Reactions with 4-hydroxy-2-methylbutananilides: Unexpected formation of a cyclopropanecarboxamide

Article abstract of DOI:10.1002/hlca.201000370

The successive treatment of the N,N-disubstituted 4-hydroxy-2- methylbutanamide 2a with lithium diisopropylamide (LDA) and diphenyl phosphorochloridate (DPPCl) led to the 1-methylcyclopropanecarboxamide 10 in good yield. This base-catalyzed cyclization of

Full text of DOI:10.1002/hlca.201000370

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Helvetica Chimica Acta – Vol. 94 (2011)
Reactions with 4-Hydroxy-2-methylbutananilides: Unexpected Formation of a
Cyclopropanecarboxamide
by Maged K. G. Mekhael1), Anthony Linden, and Heinz Heimgartner*
Organisch-Chemisches Institut der Universitꢀt Zꢁrich, Winterthurerstrasse 190, CH-8057 Zꢁrich
(phone: þ 41-44-6354282; fax: þ 41-44-6356812; e-mail: heimgart@oci.uzh.ch)
The successive treatment of the N,N-disubstituted 4-hydroxy-2-methylbutanamide 2a with lithium
diisopropylamide (LDA) and diphenyl phosphorochloridate (DPPCl) led to the 1-methylcyclopropane-
carboxamide 10 in good yield. This base-catalyzed cyclization offers a new approach to cyclopropane-
carboxamides. Under similar conditions, the N-monosubstituted 4-hydroxy-2-methylbutanamide 2b gave
the 3-methylpyrrolidin-2-one 11. The structure of the cyclopropanecarboxamide 10 was established by X-
ray crystallography.
Introduction. – In the last four decades, it has been demonstrated that 2,2-
disubstituted 2H-azirin-3-amines of type 1 are attractive building blocks for the
introduction of 2,2-disubstituted glycines into peptides, as well as for the synthesis of
heterocycles [1]. The N-methyl-N-phenyl derivatives are conveniently accessible via
successive treatment of anilides 2 with lithium diisopropylamide (LDA), diphenyl
phosphorochloridate (DPPCl), and NaN3 [2] (Scheme 1). It is assumed that 1-azido
Scheme 1
1
)
Part of the Ph.D. thesis of M. K. G. M., University of Zꢁrich, 2003; present address: National
Research Center, Chemistry of Natural Compounds Dept., Tahrir Street, Dokki, Cairo, Egypt.
ꢂ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 94 (2011)
29
enamines 3 are intermediates, which spontaneously cyclize via elimination of N2 to give
2H-azirines 1.
Two typical examples for ring-enlargement reactions with 1 are shown in Scheme 1.
The reaction with NH-acidic isothiazol-3(2H)-one 1,1-dioxides 4 leads to eight-
membered 1,2,5-thiadiazocine derivatives 5 via cleavage of the N(1)¼C(3) bond of 1
[3], whereas treatment of 1 with BF3 · OEt2 and subsequent hydrolysis gives 2-
oxindoles (¼2,3-dihydro-1H-indol-2-ones) 6 via cleavage of the N(1)ꢀC(2) bond [4].
In the second example, a 2-allyl-substituted azirine 1 (R1 ¼ allyl, R2 ¼ Me) has been
used for the preparation of a 3-allyloxindole 6 (R1 ¼ allyl, R2 ¼ Me), which was further
transformed into (ꢁ)-desoxynoreseroline [5]2). This example demonstrates that
azirines of type 1 with a functionalized side chain R1 are of high interest for the
synthesis of more complex heterocycles3).
For this reason, the synthesis of 2H-azirin-3-amines 1 with an OH group in the
residue R1 was undertaken. These attempts led to unexpected results, which are
presented in this report.
Results and Discussion. – The desired precursor 2a for the azirine synthesis was
obtained by the AlCl3-catalyzed amination of a-methyl-g-butyrolactone 7 with N-
methylaniline according to the protocol described in [8] (see also [7a]). The reaction
proceeded smoothly, and the known 2a [7a][8] was obtained in 84% yield as colorless
crystals with a m.p. of 78 – 78.88. All attempts to synthesize the 2H-azirin-3-amine 1a
(R1 ¼ HOCH2CH2, R2 ¼ Me) according to the method described in [2] (see Scheme 1)
by using ca. 1.1 equiv. of LDA failed, and only the azido derivative 8 was isolated in
48% yield as a yellow oil (Scheme 2). The structure determination was based on the
Scheme 2
The 3-allyloxindol 6 (R1 ¼ allyl, R2 ¼ Me) [4a] was transformed into 3-(2-hydroxyethyl)-1,3-
dimethyloxindole via ozonolysis and subsequent NaBH4 reduction [6]. Subsequent treatment with
SOCl2 and NH3 yielded 3-(2-aminoethyl)-1,3-dimethyloxindole, a precursor for the cyclization to
(ꢁ)-desoxynoreseroline.
