Conversion of a ketone to a geminal bisacetamide: Synthesis of 1,1-bisacetamidocyclohexane

Article abstract of DOI:10.1081/SCC-120021988

The synthesis of the title compound (6) is described. A key step in the novel sequence is the Hofmann rearrangement of an α,α-dialkyl-α-aminocarboxamide mediated by hypervalent iodine reagent.

Full text of DOI:10.1081/SCC-120021988

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Conversion of a Ketone to a Geminal Bisacetamide:
Synthesis of 1,1-Bisacetamidocyclohexane
Matthew C. Davis a , Daniel Stasko a & Robert D. Chapman a
a Research Department (Code 4T4200D), Naval Air Warfare Center Weapons Division, China
Lake, California, USA
Version of record first published: 17 Aug 2006.
To cite this article: Matthew C. Davis , Daniel Stasko & Robert D. Chapman (2003): Conversion of a Ketone to a Geminal
Bisacetamide: Synthesis of 1,1-Bisacetamidocyclohexane, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:15, 2677-2684
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 15, pp. 2677–2684, 2003
Conversion of a Ketone to a Geminal
Bisacetamide: Synthesis of
1,1-Bisacetamidocyclohexane
Matthew C. Davis,# Daniel Stasko,# and
*
Robert D. Chapman
Research Department (Code 4T4200D),
Naval Air Warfare Center WeaponsDivision,
China Lake, California, USA
ABSTRACT
The synthesis of the title compound (6 ) is described. A key step in the
novel sequence is the Hofmann rearrangement of an a,a-dialkyl-a-
aminocarboxamide mediated by hypervalent iodine reagent.
Key Words: Bisamide; Aminal; Ketoaminal.
#ASEE/ONR Postdoctoral Research Associate.
*Correspondence: Robert D. Chapman, Research Department (Code 4T4200D),
Naval Air Warfare Center WeaponsDiviison, China Lake, California 93555,
USA; Fax: (þ1) 760-939-1617; E-mail: robert.chapman@navy.mil.
2677
DOI: 10.1081/SCC-120021988
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2678
Davis, Stasko, and Chapman
Aspart of a research project concerning alternative methodsfor the
preparation of certain gem-bis(difluoramino)alkane derivatives,[1] we
required a route to gem-bisacetamides. Although aldehydes will condense
with carboxamides to furnish the corresponding aldoaminals,[2–4]
protected ketoaminalsderived from ketonesare not well known. One
example was a bisacetamide made by the Ritter reaction on a specific
bicyclic ketone, 5,5,6-trimethylbicyclo[2.2.1]heptan-2-one,[5a] a reaction
which has not proven to be general for simpler ketones, e.g., cyclo-
hexanone.[5b] Other ketoaminalswere prepared by Lewisacid-mediated
[6]
reactionsof acetalswith carboxamides
or carbamates.[7] A method of
preparing N-acylaldoaminalsby Hofmann rearrangement of a-amino-
1
carboxamides(Sch. 1; R ¼ R2 ¼ H) or a-alkyl-a-aminocarboxamides
(Sch. 1; R1 ¼ alkyl, R2 ¼ H) appeared useful.[8,9] We believed that
a,a-dialkyl-a-aminocarboxamidhesosuld react with hypervalent
iodine similarly (Sch. 1; R1, R2 ¼ alkyl), yielding N-acylketoaminals.
The latter could then be acylated conventionally to give desired gem-
bisacylamides.
We chose cyclohexanone as a model for this overall sequence (Sch. 2).
The amino nitrile 1 was furnished by using a modification of the Strecker
reaction.[10] Without presaturation with ammonia, the major product
isolated was cyclohexanone cyanohydrin.[11] In contrast to a previous
report,[12] nitrile hydration using conc. H2SO4 gave only moderate
yieldsof the a-aminocarboxamide (2). Employing a biphasic mixture of
[13]
conc. H2SO4 and CH2Cl2 improved the yieldsof thisstep dramatically.
Then acylation with acetyl chloride in the presence of triethylamine
furnished the precursor (4) for the Hofmann rearrangement. An equally
effective route to 4 wasby the short-duration, low-temperature hydration
of 3. Oxidative rearrangement of 4 with [bis(trifluoroacetoxy)iodo]-
benzene[14] gave a good yield of a-acetamidocyclohexylamine hydro-
chloride (5). Although we had difficulty purifying the material
completely, a second acylation of 5 furnished the gem-bisacetamide (6)
Scheme 1.

