Tin-free intermolecular addition of primary alkyls to imines via the dimethylzinc-air radical process

Article abstract of DOI:10.1021/ol052563r

(Chemical Equation Presented) A dimethylzinc-air initiator was applied to the generation of primary alkyl radicals from alkyl iodides. The addition of the generated primary alkyl radicals to N-tosylimines was accelerated by the action of boron trifluoride

Full text of DOI:10.1021/ol052563r

ORGANIC
LETTERS
2006
Vol. 8, No. 1
87-89
Tin-Free Intermolecular Addition of
Primary Alkyls to Imines via the
Dimethylzinc−Air Radical Process
Ken-ichi Yamada, Yasutomo Yamamoto, Masaru Maekawa, Tito Akindele,
Hiroyuki Umeki, and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity,
Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
Received October 22, 2005
ABSTRACT
A dimethylzinc
−
air initiator was applied to the generation of primary alkyl radicals from alkyl iodides. The addition of the generated primary
diethyl etherate and copper(II) triflate to give the corresponding
3 h. Air oxygen was essential for the reaction to proceed, showing involvement of a radical process in the
alkyl radicals to N-tosylimines was accelerated by the action of boron trifluoride
adducts in good yields after 2
reaction.
−
−
Development of environmentally sustainable reactions is an
important goal of recent organic chemistry. To this end, it
is essential to avoid the use and production of toxic
compounds in organic reactions. Although trialkyltin hy-
drides, which enable many transformations via radical
processes, are among the most versatile reagents in organic
synthesis, difficulty in complete removal and toxicity of tin
compounds are critical drawbacks, especially for industrial
applications.1 Herein, we describe a new tin-free method for
the generation and reaction of primary alkyl radicals.2
abstracts R-hydrogen of ethers to generate R-alkoxyalkyl
radicals. Recently, we have also developed direct generation
of cycloalkyl radicals from plain cycloalkanes and their
addition reaction to N-tosylimines.4d,6 In continuation with
our investigation, we then attempted direct generation of a
primary alkyl radical from a chain alkane. However, the
reaction of N-tosylimine 1a with hexane in the presence of
dimethylzinc and air as an initiator only gave a 1:1 mixture
of 1-methylpentyl adduct and 1-ethylbutyl adduct in 25%
combined yield after 45 h without the production of hexyl
adduct. Thus, we decided to generate primary alkyl radicals
from alkyl iodides.
Since our discovery of the radical addition of ethers to
imines by the action of dimethylzinc and air,3 we have
investigated direct generation of carbon-centered radicals via
C-H bond cleavage and their reactions.4,5 Dimethylzinc
reacts with air oxygen to release methyl radical, which
(4) (a) Yamada, K.; Yamamoto, Y.; Tomioka, K. Org. Lett. 2003, 5,
1797-1799. (b) Yamamoto, Y.; Yamada, K.; Tomioka, K. Tetrahedron
Lett. 2004, 45, 795-797. (c) Yamada, K.; Yamamoto, Y.; Maekawa, M.;
Tomioka, K. J. Org. Chem. 2004, 69, 1531-1534. (d) Yamada, K.;
Yamamoto, Y.; Maekawa, M.; Chen, J.-b.; Tomioka, K. Tetrahedron Lett.
2004, 45, 6595-6597. (e) Yamamoto, Y.; Maekawa, M.; Akindele, T.;
Yamada, K.; Tomioka, K. Tetrahedron 2005, 61, 379-384.
(5) Yamada, K.; Yamamoto, Y.; Tomioka, K. J. Synth. Org. Chem., Jpn.
2004, 62, 1158-1165.
(6) Review of radical addition to CdN bonds: (a) Friestad, G. K.
Tetrahedron 2001, 57, 5461-5496. (b) Naito, T. Heterocycles 1999, 50,
505-541. (c) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543-
17594.
(1) Review: Neumann, W. P. Synthesis 1987, 665-683.
(2) Recent examples for tin-free generation of primary alkyl radicals:
(a) Cannella, R.; Clerici, A.; Pastori, N.; Regolini, E.; Porta, O. Org. Lett.
