Synthesis of substituted 2-amino-cyclobutanones

Article abstract of DOI:10.1080/00397910801981110

A series of weakly nucleophilic nitrogen derivatives including carbamates, amides, sulfonamides, and anilines were reacted with 1,2-bis(trimethylsilyloxy) cyclobutene under acidic conditions to afford various substituted 2-aminocyclobutanone derivatives 3a-i in modest to excellent yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910801981110

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Synthesis of Substituted
2‐Amino‐cyclobutanones
Nicola Armoush a , Preeti Syal a & Daniel P. Becker a
a Loyola University Chicago, Chicago, Illinois, USA
Version of record first published: 09 May 2008.
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2‐Amino‐cyclobutanones, Synthetic Communications: An International Journal for Rapid Communication of
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Synthetic Communicationsw, 38: 1679–1687, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801981110
Synthesis of Substituted 2-Amino-
cyclobutanones
Nicola Armoush, Preeti Syal, and Daniel P. Becker
Loyola University Chicago, Chicago, Illinois, USA
Abstract: A series of weakly nucleophilic nitrogen derivatives including carbamates,
amides, sulfonamides, and anilines were reacted with 1,2-bis(trimethylsilyloxy)cyclo-
butene under acidic conditions to afford various substituted 2-aminocyclobutanone
derivatives 3a–i in modest to excellent yields.
Keywords: 2-Aminocyclobutanone, cyclobutanone, cyclobutene
Cyclobutanones are important molecules both as synthetic targets and as
synthetic intermediates with unique and useful applications.[1,2] Several
natural products contain a cyclobutanone moiety, including the diterpenes
acetylcoriacenone and isoacetylcoriacenone, isolated from the brown sea
algae Pachydictyon coriaceum; the monoterpene (1S,5S)-filifolone from the
Arizona sand sage Artemisia filifolia; (1R,5R)-filifolone from the Australian
sandfly bush Ziera smithii; and chrysanthenone from the flowers of Chry-
santhemum sinese.[3] The four-membered ring endows cyclobutanones with
a degree of conformational rigidity, and the strain inherent in the ring
makes the ketone carbonyl more electrophilic than an unstrained ketone.
Cyclobutanones have been reported to exhibit enzyme inhibitory activity
toward beta-lactamase[4] and the serine protease, elastase.[5] Fairlie et al.
have shown that protease inhibitors recognize substrate segments in the
beta-sheet conformation,[6,7] and Burgess et al. have demonstrated that cis-
1,3-disubstituted cyclobutane amino acid derivatives adopt an extended,
beta-sheet conformation,[8] which suggests that more highly functionalized
Received in the USA December 13, 2007
Address correspondence to Daniel P. Becker, Loyola University Chicago, 6525
North Sheridan Road, Chicago, IL 60626, USA. E-mail: dbecke3@luc.edu
1679

1680
N. Armoush, P. Kataria, and D. P. Becker
cyclobutanones may serve as potent and selective protease inhibitors. The
employment of small molecule peptidomimetic derivatives to mimic
peptide conformational ensembles is critical in drug discovery toward the
development of new pharmaceuticals,[9] yet the cyclobutanone moiety is
underutilized in medicinal chemistry because methods for the preparation of
more adaptable and highly substituted cyclobutanones are limited. The
synthesis of highly substituted cyclobutanones is a topic of current interest,
which has recently been addressed by Doyle et al.[10] utilizing a carbene
insertion approach to prepare 3-aryl-2-silyloxy-2-carbomethoxy cyclobuta-
nones. Thus, cyclobutanones are very important targets and intermediates,
yet methods for the preparation of more highly substituted cyclobutanones
are limited.
