Facile rearrangement of O-silylated oximes on reduction with boron trifluoride/borane

Article abstract of DOI:10.1021/jo0516178

Aromatic O-triisopropylsilyl ketoximes were efficiently rearranged to cyclic and acyclic aniline derivatives on reduction with BF₃- ethearate /borane. The bulk of the substituents on the silicon atom, the size of the aliphatic ring, and the presence of alkoxy substituents on the aryl group all play an important role in the aniline.

Full text of DOI:10.1021/jo0516178

SCHEME 1
SCHEME 2
Facile Rearrangement of O-Silylated
Oximes on Reduction with Boron
Trifluoride/Borane
Margarita Ortiz-Marciales,* Luis D. Rivera,
Melvin De Jesu´s, Sandraliz Espinosa,
Josu´e A. Benjamin, Orlando E. Casanova,
Irving G. Figueroa, Sheila Rodr´ıguez, and
Wilbert Correa
Department of Chemistry, University of Puerto
Rico-Humacao, CUH Station, Humacao, Puerto Rico 00791
mr_ortiz@webmail.uprh.edu
Received August 2, 2005
method for the selective synthesis of secondary alkyl
anilines and heterocyclic anilines including tetrahydro-
quinolines, benzazepines, and benzoxazines in good yield,
via a BF3-Et2O/BH3 reductive rearrangement of O-
silylated oximes.
Initially, we explored the borane reduction of 1.8 mmol
of O-tert-butyldimethylsilyl-2-methoxyacetophenone oxime
as a model compound, using BF3-Et2O as a Lewis catalyst
to optimize the yield of 2-methoxy-N-ethylaniline 2,
shown in Scheme 1.
Aromatic O-triisopropylsilyl ketoximes were efficiently rear-
ranged to cyclic and acyclic aniline derivatives on reduction
with BF3-ethearate /borane. The bulk of the substituents on
the silicon atom, the size of the aliphatic ring, and the
presence of alkoxy substituents on the aryl group all play
an important role in the aniline.
By the addition of 2 equiv of BF3-Et2O followed by 3
equiv of borane-dimethyl sulfide (DMS) to the O-TBS
oxime at room temperature, the reaction was complete
within 24 h, favoring 2 in 62% with only 16% of 2-meth-
oxy-R-methylbenzylamine (1). The reaction was complete
within 1 h by refluxing the oxime with 3 equiv of BF3-
Et2O and 2 equiv of borane-THF, improving the yield of
2 to 80%. For comparison, when the reaction was carry
out in the absence of BF3-Et2O, a mixture of 23% primary
amine 1, 70% aniline 2, and 7% starting material was
obtained. The type of borane complex (THF or dimethyl
sulfide) and more than 1 equiv of boron trifluoride have
a little effect on the primary and secondary amine ratios
or on the rate of reduction. More important in determin-
ing the outcome of the reaction was the use of freshly
distilled BF3-Et2O over calcium hydride to remove HF
and the sequence of steps in which the BF3-Et2O and
borane were added. The reduction time was increased to
2 h when borane was first added to the O-TBS oxime.
On the other hand, when the silyloxime was initially
treated with 3 equiv of BF3-OEt2 in THF at 55 °C for 1
h, followed by reduction with borane-THF under reflux-
ing conditions, a mixture of 33% primary amine 1 and
67% aniline 2 was obtained. In addition, a significant
amount of unknown side products was also observed, due
possibly to the decomposition of the silylated oxime.
In previous work,4 we found that the borane reduction
of O-TBS indanone oxime without BF3-Et2O under reflux
yielded only the tetrahydroquinoline. It was of interest
to investigate the reduction of other cyclic aromatic
silylated oximes with and without BF3-Et2O, as indicated
in Scheme 2. Though the reduction of the tetralone
analogue with only borane provided a mixture of both
Cyclic and acyclic anilines are very important organic
compounds used as intermediates for the synthesis of a
variety of pharmaceutical products.1 The reduction of
aromatic oxime alkyl and aryl ethers with borane and
organoboron reagents has been known to afford hydroxyl-
amines or amines, depending on their structure and the
reaction conditions.2 In earlier studies, we reported the
formation of N-alkyl anilines in the reduction of aromatic
O-silylated oximes with borane in THF under reflux
conditions. The yield of the primary aryl alkylamines
with respect to the formation of the secondary aniline
depended strongly on the electronic effects of the aro-
matic ring substituents and on the bulk of the silicon
substituents.3,4 We describe here a new and efficient
(1) (a) Danysz, W.; Parsons, C. G. Pharmacol. Rev. 1998, 50, 597-
664. (b) Dingledine, R.; Borges, K.; Bowie, D.; Traynelis, S. F.
