Convenient access to isoindolinones via carbamoyl radical cyclization. Synthesis of cichorine and 4-hydroxyisoindolin-1-one natural products

Article abstract of DOI:10.1016/j.tet.2011.01.003

An efficient and convenient access to 2-tert-butylisoindolin-1-ones via an oxidative radical cyclization process from stable carbamoylxanthates, derived from secondary tert-butylamines, is described. The proposed mechanism for this transformation involves, the generation of a carbamoyl radical, its cyclization to the aromatic system, and the dilauroyl peroxide (DLP) mediated rearomatization to generate the isoindolinone ring system. Additionally, the syntheses of cichorine and 4-hydroxyisoindolin-1-one natural products were carried out to underscore the synthetic potential of this xanthate-based carbamoyl radical-oxidative cyclization.

Full text of DOI:10.1016/j.tet.2011.01.003

Tetrahedron 67 (2011) 2693e2701
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convenient access to isoindolinones via carbamoyl radical cyclization. Synthesis
of cichorine and 4-hydroxyisoindolin-1-one natural products
a
,
b
a
a
b
ꢀ
ꢀ
ꢀ
~
German Lopez-Valdez , Simon Olguín-Uribe , Alejandra Millan-Ortíz , Rocio Gamez-Montano ,
,
Luis D. Miranda a
*
a
ꢀ
ꢀ
ꢀ
ꢀ
Instituto de Química, Universidad Nacional Autonoma de Mexico, Circuito Exterior S.N., Ciudad Universitaria, Coyoacan 04510, Mexico D.F., Mexico
b Departamento de Química, Universidad de Guanajuato, Noria Alta S/N, 36050 Guanajuato, Gto, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and convenient access to 2-tert-butylisoindolin-1-ones via an oxidative radical cyclization
process from stable carbamoylxanthates, derived from secondary tert-butylamines, is described. The
proposed mechanism for this transformation involves, the generation of a carbamoyl radical, its cycli-
zation to the aromatic system, and the dilauroyl peroxide (DLP) mediated rearomatization to generate
the isoindolinone ring system. Additionally, the syntheses of cichorine and 4-hydroxyisoindolin-1-one
natural products were carried out to underscore the synthetic potential of this xanthate-based carbamoyl
radical-oxidative cyclization.
Received 18 October 2010
Received in revised form 28 December 2010
Accepted 4 January 2011
Available online 9 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
catalytic system Pd(OAc)2eCu(OAc)2,16c
a
tandem elimi-
nationecyclizationeSuzuki approach,16d a HeckeSuzukieMiyaura
dominoreactioninvolvingynamides,16e anda Sonogashirareactionof
2-halobenzamides with terminal alkynes. Other approaches to the
isoindolinone system involve electrophilic cyclization,1b and an
intramolecular cyclization of acyl radicals onto an azide group.16f
Importantly, the majority of the aforementioned approaches require
the preparation of haloarene starting materials, which sometimes
involves multistep synthetic sequences (Fig. 1).
Isoindolin-1-ones are a common moiety in a variety of natural
products including magallanesine 1,1 lennoxamine 2,2 stachybotrin C
3,3 and also in some pharmacologically important synthetic com-
pounds, such as zopiclone 44 and pagoclone 5 (Fig.1). 2d,e,5 Numerous
synthetic and natural molecules containing the isoidolin-1-one
framework have been reported to display significant biological ac-
tivities including antimicrobials,6 anti-viral drugs for the treatment of
the common cold,7 HIV-1 inhibitors,8 TACE inhibitors,9 antitumor
activity,10 sedative, hypnotic agents,11 antidopaminergic agents, and
also protein kinase inhibiting activities.12 Their utility in DielseAlder
reactions is well established and these heterocycles frequently serve
as a building block for asymmetric synthesis.13,14 Recently these
heterocyclic scaffolds were also reported to have special fluorescent
properties.15
Several methodologies have been developed for the construction
of the isoindolinone ring system1b,16 including cyclizations of aryl
lithium species of different N-acyl-benzylamine derivatives such as
N0-benzyl-N,N-dimethylureas.16b However, such methodologies re-
quire the use of strong basic organo-lithium regents, which are nor-
mally incompatible with functional groups sensitive to nucleophilic
attack. More recently, several metal-catalyzed approaches have been
described for the synthesis of isoindolinones. Leading examples in-
clude carbonylation of benzylamines under CO atmosphere using the
OMe
O
OMe
O
O
MeO
O
MeO
N
N
Cl
N
N
MeN
O
N
O
O
O
O
O
1
2
Lennoxamine
4
Zopiclone
Magallanasine
O
O
HO
N
N
OH
N
N
Me
O
HO
O
Cl
5
Pagoclone
3
Stachybotrine C
* Corresponding author. Tel.: þ52 55 56 22 44 40; fax: þ52 55 56 16 22 17; e-mail
Fig. 1. Natural products containing the isoindolin-1-one ring system.
address: lmiranda@unam.mx (L.D. Miranda).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.003

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G. Lopez-Valdez et al. / Tetrahedron 67 (2011) 2693e2701
2694
We have been interested in the use of the addition of alkyl and
ethyl xanthate itself in the reaction media might be responsible for
the fast decomposition of related congener S-acylxanthates.24 It is
noteworthy that the use of an excess of the potassium xanthate had
no significant effect on the isolated yield of 8a.
acyl radicals to aromatic and heteroaromatic systems.17 In this
context, we examined the feasibility of implementing the oxidative
cyclization of carbamoyl radicals onto aromatic systems as an in-
novative and easy access to the isoindolin-1-one ring system.18 The
application of the cyclization of carbamoyl radicals to a benzenoid
system to prepare the isoindolinone ring system entails several
advantages: in this free radical-based process, the use of strong
bases is avoided; no high pressure of CO is required; and it occurs
through a substitution at a CeH bond of the aromatic ring, obvi-
ating the complications associated with the synthesis of haloarene
starting materials. Addition processes of carbamoyl radicals to
double bonds,19 aromatic systems,20 and oxime ethers21 have been
reported. More recently the powerful synthetic potential of these
radicals has been illustrated in the synthesis of the complex natural
product stephacidin B.22 Given the efficiency of generation of alkyl
and acyl radicals from dithiocarbonates, developed by Zard and co-
workers,23 we envisioned the possibility of using the related car-
bamoylxanthates (carbamoyldithiocarbonates) as the carbamoyl
radical source.24 Previously, while preparing carbamoyldithiocar-
bonates, Grainger and Innocenti19g observed that these species are
unstable and lost a CS or a CO molecule, affording poor yields of the
desired dithiocarbonate. This drawback was resolved by using19g
the more stable carbamoyldithiocarbamates as the carbamoyl
radical source and this methodology was used to construct several
lactams of different sizes via an intermolecular carbamoyl addition/
xanthate transfer radical process onto a double bond. Despite these
advances, the synthesis of carbamoylxanthates, their use as
a source of carbamoyl radicals and their oxidative cyclization to an
aromatic system has remained elusive.19
With the desired carbamoylxanthate 8a in hand, its ability to
undergo carbamoyl radical-mediated cyclization to the isoindolinone
11 was then evaluated under typical free radical conditions. We were
gratified to observe that the isoindolinone 11 was obtained in good
yield, upon the portionwise addition of a stoichiometric amount of
dilauroyl peroxide (DLP) (1.2 equiv over 1.5 h) to a boiling solution of
8a in dichloroethane (2 mL/mmol) (Scheme 2). The proposed mech-
anism for this transformation involves the DLP-induced generation of
the carbamoyl radical 9 by a mechanism similar to that observed in
related alkylxanthates, then the cyclization of this latter radical to
generate the radical 10, which might undergo a DLP-mediated oxi-
dative rearomatization23 to the isoindolinone 11. According to the
proposed mechanism, the DLP acts as both initiator and oxidant, and
thus, stoichiometric amounts of this reagent are needed for the
completion of the reaction.
t-Bu
O
t-Bu
N
N
O
Lauroyl
peroxide
S
S
OEt
11 (72%)
DLP
8a
t-Bu
N
N
t-Bu
O
O
10
9
2. Results and discussion
Scheme 2. Proposed mechanism.
