°C. Dilauryl peroxide (1.5 equiv) was then added portionwise (0.3
equiv/5min). The solvent was removed under reduced pressure and
the residue was purified by chromatography (silica gel, hexanes–
EtOAc); this furnished the corresponding spiro product.
HRMS–FAB: m/z [M + H]+ calcd for C23H36N2O5S2: 484.2066;
found: 484.2063.
Azaspiro[4.5]decane Derivative 2a
Yellow oil; Rf = 0.1 (hexanes–EtOAc, 7:3).
IR (CHCl3): 1664, 1627 cm–1.
S-{N-[1-(N-tert-Butylcarbamoyl)-2-methylpropyl]-N-(4-meth-
oxyphenethyl)carbamoyl}methyl O-Ethyl Dithiocarbonate (1g)
White solid; mp 153–154 °C; Rf = 0.4 (hexanes–EtOAc, 7:3).
1H NMR (300 MHz, CDCl3): d = 1.04 (t, J = 7.2 Hz, 3 H), 1.87–
1.72 (m, 1 H), 2.00–2.17 (m, 1 H), 2.18 (s, 6 H), 2.57 (d, J = 17.0
Hz, 1 H), 2.64 (d, J = 17.0 Hz, 1 H), 3.49 (d, J = 10.5 Hz, 1 H), 3.80
(d, J = 10.5 Hz, 1 H), 4.72 (dd, J = 8.4, 7.5 Hz, 1 H), 6.28–6.31 (m,
2 H), 6.88–6.91 (m, 2 H), 6.94–7.06 (m, 3 H), 7.75 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 10.8, 18.5, 22.0, 41.2, 52.2, 57.2,
127.5, 128.2, 129.4, 129.5, 133.3, 135.0, 149.3, 149.5, 168.1, 172.5,
184.7.
IR (CHCl3): 1676, 1635 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.81 (d, J = 6.6 Hz, 3 H), 0.98 (d,
J = 6.6 Hz, 3 H), 1.34 (s, 9 H), 1.41 (t, J = 7.2 Hz, 3 H), 2.37–2.41
(m, 1 H), 2.81–3.00 (m, 2 H), 3.59–3.64 (m, 2 H), 3.79 (s, 3 H), 4.05
(d, J = 15.5 Hz, 1 H), 4.15 (d, J = 15.5 Hz, 1 H), 4.22 (m, 1 H), 4.64
(q, J = 7.2 Hz, 2 H), 6.33 (br s, 1 H), 6.85 (d, J = 8.7 Hz, 2 H), 7.17
(d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.8, 18.7, 19.7, 26.5, 28.6, 35.0,
39.7, 51.2, 55.3, 70.7, 114.2, 129.9, 130.1, 158.5, 168.2, 169.5,
214.0.
HRMS–FAB: m/z [M + H]+ calcd for C21H25N2O3: 353.1865;
found: 353.1867.
HRMS–FAB: m/z [M + H]+ calcd for C23H36N2O4S2: 469.2195;
found: 469.2186.
Azaspiro[4.5]decane Derivative 2b
Yellow oil; Rf = 0.2 (hexanes–EtOAc, 7:3).
IR (CHCl3): 1665, 1629 cm–1.
Xanthate 1h was identified as its cyclized spirodienone 2h.
1H NMR (300 MHz, CDCl3): d = 0.95 (d, J = 6.6 Hz, 3 H), 1.10 (d,
J = 6.6 Hz, 3 H), 2.19 (s, 6 H), 2.20–2.39 (m, 1 H), 2.58 (d, J = 17.0
Hz, 1 H), 2.62 (d, J = 17.0 Hz, 1 H), 3.47 (d, J = 10. 6 Hz, 1 H), 3.82
(d, J = 10.6 Hz, 1 H), 4.38 (d, J = 11.0 Hz, 1 H), 6.28–6.30 (m, 2 H),
6.80 (dd, J = 10.0, 2.2 Hz, 1 H), 6.97 (dd, J = 10.0, 2.2 Hz, 1 H),
7.05–7.07 (m, 3 H), 7.78 (br s, 1 H).
