Six-membered nitrogen ring formation by radical cyclization of trichloroacetamides with enones. A synthetic entry to cis-perhydroisoquinoline- 3,6-diones

Article abstract of DOI:10.1016/j.tetlet.2004.04.104

Intramolecular reactions between 1-(carbamoyl)dichloromethyl radicals and enones acting as radical acceptors are reported for the first time. The Bu ₃SnH promoted 6-exo reaction of trichloroacetamides with enones, avoiding the 1,5-hydrogen transfer, constitutes a new synthetic entry to cis-perhydoisoquinoline-3,6-diones.

Full text of DOI:10.1016/j.tetlet.2004.04.104

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4661–4664
Six-membered nitrogen ring formation by radical cyclization of
trichloroacetamides with enones. A synthetic entry to
cis-perhydroisoquinoline-3,6-diones
Xavier Vila, Josefina Quirante, Laura Paloma and Josep Bonjoch*
ꢀ
ꢁ
ꢁ
Laboratori de Quımica Organica, Facultat de Farmacia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028 Barcelona, Spain
Received 29 March 2004; revised 20 April 2004; accepted 20 April 2004
Abstract—Intramolecular reactions between 1-(carbamoyl)dichloromethyl radicals and enones acting as radical acceptors are re-
ported for the first time. The Bu3SnH promoted 6-exo reaction of trichloroacetamides with enones, avoiding the 1,5-hydrogen
transfer, constitutes a new synthetic entry to cis-perhydoisoquinoline-3,6-diones.
Ó 2004 Elsevier Ltd. All rights reserved.
Functionalized cis-perhydroisoquinolines are a key
architectural feature in a wide array of biologically
active natural products (e.g., reserpine,1 manzamine,2
and madangamine alkaloids3) as well as a number of
pharmaceuticals, including several HIV protease inhib-
itors.4 Our interest in the madangamine alkaloids5 has
directed our attention to the synthesis of these structural
motifs. As envisioned in Scheme 1, our approach to the
synthesis of functionalized cis-perhydroisoquinolines
involves the radical cyclization of trichloroacetamides
with enones to give perhydroisoquinoline-3,6-diones,6 in
which both carbonyl groups would be useful in building
the backbone of the aforementioned natural products.
N
H
N
H
tricyclic core of
madangamines
H
H
4
G
O
X
X
O
R
4a
N
N
R
H
X
G
reference
H,H
H,H
O
CH2Br
9
CH2SC(S)OMe 10
CCl3
this work
H
4
CCl3
O
O
O
O
The usefulness of the radical processes for the synthesis of
nitrogen heterocycles is well established,7 but there are
relatively few examples of six-membered piperidine ring
elaboration.8 Until now there have been reports of two
radical approaches9;10 based on the use of carbamoyl-
methyl radicals to construct hydroisoquinoline com-
pounds by the formation of the C-4/C-4a bond in the ring
closure step, the radical acceptor being an isolated double
bond in both Stork’s9 and Zard’s work.10 The isoquino-
line derivatives formed in these approaches lack the
4a
N
N
Bn
Bn
H
Scheme 1.
functionalization at C-6 required for our purposes, but it
could be obtained if a radical cyclization upon an enone
group were achieved. This type of cyclization, leading to
six-membered rings in substrates with a hydrogen atom
in the c-position, is scarce,11;12 since it is hampered by the
competitive process of 1,5-hydrogen transfer, which can
totally13 or partially14 preclude the formation of the
six-membered ring. To avoid this unwanted reaction
pathway,15 we decided to attempt the cyclization
using dichloromethylcarbamoyl radical intermediates,
Keywords: Isoquinolines; Madangamines; Nitrogen heterocycles; Rad-
ical cyclization; Trichloroacetamides.