In contrast with the report of Grainger and Innocenti regarding
the instability of carbamoyldithiocarbonates, our initial studies
showed that the corresponding carbamoyldithiocarbonate 8a could
be isolated as a remarkably stable, crystalline compound in grati-
fying 77% yield, from the reaction of the N-tert-butylbenzylamine
6a and triphosgene, reacting the carbamoyl chloride intermediate
7a with commercial potassium ethyl xanthate in acetonitrile at rt
(Scheme 1). The structure of this compound 7a was verified by
X-ray crystallography. We further observed that the stability of 8a
relied on the steric hindrance in the amine moiety since the pu-
tative carbamoylxanthates 8b and 8c were unstable and rapidly
decomposed to complex mixtures during their preparation under
the same conditions. Remarkably, 8a remained unchanged after 2 h
in chlorobenzene at reflux temperature. This stability may be
a consequence of conformational effects of the N-tert-butyl group
either through fixing a specific conformation, engendering a high
NCO rotational barrier, or simply by steric hindrance in the vicinity
of the NCO moiety, preventing further decomposition (CO/CS
loss)19g of the carbamoylxanthate. However, at the present time we
have no convincing data to support these speculations. Previously,
Zard and co-workers had observed that an excess of potassium
To investigate the scope of this practical entry into isoindolin-1-
one scaffolds, several ring substituted tert-butylbenzylamines were
prepared from the corresponding aldehydes by reductive amination
with N-tert-butylamine. Then, all these latter benzylamines were
converted into the corresponding stable and isolable carba-
moylxanthates, under the aforementioned conditions. Furthermore,
independently of the electronegative nature of the benzenoid sub-
stituent(s), in every case but one the ring substituted N-tert-butyli-
soindolinone was obtained in excellent yield when the
carbamoylxanthates were subjected to the above carbamoyl radical
generating conditions. Isoindolinones 14a,b were isolated from the
reaction of the electron-rich substrates carbamoylxanthates 13a,b in
good yield. Electron-deficient substrates 13cee underwent carba-
moyl radical cyclization in similar good yield (Table 1, entry 1).
Comparable good yields were observed with para- and ortho-
substituted substrates (Table 1, entries 1 and 2). However, for rea-
sons that are not completely clear, the nitro derivatives 13f (4-NO2)
and 16c (2-NO2) were obtained in only low yields and did not afford
the desired isoindolinone under the same radical-oxidative condi-
tions. It was observed that 13f and 16c decomposed spontaneously
after a careful purification. Interestingly, the carbamoylxanthate
13e, also bearing an electron withdrawing ester group, afforded the
corresponding isoindolinone 14e in very good yield. The 3,4-meth-
ylenedioxy compound 19 gave a mixture of isoindolinones in which
the product derived from cyclization at C-6 (20), the less hindered
position, was only slightly favored (5.5:4.5) over that derived from
attack at C-2 (21). The 3-bromo compound 23 gave a 3:2 mixture of
products derived from cyclization at C-2 (25) and C-6 (24), re-
spectively. The data collected in Table 1 convincingly show that
R
NH
R
N
R
N
O
O
Triphosgene,
KSC(S)OEt,
Et3N, CH2Cl2,
0 °C, 10 min
CH3CN,
r. t. 15 min,
S
S
Cl
OEt
8a
6a
R = t-Bu (77%)
R = t-Bu
7a R = t-Bu
7b R = i-Pr
6b R = i-Pr
6c R = Me
8b R = i-Pr (0%)
8c R = Me, (0%)
7c
R = Me
Scheme 1.

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G. Lopez-Valdez et al. / Tetrahedron 67 (2011) 2693e2701
2695
Table 1
Synthesis of 2-tert-butylisoindolin-1-ones from tert-butylbenzylamines
Entry Amine
Xanthatea
Product
Nt-Bu
NH
Nt-Bu
t-Bu
R
Xtht
O
R
R
O
12a R = Me
12b R = OMe
12cR = Br
12d R = Cl
12e R = COOMe
12f R = NO2
13a R = Me (81%)
13b R = OMe (80%)
13c R = Br (82%)
13d R = Cl (71%)
13e R = COOMe (85%)
13f R = NO2 (42%)
14a R = Me (77%)
14b R = OMe (72%)
14cR = Br (92%)
14d R = Cl (86%)
14e R = COOMe (91%)
14f R = NO2 (0%)
1
R
R
R
Nt-Bu
NH
t-Bu
Nt-Bu
Xtht
O
2
O
15a R = Cl
15b R = F
15c R = NO2
16a R = Cl (84%)
16b R = F (65%)
17 aR = Cl (85%)
17b R = F (90%)
17c R = NO2 (0%)
16c R = NO2
(31%)
O
Nt-Bu
O
O
O
O
NH
Nt-Bu
t-Bu
3
20
O
O
Xtht
O
19 (85%)
18
Nt-Bu
O
O
O
21 (80%)
Br
Nt-Bu
O
Br
Br
Nt-Bu
NH
24
4
t-Bu
Xtht
O
Br
O
22
23 (60%)
Nt-Bu
25 (82%)
O
t-Bu
N
O
t-Bu
NH
Xtht
N
CH3
N
t-Bu
5
N
28 (0%)
t-Bu
N
CH3
CH3
26
NH
27 (51%)
N
O
CH3
29 (85%)
a
Xtht¼SC(S)OEt.
a variety of substituted isoindolinones can be readily prepared using
this technology.
corresponding carbamoylxanthate 27 in good yield, under the
conditions described above. Interestingly, under the optimized
radical conditions, xanthate 27 afforded the tert-butylamide
derivative 29 as the sole product in good yield, instead of the
desired pyrrolo-pyrrolidone ring system 28 (Table 1, entry 5).
Mechanistically, this transformation might be a result of a Smiles-
type rearrangement mechanism similar to those reported pre-
viously (Scheme 3).25 Accordingly, the carbon-centered carbamoyl
To expand the scope of the methodology, we applied the car-
bamoyl radical cyclization methodology to the pyrrole derivative 27
in an attempt to obtain the pyrrolo-pyrrolidone system 28 (Table 1,
entry 5). Thus, 1-methyl-2-formylpyrrole, afforded the corre-
sponding amine 26 through a reductive amination process with
N-tert-butylamine. Then, amine 26 was converted into the

ꢀ
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G. Lopez-Valdez et al. / Tetrahedron 67 (2011) 2693e2701
O
O
HO
O
NH
NH
Me
Me
OMe
OMe
Cichorine
35
O
Zinnimidine
36
NH
OH
4-Hydroxy isoindolin-1-one
37
Scheme 3.
