1. Protected
primary
amides
from
acyl
isocyanates
Stephen
C.
Hahneman,
Megan
M.
Hanly
and
Brian
R.
Linton
Department
of
Chemistry,
College
of
the
Holy
Cross,
Worcester,
MA
01610
Corresponding
Author:
blinton@holycross.edu
TOC
Graphic
Abstract:
A
procedure
has
been
developed
for
the
convenient
synthesis
of
primary
amides
from
carboxylic
acid
derivatives.
At
the
heart
of
this
approach
is
the
formation
of
acyl
isocyanates,
which
can
be
reacted
with
alcohols
to
produce
carbamoyl-­‐protected
primary
amides.
Different
alcohols
have
been
used
to
produce
amides
that
contain
Cbz,
Boc,
Fmoc,
Alloc,
Teoc
and
o-­‐nitrobenzyl
protecting
groups,
permitting
deprotection
using
a
variety
of
methods.
INTRODUCTION
A
variety
of
synthetic
methods
exist
for
the
production
of
primary
amides,
but
each
has
potential
downsides.
The
majority
of
approaches
require
the
use
of
gaseous
ammonia,
ammonium
hydroxide
or
other
ammonium
salts.
The
loss
of
reagent
ammonia
can
lead
to
reduced
yields,
and
the
highly
basic
nature
of
reaction
conditions
can
at
times
be
problematic.
Additionally,
traditional
organic
purification
techniques
can
be
less
successful
due
to
the
polar
nature
of
the
primary
amide
and
potential
insolubility
in
organic
solvents.
A
synthetic
scheme
that
smoothly
produces
a
primary
amide
with
a
protecting
group
that
maximizes
organic
solubility
would
be
attractive
for
a
variety
of
organic
and
peptide
targets.
Carbamate
protection
of
the
amide
nitrogen
would
be
ideal
due
to
the
well-­‐
established
methods
of
removal
and
purification,
but
few
literature
examples
of
acyl-­‐carbamates
exist.
They
have
been
synthesized
through
either
carbamoylation
of
an
amide
or
acylation
of
a
carbamate,
but
the
reduced
nucleophilicity
of
these
nitrogens
typically
requires
strongly
basic
conditions.1
Another
approach
towards
a
protected
primary
amide
is
to
introduce
the
nitrogen
atom
to
a
carboxylic
acid
derivative
using
the
cyanate
anion
(Figure
1).2,3
The
resulting
acyl
isocyanates
2
can
R Cl
O O
N
H
R
O
O
R'
R
O
NH2
1) AgNCO
2) R'OH
deprotection

2. react
with
an
appropriate
alcohol
to
lead
to
a
carbamate-­‐protected
primary
amide
3.4
The
method
of
deprotection
would
depend
on
the
choice
of
alcohol
and
should
lead
to
clean
isolation
of
the
primary
amide
4,
presumably
at
the
end
of
a
synthetic
sequence.
Figure
1.
Synthesis
and
deprotection
of
carbamate-­‐protected
primary
amides
via
acyl-­‐isocyanates.
RESULTS
AND
DISCUSSION
Our
investigation
began
with
the
conditions
to
form
acyl-­‐isocyanates
from
activated
carboxylic
acid
derivatives
and
silver
cyanate.5
After
several
attempts
to
isolate
the
acyl-­‐isocyanate
yielded
complex
mixtures,
it
became
obvious
that
the
best
approach
was
to
create
the
reactive
acyl-­‐isocyanate
2
in
situ,
and
proceed
with
a
one-­‐pot
addition
of
the
alcohol
to
ultimately
isolate
the
quite
stable
acyl-­‐
carbamates
3.
These
reactions
proved
to
be
highly
dependent
on
the
reaction
conditions
and
resulted
in
alternate
reaction
paths
(Figure
2)
that
created
varying
amounts
of
carboxylic
acid
5,
ester
6,
amide
7,
anhydride
8,
and
imide
9
side-­‐
products.
A
survey
of
reaction
conditions
and
resulting
product
ratios
can
be
seen
in
Table
1.
Figure
2.
Observed
side-­‐products
that
result
from
the
presence
of
water
in
the
reaction,
or
incomplete
consumption
of
acyl
halide.
R Cl
O O
NR
O
N
H
R
O
O
R'
R
O
NH2
C
OAgNCO R'OH
1 2 3 4
deprotection
R Cl
O O
NR
O
N
H
R
O
O
R'C
OAgNCO R'OH
1 2 3
R OH
O
5
R OBn
O
6
R
O
NH2
7
path
a
path
b
path
c
path
d
R O R
O O
8
R N
H
R
O O
9

3.
