Aerobic hydroxylation of N-borylenamine: Triethylborane-mediated hydroxyalkylation of α,β-unsaturated oxime ether

Article abstract of DOI:10.1021/ol901912j

Intermolecular hydroxyalkylatlon of α,β-unsaturated imines involving Et₃B-medlated regioselective alkyl radical addition and subsequent hydroxylation with molecular oxygen has been developed, In which N-borylenamine generated by trapping of the

Full text of DOI:10.1021/ol901912j

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4632-4635
Aerobic Hydroxylation of
N-Borylenamine:
Triethylborane-Mediated
Hydroxyalkylation of r,ꢀ-Unsaturated
Oxime Ether
Masafumi Ueda,† Hideto Miyabe,‡ Takahiro Kimura,† Eiko Kondoh,†
Takeaki Naito,*,† and Okiko Miyata*,†
Kobe Pharmaceutical UniVersity, Motoyamakita, Higashinada, Kobe 658-8558, Japan,
and School of Pharmacy, Hyogo UniVersity of Health Sciences, Minatojima,
Kobe 650-8530, Japan.
miyata@kobepharma-u.ac.jp; taknaito@kobepharma-u.ac.jp
Received August 17, 2009
ABSTRACT
Intermolecular hydroxyalkylation of r,ꢀ-unsaturated imines involving Et3B-mediated regioselective alkyl radical addition and subsequent
hydroxylation with molecular oxygen has been developed, in which N-borylenamine generated by trapping of the enaminyl radical with Et3B
was a key intermediate in the proposed aerobic hydroxylation mechanism.
Free-radical-mediated hydroxyalkylation reactions involving
both carbon-carbon bond formation and oxygenation pro-
cesses provide an attractive approach for preparing complex
molecules.1 Therefore, some investigations have focused on
oxygenation of carbon radicals, generated by radical addition
to alkenes. Intramolecular hydroxyalkylation studies of
stannyl radical-mediated or cobalt-catalyzed oxygenative
cyclization of olefinic halides have been conducted by
Nakamura,2 Prandi,3 and other groups.4 The challenging
intermolecular hydroxyalkylation has recently been achieved
by use of a Grignard reagent,5 cobalt(II),6 photochemical
irradiation,7 electrolysis,8 cerium(IV),9 manganese(III),10 and
aluminum(III).11,12 However, these reported methods have
some unavoidable drawbacks, which are generation of ketone
(5) (a) Nobe, Y.; Arayama, K.; Urabe, H. J. Am. Chem. Soc. 2005, 127,
18006. (b) de Armas, J.; Hoveyda, A. H. Org. Lett. 2001, 3, 2097. (c) Bell,
L.; Brookings, D. C.; Dawson, G. J.; Whitby, R. J.; Jones, R. V. H.; Standen,
M. C. H. Tetrahedron 1998, 54, 14617. (d) Hoveyda, A. H.; Morken, J. P.
J. Org. Chem. 1993, 58, 4237.
(6) (a) Kagayama, T.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2005,
46, 3687. (b) Hara, T.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem.
2001, 66, 6425. (c) Iwahama, T.; Sakaguchi, S.; Ishii, Y. Chem. Commun.
2000, 613. (d) Hirano, K.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. Chem.
Commun. 2000, 2457. (e) Bhatia, S.; Punniyamurthy, T.; Bhatia, B.; Iqbal,
J. Tetrahedron 1993, 49, 6101.
† Kobe Pharmaceutical University.
‡ Hyogo University of Health Sciences.
(1) Ollivier, C.; Renaud, P. In Radicals in Organic Synthesis; Renaud,
P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, p 93.
(2) (a) Sawamura, M.; Kawaguchi, Y.; Nakamura, E. Synlett 1997, 801.
(b) Nakamura, E.; Inubushi, T.; Aoki, S.; Machii, D. J. Am. Chem. Soc.
1991, 113, 8980.
(7) (a) Yoshida, M.; Ohkoshi, M.; Aoki, N.; Ohnuma, Y.; Iyoda, M.
