Highly enantioselective radical addition to N-benzoyl hydrazones using chiral ammonium salts

Article abstract of DOI:10.1021/ja807685r

In the presence of a protonated cinchonine derivative, radical addition reactions proceeded efficiently, affording addition adducts in high yields with an extremely high enantioselectivity. The chiral ammonium salt was recyclable after a simple aqueous workup. The reaction provides environmentally benign reaction conditions. Copyright

Full text of DOI:10.1021/ja807685r

This paper was withdrawn on August 7, 2013 (J. Am. Chem. Soc. 2013, DOI: 10.1021/ja406816b).
Published on Web 11/11/2008
Highly Enantioselective Radical Addition to N-Benzoyl Hydrazones Using
Chiral Ammonium Salts
Doo Ok Jang* and Sang Yoon Kim
Department of Chemistry, Yonsei UniVersity, Wonju 220-710, Korea
Received September 29, 2008; E-mail: dojang@yonsei.ac.kr
Table 1. Addition of Isopropyl Radical to 2a under Various
Radical reactions have become a powerful and versatile tool for
organic chemists since the reactions provide mild and neutral
conditions in which a wide range of functional groups are tolerated.1
Stereochemical outcomes in radical reactions have been relying
mainly on utilizing chiral auxiliaries.2 Although they allow the
diastereoselectivity of products, additional cleavage steps are
required to obtain the desired products. Recent years have witnessed
significant progress in chiral Lewis acid mediated enantioselective
radical reactions.3,4 The chiral Lewis acids interact with substrates
noncovalently and provide the chiral environment as well as the
reactivity enhancement of substrates. During the past several years,
organocatalysts have drawn considerable attention, playing an
important role in nonradical enantioselective reactions.5,6 However,
little has been reported on the development of organocatalysts for
enantioselective radical reactions.7 With several advantages such
as low toxicity, low cost, and ease of manipulation, organocatalysts
are an attractive alternative to chiral Lewis acids in enantioselective
radical reactions.
We present a highly enantioselective radical-mediated C-N bond
forming reaction that uses organocatalysts under tin-free conditions.
This reaction provides access to highly enantioenriched chiral
amines that are important chiral building blocks.8 We assumed that
protonated cinchona alkaloid derivatives (PC) might interact with
substrates that are capable of being hydrogen-bonding acceptors
through hydrogen bonding and provide a chiral environment
(Scheme 1).
Reaction Conditions
yield (%)a
of 3a (3b)b
catalyst
(equiv)
iPrI
(equiv)
temp
(°C)
ee (%)c
of 3a
entry
1
2
3
4
5
6
7
8
9
10
11
12
13
1a (1.0)
1a (1.0)
1a (1.0)
1a (0.7)
1a (0.5)
1a (0.3)
1a (0.1)
1a (3.0)
1a (1.0)
1b (0.5)
1c (0.5)
1d (0.5)
1e (0.5)
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
1.5
5.0
5.0
5.0
5.0
RT
0
82 (9)
81 (9)
81 (9)
80 (10)
80 (9)
79 (10)
78 (11)
81 (9)
82
90
99
92
92
84
40
99
99
40
20
40
40
-30
-30
-30
-30
-30
-30
-30
-30
-30
-30
-30
82 (9)
76 (11)
77 (11)
76 (11)
78 (10)
a Isolated yield. b The yield in parentheses is for 3b. c Determined by
chiral HPLC analysis and compared with authentic racemic material.
Scheme 1
We initiated our work with 2a as a model substrate to establish
the optimal conditions for the enantioselective radical addition to
the CdN bond of N-benzoyl hydrazones. The results are tabulated
in Table 1. An isopropyl radical addition reaction of 2a was
performed in the presence of 1.0 equiv of 1a at room temperature.
The reaction proceeded smoothly and was completed in 4 h,
affording the addition adduct 3a in 82% with 82% ee (entry 1).
Diphenylsilane played a role as the radical chain carrier and also
as the hydrogen atom donor.9 We chose diphenylsilane instead of
organotin hydrides that are generally used as the radical chain carrier
to avoid their disadvantages such as high toxicity and difficulty in
purifying the product. Triethylborane was chosen since it allowed
reactions to be initiated at low temperatures. The enantioselectivity
was improved by conducting the reaction at lower temperature. The
reaction at -30 °C gave more than 99% ee (entry 3). To evaluate
the potency of an asymmetric catalyst, we examined the turnover
by lowering the catalyst loading. As the amount of 1a decreased
to 0.3 equiv, the yields remained almost the same, while the
enantioselectivity decreased, suggesting a catalyst turnover (entries
3-6). In the case of a reaction with 0.1 equiv of 1a, the
enantioselectivity decreased significantly without affecting the
chemical yield, showing that at least 0.3 equiv of 1a is required to
obtain the high enantioselectivity (entry 7). The reaction with an
excess of 1a did not affect the efficiency and the selectivity (entry
8). The addition reaction of 2a with an ethyl radical generated from
triethylborane took place as a background reaction, giving 3b in
∼10% yields along with the desired product 3a. By optimizing the
reaction further, we were able to reduce the amount of isopropyl
iodide to a stoichiometric amount at no expense to the yield and
selectivity of the product (entry 9). We examined the reactivity of
catalysts 1b-e having a different counteranion for the radical
addition reactions to CdN bonds (entries 10-13). The chiral
