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New Synthetic Reactions Based on the Onium Salts of Aza-Arenes [New synthetic methods (29)].

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Volume 18 . Number 10
October 1 9 7 9
Pages 707-808
International Edition in English
New Synthetic Reactions Based on the Onium Salts of Aza-Arenes
New synthetic
methods (29)
By Teruaki Mukaiyama'']
Effective syntheses employing 2-halogenated pyridinium, benzoxazolium, benzothiazolium,
and pyridinium salts have been accomplished in the absence of strong acids and bases. Activation of carboxylic acids or alcohols with these onium salts leads to 2-acyloxy and 2-alkoxy intermediates which can be transformed into esters, amides, thiol esters, (macrocyclic) lactones,
acid fluorides, olefins, allenes, carbodiimides, isocyanates, isothiocyanates, nitriles, and isocyanates. The possibility of performing stereospecific syntheses (involving configurational inversion) with onium salts deserves attention.
1. Introduction
Remarkable progress has been achieved in the field of synthetic organic reactions by the use of readily available strong
bases such as alkyllithium and also of acidic reagents such as
TiCLI'I. However, in the synthesis of complex molecules,
such as biologically active substances having base- or acidlabile functionalities, it is highly desirable to be able to work
under neutral or neutralization conditions. One approach is
to utilize characteristic properties of trivalent phosphorus
compounds and organosulfur compounds in "oxidation-reduction condensation"[']. For example, this method affords
carboxylic thiol esters from carboxylic acids and thiols without any assistance from an acid or a base?
R'CO'H
+ R'SSR' + (C,Hs),P
R3
Table 1. Onium salts used and key to abbreviations.
Onium
salt
R'
R'
R'
R4
X
Y
Z
+
R'C(O)SR'
+ R'SH + (CeHs)sP=O
In reactions of this type, the utilization of the onium salts
seems to be promising, since ionic character in the intermediate should result in the close proximity of reacting species
around the onium salts, thus promoting smooth reaction under mild conditions. On the basis of this consideration, we
have investigated the use of onium salts of aza-arenes, and it
has become clear that the onium salts are effective for the activation of carboxyl and hydroxyl components in the pres['I
ence of such weak bases as trialkylamines under neutralization condition. Table 1 lists some of the onium salts used and
various abbreviations.
Prof. Dr. T. Mukaiyama
Department of Chemistly, Faculty of Science
The University of Tokyo, Hongo, Tokyo 113 (Japan)
Angew. Chem. Inf. Ed. Engl. 18, 707-721 (1979)
Me = methyl, Et = ethyl, Bu = butyl, Ph= phenyl,
Ts =p-toluenesulfonyl, THP = telrahydropyranyl
=acetyl, B ~ benzyl,
=
TEBA = benzyltriethylammonium
chloride,
DME =dimethoxyethane,
HMPA = hexamethylphosphoric triamide, THF = tetrahydrofuran
0 Verlog Chemie. CmbH, 6940 Weinheim, 1979
0570-0833/79/1010-0707
$ 02.50/0
707
This review describes recent synthetic advances using 2halopyridinium, 2-fluorobenzothiazolium, and 2-chlorobenzoxazolium salts with specific accounts of intermolecular and
intramolecular dehydration, and syntheses of optically active
substances.
2. Intermolecular Dehydration
2.1. Activation of Carboxylic Acids
2.1.1. Synthesis of Carboxylic Esters, Amides, and Thiol Esters
The study of these reactions was prompted by the following observations: 2-Acyloxy-I-methylpyridiniumiodide (2),
an active acylating intermediate, should be produced easily
and rapidly by a nucleophilic attack of a carboxylate ion on
2-chloro- ( l a ) or 2-bromo-I-methylpyridinium iodide (lb),
since the 2-halogen atom of these onium salts is easily replaced by nucleophiles. The intermediate (2) should in turn
be converted into stable neutral molecules, i. e. the acylated
product (3), 1-methyl-2-pyridone, and the ammonium salt,
by the attack of a nucleophile in the presence of a tertiary
amine as hydrogen iodide captor. Since all the reacting species are in close proximity to the central pyridinium ion, the
condensation reaction should be entropically advantageous.
R'CO~H, R:N
I
NUH, R:N
PorP
P o r 10
CH,
I@
(la),X
(lb), X
=
CH, X@ o r
IO
C1
= Br
d N u+
0
0
(3)
kH3
On the basis of these assumptions, the formation of carboxylic esters from equimolar amounts of carboxylic acids
and alcohols was investigated[']. In the first place, effective
hydrogen halide captors were examined for the condensation
of equimolar amounts of phenylacetic acid and benzyl alcohol using (la). Triethylamine, tributylamine, and 2,6-lutidine gave good results (98, 99, and 97% yield, respectively);
the yield of benzyl phenylacetate decreased as the basicity of
the amine decreased.
Table 2. Synthesis of esters from equimolar amounts of carhoxylic acid and a h hol with 2-chloro- (la) or 2-bromo-I-methylpyridiniumiodide (Ib) and tri-n-butylamine (3 h, reflux).
R'CO2H
+ R'OH
+
R'C02R2
Onium
salt
R'
R2
Yield [%]
in CH2C12 in toluene
(Ib)
C~HS
CLHSCH~
C~HSCH~
CJlsCHz
CH,
CHI
CeHsCH2
C6HrCH2
C~HSCHZ
C,H5CH2
CHI
(CH3)X
CeH5CH2
CzHs
C~HSCH~
(CHI)IC
C&CHz
C6H5CH=CHCH2
CnH5
ChHSCH2CH2
(CHI~C
C,HS(CHI)CH
CeHrCH2CH2
CnHXH2
80
92
97
70
80
80
(la)
708
No significant solvent effect was observed in the reaction,
benzyl phenylacetate being obtained in almost quantitative
yield in diethyl ether (97%),dichloromethane (99%),acetonitrile (98%),pyridine (98%),toluene (99%), etc.-Examples of
esterification are shown in Table 2.
The effect of changing the counterion and the halogen
atom of the pyridinium salt on the yield of carboxylic esters
urged us to look for more effective pyridinium salts. Thus ester formation from 3-phenylpropionic acid and benzyl alcohol (tri-n-butylamine, 1 h, reflux in dichloromethane) using
the 2-halopyridinium salts (la)-(ld) gave yields of 69, 61,
73, and 82%, respectively (Table 1).
Table 3. Synthesis of esters from equimolar amounts of carhoxylic acid and alcohol with 2-hromo-I-ethylpyridinium tetrafluorohorate /Id) and tri-n-butylamine
in CH2C12.
R'C02H
82
84
88
62
R'C02R'
Yield
3h
reflux [a]
R2
C*H~CHZCHZ
C,H5CH2CH2
C~HI
CzH,
ChH,CH=CH
C~HSCH=CH
(CH3)S
ChHsCHz
CI,C
ClCH2
CICH2
2-Fury1
CBHsC-C
GHsCOCH2
CH,COCH2CH2
Cyclopropyl
CH3CH-CH CH
73 (59)
57
62 (39)
60 (48)
71 (62)
43 (27)
[%I
12 h
20°C
61
71
21
54
78
40
88
80
62
97
85
87
45
62
59
[a] Values in parentheses refer to the reaction with 2-chloro-I-methylpyridinium
iodide (la).