We required protected 2-amino-cyclobutanone derivatives to serve as inter-
mediates in the preparation of peptidomimetic cyclobutanones. Lall et al.
reported the synthesis of 2-carbobenzyloxyaminocyclobutanone 2 via the
reaction of 1,2-bis(trimethylsilyloxy)cyclobutene with benzyl carbamate in the
presence of HCl in 81% yield (Scheme 1).[11] The requisite 1,2-bis(trimethylsily-
loxy)cyclobutene is in turn prepared via the acyloin cyclization of dimethyl
succinate in the presence of trimethylsilyl chloride as described by Bisel
et al.[12] For our related studies toward the preparation of more highly functiona-
lized cyclobutanones, we required N-alkylated 2-aminocyclobutanones and
derivatives with alternate protecting groups. Nucleophilic secondary amines
have also been reported to afford N,N-disubstituted 2-aminocyclobutanones
under neutral conditions.[13,14] We questioned if other poorly nucleophilic
amine derivatives would similarly react with the cyclobutene. Thus, we
undertook an exploration of the scope of the reaction of 1,2-bis(trimethylsilyl-
oxy)cyclobutene with other poorly nucleophilic nucleophiles and found that
amides and sulfonamides in addition to more hindered secondary carbamates
react efficiently with cyclobutene 1 to afford protected 2-aminocyclobutanone
derivatives.
The results of our studies are summarized in Table 1. We have explored
several sets of conditions for the reaction of N-nucleophiles with 1,2-bis(tri-
methylsilyloxy)cyclobutene and have found that reflux in 1M HCl in ether
affords the most general and reproducible results. N-Alkyl benzyl carbamates
were employed to access the N-alkylated cyclobutanone derivatives.
N-Benzyl benzylcarbamate affords cyclobutanone 3a in similar yield (60%)
to the unsubstituted parent (69% in our hands); thus the reaction does not
Scheme 1. Synthesis of benzyl (2-oxocyclobutyl)carbamate.

2-Amino-cyclobutanones
1681
Table 1. Synthesis of 2-aminocyclobutanone derivatives 3a–i
Entry
Nucleophile
Product
Yield (%)
60
3a
3b
48
3c
90
80
3d
3e
39
3f
68
42
3g
3h
3i
10
26
suffer substantially from the additional steric demand. N-Methyl benzylcarba-
mate reacted efficiently as well to give 3b, although it was quite difficult to
isolate the product cyclobutanone from the carbamate starting material
although numerous thin-layer chromatographic (TLC) solvent systems were

1682
N. Armoush, P. Kataria, and D. P. Becker
explored; hence the yield of the N-methyl derivative is somewhat lower (48%).
Given the poor nucleophilicity of the carbamate nitrogen, we were encouraged
to explore sulfonamide derivatives. We were very pleased that p-toluenesulfo-
namide reacts in very high yield (90%) to afford 3c, and the N-methyl p-tolu-
enesulfonamide affords the corresponding N-methyl-2-aminocyclobutanone
sulfonamide 3d in 80% yield. We then turned our attention to amides as nucleo-
philic partners in the reaction. Although the reaction is successful with phenyl
acetamide, affording cyclobutanone 3e, the yield is lower (39%). Benzamide, on
the other hand, gave a higher yield of cyclobutanone benzamide 3f (68%) com-
parable to the unsubstituted and N-benzyl carbamate derivatives. 4-Chloroben-
zoic acid gave a lower yield of cyclobutanone benzamide 3g (42%), presumably
because of lower electron density on the amide nitrogen. Reaction with the more
sterically demanding and electron-poor 2-chlorobenzene gave only very poor
yields of cyclobutanone adduct 3h (10%), which was difficult to purify and
characterize. Reaction with 4-cyanoaniline to afford cyclobutanone 3i
proceeded in low yield (26%) but was gratifying in contrast to the attempted
reactions under acidic conditions with aniline or N-methyl aniline, which did
not afford any cyclobutanone adducts. The difference in reactivity is presum-
ably due to protonation of the aniline and N-methyl aniline substrates,
whereas 4-cyanoaniline is significantly less basic.
In summary, the scope of the reaction of 1,2-bis(trimethylsilyloxy)cyclobu-
tene with various nitrogen nucleophiles under acidic conditions has been
explored. Sulfonamides gave high yields of cyclobutanone adducts, and carba-
mates gave generally good yields. Reaction with benzamide proceeded well, but
lower yields were obtained when employing substituted benzamides or an alkyl
amide. Several anilines failed to provide cyclobutanone adducts with the
exception of 4-cyanoaniline, which afforded the N-aryl-2-aminocyclobutanone
adduct in lower yield. Overall, the acid-catalyzed reaction of carbamates, sulfo-
namides, and amides with 1,2-bis(trimethylsilyloxy)cyclobutene is an efficient
method for the preparation of protected 2-aminocyclobutanones.