Fig. 2. Cichorine, zinnimidine, and 4-hydroxy isoindolin-1-one natural products.
radical 30, formed from the xanthate precursor 27, presumably
adds at the ipso C-2 position of the pyrrole nucleus to produce the
spiro-b-lactam intermediate 31. The reversible fragmentation of the
4-hydroxyisoindolin-1-one 37, on the other hand, has been isolated
from the dried bodies of ant lions (the larvae of Myrmeleontidae
species), which are used as a traditional Chinese medicine to treat
malaria and childhood convulsions.30 Compound 37 has been
shown to have anti-HIV31 and anti-inflammatory32 activities,
making this small molecule also an important synthetic target.
Therefore, we realized that the penta-substituted system of 35
might be prepared from the corresponding tetra-substituted tert-
butylbenzylamine 39. Thus, this later substrate was prepared by
reductive amination of the aldehyde 38 with tert-butylamine (the
aldehyde 38 was readily available from 2-methylresorcinol).28 Both
the transformation of the amine 39 into the corresponding carba-
moyl chloride 40 using triphosgene as an acylating agent, and the
subsequent conversion of 40 into the carbamoylxanthate 41, under
the conditions described previously,18 proceeded in good yield
(Scheme 4). It was gratifying to observe that the isoindolinone 42
was obtained in good yield when the xanthate 41 was reacted with
DLP in refluxing dichloroethane. Thus, exposure of 42 to neat
refluxingTFA fortuitously inducedremoval ofboth thetert-butyland
isopropyl groups to afford the expected cichorine 35 directly in 76%
strained four-membered ring would afford the stabilized radical 32
(alpha to the nitrogen atom), which could be oxidized to the imi-
nium ion 33 by the action of the dilauroyl peroxide, which is
present in a stoichiometric amount in the reaction medium.26
Hydrolysis of the iminium ion would yield the isolated amide 29
and a formaldehyde molecule.
We fully recognized the requisite elimination of the N-tert-butyl
moiety in order to validate the synthetic scope of the methodology.
After considerable experimentation, we found that the deprotected
isoindolinones 34aef could be obtained in excellent yields when 11
and 14aee were heated in refluxing neat trifluoroacetic acid (TFA)
(Table 2).27 The N-tert-butyl moiety could also be removed from 11
and 14b,d,e compounds in excellent yields simply, by stirring so-
lutions in neat trifluoromethanesulfonic acid (TFMSA) at rt; how-
ever, under these conditions, the more sensitive substrates 14b and
14e afforded low yields of the corresponding deprotected iso-
indolinones 34c and 34f (Table 2, entries 3 and 6).
yield (in 38% overall yield from the benzaldehyde 38). The 1H and 13
C
Table 2
NMR spectra of 35 were identical to the published data.28,29 Given
that the OH prenylation process of 36 has been reported,29 this
scheme thus represents a formal synthesis of zinnimidine 36. The
synthetic sequence described herein also represents one of the most
Removal of the tert-butyl group
Conditions
N
t-Bu
N H
R
R
O
O
34a-f
11, 14a-e
i-Pr
O
i-PrO
Me
t-Bu
NH
Subs.
R
Prod.
Cond. A
Time h
Cond. B
Time h
i
O
Yield
Yield
Me
OMe
H
OMe
1
2
3
4
5
6
11
H
34a
34b
34c
34d
34e
34f
0.5
0.5
24
24
3
98
97
74
100
100
42
72
72
72
72
96
96
100
100
96
100
100
95
14a
14b
14c
14d
14e
Me
OMe
Br
Cl
CO2Me
39 (85%)
38
ii
S
OEt
0.5
i-Pr
O
Cl
N
O
iii
i-Pr
O
S
O
Conditions: (A) neat TFMSA, rt. (B) neat TFA, reflux.
N
Me
t-Bu
Me
t-Bu
OMe
3. Synthesis of the natural products cichorine and
4-hydroxyisoindolin-1-one
OMe
41 (
84%)
40
iv
The naturally occurring molecules cichorine 35 and 4-hydrox-
yisoindolin-1-one 37 (Fig. 2) have a similar isoindolin-1-one core
bearing an unsubstituted hydroxyl group in the benzenoid ring.
Cichorine 35 and its prenylated derivative zinnimidine 36 are
natural phytotoxins that have been isolated from cultures of several
fungi of the genus Alternaria.28 These phytotoxins have been im-
plicated in diseases of commercially important plants.28 As a result,
this class of isoindol-1-ones has recently attracted considerable
attention in the scientific community.28,29 Certainly, constructing
the pentafunctionalized aromatic nucleus of the cichorine frame-
work represents an interesting synthetic challenge.29 The
O
i-PrO
Me
ref. 29
v
35
36
t-Bu
N
(78%)
OMe
42 (70%)
Scheme 4. Synthesis of cichorine. Reagents and conditions: (i) tert-butylamine
(4.0 equiv), anhydrous MeOH, molecular sieves, 12 h, then NaBH4 0.5 h (1.2 equiv), (ii)
triphosgene (0.7 equiv), Et3N (3.4 equiv), CH2Cl2, 0 ꢀC, 10 min, (iii) CH3CN, KSC(S)OEt
(0.85 equiv), 15 min, rt (iv) DLP added portionwise (1.2 equiv), 1,2-dichloroethane,
reflux, 4 h (v) TFA, neat, reflux. 96 h.

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G. Lopez-Valdez et al. / Tetrahedron 67 (2011) 2693e2701
2697
efficient and shortest syntheses reported to date for these natural
phytotoxins.
Synthesis of 4-hydroxyisoindolin-1-one 37 started from the
5. Experimental section
5.1. General procedure for the preparation of
carbamoylxanthates
readily available salicylaldehyde 43, as depicted in Scheme 5.
The p-methoxybenzyl group was chosen to protect the OH of the
salicylaldehyde in the first step because this group could be easily
removed using acidic conditions in the last step of the synthesis.
The subsequent reductive amination process produced 44 in 77%
yield over the two steps. Reaction of 44 with triphosgene fol-
lowed by trapping the intermediate carbamoyl chloride with the
potassium ethyl xanthate afforded the radical precursor 45. Cy-
clization of the xanthate 45 under the aforementioned radical
conditions proceeded efficiently to afford the isoindolinone 46.
Finally, exposure of 46 to acidic conditions secured the removal of
both the t-Bu and p-methoxybenzyl groups. Thus, this protocol
directly furnished the natural product 4-hydroxyisoindolin-1-one
37 in 41% overall yield from the readily available salicylaldehyde
43. The 1H and 13C NMR spectra of 37 were identical to published
data.30
To a stirred solution of triphosgene (0.7 mmol) in CH2Cl2 (5.0 mL),
at 0 ꢀC the corresponding tert-butylbenzylamine (1.0 mmol) was
added, followed by dropwise addition of Et3N (3.4 mmol). The
mixture was stirred for 10 min at rt. The solvent was removed under
reduced pressure to give the crude carbamoyl chloride. This com-
pound was used in the next step without further purification. A
solution of the crude carbamoyl chloride in acetonitrile (5.0 mL) was
treated with the O-ethylxanthic acid, potassium salt (0.95 mmol).
The reaction was stirred for 15 min, at rt, quenched with water, and
extracted with CH2Cl2. The organic layer was dried over Na2SO4 and
the solvent removed under reduced pressure. The carbamoylxan-
thate was purified by a silica gel column chromatography (hexanes/
EtOAc, 98:2) to afford the pure xanthate.
Compound 8a: IR (film) nmax/cmꢁ1: 2983, 2967, 2933, 1679; 1H
NMR (200 MHz, CDCl3)
d
/ppm: 1.44 (s, 9H), 1.46 (t, 3H), 4.66 (q, 2H),
/ppm:
4.78 (s, 2H), 7.18e7.40 (m, 5H); 13C NMR (50.3 MHz, CDCl3)
d
t-Bu
NH
i, ii
207.3, 160.2, 138.2, 128.7, 127.3, 125.8, 70.6, 60.7, 51.1, 28.3, 13.5;
HRMS (FABþ) calcd for C15H22NO2S2: [Mþ1] 312.1092, found:
312.1091.
