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Carbodiimidium Compounds as Reagents in Organic Chemistry.

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[7] A . U? Forrey, R . 5. Ulsgaard, Ch. Nolan, and E. H . Fischer, Biochimie 53,269 (1971).
[8] J . H . Fellman and E. S . Rorh, Biochemistry 10,408 (1971).
[9] S. Moore and W H . Stein, J. Biol. Chem. 176, 367 (1948).
[lo] K . Snmejima, W Dairman, and S . Udenfriend, Anal. Biochem. 42,
222 (1971).
[I13 K . Samejima, W Dairman, J . Stone, and S. Lidenfriend, Anal. Biochem. 42,237 (1971).
[12] W R. Gray and B. S. Hartley, Biochem. J . 89, 379 (1963).
[13] V N e u h o x F . uon der Haar, E. Schlimme, and M . Weise, HoppeSeylers Z. Physiol. Chem. 350, 121 (1969).
Carbodiimidium Compounds as Reagents in
Organic Chemistry["]
By Rolf Scheffold and Emil Saladin"]
1
-Buffer
50
100
150
200
250
pH3.40~4.44~4.86-5.831
Fig. Column Chromatography of a pyridoxyl amino acid mixture and
detection of the amino acids. Conditions : Ion-exchange resin Aminex
A 5 (BioRad, Richmond, California 94 804 (USA)),column 100 x 0.6 cm,
packed height 90cm, temperature 7 0 T , flow rate 33 ml/h, pressure
30-35 at, fraction volume 3 ml, elution with 0.2 N (pH 3.40-4.86) and
0.35 N (pH 5.86) sodium citrate buffer.
LiVdetermination (328 nm): 1 x lo-' mol ofeach amino acid. Pyridoxyltryptophan partially decomposed.
Fluorometric determination (E,,,,,/F,,,,,;
relative units): 1 x lo-*
mol of each amino acid. Dashed fractions were adjusted to pH 12 with
conc. NaOH and measured at E306,,/F3,0n, to achieve better determination of the histidine derivative. Pyridoxyltryptophan partially decomposed.
Radioactice determination (counts/min x 10- '). Activity measurements
with liquid scintillation counter (Tri-Carb model 3380, Packard,
Downers Grove, Illinois 60515 (USA)), yield 5 %. 1 x 10- mol of each
amino acid; reduction with radioactive NaBT, of spec. activity 3600
mCi/mmol (= 900 mCi/mg-atom). Pyridoxyltryptophan partially decomposed. No radioactivity at position corresponding to the histidine
derivative.
tion mixture is decolorized by addition of NaBH, solution
(100mg in 1 mlO.1 N NaOH). The excess of NaBH, is decomposed by acidification with HCl (pH 1-2) prior to
column chromatography.
Received: September 29,1971 [Z 563 IE]
German version: Angew. Chem. 84,255 (1972)
Publication delayed at authors' request
[11 Highly sensitive detection reactions with pyridoxine derivatives,
Part I.
[2] D. H e y / , S . A . Harris, and K . Folkers, J. Amer. Chem. SOC.70, 3429
(1948).
[3] M . Ikawa, Arch. Biochem. Biophys. 118,497 (1967).
141 T h . C. Bruice and S t . J . Eenkouic in : Bioorganic Mechanisms.
Benjamin, New York 1966, Vol. 2, pp. 250ff.
[5] M . Flauin and C. Slaughter, Biochemistry 5 , 1340 (1966).
[6] H . Simon and D. Palm, Angew. Chem. 78,993 (1966);Angew. Chem.
internat. Edit. 5,920 (1966).
Angew. Chem. internat. Edit.i Vol. 1I (1972)
i No. 3
Carbodiimidium compounds o f general structure ( I )
(R'=H) play an important role as intermediates in acidinduced addition reactions of carbodiimides. To the best
of our knowledge no reports have so far appeared in the
literature describing the isolation of carbodiimidium compounds in substance. According to Hartke and Rossbach"',
attempts to synthesize them by reaction of aliphatic carbodiimides with anhydrous tetrafluoroboric acid in methylene
chloride or by reaction with dimethyl sulfate lead exclusively
to dimeric cyclic products.
We have now found that N,N'-dicyclohexylcarbodiimide
can be alkylated by prolonged heating in pure alkyl bromides or iodides"! Treatment with methyl iodide, for
example, leads to 75 yields of N,N'-dicyclohexylcarbo-
diimidium iodide ( I a), which crystallizes as colorless
needles having m. p. 111-113 "C. Assignment of structure
is based on elemental analysis, the I
R spectrum [(CHCI,) :
bands at, inter aiia, 2119 (v N=C=N) and 1667 cm-'1,
and the NMR spectrum [(CDCI,): 6=3.50ppm (s, 3H of
N-CH,);
3.3-3.6 ppm (broad accumulation of signals,
2H on the a-C of the cyclohexyl groups); 1.0-2.1 ppm
(broad accumulation of signals, 20H on the p-C, y-C, and
6-C of the cyclohexyl groups)].