* Corresponding author. Tel.: +34-934024540; fax: +34-934024539;
e-mail: josep.bonjoch@ub.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.104

4662
X. Vila et al. / Tetrahedron Letters 45 (2004) 4661–4664
R
R
O
HN
HN
CHO
1. RNH
1. (C H ) P=CH
2
HCl, THF-H O, rt
2
2
6
5 3
ClCOCCl
3
2. NaBH
4
2. BH .THF
3
Et N
3
O
O
O
O
O
O
3. PCC
O
(75%)
4
2
3
R
N
R
N
R
N
For series a:
O
O
O
IBX
H
Bu SnH, AIBN
3
CCl
3
CCl
3
H
For series b,c:
a) TMSI
b) PhSeCl
C H , rfx, 3 h
6
6
O
O
O
c) H O
2
2
5
6
1
3
4
5
6
1
Series
a: R = Bn
b: R = Me
68%
42%
82%
94%
50%
88%
93%
75%
81%
80%
49%
36%
70%
62%
60%
CH CH
2
c: R =
2
N
H
Scheme 2. Synthesis of cis-perhydroisoquinoline-3,6-diones.
generated from trichloroacetamides, which have given
excellent results in the synthesis of 2-azabicyclo[3.3.1]-
nonanes by a 6-exo radical cyclization.5;16
overall cyclization––full reduction process from 6a to
achieve 1a was also carried out successfully using
TTMSS (66% overall yield).
As shown in Scheme 2, we tested this new synthetic
entry to cis-perhydroisoquinoline-3,6-diones using three
different trichloroacetamides. The starting material was
aldehyde 2, which was prepared from the monoethylene
acetal of 1,4-cyclohexanedione by Wittig methylena-
tion,17 followed by hydroboration and oxidation in situ
with PCC.18;19 In the first series, the reductive amination
was carried out using benzylamine to form the corres-
ponding imine, which was reduced with NaBH4. The
amine 3a20;21 was converted into the corresponding tri-
chloroacetamide 5a by hydrolysis of acetal and trichloro-
acetylation of the resulting secondary amine 4a. To
generate the enone functionalization of 6a from 5a we
initially used a classical procedure involving the silyl
enol ether formation using TMSI and HMDS followed
by phenylselenylation and hydrogen peroxide oxidation
of the a-phenylselenyl ketone intermediate. The overall
yield was 48%, which was improved up to 80% using
IBX as the oxidizing agent for ketone 5a in a one-step
procedure.22 Treatment of compound 6a in benzene with
Bu3SnH (3.5 equiv) and AIBN under a reflux tempera-
ture provided through a 6-exo radical process the iso-
quinolinedione 1a as a single diastereoisomer in 70%
yield. Under the same reaction conditions, the mono-
chloroacetamide 7 did not give the cyclized compound
1a but the reduced acetamide 8 was formed.23 This result
again shows that the carbamoylmethyl and carb-
amoyldichloromethyl radicals behave differently,5;16a
probably because the two chlorine atoms increase the
pyramidalization at the radical center, which in turn
increases the rate of radical addition to the alkene.24 The
The promising result in the cyclization of 6a prompted
us to extend this methodology to the synthesis of com-
pounds 1b and 1c, which was carried out from trichloro-
acetamides 6b and 6c, prepared in a nonoptimised way
following the protocol depicted in Scheme 2. Compound
1c25 would be of interest in the field of yohimban indole
alkaloids26 since its functionalization could allow access
to the pentacyclic framework of the natural products of
this family that bear a cis-fused isoquinoline fragment.
