Synthesis of the Adrenergic Bronchodilators (R)-Terbutalinel and (R)-Salbutamol from (R)-Cyanohydrins

Article abstract of DOI:10.1021/jo970032d

Stereoselective syntheses of (R)-terbutaline and (R)-salbutamol acetal, which are important bronchodilators, starting from O-protected (R)-cyanohydrins are described. (R)-Terbutaline hydrochloride (R)-9·HCl is obtained in an overall yield of 44% with >98% ee from the O-bisallyl-protected cyanohydrin (R)-4k via a Ritter N-tertiary butylation to the amide (R)-6a, hydrogenation to the amino alcohol (R)-7a, and deprotection of the hydroxyl functions. (R)-Salbutamol acetals (R)-7b,c can be obtained from the corresponding O-protected (R)-cyanohydrins either via the route described for (R)-terbutaline or via selective hydrogenation of the protected cyanohydrin (R)-11 to the imino derivative, transimination with tert-butylamine, followed by hydrogenation with NaBH₄ to give the 2-amino alcohol derivative (R)-12. Desilylation of (A)-12 to (R)-7c is performed with LiAlH₄. Hydrolytic cleavage of the acetals (A)-7b and c to (R)-salbutamol was not yet possible without racemization.

Full text of DOI:10.1021/jo970032d

J . Org. Chem. 1997, 62, 3867-3873
3867
Syn th esis of th e Ad r en er gic Br on ch od ila tor s (R)-Ter bu ta lin e a n d
(R)-Sa lbu ta m ol fr om (R)-Cya n oh yd r in s1
Franz Effenberger* and J u¨rgen J a¨ger2
Institut fu¨r Organische Chemie der Universita¨t Stuttgart,
Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Received J anuary 3, 1997
Stereoselective syntheses of (R)-terbutaline and (R)-salbutamol acetal, which are important
bronchodilators, starting from O-protected (R)-cyanohydrins are described. (R)-Terbutaline
hydrochloride (R)-9‚HCl is obtained in an overall yield of 44% with >98% ee from the O-bisallyl-
protected cyanohydrin (R)-4k via a Ritter N-tertiary butylation to the amide (R)-6a , hydrogenation
to the amino alcohol (R)-7a , and deprotection of the hydroxyl functions. (R)-Salbutamol acetals
(R)-7b,c can be obtained from the corresponding O-protected (R)-cyanohydrins either via the route
described for (R)-terbutaline or via selective hydrogenation of the protected cyanohydrin (R)-11 to
the imino derivative, transimination with tert-butylamine, followed by hydrogenation with NaBH4
to give the 2-amino alcohol derivative (R)-12. Desilylation of (R)-12 to (R)-7c is performed with
LiAlH4. Hydrolytic cleavage of the acetals (R)-7b and c to (R)-salbutamol was not yet possible
without racemization.
In tr od u ction
alcohols. (1R)-2-Amino alcohols can be prepared without
any racemization either directly9 from (R)-cyanohydrins
or from their O-protected derivatives10 with various
hydrogenating agents. (1R,2S)-2-Amino alcohols are
accessible with high diastereoselectivity from O-protected
(R)-cyanohydrins by addition of a Grignard reagent to
the nitrile group and subsequent hydrogenation of the
primarily obtained imino intermediate.11 Alkyl substit-
uents at the amino group can be introduced either by a
method involving the reaction of the imino intermediate
with a primary amine (transimination) and subsequent
hydrogenation12 or alternativelyswith the exception of
the tert-butyl groupsby reductive N-alkylation of the
2-amino alcohols.13
The 2-amino alcohol skeleton is a structural unit found
in a substantial number of bioactive natural products.3
Since many of these compounds are of great importance
as pharmaceuticals,4 a variety of methods for their
stereoselective synthesis have been developed.3,5 Among
the 2-amino alcohols, compounds which derive or are
analogues of (R)-(-) adrenaline or of L-(-) ephedrine are
widely used in the treatment of cardiovascular disease
and as bronchodilators.4 Although it is very well known,4,6
that only the (R)-configuration in the adrenaline-type
compounds and the (1R,2S)-configuration in the ephe-
drine-type compounds are of pharmacological relevance,
today practically all of these pharmaceuticals are used
as racemates. Because of possible side effects of the
undesired stereoisomers,7 the stereoselective synthesis
of 2-amino alcohols became an important objective in the
last years.
The biological activity and thus the pharmacological
application of 2-amino-1-phenyl alcohols significantly
depends on the kind of substituents at the amino group
as well as in the phenyl ring. Particularly interesting
sympathomimetics, i.e. substances that mimic the action
of adrenaline and noradrenaline on sympathetic nerves,
contain hydroxy groups in the ring which are required
for the interactions with adrenergic receptors. On the
other hand, the size of the N-substituents influences
decisively the interaction with R- or â-receptors; an
Optically active cyanohydrins, which became easily
available in the last decade,8 are excellent starting
compounds for the stereoselective synthesis of 2-amino
X Abstract published in Advance ACS Abstracts, May 15, 1997.
(1) Enzyme-catalyzed reactions, Part 28. Part 27: Effenberger, F.;
Eichhorn, J . Tetrahedron: Asymm. 1997, 8, 469-476.
(2) J a¨ger, J . Part of Dissertation, Universita¨t Stuttgart 1996.
(3) Kunieda, T.; Ishizuka, T. Stud. Nat. Prod. Chem. 1993, 12, 411-
444.
(4) (a) Engel, J . Chem.-Ztg. 1982, 106, 169-183. (b) Kleemann, A.;
Engel, J . Pharmazeutische Wirkstoffe, Synthesen, Patente, Anwen-
dungen, 2nd ed.; Thieme: Stuttgart, 1982; and supplementary volume
1987.
(7) Barberich, T. J .; Young, J . W. (Sepracor, Inc.), US Pat. No. 5,-
362,755 (Nov. 8, 1994).
(8) (a) Effenberger, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1555-
1564. (b) North, M. Synlett 1993, 807-820. (c) Kanerva, L. T. Acta
Chem. Scand. 1996, 50, 234-242.
(9) Ziegler, T.; Ho¨rsch, B.; Effenberger, F. Synthesis 1990, 575-
578.
(5) (a) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int.
Ed. Engl. 1987, 26, 1141-1143. (b) Reetz, M. T.; Drewes, M. W.;
Lennick, K.; Schmitz, A.; Holdgru¨n, X. Tetrahedron: Asymm. 1990, 1,
375-378. (c) Yamashita, H. Chem. Lett. 1987, 525-528. (d) Koppen-
hoefer, B.; Trettin, U.; Wa¨chtler, A. Synthesis 1994, 1141-1142. (e)
Kitamura, M.; Ohkuma, T.; Inoue, S.; Sayo, N.; Kumobayashi, H.;
Akutagawa, S.; Ohta, T.; Takaya, H.; Noyori, R. J . Am. Chem. Soc.
1988, 110, 629-631. (f) Corey, E. J .; Link, J . O. J . Org. Chem. 1991,
56, 442-444. (g) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763-
784. (h) Kawaguchi, T.; Saito, K.; Matsuki, K.; Iwakuma, T.; Takeda,
M. Chem. Pharm. Bull. 1993, 41, 639-642. (i) Li, G.; Chang, H.-T.;
Sharpless, K.-B. Angew. Chem., Int. Ed. Engl. 1996, 35, 451-454. (j)
Hong, Y.; Gao, Y.; Nie, X.; Zepp, C. M. Tetrahedron Lett. 1994, 35,
5551-5554. (k) Oppolzer, W.; Tamura, O.; Sundarababu, G.; Signer,
M. J . Am. Chem. Soc. 1992, 114, 5900-5902. (l) An, B.; Kim, H.; Cha,
J . K. J . Org. Chem. 1993, 58, 1273-1275.