13C NMR (75 MHz, CDCl3): d = 18.8, 19.2, 19.7, 26.5, 41.3, 51.9,
62.7, 127.7, 128.4, 129.5, 130.0, 133.5, 135.0, 149.5, 149.7, 167.4,
172.8, 184.9.
S-(N-{1-[N-(2,6-Dimethylphenyl)carbamoyl]-2-methylpropyl}-
N-(4-methoxyphenethyl)carbamoyl)methyl O-Ethyl Dithiocar-
bonate (1i)
White solid; mp 112–114 °C; Rf = 0.3 (hexanes–EtOAc, 7:3).
IR (CHCl3): 1682, 1635 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.94 (d, J = 6.6 Hz, 3 H), 1.14 (d,
J = 6.6 Hz, 3 H), 1.42 (t, J = 7.0 Hz, 3 H), 2.19 (s, 6 H), 2.69–2.71
(m, 1 H), 2.91–3.07 (m, 2 H), 3.60–3.74 (m, 3 H), 3.77 (s, 3 H), 4.22
(d, J = 15.5 Hz, 1 H), 4.29 (d, J = 15.5 Hz, 1 H), 4.66 (q, J = 7.0 Hz,
2 H), 6.83 (d, J = 8.4 Hz, 2 H), 7.06 (m, 3 H), 7.15 (d, J = 8.4 Hz 2
H).
HRMS–FAB: m/z [M + H]+ calcd for C22H27N2O3: 367.2022;
found: 367.2025.
13C NMR (75 MHz, CDCl3): d = 13.8, 18.7, 19.9, 35.1, 39.9, 55.2,
70.8, 114.2, 127.1, 128.2, 129.6, 129.8, 133.6, 134.9, 158.5, 168.7,
168.9, 213.7.
HRMS–FAB: m/z [M + H]+ calcd for C27H36N2O4S2: 517.2195;
found: 517.2180.
Azaspiro[4.5]decane Derivative 2c
White solid; mp 170–172 °C; Rf = 0.3 (hexanes–EtOAc, 7:3).
IR (CHCl3): 1660, 1628, 1594 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.15 (s, 6 H), 2.58 (s, 2 H), 3.10
(d, J = 9.9 Hz, 1 H), 3.90 (d, J = 9.9 Hz, 1 H), 6.11 (s, 1 H), 6.22 (dt,
J = 9.6, 1.8 Hz, 2 H), 6.70 (m, 1 H), 7.02–7.12 (m, 4 H), 7.38 (s, 1
H), 7.43 (br s, 3 H).
13C NMR (75 MHz, CDCl3): d = 18.5, 40.9, 41.5, 52.3, 58.3, 127.8,
128.3, 128.9, 129.6, 130.5, 132.0, 132.8, 135.3, 135.6, 149.2, 150.0,
167.1, 171.9, 184.8.
S-(N-(3,4-Dimethoxyphenethyl)-N-{1-[N-(2,6-dimethylphe-
nyl)carbamoyl]-2-methylpropyl}carbamoyl)methyl O-Ethyl
Dithiocarbonate (1j)
White solid; mp 93–94 °C; Rf = 0.3 (hexanes–EtOAc, 7:3).
IR (CHCl3): 1633, 1514 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.95 (d, J = 6.3 Hz 3 H), 1.15 (d,
J = 6.3 Hz 3 H), 1.43 (t, J = 7.2 Hz, 3 H), 2.18 (s, 6 H), 2.90–3.04
(m, 3 H), 3.64–3.77 (m, 2 H), 3.82–3.84 (m, 1 H), 3.84 (s, 3 H), 3.85
(s, 3 H), 4.28 (br s, 2 H), 4.67 (q, J = 7.2 Hz, 2 H), 6.76 (s, 1 H),
6.79–6.80 (m, 2 H), 7.05–7.08 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 13.8, 18.7, 19.9, 35.6, 40.2, 56.0,
70.9, 111.4, 112.0, 120.7, 127.2, 128.2, 130.1, 133.6, 134.9, 147.9,
149.1, 168.7, 213.8.
HRMS–FAB: m/z [M + H]+ calcd for C25H23ClN2O3: 435.1475;
found: 435.1480
Azaspiro[4.5]decane Derivative 2d
Colorless oil; Rf = 0.2 (hexanes–EtOAc, 7:3).