2
)
)
3
For the synthesis of 2H-azirin-3-amines with a functionalized side chain, see also [7].

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Helvetica Chimica Acta – Vol. 94 (2011)
1
analytical and the IR, H- and 13C-NMR data. The presence of the N3 group was
evidenced by the strong IR absorptions at 2096 and 1266 cmꢀ1 for the asymmetric and
symmetric stretching vibration. The base peak in the CI-MS appeared at m/z 233
([M þ 1]þ), corresponding to the formula C12H16N4O for the product.
The formation of 8 can easily be rationalized by the reaction of the alcoholate of 2a
with DPPCl to give the corresponding alkyl diphenyl phosphate 9 (see, e.g., [9]),
followed by an SN2 reaction with the azide ion.
In the next experiment, 2a was treated with ca. 2.2 equiv. of LDA, followed by ca.
1.1 equiv. of DPPCl. Surprisingly, a new, rather unpolar product was formed (TLC),
which, after chromatographic workup, was obtained as a colorless, crystalline material.
On the basis of the spectroscopic and analytical data, the structure was determined as
1,N-dimethyl-N-phenylcyclopropanecarboxamide (10; Scheme 2). Finally, this struc-
ture was established by X-ray crystallography (Fig.).
Figure. ORTEP Plot [10] of the molecular structure of 10 (50% probability ellipsoids, arbitrary atom
numbering)
A likely intermediate in the formation of 10 is the anion of 9, which undergoes
cyclization to give the cyclopropane by elimination of diphenyl phosphate (cf. [11]).
The analogous reaction of the N-monosubstituted amide 2b, which had been
prepared by the reaction of 7 with 4-methoxyaniline, with ca. 3.3 equiv. of LDA gave,
after chromatographic workup, a product with a base peak in the CI-MS at m/z 206
([M þ 1]þ), corresponding to a molecular formula of C12H15NO2, i.e., the product of the
dehydration. The 1H- and 13C-NMR data clearly indicated that the product was not the
expected cyclopropanecarboxamide: the NMR spectra showed signals of two different
CH2 groups (e.g., d(C) 46.8 and 27.0 ppm) and of a CH group (37.9 ppm). Whereas the
IR absorption at 1685 cmꢀ1 was in agreement with the structure of lactam 11 [12] as well
as with the iminolactone 11’ [13], the NMR data clearly indicated that 11 was formed
(Scheme 3). The CH2 signals at 46.8 (13C) and 3.77 – 3.72 (1H) ppm are characteristic

Helvetica Chimica Acta – Vol. 94 (2011)
31
for the CH2N group [14], whereas the CH2O signals of 11’ would be expected at ca. 62
and 4.2 ppm, respectively [15][16]. The formation of 11 may be rationalized by the
cyclization of intermediate 12. Although ring closure via nucleophilic attack of the O-
or the N-atom of the amide group is possible, it has been shown that, in the case of 4-
bromobutyranilide, under very basic conditions, i.e., in the cyclization of the
corresponding anion, the formation of the lactam is strongly preferred [17].
Scheme 3
Finally, the transformations of the OH group of 2a to an ester moiety in 13 and to a
urethane moiety in 14 were achieved via the reactions with acid chlorides and
isocyanates, respectively, under standard conditions (Scheme 4).
Scheme 4
Conclusions. – The reaction of the N,N-disubstitued 4-hydroxybutanamide 2a with 2
equiv. of LDA and DPPCl led to the cyclopropanecarboxamide 10, whereas the
analogous N-monosubstituted amide 2b under similar conditions yielded the lactam 11.
The formation of 10 via the base-catalyzed cyclization of 2a offers a new access to the
important class of cyclopropanecarboxamides4), which are known as partial structures
of physiologically active compounds (e.g., DPP-IV inhibitors [19a], melanocortin
receptor agonists [19b], antidepressants [19c], HCV NS5B inhibitors [19d][19e], etc.).
The described results show that, for the attempted synthesis of a 2H-azirin-3-amine 1
with an OH group in R1, a starting material 2 with a suitably protected OH group
should be used.
4
)
For recent syntheses of cyclopropanecarboxamides, see [18].

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Helvetica Chimica Acta – Vol. 94 (2011)
We thank the analytical units of our institute for spectra and analyses. Financial support of the work
by the Swiss National Science Foundation and F. Hoffmann-La Roche AG, Basel, is gratefully
acknowledged.
