Direct aminoalkylation of cycloalkanes through dimethylzinc-initiated radical process

Article abstract of DOI:10.1016/j.tetlet.2004.07.028

Cycloalkyl radicals were directly generated from cycloalkanes via C-H bond cleavage by the action of dimethylzinc-air and underwent an addition reaction with N-tosylimines, giving aminoalkylation products in fair to high yields.

Full text of DOI:10.1016/j.tetlet.2004.07.028

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6595–6597
Direct aminoalkylation of cycloalkanes through
dimethylzinc-initiated radical process
Ken-ichi Yamada, Yasutomo Yamamoto, Masaru Maekawa, Jingbo Chen and
Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 7 June 2004; revised 3 July 2004; accepted 8 July 2004
Available online 23 July 2004
Abstract—Cycloalkyl radicals were directly generated from cycloalkanes via C–H bond cleavage by the action of dimethylzinc–air
and underwent an addition reaction with N-tosylimines, giving aminoalkylation products in fair to high yields.
Ó 2004 Elsevier Ltd. All rights reserved.
We describe herein a direct aminoalkylation of cycloalk-
anes with imines using dimethylzinc–air as a radical ini-
( )n–4
Me2Zn–air
BF3•OEt2
X
Ts
Ts
tiator. We have recently reported the radical addition of
ethers to imines by the action of dimethylzinc–air.1 The
process is supposed to proceed through consecutive four
chemical steps: (1) generation of methyl radicals from
dimethylzinc and molecular oxygen,2 (2) subsequent
abstraction of an a-hydrogen of ethers to generate a-alk-
oxyalkyl radicals,3 (3) addition to imines, and finally
(4) zinc amide formation from the resulting aminyl rad-
icals. This reaction can be regarded as a direct substitu-
tion of an a-hydrogen of ethers for aminoalkyl groups.
The comparison of the bond dissociation energy
(BDE)4 of methyl-H (440kJ/mol), tetrahydrofuran-2-
yl-H (385kJ/mol), and cyclohexyl-H (400kJ/mol) led
us to the expectation that a methyl radical could
abstract a hydrogen atom from cycloalkanes to generate
cycloalkyl radicals. Consequently, direct aminoalkyl-
ation of cycloalkanes5 would be possible using dimethyl-
zinc–air as a radical initiator (Scheme 1).
+
R
N
( )n–4
R
N
H
1a : R = Ph
1b: R = 3-C5H4N
rt
(500 equiv)
2 (X = H)
3 (X = OH)
1c : R = PhCH2CH2
Scheme 1. Aminoalkylation of cycloalkanes with 1 using dimethylzinc.
mation of 3a was not decreased even when the reaction
was conducted under ordinary atmosphere without air
bubbling, to give 2a in 61% yield together with 3a in
13% yield. The formation of 3a was remarkably sup-
pressed by the addition of boron trifluoride etherate
(2.0mmol) to a reaction mixture, giving 2a in 80% yield
without production of 3a (entry 4).
Cycloalkanes of other ring size (n = 5, 7, and 8) also
underwent the aminoalkylation reaction under the same
conditions. Cyclopentane, cycloheptane, and cyclo-
octane were aminoalkylated to give the products in
68%, 61%, and 54% yield, respectively (entries 2, 6,
and 8). In all the reactions, the addition of boron triflu-
oride suppressed the production of oxidized products 3
to improve the yields of 2 (entries 1 vs 2, 3 vs 4, 5 vs
6, and 7 vs 8).
A
suspension of benzaldehyde N-tosylimine
1
(1.0mmol) and dimethylzinc (12mL, 1M hexane solu-
tion, 12mmol) in cyclohexane (54mL, 0.50mol) was stir-
red at rt for 48h with continuous air supply through a
bubbler (0.5mL/h) (Table 1, entry 3). Aminoalkylated
cyclohexane 2a (n = 6) was obtained in 68% yield along
with oxidized product 3a (n = 6) in 10% yield. The for-
Imine 1b derived from 3-pyridinecarbaldehyde was a
source of aminoalkylation agent, giving cyclohexane ad-
duct 2b (n = 6) in 38% yield (entry 9). Imine 1c derived
from 3-phenylpropanal underwent an addition reaction
with cyclohexane, giving 2c (n = 6) in 34% yield (entry
Keywords: Radicals; Dimethylzinc; Imines; Cycloalkanes.
*
Corresponding author. Tel.: +81-757534553; fax: +81-757534604;
e-mail: tomioka@pharm.kyoto-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.028