IR (CHCl3): 1664, 1629 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.91 (d, J = 6.6 Hz, 3 H), 0.98 (d,
J = 6.6 Hz, 3 H), 1.35 (s, 9 H), 2.20 (m, 1 H), 2.55 (d, J = 16.8 Hz,
1 H), 2.63 (d, J = 16.8 Hz, 1 H), 3.44 (d, J = 10.5 Hz, 1 H), 3.78 (d,
J = 11.0 Hz, 1 H), 3.96 (d, J = 11.0 Hz, 1 H), 5.90 (br s, 1 H), 6.31
(dd, J = 10.2, 1.8 Hz, 1 H), 6.33 (dd, J = 10.2, 1.8 Hz, 1 H), 6.85
(dd, J = 10.0, 3.0 Hz, 1 H), 6.93 (dd, J = 10.2, 3.0 Hz, 1 H).
HRMS–FAB: m/z [M + H]+ calcd for C27 H39N2O5S2: 547.2300;
found: 547.2303.
13C NMR (75 MHz, CDCl3): d = 19.0, 19.3, 26.7, 28.6, 41.2, 41.4,
51.7, 63.0, 129.5, 149.4, 149.5, 168.0, 172.2, 184.8.
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Synthesis of Azaspirodienones from Ugi Adducts
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HRMS–FAB: m/z [M + H]+ calcd for C18H27N2O3: 319.2022;
Azaspiro[5.5]undecane Derivative 2h
found: 319.2025.
White solid; mp 156–158 °C; Rf = 0.2 (hexanes–EtOAc, 7:3).
IR (CHCl3): 1660, 1593 cm–1.
Azaspiro[4.5]decane Derivative 2e
Inseparable mixture of diastereomers (~6:4); Rf = 0.3 (hexanes–
EtOAc, 7:3).
IR (CHCl3): 1667, 1616 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.88 (d, J = 6.6 Hz, 3 H), 0.99 (d,
J = 6.6 Hz, 3 H), 1.35 (s, 9 H), 1.80 (m, 1 H), 2.24 (d, J = 16.5 Hz,
1 H), 2.25 (m, 2 H), 2.97 (d, J = 16.5 Hz, 1 H), 3.51–3.43 (m, 1 H),
3.64 (ddd, J = 14.0, 9.6, 5.1 Hz, 1 H), 3.77 (s, 1 H), 4.47 (d, J = 11.0
Hz, 1 H), 5.60 (d, J = 1.5 Hz, 1 H), 5.96 (br s, 1 H), 6.20 (dd,
J = 10.0, 1.5 Hz, 1 H), 6.54 (d, J = 10.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 18.5, 19.6, 25.5, 28.7, 31.8, 39.4,
39.9, 51. 4, 56,0, 63.2, 102.3, 128.0, 146.1, 168.61, 169.0, 186.8.
HRMS–FAB: m/z [M + H]+ calcd for C20H30N2O4: 363.2284;
found: 363.2283.
1H NMR (300 MHz, CDCl3): d (1st diastereomer) = 0.93 (dd,
J = 6.6, 5.1 Hz, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.36 (s, 9 H), 2.21
(m, 1 H), 2.57 (d, J = 17.0 Hz, 1 H), 2.67 (d, J = 17.0 Hz, 1 H), 3.47
(d, J = 10.0 Hz, 1 H), 3.66 (s, 3 H), 3.82 (d, J = 10.5 Hz, 1 H), 3.96
(d, J = 11.0 Hz, 1 H), 5.80 (br s, 1 H), 5.82 (d, J = 2.7 Hz, 1 H), 6.36
(d, J = 9.6 Hz, 1 H), 6.94 (dd, J = 9.6, 2.4 Hz, 1 H).
