Synthesis of β-hydroxy nitriles and 1,3-amino alcohols from epoxides using acetone cyanohydrin as a LiCN precursor

Article abstract of DOI:10.1016/j.tetlet.2004.08.039

The reaction of acetone cyanohydrin with MeLi affords a LiCNA·acetone complex that can be made to react with epoxides in THF, either in one-pot or using isolated samples of the cyanide complex, to cleanly afford β-hydroxy nitriles upon aqueous workup; in situ hydride reduction of nitriles affords 1,3-amino alcohols.

Full text of DOI:10.1016/j.tetlet.2004.08.039

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7201–7204
Synthesis of b-hydroxy nitriles and 1,3-amino alcohols from
epoxides using acetone cyanohydrin as a LiCN precursor
*
James A. Ciaccio, Michael Smrtka, William A. Maio and David Rucando
Department of Chemistry, Fordham University, Bronx, NY 10458, USA
Received 30 June 2004;revised 6 August 2004;accepted 9 August 2004
Available online 24 August 2004
Abstract—The reaction of acetone cyanohydrin with MeLi affords a LiCNÆacetone complex that can be made to react with epoxides
in THF, either in one-pot or using isolated samples of the cyanide complex, to cleanly afford b-hydroxy nitriles upon aqueous
workup;in situ hydride reduction of nitriles affords 1,3-amino alcohols.
ꢀ
2004 Elsevier Ltd. All rights reserved.
1
. Introduction
LiCN is hygroscopic, and the limited availability and
poor quality of commercial LiCN has been a con-
1
5b,8a
8a,9
b-Hydroxy nitriles are useful synthetic intermediates
that can be prepared by reaction of epoxides with
cern.
Others
have reported improvement in nit-
rile yields and ease of handling by performing one-pot
reactions with LiCN, which they prepared from acetone
2
1,3
4
5
HCN, NaCN, KCN, LiCN, cyanide exchange re-
6
7
15
sin, TBAF/TMSCN in CH CN, or cyanide formed
3
cyanohydrin and LiH using a literature method; how-
upon treatment of acetone cyanohydrin with various
8
ever, reaction times were similar to those we reported.
LiH is flammable, moisture-sensitive, and, like LAH, it
releases an irritating and potentially explosive dust when
handled in air. The solubility of LiH in organic solvents
is poor;this precludes its storage and transfer in solu-
tion. Therefore, we investigated the reaction of acetone
cyanohydrin with alkyllithiums, since solutions of the
latter are commercially available, readily transferred
by syringe and easily titrated.
bases. The reaction of epoxides with NaCN, KCN or
1,3b,c,4c
HCN usually requires extended reaction times,
1
–3,4a,b
3a,4c
protic solvents
can afford mixtures of regio- or stereoisomers. In
992, we reported a simple and effective method to
or additives;
4
some reactions
2
c,6,7
5
a
1
convert functionalized epoxides to b-hydroxy nitriles
using LiCN in refluxing THF;its advantages are (1) high
regioselectivity, (2) short reaction times relative to
standard conditions using HCN or alkali metal cyanides
in protic solvents, (3) clean conversion of epoxide to nit-
rile and (4) the use of an inert, aprotic solvent that per-
mits in situ transformations using acid- and moisture-
sensitive reagents, such as LAH. This method has
recently been applied to the synthesis of marine diterpe-
We found that treatment of acetone cyanohydrin in
anhyd hexanes at À5 to À10ꢁC with 0.5–1.0equiv of
1
6
MeLi immediately afforded a LiCNÆacetone complex
as a white precipitate;solvent evaporation provided
good yields of the complex on either a milligram or mul-
tigram scale. Reaction of the cyanide complex with
epoxides, either in one-pot or using isolated samples of
the complex, gave the corresponding b-hydroxy nitriles
in good yields, cleanly, and in reaction times notably
shorter than those we reported for reactions using com-
9
10
nes, sugar moiety analogs of a nucleoside antibiotic,
1
1
8a
an antiviral nucleoside, and an antifungal agent.