Then the reaction of several carboxylic acids, including
functionalized ones, with strictly equimolar amounts of alcohols was carried out with 2-bromo-i-ethylpyridinium tetrafluoroborate (id)and tri-n-butylamine as coupling reagents;
favorable results were obtained especially at room temperature (Table 3). Particular mention should be made of the esterification of pivalic acid, trichloroacetic acid, and benzoylacetic acid, also with various sterically hindered alcohols,
such as tert-butyl alcohol.
When alcohols were replaced by primary or secondary
amines as nucleophiles, carboxamides were obtained in high
yields (Table 4)l51.The preparation of carboxamides using 2-
Table 4. Synthesis of carboxamides from acids and amines with the onium salt
( I n ) or ( l b ) and tri-n-butylamine (1 h, reflux in CH2C12).
+
R'CONR'RI
Onium
salt
R'
R2
R'
Yield [%]
(14
C~HS
CnHcCH,
t-C,H,
C&s
C,H,CH2
CeHsCH2
n-C4H9
I-C4HU
ChHsCHz
C,Hs
C6HsCHz
n-CxHI,
n-C4H9
H
quant.
quant.
93
85
quant.
98
93
81
-
R'
R'C02H + R'R'NH
90
85
74
31
+ R20H
(fb)
Angew. Chem. lnt.
H
H
H
H
Ed. Engl. 18, 707-721 (1979)
iodopyridinium salt as a coupling agent had been previously
studied in detail by Sutherland et al.[61.However, only modest yields were obtained. These results again indicate the significant effect of the halogen atom attached to position 2;
only chlorine and bromine derivatives give favorable results.
3-Acylthiazolidine-2-thione (5), obtained in high yield
from a carboxylic acid and thiazolidine-2-thione (4) on use
of a 2-chloro-I -methylpyridinium iodide (la), proved to be
an interesting intermediate. When (5) was treated with aluminum hydride reagents, the corresponding aldehyde was
produced selectively, free from alcohol. Thus the overall
transformation provides a new and efficient method for the
partial reduction of carboxylic acids to aldehydes['].
and triethylamine in dichloromethane at low temperature, a
2-acyloxypyridinium salt is formed immediately, and subsequent addition of thiol affords the corresponding thiol ester
in high yield (Table 5)""l. Since the yield of thiol ester from
the reaction of acid fluoride and thiol under similar conditions is generally low, this result affords indirect support for
the intervention of 2-acyloxypyridinium salts as an intermediate. The usefulness of 2-fluoropyridinium salts will be demonstrated in Section 2.1.3.
(lei
Table 5 . Synthesis of thiol esters with 2-fluoro-i-methylpyridinium tosylate (lei
and triethylamine.
(41
isulAlH or LitBu$JH
*
R'
R2
Yield [%]
CeH,
GHsCHZ
(CHdqC
CH3COCH2CH2
HO2C(CH2),
CeHKH2
C~HKHZ
C,H,CH,
C,H,CH,
ChH,
C~HS
C~HS
C,H,
C~HS
n-C4Hu
s-C4HV
f-C4HY
a-Pyridyl
87
96
(5)
RCHO
In the above syntheses of carboxylic esters or amides, the
use of two moles of tertiary amine per mole of acid is necessary to scavenge hydrogen halide formed during the reaction.
Although at the end of the reaction, tertiary amine is completely converted into the ammonium salt, the reaction medium is initially weakly basic. Development of a less basic
acid captor to replace the tertiary arnine therefore appeared
desirable. It was thought that dihydropyridopyrimidones (6)
would be most promising captors since a betaine structure (7)
can be written and, on treatment with an acid, they are converted into the onium salt (8). The pyrimidone derivatives
(6a) and (6b) are easily prepared from ethyl acrylate and 2aminopyridine or 2-aminopicoline[*].The use of (6) in place
of a tertiary amine also gave favorable results in the preparation of carboxylic esters or amides from equimolar amounts
of carboxylic acids and alcohols or aminesl'].
R
1
(6a). R = H
( 6 b ) , R = CH3
The basicity of pyrimidone (6) is low (pKb= -6.5), and
the pyrimidinium salt (8) formed by reaction with a hydrogen halide is insoluble in almost all organic solvents and precipitates from the reaction mixture. Consequently, condensation can be performed under almost completely neutral conditions. The reaction requires 2 moles of (6) per mole of acid;
the yields of esters and amides are 70-97 and 80-ca. loo%,
respectively.
A similar procedure proved unsuccessful for the preparation of thiol esters from carboxylic acids and thiols, since
competitive attack of thiols on the 2-chloropyridinium salts
caused the reaction to become rather complex. However, this
difficulty was overcome by use of a stepwise procedure and
employment of a 2-fluoropyridinium salt such as ( l e ) . When
a carboxylic acid is treated with a 2-fluoropyridinium salt
Angew Chem. I n ( . Ed Engl. 18, 707-721 (1979)
88
83
79 la1
81 [bl
81
84
79
[a] Synthesis of hexanebis(Spheny1 thioate) from adipic acid and thiophenol in
a molar ratio of i :2. [b] With tri-n-butylamine as base.
Alternative methods for the direct preparation of thiol esters from free carboxylic acids include a method utilizing triphenylphosphane and diphenyldisulfane (or 2,2'-dipyridyldisulfane) which has been reported from our
Yamada et al. used diethyl phosphorocyanidate or diphenyl
phosphorazidate'"]. However, the present reaction provides
a convenient method for the preparation of thiol esters with
respect to (i) direct synthesis from equimolar amounts of free
carboxylic acid and thiol and (ii) the mildness of the reaction
conditions.
Furthermore, preparation of the thiol ester (9) derived
from a hydroxy acid (12-hydroxyoctadecanoic acid) and
thiophenol was successfully accomplished without protecting
the hydroxyl group by adding the 2-fluoropyridinium salt
(re) to the carboxylic acid and triethylamine at room temperature, and treating the resulting mixture with thiophenol and
triethylarnine[l"].
OH
(9)
7570
2.1.2. Synthesis of Macrocyclic Lactones"'
The discovery of numerous macrolide antibiotics has generated a recent surge of interest in new solutions to the problem of macrocyclic lactone synthesis[iZ1.Since most of the
['I Lactone synthesis will be considered in connection with intermoleculardehydration because the most favorable procedure occurs in two steps.
709
macrolide antibiotics have many acid- and/or base-labile
functional groups in the molecule with many chiral carbons,
the construction of the carbon skeleton of the hydroxy carboxylic acid, the precursor of the macrolide, is a most difficult problem which, however, can be overcome by a strategy
involving properly selected reaction conditions and stereochemical control. However, the intramolecular lactonization
reaction of hydroxy carboxylic acids has also remained an
unsolved problem. In particular, two problems should be
pointed out: i) How can macrolide formation be carried out
selectively without accompanying undesirable intermolecular lactide formation?, and ii) how can the lactonization reaction be performed under neutral or neutralization conditions?
Corey et al.[131
and Gerlach et al.[141
found one of the effective routes for lactonizing hydroxy carboxylic acids via 2-pyridinethiol (10) or 2-imidazolethiol esters, prepared by employing the above-mentioned oxidation-reduction condensation[*'.
s-s 'N
HO(CH2)nCOzH
+-
0'
In the above carboxylic ester synthesis utilizing 2-halopyridinium salt, the pyridinium salt participates in all reaction
steps and the condensation reaction should be favored in
terms of entropy. The intramolecular lactonization reaction
was therefore investigated with the expectation that the reaction would proceed smoothly and effectively.