Carbodiimidium compounds of general structure (
are of interest in many respects as reagents in organic
chemistry. To illustrate this we report first on their use in
the conversion of alcohols into iodides:
Aliphatic primary and secondary alcohols (including such
types as homoallyl and neopentyl alcohols) react with
N-methyl-N,N'-dicyclohexylcarbodiimidiumiodide ( l a )
in solvents such as tetrahydrofuran, benzene or hexane at
35"-50"C to give the corresponding iodides, usually in
high yields.
Stereochemistry : The reaction involves inversion of the
configuration at the C atom bearing the OH group[41.For
example, in the case of 3~-cholestanol,thermodynamically
[*I
Prof. Dr. R. Scheffold and DipLChem. E. Saladin
Institut de chimie organique, Universite de Fribourg, Perolles
CH-I700 Fribourg (Switzerland)
["I This work was supported by the Schweizerischer Nationalfonds
zur Forderung der wissenschaftlichen Forschung, Project No. 4783.
229
less stable 3a-iodocholestane is formed in more than 84%
yield. Particularly noteworthy is the fact that cholest-5-en3B-01 (cholesterol, as a typical representative of the homoally1 alcohols) is converted in one step into the previously
unknown 3a-iodo~holest-5-ene[~~.
iodide was then removed from the pale-brown solution
by distillation under reduced pressure and the viscous,
brown residue thus obtained was dissolved in anhydrous
toluene (150ml) at 40°C. The crystalline mass which
separated out within a few hours was separated from
Table : Examples of typical reactions of alcohols with N-methyl-N,N'-dicyclohexylcarbodiimidiumiodide ( I a)
Educt
Product
Conditions [a]
Yield (%) [b]
1-Octanol
dl-2-Octanol
1,3-Dihydroxypropane
3 P-Cholestanol
Cholest-5-en-3B-01
1-Octyl iodide
dl-2-Octyl iodide
1.3-Diiodopropane
3 a-Iodocholestane
3 a-Iodocholest-Sene
3 h/35"C
2 h/35 "C
15 h/35"C
15 h/35"C
15 hI35"C
15 h/35"C [c]
89
81
72
84
38
40
13-Isopropyl-podocarpa-8,11,13trien-15-01
17&Hydroxy-androst-4-en-3-one
13-Isopropyl-l~-iodopodocarpa-8,i 1.1 3-triene
17a-Iodoandrost-4-en-3-one
48 h/50°C
62 h/60"C
18
38
[a] Each mol of alcohol treated with 2 moles of (la). Solvent: T H F unless otherwise stated.
[b] The yields relate to analytically pure product. The yields of crude iodides are sometimes much higher.
[c] In hexane.
Steric hindrance : Even extremely sterically hindered alcohols such as neopentyl alcohols can be converted under
mild conditions, albeit in low yields, into the corresponding
iodides. As examples may be mentioned the conversion of
13-isopropylpodocarpa-8,11,13-trien-l5-01(dehydroabietanol) into 13-isopropyl-I5-iodopodocarpa-8,11 ,I 3-trieneI6'
and of 17P-hydroxyandrost-4-en-3-one
(testosterone) into
17a-iodoandrost-4-en-3-0ne[~~.
Limitations : Substrates containing nucleophilic substituents other than the OH group of the alcohol, e . g . amino
groups or carboxy groups, cannot be converted directly
into the iodides without prior protection.
It seems reasonable to assume that the primary reaction
step involves addition['' of one mol of alcohol RR'CHOH
to the highly reactive carbodiimidium system with formation ofan isourea as trigonal intermediate, which, under the
conditions given, is pr~tonated[~!
The second and usually
rate-determining step consists of the nucleophilic substitution of the positively charged urea group by the iodide
ion. This substitution proceeds with inversion of configuration at the carbon atom (see Figure).
Figure. Schematic representation of the course of the reaction
the mother liquor in an inert atmosphere by filtration
on a glass Buchner filter fitted with a nitrogen bulb; the
reaction flask was then rinsed three times with 25 ml portions of ice-cold anhydrous toluene. The pale-yellowish
crystalline mass recovered on the filter was washed with
ice-cold anhydrous toluene until colorless crystals were
obtained. After 20 hours drying at room temperature/O.l
torr, a total yield of 53 g (75%) of colorless crystals, m. p.