1
and sev-
2,13
Synthetic studies towards 1-N-iminosugars
1
4
eral chiral building blocks have shown that 2,3-epoxy-
-alkanols and LiCN in THF react with high regio- and
stereoselectivity.
1
5
a
mercial samples of LiCN. In situ nitrile reduction with
either LAH or BH :THF afforded amino alcohols in sat-
3
isfactory yields (Scheme 1). The LiCN/acetone ratio of
the cyanide complex varied slightly (approx. 1:1, esti-
mated by C NMR peak intensity and integration of
CN and C@O in comparison with an authentic 1:1 sam-
ple);acetone could not be removed in vacuo (overnight,
Keywords: Epoxide;Lithium cyanide; b-Hydroxy nitrile;Amino alco-
hol;One-pot;Anhydrous conditions.
1
3
*
Corresponding author. Tel.: +1 718 817 4441;fax: +1 718 817
432;e-mail: ciaccio@fordham.edu
4
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.039

7202
J. A. Ciaccio et al. / Tetrahedron Letters 45 (2004) 7201–7204
OH
H O
2
O
NC
NH
OLi
R
OH MeLi,hexanes
CN (- MeH, Me CO)
R
.
LiCN acetone
NC
hydride
reduction
THF, reflux
R
OH
2
2
(
0.25 - 2.5 h)
R
Scheme 1.
room temp) or by sample filtration and sequential wash-
ing with solvents;however, it evaporated readily from
samples that were placed in a drying pistol (<0.1mmHg;
refluxing toluene).
cleanly afforded nitriles (62–93% yields;40min average
reaction time for all entries in Table 1;entries 7–9 re-
acted within 15min). All reactions were highly regio-
and stereoselective;only one isomer was detected by
NMR spectroscopy.
1
.1. Conversion of epoxides to b-hydroxy nitriles
1
.2. One-pot conversion of epoxides to 1,3-amino alcohols
We previously reported that treatment of epoxides with
–4equiv of commercial LiCN in refluxing anhyd THF
3
In situ LAH reduction of nitriles (LAH/epoxide = 1.5:1)
was complete within 1h at reflux (Table 2);BH :THF
could also be used for nitrile reduction (8:1 BH /epox-
3
ide, 3h reflux, followed by overnight heating with 10%
NaOH; Table 2, entries 1 and 2). Amino alcohols were
afforded in good purity and in satisfactory yields.
gave the corresponding nitriles (60–88% yields) in aver-
age reaction times of 4h for monosubstituted epoxides
3
5
a
and 8h for di- and trisubstituted epoxides. Reaction
of monosubstituted epoxides (Table 1, entries 1, 5–9)
with the LiCNÆacetone complex using a one-pot proce-
dure afforded nitriles (68–85% yields) cleanly, in reac-
tions using less LiCN and much less time (an average
of 40min);some epoxides reacted completely within
In summary, we report that LiCN can be conveniently
prepared by reaction of MeLi and acetone cyanohydrin
in anhyd hexanes: solvent evaporation affords a cyanide–
acetone complex that can be stored indefinitely in a
desiccator;heating in vacuo removes acetone;reaction
of the cyanide–acetone complex with epoxides in THF
affords the corresponding b-hydroxy nitriles in good
2
0min (Table 1, entries 7–9). Disubstituted epoxides re-
acted in 0.3–2.5h when treated with 2.5–4.5equiv LiCN
Table 1, entries 2–4). Reactions of epoxides with sam-
(
ples of the cyanide complex (2–3.5equiv) that were iso-
lated and stored for several weeks or longer also
a
Table 1. Conversion of epoxides to b-hydroxy nitriles with LiCNÆacetone in THF
Entry
Substrate
Product
LiCN (equiv)
Using isolated cyanide
One-pot preparation
Ref.
