Chemoselective Reductions of Imino Groups by Dibutyltin Chloride Hydride Complex

Full text of DOI:10.1021/jo971358p

J . Org. Chem. 1998, 63, 383-385
383
SnClH-HMPA (I) to the corresponding secondary amine
2 in 77% yield at room temperature for 1 h (eq 1). Among
the ligands used, HMPA was best to give a high yield of
2. The low reducing ability of I toward acetophenone 3
is noteworthy, as the corresponding alcohol 4 was formed
in only 14% yield at room temperature after 24 h (eq 2).
This fact indicates that the tin hydride system I would
exhibit a high imino-selectivity even in the presence of
carbonyl groups. As shown in Table 1, a mixture of
Ch em oselective Red u ction s of Im in o
Gr ou p s by Dibu tyltin Ch lor id e Hyd r id e
Com p lex
Ikuya Shibata, Takayo Moriuchi-Kawakami,†
Daisuke Tanizawa, Toshihiro Suwa, Erika Sugiyama,
Haruo Matsuda,† and Akio Baba*
Department of Applied Chemistry, Faculty of Engineering,
Osaka University, 2-1 Yamadaoka, Suita,
Osaka 565, J apan
Received J uly 23, 1997
Chemoselective reductions of imino groups are very
important for the synthesis of multifunctionalized amines.
Nevertheless, little attention has been paid to imino-
selective reductions by metal hydrides in the presence
of carbonyl groups because of the lower electrophilicity
of imino groups.1 Organotin hydrides have been gener-
ally used for the selective removal of halide moieties via
a radical process,2 while ionic reactions with tin hydrides
have been rarely reported.3 Recently, we have developed
a set of organotin hydrides that reduce polar multiple
bonds such as CdO and CdN in an ionic manner,4 and
with which chemoselective reductions of bifunctional
substrates could be achieved.5 For example, in the
reaction with 2,3-epoxy ketones, Bu2SnFH-HMPA se-
lectively reduced the carbonyl group to furnish predomi-
nantely the anti-2,3-epoxy alcohols,5a whereas Bu2SnIH-
HMPA preferentially reduced the epoxy group to provide
3-hydroxy ketones.5c Thus, the introduction of a halogen
substituent or a ligand onto the tin atom can change the
character of the original tin hydrides5c to provide different
chemoselectivities in the reduction of multifunctional
substrates. We now present use of Bu2SnClH-HMPA
(I) as a chemoselective reductant of imines in the pres-
ence of carbonyls.
aromatic imine 1 (1 mmol) and acetophenone 3 (1 mmol)
was treated with tin hydride I (1 mmol) at room tem-
perature for 2 h.7 After hydrolysis of the mixture, amine
2 was obtained in 85% yield (Table 1, entry 2), and
unreacted ketone 3 was recovered quantitatively. In
place of HMPA, other ligands such as Ph3PO and DMI
were not effective, although imino selectivities were
observed (Table 1, entries 3 and 4). An iodo-substituted
tin hydride, Bu2SnIH-HMPA, also gave chemoselective
reduction of imine 1. The yield of 2, however, was lower
compared with the case of tin hydride I (Table 1, entry
5). Either reaction using Bu2SnClH or Bu2SnIH without
HMPA was accompanied by the reduction of ketone 3
(Table 1, entries 1 and 6). Thus the complexation of tin
hydrides with HMPA is important for the chemoselective
reductions,8 where the reducing ability for imino groups
was also increased.4e In contrast, the introduction of a
fluorine substituent into the tin hydride (Bu2SnFH-
HMPA) afforded the predominant reduction of the car-
bonyl group to give the corresponding alcohols 4 in 69%
yield, where only 4% of imine 1 was reduced (Table 1,
entry 7).
Further, Bu2SnClH-HMPA (I) possessed higher imino-
selectivity compared with other conventional reductants
such as LiAlH4, DIBAL, and NaBH4 which reduced the
carbonyl group predominantly (Table 1, entries 8-10).
