Atom transfer radical cyclization of trichloroacetamides to electron-rich acceptors using Grubbs' catalysts: Synthesis of the tricyclic framework of FR901483

Article abstract of DOI:10.1021/jo501110c

Intramolecular Kharasch-type additions of trichloroacetamides on anisole and enol acetates catalyzed by Grubbs' ruthenium carbenes are described. This protocol provides access to highly functionalized 2-azaspiro[4.5]decanes, morphan compounds, and the aza

Full text of DOI:10.1021/jo501110c

Note
pubs.acs.org/joc
Atom Transfer Radical Cyclization of Trichloroacetamides to
Electron-Rich Acceptors Using Grubbs’ Catalysts: Synthesis of the
Tricyclic Framework of FR901483
Faïza Diaba,* Agustín Martínez-Laporta, and Josep Bonjoch*
̀ ̀
Laboratori de Química Organica, Facultat de Farmacia, IBUB, Universitat de Barcelona, Av. Joan XXIII s/n, 08028-Barcelona, Spain
S
* Supporting Information
ABSTRACT: Intramolecular Kharasch-type additions of trichlor-
oacetamides on anisole and enol acetates catalyzed by Grubbs’
ruthenium carbenes are described. This protocol provides access to
highly functionalized 2-azaspiro[4.5]decanes, morphan compounds,
and the azatricyclic core of FR901483.
ince 1999, when Snapper reported the use of Grubbs’ first
S
generation catalyst (G-1) as a promoter in the Kharasch
intermolecular reaction of chloroform and alkenes,1 the number
of reported atom transfer radical reactions catalyzed by Grubbs’
ruthenium carbene complexes has been growing. An extended
version of the process has been applied intramolecularly in the
synthesis of γ-lactones and γ-lactams,2 as well as in both intra-
and intermolecular tandem processes involving olefin ring-
closing metathesis (RCM) and atom transfer radical processes
(ATRC).3 These two C−C bond-forming steps were also
mediated by Grubbs’ second generation catalyst (G-2) in
preparative yields.4
The intramolecular processes reported to date are limited to
substrates embodying simple alkenes as radical acceptors. This
encouraged us to investigate ATRC5 promoted by Grubbs’
catalysts using substrates in which electron-rich double bonds
(e.g., anisole or enol acetate substrates) act as radical acceptors.
We report herein the use of a Grubbs’ catalyst (G-2) to promote
reactions of trichloroacetamides upon anisoles to afford,
through a dearomative cyclization, 2-azaspiro[4.5]decane
derivatives (Figure 1), whose skeleton occurs in several natural
compounds,6 as well as upon cyclic enol acetates to give
morphan compounds.7 The latter procedure was also applied to
synthesize the azatricyclic framework of the immunosuppressant
FR9014838,9 by the elaboration of the bridged nucleus.
We began by examining the feasibility of applying the G-2-
mediated ATRC to anisole derivatives bearing a trichloroace-
tamide handle (i.e., 1) to achieve 1-azaspiro[4.5]decane
compounds.10,11 On the basis of our previous results in
dearomatizing radical spirocyclization upon inactivated benzene
promoted by Cu(I),11d we used the tert-butyl derivative 1a as
the substrate. The required trichloroacetamide 1a was prepared
through imine formation from 4-methoxybenzaldehyde and tert-
butylamine, followed by reduction and trichloroacetylation.
Treatment of 1a with 5% of G-2 at 155 °C for 30 min in 0.2
mL of toluene provided 2a in very good yield (Table 1, entry 1).
The importance of having a tert-butyl group on the nitrogen to
Figure 1. An approach to 2-azaspiro[4.5]decanes and 2-
azabicyclo[3.3.1]nonanes by a radical cyclization using Grubbs’ catalyst.
lock the substrate in a conformation prone to cyclization was
once again evident, since the reaction with 1b in the same
conditions provided the corresponding azaspirocycle 2b in poor
yield (entry 2). Microwave activation gave the azaspirodecane
derivative with a lower yield (entry 3), and switching to G-1 or
Hoveyda−Grubbs’ second generation catalyst (G-3) did not
improve the results (entries 4 and 5). When 1a was treated
overnight with 30% of CuCl at 80 °C, 2a was also isolated in an
acceptable yield (61%), although accompanied by the secondary
amide 1g (R1 = R2 = H) arising from the cleavage of the tert-
butyl group in 1a (entry 6).
The results of optimization studies carried out with 1a
prompted us to apply the cyclization procedure to more
substituted methoxybenzenes (Table 1, entries 7 and 8). It was
Received: May 20, 2014
Published: September 9, 2014
© 2014 American Chemical Society
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Note
reaction at 155 °C, 4 was isolated in 61% yield, together with
some starting material (Table 2, entry 1). A longer reaction time
Table 1. Ruthenium(II)-Catalyzed ATRC in the Synthesis of
2-Azaspirodecanes
Table 2. Ruthenium(II)-Catalyzed ATRC in Morphan
Synthesis
a
entry
catalyst (%)
conditions
yield (%)
b
1
2
3
4
5
G-2 (5)
G-2 (5)
G-2 (5)
G-2 (5)
G-1 (5)
G-2 (5)
2 h, 155 °C, 0.64 M
4 h, 155 °C, 0.64 M
30 min, 155 °C, 1.3 M
15 min, 155 °C μW, 0.26 M
15 min, 155 °C μW, 0.26 M
61
a
b
c
entry
compd
catalyst (mol %)
method
compd (yield %)
67
68
1
2
1a
1b
1a
1a
1a
1a
1c
1d
1e
1f
G-2 (5)
G-2 (5)
G-2 (5)
G-1(5)
A
A
B
A
A
C
A
A
A
A
2a (81)
2b (17)
c
65
d
d
3
2a (32)
52
e
e
e
4
2a (58)
6
6 h, 155 °C, 0.23 M
50
e
5
G-3 (5)
CuCl (30)
G-2 (5)
G-2 (5)
G-2 (5)
G-2 (5)
2a (35)
a
b
Reactions on 100 mg scale in toluene. 12% of 3 was recovered.
e
6
2a (61)
c
d
Overall yield of a 4:1 mixture of 4 and 4A, respectively. 10% of
e
7
2c (72)
2d (54)
2e (52)
2f (37)
starting material was recovered. Reaction from 3b leading to a 1:1
8
mixture of 5 and epi-5.
