A facile deprotection of secondary acetamides

Article abstract of DOI:10.1021/ol802482d

(Chemical Equation Presented) Imidoyl chlorides, generated from secondary acetamides and oxalyl chloride, can be harnessed for a selective and practical deprotection sequence. Treatment of these intermediates with 2 equiv of propylene glycol and warming enables the rapid release of amine hydrochloride salts in good yields. Notably, the reaction conditions are mild enough to allow for a swift deprotection with no observed epimerization of the amino center.

Full text of DOI:10.1021/ol802482d

ORGANIC
LETTERS
2009
Vol. 11, No. 2
433-436
A Facile Deprotection of Secondary
Acetamides
Stefan G. Koenig,* Charles P. Vandenbossche, Hang Zhao, Patrick Mousaw,†
Surendra P. Singh, and Roger P. Bakale‡
Chemical Process Research and DeVelopment, Sepracor Inc., 84 Waterford DriVe,
Marlborough, Massachusetts 01752
stefan.koenig@sepracor.com
Received October 27, 2008
ABSTRACT
Imidoyl chlorides, generated from secondary acetamides and oxalyl chloride, can be harnessed for a selective and practical deprotection
sequence. Treatment of these intermediates with 2 equiv of propylene glycol and warming enables the rapid release of amine hydrochloride
salts in good yields. Notably, the reaction conditions are mild enough to allow for a swift deprotection with no observed epimerization of the
amino center.
Recent years have seen an explosion in the design of novel
asymmetric ligands for the catalytic hydrogenation of ena-
mides to give protected chiral amines.1 The acetyl group,
widely utilized for its contribution to high stereoselectivities,
is typically introduced at the enamide stage. We recently
reported a metal-free, phosphine-based conversion of ke-
toximes to enacetamides, enabling in particular the formation
of the difficult-to-access tetralone series of substrates.2
However, as with the formation of these catalytic hydrogena-
tion precursors, limited work has been reported to address
the necessary deprotection of the chiral products.
Traditional methods of deacylation require harsh condi-
tions and long reaction times.3 Newer reports often utilize
complex conditions or costly reagents or provide access only
to the corresponding carboxylic acids or esters.4 As none of
the literature-based methods served our purpose, we chose
to investigate alternatives to deliver target molecule 1
(Scheme 1). Herein we disclose the rapid and selective
(3) (a) White, E. J. Am. Chem. Soc. 1955, 77, 6011. (b) Corey, E. J.
J. Am. Chem. Soc. 1959, 81, 2225. (c) Hanessian, S. Tetrahedron Lett. 1967,
8, 1549. (d) Hamilton, D. J.; Price, M. J. J. Chem. Soc. D 1969, 414. (e)
Franz, J. A.; Martin, J. C. J. Am. Chem. Soc. 1973, 95, 2017. (f) Franz,
J. A.; Martin, J. C. J. Am. Chem. Soc. 1975, 97, 6137. (g) Shahak, I. J. Am.
Chem. Soc. 1973, 95, 3440. (h) Vaughn, H. L. J. Org. Chem. 1975, 40,
1187. (i) Keith, D. D. J. Org. Chem. 1978, 43, 3711. (j) Obayashi, M.;
Schlosser, M. Chem. Lett. 1985, 1715. (k) Kim, Y. H.; Kim, K.; Park, Y. J.
Tetrahedron Lett. 1990, 31, 3893. (l) Gomez-Reyes, B.; Yatsimirsky, A. K.
Org. Lett. 2003, 5, 4831. (m) Zahn, D. Eur. J. Org. Chem. 2004, 4020, and
references therein.
† Current address: University of Notre Dame, South Bend, IN.
‡ Current address: Cephalon, Inc., Malvern, PA.