Pharmacol. Rev. 1999, 51, 7-62. (c) Hino, K.; Nagai, Y.; Uno, H. Chem.
Pharm. Bull. 1988, 36, 2386-2400. (d) Aramaki, Y.; Seto, M.; Okawa,
T.; Kansaki, N. Shiraishi, M. Chem. Pharm. Bull. 2004, 52, 254-258.
(e) Wallace, O. B.; Lauwers, K. S.; Jones, S. A.; Dodge, J. A. Biorg.
Med. Chem. Lett. 2003, 13, 1907-1910.
(2) Cho, T. B.; Ryu, M. H. Bull. Korean Chem. Soc. 1994, 15, 191-
192. (b) Dougherty, J. T.; Flisak, J. R.; Hayes, J.; Lantos, I.; Tucker,
L. Tetrahedron: Asymmetry 1997, 8, 497-499. (c) Feuer, H.; Braun-
stein, D. M. J. Org. Chem. 1969, 34, 1817-1821. (d) For further
information on reduction of oximes and oxime derivatives, see: Hem-
mer R.; Lurken, W. In Houben-Weyl, Methoden der Organischen
Chemie, 4th ed.; Klamann, D., Hagermann H., Eds.; Thieme Verlag:
Stuttgart, 1992; E 16 d/2, pp 878-893.
(3) (a) Ortiz-Marciales, M. Cruz, E.; Alverio, I.; Figueroa, D.;
Cordero, J. F.; Morales, J. A.; Dashmana, H.; Burgos, C. J. Chem. Res.
(S) 1998, 10-1. (b) Ortiz-Marciales, M. Cruz, E.; Alverio, I.; Figueroa,
D.; Cordero, J. F.; Morales, J. A.; Dashmana, H.; Burgos, C. J. Chem.
Res., Miniprint 1998, 151-167.
(4) Ortiz-Marciales, M. C. E.; Figueroa, D.; Lo´pez J. A.; De Jesu´s,
M.; Vega, R. Tetrahedron Lett. 2000, 41, 6567-6570.
10.1021/jo0516178 CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/28/2005
10132
J. Org. Chem. 2005, 70, 10132-10134

TABLE 1. Reduction of AromaticO -TBS Oximes Using BH3-THF or BH3-DMS/BF3-Et2O
a Determined by GC-MS analysis of crude products. b Yield of isolated crude products. c Isolated pure compound characterized by
spectroscopic methods. d Ratio of pure compounds isolated by column chromatography. e Unresolved peaks by GC-MS.
amines in about equal amounts, as shown in Table 1, it
seems that on heating, the rearrangement of the five-
membered ring was preferred, perhaps to relieve the
angular ring strain. On the contrary, reduction of 1-in-
danone O-TBS oximes with borane and BF3-Et2O at room
temperature (entry 2) produced both, a mixture of
primary and secondary amines in a 2:3 ratio, respectively.
In the case of the tetralone oxime, BF3-Et2O influenced
only the reduction rate, affording similar amounts of the
amine products (entry 4). Noteworthy is the fact that the
BF3/borane reduction of 6-methoxy-1-tetralone oxime
favored completely the formation of 7-methoxy-1-benza-
zepine, as shown in Table 1.
