Crossed pinacol coupling reaction between aldehydes and imines: A rapid access to 1,2-amino alcohols

Article abstract of DOI:10.1055/s-2002-33510

In the presence of zinc, boron trifluoride etherate, and methyltrichlorosilane, aldehydes and imines underwent a crossed pinacol coupling reaction to give 1,2-amino alcohols in good to excellent yields.

Full text of DOI:10.1055/s-2002-33510

1538
LETTER
Crossed Pinacol Coupling Reaction between Aldehydes and Imines:
A Rapid Access to 1,2-Amino Alcohols
C
rossedPinacol Coupl
a
ing
R
eactio
k
n
oto Shimizu,* Atsushi Iwata, Hiroaki Makino
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan
Fax +81(59)2319413; E-mail: mshimizu@chem.mie-u.ac.jp
Received 26 June 2002
Abstract: In the presence of zinc, boron trifluoride etherate, and
methyltrichlorosilane, aldehydes and imines underwent a crossed
pinacol coupling reaction to give 1,2-amino alcohols in good to ex-
cellent yields.
Key words: crossed pinacol coupling, 1,2-amino alcohols, methyl-
trichlorosilane, boron trifluoride etherate, zinc-copper couple
Scheme 1
1,2-Amino alcohol moieties have been found in many of
As shown in Table 1, among the halotrialkylsilanes used
chlorotrimethylsilane and its triethyl counterpart promot-
ed the desired crossed coupling most effectively, whereas
the use of the bulky t-butyldimethyl derivative slightly de-
creased the product yield (entries 1–5). In order to in-
crease the Lewis acidity of the chlorosilanes, dichloro-
and trichlorosilyl derivatives were next used. As expected
the use of methyltrichlorosilane recorded the best result,
where the desired crossed coupling product, 1,2-diphenyl-
biologically important natural products. In recent years
several synthetic 1,2-amino alcohol derivatives have also
been employed as drugs for therapeutic purpose as well as
chiral auxiliaries or metal ligands in catalytic asymmetric
synthesis.1
So far, several strategies have been employed to construct
such units. For example, amino alcohol entities are intro-
duced without altering the carbon skeleton of a molecule.2
Alternatively, the 1,2-amino alcohol array is elaborated
with the simultaneous construction of the interconnecting
carbon-carbon bond.3 Among such processes, the crossed
pinacol coupling between carbonyl and imino compounds
is one of the most direct ways to synthesize 1,2-amino al-
cohols, and therefore, it is an attractive and useful reaction
for the synthesis of such valuable materials. However, it
is not trivial to control the chemoselectivity in the crossed
pinacol coupling due to simultaneous homo-couplings.
There are only limited examples reported on intermolecu-
lar crossed pinacol coupling between imines and carbonyl
compounds.4 There still appear to be some room for fur-
ther improvements, regarding starting materials and re-
agents. We have now found that a simple combination of
two different Lewis acids induces discrimination of subtle
difference of reactivity between aldehydes and imines,
and herein, we wish to report a convenient method for the
crossed pinacol coupling of various imines with alde-
hydes using inexpensive and readily accessible reagents,
zinc, boron trifluoride etherate, and chlorosilane
(Scheme 1).
Table 1 Effects of the Silicon Reagentsa
Entry
Silicon
reagent
3(%)b
syn:antic
4(%)b
5(%)b
1
2
3
4
5
6
7
8
Me3SiCl
Me3SiBr
Me3SiI
66
22
8
62:38
21:79
13:87
65:35
68:32
64:36
66:34
65:35
10
4
0
9
0
14
6
Et3SiCl
69
11
8
t-BuMe2SiCl 50
0
Me2SiCl2
Ph2SiCl2
MeSiCl3
76
61
85
1
2
We initially investigated the effect of halosilanes for
crossed pinacol coupling using the reaction of N-benz-
ylidene-p-anisidine 1 and benzaldehyde 2, and the results
are summarized in Table 1.5
1
2
1
0
a The reaction was carried out according to the typical experimental
procedure (ref.7).
b Isolated yield.
Synlett 2002, No. 9, Print: 02 09 2002.
Art Id.1437-2096,E;2002,0,09,1538,1540,ftx,en;U03602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
c Determined by 270 MHz 1H NMR.

