Peroxide-mediated efficient addition of cycloalkanes to imines

Article abstract of DOI:10.1016/j.tetlet.2008.07.040

A novel direct addition of cycloalkanes to imines mediated by peroxide was developed. The reaction tolerates a wide range of functionalities as well as aqueous conditions.

Full text of DOI:10.1016/j.tetlet.2008.07.040

Tetrahedron Letters 49 (2008) 5601–5604
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Tetrahedron Letters
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Peroxide-mediated efficient addition of cycloalkanes to imines
*
Guojun Deng, Chao-Jun Li
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quebec, Canada 3HA 2K6
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel direct addition of cycloalkanes to imines mediated by peroxide was developed. The reaction
tolerates a wide range of functionalities as well as aqueous conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 4 June 2008
Revised 20 June 2008
Accepted 7 July 2008
Available online 11 July 2008
Keywords:
Peroxide
C–H transformation
Alkanes
Imines
The Grignard reaction1 is an important reaction in organic
chemistry and has made the synthesis of numerous important
organic compounds possible.2 In their most general form, an
organometallic reagent such as an organomagnesium reagent
reacts with C@O, C@N, and C„N bonds to form nucleophilic
addition products (route A, Fig. 1).3–5 A fundamental drawback of
Grignard-type reactions is the requirement for generating an
organometallic reagent from organic halides and a stoichiometric
amount of metal. On the other hand, we envisioned an alternative
transformation to generate Grignard-type reaction products via the
catalytic reaction of simple alkanes with C@O, C@N, and C„N
bonds without using an organometallic reagent, with the potential
of high atom-economy6 (route B, Fig. 1). Toward such a goal, herein
we wish to report a highly efficient direct addition of cycloalkanes
with imines mediated by peroxide to give Grignard-type addition
products (Scheme 1).
followed by
hydrolysis, H+
X
C
+
MX
R
route A
XH
X=O, N
R
X
C
cat.
+
R
H
route B
X=O, N
Figure 1. Classical Grignard-type reaction and Grignard-type reaction with alkane.
The 1,2-addition of alkyl group to C@N bonds is a key method
for the preparation of various amines.7,8 To begin our study, we
discovered that the reaction of (E)-N-benzylidenebenzenamine
(1a) with cyclooctane (2a) at 135 °C under an atmosphere of air
generated 13% of N-(cyclooctyl(phenyl)methyl)benzenamine (4a)
(Table 1, entry 1). The yield was increased to 36% by using 2 equiv
of tert-butyl hydroperoxide (3a) (Table 1, entry 2). Other peroxides
such as 3b and 3c are also effective. When dicumyl peroxide (3d)
was used, the desired product was obtained in 89% yield (Table
1, entry 5). The best yield was observed by using tert-butyl perox-
ide (3e) as a mediator (Table 1, entry 6). Decreasing the reaction
temperature (Table 1, entry 7) or the amount of the peroxide (Table
R2
R2
HN
ROOR
N
+
H
R1
R1
H
Scheme 1. Addition of cycloalkanes to imines.
1, entries 8 and 9) decreased the product yield. Most importantly, it
is also possible to perform the reaction with only a catalytic
amount of peroxide, albeit with a decreased yield (Table 1, entry
9). Furthermore, an excellent yield was also achieved in the pres-
ence of water (Table 1, entry 10).9
With the optimized conditions in hand, we examined the scope
of the addition of various cycloalkanes to imines (Table 2). In
* Corresponding author. Tel.: +1 514 398 8457; fax: +1 514 398 3797.
E-mail address: cj.li@mcgill.ca (C.-J. Li).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.040