6596
K. Yamada et al. / Tetrahedron Letters 45 (2004) 6595–6597
Table 1. Aminoalkylation of cycloalkanes with imines 1 by dimethylzinc–aira in the presence or absence of boron trifluoride diethyl etherate
Entry
Cycloalkane (n)
1
Me2Zn (equiv)
BF3ÆOEt2 (equiv)
Time (h)
2 (%)
3 (%)
1
2
3
4
5
6
7
8
9
10
5
5
6
6
7
7
8
8
6
6
a
a
a
a
a
a
a
a
b
c
12b
9b
12
9b
12
9b
9b
9b
9b
9b
0
2
0
2
0
2
0
2
0
0
61
70
48
59
68
68
80
48
61
34
54
38
34
12
0
10
0
56
108
72
64
72
72
72
3
2
5
1
0
0
a The reaction was conducted under ordinary atmosphere (entries 2, 4, 6, and 8) in a round bottom flask equipped with a drying tube, or air was
introduced into a reaction mixture through a bubbler at the rate of 0.1 (entries 1 and 5) or 0.5L/(hÆmol) (entries 3 and 7).
b Dimethylzinc (3equiv each) was portionwise added.
initiator (3 x 3 equiv)
in-Aid for Scientific Research on Priority Areas (A)
ꢀExploitation of Multi-Element Cyclic Moleculesꢁ from
the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
Et
air
Ts
Ts
BF3•OEt2 (2 equiv)
Ph
N
Ph
+
N
+
+
2a
1
H
H
rt
4
5
(500 equiv)
Et2Zn: 54 h
Et3B : 70 h
26%
22%
44%
44%
11%
0%
Scheme 2. Aminoalkylation of cyclohexane with imine 1a using
diethylzinc or triethylborane as an initiator.
References and notes
1. (a) Yamada, K.; Yamamoto, Y.; Maekawa, M.; Tomioka,
K. J. Org. Chem. 2004, 69, 1531–1534; (b) Yamamoto, Y.;
Yamada, K.; Tomioka, K. Tetrahedron Lett. 2004, 45,
795–797; (c) Yamada, K.; Yamamoto, Y.; Tomioka, K.
Org. Lett. 2003, 5, 1797–1799; (d) Yamada, K.; Fujihara,
H.; Yamamoto, Y.; Miwa, Y.; Taga, T.; Tomioka, K. Org.
Lett. 2002, 4, 3509–3511.
2. The alkylzinc–oxygen derived complex has been isolated as
a possible radical precursor: Lewinski, J.; Marciniak, W.;
Lipkowski, J.; Justyniak, I. J. Am. Chem. Soc. 2003, 125,
12698–12699.
10). Boron trifluoride negatively influenced these two
reactions, giving messy mixtures of products.
Efficiency of other radical initiators was tested in the
reaction of cyclohexane with 1a (Scheme 2). When the
reaction was performed using diethylzinc6 as an initia-
tor, instead of dimethylzinc, 2a was obtained in 26%
yield after 54h, and ethyl adduct 4 was a main product
in 44% yield along with reduction product 5 in 11%
yield. By the initiation with triethylborane–air, the yield
of 2a was 22%, and ethyl adduct 4 was mainly produced
in 44% yield after 70h. Because an ethyl radical is more
stable (BDE of ethyl-H = 411kJ/mol)4 than a methyl
radical, the hydrogen abstraction from cyclohexane by
an ethyl radical would be slower than that by a methyl
radical, and the addition of an ethyl radical and/or the
reduction of imine 1 could be competitive.1d Accord-
ingly, dimethylzinc–air was the most efficient initiator