Experimental Part
1. General. Solvents were purified by standard procedures. TLC: aluminium sheets, silica gel 60 F254
(Merck). Prep. TLC: glass plates, silica gel 60 F254 (2 mm; Merck). Column chromatography (CC): silica
gel C-560 (0.04 – 0.063 mm; Uetikon-Chemie). Medium-pressure liquid chromatography (MPLC):
LiChroprep Si 60, 15 – 25 mm (Merck); column: Kron-Lab 4/98-Pro, 480 ꢂ 30 mm or Labomatic, 380 ꢂ
20 mm. M.p.: Mettler-FP-5 or Bꢀchi 510 apparatus; uncorrected. IR Spectra: Perkin-Elmer 781 or
Perkin-Elmer 1600 FT-IR spectrophotometer; in KBr unless otherwise stated. 1H- and 13C-NMR Spectra:
Bruker ARX-300 instrument (300 and 75.5 MHz, resp.), in CDCl3; multiplicities of C-atoms from DEPT
spectra. MS: Finnigan MAT-90, Finnigan SSQ-700 (CI with NH3), or Finnigan TSQ-700 instrument
(ESI). Elemental analyses were performed by the Mikroanalytisches Laboratorium des Organisch-
chemischen Instituts der Universitꢀt Zꢁrich (Elementar Vario EL instrument).
2. Starting Materials. The preparation of 4-hydroxy-2,N-dimethyl-N-phenylbutanamide (2a) was
carried out according to [8] and has been previously described in [7a]. All other reagents were
commercially available.
3. Reactions with 4-Hydroxy-2,N-dimethyl-N-phenylbutanamide (2a). 3.1. 4-Azido-2,N-dimethyl-N-
phenylbutanamide (8). To a stirred soln. of iPr2NH (0.47 ml, 3.32 mmol) in THF (10 ml) at ꢀ 208, BuLi
(2m soln. in pentane, 1.60 ml, 3.20 mmol) was added under Ar, and the mixture was allowed to warm to
08. A soln. of 2a (600 mg, 2.89 mmol) in THF (5 ml) was added dropwise, and the mixture was stirred at
08 for 1 h. Then, diphenyl phorphorochloridate (DPPCl; 0.62 ml, 2.98 mmol) was added dropwise. After
30 min, the ice bath was removed, and the mixture was stirred at r.t. for 24 h. The formed precipitate was
filtered off under Ar, the THF soln. was dropped into a suspension of NaN3 (0.565 mg, 8.69 mmol) in dry
DMF (1.5 ml), and the mixture was stirred at r.t. for 4 d. Then, Et2O was added, and the mixture was
filtered over a Celite pad, the solvent was evaporated, and the residue was dissolved in Et2O. The soln.
was washed with 5% aq. NaHCO3 (2ꢂ), the aq. layer was washed with Et2O, the combined org. layers
were dried (MgSO4), the solvent was evaporated under reduced pressure, and the crude product was
purified by bulb-to-bulb distillation and CC (Et2O/hexane 2 :5): 322 mg (48%) of 8. Yellow oil. IR
(film): 3061w, 2971m, 2934m, 2875m, 2096s, 1654s, 1595s, 1496s, 1462s, 1426s, 1390s, 1328m, 1266s, 1173w,
1
1116s, 1074m, 1037m, 1001w, 916w, 775m, 750w, 701s. H-NMR: 7.50 – 7.36, 7.23 – 7.19 (2m, 5 arom. H);
3.32 – 3.14 (m, CH2N3); 3.28 (s, MeN), 2.64 – 2.49 (m, CH); 2.09 – 1.93, 1.60 – 1.47 (2m, CH2); 1.05 (d, J ¼
6.8, Me). 13C-NMR: 175.6 (s, CO); 143.7 (s, 1 arom. C); 129.7, 127.9, 127.2 (3d, 5 arom. CH); 49.3, 32.9 (2t,
2 CH2); 37.4 (q, MeN); 33.8 (d, CH); 18.0 (q, Me). CI-MS: 234 (14), 233 (100, [M þ 1]þ), 205 (13), 190
(11), 107 (9).
i
3.2. 1,N-Dimethyl-N-phenylcyclopropanecarboxamide (10). To a stirred soln. of Pr2NH (0.94 ml,
6.65 mmol) in THF (10 ml) at ꢀ 208, BuLi (2m soln. in pentane; 3.19 ml, 6.38 mmol) was added under Ar,
and the mixture was allowed to warm to 08. A soln. of 2a (600 mg, 2.89 mmol) in THF (5 ml) was added
dropwise, and the mixture was stirred at 08 for 1 h. Then, DPPCl (1.23 ml, 5.96 mmol) was added
dropwise. After 30 min, the ice bath was removed, and the mixture was stirred at r.t. for 24 h. The formed
precipitate was filtered off under Ar, the solvent was evaporated, and Et2O was added. The mixture was
filtered over a Celite pad, the solvent was evaporated, and the residue was dissolved in Et2O. The soln.