21
Time (h)
Yield (%)
Time (h)
Yield (%)
OH
CH2)10CH3
O
HO
NC
OH
(CH
O
1
3.5–4
2.0
89
1
82
(
)10CH
2 3
OH
CN
2
3
4
2.5
0.5 (4)
1.5 (3)
0.3
70 (71)
93 (79)
62
2
67
90
66
4c,5a
5a,22
23
O
O
OH
O
O
3.5
2.5
0.3
CN
OH
O
O
O
O
3.0–4.5
CN
O
O
OH
O
NC
5
6
7
2.5
2.5–3
2
0.5 (2.3)
0.5 (6.5)
0.25 (5.5)
89 (60)
92 (88)
86 (78)
1
84
85
68
1,5a
OH
OH
O
O
1
4c,5a,8b
5a,19
(
CH ) CH
NC
NC
2
4
3
(CH ) CH
2 4 3
0.25
OC(CH3)3
OPh
OC(CH3)3
OPh
OH
OH
O
O
8
9
2
0.25 (13.5)
0.25 (3)
93 (81)
75 (79)
0.3
0.3
80
71
3b,5a
5a
NC
NC
2.5
CH CH=CH
2
2
CH CH=CH
2
2
a
All yields are for isolated products. Parenthetical data are those we reported in Ref. 5a using commercial LiCN, and are included for comparison.

J. A. Ciaccio et al. / Tetrahedron Letters 45 (2004) 7201–7204
Table 2. One-pot preparation of amino alcohols: in situ LAH reduction of nitriles
7203
a
Entry
Substrate
Product
Isolated yield (%)
Ref.
O
OH
OC(CH3)3
1
77 (66)
19
20
H N
2
OC(CH3)3
OH
O
2
3
81 (83)
65
(
CH ) CH
2
5
3
H N
2
(CH ) CH3
2 5
OH
O
2
NH2
a
3
Parenthetical yields: reduction using 8:1 BH /epoxide, 3h reflux, overnight heating with 10% NaOH.
yields and in greatly shortened reaction times in compari-
son to previous reports by our group and others. We
also report an effective one-pot, two-step synthesis of
1,3-amino alcohols by in situ hydride reduction of nit-
riles obtained from reaction of epoxides with LiCN.
LAH in THF (1.5equiv) and refluxed until TLC analysis
revealed absence of unreacted nitrile (1h). Water
(4equiv based on LAH) was added slowly via syringe
to the ice-cold mixture followed by ethyl acetate
(3mL), stirring at room temperature (30min), filtration
ꢂ
through Celite (30 · 15mm;ethyl acetate as eluent)
and drying (MgSO ). Filtration, addition of toluene
(2mL, to drive off water) and concentration in vacuo
afforded amino alcohols (65–81% yields; Table 2).
4
1
7
2
. Experimental
1
8
2
.1. LiCNÆacetone complex. CAUTION: TOXIC
MeLi in diethyl ether (1.6M, 24mL, 38mmol) was
added via syringe over 15min to an anhyd hexane
Acknowledgements
(
5
150mL) solution of acetone cyanohydrin (5.00g,
We are grateful for financial support provided by Re-
search Corporation Cottrell College Science Award
No. C-3698, National Science Foundationꢀs Division
of Undergraduate Education through Grant DUE
8.7mmol) stirring at ꢀÀ10ꢁC under N . The resulting
2
white suspension was quickly warmed to room temper-
ature and stirred for 15min. Rotary evaporation (1h)
and exposure to <0.1mmHg (1h) afforded LiCNÆace-
#
9650684, and Mr. Stephen Bepler and Mr. Jack Wal-
tone as a white solid (3.4g, 98% yield for a 1:1 complex).
H NMR (DMSO-d , 300MHz) d 2.05 (s, CH COCH ).
ton, Members of the Fordham College at Rose Hill
Board of Visitors. We also thank Prof. J. J. McMahon
for HRMS analyses.
1
6
3
3
1
3
C NMR (DMSO-d , 75MHz): d 30.95 (CH ), 166.73
6
3
(
CN), 206.95 (C@O); only d 167.35 (CN) for a sample
exposed to <0.1mmHg in a drying pistol warmed with
refluxing toluene.