EXPERIMENTAL SECTION
All reactions were performed under an atmosphere of nitrogen, and all
solvents and reagents were used without further purification unless
otherwise noted. Merck silica gel 60 (230–400 mesh) was used for flash
chromatography. Merck Kieselgel 60 F254 DC-Fertigplatten (0.25 mm, Art.
1
5719) were used for TLC. H NMR spectra were obtained from either a
Varian Inova 300 or Varian Gemini 2000 300-MHz spectrometer with
tetramethylsilane (TMS) as an internal standard. Melting points were deter-
mined on a Thomas-Hoover melting-point apparatus and are uncorrected.
Noise-decoupled and 13C NMR spectra were recorded at 75 MHz on either
the Varian Inova 300 or Varian Gemini 2000 spectrometer. IR spectra were
recorded on a Thermo Nicolet Nexus 670 FT-IR. Mass spectra were run on

2-Amino-cyclobutanones
1683
a Thermo Finnigan LCQ Advantage instrument. 1,2-Bis(trimethylsilyloxy)
cyclobutene was prepared according to the procedure of Bisel et al.[12]
Benzyl Benzyl(2-oxocyclobutyl)carbamate (3a)
1,2-Bis(trimethylsilyloxy)cyclobutene (143 mg, 0.62 mmol) was added
a
solution of N-benzyl benzylcarbamate[15] (150 mg,
dropwise to
0.62 mmol) in 1.0 M HCl solution in diethyl ether (3 mL) cooled to 0 8C
over 5 min. The reaction was then allowed to reflux for 4 h at 80 8C. Concen-
tration gave a residue, which was purified on silica gel eluting with Et2O/
hexane (1/1) to afford the desired carbamate-cyclobutanone 3a (110 mg,
58%) as a pale yellow oil. Rf ¼ 0.3 (Et2O–hexane, 1:1. FT-IR (thin film)
1
3054, 1794, 1697, 1421 cm21; H NMR (300 MHz, CDCl3) d 7.36–7.20
(10H, m), 5.15 (1H, m), 4.56–4.38 (4H, m), 2.81–2.52 (2H, m), 2.34–2.05
(2H, m); 13C NMR (75 MHz, CDCl3) d 205.3, 178.1, 128.8, 128.6, 128.2,
128.0, 127.6, 127.1, 67.9, 51.8, 41.5, 40.9, 18.4. MS m/z (% rel. int.)
309.07 (40, Mþ), 219.27 (100, M-benzyl). HRMS calcd. for C19H19NO3Na
(M þ Naþ): 332.1263; found: 332.1253.
Benzyl Methyl(2-oxocyclobutyl)carbamate (3b)
1,2-Bis(trimethylsilyloxy)cyclobutene (405 mg, 1.7 mmol) at 0 8C was added
to a solution of N-methyl carbamate[16] (175 mg, 1.06 mmol) in 1.0 M HCl/
ether (12 ml). The reaction mixture was heated at 55 8C for 4 h, and then
the solvent was removed under vacuum. Chromatography on silica gel
eluting with 2/98 i-PrOH/CH2Cl2 provided benzyl methyl(2-oxocyclobutyl)-
carbamate 3b as an oil (118 mg, 48%). Rf ¼ 0.3 (EA-DCM, 5:95). IR (thin
1
film) 1792, 1697, 1153, 145, 908, 731 cm21; H NMR (300 MHz, CDCl3) d
7.35 (5H, m), 5.13 (2H, s), 5.10 (1H, m), 2.90 (3H, s), 2.81 (2H, m), 2.48
(1H, m), 2.33 (1H, m); 13C NMR (75 MHz, CDCl3) d 205.1, 195.5, 155.7,
136.3, 136.0, 129.2, 128.6, 111.7, 71.2, 67.8, 41.2, 33.1, 17.1; MS m/z ¼ 91
(tropylium ion), m/z ¼ 98 (Mþ 2 135, M-Cbz group), m/z ¼ 191
(Mþ 2 42, loss of ketene), m/z ¼ 205 (Mþ 2 28, loss of CO), m/z ¼ 233
(Mþ). HRMS calcd. for C13H15NO3 (M þ Naþ): 256.0950; found: 256.0945.