was washed with 5% aq. NaHCO3 (2ꢂ), the aq. layer was washed with Et2O, the combined org. layers
were dried (MgSO4), the solvent was evaporated under reduced pressure, and the crude product was
purified by CC (Et2O/hexane 1:5): 412 mg (75%) of 10. Crystallization from hexane gave colorless
prisms. M.p. 77.5 – 78.58. IR: 3089w, 3046w, 2969m, 2951m, 2924m, 2867w, 1637s, 1594s, 1496s, 1469m,
1434m, 1413s, 1383s, 1370s, 1311m, 1284w, 1246s, 1158w, 1118s, 1076w, 948w, 910w, 859w, 811w, 198w,
779m, 750m, 706s. 1H-NMR: 7.45 – 7.35, 7.31 – 7.20 (2m, 5 arom. H); 3.29 (s, MeN); 1.12 – 1.05, 0.44 – 0.37
(2m, 2 CH2); 0.92 (s, Me). 13C-NMR: 174.5 (s, CO); 144.5 (s, 1 arom. C); 129.1, 127.1, 126.8 (3d, 5 arom.
CH); 39.0 (q, MeN); 21.9 (q, Me); 20.8 (s, C(1)); 15.5 (t, 2 CH2). CI-MS: 191 (12), 190 (100, [M þ 1]þ).
Anal. calc. for C12H15NO (189.25): C 76.16, H 7.99, N 7.40; found: C 76.14, H 7.85, N 7.44.

Helvetica Chimica Acta – Vol. 94 (2011)
33
Crystals suitable for the X-ray crystal-structure determination were grown from hexane by slow
evaporation of the solvent.
4. Reaction with 4-Hydroxy-N-(4-methoxyphenyl)-2-methylbutanamide (2b). 4.1. Preparation of 2b.
In analogy to [8], a soln. of 4-methoxyaniline (1.54 g, 12.51 mmol) in 1,2-dichloroethane (4.5 ml) was
added to a stirred suspension of AlCl3 (0.87 g, 6.50 mmol) in 1,2-dichloroethane (2.5 ml) at 15 – 258. Then,
a-methyl-g-butyrolactone (7; 0.5 ml, 5.28 mmol) was added, and the mixture was stirred at r.t. for 4 h.
After quenching the reaction with ice/H2O (5 ml), the mixture was stirred for an additional 0.5 h, the
resulting suspension was filtered over Celite, and the org. phase was separated. The aq. phase was
extracted with CH2Cl2, and the combined org. phase was washed with H2O and brine, and dried
(Na2SO4). Evaporation of the solvent and CC (CH2Cl2/MeOH 100 :1) yielded 575 mg (52%) of 2b. Pale
rosa powder. M.p. 95.2 – 95.78. IR: 3443m, 3283s, 3193m, 3133m, 3071w, 2974m, 2953m, 2934m, 2837m,
1652s, 1603s, 1549s, 1514s, 1459m, 1444m, 1415m, 1380m, 1348m, 1298s, 1239s, 1185m, 1170m, 1134w,
1098m, 1053s, 1035s, 1000m, 944w, 828s, 807w, 762w, 716m. 1H-NMR: 7.88 (br. s, NH); 7.37, 6.79 (AA’BB’,
4 arom. H); 3.75 (s, MeO); 3.71 – 3.64 (m, CH2O); 2.87 (br. s, OH); 2.68 – 2.54 (m, CH); 1.97 – 1.84, 1.76 –
1.62 (2m, CH2); 1.22 (d, J ¼ 6.9, Me). 13C-NMR: 175.0 (s, CO); 156.3, 130.9 (2s, 2 arom. C); 121.9, 114.0
(2d, 4 arom. CH); 60.1, 36.5 (2t, 2 CH2); 55.4 (q, MeO); 38.5 (d, CH); 17.6 (q, Me). CI-MS: 225 (12), 224
(100, [M þ 1]þ), 207 (9), 206 (77). Anal. calc. for C12H17NO3 (223.27): C 64.55, H 7.67, N 6.27; found: C
64.53, H 7.85, N 6.15.