(10) (a) Elliott, J . D.; Choi, V. M. F.; J ohnson, W. S. J . Org. Chem.
1983, 48, 2294-2295. (b) Ohta, H.; Miyamae, Y.; Tsuchihashi, G.
Agric. Biol. Chem. 1986, 50, 3181-3184; ibid 1989, 53, 215-222. (c)
Matsuo, N.; Ohno, N. Tetrahedron Lett. 1985, 26, 5533-5534.
(11) (a) Brussee, J .; Dofferhoff, F.; Kruse, C. G.; van der Gen, A.
Tetrahedron 1990, 46, 1653-1658. (b) J ackson, W. R.; J acobs, H. A.;
Matthews, B. R.; J ayatilake, G. S.; Watson, K. G. Tetrahedron Lett.
1990, 31, 1447-1450. (c) Effenberger, F.; Gutterer, B.; Ziegler, T.
Liebigs Ann. Chem. 1991, 269-273.
(12) (a) Brussee, J .; van der Gen, A. Recl. Trav. Chim. Pays-Bas
1991, 110, 25-26. (b) Zandbergen, P.; van den Nieuwendijk, A. M. C.
H.; Brussee, J .; van der Gen, A.; Kruse, C. G. Tetrahedron 1992, 48,
3977-3982. (c) de Vries, E. F. J .; Brussee, J .; Kruse, C. G.; van der
Gen, A. Tetrahedron: Asymm. 1994, 5, 377-386.
(13) (a) Effenberger, F.; Gutterer, B.; J a¨ger, J . Tetrahedron: Asymm.
1997, 8, 459-467. (b) Noe, C. R.; Knollmu¨ller, M.; Ga¨rtner, P.;
Fleischhacker, W.; Katikarides, E. Monatsh. Chem. 1995, 126, 557-
564.
(6) (a) Hawkins, C. J .; Klease, G. T. J . Med. Chem. 1973, 16, 856-
857. (b) Wetterlin, K. J . Med. Chem. 1972, 15, 1182-1183.
S0022-3263(97)00032-7 CCC: $14.00 © 1997 American Chemical Society

3868 J . Org. Chem., Vol. 62, No. 12, 1997
Effenberger and J a¨ger
Ta ble 1. F or m a tion of Hyd r oxyben za ld eh yd e
Cya n oh yd r in s (R)-2 by (R)-Oxyn itr ila se-Ca ta lyzed HCN
Ad d ition to Ald eh yd es 1 in Diisop r op yl Eth er a n d
Citr a te Bu ffer , Resp ectively
Sch em e 1
(R)-cyanohydrins 2
aldehydes (R)-oxynitrilase reactn
conversion
(%)a
1
(U/mmol 1)
time(h)
ee (%)
1a
1b
1c
1d
50 (100)b
50
25 (60)b 2a
76 (90)b
67
98 (97)b
98
25
25
2b
2c
130
35
90
50 (100)b
100
40 (130)b 2d
26
58 (30)b
70
61 (54)b
69
exclusively â2-adrenergic activity results by introduction
of a tert-butyl substituent in the amino function. There-
fore, many of the important adrenergic bronchodilators
like terbutaline or salbutamol contain hydroxy groups in
the phenyl ring and tert-butyl groups in the amino
function.
1e
100 (100)b
20 (85)b 2e
60 (29)b
0 (21)b
a
1
b
Determined by H NMR spectroscopy. Conversion in citrate
buffer (0.05 M, pH 3.25) in parentheses.
for the (R)-3-hydroxybenzaldehyde cyanohydrins (R)-2a ,b
whereas (R)-2c was obtained with only 35% conversion
and 90% ee. (R)-3,5-Dihydroxybenzaldehyde cyanohy-
drin ((R)-2d ), an important starting compound for the
synthesis of (R)-terbutaline, is accessible, however, only
with ee-values of 61-69% (Table 1). The enzyme-
catalyzed reaction in aqueous citrate buffer (pH 3.25)
generally requires higher amounts of enzyme and longer
reaction times (Table 1), and moreover the substrate
concentration is lower due to lesser solubility of the
aldehydes 1 in water. Only with (R)-2a in citrate buffer
were results comparable to those in diisopropyl ether. 3,4-
Dihydroxybenzaldehyde 1e is a poor substrate for (R)-
oxynitrilase in both solvents (Table 1).
For the synthesis of (R)-terbutaline and (R)-salbuta-
mol, starting from optically active cyanohydrins, it is of
interest first to see if the corresponding (R)-cyanohydrins
can be prepared and if the tert-butylamino substituent
can be introduced using the nitrogen of the cyanohydrins.
Because of these results we have investigated generally
the acceptance of O-protected hydroxybenzaldehydes as
substrates for (R)-oxynitrilase. In view of the different
follow-up reactions of the cyanohydrins, compounds were
chosen which are stable against both organometallic
compounds and acids.
J ackson et al. have already synthesized successfully
some biologically active 2-amino-1-phenylethanols start-
ing from (R)-cyanohydrins,14a but in the preparation of
(R)-terbutaline predominantly racemization was ob-
served.14b
The protected hydroxy- and dihydroxybenzaldehydes
3b,c,f,k ,n ,o were prepared based on known procedures
for the protection of the hydroxybenzaldehydes 3a ,d ,e,g-
j,l,m 16 (see Experimental Section). The enzyme-cata-
lyzed addition of HCN to the protected aldehydes 3a -o
to give the corresponding (R)-cyanohydrins (R)-4a -o was
performed in diisopropyl ether (Scheme 2, Table 2).
With the exception of a few examples,13a,17 the influence
of protecting groups in hydroxybenzaldehydes in the (R)-
oxynitrilase-catalyzed HCN addition has not been de-
scribed so far. As can be seen from Table 2, protected
hydroxybenzaldehydes in general are accepted as sub-
strates by (R)-oxynitrilase. The conversion, however, is
not complete in all cases. Since addition of more enzyme
does not increase the conversion, the equilibrium con-
centration of the reaction obviously is reached in these
cases. From donor-substituted benzaldehydes it is known
that the equilibrium concentration of the HCN addition
is not completely on the product side.18
In contrast to the published results,14b in the present
publication we describe the preparation of optically pure
(R)-terbutaline starting from (R)-cyanohydrins. We also
describe the synthesis of O-protected (R)-salbutamol. All
attempts, however, to remove the acetal protecting
groups have not been successful so far.
Resu lts a n d Discu ssion
(R)-Oxyn itr ila se-Ca ta lyzed Ad d ition of HCN to
Un p r otected a n d O-P r otected Hyd r oxyben za ld e-
h yd es. Previous publications15,8a have demonstrated
that (R)-oxynitrilase [EC 4.1.2.10] accepts 3-hydroxybenz-
aldehyde as substrate but not 4-hydroxybenzaldehyde.
Now we have investigated the reaction of a variety of
substituted hydroxy- and dihydroxybenzaldehydes 1 with
HCN under (R)-oxynitrilase catalysis in diisopropyl ether
as solvent as well as in aqueous citrate buffer to give the
(R)-cyanohydrins (R)-2 (Scheme 1). The chemical and
optical yields obtained are summarized in Table 1.
