Favorskii-like rearrangement of an aliphatic α-halo amide

Article abstract of DOI:10.1080/00397911.2011.629357

The reaction of the α-bromoamide 2a with 1-cyclopentylpiperazine gives the Favorskii-like rearranged product 4 when the reaction is heated to 70 °C in a mixture of aqueous potassium hydroxide and ethanol. However, when solid sodium carbonate/potassium iodide is used in ethanol, the nonrearranged product 3a is formed instead. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2011.629357

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Favorskii-Like Rearrangement of an
Aliphatic α-Halo Amide
Nicholas M. Kelly a , Anja Wellejus a , Heidi Elbrønd-Bek a , Morten
Sloth Weidner a & Signe Humle Jørgensen a
a Nensius Research A/S, Copenhagen, Denmark
Accepted author version posted online: 14 Mar 2012.Version of
record first published: 21 Feb 2013.
To cite this article: Nicholas M. Kelly , Anja Wellejus , Heidi Elbrønd-Bek , Morten Sloth Weidner &
Signe Humle Jørgensen (2013): Favorskii-Like Rearrangement of an Aliphatic α-Halo Amide, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:9, 1243-1249
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Synthetic Communications1, 43: 1243–1249, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.629357
FAVORSKII-LIKE REARRANGEMENT OF AN ALIPHATIC
a-HALO AMIDE
Nicholas M. Kelly, Anja Wellejus, Heidi Elbrønd-Bek,
Morten Sloth Weidner, and Signe Humle Jørgensen
Nensius Research A=S, Copenhagen, Denmark
GRAPHICAL ABSTRACT
Abstract The reaction of the a-bromoamide 2a with 1-cyclopentylpiperazine gives the
Favorskii-like rearranged product 4 when the reaction is heated to 70 ꢀC in a mixture of
aqueous potassium hydroxide and ethanol. However, when solid sodium carbonate=
potassium iodide is used in ethanol, the nonrearranged product 3a is formed instead.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Amino amide; a-bromoamide; Favorskii-like rearrangement; neuroprotective;
neurotrophic
INTRODUCTION
Esaprazole, a compound initially designed as an antiulcer drug,[1] also shows
interesting neuroprotective and neurotrophic properties.[2] Compounds having these
properties may be beneficial to patients suffering from cerebral ischemia or from
neurodegenerative diseases such as Alzheimer’s disease or multiple sclerosis. In an
Received September 18, 2011.
Address correspondence to Nicholas M. Kelly, Nensius Research A=S, Symbion Science Park,
Fruebjergvej 3, DK-2100 Copenhagen, Denmark. E-mail: nk.nensius@gmail.com
1243

1244
N. M. KELLY ET AL.
attempt to explore the structure–activity space around esaprazole, a range of mod-
ifications were made to the core structure.[3] However, during the preparation of
the esaprazole analogs, it became clear from the analytical data that one analog
was structurally different from the other molecules. Because the biological activity
of this analog was very interesting,[4] we aimed at identifying the chemical structure
of this unexpected compound and at preparing the initially desired compound.
RESULTS
Reaction of bromoacylbromide 1a with cyclohexylamine gave the pure amide
2a in 94% yield (Scheme 1). Amide 2a was then reacted with 1-cyclopentylpiperazine
in a mixture of aqueous sodium carbonate and ethanol at reflux. Although the vast
majority of amide 2a was converted into N-cyclohexylmethacrylamide 5 by elimin-
ation of HBr, as determined by high-performance liquid chromatography (HPLC),
a small amount of another material was recovered that was not the expected com-
pound 3a. Compounds 1 to 4 have poor uv absorbance compared to compound 5
and so care has to be taken when determining the amount of product from in process
samples and the crude product by uv detection at 220 nm. Re-examination of the in
process HPLC gave a ratio of 10:90 for compounds 3a and 4, taking into account
that the uv profile of compound 4 is about 2.5 times stronger than that of compound
3a. However, re-examination of the crude HPLC did not show any 3a. The 1H NMR
of this compound showed signals consistent with the expected cyclohexyl, cyclopen-
tyl, and dimethyl groups, but the piperazine signals were an unexpectedly broad peak
over 1 ppm wide. Liquid chromatography–mass spectrometry (LC=MS) analysis of
the compound gave the correct molecular mass, but the compound eluted ca.
2.5 min earlier than the structurally very similar analogs 3b and 3c, which were
prepared in good yield using the same reaction conditions.[3,5]
Scheme 1. Synthesis of amino amides 3b and 3c.