The relative stereochemistry of 1a was elucidated by 2D
NMR spectra (COSY, HSQC, NOESY) (Scheme 3).27
The stereoselective cis-perhydroisoquinoline formation
agrees with the stereochemical outcome observed in the
related radical cyclizations through a 6-exo process and
with both the steric and electronic preference for a
pseudo axial addition of the dichlorocarbamoylmethyl
radical to the cyclohexenone moiety.28 The key evidence
for the conformational elucidation of 1a was found in the
1H NMR coupling pattern for the methylene protons at
C-1, which appear as dd (J ¼ 12:6 and 5.4 Hz). The rel-
ative configuration for the other azabicyclic compounds
1b and 1c is the same as observed in 1a and their NMR
data follows the same pattern of chemical shifts. Inter-
estingly, the monochloro derivative 9, which was isolated
in 56% yield when the cyclization of 6a was carried out
using 2.2 equiv of TTMSS,29 shows a different preferred
conformation to that of 1a (Scheme 3).30
In summary, we report a new method for the synthesis
of functionalized cis-perhydroisoquinolines consisting of

X. Vila et al. / Tetrahedron Letters 45 (2004) 4661–4664
4663
7. (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinhem, 2001; (b) Bowman, W. R.;
Cloonan, M. O.; Krintel, S. L. J. Chem. Soc., Perkin
Trans. 1 2001, 2885–2902; (c) Zhang, W. Tetrahedron
2001, 57, 7237–7262.
8. Inter alia, see: (a) Hirai, Y.; Hagiwara, A.; Terada, T.;
Yamazaki, T. Chem. Lett. 1987, 2417–2418; (b) Knapp, S.;
Gibson, F. S. J. Org. Chem. 1992, 57, 4802–4809; (c) Sibi,
M. P.; Ji, J. J. Am. Chem. Soc. 1996, 118, 3063–3064; (d)
Takayama, H.; Watanabe, F.; Kitajima, M.; Aimi, M.
Tetrahedron Lett. 1997, 30, 5307–5310; (e) Kuehne, M.;
Bandarage, U. K.; Hammach, A.; Li, Y.-L.; Wang, T.
J. Org. Chem. 1998, 63, 2172–2183; (f) Eichbert, M. J.;
Dorta, R. L.; Grotjahn, D. B.; Lamottke, K.; Schmidt,
M.; Volhardt, K. P. C. J. Am. Chem. Soc. 2001, 123, 9324–
9327; (g) Rashatasakhon, P.; Ozdemir, A. D.; Willis, J.;
Padwa, A. Org. Lett. 2004, 6, 917–920.
O
H
O
H
1
δ C(5): 44.4
H
Bn
H
Bn
N
8a
N
H
Cl
H
O
O
δ C(1): 49.2
Bu SnH
3
J
,
= 5.4 Hz
1ax 8a
AIBN
O
O
N
1
H
H
N
Bn
Bn
H
Cl
H
8a
H
H
δ C(5): 39.1
δ C(1): 47.5
J
,
= 10.4 Hz
1ax 8a
O
O
1a
9
Scheme 3. Conformational behavior of 1a and 9.
9. Stork, G.; Mah, R. Heterocycles 1989, 28, 723–727.
10. Kaoudi, T.; Miranda, L. D.; Zard, S. Z. Org. Lett. 2001, 3,
3125–3127.
11. In the most noteworthy example an stabilized aminoalkyl
radical was used in a SET-sensitized photocyclization
reaction, generated from a N-(trimethylsilyl)methyl deriva-
tive: Xu, W.; Zhang, X.-M.; Mariano, P. S. J. Am. Chem.
Soc. 1991, 113, 8863–8878.
Bu3SnH or TTMSS/AIBN-promoted radical cyclization
of trichloroacetamides with enones. This constitutes an
example of the otherwise scarce radical process involv-
ing a reaction of a carboradical upon enones to generate
a six-membered ring. Extension of this methodology to
the synthesis of tricyclic skeleton of madangamines is
now underway.
12. Yu, J.; Wang, T.; Liu, X.; Deschamps, J.; Flippen-
Anderson, J.; Liao, X.; Cook, J. M. J. Org. Chem. 2003,
68, 7565–7581.
ꢀ
ꢀ
13. Bonjoch, J.; Sole, D.; Garcıa-Rubio, S.; Bosch, J. J. Am.
Chem. Soc. 1997, 119, 7230–7240.
