A radical cyclization route to cyclic imines

Article abstract of DOI:10.1016/j.tetlet.2009.12.104

A novel route to cyclic imines based on 5-exo radical cyclization is explored. The radical precursors are imines prepared from allylamine and readily available α-phenylselenenyl ketones.

Full text of DOI:10.1016/j.tetlet.2009.12.104

Tetrahedron Letters 51 (2010) 1149–1151
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Tetrahedron Letters
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A radical cyclization route to cyclic imines
*
Puneet Srivastava, Lars Engman
Department of Biochemistry and Organic Chemistry, Uppsala University, PO Box 576, 751 23 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel route to cyclic imines based on 5-exo radical cyclization is explored. The radical precursors are
Received 26 November 2009
Revised 11 December 2009
Accepted 16 December 2009
Available online 24 December 2009
imines prepared from allylamine and readily available
a
-phenylselenenyl ketones.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Radicals
a
-Phenylselenenyl ketones
1-Pyrrolines
5-exo cyclization
D
Cyclicimines form an importantclass of nitrogen-containing het-
erocycles found in several pharmacologically important alkaloids.
Thus, many methods are available for their synthesis1 including
O
N
N
N
SePh
N
SePh
SePh
+
R
R
R
addition of organometallics to lactam derivatives2 or to
x-bromo
nitriles,3 transition metal-catalyzed intramolecular oxidative ami-
nation of alkenes4 or hydroamination of alkynes,5 cyclization of
N
N
R
-amino ketones,6 1,3-dipolar cycloaddition of münchnones to
R
R
R
x
alkenes,7 thermally-induced C–H nitrene insertion in trans-oximes,8
Scheme 1.
and transition metal-catalyzed cyclization of
c
-olefinic oximes.9
Free radical cyclization methodologies have been used exten-
sively in the synthesis of heterocycles and natural products.10 How-
ever, their use for cyclic imine synthesis has received only scant
attention. Thus, 5-exo radical cyclization of iminyl radicals was used
dichloride, convenient for large scale preparation12 of such com-
pounds (as exemplified in Scheme 2).
for
methodology, it occurred to us that readily available
D
1-pyrroline synthesis.11 In our search for novel radical-based
The PhSe-group is an excellent precursor of carbon-centred rad-
icals, but a poor leaving group. Thus, reaction of
a-phenylselenenyl
a-phenylse-
acetophenone with excess allylamine in the presence of TiCl4
lenenyl ketones, after condensation with allylic amines, could serve
as precursors of 3-aza-2,5-hexadienyl radicals (Scheme 1). It was
our hope that such radicals, despite increased stability due to
resonance stabilization, would cyclize at a decent rate in a 5-exo
fashion to provide cyclic imines. In the event, the imine-forming
reaction would result in a mixture of E- and Z-isomers, resonance
in the radical intermediate would in turn allow for conversion of
the unreactive (in cyclization) Z-isomer into the reactive E-isomer
(Scheme 1).
O
O
N
i
ii
iii
SePh
SePh
80%
95%
SePh
O
N
N
A variety of methods are available for the introduction of a
PhSe-group into the a-position of ketones. We found the two-step
procedure involving reaction of ketones with PhSeCl3, followed by
iv
+
+
the reduction of the resulting crystalline organyl phenyl selenium
trace
46%
15%
Scheme 2. Reagents and conditions: (i) PhSeCl3, dry Et2O, rt, overnight, (ii) Na2S2O5,
H2O, Et2O, (iii) allylamine, TiCl4, dry Et2O, À78 °C to rt overnight, (iv) AIBN, TTMSS,
C6H6, reflux, 8 h.
* Corresponding author. Tel.: +46 184713784; fax: +46 184713818.
E-mail address: Lars.Engman@biorg.uu.se (L. Engman).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.104

1150
P. Srivastava, L. Engman / Tetrahedron Letters 51 (2010) 1149–1151
afforded the corresponding imine in good yield (80%) and purity
according to 1H NMR analysis, as an E/Z-mixture.13 In contrast,
phenacyl bromide, when subjected to the conditions for imine for-
mation, produced a complex mixture where nucleophilic displace-
ment of bromide had occurred.
