A simple and convenient high yielding synthesis of substituted isoindolines

Article abstract of DOI:10.3987/COM-09-S(S)61

Trifluoroacetic anhydride-induced dehydration of substituted 2-(pivaloylaminomethyl)phenyl- and 2-(dimethylaminocarbonylmethyl)phenyl- methanols gives the corresponding isoindolines in excellent yields when there are aryl substituents at the methanol carbon atom.

Full text of DOI:10.3987/COM-09-S(S)61

HETEROCYCLES, Vol. 80, No. 2, 2010
941
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 941 - 956. © The Japan Institute of Heterocyclic Chemistry
Received, 20th July, 2009, Accepted, 4th September, 2009, Published online, 7th September, 2009
DOI: 10.3987/COM-09-S(S)61
A SIMPLE AND CONVENIENT HIGH YIELDING SYNTHESIS OF
SUBSTITUTED ISOINDOLINES
Keith Smith,* Gamal A. El-Hiti, Amany S. Hegazy, and Ahmed Fekri
School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff,
CF10 3AT, UK; e-mail: smithk13@cardiff.ac.uk and el-hitiga@cardiff.ac.uk
Abstract – Trifluoroacetic anhydride-induced dehydration of substituted
2-(pivaloylaminomethyl)phenyl- and 2-(dimethylaminocarbonylmethyl)phenyl-
methanols gives the corresponding isoindolines in excellent yields when there are
aryl substituents at the methanol carbon atom.
INTRODUCTION
Isoindoles represent the core unit of numerous naturally occurring substances.1-7 However, isoindoles are
commercially less important than indoles, at least partly because of a lack of good methods for their
synthesis. Simple isoindoles can be prepared from 1,2-bis(bromomethyl)benzene, 2-cyanobenzyl chloride,
phthalaldehyde or other carbonyl compounds.8-14 Unfortunately, such methods are less useful for isoindole
compounds with substituents on the benzene ring. However, Clayden has developed a very useful approach
to dihydroisoindolones with particular substitution patterns using dearomatising cyclization of lithiated
N-benzylbenzamides and demonstrated its utility for synthesis of natural products such as kainic acid.15-19
We have also been interested in efficient lithiation procedures for the production of substituted aromatics
and heteroaromatics that might be difficult to prepare by other means.20 We have recently developed
convenient procedures for the directed lithiation of compounds of the general formula 1 (Figure 1) using
t-BuLi in anhydrous THF at -78 C, followed by reactions with carbonyl compounds (aldehydes and
ketones) to give the corresponding ortho-disubstituted products 2 in high yields.21 In principle, compounds
2 could be cyclized to the corresponding isoindolines 3. We therefore decided to investigate this possibility
using trifluoroacetic anhydride (TFAA) as the dehydrating agent and now report success in obtaining the
corresponding isoindolines 3 in excellent yields when at least one of the groups R3 or R4 is an aryl group.
_____________________________________________________________________________________
Dedicated to Professor Akira Suzuki on the occasion of his 80th birthday.

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HETEROCYCLES, Vol. 80, No. 2, 2010
R2
O
NHCOR2
OH
NHCOR2
N
R1
R1
R1
R4
R4
R3
R3
1
2
3
t
R1 = H, OMe, Me, Cl, F; R2 = Bu, NMe2; R3, R4 = H, Ar, (CH2)5
Figure 1. Structures of compounds 1-3.
RESULTS AND DISCUSSION
An initial reaction was carried out between compound 4 and few drops of TFAA at room temperature in
dichloromethane (DCM, Scheme 1). TLC was used to monitor the progress of the reaction and indicated the
formation of a new product, the formation of which was complete within 5 minutes. The mixture was
quenched by the addition of water and worked-up. The residue obtained was subjected to flash column
chromatography (silica gel; Et2O–hexane, 1:3) to give the pure product, identified as compound 5, as a
white solid in 85% yield. The structure of 5 was confirmed by X-ray crystallography (Figure 2).
But
NHCOBut
TFAA, RT
N
DCM, 5 min
OH
Ph
O
Ph
Ph
Ph
5
4
(85%)
Scheme 1. Synthesis of 5 via dehydration of 4 with TFAA.
Figure 2. X-Ray crystal structure of compound 5

HETEROCYCLES, Vol. 80, No. 2, 2010
943
A possible mechanism for the formation of 5 is shown in Scheme 2.
O
O
O
HN
But
HN
But
O
HN
+
But
:
-
- CF3CO2
TFAA
OH
O
-
- CF3CO2
Ph
CF3
Ph
Ph
Ph
Ph
Ph
4
H
But
O
But
O
- H+
N
Ph
N
+
Ph
Ph
Ph
5
Scheme 2. A possible mechanism for the dehydration of 4 on treatment with TFAA
Having found that reaction of compound 4 with TFAA occurred smoothly and rapidly, it was of interest to
see if the cyclization reaction of other compounds related to 4 would be useful and general. Consequently,
reactions of various compounds of the type 2 with TFAA were carried out at room temperature in DCM for
5 minutes (Scheme 3). Each reaction was conducted under identical conditions and the crude products were
subjected to flash column chromatography to give the corresponding isoindolines 6-24 (Scheme 3) in
excellent yields (Table 1).
R2
NHCOR2
TFAA, RT
N
DCM, 5 min
OH
R4
R1
O
R1
R4
R3
6-24
R3
2
Scheme 3. Synthesis of various substituted isoindolines 6-24
The 1H NMR spectra of compounds where R3 and R4 are different (i.e. compounds 6-8, 10, 11, 13, 15, 17,
19 and 21-24) showed diastereotopicity for the two hydrogens of the CH2 group at position 3 of the
isoindoline ring. The two-dimensional NMR correlation spectroscopy (COSY) for compound 17 showed
that one of the hydrogens at the 3-position was also coupled to H-1. The structures of compounds 8 (Figure
3) and 17 (Figure 4) were confirmed by X-ray crystallography.

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HETEROCYCLES, Vol. 80, No. 2, 2010
Table 1: Synthesis of isoindolines 5-24 via dehydration of 2 according to Schemes 1 and 3
Product
R1
H
R2
R3
Ph
R4
Ph
Yield (%)a
85
5
6
tBu
H
H
OMe
OMe
Me
Cl
Cl
F
F
H
tBu
H
H
H
Ph
H
H
Ph
H
Ph
H
Ph
H
Ph
H
Ph
H
H
H
4-MeOC6H4
Ph
4-MeOC6H4
Ph
4-MeOC6H4
4-MeOC6H4
Ph
4-MeOC6H4
Ph
4-MeOC6H4
Ph
4-MeOC6H4
Ph
4-MeOC6H4
Ph
4-MeOC6H4
Ph
89
87
90
98
88
88
77
84
84
89
91
91
88
91
88
78
78
85
85
7
8
9
tBu
tBu
tBu
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
tBu
tBu
tBu
tBu
tBu
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
H
OMe
OMe
Me
Me
Cl
Cl
F
F
4-MeOC6H4
Ph
H
a Yield of isolated product after purification by column chromatography.
Figure 3. X-Ray crystal structure of compound 8