9
10
was required to achieve a full conversion, providing 4 in 67%
yield (entry 2), but the reaction time was shortened to 30 min
by increasing the concentration in the reaction mixture to 1.5 M
(entry 3). Microwave activation (entry 4) also reduced the
reaction time, giving a similar result, although 4 was partially
monodechlorinated to morphan 4A,13 and no improvement was
obtained when using G-1 (entry 5). The procedure was also
applied to dichloroester 3b, which furnished morphan 5 in 52%
yield as a mixture of diastereomers at C-4 (entry 6).
a
In summary, to our knowledge, using this protocol to obtain
morphan compounds (3 → 4/5), we have described the first
intramolecular C−C bond between a trichloroacetamide and an
enol acetate promoted by Grubbs’ ruthenium carbenes,14 thus
expanding the scope of these catalysts beyond the metathesis
reaction.15
b
A: 100 mg scale in 0.2 mL of toluene at 155 °C for 30 min. B: 200
mg scale in 1.5 mL of toluene at 120 °C for 1 h, μW. C: 200 mg scale
in 2 mL of CH3CN at 80 °C, overnight. Yields refer to pure products
isolated by flash chromatography. 1a was also recovered (20%). The
de-tert-butyl derivative 1g (R1 = R2 = H) was also isolated (36%, entry
4, 21%, entry 5, 35%, entry 6).
c
d
e
With these results in hand, we investigated the potential
synthetic utility of the procedure to achieve the core structure of
the immunosuppressant FR901483.8,9 The major stumbling
blocks in the synthesis of this alkaloid16 are the generation of the
spirocenter at C(10a) and the assembly of the bridged
framework.17 The synthetic strategies adopted to construct
the bridged framework of FR901483 from a functionalized 1-
azaspiro[4.5]decanone, involving the formation of C(6)−C(7),
are outlined in Scheme 1, which for the sake of clarity omits the
substituents in the tricyclic framework. Almost all of the
strategies developed for the synthesis of the FR901483 skeleton
based on a ring closure of a 1-azaspiro[4.5]decane derivative
utilize aldol processes,16a−e,h,17g while the other procedures are
based on a palladium-promoted coupling of a vinyl halide and
ketone enolate17d,e,i,j or a Bu3SnH-promoted radical closure
from an alkyne tethered with a trimethylsilyl enol ether.17b
We observed some time ago that using reductive processes to
form the FR901483 skeleton,18 such as the radical cyclization of
trichloroacetamides upon silyl enol ether analogues of A (TMS
instead of Ac, Scheme 1), gave poor results,19 probably because
the starting trichloroacetamide was reluctant to undergo the
required conformational change. The energy barrier required to
axially locate the trichloroacetamide unit has been evaluated to
found that the substrate 1d, with an electron-withdrawing group
(F) at the arene ring, underwent spirocyclization in lower yield
than from the anisole 1c bearing an electron-neutral group
(Me). We also explored the spirocyclization using substrates
embodying two aromatic rings with different electronic
properties (Table 1, entries 9 and 10). In both cases the
cyclization took place on the anisole ring, and once again the
substrate with the higher electron density in the aromatic ring
(i.e., 1e) underwent the spirocyclization in better yield than
compound 1f bearing a fluorine atom in the aromatic ring. The
lower yield in the series with a N-benzyl substituent (1e, 1f)
compared with the series with a N-tert-butyl substituent (1a, 1c,
1d) may be attributed to the mixture of rotamers (1:1 ratio) in
the former.
To our knowledge, this 2-azaspiro[4.5]decadienone synthetic
entry is the first reported Grubbs’ catalyst-promoted dearoma-
tizing cyclization of benzene compounds.
These promising results encouraged us to explore the Ru-
catalyzed coupling of the amino-tethered trichloroacetamide
and enol acetate 3a to achieve morphan compounds.12 Thus, 3a
was treated with G-2 (5%) in 0.4 mL of toluene, and after 2 h of
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Note
substituent with the trichloroacetyl group in the conformer
required for the cyclization of 9b to 11. This steric effect was not
present in the transition state of the cyclization leading to 10
from 9a (Scheme 3).
Scheme 1. Synthesis of the FR901483 Core by Piperidine
Ring Closure
Scheme 3. Steric Grounds for the ATRC of 9
be approximately 3 kcal/mol in similar systems.20 Since the
process is slow, the reduction of the dichlorocarbamoylmethyl
radical strongly competed with the cyclization process.
In the light of these previous results, a nonreductive process
such as the ATRC studied here seemed a promising alternative
to achieve the radical cyclization toward the diazatricyclic core of
the natural product. The proradical trichloroacetamide required
was prepared from azaspirodecane 6,21 via carbamate 7,17d
following the transformations depicted in Scheme 2, with a final
The formation of enones 12 from 9 arises from a 1,5-H
hydrogen transfer from the same dichlorocarbamoyl radical
intermediate that gave 10 and 12a from 9a. The formation of
12a again made evident that, for conformational reasons, the
activation required for the radical cyclization allows competitive
reaction pathways. As illustrated in Figure 2, we have
Scheme 2. Grubbs II Catalyst-Mediated ATRC Leading to the
FR901483 Framework
Figure 2. Competing radical pathways: cyclization versus 1,5-hydrogen
atom transfer.
rationalized these observations in terms of conformers I and
II. While I can adopt the geometry necessary for 6-exo
cyclization to take place, II is unable to cyclize.17b However,
II does meet the stereoelectronic requirements for a 1,5-transfer
of the adjacent allylic hydrogen atom. The allylic radical thus
generated undergoes an atom transfer with the pendant
trichloroacetamide to form 12a. The same pathway led to 12b
from 9b.
The structure of 12a, with relative configuration (3S,5R), was
ascertained by chemical correlation with azaspiro 12c,23 which
has a N-Boc substituent and known configuration.24
Treatment of 10 and 11 with zinc afforded the corresponding
dechlorinated derivatives 13 and 14, the partially reduced
compound 15 also being isolated from 11. The stereochemistry
of the synthesized azatricyclic compounds was elucidated by 2D
NMR spectra (COSY, HSQC, NOESY). The relative
configuration (relationship between C-2 and C-10a) in both
series of FR901483 skeletons was fixed by NOESY experiments.
The NOESY correlation of the N-methyl group with the H-10eq
in compound 13 indicated that this group is on the same side of
the pyrrolidine ring as C-10, which occurs only when the relative
configuration is (2S,10aS). This assignment for 13 established
the relative configuration of its dichlorinated precursor 10. The
relative configuration (2R,10aS) for the epimeric series was
confirmed in compound 15 (Figure 3), based on the correlation
between H-2 and H-10eq observed in the NOESY NMR
spectrum.25 In turn, this assignment ensured the relative
stereochemistry of the synthetically interrelated 11 and 14.
The 1H and 13C NMR spectra of azatricyclic compounds show
two patterns, according to the relative configuration at C-2
versus C-10a. Hence, the isomers 10 and 13 with the chemical
treatment of ketone 8 with isopropenyl acetate to yield a
regioisomeric mixture of enol acetates 9 in a 1.8:1 ratio. When
the nonseparated mixture of 9 was treated with G-2 at 155 °C
for 2 h, the diazatricyclic derivative 10 and its epimer 11 were
obtained in a 4.4:1 ratio and 54% overall yield,22 in addition to
the unexpected epimeric mixture of enones 12 (Scheme 2).
The yield for the cyclization step was 67% in the case of 9a,
but only 30% for 9b. It is plausible that this different behavior
could be due to the steric crowding of the N-methyl carbamate
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Note
(d, J = 13.2 Hz, 1H), 1.81 (d, 2H), 1.90 (d, J = 11.2 Hz, 2H), 3.78 (s,
3H), 4.44 (t, J = 11.4 Hz, 1H), 4.53 (s, 2H), 6.84 (d, J = 8.4 Hz, 2H),
7.15 (d, J = 8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 25.1 (CH2),
25.6 (CH2), 31.0 (CH2), 47.3 (CH2), 55.2 (CH3), 59.3 (CH), 93.9
(C), 113.8 (CH), 127.8 (C), 129.7 (CH), 158.5 (CH), 160.6 (CO).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H21Cl3NO2 364.0632;
found 364.0642.