FAVORSKII-LIKE REARRANGEMENT
1245
It was hypothesized that the compound had undergone a Favorskii-like
1
rearrangement to give compound 4. Structure 4 would fit with the H NMR data
and 4 would also be expected to elute off the HPLC column earlier than 3a because
the two protonatable nitrogen atoms are spatially separated in 4.
The reaction conditions were modified with the intention of both preparing the
initially desired compound 3a and improving the yield of the unexpected product 4.
Reacting 2a with aqueous potassium hydroxide in ethanol at 50–70 ꢀC afforded 4 in
20% yield whereas 3a could be prepared using solid potassium iodide and sodium
carbonate in ethanol at reflux in 14% yield (Scheme 2). In both cases, the majority
of starting material 2a was converted into the acrylamide 5. It is interesting to note
that compound 4 was not detected by HPLC in either the reaction mixture or the
crude product when KI=Na2CO3 was used. In addition, only traces of compound
3a were detected by HPLC when using aqueous KOH in ethanol. N-
Cyclohexyl-3-(4-cyclopentylpiperazin-1-yl)-2-methylpropanamide, coming from the
Michael addition of 4-cyclopentylpiprazine with acrylamide 5, was also isolated in
a yield of 3%. The ratio of compounds 3a to 4 was <1:99 when the reaction was
heated to reflux. When the reaction was carried at 75 ꢀC (oil bath temperature),
the ratio of compounds 3a to 4 was 3:97.
The structure of 3a was confirmed by comparing the 1H NMR and HPLC data
of 3a with compounds 3b and 3c. In all three cases, the a-proton of the cyclohexyl
group was found to be 3.66 ꢁ 0.02 ppm. HPLC retention times decreased from
10.50 min to 9.63 min to 8.84 min for compounds 3a, 3b, and 3c respectively, in keeping
with expectations. In addition, LC=MS confirmed that 3a had the correct mass and
also gave a strong peak at 195.2 Da corresponding to the well-stabilized cation 6.[6]
Scheme 2. Synthesis of amino amides 3a and 4.

1246
N. M. KELLY ET AL.
Scheme 3. Alternative route to the synthesis of amino piperazine 4.
In comparison to 3a, the a-proton of the cyclohexyl group for compound 4 was
observed at 2.61 ppm and the HPLC retention time was 7.15 min. Although 4 gave
the same molecular ion as 3a, no peak at 195 Da was detected. Instead, a strong peak
at 140.1 Da, corresponding to the stabilized cation 7 was detected. To confirm the
structure of amino piperazine 4, the compound was prepared using a second, unam-
biguous route (Scheme 3). Reaction of ethyl bromoisobutyrate 8 and cyclohexyla-
mine in methanol in an autoclave at 100 ꢀC gave the transesterified product
methyl 2-(cyclohexylamino)-2-methylpropanoate 9, which underwent hydrolysis
under basic conditions to give the amino acid 10 in 14% yield for the two steps.
Amino acid 10 was then reacted with 1-cyclopentylpiperazine using the peptide
coupling reagent O-(benzotriazol-1-yl)-N,N,N0,N0-tetramethyluronium hexafluoro-
phosphate (HBTU) to give amino piperazine 4 in 38% yield. Analysis of the product
by 1H NMR, HPLC, and LC=MS showed it to be identical to the amino piperazine 4
prepared by the route given in Scheme 2.
DISCUSSION
A search of the literature based around the Favorskii-like rearrangement
revealed only a few references to similar rearrangements of a-halo amides in the pres-
ence of an amine. Sheehan and Lengyel[6] demonstrated in 1964 that treating a-
bromoamides with potassium tert-butoxide in diethyl ether at ꢂ25 ꢀC afforded the
corresponding a-lactam, which could be isolated. The reaction of the a-lactam with
nonionic nucleophiles (e.g., alcohol, amine) at rt resulted in alkyl–nitrogen bond
cleavage whereas using ionic=aprotic nucleophiles (e.g., alkoxide) in diethyl ether
at reflux resulted in an 8:4:1 mixture of dehydrohalogenation–acyl-nitrogen cleavage–
alkyl-nitrogen cleavage.
Both Guziec and Torres[7] and Lai[8] found that the reaction of a-haloisobutyr-
amide in a neat amine with powdered NaOH at 0–5 ꢀC resulted in alkyl-nitrogen
bond cleavage. Scrimin et al.[9] showed that dropwise addition of an a-haloamide
to a primary or secondary amine in NaH=THF at rt or stirring an a-haloamide with