HETEROCYCLES, Vol. 80, No. 2, 2010
945
Figure 4. X-Ray crystal structure of compound 17
From the results in Table 1 it is clear that the cyclization is quite a general process, producing various
substituted isoindolines in excellent yields regardless of the nature of the ring substituent R1, of whether R2
was But or NMe2, or whether the groups at position 1 were two phenyl groups or one hydrogen and one aryl
group. The combination of directed lithiation of N-pivaloyl- or N-dimethylaminocarbonyl-benzylamines,
addition of an aromatic aldehyde or ketone,21 and then treatment with TFAA therefore represents a very
simple and direct approach to substituted isoindolines.
We next attempted to extend the process to compounds of type 2 in which the group C(OH)R3R4 had been
derived from cyclohexanone. It was found, however, that reactions of N-(2-(1-hydroxy-
cyclohexyl)benzyl)pivalamide (25) and N-(2-(1-hydroxycyclohexyl)-4-methoxybenzyl)pivalamide (26)
with TFAA in DCM at room temperature proceeded in a different manner (Scheme 4). The crude products
were purified by column chromatography to give 27 and 28, respectively, in high yields (Scheme 4).
NHCOBut
NHCOBut
TFAA, DCM
RT, 5 min
R
R
HO
25
27
R = H
26 R = OMe
R = H (82%)
28 R = OMe (83%)
Scheme 4. Synthesis of compounds 27 and 28
The reaction presumably proceeds via a cation similar to that shown in Scheme 2, but loss of a proton from
the adjacent position, impossible when the attached groups are aromatic, is easier, leading to an E1
elimination process.

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HETEROCYCLES, Vol. 80, No. 2, 2010
We attempted reactions of 25 and 26 with TFAA at room temperature for longer reaction times (up to 24 h)
but products 27 and 28 were obtained, respectively, in yields comparable to those obtained from the
reactions shown in Scheme 4. No further attempts were made to try to find conditions under which
cyclization of 25 and 26 to the corresponding substituted isoindolines could be effective.
CONCLUSION
Dehydration of various substituted benzylamines with trifluoroacetic anhydride gave the corresponding
isoindolines in excellent yields. The process is general, simple and convenient for compounds having
aromatic groups attached to the carbinol carbon atom. However, when a hydroxycyclohexyl group is
present at the 2-position, dehydration produces cyclohexenyl derivatives in high yield, rather than giving
isoindoline derivatives.
EXPERIMENTAL
GENERAL METHODS: Melting point determinations were performed by the open capillary method
using a Gallenkamp melting point apparatus and are reported uncorrected. 1H and 13C NMR spectra were
recorded on a Bruker AV400 or AV500 spectrometer operating at 400 or 500 MHz for 1H and 100 or 125
MHz for 13C measurements, respectively. Chemical shifts  are reported in parts per million (ppm) relative
13
to TMS and coupling constants J are in Hz and have been rounded to the nearest whole number. C
multiplicities are based on DEPT signals. Assignments of signals are based on coupling patterns and
expected chemical shift values and have not been rigorously confirmed. Signals with similar characteristics
might be interchanged. Low-resolution mass spectra were recorded on a Quattro II spectrometer, electron
impact (EI) at 70 eV and chemical ionization (CI) at 50 eV by the use of NH3 as ionization gas. Accurate
mass data were obtained on a MAT900 instrument. Electrospray (ES) analyses were performed on a
ZQ4000 spectrometer in positive and negative ionisation modes. IR spectra were recorded on a Perkin
Elmer Spectrum One FT-IR spectrometer or a Perkin Elmer 1600 series FT-IR Spectrometer.
Microanalyses were performed by Warwick analytical service at the University of Warwick. Column
chromatography was carried out using Fischer Scientific silica 60A (35-70 micron). Alkyllithiums were
obtained from Aldrich Chemical Company and were estimated prior to use by the method of Watson and
Eastham.22 Other chemicals were obtained from Aldrich Chemical Company and used without further
purification. THF was distilled from sodium benzophenone ketyl. Other solvents were purified by standard
procedures.23,24
Substituted aryl methanols 2: A solution of t-BuLi in heptane (2.6 mL, 1.7 M, 4.4 mmol) was added to a
cold (-78 C), stirred solution of 1 (2.0 mmol) in anhydrous THF (20 mL) under N2. The mixture was stirred

HETEROCYCLES, Vol. 80, No. 2, 2010
947
at –78 °C for 4 h, after which an aldehyde or ketone (2.2 mmol), in anhydrous THF (8 mL) if solid,
otherwise neat, was added. The mixture was stirred for 2 h at –78 °C then the cooling bath was removed and
the mixture allowed to warm to room temperature. It was then diluted with Et2O (10 mL) and quenched
with aq. sat. NH4Cl (10 mL). The organic layer was separated, washed with H2O (2 x 10 mL), dried
(MgSO4), and evaporated under reduced pressure. The residue obtained was purified by column
chromatography (silica gel; Et2O–hexane, 1:3) to give the corresponding product 2.21
1,1-Diphenyl-2-pivaloylisoindoline (5): Trifluoroacetic anhydride (0.5 mL) was added to a stirred
solution of N-(2-(hydroxydiphenylmethyl)benzyl)pivalamide (4; 0.50 g, 1.34 mmol) in DCM (10 mL) at
room temperature. The mixture was stirred for 5 min at room temperature, after which TLC showed the
formation of a single product. The reaction mixture was quenched with H2O (10 mL). The organic layer
was separated, washed with aq. sat. NaHCO3 (10 mL), H2O (2 x 10 mL), dried (MgSO4), and evaporated
under reduced pressure. The residue obtained was subjected to flash column chromatography (silica gel;
1
Et2O–hexane, 1:3) to give pure 5 (0.40 g, 1.14 mmol, 85%) as a white solid. Mp 150 °C. H NMR (400
MHz, CDCl3):  = 7.41–7.23 (m, 13 H, 2 Ph, H-4, H-5 and H-6), 7.04 (d, J = 8 Hz, 1 H, H-7), 5.30 (s, 2 H,
H-3), 1.35 [s, 9 H, C(CH3)3]. 13C NMR (100 MHz, CDCl3):  = 174.8 (s, C=O), 146.5 (s, C-7a), 143.1 (s,
C-1 of 2 Ph), 135.7 (s, C-3a), 128.8 (d, C-2/C-6 of 2 Ph), 128.5 (d, C-4), 128.0 (d, C-7), 127.9 (d, C-3/C-5 of
2 Ph), 127.0 (d, C-4 of 2 Ph), 125.1 (d, C-6), 122.2 (d, C-5), 80.9 (s, C-1), 53.9 (t, C-3), 40.1 [s, C(CH3)3],
28.0 [q, C(CH3)3]. MS (EI): m/z (%) = 355 (22) [M+], 298 (55), 278 (20), 255 (42), 239 (21), 220 (19), 206
(12), 194 (40), 178 (28), 165 (32), 116 (11), 105 (23), 91 (9), 77 (20), 57 (100), 41 (27). MS (CI): m/z (%) =
356 (100) [MH]+. HRMS (CI): m/z calcd. for C25H26NO [MH]+ 356.2009; found 356.2010. IR (FT):  =
2957, 1618, 1510, 1371, 1348, 1242, 1173, 1030 cm-1. Anal. Calcd for C25H25NO (355.194): C 84.47, H
7.09, N, 3.94. Found: C 84.35, H 7.03, N 3.83%.
Substituted isoindolines 6-24: The procedure was identical to that described for the synthesis of 5 except
that compounds 2 (0.50 g) were used as starting materials instead of 4. The residues obtained after work-up
were subjected to flash column chromatography (silica gel; Et2O–hexane, 1:3) to give the pure products
6–24 as white solids.
1
1-(4-Methoxyphenyl)-2-pivaloylisoindoline (6): 0.42 g (89%). Mp 112–114 °C. H NMR (400 MHz,
CDCl3):  = 7.32 (app. t, J = 8 Hz, 1 H, H-6), 7.29 (d, J = 8 Hz, 1 H, H-4), 7.25 (app. t, J = 8 Hz, 1 H, H-5),
7.19 (d, J = 9 Hz, 2 H, H-2/H-6 of 4-methoxyphenyl), 7.09 (d, J = 8 Hz, 1 H, H-7), 6.83 (d, J = 9 Hz, 2 H,
H-3/H-5 of 4-methoxyphenyl), 6.32 (s, 1 H, H-1), 5.26-5.16 (m, 2 H, H-3a and H-3b), 3.78 (s, 3 H, OCH3),
1.24 [s, 9 H, C(CH3)3]. 13C NMR (100 MHz, CDCl3):  = 176.8 (s, C=O), 159.0 (s, C-4 of