O
OPMB
OH
43
H
Compound 13a: IR (film) nmax/cmꢁ1: 2978, 2927, 1691; 1H NMR
44 (
77%)
(200 MHz, CDCl3) d/ppm: 1.42 (s, 9H), 1.45 (t, 3H), 4.65 (c, 2H), 4.73
(s, 2H), 7.14 (d, J¼8.4 Hz, 2H), 7.31 (d, J¼8.2 Hz, 2H); 13C NMR
iii
(50.3 MHz, CDCl3) d/ppm: 207.3, 160.1, 136.9, 135.1, 129.3, 125.7,
70.5, 60.6, 50.8, 28.3, 20.9, 13.5; HRMS (FABþ) calcd for
C16H24O2NS2: [Mþ1] 326.1248, found: 326.1247.
S
S
OEt
O
Compound 13b: IR (film) nmax/cmꢁ1: 2978, 2934, 1690; 1H NMR
O
iv
N
t-Bu
(200 MHz, CDCl3) d/ppm: 1.43 (s, 9H), 1.45 (t, 3H), 3.79 (s, 3H) 4.66
N
(c, 2H), 4.71 (s, 2H), 6.88 (d, J¼8.8 Hz, 2H), 7.12 (d, J¼8.8 Hz, 2H); 13C
t-Bu
OPMB
NMR (50.3 MHz, CDCl3) d/ppm: 207.3, 160.0, 158.8, 130.0, 127.0,
OPMB
114.0, 70.5, 60.5, 55.2, 50.4, 28.3, 13.5; HRMS (CIþ) calcd for
C16H23NO3S2: [Mþ] 341.1119, found: 341.1111.
46 (
70%)
45 (
75%)
v
Compound 13c: IR (film) nmax/cmꢁ1: 2976, 2932, 1692; 1H NMR
(200 MHz, CDCl3) d/ppm: 1.43 (s, 9H), 1.46 (t, 3H), 4.63 (c, 2H), 4.71
37 (
92%)
(s, 2H), 7.09 (d, J¼8.4 Hz, 2H), 7.48 (d, J¼8.4 Hz, 2H); 13C NMR
Scheme 5. Synthesis of 4-hydroxyisoindolin-1-one. Reagents and conditions: (i)
4-methoxybenzyl bromide (2.0 equiv), K2CO3 (1.2 equiv), acetone, reflux, 12 h. 91%. (ii)
tert-butylamine (4.0 equiv), anhydrous MeOH, molecular sieves, 12 h. Then, NaBH4
0.5 h (1.2 equiv), 85%, (iii) (a) Triphosgene (0.7 equiv), Et3N (3.4 equiv), CH2Cl2, 0 ꢀC,
10 min (b) KSC(S)OEt (0.85 equiv), CH3CN, 15 min, rt (iv) DLP (1.2 equiv), 1.2-di-
chloroethane, reflux, 4 h (v) neat TFA, reflux 48 h.
(50.3 MHz, CDCl3) d/ppm: 206.7, 160.2, 137.3, 131.8, 127.5, 121.1, 70.7,
60.7, 50.4, 28.3, 13.5; HRMS (FABþ) calcd for C15H21O2NBrS2: [Mþ1]
390.0197, found: 390.0196.
Compound 13d: IR (film) nmax/cmꢁ1: 2979, 2933, 1692; 1H NMR
(200 MHz, CDCl3) d/ppm: 1.43 (s, 9H), 1.45 (t, 3H), 2.33 (s, 3H), 4.65
(c, 2H), 4.73 (s, 2H), 7.08 (d, J¼8.2 Hz, 2H), 7.15 (d, J¼8.2 Hz, 2H); 13C
4. Conclusions
NMR (50.3 MHz, CDCl3) d/ppm: 206.6, 160.0, 136.7, 132.9, 128.7,
127.1, 70.6, 60.6, 50.3, 28.2, 13.4; HRMS (FABþ) calcd for
C15H21O2NClS2: [Mþ1] 346.0702, found: 346.0704.
In this work we have demonstrated that carbamoylxanthates
derived from secondary tert-butyl-amines are stable compounds
that serve as efficient sources of carbamoyl radicals by thermally
induced DLP-fragmentation. Carbamoylxanthates derived from
tert-butylbenzylamines are transformed into 2-tert-butylisoindo-
lin-1-ones by oxidative radical cyclization of the corresponding
carbamoyl radical onto the benzenoid system, a process scarcely
exploited so far. In this metal-free approach to isoindolin-1-ones
the use of strong bases is avoided; no high pressure of CO is re-
quired; and the transformation occurs through a substitution on
a CeH bond of the aromatic ring, avoiding synthesis of haloarene
starting materials. The synthesis of cichorine and 4-hydrox-
yisoindolin-1-one underscores the synthetic potential of this xan-
thate-based carbamoyl radical-oxidative cyclization. Moreover, the
synthesis of cichorine 35 described herein represents the shortest
method reported to date and to our knowledge, our synthesis of 4-
hydroxyisoindolin-1-one 37 is the first ever reported for this nat-
ural product. The use of TFA to remove the t-Bu group from the
isoindolinones also proved to be very efficient and general.
Compound 13e: IR (film) nmax/cmꢁ1: 2980, 2955, 2930, 1723,
1694; 1H NMR (200 MHz, CDCl3)
d/ppm: 1.43 (s, 9H),1.46 (t, 3H), 3.92
(s, 3H) 4.66 (c, 2H), 4.82 (s, 2H), 7.29 (d, J¼8.6 Hz, 2H), 8.03 (d,
J¼8.8 Hz, 2H); 13C NMR (50.3 MHz, CDCl3)
d/ppm: 206.7,166.5,160.1,
143.5, 130.0, 129.2, 125.7, 70.6, 60.7, 52.0, 50.8, 28.2, 13.4; HRMS
(FABþ) calcd for C17H24NO4S2: [Mþ1] 370.1147, found: 370.1150.
Compound 13f: IR (film) nmax/cmꢁ1: 2984, 2964, 2933, 1694; 1
H
NMR (200 MHz, CDCl3) d/ppm: 1.42 (s, 9H), 1.43 (t, 3H), 4.63 (c, 2H),
4.85 (s, 2H), 7.40 (d, J¼8.6 Hz, 2H), 8.20 (d, J¼8.8 Hz, 2H); 13C NMR
(50.3 MHz, CDCl3) d/ppm: 206.0, 159.8, 149.5, 145.8, 128.4, 123.1,
70.6, 60.6, 50.3, 28.8, 13.2; HRMS (FABþ) calcd for C15H20N2O4S2:
[Mþ] 356.4603, found: 356.4603.
Compound 16a: IR (film) nmax/cmꢁ1: 2979, 2935, 1738, 1695; 1H
NMR (200 MHz, CDCl3)
d
/ppm: 1.45 (s, 9H), 1.46 (t, 3H), 4.66 (c, 2H),
/ppm:
4.80 (s 2H), 7.20e7.40 (m, 4H); 13C NMR (50.3 MHz, CDCl3)
d
206.8, 160.6, 135.5, 131.4, 129.6, 128.5, 127.2, 127.0, 70.6,.60.7, 48.7,
28.1, 13.5; HRMS (FABþ) calcd for C15H21ClNO2S2: [Mþ1] 346.0702,
found: 346.0710.

