High yielding allylation of a chiral secondary alcohol containing base sensitive functional groups

Article abstract of DOI:10.1016/j.tetlet.2011.12.120

Inhibitors of neuronal nitric oxide synthase, based on a chiral pyrrolidine scaffold, show promise for the treatment of certain neurodegenerative diseases. We recently reported the synthesis of a series of selective inhibitors, but the method was limited at a key step of forming an allyl ether intermediate. Yields for this step were very inconsistent, and the presence of base sensitive functional groups limited the range of available methods for forming this ether bond. This work describes a novel application of palladium catalyzed decarboxylative allylation, consistently resulting in a 90% isolated yield, which is crucial for the synthesis of this critical late stage intermediate. We also report a new quantitative yielding and straightforward synthesis of the allyl-t-butylcarbonate precursor.

Full text of DOI:10.1016/j.tetlet.2011.12.120

Tetrahedron Letters 53 (2012) 1319–1322
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
High yielding allylation of a chiral secondary alcohol containing base
sensitive functional groups
⇑
James M. Kraus, Hunter C. Gits, Richard B. Silverman
Department of Chemistry, Chemistry of Life Processes Institute, and Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208-3113, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Inhibitors of neuronal nitric oxide synthase, based on a chiral pyrrolidine scaffold, show promise for the
treatment of certain neurodegenerative diseases. We recently reported the synthesis of a series of selec-
tive inhibitors, but the method was limited at a key step of forming an allyl ether intermediate. Yields for
this step were very inconsistent, and the presence of base sensitive functional groups limited the range of
available methods for forming this ether bond. This work describes a novel application of palladium cat-
alyzed decarboxylative allylation, consistently resulting in a 90% isolated yield, which is crucial for the
synthesis of this critical late stage intermediate. We also report a new quantitative yielding and straight-
forward synthesis of the allyl-t-butylcarbonate precursor.
Received 29 November 2011
Revised 23 December 2011
Accepted 28 December 2011
Available online 14 January 2012
Keywords:
Decarboxylative allylation
Tetrakis(triphenylphosphine)palladium(0)
Neutral O-allylation
Ó 2012 Elsevier Ltd. All rights reserved.
Introduction
of 3 via the aforementioned rearrangement; however, the yields
were very inconsistent, often as low as 20%. There is considerable
In our ongoing research to develop potential chemotherapeutic
agents to prevent neurodegeneration, we identified a series of
compounds, based on a chiral pyrrolidine core that selectively
inhibited neuronal nitric oxide synthase (nNOS) with respect to
the other two enzyme isoforms, inducible (iNOS) and endothelial
effort associated with obtaining this late stage intermediate in enan-
tiomerically pure form, so we were interested in the identification
of a more reliable and high yielding methodology for O-allylation
of 1.
1
nitric oxide synthase (eNOS). A key intermediate in the synthesis
of these compounds from (3R,4R)-1 is (3R,4R)-allyloxypyrrolidine
Allylation strategies and their outcomes
2
. Earlier work showed that the 2-amino nitrogen on the pyridine
Several general methods were explored to identify a method for
forming 2. Based on the observation that the second Boc group is
requires bulky
protecting groups to prevent a side reaction, and for various reasons,
we decided to employ a diBoc strategy.2 We discovered that an
unexpected rearrangement takes place when Williamson conditions
are used to convert precursor alcohol 1 into allyl ether 2. Formally,
the mechanism is N- to O transfer of a tert-butylcarbonyl (Boc) group
and allylation of the 2-amino group at the pyridine ring, forming N-
allyl 3 in a 95% yield. Recently, we reported an improved synthesis of
labile under basic and acidic conditions, we explored ether forma-
tion reactions that take place under neutral, or nearly neutral,
conditions.
Des-Boc alcohol precursor
As mentioned above, we require the second Boc group on the
2-aminopyridine to prevent a side reaction at an earlier step in
the synthesis, and having already served its purpose, we specu-
lated that it might be possible to remove it at this stage, generating
3
intermediate 2. By using a method for allylation that proceeds un-
der neutral conditions, we were successful in avoiding the formation
4
, which might be relatively easier to allylate, compared to 1. We
⇑
Corresponding author. Tel.: +1 847 491 5653.
E-mail address: Agman@chem.northwestern.edu (R.B. Silverman).
screened various different conditions to find optimum parameters
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.120