4.2. 1-(4-Methoxyphenyl)-3-methylpyrrolidin-2-one (11). To a stirred soln. of iPr2NH (0.66 ml,
4.66 mmol) in THF (20 ml) at ꢀ 208, BuLi (2m soln. in pentane; 2.20 ml, 4.44 mmol) was added under Ar,
and the mixture was allowed to warm to 08. A soln. of 2b (300 mg, 1.34 mmol) in THF (5 ml) was added
dropwise, and the mixture was stirred at 08 for 1 h. Then, DPPCl (0.86 ml, 4.13 mmol) was added
dropwise. After 30 min, the ice bath was removed, and the mixture was stirred at r.t. for 24 h. The mixture
was worked up as described in Sect. 3.2, and the crude product was purified by CC (Et2O/hexane 1:2):
240 mg (87%) of 11. Colorless crystals. M.p. 83.1 – 84.88. IR: 2952m, 2836w, 1685s, 1515s, 1482m, 1442m,
1397s, 1324m, 1290m, 1252s, 1226s, 1180m, 1121m, 1098m, 1050m, 1030s, 918w, 884w, 830s, 790w, 720w,
1
704w. H-NMR: 7.53, 6.90 (AA’BB’, 4 arom. H); 3.81 (s, MeO); 3.77 – 3.72 (m, CH2O); 2.73 – 2.59 (m,
CH); 2.43 – 2.30, 1.83 – 1.70 (2m, CH2); 1.30 (d, J ¼ 6.7, Me). 13C-NMR: 176.2 (s, OꢀC¼N); 156.3, 132.9
(2s, 2 arom. C); 121.4, 113.9 (2d, 4 arom. CH); 55.4 (q, MeO); 46.8, 27.0 (2t, 2 CH2); 37.9 (d, CH); 16.2 (q,
Me). CI-MS: 411 (9, [2M þ 1]þ), 223 (8, [M þ NH4]þ), 207 (13), 206 (100, [M þ 1]þ). Anal. calc. for
C12H15NO2 (205.25): C 70.22, H 7.37, N 6.82; found: C 70.10, H 7.65, N 6.92.
5. Reaction of 2a with Acid Chlorides. General Procedure 1 (GP 1). To a soln. of 2a in dioxane, the
corresponding acid chloride and Et3N were added, and the mixture was heated to reflux for 2 h. The
solvent was evaporated, and CH2Cl2 was added, the org. phase was washed with 10% aq. HCl, sat. aq.
NaHCO3, and brine, and dried (Na2SO4). After filtration, the solvent was evaporated under reduced
pressure, and pure product was obtained after CC.
5.1. 3-Methyl-4-[methyl(phenyl)amino]-4-oxobutyl Acetate (13a). According to GP 1, with 2a
(100 mg, 0.48 mmol), dioxane (5 ml), AcCl (0.04 ml, 0.56 mmol), and Et3N (0.05 ml, 0.36 mmol). Yield:
108 mg (90%) of 13a. Colorless, viscous oil, which solidified on cooling. IR: 3062w, 3039w, 2970m, 2937m,
2878m, 1745s, 1650s, 1596s, 1497s, 1463m, 1429s, 1391s, 1365m, 1329m, 1244s, 1118s, 1074m, 1039s, 776s,
703s. 1H-NMR: 7.38 – 7.22, 7.13 – 7.07 (2m, 5 arom. H); 3.89 (t, J ¼ 6.2, CH2O); 3.18 (s, MeN); 2.53 – 2.40,
2.02 – 1.89, 1.55 – 1.42 (3m, CH, CH2); 1.83 (s, MeCO); 0.98 (d, J ¼ 6.8, Me). 13C-NMR: 174.8 (s,
OꢀC¼O); 169.8 (s, CO); 143.0 (s, 1 arom. C); 128.8, 126.8, 126.4 (3d, 5 arom. CH); 61.5 (t, CH2O) 36.4 (q,
MeN); 32.3 (d, CH); 32.1 (t, CH2); 19.8 (q, MeCO); 17.1 (q, Me). CI-MS: 516 (54, [2M þ NH4]þ), 499 (21,
[2M þ 1]þ), 267 (33, [M þ NH4]þ), 251 (15), 250 (100, [M þ 1]þ), 249 (13, Mþ), 190 (24).
5.2. 3-Methyl-4-[methyl(phenyl)amino]-4-oxobutyl Dichloroacetate (13b). According to GP 1, with
2a (150 mg, 0.72 mmol), dioxane (10 ml), dichloroacetyl chloride (0.11 ml, 1.14 mmol), and Et3N (0.1 ml,
1
0.72 mmol). Yield: 200 mg (87%) of 13b. Yellowish, viscous oil. H-NMR: 7.39 – 7.25, 7.16 – 7.09 (2m, 5
arom. H); 5.73 (s, CHCl2); 4.20 – 4.03 (m, CH2O); 3.19 (s, MeN); 2.58 – 2.45, 2.11 – 1.98, 1.64 – 1.50 (3m,
CH, CH2); 0.98 (d, J ¼ 6.8, Me). 13C-NMR: 175.2 (s, OꢀC¼O); 164.2 (s, CO); 143.7 (s, 1 arom. C); 129.8,
127.8, 127.2 (3d, 5 arom. CH); 65.6 (t, CH2O); 64.1 (s, CHCl2); 37.4 (q, MeN); 33.0 (d, CH); 32.5 (t, CH2);
18.0 (q, Me). CI-MS: 335 (17, [M þ NH4]þ), 318 (100, [M þ 1]þ), 284 (19), 228 (21), 226 (64). Anal. calc.
