General and facile synthesis of 1,2-amino alcohols

Article abstract of DOI:10.1055/s-2004-822926

Facile preparation of 1,2-amino alcohols has been achieved by the reaction of benzyloxymethyl lithium with imines, which are generated from α-amido sulfones and benzyloxymethyl lithium in situ at -78°C in THF.

Full text of DOI:10.1055/s-2004-822926

LETTER
1315
General and Facile Synthesis of 1,2-Amino Alcohols
G
eneral and Facile
o
S
ynthesis of
o
1,2-Amino Alcoh
Y
Center for Molecular Design and Synthesis, Department of Chemistry, School of Molecular Science (BK-21), Korea Advanced Institute of
Science and Technology, 373-1, Guseong Dong, Yuseong Gu, Taejon, 305-701, Korea
Fax +82(42)8695818; E-mail: kyh@kaist.ac.kr
Received 11 March 2004
convenient way to prepare 1,2-amino alcohols. During the
Abstract: Facile preparation of 1,2-amino alcohols has been
course of preparation of chiral 1,2-amino alcohols, we
achieved by the reaction of benzyloxymethyl lithium with imines,
have found the general addition of alkoxymethyl lithium
agents to activated imines.
which are generated from a-amido sulfones and benzyloxymethyl
lithium in situ at –78 °C in THF.
Key words: amino alcohol, a-amidoalkyl phenylsulfone, benzyl- Considering reactivity, experimental convenience and
oxymethyl lithium, nucleophilic addition, activated imine
further modification, we examined the reactions of
various a-amidoalkyl phenylsulfones 1,12 with benzyl-
oxymethyl lithium 213 (Scheme 2).
The 1,2-amino alcohol units have been found in a number
of bioactive natural products1 such as alkaloids,2a–2c amino
sugars,2d enzyme inhibitors,2e,3a–3c and antibiotics.3d,e Al-
so, they are frequently employed in asymmetric synthesis
as chiral auxiliaries or chiral catalysts.4 Thus, the develop-
ment of new methods for general, facile and selective
preparations of amino alcohols remains an important goal
in synthetic organic chemistry.5 Many methods to synthe-
size amino alcohols and their derivatives, especially, ami-
no acids have been developed.5–8 Among the numerous
synthetic methods, usually two methods are typically em-
ployed to prepare amino alcohols.9,10 Nucleophilic cleav-
age of epoxides with nitrogen nucleophiles gives the
amino alcohols.7a,b,9 But this method requires several steps
and in some cases, low regioselectivity can be problemat-
ic. Reduction of a-amino acid derivatives affords the ami-
no alcohols.10 However, a-amino acids, which are
available as substrates are fairly limited. Although, many
methods to prepare amino alcohols have been developed,
only a few reports describes the process in which activat-
ed nucleophiles condenses with imines to give amino al-
cohols directly.11 Nevertheless, the efforts to employ
hydroxymethyl or alkoxymethyl organometallic nucleo-
philes has not been made yet. As shown in Scheme 1, if
successful, this approach will provide the most direct and
O
O
LiCH2OBn
2
OR2
HN
R1
OR2
N
THF/–78 °C
R1
H
3
SO2Ph
1
O
LiCH2OBn
HN
R1
OR2
OBn
THF/–78 °C
R1 = Aryl, alkyl, vinyl
R2 = t-Butyl, CH2Ph
4
Scheme 2
Sulfones 1 were known to react with strong bases to give
activated imines 3.12 On supposition that the use of 2
equivalents or more excess of 2 may afford fully protected
amino alcohols 4, one step reaction of 1 to 4 was attempt-
ed. Thus a-amido sulfones 1 and benzyloxymethyl lithi-
um 2 were prepared according to the procedure by
Pearson et al.12 and by Still,13 respectively. Firstly, 1a,
prepared from Boc-carbamate and benzaldehyde, was re-
acted with 2 under various reaction conditions (Table 1).
After careful optimization of reaction conditions, we
found that the one step reaction using 2.5 equivalents of
benzyloxymethyl lithium reagents gave 4 in high yields at
low temperature.14 To investigate whether the reaction
proceeds through the intermediacy of 3, we tested the re-
action of 2 with imines 3, which are generated in situ by
treatment of 1 with 1.2 equivalents of sodium hydride.15
Under this condition, the outcome is identical to the case
where 2.5 equivalents of 2 was employed.