111-1 13"C, was obtained. For analysis, the product was
recrystallized three times from methyl iodidehexane and
dried at 2OoC/0.005 torr for 48 hours, m. p. 111--113°C.
Typical example of a alcohol -P iodide conversion: 3U-iOdOcholestane
A mixture of 3 ~ - ~ h o l e s t a n o l(1.940g,
[ ' ~ ~ 5 mmol) and (1 a )
(3.475 g, 10 mmol) was dissolved in tetrahydrofuran (50 ml)
in a 100 ml round-bottom flask fitted with a nitrogen bulb.
The colorless solution was allowed to stand for 15 hours at
35°C. The solvent was then removed at reduced pressure
in a rotary evaporator. The residue was taken up in 50 ml
hexane, transferred to a separatory funnel, and washed
three times with 25-ml portions of methanol/water (4: 1)to
remove N-methyl-N,N'-dicyclohexylurea. The combined
washings were extracted three times with 25 ml portions
of hexane; the combined hexane phase was dried over
sodium sulfate and then filtered through silica gel (ca. 10 g).
The clear filtrate, after removal of solvent under reduced
pressure and subsequent drying at 2O0C/O.1 torr, yielded
2.359 g (95%) of crude iodide. Recrystallization of the crude
product from anhydrous acetone (40 ml) afforded 2.086 g
(84%) of pure 3a-iodocholestane, colorless needles, m. p.
111-11 1.5oC[lll.
Received: September 10,1971 [Z 547a IE]
Revised: December I, 1971
German version: Angew. Chem. 84,158 (1971)
N - M ethyl-N,N '-dicyclohex y lcarbod iimidium iodide ( I a )
Freshly distilled N,N'-dicyclohexylcarbodiimide (42 g, 0.204
mol) was dissolved in methyl iodide (90 ml, 1.45 mol) under
nitrogen at room temperature in a 250 ml round-bottom
flask fitted with magnetic stirrer, reflux condenser, and
a nitrogen bulb. The colorless reaction mixture was stirred
for 72 h a t a bath temperature of 70°C. The excess of methyl
p] Note added in proof(February 8,1972): A dimer of ( I a) cannot be
ruled out on the basis of the available data.
230
[I] K. Hartke and F . Rossbach, Angew. Chem. 80, 83 (1968); Angew.
Chem. internat. Edit. 7, 72 (1968).
[2] It had been established as long ago as 1925 that N,N'-di-n-propylcarbodiimide does not add methyl iodide: H. Lecher, F . Graf, C. Heuck,
K . Koberfe, F . Gniidinger, and F. Heydweiller, Liebigs Ann. Chem. 445,
35 (1925).
[3] ( I a ) is a crystalline, colorless, slightly hygroscopic compound
that can be stored in the refrigerator for several months. Variation of
R,R', and X - in ( I ) can be realized by suitable choice of carbodiimide
and alkylating reagent. The anion I - in ( l a ) can be replaced by Xby treatment with AgX.
Angew. Chem. internat. Edit. / Vol. I 1 (1972) / No. 3
[4] Although, strictly speaking, the reaction proceeds with inversion
of configuration, it is possible that a certain amount of the iodoalkane
shows retention of configurarion. This part of the product arises by
nucleophilic substitution of the initially formed iodoalkane by iodide
ions in solution. Consequently a decrease in stereoselectivity is always
observed, if the reaction conditions are too vigorous (too high a temperature, too long a reaction time, too great an excess of reagent).
[ 5 ] Recrystallized from acetone three times and dried at 0.01 torr;
m. p. 130-130.5"C. In the NMR spectrum in CDCI,, the signal of the
p proton on C-3 appears as a multiplet at 6 =4.90 and that ofthe olefinic
proton on C-6 as a multiplet at S= 5.30 ppm (TMS = 0).
[6] Colorless, viscous oil. NMR spectrum in CDCI,: 6 = 1.09 (s, 3H);
1.20 (s, 3H); 1.22 (d, J = 7 H z , 6H); 1.45 -1 76 (accumulation of signals,
9H); 2.0-3.0(m, 2H); 2.91 (septet 1 H);AB system with 3 20(d, J = 11 Hz,
1H)and 3.33(d,J=11 Hz. lH);6.9-7.1 (m,3H)(TMS=0).
[7] Recrystallized from anhydrous acetone and dried at 0.01 tom;
m. p. 154-155°C. IR spectrum in chloroform: 1670cm-' (v C=O).
In the NMR spectrum in CDCI, the signal of the P-proton on C-I7
appears as the X part of an ABX system at S=4.40 (4. J,,=2 Hz,
J,, = 6 Hz, 1H) and the signal due to the olefinic proton on C-4 occurs
at 6=5.77 (d, J=1. 5 Hz, 1H).