Tetrahedron Lett. 1999, 40, 5731. (b) Yoshida, M.; Ohkoshi, M.; Muraoka,
T.; Matsuyama, H.; Iyoda, M. Bull. Chem. Soc. Jpn. 2002, 75, 1833.
(8) Sato, Y.; Watanabe, S.; Uneyama, K. Bull. Chem. Soc. Jpn. 1993,
66, 1840.
(3) (a) Chaumontet, M.; Pons, V.; Marotte, K.; Prandi, J. Tetrahedron
Lett. 2006, 47, 1113. (b) Desire, J.; Prandi, J. Tetrahedron Lett. 1997, 38,
6189. (c) Mayer, S.; Prandi, J. Tetrahedron Lett. 1996, 37, 3117.
(4) For selected examples, see: (a) Klement, I.; Lu¨tjens, H.; Knochel,
P. Tetrahedron Lett. 1995, 36, 3161. (b) Fukunishi, K.; Shimode, M.;
Hisamune, R.; Akita, M.; Kuwabara, M.; Yamanaka, H.; Nomura, M. Chem.
Lett. 1991, 337. (c) Nagashima, T.; Curran, D. P. Synlett 1995, 330.
(9) Nair, V.; Sheeba, V.; Panicker, S. B.; George, T. G.; Rajan, R.;
Balagopal, L.; Vairamani, M.; Prabhakar, S. Tetrahedron 2000, 56, 2461.
(10) Chowdhury, F. A.; Nishino, H.; Kurosawa, K. Tetrahedron Lett.
1998, 39, 7931.
10.1021/ol901912j CCC: $40.75
Published on Web 09/22/2009
 2009 American Chemical Society

as an overoxidation product or low reaction efficiency.
Nothing is known about intermolecular hydroxyalkylation
using a conventional radical initiator such as Et3B13 or AIBN.
Herein, we report the Et3B-induced hydroxyalkylation reac-
tion of R,ꢀ-unsaturated imines in connection with our recent
study on hydroxysulfenylation.14 In hydroxysulfenylation
reaction, the stabilization of intermediate radical, generated
by the thiyl radical addition to carbon-carbon double bond,
by homoconjugative interaction between the carbon-centered
radical and the sulfur atom was key factor. On the other hand,
the hydroxyalkylation without such a stabilizing functional
group might be difficult and therefore challenging.
Scheme 2. Hydroxyalkylation of R,ꢀ-Unsaturated Imines
In an initial attempt, we treated R,ꢀ-unsaturated aldehyde
1 with Et3B in the presence of molecular oxygen in toluene
(Scheme 1).15
to produce R-oxygenated D,17 facilitated by the lower bond
dissociation energy of B-N compared with B-O.18
Promising results were obtained using R,ꢀ-unsaturated
oxime ether 3 (Table 1).19 We conducted investigations to
Scheme 1. Ethyl Radical Addition to R,ꢀ-Unsaturated Aldehyde
Table 1. Hydroxyalkylation of R,ꢀ-Unsaturated Oxime Ether 3
yielda (%)
entry
solvent
additive
4ab
5a
1c
2d
3f
toluene
toluene
toluene
benzene
Et2O
78
26 (64)e
n.d.
61
Although the substrate 1 was consumed within 10 min,
instead of the desired hydroxyalkylation product only the
simple Michael-type adduct 2 was isolated in 43% yield.