2005, 7, 645-648. (b) Friestad, G. K.; Qin, J. J. Am. Chem. Soc. 2001,
123, 9922-9923. (c) Kim, S.; Song, H.-J.; Choi, T.-L.; Yoon, J.-Y. Angew.
Chem., Int. Ed. 2001, 40, 2524-2526.
(3) Yamada, K.; Fujihara, H.; Yamamoto, Y.; Miwa, Y.; Taga, T.;
Tomioka, K. Org. Lett. 2002, 4, 3509-3511.
10.1021/ol052563r CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/08/2005

For the generation of alkyl radicals, triethylborane-air
initiation has been a popular tin-free method.7 Ethyl radical,
generated from triethylborane, abstracts iodine from alkyl
iodides8 or hydrogen from solvent ethers9 to give carbon-
centered radicals. However, the scope of this method is
limited to the generation of secondary, tertiary, and stabilized
alkyl radicals. Production of primary alkyl radicals by the
triethylborane method is inefficient because ethyl radical is
as stable as other primary alkyl radicals. The most common
solution to this problem is the use of a stoichiometric amount
of tributyltin hydride as a source of a tin radical that
efficiently abstracts halogen.10 Because a methyl radical is
less stable than primary alkyl radicals (bond dissociation
energy in kJ/mol; Me-H ) 439 vs Et-H ) 421),11 we
expected that a methyl radical, generated from dimethylzinc,
should be able to abstract an iodine atom from a primary
alkyl iodide to give a primary alkyl radical.
First, the reaction of imine 1a and hexyl iodide was carried
out by using a large excess amount of the iodide and
dimethylzinc, without solvent. The expected generation of
hexyl radical seemed to take place, giving hexyl adduct 2 in
40% yield after 110 h (Table 1, entry 1). In the presence of
6 equiv of boron trifluoride-diethyl etherate,4d the reaction
was accelerated to give 2 in 62% yield after 10 h with 5
equiv of the iodide, 6 equiv of dimethylzinc, and dichlo-
romethane as solvent (entry 2).
To our delight, the reaction was further accelerated with
0.1 equiv of copper(I) iodide12 to give 2 in 64% yield after
6 h (entry 3). Other copper salts were also tested. The results
with copper(I) halides (entries 3-5) were less satisfactory
than those with other copper(I) and copper(II) salts (entries
6-10). Copper(II) triflate gave the best results to afford 2
in 71% yield after 1.5 h (entry 10). Without boron trifluo-
ride-diethyl etherate, the reaction was rather slower, giving
2 in 45% yield even after 24 h (entry 11). [1,1′-Bis-
(diphenylphosphino)ferrocene]dichloropalladium also ac-
celerated the reaction, but less efficiently, to give 2 in 57%
yield after 4 h (entry 14). Interestingly, when nickel(II)
acetylacetonate was used as an additive, the addition of a
methyl group took place very quickly to give methyl adduct
in 97% yield after 0.5 h (entry 15). Finally, it was found
that the reaction with copper(II) triflate was as efficient when
cooled in an ice-water bath to give 2 in 74% yield after 1.5
h (entry 12). Under argon atmosphere, the reaction was
dramatically retarded (entry 13). These results suggest that
the initiation of a radical process by dimethylzinc and air
oxygen is required for the reaction.