[ 8 ] The isourea hydroiodide formulated as intermediate in the reaction
of 2,Z-dimethylpropanol (neopentyl alcohol) with ( l a ) in T H F can in
fact be isolated as colorless crystals after a few hours at 35% This
shows that sterically hindered alcohols also undergo smooth addition
to the C=N double bond of carbodiimidium system.
[9] The pK',,,
of the isourea hydroiodide formed from ( l a ) and
neopentyl alcohol is 9.5. (For the definirion of pK',,, value cf. W Simon.
Helv. Chim. Acta 41, 1835 (1958).
[lo] The 3B-Hydroxycholestane used was obtained from Fluka AG,
Buchs; its melting point after one recrystallization was 140-142'C.
1111 The melting point and all spectroscopic data are identical with
the values quoted for 3n-iodocholestane by J . P . Verheiden and J . G .
Moffat, J. Org. Chem. 35,2319 (1 970) and by A . I.:Bavless and H . Zimmer.
Tetrahedron Lett. 1968, 381 1.
Organomercury Carbenoids for the Synthesis of
Cyclopropane Derivatives'**]
By RolfScheSfold and Vrs Michel'*'
Organometallic compounds of general structure (1) can
be used for the synthesis of cyclopropanes['!
substance. Seyferth et
shown that mercury(I1) carbenoids are suitable reagents for the synthesis of 1,1dihalogenocyclopropanes. Similar methods['] for the preparation of the cyclopropanes ( 4 ) (R=R'=H) are,
however, comparatively less satisfactory since the mercury(1r) carbenoids seem to be insufficiently reactive.
We have investigated the organomercury(I1) carbenoids
regarding their suitability as reagents for a mild, versatile,
and selective synthesis of cycfopropane and alkylcyclopropane derivatives. As first example we report here on the
synthesis and reactions of benzylmercurioiodomethane
(1 A )
Addition of an ethereal solution of diazomethane to a
solution of benzylmercury iodide ( 3 a ) in tetrahydrofuran
at 0°C leads to immediate formation of the carbenoid
( I a) 19] in quantitative yield. This compound, a colorless
oil, is so stable towards heat that it remains unchanged
for several hours in benzene at 90-100°C under nitrogen.
i la)
IR(CC1,): Bands at 1500-1600
690 (s) cm - '.
(broad), 1490 (s), 1450 (s),
'H-NMR (CDCI,): 6=2.25 ppm, singlet (2H of the
methylene group, satellite signals JI - 199 Hg =47 Hz' l o ] ) ;
2.65 ppm, singlet (2 H of the benzyl group, satellite signals
J 1 ~ - - 9 9154
~ ~ Hz['O1);
=
7.1-7.2ppm, multiplet (5 H of the
aromatic ring).
Benzylmercurioiodomethane ( 1 a ) reacts with olefins
under mild conditions to give benzyl(molar ratio 1 :I)
mercury iodide (3A ) and cyclopropane derivatives ( 4 )
(R=R'= H) in accordance with eq. (1);duration of reaction
a few minutes to a few hours at temperatures of 0-90°C.
Depending on the nature of the olefin (solid or liquid) the
reaction can be carried out without or with solvent,
Table Examples of typical cyclopropane syntheses with benzylmercurioiodomethane ( l a ) .
X = leaving group, e . g . halogen
M = metal or metal complex cation
R,R' = H, organic group, halogen, etc
Olefin
Reaction
conditions [a]
Product
&
Zinc(I1) and copper(1) carbenoids of type ( I ) , with
R =R'= H, are of particular importance in preparative
organic chemistry ;they are unstable and must be prepared
in situ-from diiodomethane and zinc/copper
or
diethyl~inc[~j
or from diazomethane and zinc iodider4'-or
they are formed as an intermediate, e. g . as in the synthesis
of cyclopropane by Cu(1)-catalyzeddecomposition of diazomethane15].
Yield [b]
(4b)
90
In contrast, the corresponding mercury(I1) compounds
are considerably more stable and can be isolated in
~ C O ~ ? C , I I ,
[*] Prof. Dr. R. Scheffold and U. Michel
Institut de chimie organique
Universite de Fribourg Perolles
CH-1700 Fribourg (Switzerland)
This work was supported by rhe Schweizerischer Nationalfonds
zur Forderung der wissenschaftlichen Forschung, Project No. 2185
[**I
Angew. Chem. internat. Edit. 1 Vol. 11 11972) 1 No. 3
several hi90
no
reaction
[a] Molar ratio olefin: carbenoid ( 1 0 ) = 1 : 1, no solvent. Quoted after
the oblique is the bath temperature ("C).
[b] Referred t o pure product in reactions using quantities of the order
of 10 mmol.
231
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