Copper(I)-catalyzed intramolecular addition of N-chloroamines to double bonds under aprotic conditions. Towards a stereoselective catalytic radical reaction

Article abstract of DOI:10.1055/s-2000-7605

Copper(I) complexes catalyze the intramolecular addition of N-chloramines to carbon-carbon double bonds under neutral conditions, a reaction that proceeds via a metal complexed aminyl radical. A high diastereoselectivity is obtained in the cyclization step due to the sterically demanding copper complex.

Full text of DOI:10.1055/s-2000-7605

PAPER
1561
Copper(I)-Catalyzed Intramolecular Addition of N-Chloroamines to Double
Bonds under Aprotic Conditions. Towards a Stereoselective Catalytic Radical
Reaction
Richard Göttlich*
Organisch-Chemisches Institut der Westfälischen Wilhelms-Universität Münster, Corrensstr. 40, 48149 Münster, Germany
E-mail: gottlir@uni-muenster.de
Received 17 December 1999; revised 9 June 2000
double bonds is known for a long time,6,7 albeit under
Abstract: Copper(I) complexes catalyze the intramolecular addi-
highly acidic conditions, inhibiting the coordination of the
aminyl radical to a Lewis acid by protonation. Therefore,
tion of N-chloramines to carbon–carbon double bonds under neutral
conditions, a reaction that proceeds via a metal complexed aminyl
we tried to perform this reaction under aprotic conditions,
using a redox active metal, which acts as a catalyst to ini-
tiate and terminate the radical reaction as well as a Lewis
acid activating the aminyl radical for the addition reac-
tion.6,7
radical. A high diastereoselectivity is obtained in the cyclization
step due to the sterically demanding copper complex.
Key words: catalysis, copper, diastereoselectivity, piperidines, rad-
ical reactions
We started our studies by using different redox active
metal salts5 to achieve cyclization of the N-chloro-N-pen-
tenylamine 1a (Scheme 1) and indeed were able to per-
form the cyclization reaction under almost neutral
conditions.
During the last years the importance of free radical chem-
istry has increased continuously, and today radical reac-
tions are no longer considered uncontrollable and
unselective.1 As a direct consequence radical reactions are
already used as key-steps in the synthesis of complex nat-
ural products. This is especially due to the pioneering
studies of Giese, Curran, Porter and others, who showed
that in radical reactions high diastereoselectivities can be
obtained.1 Compared to these reactions, to date only little
is known about a catalyst influenced stereoselectivity in
radical reactions.2
However, we did not isolate the expected pyrrolidine 2
(which we could only detect in the NMR of the reaction-
mixture) but piperidine 3a. The formation of which is
most likely due to a rearrangement of the primary reaction
product, the 2-chloromethyl-pyrrolidine 2, via an aziridin-
ium ion 4 to the thermodynamically more stable 3-chloro-
piperidine,5,8 thereby allowing us to form piperidines via
a kinetically favourable 5-exo cyclization.
In our own work, we are searching for catalysts, which ac-
tivate the radical for an addition to double bonds, thereby
allowing us to study its influence on the stereoselectivity
of the reaction. For this purpose the addition of aminyl
radicals to double bonds seemed ideal, as neutral aminyl
radicals add only slowly or not at all to double bonds,
whilst cationic amminium radicals react readily.3 This al-
lows the activation of aminyl radicals by Lewis acids.4
Amongst various potential catalysts screened for this re-
action copper(I) chloride produced the best yields. How-
ever, the catalysis seems to stop after a few cycles
(Scheme 1). This might be due to product inhibition, as
the piperidine can act as a ligand for copper(II) and there-
by reduces its Lewis acidity. Addition of copper(II) chlo-
ride as a Lewis acid produced higher yields of piperidine,
however, this approach does not meet with our aim to use
only substoichiometric amounts of metal salts. As an al-
ternative, we decided to raise the reaction temperature in
order to accelerate ligand exchange reactions on cop-
per(II). This was successful, as can be seen from the good
A very recent report on the diastereoselectivity in the cy-
clization of cationic aminyl radicals5 prompted us to re-
port here our own results.
As a radical precursor, we chose the easily available N-
chloro-N-(4-pentenyl)amines, the addition of which to
Bu
N
Bu
N
Bu
Cl
N
Cl
Cat.
N
Bu
rt, THF
Cl
Cl
2
4
3
1
Cat. = 50 mol% CuCl
Cat. = 10 mol% CuCl
58%
16%
Scheme 1
Synthesis 2000, No. 11, 1561–1564 ISSN 0039-7881 © Thieme Stuttgart · New York

1562
R. Göttlich
PAPER
yields of cyclization products for various N-chloroamines
(using 10% copper(I) chloride) given in Table 1 (for ana-
lytical data see Table 2).