Another hydride, NaBH3CN, which has been known as
an effective reductant for imino groups,9 exhibited no
reducing ability under the neutral conditions employed
here (Table 1, entry 11). NaBH3CN reduction under
acidic conditions also resulted in the predominant reduc-
tion of carbonyl group (Table 1, entry 12).
The five-coordinate tin hydride, prepared from Bu2-
SnClH6 and a ligand, has been briefly reported to reduce
imines effectively under mild conditions.4e For example,
N-R-phenethylidene phenylamine (1) was reduced by Bu2-
† Present address: Department of Applied Chemistry, Osaka Insti-
tute of Technology, 5-16-1 Omiya, Asahi, Osaka 535, J apan.
(1) Alcaide, B.; Lo´pez-Mardomingo, C.; Pe´rez-Ossorio, R.; Plumet,
J . J . Chem. Soc., Perkin Trans. 2 1983, 1649.
(2) Pereyre, M.; Quintard, P. J .; Rahm, A. Tin in Organic Synthesis;
Butterworths: London, 1987.
(3) (a) Neumann, W. P.; Heymann, E. Liebigs Ann. Chem. 1965, 683,
11. (b) Fung, N. Y. M.; Mayo, P.; Schauble, J . H.; Weedon, A. C. J .
Org. Chem. 1978, 43, 3977. (c) Castaing, M. D.; Rahm, A. J . Org. Chem.
1986, 51, 1672. (d) Kikukawa, K.; Umekawa, H.; Wada, F.; Matsuda,
T. Chem. Lett. 1988, 881.
(4) (a) Shibata, I.; Suzuki, T.; Baba, A.; Matsuda, H. J . Chem. Soc.,
Chem. Commun. 1988, 882. (b) Shibata, I.; Yoshida, T.; Baba, A.;
Matsuda, H. Chem. Lett. 1989, 619. (c) Shibata, I.; Yoshida, T.; Baba,
A.; Matsuda, H. Chem. Lett. 1991, 307. (d) Shibata, I.; Yoshida, T.;
Kawakami, T.; Baba, A.; Matsuda, H. J . Org. Chem. 1992, 57, 4049.
(e) Kawakami, T.; Sugimoto, T.; Shibata, I.; Baba, A.; Matsuda, H.;
Sonoda, N. J . Org. Chem. 1995, 60, 2677.
(5) (a) Kawakami, T.; Shibata, I.; Baba, A.; Matsuda, H. J . Org.
Chem. 1993, 58, 7608. (b) Kawakami, T.; Shibata, I.; Baba, A.;
Matsuda, H.; Sonoda, N. Tetrahedron Lett. 1994, 35, 8625. (c)
Kawakami, T.; Shibata, I.; Baba, A. J . Org. Chem. 1996, 61, 82. (d)
Kawakami, T.; Miyatake, M.; Shibata, I.; Baba, A.; Matsuda, H. J .
Org. Chem. 1996, 61, 376.
(6) Bu2SnClH was prepared from Bu2SnCl2 and Bu2SnH2. (a)
Neumann, W. P.; Pedain, J . Tetrahedron Lett. 1964, 5, 2461. (b)
Sawyer, A. K.; Brown, J . E.; Hanson, E. L. J . Organomet. Chem. 1965,
3, 464.
(7) We used N-aryl imines as substrates because the reduction of
N-alkyl imines resulted in low yields. For example, when a mixture of
N-benzylidene methylamine and benzaldehyde was reduced with tin
hydride I at 0 °C for 1 h, the reaction barely proceeded. Benzyl alcohol
was obtained in 6% yield and the imine was recovered quantitatively.
(8) When Bu2SnClH was reacted with acetophenone 3 at room
temperature for 24 h, 1-phenylethanol 4 was obtained in 20% yield.
On the other hand, Bu2SnClH-HMPA provided 4 in lower yield (14%)
as shown in eq 2.