14. Wardrop, D. J.; Zhang, W. Org. Lett. 2001, 3, 2353–2356.
15. For the synthetic applications of the 1,5-hydrogen transfer
followed by a 5-exo-trig cyclization using vinyl radicals,
see: (a) Parsons, P. J.; Caddick, S. Tetrahedron 1994, 50,
13523–13532; (b) Robertson, J.; Pillai, J.; Lush, R. K.
Chem. Soc. Rev. 2001, 30, 94–103.
16. In this field, we have used trichloroacetamides as prorad-
ical groups with a,b-unsaturated nitriles and esters,
alkenes, enol acetates, and silylenol ethers. See, inter alia:
(a) Quirante, J.; Escolano, C.; Merino, A.; Bonjoch, J. J.
Org. Chem. 1998, 63, 968–976; (b) Quirante, J.; Escolano,
C.; Diaba, F.; Bonjoch, J. J. Chem. Soc., Perkin Trans. 1
1999, 1157–1162; (c) Quirante, J.; Diaba, F.; Vila, X.;
Bonjoch, J.; Lago, E.; Molins, E. Comp. Rend. Acad. Sci.
2001, 4, 513–521.
Acknowledgements
This research was supported by the MCYT (Spain)
through Grant BQU2001-3551. Thanks are also due to
the DURSI (Catalonia) for Grant 2001SGR-00083 and
a fellowship for X.V.
References and notes
1. Sparks, S. M.; Gutierrez, A. J.; Shea, K. J. J. Org. Chem.
2003, 68, 5274–5285, and references cited therein.
2. Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong,
Y.-L.; Chen, H.-J.; Courtney, A. K.; Martin, S. F. J. Am.
Chem. Soc. 2002, 124, 8584–8592, and references cited
therein.
17. Nicolaou, K. C.; Magolda, R. L.; Claremon, D. A. J. Am.
Chem. Soc. 1980, 102, 1404–1409.
18. Rosowsky, A.; Forsch, R. A.; Moran, R. G. J. Med.
Chem. 1989, 32, 709–715.
3. (a) Kong, F.; Andersen, R. J.; Allen, T. M. J. Am. Chem.
Soc. 1994, 116, 6007–6008; (b) Kong, F.; Graziani, E. I.;
Andersen, R. J. J. Nat. Prod. 1998, 61, 267–271; For
synthetic studies, see: (c) Matzanke, N.; Gregg, R. J.;
Weinreb, S. M. J. Org. Chem. 1997, 62, 1920–1921.
4. Kaldor, S. W.; Kalish, V. J.; Davies, J. F.; Shetty, B. V.;
Fritz, J. E.; Appelt, K.; Burgess, J. A.; Campanale, K. M.;
Chirgadze, N. Y.; Clawson, D. K.; Dressman, B. A.;
Hatch, S. D.; Khalil, D. A.; Kosa, M. B.; Lubbehusen, P.
P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K. S.;
Tatlock, J. H. J. Med. Chem. 1997, 40, 3979–3985.
5. For our previous studies in the synthesis of the
2-azabicyclo[3.3.1]nonane nucleus of madangamine alka-
loids, see: Quirante, J.; Escolano, C.; Massot, M.; Bonj-
och, J. Tetrahedron 1997, 53, 1391–1402.
19. For an alternative synthesis of 2: Pearson, A. J.; Fang, X.
J. Org. Chem. 1997, 62, 5284–5292.
20. For an alternative synthesis of 3 (R ¼ H), see: Kelly, T. R.;
Lebedev, R. L. J. Org. Chem. 2002, 67, 2197–2205.