N-tert-Butyl-2,2,2-trichloro-N-(4-methoxy-3-methylbenzyl)-
acetamide (1c). Operating as above, from 4-methoxy-3-methylben-
zaldehyde (2 g, 13.3 mmol) and tert-butylamine (1.85 mL, 17.3 mmol),
1c was obtained (1.90 g, 40% over three steps) after chromatography
(hexane/CH2Cl2 3:1 to CH2Cl2) as an amorphous solid: mp 113−114
1
°C; IR (KBr) 3014, 2955, 2926, 2837, 1678, 1611 cm−1; H NMR
(CDCl3, 400 MHz) δ 1.42 (s, 9H), 2.21 (s, 3H), 3.82 (s, 3H), 4.95 (br
s, 2H), 6.78 (d, J = 8.4 Hz, 1H), 7.01 (br s, 1H), 7.06 (dd, J = 8.4, 2 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ 16.3 (CH3), 28.0 (CH3), 50.5
(CH2), 55.3 (CH3), 61.7 (C), 95.4 (C), 109.6 (CH), 124.9 (CH),
126.6 (C), 128.7 (CH), 129.8 (C), 156.8 (C), 160.7 (CO). HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C15H20Cl3NNaO2 374.0452;
found 374.0457.
Figure 3. Representative NMR data of azatricyclic compounds 13−15.
N-tert-Butyl-2,2,2-trichloro-N-(3-fluoro-4-methoxybenzyl)-
acetamide (1d). Operating as above, from 3-fluoro-4-methoxyben-
zaldehyde (0.5 g, 3.24 mmol) and tert-butylamine (0.45 mL, 4.21
mmol), 1c was obtained (0.72 g, 63%) after chromatography (hexane/
CH2Cl2 3:1 to CH2Cl2) as an amorphous solid: mp 131−132 °C; IR
shift δ 4.55 for H-2 and δ ∼53.5 for C-2 correspond to the
FR901483 relative configuration, while the epimeric isomers 11,
14, and 15 showed a chemical shift δ ∼5.15 for H-2 and δ ∼51.5
for C-2. These downfield and upfield effects, compared with the
data in the FR901483 stereochemistry series, are a consequence
of the compression26 of the C10−C10a bond with the H-2 in
compounds with the relative configuration (2R,10aS) for the key
stereogenic atoms in the azatricyclic ring.
In summary, we have reported here the first intramolecular
ATRC between a trichloroacetamide and an enol acetate using
Grubbs’ second generation catalyst, which was applied to
synthesize the morphan ring. The reaction then enabled us to
build the tricyclic skeleton of the immunosuppressant
FR901483. Moreover, the process was also used with
electron-rich arenes for the preparation of 2-azaspirodecadienes.
We have therefore described the first ATRC using Grubbs II
catalyst on substituted electron-rich double bonds as radical
acceptors.
1
(KBr) 3007, 2975, 2938, 2845, 1663, 1628 cm−1; H NMR (CDCl3,
400 MHz) δ 1.42 (s, 9H), 3.89 (s, 3H), 4.96 (br s, 2H), 6.91−7.04 (m,
3H); 13C NMR (CDCl3, 100 MHz) δ 28.1 (CH3), 50.1 (CH2), 56.3
(CH3), 61.9 (C), 95.2 (C), 113.3 (d, J = 2.3 Hz, CH), 114.4 (d, J = 19.3
Hz, CH), 122.11 (d, J = 3.9 Hz, CH), 131.5 (d, J = 5.4 Hz, C), 146.7 (d,
J = 10.1 Hz, C), 152.3 (d, J = 245.4 Hz, CF), 160.7 (CO). HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C14H17Cl3FNNaO2 378.0201; found
378.0205.
N-Benzyl-2,2,2-trichloro-N-(4-methoxy-3-methylbenzyl)-
acetamide (1e). Operating as above, from 4-methoxy-3-methylben-
zaldehyde (2 g, 13.3 mmol) and benzylamine (1.9 mL, 17.3 mmol), 1e
was obtained (4.6 g, 89% over three steps) after chromatography
(hexane/CH2Cl2 1:1 to CH2Cl2) as a yellow oil: IR (film) 3063, 3029,
1
3003, 2948, 2835, 1680, 1610 cm−1; H NMR (CDCl3, 400 MHz): 2
rotamers δ 2.18 and 2.21 (2s, 3H), 3.80 and 3.82 (2s, 3H), 4.49 and
4.55 (2s, 2H), 4.81 and 4.88 (2s, 2H), 6.70−7.42 (m, 8H); 13C NMR
(CDCl3, 100 MHz) δ 16.2 (CH3), 49.6 and 49.8 (CH2), 51.6 (CH2),
55.2 (CH3), 93.3 (C), 109.9 (CH), 125.8 (CH), 126.2 (C), 126.8
(CH), 126.9 (C),127.1 (CH), 127.6 (CH), 127.8 (CH), 127.9 (CH),
128.7 (CH), 128.8 (CH), 129.5 (CH), 130.6 (CH), 135.1 and 135.7
(C), 157.4 (C), 161.1 (CO). HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C18H19Cl3NO2 386.0476; found 386.0475.
EXPERIMENTAL SECTION
■
General. All product mixtures were analyzed by thin layer
chromatography using TLC silica gel plates with a fluorescent indicator
(λ = 254 nm). The spots were located by UV light or a 1% KMnO4
aqueous solution. Unless otherwise noted, chromatography refers to
flash chromatography and was carried out on SiO2 (silica gel 60, 200−
500 mesh). Drying of the organic extracts during the reaction workup
was performed over anhydrous Na2SO4. A CEM Discover microwave
reactor with an external sensor was used. Infrared spectra were
N-Benzyl-2,2,2-trichloro-N-(3-fluoro-4-methoxybenzyl)ace-
tamide (1f). Operating as above, from 3-fluoro-4-methoxybenzalde-
hyde (0.5 g, 3.24 mmol) and benzylamine (0.46 mL, 4.21 mmol), 1f
(1.18 g, 93%) was obtained after chromatography (hexane/CH2Cl2 1:1
to CH2Cl2) as a yellow oil: IR (film) 3065, 3031, 2935, 2839, 1678,
recorded on a FT-IR spectrometer. Chemical shifts of H and 13C
1
NMR spectra are reported in ppm downfield (δ) from Me4Si. All NMR
data assignments are supported by gCOSY and gHSQC experiments.
N-(tert-Butyl)-2,2,2-trichloro-N-(4-methoxybenzyl)aceta-
mide (1a). From 4-methoxybenzaldehyde (2 g, 14.7 mmol) and tert-
butylamine (1.75 g, 23.9 mmol), following the three-step procedure
previously described,11d 1a was obtained as a white solid (4.43 g, 85%):
mp 68−70 °C; IR (film) 2998, 2968, 2934, 2835, 1714, 1683, 1613
cm−1; 1H NMR (CDCl3, 400 MHz) δ 1.41 (s, 9H, CH3), 3.81 (s, 3H,
OCH3), 4.98 (br s, 2H, CH2Ar), 6.88 (d, J = 8.4 Hz, 2H, ArH), 7.19 (d,
J = 8.8 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz) δ 28.1 (CH3), 50.5
(CH2Ar), 55.3 (OCH3), 61.8 (C), 95.5 (CCl3), 113.8 (m-C), 127.7
(ipso-C), 130.4 (o-C), 158.7 (p-C), 160.8 (CO). HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C14H19Cl3NO2 338.0476; found 338.0484.