(1) (a) Knowles, W. S. Asymmetric Catalysis on Industrial Scale; Blaser,
H.-U., Schmidt, E., Eds.; Wiley-VCH Verlag: Weinheim, Germany, 2004;
p 23. (b) Chi, Y.; Tang, W.; Zhang, X. Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH Verlag: Weinheim, Germany,
2005; p 1. (c) Flanagan, S. P.; Guiry, P. J. J. Organomet. Chem. 2006,
691, 2125. (d) Gomez Arrayas, R.; Adrio, J.; Carretero, J. C. Angew. Chem.,
Int. Ed. 2006, 45, 7674. (e) Hugl, H. Asymmetric Synthesis; Christmann,
M., Braese, S., Eds.; Wiley-VCH Verlag: Weinheim, Germany, 2007; p
219. (f) Zhang, W.; Chi, Y.; Zhang, X. Acc. Chem. Res. 2007, 40, 1278.
(g) Shimizu, H.; Nagasaki, I.; Matsumura, K.; Sayo, N.; Saito, T. Acc. Chem.
Res. 2007, 40, 1385. (h) Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de
Vries, J. G. Acc. Chem. Res. 2007, 40, 1267. (i) Li, Y.-M.; Kwong, F.-Y.;
Yu, W.-Y.; Chan, A. S. C. Coord. Chem. ReV. 2007, 251, 2119.
(2) Zhao, H.; Vandenbossche, C. P.; Koenig, S. G.; Singh, S. P.; Bakale,
R. P. Org. Lett. 2008, 10, 505, and references therein.
(4) (a) Karady, S.; Amato, J. S.; Weinstock, L. M.; Sletzinger, M.
Tetrahedron Lett. 1978, 19, 407. (b) Flynn, D. L.; Zelle, R. E.; Grieco,
P. A. J. Org. Chem. 1983, 48, 2424. (c) Webster, F. X.; Millar, J. G.;
Silverstein, R. M. Tetrahedron Lett. 1986, 27, 4941. (d) Tsunoda, T.; Sasaki,
O.; Takeuchi, O.; Ito, S. Tetrahedron 1991, 47, 3925. (e) Singh, L.; Ram,
R. N. J. Org. Chem. 1994, 59, 710. (f) Evans, D. A.; Carter, P. H.; Dinsmore,
C. J.; Barrow, J. C.; Katz, J. L.; Kung, D. W. Tetrahedron Lett. 1997, 38,
4535. (g) Charette, A. B.; Chua, P. Synlett 1998, 163. (h) Gomez-Reyes,
B.; Yatsimirsky, A. K. Org. Biomol. Chem. 2003, 1, 866. (i) Spaggiari, A.;
Blaszczak, L. C.; Prati, F. Org. Lett. 2004, 6, 3885. (j) Bell, C. M.;
Kissounko, D. A.; Gellman, S. H.; Stahl, S. S. Angew. Chem., Int. Ed. 2007,
46, 761.
10.1021/ol802482d CCC: $40.75
Published on Web 12/12/2008
2009 American Chemical Society

Scheme 1
.
Acetamide Deprotection
Table 1. Screening of Acid Scavenging Reagents
entrya
base
equiv
% amineb
1
2
3
4
5
6
7
8
9
10
2,6-lutidine
EtN(iPr)2
4-Me-morpholine
1-Me-piperidine
4Å MS
NaOAc
NaHCO3
K2CO3
2,6-lutidine
pyridine
3.0
3.0
3.0
3.0
excess
3.0
3.0
3.0
2.0
72
18
23
9
12
<5
<5
6
cleavage of secondary acetamides with no epimerization of
the highly valuable chiral amino centers. The products may
be obtained directly as stable hydrochloride salts or further
derivatized.
94
93
2.0
a All reactions were run with acetamide 2, (COCl)2 (1.3 equiv) and
propylene glycol (3.0 equiv) at 0 °C. They were all conducted in CH2Cl2
with the exception of entries 9 and 10, which were run in THF. b HPLC
area % of amine product relative to other components.
