Radical amination with trimethylstannylated benzophenone imine

Article abstract of DOI:10.1021/ol1005455

Figure presented Intermolecular radical amination reactions of various primary, secondary, and tertiary alkyl radicals by using trimethylstannylated benzophenone imine A as a novel radical acceptor to provide imines of type B are described. These imines are readily reduced with NaBH₄ to the corresponding secondary amines C. The novel radical amination can be combined with typical radical cyclization reactions.

Full text of DOI:10.1021/ol1005455

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2072-2075
Radical Amination with
Trimethylstannylated Benzophenone
Imine
Marie-Ce´line Lamas, Santiago E. Vaillard, Birgit Wibbeling, and Armido Studer*
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t, Corrensstrasse 40,
48149 Mu¨nster, Germany
studer@uni-muenster.de
Received March 8, 2010
ABSTRACT
Intermolecular radical amination reactions of various primary, secondary, and tertiary alkyl radicals by using trimethylstannylated benzophenone
imine A as a novel radical acceptor to provide imines of type B are described. These imines are readily reduced with NaBH4 to the corresponding
secondary amines C. The novel radical amination can be combined with typical radical cyclization reactions.
Radical chemistry has found great attention during the last
20 years and is amply used in complex natural product
synthesis.1 Many functional groups are tolerated under radical
conditions, and complex sequential processes can readily be
performed by using this approach. As compared to radical
C-C bond-forming reactions and C-radical reductions,
radical carbon-heteroatom bond formation has been less
intensively investigated. However, many natural products and
most biologically interesting compounds (drugs) contain
N-atoms. Therefore, development of new methods for C-N
bond formation is important. By using radical chemistry, this
bond connection can be performed by either addition of
N-centered radicals to olefinic acceptors2,3 or by addition of
C-centered radicals to N-type acceptors.4 The present paper
focuses on the latter approach. Different reagents such as
nitric oxide,5 azo compounds,6 diazirines,7 diazonium salts,8
and azides9 have been successfully used as N-type acceptors
for radical amination reactions. Moreover, appropriately
substituted imines have been shown to be able to act as
N-type radical acceptors.10 However, to the best of our
knowledge, all reports on imines as radical acceptors deal
(5) Okamoto, T.; Oka, S. J. Chem. Soc., Chem. Commun. 1984, 289.
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Renaud, P. J. Am. Chem. Soc. 2001, 123, 4717. Panchaud, P.; Chabaud,
L.; Landais, Y.; Ollivier, C.; Renaud, P.; Zigmantas, S. Chem.sEur. J.
2004, 10, 3606. Nyfeler, E.; Renaud, P. Org. Lett. 2008, 10, 985. Mantrand,
N.; Renaud, P. Tetrahedron 2008, 64, 11860. Cren, S.; Scha¨r, P.; Renaud,
P.; Schenk, K. J. Org. Chem. 2009, 74, 2942.
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10.1021/ol1005455  2010 American Chemical Society
Published on Web 04/02/2010