Table
1.
Product
ratios
from
the
reaction
of
hexanoyl
chloride
with
AgNCO,
and
then
ethanol.
conditions
product
ratios
entry
solvent/reagents
temp
time
3
5
6
7
8
9
1
Et2O
reflux
10
min
0
79
0
14
7
0
2
Et2O
RT
5
hr
0
77
0
12
11
0
3
Et2O
(anhydrous)
RT
5
hr
50
2
4
16
4
24
4
Et2O
(anhydrous)
reflux
5
min
94
1
1
1
1
2
5
C6H6
(anhydrous)
reflux
5
min
85
4
0
1
7
3
6
PhCH3
(anhydrous)
reflux
5
min
83
2
0
2
7
6
7
NaNCO
Et2O
(anhydrous)
reflux
5
min
0
0
100
0
0
0
Hexanoyl
chloride
was
chosen
as
a
simple
carboxylic
acid
derivative
and
the
initial
reactions
(entries
1-­‐2)
began
to
show
the
unanticipated
reactivity
of
intermediates.
The
reaction
with
silver
cyanate
in
commercial
ethyl
ether
followed
by
addition
of
ethanol
resulted
in
the
isolation
of
carboxylic
acid
5
and
anhydride
8,
presumably
formed
from
the
reaction
of
the
acyl
halide
with
water
(path
a).
The
isolation
of
hexanamide
7
showed
that
acyl-­‐isocyanate
was
being
formed,
but
also
being
consumed
by
water
as
shown
in
path
d.
Simply
switching
to
anhydrous
ethyl
ether
resulted
in
formation
of
the
desired
acyl-­‐carbamate,
but
time
and
temperature
were
also
important
factors.
Extended
reaction
at
room
temperature
(entry
3)
showed
the
side-­‐products
seen
above,
but
also
showed
ester
6
that
resulted
from
unreacted
acyl
halide
via
path
b,
and
the
symmetric
imide
9
that
presumably
forms
from
an
additional
acylation
of
amide
7.
Raising
the
temperature
to
reflux
for
five
minutes
(entry
4)
produced
the
best
product
ratios
for
these
substrates,
with
near
complete
conversion
from
acyl
halide
to
acyl-­‐isocyanate
but
limited
side-­‐products.
Acceptable
results
were
also
obtained
with
refluxing
anhydrous
benzene
or
toluene
(entries
5
and
6),
with
complete
consumption
of
starting
material
but
greater
production
of
side-­‐products
at
these
elevated
temperatures.
Replacement
of
the
silver
salt
with
sodium
cyanate
(entry
7)
resulted
in
no
detectable
acyl-­‐carbamate
4,
but
rather
only
ester
6
was
observed
suggesting
that
there
was
no
reaction
of
cyanate
without
the
assistance
of
the
silver
ion.6

4. This
approach
has
been
shown
to
be
successful
for
other
acyl
halide
derivatives,
with
the
ideal
reaction
conditions
dependent
on
the
reactivity
of
the
carboxylic
acid
derivative
(see
Table
2).
Application
of
the
experimental
conditions
above
for
hexanoyl
chloride,
silver
cyanate
and
benzyl
alcohol
produced
the
CBZ-­‐
protected
amide
11
in
excellent
isolated
yield
(entry
1).
Under
identical
conditions,
isobutyryl
chloride
showed
some
reduction
in
the
yield
of
12
(entry
2),
but
pivaloyl
chloride
produced
only
ester
6.
This
suggests
that
when
the
attack
by
the
cyanate
was
hindered,
the
reaction
followed
alternate
path
b
with
the
alcohol
attacking
the
unreacted
acyl
halide.
These
competing
reaction
paths
could
be
attenuated
by
changing
the
reaction
conditions.
Increasing
the
reflux
time
to
ten
minutes
and
adding
two
equivalents
of
silver
cyanate
produced
the
CBZ-­‐pivalamide
13
with
an
acceptable
yield.
A
similar
effect
was
observed
with
benzoyl
chloride,
where
ester
was
the
major
product
under
the
conditions
above,
but
five
equivalents
of
silver
cyanate
and
an
hour
reflux
led
to
a
good
yield
of
the
CBZ-­‐benzamide
14.
Even
under
the
most
strenuous
conditions,
similar
reactions
of
the
hexanoyl-­‐N-­‐hydroxy-­‐
succinimide
ester
(entry
5)
led
to
only
the
ester
6,
again
suggesting
that
the
cyanate
ion
was
unable
to
add
to
the
carbonyl
without
the
concomitant
formation
of
silver
chloride.