2,2,2-Trichloro-N-cyclohexyl-N-(4-methoxybenzyl)aceta-
mide (1b). Operating as above, 1b was obtained from 4-
methoxybenzaldehyde (4 g, 29.4 mmol) and cyclohexylamine (3.5 g,
35.29 mmol) as a white solid (9.73 g, 91% over three steps): mp 109−
1
1624 cm−1; H NMR (CDCl3, 400 MHz): 2 rotamers δ 3.87 (s, 3H),
4.47 and 4.55 (2s, 2H), 4.81 and 4.90 (2s, 2H), 6.92 (m, 3H), 7.12−
7.42 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 49.3 and 49.9 (CH2),
51.0 and 52.0 (CH2), 56.1 (CH3), 93.0 (C), 113.4 (CH), 115.0 (d, J =
18.6 Hz, CH), 116.0 (d, J = 18.6 Hz, CH), 123.2 (CH), 124.2 (CH),
127.3 (CH), 128.1 (CH), 128.9 (CH), 134.7 (C), 135.3 (C), 147.2 (d,
J = 10.1 Hz, C), 152.2 (d, J = 245.4 Hz, CF), 161.1 (CO). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C17H16Cl3FNO2 390.0225; found
390.0226.
2-tert-Butyl-4,4-Dichloro-2-azaspiro[4.5]deca-6,9-diene-3,8-
dione (2a). Method A: A mixture of Grubbs II catalyst (12.5 mg, 0.015
mmol, 5%) and 1a (100 mg, 0.3 mmol) in toluene (0.2 mL) was heated
at 155 °C for 30 min in a sealed tube. The dark solution was allowed to
reach rt and purified by chromatography (hexane/CH2Cl2 1:1 to
CH2Cl2) to yield 2a11d (70 mg, 81%). Method B: In a 10 mL vessel were
placed Grubbs II catalyst (25 mg, 0.03 mmol, 5%) and 1a (200 mg, 0.59
mmol) in toluene (1.5 mL), and the mixture was heated to 120 °C
while stirring using microwave irradiation for 1 h. After concentration,
1
110 °C; IR (film) 3004, 2935, 2855, 1673, 1613 cm−1; H NMR
(CDCl3, 400 MHz) δ 1.08 (m, 1H), 1.32 (m, 2H), 1.51 (m, 2H), 1.66
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the reaction mixture was purified by chromatography (hexane/CH2Cl2
4:6 to CH2Cl2) to yield 1a (40 mg, 20%) and then 2a (54 mg, 32%).
Method C: To a suspension of CuCl (17.5 mg, 0.18 mmol, 30%) in
acetonitrile (2 mL) was added 1a (200 mg, 0.59 mmol), and the
mixture was heated at 80 °C overnight in a sealed tube. The solution
was then allowed to reach rt, concentrated, and purified by
chromatography (hexane/CH2Cl2 1:1 to CH2Cl2) to yield 2a11d (104
mg, 61%) and secondary amide 1g27 as a solid (58 mg, 35%). For 1g
(see Table 1): IR (film) 3316, 3044, 3002, 2955, 2838, 1693, 1659,
1615, 1583 cm−1; 1H NMR (CDCl3, 400 MHz) δ 3.81 (s, 3H), 4.48 (s,
2H), 6.90 (dm, J = 8.6 Hz, 2H), 7.24 (dm, J = 8.6 Hz, 2H); 13C NMR
(CDCl3, 100 MHz) δ 44.9 (CH2), 55.3 (CH3), 92.6 (CCl3), 114.3,
129.2, 128.3, 159.5, 161.7 (NCO). HRMS (ESI-TOF) m/z: [M + H]+
calcd for C10H11Cl3NO2 281.9850; found 281.9835.
2-Benzyl-4,4-dichloro-7-fluoro-2-azaspiro[4.5]deca-6,9-
diene-3,8-dione (2f). A mixture of Grubbs II catalyst (11 mg, 0.013
mmol, 5%) and 1f (100 mg, 0.26 mmol) in toluene (0.2 mL) was
heated at 155 °C for 1.5 h in a sealed tube. Chromatography (3:1
hexane/CH2Cl2 to CH2Cl2) afforded 2f (32 mg, 37%) as a yellow oil:
IR (film) 2954, 2923, 2853, 1731, 1689, 1666 cm−1; 1H NMR (CDCl3,
400 MHz) δ 3.32 (d, J = 10 Hz, 1H, H-1), 3.43 (d, J = 10 Hz, 1H, H-1),
4.60 (s, 2H, CH2), 6.44 (dd, J = 10, 6.8 Hz, 1H, H-9), 6.51 (dd, J = 12.4,
3.2 Hz, 1H, H-6), 6.84 (dd, J = 10, 3.2 Hz, 1H, H-10), 7.27 (m, 2H),
7.37 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 48.1 (CH2), 50.9 (d, J =
2.3 Hz, C-1), 53.9 (d, J = 7.2 Hz, C-5), 86.6 (C-4), 119.6 (d, J = 17.8
Hz, CH), 128.4 (CH), 128.7 (CH), 129.3 (CH), 131.2 (d, J = 4.6 Hz,
CH), 133.8 (C), 144.0 (d, J = 2.4 Hz, CH), 155.8 (d, J = 268.7 Hz, CF),
164.6 (C-3), 176.7 (d, J = 22.4 Hz, C-8). HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C16H13Cl2FNO2 340.0302; found 340.0311. [M + Na]+
calcd for C16H12Cl2FNNaO2 362.0121; found 362.00128.
2-Benzyl-4,4-dichloro-2-azabicyclo[3.3.1]nonane-3,6-dione
(4). Method A: A mixture of Grubbs II catalyst (11 mg, 0.013 mmol,
5%) and enol acetate 3a13 (100 mg, 0.26 mmol) in toluene (0.4 mL)
was heated at 155 °C for 4 h in a sealed tube. The dark solution was
allowed to reach rt and purified by chromatography (hexane/EtOAc
8:2 to 7:3) to yield morphan 4 (54 mg, 67%). NMR spectra matched
those previously reported.13 Method B: In a 10 mL vessel were placed
Grubbs II catalyst (11 mg, 0.013 mmol, 5%) and 3a (100 mg, 0.26
mmol) in toluene (1 mL), and the mixture was heated to 155 °C while
stirring using microwave irradiation for 15 min. After concentration the
reaction mixture was purified by chromatography (hexane/EtOAc 8:1
to 1:1) to yield successively 413 (38 mg, 47%) and 4A13 (13 mg, 18%).