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4-methoxyphenyl), 141.4 (s, C-7a), 136.3 (s, C-3a), 128.3 (d, C-4 and C-7), 128.1 (s, C-1 of
4-methoxyphenyl), 128.0 (d, C-2/C-6 of 4-methoxyphenyl), 123.9 (d, C-6), 122.7 (d, C-5), 114.3 (d,
C-3/C-5 of 4-methoxyphenyl), 69.0 (d, C-1), 55.6 (q, OCH3), 54.0 (t, C-3), 39.7 [s, C(CH3)3], 28.0 [q,
C(CH3)3]. MS (EI): m/z (%) = 309 (12) [M]+, 294 (3), 278 (7), 252 (15), 224 (12), 209 (23), 194 (8), 165 (9),
135 (7), 116 (6), 57 (100), 41 (73). MS (CI): m/z (%) = 310 (100) [MH]+. HRMS (CI): m/z calcd. for
C20H24NO2 [MH]+ 310.1802; found 310.1802. IR (FT):  = 2958, 1616, 1510, 1371, 1357, 1242, 1117 cm-1.
Anal. Calcd for C20H23NO2 (309.173): C 77.64, H 7.49, N 4.53. Found: C 77.65, H 7.54, N 4.52%.
1
1-Phenyl-2-pivaloylisoindoline (7): 0.41 g (87%). Mp 110–111 °C. H NMR (400 MHz, CDCl3):  =
7.23–7.11 (m, 8 H, Ph, H-4, H-5 and H-6), 7.00 (d, J = 8 Hz, 1 H, H-7), 6.24 (s, 1 H, H-1), 5.17-5.07 (m, 2
H, H-3a and H-3b), 1.24 [s, 9 H, C(CH3)3]. 13C NMR (100 MHz, CDCl3):  = 175.2 (s, C=O), 143.9 (s, C-1
of Ph), 141.0 (s, C-7a), 136.2 (s, C-3a), 129.0 (d, C-3/C-5 of Ph), 128.4 (d, C-4), 128.1 (d, C-2/C-6 of Ph),
127.6 (d, C-4 of Ph), 126.7 (d, C-7), 123.9 (d, C-6), 122.7 (d, C-5), 69.7 (d, C-1), 54.2 (t, C-3), 39.8 [s,
C(CH3)3], 28.0 [q, C(CH3)3]. MS (EI): m/z (%) = 279 (11) [M]+, 222 (10), 194 (11), 179 (32), 178 (29), 165
(16), 116 (12), 105 (6), 91 (9), 89 (15), 77 (18), 57 (100), 41 (95). MS (CI): m/z (%) = 297 (2) [M + NH4]+,
280 (100) [MH]+. HRMS (CI): m/z calcd. for C19H22NO [MH]+ 280.1696; found 280.1694. IR (FT):  =
2962, 1616, 1510, 1410, 1369, 1357, 1209, 1093 cm-1.
1
6-Methoxy-1-(4-methoxyphenyl)-2-pivaloylisoindoline (8): 0.43 g (90%). Mp 133–134 °C. H NMR
(400 MHz, CDCl3):  = 7.21 (d, J = 8 Hz, 1 H, H-4), 7.18 (d, J = 9 Hz, 2 H, H-2/H-6 of 4-methoxyphenyl),
6.85 (dd, J = 2, 8 Hz, 1 H, H-5), 6.83 (d, J = 9 Hz, 2 H, H-3/H-5 of 4-methoxyphenyl), 6.58 (d, J = 2 Hz, 1
H, H-7), 6.25 (s, 1 H, H-1), 5.20-5.09 (m, 2 H, H-3a and H-3b), 3.78 (s, 3 H, OCH3), 3.74 (s, 3 H, OCH3),
1.32 [s, 9 H, C(CH3)3]. 13C NMR (100 MHz, CDCl3):  = 176.7 (s, C=O), 160.2 (s, C-6), 159.0 (s, C-4 of
4-methoxyphenyl), 142.8 (s, C-7a), 136.2 (s, C-1 of 4-methoxyphenyl and C-3a), 128.2 (d, C-4), 123.5 (d,
C-7), 114.9 (d, C-5), 114.3 (d, C-2/C-6 of 4-methoxyphenyl), 108.5 (d, C-3/C-5 of 4-methoxyphenyl), 69.1
(d, C-1), 55.9 (q, OCH3), 55.6 (q, OCH3), 53.5 (t, C-3), 39.7 [s, C(CH3)3], 28.0 [q, C(CH3)3]. MS (EI): m/z
(%) = 339 (8) [M]+, 282 (41), 254 (12), 239 (16), 238 (20), 224 (7), 208 (6), 195 (5), 165 (8), 152 (8), 139
(7), 104 (8), 92 (5), 77 (14), 57 (100), 41 (73). MS (CI): m/z (%) = 340 (100) [MH]+. HRMS (CI): m/z calcd.
for C21H26NO3 [MH]+ 340.1907; found 340.1913. IR (FT):  = 2959, 1615, 1511, 1477, 1400, 1358, 1243,
1171, 1023 cm-1. Anal. Calcd for C21H25NO3 (339.183): C 74.31, H 7.42, N 4.13. Found: C 74.42, H 7.46,
N 4.08%.
6-Methoxy-1,1-diphenyl-2-pivaloylisoindoline (9): 0.47 g (98%). Mp 119–121 °C. 1H NMR (400 MHz,
CDCl3):  = 7.26–7.10 (m, 11 H, 2 Ph and H-4), 6.73 (dd, J = 2, 8 Hz, 1 H, H-5), 6.37 (d, J = 2 Hz, 1 H, H-7),