with cyclization reactions. Herein we present the first
intermolecular radical aminations onto imines by using
N-trimethylstannylated benzophenone imine 3 as a novel
radical acceptor (Scheme 1).
experiments were conducted in sealed tubes. With R,R′-
azobisisobutyronitrile (AIBN) as an initiator, the reaction did
not work (entries 1 and 2). With 1,1′-azobis(cyclohexane-
1-carbonitrile) (V-40) as an alternative azo initiator product
formation was not observed (entry 6). Pleasingly, with di-
tert-butyl hypodinitrite14 at 60 °C in benzene, imine 5 was
obtained, clearly showing that our new approach for inter-
molecular radical amination is working. However, the
product was isolated in a moderate 24% yield (entry 3). A
similar result was achieved in n-heptane (entry 4) and
Scheme 1. Radical Amination with 3
15
initiation with Et3B/O2 afforded 5 in a lower yield (entry
5). Benzoyl and lauroyl peroxide turned out to be less
efficient initiators for our radical amination (entries 7 and
8). Di-tert-butyl peroxide (DTBP) as initiator in benzene gave
5 in 15% yield (entry 9). We assumed that radical addition to
benzene might occur as a side reaction that would lead to chain
termination. Indeed, in tert-butylbenzene, which is less prone
to undergo homolytic aromatic substitution, yield could be
improved to 38% (entry 10). Along this line, yield was further
improved in n-heptane under otherwise identical conditions
(61%, entry 11).16 The radical nature of the process was
supported by running the amination in the absence of any
initiator. As expected for a radical process, no product was
identified by GC analysis under these conditions (entry 12).
This experiment clearly showed that 5 was not formed via a
SN2-type process. Lowering the amount of 3 from 1.5 to 1.25
equiv led to a decrease in yield, whereas increasing reagent
loading to 1.75 did not significantly change reaction outcome
and with 2 equiv of 3 the best result was achieved (entries
13-15). Di-tert-butyl peroxide (0.25 equiv) turned out to be
the ideal initiator loading since lowering the peroxide amount
led to a decrease in yield (entries 16-18).17
We next studied the scope and limitations of the
amination reaction applying the optimized conditions (di-
tert-butyl peroxide (0.25 equiv) in n-heptane in a sealed
tube at 140 °C oil bath temperature and 2 equiv of 3).
For some derivatives we observed partial decomposition
of the product imines of type 5 during SiO2 chromatog-
raphy. In those cases, the crude imine was reduced with
NaBH4 in MeOH to give the corresponding bulky second-
ary amines of type 6, which were readily isolated by
Recently, we reported on radical phosphanylations with
stannylated phosphine 1.11 C-Radical addition to the P-atom
of 1 turned out to be very fast. The adduct radical then
liberates the trimethyltin radical which is able to propagate
the chain. This process corresponds to a formal homolytic
substitution at phosphorus. Based on these results, we decided
to test homolytic substitution at the trimethylstannylated
amine 2.12 Unfortunately, all amination attempts with 2 by
using various C-radicals under different conditions failed.
We therefore decided to approach the intermolecular
radical amination by an addition/elimination sequence with
an imine as a radical acceptor. In order to get regiose-
lective N-addition, phenyl groups were installed at the
imine functionality (see 3). Addition of a C-radical to 3
should generate adduct radical 4 which will then eliminate
the chain propagating trimethyltin radical to provide the
targeted imine 5.
The known amination reagent 3 was readily prepared by
reaction of benzonitrile with commercially available Ph-Li
and subsequent treatment with Me3SnCl in Et2O (see the
Supporting Information).13 Imine 3, which was purified by
distillation, could be stored under argon in the refrigerator
for months.
As a test reaction we studied amination of cyclohexyl
iodide with 3 under different conditions (Table 1). All
(14) Mendelhall, G. D. Tetrahedron Lett. 1983, 24, 451.
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S.; Suzuki, M.; Kijima, A.; Ogasawara, K. Chem. Lett. 1990, 315.
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Tomaszewski, M. T.; Warkentin, J. J. Chem. Soc., Chem. Commun. 1993,
11, 966. Takano, S.; Suzuki, M.; Ogasawara, K. Heterocycles 1994, 37,
149. Bowman, R. W.; Stephenson, P. T.; Terret, N. K.; Young, A. R.
Tetrahedron Lett. 1994, 35, 6369. Bowman, R. W.; Stephenson, P. T.; Terret,
N. K.; Young, A. R. Tetrahedron 1995, 51, 7959. Gioanola, M.; Leardini,
R.; Nanni, D.; Pareschi, P.; Zanardi, G. Tetrahedron 1995, 51, 2039.
McClure, C. K.; Kiessling, A. J.; Link, J. S. Tetrahedron 1998, 54, 7121.
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120, 5838. Depature, M.; Diewok, J.; Grimaldi, J.; Hatem, J. Eur. J. Org.
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E. N.; Plotkin, M. A.; Johnston, J. N. J. Am. Chem. Soc. 2003, 125, 163.
Tojino, M.; Otsuka, N.; Fukuyama, T.; Matsubara, H.; Ryu, I. J. Am. Chem.
Soc. 2006, 128, 7712.
(16) As side products, protected amines derived from amination of
heptane were identified. Alkoxyl radicals abstract H-atoms from n-heptane
under the applied conditions. All possible regioisomeric n-heptane amination
products were identified by GC analysis.
(17) Further increase of the di-tert-butyl concentration (>0.2 equiv)
provided larger amounts of heptane amination side products.
(18) For conversion of imines to free amines, see: Sampson, P. B.;
Honek, J. F. Org. Lett. 1999, 1, 1395. Ooi, T.; Takeuchi, M.; Kato, D.;
Uematsu, Y.; Tayama, E.; Sakai, D.; Maruoka, K. J. Am. Chem. Soc. 2005,
127, 5073.
(19) Jereb, M.; Zupan, M.; Stavber, S. Green. Chem. 2005, 7, 100.
(20) Hackmann, C.; Scha¨fer, H. J. Tetrahedron 1993, 49, 4559.
(21) Review: Fensterbank, L.; Malacria, M.; Sieburth, S. M. Synthesis
1997, 813. See also: Studer, A. Angew. Chem., Int. Ed. 1998, 31, 462. Studer,
A.; Steen, H. Chem.sEur. J. 1999, 5, 759.
(11) Vaillard, S. E.; Mu¨ck-Lichtenfeld, C.; Grimme, S.; Studer, A.
Angew. Chem., Int. Ed. 2007, 46, 6533.
(22) CCDC 760806 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at www.ccdc.ca-
m.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (int.) +44(1223)336-
033, E-mail: deposit@ccdc.cam.ac.uk].
(12) For a formal homolytic substitution at N, see: Uenoyama, Y.;
Fukuyama, T.; Ryu, I. Org. Lett. 2007, 9, 935.
(13) Chan, L. H.; Rochow, E. G. J. Organomet. Chem. 1967, 9, 231.
Org. Lett., Vol. 12, No. 9, 2010
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Table 1. Amination of Cyclohexyl Iodide with 3 under Different Conditions (0.5 M)
entry
3 (equiv)
solvent
initiator (equiv)
AIBN (0.25)
temp (°C)
yielda (%)
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.5
n-heptane
benzene
benzene
n-heptane
benzene
n-heptane
n-heptane
n-heptane
benzene
t-Bu-benzene
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
n-heptane
140
115
60
60
60
<2
<2
24
22
14
<2
19
8
15
38
61
<2
37
54
62
9
AIBN (0.25)
t-BuONdNO-t-Bu (0.25)
t-BuONdNO-t-Bu (0.25)
Et3B/O2 (0.25)
1.5
1.5
V-40 (0.25)
80
1.5b
1.5b
1.5
lauroyl peroxide (0.25)
benzoyl peroxide (0.25)
t-BuOO-t-Bu (0.25)
t-BuOO-t-Bu (0.25)
t-BuOO-t-Bu (0.25)
140
140
115
140
140
140
140
140
140
140
140
140
9
10
11
12
13
14
15
16
17
18
1.5
1.5
1.5
1.25c
1.75cc
2.0
t-BuOO-t-Bu (0.25)
t-BuOO-t-Bu (0.25)
t-BuOO-t-Bu (0.25)
t-BuOO-t-Bu (0.10)
t-BuOO-t-Bu (0.15)
t-BuOO-t-Bu (0.20)
1.5
1.5
1.5
37
60
a Isolated yield after SiO2 chromatography. b Conducted at 0.2 M concentration. c Conducted at 0.7 M concentration.
chromatography.18 All aminations were conducted with
the corresponding alkyl iodides since reactions did not
work well starting with bromides.
Amination of cyclohexyl iodide with subsequent reduction
provided amine 6a in 84% yield (Figure 1). This result
showed that during purification of imine 5a some product
was decomposed (compare Table 1, entry 15). An even better
result was obtained for amination of pentyl iodide to give
6b (87% yield). Functionalized primary alkyl radicals also
underwent amination as shown for the preparation of 5f and
6d. Pleasingly, tertiary-alkyl radicals reacted efficiently with
3 (see 6c). Amination of R-silyloxy or R-alkoxyalkyl radicals
provided the corresponding protected R,ꢀ-amino alcohols 6e
and 6g. Due to the high temperatures used it was not
surprising that amination occurred with low diastereoselec-
tivity (trans/cis ) 1.2:1, see 6e). Protected amino sugars such
as 5h can be obtained via our approach starting with readily
available iodo glycosides.19 Unfortunately, aryl and vinyl
radicals could not be aminated with reagent 3 under the tested
conditions.
Finally, we looked at cascade reactions comprising a
typical radical cyclization reaction followed by amination.
To this end, iodide 7 was reacted with imine 3 under our
optimized amination conditions. The crude product was
reduced with NaBH4, and bicycle 8 was isolated as a 7.3:1
1
mixture of diastereoisomers (checked by H NMR spec-
troscopy) in 49% yield. The relative configuration of the
major isomer depicted in Scheme 2 was assigned by
comparison with product assignments of similar radical
cyclization reactions.20 Iodinated silyl ether 9 underwent
radical 5-exo-cyclization with subsequent amination. The
intermediately formed cyclic silyl ether was then reacted
with MeLi21 to give imine 10 as a single isomer. The
relative configuration of 10 was unambiguously assigned
by X-ray analysis (Figure 2).22
The 5-exo-radical cyclization reaction of the 5-hexenyl
radical has been intensively used as a radical clock for
Figure 1. Amination products.
2074
Org. Lett., Vol. 12, No. 9, 2010