Table 1. The Addition of Hexyl to Imine 1a Initiated by
Me2Zn-Aira
Me2Zn n-C6H13
I
time yield
entry (equiv) (equiv)
additives (equiv)
none
BF3‚OEt2 (6)
BF3‚OEt2 (6)
CuI (0.1)
temp
(h)
(%)
1b
2
3
9
6
6
60
5
5
rt
rt
rt
110
10
6
40
62
64
4
5
6
7
4
4
4
4
5
5
5
5
BF3‚OEt2 (4)
CuBr (0.1)
BF3‚OEt2 (4)
CuCl (0.1)
BF3‚OEt2 (4)
CuCN (0.1)
BF3‚OEt2 (4)
Cu(ClO4)(MeCN)4
(0.1)
rt
rt
rt
rt
3
3
3
3
53
47
65
64
8
9
4
4
2
5
5
5
BF3‚OEt2 (4)
(CuOTf)2‚C6H6 (0.1)
BF3‚OEt2 (4)
CuCl2 (0.1)
BF3‚OEt2 (2)
Cu(OTf)2 (0.1)
Cu(OTf)2 (0.1)
BF3‚OEt2 (2)
Cu(OTf)2 (0.1)
BF3‚OEt2 (2)
Cu(OTf)2 (0.1)
BF3‚OEt2 (2)
PdCl2(dppf)‚CHCl3
(0.1)
rt
rt
rt
3
3
63
63
10
1.5 71
11
12
2
2
5
5
rt
0 °C
24
1.5 74
45
13c
14
2
2
5
5
0 °C
rt
1.5
5
4
57
15
2
5
BF3‚OEt2 (2)
Ni(acac)2 (0.1)
rt
0.5
0d
a The reaction was conducted under ordinary air atmosphere with a CaCl2
drying tube unless otherwise mentioned. b Without solvent CH2Cl2. c Under
argon atmosphere. d Methyl adduct was obtained in 97% yield.
Other radical initiators, diethylzinc13 and triethylborane,14
were tested with regard to their reaction efficiency. The
reactions were conducted under the same conditions as in
Table 1, entry 12. Diethylzinc or triethylborane, in place of
dimethylzinc, gave ethyl adduct 3 as the major product in
82% and 32% yield, respectively (Scheme 1). Adduct 2 was
Scheme 1. The Reaction of 1a and n-C6H13I Initiated by Et2Zn
or Et3B in the Presence of BF3‚OEt2 and Cu(OTf)2
(7) Ollivier, C.; Renaud, P. Chem. ReV. 2001, 101, 3415-3434.
(8) (a) Nozaki, K.; Oshima, K.; Uchimoto, K. Tetrahedron Lett. 1988,
29, 1041-1044. (b) Suzuki, A.; Nozawa, S.; Harada, M.; Itoh, M.; Brown,
H. C.; Midland, M. M. J. Am. Chem. Soc. 1971, 93, 1508-1509.
(9) (a) Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Org. Chem. 2005, 70,
2342-2345. (b) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem.
2003, 68, 7548-7550. (c) Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Org.
Chem. 2003, 68, 625-627. (d) Yoshimitsu, T.; Tsunoda, M.; Nagaoka, H.
Chem. Commun. 1999, 1745-1746.
(10) Unfortunately, the tin method sometimes fails: Friestad, G. K.;
Draghici, C.; Soukri, M.; Qin, J. J. Org. Chem. 2005, 70, 6330-6338.
(11) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic
Compounds; CRC Press: Boca Raton, FL, 2003; p 11.
the minor product as expected.15
Other primary alkyl iodides were also applicable to the
reaction. Butyl adduct 4a was obtained in 80% yield (Table
2, entry 1). The addition of 4-acetoxybutyl proceeded without
(13) Bertrand, M. P.; Coantic, S.; Feray, L.; Nouguier, R.; Perfetti, P.
Tetrahedron 2000, 56, 3951-3961.
(14) Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004, 1140-1157.
(12) (a) Knochel, P. Synlett 1995, 393-403. (b) Knochel, P.; Singer, R.
D. Chem. ReV. 1993, 93, 2117-2188.
88
Org. Lett., Vol. 8, No. 1, 2006

As a utility of this reaction, cyclization of adducts 6 and
7 into piperidine and pyrrolidine, respectively, was carried
out. To this end, treatment of 6 with potassium carbonate in
DMF for 1 h gave 2-phenylpiperidine 10 in 96% yield
(Scheme 2). 2-Phenylpyrrolidine 11 was also obtained from
Table 2. The Addition of Alkyls to Imines 1 Initiated by
Me2Zn-Air in the Presence of BF3‚OEt2 and Cu(OTf)2
a
Scheme 2. Cyclization of 6 and 7 to Form 2-Phenylpiperidine
10 and Pyrrolidine 11
time
(h)
yield
adduct (%)
entry imine
R1
R2
1
2
3
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Bu
1.5
4a
5
6
7
8
80
77
84
77
95
91
82
83
57
58
67
69
AcO(CH2)4 1.5
Cl(CH2)4
Cl(CH2)3
i-Pr
c-C6H11
Bu
1.5
1.5
0.5
1.0
2
2
3
3
2
4b
5c
7 in 95% yield.16 Other 2-substituted piperidines and
pyrrolidines may be easily synthesized in the same manner.