HETEROCYCLES, Vol. 80, No. 2, 2010
949
5.11 (s, 2 H, H-3), 3.56 (s, 3 H, OCH3), 1.20 [s, 9 H, C(CH3)3]. 13C NMR (100 MHz, CDCl3):  = 175.2 (s,
C=O), 160.2 (s, C-6), 147.6 (s, C-7a), 142.7 (s, C-1 of 2 Ph), 128.7 (d, C-3/C-5 of 2 Ph), 128.4 (s, C-3a),
127.9 (d, C-2/C-6 of 2 Ph), 127.15 (d, C-4 of 2 Ph), 123.0 (d, C-4), 114.8 (d, C-7), 110.0 (d, C-5), 81.2 (s,
C-1), 55.8 (q, OCH3), 53.5 (t, C-3), 40.2 [s, C(CH3)3], 27.88 [q, C(CH3)3]. MS (EI): m/z (%) = 386 (22) [M
+ 1]+, 385 (81) [M]+, 328 (100), 308 (42), 300 (38), 292 (21), 220 (16). MS (CI): m/z (%) = 386 (100)
[MH]+, 328 (3), 303 (19), 284 (5). HRMS (CI): m/z calcd. for C26H28NO2 [MH]+ 386.2115; found 386.2113.
IR (FT):  = 2957, 1638, 1599, 1490, 1444, 1351, 1210, 1172 cm-1.
1
1-(4-Methoxyphenyl)-6-methyl-2-pivaloylisoindoline (10): 0.42 g (88%). Mp 148–149 °C. H NMR
(400 MHz, CDCl3):  = 7.22 (d, J = 8 Hz, 1 H, H-4), 7.18 d, J = 9 Hz, 2 H, H-2/H-6 of 4-methoxyphenyl),
7.10 (d, J = 8 Hz, 1 H, H-5), 6.90 (s, 1 H, H-7), 6.84 (d, J = 9 Hz, 2 H, H-3/H-5 of 4-methoxyphenyl), 6.26
(s, 1 H, H-1), 5.21-5.11 (m, 2 H, H-3a and H-3b), 3.78 (s, 3 H, OCH3), 2.30 (s, 3 H, CH3), 1.33 [s, 9 H,
C(CH3)3]. 13C NMR (100 MHz, CDCl3):  = 176.7 (s, C=O), 159.0 (s, C-4 of 4-methoxyphenyl), 141.5 (s,
C-7a), 138.1 (s, C-1 of 4-methoxyphenyl), 136.5 (s, C-6), 133.4 (s, C-3a), 128.9 (d, C-2/C-6 of
4-methoxyphenyl), 128.1 (d, C-7), 124.3 (d, C-4), 122.4 (d, C-5), 114.3 (d, C-3/C-5 of 4-methoxyphenyl),
70.0 (d, C-1), 55.6 (q, OCH3), 53.8 (t, C-3), 39.7 [s, C(CH3)3], 28.0 [q, C(CH3)3], 21.7 (q, CH3). MS (EI):
m/z (%) = 323 (4) [M]+, 266 (3), 238 (8), 223 (13), 208 (9), 194 (6), 165 (8), 130 (7), 77 (14), 57 (100), 41
(77). MS (CI): m/z (%) = 324 (100) [MH]+, 266 (3), 216 (5). HRMS (CI): m/z calcd. for C21H26NO2 [MH]+
324.1958; found 324.1953. IR (FT):  = 2958, 1637, 1535, 1357, 1231 cm-1. Anal. Calcd for C21H25NO2
(323.189): C 77.98, H 7.79, N 4.33. Found: C 77.84, H 7.83, N, 4.41%.
1
6-Chloro-1-(4-methoxyphenyl)-2-pivaloylisoindoline (11): 0.42 g (88%). Mp 137–139 ºC. H NMR
(500 MHz, CDCl3):  = 7.25 (s, 1 H, H-7), 7.20 (d, J = 8 Hz, 1 H, H-5), 7.10 (d, J = 9 Hz, 2 H, H-2/H-6
of 4-methoxyphenyl), 7.0 (d, J = 8 Hz, 1 H, H-4), 6.75 (d, J = 9 Hz, 2 H, H-3/H-5 of 4-methoxyphenyl),
13
6.20 (s, 1 H, H-1), 5.14-5.10 (m, 2 H, H-3a and H-3b), 3.70 (s, 3 H, OCH3), 1.25 [s, 9 H, C(CH3)3]. C
NMR (125 MHz, CDCl3):  = 178.4 (s, C=O), 162.7 (s, C-4 of 4-methoxyphenyl), 159.0 (s, C-7a), 142.1
(s, C-3a), 134.1 (s, C-1 of 4-methoxyphenyl), 133.7 (s, C-6), 128.2 (d, C-2/C-6 of 4-methoxyphenyl),
127.9 (d, C-4), 123.8 (d, C-7), 123.5 (d, C-5), 114.1 (d, C-3/C-5 of 4-methoxyphenyl), 68.9 (d, C-1), 55.2
37
(q, OCH3), 53.3 (t, C-3), 39.5 [s, C(CH3)3], 27.3 [q, C(CH3)3]. MS (EI): m/z (%) = 345 (22) [M Cl]+,
343 (67) [M 35Cl]+, 312 (28), 286 (100), 258 (29), 243 (45), 208 (50), 165 (18), 116 (16), 57 (40). HRMS
35
(EI): m/z calcd. for C20H22NO2 Cl [M]+ 343.1339; found 343.1340. IR (FT):  = 2921, 1635, 1460, 1383,
1260, 1154, 1106 cm-1.
1
6-Chloro-1,1-diphenyl-2-pivaloylisoindoline (12): 0.37 g (77%). Mp 166–168 ºC. H NMR (500 MHz,
CDCl3):  = 7.24-7.18 (m, 10 H, 2 Ph), 7.15 (s, 1 H, H-7), 7.10 (d, J = 8 Hz, 1 H, H-5), 6.85 (d, J = 8 Hz,