This indicates that oxygenation of radical intermediate A by
molecular oxygen would be difficult due to rapid transforma-
tion of A into the corresponding borylenolate B.16
4c
5c
6c
7c
8g
9g
10
76
44
4
69
THF
10
92
7
CH2Cl2
CH2Cl2
toluene
Me3Al
Me3Al
53
We then directed our attention to the potential of R,ꢀ-
unsaturated imines as substrates. Since R-imino radical C
would be more stable than R-carbonyl radical A, this should
allow trapping by molecular oxygen (Scheme 2). Borylena-
mine F should also undergo an ene-type reaction with
molecular oxygen via homolytic cleavage of the B-N bond
a Isolated yield. b 4a was obtained as an E/Z mixture with anti/syn )
3:2-2:1. c The reaction was carried out with Et3B (3.0 equiv) and bubbling
of O2 gas (3.6 equiv). d The reaction was carried out with Et3B (1.0 equiv)
and bubbling of O2 gas (3.6 equiv). e Yield in parentheses is for recovered
starting substrate 3. f The reaction was carried out with Et3B (3.0 equiv)
under O2 atmosphere. g The reaction was carried out with Et3B (3.0 equiv),
Me3Al (2.2 equiv), and bubbling of O2 gas (3.6 equiv).
(11) Ru¨ck, K.; Kunz, H. Angew. Chem., Int. Ed. 1991, 30, 694.
(12) (a) Negishi, E.; Tan, Z.; Liang, B.; Novak, T. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5782. (b) Wipf, P.; Ribe, S. Org. Lett. 2000, 2, 1713.
(c) Kondakov, D. Y.; Negishi, E. J. Am. Chem. Soc. 1995, 117, 10771. (d)
Shaughnessy, K. H.; Waymouth, R. M. J. Am. Chem. Soc. 1995, 117, 5873.
(13) (a) Ollivier, C.; Renaud, P. Chem. ReV. 2001, 101, 3415. (b)
Yorimitsu, H.; Oshima, K. In Radicals in Organic Synthesis; Renaud, P.,
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, p 11.
(14) Ueda, M.; Miyabe, H.; Shimizu, H.; Sugino, H.; Miyata, O.; Naito,
T. Angew. Chem., Int. Ed. 2008, 47, 5600.
determine optimal conditions for the hydroxyalkylation of
3, which showed high reactivity in our recent studies.14,20
First, O2 gas (3.6 equiv) was bubbled into a mixture of 3
and Et3B (3.0 equiv) in toluene (entry 1). As expected, the
hydroxyalkylation reaction proceeded regioselectively to give
the desired product 4a in 78% yield as an E/Z mixture with
(15) Carboaminoxylation reactions of olefins have been reported by
Studer’s group. For reviews, see: (a) Vogler, T.; Studer, A. Synthesis 2008,
1979. (b) Studer, A.; Schulte, T. Chem. Rec. 2005, 5, 27. (c) Studer, A.
Chem. Soc. ReV. 2004, 33, 267. For recent examples, see: (d) Pouliot, M.;
Renaud, P.; Schenk, K.; Studer, A.; Vogler, T. Angew. Chem., Int. Ed. 2009,
48, 6037. (e) Wienho¨fer, I. C.; Studer, A.; Rahman, M. T.; Fukuyama, T.;
Ryu, I. Org. Lett. 2009, 11, 2457. (f) Siegenthaler, K. O.; Scha¨fer, A.; Studer,
A. J. Am. Chem. Soc. 2007, 129, 5826.
(17) Hydroxyalkylation of 1,2-oxazines with organolithium reagent was
reported, see: Buchholz, M.; Reissig, H.-U. Synthesis 2002, 1412.
(18) The formation of the B-OR bond is thermodynamically favored
over the B-NR2 bond according to the following bond energies: BDE
(B-O) for (EtO)3B ) 519 kJmol-1; BDE (B-N) for (Me2N)3B ) 422
kJmol-1; for reviews on alkylboranes, see: (a) Reference 13. (b) Yorimitsu,
H.; Shinokubo, H.; Oshima, K. Synlett 2002, 674.
(16) (a) Nozaki, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn.
1991, 64, 403. (b) Muraki, M.; Inomata, K.; Mukaiyama, T. Bull. Chem.
Soc. Jpn. 1975, 48, 3200. (c) Brown, H. C.; Kabalka, G. W. J. Am. Chem.
Soc. 1970, 92, 714.
(19) A review of the nucleophilic addition to conjugated imines, see:
Shimizu, M.; Hachiya, I.; Mizota, I. Chem. Commun. 2009, 874.