21. All yields reported herein refer to isolated, pure materials,
whose 1H and 13C NMR, and elemental combustion
analysis correspond with the proposed structures. 13C
NMR data (75 MHz, DEPT) for selected compounds of
Scheme 1 in the series a: (1a, 100 MHz, gHSQC). 25.6 (C-
8), 31.9 (C-8a), 33.8 (C-4a), 34.6, (C-4), 38.7 (C-7), 44.4
(C-5), 49.2 (C-1), 49.8 (NCH2Ar), 127.4, 127.9, and 128.5
(Ar), 136.7 (ipso-Ar), 167.7 (C-3), 209.3 (C-6). (3a) 28.2 (t),
34.2 (t), 36.6 (d), 54.0(t), 54.9 (t), 64.0(t), 108.9 (s), 126.6
(d), 127.8 (d), 128.1 (d), 140.3 (s). (5a) 29.7 (t), 33.5 (d),
39.9 (t), 52.2 (t), 53.7 (t), 92.9 (s), 126.6 (d), 127.6 (d), 128.5
(d), 134.7 (s), 160.7 (s), 210.3 (s). (6a) 26.5 (t), 34.0(d), 36.3
(t), 51.2 (t), 54.2 (t), 92.9 (s), 127.0(d), 128.2 (d), 129.0(d),
130.3 (d), 134.7 (s), 150.0 (d), 161.4 (s), 198.6 (s).
22. Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong,
Y.-L. J. Am. Chem. Soc. 2002, 124, 2245–2258.
6. For the two previous syntheses of cis-perhydroisoquino-
line-3,6-diones, see: by intramolecular Diels–Alder: (a)
Godleski, S. A.; Villhauer, E. B. J. Org. Chem. 1984, 49,
2246–2252; by an intramolecular Michael process: (b)
Stork, G.; Livingston, D. A. Chem. Lett. 1987, 105–108.

4664
23.
X. Vila et al. / Tetrahedron Letters 45 (2004) 4661–4664
26. (a) Baxter, E. W.; Mariano, P. S. In Alkaloids: Chemical &
Biological Perspectives; Pelletier, S. W., Ed.; Springer:
Bn
Bn
ꢀ
New York, 1992; Vol. 8, pp 197–319; (b) Szantay, C.;
N
Honty, K. In Monoterpenoid Indole Alkaloids; Saxton,
J. E., Ed.; The Chemistry of Heterocyclic Compounds,
Taylor, E. C., Eds. WIley: Chichester, 1994; Supplement
to Vol. 25, Part 4, pp 161–216.
O
N
O
Bu3SnH,AIBN
C6H6, rfx, 3 h
Me
Cl
27. For NMR studies of cis-fused hydroisoquinolines, see:
Booth, H.; Bailey, J. M. J. Chem. Soc., Perkin Trans. 2
1979, 510–513.
O
O
7
8
28. Stereoelectronic controls of this type in radical additions
to cyclohexenones have been noted earlier: Benko, Z.;
Fraser-Reid, B.; Mariano, P. S.; Beckwith, A. L. J. J. Org.
Chem. 1988, 53, 2066–2072, see also Ref. 11.
29. In the same reaction, the corresponding dichloro deriva-
tive was isolated in 19% yield.
30. For conformational studies in cis-decahydroisoquinolines,
see: (a) Bailey, J. M.; Booth, H.; Al-Shirayda, H. A. R. Y.
J. Chem. Soc., Perkin Trans. 2 1984, 583–587; (b)
Ornstein, P. L.; Augenstein, N. K.; Arnold, M. B.
J. Org. Chem. 1994, 59, 7862–7869.
24. The greater reactivity of ‘bent’ r-radicals relative to
planar p-radicals has been noted earlier: (a) Fischer,
H.; Radom, L. Angew. Chem., Int. Ed. 2001, 40,
1340–1371; (b) Bartberger, M. D.; Dolbier, W. R.;
Lusztyk, J.; Ingold, K. U. Tetrahedron 1997, 53, 9857–
9880.
25. Interestingly no cyclization was observed upon the indole
2-position in the radical cyclization of 6c, as has been
reported when the radical acceptor is an isolated alkene
(see Ref. 10).