(9) (a) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J . Am. Chem.
Soc. 1971, 93, 2897. (b) Wrobel, J . E.; Canem, B. Tetrahedron Lett.
1981, 22, 3447.
S0022-3263(97)01358-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/23/1998

384 J . Org. Chem., Vol. 63, No. 2, 1998
Notes
Ta ble 1. In ter m olecu la r ly Com p etitive Red u ction of
Ketim in e a n d Keton ea
Ta ble 3. Syn th esis of Ter tia r y Am in esa
yield (%)
entry
reducing system
Bu2SnClH
Bu2SnClH-HMPA (I)
Bu2SnClH-Ph3PO
Bu2SnClH-DMI
Bu2SnIH-HMPA
Bu2SnIH
conditions
rt, 2 h
rt, 2 h
rt, 2 h
rt, 2 h
rt, 2 h
rt, 2 h
rt, 2 h
0 °C f rt, 2 h
0 °C f rt, 2 h
0 °C f rt, 2 h
0 °C f rt, 2 h
0 °C f rt, 2 h
2
4
1
2
3
4
5
6
7
8
9
60
85
27
42
68
63
4
43
0
21
0
9
0
5
3
0
13
69
49
42
70
0
Bu2SnFH-HMPA
b
LiAlH4
DIBALc
b
10
11
12
NaBH4
NaBH3CNb
NaBH3CNb,d
9
77
a
Ketimine 1/ketone 3/reducing system ) 1/1/2 mmol, THF 2
mL. Reducing system 1 mmol. c DIBAL 5 mmol. Reaction was
b
d
performed in acidic media (HCl/MeOH pH ∼ 3).
Ta ble 2. In tr a m olecu la r ly Ch em oselective Red u ction of
Im in o Keton esa
revealed as a suitable ligand to tin species because using
Ph3PO in place of HMPA gave 10a in only 8% yield (entry
2). It is noteworthy that not only carbonyl but also
halogen groups were tolerated in the reduction of 9b and
9c (Table 2, entries 3 and 4).
entry
R
conditions
rt, 20 h
rt, 20 h
rt, 20 h
rt, 20 h
0 °C f rt, 20 h
product
yield (%)
The above reductions progress stoichiometrically, where
the adducts bearing a nucleophilic Sn-N bond are
generated in situ without protonation by tin hydride I.
Multifunctionalized unsymmetric amines 11 could be
prepared directly by the subsequent N-alkylation of the
tin amide with benzyl bromide and allyl bromide to afford
unsymmetric tertiary amines 11a and 11b, respectively
(Table 3).
1
2
3
4
5
Ph
Ph
10a
10a
10b
10c
10d
73
8b
54
57
78
p-ClC6H4
p-BrC6H4
p-MeOC6H4
a
Imino ketone 9/Bu2SnClH-HMPA (I) ) 1/2 mmol, THF 1 mL.
b
Ph3PO was used instead of HMPA.
The tin hydride I also allows the coexistence of more
Although the mechanism of the activation of imines is
not yet clear, we believe that the ability of Bu2SnClH-
HMPA (I) to act as hydride donor is low, hence iminium
salts are formed from imines 1 before hydride attack. The
electrophilicity of the imino group would be increased by
the formation of the iminium salt. In the tin hydride
complex I, we have shown that Cl and HMPA occupy
apical positions on the trigonel bipyramidal geometry.4e
Thus the Sn-Cl bond is effectively activated by the
coordination of HMPA in tin hydride I and would play
an important part for the formation of the iminium salts.
In the case of Bu2SnFH-HMPA, the iminium salt could
not be formed because of the strong Sn-F bond.
reducible aldehydes during the reduction of the imino
group. In a competitive reduction between aldimine 5
and aldehyde 6a at room temperature, amine 7 was
obtained in 89% yield, whereas aldehyde 6a was reduced
to alcohol 8a in only 5% yield (eq 3). Moreover, aldehydes
6b and 6c were not affected by tin hydride I.