Table
2.
Isolated
yields
for
Cbz-­‐protected
amide
3
in
refluxing
ethyl
ether.
entry
electrophile
major
product
yield
of
3
Eq.
AgNCO
reflux
time
1
hexanoyl
chloride
11
91
1.1
5
min
2
isobutyryl
chloride
12
77
1.1
5
min
3
pivaloyl
chloride
13
67
2
10
min
4
benzoyl
chloride
14
78
5
1
hr
5
hexanoyl-­‐OSu
0
5
1
hr
O
N
H
O
O
O
N
H
O
O
O
N
H
O
O
O
N
H
O
O
O
O
ester only

5.
Since
the
identity
of
the
protecting
group
is
entirely
dependent
on
the
alcohol
chosen,
numerous
protecting
groups
can
be
employed
using
this
approach.
Table
3
demonstrates
that
synthetic
flexibility,
with
the
five
minute
reflux
of
hexanoyl
chloride
and
silver
cyanate,
followed
by
the
addition
of
various
alcohols.
All
six
alcohols
tested
led
to
good
yields
of
acyl-­‐carbamates
15-­‐19
regardless
of
differing
chemical
characteristics.
All
crude
reactions
showed
product
ratios
similar
to
the
best
conditions
in
Table
1,
and
reduced
yields
are
largely
a
result
of
purification
conditions
rather
than
restrictions
on
the
reaction
itself.
Examples
that
use
alcohols
that
could
be
more
easily
removed
during
purification
tended
to
lead
to
higher
isolated
yields.
The
chosen
alcohols
permit
deprotection
using
respectively
hydrogenation,
acid,
base,
Pd,
fluoride,
and
photolytic
cleavage,
and
certainly
other
alcohols
should
be
applicable
as
well.
Table
3.
Isolated
yields
for
the
reaction
of
hexanoyl
chloride
with
AgNCO,
and
then
alcohol.
entry
alcohol
(R’OH)
product
protecting
group
yield
3
1
benzyl
alcohol
11
Cbz
91
2
tert-­‐butanol
15
Boc
92
3
9-­‐fluorenyl
methanol
16
Fmoc
83
4
allyl
alcohol
17
Alloc
86
5
2-­‐TMS-­‐ethanol
18
Teoc
89
6
o-­‐nitrobenzyl
alcohol
19
oNb
78
O
N
H
O
O
O
N
H
O
O
O
N
H
O
O
O
N
H
O
O
O
N
H
O
O
Si
O
N
H
O
O NO2

6. Acyl-­‐isocyanates
have
proven
to
be
an
exceptional
intermediates
in
the
formation
of
carbamate-­‐protected
primary
amides.
Acyl
chloride
derivatives
can
be
cleanly
converted
to
acyl-­‐isocyanates
with
silver
cyanate
in
refluxing
ethyl
ether,
and
addition
of
an
appropriate
alcohol
leads
to
the
carbamate-­‐protected
primary
amide.
Each
electrophile
provides
a
different
balance
of
competing
pathways,
so
each
new
substrate
requires
optimization
of
reaction
times,
equivalents
of
reagents
and
potentially
solvent.
Since
the
protecting
group
is
purely
a
consequence
of
the
alcohol
chosen,
a
variety
of
orthogonal
protecting
groups
can
be
utilized.
With
this
in
mind,
primary
amides
can
be
synthesized
in
a
straightforward
fashion,
remain
protected
through
a
synthetic
sequence,
and
be
subjected
to
facile
deprotection
through
a
variety
of
methods.
Experimental
General information. Anhydrous solvents (ethyl ether, benene, toluene) used in
moisture sensitive reactions were obtained from an MBraun solvent purification
system (MB-SPS). Glassware in these reactions was oven-dried overnight. Ethyl
ether for non-anhydrous conditions was purchased from Fisher Scientific and used
directly. Silver cyanate was placed under high-vacuum for several hours in an
effort to remove any residual moisture. Reagent quality hexanoyl chloride,
benzoyl chloride, isobutyryl chloride, pivaloyl chloride, benzyl alcohol, 9-
fluorenylmethanol, allyl alcohol, 2-(trimethylsilyl)ethanol, 2-nitrobenzyl alcohol,
hexanoic acid, hexanoic anhydride, and hexanoamide were obtained from Aldrich
and used directly. Anhydrous tert-butanol was obtained from Aldrich.