As can be seen in Table 1, in diisopropyl ether rela-
tively good chemical and high optical yields are attainable
(16) (a) Edwards, R. L.; Mir, I. J . Chem. Soc. (C) 1967, 411-413.
(b) Yardley, J . P.; Fletcher, H. Synthesis 1976, 244. (c) Papadakis, P.
E. J . Am. Chem. Soc. 1945, 67, 1799-1800. (d) Spa¨th, E.; Liebherr,
F. Ber. Dtsch. Chem. Ges. 1941, 74, 869-872. (e) Claisen, L.; Eisleb,
O. Liebigs Ann. Chem. 1913, 401, 21-119. (f) Bergmann, E. D.;
Sulzbacher, M. J . Org. Chem. 1951, 16, 84-89. (g) Nelson, W. L.;
Burke, T. R. J . Med. Chem. 1979, 22, 1082-1088. (h) Duffley, R. P.;
Handrick, G. R.; Uliss, D. B.; Lambert, G.; Dalzell, H. C.; Razdan, R.
K. Synthesis 1980, 733-736. (i) Denis, G.; Delmas, M.; Gaset, A. J .
Heterocycl. Chem. 1984, 21, 517-519.
(17) Effenberger, F.; Gutterer, B.; Syed, J . Tetrahedron: Asymm.
1995, 6, 2933-2943.
(18) (a) Ching, W.-M.; Kallen, R. G. J . Am. Chem. Soc. 1978, 100,
6119-6124. (b) Young, P. R.; McMahon, P. E. J . Am. Chem. Soc. 1979,
101, 4678-4680.
(14) (a) Brown, R. F. C.; Donohue, A. C.; J ackson, W. R.; McCarthy,
T. D. Tetrahedron 1994, 50, 13739-13752. (b) Donohue, A. C.;
J ackson, W. R. Aust. J . Chem. 1995, 48, 1741-1746.
(15) Smitskamp-Wilms, E.; Brussee, J .; van der Gen, A.; van
Scharrenburg, G. J . M.; Sloothaak, J . B. Recl. Trav. Chim. Pays-Bas
1991, 110, 209-215.

(R)-Terbutaline and (R)-Salbutamol from (R)-Cyanohydrins
J . Org. Chem., Vol. 62, No. 12, 1997 3869
Sch em e 2
Sch em e 3
Ta ble 2. F or m a tion of (R)-Cya n oh yd r in s (R)-4a -o by
(R)-Oxyn itr ila se-Ca ta lyzed HCN Ad d ition to th e
P r otected Hyd r oxyben za ld eh yd es 3a -o in Diisop r op yl
Eth er a t Room Tem p er a tu r e
With regard to the synthesis of (R)-terbutaline and (R)-
salbutamol, the protected benzaldehydes 3k and 3m are
the most suitable substrates. The corresponding (R)-
cyanohydrins (R)-4k and (R)-4m can be obtained with
high conversion and excellent optical yields >98% ee and
97% ee, respectively (Table 2).
P r ep a r a tion of (R)-Ter bu ta lin e (R)-9 fr om (R)-3,5-
Bis(allyloxy)ben zaldeh yde Cyan oh ydr in (R)-4k. Vari-
ous procedures have been developed for preparing race-
mic terbutaline.19 The most common route involves the
reaction of 3,5-bis(benzyloxy)bromoacetophenone with
benzyl-tert-butylamine and subsequent catalytic hydro-
genation of the keto group to the corresponding alcohol
with simultaneous removal of the N-benzyl group.19a
We have now synthesized optically active (R)-terbuta-
line (R)-9 starting from the (R)-cyanohydrin (R)-4k as
outlined in Scheme 3.
(R)-cyanohydrins 4
aldehydes (R)-oxynitrilase reactn
conversion
(%)a
ee
(%)
3
(U/mmol 3)
time (h)
3a
3b
3c
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
100
40
60
84
42
24
40
165
50b
26
28
24
16
16
43
45
24
24
18
72
17
4a
4b
4c
4c
4d c
4e
4f
90
73
54
60
85
90
92
74
48
89
68
92
23
93
46
60
96.5
>98
81
83
94
93
50
100
100
150
100
50
50
100
60
95
4gd
4h
4i
>99
>99
81
4j
4k
4l
4m
4n
4o
>99
>98
86.5
97
95
96
100
60
Our attempts13a to prepare 2-N-tert-butylamino alco-
hols starting from O-silylated cyanohydrins, according
to a procedure described by J ackson,14a were unsuccess-
ful. J ackson et al.14a applied the reaction sequence
developed by Brussee et al.12b which includes selective
hydrogenation of O-silylated cyanohydrins with DIBALH
to the imino compounds, their transimination with tert-
butylamine, and subsequent hydrogenation with NaBH4.
We have chosen the Ritter reaction20 for the introduc-
tion of the N-tert-butyl group in a nitrile function (Scheme
3), a methodology already applied by J ackson et al.14b to
optically active cyanohydrins.
Preliminary investigations of the Ritter reaction with
(R)-mandelonitrile resulted in partial racemization under
the strong acidic reaction conditions. With O-acetylated
(R)-mandelonitrile, however, the reaction proceeds with-
out racemization (see Experimental Section). On the
basis of these results, (R)-4k was first acetylated to give
a
b
Determined by 1H NMR spectroscopy. Reaction at 30 °C.
c See ref 17. Compare ref 22.
d
The (R)-cyanohydrins (R)-4a ,b,d ,g are accessible with
high conversion (73-90%) and excellent enantiomeric
excesses (94-99% ee) from the methoxymethyl-protected
hydroxybenzaldehydes 3a ,b,d and 4-(allyloxy)benzalde-
hyde (3g).
Although 4-(benzyloxy)benzaldehyde (3h ) is a poor
substrate for (R)-oxynitrilase, the cyanohydrin (R)-4h is
obtained with >99% ee. The conversion of 48%, however,
is insufficient for a large scale preparation. The acyl-
protected cyanohydrins (R)-4e,f,i, on the other hand,
were obtained with lower ee-values (81-95% ee) but
excellent conversion (Table 2).
The size of the protecting groups influences both the
reaction rate and the conversion. So the conversion of
aldehydes 3c and 3n with larger protecting groups is very
slow, nevertheless (R)-4n was obtained even after long
reaction time with 95% ee (Table 2). In the reaction of
3c, however, neither the conversion nor the enantiose-
lectivity could be improved by variation of reaction
conditions (Table 2).
(19) (a) Ahuja, S.; Ashman, J . Anal. Profiles Drug Subst. 1990, 19,
601-625; Chem. Abstr. 1991, 114, 149988h. (b) Calzada Badia, J . M.
Span. ES 498,812 (Cl. C07C83/04), 1.12.1981; Chem. Abstr. 1982, 97,
5970d.
(20) Do¨pp, D.; Do¨pp, H. In Houben Weyl, Methoden der Organischen
Chemie; Thieme: Stuttgart, 1985; vol. E5/2, pp 1032-1040.