A preliminary investigation was undertaken to determine
the efficacy of various bases as hydrogen halide acceptors;
triethylamine was found to be the most suitable base. Further, it became clear that the lactonization could be successfully carried out in a variety of solvents; the optimum yield
was obtained in refluxing acetonitrile. In this way various ohydroxy carboxylic acids (11) were lactonized to give the medium and large ring lactones (12) in better yields~'51than
those obtained by previous methods (Table 6)113a1.
Subsequently we developed an efficient two-step method
for cyclization of long chain hydroxy acids to macrocyclic
lactones via 6-phenyl-2-pyridyl esters (14)[161.
This method
was successfully applied to the syntheses of recifeiolide (15)
and ricinelaidic acid lactone (17)["l; however, it was feared
that the cyclization of 6-phenyl-2-pyridyl ester with p-toluenesulfonic acid in the second step would limit its application to more complex molecules. In order to develop a more
promising method for lactonization of complex molecules,
the previous method['51using 2-chloro-I-methylpyridinium
salts such as (la) was re-examined. The treatment of hydroxy
acids with these salts and triethylamine afforded macrocyclic
710
Table 6. Formation o f lactones (12) and (undesired) lactides (13) from w-hydroxy carboxylic acids (1 1) with 2-chloro-1-methylpyridinium iodide (to) in
boiling acetonitrile.
Yield [%]
n
(14
(13)
5
7
10
11
14
89
13
61
69
84
0
34
24
14
3
lactones in reasonable but not entirely satisfactory yields.
This result was mainly due to the decomposition of the pyridinium salts under the cyclization conditions by the attack
of triethylamine on the I-methyl group or position 2 of the
pyridinium ring to form 2-chloropyridine or 2-ammoniopyridinium salts.
In view of the above facts, a stable pyridinium salt, 2-chloro-6-methyl-l,3-diphenylpyridiniumtetrafluoroborate (18,
was prepared according to the procedure developed in our
laboratory["] and tested as a reagent for the lactonization
reaction["I. When 15-hydroxypentadecanoic acid (11e) was
treated with (13 and 2,4,6-triphenylpyridine in refluxing
dichloroethane by the dilution method, no pentadecanolide
(12e) could be obtained and the hydroxy acid ( l l e ) was recovered. On the other hand, the transformation of (11e) into
(12e) could be achieved by addition of benzyltriethylammonium chloride (TEBA). For example, a dichloroethane
(50 ml) solution of (Ile) (0.25 mmol) and 2,4,6-triphenylpyr-
HO(C H2)"C OzH
n
A
*
0
(17), 96%
Angew. Chem. Inr.
Ed. Ettgi. 18, 707-721 (1979)
idine (1 .O mmol) was added during 7 h to a refluxing dichloroethane (30 ml) solution of (If) (0.5 mmol) and TEBA (0.5
mmol) under argon. The reaction mixture was refluxed for
an additional 1 h and pentadecanolide (12e) was isolated in
99% yield. Similarly, 12-hydroxydodecanoic acid (1Id) was
lactonized to dodecanolide (12d) in 85% yield.
The use of the 2-chloropyridinium salt (18 for lactonization of optically active hydroxy acids is illustrated by the lactonization of (R)-(+ )-ricinelaidic acid. @)-(+)-Lactone (I7)
was obtained in 91% yield without racemization upon treatment of the hydroxy acid (16) with (lj),2,4,6-triphenylpyridine, and TEBA in refluxing dichloroethane. On use of 2,6dimethylpyridine the yield was 86%.
To demonstrate the applicability of this macrolactonization process to more complex hydroxy acids, the cyclization
of prostaglandin F2,,-9,1I-bis(tetrahydropyrany1) derivative
(18) was attempted"']; the protected 1,15-lactone (19) was
isolated in 91% yield. Removal of the protecting group gave
prostaglandin FZm-l
,15-lactone (20) (79%).
R = n-C7H15, ~ - C ~ H ~ ~ C H = C H ( CCHH~3 0) zBC, C H ~ C H 2 .
CH3C OCHzCHz
n = 2,3
Using this method, DL-variotin (25), an antifungal antibiotic, could be synthesized in simplified manner, i e. without protection of the hydroxyl group[221.
-
7
OTHP
iH
0
-
=OH
OH
OH
OH
H
N5'H5
-
0
0
Toluene, 90°C
(25), 3 7%
In the reactions discussed so far, carboxylic acids are
transformed, by treatment with a 2-chloropyridinium salt,
into the active intermediate, the 2-acyloxypyridinium salt,
which then reacts with various nucleophiles to produce the
corresponding condensation product. In the absence of a nucleophile, competitive nucleophilic attack of chloride ion
and carboxylate ion takes place, and a mixture of carboxylic
anhydride and acid chloride is formed.
2-Fluoro-I ,3-dimethylpyridinium tosylate (lg) is more
reactive than 2-chloropyridinium salts such as (la).Carboxylate ion reacts with 2-fluoropyridinium salt much faster than
with 2-acyloxypyridinium salt, and 2-acyloxypyridinium salt
is formed exclusively. Thus it follows that, in the absence of
the other nucleophiles, fluoride ion attacks the 2-acyloxypyridinium salt; this is the basis of a convenient synthesis of acid
fluorides[231.
OH
The lactonization of prostaglandin FZU(21) under the
same conditions as for (18)+ (19) gave the 1,9-lactone (22) in
75% yield along with a small amount (4%)of the 1,15-lactone
(20). The successful synthesis of lactones (16), (20), and (22)
described above demonstrates the utility of the present macrolactonization process.
2.1.3. Miscellaneous Acylation Reactions
Lactim ethers (23) can also act as nucleophiles toward the
active key intermediates, 2-acyloxypyridinium salts; N-acyl
lactams (24) are obtained in good yield[201.N-Acyl lactams
have been most widely prepared by reaction of acyl halide
with lactim ether or N-trimethylsilyl lactam'"]. However, little work has been reported on the preparation of N-acyl lactams directly from free carboxylic acids and lactim ethers.
On utilization of the 2-chloropyridinium salt (la), N-acyl
lactams (24) can be produced in good yields from equimolar
amounts of free carboxylic acids and lactim ethers (five- or
six-membered ring system).
Angew. Chrm. Ini. Ed. Engl. IN. 707-721 (1979)
z
(fa).Bu3N
*
CICHzCHzCl (reflux)
O
OH
OTHP
COOH
C
R = n-C11Hz3, quant.; CsHsCHzCHz, 88%; C ~ H ~ C H80%;
Z,
CBH,, 9370; C ~ H , C H ( C Z H ~87%;
),
CH3CH=CH, 64%;
HO&(CHz),, 93%
2.2. Activation of Hydroxylic Compounds
2.2.1. Formation of 2-Alkyloxypyridinium Salts
In this section, alkylation reactions involving 2-alkyloxypyridinium salt or other onium salts of 2-alkyloxyazaarenes
are discussed. At first, an unsuccessful attempt was made to
produce the 2-alkyloxypyridinium salt by the reaction of 2chloropyridinium salt and alcohol. As mentioned in Section
2.1.3, the 2-fluoropyridinium salt is more active than the 2chloro salt; the desired 2-alkyloxypyridinium salt was readily
obtained from the 2-fluoropyridinium salt (le), alcohol, and
tertiary amine. Treatment of the 2-alkyloxypyridinium salt
prepared in situ with thiolate ion or iodide ion gave the correor
in good yield. In this methsponding
od, 1-methyl-2-pyridone and unchanged pyridinium salts are
easily removed by washing with water.