N-­‐hexanoylhexamide
(9)
Hexanoamide
(90
mg,
0.78
mmol)
was
dissolved
in
15
mL
anhydrous
THF.
Sodium
hydride
was
added
as
a
60%
suspension
in
mineral
oil
(65mg,
1.63
mmol).
The
solution
formed
a
slush
and
was
stirred
for
30
min.
Hexanoyl
chloride
(108
mg,
0.80mmol)
was
added
and
the
solution
was
stirred
O
N
H
O

7. for
an
additional
hour.
A
solution
of
10%
aqueous
HCl
(30
mL)
was
slowly
added,
followed
by
50
mL
of
dichloromethane.
The
organic
layer
was
separated,
dried
with
sodium
sulfate
and
evaporated
to
dryness.
The
resulting
pale
solid
with
obvious
liquid
was
triturated
with
diethyl
ether.
The
soluble
fraction
contained
unreacted
hexanoamide,
hexanoic
acid
and
product,
while
the
insoluble
fraction
contained
only
product
(21
mg).
1H-­‐NMR
δ
8.72
(br,
1H),
2.59
(t,
J
=
7.5
Hz,
4H),
1.65
(m,
4H),
1.33
(m,
4H),
0.90
(t,
7.1
Hz);
13C-­‐NMR
δ
175.8,
150.9,
135.0,
128.7,
67.6,
40.2,
27.0;
HRMS
calcd.
for
[C12H23NO2
-­‐
M+Na]
requires
m/z
236.1626,
observed
236.1632.
ethyl
hexanoylcarbamate
(10)
The
general
procedure
for
the
evaluation
of
reaction
conditions
shown
in
Table
1
started
by
dissolving
hexanoyl
chloride
(100
mg,
0.74
mmol)
in
5
mL
anhydrous
ethyl
ether.
Silver
cyanate
(122
mg,
0.81
mmol)
was
added
at
which
point
the
reaction
flask
was
fitted
with
a
reaction
condenser,
placed
under
an
atmosphere
of
nitrogen
and
the
solution
was
immediately
placed
on
a
pre-­‐
warmed
heating
mantle.
The
heterogeneous
solution
was
refluxed
for
the
indicated
time.
The
heat
was
then
removed
and
ethanol
(45
mg,
0.98
mmol)
was
added.
The
reaction
was
stirred
at
room
temperature
for
one
hour
under
nitrogen.
The
insoluble
solids
were
removed
using
vacuum
filtration,
and
the
solvent
was
removed
under
reduced
pressure.
NMR
product
ratios
were
reported
from
the
integrations
of
the
alpha-­‐methylene
signals,
which
were
distinguishable
for
each
side-­‐product.
An
analytical
sample
was
obtained
by
recrystallizing
the
white
solid
in
dichloromethane/hexanes
at
-­‐20˚C.
1H-­‐NMR
δ
7.89
(br,
1H),
4.21
(q,
J
=
7.1
Hz,
2H),
2.75
(t,
J
=
7.6
Hz,
2H),
1.66
(m,
2H),
1.33
(m,
4H),
1.31
(t,
J
=
7.1
Hz,
3H),
0.90
(t,
7.1
Hz);
13C-­‐NMR
δ
175.3,
152.1,
62.,
36.3,
31.5,
24.2,
22.6,
14.4,
14.1;
HRMS
calcd.
for
[C9H18NO3
-­‐
M+H]
requires
m/z
188.1287,
observed
188.1286.
benzyl
hexanoylcarbamate
(11)
Hexanoyl
chloride
(200
mg,
1.49
mmol)
was
dissolved
in
5
mL
anhydrous
ethyl
ether.
Silver
cyanate
(245
mg,
1.63
O
N
H
O
O
O
N
H
O
O

8. mmol)
was
added
and
the
reaction
flask
was
fitted
with
a
reaction
condenser,
placed
under
an
atmosphere
of
nitrogen
and
the
solution
was
immediately
placed
on
a
pre-­‐
warmed
heating
mantle
where
the
heterogeneous
solution
was
refluxed
for
five
minutes.
After
this
time,
the
heat
was
removed
and
benzyl
alcohol
(177
mg,
1.64
mmol)
was
added.
The
reaction
was
stirred
at
room
temperature
for
one
hour
under
nitrogen.
The
insoluble
solids
were
removed
using
vacuum
filtration,
and
the
solvent
was
removed
under
reduced
pressure.
yielding
337
mg
(91%)
of
white
solid.