3870 J . Org. Chem., Vol. 62, No. 12, 1997
Effenberger and J a¨ger
Sch em e 4
(R)-5a followed by the Ritter reaction to yield after
chromatography optically pure acid amide (R)-6a . In
contrast to published results,14b a partial hydrolysis of
the acetate was not observed. Hydrogenation of the acid
amide (R)-6a was possible only under drastic conditions
using LiAlH4 in THF under reflux14b (24 h) to give the
amino compound (R)-7a with 90% ee, indicating only
minor racemization. These reaction conditions led also
to removal of the acetyl protecting group. The hydroge-
nation of (R)-6a with sodium in alcohol19b as well as the
catalytic hydrogenation for deprotection failed. Although
numerous procedures for the cleavage of allyl ethers have
been published,21 the deprotection of (R)-7a turned out
to be very difficult. Mild methods using Pd/C and
p-toluenesulfonic acid21b as well as PPh3/PdAc2 in formic
acid21c or PdCl2 in acetic acid failed to isomerize (R)-7a
to the bisenol ether (R)-8. The cleavage with Pd(PPh3)4
and tributyltin hydride,21d already used for the prepara-
tion of 2-amino alcohols,22 was not applied because of the
difficult isolation of the deprotected hydroxy compound.
We therefore have applied a base-catalyzed isomeriza-
tion.23 Under base catalysis allyl ethers isomerize nearly
exclusively to cis-enol ethers.23b By heating (R)-7a with
tert-butanolate in DMSO at 100 °C the 3,5-bisenol ether
(R)-8 was isolated without racemization in 92% yield and
90% ee. The hydrolytic cleavage of (R)-8 was performed
with methanolic HCl solution to yield quantitatively (R)-
terbutaline hydrochloride (R)-9‚HCl. Optically pure
(R)-9‚HCl was obtained after recrystallization from
THF/diethyl ether with 73% yield and >98% ee. (R)-
9‚HCl is extremely sensitive to oxidation,19a and crystal-
lization is difficult. THF was incorporated in the crystals
of the recrystallized (R)-9‚HCl in a molar ratio of (R)-
9‚HCl:THF ) 4:3. A similar effect was published already
for racemic terbutaline sulfate which contains 6 mol of
crystal water.24
duction of the N-tert-butyl group via the Ritter reaction
followed by hydrogenation and deprotection, as sum-
marized in Scheme 4.
Starting from the (R)-cyanohydrin (R)-4m the formal-
dehyde acetal of (R)-salbutamol (R)-7b could be obtained
via acetylation, Ritter reaction, and subsequent hydro-
genation in a good overall yield without detectable
racemization. The hydrolytic cleavage of the acetal (R)-
7b, however, to accomplish the synthesis of (R)-salbuta-
mol, was not possible so far. Acidic conditions in all cases
led to racemization and partial decomposition. Under
basic conditions, using sodium thioethoxide in DMF,27
deacetalization did not occur.
Since the acid-catalyzed hydrolysis of acetaldehyde
acetals is easier than the hydrolysis of formaldehyde
acetals, we have also used the protected cyanohydrin (R)-
4o to prepare (R)-salbutamol (Scheme 4). The O-acety-
lated cyanohydrin (R)-5c, however, which could be pu-
rified by chromatography, is less stable than (R)-5b, and
thus only polymerization was observed under the condi-
tions of the Ritter reaction. At lower temperature and
lower concentration of sulfuric acid only traces of the
amide (R)-6c could be obtained.
P r ep a r a tion of (R)-Sa lbu ta m ol Aceta ls 7b,c fr om
th e P r otected (R)-Cya n oh yd r in s (R)-4m a n d (R)-4o.
Synthetic approaches to racemic salbutamol have been
comprehensively reported recently.25 Possible routes to
the optically active compound are also included in this
report. Until now, only one procedure for the preparation
of (S)-salbutamol has been published,5j including a ste-
reoselective hydrogenation with an oxazaborolidine26a as
the decisive step. Asymmetric hydrogenation of the
carbonyl group of the corresponding halo ketone with
chiral oxazaborolidines as catalysts has been applied
successfully for the enantioselective syntheses of both
enantiomers of salmeterol.26b
With regard to results described by J ackson et al.,14a
who succeeded in the synthesis of 2-amino-1-phenyl-
ethanols, we have also tried the transimination method12b
for the preparation of (R)-salbutamol. The reaction
sequence, starting from the cyanohydrin (R)-4o, is rep-
resented in Scheme 5.
In this paper we describe our investigations of the
preparation of (R)-salbutamol starting from O-protected
(R)-cyanohydrins analogous to (R)-terbutaline, i.e. intro-
(21) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991. (b) Boss, R.; Scheffold, R.
Angew. Chem., Int. Ed. Engl. 1976, 15, 558-559. (c) Hey, H.; Arpe,
H.-J . Angew. Chem., Int. Ed. Engl. 1973, 12, 928-929. (d) Dangles,
O.; Guibe´, F.; Balavoine, G.; Lavielle, S.; Marquet, A. J . Org. Chem.
1987, 52, 4984-4993.
Under optimized reaction conditions using a threefold
excess of DIBALH and a sixfold excess of tert-butylamine
based on (R)-11, the acetal protected (R)-salbutamol (R)-
7c was isolated in 93% yield (Scheme 5). From the
measured specific rotations and previous experience of
this procedure we assume that all reactions proceed
nearly without racemization leading to the (R)-salbuta-
mol acetal (R)-7c with an optical purity of >90% ee.
Again, however, a hydrolytic cleavage of the acetal (R)-
7c was not successful. While the acid-catalyzed hydroly-
(22) Brown, R. F. C.; J ackson, W. R.; McCarthy, T. D. Tetrahedron:
Asymm. 1993, 4, 2149-2150.
(23) (a) Prosser, T. J . J . Am. Chem. Soc. 1961, 83, 1701-1704. (b)
Price, C. C.; Snyder, W. H. J . Am. Chem. Soc. 1961, 83, 1773.
(24) Hickel, D.; Carpy, A.; Laguerre, M.; Leger, J . M. Acta Crystal-
logr., Sect. B 1982, B38, 632-635.
(25) Bakale, R. P. Spec. Chem. 1995, 15, 249-250, 253; Chem. Abstr.
1996, 124, 175471k.
(26) (a) Corey, E. J .; Cimprich, K. A. Tetrahedron Lett. 1992, 33,
4099-4102. (b) Hett, R.; Stare, R.; Helquist, P. Tetrahedron Lett. 1994,
35, 9375-9378.
(27) Feutrill, G. I.; Mirrington, R. N. Aust. J . Chem. 1972, 25, 1731-
1735.

(R)-Terbutaline and (R)-Salbutamol from (R)-Cyanohydrins
J . Org. Chem., Vol. 62, No. 12, 1997 3871
OV 1701 or PS086 with 10% permethylated â-cyclodextrin or
Amid-Dex (amide phase); (b) Carlo Erba Fractovap 4160 with
FID, Spectra Physics Minigrator, 0.5 bar hydrogen, column
50 m, phase OV 1701 with 10% permethylated â-cyclodextrin;
(c) Hewlett Packard 5890 Series II with HP 7673-injector with
FID, Software HP 3365 Series II, Chem Station, version
A.03.21, hydrogen, columns FS-Lipodex C (50 m × 0.25 mm,
Macherey Nagel), Chiraldex B-TA and Chiraldex G-TA (30 m
× 0.32 mm, ITC), Permabond OV 1701-DF0.35 (25 m × 0.32
mm, Macherey Nagel). Capillary electrophoresis was per-
formed using a BioFocus 3000 capillary electrophoresis system
with BioFocus Software V3.10A (Bio-Rad) and uncoated glass
capillary (50 µm × 50 cm). Avicel cellulose was purchased
from Merck, hydroxybenzaldehydes 1a ,c,d ,e from Fluka. All
solvents were dried and distilled, and all reactions with
organometallic compounds were carried out under an argon
or nitrogen atmosphere in dried glassware.