R1
R1
R2
N
NH
Li
OR
+
OR
R2
H
activated
imines
protected
amino alcohols
NH2
deprotection
OH
To test the scope of the reaction, several a-amidoalkyl
phenylsulfones, prepared by condensing Boc- or Cbz-car-
bamate with various aldehydes, were reacted with 2 to
give fully protected amino alcohols 4. The results are
summarized in Table 2.
R2
amino alcohols
Scheme 1
SYNLETT 2004, No. 7, pp 1315–1317
Advanced online publication: 10.05.2004
DOI: 10.1055/s-2004-822926; Art ID: U07204ST
© Georg Thieme Verlag Stuttgart · New York
0
3.
0
6.
2
0
0
4
Amido sulfones derived from electron rich (entry 2, 3) or
electron deficient (entry 4, 5) gave amino alcohols in good

1316
D. Y. Jung et al.
LETTER
Table 2 Additions of Benzyloxymethyl Lithium to Various a-Ami-
to excellent yields. a-Amido sulfone derived from trans-
crotonaldehyde also gave a good result (entry 12). No side
products resulting from the corresponding 1,4-addition of
benzyloxymethyl lithium reagents were detected. Ali-
phatic amido sulfones also gave excellent results (entry 6–
11). No enolization can be detected even in the case when
R1 is isopropyl or n-butyl (entry 6–7, 10, 11). Both tert-
butoxycarbonyl and benzyloxycarbonyl group can be
employed as amine protections without any significant
change in results.
doalkyl Phenylsulfones
O
O
LiCH2OBn
HN OR2
HN OR2
OBn
2
R1 SO2Ph
R1
THF/–78 °C
1
4
Entry Product R1
R2
Time (h) Yield (%)a
1
2
4b
4c
4d
4e
4f
Ph
CH2Ph
t-Bu
0.5
2
87
80
81
95
97
81
84
90
91
81
86
82
4-MeOPh
4-MeOPh
4-Br-Ph
4-Br-Ph
i-Pr
Table 1 Addition of Benzyloxymethyl Lithium (2) to a-Amidophe-
nyl Phenylsulfone 4a
3
CH2Ph
t-Bu
2
LiCH2OBn
NHBoc
SO2Ph
NHBoc
OBn
4
0.5
0.5
1.5
1.5
1.0
1.0
1.5
1.5
2
2
5
CH2Ph
t-Bu
THF/–78 °C
1a
4
Time (h)
4.0
6
4g
4h
4i
Entry
Equiv of 2
Yield (%)a
7
i-Pr
CH2Ph
t-Bu
1
2
3
4
5
6
7
8
1.0
1.5
2.0
2.5
2.5
3.0
3.0
1.5
–
8
t-Bu
4.0
35
71
85
85
85
85
83b
9
4j
t-Bu
CH2Ph
t-Bu
3.0
10
11
12
4k
4l
n-Bu
3.0
n-Bu
CH2Ph
t-Bu
0.5
4m
0.5
a Isolated yields.
3.0
0.5
In conclusion, general and efficient synthesis of amino al-
cohols has been achieved by addition of benzyloxymethyl
lithum reagent to various a-amidoalkyl phenylsulfones
derived from aldehydes to provide amino alcohols in good
yields for short reaction times. In addition, since a-ami-
doalkyl phenylsulfones can be prepared from numerous
aldehydes, the scope of 1,2-amino alcohols are diverse.
a Isolated yields.
b 1a and 1.2 equiv of NaH in THF was added to 2 in THF.
The protected amino alcohols 4 could be readily convert-
ed to amino alcohols 7 (Scheme 3). The Boc-group can be
selectively removed to give amine 5 in acidic condi-
tions.16 Also, palladium hydroxide catalyzed hydrogeno-
lysis gave N-protected amino alcohol 6 or free amino
alcohol 7 in good yields.
Acknowledgment
This work was financially supported by grant No. R02-2002-000-
00097-0 from the Korea Science & Engineering Foundation.
NHBoc
OBn
NH3+Cl–
OBn
4 N HCl in 1,4-dioxane
References
MeOH, 25 °C, 3 h
92% yield
(1) Bergmeier, S. C. Tetrahedron 2000, 56, 2561.
(2) (a) Reetz, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531.
(b) Ohfune, Y. Acc. Chem. Res. 1992, 25, 360.