1H NMR (300 MHz, CDCl3): d (2nd diastereomer) = 0.93 (dd,
J = 6.6, 5.1 Hz, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.35 (s, 9 H), 1.71
(br s, 1 H), 2.21 (m, 1 H), 2,59 (d, J = 17.0 Hz, 1 H), 2.66 (d,
J = 17.0 Hz, 1 H), 3.44 (d, J = 10.0 Hz, 1 H), 3.68 (s, 3 H), 3.80 (d,
J = 10.5 Hz, 1 H), 3.91 (d, J = 11.0 Hz, 1 H), 5.75 (d, J = 2.7 Hz, 1
H), 6.34 (d, J = 9.6 Hz, 1 H), 6.84 (dd, J = 9.6, 2.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 19.2, 19.4, 26.7, 28.6, 42.2, 42.3,
51.7, 52.8, 54.9, 63.0, 116.8, 128.9, 149.8, 151.7, 168.3, 172.6,
180.1.
HRMS–FAB: m/z [M + H]+ calcd for C19H28N2O4: 349.2127;
found: 349.2118.
Azaspiro[5.5]undecane Derivative 2i
Rf = 0.4 (hexanes–EtOAc, 7:3).
IR (film): 1654, 1629 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.00 (d, J = 6.6 Hz, 3 H), 1.14 (d,
J = 6.6 Hz, 3 H), 1.95 (m, 2 H), 2.20 (s, 6 H), 2.45 (m, 1 H), 2.47 (d,
J = 17.0 Hz, 1 H), 2.58 (d, J = 17.0 Hz, 1 H), 3.52 (ddd, J = 13.5,
7.2, 6.3 Hz, 1 H), 3.83–3.75 (m, 1 H), 4.83 (d, J = 11.0 Hz, 1 H),
6.31 (dd, J = 10.0, 1.8 Hz, 1 H,), 6.36 (dd, J = 10.0, 1.8 Hz, 1 H),
6.78 (dd, J = 10.0, 3.0 Hz, 1 H), 6.90 (dd, J = 10.0, 3.0 Hz, 1 H),
7.09–7.05 (m, 3 H), 7.65 (br s, 1 H),
13C NMR (75 MHz, CDCl3): d = 18.5, 19.0, 19.7, 25.2, 32.6, 40.7,
63.6, 127.4, 128.3, 129.6, 129.9, 133.5, 134.8, 149.9, 150.6, 167.7,
168.1, 184.7,
HRMS–FAB: m/z [M + H]+ calcd for C23H29N2O3: 381.2178;
found: 381.2179.
Azaspiro[4.5]decane Derivative 2f
Inseparable mixture of diastereomers (~7:3); Rf = 0.3 (hexanes–
EtOAc, 7:3).
IR (CHCl3): 1661, 1626 cm–1.
1H NMR (300 MHz, CDCl3): d (1st diastereomer) = 0.91 (dd,
J = 6.9, 6.6 Hz, 3 H), 0.97 (d, J = 6.6 Hz, 3 H), 1.35 (s, 9 H), 2.21
(m, 1 H), 2.44 (d, J = 17.0 Hz, 1 H), 2.95 (d, J = 17.0 Hz, 1 H), 3.68
(s, 2 H), 3.79 (s, 3 H), 3.96 (d, J = 11.1 Hz, 1 H), 5.64 (s, 1 H), 5.78
(br s, 1 H), 6.18 (dd, J = 10.0, 1.5 Hz, 1 H), 6.59 (d, 1 H, J = 10.0
Hz).
Azaspiro[5.5]undecane Derivative 2j
Inseparable mixture of diastereomers (~1:1); white solid; mp 123–
124 °C; Rf = 0.2 (hexanes–EtOAc, 7:3).
IR (CHCl3): 1672, 1641, 1625 cm–1.
1H NMR (300 MHz, CDCl3): d (1st diastereomer) = 1.01 (dd,
J = 3.3, 6.5 Hz, 3 H), 1.14 (d, J = 6.5 Hz, 3 H), 1.95 (m, 2 H), 2.21
(s, 6 H), 2.51 (d, J = 17.1 Hz, 1 H), 2.57 (s, 1 H), 2.63 (d, J = 17.1,
1.2 Hz, 1 H), 3.42–3.60 (m, 1 H), 3.67 (s, 3 H), 3.74–3.85 (m, 2 H),
4.80 (m, 1 H), 5.79 (d, J = 2.7 Hz, 1 H), 6.39 (d, J = 10.0 Hz, 1 H),
6.90 (dd, J = 10.0, 3.0 Hz, 1 H), 7.04–7.12 (m, 3 H), 7.64 (br s, 1 H).