Sch em e 5
The protected hydroxybenzaldehydes 3a ,d ,e,g-j,l,m were
prepared as described in the literature,16b-i 4-(propionyloxy)-
benzaldehyde (3f) according to ref 16c, 3-hydroxy-4-methyl-
benzaldehyde (1b) according to ref 29, and (R)-oxynitrilase
according to ref 30.
3-(Meth oxym eth oxy)-4-m eth ylben za ld eh yd e (3b). Po-
tassium carbonate (5.0 g, 36 mmol) was suspended in a
solution of 1b (4.9 g, 36 mmol) in acetonitrile (50 mL), and
chloromethyl methyl ether31 (5 mL of a 65% ic solution) was
added dropwise. After stirring for 18 h, the solid was filtered
off and washed with acetonitrile. The combined filtrates were
concentrated, and the residue was distilled in high vacuo: yield
1
6.1 g (94%); bp 71-75 °C/ 0.01 Torr; H NMR (CDCl3) δ 2.32
(s, 3 H), 3.50 (s, 3 H), 5.28 (s, 2 H), 7.29-7.54 (m, 3 H), 9.95
(s, 1 H). Anal. Calcd for C10H12O3: C, 66.65; H, 6.71. Found:
C, 66.43; H, 6.84.
sis with 0.01 M HCl gives racemic salbutamol hydrochlo-
ride 10‚HCl (Scheme 5), deprotection of the acetal under
neutral conditions, e.g., aqueous dimethyl sulfoxide,28a
PdCl2(CH3CN)2 in aqueous acetonitrile,28b SnCl2‚2H2O in
dichloromethane,28c or CuSO4 adsorbed on silica gel,28d
failed.
3-(Meth oxym eth oxy)-4-m eth oxyben zaldeh yde (3c). Po-
tassium carbonate (43 g, 0.31 mol) was suspended in a solution
of 1c (15 g, 98 mmol) in acetone (200 mL), and chloromethyl
methyl ether (25 mL of a 65% ic solution) was added dropwise.
After stirring for 1 h at 50 °C, the solid was filtered off and
washed with acetone, and the combined filtrates were con-
centrated in vacuo. The residue was dissolved in diethyl ether,
washed with NaOH solution, dried (MgSO4), and concentrated.
The residue was distilled in high vacuo: yield 14.6 g (76%);
Con clu sion
1
bp 105 °C/0.001 Torr; mp 38-39 °C; H NMR (CDCl3) δ 3.53
We were able to demonstrate, that optically active
cyanohydrins are excellent starting compounds for the
stereoselective synthesis of pharmacologically important
2-amino-1-arylethanols like (R)-terbutaline and (R)-sal-
butamol. The optically active cyanohydrins can be
obtained by oxynitrilase-catalyzed addition of HCN to
suitable benzaldehydes. Since most of the desired benz-
aldehydes are hydroxy substituted, it was necessary to
investigate the influence of O-protecting groups on the
substrate acceptance of the enzyme. For the introduction
of a tert-butylamino group in the nitrile function of an
optically active cyanohydrin without racemization, the
Ritter reaction is the most suitable procedure.
(s, 3 H), 3.95 (s, 3 H), 5.33 (s, 2 H), 7.26-7.46 (m, 3 H), 9.87
(s, 1 H). Anal. Calcd for C10H12O4: C, 61.22; H, 6.16. Found:
C, 61.17; H, 6.24.
3,5-Bis(a llyloxy)ben za ld eh yd e (3k ) Accor d in g to Ref
16h . (a) A solution of allyl 3,5-bis(allyloxy)benzoate, prepared
from 65 mmol of 3,5-dihydroxybenzoic acid,32 (18.0 g, 37 mmol)
in diethyl ether was added dropwise at 0 °C to a suspension
of LiAlH4 (1.5 g, 40 mmol) in diethyl ether (200 mL), and the
reaction mixture was stirred for 16 h at rt. After hydrolysis,
the organic phase was dried (MgSO4) and concentrated: yield
8.07 g (99%) of 3,5-bis(allyloxy)benzyl alcohol which was used
without further purification.
(b) A solution of the alcohol (8.07 g, 36.7 mmol) in dichlo-
romethane (35 mL) was added dropwise at 10 °C to a
suspension of pyridinium chlorochromate (16.2 g, 75 mmol)
and sodium acetate (1.4 g, 17 mmol) in dichloromethane (70
mL). After stirring for 2 h, diethyl ether (200 mL) was added,
and the formed solid was crushed. After being stirred for a
further 1 h, the solid was filtered off and washed with diethyl
ether. The combined filtrates were slurried with charcoal to
remove color. After filtration the solvent was removed in
vacuo, and the residue fractionally distilled in high vacuo:
yield 9.23 g (65%, based on 3,5-dihydroxybenzoic acid) of 3k :
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were determined on
a Bu¨chi SMP-20 apparatus and are uncorrected. 1H NMR
spectra were recorded with TMS as internal standard using a
Bruker AC 250 F (250 MHz) instrument. Preparative chro-
matography was carried out on columns packed with silica gel
S (Riedel-de Haen, size: 0.032-0.063 mm). Specific rotations
were measured with a Perkin-Elmer polarimeter 241 LC. GC
for ee-determination was performed on: (a) Carlo Erba HRGC
5300 Mega Series with FID, Carlo Erba Mega Series Integra-
tor, 0.4-0.5 bar or 0.36 bar hydrogen, column 20 m, phases
(29) Fukumi, H.; Kurihara, H.; Mishima, H. Chem. Pharm. Bull.
1978, 26, 2175-2180.
(30) (a) Hochuli, E. Helv. Chim. Acta 1983, 66, 489-493. (b) Kaul,
R.; Mattiasson, B. Biotechnol. Appl. Biochem. 1987, 9, 294-302. (c)
Lauble, H.; Mu¨ller, K.; Schindelin, H.; Fo¨rster, S.; Effenberger, F.
Proteins: Struct., Funct., Genet. 1994, 19, 343-347.
(31) Lo¨bering, J .; Fleischmann, A. Ber. Dtsch. Chem. Ges. 1937, 70,
1680-1683.
(28) (a) Kametani, T.; Kondoh, H.; Honda, T.; Ishizone, H.; Suzuki,
Y.; Mori, W. Chem. Lett. 1989, 901-904. (b) Lipshutz, B. H.; Pollart,
D.; Monforte, J .; Kotsuki, H. Tetrahedron Lett. 1985, 26, 705-708. (c)
Ford, K. L.; Roskamp, E. J . Tetrahedron Lett. 1992, 33, 1135-1138.
(d) Caballero, G. M.; Gros, E. G. Synth. Commun. 1995, 25, 395-404.
(32) Coqueret, X.; Wegner, G. Makromol. Chem. 1992, 193, 2929-
2943.

3872 J . Org. Chem., Vol. 62, No. 12, 1997
Effenberger and J a¨ger
1
bp 115 °C/0.01 Torr; H NMR (CDCl3) δ 4.55-4.59 (m, 4 H),
excess of pyridine were removed in vacuo, and the products
were reacted without further purification.