Ethyl (1RS,4SR,5RS)- and (1RS,4RS,5RS)-2-Benzyl-4-chloro-
3,6-dioxo-2-azabicyclo[3.3.1]nonane-4-carboxylate (5a and
epi-5). According to the above Method A, the reaction of 4b (100
mg, 0.23 mmol), toluene (0.2 mL), and Grubbs II catalyst (10 mg, 5%
catalyst loading) for 6 h at 155 °C afforded a 1:1 epimeric mixture of 5
and epi-5 (41 mg, 50%). Spectroscopic properties matched those
previously described.28
4,4-Dichloro-2-cyclohexyl-2-azaspiro[4.5]deca-6,9-diene-
3,8-dione (2b). See Table 1. Yellow oil; IR (film) 2923, 2854, 1727,
1
1670 cm−1; H NMR (CDCl3, 400 MHz) δ 1.10 (m, 1H), 1.38 (m,
4H), 1.72 (br d, J = 13.6 Hz, 1H), 1.84 (m, 4H), 3.44 (s, 2H,), 4.03 (tt, J
= 12, 3.6 Hz, 1H), 6.50 (dm, J = 10.4 Hz, 2H), 6.96 (dm, J = 10.4 Hz,
2H); 13C NMR (CDCl3, 100 MHz) δ 25.1 (two signals, CH2), 29.7
(CH2), 48.1 (C-1), 52.0 (C-5), 52.5 (CH), 87.4 (C-4), 132.3 (C-7 and
C-9), 143.5 (C-6 and C-10), 164.3 (C-3), 184.0 (C-8). HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C15H18Cl2NO2 314.0709; found
314.0708.
2-tert-Butyl-4,4-dichloro-7-methyl-2-azaspiro[4.5]deca-6,9-
diene-3,8-dione (2c). A mixture of Grubbs II catalyst (12 mg, 0.014
mmol, 5%) and 1c (100 mg, 0.28 mmol) in toluene (0.2 mL) was
heated at 155 °C for 4 h in a sealed tube. Chromatography (hexane to
hexane/CH2Cl2 1:9) afforded 2c (62 mg, 72%) as a yellow oil: IR
1
(film) 2953, 2923, 2854, 1724, 1668, 1644 cm−1; H NMR (CDCl3,
400 MHz) δ 1.47 (s, 9H, CH3), 1.99 (d, J = 1.6 Hz, 3H, CH3), 3.48 (d, J
= 10.4 Hz, 1H, H-1), 3.51 (d, J = 10.4 Hz, 1H, H-1), 6.48 (d, J = 10 Hz,
1H, H-9), 6.75 (m, 1H, H-6), 6.92 (dd, J = 10, 3.2 Hz, 1H, H-10); 13C
NMR (CDCl3, 100 MHz) δ 16.2 (CH3), 27.1 (CH3), 50.1 (C-1), 51.3
(C-5), 55.9 (C), 88.4 (C-4), 131.9 (CH), 138.6 (CH), 139.5 (C-7),
143.5 (CH), 164.7 (C-3), 184.8 (C-8). HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C14H18Cl2NO2 302.0709; found 302.0721. [M + Na]+
calcd for C14H17Cl2NNaO2 324.0529; found 324.0531.
1-Benzyl-3-(N-methyl-N-methoxycarbonyl)amino-1-aza-
spiro[4.5]decan-8-one Ethylene Acetal (7). A solution of iodo
derivative 621 (4.51 g, 10.9 mmol) in an aqueous solution of
methylamine at 40% (50 mL) was heated in a sealed tube at 100 °C
overnight. The mixture was extracted with CH2Cl2, and the organic
extracts were dried and concentrated to yield the corresponding amine,
which was used in the next step without further purification (3.4 g): 1H
NMR (300 MHz, CDCl3) δ 1.45 (m, 1H), 1.54 (dd, J = 12.9, 5.7 Hz,
1H), 1.55 (m, 1H), 1.61−1.82 (m, 5H), 1.91 (td, J = 13.2, 4.2 Hz, 1H),
2.17−2.25 (dd, J = 12.9, 8.4 Hz, 1H), 2.31 (s, 3H), 2.55 (dd, J = 9.5, 4.5
Hz, 1H), 2.80 (dd, J = 9.5, 6.6 Hz, 1H), 3.11 (m, 1H), 3.54 and 3.69
(2d, J = 13.2 Hz, 1H each), 3.94 (s, 4H), 7.30 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 28.8 (CH2), 30.9 (CH2), 32.4 (CH2), 32.5 (CH2), 34.6
(CH3), 41.7 (CH2), 51.8 (CH2), 56.4 (CH2), 56.7 (CH), 61.9 (C),
64.1 (CH2), 108.4 (C), 126.3 (CH), 127.9 (CH), 128.0 (CH), 140.6
(C). To a solution of the above amine (3.4 g, 10.7 mmol) in CH3CN
(180 mL) were added K2CO3 (3.02 g, 21.8 mmol) and methyl
chloroformate (1.7 mL, 21.8 mmol), and the mixture was stirred at rt
for 4 h. After concentration the residue was treated with a saturated
aqueous sodium bicarbonate solution (100 mL) and extracted with
CH2Cl2. The combined organic phases were dried, concentrated, and
purified by chromatography (CH2Cl2 to 98:2 CH2Cl2/MeOH) to yield
2-tert-Butyl-4,4-dichloro-7-fluoro-2-azaspiro[4.5]deca-6,9-
diene-3,8-dione (2d). A mixture of Grubbs II catalyst (12 mg, 0.014
mmol, 5%) and 1d (100 mg, 0.28 mmol) in toluene (0.2 mL) was
heated at 155 °C for 4 h in a sealed tube. After chromatography
(hexane/CH2Cl2 3:1 to CH2Cl2), 2d (46 mg, 54%) was obtained as a
1
yellow oil: IR (film) 2954, 2924, 2854, 1724, 1691, 1666 cm−1; H
NMR (CDCl3, 400 MHz) δ 1.47 (s, 9H, CH3), 3.54 (dd, J = 10.4, 1.2
Hz, 1H, H-1), 3.61 (d, J = 10.4 Hz, 1H, H-1), 6.52 (dd, J = 10.4, 6.8 Hz,
1H, H-9), 6.59 (dd, J = 12.4, 3.2 Hz, 1H, H-6), 6.96 (dd, J = 10, 3.2 Hz,
1H, H-10); 13C NMR (CDCl3, 100 MHz) δ 27.1 (CH3), 50.0 (d, J =
3.1 Hz, C-1), 53.3 (d, J = 7 Hz, C-5), 56.1 (C), 87.6 (C-4), 119.9 (d, J =
17.8 Hz, CH), 131.3 (d, J = 4.6 Hz, CH), 144.5 (d, J = 2.3 Hz, CH),
155.9 (d, J = 267.8 Hz, CF), 164.2 (C-3), 176.8 (d, J = 21.7 Hz, C-8).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H15Cl2FNO2
306.0458; found 306.0469. [M + Na]+ calcd for C13H14Cl2FNNaO2
328.0278; found 328.0278.