711
Table 8. Synthesis of allenes (28) from propargyl alcohols and Grignard comtetrafluoroborate (il).
pounds with l-ethyl-2-fluoro-4,6-dimethylpyridinium
1
Nu@ =
CH3
I
TsOO]
Yield
R'
ose
, 63-900/0; I@, 80.94%
2.2.2. Olefin and Allene Synthesis by Selective Alkylation of
Allylic and Acetylenic Alcohol
A Grignard reagent can also be employed as nucleophile
in this reaction, and forms a carbon-carbon bond directly
with the alcohol. Addition of 2-allyloxypyridinium salt to a
tetrahydrofuran solution of Grignard reagent affords the corresponding coupling product in good yield. Primary and secondary alkylmagnesium bromides coupled with allyloxypyridinium salt exclusively at c - 3 (sN2' reaction). The situation
is completely different in the case of phenylmagnesium
bromide which attacks only C-I (sN2 reaction) (Table 7)[261.
H
H
H
H
n-C4H9
R2
C,H,
CtSjCH2
C6H5CH2CH2
n-CxH17
C6H5CH2CH2
[%I
R'=
R'=
R'=
n-C4Hv
C-CnH,,
i-C4HV
90
83
92
95
77
82
89
99
97
78
91
94
2.2.3. Olefin Formation by Reductive 0-Elimination
The reductive 0-elimination of P-hydroxysulfides is also
possible on use of a 2-fluoropyridinium salt. Treatment of an
alkyloxypyridinium salt (29) derived from a P-hydroxysultide with lithium iodide in refluxing acetone furnishes the
olefin in good yield (Table 9)[291.
2) R'MgBr
Table 9. Synthesis of olefins by reductive p-elimination from p-hydroxysulfides
with 1 -ethyl-2-fluoropyridinium tetrafluoroborate (fh) in boiling acetone.
Table 7. Synthesis of olefins from ally1 alcohols and Grignard compounds with
1-ethyl-2-fluoropyridinium tetrafluoroborate (Ih).
R'
R'
R2
(26)
Yield [%]
(27)
95
quant.
84
94
92
99
84
85
76
85 la1
92 [a1
[a] Yield of (26)
+
(27).
There are two potential pathways for attack on 2-pyridiniooxyethyl sulfides (29) by iodide ion: (i) attack at the sulfur
atom to afford olefins with synchronous elimination of sulfenyl iodide and l-ethyl-2-pyridone, and (ii) attack at the pcarbon to afford sN2 displacement products. Since exclusive
formation of olefins is observed (Table 9) the former reaction
must be much faster than the latter. The sulfenyl iodide thus
formed readily disproportionates into diphenyldisulfane and
iodine. The stereospecificity of this reaction is demonstrated
in the exclusive reduction of erythro-2-phenylthiocyclododecanol (30) and its threo isomer to trans- and cis-cyclododecene (31), respectively.
The 2-propargyloxypyridinium salt can be also attacked at
the y-position by Grignard reagents in the presence of a catalytic amount of cuprous iodide, and the corresponding allene
(28) was obtained in high yield (Table S)[281.
These results indicate that the reductive elimination proceeds with perfect stereospecificity.Thus, a trans elimination
mechanism involving direct attack of iodide ion at sulfur
atom is suggested for 2-pyridiniooxyethyl sulfides (29).
r
i
H3C
712
CH2
AR>CH-C.C-R'
N
I
CzH,
1
-
R'MgBr,
Cat. CUI
RZCH=C=CR1R3
CHxCli/THF
0
BF,@
- 20°C ...20°C
(28)
R2,
/R4
/c=c,
R'
R3
BF$
Angew. Chem. Int. Ed. Engl.
IS, 707-721 (1979)
When 2-hydroxythioacetals (32) are used instead of P-hydroxysulfide, the corresponding vinyl sulfides are obtained
in moderate yieldslZ9l.
"""b"
7
1)
(1 h), Et3N
C6H5SmR
CBH5S
OH
(32)
In order to examine the utility of the method, we employed two carbohydrates as substrates. When 2,3 : 5,6-di-0isopropylidene-a-D-mannofuranose (35) or 2,3,4,6-tetra-Obenzyl-a-D-glucopyranose (37) is treated with (33) and tetraethylammonium chloride, one isomer [(36) or (38)],having
the same configuration with the starting material, is obtained
exclusively in excellent yield1321.
R = C,H5CH2CHz. 70%; n-CIHIS. 11%
Since p-hydroxysulfides can be prepared from ketones or
aldehydes, the reductive elimination of P-hydroxysulfides
provides a useful method for the preparation of olefins starting from carbonyl compounds.-Alternative reductive elimi0
RlARZ
i
C6H5SCH2Li
-
OH
R1eSc6H5-
R'\
,C=CH2
R2
nation procedure~[~~l
require rather drastic conditions (strong
base or basic media) except when low valent titanium compounds are used as reducing a g e d 3 ' ] .
2.2.4. Preparation of Alkyl Chlorides
2-Chlorobenzoxazolium salt (33) reacts with alcohols in
the presence of triethylamine to afford the corresponding alkyl chlorides in good yields. Addition of tetraethylammonium chloride improves the yield[321.
OB z l
OBzl
(37), B z l = C B H ~ C H ~
( 3 8 ) , 89%
It is noted that the present method is suitable for the transformation of a wide variety of alcohols including alicyclic alcohols such as steroidal alcohols and carbohydrates. Thus,
the benzoxazolium salt (33) is a promising reagent for the
preparation of various optically active chlorides (see Section
4).
2.2.5. Nucleoside Synthesis
Et3HN%le, EhN%le
*
R-Cl+
m
)
=
O
' N
Nucleosides have also been prepared[331from 1-hydroxy
sugars and heterocycles utilizing the benzoxazolium salt (33).
The following procedure was adopted: To a stirred suspension of (33) and benzimidazole in 1,2-dichloroethane was ad-
I
ZH5
Table 10. Synthesis of alkyl chlorides from alcohols and 2-chloro-3-ethylbenzoxazolium tetrafluoroborate (33).
T ["Cl
I
[hl
Alkyl chloride
Yield [%]
AcOi
(40)
+
H
(39)
[a] Obtained from (R)-(
-)-2dctanol with inversion of configuration. [b] Obtained from 3p-cholestanol with inversion of configuration.
As shown in Table 10, an alicyclic alcohol (3P-cholestanol) as well as acyclic alcohols (primary and secondary) are
converted into the chlorides in high yields. 3P-Cholestanol
and (R)-(-)-2-octanol react with inversion of configuration.
The reaction may be explained by assuming initial formation of the 2-alkyloxybenzoxazolium salt (34), which in turn
reacts with chloride ion to aEord alkyl chloride and 3-ethyl2-benzoxazolinone. The high stereospecificity in the reactions of cholestanol and 2-octanol strongly indicates that (34)
reacts with chloride ion in an SN2type process.
Angmv. Client. Inl. Ed. Engl. 18, 707-721 (1979)
+
ded triethylamine in the same solvent at - 23 "C,and the resulting mixture was heated for 5 h at 60 "C. The cooled reaction mixture was treated with triethyloxonium tetrafluoroborate in order to remove the resulting chloride ion as ethyl
chloride. To this mixture was added a 2,3,4,6-tetra-O-acetylB-D-glucopyranose (39) and benzimidazole in 1,2-dichloroethane and 1,24imethoxyethane, and the resulting mixture
was heated for 10 h at 60"C. Thus the desired 2,3,4,6-tetra-
713
0-acetyl-P-D-glucopyranosylbenzimidazole(41) was obtained in 73% yield along with a trace of substituted glucopyranose (42).