Due to the lability of the imine towards chromatographic puri-
fication, radical cyclization had to be attempted using the crude
reaction mixture. Addition of Bu3SnH with AIBN initiation afforded,
were obtained as E/Z-mixtures (isomeric ratios were in the range
of 100/0–70/30 according to 1H NMR analysis). However, the struc-
tures of the predominating isomers were not known. Therefore we
do not know if E/Z-isomerisation in the carbon-centred radical as
outlined in Scheme 1 occurs rapidly enough that both isomers of
the starting material can indeed be converted into cyclized
product.
In summary we have described a novel radical cyclization route
after work-up, an 18% yield (based on starting
a
-phenylselenenyl
to substituted D
1-pyrrolines using readily available organosele-
acetophenone) of cyclic imine together with reduced, hydrolyzed,
starting material (acetophenone; 57%). Slow addition of tris(tri-
methylsilyl)silane (TTMSS) and AIBN over 8 h in refluxing benzene
afforded an overall 37% isolated yield of the desired cyclic imine
along with 8% of the reduced product. Another by-product (10%)
in this reaction was the corresponding group transfer product
which could be hydrodeselenated by treatment with Bu3SnH
(Scheme 2). By adding TTMSS-AIBN slowly over 2–3 h, the yield
of the cyclic imine increased to 46% (51% by NMR), the group trans-
fer product was hardly seen and the amount of reduced product in-
creased to 15%.14
nium radical precursors. Considering the biological and synthetic
(for face selective addition of nucleophiles to the C@N bond) utility
of pyrrolines, we feel our methodology should be useful for the
preparation of cyclic imines.
Acknowledgements
Financial support from the Swedish Research Council is grate-
fully acknowledged. The authors would like to thank Dr. Suresh
Gohil, Department of Chemistry, Swedish University of Agricul-
tural Sciences (SLU), Uppsala, and Dr. Per Sjöberg, Department of
Physical and Analytical Chemistry, Uppsala University for record-
ing high resolution mass spectra.
Table 1 shows the cyclic imines prepared and the yields ob-
tained over two steps (imine formation and cyclization).
Unfortunately, our efforts to extend the methodology to cyclic
a
-phenylselenenylketones and a-phenylselenenyl aldehydes failed
References and notes
at the imine-forming step. As observed for pinacolone and 2-ace-
tylthiophene (Table 1), pyrrolines from low molecular weight ali-
phatic ketones were volatile and difficult to isolate. Imines
1. Shvekhgeimer, M.-G. A. Chem. Heterocycl. Compd. 2003, 39, 405–448.
2. (a) Hua, D. H.; Miao, S. W.; Bharathi, S. N.; Katsuhira, T.; Bravo, A. A. J. Org. Chem.
1990, 55, 3682–3684; (b) Ahn, Y.; Cardenas, G. I.; Yang, J.; Romo, D. Org. Lett.
2001, 3, 751–754; (c) Giovannini, A.; Savoia, D.; Umani-Ronchi, A. J. Org. Chem.
1989, 54, 228–234.
prepared in situ from
a-phenylselenenyl ketones and allylamine
3. Fry, D. F.; Fowler, C. B.; Dieter, R. K. Synlett 1994, 836–838.
4. Kondo, T.; Okada, T.; Mitsudo, T. J. Am. Chem. Soc. 2002, 124, 186–187.
5. (a) Fukuda, Y.; Matsubara, S.; Utimoto, K. J. Org. Chem. 1991, 56, 5812–5816; (b)
Müller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675–703.
6. Pal, K.; Behnke, M. L.; Tong, L. Tetrahedron Lett. 1993, 34, 6205–6208.
7. (a) Melhado, A. D.; Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2007, 129,
12638–12639; (b) Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc. 2004, 126,
12776–12777.
Table 1
Structures of the cyclic imines prepared
Product
Yielda
Crudeb (%)/isolated (%)
N
8. Savarin, C. G.; Grisé, C.; Murry, J. A.; Reamer, R. A.; Hughes, D. L. Org. Lett. 2007,
9, 981–983.