2-Benzyl-4,4-dichloro-7-methyl-2-azaspiro[4.5]deca-6,9-
diene-3,8-dione (2e). A mixture of Grubbs II catalyst (22 mg, 0.026
mmol, 5%) and 1e (200 mg, 0.51 mmol) in toluene (0.4 mL) was
heated at 155 °C for 4 h in a sealed tube. After chromatography (3:1
hexane/CH2Cl2 to CH2Cl2), 2e (90 mg, 52%) was isolated as a yellow
1
carbamate 7 (3.3 g, 81% over two steps) as a colorless oil: H NMR
(300 MHz, CDCl3, COSY) δ 1.51−1.56 (m, 3H, H-4, H-7 and H-10),
1.65−1.73 (m, 3H, H-6, H-7 and H-10), 1.78−1.82 (m, 2H, H-6 and
H-9eq), 2.06 (td, J = 12.2, 3.8 Hz, 1H, H-9ax), 2.35−2.48 (m, 1H, H-
4), 2.68 (m, 2H, H-2), 2.77 (s, 3H, NCH3), 3.24 (d, J = 13.2, 4.5 Hz,
1H, CH2Ar), 3.64 (s, 3H, OCH3), 3.92 (d, J = 13.2 Hz, 1H, CH2Ar),
3.95 (s, 4H, CH2O), 4.79 (m, 1H, H-3), 7.27 (m, 5H, ArH); 13C NMR
(75 MHz, CDCl3, HSQC) δ 25.0 (br, C-10), 28.4 (br, NCH3), 30.9 (C-
6), 32.3 (C-7), 32.9 (C-9), 38.2 (C-4), 51.9 (C-3), 52.0 (CH2Ar), 52.4
(OCH3), 53.6 (C-2), 62.5 (C-5), 64.1 and 64.2 (OCH2), 108.4 (C-8),
126.5 (p-Ar), 128.0 (o-, m-Ar), 140.4 (ipso-Ar), 156.8 (CO2Me).
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H31N2O4 375.2278;
found 375.2275.
1
oil: IR (film) 3031, 2918, 2849, 1730, 1671, 1645 cm−1; H NMR
(CDCl3, 400 MHz) δ 1.92 (d, J = 1.6 Hz, 3H, CH3), 3.28 (d, J = 10.4
Hz, 1H, H-1), 3.32 (d, J = 10.4 Hz, 1H, H-1), 4.57 (d, J = 14.8 Hz, 1H),
4.61 (d, J = 14.8 Hz, 1H), 6.41 (d, J = 9.6 Hz, 1H, H-9), 6.66 (m, 1H,
H-6), 6.83 (dd, J = 9.6, 3.2 Hz, 1H, H-10), 7.27 (m, 2H), 7.37 (m, 3H);
13C NMR (CDCl3, 100 MHz) δ 16.1 (CH3), 48.0 (CH2), 51.1 (C-1),
51.9 (C-5), 87.3 (C-4), 128.3 (CH), 128.5 (CH), 129.1 (CH), 131.8
(CH), 134.0 (C), 138.3 (CH), 139.3 (C-7), 143.0 (CH), 165.1 (C-3),
184.6 (C-8). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C17H16Cl2NO2 336.0553; found 336.0553.
9369
dx.doi.org/10.1021/jo501110c | J. Org. Chem. 2014, 79, 9365−9372

The Journal of Organic Chemistry
Note
1-Tricloroacetyl-3-(N-methyl-N-methoxycarbonyl)amino-1-
azaspiro[4.5]decan-8-one (8). To a solution of carbamate 7 (1.04 g,
2.78 mmol) in MeOH (70 mL) was added 10% Pd(OH)2/C (0.23 g),
and the mixture was stirred at 60 °C under 400 psi hydrogen
atmosphere overnight. The mixture was filtered on a Celite pad,
concentrated, and purified by chromatography (Al2O3, CH2Cl2 to
CH2Cl2/MeOH 95:5) to yield the corresponding secondary amine
(0.64 g, 81%): 1H NMR (300 MHz, CDCl3) δ 1.65 (m, 2H), 1.81−2.38
(m, 8H), 2.95 (s, 3H), 3.38 (dd, J = 12.3, 7.8 Hz, 1H), 3.62 (dd, J =
12.3, 9.5 Hz, 1H), 3.72 (s, 3H), 3.94 (s, 4H), 4.99 (m, 1H); 13C NMR
(75 MHz, CDCl3) δ 30.6 (CH3), 30.9 (CH2), 31.6 (CH2), 32.7 (2
CH2), 36.6 (CH2), 43.9 (CH2), 52.9 (CH3), 53.4 (CH), 64.2 (CH2),
64.3 (CH2), 65.8 (C), 106.7 (C), 156.5 (CO2Me). To a solution of the
above amine (1.58 g, 5.56 mmol) in THF (80 mL) was added a 10%
HCl aqueous solution (160 mL), and the mixture was stirred at rt
overnight. The solution was basified with K2CO3 and extracted with
CH2Cl2. The organic extracts were dried and concentrated, and the
residue was purified by chromatography (Al2O3, hexane/CH2Cl2 3:2 to
CH2Cl2/MeOH 99:1) to yield the corresponding deprotected ketone
(0.92 g, 73%), which was used directly in the next step: 1H RMN (300
MHz, CDCl3) δ 1.66−1.74 (m, 2H), 1.82−1.94 (m, 3H), 1.98 (dd, J =
7.5, 6.3 Hz, 1H), 2.07 (dd, J = 12.9, 9.0 Hz, 1H), 2.25−2.35 (m, 2H),
2.50−2.68 (m, 2H), 2.87 (s, 3H), 2.98 (dd, J = 12.0, 6.9 Hz, 1H), 3.20
(dd, J = 12.0, 7.9 Hz, 1H), 3.70 (s, 3H), 4.69 (dt, J = 15.6, 8.4 Hz, 1H);
13C RMN (75 MHz, CDCl3) δ 28.9 (CH2), 29.7 (CH2) 30.0 (CH3),
different signals are mentioned. HRMS (ESI-TOF) m/z: [M + H]+
calcd for C16H22Cl3N2O5 427.0589; found 427.0581.
(2RS,7RS,10aRS)- and (2RS,7SR,10aSR)-6,6-Dichloro-2-[N-
(methoxycarbonyl)-N-methylamino]hexahydro-1H-7,10a-
methanopyrrolo[1,2-a]azocin-5,8-dione (10 and 11). A mixture
of 9 (100 mg, 0.23 mmol) and Grubbs II catalyst (10 mg, 0.012 mmol)
in toluene (0.15 mL) was heated in a sealed tube at 155 °C for 2 h. The
mixture was concentrated and purified by chromatography (CH2Cl2 to
CH2Cl2/EtOAc 1:1) to afford the following three products: 10 (32 mg,
39%) as a brown oil, a 2:1 ratio of 10 and 11 (12 mg, 15%), and a 1.6:1
epimeric mixture of azaspiro derivatives 12 (21 mg, 26%). A more
enriched sample of 11 was obtained with an additional chromatography
using the same conditions.
10: IR (film) 2954, 1723, 1678 cm−1; 1H NMR (CDCl3, 400 MHz)
δ 1.96 (m, 1H, H-10ax), 2.12 (m, 1H, H-1), 2.30 (d, J = 14.4 Hz, 1H,
H-11 pro-S), 2.33 (dd, J = 14, 10.4 Hz, 1H, H-1), 2.51 (m, 3H, H-9 and
H-10eq), 2.63 (dt, J = 14, 3.2 Hz, 1H, H-11pro-R), 2.93 (s, 3H, NCH3),
3.50 (brt, J = 11.6 Hz, 1H, H-3), 3.55 (m, 1H, H-7), 3.72 (s, 3H,
OCH3), 4.33 (dd, J = 12, 8 Hz, 1H, H-3), 4.53 (br s, 1H, H-2); 13C
NMR (CDCl3, 100 MHz) δ 32.3 (NCH3), 35.9 (C-9), 36.9 (C-11),
37.9 (C-10), 39.7 (C-1), 45.2 (C-3), 52.9 (OCH3), 53.9 (C-2), 60.8
(C-10a), 63.0 (C-7), 80.5 (C-6), 156.3 (CO2), 161.4 (C-5), 203.4 (C-
8). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H19Cl2N2O4
349.0716; found 349.0722.