In the first stage of this reaction, a considerable amount of
glucopyranose (42) was formed along with the desired nucleoside (41) (ca. 2: 1). This may be explained as follows; the
transient 2-(l-benzimidazolyl)benzoxazolium tetrafluoroborate (40) reacts with acetyl glucose (39) to give the intermediate (43). With the assistance of the 2-acetoxy group of the
sugar moiety, the elimination of 3-ethyl-2-benzoxazolinone
from (43) takes place easily to give the acetoxonium ion (44).
This ion is then converted into the glucopyranose (42) or the
trans nucleoside (41) by the nucleophilic attack of benzimidazole either on the electrophilic C atom or on the glycosidic
center.
(40)+ (39)
-
2.2.6. Phosphorylation
The concept of the activation of alcohols by the onium salt
method was further extended to the phosphorylation of alcohols involving 2-alkyloxybenzoxazolesas intermediate^[^". It
was hoped that the N-protonation of the 2-alkyloxybenzoxazole by certain phosphoric acid derivatives would result in
an active intermediate, similar to 2-alkyloxybenzoxazolium
salts, which would attack the phosphate anion formed at the
same time. Many methods are known for the phosphorylation of alcohols, most of them involving activation of the
phosphoryl group; methods based on activation of the alcohol have scarcely been reported[’*]. Nevertheless the latter
type of phosphorylation has the advantage of avoiding pyrophosphate formation.
::
AcO
+
RO-P-02
I
+
I
HO-R’
0
II
+
RO-P-OR’
I
00
00
+
HzO
(43)
C13CC=N [3Ba]
85)
CzH50CN=NCOCzHs/ (C6H5)3P [38bI
(44)
On heating (42) is converted into the thermodynamically
more stable (41). This transformation is assumed to proceed
in a similar manner to the rearrangement of orthoesters of
sugars to trans glyc~sides[~~].
In a similar manner, the frans
nucleosides (41a-c) were prepared in high yields.
When 2-alkyloxybenzoxazoles (45), easily prepared from
alcohols and 2-fluorobenzoxazole (Table 1I),are treated
with diphenyl hydrogen phosphate in refluxing benzene, the
corresponding alkyl diphenyl phosphates (46) are obtained
in good yields (Table 11).This method is seen to be superior
in terms of reaction time, yields, and amount of the alcohols
used when compared with former methods.
I
I
OA c
OAc
( 4 1 a ) , 86%
( 4 l b ) , 9 370
Table 1 1 . Synthesis of 2-alkoxybenzoxazoles (45) from alcohols and 2-fluorobenzoxazole at room temperature and transformation of (45) into alkyl diphenyl
phosphate (46).
(45)
R
BzO
nz = C ~ H ~ C O
[h]
( ~ I c ) ,6670
Yield
T[a]
(46)
t [h]
[%I
OBz
There are two general methods for the preparation of nucleosides: (i) the reaction of heavy metal salts of heterocycles
and glycosyl chlorides’35],and (ii) the fusion of heterocycles
with acylated sugars in the presence of acidic catalyst~l’~~.
The striking feature of our onium salt method is that trans
nucleosides are produced in good yields under mild conditions without any assistance from heavy metals or acidic catalysts.
114
I
GHsCH~CH~
14
75
n-CxHt,
20
66
(CHI~CHCHI
HC-CCH2
CH,0CH2CH2
C6HSCH2CHZC02CH2CH2
fl-Cr7H&02CHICH2
2.2-Dimethyl-I ,3dioxolan-4-ylmethyl
[%I
RT
R
RT
R
R
81
RT
13.5
20
88
90
R
R
R
13
89
30
Yield
69
4
48
6
8
68
7
5
74
89
71
93
6 4
67
74
68
6.5
68
[a] RT = room temp., R = reflux
Angew.
Chem. Inf. Ed. Engl. 18, 707-721 (1979)
3. Intramolecular Dehydration
3.1. Biogenetic-Like Cyclization
During the course of further investigation on the reaction
of 2-fluoropyridinium salts and alcohols, 2-alkyloxypyridinium salts derived from the terpene alcohols nerol or geraniol
were found to be unstable even at - 78 "C, they are readily
converted into hydrocarbon and I-methyl-2-pyridone. For
example, when nerol (47) is allowed to react with 1,3-dimethyl-2-fluoropyridinium tosylate (lg) and tri-n-butylamine in
methylene chloride at - 40 "C for 7 h, limonene (48) and terpinolene (49) are produced in 82% and 15%yield, respectively[391.In the case of the reaction of geraniol (N),
uncyclized
monoterpene hydrocarbons, myrcene (51) and ocimene (52),
were formed in smaller amounts. The cis configuration of the
2,3-double bond in the nerol moiety of the 2-neryloxypyridinium salt causes C-1 and the 6,7-double bond to be in close
proximity and this leads to both the high reactivity and the
high product selectivity. Thus no uncyclized product was detected when the reaction was carried out at low temperature.
However, when the same reaction was undertaken at room
temperature, myrcene and ocimene were also formed in cu.
10-15% yield along with the cyclized products.
yield of bisabolene (35%); a similar result is obtained in the
reaction of geraniol.
Using this method, nerolidol (56) was cyclized to bisabolene (54) in 79% yield, together with a small amount (less
than 10%) of farnesene (57).
poH
-@
-2OT.7 h
+
(571, < 10%
( 5 4 ) , 79%
(56)
@
The allylic cation is more easily generated from nerolidol
(56) than from farnesol (53), so the competitive deprotonation would lead to farnesene. Naturally occurring terpenes
are derived directly, or by way of stereospecific cyclizations
and rearrangements, from the acyclic precursors such as geraniol or farnesol.
Non-enzymatic biogenetic-like conversion of such a precursor into the other terpenes has been of much interest and
widely inve~tigated'~''.However, most conversions of this
kind involve the activation of hydroxyl group with protic
acids or Lewis acids. Moreover, no method in a weakly basic
medium has previously been reported, so the onium salt
method provides a new entry among the biogenetic-like cyclization methods.
3.2. The Beckmann and Pinacol Rearrangements
The results of the cyclization studies on terpene alcohols
suggest that the onium salts of 2-haloaza-arenes are useful
reagents both for intramolecular dehydrations or rearrangements and for intermolecular reactions. Since such dehydrations or rearrangements are usually carried out in acidic media the utilization of the onium salt in weakly basic media
could cause reactions to take a different course. These considerations prompted us to examine the pinacol and the
Beckmann rearrangements as reactions usually carried out
under strongly acidic conditions.
When a mixture of a pinacol and 2-chloro-1-methylpyrimidinium fluorosulfate (58) in dimethoxyethane is stirred at
0°C for half an hour, and then refluxed for an additional
half an hour, rearranged products (ketone or aldehyde) are
obtained in good yield[42'.This is illustrated for phenylethanediol derivatives in Table 12.
(47)
( 4 8 ) , 40%
(49), 4%
( S l ) , 9%
(52), 9%
Application of this method to sesquiterpene alcohols was
then examinedLm'.In the first place the reaction of truns,cisfarnesol (53) with (lg) was tried, but the yield of cyclized
product, bisabolene (54), was low and many undetermined
by-products were formed. Cyclization of truns,cis-farnesol
using the onium salts such as 2-fluoro-3-methylbenzothiazoliurn fluorosulfate (554 gave the best results (max. yield
75%). On the other hand, truns,truns-farnesol gave only a low
a&
CH3
I
FSOP
+
+
(53)
Angew. Chem. In!. Ed.