1H-­‐NMR
δ
7.84
(br,
1H),
7.36
(m,
5H),
5.17
(s,
2H),
2.73
(t,
J
=
7.6
Hz,
4H),
1.64
(m,
2H),
1.32
(m,
4H),
0.89
(t,
7.1
Hz);
13C-­‐NMR
δ
175.0,
151.9,
135.2,
128.9,
128.8,
128.5,
67.9,
36.3,
31.5,
24.1,
22.6,
14.1;
HRMS
calcd.
for
[C14H19NO3
-­‐
M+H]
requires
m/z
250.1443,
observed
250.1445.
benzyl
isobutyrylcarbamate
(12)
Isobutyryl
chloride
(211
mg,
1.98
mmol)
was
dissolved
in
5
mL
anhydrous
ethyl
ether.
Silver
cyanate
(366
mg,
2.44
mmol)
was
added
and
the
reaction
flask
was
fitted
with
a
reaction
condenser,
placed
under
an
atmosphere
of
nitrogen
and
the
solution
was
immediately
placed
on
a
pre-­‐warmed
heating
mantle
where
the
heterogeneous
solution
was
refluxed
for
five
minutes.
After
this
time,
the
heat
was
removed
and
benzyl
alcohol
(214
mg,
1.98
mmol)
was
added.
The
reaction
was
stirred
at
room
temperature
for
one
hour
under
nitrogen.
The
insoluble
solids
were
removed
using
vacuum
filtration,
and
the
solvent
was
removed
under
reduced
pressure.
yielding
338
mg
(77%)
of
white
solid.
1H-­‐NMR
δ
8.19
(br,
1H),
7.33
(m,
5H),
5.14
(s,
2H),
3.12
(m,
1H),
1.14
(d,
J
=
7.2
Hz,
9H);
13C-­‐
NMR
δ 178.1,
151.5,
135.1,
128.6,
128.6,
128.3,
67.6,
34.4,
18.8,
18.7;
HRMS
calcd.
for
[C12H15NO3
-­‐
M+Na]
requires
m/z
244.0950,
observed
244.0951.
benzyl
pivaloylcarbamate
(13)
Pivaloyl
chloride
(210
mg,
1.74
mmol)
was
dissolved
in
5
mL
anhydrous
ethyl
ether.
Silver
cyanate
(536
mg,
3.59
mmol)
was
added
and
the
reaction
flask
was
fitted
with
a
reaction
condenser,
placed
under
an
atmosphere
O
N
H
O
O
O
N
H
O
O

9. of
nitrogen
and
the
solution
was
immediately
placed
on
a
pre-­‐warmed
heating
mantle
where
the
heterogeneous
solution
was
refluxed
for
ten
minutes.
After
this
time,
the
heat
was
removed
and
benzyl
alcohol
(197
mg,
1.82
mmol)
was
added.
The
reaction
was
stirred
at
room
temperature
for
one
hour
under
nitrogen.
The
insoluble
solids
were
removed
using
vacuum
filtration,
and
the
solvent
was
removed
under
reduced
pressure.
yielding
276
mg
(67%)
of
white
solid.
1H-­‐NMR
δ
7.99
(br,
1H),
7.36
(m,
5H),
5.16
(s,
2H),
1.21
(s,
9H);
13C-­‐NMR
δ 174.8, 37.6, 31.5, 24.3, 22.6, 14.1;
HRMS
calcd.
for
[C13H18NO3
-­‐
M+H]
requires
m/z
236.1287,
observed
236.1292.
benzyl
benzoylcarbamate
(14)
Benzoyl
chloride
(200
mg,
1.42
mmol)
was
dissolved
in
5
mL
anhydrous
ethyl
ether.
Silver
cyanate
(1.07
g,
7.14
mmol)
was
added
and
the
reaction
flask
was
fitted
with
a
reaction
condenser,
placed
under
an
atmosphere
of
nitrogen
and
the
solution
was
immediately
placed
on
a
pre-­‐warmed
heating
mantle
where
the
heterogeneous
solution
was
refluxed
for
one
hour.
After
this
time,
the
heat
was
removed
and
benzyl
alcohol
(150
µL,
1.45
mmol)
was
added.
The
reaction
was
stirred
at
room
temperature
for
one
hour
under
nitrogen.
The
remaining
solids
were
removed
using
vacuum
filtration,
and
the
solvent
was
removed
under
reduced
pressure.
The
crude
oil
was
recrystallized
using
diethyl
ether/hexanes
to
yield
283
mg
(78%)
white
solid.