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HETEROCYCLES, Vol. 80, No. 2, 2010
13
1 H, H-4), 5.14 (s, 2 H, H-3), 1.18 [s, 9H, C(CH3)3]. C NMR (125 MHz, CDCl3):  = 174.4 (s, C=O),
147.9 (s, C-7a), 142.0 (s, C-1 of 2 Ph), 133.9 (s, C-3a), 133.8 (s, C-6), 128.3 (d, C-3/C-5 of 2 Ph), 128.1
(d, C-4), 127.7 (d, C-2/C-6 of 2 Ph), 126.9 (d, C-4 of 2 Ph), 124.9 (d, C-7), 123.2 (d, C-5), 80.5 (s, C-1),
53.0 (t, C-3), 39.7 [s, C(CH3)3], 27.6 [q, C(CH3)3]. MS (ES+): m/z (%) = 392 (33) [37Cl MH]+, 390 (100)
[35Cl MH]+. HRMS (ES+): m/z calcd. for C25H25NO35Cl [MH]+ 390.1625; found 390.1630. IR (FT):  =
2921, 1632, 1420, 1310, 1291, 1113, 1023 cm-1.
1
6-Fluoro-1-(4-methoxyphenyl)-2-pivaloylisoindoline (13): 0.40 g (84%). Oil. H NMR (500 MHz,
CDCl3):  = 7.20 (m, 1 H, H-4), 7.09 (d, J = 9 Hz, 2 H, H-2/H-6 of 4-methoxyphenyl) 6.92 (m, 1 H, H-5),
6.72 (d, J = 9 Hz, 2 H, H-3/H-5 of 4-methoxyphenyl), 6.61 (m, 1 H, H-7), 6.21 (s, 1 H, H-1), 5.12-5.07
(m, 2 H, H-3a and H-3b), 3.70 (s, 3 H, OCH3), 1.23 [s, 9 H, C(CH3)3]. 13C NMR (125 MHz, CDCl3):  =
177.6 (s, C=O), 162.8 (appears as two lines due to coupling with F, C-6), 158.9 (s, C-4 of
4-methoxyphenyl), 142.7 (s, C-7a), 134.5 (s, C-3a), 130.9 (s, C-1 of 4-methoxyphenyl), 127.9 (d, C-2/C-6
of 4-methoxyphenyl), 123.7 (appears as two lines due to coupling with F, C-4), 115.3 (appears as two
lines due to coupling with F, C-7), 114.1 (d, C-3/C-5 of 4-methoxyphenyl), 110.6 (appears as two lines
due to coupling with F, C-5), 69.0 (d, C-1), 55.2 (q, CH3), 53.1 (t, C-3), 39.4 [s, C(CH3)3], 27.4 [q,
C(CH3)3]. MS (ES+): m/z (%) = 328 (100) [MH]+ 146 (12), 130 (8). HRMS (ES+): m/z calcd. for
C20H23NO2F [MH]+ 328.1713; found 328.1709. IR (FT):  = 2963, 1722, 1440, 1311, 1199, 1161, 1011
cm-1.
1
6-Fluoro-1,1-diphenyl-2-pivaloylisoindoline (14): 0.40 g (84%). Oil. H NMR (500 MHz, CDCl3):  =
7.20-7.09 (m, 11 H, 2 Ph and H-7), 6.85 (m, 1 H, H-4), 6.58 (m, 1 H, H-5), 5.18 (s, 2 H, H-3), 1.20 [s, 9
13
H, C(CH3)3]. C NMR (125 MHz, CDCl3):  = 177.1 (s, C=O), 163.4 (appears as two lines due to
coupling with F, C-6), 147.6 (s, C-7a), 141.1 (s, C-1 of 2 Ph), 129.8 (s, C-3a), 128.2 (d, C-3/C-5 of 2 Ph),
127.9 (d, C-2/C-6 of 2 Ph), 127.3 (s, C-4 of 2 Ph), 123.3 (appears as two lines due to coupling with F,
C-4), 115.6 (appears as two lines due to coupling with F, C-7), 111.7 (appears as two lines due to
coupling with F, C-5), 81.5 (d, C-1), 53.2 (t, C-3), 40.1 [s, C(CH3)3], 27.2 [q, C(CH3)3]. MS (ES+): m/z
(%) = 374 (100) [MH]+, 273 (6). HRMS (ES+): m/z calcd. for C25H25NOF [MH]+ 374.1920; found
374.1914. IR (FT):  = 2931, 1612, 1496, 1454, 1411, 1289, 1072 cm-1.
1
1-(4-Methoxyphenyl)-2-dimethylaminocarbonylisoindoline (15): 0.42 g (89%). Mp 111–112 °C. H
NMR (400 MHz, CDCl3):  = 7.28–7.21 (m, 5 H, H-4, H-5, H-6 and H-2/H-6 of 4-methoxyphenyl), 7.03 (d,
J = 8 Hz, 1 H, H-7), 6.83 (d, J = 9 Hz, 2 H, H-3/H-5 of 4-methoxyphenyl), 6.37 (d, J = 3 Hz, 1 H, H-1), 5.10
(dd, J = 3, 14 Hz, 1 H, H-3a), 4.66 (d, J = 14 Hz, 1 H, H-3b), 3.78 (s, 3 H, OMe), 2.90 [s, 6 H, N(CH3)2]. 13C