ammonium salts afforded comparable chemical yields with lower
enantioselectivity. It proved that 1a is a good choice.
Under optimal conditions, we investigated the efficiency of
reaction toward different kinds of alkyl halides. The results are
presented in Table 2. As demonstrated earlier, the addition reaction
of a secondary isopropyl radical gave high yields with excellent
enantioselectivity (see Table 1). Similar results were obtained in
the addition of a cyclohexyl radical (Table 2, entry 1). When tertiary
radicals such as tert-butyl and 1-adamantyl radicals were added,
good chemical yields and extremely high enantioselectivity were
obtained (entries 2 and 3). Addition of a primary octyl radical gave
a moderate yield and reduced enantioselectivity (entry 4).
9
16152 J. AM. CHEM. SOC. 2008, 130, 16152–16153
10.1021/ja807685r CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Alkyl Radical Addition to 2a in the Presence of 1aa
chemical yield and enantioselectivity were as high as when the
freshly prepared 1a was used. The product 3j was converted to
1-phenylpropane-1-amine using SmI2.10 The absolute configuration
of 3j was determined to be S by comparing the optical rotation
with that reported in the literature.
In conclusion, we have developed a chiral ammonium salt
mediated radical addition reaction with high enantioselectivity that
offers a method of approaching enantioenriched chiral amines. To
the best of our knowledge, the level of enantioselectivity and
generality reported herein is the highest among those previously
reported. The radical reactions can be performed under metal-free,
especially tin-free conditions. The chiral ammonium salts are
recyclable after a simple aqueous workup, and the reaction
conditions are environmentally benign. Further work to expand the
scope of the reaction is underway.
entry
R
product
yield (%)b
ee (%)c
1
2
3
4
chexyl
3c
3d
3e
3f
80
71
70
55
99
99
99
81
tbutyl
1-adamantyl
noctyl
a Reactions were run with 1a (0.4 mmol), 2a (0.4 mmol), RI (0.6
mmol), Ph2SiH2 (0.4 mmol), and Et3B (0.4 mmol) in CH2Cl2 (4 mL)
with addition of air (80 mL) at -30 °C for 4 h. b Isolated yield.
c Determined by chiral HPLC analysis and compared with authentic
racemic material.
Acknowledgment. This work was supported by the Center for
Bioactive Molecular Hybrids.
Table 3. Scope of Isopropyl Radical Addition to N-Benzoyl
Hydrazones Catalyzed by 1aa
Supporting Information Available: Experimental procedures,
compound characterization, NMR spectra, and HPLC traces. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For reviews on radical reactions: Radicals in Organic Synthesis; Sibi, M. P.,
entry
R
product
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ee (%)c
Renaud, P., Eds: Wiley-VCH: New York, 2001.
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1
2
3
4
5
6
7
8
9
2b
2c
2d
2e
2f
2g
2h
2i
4-Cl-Ph-
3g
3h
3i
3j
3k
3l
3m
3n
3o
81
80
81
81
79
80
77
81
72
99
99
99
99
98
98
99
99
80
4-MeC(O)-Ph-
4-NO2-Ph-
Ph-
4-OH-Ph-
4-OMe-Ph-
4-MeC(O)NH-Ph-
4-Et-Ph-
2j
CH3(CH2)6-
a Reactions were run with 1a (0.4 mmol), 2a (0.4 mmol), RI (0.6
mmol), Ph2SiH2 (0.4 mmol), and Et3B (0.4 mmol) in CH2Cl2 (4 mL)
with addition of air (80 mL) at -30 °C for 4 h. b Isolated yield.
c Determined by chiral HPLC analysis and compared with authentic
racemic material.
To evaluate the generality and the scope of the reaction, a wide
range of N-benzoyl hydrazones derived from aldehydes were
subjected to optimized conditions. Table 3 presents the results.
Radical addition reactions to aryl aldehyde derived N-benzoyl
hydrazones were all highly enantioselective (Table 3, entries 1-8).
In these cases, the trace of minor enantiomer was hardly detectable
in the chiral HPLC analysis. Aryl aldehyde derived N-benzoyl
hydrazones with an electron-poor benzene ring or an electron-rich
benzene ring gave similar results in terms of chemical yield and
enantioselectivity, showing the generality of reaction. The addition
reaction to N-benzoyl hydrazone derived from an aliphatic aldehyde
gave a moderate yield and reduced enantioselectivity (entry 9).
Radical addition to N-benzoyl hydrazone derived from a ketone
did not take place under the reaction conditions.
(6) For recent reports on organocatlysis: (a) Liu, K.; Cui, H.-F.; Nie, J.; Dong,
K.-Y.; Li, X.-J.; Ma, J.-A. Org. Lett. 2007, 9, 923. (b) Tsogoeva, S. B.;
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Chem., Int. Ed. 2004, 43, 5849.
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J.-C.; Suh, Y.; Qin, J. J. Org. Chem. 2006, 71, 7016. (b) Friestad, G. K.;
Draghici, C.; Soukri, M.; Qin, J. J. Org. Chem. 2005, 70, 6330. (c) Miyabe,
H.; Ueda, M.; Naito, T. Synlett 2004, 1140. (d) Yamada, K.; Yamamoto,
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(9) The reaction became sluggish without diphenylsilane: Barton, D. H. R.;
Jang, D. O.; Jaszberenyi, J. C. Tetrahedron Lett. 1990, 31, 4681.
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Although high loading of 1a was required to attain a high level
of enantioselectivity, 1a was readily recovered after a simple
aqueous workup in more than 95% yield. When the recovered 1a
was reused in the isopropyl radical addition reaction to 2a, the
JA807685R
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J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16153