Tetrahedron Letters No. 15, pp 1299 - 1302, 1977. Pergamon Press. Printed in Great Britain.
ADDITION
OF GRIGNARD AND LITHIUM
SALT. John
L.
A CONVENIENT
Roberts,
Peter
Department
of
Salt
(Received in USA
Terminal useful for
double
construction
simple
or
ducing
this
of
proceed
it
bond
is
to
oxide
functionality
it
is
not
In
this
moiety.
an
in
occurring methylene
yield.
to
Pyrolysis the add
C.
0LEFINS.l
Dale of
Poulter*2*3
Utah
84112
the
with
we describe oxidation
that
from
a major
of
for
afford
the
are
for
intro-
In most
construct
the
the
with
operationally
portion
the
methods
method
methylene
as
introducing
synthetically
several
procedure
such
olefins
many
limitation.
the to
approaches
method
elimination
procedures an excellent
become
time)
in are
is
required
and
found there
the
oxides
will
one-pot
a direct
and
of
4 few
amine
(yield
yield
are
group,
manipulations
efficiency
moderate
which
Although
suffers
carbon
The
groups compounds.
of
approach
the
fragment.
reduce
communication
and
University
Utah
common functional
However,
competitive
City,
are
desirable
Subsequent
Lake
unsaturated
a simpler
Borromeo,
Chemistry,
naturally
high
moiety.4a
sequences, double
and
S.
OF TERMINAL
January 1977; received in UK for publication 2 March 1977)
12
bonds
intermediates
REAGENTS TO ESCHENMOSER’S
SYNTHESIS
to
synthetic
of
the
desired the
Wittig
amine
point
where 4b
reaction.
dimethylaminomethyl
terminal
methylenes
in
high
yield. Our
approach
R’
to
1)
H-:-X 2)
R
addition typical
of
(ca. -
appropriate sion
at
construction
Mg or
10% excess)
mixture
was
addition
of
vigorously water
until
(Grignard
or
ether
(I-2H
a gentle
stirred
for
one
the
suspended
lithium
in
was (ca -*
ether)
hour salts
at just
150”
reagent)
to
5 ml/rmmol added
of -via
1299
C=CH2
Eschenmoser’s
salt.5
In
a
dimethyl(methylene)atmnonium salt).
A solution
syringe was
temperature.
dissolved,
involves
R’
with
When addition room
R’ \
H7.02
charged
was
reflux.’
group
) 2)
flask
anhydrous
reagent
maintained
1)
functional
2
R
nitrogen-filled and
dimethylaminomethyl
7’ H-y-CHzN(CHs)
+
nucleophile a dry,
which
the
Li
organometallic a rate
of
+ CH2=N(CH3)21
a carbon
experiment,
iodide5’6
the
followed
to
the
complete,
Work-up
the
stirred the
involved
by vigorous
of
suspen-
resulting careful
stirring
for
wo
No. 15
30 min. times
The with
anhydrous a 500’
by
test)
For
in
The
usual
layers
tubular
column
(Carbowax
oxidation,
the
amount residue was
platinum
was
heated
complete,
layer,
washed
removed
ZOM) was
one
was
oxide,
the
to -ca.
160”
water
was
to
(I the
equivalent
solution with
other
of
quenched
added
brine
methanol
progress
additional
latter
pressure.B
no products in
The
the
saturated
reduced
dissolved
peroxide
and
with
at
showed
added.
and
Excess of
were
was
test,4a
aqueous
was
amine
peroxide
periodically.
reaction
and
over
than
filtered,
dried
on
desired
of
amine),
ml/mnol
and
analysis
the
reaction
was of
a negative
30% hydrogen
solvent
stirring,
and
olefin
and
the
and
monitored
potassium
the
trap,
three
Glpc
portions
(to
extracted
was
iodide
removed
at
trapped
at
product
was
worked-
way.4a
results
isolated
ether
the
solvent
The
the
fran
before
a catalytic
oxides,
amine
combined
phenolphthalein
pressure.
the
separated
30% hydrogen
added
After
was
sulfate
the
of
were
reduced
an
open
alcoholic
with
-780.
when
The
(>95%).
peroxide
up
ether.
equivalent the
layer
magnesium
x 0.03”
amine one
ether
for and
yield
workingon
a
four
representative
olefins
gave
of
material,
I-15
pure IWlOl
alkyl
satisfactory and
Scale.