HETEROCYCLES, Vol. 80, No. 2, 2010
951
NMR (100 MHz, CDCl3):  = 163.4 (s, C=O), 159.2 (s, C-4 of 4-methoxyphenyl), 142.2 (s, C-7a), 136.6 (s,
C-3a), 136.3 (s, C-1 of 4-methoxyphenyl), 128.8 (d, C-2/C-6 of 4-methoxyphenyl), 128.0 (d, C-4), 127.8 (d,
C-7), 123.9 (d, C-6), 122.4 (d, C-5), 114.3 (d, C-3/C-5 of 4-methoxyphenyl), 67.8 (d, C-1), 55.6 (q, OMe),
55.5 (t, C-3), 38.7 [q, N(CH3)2]. MS (EI): m/z (%) = 296 (7) [M]+, 252 (11), 224 (23), 208 (13), 194 (4), 180
(5), 165 (7), 135 (5), 116 (8), 87 (12), 72 (100), 44 (22). MS (CI): m/z (%) = 297 (100) [MH]+, 91 (14).
HRMS (CI): m/z calcd. for C18H21N2O2 [MH]+ 297.1598; found 297.1598. IR (FT):  = 2959, 1613, 1510,
1371, 1357, 1243, 1028 cm-1. Anal. Calcd for C18H20N2O2 (296.152): C 72.95, H 6.80, N 9.45. Found: C
72.80, H 6.78, N 9.30%.
2-Dimethylaminocarbonyl-1,1-diphenylisoindoline (16): 0.43 g (91%). Mp 161–163 °C. 1H NMR (400
MHz, CDCl3):  = 7.29–7.09 (m, 13 H, 2 Ph, H-4, H-5 and H-6), 6.90 (d, J = 8 Hz, 1 H, H-7), 4.90 (s, 2 H,
H-3), 2.61 [s, 6 H, N(CH3)2]. 13C NMR (100 MHz, CDCl3):  = 160.7 (s, C=O), 146.1 (s, C-7a), 142.3 (s,
C-1 of 2 Ph), 134.7 (s, C-3a), 127.6 (d, C-2/C-6 of 2 Ph), 126.7 (d, C-4), 126.5 (d, C-3/C-5 of 2 Ph), 126.3
(d, C-7), 125.7 (d, C-4 of 2 Ph), 123.4 (d, C-6), 120.9 (d, C-5), 80.0 (s, C-1), 52.5 (t, C-3), 38.0 [q, N(CH3)2].
MS (EI): m/z (%) = 342 (10) [M]+, 265 (22)+, 254 (24), 239 (9), 193 (7), 178 (15), 165 (20), 72 (100), 42
(10). MS (CI): m/z (%) = 343 (100) [MH]+, 272 (10), 106 (12), 89 (16), 63 (17), 52 (89), 46 (47). HRMS
(CI): m/z calcd. for C23H23N2O [MH]+ 343.1805; found 343.1809. IR (FT):  = 2957, 1617, 1510, 1371,
1358, 1242, 1173, 1037 cm-1.
2-Dimethylaminocarbonyl-6-methoxy-1-(4-methoxyphenyl)isoindoline (17): 0.43 g (91%). Mp
98–100°C. 1H NMR (400 MHz, CDCl3):  = 7.12 (d, J = 9 Hz, 2 H, H-2/H-6 of 4-methoxyphenyl), 7.05 (d,
J = 8 Hz, 1 H, H-4), 6.74–6.71 (m, 3 H, H-5 and H-3/H-5 of 4-methoxyphenyl), 6.42 (d, J = 2 Hz, 1 H, H-7),
6.23 (d, J = 3 Hz, 1 H, H-1), 4.90 (dd, J = 3, 13 Hz, 1 H, H-3a), 4.46 (d, J = 13 Hz, 1 H, H-3b), 3.67 (s, 3 H,
13
OCH3), 3.61 (s, 3 H, OCH3), 2.77 [s, 6 H, N(CH3)2]. C NMR (100 MHz, CDCl3):  = 163.4 (s, C=O),
160.0 (s, C-6), 159.3 (s, C-4 of 4-methoxyphenyl), 143.6 (s, C-7a), 136.2 (s, C-1 of 4-methoxyphenyl),
129.7 (d, C-2/C-6 of 4-methoxyphenyl), 129.1 (s, C-3a), 123.5 (d, C-4), 115.0 (d, C-7), 114.7 (d, C-3/C-5 of
4-methoxyphenyl), 108.9 (d, C-5), 67.9 (d, C-1), 55.8 (q, OCH3), 55.7 (q, OCH3), 55.0 (t, C-3), 38.7 [q,
N(CH3)2]. MS (EI): m/z (%) = 326 (3) [M]+, 282 (5), 254 (10), 238 (16), 218 (5), 146 (4), 72 (100), 44 (10).
MS (CI): m/z (%) = 327 (100) [MH]+, 105 (5), 91 (6), 52 (8), 46 (13). HRMS (CI): m/z calcd. for
C19H23N2O3 [MH]+ 327.1703; found 327.1702. IR (FT):  = 2931, 1616, 1511, 1400, 1370, 1251, 1023
cm-1. Anal. Calcd for C19H22N2O3 (326.163): C 69.92, H 6.79, N 8.58. Found: C 69.97, H 6.73, N 5.42%.
2-Dimethylaminocarbonyl-1,1-diphenyl-6-methoxyisoindoline (18): 0.42 g (88%). Mp 157–158 °C. 1H
NMR (400 MHz, CDCl3):  = 7.29–7.11 (m, 10 H, 2 Ph), 7.08 (d, J = 8 Hz, 1 H, H-4), 6.70 (dd, J = 2, 8 Hz,
1 H, H-5), 6.42 (d, J = 2 Hz, 1 H, H-7), 4.85 (s, 2 H, H-3), 3.58 (s, OCH3), 2.61 [s, 6 H, N(CH3)2]. 13C NMR

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(100 MHz, CDCl3):  = 162.0 (s, C=O), 159.9 (s, C-6), 148.9 (s, C-7a), 143.6 (s, C-1 of 2 Ph), 129.3 (d,
C-3/C-5 of 2 Ph), 128.2 (s, C-3a), 128.0 (d, C-2/C-6 of 2 Ph), 127.2 (d, C-4 of 2 Ph), 123.1 (d, C-4), 114.3
(d, C-5), 109.9 (d, C-7), 79.5 (s, C-1), 55.8 (q, OCH3), 53.6 (t, C-3), 39.5 [q, N(CH3)2]. MS (EI): m/z (%) =
372 (20) [M]+, 295 (6), 284 (41), 165 (7), 91 (8), 88 (19), 72 (100), 42 (22). MS (CI): m/z (%) = 373 (100)
[MH]+. HRMS (CI): m/z calcd. for C24H25N2O2 [MH]+ 373.1911; found 373.1911. IR (FT):  = 2997, 1617,
1510, 1371, 1242, 1172, 1029 cm-1. Anal. Calcd for C24H24N2O2 (372.184): C 77.39, H 6.49, N 7.52.
Found: C 77.37, H 6.51, N 7.47%.
2-Dimethylaminocarbonyl-1-(4-methoxyphenyl)-6-methylisoindoline (19): 0.43 g (91%). Mp
125–126 °C. 1H NMR (400 MHz, CDCl3):  = 7.13 (d, J = 9 Hz, 2 H, H-2/H-6 of 4-methoxyphenyl), 7.05 (d,
J = 8 Hz, 1 H, H-4), 6.97 (d, J = 8 Hz, 1 H, H-5), 6.75–6.73 (m, 3 H, H-7 and H-3/H-5 of 4-methoxyphenyl),
6.22 (d, J = 2 Hz, 1 H, H-1), 4.94 (dd, J = 2, 14 Hz, 1 H, H-3a), 4.50 (d, J = 14 Hz, 1 H, H-3b), 3.68 (s, 3 H,
OCH3), 2.78 [s, 6 H, N(CH3)2], 2.18 (s, 3 H, CH3). 13C NMR (100 MHz, CDCl3):  = 163.4 (s, C=O), 159.2
(s, C-4 of 4-methoxyphenyl), 142.3 (s, C-7a), 137.7 (s, C-6), 136.4 (s, C-1 of 4-methoxyphenyl), 133.6 (s,
C-3a), 128.5 (d, C-2/C-6 of 4-methoxyphenyl), 128.2 (d, C-7), 124.3 (d, C-4), 122.2 (d, C-5), 114.3 (d,
C-3/C-5 of 4-methoxyphenyl), 67.8 (d, C-1), 55.6 (q, OCH3), 55.3 (t, C-3), 38.7 [q, N(CH3)2], 15.7 (q, CH3).
MS (EI): m/z (%) = 310 (5) [M]+, 266 (14), 238 (22), 222 (19), 165 (13), 130 (12), 72 (100), 44 (15), 42 (23).
MS (CI): m/z (%) = 311 (100) [MH]+, 52 (22). HRMS (CI): m/z calcd. for C19H23N2O2 [MH]+ 311.1754;
found 311.1749. IR (FT):  = 2958, 1616, 1511, 1371, 1358, 1243, 1029 cm-1. Anal. Calcd for C19H22N2O2
(310.168): C 73.52, H 7.14, N 9.03. Found: C 73.50, H 7.15, N 9.01%.
1
2-Dimethylaminocarbonyl-1,1-diphenyl-6-methylisoindoline (20): 0.42 g (88%). Mp 158–160 °C. H
NMR (400 MHz, CDCl3):  = 7.27–7.13 (m, 10 H, 2 Ph), 7.07 (d, J = 8 Hz, 1 H, H-4), 6.95 (d, J = 8 Hz, 1
H, H-5), 6.72 (s, 1 H, H-7), 3.25 (s, 2 H, H-3), 2.61 [s, 6 H, N(CH3)2], 2.15 (s, 3 H, CH3). 13C NMR (100
MHz, CDCl3):  = 161.9 (s, C=O), 147.6 (s, C-7a), 143.8 (s, C-1 of 2 Ph), 137.9 (s, C-6), 133.1 (s, C-3a),
129.0 (d, C-3/C-5 of 2 Ph), 128.8 (d, C-7), 127.9 (d, C-2/C-6 of 2 Ph), 127.1 (d, C-4 of 2 Ph), 125.2 (d, C-4),
122.1 (d, C-5), 79.4 (s, C-1), 53.8 (t, C-3), 39.5 [q, N(CH3)2], 21.9 (q, CH3). MS (EI): m/z (%) = 356 (7)
[M]+, 279 (13), 268 (31), 253 (7), 165 (13), 72 (100), 42 (15). MS (CI): m/z (%) = 357 (100) [MH]+, 193
(12), 106 (14), 89 (16), 46 (30). HRMS (CI): m/z calcd. for C24H25N2O [MH]+ 357.1961; found 357.1960.
IR (FT):  = 2852, 1619, 1520, 1363, 1340, 1218 cm-1.
1
6-Chloro-2-dimethylaminocarbonyl-1-(4-methoxyphenyl)isoindoline (21): 0.37 g (78%). Oil. H
NMR (500 MHz, CDCl3):  = 7.25 (s, 1 H, H-7), 7.20 (d, J = 8 Hz, 1 H, H-5), 7.10 (d, J = 9 Hz, 2 H,
H-2/H-6 of 4-methoxyphenyl), 6.90 (d, J = 8 Hz, 1 H, H-4), 6.75 (d, J = 9 Hz, 2 H, H-3/H-5 of

