Dearomative radical spirocyclization from N-ce: Raghubenzyltrichloroacetamides revisited using a copper(I)-mediated atom transfer reaction leading to 2-azaspiro[4.5]decanes

Article abstract of DOI:10.1016/j.tetlet.2013.03.019

An atom transfer radical dearomatizing spirocyclization from N-benzyltrichloroacetamides using CuCl regioselectively leads to 2-azaspiro[4.5]decadienes, in which the labile allylic chlorine atom is easily replaced by a hydroxyl group in aqueous medium or by quenching with methanol or allylamine. After oxidation of the target compound, the N-tert-butyl group can be removed from the resulting spirocyclohexanedienone.

Full text of DOI:10.1016/j.tetlet.2013.03.019

Accepted Manuscript
Dearomative radical spirocyclization from N-benzyltrichloroacetamides revis‐
ited using a copper(I)-mediated atom transfer reaction leading to 2-azas‐
piro[4.5]decanes
Faïza Diaba, Juan A. Montiel, Agustín Martínez-Laporta, Josep Bonjoch
PII:
S0040-4039(13)00400-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.03.019
TETL 42634
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 January 2013
5 March 2013
6 March 2013
Please cite this article as: Diaba, F., Montiel, J.A., Martínez-Laporta, A., Bonjoch, J., Dearomative radical
spirocyclization from N-benzyltrichloroacetamides revisited using a copper(I)-mediated atom transfer reaction
leading to 2-azaspiro[4.5]decanes, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.03.019
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Dearomative radical spirocyclization from N-benzyl
trichloroacetamides revisited using a copper(I)-mediated
atom transfer reaction leading to 2-azaspiro[4.5]decanes
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Faïza Diaba, Juan A. Montiel, Agustín Martínez-Laporta, Josep Bonjoch

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Tetrahedron Letters
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Dearomative radical spirocyclization from N-benzyltrichloroacetamides revisited
using a copper(I)-mediated atom transfer reaction leading to 2-azaspiro[4.5]decanes
Faïza Diaba,* Juan A. Montiel, Agustín Martínez-Laporta and Josep Bonjoch∗
Laboratori de Química Orgànica, Facultat de Farmàcia, Institut de Biomedicina (IBUB), Universitat de Barcelona, Av. Joan XXIII s/n, 08028-Barcelona, Spain.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An atom transfer radical dearomatizing spirocyclization from N-benzyltrichloroacetamides using
CuCl regioselectively leads to 2-azaspiro[4.5]decadienes, in which the labile allylic chlorine
atom is easily replaced by a hydroxyl group in aqueous medium or by quenching with methanol
or allylamine. After oxidation of the target compound, the N-tert-butyl group can be removed
from the resulting spirocyclohexanedione.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Atom transfer radical cyclization
Azaspirodecanes
Copper
Dearomatization
Heterocycles
Spirocyclic structures are prevalent in a variety of natural
products.1 Among them, the 2-azaspiro[4.5]decane ring system is
found embedded in a small number of compounds of diverse
biogenetic origin, such as annosqualine,2 the fungal metabolites
triticones3 and spirostaphylotricins,4 and some stereoidal
alkaloids.5 Additionally, several synthetic compounds embodying
this framework exhibit a wide range of biological activities,
including antiangiogenic (e.g. atiprimod),6 antigastrin,7 and
antiarthritic,8 as well as HIV-1 protease inhibiton9 (Figure 1).
Figure 1. Structures of 2-azaspiro[4.5]decane natural and unnatural products.
2-Azaspiro[4.5]decanes are generally prepared from
cyclohexylmethylamine starting materials10,11 or through
a
dearomatizing process as the key step from benzene derivatives.
In the latter approach, the typical method to construct the
spirocyclic core involves oxidative spirocyclization of phenol
———
∗ Corresponding author. Tel.: +34 934024540; fax: +34 934024539; e-mail: faiza.diaba@ub.edu; josep.bonjoch@ub.edu