4-Methyl-N-(2-oxocyclobutyl)benzenesulfonamide (3c)
1,2-Bis(trimethylsilyloxy)cyclobutene (150 mg, 0.65 mmol) was added drop
wise to a solution of 4-methylbenzenesulfonamide (111 mg, 0.65 mmol) in
1.0 M HCl solution in diethyl ether (3 mL) cooled to 0 8C over 5 min.
The reaction was then allowed to reflux for 4 h at 80 8C. Concentration
gave a residue, which was purified on silica gel eluting with EtOAc/toluene

1684
N. Armoush, P. Kataria, and D. P. Becker
(10/90) to afford the desired sulfonamide-cyclobutanone 3c (140 mg, 90%) as
a white crystalline solid: mp 173–176 8C. Rf ¼ 0.3 (EA–toluene, 10:90). FT-
IR (KBr) 3582, 3054, 1791, 1421, 896 cm21; 1H NMR (300 MHz, CDCl3) d
7.77 (2H, d, J ¼ 8.2 Hz), 7.32 (2H, d, J ¼ 8.1 Hz), 5.04 (1H, d, J ¼ 7.9 Hz),
4.69 (1H, q, J ¼ 8.6 Hz), 3.00–2.71 (2H, m), 2.44 (3H, t, J ¼ 5.1 Hz), 2.37
(1H, m), 1.81 (1H, m). 13C NMR (75 MHz, CDCl3) d 207.8, 137.6, 133.9,
129.2, 118.3, 62.9, 46.1, 35.8, 29.8. MS m/z (% rel. int.) 238.47 (25,
M 2 1), 219.27 (100, M-benzyl). HRMS calcd. for C11H13NO3S (MHþ):
240.0694; found: 240.0694.
N,4-Dimethyl-N-(2-oxocyclobutyl)benzenesulfonamide (3d)
1,2-Bis(trimethylsilyloxy)cyclobutene (160 mg, 0.60 mmol) was added to a
solution of N-methyl-p-toluene sulfonamide (144 mg, 0.78 mmol) in 1.0 M
HCl/ether (3 ml) at 0 8C. The reaction mixture was heated at 55 8C for
3.5 h, and then the solvent was removed under vacuum. Chromatography
on silica gel eluting with 1/99 ethyl acetate/dichloromethane provided
N,4-dimethyl-N-(2-oxocyclobutyl)benzenesulfonamide 3d as an oil (123 mg,
80%). Rf ¼ 0.4 (EtOAc–DCM, 10:90). IR (thin film) 1790, 1661, 1513,
1
908, 731 cm21; H NMR (300 MHz, CDCl3) d 7.71 (2H, d, J ¼ 8.24 Hz),
7.30 (2H, d, J ¼ 7.96 Hz), 5.34 (1H, t, J ¼ 8.7, 10.7 Hz), 2.88–2.78 (2H,
m), 2.70 (3H, s), 2.64 (3H, s), 2.23 (1H, dd, J ¼ 4.6, 10.7 Hz), 1.97 (1H,
m); 13C NMR (75 MHz, CDCl3) d 204.0, 144.1, 135.9, 130.0, 127.3, 71.4,
41.9, 31.0, 22.1, 16.2; MS m/z ¼ 91 (tropylium ion), m/z ¼ 155
(Mþ 2 98, loss of Me-N-cyclobutanone), m/z ¼ 225 (Mþ 2 28, loss of
CO), m/z ¼ 211 (Mþ 2 42, loss of ketene), m/z ¼ 254 (MHþ). HRMS
calcd. for C12H15NO3SNa (M þ Naþ): 276.0670; found: 276.0676.