(20) Ueda, M.; Miyabe, H.; Sugino, H.; Miyata, O.; Naito, T. Angew.
Chem., Int. Ed. 2005, 44, 6190
.
Org. Lett., Vol. 11, No. 20, 2009
4633

anti/syn ) 2:1.21 The reaction proceeded effectively without
a reducing agent such as Bu3SnH, because Et3B played an
important role in reduction of the hydroperoxy radical or
hydroperoxide to the corresponding alcohol. Therefore, a
significant decrease in the chemical yield was observed when
the amount of Et3B was reduced to 1.0 equiv (entry 2). An
excess of O2 prevented hydroxyalkylation due to decomposi-
tion of Et3B (entry 3). This hydroxyalkylation was strongly
influenced by the reaction solvent, with the use of benzene
or THF leading to a decrease in chemical yield of 4a (entries
4 and 6). Under similar reaction conditions, the reaction of
3 in CH2Cl2 produced simple Michael-type 5a in 92% yield
(entry 7). Interestingly, the use of trimethylaluminum as an
additive-promoted hydroxyalkylation even in CH2Cl2, pro-
ducing 4a in 69% yield (entry 8).22
Scheme 3. Possible Reaction Pathway
Using the optimized reaction conditions, a range of alkyl
iodides were examined as carbon radical precursors in the
iodine atom-transfer reaction (Table 2).23
4. In this reaction, Et3B acted as a multirole reagent inducing
radical initiation, radical termination, and reduction.24
Our proposed reaction pathway was supported by the
following experiments. In marked contrast to ester 3, the
reaction of carboxylic acid 6 exclusively gave Michael-type
adduct 7a under the optimized hydroxyalkylation conditions.
This was because the intermediate borylenamine would be
immediately protonated by free carboxylic acid (eq 1).
Table 2. Hydroxyalkylation of 3 with Alkyl Iodide
entry
RI
i-PrI
conditionsa
yield (%)b (anti/syn)
1
2
3
4
5
6
A
B
A
B
A
B
61 (2:1)
41 (2:1)
51 (3:1)
50 (2:1)
60 (3:1)
64 (3:1)
i-PrI
c-pentyl I
c-pentyl I
t-BuI
t-BuI
a Conditions A: RI (20 equiv), Et3B (3.0 equiv), Me3Al (2.2 equiv) O2
bubbling (3.6 equiv) in CH2Cl2. Conditions B: RI (20 equiv), Et3B (3.0
equiv), O2 bubbling (3.6 equiv) in toluene. b Isolated yield.
This supports the presence of borylenamine H as a key
Hydroxyalkylation of 3 was run either with alkyl iodide
and Et3B in the presence of Me3Al in CH2Cl2 (conditions
A: entry 8 in Table 1) or in the absence of Me3Al in toluene
(conditions B: entry 1 in Table 1). Both secondary and bulky
tertiary alkyl radicals worked well to afford the desired
products 4b-d in moderate to good yields. We propose a
possible reaction pathway for this hydroxyalkylation reaction
(Scheme 3). The first step involves regioselective alkyl
radical addition to 3 followed by trapping of aminyl radical
G with Et3B to generate borylenamine H. The borylenamine
H undergoes either an ene-type reaction with molecular
oxygen or an addition reaction of the borylperoxy radical to
form borylperoxide I. The reduction of I with Et3B, followed
by the hydrolysis of the resulting borinate J produced alcohol
intermediate in the proposed aerobic hydroxylation mecha-
1
nism. In addition, H NMR and APCI mass spectra of a
mixture of 3, Et3B, and a catalytic amount of O2 in C6D6
supported complete conversion of 3 into N-borylenamine H
(eq 2). After spectral confirmation of borylenamine forma-
tion, treatment of H with oxygen gas afforded the desired
product 4a in 63% yield. An alternative mechanistic hy-
pothesis that the hydroxyl group originates from H2O can
be excluded based on a H218O-labeled experiment, where
hydroxyalkylation in the presence of H218O exclusively gave
unlabeled 4a (eq 3).25
Further investigations using various R,ꢀ-unsaturated im-
ines as substrates were performed (Table 3). The reaction
of acrolein derivative 8 produced secondary alcohol 9 in 60%
yield (entry 1). The hydroxyalkylation reaction of conjugated
hydrazone 10 also proceeded, albeit with relatively lower
yield (entry 2). Oxazolidinone 12 was converted into alcohol
(21) The relative configurations of anti-4a and syn-4a were deduced by
NOESY experiments of γ-lactam derivatives which were prepared from a
mixture of diastereomers 4a; for details see the Supporting Imformation.