2
Tetrahedron
derivatives,12,13 while there are limited examples of the use of
non-activated benzene substrates that could deliver
spirocyclohexadienes through a dearomatiszation.14
We have recently been interested in copper(I)-mediated atom
transfer radical cyclisation (ATRC)15 of trichloroacetamides
leading to six-membered ring formation.16 During the course of
these studies, we disclosed a copper-catalysed ATRC leading to
an azaspirocyclohexadienol as a by-product (less than 10%) from
trichloroacetamide I (Scheme 1).
Scheme 2. Synthesis of trichloroacetamides: 1a (R = Bn, 78%); 1b (R = Bu,
96%); 1c (R = iPr (98%); 1d (R = cHex, 96%); 1e (R = tBu, 85%).
Initially, we chose trichloroacetamide 1e as the preferred
substrate to develop the methodology, since the bulky tert-butyl
substituent on the nitrogen atom accelerates radical reactions
leading to five-membered rings. This well-established helpful
effect is due to the favoring of the productive Z rotamer in the
proradical haloacetamide.19
Using 30 % of CuCl and after 16 h of heating at 80 ºC, we
were pleased to see that the main signals in the 1H NMR
spectrum of the crude product belonged to a mixture of epimers
of spirolactam 2. However, purification of 2 on silica gel gave a
mixture of compounds, showing the instability of the chloro
derivatives. Luckily, a simple treatment of the reaction mixture
with water at the end of the reaction generated the corresponding
alcohols 3, which were stable enough to be easily separated by
chromatography in 65% yield and as a 1.4:1 mixture of epimers
(Table 2, entry 1).
Scheme 1. Radical cyclization of trichloroacetamide I.
Inspired
by
this
unprecedented
Cu(I)-catalysed
spirocyclization, we went on to explore other ways of
constructing spirocycles. In this paper we report the first
dearomative spirocyclization of benzyltrichloroacetamides
mediated by Cu(I) leading to 2-azaspiro[4.5]decane compounds
through an ATRC process.17
Table 2. CuCl-promoted spirocyclization of trichloroacetamides 1a
The only precedents for dearomative spirocyclization leading
to 2-azaspirodecadienes via a radical process are the following:
(i) When working with benzyl derivatives as starting material, the
use of Ni-AcOH leads to 1,2-cyclohexadienes, p-tolyl
compounds lead to a mixture of cyclohexadienes, while adding
(PhSe)2 to the reaction medium to trap the cyclohexadienyl
radical intermediate
regioselectivity provides 1,4-
cyclohexadienes.14 (ii) Using phenol derivatives as substrates in
an oxidative process from xanthates, which is initiated and
Entry
R
CuCl [%]
Time
Yieldb [%]
Ratioc
terminated
by
dilauryl
peroxide,
provides
16 hd
65
49
74
68
29
42
17
24
1.4:1
3:2
3:2
3:2
3:2
2:3
3:2
2:3
spirocyclohexanediones13 (Table 1).
1
2
tBu (1e)
1e
1e
30
30
60
60
60
60
60
60
15 min
15 min
30 min
15 min
15 min
15 min
15 min
3e
4
1e
5
6
7
8
cHex (1d)
iPr (1c)
Bu (1b)
Bn (1a)
Table 1. Dearomative radical spirocyclization
a
Unless otherwise noted, all reactions were carried out from 200 mg of
trichloroacetamide 1 at 80 ºC and using microwave activation. b Isolated yield
c
d
of alcohols 3. Diastereoisomeric ratio of less and more polar alcohols.
Reaction carried out at 80 ºC in a sealed tube. e Reaction carried out on a 100
mg scale.
Thus, unlike Zard,14 who achieved 1,2-dihydrobenzenes by a
Ni-AcOH-promoted spirocyclisation,20 we obtained 1,4-
dihydrobenzenes after cyclisation and atom transfer using Cu(I)
(Table 1). The sequence involved the generation of the
carbamoyldichloromethyl radical, an intramolecular ipso attack
on the benzene ring, followed by consecutive regioselective C-Cl
bond formation on the initially formed cyclohexadienyl radical.21
Upon hydrolysis, the lability of the allylic chloride gave the
corresponding alcohol 3. Thus, the overall process constitutes a
1,4-carbooxygenation of the benzene ring present in 1.
Promoter
ref
X
R
R´
X/R´ or
Y
Ni-AcOH
(RO)2
CuCl
14
13
Cl
SC(S)OEt
Cl
Cl
H
Cl
H
OMe
H
Cl/H
---
---
H, SePha
O
H, Cl
This work
a If (PhSe)2 was added to the reaction mixture.
The trichloroacetamides 1(a-e)18 required for our studies were
easily available by reductive amination of the corresponding
alkylamine with benzaldehyde and acylation of the resulting
secondary amines using trichroacetyl chloride (Scheme 2).
To optimize the process we decided to use microwave
activation, but the same catalyst loading, a 15-minute reaction
time and further treatment with water gave the same mixture of