1
320
J. M. Kraus et al. / Tetrahedron Letters 53 (2012) 1319–1322
in three steps (Scheme 3): In step 1, methoxide is generated by
decarboxylation. In step 2, the pyrrolidine alkoxide is generated
from an acid-base reaction with methoxide, but the equilibrium
is expected to lie to the left side (favoring the secondary alcohol),
a
which should have a slightly higher pK . In step 3, both alkoxide
species compete for the allyl cation; however, the nucleophilicity
of the secondary pyrrolidine oxide is not expected to exceed that
of the methoxide ion.
Scheme 1. Generation of 4 by mono deprotection of precursor 1.
Therefore, when allyl methyl carbonate is used, we are penal-
ized twice, first in the acid-base reaction, then again in the nucle-
ophilic attack on the p-allyl complex. In general, this hypothesis is
for quantitative removal of just one of the three Boc groups of 1.
When 1 was treated with 1 M TFA in methylene chloride, the Boc
group was removed selectively in a near quantitative yield in only
attributed to Sinou and coworkers, who used allyl ethyl carbonate
with Pd0 to form the allyl ether of carbohydrate substrates,6 but
there are also other variations. In one example, an allyl carbonate
1
5 min, yielding 4 (Scheme 1).
We predicted a priori that the alkoxide would be a better nucle-
7
ophile than the carbamate nitrogen anion and hypothesized that 4
could be subjected to >2 equiv of sodium hydride in the presence
of a stoichiometric amount of allyl bromide to afford the O-allyl
product under Williamson conditions. Subsequent aqueous work-
up would neutralize the carbamate nitrogen anion. Surprisingly,
the only major product that was isolated was the N,O-diallyl spe-
cies in a 20% yield. There is precedence for using trichloroalkylim-
idates along with an acid catalyst for the allylation of hindered
precursor was formed from the alcohol substrate, which was then
treated with the palladium catalyst. Under strictly anhydrous con-
ditions, this implies that only one nucleophile (the alkoxide of the
substrate) would be present to trap the allyl species, and the rate
limiting step in the reaction would be the attack of the
p-allyl
complex by the alkoxide, since the acid-base equilibrium shown
in step 2 of Scheme 3 would not be present in the mechanism.
Similarly, forming allyl carbonate 8 from alcohol 1, then subjecting
it to palladium catalyzed decarboxylation conditions seemed
promising. The requisite allyl chloroformate is commercially avail-
able, but we were unsuccessful in forming 8. These results suggest
that formation of the carbonate precursor might be of comparable
difficulty to forming the ether product (2) from this sterically hin-
dered alcohol, so we did not pursue this method further (Scheme 4).
It has been reported that using a less nucleophilic alkoxide, such
as tert-butoxide (generated from decarboxylation of allyl-t-butyl-
carbonate) should minimize the formation of side products.8 In
that work, they were able to obtain selective allylation of a hin-
dered tertiary hydroxyl group on a carbohydrate substrate, in the
presence of two unmasked secondary alcohols, while using only
a slight excess (1.2 equiv) of allyl-t-butylcarbonate (9). The re-
quired allyl tert-butylcarbonate precursor is not commercially
available. It has previously been synthesized from allyl alcohol
4
alcohols, such as carbohydrate secondary hydroxyl groups. We
tried the trichloroacetimidate methodology on des-Boc 4, but only
obtained a trace amount of product along with the loss of starting
material. This seems to indicate that the substrate is not stable un-
der the conditions of the reaction. Interestingly, treating 4 with
palladium and allyl carbonate gave the N-allyl product in a high
yield, but did not lead to any significant O-allylation, confirming
the difficulty in forming the allyl ether of this substrate (Scheme 2).
Sterically hindered carbonate precursor
0
Next we revisited palladium catalyzed decarboxylative allyla-
tion; an advantage of this reaction is that it takes place under
nearly neutral conditions, since the amount of alkoxide that is
present is never greater than the amount of catalyst. A disadvan-
tage of Pd-catalyzed decarboxylative allylations, in general, is that
2
and di-tert-butyl-dicarbonate (Boc O) in dichloromethane, using
5
8
water competes as a nucleophile twice, first to attack the Pd
p
-al-
phase transfer catalysis and sodium hydroxide as base. In our
hands, the reaction is very sluggish and, even after 48 h, it does
not go to completion. It is difficult to separate the carbonate prod-
lyl complex, then again, when the newly formed alcohol attacks
another Pd -allyl complex. We had limited success with allyl
p
methyl carbonate, but inspection of the mechanism suggests that
the reason may be because the pyrrolidine hydroxyl group is a sec-
ondary alcohol. The overall reaction can be viewed as proceeding
uct from the unreacted Boc
cause the difference in the R
2
O using silica gel chromatography be-
values is very small. With these
f
factors in mind, we set out to optimize the reaction conditions. It
seems likely that the reaction is sluggish because the generation
of the alkoxide is not very efficient. Enhancing the activity of the
tert-butylcarbonyl group would be expected to facilitate the reac-
tion with neutral allyl alcohol. 4-(N,N-Dimethyl)aminopyridine,
DMAP, seemed promising based on the known mechanism in-
volved in DMAP catalysis of acylations using acetic anhydride. It
2
was speculated that running the reaction neat (Boc O in allyl alco-
hol) would allow kinetics that are limited by diffusion rather than
phase transfer. The hypothesis turned out to be correct; using
DMAP catalysis enabled facile production of the required carbon-
ate. The optimized conditions are as follows: Di-tert-butyl-dicar-
bonate (10 g) was dissolved in 20 mL of anhydrous allyl alcohol.
DMAP (275 mg, 5 mol %) was added all at once, and a reflux con-
denser was attached. Immediate evolution of CO
proceeded at a constant rate for about 1 h, at which time the
reaction was complete, and Boc O was undetectable in the crude
2
occurred, which
2
mixture by TLC. The crude product was a solution in allyl alcohol,
which was used in excess. It would be desirable to remove the
excess unreacted allyl alcohol before attempting the chromato-
graphic purification of the carbonate, but when the crude reaction
mixture was placed on the rotary evaporator, both the carbonate
product and allyl alcohol were removed. Fractional distillation
Scheme 2. Attempted O-allylation of 4 using various conditions.