for this aminoalkylation reaction among those exam-
ined.
3. Selected recent examples of reactions of a-alkoxyalkyl
radicals: (a) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J.
Org. Chem. 2003, 68, 7548–7550; (b) Yoshimitsu, T.;
Arano, Y.; Nagaoka, H. J. Org. Chem. 2003, 68, 625–627;
´
(c) Fernandez, M.; Alonso, R. Org. Lett. 2003, 5,
2461–2464; (d) Tsujimoto, S.; Sakaguchi, S.; Ishii, Y.
Tetrahedron Lett. 2003, 44, 5601–5604; (e) Hirano, K.;
Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2002, 43,
3617–3620; (f) Mosca, R.; Fagnoni, M.; Mella, M.; Albini,
A. Tetrahedron 2001, 57, 10319–10328; (g) Torrente, S.;
Alonso, R. Org. Lett. 2001, 3, 1985–1987; (h) Kim, S.; Kim,
N.; Chung, W.-J.; Cho, C. H. Synlett 2001, 937–940.
4. McMillen, D. F.; Golden, D. M. Annu. Rev. Phys. Chem.
1982, 33, 493–532.
In conclusion, direct aminoalkylation of cycloalkanes
was achieved in fair to high yields at rt through a radical
process by the action of dimethylzinc–air. Since hydroxy-
alkylation7 and aminoalkylation5 reactions of alkanes
are quite few, the present aminoalkylation provides a
new methodology for the direct functionalization of sim-
ple alkanes under mild conditions.
5. Imidoylation of cycloalkanes has been reported: Citterio,
A.; Filippini, L. Synthesis 1986, 473–474.
6. (a) Bertrand, M. P.; Coantic, S.; Feray, L.; Nouguier, R.;
Perfetti, P. Tetrahedron 2000, 56, 3951–3961; (b) Bertrand,
M. P.; Feray, L.; Nouguier, R.; Perfetti, P. J. Org. Chem.
1999, 64, 9189–9193; (c) Bertrand, M. P.; Feray, L.;
Nouguier, R.; Perfetti, P. Synlett 1999, 1148–1150; (d)
Ryu, I.; Araki, F.; Minakata, S.; Komatsu, M. Tetrahedron
Lett. 1998, 39, 6335–6336.
7. (a) Brown, A. H.; Crabtree, R. H. J. Am. Chem. Soc. 1989,
111, 2946–2953; (b) Howard, E. G.; Sargeant, P. B.;
Krespan, C. G. J. Am. Chem. Soc. 1967, 89, 1422–1430;
(c) Fulier, G.; Rust, F. F. J. Am. Chem. Soc. 1958, 80,
6148–6149; For carbonylation or acylation: (d) Jaynes, B.
S.; Hill, C. L. J. Am. Chem. Soc. 1995, 117, 4704–4705; (e)
Boese, W. T.; Goldman, A. S. Tetrahedron Lett. 1992, 33,
Acknowledgements
This research was partially supported by the 21st Cen-
tury COE (Center of Excellence) Program ꢀKnowl-
edge Information Infrastructure for Genome Scienceꢁ,
a Grant-in-Aid for Young Scientists (B), and a Grant-

K. Yamada et al. / Tetrahedron Letters 45 (2004) 6595–6597
6597
2119–2122; (f) Boese, W. T.; Goldman, A. S. J. Am. Chem.
Soc. 1992, 114, 350–351; (g) Nakata, K.; Watanabe, J.;
Takaki, K.; Fujiwara, Y. Chem. Lett. 1991, 1437–1438;
(h) Bentrude, W. G.; Darnall, K. R. J. Am. Chem. Soc.
1968, 90, 3588–3589; (i) Odaira, Y.; Tominaga, T.; Sugihara,
T.; Tsutsumi, S. Tetrahedron Lett. 1964, 2527–2529.