(R)-2-Acet oxy-2-[3,5-b is(a llyloxy)p h en yl]a cet on it r ile
(5a ). From (R)-4k (30 mmol), acetic anhydride (10 mL),
5.29-5.47 (m, 4 H), 5.97-6.13 (m, 2 H), 6.75 (t, J ) 2.3 Hz, 1
H), 7.02 (d, J ) 2.3 Hz, 2 H). Anal. Calcd for C13H14O3: C,
71.64; H, 6.47. Found: C, 71.33; H, 6.38.
pyridine (5 mL): bp 125-130 °C/0.001 Torr; [R]20
+7.2 (c
578
In tr od u ction of P r otectin g Gr ou p s in 5-Br om o-2-
h yd r oxyben zyl Alcoh ol. (a) A solution of 5-bromo-2-hy-
droxybenzyl alcohol (10.15 g, 50 mmol) in THF (20 mL) was
added dropwise at 0 °C to a suspension of NaH (3.7 g, 154
mmol) in THF (80 mL). After stirring for 30 min at rt, allyl
bromide (13 mL, 154 mmol) was added dropwise, and the
reaction mixture was stirred for further 16 h and then refluxed
for 8 h. Sodium bromide was filtered off, the filtrate concen-
trated in vacuo, and the residue distilled in high vacuo: yield
10.8 g (76%) 3-[(allyloxy)methyl]-4-(allyloxy)bromobenzene: bp
1.0, MeOH); 1H NMR (CDCl3) δ 2.17 (s, 3 H), 4.50-4.56 (m, 4
H), 5.26-5.46 (m, 4 H), 5.95-6.13 (m, 2 H), 6.32 (s, 1 H), 6.55
(t, J ) 2.2 Hz, 1 H), 6.65 (d, J ) 2.2 Hz, 1 H). Anal. Calcd for
C16H17NO4: C, 66.89; H, 5.96; N, 4.87. Found: C, 66.69; H,
6.10; N, 4.91.
(R )-2-Ace t oxy-2-(1,3-b e n zod ioxin -6-yl)a ce t on it r ile
(5b): From (R)-4m (15 mmol), acetic anhydride (4 mL),
pyridine (1.6 mL): [R]20
-7.5 (c 1.5, CH2Cl2), 97% ee; 1H
578
NMR (CDCl3) δ 2.14 (s, 3 H), 4.92 (s, 2 H), 5.26 (s, 2 H), 6.32
(s, 1 H), 6.93 (d, J ) 8.5 Hz, 1 H), 7.16 (d, J ) 2.0 Hz, 1 H),
7.31 (dd, J ) 8.5, 2.0 Hz, 1 H). Anal. Calcd for C12H11NO4:
C, 61.80; H, 4.75; N, 6.00. Found: C, 61.58; H, 4.75; N, 5.92.
(R)-2-Acetoxy-2-(2-m eth yl-1,3-ben zod ioxin -6-yl)a ceto-
n itr ile (5c): From (R)-4o (34 mmol), acetic anhydride (10 mL),
1
115-120 °C/0.001 Torr; H NMR (CDCl3) δ 4.06-4.10 (m, 2
H), 4.55 (s, 2 H), 4.67 (d, J ) 6.4 Hz, 2 H), 5.10-5.40 (m, 4 H),
5.90-6.10 (m, 2 H), 6.73 (d, J ) 8.7 Hz, 1 H), 7.34 (dd, J )
8.7, 2.5 Hz, 1 H), 7.53 (d, J ) 2.5 Hz, 1 H).
(b) Ethyl vinyl ether (15 mL, 157 mmol) was added dropwise
to a stirred solution of 5-bromo-2-hydroxybenzyl alcohol (22
g, 108 mmol) and p-toluenesulfonic acid (100 mg) in DMF
(100 mL). The reaction mixture was stirred for 17 h, and after
addition of the double volume of NaOH solution (0.1 N)
extracted with diethyl ether. The combined extracts were
dried (MgSO4) and concentrated in vacuo, and the residue
was distilled in high vacuo: yield 22.8 g (92%) of 6-bromo-
2-methyl-1,3-benzodioxin: bp 94 °C/0.02 Torr; 1H NMR (CDCl3)
δ 1.54 (d, J ) 5.1 Hz, 3 H), 4.78 and 4.94 (AB system, J )
14.8 Hz, 2 H), 5.14 (q, J ) 5.1 Hz, 1 H), 6.73 (d, J ) 8.7 Hz, 1
H), 7.09-7.10 (m, 1 H), 7.24 (dd, J ) 8.7, 2.3 Hz, 1 H).
P r ep a r a tion of Com p ou n d s 3n a n d 3o. A small amount
of the respective bromo compound (see above) was added to
Mg in THF, and the Grignard reaction was started by heating
to 50 °C and addition of 1,2-dibromoethane as entrainer. The
residual educt was added dropwise with stirring, and the
reaction mixture was heated to 60 °C for 1 h and after addition
of DMF at 0 °C stirred for further 16 h. The reaction mixture
was hydrolyzed with HCl (5%) and extracted with diethyl
ether. The combined extracts were dried (MgSO4) and con-
centrated, and the residue was distilled in vacuo.
3-[(Allyloxy)m et h yl]-4-(a llyloxy)b en za ld eh yd e (3n ).
From Mg (50 mmol), bromo compound (10.5 g, 37 mmol), and
DMF (50 mmol): yield 4.6 g (54%); bp 115-120 °C/0.001 Torr;
1H NMR (CDCl3) δ 4.09-4.10 (m, 2 H), 4.61 (s, 2 H), 4.64-
4.67 (m, 2 H), 5.20-5.50 (m, 4 H), 5.90-6.10 (m, 2 H), 6.95 (d,
J ) 8.5 Hz, 1 H), 7.80 (dd, J ) 8.5, 2.1 Hz, 1 H), 7.97 (d, J )
2.1 Hz, 1 H), 9.93 (s, 1 H). MS (EI 70 eV) m/ z 232 (20), 202
(15), 174 (65), 135 (100).
6-F or m yl-2-m eth yl-1,3-ben zod ioxin (3o). From Mg (150
mmol), bromo compound (22 g, 96 mmol), and DMF (150
mmol): yield 10.5 g (61%); bp 95-100 °C/0.01 Torr, mp 68 °C;
1H NMR (CDCl3) δ 1.58 (d, J ) 5.1 Hz, 3 H), 4.90 and 5.03
(AB system, J ) 14.7 Hz, 2 H), 5.26 (q, J ) 5.1 Hz, 1 H), 6.96
(d, J ) 8.4 Hz, 1 H), 7.54-7.55 (m, 1 H), 7.71 (dd, J ) 8.4, 1.9
Hz, 1 H), 9.85 (s, 1 H). Anal. Calcd for C10H10O3: C, 67.40;
H, 5.65. Found: C, 67.49; H, 5.73.
pyridine (2.7 mL): bp 110-115 °C/0.01 Torr; [R]20 -17.0 (c
578
1
1.0, CH2Cl2), 96% ee; H NMR (CDCl3) δ 1.56 (d, J ) 5.1 Hz,
3 H), 2.15 (s, 3 H), 4.81 and 4.98 (AB system, J ) 14.8 Hz, 2
H), 5.19 (q, J ) 5.1 Hz, 1 H), 6.35 (s, 1 H), 6.90 (d, J ) 8.5 Hz,
1 H), 7.15 (s, 1 H), 7.30 (d, J ) 8.5 Hz, 1 H). Anal. Calcd for
C13H13NO4: C, 63.15; H, 5.30; N, 5.66. Found: C, 63.09; H,
5.39; N, 5.43.
Ritter Rea ction to ter t-Bu tyl Am id es (R)-6. Gen er a l
P r oced u r e. At 15 °C H2SO4 (80 mmol) was slowly added to
a stirred solution of 5 in acetic acid (80 mL) and tert-butyl
alcohol (80 mmol). The reaction mixture, allowed to warm up
to 30 °C, was diluted after 4-5 h with water to the double
volume and extracted with diethyl ether. The combined
extracts were concentrated, and the residue was chromato-
graphed on silica gel with ethyl acetate/petroleum ether (3:7).