N-(2-Oxocyclobutyl)-2-phenylacetamide (3e)
1,2-Bis(trimethylsilyloxy)cyclobutene (255 mg, 1.11 mmol) was added to a
solution of phenylacetamide (150 mg, 1.11 mmol) in 1.0 M HCl/ether
(3 ml) and dichloromethane (2 ml) at 0 8C. The reaction mixture was
heated at 55 8C for 3.5 h, and then the solvent was removed under
vacuum. Chromatography on silica gel eluting with 30/70 ethyl acetate/
dichloromethane provided N-(2-oxocyclobutyl)-2-phenylacetamide 3e as
an oil (88 mg, 39%). Rf ¼ 0.3 (EtOAc–DCM, 10:90). IR (thin film) 3274,
1790, 1647, 907, 731 cm21 1H NMR (300 MHz, CDCl3) d 7.23–7.37
;
(5H, m), 5.38 (1H, s), 5.19 (2H, s), 4.78–4.87 (1H, q, J ¼ 7.91, 8.05 Hz),
2.86 (2H, m), 2.29–2.41 (1H, m), 1.95–2.08 (1H, m); 13C NMR (75 MHz,
CDCl3) d 205.9, 171.3, 134.5, 129.6, 127.7, 64.4, 43.3, 42.2, 19.6; MS:
m/z ¼ 91.1 (tropylium ion), m/z ¼ 119 (Mþ 2 84, loss of N-H cyclobuta-
none), m/z ¼ 161 (Mþ 2 42, loss of ketene), m/z ¼ 175 (Mþ 2 28, loss

2-Amino-cyclobutanones
1685
of CO), m/z ¼ 202 (Mþ 2 1). HRMS calcd. for C12H13NO2 (M þ Naþ):
226.0844; found: 226.0838.
N-(2-Oxocyclobutyl)benzamide (3f)
1,2-Bis(trimethylsilyloxy)cyclobutene (150 mg, 0.65 mmol) was added
dropwise to a solution of benzamide (78.7 mg, 0.65 mmol) in 1.0 M HCl
solution in diethyl ether (3 mL) cooled to 0 8C over 5 min. The reaction
was then allowed to reflux for 4 h at 80 8C. Concentration gave a residue,
which was purified on silica gel eluting with EtOAc/toluene (15/85) to
afford the desired benzamide-cyclobutanone 3f (84 mg, 68%) as a
colorless oil. Rf ¼ 0.2 (EA–toluene, 15:85. FT-IR (KBr) 3582, 3054,
1
1791, 1665, 1421 cm21; MS H NMR (300 MHz, CDCl3) d 7.76 (2H, d,
J ¼ 6.9 Hz), 7.51 (2H, t, J ¼ 7.4 Hz), 7.41 (1H, t, J ¼ 7.3 Hz), 6.87 (1H,
d, J ¼ 6.7 Hz), 5.15 (1H, q, J ¼ 8.5 Hz), 3.01 (2H, t, J ¼ 8.7 Hz), 2.52
(1H, m), 2.18 (1H, m); 13C NMR (75 MHz, CDCl3) d 205.7, 167.0, 133.1,
132.7, 128.7, 127.2, 64.6, 42.3, 19.8. m/z (% rel. int.) 189.13 (55, Mþ),
144.13 (65, M-NHCO), 105.07 (100, M-NHCHCOCH2CH2). HRMS
calcd. for C11H11NO2Na (M þ Naþ): 212.0687; found: 212.0688; calcd.
for C12H15NO3Na (M þ Naþ þ MeOH, hemiacetal): 244.0950; found:
244.0944.
4-Chloro-N-(2-oxocyclobutyl)benzamide (3g)
1,2-Bis(trimethylsilyloxy)cyclobutene (230 mg, 1.00 mmol) was added to a
solution of 4-chlorobenzamide (100 mg, 0.64 mmol) in HCl/ether (2 ml)
and THF (4 ml) at 0 8C. The reaction mixture was heated at 80 8C for
3.5 h, and then the solvent was removed under vacuum. Chromatography
on silica gel eluting with 2/98 ethyl acetate/dichloromethane provided
4-chloro-N-(2-oxocyclobutyl)benzamide 3g as a solid (60 mg, 42%): mp
106–108 8C; Rf ¼ 0.4 (EtOAc–DCM, 10:90). IR (thin film) 2253, 1792,
1
1662, 1483, 905, 742 cm21; H NMR (300 MHz, CDCl3) d 7.69 (2H, d,
J ¼ 2.2 Hz), 7.38 (2H, d, J ¼ 4.8 Hz), 6.84 (1H, s), 5.14 (1H, m), 3.02
(2H, m), 2.57–2.49 (1H, m), 2.22–2.14 (1H, m); 13C NMR (75 MHz,
CDCl3) d 206.0, 166.0, 161.0, 138.0, 132.0, 129.0, 64.6, 42.3, 19.7; MS:
m/z ¼ 111 (Mþ 2 112 loss of chlorobenzyl), m/z ¼ 139 (Mþ 2 84, loss
of H-N-cyclobutanone), m/z ¼ 181 (Mþ 2 42, loss of ketene), m/z ¼ 223
(Mþ). HRMS calcd. for C11H10ClNO2Na (M þ Naþ): 246.0298; found.