11: IR (film) 2954, 2926, 1718, 1697, 1676 cm−1; 1H NMR (CDCl3,
400 MHz) δ 1.83 (ddd, J = 14, 12, 6 Hz, 1H, H-10ax), 2.06 (dd, J =
12.4, 10.4 Hz, 1H, H-1), 2.17 (dd, J = 12.4, 7.6 Hz, 1H, H-1), 2.22 (m,
1H, H-10eq), 2.38 (dd, J = 14.4, 3.6 Hz, 1H, H-11 pro-S), 2.49 (m, 2H,
H-9), 2.61 (dt, J = 14.4, 3.6 Hz, 1H, H-11 pro-R), 2.84 (s, 3H, NCH3),
3.59 (m, 1H, H-7), 3.73 (s, 3H, OCH3), 3.75 (m, 2H, H-3), 5.17 (br s,
1H, H-2); 13C NMR (CDCl3, 100 MHz) δ 29.0 (NCH3), 35.4 (C-9),
35.7 (C-10), 36.6 (C-11), 40.7 (C-1), 46.7 (C-3), 51.7 (C-2), 53.1
(OCH3), 61.5 (C-10a), 63.1 (C-7), 80.5 (C-6), 156.7 (CO2), 161.7 (C-
5), 203.1 (C-8). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H19Cl2N2O4 349.0716; found 349.0723.
37.4 (CH2), 38.0 (CH2), 39.1 (CH2), 47.4 (CH2), 52.3 (CH3 and CH),
59.8 (C), 156.4 (NCO), 210.6 (CO). To a solution of the above ketone
(0.55 g, 2.3 mmol) in CH2Cl2 (5 mL) were added successively Et3N
(0.63 mL, 0.45 mmol) and trichloroacetyl chloride (0.39 mL, 3.4
mmol) at 0 °C, and the mixture was stirred at rt overnight. The mixture
was quenched with water, extracted with CH2Cl2, dried, and
concentrated. After chromatography (CH2Cl2 to CH2Cl2/EtOAc 9:1)
8 was isolated (0.85 g, 96%) as a colorless viscous oil: IR (film) 2954,
1
2880, 1708, 1681 cm−1; H NMR (400 MHz) δ 1.80 (m, 2H, H-6eq
and H-10eq), 2.04 (t, J = 12.4 Hz, 1H, H-4), 2.30−2.42 (m, 2H, H-7ax
and H-9ax), 2.48 (dd, J = 12.4, 6.4 Hz, 1H, H-4), 2.54 (dm, J = 16.2 Hz,
1H, H-9eq), 2.68 (dtd, J = 16.2, 5.2, 1.6 Hz, 1H, H-7eq), 2.91 (s, 3H,
NCH3), 3.00 (td, J = 13.2, 6 Hz, 1H, H-10ax), 3.19 (td, J = 12.4, 5.2 Hz,
1H, H-6ax), 3.69 (t, J = 10.8 Hz, 1H, H-2), 3.75 (s, 3H, CH3O), 4.39
(dd, J = 10.8, 7.2 Hz, 1H, H-2), 4.79 (br s, 1H, H-3); 13C NMR (100
MHz) δ 29.0 (C-10), 29.4 (NCH3), 32.9 (C-6), 37.7 (C-9), 38.1 (C-4
and C-7), 50.5 (C-2), 52.2 (C-3), 53.1 (OCH3), 67.1 (C-5), 94.2
(CCl3), 156.8 (CO2Me), 158.6 (NCO), 209.5 (C-8). Anal. Calcd For
C14H19Cl3N2O4: C, 43.60; H, 4.97; N, 7.26. Found: C, 43.53; H, 5.00;
N, 7.09. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H20Cl3N2O4
385.0483; found 385.0477.
1-Dicloroacetyl-3-[(N-methoxycarbonyl)-N-methyl]amino-1-
azaspiro[4.5]dec-6-en-8-one (12a and 12b). Two isomers were
observed in the NMR spectra in a 1.6:1 ratio. IR (film) 2955, 1680
cm−1. For NMR data of the major epimer 12a, see below (12c → 12a).
1
Minor epimer 12b: H NMR (400 MHz) δ 1.82 (ddd, J = 14.4, 12.4,
6.4 Hz, 1H, H-10ax), 2.00 (m, 1H, H-4), 2.21 (m, 1H, H-10eq), 2.32
(m, 1H, H-4), 2.49 (m, 2H, H-9), 2.90 (s, 3H, NCH3), 3.65 (m, 1H, H-
2), 3.74 (s, 3H, OCH3), 4.03 (dd, J = 10, 8.4 Hz, 1H, H-2), 4.95 (m,
1H, H-3), 5.97 (d, J = 10 Hz, 1H, H-7), 6.06 (s, 1H, CHCl2), 6.77 (dd, J
= 10, 2 Hz, 1H, H-6); 13C NMR (100 MHz) δ 30.0 (NCH3), 34.6 (C-
4), 34.9 (C-9), 35.7 (C-10), 47.3 (C-2), 53.1 (C-3), 53.1 (OCH3), 64.0
(C-5), 66.0 (CHCl2), 127.6 (C-7), 153.5 (C-6), 156.7 (CO2), 161.7
(NCO), 196.8 (C-8). HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H19Cl2N2O4 349.0716; found 349.0717.