1H-­‐NMR
δ
8.43
(br,
1H),
7.81
(d,
,
J
=
8.2,
2H),
7.56
(t,
J
=
7.4,
1H),
7.44
(t,
J
=
7.4,
1.4
Hz
2H),
7.34
(m,
5H),
5.20
(s,
2H);
13C-­‐NMR
δ
165.2,
151.2,
135.1,
133.2,
133.0,
129.0,
128.9,
128.8,
127.9,
68.1;
HRMS
calcd.
for
[C15H14NO3
-­‐
M+H]
requires
m/z
256.0974,
observed
256.0974.
tert-­‐butyl
hexanoylcarbamate
(15)
Hexanoyl
chloride
(200
mg,
1.49
mmol)
was
dissolved
in
5
mL
anhydrous
ethyl
ether.
Silver
cyanate
(234
mg,
1.56
mmol)
was
added
and
the
reaction
flask
was
fitted
with
a
reaction
condenser,
placed
under
an
atmosphere
of
nitrogen
and
the
solution
was
immediately
placed
on
a
pre-­‐warmed
O
N
H
O
O
O
N
H
O
O

10. heating
mantle
where
the
heterogeneous
solution
was
refluxed
for
5
minutes.
After
this
time,
the
heat
was
removed
and
tert-­‐butanol
(212
µL,
2.23
mmol)
was
added.
The
reaction
was
stirred
at
room
temperature
for
one
hour
under
nitrogen.
The
remaining
solids
were
removed
using
vacuum
filtration,
and
the
solvent
was
removed
under
reduced
pressure.
The
crude
oil
was
purified
using
column
chromatography
(silica:
dichloromethane)
to
yield
294
mg
(92%)
clear
oil.
1H-­‐NMR
δ
7.44
(br,
1H),
2.71
(t,
J
=
7.5
Hz,
4H),
1.65
(m,
2H),
1.50
(s,
9H),
1.32
(m,
4H),
0.90
(t,
7.1
Hz);
13C-­‐NMR
δ
175.3,
150.8,
82.4,
36.2,
31.4,
28.1,
24.1,22.5,14.0;
HRMS
calcd.
for
[C11H21NO3
-­‐
M+Na]
requires
m/z
238.1419,
observed
238.1427.
fluorenylmethyl
hexanoylcarbamate
(16)
Hexanoyl
chloride
(203
mg,
1.51
mmol)
was
dissolved
in
5
mL
anhydrous
ethyl
ether.
Silver
cyanate
(248
mg,
1.65
mmol)
was
added
and
the
reaction
flask
was
fitted
with
a
reaction
condenser,
placed
under
an
atmosphere
of
nitrogen
and
the
solution
was
immediately
placed
on
a
pre-­‐warmed
heating
mantle
where
the
heterogeneous
solution
was
refluxed
for
5
minutes.
After
this
time,
the
heat
was
removed
and
9-­‐fluorenylmethanol
(300mg,
1.53
mmol)
was
added.
The
reaction
was
stirred
at
room
temperature
for
one
hour
under
nitrogen,
during
which
time
an
obvious
white
precipitate
formed.
The
remaining
solids
were
removed
using
vacuum
filtration
and
washed
with
dichloromethane,
after
which
the
solvents
were
removed
under
reduced
pressure.
The
crude
white
solid
was
recrystallized
using
dichloromethane/hexanes
to
yield
422
mg
(83%)
white
solid.
1H-­‐NMR
δ
7.82
(br,
1H),
7.77
(d,
J
=
7.6
Hz,
2H),
7.59
(d,
J
=
7.6
Hz,
2H),
7.42
(t,
J
=
7.6
Hz,
1H),
7.32
(t,
J
=
7.6
Hz,
2H),
4.49
(d,
J
=
6.8
Hz,
2H),
4.24
(t,
J
=
6.8
Hz,
1H),
2.72
(t,
J
=
7.5
Hz,
2H),
1.66
(m,
2H),
1.32
(m,
4H),
0.89
(t,
J
=
7.1
Hz,
3H);
13C-­‐NMR
δ 175.4,
152.0,
143.4,
141.6,
128.2,
127.4,
125.2,
120.4,
67.9,
46.9,
36.3,
31.5,
24.1,
2
2.6,
14.1;
HRMS
calcd.
for
[C21H24NO3
-­‐
M+H]
requires
m/z
338.1756,
observed
338.1756.