for C14H17Cl2NO3 (318.20): C 52.84, H 5.39, N 4.40, Cl 22.28; found: C 53.10, H 5.32, N 4.42, Cl 21.94.

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Helvetica Chimica Acta – Vol. 94 (2011)
5.3. 3-Methyl-4-[methyl(phenyl)amino]-4-oxobutyl Cyclopropanecarboxylate (13c). According to
GP 1, with 2a (100 mg, 0.48 mmol), dioxane (10 ml), cyclopropanecarbonyl chloride (0.04 ml,
0.44 mmol), and Et3N (0.07 ml, 0.50 mmol). Yield: 127 mg (95%) of 13c. Pale yellow oil. IR (film):
3061w, 3014w, 2968m, 2935m, 1719s, 1654s, 1595s, 1496s, 1454s, 1390s, 1366s, 1328m, 1270s, 1199s, 1178s,
1
1117s, 1074m, 1034m, 1000w, 938w, 913w, 853w, 824w, 775m, 747w, 702s. H-NMR: 7.38 – 7.21, 7.11 – 7.07
(2m, 5 arom. H); 3.88 (t, J ¼ 6.2, CH2O); 3.17 (s, MeN); 2.53 – 2.40, 2.02 – 1.90, 1.54 – 1.42, 1.41 – 1.32 (4m,
2 CH, CH2); 0.98 (d, J ¼ 6.8, Me); 0.89 – 0.79, 0.78 – 0.69 (2m, 2 CH2). 13C-NMR: 175.7 (s, OꢀC¼O); 174.5
(s, CO); 143.9 (s, 1 arom. C); 129.6, 127.7, 127.2 (3d, 5 arom. CH); 62.5 (t, CH2O); 37.3 (q, MeN); 33.2 (d,
CH); 33.1 (t, CH2); 12.7 (d, CH); 8.2, 8.1 (2t, 2 CH2). CI-MS: 277 (16), 276 (100, [M þ 1]þ), 190 (11).
5.4. 3-Methyl-4-[methyl(phenyl)amino]-4-oxobutyl Benzoate (13d). According to GP 1, with 2a
(300 mg, 1.45 mmol), dioxane (20 ml), BzCl (0.17 ml, 1.45 mmol), and Et3N (0.2 ml, 1.43 mmol). Yield:
370 mg (82%) of 13d. Colorless, viscous oil, which solidified in h.v. IR (film): 3062w, 2970m, 1716s, 1654s,
1596s, 1496s, 1452s, 1428m, 1391s, 1315m, 1274s, 1176m, 1117s, 1071m, 1028m, 1001w, 950w, 846w, 775m,
1
749w, 713s. H-NMR: 7.85 – 7.80, 7.50 – 7.45, 7.35 – 7.30, 7.10 – 7.00 (4m, 10 arom. H); 4.18 (br. s, CH2O);
3.18 (br. s, MeN); 2.65 – 2.60, 2.20 – 2.10, 1.70 – 1.60 (3m, CH, CH2); 1.04 (br. s, Me). 13C-NMR: 175.6 (s,
OꢀC¼O); 166.2 (s, CO); 143.8, 135.5 (2s, 2 arom. C); 132.7, 129.6, 129.4, 128.1, 127.5, 127.1 (6d, 10 arom.
CH); 62.9 (t, CH2O) 37.2 (q, MeN); 33.3 (d, CH); 33.1 (t, CH2); 18.1 (q, Me). CI-MS: 329 (7, [M þ
NH4]þ), 313 (18), 312 (100, [M þ 1]þ), 190 (5), 178 (19). Anal. calc. for C19H21NO3 (311.37): C 73.29,
H 6.80, N 4.50; found: C 73.04, H 6.69, N 4.50.