1H NMR (300 MHz, CDCl3): d (2nd diastereomer) = 0.91 (dd,
J = 6.9, 6.6 Hz, 3 H), 0.97 (d, J = 6.6 Hz, 3 H), 1.35 (s, 9 H), 2.21
(m, 1 H), 2.43 (d, J = 17.0 Hz, 1 H), 2.90 (d, J = 17.0 Hz, 1 H), 3.30
(d, J = 11.0 Hz, 1 H), 3.75 (s, 3 H), 3.90 (d, J = 10.0 Hz, 1 H), 3.93
(d, J = 11.0 Hz, 1 H), 5.85 (br s, 1 H), 6.21 (dd, J = 9.6, 1.5 Hz, 1
H), 6.70 (d, 1 H, J = 10.0 Hz).
1H NMR (300 MHz, CDCl3): d (2nd diastereomer) = 1.02 (dd,
J = 3.3, 6.5 Hz, 3 H), 1.14 (d, J = 6.5 Hz, 3 H), 1.95 (m, 2 H), 2.20
(s, 6 H), 2.4 (m, 1 H), 2.51 (d, J = 17.1 Hz, 1 H), 2.63 (d, J = 17.1,
1.2 Hz, 1 H), 3.49–3.59 (m, 1 H), 3.62 (m, 3 H), 3.74–3.85 (m, 1 H),
4.80 (m, 1 H), 5.64 (d, J = 2.7 Hz, 1 H), 6.35 (d, J = 10.0 Hz, 1 H),
6.79 (dd, J = 10.0, 3.0 Hz, 1 H), 7.04–7.12 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 19.3, 19.8, 27.3, 29.0, 40.9, 42.4,
52.0, 52.2, 56.5, 63.4, 103.4, 127.5, 146.7, 168.6, 172.4, 174.7,
187.4.
HRMS–FAB: m/z [M + H]+ calcd for C19H28N2O4: 348.2049;
found: 348.2058.
13C NMR (75 MHz, CDCl3): d = 18.6, 18.8, 19.1, 19.7, 25.2, 33.4,
33.6, 39.6, 41.9, 55.0, 63.0, 116.5, 117.7, 127.4, 128.3, 128.9,
129.2, 133.4, 134.8, 150.4, 151.1, 151.9, 167.7, 168.4, 180.1.
HRMS–FAB: m/z [M + H]+ calcd for C24H30N2O4: 411.2284;
found: 411.2281.
Azaspiro[5.5]undecane Derivative 2g
Rf = 0.4 (hexanes–EtOAc, 7:3).
IR (CHCl3): 1667, 1635 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.90 (d, J = 6.5 Hz, 3 H), 1.01 (d,
J = 6.5 Hz, 3 H), 1.35 (s, 9 H), 1.94 (m, 2 H), 2.34 (m, 1 H), 2.43
(dd, J = 17.0, 0.9 Hz, 1 H), 2.55 (d, J = 17.0 Hz, 1 H), 3.41–3.49 (m,
1 H), 3.75 (ddd, J = 13.5, 7.8, 6.0 Hz, 1 H), 4.49 (d, J = 11.0 Hz, 1
H), 6.00 (br s, 1 H), 6.29–6.35 (m, 2 H), 6.77 (dd, J = 10.0, 3.6 Hz,
1 H), 6.83 (dd, J = 10.0, 3.6 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 18.8, 19.6, 25.3, 28.7, 32.4, 39.1,
40.0, 40.6, 51.4, 63.4, 129.6, 150.2, 150.8, 167.8, 168.5, 184.8.
HRMS–FAB: m/z [M + H]+ calcd for C23H29N2O3: 333.2178;
found: 333.2180.
Benzazepine 6
Yield: 45%; white solid; mp 172–173 °C; Rf = 0.7 (hexanes–
EtOAc, 7:3).