5
4a
NHBoc
NHBoc
Pd(OH)2/H2 (1 atm)
(c) Yokomatsu, T.; Yuasa, Y.; Shibuya, S. Heterocycles
1992, 33, 1051. (d) Golebiowski, A.; Jurczak, J. Synlett
1993, 241. (e) Gante, J. Angew. Chem., Int. Ed. Engl. 1994,
33, 1699.
OBn
OH
MeOH, 25 °C, 12 h
87% yield
6
4a
(3) (a) Umezawa, H.; Aoyagi, T.; Morishima, H.; Matsuzaki,
M.; Hamada, M.; Takeuchi, T. J. Antibiot. 1970, 23, 259.
(b) Aoyagi, T.; Tobe, H.; Kojima, F.; Hamada, M.;
Takeuchi, T.; Umezawa, H. J. Antibiot. 1978, 31, 636.
(c) Umezawa, H.; Aoyagi, T.; Suda, H.; Hamada, M.;
Takeuchi, T. J. Antibiot. 1976, 29, 97. (d) Arcamone, F.;
Cassinelli, G.; Orezzi, P.; Franceschi, G.; Mondelli, R. J.
Am. Chem. Soc. 1964, 86, 5334. (e) Iwamoto, R. H.; Lim,
P.; Bhacca, N. S. Tetrahedron Lett. 1968, 36, 3891.
NHCbz
NH2
Pd(OH)2/H2 (1 atm)
OBn
OH
MeOH, 25 °C, 12 h
85% yield
4b
7
Scheme 3
Synlett 2004, No. 7, 1315–1317 © Thieme Stuttgart · New York

LETTER
General and Facile Synthesis of 1,2-Amino Alcohols
1317
(4) (a) Kim, Y. H. Acc. Chem. Res. 2001, 34, 955. (b) Anand,
N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
(c) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed. 1998, 37,
1986.
(5) Chen, Y. K.; Lurain, A. E.; Walsh, P. J. J. Am. Chem. Soc.
2002, 124, 12225; and references therein.
charged with argon. This solution was cooled to –78 °C and
n-BuLi (1.24 mL, 2.48 mmol, 2.0 M solution in
cyclohexane) was added dropwise to this cooled solution.
After stirring for 10 min, the solution became yellowish, and
the solution of a-amidoalkyl phenylsulfone 1 g (1 mmol) in
2 mL of THF was added in one portion. The mixture was
stirred for 1.5 h. The reaction mixture was quenched with
sat. aq solution of NH4Cl, diluted and extracted with Et2O,
dried over MgSO4 and evaporated to give crude 4g, which
was purified by silica gel chromatography, (eluent: EtOAc–
n-hexane, 1:10) to give pure 4g in 81% yield. 1H NMR (300
MHz, CDCl3): d = 0.88 (d, 3 H), 0.91 (d, 3 H), 1.42 (s, 9 H),
1.87 (m, 1 H), 3.46 (m, 3 H), 4.46 (q, 2 H), 4.71 (d, 1 H), 7.28
(m, 5 H). 13C NMR (75 MHz, CDCl3): d = 18.5, 19.5, 28.4,
29.7, 55.7, 70.6, 73.2, 78.9, 127.4, 127.6, 128.3, 138.3,
155.9. MS (EI): Anal. Calcd for C17H27NO3: 293.1991.
Found: 292.21.
(6) (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996,
96, 835. (b) Larrow, J. F.; Schaus, S. E.; Jacobsen, E. N. J.
Am. Chem. Soc. 1996, 118, 7420. (c) Barret, A. G. M.;
Seefeld, M. A.; White, A. J. P.; Williams, D. J. J. Org. Chem.
1996, 61, 2677. (d) Shibasaki, M.; Sasai, H. Pure. Appl.
Chem. 1996, 68, 523. (e) DuBois, J.; Tomooka, C. S.; Hong,
J.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 3179.
(f) Bruncko, M.; Schilingloff, G.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1483. (g) Kobayashi, S.;
Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120, 431.
(h) Tomoyasu, T.; Tomooka, K.; Nakai, T. Synlett 1998,
1147. (i) Chung, S. K.; Lee, J. M. Tetrahedron: Asymmetry
1999, 10, 1441.
(7) (a) Nugent, W. A. J. Am. Chem. Soc. 1992, 114, 2768.