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G. Lopez-Valdez et al. / Tetrahedron 67 (2011) 2693e2701
2698
Compound 16b: IR (film) nmax/cmꢁ1: 2978, 2935, 1738, 1694; 1H
NMR (200 MHz, CDCl3) /ppm: 1.44 (s, 9H), 1.46 (t, 3H), 4.66 (c, 2H),
4.81 (s 2H), 7.00e7.29 (m, 4H); 13C NMR (50.3 MHz, CDCl3)
/ppm:
206.9, 161.7, 160.3, 156.8, 128.9, 128.8, 127.6, 127.5, 125.5, 125.3,
124.3, 124.2, 115.5, 115.1, 70.6, 60.6, 44.8, 44.6, 28.1, 13.5; HRMS
(FABþ) calcd for C15H21FNO2S2: [Mþ1] 330.0998, found: 330.0997.
Compound 16c: IR (film) nmax/cmꢁ1: 2964, 2934, 2871, 1689; 1H
123.9, 121.9, 54.6, 48.1, 27.9; HRMS (CIþ) calcd for C12H15BrNO:
d
[Mþ1] 268.0332, found: 268.0283.
d
Compound 14d: IR (film) nmax/cmꢁ1: 3065, 2982, 2958, 2869,
1672; 1H NMR (200 MHz, CDCl3)
d/ppm: 1.56 (s, 9H), 4.43 (s, 2H),
7.33 (dd, J¼8.0, 0.6 Hz, 1H), 7.46 (dd, J¼8.0, 2.0 Hz, 1H) 7.74 (d,
J¼2.0 Hz, 1H); 13C NMR (50.3 MHz, CDCl3)
d/ppm: 167.4, 138.7,
136.2, 134.1, 131.0, 123.6, 123.3, 54.6, 48.1, 27.9; HRMS (CIþ) calcd for
C12H14ClNO: [Mþ] 223.0764, found: 223.0781.
NMR (200 MHz, CDCl3) d/ppm: 1.46 (s, 9H), 1.46 (t, 3H), 4.66 (c, 2H),
5.15 (s 2H), 7.46e7.57 (m, 2H), 7.72 (td, J¼8.0, 1.2 Hz, 1H), 8.14 (dd,
Compound 14e: IR (film) nmax/cmꢁ1: 2972, 2931, 1725, 1666; 1H
J¼8.2, 1.2 Hz, 1H); 13C NMR (50.3 MHz, CDCl3)
d
/ppm: 206.0, 160.6,
NMR (200 MHz, CDCl3) d/ppm: 1.58 (s, 9H), 3.94 (s, 3H), 4.51 (s, 2H),
146.5,134.4,133.8,128.2,128.0,125.4, 70.6, 60.6, 48.5, 27.9,13.3; HRMS
(FABþ) calcd for C15H20N2O4S2: [Mþ] 356.4603, found: 356.4603.
Compound 19: IR (film) nmax/cmꢁ1: 2978, 2929, 1690; 1H NMR
7.48 (dd, J¼7.8, 0.6 Hz, 1H), 8.20 (dd, J¼8.2, 1.8 Hz, 1H), 8.44 (dd,
J¼0.8 Hz,1H); 13C NMR (50.3 MHz, CDCl3)
d/ppm: 168.1,166.5,145.1,
132.1, 130.3, 124.7, 122.5, 54.5, 52.2, 48.5, 27.9; HRMS (FABþ) Calcd
for C14H18NO3: [Mþ1] 248.1281, found: 248.1287.
(200 MHz, CDCl3)
(s 2H), 5.96 (s, 2H), 6.62e6.80 (m, 3H); 13C NMR (50.3 MHz, CDCl3)
/ppm: 207.2, 160.1, 148.1, 146.8, 132.0, 118.9, 108.4, 106.4, 101.1,
70.3,.60.7, 50.8, 28.3, 13.5; HRMS (FABþ) calcd for C16H22NO4S2:
[Mþ1] 356.0990, found: 356.0995.Compound 23: IR (film) nmax
cmꢁ1: 2979, 2933, 1734, 1692; 1H NMR (200 MHz, CDCl3)
/ppm:
1.43 (s, 9H), 1.46 (t, 3H), 4.66 (c, 2H), 4.74 (s 2H), 7.12e7.42 (m, 4H);
d/ppm: 1.44 (s, 9H), 1.46 (t, 3H), 4.66 (c, 2H), 4.67
Compound 17a: IR (film) nmax/cmꢁ1: 2962, 2923, 2869, 1673; 1H
d
NMR (200 MHz, CDCl3)
d/ppm: 1.58 (s, 9H), 4.43 (s, 2H), 7.39 (t,
J¼8.2 Hz,1H), 7.46 (dd, J¼8.0,1.6 Hz,1H), 7.68 (dd, J¼8.0,1.6 Hz,1H);
/
13C NMR (50.3 MHz, CDCl3)
d/ppm: 167.7, 138.6, 136.3, 130.7, 129.4,
d
128.6, 121.5, 54.6, 47.5, 27.9; HRMS (CIþ) calcd for C12H15ClNO:
[Mþ1] 224.0837, found: 224.0855.
13C NMR (50.3 MHz, CDCl3)
d
/ppm: 206.6, 159.9, 140.6, 130.3, 130.2,
Compound 17b: IR (film) nmax/cmꢁ1: 3072, 2970, 2924, 2868,
128.7,124.3,122.8, 70.2, 60.7, 50.4, 28.2,13.5; HRMS (FABþ) calcd for
C15H21BrNO2S2: [Mþ1] 390.0197, found: 390.0199.
1676; 1H NMR (200 MHz, CDCl3)
d
/ppm: 1.57 (s, 9H), 4.50 (s, 2H),
7.17 (td, J¼8.2, 1.0 Hz, 1H), 7.36e7.47 (m, 1H), 7.59 (dt, J¼7.6, 1.0 Hz,
Compound 27: IR (film) nmax/cmꢁ1: 2978, 2935, 1690; 1H NMR
1H); 13C NMR (50.3 MHz, CDCl3)
d/ppm: 159.7, 154.8, 130.0, 129.9,
(200 MHz, acetone-d6)
d/ppm: 1.42 (t, 3H), 1.47 (s, 9H), 3.57 (s, 3H)
126.8, 126.4, 119.1, 119.0, 117.6, 117.2, 54.6, 45.2, 27.9; HRMS (CIþ)
calcd for C12H15FNO: [Mþ] 207.1059, found: 207.1044.
4.62 (c, 2H), 4.76 (s, 2H), 5.88 (d, J¼2.8 Hz, 1H), 5.95 (dd, J¼3.4 Hz,
2.8,1H), 5.88 (d, J¼2.2,1H);13 C RMN (50.3 MHz, acetone-d6)
d
/ppm:
Compound 20: IR (film) nmax/cmꢁ1: 3069, 2974, 2911, 2871; 1H
209.7, 159.6, 130.3, 123.0, 107.6, 107.4, 71.3, 60.8, 45.1, 33.7, 28.2,
13.7; EMARFAB Calcd. For C14H23N2O2S2: [Mþ1] 315.1201. Found:
315.1182.
NMR (200 MHz, CDCl3)
d
/ppm: 1.54 (s, 9H), 4.33 (d, J¼0.6 Hz, 2H),
6.03 (s, 2H), 6.80 (d, J¼0.6 Hz, 1H), 7.16 (s, 1H); 13C NMR (50.3 MHz,
CDCl3) d/ppm: 168.5, 150.8, 147.9, 135.8, 128.3, 102.9, 102.5, 101.6,
54.3, 48.1, 28.0; HRMS (FABþ) calcd for C13H16NO3: [Mþ1] 234.1125,
found: 234.1144.