246.0295.
2-Chloro-N-(2-oxocyclobutyl)benzamide (3h)
1,2-Bis(trimethylsilyloxy)cyclobutene (384 mg, 1.6 mmol) was added to a
solution of 2-chlorobenzamide (260 mg, 1.6 mmol) in 1.0 HCl/ether (3 ml)

1686
N. Armoush, P. Kataria, and D. P. Becker
and dichloromethane (3 ml) at 0 8C. The reaction mixture was heated at 80 8C
for 3.5 h, and then the solvent was removed under vacuum. Chromatography
on silica gel eluting with 10/90 ethyl acetate/dichloromethane provided
2-chloro-N-(2-oxocyclobutyl)benzamide 3h as a white solid (40 mg, 10%):
mp 109–110 8C; Rf ¼ 0.4 (EtOAc–DCM, 10:90). FT-IR (thin film) 2253,
1
1793, 1666, 907, 733, 665 cm21; H NMR (300 MHz, CDCl3) d 7.62 (1H, d,
J ¼ 1.1 Hz), 7.39–7.08 (3H, m), 7.08 (1H, s), 5.14 (1H, q, J ¼ 10 Hz), 3.04–
2.91 (2H, m), 2.53–2.50 (1H, m), 2.22–2.04 (1H, m); 13C NMR (75 MHz,
CDCl3) d 205.1, 166.3, 133.9, 131.9, 131.0, 130.5, 128.9, 127.3, 64.7, 42.5,
19.7; MS m/z ¼ 91 (tropylium ion), m/z ¼ 139 (Mþ 2 84, loss of H-N-cyclo-
butanone), m/z ¼ 224 (Mþ þ 1). HRMS calcd. for C11H10ClNO2Na
(M þ Naþ): 246.0298; found: 246.0291; calcd. for C12H14ClNO3Na (M þ
Naþ þ MeOH, hemiketal): 278.0560; found: 278.0550.
4-[(2-Oxocyclobutyl)amino]benzonitrile (3i)
1,2-Bis(trimethylsilyloxy)cyclobutene (121 mg, 0.52 mmol) was added to a
solution of 4-aminobenzonitrile (75 mg, 0.63 mmol) in 1.0 M HCl/ether
(1 ml), dichloromethane (4 ml), and THF (5 ml) at 0 8C. The reaction
mixture was heated at 80 8C for 3.5 h, and then the solvent was removed
under vacuum. Chromatography on silica gel eluting with 80/20 ether/
petroleum ether provided the 4-cyano aniline cyclobutanone derivative 3i as
yellow oil (25 mg, 26%). Rf ¼ 0.3 (ether–petroleum ether 50:50). IR (thin
1
film) 3583, 2253, 1790, 1608, 1520, 908, 731 cm21; H NMR (300 MHz,
CDCl3) d 7.48–7.46 (2H, m), 6.62–6.60 (2H, m), 4.85 (2H, m), 3.15 (1H,
m), 3.02 (1H, m), 2.68–2.65 (1H, m), 1.88–1.85 (1H, m); 13C NMR
(75 MHz, CDCl3) d 224.1, 149.5, 133.6, 120.1, 112.9, 102.0, 67.7, 42.5,
21.0. MS: m/z ¼ 102 (Mþ 2 84, loss of H-N-cyclobutanone), m/z ¼ 187
(Mþ þ 1). HRMS calcd. for C11H11N2O (MHþ): 187.0871; found:
187.0862; calcd. for C11H10N2ONa (M þ Naþ): 209.0691; found: 209.0691.
ACKNOWLEDGMENTS
NSF Grant DBI-0216630 is gratefully acknowledged for the Varian Unity-300
NMR obtained through the NSF Biological Major Instrumentation Program,
and the NSF REU Program (Research Experience for Undergraduates) is
gratefully acknowledged for summer financial support for N. A.
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