Inspired by the utility of the Vilsmeier-Haack reagent,5
we applied oxalyl chloride to the deprotection of our amide
2.6 While this reagent has been used for further functional-
ization, it has not been exploited for a straightforward
deacetylation method.7 Nonetheless, in the presence of base
at 0 °C, secondary acetamides are activated to imidoyl
chlorides for a subsequent reaction leading to amide bond
cleavage.
Beyond amide activation, the quenching reagent played a
significant role in determining the best overall method (Table
2). Initially, we relied on driving the reaction with an excess
In our initial attempts, we employed an excess of simple
alcohols to quench the imidoyl chloride intermediates.4g,i
However, we eventually settled on propylene glycol, a
nontoxic reagent. Two equivalents of this additive caused
complete collapse of the reactive intermediates to give amine
hydrochlorides. In addition, it appears that this one-pot, two-
step method shows selectivity for secondary acetamides over
tertiary substrates or analogous secondary benzamides.
For selection of the ideal medium, we examined a series
of solvents. Despite the fact that these reactions occur in
biphasic slurries, tetrahydrofuran, ethyl acetate, dichlo-
romethane, and acetonitrile all accomplished the desired
transformation. We chose to proceed with THF for its overall
preferable attributes.
Base is required to prevent decomposition of the imidoyl
chloride intermediate. However, screening showed that
only a select group could be utilized (Table 1). Though
initially used in excess, we discovered that stoichiometric
base was sufficient (vide infra). Pyridine and 2,6-lutidine
worked best (entries 1, 9, and 10). The others, including
aliphatic amines (entries 2-4) and heterogeneous reagents
(entries 5-8), were detrimental to the reaction. Presum-
ably, the pyridine-type reagents provided the appropriate
basicity.
Table 2. Screening of Quenching Agents
entrya
quench
equiv
% amineb
1
2
3
4
5
6
7
8
EtOH
excess
excess
excess
3.0
6.0
6.0
24
23
38
35
67
72
91
75
1.25 M HCl in MeOH
25 wt % NaOMe in MeOH
iBuOH
ethylene glycol
propylene glycol
propylene glycol
1,3-propanediol
2.0
3.0
a All reactions run with acetamide 2, (COCl)2 (1.3 equiv), and 2,6-
lutidine (3.0 equiv) at 0 °C except for entry 2 ((COCl)2 (1.1 equiv)) and
entries 7 and 8 (pyridine (2.0 equiv)). The reactions were all conducted in
CH2Cl2 with the exception of entries 7 and 8, which were run in THF.
b HPLC area % of amine product relative to other components.
of conventional alcohols (entry 1). Because our substrate
showed difficulty in releasing the desired amine product from
the intermediate, we explored alternative conditions. Treating
the reactions with acid (entry 2) or base (entry 3) only
accelerated decomposition pathways. However, a previous
report employed iso-butyl alcohol (entry 4) or ethylene glycol
(entry 5) for difficult substrates.4i In our case, the latter
worked better, revealing accelerated collapse of the inter-
mediate on prolonged agitation.
(5) Tasneem, Synlett 2003, 138–139.
(6) We chose oxalyl chloride for ease of handling but also screened
alternative agents to effect a similar reaction. Of these, triphosgene and
phosphorus pentachloride provided positive data points, while thionyl
chloride and phosphoryl chloride did not. For a related reference, see:
Chauvette, R. R.; Pennington, P. A.; Ryan, C. W.; Cooper, R. D. G.; Jose´,
F. L.; Wright, I. G.; Van Heyningen, E. M.; Huffman, G. W. J. Org. Chem.
1971, 36, 1259.
Because of the toxicity concerns of ethylene glycol, we
also investigated propylene glycol, a commonly used food
additive. Interestingly, this diol provided a more dramatic
accelerating effect, requiring only warming of the reaction
to room temperature (Table 2, entries 6 and 7). Instead of a
large excess of diol, 2 equiv was sufficient to drive the
reaction to completion and allow direct isolation of the amine
salt product. This final modification enabled the quick yet
mild acetamide deprotection we desired.