References and notes
2
.2. b-Hydroxy nitriles
1
. Kamal, A.;Ramesh Khanna, G. B.;Ramu, R. Tetrahe-
dron: Asymmetry 2002, 13, 2039–2051, and references cited
therein.
LiCNÆacetone (stored in a desiccator for several weeks
or longer) and epoxide in anhyd THF (6mL) were ref-
luxed until TLC analysis revealed absence of unreacted
epoxide (see Table 1 for LiCN/epoxide ratios and reac-
tion times). Treatment with water (40mL), ether extrac-
2. F u¨ l o¨ p, F.;Huber, I.;Berna ´th, G.;Ho¨nig, H.;Seufer-
Wasserthal, P. Synthesis 1991, 43–46, and references cited
therein.
3
. For examples, see: (a) Iranpoor, N.;Firouzabadi, H.;
Shekarize, M. Org. Biomol. Chem. 2003, 1, 724–727;(b)
Kamal, A.;Ramesh Khanna, G. B. Tetrahedron: Asym-
metry 2001, 12, 405–410;(c) Pa`mies, O.;Ba¨ckvall, J.-E.
Adv. Synth. Catal. 2001, 343, 726–731.
tion, drying (MgSO ), filtration, rotary evaporation and
4
concentration in vacuo afforded nitriles (62–93% yields).
2
epoxides
.3. b-Hydroxy nitriles by one-pot reaction of LiCN with
4
. For examples, see: (a) Jin, J.;Weinreb, S. M. J. Am. Chem.
Soc. 1997, 119, 2050–2051;(b) Itoh, T.;Mitsukura, K.;
Kanphai, W.;Takagi, Y.;Kihara, H.;Tsukube, H. J. Org.
Chem. 1997, 62, 9165–9172;(c) Chini, M.;Crotti, P.;
Favero, L.;Macchia, F. Tetrahedron Lett. 1991, 32, 4775–
LiCNÆacetone was prepared as described above (MeLi/
cyanohydrin = 1:1.5 or 1:2) and exposed to <1.0mmHg
for 20 min. Immediate addition of an anhyd THF solu-
tion of epoxide (see Table 1 for LiCN/epoxide ratios and
reaction times) and heating to reflux afforded nitriles
4
778.
5
. (a) Ciaccio, J. A.;Stanescu, C.;Bontemps, J. Tetrahedron
Lett. 1992, 33, 1431–1434;(b) Ciaccio, J. A.;Smrtka, M.;
Maio, W. Abstracts of Papers, 226th ACS National
Meeting, New York, NY, 2003;American Chemical
Society: Washington, DC, ORGN-123.
(
66–90% yields) after an aqueous workup.
2
.4. 1,3-Amino alcohols by in situ nitrile reduction
6
. Tamami, B.;Iranpoor, N.;Rezaei, R. Synth. Commun.
2003, 33, 3153–3157.
7. Konno, H.;Toshiro, E.;Hinoda, N. Synthesis 2003, 2161–
2164.
After reaction of epoxide with cyanide was complete, the
mixture was cooled to room temperature, treated with

7204
J. A. Ciaccio et al. / Tetrahedron Letters 45 (2004) 7201–7204
1
3
1
8
. (a) Tsuruoka, A.;Negi, S.;Yanagisawa, M.;Nara, K.;
Naito, T.;Minami, N. Synth. Commun. 1997, 27, 3547–
TLC, C (75MHz) and H NMR (300MHz) analyses.
Product entries 4 and 8 (one-pot preparation), Table 1,
were purified by column chromatography (SiO , pet.
3
9
557;(b) Ohno, H.;Mori, A.;Inoue, S. Chem. Lett. 1993,
75–978;(c) Mitchell, D.;Koenig, T. M. Tetrahedron
2
ether/EtOAc);product entry 2 (one-pot preparation),
Table 1, was purified by recrystallization (hexanes/
EtOH);product entry 3, Table 2, was purified by vacuum
distillation.
Lett. 1992, 33, 3281–3284.
. Renneberg, D.;Pfander, H.;Leumann, C. J. J. Org. Chem.
000, 65, 9069–9079.