FAVORSKII-LIKE REARRANGEMENT
1247
a primary or secondary amine in NaOH=H2O=DCM=TBAB at rt only resulted in
alkyl-nitrogen bond cleavage whereas no acyl-nitrogen bond cleavage was observed.
However, Sanchez and Parcell[10] have reported that 3-(a-haloacyl)indoles react with
primary amines in methanol at reflux to give the rearranged indole-3-acetamides,
whereas using more sterically hindered amines resulted in dehydrohalogenation fol-
lowed by Michael addition to afford b-amino acids. Du et al.[11] has reported that the
reaction of a ‘‘hard’’ nucleophile, generated from an amine and NaH in tetrahydro-
furan (THF), resulted in the rearranged product via acyl-nitrogen bond cleavage. In
comparison, using a ‘‘soft’’ nucleophile, generated from an amine and aqueous
NaOH in dichloromethane (DCM), resulted in alkyl-nitrogen bond cleavage.
From the literature it is apparent that the reaction of a-haloamides 11 with
protic or ‘‘soft’’ nucleophiles forms nonrearranged products 15 (Scheme 4). Below
approximately rt this is probably via alkyl-nitrogen cleavage of the a-lactam inter-
mediate 13.[6] At higher temperatures the a-lactam 13 is unstable and rearranges,
or can be formed directly from the deprotonated amide 12, to zwitterion 14,[8,9] cre-
ating the nonrearranged product 15. This is in keeping with our results where the
reaction of an a-haloamide 11 with KI=Na2CO3 in ethanol at reflux resulted in
the formation of the nonrearranged product 15.
However, aprotic or ‘‘hard’’ nucleophiles do not necessarily result in the for-
mation of the rearranged product 16 via acyl-nitrogen cleavage. The conditions
described by Guziec and Torres,[7] Lai,[8] and Scrimin et al.[9] can all be considered
hard, but only resulted in alkyl-nitrogen cleavage. In comparison, both Sheehan
and Lengyel[6] and Sanchez and Parcell[10] carried out their reactions at elevated tem-
peratures to afford the rearranged product 16 via acyl-nitrogen cleavage. We found
that using a hard nucleophile at elevated temperatures (50–70 ꢀC) also afforded the
rearranged product 16, which would indicate that higher temperatures are required
for this rearrangement to take place. Therefore while preferably preparing the
rearranged product 16 over the nonrearranged product 15 is possible, it will be dif-
ficult to avoid the formation of acrylamides such as 5 via the competing elimination
reaction.
Scheme 4. Proposed mechanism for the formation of 15 and 16.