5.5. 3-Methyl-4-[methyl(phenyl)amino]-4-oxobutyl 4-Nitrobenzoate (13e). According to GP 1, with
2a (150 mg, 0.72 mmol), dioxane (10 ml), 4-nitrobenzoyl chloride (134 mg, 0.72 mmol), and Et3N
(0.1 ml, 0.72 mmol). Yield: 128 mg (50%) of 13e. Pale yellow solid. M.p. 98.5 – 99.08. IR: 3115w, 2970w,
2934w, 1724s, 1651s, 1610m, 1594m, 1527s, 1516s, 1496m, 1458m, 1427m, 1394m, 1350m, 1324m, 1280s,
1154w, 1122s, 1106m, 1080w, 1021m, 948w, 874w, 848w, 819w, 777w, 746w, 719s, 705m. 1H-NMR: 8.17, 7.97
(AAꢁBBꢁ, 4 arom. H); 7.27 – 7.13, 7.10 – 7.04 (2m, 5 arom. H); 4.22 (t-like, CH2O); 3.18 (s, MeN); 2.68 –
2.53, 2.25 – 2.08, 1.73 – 1.61 (3m, CH, CH2); 1.05 (d, J ¼ 6.8, Me). 13C-NMR: 175.5 (s, OꢀC¼O); 164.3 (s,
CO); 150.4, 143.9, 135.4 (3s, 3 arom. C); 130.6, 129.7, 127.7, 127.1, 123.3 (5d, 9 arom. CH); 64.0 (t, CH2O)
37.4 (q, MeN); 33.4 (d, CH); 32.9 (t, CH2); 18.1 (q, Me). CI-MS: 358 (19), 357 (100, [M þ 1]þ), 328 (7),
327 (37), 240 (17), 223 (43). Anal. calc. for C19H20N2O5 (356.38): C 64.04, H 5.66, N 7.86; found: C 63.88,
H 5.76, N 7.93.
6. Reaction of 2a with Isocyanates. General Procedure 2 (GP 2). To a soln. of 2a in dry benzene, the
corresponding isocyanate was added, and the mixture was heated to reflux for 4 h. The solvent was
evaporated, and the crude product was purified by CC.
6.1. 3-Methyl-4-[methyl(phenyl)amino]-4-oxobutyl (tert-Butyl)carbamate (14a). According to GP 2,
with 2a (100 mg, 0.48 mmol), benzene (10 ml), t-BuNCO (0.06 ml, 0.51 mmol). Yield: 100 mg (68%) of
14a. Colorless, viscous oil. IR (CHCl3): 3441w, 3007m, 2970m, 2874w, 1719s, 1641s, 1596m, 1508s, 1498s,
1457m, 1431m, 1092m, 1038w, 1001w, 921w, 839w. 1H-NMR: 7.69 – 7.54, 7.44 – 7.38 (2m, 5 arom. H); 4.70
(br. s, NH); 4.22 – 4.05 (m, CH2O); 3.49 (s, MeN); 2.82 – 2.69, 2.32 – 2.17, 1.85 – 1.70 (3m, CH, CH2); 1.52
(s, 3 Me); 1.29 (d, J ¼ 6.8, Me). 13C-NMR: 175.8 (s, CO); 154.7 (s, OꢀC(O)ꢀN); 144.0 (s, 1 arom. C);
129.6, 127.6, 127.3 (3d, 5 arom. CH); 62.1 (t, CH2O); 50.0 (s, Me3C); 37.3 (q, MeN); 33.4 (t, CH2); 33.3 (d,
CH); 28.8 (q, Me3C); 18.0 (q, Me). ESI-MS: 329 (27, [M þ Na]þ), 307 (85, [M þ 1]þ), 208 (47), 190 (100).
6.2. 3-Methyl-4-[methyl(phenyl)amino]-4-oxobutyl Cyclohexylcarbamate (14b). According to GP 2,
with 2a (150 mg, 0.72 mmol), benzene (20 ml), cyclohexyl isocyanate (0.095 ml, 0.75 mmol). Yield:
175 mg (73%) of 14b. Colorless, viscous oil. IR (CHCl3): 3445w, 3023s, 2977s, 2896m, 1709s, 1642m,
1590m, 1521s, 1477m, 1424s, 1047s, 929s, 877m, 850s. 1H-NMR: 7.48 – 7.32, 7.25 – 7.17 (2m, 5 arom. H); 4.49
(br. d, NH); 4.03 – 3.88 (m, CH2O); 3.27 (s, MeN); 2.62 – 2.45 (m, CH); 2.08 – 1.10 (m, CH2, 11 H of
cyclohexyl); 1.05 (d, J ¼ 6.8, Me). 13C-NMR: 175.8 (s, CO); 155.5 (s, OꢀC(O)ꢀN); 144.0 (s, 1 arom. C);
129.6, 127.6, 127.3 (3d, 5 arom. CH); 62.6 (t, CH2O); 49.6 (d, CH of cyclohexyl); 37.3 (q, MeN); 33.4 (t,
CH2); 33.2 (d, CH); 33.3, 25.3, 24.6 (3t, 5 CH2 of cyclohexyl); 18.0 (q, Me). ESI-MS: 371 (9, [M þ K]þ),
356 (13), 355 (100, [M þ Na]þ), 333 (10, [M þ 1]þ), 190 (11), 156 (8).