9. Narasaka, K. Pure Appl. Chem. 2003, 75, 19–28.
52/47
10. Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991, 91, 1237–1286.
11. (a) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543–17594; (b) Boivin, J.;
Fouquet, E.; Zard, S. Z. Tetrahedron Lett. 1990, 31, 85–88; (c) Zard, S. Z. Synlett
1996, 1148–1154; (d) Bowman, W. R.; Bridge, C. F.; Brookes, P. Tetrahedron Lett.
2000, 41, 8989–8994; (e) Cubillo, F. P.; Scott, J. S.; Walton, J. C. J. Org. Chem.
2008, 73, 5558–5565.
12. (a) Engman, L. Tetrahedron Lett. 1985, 26, 6385–6388; (b) Engman, L. J. Org.
Chem. 1988, 53, 4031–4037; (c) Houllemare, D.; Ponthieux, S.; Outurquin, F.;
Paulmier, C. Synthesis 1997, 101–106.
1
N
50 /46
MeO
2
13. General procedure for imine formation: The
a-phenylselenenyl ketone
N
(1 mmol), allylamine (5 mmol) and dry Et2O (10 mL) were cooled to
À78 °C. TiCl4 (0.5 mmol) in C6H6 (2 mL) was then added dropwise to the
mixture. The cold-bath was removed after 30 min and the reaction was left
to stir overnight at room temperature. After work-up with saturated
aqueous NaHCO3, drying and evaporation, the crude imine was obtained,
sometimes as a mixture of isomers.
51/46
33/—
3
N
14. General procedure for cyclization: To the crude imine (1 mmol) in refluxing C6H6
(30 mL) under N2 were added TTMSS (1.5 mmol) in C6H6 (10 mL) and AIBN
(0.5 mmol) in C6H6 (10 mL) at a rate of 1 mL per 10 min. The mixture was then
refluxed overnight. After evaporation, the crude yield was determined by 1H
NMR using DMAP as an internal standard. Pure imine was obtained by flash
chromatography on silica (ether–pentane, 0–30% v/v; 1.5% pyridine).
3-Methyl-5-(2-naphthyl)-3,4-dihydro-2H-pyrrole (1): 1H NMR (500 MHz,
CDCl3): d 8.14 (s, 1 H), 8.09 (dd, J = 8.5, 1.8 Hz, 1H), 7.86 (m, 3H), 7.51 (m,
2H), 4.24 (dddd, J = 16.0, 8.0, 1.8, 1.8 Hz, 1H), 3.71 (dddd, J = 16.0, 5.0, 1.85,
1.85 Hz, 1H), 3.24 (dddd, J = 16.0, 8.0, 1.9, 1.9 Hz, 1H), 2.71 (dddd, J = 16.0, 5.0,
1.85, 1.85 Hz, 1H), 2.60 (m, 1H), 1.15 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz,
CDCl3): d 172.9, 134.4, 133.1, 132.3, 128.7, 128.2, 127.8, 127.1, 126.4, 124.4,
69.1, 43.2, 31.6, 20.5. HRMS (ESI) for C15H16N; found (210.1280 [M+H]+), calcd
(210.1283 [M+H]+).
S
4
N
49/38
cis/trans=82/18
5
N
5-(4-Methoxyphenyl)-3-methyl-3,4-dihydro-2H-pyrrole (2): 1H NMR (500 MHz,
CDCl3): d 7.78 (d, J = 9.0 Hz, 2H), 6.91 (d, J = 9.0 Hz, 2H), 4.15 (dddd, J = 15.0, 8.0,
1.8, 1.8 Hz, 1H), 3.84 (s, 3H), 3.61 (dddd, J = 15.0, 5.0, 2.0, 1.8 Hz, 1H), 3.09
(dddd, J = 16.0, 8.0, 1.8, 1.8 Hz, 1H), 2.55 (dddd, J = 16.0, 5.5, 2.0, 2.0 Hz, 1H),
2.52 (m, 1 H), 1.10 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): d 172.2,
161.4, 129.2, 127.8, 113.8, 68.9, 55.5, 43.2, 31.6, 20.5. HRMS (ESI) for C12H16NO;
found (190.1229 [M+H]+), calcd (190.1232 [M+H]+).