In conclusion, a highly coordinated tin hydride, Bu2-
SnClH-HMPA, effectively reduces imines even in the
presence of carbonyl groups to furnish secondary amines.
Moreover, the resulting tin amides from hydrostannation
of imines subsequently react with organic halides to
furnish unsymmetrical tertiary amines in a one-pot
procedure.
Next, we performed the reduction of 1, 2-imino ketones
9 which bear both reducible imino and carbonyl groups
(Table 2). In this case, imino-selective reduction is very
difficult because the facile reduction of both functional
groups provides 1,2-amino alcohols.1,10 For example, the
reduction of 9a was performed with tin hydride I at room
temperature for 20 h. After the reaction mixture was
quenched with MeOH, 2-amino ketone 10a was obtained
selectively, where no formation of 1,2-amino alcohol was
detected at all (Table 2, entry 1). Here HMPA was
(10) (a) Haro-Ramos, R.; J imenz-Tebar, A.; Pe´rez-Ossorio, R.; Plu-
met, J . Tetrahedron Lett. 1979, 15, 1355. (b) Alcaide, B.; Pradilla, R.
F.; Lo´pez-Mardomingo, C.; Pe´rez-Ossorio, R.; Plumet, J . J . Org. Chem.
1981, 46, 3234. (c) Alcaide, B.; Dominguez, G.; Lo´pez-Mardomingo, C.;
Pe´rez-Ossorio, R.; Plumet, J . J . Chem. Soc., Perkin Trans. 2 1986, 99.
(d) Alcaide, B.; Arjona, O.; Pradilla, R. F.; Plumet, J . J . Chem. Res.,
Synop. 1988, 98. (e) Garry, S. W.; Neilson, D. G. J . Chem. Soc., Perkin
Trans. 1 1987, 601.

Notes
J . Org. Chem., Vol. 63, No. 2, 1998 385
1
(4:1); IR (KBr) 3400, 1670, 1510 cm-1; H NMR (CDCl3) δ 5.44
Exp er im en ta l Section
(d, 1H, J ) 6.35 Hz), 5.88 (d, 1H, J ) 6.35 Hz), 6.56-8.00 (m,
14H); 13C NMR (CDCl3) δ 62.7, 114.6, 122.4, 128.1, 128.2, 128.7,
128.8, 129.1, 129.1, 133.6, 134.9, 137.2, 144.6, 196.6; HRMS calcd
for C20H16ONCl 321.0922, found 321.0918.
N-(p-Br om oph en yl)-2-am in odeoxyben zoin (10c): pale yel-
low solid, purified by recrystallization from hexanes-EtOAc (4:
1); IR (KBr) 3390, 1665, 1500 cm-1; 1H NMR (CDCl3) δ 5.47 (d,
1H, J ) 6.83 Hz), 5.97 (d, 1H, J ) 6.83 Hz), 6.52-8.00 (m, 14H);
13C NMR (CDCl3) δ 62.6, 109.5, 115.1, 128.1, 128.3, 128.7, 128.8,
129.1, 131.9, 133.6, 134.8, 137.2, 145.0, 196.5; HRMS calcd for
C20H16ON79Br, 365.0416, found 365.0421.
An a lysis. 1H and 13C spectra were recorded at 400 and 100,
MHz, respectively. Samples for 1H and 13C NMR spectra of
produced amines were examined in deuteriochloroform (CDCl3)
containing 0.03% (w/v) of tetramethylsilane. GLC analyses were
performed with a FFAP (2-m × 3-mm glass column). Column
chromatography was performed by using Wakogel C-200 mesh
silica gel. Preparative TLC was carried out on Wakogel B-5F
silica gel. Yields were determined by 1H NMR or GLC using
internal standards.