L
L
Cu
N
R
N
L
Cu
L
R
These conditions are also suitable for performing a 6-exo
radical cyclization (1e to 3e) in good yield,9 even though
this process is slow compared to the analogous 5-exo cy-
clization.
Scheme 2
The remarkable influence of the catalyst on the stereo-
selectivity of the reaction can be deduced from the dia-
stereoselectivities obtained using the chloroamines 1c and
1d.10 As the metal complex with its ligand-sphere prefers
the sterically less demanding position in the chair-like
transition state (Scheme 2),11 essentially higher diastereo-
selectivities compared to cyclizations of simple carbon
radicals1 (1c to 3c) and to previously reported diastereo-
meric ratios for the cyclization of this aminyl radical12 are
obtained.
When the distance between the catalyst and the group in
the transition state is increased (as is the case for 1d),
these steric interactions are reduced and a lower diastereo-
selectivity is obtained.
We are currently performing further investigations to-
wards the influence of copper catalysts on the stereoselec-
tivity of these cyclizations, results will be reported in due
course.
All solvents were purified by distillation and dried, if necessary, pri-
or to use. Products were purified by flash chromatography on silica
1
gel (40-63 mm). H (300 MHz) and 13C NMR (75 MHz) spectra
Table 1 Yields and Diastereomeric Ratios of the Cyclizations
were recorded on a Bruker WM 300 spectrometer in CDCl3 using
TMS as internal standard. With the exception of N-butyl-(2-phenyl-
pent-4-enyl)amine the required alkenylamines were prepared ac-
cording to reported procedures.12,13
N-Butyl-(2-phenylpent-4-enyl)amine
To a solution of p-toluenesulfonyl chloride (57 g, 0.3 mol) in
CH2Cl2 (300 mL) were added pyridine (23.2 mL, 0.3 mol) and 2-
phenyl-4-pentenol14 (40.6 g, 0.25 mol) at 0 °C. The reaction was
stirred overnight at r.t. and then poured into H2O (300 mL). The or-
ganic layer was separated and the aqueous layer extracted once with
CH2Cl2 (100 mL). The combined organic layers were dried
(Na2SO4) and the solvent was removed in vacuo. The residue was
added to butylamine (150 mL, 1.5 mol) and the solution was heated
under reflux for 14 h. Butylamine was removed in vacuo, the resi-
due was dissolved in CH2Cl2 (300 mL), and extracted with 2 M
NaOH (5 ¥ 100 mL). The organic layer was dried (Na2SO4) and the
solvent was removed in vacuo. Distillation of the residue gave the
pure amine (39.4 g, 0.18 mol, 72%), bp: 110 °C, 0.5 mbar.
1H NMR: d = 0.85 (t, 3H, 7.3 Hz), 1.09 (s, 1H), 1.18 (m, 4H), 2.15-
2.58 (m, 4H), 2.83 (m, 3H), 5.10 (m, 2H), 5.68 (ddt, 1H, 17.7, 10.5,
6.6 Hz), 7.25 (m, 5H).
13C NMR: d = 14.0, 20.4, 32.2, 39.1, 45.7, 49.7, 55.1, 116.0, 126.0,
127.8, 128.5, 136.7, 143.5.
For the elemental analysis, the hydrochloride salt was prepared.
Anal. calcd for C15H24NCl: C, 70.98; H, 9.53; N, 5.52. Found: C,
71.05; H, 9.78; N, 5.73.
N-Chloroamines 1a-e; General Procedure
To a solution of the amine (20 mmol) in CH2Cl2 (50 mL) was added
NCS (2.7 g, 20 mmol) at 0 °C, and the solution was stirred at this
temperature for 2 h. The solvent was removed in vacuo and the res-
idue washed with pentane (2 ¥ 50 mL). The pentane was removed
in vacuo and the residue purified by flash chromatography (t-
BuOMe/pentane, 1:25). The chloroamines were obtained as color-
less oils that could be stored at -30 °C. Due to their instability, sat-
isfying elementary analysis of the N-chloroamines could not be
obtained (for analytical data, see Table 2).
a dr (Diastereomeric ratio) determined by NMR.