(55a)
EngI. 18, 707-721 (1979)
B W
,
@
c H3
Table 12. Pinacol rearrangement with the 2-chloropyrimidinium salt (58) in 1.2dimethoxvethane (DME).
R'
R'
R'
Yield
['%I
CHzaz
-4OT.2.5 h
(54), 75%
715
Further, the pinacol rearrangement of trisubstituted
ethanediol derivatives by the onium salt method involves
elimination of the secondary hydroxyl group; the tertiary hydroxyl group is usually lost under acidic conditions. The peculiarity of this reaction may be explained by assuming that
the 2-chloropyrimidinium salt (58) reacts mainly with the
less hindered hydroxyl group of diols to form 2-(2-hydroxyethoxy)pyrimidinium salts, which in turn are immediately
converted into the corresponding ketones with concomitant
elimination of 1-methyl-2-pyrimidinone.
When oximes are treated at low temperature with l-ethyl2-fluoro-3-methylpyridinium tetrafluoroborate (lk) and triethylamine or with the 2-chloropyrimidinium salt (58) alone,
they rearrange smoothly to the amides in high yields. The facility of rearrangement may be explained by assuming initial
formation of 0-(2-pyridinio)oximes or U-(2-pyrimidinio)oximes, which in turn rearrange to the amides on treatment
with water (Table 13)[431.Rearrangement proceeds particularly smoothly when the pyrimidinium salt (58) is used; oximes are simply mixed with (58) (even in the absence of tertiary amine).
Furthermore, the present method gives N-tert-butylbenzamide in high yield from pivalophenone oxime. This oxime
rearranges to pivalanilide under the acidic conditions generally employed and to N-tert-butylbenzamide on heating with
p-toluenesulfonyl chloride in alkaline solution[u1.
2H5
c H3
Table 13. Beckmann rearrangement of oximes with the onium salts (fk)
( + Et3N) and (58).
Onium
salt
R'
R2
Yield [%)
~
94
92
93
95
94
92
91
quant
94
716
3.3. Preparation of Isothiocyanates and Carbodiimides
The ability of the sulfidopyridinium function to act as an
effective leaving group was further demonstrated in the following preparation of isothiocyanate and carbodiimide.
When triethylammonium dithiocarbamate, easily prepared from amine, carbon disulfide, and triethylamine, is
treated with the 2-chloropyridinium salt (la) at room temperature, isothiocyanate is produced in high yield1451.
R N H 2 + CS2 + (C2H5),N
-
S
RNH-C-SQ
II
HN(C2H5)3
0
8 0 - 100%
On treatment of N,N'-disubstituted thioureas with (la) at
room temperature in the presence of triethylamine, a similar
8-elimination occurs smoothly to afford the corresponding
carbodiiniides in good
Carbodiimides are particularly important coupling reagents in the synthesis of peptides and nucleotides, and numerous publications have appeared which describe their preparationf4']. These involve, e. g., catalytic conversion of isocyanates, dehydration of N,N-disubstituted ureas, and desulfurization of thioureas with metal oxides and other metallic compounds, and also with alkaline hypochlorite. The new
method is of quite general utility; aromatic and aliphatic carbodiimides are obtained by a simple procedure.
3.4. Preparation of Isocyanates
Methyl thiocarbamates are easily converted to the corresponding isocyanates in good yields on treatment with the
more active onium salt, 2-chloro-I-ethylbenzoxazoliumtetrafluoroborate (33), in the presence of an equimolar amount
of t~iethylamine[~*l.
The reaction proceeds oia the initial attack of sulfur on the benzoxazolium salt to produce a 2-(iminomethy1thio)benzoxazolium salt, which suffers nucleophilic
attack by chloride ion at the methyl group. The method can
be used for synthesis of both aliphatic and aromatic isocyanates at room temperature under neutral conditions. It also
permits the preparation of ally1 isocyanates which are accessible only in low yield by conventional m e t h o d ~ f ~ ~ ] .
Angew. Chem. Inl. Ed. Engl. 18, 707-721 (1979)
Table 14. Synthesis of 1,2-dichloroalkanes from epoxides.
R'
-
t
R-N=C=O
+
CH,C1
C z ~ 5BF,@
+
R2
R'
R4
r [h]
Yield
[%I
1
WFS
N
I
c 2%
ChHs
CoHs
~-C~HIS
p-CH,C6H40CHz
n-C8H,70CH2
(CH2)4
H
H
H
H
H
H
H
H
H
H
H
H
CaHs
H
H
H
H
48
48
48
81
77 [a1
75
95
84
58 P I
12
12
48
[a] DL :meso = 77 :23. [b] cis:rrans= 98: 2.
3.5. Preparation of Nitriles and lsocyanides
The 2-chlorobenzoxazolium salt (33) is very reactive; in
the presence of triethylamine at room temperature it transforms carboxamides into nit rile^[^'].
Conventional preparations of 1,2-dichloroalkanes from
1,2-epoxides require prolonged heating in a solvent such as
pyridine or chloroform for the completion of the reaction[541.
The transformation of cyclohexene oxide demonstrates the
high stereospecificity of this reaction. truns-1,2-Dichloroalkane can generally be obtained directly from olefins and
chlorine; the new method provides complementary effective
and stereospecific route to the cis isomers.
3.7. Preparation of Ketones from cu-Hydroxy Acids
L
p-Elimination reactions of N-substituted formamides leading to isocyanide formation are also possible utilizing (33).
The reaction proceeds at room temperature under neutralization conditions. This isocyanide synthesis can be applied to
L
BF,~
d z ~ ,J
Another example of the high reactivity of 2-chlorobenzoxazolium salts such as (33) is seen in the elimination of carbon
monoxide and water from a-hydroxy carboxylic acids. When
a mixture of a-hydroxy carboxylic acid and 2-chlorobenzoxazolium salt is added to a methylene chloride solution of triethylamine at room temperature, carbon monoxide is evolved
rapidly, and the ketone is obtained in high yieId (Table
15)IS5l.
The direct preparation of ketones from a-hydroxy carboxylic acids without using any oxidizing reagent was formerly
unknown. Use of the onium salt (33) affords ketones in good
yields under mild conditions.
P'
R = C & , , 81%; 2 , 6 - C l z C ~ H 3 ,6 9 % ; m-N02-C6H,, 8 6 % ;
C&CHz, 8 2 % ; n - C l z H Z , 71%; n-C6H13<H(CH3), 78%
both aliphatic and aromatic formamide~[~'].
It is also applicable to the preparation of secondary alkyl isocyanides such as
I-methylheptyl isocyanide, which are not accessible by other
methodscs2'.
R~-C-CO~H
I
OH
a-
R1
R2
R3&-C'LR4
'
c1
'Cl
Angew. Chem. Int. Ed. Engl. 18. 707-721 (1979)
(33),EtsN
CHzG
9
R'-C-R~
+ co
Table 15. Synthesis of ketones from a-hydroxy carboxylic acids.
R'
Yield [%]
83
84
85
90
71
3.6. Preparation of 1,2-Dichloroakanes
The pronounced reactivity of 2-chlorobenzoxazolium salts
such as (33) also enabled the following reactions to be carried out: Treatment of epoxides with (33) in the presence of
tetraethylammonium chloride and triethylamine gives 1,2dichloroalkanes in good yields (Table 14)f531.The reaction
probably proceeds via a chlorohydrin intermediate which is
immediately converted into a 2-alkyloxybenzoxazolium salt.