The influence of the triisopropylsilyl (TIPS) groups in
directing the reaction pathway toward the rearranged
product was previously observed in the borane reduction
of 4-methoxy acetophenone O-silylated oximes.4 For this
reason we initiated a study of the effect of the triisopropyl
silyl group on the product distribution of boron trifluo-
ride/borane reduction of (E)-2-methoxy acetophenone
O-TIPS oxime.5 Using 1 equiv of boron trifluoride ether-
ate and 3 equiv of borane-DMS at room temperature, the
reduction was completed within 24 h, producing 85%
N-ethyl-4-methoxyaniline and 15% 2-methoxy-R-meth-
ylbenzylamine. However, by heating the reaction mixture
under reflux for 4 h, only the secondary aniline was
detected by GC/MS. Thus, the O-TIPS oximes, indicated
in Table 2, were prepared in more that 98% of the (E)-
stereoisomer (entry 1-6) and reduced with the optimized
BH3/BF3 system.
ary.3 Reduction of these oximes in the presence of boron
trifluoride may involve a rearrangement via a hydroxy-
lamine intermediary, as was postulated for the LiAlH4/
AlCl3 reduction of aromatic oximes.6 Further more,
similar intermediates have been proposed in the rear-
rangement of aliphatic hydroxylamine carbonates by
trialkylaluminum compounds by Yamamoto and co-
workers.7 Recently, a mechanism involving an initial
heterolytic N-O cleavage of the oxygen complexed with
Lewis acids such as AlCl3 and ZrCl4 was proposed by
Kikugawa et al.8 for the intramolecular imino migration
of O-arylketoximes. Reduction with sodium bis(2-meth-
oxyethoxy)aluminum hydride (Red Al) gave o-aminophe-
nols. However, the high anti stereoselectivity observed
in the reductive rearrangement of (E)-O-TIPS oximes in
the presence of BF3 indicates that the mechanism may
be related to the concerted anti migration of the aryl
group of the well-known Beckmann rearrangement of
oxime ethers or esters, mediated by strong Bronsted or
Lewis acids, to obtain amides/lactams.9 Moreover, the
reduction of O-silylated oximes may be closer to the
proposed Yamamoto’s mechanism10 for the reduction of
oximes using diisobutylaluminum hydride and was also
proposed in the alkylation-reduction of oxime sulfonates
with organoaluminum reagents. On the other hand, the
large triisopropyl group on the silicon atom may hinder
the initial coordination of boron trifluoride on the oxygen
of the of O-TIPS oximes in the BF3/BH3 system. There-
fore, a more complex mechanism may be involved.
In summary, we have achieved a highly efficient, mild,
and facile method for the synthesis of secondary acyclic
Our previous results suggest that the change in
product distribution and reactivity of the silylated oximes
depends on the size of the silicon substituents, the
reaction conditions, and more significantly, if the borane
reduction is carried out in the presence of boron trifluo-
ride. This may be due to possible different reaction
mechanisms. The reductive rearrangement of O-silylated
oximes by borane without boron trifluoride was previ-
ously proposed to occur via a hydroxylamine intermedi-
(6) Rerick, M. N.; Trottier, C. H.; Daignault, R. A.; Defoe, J. D.
Tetrahedron Lett. 1963, 10, 629-634.
(7) Fujiwara, J.; Sano, H.; Maruoka, K.; Yamamoto, H. Tetrahedron
Lett. 1984, 25, 2367-2370.
(8) Kikugawa, Y.; Tsuji, C.; Miyazawa, E.; Sakamoto, T. Tetrahedron
Lett. 2001, 42, 2337-2339.
(9) (a) Anilkumar, R.; Chandrasekhar, S. Tetrahedron Lett. 2000,
41, 5427-5429. (b) Lee, B. S.; Chu, S.; Lee, I. Y.; Lee, B.-S.; Song, C.
E.; Chi, D. Y. Bull. Korean Chem. Soc. 2000, 21, 860-866.
(10) (a) Hattori, K.; Matsumura, Y.; Miyazaki, T.; Maruoka, K.;
Yamamoto, H. J. Am. Chem. Soc. 1981, 103, 7368-7370. (b) Sasatani,
S.; Miyazaki, T.; Maruoka, K.; Yamamoto, H. Tetrahedron Lett. 1983,
24, 4711-4712. (c) Maruoka, K.; Yamamoto, H. Angew. Chem., Int.
Ed. Engl. 1985, 24, 668-682 and references therein.
(5) (a) For the synthesis of O-silylated oximes, see: Ortiz-Marciales,
M.; De Jesu´s, M.; Figueroa, D.; Herna´ndez, J.; Va´zquez, L.; Vega, R.;
Morales, E. M.; Lo´pez, J. A. Synth. Commun. 2003, 33, 311-323.