18/—
6
a
Yield over two steps (imine formation and cyclization).
As determined by 1H NMR spectroscopy using DMAP as an internal standard.
b

P. Srivastava, L. Engman / Tetrahedron Letters 51 (2010) 1149–1151
3-Methyl-5-phenyl-3,4-dihydro-2H-pyrrole (3): 1H NMR (400 MHz, CDCl3): d [M]+), calcd (165.0612 [M]+).
1151
7.84 (m, 2H), 7.40 (m, 3H), 4.17 (dddd, J = 16.0, 9.5, 2.4, 2.4 Hz, 1H), 3.65
(dddd, J = 16.0, 7.0, 2.4, 2.4 Hz 1H), 3.12 (dddd, J = 16.0, 9.5, 2.4, 2.4 Hz, 1H),
2.59 (dddd, J =16.0, 7.0, 2.4, 2.4 Hz, 1H), 2.55 (m, 1H), 1.11 (d, J = 7.5 Hz, 3H).
13C NMR (100 MHz, CDCl3): d 172.8, 135.0, 130.4, 128.5, 127.6, 69.1, 43.3,
31.6, 20.5. HRMS (EI) for C11H13N; found (159.1049 [M]+), calcd (159.1048
[M]+).
cis-3,4-Dimethyl-5-phenyl-3,4-dihydro-2H-pyrrole (5): 1H NMR (500 MHz,
CDCl3): d 7.80 (m, 2H), 7.41 (m, 3H), 4.12 (ddd, J = 15.0, 7.0, 2.0 Hz, 1H),
3.63 (ddd, J = 15.0, 3.7, 1.0 Hz, 1H), 2.96 (m, 1H), 2.08 (m, 1H), 1.17 (d,
J = 7.0 Hz, 3H), 1.07 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): d 177.1,
134.3, 130.3, 128.7, 128.0, 66.7, 50.0, 40.4, 20.3, 17.8. HRMS (EI) for
C12H15N; found (173.1210 [M]+), calcd (173.1204 [M]+).
3-Methyl-5-(2-thienyl)-3,4-dihydro-2H-pyrrole (4): 1H NMR (500 MHz, CDCl3):
d 7.40 (dd, J = 5.0, 1.2 Hz, 1H), 7.29 (dd, J = 3.6, 1.2 Hz, 1H), 7.06 (dd, J = 5.0,
3.6 Hz, 1H), 4.14 (dddd, J = 16.0, 8.0, 1.9, 1.9 Hz, 1H), 3.61 (dddd, J = 16.0, 4.8,
1.9, 1.9 Hz, 1H), 3.11 (dddd, J = 16.0, 10.0, 1.9, 1.9 Hz, 1H), 2.57 (m, 2 H),
1.11 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3): d 167.6, 140.0, 131.0,
129.0, 127.5, 68.8, 43.9, 32.0, 20.4. HRMS (EI) for C9H11NS; found (165.0613
5-tert-Butyl-3-methyl-3,4-dihydro-2H-pyrrole (6): 1H NMR (500 MHz, CDCl3):
d
3.88 (dddd, J = 15.0, 7.5, 1.6, 1.6 Hz, 1H), 3.38 (dddd, J = 15.0, 5.0, 1.6,
1.6 Hz, 1H), 2.67 (dddd, J = 15.0, 7.5, 1.6, 1.6 Hz, 1H), 2.34 (m, 1H), 2.15
(dddd, J = 15.0, 5.0, 1.6, 1.6 Hz, 1H), 1.15 (s, 9H), 0.98 (d, J = 7.0 Hz, 3H). 13C
NMR (125 MHz, CDCl3): d 184.4, 67.9, 41.5, 35.7, 31.6, 27.9, 20.0. HRMS (EI)
for C9H17N; found (139.1354 [M]+), calcd (139.1361 [M]+).