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4-methoxyphenyl), 6.25 (d, J = 3 Hz, 1 H, H-1), 4.95 (dd, J = 3, 14 Hz, 1 H, H-3a), 4.50 (d, J = 14 Hz, 1
H, H-3b), 3.65 (s, 3 H, OCH3), 2.75 [s, 6 H, N(CH3)2]. 13C NMR (125 MHz, CDCl3):  = 162.8 (s, C=O),
159.1 (s, C-4 of 4-methoxyphenyl), 143.8 (s, C-7a), 135.1 (s, C-3a), 134.7 (s, C-6), 133.4 (s, C-1 of
4-methoxyphenyl) 128.3 (d, C-2/C-6 of 4-methoxyphenyl), 127.8 (d, C-4), 123.8 (d, C-7), 123.3 (d, C-5),
114.0 (d, C-3/C-5 of 4-methoxyphenyl), 67.2 (d, C-1), 55.2 (q, OCH3), 54.6 (t, C-3), 38.3 [q, N(CH3)2].
MS (APCI): m/z (%) = 333 (33) [37Cl MH]+, 331 (100) [35Cl MH]+, 243 (10), 223 (22). HRMS (APCI):
35
m/z calcd. for C18H20N2O2 Cl [MH]+ 331.1213; found 331.1215. IR (FT):  = 2963, 1644, 1485, 1438,
1261, 1098 cm-1.
6-Chloro-2-dimethylaminocarbonyl-1-phenylisoindoline (22): 0.37 g (78%). Oil. 1H NMR (500 MHz,
CDCl3):  = 7.25 (s, 1 H, H-7), 7.20-7.10 (m, 5 H, Ph), 7.09 (d, J = 8 Hz, 1 H, H-5), 6.90 (d, J = 8 Hz, 1
H, H-4), 6.25 (d, J = 3 Hz, 1 H, H-1), 4.95 (dd, J = 3, 14 Hz, 1 H, H-3a), 4.53 (d, J = 14 Hz, 1 H, H-3b),
2.80 [s, 6 H, N(CH3)2]. 13C NMR (125 MHz, CDCl3):  = 162.8 (s, C=O), 143.5 (s, C-7a), 142.8 (s, C-3a),
134.6 (s, C-1 of Ph), 133.5 (s, C-6), 128.7 (d, C-3/C-5 of Ph), 127.9 (d, C-4), 127.7 (d, C-7), 127.0 (d,
C-2/C-6 of Ph), 123.7 (d, C-5), 123.4 (d, C-4 of Ph), 67.8 (d, C-1), 54.9 (t, C-3), 38.3 [q, N(CH3)2]. MS
(APCI): m/z (%) = 303 (33) [37Cl MH]+, 301 (100) [35Cl MH]+, 256 (10), 213 (13). HRMS (APCI): m/z
calcd. for C17H18N2O35Cl [MH]+ 301.1108; found 301.1096. IR (FT):  = 2971, 1698, 1540, 1466, 1427,
1368, 1156, 1087 cm-1.
2-Dimethylaminocarbonyl-6-fluoro-1-(4-methoxyphenyl)isoindoline (23): 0.40 g (85%). Oil. 1H NMR
(500 MHz, CDCl3):  = 7.15 (d, J = 9 Hz, 2 H, H-2/H-6 of 4-methoxyphenyl), 7.10 (m, 1 H, H-4), 6.90
(m, 1 H, H-5), 6.75 (d, J = 9 Hz, 2 H, H-3/H-5 of 4-methoxyphenyl), 6.60 (m, 1 H, H-7), 6.28 (s, 1 H,
H-1), 4.92 (d, J = 13 Hz, 1 H, H-3a), 4.50 (d, J = 13 Hz, 1 H, H-3b), 3.70 (s, 3 H, OCH3), 2.80 [s, 6 H,
N(CH3)2]. 13C NMR (125 MHz, CDCl3):  = 163.7 (s, C=O), 162.3 (appears as two lines due to coupling
with F, C-6), 159.1 (s, C-4 of 4-methoxyphenyl), 143.9 (s, C-7a), 135.2 (s, C-3a), 131.6 (s, C-1 of
4-methoxyphenyl), 128.3 (d, C-2/C-6 of 4-methoxyphenyl), 123.4 (appears as two lines due to coupling
with F, C-4), 114.9 (appears as two lines due to coupling with F, C-7), 114.0 (d, C-3/C-5 of
4-methoxyphenyl), 110.5 (appears as two lines due to coupling with F, C-5), 67.4 (d, C-1), 55.2 (q, CH3),
54.5 (t, C-3), 38.3 [q, N(CH3)2]. MS (ES+): m/z (%) = 315 (100) [MH],+ 146 (15), 130 (8). HRMS (ES+):
m/z calcd. for C18H20N2O2F [MH]+ 315.1509; found 315.1501. IR (FT):  = 2960, 1639, 1465, 1423, 1367,
1321, 1251, 1133, 1072 cm-1.
1
2-Dimethylaminocarbonyl-6-fluoro-1-phenylisoindoline (24): 0.40 g (85%). Oil. H NMR (500 MHz,
CDCl3):  = 7.25-7.10 (m, 6 H, Ph, H-7), 6.85 (m, 1 H, H-4), 6.63 (m, 1 H, H-5), 6.30 (s, 1 H, H-1), 5.00