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G. Deng, C.-J. Li / Tetrahedron Letters 49 (2008) 5601–5604
Table 1
general, the tert-butyl peroxide-mediated addition occurs
Optimization of reaction conditionsa
smoothly to provide the desired Grignard-type reaction products
in good to excellent yields. Various electron-withdrawing and elec-
tron-donating substituents at different positions of the N-aryl-
arylimines did not affect the reaction significantly (Table 2, entries
2–15). The reaction showed a good regio-selectivity when a long
chain substituted imine was used: only the imine–cycloalkane
addition product was observed (Table 2, entry 4) and no reaction
was observed due to the alkyl chain. The reaction also showed
good functional group tolerance: an arylimine bearing an ester
group (unlikely to survive under the classical Grignard-type reac-
tions) at the para-position reacted with cyclooctane to give the cor-
responding product in 82% yield (Table 2, entry 8). It is noteworthy
mentioning that the reaction also tolerates the presence of halo-
gens (Table 2, entries 5–7, 9, and 12). Other cycloalkanes such as
cycloheptane and cyclohexane also reacted smoothly with (E)-N-
benzylidenebenzenamine to give the desired addition products in
good yields (Table 2, entries 16–18). A decreased yield was ob-
served when cyclopentane was used as a reagent due to its low
boiling point. It should be noted that imines pre-synthesized or
generated in situ from the corresponding aldehyde and aniline pro-
vided similar results.
Ph
HN
Ph
Ph
peroxide (3)
N
+
Ph
1a
2a
4a
Entry
1
Peroxide (equiv)
—
T (°C)
Yieldb (%)
13
135
2
3
4
5
6
(3a) (2.0)
135
135
135
135
135
36
33
42
89
96
O OH
Ph O-OH
PhC(O)O
(3b) (2.0)
(3c) (2.0)
(3d) (2.0)
O
Ph O O Ph
(3e) (2.0)
O O
A tentative mechanism to rationalize this reaction of cycloal-
kane with imine is illustrated in Scheme 2. When heated, the per-
oxide 3 decomposes to generate an alkoxide radical. The alkoxyl
radical then abstracts a hydrogen from cycloalkane 2 to give a
cycloalkyl radical together with an alcohol.10 Addition of the cyclo-
alkyl radical to imine 1 generates an addition product bearing a
nitrogen radical,11 which gives the desired product 4 by abstract-
ing a hydrogen from another cycloalkane and regenerates the
cycloalkane radical at the same time.
7
(3e) (2.0)
(3e) (1.0)
(3e) (0.2)
(3e) (2.0)
120
135
135
135
50
88
47
81
8c
9c
10d
a
Conditions: all reactions were carried out with 1a (0.2 mmol) and 2a (0.6 mL,
4.5 mmol) in 15 h under an atmosphere of air, unless otherwise noted.
b
H NMR yields were determined by using 1,2-dichloroethane as an internal
standard.
c
Reaction time: 30 h.
Water (100 lL, 5.5 mmol) was added.
In summary, we have developed a novel direct addition of
d
cycloalkanes to imines mediated by peroxide.12 The study provides
Table 2
Addition of cycloalkanes to iminesa
Entry
Product
Yieldb (%)
Entry
10
Product
Yieldb (%)
Ph
Ph
Ph
HN
Ph
HN
1
81
75
4j
HN
4a
Ph
HN
O
2
65
11
84
4k
Ph
4b
Ph
HN
Cl HN
3
62
12
83
H3CO
Cl
4l
4c
Ph
HN
HN
Ph
4
83
13
72
H3C(H2C)4O
4d
4m