IR (CHCl3): 1633 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.93 (d, J = 6.6 Hz, 3 H), 1.10 (d,
J = 6.6 Hz, 3 H), 1.90 (s, 6 H), 2.52–2.50 (m, 1 H), 2.91–3.00 (m, 1
H), 3.15–3.04 (m, 1 H), 3.59 (d, J = 14.4 Hz, 1 H), 3.79 (s, 3 H),
3.85 (s, 3 H), 3.80–3.85 (m, 1 H), 3.94–4.04 (m, 1 H), 4.20 (d,
J = 14.4 Hz, 1 H), 4.68 (br s, 1 H), 6.48 (s, 1 H), 6.60 (s, 1 H), 6.93–
7.05 (m, 3 H).
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R. Gámez-Montaño et al.
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B.; Blunt, J. W.; McCombs, J. D.; Munro, M. H. J. Org.
13C NMR (75 MHz, CDCl3): d = 17.9, 18.7, 19.7, 25.8, 32.0, 42.3,
55.9, 113.2, 113.8, 122.3, 127.1, 128.0, 133.5, 134.9, 147.2, 148.2,
168.9, 173.7.
HRMS–FAB: m/z [M + H]+ calcd for C25H32N2O4: 424.2362;
found: 424.2371.
Chem. 1986, 51, 5476. (c) Blunt, J. W.; Calder, V. L.;
Fenwick, G. D.; Lake, R. J.; McCombs, J. D.; Munro, M. H.;
Perry, N. B. J. Nat. Prod. 1987, 59, 290. (d) Perry, N. B.;
Blunt, J. W.; Munro, M. H.; Higa, T.; Sakai, R. J. Org.
Chem. 1988, 53, 4127. (e) Perry, N. B.; Blunt, J. W.; Munro,
M. H. Tetrahedron 1988, 44, 1727. (f) Martin, S. F. In
Alkaloids, Vol. 30; Brossi, A., Ed.; Academic Press: New
York, 1987, 251. (g) Tanaka, A.; Kawai, T.; Takabatake, T.;
Oka, N.; Okamoto, H.; Bersohn, M. Tetrahedron Lett. 2006,
47, 6733. (h) Badger, A. M.; Schwartz, D. A.; Picker, D. H.;
Dorman, J. W.; Bradley, F. C.; Cheeseman, E. N.;
DiMartino, M. J.; Hanna, N.; Mirabelli, C. K. J. Med. Chem.
1990, 33, 2963. (i) Shigehisa, H.; Takayama, J.; Honda, T.
Tetrahedron Lett. 2006, 47, 7301.
Acknowledgment
We acknowledge financial support from CONCYTEG (GTO-2003-
C02-11945) and CONACYT (J42673Q and J50922). We also thank
Dr. Joseph M. Muchowski for helpful discussions and R. Patiño, J.
Pérez, L. Velazco, H. Rios, N. Zavala, E. Huerta, and A. Peña for
technical support.
(7) Santra, S.; Andreana, P. R. Org. Lett. 2007, 9, 5035.
(8) For reviews, see: (a) Sinnwell, S.; Ritter, H. Aust. J. Chem.
2007, 60, 729. (b) Wiesbrock, F.; Hoogenboom, R.;
Schubert, U. S. Macromol. Rapid Commun. 2004, 25, 1739.
See also: (c) Pawluczyk, J. M.; McClain, R. T.; Denicola, C.
M.; James, J.; Rudd, D. J.; Lindsley, C. W. Tetrahedron Lett.
2007, 48, 1497.
(9) (a) Portela-Cubillo, F.; Scott, J. S.; Walton, J. C. Chem.
Commun. 2007, 4041. (b) Bull, J. A.; Hutchings, M. G.;
Quayle, P. Angew. Chem. Int. Ed. 2007, 46, 1869.
(c) Jessop, C. M.; Parsons, A. F.; Routledge, A.; Irvine, D. J.
Eur. J. Org. Chem. 2006, 1547. (d) Zhang, W. Top. Curr.
Chem. 2006, 266, 145. (e) Schulte, B.; Studer, A. Synthesis
2006, 2129. (f) Wetter, C.; Studer, A. Chem. Commun.
2004, 174.
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Synthesis 2010, No. 8, 1285–1290 © Thieme Stuttgart · New York