5.2. General procedure for the synthesis of isoindolin-1-ones
Compound 21: IR (film) nmax/cmꢁ1: 2968, 2913, 2789; 1H NMR
(200 MHz, CDCl3)
d
/ppm: 1.54 (s, 9H), 4.41 (d, J¼0.8 Hz, 2H), 6.10 (s,
A deaerated solution of the corresponding xanthate (1.0 mmol) in
1,2-dichloroethane (10 mL) was heated at reflux, and 1.2 mmol of
dilauroyl peroxide was added portionwise (0.3 mmol/h). After com-
pletion (4 h) the solution was cooled and the 1,2-dichloroethane
evaporated under reduced pressure. In order to precipitate the by-
products derived from DLP, the reaction crude was suspended in
acetonitrile (10 mL). The reaction mixture was then filtered and
acetonitrile was removed under reduced pressure. The residue con-
centrated and purified by a silica gel column chromatography (hex-
anes/EtOAc, 90:10) to afford the corresponding isoindolin-1-one.
Compound 11: IR (film) nmax/cmꢁ1: 3013, 2956, 2923, 2854,
2H), 6.80 (dt, J¼8.0, 1.0 Hz, 1H), 6.93 (d, J¼8.0 Hz, 1H); 13C NMR
(50.3 MHz, CDCl3) d/ppm: 168.3, 148.0, 142.8, 134.0, 117.1, 114.6,
110.6, 102.4, 54.4, 48.6, 27.8; HRMS (FABþ) calcd for C13H16NO3:
[Mþ1] 234.1125, found: 234.1144.
Compounds 24 and 25 mixture: IR (film) nmax/cmꢁ1: 3069, 2970,
2925, 2856, 1683; 1H NMR (200 MHz, CDCl3)
d
/ppm: 1.562 (s, 9H),
1.569 (s, 9H), 4.404 (s, 2H), 4.435 (s, 2H), 7.28e7.38 (m, 3 H),
7.52e7.67 (m, 3H); 13C NMR (50.3 MHz, CDCl3)
/ppm: 143.3, 142.3,
d
132.8, 131.7, 131.2, 125.6, 125.4, 124.5, 121.5, 118.2, 54.6, 54.5, 47.9,
47.1, 27.9; HRMS (CIþ) calcd for C12H15BrNO: [Mþ1] 268.0332,
found: 268.0354.
1660; 1H NMR (200 MHz, CDCl3)
d
/ppm: 1.57 (s, 9H), 4.45 (s, 2H),
Compound 29: IR (film) nmax/cmꢁ1: 3392, 3101, 2998, 2966, 2929,
7.37e7.54 (m, 3H), 7.78 (dt, J¼6.8, 1.6 Hz, 1H); 13C NMR (50.3 MHz,
1637; 1H NMR (200 MHz, CDCl3)
d/ppm: 1.42 (s, 9H), 3.91 (s, 3H),
CDCl3)
d
/ppm: 168.8, 140.6, 134.4, 130.8, 127.7, 123.0, 122.2, 54.2,
6.045 (dd, J¼4.0, 2.6 Hz, 1H), 6.432 (dd, J¼4.0, 1.8 Hz, 1H), 6.671 (t,
48.4, 27.9; HRMS (FABþ) calcd for C12H16NO: [Mþ1] 190.1232,
found: 190.1236.
J¼2.2 Hz, 1H); 13C NMR (50.3 MHz, CDCl3)
d/ppm: 161.6, 127.4,
126.8, 110.7, 106.7, 51.1, 36.6, 29.0; EMARFAB calcd for C14H18NO3:
Compound 14a: IR (film) nmax/cmꢁ1: 3010, 2970, 2918, 2869,
[Mþ1] 180.1263. Found: 180.1282.
1671; 1H NMR (200 MHz, CDCl3)
d
/ppm: 1.56 (s, 9H), 2.42 (s, 3H),
4.41 (s, 2H), 7.29 (2H), 7.58 (s, 1H); 13C NMR (50.3 MHz, CDCl3)
d/
5.3. General procedure for the removal of the N-tert-butyl
ppm: 169.0, 137.9, 137.7, 134.5, 131.8, 123.3, 122.0, 54.3, 48.2, 27.9,
21.3; HRMS (FABþ) calcd for C13H18NO: [Mþ1] 204.1383, found:
204.1388.
group
The corresponding N-tert-butylisoindolin-1-one was dissolved
in neat trifluoroacetic acid and refluxed until the starting material
was consumed indicated by TLC. The trifluoroacetic acid was then
removed under reduced pressure and the residue was purified by
column chromatography (hexanes/AcOEt).
Compound 14b: IR (film) nmax/cmꢁ1: 3065, 2963, 2923, 2855,
1679; 1H NMR (200 MHz, CDCl3)
d
/ppm: 1.56 (s, 9H), 3.84 (s, 3H),
4.38 (s, 2H), 7.06 (dd, J¼8.2, 2.4 Hz, 2H), 7.29 (dd, J¼6.0, 0.6 Hz, 1H);
13C NMR (50.3 MHz, CDCl3)
d/ppm: 159.8, 135.7, 132.8, 123.1, 119.4,
105.7, 55.5, 54.3, 48.0, 29.6, 27.9; HRMS (FABþ) calcd for
C13H18NO2: [Mþ1] 220.1332, found: 20.1338.
Compound 34a. A mixture of isoindolin-1-ona 11 (0.04 g,
0.211 mmol) and TFA (0.53 mL, 28 mmol) refluxed for 30 min.
Product 34a as an oil (0.028 g, 100%); IR (KBr), nmax cmꢁ1: 3481,
Compound 14c: IR (film) nmax/cmꢁ1: 3061, 2980, 1671; 1H NMR
(200 MHz, CDCl3)
d
/ppm: 1.56 (s, 9H), 4.41 (s, 2H), 7.29 (dd, J¼7.4,
3209, 3080, 3024, 2928, 2862, 1682; 1H NMR (300 MHz, CDCl3)
d/
0.6 Hz, 1H), 7.61 (dd, J¼8.0, 2.0 Hz, 1H) 7.90 (d, J¼1.8 Hz, 1H); 13C
ppm: 4.47 (s, 2H), 7.45 (br s, 1H, NeH), 7.45e7.60 (m, 3H), 7.88 (d,
NMR (50.3 MHz, CDCl3)
d/ppm: 167.3, 139.2, 136.5, 133.8, 126.3,
J¼8.1, Hz,1H); 13C NMR (75.4 MHz, CDCl3)
d/ppm: 171.8,132.1, 131.8,

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G. Lopez-Valdez et al. / Tetrahedron 67 (2011) 2693e2701
2699
143.6, 131.8, 128.0, 123.8, 123.1, 45.6; HRMS (FABþ) calcd for
C8H8NO: [Mþ1] 134.0606, found: 134.0609.
42.1, 28.9, 22.2, 9.3; HRMSFAB calcd for C16H28NO2: [Mþ1] 266.2120,
found: 266.2124.
Compound 34b. A mixture of the isoindolin-1-ona 14a (0.05 g,
0.246 mmol), and TFA (0.60 mL, 28 mmol) refluxed for 30 min.