Scheme 2. Radical Cyclization/Amination with 3
Figure 2. Molecular structure of 10.
In summary, we introduced stannylated imine 3 as a novel
reagent for intermolecular radical aminations. Aminations
can be conducted as cascade processes comprising typical
radical cyclizations with subsequent C-N bond formations.
Product imines are protected amines since the imine moiety
installed by the radical reaction can be regarded as the
N-protecting group. Moreover, imines can be reduced to the
corresponding secondary amines.
determination of the rate constant for reaction of a primary
alkyl radical with a given radical trapping reagent.23 To get
an idea about the efficiency of our amination process, we
reacted iodide 11 under radical conditions with either 3 or 4
equiv of imine 3 to give a mixture of cyclized 12a and
noncyclized imine 12b. The two experiments were repeated
two times (each) and the rate constant was estimated on the
basis of averaged 12a/12b ratios of these six experiments.
By using the experimentally determined rate constant for that
particular 5-exo cyclization at 140 °C (6.15 × 106 s-1),24
we calculated the rate constant for trapping of a primary alkyl
radical with imine 3 to lie in the order of 5 × 106 M-1 s-1
at 140 °C.
Acknowledgment. We thank the DFG for funding our
work. Novartis Pharma AG (Young Investigator Award to
A.S.) and the Alexander von Humboldt foundation (stipend
to S.E.V) are acknowledged for supporting our work.
Supporting Information Available: Experimental details,
characterization data for the products, and the X-ray structure
of 10 (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(23) Newcomb, M. Tetrahedron 1993, 49, 1151.
(24) Chatgilialoglu, C.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc.
1981, 103, 7739.
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