Synthesis 2000, No. 11, 1561–1564 ISSN 0039-7881 © Thieme Stuttgart · New York

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Copper(I)-Catalyzed Intramolecular Addition of N-Chloroamines to Double Bonds
1563
Table 2 Selected Data of N-Chloroamines and Piperidinesa
Product
1H NMR (300 MHz, CDCl3) d (ppm), J (Hz)
13C NMR (75 MHz, CDCl3) d (ppm)
1a
0.91 (t, 3 H, J = 7.3), 1.35 (m, 2 H), 1.63 (m, 2 H), 1.74 (m, 2 H), 2.10 (m, 2 H),
2.89 (m, 4 H), 4.98 (m, 2 H), 5.78 (ddt, 1 H, J = 17.2, 10.2, 6.6)
13.9, 20.0, 27.1, 30.0, 30.9, 63.5, 64.1,
114.9, 138.1
1b
1c
0.93 (t, 3 H, J = 7.3), 0.94 (s, 6 H), 1.30-1.70 (m, 4 H), 2.07 (dt, 2 H, J = 6.0,
14.0, 19.9, 25.7, 30.3, 35.6, 44.9, 66.6,
74.8, 117.2, 135.3
1.2), 2.83 (s, 2 H), 2.92 (m, 2 H), 4.98 (m, 2 H), 5.81 (m, 1 H)
0.92 (t, 3 H, J = 7.3), 1.13 (d, 3 H, J = 6.2), 1.30-1.80 (m, 6 H), 2.12 (m, 2 H),
2.82 (m, 1 H), 2.95 (m, 1 H), 3.63 (m, 1 H), 5.01 (m, 2 H), 5.80 (ddt, 1 H, J =
16.9, 10.2, 6.7)
13.9, 14.5, 20.0, 30.5, 30.6, 33.7, 59.6,
63.7, 114.7, 138.5
1d
0.88 (t, 3 H, J = 7.4), 1.31 (m, 2 H), 1.59 (m, 2 H), 2.35 (m, 1 H), 2.59 (m, 1 H),
2.92 (m, 2 H), 3.09 (m, 2 H), 3.13 (m, 1 H), 4.95 (m, 2 H), 5.65 (ddt, 1 H, J =
17.1, 10.0, 6.9), 7.25 (m, 5 H)
13.8, 20.0, 29.9, 37.8, 44.1, 64.5, 69.3,
116.3, 126.4, 127.9, 128.3, 136.3, 142.9
1e
0.86 (t, 3 H, J = 7.6), 1.30 (m, 4 H), 1.60 (m, 4 H), 2.01 (dt, 2 H, J = 7.2, 7.2),
2.84 (m, 4 H), 4.92 (m, 2 H), 5.74 (ddt, 1 H, J = 17.6, 10.0, 6.8)
12.1, 19.1, 26.0, 28.1, 29.0, 32.5, 63.1,
63.2, 113.6, 137.6
3a
3b
3c
0.92 (t, 3 H, J = 7.2), 1.30-1.80 (m, 8 H), 2.10 (m, 2 H), 2.35 (m, 2 H), 2.70 (m,
13.6, 20.4, 24.5, 28.6, 34.7, 52.8, 55.8,
58.9, 61.3
2 H), 3.06 (m, 2 H), 3.96 (m, 1 H)
0.90 (t, 3 H, J = 7.1), 0.91 (s, 3 H), 1.03 (s, 3 H), 1.36 (m, 5 H), 1.68 (d, 1 H,
J = 8.4), 1.92 (m, 2 H), 2.37 (m, 3 H), 3.15 (m, 1 H), 4.06 (m, 1 H)
14.0, 20.5, 25.2, 29.1, 29.4, 33.2, 48.5,
54.2, 57.7, 62.4, 64.8
0.92 (t, 3 H, J = 7.3), 1.07 (d, 3 H, J = 6.2), 1.20-1.70 (m, 6 H), 2.10-2.50 (m,
4 H), 2.71 (m, 2 H), 3.19 (m, 1 H), 3.94 (m, 1 H) [minor isomer: 4.15 (m, 1 H)]
14.0, 19.6, 20.8, 22.6, 27.2, 34.5, 35.7,
53.0, 55.2, 60.5
3d
3db
3e
0.91 (d, 3 H, J = 7.1), 1.35 (m, 2 H), 1.47 (m, 2 H), 1.75 (m, 1 H), 2.07 (m,
2 H), 2.41 (m, 3 H), 2.93 (m, 2 H), 3.27 (m, 1 H), 4.07 (m, 1 H), 7.27 (m, 5 H)
14.0, 20.6, 28.7, 42.0, 42.4, 54.9, 57.8,
59.8, 61.1, 126.8, 127.1, 128.6, 142.5
0.91 (t, 3 H, J = 7.2), 1.34 (m, 2 H), 1.49 (m, 2 H), 2.00 (m, 1 H), 2.18 (m, 2 H),
2.42 (m, 3 H), 3.00 (m, 2 H), 3.39 (m, 1 H), 4.41 (m, 1 H), 7.22 (m, 5 H)
14.0, 20.7, 28.8, 37.5, 39.4, 56.4, 58.2,
59.5, 60.5, 126.6, 127.4, 128.5, 143.4
1.03 (t, 3 H, J = 7.2), 1.36-1.83 (m, 10 H), 2.40 (m, 1 H), 2.57 (m, 1 H), 2.67
(m, 1 H), 2.76 (m, 1 H), 2.96 (m, 1 H), 3.72 (m, 2 H)
13.0, 19.8, 21.9, 24.5, 26.0, 27.0, 44.4,
50.5, 52.7, 59.8
a All new compounds gave satisfactory elemental analysis or HRMS.
b Minor diastereomer.