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Geminal Bisacetamide
2679
Scheme 2.
Figure 1.
in moderate yield. The latter was crystallized, and the structure was
solved by X-ray diffraction (see Fig. 1).
The gem-bisacetamide (6) crystallizes in a triclinic crystal system with
a P1 space group.[15] The structure was found to contain two molecules in
the asymmetric unit with the four geminal nitrogen-carbon distances
averaging 1.46 A. The conformationsof these two moleculesare for all
purposes identical with respect to overall geometry (Fig. 1a), though they
differ in intramolecular hydrogen bonding. Both amide functionalitiesof

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2680
Davis, Stasko, and Chapman
the bisamide engage in hydrogen bonding through the carbonyl and a
separate amide hydrogen (ꢀ2.05 A O–H distances), one molecule forming
a distributed hydrogen bonding network, while the other’s hydrogen
bonding motif can be described as cooperative: multiple hydrogen
bonds between the same set of bonding partners (Fig. 1b).
In summary, a method for the synthesis of the new gem-bisacetamide
6 isreported. To our knowledge, thisisthe firts demontsration of the
Hofmann rearrangement of an a,a-dialkyl-a-aminocarboxamide
mediated by hypervalent iodine. Thisreaction, and the ease with which
the latter intermediates can be prepared, suggests that a wide range of
gem-bisacylamides should be accessible ketoaminals. For example,
Viennoishasreported a different, poisbsly general method for the
preparation of other a,a-disubstituted a-acylaminocarboxamides,[16]
such as the cyclopentylidene homologue of 4.
EXPERIMENTAL
Reagentswere commercially available and ueds asreceived.
Multinuclear NMR spectra were obtained on a Bruker AC-200 spectrom-
eter (200 MHz 1H) and referenced to solvent or tetramethylsilane.
Purified water (18 Mꢀ) was obtained with a Milli-Q system from
Millipore (Bedford, MA). Microanalysis was performed by Galbraith
Laboratories(Knoxville, TN). Crystalsof 6 suitable for X-ray diffraction
were obtained by direct crystallization from saturated acetonitrile
solutions, with the data set being collected at 298K using a Siemens P3
single-crystal X-ray diffractometer. The resulting structure was solved
and refined using the Bruker SHELXTL software suite (ver. 6.10).
1-Aminocyclohexanecarbonitrile, 1. Ammonia wasbubbled for 1 h
through a solution of 50 g (0.51 mol) cyclohexanone in 200 mL MeOH
cooled to 0ꢁC. Afterwards, the solution was poured into a mixture of
powdered KCN (44 g, 0.68 mol) and NH4Cl (62 g, 1.17 mol) in 500 mL
28% aqueousNH . The mixture was stoppered and mechanically stirred
3
at room temperature for 18 h. The mixture wasfiltered of oslidsand
extracted with CH2Cl2 (4 Â 250 mL). The extractswere collected, dried
(MgSO4), and evaporated to a pale yellow liquid. The liquid was
vacuum-distilled (0.05 torr) to furnish 1 as a colorless liquid that crys-
tallizesnear 0 ꢁC; yield 59.8 g (93%). NMR ꢀH (CDCl3) 2.05–1.95 (m, 2H),
1.9–1.35 (m, 9H), 1.3–1.1 (m, 1H); ꢀC (CDCl3) 124.16, 51.36, 37.88,
24.55, 22.52.
1-Aminocyclohexanecarboxamide, 2. To 10 g conc. H2SO4 stirred in
an ice-cooled water bath was added dropwise a solution of 5.1 g