(b) Enders, D.; Jegelka, U.; Ducker, B. Angew. Chem., Int.
Ed. Engl. 1993, 32, 423. (c) Barrett, A. G. M.; Seefeld, M.
A. Tetrahedron 1993, 49, 7857. (d) Matsubara, S.; Ukita,
H.; Kodama, T.; Utimoto, K. Chem. Lett. 1994, 831.
(e) Lingibe, O.; Graffe, B.; Sacquet, M. C.; Lhommet, G.
Heterocycles 1994, 37, 1469. (f) Besse, P.; Veschambre, H.;
Chenevert, R.; Dickman, M. Tetrahedron: Asymmetry 1994,
5, 1727.
(8) Enders, D.; Reinhold, U. Angew. Chem., Int. Ed. Engl. 1995,
34, 1219.
(9) Caron, M.; Carlier, P. R.; Sharpless, K. B. J. Org. Chem.
1985, 53, 5185.
(10) Wuts, P. G.; Pruitt, L. E. Synthesis 1989, 622.
(11) (a) Youn, S. W.; Choi, J. Y.; Kim, Y. H. Chirality 2000, 12,
404. (b) Tang, T. P.; Volkman, S. K.; Ellman, J. A. J. Org.
Chem. 2001, 66, 8772. (c) Petasis, N. A.; Zavialov, I. A. J.
Am. Chem. Soc. 1998, 120, 11798.
(15) Experimental Procedure for Addition of
Benzyloxymethyl Lithium Reagent to in situ-Generated
Imine 3 (Table 1, Entry 8).
To a suspension of 40 mg of NaH in 2 mL of THF under
argon, 1 mmol of 1a in 1 mL of THF was added and the
resulting mixture was stirred for 30 min. The solution was
added to the cold (–78 °C) benzyloxymethyl lithium solution
containing 1.5 mmol of benzyloxymethyl lithium.14 After
stirring for 30 min, the reaction mixture was quenched with
sat. aq solution of NH4Cl, diluted and extracted with Et2O,
dried over MgSO4 and evaporated to give crude 4a, which
was purified by silica gel chromatography, (eluent: EtOAc–
n-hexane, 1:10) to give 4a in 83% yield. 1H NMR (300
MHz, CDCl3): d = 1.25 (s, 9 H), 3.61 (q, 2 H), 3.70 (q, 2 H),
4.48 (q, 2 H), 4.84 (br, 1 H), 5.25 (br, 1 H), 7.28 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 28.3, 54.7, 70.3, 73.1, 79.5,
126.7, 127.2, 127.5, 127.6, 127.8, 137.9, 140.6, 155.3. MS
(EI): Anal. Calcd for C20H25NO3: 327.1834. Found: 326.41.
(16) Representative Procedure for Acidic Deprotection of Boc
Group (compound 5).
(12) (a) Pearson, W. H.; Lindbeck, A. C. J. Am. Chem. Soc. 1991,
113, 8546. (b) Mecozzi, T.; Petrini, M. J. Org. Chem. 1999,
64, 8970. (c) Bernacka, E.; Klepacz, A.; Zwierzak, A.
Tetrahedron Lett. 2001, 42, 5093.
(13) Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481.
(14) Representative Experimental Procedure for Addition of
Benzyloxymethyl Lithium Reagent to a-Amidoalkyl
Phenylsulfones (Table 2, Entry 6).
To 4a (50 mg) in MeOH (2 mL) was added 2 mL of 4 N HCl/
1,4-dioxane. The solution was stirred for 3 h at 25 °C. After
TLC analysis of the completion of the reaction, the solution
was concentrated in vacuo. The resulting crude 5 was
recrystallized from CHCl3–Et2O to give pure 5 in 92% yield.
1H NMR (300 MHz, CDCl3): d = 3.73 (m, 2 H), 4.33 (br, 1
H), 4.50 (q, 2 H), 7.25 (m, 10 H), 8.96 (br, 3 H). 13C NMR
(75 MHz, CDCl3): d = 52.6, 74.9, 76.1, 125.7, 126.6, 127.1,
127.3, 128.1, 129.5, 137.2, 141.3.
Benzyloxymethyltributylstannane (2.5 mmol), prepared
according to ref.13, was dissolved in THF (5 mL) and
Synlett 2004, No. 7, 1315–1317 © Thieme Stuttgart · New York