J. Org. Chem, Vol. 70, No. 24, 2005 10133

TABLE 2. Synthesis and Reduction of Aromatic (E)-O-TIPS Oximes Using BH3-DMS/BF3-Et2O/THF under Reflux
Conditions
a Composition of both amines determined by GC-MS analysis of crude products. b Pure products isolated by column chromatography
and characterized by spectroscopic methods. c Isolated crude compounds characterized by spectroscopic methods. d Isolated as the pure
hydrochloride salt.
reduced pressure (20 mmHg) and then under high vacuum (0.01
mmHg). The crude product (0.92 g, 75%) was analyzed by GC
and purified by flash chromatography on a silica gel column (28.5
cm length × 3.0 cm diameter, 81 g) with hexane/ethyl acetate
(80/20 v/v). The product, 6-methoxy-1,2,3,4-tetrahydroquinoline,
was obtained as a clear yellow oil. Yield: 66% (0.81 g). IR (neat)
ν cm-1: 3366 (NH). 1H NMR (CDCl3) (δ ppm): 1.91 (m, J ) 6.8,
2H), 2.74 (m, J ) 6.4 Hz, 2H), 3.23 (t, J ) 5.6 2H), 3.29(bs, 1H),
3.71(s, 3H), 6.43 (d, J ) 8.4, 1H), 6.55 (dd, J ) 8.4, and 2.4 Hz,
1H), 6.59 (d, J ) 2.8 Hz, 1H). 13C NMR: 150.8, 137.8, 121.8,
114.5, 114, 113.9, 54.8, 41.3, 26.1, 21.4. MS m/z: 163 (M‚ +, 100).
Hydrochloride salt (0.46 g, 77%): mp 145-148 °C. The reaction
was repeated with 2 equiv of boron trifluoride, obtaining 76%
of the desired amine, which was purified as the hydrochloride
salt in 58% yield.
and cyclic anilines by the reductive rearrangement of
triisopropyl silylated oximes. This new procedure repre-
sents a useful method for the preparation of important
biologically active acyclic and heterocyclic anilines em-
ploying user-friendly conditions and less toxic reagents.
Experimental Section
6-Methoxy-1,2,3,4-tetrahydroquinoline.11 To a stirred so-
lution of 5-methoxy-1-indanone O-triisopropylsilyl oxime (2.5 g,
7.5 mmol) in ether (2.5 mL) under nitrogen was added, via
syringe, a freshly distilled boron trifluoride ethearate (0.93 mL,
7.5 mmol). Immediately following the addition, a solution of
borane dimethyl sulfide in THF (7.5 mL, 2 M, 15 mmol) was
added dropwise to the reaction flask at room temperature. The
reaction mixture was refluxed for 5 h (or until a GC analysis
indicated the complete formation of the product). At this time
the solution was cooled to -30 °C, and the reaction mixture
cautiously quenched by addition of distilled water (2.4 mL). To
complete the hydrolysis, a solution of hydrochloric acid (6 mL,
6 M) was slowly added, and the reaction mixture was refluxed
at 70 °C for 1 h. After the organic solvent was removed under
reduced pressure, the solution was basified (pH >10) with
aqueous NaOH, extracted with ether (2 × 7 mL), washed with
brine, and dried (K2CO3). The solution was concentrated at
Acknowledgment. Financial support by the Na-
tional Institute of Health through their MBRS (GM
08216) and NIH-IMBRE (NC P20 RR-016470) grants
is greatly appreciated. NIH-IMBRE and NSF-AMP
undergraduate support is also gratefully acknowledged.
Supporting Information Available: Representative pro-
cedure for the synthesis of all new O-TBS and O-TIPS oximes,
the synthesis of anilines, and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(11) (a) Fujita, K.; Kitatsuji, C.; Furukawa, S.; Yamaguchi, R.
Tetrahedron Lett. 2004, 45, 3215-3217. (b) Fujita, K.; Kitatsuji, C.;
Furukawa, S.; Yamaguchi, R. Org. Lett. 2002, 4, 2691-2694.
JO0516178
10134 J. Org. Chem., Vol. 70, No. 24, 2005