The
halides IR and
some overall
TABLE Organometallic
Reagent
Yield Amine
of (%)
Yield, methyl
losses
I.
listed
in
are
Table
Each
inevitably
yields
occurred
higher
than
I.
All
reported during shown
of
yield
in
the
amines,
represents
purification the
Table
when
YIELDS
Isolated iodide (%)
n-Octylmagnesium
are
NMR spectra.
as salt
Yield Amine
of Dlefin via Oxide (%)
Overal Yield Halide
I from
91CVd
90-95h,i
a7
78-83
_-
92-9Sh’j
(88) p
al-84
asCpf
______ I
a3
70
-_
84”
__
__
bromidea Cyclohexylmagnesium bromidea Benzylmagnesium chloride n-Butyll
ithium
a b
a) Stock solutions of Grignard reagent were prepared in diethyl ether. R. Lespieau and M. Bourguel, O&g. Syn., Coll. Vol. 1, (Second Ed.), 186 (1941) and F.S. Prout, R.J. Hartman, E.P.Y. Huang, C.J. Korpics and G.R. Tichelaar, o&g. Sgn.,Coll. Vol. IV, 93 (1963). Excess magnesium was used to insure complete reaction, and the ether solutions of the Grignard reagents G.1.c. analysis of hydrolyzed aliquots were f i 1tered through a Schlenk f i I ter before storage. showed no starting halide and only traces (<5%) of other impurities, presumably from coupling during Grignard formation. Molarity of the Grignard solutions were determined by the procedure of Watson and Eastham; S.C. Watson and J.F. Eastham, 1. O~g~norn~. C&m., 2, 165 (1967). b) c) From experiments carried out on a Commercial product from Alfa Ventron, 2.4H in hexane. e) H. King and T. Work, J. Chem. SOC., IO-15 mnol scale. 20 mm (lit.e 209”, 741 mn). d) bp 97”. g) R.N. Icke, B.B. Wisegarver and G.A. Alles, 403 (1942). f) bp 850, 12 mm (lit.g 980, 22 mm). scale. o&g. Sgn., Coil. Vol. III, 723 (1955). h) From experiments carried out on a l-5 mmol i) mp 180-181.5° (1it.e 170”) j) mp 227-227.5O (lit. k 226.5-227.5’), k) 0. Wallach, Ann., 353, 284 (1907). I) mp 228-229” (lit.“’ 229”). m) T. Kato, T. Morikawa, and Y. Suzuki, J. Phaiim’Y1.SOC. Japan, 2, 1177 (1952); Chtic& AbHxuCt6, 42, 7433f (1953). n) mp 222-224” (lit.0 222-223”). p) Ref. 4. o) R. Willstatter and E. Waser, BQA., 9, 1176 (1910).
1301
No. 15
the
amines
the
intermediates.
large the
are
batches
should
the
the
ful
a variety
enolates ing
until
only
limiting
synthesis
of
Wittig
in
the
amine
oxides
be emphasized
needed;
that
thereby,
factor
in
pyrolyzed
eliminating
using
without
Eschenmoser’s
the
the
iminium
attempting
salt
need
salt
can
to
freshly
approach
to
purify
be prepared
in
prepare
appears
to
one
of
be pre-
reagent.g
methylene-containing
reaction of
in
carbon
olefins
convenience
and
nucleophiles12
preparation
a-methylene
resulting
also
organometallic
plements with
the
stored
The
of
The
and
It and
reagents.
paration
oxidized,
of
-via
such
Mannich
the
amine
Also,
yield. as
ketone,“’
intermediates
that
oxide
the
route
ester,14 can
now nicely
procedure
is
and
com-
apparently
use-
lactone14y15
be converted
into
the
correspond-
derivatives.