(R)-2-Ace t oxy-2-[3,5-b is(a llyloxy)p h e n yl]-N-ter t-b u -
tyla ceta m id e (6a ). From (R)-5a (obtained from 43.5 mmol
of 3k as starting compound): yield 12.2 g (78% based on 3k );
[R]20 -25.0 (c 1.46, MeOH); 1H NMR (CDCl3) δ 1.34 (s, 9 H),
D
2.17 (s, 3 H), 4.49-4.52 (m, 4 H), 5.25-5.44 (m, 4 H), 5.79 (s,
1 H), 5.85 (s, 1 H), 5.95-6.11 (m, 2 H), 6.46 (t, J ) 2.2 Hz, 1
H), 6.58 (d, J ) 2.2 Hz, 2 H). Anal. Calcd for C20H27NO5: C,
66.46; H, 7.53; N, 3.87. Found: C, 66.31; H, 7.64; N, 3.65.
(R)-2-Ace t oxy-2-(1,3-b e n zod ioxin -6-yl)-N-ter t -b u t yl-
a ceta m id e (6b). From (R)-5b (40 mmol): yield 7.80 g (63%);
1
mp 125 °C; [R]20 -29.6 (c 1.5, CH2Cl2); H NMR (CDCl3) δ
578
1.36 (s, 9 H), 2.16 (s, 3 H), 4.89 (s, 2 H), 5.23 (s, 2 H), 5.86 (s,
1 H), 5.94 (bs, 1 H), 6.86 (d, J ) 8.5 Hz, 1 H), 7.05 (d, J ) 2.1
Hz, 1 H), 7.18 (dd, J ) 8.5, 2.1 Hz, 1 H). Anal. Calcd for
C16H21NO5: C, 62.53; H, 6.88; N, 4.56. Found: C, 62.33; H,
6.91; N, 4.42.
Red u ction to Am in o Alcoh ols (R)-7. Gen er a l P r oce-
d u r e. A solution of 6 or 12 in THF was added dropwise at 0
°C under Ar to a suspension of LiAlH4 in dry THF, and the
reaction mixture was refluxed for 20 h (6) or 5 h (12). After
cooling to 0 °C, the reaction mixture was diluted with diethyl
ether and hydrolyzed with a small volume of water. The
ethereal phase was decanted from precipitated aluminum
hydroxide, and the aqueous phase was washed several times
with diethyl ether. The combined organic phases were dried
(MgSO4) and concentrated, and the residue was crystallized
from diethyl ether/hexane or diethyl ether/petroleum ether.
(R )-1-[3,5-Bis(a llyloxy)p h e n yl]-2-(t er t -b u t yla m in o)-
eth a n ol (7a ). From (R)-6a (5.4 g, 15 mmol), LiAlH4 (2.3 g,
P r ep a r a tion of (R)-Cya n oh yd r in s 4. Gen er a l P r oce-
d u r e. A solution of (R)-oxynitrilase (100 U/0.2 g support) was
added to the support (2 g, soaked in 50 mL of 0.02 M sodium
acetate solution, pH 3.3 or 4.5, filtered off and centrifuged)
followed by addition of a solution of 3 (0.5-51 mmol) in
diisopropyl ether and a two- to fourfold excess of HCN. After
stirring for the time given in Table 2, the support was filtered
off and the filtrate dried (MgSO4) and concentrated in vacuo.
60 mmol), and THF (100 mL): yield 4.35 g (85%) as hydro-
1
chloride; mp 143 °C; [R]20 -28.0 (c 1.0, MeOH), 90% ee; H
D
Deter m in a tion of En a n tiom er ic Excess of (R)-4. Acetic
anhydride (50 µL) and pyridine (10 µL) were added to a
solution of crude (R)-4 (5 µL) in dichloromethane (200 µL).
After heating to 60 °C for 2-3 h, the reaction mixture was
filtered through a silica gel column (0.5 × 3 cm) with dichlo-
romethane (3 mL). The enantiomeric excess was directly
determined from the filtrate.
Acet yla t ion of (R)-4k ,m ,o t o Com p ou n d s (R)-5a -c.
Gen er a l P r oced u r e. As described for the ee-determination,
from (R)-4k , -4m , or -4o in dichloromethane, acetic anhydride,
and pyridine. After stirring for 2 h at 60 °C, solvent and the
NMR (CDCl3) δ 1.09 (s, 9 H), 2.58 (ABX system, J ) 11.8, 8.4
Hz, 1 H), 2.88 (ABX system, J ) 11.8, 3.8 Hz, 1 H), 4.50-4.55
(m, 5 H), 5.24-5.45 (m, 4 H), 5.97-6.12 (m, 2 H), 6.41 (t, J )
2.3 Hz, 1 H), 6.55 (d, J ) 2.3 Hz, 2 H). Anal. Calcd for
C18H27NO3‚HCl: C, 63.24; H, 8.25; N, 4.10; Cl, 10.37. Found:
C, 63.25; H, 8.33; N, 3.97; Cl, 10.62.
(R)-1-(1,3-Ben zod ioxin -6-yl)-2-(ter t-b u t yla m in o)et h a -
n ol (7b). From (R)-6b (3.6 g, 11.7 mmol), LiAlH4 (1.8 g, 47
mmol), THF (60 mL): yield 2.50 g (85%); mp 129-130 °C;
[R]20 -24.0 (c 1.10, CH2Cl2); 1H NMR (CDCl3) δ 1.10 (s, 9 H),
D
2.53 (ABX system, J ) 11.8, 9.0 Hz, 1 H), 2.85 (ABX system,

(R)-Terbutaline and (R)-Salbutamol from (R)-Cyanohydrins
J . Org. Chem., Vol. 62, No. 12, 1997 3873
J ) 11.8, 3.6 Hz, 1 H), 4.50 (dd, J ) 3.6, 9.0 Hz, 1 H), 4.90 (s,
2 H), 5.23 (s, 2 H), 6.85 (d, J ) 8.4 Hz, 1 H), 7.00 (d, J ) 1.2
Hz, 1 H), 7.13 (dd, J ) 8.4, 1.2 Hz, 1 H). Anal. Calcd for
C14H21NO3: C, 66.91; H, 8.42; N, 5.57. Found: C, 66.82; H,
8.39; N, 5.46.