3
alcohols with a lower yield of 49% (entry 2). The best results
were obtained with 60% of CuCl, which gave 3e in 74% yield
(entry 3).22 Prolonging the reaction time to 30 min did not
improve the yield (entry 4).23 The optimum conditions were then
applied to the other trichloroacetamides, and in all cases the
corresponding alcohols were obtained in low to moderate yields.
As expected, substrates 1a and 1b, with non-hindering groups,
gave the worst results, whereas isopropyl and cyclohexyl
substrates provided alcohols 3 with slightly better yields (Table
2).
Scheme 4. Substrate scope of the ATRC. Reagents and conditions: CuCl
(60%), CH3CN, μW, 80 ºC, 15 min. Compounds 3f (54%); 6 (21%); 2h
(42%).
Finally, we used trapping reagents other than water for the
allylic chlorides formed after the ATRC, starting from 1e as the
radical precursor (Scheme 5). Thus, when MeOH was added to
the reaction in the work-up, a mixture of ethers 8 was isolated.
These were noted to be sensitive to the oxygen atmosphere since
substantial amounts of ketone 4 were formed on standing in air.
Otherwise, when the reaction mixture containing 2e was treated
with allylamine, an epimeric mixture of dienylallylamine epimers
9 was isolated.
The mixture of alcohols 3e was readily converted to the
corresponding ketone 4 in excellent yields using Dess-Martin
periodinane or TEMPO. Further cleavage of the tert-butyl group
in acid medium24 provided secondary amide 5 in 76% yield
(Scheme 3).
Scheme 5. Trapping of chloride 2e with MeOH or allylamine.
Scheme 3. Synthetic transformations from azaspirolactam 3e.
In summary, we have described the first dearomative
spirocyclization promoted by CuCl upon a benzene ring. The
results obtained with the different trichloroacetamides used in
this work again showed the importance of having a bulky group
on the nitrogen to achieve the cyclization process. Oxidation of
the epimeric alcohol mixture 3e to the corresponding ketone and
further cleavage of the tert-butyl group provided
polyfunctionalized 2-azaspiro[4.5]decadienone 5, which is now
under study for use as a building block in the synthesis of natural
and unnatural compounds.25
We next sought to explore the scope of the reaction and
examined a number of substituted benzene derivatives (Scheme
4). Starting materials were prepared following the same reaction
sequence of reductive amination and trichloroacetylation as
depicted above in Scheme 2. Treatment of 3-methylsubstituted
benzene 1f with CuCl gave a result similar to that observed in the
unsubstituted series 1e, the allylic alcohol 3f being isolated as a
diastereomeric mixture. In contrast, in the 2-methyl substituted
benzene 1g, the trapping of the cyclohexadienyl radical seems to
have occurred at C-2, and the chloride derivative evolved to
exocyclic methylene derivative 6 through an elimination process.
Moreover, for steric reasons the spirocyclization was disfavoured
with respect to the ortho-unsubstituted derivatives (1e, 1f), and a
remarkable increase in the de-tert-butylation reaction from 1g
occurred leading to secondary amide 7 in 25% yield (not shown;
see supplementary material). The 3,5-difluorobenzyl derivative
1h behaved in a particular way, since after the ATRC cyclization
the allyl chloride showed a low reactivity in the aqueous
medium, and the initially formed chloride 2h, remaining
unchanged, was isolated.