(7) (COCl)2 has been used to form other adducts with amides. For related
references, see: (a) Sheehan, J. C.; Corey, E. J. J. Am. Chem. Soc. 1952,
74, 360. (b) Speziale, A. J.; Smith, L. R. J. Org. Chem. 1963, 28, 1805. (c)
Shiozaki, M.; Ishida, N.; Iino, K.; Hiraoka, K. Tetrahedron 1980, 36, 2735.
(d) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4, 3127. (e) Lindstro¨m,
J.; Johansson, M. H. Synth. Commun. 2006, 36, 2217.
434
Org. Lett., Vol. 11, No. 2, 2009

The alcohol quenching process is also operative in the
triflic anhydride-mediated amide cleavage methodology
developed by Charette et al.4g With the imidoyl triflates,
however, cryogenic conditions are necessary and an excess
of base is recommended. With (COCl)2, cooling to 0 °C with
stoichiometric base is adequate. In addition, whereas the Tf2O
methodology has been demonstrated to deprotect a multitude
of amides, it is surprisingly not applicable to all substrates,
and in our case, this sequence led to an undesired product.8
Table 3 demonstrates that a variety of chiral benzylic
substrates could be deprotected using this methodology,
without epimerization. Our desired product (1, from aceta-
Table 4. Deprotection of Nonbenzylic Acetamidesa
Table 3. Deprotection of Benzylic Acetamidesa
a Unoptimized yields. Conditions: (a) (COCl)2 (1.1 equiv), pyridine (1.2
equiv), THF, 0 °C; (b) propylene glycol (2.0 equiv), warm to rt. b Yields
refer to isolated products. A: amine hydrochloride salt; B: phthalimide
derivative; and C: Cbz-derivative.
Secondary benzamides and tertiary acetamides, including
N-benzylbenzamide, N-phenethylbenzamide, (S)-N-(1-phe-
nylethyl)benzamide, and N,N-dibenzyl-acetamide were sur-
prisingly not susceptible to the described conditions and were
recovered from the reaction mixture. In order to confirm this
selectivity, competition experiments were run with 1 equiv
each of reactive secondary acetamide 3 and the unreactive
substrate present in the same reaction (Schemes 2 and 3).
a Unoptimized yields. Conditions: (a) (COCl)2 (1.1 equiv), pyridine (1.2
equiv), THF, 0 °C; (b) propylene glycol (2.0 equiv), warm to rt. b Yields
refer to isolated products; A ) amine hydrochloride salt, and B )
phthalimide derivative. c Ar ) 3,4-dichlorophenyl.
Scheme 2. Secondary Benzamide versus Secondary Acetamide
mide 2, entry 1) could be readily isolated from the reaction
mixture as the HCl salt due to low solubility in the reaction
medium.9 However, since the solubilities of amine hydro-
chloride salts vary considerably, most amine products were
further converted to phthalimide derivatives for ease of
isolation.
Table 4 exhibits that other substrates could also be
successfully converted to the desired products. An aniline-
type acetamide reacted favorably under these conditions
(entry 5). Likewise, a protected amino acid was transformed
successfully without detectable epimerization (entry 6). The
product was derivatized as the benzyl carbamate for ease of
isolation. This particular example illustrates that syntheses
of unnatural amino acids could benefit tremendously from
this methodology.10
In both cases, the unreacted amide substrate (4 and 6,
respectively) could be extracted from the crude residue, while
the deprotected component, benzyl amine, could be carried
forward. This subtle specificity for secondary acetamides
(10) (a) Au-Yeung, T. T.-L.; Chan, S.-S.; Chan, A. S. C. Transition
Metals for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-
VCH Verlag: Weinheim, Germany, 2004; Vol 2, p 14. (b) Ager, D. J.;
Laneman, S. A. Asymmetric Catalysis on Industrial Scale: Challenges,
Approaches and Solutions, 1st ed.; Blaser, H.-U., Schmidt, E., Eds.; Wiley-
VCH Verlag: Weinheim, Germany, 2004; Chapter III, p 259.