imidazole (5.4 g, 80 mmol) in DMF (80 mL). After stirring for
15 min, (R)-4o (prepared from 42 mmol 3o) in DMF (5 mL)
was added dropwise, and the reaction mixture was stirred for
3 h at rt. After hydrolysis with water (150 mL), the aqueous
phase was extracted with diethyl ether. The combined extracts
were dried (MgSO4) and concentrated, and the residue frac-
tionally distilled in high vacuo: yield 7.70 g (58%); bp 125 °C/
(R)-2-(ter t-Bu tyla m in o)-1-(2-m eth yl-1,3-ben zod ioxin -6-
yl)eth a n ol (7c). From (R)-12 (1.4 g, 3.69 mmol), LiAlH4 (0.3
0.005 Torr; [R]20 -7.86 (c 1.4, CH2Cl2); 1H NMR (CDCl3) δ
g, 7.9 mmol), THF (47 mL): yield 0.91 (93%); mp 103 °C; [R]20
D
D
0.13, 0.21 (each s, 6 H), 0.92 (s, 9 H), 1.55 (d, J ) 5.1 Hz, 3 H),
4.84 (AB system, J ) 14.7 Hz, 1 H), 5.00 (AB system, J ) 14.7
Hz, 1 H), 5.19 (q, J ) 5.1 Hz, 1 H), 5.42 (s, 1 H), 6.87 (dd, J )
8.5, 2.1 Hz, 1 H), 7.08 (dd, J ) 7.4, 1.7 Hz, 1 H), 7.19-7.26
(m, 1 H). Anal. Calcd for C17H25NO3Si: C, 63.91; H, 7.89; N,
4.38. Found: C, 63.63; H, 7.93; N, 4.25.
P r ep a r a tion of Silyla ted Am in o Alcoh ol (R)-12 Ac-
cor d in g to Ref 14a . A 1.5 M solution of DIBALH in toluene
(10 mL) was added at -70 °C under Ar via syringe to a solution
of (R)-11 (1.7 g, 5.3 mmol) in dry diethyl ether (60 mL). After
stirring for 4 h, a solution of NH4Br (1.35 g, 13.7 mmol) in
methanol (25 mL) was added dropwise via syringe followed
after 10 min by tert-butylamine (3.2 mL, 30 mmol). The stirred
reaction mixture was allowed to warm to 0 °C within 2 h and
cooled to -50 °C, and NaBH4 (0.4 g, 10.5 mmol) was added in
two portions. The reaction mixture was stirred for 16 h at rt
and hydrolyzed with 1 N HCl (80 mL), and the aqueous phase
was extracted twice with diethyl ether. The combined extracts
were washed with NaOH solution (1 N), dried (MgSO4), and
concentrated, and the residue was chromatographed on silica
1
-73.0 (c 1.0, CH2Cl2); H NMR (CDCl3) δ 1.10 (s, 9 H), 1.54
(d, J ) 5.1 Hz, 3 H), 2.45-2.58 (m, 1 H), 2.82-2.89 (m, 1 H),
4.60 (dd, J ) 3.5, 8.9 Hz, 1 H), 4.83 and 4.99 (AB system, J )
14.6 Hz, 2 H), 5.16 (q, J ) 5.1 Hz, 1 H), 6.80 (d, J ) 8.4 Hz, 1
H), 7.00 (bs, 1 H), 7.12 (d, J ) 8.4 Hz, 1 H). Anal. Calcd for
C15H23NO3: C, 67.89; H, 8.74; N, 5.28. Found: C, 67.68; H,
8.60; N, 5.36.
Isom er iza tion of (R)-7a to Com p ou n d (R)-8. Potassium
tert-butanolate (90 mg, 0.8 mmol) was added under Ar to a
solution of 7a (2.4 g, 7.8 mmol) in dry DMSO (30 mL). After
heating to 120 °C for 16 h, DMSO was removed at 10 Torr,
and the residue was mixed with water (50 mL) and extracted
with diethyl ether. The combined extracts were dried (MgSO4)
and concentrated: yield 2.20 g (92%); as sulfate: mp 243 °C
1
dec; [R]20 -25.4 (c 0.5, MeOH), 90% ee; H NMR (CDCl3) δ
D
1.10 (s, 9 H), 1.70 (d, J ) 6.9 Hz, 3 H), 1.71 (d, J ) 6.9 Hz, 3
H), 2.57 (ABX system, J ) 11.9, 8.5 Hz, 1 H), 2.90 (ABX
system, J ) 11.9, 3.6 Hz, 1 H), 4.53 (dd, J ) 8.5, 3.6 Hz, 1 H),
4.83-4.94 (m, 2 H), 6.35-6.39 (m, 2 H), 6.55 (t, J ) 2.2 Hz, 1
H), 6.71 (d, J ) 2.2 Hz, 2 H). Anal. Calcd for C18H27NO3‚1/2
H2SO4: C, 60.99; H, 7.96; N, 3.95; S, 4.52. Found: C, 60.79;
H, 8.10; N, 3.97; S, 4.59.
gel with ethyl acetate/petroleum ether (7:3): yield 0.85 g (42%)
1
as colorless oil; [R]20 -77.8 (c 1.1, CH2Cl2); H NMR (CDCl3)
D
δ -0.17 and 0.45 (each s, 6 H), 0.88 (s, 9 H), 1.07 (s, 9 H), 1.54
(d, J ) 5.1 Hz, 3 H), 2.52 (ABX system, J ) 10.8, 3.8 Hz, 1 H),
2.67 (ABX system, J ) 10.8, 8.8 Hz, 1 H), 4.66 (dd, J ) 3.8,
8.8 Hz, 1 H), 4.83 and 4.98 (each AB system, J ) 14.6 Hz, 2
H), 5.18 (q, J ) 5.1 Hz, 1 H), 6.80 (d, J ) 8.4 Hz, 1 H), 6.91 (d,
J ) 1.8 Hz, 1 H). MS (CI methane) m/ z 408 (10), 380 (60),
364 (80), 336 (90), 248 (100).
P r ep a r a tion of (R)-Ter bu ta lin e Hyd r och lor id e (R)-
9‚HCl. An ethereal solution of HCl (1 mL) was added
dropwise under N2 at rt to a solution of 8 (1.0 g, 3.28 mmol) in
methanol (50 mL), and the reaction mixture was stirred for
18 h. The solvent was removed in vacuo, and the residue was
recrystallized from THF/diethyl ether and dried at 40 °C in
high vacuo: yield 0.63 g (73%); mp 215 °C dec; [R]20 -32.5 (c
D
0.76, MeOH), >98% ee; 1H NMR (CD3OD) δ 1.27 (s, 9 H), 2.86
(ABX system, J ) 12.4, 10.1 Hz, 1 H), 2.98 (ABX system, J )
12.4, 3.2 Hz, 1 H), 4.65 (dd, J ) 10.1, 3.2 Hz, 1 H), 6.10 (t, J
) 2.2 Hz, 1 H), 6.27 (d, J ) 2.2 Hz, 1 H). Anal. Calcd for
Ack n ow led gm en t. This work was generously sup-
ported by the Bundesministerium fu¨r Bildung und
Forschung (Zentrales Schwerpunktprogramm Biover-
fahrenstechnik, Stuttgart) and the Fonds der Chemisc-
hen Industrie. We thank Katja Sovarasteanu for her
experimental contributions.
C
12H19NO3‚HCl: C, 55.06; H, 7.70; N, 5.35; Cl, 13.54. Found:
C, 55.12; H, 7.62; N, 5.44; Cl, 13.22.
Det er m in a t ion of E n a n t iom er ic E xcess of (R)-7a , 8,
a n d 9. By capillary electrophoresis according to ref 33 using
the conditions 20 kV; 20 mM â-cyclodextrin, 150 mM
(N(C4H9)4)3PO4, 10% MeOH, pH 2.5; uncoated capillary column
(50 cm × 50 µm); 40 °C and detection at 214 nm.
J O970032D
(33) (a) Quang, C.; Khaledi, M. G. Anal. Chem. 1993, 65, 3354-
3358. (b) Quang, C.; Khaledi, M. G. J . Chromatogr. 1995, 692, 253-
265.
(34) Brussee, J .; Loos, W. T.; Kruse, C. G.; van der Gen, A.
Tetrahedron 1990, 46, 979-986.
P r ep a r a tion of (R)-11 Accor d in g to Ref 34. At 0 °C tert-
butyldimethylchlorosilane (6.78 g, 45 mmol) was added to