J. M. Kraus et al. / Tetrahedron Letters 53 (2012) 1319–1322
1321
Step 1
O
O
Pd2+
Me
+
Me
MeO
+
CO2
O
O
O
O
L
L
Boc
N
Boc
N
Step 2
+
+
MeO
MeOH
Boc
Boc
N
Boc
N
O
N
Boc
N
OH
Boc
N
Step 3:
Pd2+
Boc
OMe
N
N
O
L
L
Boc
Scheme 3. Three-step mechanism for palladium catalyzed decarboxylative allylation reaction.
Scheme 4. Attempted formation of 2 by direct decarboxylative allylation of 8.
On the basis of our previous work, we expected the second Boc
group to be very labile under basic conditions. We predicted that
we could use a very low catalyst loading to minimize the concen-
tration of alkoxide, and utilize tert-butylcarbonate precursor to
prevent side reactions. Using 2.5% palladium catalyst and 5 equiv
of 9 led to the formation of the desired product in a 90% isolated
yield in 6 h (Scheme 6). Further optimization could include using
a lower stoichiometric ratio of carbonate, but will also require
more rigorous exclusion of water, and 9 is easily synthesized in
one step from inexpensive starting materials.
Scheme 5. Synthesis of allyl-t-butylcarbonate (9).
was not practical because the boiling points of the two compounds
are very similar. Ultimately, the purification of the product was
achieved by loading the crude reaction mixture directly onto silica
gel. A mobile phase consisting of 5% ethyl acetate in hexanes eluted
Conclusions
the product with an R
f
of 0.5, while the DMAP catalyst and allyl
A simple protocol for the allylation of a complex substrate alco-
hol is reported. This robust method should be a useful addition to
the synthetic tool kit for researchers interested in the allylation of
sterically-hindered alcohols in key pharmacophoric scaffolds con-
taining base-sensitive functional groups. By using commercially
alcohol were not eluted from the silica gel under these conditions.
Potassium permanganate was used to visualize the olefin product
by TLC. In this way, 7.3 g of 9 was produced from 10 g of di-tert-bu-
tyl-dicarbonate (Scheme 5).
Scheme 6. Decarboxylative allylation of 1 to form 2 in high yields.