Ma ter ia ls. Di-n-butyltin dihydride (Bu2SnH2) was prepared
by the reduction of di-n-butyltin dichloride (Bu2SnCl2) with
LiAlH4.11 Di-n-butyltin halide hydrides (Bu2SnXH; X ) Cl, I)
were synthesized from Bu2SnH2 and Bu2SnX2.12 Bu2SnFH-
HMPA was synthesized by the mixing of Bu2SnH2 and Bu2SnF2
in the presence of HMPA. Ketimine 1 and 1,2-imino ketones 9
were prepared by the azeotropic dehydration of a ketone or
diketones and anilines in toluene at reflux temperature.13 THF
was freshly distilled over sodium benzophenone ketyl, and
HMPA was distilled over finely powdered calcium hydride. All
reactions were carried out under dry nitrogen.
Rep r esen ta tive P r oced u r e for th e Com p etitive Red u c-
tion betw een Im in es a n d Keton e or Ald eh yd e. To the
solution of Bu2SnH2 (1 mmol) and Bu2SnCl2 (1 mmol) in 1 mL
of THF was added HMPA (2 mmol). The mixture was stirred
at room temperature for 10 min. To the solution of N-R-
phenethylidenephenylamine 1 (1 mmol) and acetophenone 3 (1
mmol) in 1 mL of THF was added the mixture of tin hydride
system at rt, and then the solution was stirred until the Sn-H
absorption (1862 cm-1) disappeared in the IR spectrum. After
quenching with MeOH (5 mL), volatiles were removed under
reduced pressure. The residue was subjected to column chro-
matography eluting with hexanes-EtOAc (9:1) to give almost
pure product 2. Further purification of 2 was performed by TLC
eluting with hexanes-EtOAc (9:1).
Amines 2 and 7 were identified in comparison with the
authentic spectral data which we have previously reported.4e sec-
Phenethyl alcohol (4) [98-85-1], benzyl alcohol (8a ) [100-51-6],
2-phenyl-1-propanol (8b) [1123-85-9], and cyclohexymethanol
(8c) [100-49-2] were identified in comparison with commercially
available samples.
N-(p-Meth oxyp h en yl)-2-a m in od eoxyben zoin (10d ): pale
yellow solid, purified by flash chromatography (eluted by hex-
anes-EtOAc, 5:1); IR (KBr) 3400, 1675, 1520 cm-1 1H NMR
;
(CDCl3) δ 3.70 (s, 3H), 5.11 (br, 1H), 5.96 (s, 1H), 6.61-8.00 (m,
14H); HRMS calcd for C21H19O2N, 317.1417, found 317.1435.
N-(p-Methoxyphenyl)-2-aminodeoxybenzoin (10d ) [RN 19339-
72-1] was identified in comparison with the authentic data.14
Rep r esen ta tive P r ep a r a tion of Un sym m etr ic Ter tia r y
Am in es. To the solution of Bu2SnH2 (0.6 mmol) and Bu2SnCl2
(0.6 mmol) in 1 mL of THF was added HMPA (1.2 mmol). The
mixture was stirred at room temperature for 10 min. Imino
ketone 9 (1 mmol) was added, and the solution was stirred for
3 h. Benzyl bromide (15 mmol) was added to the mixture and
stirred at 80 °C for 2 h. After quenching with MeOH (5 mL),
volatiles were removed under reduced pressure. The residue
was subjected to column chromatography eluting with hexanes-
EtOAc (9:1) to give the product 11a . Further purification of 11a
was achieved by recrystallization from hexane.
N-Ben zyl-N-p h en yl-2-a m in od eoxyb en zoin (11a ): pale
yellow solid; IR (KBr) 1680, 1260, 1220 cm-1; 1H NMR (CDCl3)
δ 4.62 (d, 1H, J ) 17.81 Hz), 4.72 (d, 1H, J ) 17.81 Hz), 6.67 (s,
1H), 6.71-7.93 (m, 20H); 13C NMR (CDCl3) δ 52.6, 67.7, 114.2,
118.2, 126.1, 126.4, 127.9, 128.1, 128.3, 128.5, 128.7, 129.2, 130.0,
133.3, 135.5, 135.9, 139.9, 149.3, 199.0; HRMS calcd for C27H23
-
ON, 377.1781, found 377.1786. Anal. Calcd for C27H23ON, C,
85.91: H, 6.14; N, 3.71. Found: C, 85.04; H, 6.15; N, 3.70.