(8) This material was not further characterized.
(9) Acetamide 2 was run successfully at 40 kg scale.
Org. Lett., Vol. 11, No. 2, 2009
435

dissimilar solubility profiles have a pronounced effect in the
quenching phase of this slurry-based system.12 After the
quench, the additional methyl substituent of propylene glycol
may contribute to an accelerated collapse of the intermediate
imidoyl ester 9 by encouraging intramolecular attack of the
second hydroxyl group. While simpler substrates can take
advantage of this accelerated cleavage, they would also be
likely to react with methanol or ethanol.
Scheme 3. Tertiary Acetamide versus Secondary Acetamide
Most significant for this methodology from a safety
standpoint is the rapid gas evolution upon initial reaction of
(COCl)2.13 The exothermic process is readily handled on
laboratory scale and is well-tolerated on scale-up with
appropriate precautions. In addition, the evolution of CO is
accompanied by 1 equiv of CO2, diluting the gaseous
byproduct stream. The base traps the HCl in solution until
the primary amine is liberated at the end of the reaction cycle.
Lastly, the imidoyl chloride intermediate calls for anhydrous
conditions in order to prevent reversion to starting material.
In conclusion, we have developed a facile deprotection
of secondary acetamides. The mild conditions enable a
selective transformation with no epimerization of the prized
amino center and isolation of the amine in hydrochloride
salt form. This practical methodology should further encour-
age the use of catalytic asymmetric hydrogenation approaches
to access chiral amines.
should prove useful in the deprotection of differentially
protected amines. In addition, it further demonstrates the mild
nature of the conditions described in this communication.
With regard to reaction progression, it is well-known that
in the presence of base, (COCl)2 reacts with amide 7 to form
imidoyl chloride 8 by loss of carbon monoxide and carbon
dioxide (Scheme 4).7d Previously, similar species have been
Scheme 4. Proposed Reaction Progression
Acknowledgment. We thank Sepracor colleagues Drs.
Tom Wagler and John Dankwardt for support, as well as
Dr. Hal Butler and Ms. Denise Thompson for providing
analytical assistance.
Supporting Information Available: Experimental details,
1H and 13C NMR spectra, and chiral assays for pertinent
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL802482D
(11) (a) Schmir, G. L.; Cunningham, B. A. J. Am. Chem. Soc. 1965,
87, 5692. (b) Pletcher, T. C.; Koehler, S.; Cordes, E. H. J. Am. Chem. Soc.
1968, 90, 7072. (c) Okuyama, T.; Sahn, D. J.; Schmir, G. L. J. Am. Chem.
Soc. 1973, 95, 2345. (d) Deslongchamps, P.; Dube, S.; Lebreux, C.;
Patterson, D. R.; Taillefer, R. J. Can. J. Chem. 1975, 53, 2791. (e)
Deslongchamps, P.; Taillefer, R. J. Can. J. Chem. 1975, 53, 3029. (f) Perrin,
C. L. Acc. Chem. Res. 2002, 35, 28.
quenched with simple alcohols to effect conversion to
imidoyl esters, followed by the eventual release of carboxylic
ester and amine salt.4g,i With propylene glycol, we believe
that a similar process occurs to yield 9, requiring only
warming to room temperature to release the desired amine
hydrochloride salt 10.11
(12) The Merck Index: An Encyclopedia of Chemicals, Drugs, and
Biologicals, 11th ed.; Budavari, S., O’Neal, M. J., Smith, A., Heckelman,
P. E., Eds.; Merck & Co.: Rahway, NJ, 1989; entries 3755 and 7868.
(13) Bretherick, L. Chem. Health Saf. 2003, 10 (4), 47.
On the basis of the observed difference in cleavage rates
between ethylene and propylene glycol, we surmise that their
436
Org. Lett., Vol. 11, No. 2, 2009