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13
(d, J = 13 Hz, 1 H, H-3a), 4.55 (d, J = 13 Hz, 1 H, H-3b), 2.82 [s, 6 H, N(CH3)2]. C NMR (125 MHz,
CDCl3):  = 163.7 (s, C=O), 162.5 (appears as two lines due to coupling with F, C-6), 143.2 (s, C-7a),
142.4 (s, C-1 of Ph), 131.2 (s, C-3a), 129.0 (d, C-3/C-5 of Ph), 127.9 (d, C-4 of Ph), 126.9 (d, C-2/C-6 of
Ph), 123.5 (appears as two lines due to coupling with F, C-4), 115.2 (appears as two lines due to coupling
with F, C-7), 110.6 (appears as two lines due to coupling with F, C-5), 68.2 (d, C-1), 54.8 (t, C-3), 38.5 [q,
N(CH3)2]. MS (ES+): m/z (%) = 285 (100) [MH]+, 197 (8). HRMS (ES+): m/z calcd. for C17H18N2OF
[MH]+ 285.1403; found 285.1392. IR (FT):  = 2951, 1632, 1586, 1517, 1486, 1376, 1285, 1178, 1038
cm-1.
N-(2-(Cyclohexenyl)pivalamides 27 and 28: The procedure was identical with that described for the
synthesis of 5 except that compounds 25 and 26 (0.50 g) were used as starting materials instead of 4. The
reaction mixtures were worked-up and the residues obtained were subjected to flash column
chromatography (silica gel; Et2O–hexane, 1:3) to give the pure products 27 and 28 as white solids.
1
N-(2-Cyclohexen-1-ylbenzyl)pivalamide (27): 0.38 g (82%). Mp 118–119 °C. H NMR (400 MHz,
CDCl3):  = 7.19–7.03 (m, 4 H, H-3, H-4, H-5 and H-6), 5.78 (br, exch., 1 H, NH), 5.52 (m, 1 H, H-2 of
cyclohexenyl), 4.34 (d, J = 5 Hz, 2 H, CH2), 2.15–2.07 (m, 4 H, H-3 and H-6 of cyclohexenyl), 1.71–1.58
(m, 4 H, H-4 and H-5 of cyclohexenyl), 1.13 [s, 9 H, C(CH3)3]. 13C NMR (100 MHz, CDCl3):  = 178.4 (s,
C=O), 144.8 (s, C-1 of cyclohexenyl), 138.4 (s, C-1), 135.5 (s, C-2), 129.3 (d, C-5), 128.9 (d, C-6), 127.7 (d,
C-3), 127.4 (d, C-4), 127.2 (d, C-2 of cyclohexenyl), 42.2 (t, CH2NH), 39.1 [s, C(CH3)3], 31.0 (t, C-6 of
cyclohexenyl), 28.0 [q, C(CH3)3], 25.8 (t, C-3 of cyclohexenyl), 23.4 (t, C-5 of cyclohexenyl), 22.4 (t, C-4
of cyclohexenyl). MS (EI): m/z (%) = 271 (4) [M]+, 186 (8), 171 (17), 170 (56), 157 (11), 142 (50), 128 (32),
115 (26), 102 (12), 91 (11), 77 (5), 57 (100), 41 (71). MS (CI): m/z (%) = 543 (4) [2 M + 1]+, 289 (6) [M +
NH4]+, 272 (100) [MH]+, 170 (15), 119 (17), 102 (9), 52 (24). HRMS (CI): m/z calcd. for C18H26NO [MH]+
272.2009; found 272.2012. IR (FT):  = 3328, 2921, 1638, 1512, 1540, 1368, 1210, 1003 cm-1. Anal. Calcd
for C18H25NO (271.194): C 79.66, H 9.28, N 5.16. Found: C 79.73, H 9.33, N 5.09%.
N-(2-Cyclohexen-1-yl-4-methoxybenzyl)pivalamide (28): 0.39 g (83%). Mp 99–100 °C. 1H NMR (400
MHz, CDCl3):  = 7.09 (d, J = 8 Hz, 1 H, H-6), 6.68 (dd, J = 2, 8 Hz, 1 H, H-5), 6.58 (d, J = 2 Hz, 1 H, H-3),
5.70 (br, exch., 1 H, NH), 5.52 (m, 1 H, H-2 of cyclohexenyl), 4.26 (d, J = 5 Hz, 2 H, CH2), 3.71 (s, 3 H,
OCH3), 2.15–2.06 (m, 4 H, H-3 and H-6 of cyclohexenyl), 1.71–1.58 (m, 4 H, H-4 and H-5 of
cyclohexenyl), 1.11 [s, 9 H, C(CH3)3]. 13C NMR (100 MHz, CDCl3):  = 178.2 (s, C=O), 159.1 (s, C-4),
146.2 (s, C-1 of cyclohexenyl), 138.5 (s, C-2), 130.5 (d, C-6), 127.7 (s, C-1), 127.1 (d, C-2 of cyclohexenyl),
114.7 (d, C-5), 112.7 (d, C-3), 55.7 (q, OCH3), 41.8 (t, CH2NH), 39.0 [s, C(CH3)3], 30.9 (t, C-6 of

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cyclohexenyl), 28.0 [q, C(CH3)3], 25.7 (t, C-3 of cyclohexenyl), 23.4 (t, C-5 of cyclohexenyl), 21.9 (t, C-4
of cyclohexenyl). MS (EI): m/z (%) = 301 (2) [M]+, 200 (22), 172 (13), 159 (9), 128 (6), 115 (8), 77 (5), 57
(100), 41 (93). MS (CI): m/z (%) = 319 (3) [M + NH4]+, 302 (100) [MH]+, 200 (11), 119 (17), 102 (12), 52
(15). HRMS (CI): m/z calcd. for C19H28NO2 [MH]+ 302.2115; found 302.2115. IR (FT):  = 3347, 2940,
1647, 1505, 1492, 1330, 1207, 1029 cm-1.
ACKNOWLEDGEMENTS
We thank Dr Benson Kariuki, X-ray crystallography service at Cardiff School of Chemistry, for the crystal
structures and Cardiff University and the Egyptian Government for financial support.
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