Acknowledgments
Support of this research was provided by the Spanish Ministry
of Economy and Competitiveness (Project CTQ2010-
14846/BQU).
Supplementary Material
Experimental and NMR data of all compounds and copies of
1H and 13C NMR spectra can be found, in the online version, at
hhttp://.
References and notes
1.
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4
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(ESI-TOF): Calcd for C13H18Cl2NO2 290.0709 (M++1). Found
290.0719. More polar: IR (NaCl, neat): 3254, 3034, 2972, 2871,
1713, 1474, 1400, 1367, 1306, 1245, 1216, 1015, 923, 885, 777, 741,
Badger, A. M.; Schwartz, D. A.; Picker, D. H.; Dorman, J. W.;
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1
694, 682, 563, 516 cm-1; H NMR (CDCl3, 400 MHz): δ 1.43 (9H, s,
CH3), 1.58 (1H, br s, OH), 3.34 (2H, s, 1-H), 4.52 (1H, br s, 8-H), 5.96
(2H, dq, J = 10.4, 1.6 Hz, 6-H and 10-H), 6.24 (2H, ddt, J = 10.4, 3.6,
2 Hz, 7-H and 9-H); 13C NMR (CDCl3, 100 MHz): δ 27.1 (CH3-tBu),
48.6 (C-5), 52.7 (C-1), 55.4 (C), 62.1 (C-8), 89.7 (C-4), 126.9 (C-6 and
C-10), 132.4 (C-7 and C-9), 165.3 (C-3). HRMS (ESI-TOF): Calcd for
C13H18Cl2NO2 290.0709 (M++1). Found 290.0698.
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3982; (b) Albrecht, D.; Basler, B.; Bach, T. J. Org. Chem. 2008, 73,
2345-2356.
25. As suggested by the reviewers, an extension of the ATRC process
reported here to different aromatic rings25a,b and tethers25c,d could be of
interest: (a) Kaoudi, T.; Quiclet-Sire, B.; Seguin, S.; Zard, S. Z.
Angew. Chem. Int. Ed. 2000, 39, 31-733. (b) Guindeuil, S.; Zard, S. Z.
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El Kaïm, L.; Miranda, L. D. Synthesis 2010, 1285-1290.
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8799-8801.
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18. Compound 1d was prepared by reductive amination of cyclohexanone
using benzylamine, followed by reaction with trichloroacetyl chloride.
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20. When no radical trapping reagent was used, the capture of the
cyclohexanedienyl radical probably occurred by an oxidation and later
nucleophilic addition.
21. The formation of 1,4-dienes reflects the known propensity of
cyclohexanedienyl radicals for kinetic trapping at the internal position:
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1986, 108, 6408-6409. See also, Crich D.; Krishnamurthy, V.
Tetrahedron 2006, 62, 6830-6840.
22. Reaction procedure: In a 10 mL vessel were placed trichloroacetamide
1e (100 mg, 0.32 mmol), CuCl (19 mg, 0.19 mmol, 60%) and
acetonitrile (1 mL). The stirred reaction mixture was heated at 80 ºC
using microwave irradiation for 15 min. After reaching rt, water (1
mL) was added, the mixture was stirred for an additional 1 h, and then
extracted with CH2Cl2. The organics were dried, concentrated and
purified by chromatography (CH2Cl2 to CH2Cl2/AcOEt 98:2) to give
separable alcohols 3e (70 mg, 74%) in a 3:2 proportion. Less polar: IR
(NaCl, neat): 3529, 3399, 3284, 3039, 2977, 2934, 2870, 1720,
1478,1399, 1365, 1305, 1246, 1222, 1032, 1010, 895, 872, 829, 775,
1
739, 681, 582, 525 cm-1; H NMR (CDCl3, 400 MHz, COSY): δ 1.43
(9H, s, CH3), 1.97 (1H, br s, OH), 3.39 (2H, s, 1-H), 4.66 (1H, br s, 8-
H), 5.88 (2H, dq, J = 10.4, 2 Hz, 6-H and 10-H), 6.23 (2H, ddt, J =
10.4, 3, 2 Hz, 7-H and 9-H); 13C NMR (CDCl3, 100 MHz, HSQC): δ