(22) Kunz’s group reported hydroxylation of aluminum enolate with
molecular oxygen. However, our hydroxyalkylation with Me3Al did not
proceed in the absence of Et3B; see ref 11.
(24) Kihara, N.; Ollivier, C.; Renaud, P. Org. Lett. 1999, 1, 1419.
(25) Yajima, T.; Saito, C.; Nagano, H. Tetrahedron 2005, 61, 10203.
(23) Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004, 1140.
4634
Org. Lett., Vol. 11, No. 20, 2009

In conclusion, we have developed for the first time an
Et3B-mediated aerobic hydroxyalkylation reaction of R,ꢀ-
unsaturated imines. The reaction is characterized by mild
conditions, is straightforward, and allows for the efficient
and concomitant construction of a carbon-carbon bond and
a carbon-oxygen bond. In the proposed reaction pathway,
the borylenamine was characterized and confirmed as a key
intermediate of the proposed hydroxylation mechanism.
Table 3. Hydroxyalkylation of Various R,ꢀ-Unsaturated Imines
Acknowledgment. We thank the Ministry of Education,
Culture, Sports, Science and Technology of Japan for Grant-
in Aid for Scientific Research (B) (T.N.), for Scientific
Research (C) (H.M. and O.M.), and for Young Scientists
(B) (M.U.) and the Science Research Promotion Fund of
the Japan Private School Promotion Foundation for re-
search grants. We also thank Dr. Atsuko Takeuchi at Kobe
Pharmaceutical University for APCI mass spectrometric
analysis.
a Conditions C: Et3B (3.0 equiv), Me3Al (2.2 equiv) O2 bubbling (3.6
equiv) in CH2Cl2. Conditions D: Et3B (3.0 equiv), O2 bubbling (3.6 equiv)
in toluene. b Isolated yield.
Supporting Information Available: Experimental pro-
1
cedure and characterization data and H and 13C NMR
13 with good yield and stereoselectivity. Finally, we extended
our hydroxyalkylation to a diastereoselective reaction using
chiral R,ꢀ-unsaturated oxime ether 14 which bears Oppolz-
er’s camphorsultam.26,27 The stereoselectivity on ethyl radical
addition was completely controlled by the chiral auxiliary.
The hydroxyalkylated product 15 was obtained in good yield
but with moderate anti/syn selectivity.
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL901912J
(27) We previously reported highly diastereoselective radical addition
reaction to the substrates bearing Oppolzer’s camphorsultam, see: (a) Ueda,
M.; Miyabe, H.; Sugino, H.; Naito, T. Org. Biomol. Chem. 2005, 3, 1124.
(b) Ueda, M.; Miyabe, H.; Nishimura, A.; Sugino, H.; Naito, T. Tetrahedron:
Asymmetry 2003, 14, 2857. (c) Miyabe, H.; Ushiro, C.; Ueda, M.;
Yamakawa, K.; Naito, T. J. Org. Chem. 2000, 65, 176.
(26) (a) Nanni, D.; Curran, D. P. Tetrahedron: Asymmetry 1996, 7, 2417.
(b) Stack, J. G.; Curran, D. P.; Geib, S. V.; Rebek, J., Jr.; Ballester, P.
J. Am. Chem. Soc. 1992, 114, 7007
.
Org. Lett., Vol. 11, No. 20, 2009
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