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Geminal Bisacetamide
2681
(41 mmol) of 1 in 30 mL CH2Cl2, maintaining the internal temperature at
15ꢁC. Then the bath wasremoved and the mixture heated to 40 ꢁC for 1 h.
The mixture wascooled in an ice bath and poured onto 200 mL crushed
ice. The mixture wasmade pH 7–8 with 28% aqueousNH 3 and extracted
with EtOAc (3 Â ꢀ100 mL). The extractswere collected, dried (MgSO ),
4
and evaporated to a white crystalline solid (4.7 g, 80%) that was not
further purified; m.p. 94–95ꢁC, lit. 101–102ꢁC.[12] NMR ꢀH (CDCl3)
7.56 (bs, 1H), 6.19 (bs, 1H), 2.1–1.8 (m, 2H), 1.75–1.6 (m, 3H),
1.5–1.15 (m, 9H); ꢀC (CDCl3) 181.73, 57.34, 34.77, 25.36, 21.34.
1-Acetamidocyclohexanecarbonitrile, 3. To a stirred solution of 38 g 1
(0.31 mol) and 37.1 g triethylamine (0.367 mol) in 500 mL Et2O cooled in
an ice bath wasadded dropwies acetyl chloride (26.6 g, 0.337 mol) by
addition funnel. The bath wasthen removed and the reaction stirred at
RT for 3 h. The mixture wasfiltered through a fritted-glassfunnel
(medium porosity), and the Et2O was discarded. Using a second filter
flask, the filter cake was washed 4 times with EtOAc, leaving triethyl-
amine hydrochloride on the frit. The EtOAc extractswere collected
and evaporated to 38 g (74% crude yield) of 3 asa white solid that did
not require purification for subsequent reactions; m.p. 75–85ꢁC
(EtOAc–hexanes), lit. 91ꢁC.[17] NMR ꢀH (CDCl3) 6.52 (bs, 1H),
2.38–2.25 (m, 2H), 2.02 (s, 3H), 1.75–1.55 (m, 7H), 1.35–1.15 (m, 1H);
ꢀC (CDCl3) 170.01, 120.08, 51.75, 35.41, 24.87, 23.40, 22.22.
1-Acetamidocyclohexanecarboxamide, 4. To a mixture of 8.1 g
2 (57 mmol) and 11.52 g triethylamine (114 mmol) in 250 mL CH2Cl2
cooled in an ice bath wasadded dropweis acetyl chloride
(4.4 g, 57 mmol). The mixture wasthen stirred at room temperature for
6 h. The precipitate wasfiltered and recrystallized from MeCN to afford
4, 8.23 g (78%), sufficiently pure for subsequent reactions; m.p.
168–170ꢁC, lit. 181ꢁC.[16] NMR ꢀH (DMSO-d6) 7.5 (s, 1H), 6.91
(bs, 1H), 6.69 (bs, 1H), 2.0–1.89 (m, 2H), 1.86 (s, 3H), 1.65–1.05
(m, 8H); ꢀC (DMSO-d6) 176.76, 169.41, 58.85, 31.59, 25.15, 23.27, 21.09.
Alternative procedure for 4. A 0ꢁC solution of 7.6 g 3 (46 mmol) in
30 mL CH2Cl2 was transferred dropwise via pipet over 15 min into 36 mL
conc. H2SO4 vigorously stirred at 0ꢁC. After another 5 min, the reaction
waspoured onto 200 mL crushed ice. The mixture wasthen neutralized
with 28% aqueousNH ; halfway through addition, the crude product
3
precipitated. It wasfiltered, usction-dried, and recrytasllized from
MeCN (6 g, 81%). NMR spectra were identical to those from the
above preparation.
1-Acetamidocyclohexylamine hydrochloride, 5. To a solution of 1 g
(5.9 mmol) of 4 in a mixture of 12 mL MeCN and 12 mL H2O was
added 2.64 g (5.9 mmol) [bis(trifluoroacetoxy)iodo]benzene. The mixture