O
N
H
O
O

11. allyl
hexanoylcarbamate
(17)
Hexanoyl
chloride
(200
mg,
1.49
mmol)
was
dissolved
in
5
mL
anhydrous
ethyl
ether.
Silver
cyanate
(234
mg,
1.56
mmol)
was
added
and
the
reaction
flask
was
fitted
with
a
reaction
condenser,
placed
under
an
atmosphere
of
nitrogen
and
the
solution
was
immediately
placed
on
a
pre-­‐warmed
heating
mantle
where
the
heterogeneous
solution
was
refluxed
for
5
minutes.
After
this
time,
the
heat
was
removed
and
allyl
alcohol
(110
µL,
1.62
mmol)
was
added.
The
reaction
was
stirred
at
room
temperature
for
one
hour
under
nitrogen.
The
remaining
solids
were
removed
using
vacuum
filtration,
and
the
solvent
was
removed
under
reduced
pressure.
The
crude
oil
was
recrystallized
using
dichloromethane/hexanes
to
yield
255
mg
(86%)
white
solid.
1H-­‐NMR
δ
8.00
(br,
1H),
7.33
(m,
5H),
5.92
(ddt,
J
=
17.2,
10.4,
5.7
Hz
1H),
5.37
(dq,
J
=
17.2,
1.4
Hz
1H),
5.29
(dq,
J
=
10.4,
1.4
Hz
1H),
4.65
(dt,
J
=
5.7,
1.4
Hz
1H),
2.75
(t,
J
=
7.6
Hz,
2H),
1.65
(m,
2H),
1.33
(m,
4H),
0.89
(t,
J
=
7.2
Hz,
3H);
13C-­‐NMR
δ
175.3,
151.8,
131.6,
119.2,
66.8,
36.3,
31.5,
24.1,
22.6,
14.1;
HRMS
calcd.
for
[C10H17NO3
-­‐
M+Na]
requires
m/z
222.1106,
observed
222.1108.
2-­‐(trimethylsilyl)ethyl
hexanoylcarbamate
(18)
Hexanoyl
chloride
(200
mg,
1.49
mmol)
was
dissolved
in
5
mL
anhydrous
ethyl
ether.
Silver
cyanate
(234
mg,
1.56
mmol)
was
added
and
the
reaction
flask
was
fitted
with
a
reaction
condenser,
placed
under
an
atmosphere
of
nitrogen
and
the
solution
was
immediately
placed
on
a
pre-­‐warmed
heating
mantle
where
the
heterogeneous
solution
was
refluxed
for
5
minutes.
After
this
time,
the
heat
was
removed
and
2-­‐(trimethylsilyl)ethanol
(194
mg,
1.64
mmol)
was
added.
The
reaction
was
stirred
at
room
temperature
for
one
hour
under
nitrogen.
The
remaining
solids
were
removed
using
vacuum
filtration,
and
the
solvent
was
removed
under
reduced
pressure.
The
crude
oil
was
purified
using
column
chromatography
(silica:
dichloromethane)
to
yield
342
mg
(89%)
clear
oil.
1H-­‐NMR
δ
7.85
(br,
1H),
4.22
(m,
2H),
2.72
(t,
J
=
7.6
Hz,
2H),
1.63
(m,
2H),
1.31
(m,
4H),
1.01
(m,
2H),
0.87
(t
J
=
7.0
Hz,
3H),
0.03
(s,
9H);
13C-­‐NMR
δ
175.4,
152.2,
64.9,
O
N
H
O
O
Si
O
N
H
O
O

12. 36.3,
31.5,
24.2,
22.6,
17.7,
14.1,
-­‐1.3;
HRMS
calcd.
for
[C12H25NO3Si
-­‐
M+Na]
requires
m/z
282.1501,
observed
282.1500.
2-­‐nitrobenzyl
hexanoylcarbamate
(19)
Hexanoyl
chloride
(200
mg,
1.49
mmol)
was
dissolved
in
5
mL
anhydrous
ethyl
ether.
Silver
cyanate
(234
mg,
1.56
mmol)
was
added
and
the
reaction
flask
was
fitted
with
a
reaction
condenser,
placed
under
an
atmosphere
of
nitrogen
and
the
solution
was
immediately
placed
on
a
pre-­‐warmed
heating
mantle
where
the
heterogeneous
solution
was
refluxed
for
5
minutes.
After
this
time,
the
heat
was
removed
and
2-­‐nitrobenyl
alcohol
(228
mg,
1.49
mmol)
was
added.
The
reaction
was
stirred
at
room
temperature
for
one
hour
under
nitrogen.