1248
N. M. KELLY ET AL.
CONCLUSION
In conclusion, we have shown that the reaction of 2-bromo-N-cyclohexyl-2-
methylpropanamide 2a with 1-cyclopentylpiperazine in the presence of solid potassium
iodide and sodium carbonate in ethanol at reflux afforded 1-(cyclohexylamino)-2-
(4-cyclopentylpiperazin-1-yl)-2-methylpropan-1-one 3a. However, changing the reac-
tion conditions to aqueous potassium hydroxide in ethanol at 50–70 ꢀC resulted in the
preparation of 2-(cyclohexylamino)-1-(4-cyclopentylpiperazin-1-yl)-2-methylpropan-1-
one 4 via a Favorskii-like rearrangement. The structure of compound 4 was proved
using an unambiguous route.
EXPERIMENTAL
Synthesis of 1-(Cyclohexylamino)-2-(4-cyclopentylpiperazin-1-yl)-2-
methylpropan-1-one (3a)
1-Cyclopentylpiperazine (40 mmol, 6.17 g) in ethanol (40 mL) was added to 2a
(40 mmol, 9.93 g), potassium iodide (44 mmol, 7.3 g), and sodium carbonate
(80 mmol, 8.48 g) in ethanol (40 mL). The reaction was heated to reflux for 2 days,
then HCl (1.2 M, 50 mL) was added, and the pH was adjusted to pH 1–2 using con-
centrated HCl (10 mL). The aqueous phase was washed with DCM (50 mL), and
then KOH was added so the pH was >9. NaCl (15 g) was added and the product
was extracted with DCM (3 ꢃ 50 mL), dried over MgSO4, filtered, and concentrated
to give an orange oil. The crude material was purified using the Combiflash using a
80-g silica column eluting 0% buffer B for 2 min, then 0–100% buffer B over 21 min,
1
and 100% buffer B for 9 min to give 3a (1.78 g, 14%) as a colorless oil; H NMR
(CD3OD) d 3.64 (m, 1H), 2.96ꢂ2.17 (m, 9H), 1.91 (m, 2H), 1.86ꢂ1.51 (m, 3H),
1.86ꢂ1.51 (m, 6H), 1.50ꢂ1.21 (m, 2H), 1.50ꢂ1.21 (m, 5H), 1.18 (s, 6H); HPLC Rt
10.47 min (98.8% pure); LC=MS-ESI (m=z): [M þ H]þ 322.3, [C5H11-
piperazin-C(Me)2]þ 195.2; HRMS (TOF ESþ, m=z): calc. for C19H36N3O [M þ H]þ
322.2858; found 322.2845.
Synthesis of 2-(Cyclohexylamino)-1-(4-cyclopentylpiperazin-1-yl)-2-
methylpropan-1-one (4)
1-Cyclopentylpiperazine (50 mmol, 7.73 g) was added to 2a (150 mmol, 13.67 g)
in ethanol (100 mL). Aqueous potassium hydroxide (2 M, 75 mL) was added, and the
reaction was heated to 70 ꢀC for 18 h. The reaction was cooled to room temperature,
aqueous hydrochloric acid (3 M, 60 mL) was added, and the aqueous phase was
washed with dichloromethane (2 ꢃ 25 mL). The organic phase was extracted with
aqueous hydrochloric acid (1.2 M, 25 mL) and the aqueous phases were combined.
Potassium hydroxide (14 g) was added, and the product was extracted with dichlor-
omethane (3 ꢃ 50 mL). The organic layer was washed with brine (25 mL), dried over
magnesium sulfate, filtered, and concentrated. The crude material purified on the
Combiflash using a 120-g silica column running at 85 mL=min, eluting 0% buffer
B for 3 min, then 0–30% buffer B over 24 min, and 30% buffer B for 1 min to give
1
4 (3.16 g, 20%) as a white powder; H NMR (CD3OD) d 3.96 (very br. s, 4H),
2.61 (m, 1H), 2.53 (m, 5H), 1.92 (m, 2H), 1.71 (m, 6H), 1.59 (m, 3H), 1.43 (m,

FAVORSKII-LIKE REARRANGEMENT
1249
2H), 1.35 (s, 6H), 1.16 (m, 5H); HPLC Rt 7.15 min (98.8% pure); LC=MS-ESI (m=z):
[M þ H]þ 322.2, [C6H11NHC(Me)2]þ 140.1; HRMS (TOF ESþ, m=z): calc. for
C19H36N3O [M þ H]þ 322.2858; found 322.2876.
Additional details are available online in the Supplementary Information.
ACKNOWLEDGMENTS
The authors thank Andrew Norbury and Mark Ruston at Peakdale Molecular
for preparing compound 4 via the route in Scheme 3; Anette Andersen at the Depart-
ment of Chemistry, Copenhagen University, for running the HRMS; Brian Kreiser
at Niels Clauson-Kaas A=S for running the LC=MS; and Knud J. Jensen at Faculty
of Life Sciences, Copenhagen University, for helpful discussions.
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