5.3.2. Carbamoylxanthate (41). tert-Butylbenzylamine 39 (0.5 g,
1.88 mmol) was added to a solution at 0ꢀ C of triphosgene (0.39 g,
1.32 mmol) dissolved in CH2Cl2 (10.0 mL), after which Et3N
(0.89 mL, 6.41 mmol) was added dropwise. The reaction mixture
was stirred for 10 min at rt and the solvent was removed under
reduced pressure to give the crude carbamoyl chloride. The crude
carbamoyl chloride was dissolved in acetonitrile (5.0 mL) and O-
ethylxantic acid potassium salt (0.27 g, 0.90 mmol) was added to
the resulting solution. The reaction mixture was stirred for 15 min
at rt. The solvent was evaporated to dryness and the residue was
treated with distilled water and extracted with CH2Cl2. The organic
phase was dried over Na2SO4 and the solvent was removed under
reduced pressure to give the crude carbamoylxanthate as an oil,
which was then purified by column chromatography (hexane/
EtOAc, 98:2) to give the pure carbamoylxanthate 41 (0.65 g, 84%); IR
(film) nmax/cmꢁ1: 3369, 2977, 2934, 1692, 1601; 1H NMR (300 MHz,
Product 34b as a white solid (0.036 g, 100%); IR (KBr), nmax cmꢁ1
:
3452, 3207, 3080, 3024, 2927, 2862, 1682; 1H NMR (300 MHz,
CDCl3) d/ppm: 2.44 (s, 3H), 4.42 (s, 2H), 7.33e7.66 (m, 2H), 7.92
(br s, 1H, NeH), 7.88 (d, J¼8.1, Hz, 1H); 13C NMR (75.4 MHz, CDCl3)
d
/ppm: 172.3, 140.9, 137.9, 132.7, 132.2, 123.8, 122.8, 45.5, 21.2;
HRMS (FABþ) calcd for C9H10NO: [Mþ1] 148.0762, found:
148.0763.
Compound 34c. A mixture of the isoindolin-1-ona 14b (0.031 g,
0.141 mmol), and TFA (0.35 mL, 28 mmol) refluxed for 2.5 h.
Product 34c as a white solid (0.017 g, 74%); IR (KBr), nmax cmꢁ1
:
3328, 3215, 3085, 3018, 2932, 2864, 1681; 1H NMR (300 MHz,
CDCl3)
d
/ppm: 3.85 (s, 3H), 4.38 (s, 2H), 7.13 (dd, J¼8.4, 2.34 Hz,
1H), 7.34 (d, J¼7.34 Hz, 1H), 7.35 (s, 1H); 13C NMR (75.4 MHz,
CDCl3) d/ppm: 171.8, 160.0, 135.7, 123.9, 120.4, 106.3, 55.6, 45.3,
29,6; HMRS (FABþ) Calcd for C9H10NO2: [Mþ1] 164.0712, found:
164.0713.
CDCl3)
d
/ppm: 1.33 (d, J¼6.0 Hz, 6H), 1.44 (s, 9H), 1.46 (t, J¼7.2 Hz,
Compound 34d. A mixture of the isoindolin-1-ona 14c (0.025 g,
0.093 mmol), and TFMSA (0.60 mL, 28 mmol) was refluxed for 24 h.
Product 34d as oil (0.019 g, 100%); IR (KBr), nmax cmꢁ1: 3201, 3079,
3H), 2.21 (s, 3H), 3.70 (s, 3H), 4.50 (m, 1H), 4.66 (q, J¼7.2 Hz, 2H),
4.74 (s, 2H), 6.64 (d, J¼8.4 Hz, 1H), 6.94 (d, J¼8.4 Hz, 1H); 13C NMR
(75.4 MHz, CDCl3) d/ppm: 207.6, 160.3, 156.5, 155.6, 123.9, 122.7,
2959, 2928, 2863,1684; 1H NMR (300 MHz, DMSO-d6)
d/ppm:4.33 (s,
120.9, 108.7, 70.5, 70.4, 60.5, 60.2, 45.9, 28.2, 22.2, 13.5, 9.1;
2H), 7.54 (d, J¼7.8 Hz, 1H), 7.75 (d, J¼7.8 Hz, 1H), 7.77 (s, 1H) 8.70 (s,
HRMSFAB calcd for C20H32NO4S2: [Mþ1] 414.1773, found: 414.1770.
1H); 13C NMR (75.4 MHz, DMSO-d6)
d/ppm: 168.4,143.2, 134.9, 131.7,
126.0, 125.4, 120.8, 44.8; MS m/z (%): [Mþ2] 213 (65), [Mþ] 211 (63),
167 (30), 132 (100). HMRS (FABþ) Calcd for C8H6NBrO: [Mþ1]
211.9605, found: 211.9687.
5.3.3. Isoindolin-1-one (42). The carbamoylxanthate 41 (0.61 g,
1.47 mmol) was dissolved in 1,2-dichloroethane (10 mL), and the
solution was warmed to reflux. DLP (0.70 g, 1.77 mmol) was added
in portions of 0.3 equiv each hour to a total of 1.2 equiv After the
addition of peroxide was complete, the solution was cooled and the
1,2-dichloroethane was removed under reduced pressure. To pre-
cipitate by-products derived from the DLP, the crude reaction was
suspended in acetonitrile (10 mL). The reaction mixture was then
filtered and acetonitrile was removed under reduced pressure. The
residue was purified by column chromatography (hexane/EtOAc,
90:10) to afford the pure isoindolin-1-one 42 (0.30 g, 70%): IR
(CH3Cl) nmax/cmꢁ1: 3207, 2976, 2930, 2872, 1673, 1619; 1H NMR
Compound 34e. A mixture of the isoindolin-1-ona 14d (0.05 g,
0.246 mmol), and TFMSA (0.60 mL, 28 mmol) was refluxed for
3 h. Product 34e (0.041 g, 100%); IR (KBr), nmax cmꢁ1: 3201, 3078,
2929, 2862, 1684; 1H NMR (300 MHz, DMSO-d6)
d
/ppm: 4.36 (s,
2H), 7.58e7.64 (m, 3H), 8.71 (s, 1H); 13C NMR (75.4 MHz, DMSO-
d6) d/ppm: 168.5, 142.7, 134.6, 132.6, 131.2, 125.6, 122.4, 44.7; MS
m/z (%): [Mþ2] 169 (19), [Mþ] 167 (60), 139 (26), 132 (100).
HMRS (FABþ) Calcd for C8H6NClO: [Mþ1] 168.0112, found:
168.0124.
Compound 34f. A mixture of the isoindolin-1-ona 14e (0.04 g,
0.161mmol), and TFMSA (0.35 mL, 28 mmol) was refluxed for
30 min. Product 34f as a white solid (0.012 g, 42%); IR (KBr),
nmax cmꢁ1: 3422, 3217, 3084, 2932, 2859, 1726, 1684; 1H NMR
(300 MHz, CDCl3)
3H), 3.86 (s, 3H), 4.45 (s, 2H), 4.58 (m, 1H), 7.02 (s, 1H); 13C NMR
(75.4 MHz, CDCl3) /ppm: 168.9, 157.5, 153.3, 133.5, 123.4, 123.0,
d
/ppm: 1.34 (d, J¼6.0 Hz 6H), 1.56 (s, 9H), 2.16 (s,
d
102.0, 70.6, 59.7, 54.2, 46.4, 27.9, 22.0, 9.5; HRMSFAB calcd for
(300 MHz, DMSO-d6)
d
/ppm: 3.87 (s, 3H), 4.45 (s, 2H), 7.72 (d,
C17H26NO3: [Mþ1] 292.1913, found: 292.1905.