Chemical Correlation of 12a from 12c. To a solution of enone
12c23 (30 mg, 0.09 mmol) in CH2Cl2 (1 mL) was added TFA (0.068
mL, 0.9 mmol), and the mixture was stirred at rt for 2 h. The reaction
was concentrated, to the resulting residue dissolved in CH2Cl2 (1 mL)
were added Et3N (0.06 mL, 0.45 mmol) and dichloroacetyl chloride
(0.026 mL, 0.27 mmol), and the mixture was stirred at rt for 2 h. Water
was added, and the mixture was extracted with CH2Cl2. The organics
were dried, concentrated, and purified by chromatography (from
CH2Cl2 to 3:1 CH2Cl2/EtOAc) to yield 12a (22 mg, 71%): 1H NMR
(400 MHz) δ 1.92 (dm, J = 12.8 Hz, 1H, H-10eq), 2.35 (dd, J = 12.4,
7.2 Hz, 1H, H-4), 2.43 (t, J = 12.4 Hz, 1H, H-4), 2.50 (ddd, J = 17.6, 14,
4.8 Hz, 1H, H-9ax), 2.66 (dm, J = 17.6, 1H, H-9eq), 2.91 (s, 3H,
NCH3), 3.23 (ddd, J = 14, 12.8, 4.8 Hz, 1H, H-10ax), 3.66 (t, J = 10.4
Hz, 1H, H-2), 3.75 (s, 3H, OCH3), 4.18 (dd, J = 10.4, 7.2 Hz, 1H, H-2),
4.73 (tt, J = 10.8, 7.2 Hz, 1H, H-3), 5.96 (d, J = 10 Hz, 1H, H-7), 6.09
(s, 1H, CHCl2), 6.90 (dd, J = 10, 2 Hz, 1H, H-6); 13C NMR (100
MHz) δ 30.0 (NCH3), 32.9 (C-10), 35.0 (C-9), 39.8 (C-4), 48.0 (C-2),
53.1 (C-3 and OCH3), 64.1 (C-5), 66.4 (CHCl2), 127.8 (C-7), 154.1
(C-6), 156.7 (CO2), 161.8 (NCO), 196.8 (C-8)
8-Acetyloxy-1-tricloroacetyl-3-(N-methyl-N-methoxycarb-
onyl)amino-1-azaspiro[4.5]dec-7-ene (9). A mixture of 8 (0.64 g,
1.66 mmol) and p-toluenesulfonic acid monohydrate (0.32 g, 1.66
mmol) in isopropenyl acetate (5 mL) was heated to reflux for 4 h. The
mixture was allowed to reach rt, treated with sodium hydrogen
carbonate, filtered, concentrated, and purified by chromatography
(CH2Cl2 to CH2Cl2/EtOAc 9:1) to yield 9, a colorless viscous oil, as a
1.8:1mixture of epimers (0.76 g, 93%): IR (film) 2953, 2850, 1749,
1
1680 cm−1; H NMR (400 MHz) major epimer δ 1.55 (dm, J = 12.8
Hz, 1H, H-10eq), 1.87 (m, 1H, H-4), 1.98 (dm, J = 16.8 Hz, 1H, H-6),
2.12 (s, 3H, CH3CO), 2.19 (m, 1H, H-9ax), 2.34 (dd, J = 12, 6,4 Hz,
1H, H-4), 2.44 (m, 1H, H-9eq), 2.87 (s, 3H, NCH3), 3.17 (td, J = 12.8,
6.4 Hz, 1H, H-10ax), 3.30 (br d, J = 16.8 Hz, 1H, H-6), 3.64 (q, J = 10.8
Hz, 1H, H-2), 3.73 (s, 3H, OCH3), 3.37 (dt, J = 10.8, 6.4 Hz, 1H, H-2),
4.74 (br s, 1H, H-3), 5.29 (dm, J = 5.2 Hz, 1H, H-7); minor epimer δ
1.60 (dm, J = 12.4 Hz, 1H, H-10eq), 1.93 (m, 1H, H-6), 2.11 (s, 3H,
COCH3), 2.87 (s, 3H, NCH3), 3.02 (td, 1H, J = 12.4, 6.8 Hz, H-10ax),
3.74 (s, 3H, OCH3), 5.36 (dm, 1H, J = 6 Hz, H-7). Only the different
signals are mentioned: 13C NMR (100 MHz) major epimer δ 20.9
(CH3CO), 25.2 (C-9), 29.1 (NCH3), 29.5 (C-6), 30.4 (C-10), 37.2 (C-
4), 50.6 (C-2), 52.1 (C-3), 52.9 (OCH3), 66.7 (C-5), 94.3 (CCl3),
112.3 (C-7), 147.2 (C-8), 156.8 (NCO2), 158.3 (NCO), 169.4 (CO);
minor epimer δ 25.3 (C-9), 26.1 (C-10), 29.1 (NCH3), 32.5 (C-6),
50.8 (C-2), 52.0 (C-3), 66.8 (C-5), 112.1 (C-7), 146.8 (C-8). Only the
1-Acetyl-3-[N-(methoxycarbonyl)-N-methyl]amino-1-aza-
spiro[4.5]decan-8-one (12d). Yellow oil; IR (film) 2955, 2924, 1853,
9370
dx.doi.org/10.1021/jo501110c | J. Org. Chem. 2014, 79, 9365−9372

The Journal of Organic Chemistry
Note
1698, 1644 cm−1; 1H NMR (400 MHz) δ 1.73 (m, 2H, H-6eq and H-
10eq), 1.99 (t, J = 12.4 Hz, 1H, H-4), 2.04 (s, 3H, CH3CO), 2.32 (m,
2H, H-7ax and H-9ax), 2.45 (dd, J = 12.4, 7.2 Hz, 1H, H-4), 2.45
(masked, 1H, H-9eq), 2.63 (dtd, J = 15.6, 4.8, 1.6 Hz, 1H, H-7eq), 2.89
(s, 3H, NCH3), 2.97 (tdd, J = 13.6, 5.6, 1.2 Hz, 1H, H-10ax), 3.29 (td, J
= 13.2, 5.2 Hz, 1H, H-6ax), 3.42 (t, J = 10.4 Hz, 1H, H-2), 3.70 (t, J =
8.8 Hz, 1H, H-2), 3.75 (s, 3H, OCH3), 4.81 (br s, 1H, H-3); 13C NMR
(100 MHz) δ 24.9 (CH3CO), 29.1 (NCH3), 30.0 (C-10), 33.6 (C-6),
37.9 (C-7 and C-9), 38.5 (C-4), 49.4 (C-2), 51.5 (C-3), 53.0 (OCH3),
63.2 (C-5), 157.0 (CO2Me), 169.5 (NCOCH3), 210.2 (C-8). HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C14H23N2O4 283.1652; found
283.1656.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: faiza.diaba@ub.edu.
*E-mail: josep.bonjoch@ub.edu.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this research was provided by Projects
CTQ2010-14846/BQU and CTQ2013-41338-P from the
Ministry of Economy and Competitiveness of Spain. The
(2RS,7SR,10aRS)-2-[N-(Methoxycarbonyl)-N-methylamino]-
hexahydro-1H-7,10a-methanopyrrolo[1,2-a]azocine-5,8-dione
(13). To a solution of 10 (36 mg, 0.10 mmol) in MeOH (2 mL) at 0 °C
were added NH4Cl (33 mg, 0.62 mmol) and then Zn (67.4 mg, 1.03
mmol) portionwise over 1 h. The mixture was allowed to reach rt,
stirred overnight, filtered on a Celite pad, concentrated, and purified by
chromatography (CH2Cl2 to CH2Cl2/MeOH 95:5) to yield 13 (16 mg,
58%) as a white solid: mp 152−154 °C; IR (film) 2953, 1697, 1636
cm−1; 1H NMR (CDCl3, 400 MHz) δ 1.95 (td, J = 14, 5.2 Hz, 1H, H-
10ax), 2.01 (m, 1H, H-1), 2.05 (m, 1H, H-11 pro-R), 2.27 (m, 2H, H-1
and H-11 pro-S), 2.36 (m, 1H, H-10eq), 2.37 (dd, J = 16, 6 Hz, 1H, H-
9eq), 2.44 (d, J = 19.2 Hz, 1H, H-6eq), 2.57 (ddd, J = 16, 13.2, 7.2 Hz,
1H, H-9ax), 2.67 (dd, J = 19.2, 7.2 Hz, 1H, H-6ax), 2.83 (br s, 1H, H-
7), 2.90 (s, 3H, NCH3), 3.29 (t, J = 10.8 Hz, 1H, H-3), 3.72 (s, 3H,
authors thank Dr. Gemma Puigbo
experimental contributions.
́
and Dr. Eva Ricou for their
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S
* Supporting Information
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9372
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