The salt is in turn attacked by chloride ion to give the 1,2dichloroalkane.
-
85
e
66
4. Preparation of Optically Active Substances
Structure-bioactivity relationships show that often only
one enantiomer exhibits activity. Consequently, interest in
the synthetic approach to a specific enantiomer of natural
products has created a need for efficient and practical syntheses of optically active compounds. The fact that stereospecific reactions with inversion occur on use of the onium salts
prompted us to examine the optical interconversion of chiral
alcohols and the transformation of the alcohols into other
derivatives.
717
4.1, Optical Interconversion of Enantiomeric Alcohols
Optically active 2-alkyloxybenzothiazolium salts, formed
in situ from an optically active (secondary) alcohol and 2-
fluorobenzothiazolium salt (55b). react in the presence of
triethylamine with a strong acid such as trichloroacetic acid
to yield the ester (59). This undergoes facile base-catalyzed
hydrolysis to afford the enantiomer of the starting alcohol.
Thus this sequence makes possible the interconversion of the
QCCOOH, Et3N
*
5:
C13CC-OR"
OH'
R"OH
(591
Table 16. Interconversion of enantiomeric alcohols using the oniurn salt (556).
Starting material
[a10 ["I
Product
lalo ["I
(S)-(+ )-2-Butanol
(R)-(- )-2-Butanol
(S)-(+ )-2-Octanol
( R ) - (- )-2-Octanol
(S)-(+ )-3-Nonanol
+
(R)-( - )-2-Butanol
7.8
8.6
-11.2
+ 10.2
- 7.4
9.4
9.7
+12.3
- 12.0
+ 9.6
~
~
(.Y-( + )-2-Butanol
(R)-( )-2-Octanol
(8-(
+ )-2-Octanol
(R)-( -)-3-Nonanol
+
~
enantiomeric secondary alcohols by a simple procedure (Table 16)i561.For instance, (S)-(+)-2-octanol was converted
into (R)-(-)-2-octanol in 70% overall yield.
4.2. Preparation of Alkyl Halides
The intermediate 2-alkyloxybenzothiazoliumsalt (see Section 4.1) also reacts with alkali metal halides to afford the alkyl halide in good yields (Table 17)[571.
Table 17. Synthesis of alkyl halides from alcohols. Isolated yields are given
MX
RX
Yield (161
92
90
90
82
87
75
72
87
64
56
NaI
LiBr
LlCl
NaI
LiBr
NaI
LiBr
NaI
LiBr
LlCl
The stereochemical course of the reaction was exemplified
by (s)-(+)- and (R)-(-)-2-octanol. The results shown in Table 18 clearly indicate that the benzothiazolium moiety of
the salt is displaced by a halide ion with inversion of configuration to give 2-halooctane of high optical purity. Among the
many examples of the preparation of optically active alkyl
halides from alcohols, only a few (e. g. the reaction of tosylate
carried out under strictly controlled experimental condit i o n ~ ) ~have
~ ' ] been found satisfactory in practice. Under the
usual reaction conditions alkyl iodides in particular are generally attacked by iodide, thus resulting in racemization. The
present halogenation method has several advantages over
others with respect to the generality, yields, and the mildness
of the reaction condition (low temperature, almost neutral
medium, and equimolar amounts of the reagents, etc.). Side
reactions and a halide ion exchange are minimized.
4.3. Preparation of Thiols
Thiols are widely used as versatile synthetic intermediates
and many syntheses have been reported'59], most of them
consisting of three steps: (i) conversion of alcohols into halides or tosylates; (ii) bimolecular substitution with sulfurcontaining nucleophiles; and (iii) conversion of the intermediates into thiols. Although Walden inversion occurs in most
of the methods, some stereochemical ambiguities remain to
be resolved[601.The utilization of the onium salts of azaarenes
for the preparation of thiols appears promising, provided
that a suitable combination of sulfur-containing nucleophiles
and onium salts can be found.
After screening several possible combinations, it was
found that 1-fluoro-2-methylpyridinium tosylate (le)/sodium NJ"dimethy1dithiocarbamate is effective for this purpose. Thus various alcohols including steroids and carbohydrates have been successfully converted into the corresponding thiols in high yields with high stereospecificity[6'1.The
procedure consists of: (i) reaction of alcohols with (Ze) to give
2-alkyloxypyridinium salts; (ii) SN2 type reaction of these
salts with sodium N,N-dimethyldithiocarbamate to give alkyl
dithiocarbamates (60); and (iii) reductive cleavage to thiols.
[a] Starting material: DL-alcohol. [b] Starting material: (S)-(+)-alcohol. [c] Starting material: (R)-( -)-alcohol.
Table 18. Optical rotation of 2-halooctanes
Alcohol [a]
( S ) - (+)-2-Octanol
(R)-(-)-Z-Octanol
(8-(
+ )-2-Octanol
LIAIH,
2,Halooctane
[a]: IbI
(R)-(-)-2-Iodooctane
(S)-(+)-2-Bromooctane
(R)-(- )-2-Chlorooctane
-53.1"
+39.9"
- 33.7"
---+
c [g/100 mll
4.07
4.16
17.0
[a] Our samples of (S)-(+)and (R)-(-)-2-octanol had [a]:" (0.1 dm, neat)
+ 9.9 and -9.7", respectively. Literature values: +9.9 and -9.9". [b] Optical rotation measurements recorded in a 0.1 dm tube in ether with an automatic polarimeter. Reported maximum rotations of (R)-( - )-2-halooctanes [a]:" (neat) are:
-64.6 (I), -44.9 (Br), and -36.2" (CI).
718
(601,R
RSH
C&CHz, 98%; C ~ K S C H = C H C H989
~,
-C6HI3CH(CH3), 9470; product f r o m (-)-menthol, 66'
= n-CI2H2,, 97%;
DL
(R)-(-)-2-Octanethiol was obtained with complete inversion of configuration from an optically active alcohol, e.g.
(5')-( +)-2-octanol ([a]: +9.9" (neat)), by treatment with
(le) and dithiocarbamate and subsequent reduction. The rotatory power of the thiol was [a]:= -32.7" (1.74, C,H,OH).
Angew. Chem. Int. Ed. Engl.
IS, 707-721 (1979)
Sterically controlled introduction of amino groups is of special synthetic importance, and extensive investigations have
been conducted in recent
Among the various combinations of nitrogen-containing
nucleophiles and onium salts examined, lithium azide/2fluoro-l -methylpyridinium tosylate (le) gave favorable results. Treatment of the intermediate 2-alkyloxypyridinium salt
with potassium phthalimide, ammonia, and lithium diaryl~ulfenamide[~~'~
proved unsuccessful. The use of the 2-
A clean inversion of configuration also occurred in the case
of alicyclic alcohols. For instance, 3P-cholestanol could be
converted into 3a-cholestanethiol in 97% overall yield.
Similar treatment of 3P-cholesteroi afforded a 5 :1 mixture
of isomeric dithiocarbamates (together 76%),where the major
component was the a-isomer (61) (inversion) and a minor
component was the p-isomer (62) (retention), both of which
were converted into the corresponding thiols and their acetyl
derivatives.
H
O
M
S
5
Since preparative methods for cholestenethiol using 3pcholesteryl chloride and potassium thiocyanatel6'', or 3P-cholesteryl tosylate and thiourea[631,give only the p-isomer, the
formation of a-isomer with inversion according to this method
seems of particular synthetic importance.