Cyclization of N-Chloroamines; General Procedure
Porter, N. A.; Wu, J. H.; Zhang, G.; Reed, A. D. J. Org. Chem.
1997, 62, 6702.
(3) Newcomb, M.; Deeb, T. M.; Marquardt, D. J. Tetrahedron
1990, 46, 2317.
Horner, J. H.; Martinez, F. N.; Musa, O. M.; Newcomb, M.;
Shahin, H. E. J. Am. Chem. Soc. 1995, 117, 11124.
(4) Murphy, J. A., Dickinson, J. M. J. Chem. Soc., Chem.
Commun. 1990, 434.
To a solution of the chloroamine 1 (3 mmol) in anhyd THF (5 mL)
under an Ar atm was added CuCl (30 mg, 10 mol%) at 50 °C and
the reaction was kept at this temperature for 12 h. Then H2O (40
mL) and concd aqueous ammonia (2 mL) were added and the mix-
ture was extracted with CHCl3 (3 ¥ 30mL). The combined organic
layers were dried (Na2SO4), the solvent was removed in vacuo, and
the residue purified by flash chromatography (t-BuOMe/pentane,
1:10 to 1:1) to give 3a-e. For analytical data, see Table 2.
Newcomb, M.; Ha, C. Tetrahedron Lett. 1991, 32, 6493.
Ha, C.; Musa, O. M.; Martinez, F. N.; Newcomb, M. J. Org.
Chem. 1997, 62, 2704.
Bowman, W. R.; Stephenson, P. T.; Young, A. R.
Tetrahedron 1996, 52, 11445.
Acknowledgement
Financial support by the Fonds der Chemischen Industrie (Liebig
fellowship) and by the Alfried Krupp von Bohlen und Halbach-Stif-
tung is gratefully acknowledged.
(5) Hemmerling, M.; Sjöholm, A.; Somfai, P. Tetrahedron:
Asymmetry 1999, 4091.
(6) Iron(II) and copper(I) salts have been used previously to
generate aminyl radicals from N-chloroamines, which were
used for addition to double bonds: Minisci, F.; Galli, R.;
Cecere, M. Chim. Ind. 1966, 48, 347.
References
(1) For an overview see: Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions; VCH, Weinheim:
1996.
Neale, R. S. J. Org. Chem. 1967, 32, 3263.
Surzur, J.-M.; Stella, L.; Tordo, P. Bull. Soc. Chim. Fr. 1970,
115.
(2) The work in this field is dominated by Lewis acid catalyzed
radical additions to a,b-unsaturated carbonyls: Sibi, M. P.; Ji,
J. Angew. Chem. Int. Ed. Engl. 1997, 36, 274.
Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem.
Soc. 1998, 120, 6615.
Minisci, F. Synthesis 1973, 1.
(7) For a review, see: Stella, L. Angew. Chem. 1983, 95, 368.
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R. Göttlich
PAPER
(13) a) Surzur, J.-M.; Stella, L.; Tordo, P. Bull. Soc. Chim. Fr.
(8) a) Fusaon, R. C.; Zirkle, C. L. J. Am. Chem. Soc. 1948, 70,
2760.
1975, 1425.
b) Hammer, C. F.; Heller, S. R.; Craig, J. H. Tetrahedron
1972, 28, 239.
Surzur, J.-M.; Tordo, P.; Stella, L. Bull. Soc. Chim. Fr. 1970,
111.
(9) In this case no rearranged seven-membered ring is formed.
(10) The rearrangement is known to proceed without epimerization
of the stereocenter, see ref. (8b).
(11) Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K.; J. Chem. Soc.,
Chem. Commun. 1980, 482.
b) Tiecco, M.; Testaferri, L.; Bagnoli, L. Tetrahedron 1996,
52, 6811.
(14) Bloodworth, A. J.; Courtneidge, J. L.; Curtis, R. J.; Spencer,
M. D. J. Chem. Soc., Perkin Trans. 1 1990, 2951.
Beckwith, A. L. J.; Lawrence, T.; Serelis, A. K.; J. Chem.
Soc., Chem. Commun. 1980, 484.
Article Identifier:
Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959.
(12) Newcomb, M.; Marquardt, D. J.; Deeb, T. M. Tetrahedron
1990, 46, 2329.
1437-210X,E;2000,0,11,1561,1564,ftx,en;H10099SS.pdf
Synthesis 2000, No. 11, 1561–1564 ISSN 0039-7881 © Thieme Stuttgart · New York