In conclusion, we have developed a new tin-free method
for the generation of primary alkyl radicals and their addition
to N-tosylimines. The use of a stoichiometric amount of
boron trifluoride-diethyl etherate and a catalytic amount of
copper(II) triflate accelerated the reaction and improved the
efficiency of the reaction. The reaction was extremely slow
under argon atmosphere, showing that a radical process
initiated by dimethylzinc and air oxygen should be in-
volved.17
6c
9
7
4-ClC6H4
4-MeOC6H4 Bu
1-Naph
2-Naph
PhCH2CH2 Bu
c-C6H11 Bu
4b
4c
4d
4e
4f
4g
8b
9d
10d
11e
12b
Bu
Bu
1g
3
a Unless otherwise mentioned, iodide (5 equiv), Me2Zn and BF3‚OEt2
(2 equiv each), and Cu(OTf)2 (0.1 equiv) were used. b Me2Zn and BF3‚OEt2
(3 equiv each) were used. c Iodide, Me2Zn, and BF3‚OEt2 (1.5 equiv each)
were used. d Me2Zn (3 equiv), BF3‚OEt2 (5 equiv), and Cu(OTf)2 (0.2 equiv)
were used. e Me2Zn (2 equiv) and BF3‚OEt2 (3 equiv) were used.
Acknowledgment. This research was partially supported
by the 21st Century COE (Center of excellence) Program
“Knowledge Information Infrastructure for Genome Sci-
ence”, a Grant-in-Aid for Young Scientists (B), and a Grant-
in-Aid for Scientific Research on Priority Areas 17035045
and “Advanced Molecular Transformations” from the Min-
istry of Education, Culture, Sports, Science and Technology,
Japan.
problems to give 5 in 77% yield (entry 2). The reaction with
chloroalkyl iodides gave chloroalkyl adducts 6 and 7 without
the production of the corresponding iodoalkyl adducts
(entries 3 and 4). When secondary alkyl iodides were used
as alkyl sources, the reactions required only 1.5 equiv each
of the iodide, boron trifluoride-diethyl etherate, and di-
methylzinc to give adducts 8 and 9 in high yields after 0.5
or 1 h (entries 5 and 6).
Supporting Information Available: The reaction pro-
cedure and the characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The reaction proceeded with other N-tosylimines 1. The
reaction with imines 1b and 1c having an electron-withdraw-
ing 4-chloro or donating 4-methoxy group on the aromatic
rings gave 4b and 4c in 82% and 83% yield, respectively
(entries 7 and 8). With imine 1d and 1e bearing a naphthyl
group, 4d and 4e were obtained in 57% and 58% yield,
respectively (entries 9 and 10). Aliphatic hydrocinnamalde-
hyde and cyclohexanecarbaldehyde imines 1f and 1g were
also good acceptors, giving the corresponding adducts 4f and
4g in 67% and 69% yield, respectively (entries 11 and 12).
OL052563R
(16) Attempts to obtain 10 in a one-pot reaction by heating the reaction
mixture after the radical addition failed, probably due to low nucleophilicity
of the zinc amide formed by the alkyl addition.
(17) An alternative pathway of nonradical addition of dialkylzincs
generated from alkyl iodides and dimethylzinc may be negligible because
only a trace amount (<1%) of methyl adduct was obtained in the reaction
under argon atmosphere (Table 1, entry 13). Moreover, the iodine-zinc
exchange between alkyl iodides and dimethylzinc is unlikely because the
process would involve displacement of the less stable methyl radical by
more stable primary or secondary alkyl radicals: Micouin, L.; Knochel, P.
Synlett 1997, 327-328.
(15) Miyabe, H.; Ueda, M.; Yoshioka, N.; Yamakawa, K.; Naito, T.
Tetrahedron 2000, 56, 2413-2420.
Org. Lett., Vol. 8, No. 1, 2006
89