LETTER
Crossed Pinacol Coupling Reaction
1539
2-(4-methoxy-phenylamino)ethanol 36 was obtained in next investigated, and the results are summarized in
85% yield and moderate diastereoselectivity along with a Table 3.
Table 3 The Reaction of Benzaldehyde with Various Iminesa
negligible amount of the homo-coupling product (entry
8). We next examined the range of aldehydes employable
for the present crossed coupling using the reaction with N-
benzylidene-p-anisidine under the best conditions found
as in the above cases, and the results are summarized in
Table 2.
The use of a slightly increased amount of benzaldehyde
gave the 1,2-amino alcohol 7 in excellent yield (entries
1–3) and, therefore, 1.2 equivalents of aldehydes were
used throughout the examples in Table 2. In general, the
reaction with the aldehydes possessing electron-with-
drawing substituents gave the adducts in high yields, in
which the use of 4-chlorobenzaldehydes gave the best
yield (entry 5), whereas the reaction with acetylene deriv-
ative gave the adduct with moderate selectivity in lower
yield (entry 12). Use of other aliphatic aldehydes such as
3-phenylpropanal did not give the desired product, but
gave a homo-coupling product arising from the imine.
The reaction of benzaldehyde with various imines was
Entry Ar
R
Yield of 9 syn:antic
(%)b
1
2
2-MeOC6H4
Ph
74
60
87
72
74
76
25
62
39
85d
52:48
63:37
60:40
56:44
54:46
45:55
57:43
77:23
56:44
56:44e
54:46
2,4-(MeO)2C6H3 Ph
3
4-MeSC6H4
4-Me2NC6H4
Ph
Ph
4
Ph
5
Ph
6
4-ClC6H4
Ph
7
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
cyclo-Pr
cyclo-Hex
2-Phenylethyl
Phenylethynyl
8
Table 2 The Reaction of N-Benzylidene-p-anisidine with Various
9
Aldehydesa
10
11
Ethoxycarbonyl 45
a The reaction was carried out according to the typical experimental
procedure (ref.7).
b Isolated yield.
c Determined by 270 MHz 1H NMR.
d CH3CN–CH2Cl2 (9:1) was used as a solvent.
e Major:minor.
Entry
1
R
Yield of 7(%)b
syn:antic
62:38
65:35
65:35
68:32
70:30
61:39
58:42
69:31
82:18
54:46
62:38
65:35f
Ph
85d
90e
97
93
97
81
76
72
50
82
95
29
2
Ph
In general, the effect of the substituents at the nitrogen
atom was not prominent, and the reaction usually pro-
ceeded to give the coupling products in good yields (en-
tries 1–6). The reaction with the imine possessing a
phenylacetylene moiety gave the adducts in good yield
(entry 10). A lower yield was observed in the reaction of
N-cyclopropylmethylene-p-anisidine with benzaldehyde
(entry 7). In this case reduction product of the imine, diol,
and p-anisidine were isolated as by-products. The in situ
preparation of a relatively unstable imine followed by the
coupling reaction also afforded the desired amino alcohol
but in moderate yield (entry 9).
3
Ph
4
4-BrC6H4
4-ClC6H4
2-ClC6H4
4-FC6H4
4-CF3C6H4
4-MeOC6H4
4-MeC6H4
1-Naphtyl
Phenylethynyl
5
6
7
8
9
10
11
12
Although there are several arguments on the reaction
pathways, a possible reaction mechanism is shown in
Scheme 2.
a The reaction was carried out according to the typical experimental
A mixture of boron trifluoride etherate and methyltri-
chlorosilane would form a bimetallic complex 10. On the
basis of affinity and steric repulsion, the oxygen atom is
coordinated with the more Lewis acidic silicon atom of
methyltrichlorosilane, whereas the nitrogen atom is coor-
dinated with the boron atom of boron trifluoride. Imine
and aldehyde are reduced with zinc via a SET mechanism,
procedure (ref.7).
b Isolated yield.
c Determined by 270 MHz 1H NMR.
d Zn-Cu (3.0 equiv), BF3•Et2O (2.0 equiv), and aldehyde (1.0 equiv)
were used.
e BF3•Et2O (2.0 equiv) and aldehyde (1.2 equiv) were used.
f Major:minor.
Synlett 2002, No. 9, 1538–1540 ISSN 0936-5214 © Thieme Stuttgart · New York