REFERENCES
I.
We wish and
to
acknowledge
2.
Alfred
P.
3.
Career
Development
4.
a)
A.C.
Sloan
Cope
Schoelkopf,
support
from
the
National
Institutes
of
Health,
GM 19557
J.
E.
Am.
the
Vol.
5,
Sot.,
72,
N.
Institutes Coil.
751
7_9, 4729
Sot.,
Maag,
National
O/Lg. Syn.,
Coil.
C&m.
C&m.
H.
from
Ciganek,
Syn.,
Am.
Schreiber,
1975-1977.
Award
and
J.
Okamoto, J.
Fellow,
&cg.
Schweizer,
5.
financial
CA 16824.
3145
(1973); d)
and
e)
A.
Health
A.C.
H.E.
C.L.
(HL
000841,
612 (1963); b)
4, c)
(1957); (1957);
Hashimoto,
of
Vol.
Cope,
C.L.
Eschenmoser,
F.A.
Chem.
and
and
lnd.,
Tti.
U.
and
Bower,
Chem.
Angm.
and
Bumgardner,
Baumgarten, Bumgardner,
1975-1980.
G. Wittig
E.E. T.T.
1555
Ed.,
I$,
(1958).
330
(1971). 6.
Other M.
dimethyl(methylene)arrmonium
Gaudry,
Tietze,
7.
8.
9.
and
A.
Angu.
1917
(1970).
Salt
can
C&m.
obta i ned.
For
isolation
of
an ether
solution
the
was
salt
New high R.D.
Rieke
II.
P.K.
Freeman
the of
the with
S.E.
and
L.F.
L.L.
N.Y.,
lminium
salts
have
served
Dean,
H.C.
Padgett,
and
as
F.P.
its
239
c)
iodide 5-10
Am.
H.
as
Chem.
SOC.,
Jtihedrron
J.
Volz
the
Y.
(1974); and
reagent
and
excess resulting
Jasor, b)
H.H.
G.
H.J.
and
L.F.
Tetrraheo%on
comparable
yields
iodide
suspension
luche,
Kinast
Kiltz,
methyl
570,
H. Am.
and
organolithium”
9_6,
1775 (1974).
Lett.,
“Reagents
was
was
La.,
of
added
amine
to
filtered
and
for
1849 Organic
compounds
(19761,
and
Synthesis”,
are
references Vol.
1,
available.
cited Wiley
and
618.
synthetically and
a)
263
dried.
Fieser, pp.
H.
salt,
hr
organomagnesiuml” J.
prepared.
Comm.,
organometallic
methyl
and
been
Chern.
(1976);
After
ether
Hauck,
have
SOC.
the
amine.
1967,
a)
Leonard
into
Hutchinson, and
12.
N.J.
12,
of
13.
R.T.
Ed.,
Bales,
Fieser
New York,
Chum.
amine
syntheses
and
salts
J.
ladled
washed
yield
IO.
Sons,
7ti.
be carefully
are
therein;
Marquet,
useful
J.
Rapoport, Chem.
Sot.,
electrophiles
Am. Chm. 72,
5279
Sot., (1957).
for
a number
9_8, 7448
c)
G.H.
of
(1976). Alt
and
years.13 b) A.J.
No. 15
1302
Speziale,
sot., 14.
J.L.
15.
S.
J. O&g. Chem., 3,‘, 8_2, 5148 (I!+%),
Roberts, Oanishefsky,
P.S. T.
e)
1340 (1966)) d) N.J.
L.A.
Te,?hzhhon
Paquette,
Borromeo,
C.D.
Kitahara,
R.
Poulter, McKee,
Leonard
P. F.
unpublished Schuda,
and
Lett.,
W. K.
Musker,
J. hi.
Chem.
1291 (1965).
results.
J. ht.
Chem. Sot.,
9_8, 6715 (1976).