G. Deng, C.-J. Li / Tetrahedron Letters 49 (2008) 5601–5604
5603
Table 2 (continued)
Entry
Product
Yieldb (%)
Entry
14
Product
Yieldb (%)
OCH3
Ph
HN
HN
Ph
5
68
53
58
71
Cl
4e
4n
I
Ph
HN
HN
Ph
6
80
15
F
4f
4o
Ph
Ph
HN
HN
Ph
7
71
16
F3C
4p
4g
Ph
Ph
HN
HN
Ph
8
82
70
17
18
60
37
H3CO2C
4q
Ph
4h
Ph
HN
HN
Cl
9
Ph
4r
4i
a
Conditions: al reactions were carried out with imine (0.2 mmol), tert-butyl peroxide (0.4 mmol), cycloalkane (4.5 mmol), 15 h in air at 135 °C.
Isolated yields.
b
a new avenue for synthesizing Grignard-type imine addition prod-
ucts by using cycloalkanes rather than organometallic reagents.
Further investigations including the scope, mechanism, a catalytic
reaction, and asymmetric addition of this reaction are in progress
in our laboratory.
.
RO
R O O R
3
.
.
RO
+
alkyl
+
ROH
alkyl
H
Acknowledgments
2
We thank the Canada Research Chair (Tier I) foundation (to CJL),
CFI, NSERC, and the ACS-GCI Pharmaceutical Roundtable for partial
support of our research.
Ar'
H
Ar'
.
N
N
.
+
alkyl
Ar
Ar
References and notes
alkyl
1
1. (a) Grignard, V. Compt. Rend. 1890, 130, 1322; (b) Barbier, P. Compt. Rend. 1899,
128, 110.
Ar'
.
2. Blomberg, C. The Barbier Reaction and Related One-Step Processes. In Reactivity
and Structure: Concepts in Organic Chemistry; Hafner, K., Lehn, J. M., Rees, C. W.,
von Ragué Schleyer, P., Trost, B. M., Zahradnîk, R., Eds.; Springer, 1993.
3. (a) Wakefield, B. J. Organomagnesium Methods in Organic Chemistry; Academic
Press: San Diego, CA, 1995; (b) Silverman, G. S.; Rakita, P. E. Handbook of
Grignard Reagents; Marcel Dekker: New York, 1996; (c) Richey, H. G., Jr.
Grignard Reagents; Wiley: Chichester, UK, 2000; (d) Knochel, P. Handbook of
Functionalized Organometallics; Wiley-VCH: Weinheim, Germany, 2005.
N
Ar'
HN
Ar
alkyl
+
.
+
H
alkyl
Ar
alkyl
alkyl
2
4
Scheme 2. Tentative mechanism for the addition of cycloalkanes to imines
mediated by peroxides.

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G. Deng, C.-J. Li / Tetrahedron Letters 49 (2008) 5601–5604
4. For reviews: (a) Lai, Y. H. Synthesis 1981, 585; (b) Enders, D.; Reinhold, U.
Tetrahedron: Asymmetry 1997, 8, 1895; (c) Bloch, R. Chem. Rev 1998, 98, 1407;
(d) Eisch, J. J. Organometallics 2002, 21, 5439; (e) Hatano, M.; Miyamoto, T.;
Ishihara, K. Curr. Org. Chem. 2007, 11, 127.
7061; (e) Cougnon, F.; Feray, L.; Bazin, S.; Bertrand, M. P. Tetrahedron 2007,
63, 11959.
9. (a) Li, C. J.; Chan, T. H. Tetrahedron 1999, 55, 11149; (b) Li, C. J. Tetrahedron 1996,
52, 5643.
5. For Grignard-type cycloalkylation of imines, see: Hatano, M.; Suzuki, S.;
Ishihara, K. J. Am. Chem. Soc. 2006, 128, 9998.
10. For fragmentation of alkoxy radical, see: Kochi, J. K. J. Am. Chem. Soc. 1962, 84,
1193.
6. (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259; (b) Trost, B. M. Science
1991, 254, 1471.
7. For reviews on the radical additions to C@N bonds, see: (a) Friestad, G. K.
Tetrahedron 2001, 57, 5461; (b) Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004,
1140; (c) Friestad, G. K. Eur. J. Org. Chem. 2005, 3157.
8. For recent examples on radical alkylations to C@N bonds, see: (a) Yamada, K.;
Yamamoto, Y.; Mackawa, M.; Tomioka, K. J. Org. Chem. 2004, 69, 1531; (b)
Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T. Tetrahedron 2004, 60, 4227; (c)
Friestad, G. K.; Draghici, C.; Soukri, M.; Qin, J. J. Org. Chem. 2005, 70, 6330; (d)
Friestad, G. K.; Marié, J. C.; Suh, Y. S.; Qin, J. J. Org. Chem. 2006, 71,
11. For monographs on free-radical reactions, see: Curran, D. P.; Porter, N. A.;
Giese, B. Stereochemistry of Radical Reactions; VCH: Weinheim, 1996; Togo, H.
Advanced Free Radical Reactions for Organic Synthesis; Elsevier: London, 2004.
12. Typical experimental procedures:
A reaction vessel was charged with 1
(0.2 mmol), peroxide 2 (0.4 mmol), and cycloalkane 3 (4.5 mmol). Then the
reaction vessel was sealed and the resulting solution was stirred at 135 °C for
15 h. After cooling to room temperature, the volatiles were removed in vacuo
and the residue was purified by column chromatography (silica gel, hexane/
dichloromethane = 9:1) to give product 4. All new compounds were
characterized by means of 1H NMR, 13C NMR, MS (EI), and HRMS.