1540
M. Shimizu et al.
LETTER
(4) (a) Corey, E. J.; Pyne, S. G. Tetrahedron Lett. 1983, 24,
Cl
Me
F
F
Cl
Me
Cl
Cl
F
F
Cl
F
Si
B
2821. (b) Roskamp, E. J.; Pedersen, S. F. J. Am. Chem. Soc.
1987, 109, 6551. (c) Shono, T.; Kise, N.; Kunimi, N.;
Nomura, R. Chem. Lett. 1991, 2191. (d) Hanamoto, T.;
Inanaga, J. Tetrahedron Lett. 1991, 32, 3555. (e) Ito, H.;
Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992, 33, 4469.
(f) Takai, K.; Mashima, K.; Tani, K. Organometallics 1998,
17, 5128. (g) Machrouchi, F.; Namy, J.-L. Tetrahedron Lett.
1999, 40, 1315. (h) Ma, Y.; Zhang, Y.; Zhou, L. J. Chem.
Res. 2000, 250. (i) Taniguchi, N.; Uemura, M. J. Am. Chem.
Soc. 2000, 122, 8301. (j) Liu, Y.-K.; Zhang, Y.-M.; Liu, X.
Chin. J. Chem. 2001, 19, 500.
Si
B
F
Cl
pAn
10
O
N
MetXn
Ph
Ph
pAn
Zn
Zn
O
N
pAn
NH
pAn
NH
Ph
Ph
Ph
Ph
Ph
Ph
OH
OH
syn-3
anti-3
Scheme 2
(5) Control experiments indicate that the presence of plural
Lewis acids is crucial for the chemoselective addition. The
following example (in Scheme 3) shows one of the
examples. (Since no coupling reaction was observed in the
absence of acid additives, the reaction was conducted in the
presence of methanesulfonic acid.)
and the subsequent coupling of the radical species gives
the adduct 3.
In conclusion, we have developed a new convenient
crossed pinacol coupling reaction of various imines with
aldehydes using inexpensive and readily accessible re-
agents, where the use of more than one Lewis acid is cru-
cial for the crossed coupling. Although the
diastereoselectivity is not high, this reaction offers a use-
ful method for a rapid assembly of 1,2-amino alcohols us-
ing an operationally simple procedure.
pAn
pAn
pAn
NH
N
O
Zn-Cu (3.0 eq),
MsOH (6.0 eq),
NH
OH
Ph
Ph
H
H
Ph
Ph
Ph
Ph
Ph
HN
20%
Ph
CH3CN
0 °C ~ r.t.,
28 h
OH
OH
16%
pAn
35%
Scheme 3
(6) (a) Alcaide, B.; López-Mardomingo, C.; Pérez-Ossorio, R.;
Plumet, J. J. Chem. Soc., Perkin Trans. 1 1983, 1649.
(b) Burton, R. D.; Bartberger, M. D.; Zhang, Y.; Eyler, J. R.;
Schanze, K. S. J. Am. Chem. Soc. 1996, 118, 5655.
(7) A typical experimental procedure is as follows: To a
suspension of zinc–copper couple (65 mg, 1.0 mmol) in
acetonitrile (0.5 mL) was added a mixture of boron
References
(1) Anger, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835.
(2) (a) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30,
1531. (b) Nugent, W. A. J. Am. Chem. Soc. 1992, 114, 2768.
(c) Evans, D. A.; Faul, M. M.; Bilodeau, M. T.; Anderson,
B. A.; Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5328.
(d) Li, G.; Chang, H. T.; Sharpless, K. B. Angew. Chem., Int.
Ed. Engl. 1996, 35, 451. (e) Bruncko, M.; Schlingloff, G.;
Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1997, 36,
1483. (f) Shimizu, M.; Tsukamoto, K.; Fujisawa, T.
Tetrahedron Lett. 1997, 38, 5193. (g) Shimizu, M.;
Fujisawa, T. J. Synth. Org. Chem. Jpn. 1998, 56, 672.
(3) (a) Evans, D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108,
6757. (b) Ciufolini, M. A.; Spencer, G. O. J. Org. Chem.
1989, 54, 4739. (c) Yamamoto, H.; Hattori, K. Tetrahedron
1994, 50, 2785. (d) Shibasaki, M.; Sasai, H. Pure. Appl.
Chem. 1996, 68, 523. (e) Barrett, A. G. M.; Seefeld, M. A.;
White, A. J. P.; Williams, D. J. J. Org. Chem. 1996, 61,
2677. (f) Kobayashi, S.; Ishitani, H.; Ueno, M. J. Am. Chem.
Soc. 1998, 120, 431. (g) Marshall, J. A.; Gill, K.; Seletsky,
B. M. Angew. Chem. Int. Ed. 2000, 39, 953. (h) Okamoto,
S.; Fukuhara, K.; Sato, F. Tetrahedron Lett. 2000, 41, 5561.
trifluoride diethyl etherate (156 mg, 1.1 mmol) and
methyltrichlorosilane (0.24 mL, 2.0 mmol) in acetonitrile
(1.5 mL) at 0 °C under an argon atmosphere. To the resulting
mixture was added a solution of N-benzylidene-p-anisidine
(106 mg, 0.5 mmol) and benzaldehyde (64 mg, 0.60 mmol)
in acetonitrile (3.0 ml) at 0 °C. After being stirred at r.t. for
40 min, the reaction was quenched with sat. aqueous
NaHCO3. The mixture was filtered through a Celite pad. The
layers were separated and the aqueous layer was extracted
with ethyl acetate (3 10 mL). The combined organic
extracts were washed with sat. aqueous NaHCO3 and brine,
and then dried over anhydrous Na2SO4. Purification on
preparative silica gel TLC gave 1,2-diphenyl-2-(4-methoxy-
phenylamino)ethanol (155 mg, 97%) as a colorless oil.
Synlett 2002, No. 9, 1538–1540 ISSN 0936-5214 © Thieme Stuttgart · New York