N-Allyl-N-p h en yl-2-a m in od eoxyben zoin (11b): pale yel-
low liquid, purified by Kugelrohr distillation at 120 °C (0.09
mmHg); IR (neat) 1670, 1320, 1205 cm-1 1H NMR (CDCl3) δ
;
2.97 (dd, 1H, J ) 6.84 and 13.67 Hz), 3.14 (dd, 1H, J ) 7.33 and
13.67 Hz), 4.18 (s, 1H), 5.07 (m, 2H), 5.73 (m, 1H), 6.86-8.00
(m, 15H); 13C NMR (CDCl3) δ 43.9, 81.4, 120.4, 125.6, 128.1,
128.1, 128.8, 128.9, 129.0, 129.1, 129.3, 129.9, 130.1, 132.3, 132.7,
R ep r esen t a t ive P r oced u r e for t h e In t r a m olecu la r
Ch em oselective Red u ction of Im in o Keton es. To the solu-
tion of Bu2SnH2 (1 mmol) and Bu2SnCl2 (1 mmol) in 1 mL of
THF was added HMPA (2 mmol). The mixture was stirred at
room temperature for 10 min. Imino ketone 9 (1 mmol) was
added, and the solution was stirred until the Sn-H absorption
(1862 cm-1) disappeared in the IR spectrum. After quenching
the reaction with MeOH (5 mL), volatiles were removed under
reduced pressure. The residue was subjected to column chro-
matography eluting with hexanes-EtOAc (9:1) to give a crude
product 10. Further purification was performed by TLC eluting
with hexanes-EtOAc (9:1).
134.9, 200.8; HRMS calcd for
327.1628.
C23H21ON, 327.1624, found
Ack n ow led gm en t. This work was supported by the
Grant-Aid for Scientific Research from Ministry of
Education, Science and Culture. Thanks are due to Ms.
Y. Miyaji, and Mr. H. Moriguchi, Faculty of Engineer-
ing, Osaka University, for assistance in obtaining NMR
(J EOL, J NM-GSX-400) and MS (J EOL, J SM-DX-303)
spectra.
N-P h en yl-2-a m in od eoxyben zoin (10a ): pale yellow solid;
IR (KBr) 3360, 1670, 1490 cm-1; 1H NMR (CDCl3) δ 5.40 (d, 1H,
J ) 6.83 Hz), 6.02 (d, 1H, J ) 6.83 Hz), 6.65-8.01 (m, 15H); 13
C
NMR (CDCl3) δ 62.7, 113.5, 117.9, 128.1, 128.1, 128.7, 128.9,
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra (16 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
129.1, 129.2, 133.5, 135.1, 137.7, 146.1, 197.1; HRMS calcd for
C
20H17ON, 287.1311, found 287.1306.
N-(p-Ch lor op h en yl)-2-a m in od eoxyben zoin (10b): pale
yellow solid, purified by recrystallization from hexanes-EtOAc
(11) Keck, G. J . M.; Noltes, J . G.; Luijiten, J . G. A. J . Appl. Chem.
1957, 7, 366.
J O971358P
(12) Neumann, W. P.; Pedain, J . Tetrahedron Lett. 1964, 2461.
(13) Wagner, R. B.; Zook, H. D. Synthetic Organic Chemistry; J ohn
Wiley & Sons, Inc.: New York, 1953.
(14) Alcaide, B.; Lo´pez-Mardomingo, C.; Pe´rez-Ossorio, R.; Plumet,
J . J . Chem. Soc., Perkin Trans. 2 1983, 1649.