1
322
J. M. Kraus et al. / Tetrahedron Letters 53 (2012) 1319–1322
available tetrakis(triphenylphosphine)palladium catalyst and a
new simplified method for the synthesis of allyl-t-butylcarbonate
yellow. The mixture was heated to reflux for several minutes. A
solution of 9 (320 mg, 1.74 mmol) in 5 mL anhydrous THF was in-
jected into the preheated, refluxing THF solution over approxi-
mately 1 min. The reaction was allowed to stir under reflux for
(9), selective allylation of hindered alcohols proceeds in greater
than 90% isolated yield.
6
h, at which time, complete consumption of starting material
was indicated by TLC, and a new spot was observed R = 0.8, 25%
ethyl acetate/75% hexanes. Silica gel chromatography gave 2 as a
Experimental
f
1
3
white solid (172 mg, 90%) H NMR (500 MHz, CDCl , d): 6.91 (d,
Allyl tert-butylcarbonate (9)
J = 8.5 Hz, 1H), 6.90 (s, 1H), 5.88 (m, 1H), 5.27 (m, 1H), 5.16 (d,
J = 10.5 Hz, 1H), 4.03 (dt, J = 5.5, 13 Hz, 1H), 3.78 (m, 2H), 3.52
A flame-dried flask containing a stir bar was charged with di-
tert-butyl-dicarbonate (10.0 g, 45.8 mmol), and anhydrous allyl
alcohol (10.0 mL, 147 mmol) was added. A water-cooled condenser
was attached and fitted with a calcium chloride drying tube. When
the solids had dissolved, 4-(dimethylamino)-pyridine (275 mg,
(
m, 2H), 3.27 (dd, J = 3.5, 12.5 Hz, 1H), 3.16 (m, 1H), 3.01 (m, 1H),
2
9
1
1
7
2
.81 (m, 1H), 2.69 (m, 1H), 2.33 (m, 3H), 1.44 (s, 18H), 1.43 (s,
1
3
H);
3
C NMR (125 MHz, CDCl , d): 159.25, 159.19, 154.78,
54.48, 151.81, 151.48, 151.43, 149.50, 134.67, 134.62, 122.94,
19.55, 116.87, 116.67, 82.82, 79.21, 79.13, 78.61, 77.78, 70.26,
0.18, 51.00, 50.43, 49.20, 48.87, 43.32, 42.67, 34.76, 34.66,
8.51, 27.92, 20.90. HR ESI-MS: m/z = 548.3325 (mono-isotopic
2
.25 mmol, 5%) was added all at once. Gas was evolved immedi-
ately, and continued at a steady rate for approximately 1 h. At this
time, TLC indicated that the di-tert-butyl-dicarbonate starting
mass = 547.3258).
material had been completely consumed, as visualized with I
The product was purified by flash chromatography using a
.5 cm (od) column. The crude mixture was loaded directly onto
2
.
5
Acknowledgments
the silica gel and eluted using a mobile phase consisting of 5% ethyl
acetate/95% hexanes, producing 7.3 g (quantitative) of 9. The prod-
The authors are grateful for financial support from the National
Institutes of Health (GM049725). J.M.K. thanks the Center for
Molecular Innovation and Drug Discovery at Northwestern Univer-
sity for a postdoctoral fellowship from the NIH training grant, Drug
Discovery in Age Related Disorders (T32 AG000260).
uct was visualized with potassium permanganate staining, R
f
0.4.
, d): 5.94 (m, 1H), 5.35 (ddd, J = 1.5, 3,
7.5 Hz, 1H), 5.26 (dd, J = 1.5, 10.5 Hz, 1H), 4.56 (m, 2H), 1.50 (s,
1
H NMR (500 MHz, CDCl
3
1
9
6
1
3
H); C NMR (125 MHz, CDCl
7.62, 27.77.
3
, d): 153.31, 131.96, 118.60, 82.21,
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1
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8
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