In allylic systems, e. g. cinnamyl alcohol, substitution takes
place exclusively at the OH-substituted carbon atom; and no
isomeric dithiocarbamate (SN2') was detected.
Treatment of 2,3,4,6-tetra-@acetyl-p-~-glucopyranose
(39) with (le) and sodium dithiocarbamate produces a single
dithiocarbamate, the p-isomer (64), formed with retention of
configuration. The result can be explained by invoking participation of the neighboring acetoxy group trans to the leaving
group.
Acob
OH
AcO
l)(le).EtsN
~
~
:
1
trace
fluorobenzothiazolium salt (Ha) instead of ( l e ) gave poor
yields of alkyl azides. This method seems to have general applicability, since the conversion of alkyl azides into primary
amines is known to be effected under a variety of mild reductive conditions, with most of the functional groups present in a
molecule remaining
4.5. Preparation of Secondary Glcohols by Asymmetric Reduction and Alkylation
We have described an effective and convenient method for
the preparation of chiral halides, thiols, and amines from chiral secondary alcohols by utilizing the onium salts of aza-arenes. Thus various types of optically active compounds are ac-
Ac0b".'..3)2
2) NaSCN(CHd2
OAc
OAc
(39)
(64), 93%
MX = LICI, LiBr, Nal
4.4. Preparation of Primary Amines
The last example utilizing the onium salt of azaarenes is the
stereospecific synthesis of primary amines from alcohols.
HI
L
7 7%
TsOB
Scheme 1
R2
cessible when an effective route to chiral secondary alcohols
could be found. Hence, we have recently investigated the
asymmetric reduction and alkylation of carbonyl compounds
to chiral alcohols.
Angew. Chem. I n t Ed. Engl. 18,
707-721 (1979)
719
For the asymmetric reduction of prochiral ketones, chiral
hydride reagents (66), prepared in situ from (S)-2-(anilinomethy1)pyrrolidine( 6 5 ~or
) (S)-2-(2,6-~ylidinomethyl)pyrrolidine (656) and LiA1H4,were found to be efficient[661.
For example, acetophenone was reduced to I-phenylethanol in 95%
optical yield (enantiomeric excess). As shown in Table 19,
these chiral hydride reagents afford higher optical yields than
previously reported reagents of this kind[67I.'
( a ) , R = Ph;
(66)
cnp
h,
Although the precise mechanism of this asymmetric reduction is not clear, we assume that the high enantioselectivity (all
the alcohols produced have mainly S-configuration except
when THF was used as solvent) to be due to the following factors: (i) The diamines (65), simple compounds having only one
asymmetric carbon, produce the effective chiral environment
on treatment with LiA1H4.This may be due to the formation of
Table 19. Asymmetric reduction of ketones. Comparison of chiral reagents produced from LiAIH, and chiral ligands. (Values in parentheses: at - 100 "C.) The
enantiomeric excess is given.
~
Ketone
(65a)
PhCOMe
84(92)
PhCOEt
85
PhCOCHMe2 57
a-Tetralone
50
PhCH2COMe 31 (42)
n-C6H,,COMe 13
(656) Sugar
[a]
derivative
(see [67])
(95)
(96)
(89)
(85)
(11)
(26)
71
46
-
25
Ligand
Darhon
Chiral
oxazoline
Chiral
amine
(see [68])
(see [69])
(see [70])
75
65
62
43
4
1
4 (6)
~
48
~
43
52
~
~
-
[a] M. Asami. T. Mukaivama, unpublished results.
sterically restricted cis-fused bicyclic hydride reagents, creating the additional chiral center on the nitrogen atom in the pyrrolidine ring. (ii) The reactivity of the two hydrogen atoms
present in this chiral reagent is remarkably different; only one
of them reacts with ketones, the other being subject to steric
hindrance. (iii) The lithium ion, which presumably coordinates to the nitrogen atom of the pyrrolidine ring and/or the
side chain in (66), restricts the direction of approach of the ketones.
In contrast to the asymmetric reduction of carbonyl compounds where relatively high enantiomeric excess were realized. the enantiomeric excessesin the asymmetric alkylation of
720
Table 20. Asymmetric addition of alkyllithium to aldehydes in the presence of the
dipyrrolidine derivative (67). e.e. = enantiomeric excess.
R'
H
n-C&
H
H
H
H
R'
R2
____
~~
CH,
CH,
C2Hq
n-C3H7
n-C4Hq
n-C4H9
Yield
[%I
e.e. [%]
~
CJI5
ChHs
C6H5
C,Hs
CJIS
i-C,H,
81
82
59
64
71
57
40
86
54
60
95
80
organometallic reagents, such as Grignard reagentsf7'],alkyllithium17'b.721, organo~opper['~l
or alkyl~admium~'~~,
with carbony1 compounds by using chiral ligand are very low (0-40%).
However, the concept of the cis-fused five-membered ring system formed from the aminomethylpyrrolidine moiety was also
found to be effective for the asymmetric alkylation of carbonyl
compounds. Thus various optically active alcohols were obtained by the asymmetric reaction of alkyllithium with aldehydes using the dipyrrolidine derivative (67) as the chiral
ligand (Table 2O)"'].
Received: September 7 , 197X [ A 290 IE]
German version: Angew. Chem. 91. 798 (1979)
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1,3-Dipolar Cycloreversions
By Giorgio Bianchi, Carlo De Micheli, and Remo Gandolfi"]
The 1,3-dipolar cycloreversion reaction represents a general scheme of fragmentation of pentaatomic heterocycles to produce 1,3-dipolar systems and dipolarophiles. This review summarizes cycloreversions which give rise to octet-stabilized 1,3-dipoles. The reaction can be either
thermal or photochemical or electron impact induced. The aim of the article is to survey the
published results, to emphasize the synthetic potential of this reaction, and to stimulate the
study of its several not yet unambiguously defined mechanistic aspects.
1. General
The general concept of the 1,3-dipolar cycloadditions was
recognized by Huisgen in the early 1960's['I. Since then, an
increasing number of researchers has produced an enormous
and numeramount of data on this branch of chemistry[2-111
ous examples have been found of the reverse reaction of 1,3dipolar cycioaddition, i. e. [5+3 + 2][1211,3-dipolar cycloreversion. Scheme 1 exemplifies the cycloadditions of dipolarophiles with octet-stabilized"' 1.3-dipoles of the ally1 and propargyl-allenyl type and the corresponding cycloreversions["'.
Very often a [3 + 2]-cycloaddition/[3 + 21-cycloreversion
sequence generates a 1,3-dipole/dipolarophile couple differ[*] Dr. G . Bianchi, Dr. R. Gandolfi
Istituto di Chimica Organica, Universita di Pavia
Via Taramelli 10, 1-27100 Pavia (Italy)
Dr. C. De Micheli
Istituto di Chimica Farmaceutica e Tossicologica, Universita di Milano
Viale Abruzzi 42, 20100 Milano (Italy)
Angew. Chem. In:. Ed. Engl. 18, 721-738 (1979)
#
c-
Scheme 1. 1.3-Dipolar cycloadditions and cycloreversions. Above: reactions with
1,3-dipoles of ally1 type. Below: Reactions with 1,3-dipoles of propargyl-allenyl
type. In the reactant shown at top left of scheme, all [5-.3+2]-fragmentations
are apriori possible. (a)-(e), see text.
0 Verlag Chemie, GmbH, 6940 Weinheim, 1979
0570-0833/79/1010-0721
$ 02.50/0
721
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