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2682
Davis, Stasko, and Chapman
wasstirred at RT for 1 h. Then 1.45 mL of conc. HCl wasadded, and the
mixture wasextracted with toluene. The aqueousphaes wasrotary-
evaporated (35ꢁC) under vacuum (1 torr). The remaining solid was
triturated with Et2O–EtOH to furnish 950 mg (83%) of 5. NMR
ꢀH (D2O) 2.4 (d, J ¼ 12 Hz, 2H), 2.1 (s, 3H), 1.9–1.3 (m, 8H); ꢀC
(DMSO-d6) 171.67, 67.49, 32.61, 24.15, 23.13, 21.05.
1,1-Bisacetamidocyclohexane, 6. To a mixture of 2.16 g (11.3 mmol)
of 5 in 100 mL CH2Cl2 wasadded triethylamine (3.4 g, 33.8 mmol), and
the mixture wascooled in an ice bath. Acetyl chloride (1.2 mL, 17 mmol)
wasthen added dropwies and the reaction wastsirred overnight at
RT. The reaction waspartitioned between CH Cl2 and H2O, and the
2
organic phase was separated, dried (MgSO4), and evaporated to a
solid. Recrystallization (EtOH–MeCN) afforded 6 aswhite crytsals
(1.3 g, 60%); m.p. 180ꢁC. NMR ꢀH (DMSO-d6) 7.77 (s, 2H), 2.1–1.95
(m, 4H), 1.75 (s, 6H), 1.45–1.2 (m, 6H); ꢀC (DMSO-d6) 168.77, 66.79,
33.87, 24.97, 23.43, 21.62. Elemental analysis calcd. for C10H18N2O2:
C, 60.58; H, 9.15; N, 14.13. Found: C, 60.37; H, 9.19; N, 14.07.
ACKNOWLEDGMENTS
Financial support, managed by Dr. Judah Goldwasser, of the Office
of Naval Research is gratefully acknowledged. MCD and DJS thank the
American Society for Engineering Education (Washington, DC) for their
research fellowship program.
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3. Zhu, S.; Xu, G.; Chu, Q.; Xu, Y.; Qui, C. Synthesis of fluorine-
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4. Herrera Fernandez, A.; Martınez Alvarez, R.; MoralesAbajo, T.
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Geminal Bisacetamide
2683
5. (a) Kozlov, N.G.; Popova, L.A.; Biba, V.I.; Potkina, T.N.;
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11. Postel, D.; Nhien, A.N.V.; Pillon, M.; Villa, P.; Ronco, G.
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12. Los, M. Method of Preparing Imidazoisoindolediones. US Patent
4,125,727, November 14, 1978.
13. Boesten, W.H.J.; Seerden, J.-P.G.; Lange, B.; Dielemans, H.J.A.;
Eisenberg, H.L.M.; Kapstein, B.; Moody, H.M.; Kellogg, R.M.;
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acetate). In Encyclopedia of Reagents for Organic Synthesis;
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15. Structural summary: Triclinic, P1, a ¼ 8.4228(17) A, b ¼ 10.253(2) A,
c ¼ 13.506(3) A, a ¼ 90.92(3)ꢁ, b ¼ 106.18(3)ꢁ, g ¼ 99.19(3)ꢁ,
density ¼ 1.193 g/cm3, R1 ¼ 0.0462 for 3800 Fo>4ꢁ(Fo) and 0.0665
for all 5086 data with 276 parameters. The structure was refined as

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2684
Davis, Stasko, and Chapman
full-matrix least-squares on F2 with a goodness-of-fit on F2 of 1.021.
A copy of the crystallographic data has been archived with the
Cambridge Crystallographic Data Centre under the reference code
189955.
16. Viennois, P. New Derivatives of Esters of N-Substituted alpha-
Amino Acids. US Patent 3,513,187, May 19, 1970.
17. Granger, R.; Orzalesi, H.; Robbe, Y. Radioprotective agents.
I. Diaminesand apparent derivativesof phencyclidine. Trav. Soc.
Pharm. Montpellier 1965, 24, 244–255.
Received in the USA December 11, 2002