9
2
1
0. Rauter, A.;Ferreira, M.;Borges, C.;Duarte, T.;Piedade,
F.;Silva, M.;Santos, H. Carbohydr. Res. 2000, 325, 1–15.
1. Faul, M. M.;Huff, B. E.;Dunlap, S. E.;Frank, S. A.;
Fritz, J. E.;Kaldor, S. W.;Le Tourneau, M. E.;Staszak,
M. A.;Ward, J. A.;Werner, J. A.;Winneroski, L. L.
Tetrahedron 1997, 53, 8085–8104.
18. (a) Flanagan, B. Chemistry Review 2003, 13, 2–4;(b)
Labianca, D. A. J. Chem. Educ. 1979, 56, 788–791.
19. Chen, R.;Zhang, M. Sci. China, Ser. B 1995, 38, 152–159;
Chem. Abstr. 1995, 123, 144000.
1
20. Katritzky, A. R.;Shcherbakova, I. V.;Tack, R. D.;Dai,
X. Q. Tetrahedron 1993, 49, 3907–3918.
21. (±)-threo-3,4-Dihydroxypentadecanenitrile (Table 1, prod-
1
1
1
2. Makino, K.;Ichikawa, Y. Tetrahedron Lett. 1998, 39,
1
8
245–8248.
3. Kim, Y. J.;Ichikawa, M.;Ichikawa, Y. J. Org. Chem.
000, 65, 2599–2602.
4. Guanti, G.;Merlo, V.;Narisano, E. Tetrahedron 1994, 50,
2245–12258.
uct entry 1): H NMR (CDCl
3
) d 0.90 (t, 3H), 1.36–1.53
1
3
(m, 20H), 2.64 (d, 2H), 3.55 (m, 1H), 3.82 (m, 1H);
NMR (CDCl ) d 14.0, 22.6, 22.7, 25.2, 29.3, 29.51, 29.56,
29.59, 29.6, 31.8, 33.2, 69.8, 73.0, 118.1;HRMS calcd for
C
2
3
1
C
22. (±)-trans-6-Hydroxy-2,2-dimethyl-1,3-dioxepane-5-carbo-
15
H
28NO (M À OH) 238.21709, found 238.21756.
1
1
5. Livinghouse, T. Org. Synth. Coll. 1990, 7, 517–521.
6. LiCN from reaction of acetone cyanohydrin and n-BuLi
afforded nitriles rapidly and in good yields, but with
occasional traces of 2-methyl-2-hexanol formed by addi-
tion of n-BuLi to acetone. Any t-butanol that might have
formed by addition of MeLi to acetone would have been
removed in vacuo or during an aqueous workup.
1
nitrile (Table 1, product entry 3): H NMR (CDCl ) d 1.35
3
(s, 3H), 1.40 (s, 3H), 2.8 (m, 1H), 3.50 (s, 1H, exchangeable
1
3
C
with D
NMR (CDCl
118.5;HRMS calcd for C H DNO (sample from D O
2
O), 3.65 (dd, 1H), 3.78 (dd, 1H), 3.93 (m, 3H);
3
) d 24.2, 24.3, 39.2, 56.9, 62.4, 69.0, 102.0,
8
12
3
2
exchange reaction) 172.09582, found 172.09558.
23. (8-Hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)acetonitrile (Table
1
7. Reactions were performed using 0.44–31mmol epoxide.
Spectroscopic and physical data were consistent with
previous reports (see references in Tables 1 and 2) and
new compounds displayed satisfactory spectroscopic
data (Refs. 21–23);crude products were generally pure
enough to be used for further reactions, as determined by
1
1, product entry 4): H NMR (CDCl
2H), 1.70–2.00 (m, 6H), 2.55 (s, 2H), 2.95 (s, 1H,
3
) d 1.55–1.65 (m,
1
3
2
exchangeable with D O), 3.95 (m, 4H); C NMR d 30.0,
31.8, 34.2, 64.0, 64.2, 68.8, 107.8, 117.4;HRMS calcd for
C H NO 197.10519, found 197.10522.
1
0
15
3