6.3. 3-Methyl-4-[methyl(phenyl)amino]-4-oxobutyl Phenylcarbamate (14c). According to GP 2, with
2a (150 mg, 0.72 mmol), benzene (20 ml), PhNCO (0.08 ml, 0.72 mmol). Yield: 161 mg (68%) of 14c.
Colorless, viscous oil. IR (CHCl3): 3436w, 3023s, 2977s, 2896m, 1732s, 1642m, 1597m, 1521s, 1477m, 1424s,

Helvetica Chimica Acta – Vol. 94 (2011)
35
1
1047s, 929s, 877m, 850s. H-NMR: 7.52 – 7.30, 7.27 – 7.20, 7.17 – 7.08 (3m, 10 arom. H); 5.20 (br. s, NH);
4.20 – 4.02 (m, CH2O); 3.30 (s, MeN); 2.70 – 2.56, 2.22 – 2.07, 1.72 – 1.59 (3m, CH, CH2); 1.13 (d, J ¼ 6.8,
Me). 13C-NMR: 175.8 (s, CO); 153.4 (s, OꢀC(O)ꢀN); 143.8, 138.1 (2s, 2 arom. C); 129.7, 128.8, 127.7,
127.2, 123.1, 118.4 (6d, 10 arom. CH); 63.1 (t, CH2O); 37.3 (q, MeN); 33.4 (t, CH2); 33.2 (d, CH); 18.1 (q,
Me). CI-MS: 328 (20), 327 (100, [M þ 1]þ), 208 (11), 191 (10), 190 (81).
7. X-Ray Crystal-Structure Determination of 10 (Table and Fig.)5). All measurements were
performed on a Rigaku AFC5R diffractometer using graphite-monochromated MoKa radiation (l
0.71069 ꢃ) and a 12-kW rotating anode generator. The data collection and refinement parameters are
given in the Table, and a view of the molecule is shown in the Figure. The intensities were corrected for
Lorentz and polarization effects, but not for absorption. The structure was solved by direct methods using
SHELXS97 [20], which revealed the positions of all non-H-atoms. The non-H-atoms were refined
anisotropically. All of the H-atoms were fixed in geometrically calculated positions (d(CꢀH) ¼ 0.95 ꢃ),
and each was assigned a fixed isotropic displacement parameter with a value equal to 1.2 Ueq of its parent
Table. Crystallographic Data for Compound 10
Crystallized from
Empirical formula
Formula weight
Crystal color, habit
Crystal dimensions [mm]
Temp. [K]
hexane
C12H15NO
189.26
colorless, prism
0.28 ꢂ 0.48 ꢂ 0.48
173(1)
Crystal system
Space group
orthorhombic
Pbca
Z
8
Reflections for cell determination
2q Range for cell determination [8]
Unit cell parameters
a [ꢃ]
25
34 – 40
20.820(2)
14.230(3)
7.055(2)
2090.2(6)
1.203
b [ꢃ]
c [ꢃ]
V [ꢃ3]
Dx [g cmꢀ3
]
m(MoKa) [mmꢀ1
Scan type
]
0.0763
w/2q
2q(max) [8]
55
Total reflections measured
Symmetry independent reflections
Reflections used [I > 2s(I)]
Parameters refined
3338
2391
1671
128
Final R
wR
0.0445
0.0403
0.005
Weights: p in w ¼ [s 2(Fo) þ (pFo)2]ꢀ1
Goodness of fit
1.879
Secondary extinction coefficient
Final Dmax/s
2.0(1) ꢂ 10ꢀ6
0.0003
0.24; ꢀ 0.19
D1 (max; min) [e ꢃꢀ3
]
5
)
CCDC-794912 contains the supplementary crystallographic data for this article. These data can be
obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.ca-
m.ac.uk/data_request/cif.

36
Helvetica Chimica Acta – Vol. 94 (2011)
C-atom. Refinement of the structure was carried out on F using full-matrix least-squares procedures,
which minimized the function Sw(j Fo jꢀj Fc j )2. A correction for secondary extinction was applied.
Neutral atom scattering factors for non-H-atoms were taken from [21a], and the scattering factors for H-
atoms were taken from [22]. Anomalous dispersion effects were included in Fc [23]; the values for f ’ and
f ’’ were those of [21b]. The values of the mass attenuation coefficients are those of [21c]. All calculations
were performed using the teXsan [24] crystallographic software package.
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Received September 30, 2010