The
remaining
solids
were
removed
using
vacuum
filtration,
and
the
solids
were
washed
twice
with
10
mL
dichloromethane.
The
organic
filtrates
were
combined
and
all
volatiles
were
removed
under
reduced
pressure.
The
crude
solid
was
purified
using
recrystallization
from
hot
ethyl
ether
to
yield
342
mg
(78%)
white
solid.
1H-­‐NMR
δ
8.15
(dd,
J
=
8.2,
1.1
Hz,
9H),
7.98
(br,
1H),
7.68
(m,
2H),
7.53
(dt,
J
=
7.6,
1.8
Hz,
9H),
5.62
(s,
2H),
2.75
(t
J
=
7.5
Hz,
2H);
1.67
(m,
2H),
1.34
(m,
4H),
0.90
(t
J
=
7.0
Hz,
3H);
13C-­‐NMR
δ 175.0,
151.5,
147.9,
134.3,
131.7,
129.3,
129.2,
125.5,
64.6,
36.4,
31.4,
24.1,
22.6,
14.1;
HRMS
calcd.
for
[C14H19N2O5
-­‐
M+H]
requires
m/z
295.1294,
observed
295.1297.
Acknowledgments.
This
work
was
supported
by
the
National
Science
Foundation
(CHE-­‐0852232)
and
by
the
American
Chemical
Society
Petroleum
Research
Fund.
Supporting
Information.
1
H and 13
C NMR spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
O
N
H
O
O NO2

13.
References
1
Bach,
A.;
Stuhr-­‐Hansen,
N.;
Thorsen,
T.
S.;
Bork,
N.;
Moreira,
I.
S.;
Frydenvang,
K.;
Padrah,
S.;
Christensen,
B.;
Madsen,
K.
L.;
Weinstein,
H.;
Gether,
U.;
Strømgaard,
K.
Org.
Biomol.
Chem.,
2010,
8,
4281-­‐4288.
DeRisi,
C.;
Ferrano,
L.;
Pollini,
G.
P.;
Tanganelli,
S.;
Valente,
F.;
Veronese,
A.
Bioorg.
Med.
Chem.
2008,
16,
9904-­‐9910.
Yeung,
Y.-­‐Y.;
Corey,
E.
J.
Tetrahedron
Lett.,
2007,
48,
7567-­‐7570.
Li,
K.;
Cheng,
X.;
Hii,
K.
K.
Eur.
J.
Org.
Chem.,
2004,
959-­‐964.
Hayashi,
Y.;
Shoji,
M.;
Yamaguchi,
S.;
Mukaiyama,
T.;
Yamaguchi,
J.;
Kakeya,
H.;
Osada,
H.
Org.
Lett.,
2003,
5,
2287-­‐
2290.
2
For
a
review
of
acyl
isocyanate
chemistry
see:
Nuridzhanyan,
K.
A.
Russ.
Chem.
Rev.,
1970,
39,
130-­‐139.
3
Acyl-­‐isocyanates
have
also
been
synthesized
from
the
reaction
of
an
already-­‐
formed
primary
amide
and
oxalyl
chloride,
but
this
typically
requires
a
period
of
elevated
reaction
temperatures.
Speziale,
J.;
Smith,
L.
R.
Org.
Synth.
Coll.
Vol.
V,
1973,
46,
16-­‐17.
4
Roos,
G.
H.
P.;
Donovan,
A.
R.
Sci.
Tech,
2000,
5,
11-­‐23.
Koppel,
I.;
Koppel,
J.;
Koppel,
I.;
Leito,
I.;
Pihl,
V.;
Wallin,
A.;
Grehn,
L.;
Ragnarsson,
U.
J.
CHem.
Soc.
Perkin
Trans
2,
1993,
655-­‐658.
Smith,
L.
R.;
Speziale,
A.
J.;
Fedder,
J.
E.,
J.
Org.
Chem.,
1969,
34,
633-­‐637.
5
Hill,
A.
J.;
Degnan,
W.
M.
J.
Am.
Chem.
Soc.,
1940,
62,
1595-­‐1596.
Steinman,
H.
G.;
Doak,
G.
O.;
Eagle,
H.
J.
Am.
Chem.
Soc.,
1944,
66,
192-­‐194.
Ludek,
O.
R.;
Marquez,
V.
E.
Synthesis,
2007,
3451-­‐3460.
6
Deng,
M.-­‐Z.;
Caubere,
P.;
Senet,
J.
P.;
Lecolier,
S.,
Tetrahedron,
1988,
44,
6079-­‐6086.