J¼8.7 Hz, 1H), 8.15 (d, J¼1.8 Hz, 1H), 8.16 (dd, J¼8.4, 1.6 Hz, 1H), 8.75
(s, 1H); 13C NMR (75.4 MHz, DMSO-d6)
d/ppm: 168.9, 165.8, 149.9,
5.3.4. Cichorine (35). Isoindolin-1-one 42 (0.047 g, 0.16 mmol) was
dissolved in neat trifluoroacetic acid (5 mL) and warmed to reflux
for 96 h. The trifluoroacetic acid was then removed under reduced
pressure and the residue was purified by column chromatography
using hexane/EtOAc (50:50) as eluent to produce the pure cichorine
(0.025 g, 78%) as withe crystals, mp 216e218ꢀ (lit.35 215e216ꢀ): the
1H and 13C NMR spectra of 35 were identical to the published
131.9, 131.6, 128.6, 124.4, 123.4, 52.4, 45.2; MS m/z (%): [Mþ] 191
(48), [Mꢁ15] 176 (11), 160 (34), 132 (100). HMRS (FABþ) Calcd for
C10H9NO3: [Mþ1] 192.0322, found: 192.0326.
5.3.1. tert-Butylbenzylamine (39). tert-Butylamine (0.74 mL,
14.7 mmol) was added to a solution of aldehyde 38 (1.53 g,
7.35 mmol) in anhydrous methanol (10 mL) containing molecular
sieves, and the resulting mixture was stirred for 12 h at rt. The
reaction mixture was then cooled in an ice bath, after which NaBH4
(0.42 g, 11.0 mmol) was added and the mixture was stirred for
30 min. The reaction mixture was filtered through a layer of Celite,
the solvent was removed under reduced pressure, and the organic
residue was suspended in water and extracted with CH2Cl2. The
organic phase was dried over Na2SO4 and the solvent was removed
under reduced pressure to give the pure tert-butylbenzylamine 53
(1.64 g, 85%); IR (film) nmax/cmꢁ1: 3316, 2970, 2870, 2743, 1601; 1H
data.28,29 1H NMR (300 MHz, DMSO-d6)
3H), 4.40 (s, 2H), 6.81 (s, 1H), 8.43 (s, 1H), 9.72 (s, 1H); 13C NMR
(75.4 MHz, DMSO-d6) /ppm: 9.29, 43.18, 58.87, 103.05,
d/ppm: 2.04 (s, 3H), 3.83 (s,
d
119.15,123.19, 132.07, 153.67, 156.55, 170.03.
5.3.5. tert-Butylbenzylamine (44). Protection of salicylaldehyde:
a mixture of salicylaldehyde 43 (1.0 g, 8.19 mmol), 4-methox-
ybenzyl bromide (1.41 mL, 9.80 mmol), K2CO3 (1.13 g, 8.18 mmol),
and acetone (10 mL) was refluxed for 12 h. After cooling to rt, the
reaction mixture was filtered and the solvent was removed under
reduced pressure. The residue was purified by column chroma-
tography using hexane/EtOAc/acetone (80:10:10) as eluent to
NMR (300 MHz, CDCl3)
d
/ppm: 1.18 (s, 9H), 1.30 (d, J¼6.0 Hz,
6H),1.76 (NeH), 2.13 (s, 3H), 3.68 (s, 2H), 3.75 (s, 3H), 4.45 (m, 1H),
produce pure the desired product (1.81 g, 91%): IR (film) nmax/cmꢁ1
3007, 2958, 2873, 2763, 1687, 1596; 1H NMR (300 MHz, acetone-d6)
/ppm: 3.80 (s, 3H), 5.22 (s, 2H), 6.96 (d, J¼8.7 Hz, 2H), 7.06 (t,
:
6.60 (d, J¼8.4 Hz, 1H), 7.08 (d, J¼8.4 Hz, 1H); 13C NMR (75.4 MHz,
CDCl3) d/ppm: 157.6, 156.3, 127.2, 125.8, 121.0, 109.4, 70.5, 60.8, 50.7,
d

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G. Lopez-Valdez et al. / Tetrahedron 67 (2011) 2693e2701
2700
J¼7.5 Hz, 1H), 7.30 (d, J¼8.4 Hz, 1H), 7.47 (d, J¼8.4 Hz, 1H), 7.61 (td,
J¼7.2, 2.0, Hz, 1H), 7.75 (dd, J¼7.8, 1.8, Hz, 2H); 13C NMR (75.4 MHz,
under reduced pressure and the residue was purified by column
chromatography using hexane/EtOAc (50:50) as eluent, affording
acetone-d6)
d
/ppm: 55.51, 71.00, 114.69, 114.76, 121.60,126.09,
the pure 4-hydroxyisoindolin-1-one 37 (0.82 g, 92%); the 1H and 13
C
128.41,129.37,130.26,136.75,160.64,162.08,189.45; HRMSFAB calcd
NMR spectra of 37 were identical to the published data.30 1H NMR
for C15H15Oþ3 : [Mþ1] 243.1021, found: 243.1023.
(300 MHz, CD3OD)
d
/ppm: 4.34 (s, 2H), 6.98 (dd, J¼7.5, 1.2 Hz, 1H),
tert-Butylamine (1.22 mL, 11.62 mmol) was added to a solution
of the protected salicylaldehyde (1.41 g, 5.82 mmol) in anhydrous
methanol (10 mL) containing molecular sieves and the resulting
mixture was stirred for 12 h at rt. The reaction mixture was then
cooled in an ice bath and NaBH4 (0.33 g, 8.72 mmol) was added,
after which the solution was stirred for 30 min. The reaction mix-
ture was then filtered and the solvent was removed under reduced
pressure. The organic residue was suspended in water and extrac-
ted with CH2Cl2. The organic phase was dried over Na2SO4, and the
solvent was removed under reduced pressure to afford the pure
tert-butylbenzylamine 44 (1.5 g, 86%): IR (film) nmax/cmꢁ1: 3065,
7.26 (dd, J¼7.5, 1.2 Hz, 1H), 7.31 (t, J¼7.5, 1H); 13C NMR (75.4 MHz,
CD3OD) d/ppm: 174.0, 154.1, 134.8, 131.5, 130.5, 119.0, 115.3, 44.6.
Acknowledgements
We thank PAPIIT (DGPA, UNAM, No. IN204910) for financial
support and Dr. Joseph M. Muchowski for many helpful discussions.
~
ꢀ
We also thank R. Patino, J. Perez, L. Velasco, H. Rios, N. Zavala, E.
~
Huerta and A. Pena, for technical support and Dr. A. Toscano for
X-ray crystallography. S.O.-U. in a sabatical leave from Universidad
ꢀ
Autonoma Metropolitana.
2961, 2836, 1610, 1587, 1619; 1H NMR (300 MHz, CDCl3)
d/ppm: 1.09
(s, 9H), 3.72 (s, 2H), 3.81 (s, 3H), 5.00 (s, 2H), 6.88e6.93 (m, 4H), 7.19
(td, J¼7.8, 1.8 Hz, 1H), 7.30 (dd, J¼7.2, 1.8 Hz, 1H), 7.35 (d, J¼8.8 Hz,
Supplementary data
1H); 13C NMR (75.4 MHz, CDCl3)
d/ppm: 159.3, 156.8, 130.1, 129.7,
Copies of the 1H and 13C NMR spectra for all new compounds.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.01.003. These data include
MOL files and InChiKeys of the most important compounds
described in this article.
129.1, 129.0, 127.9, 120.9, 113.8, 111.6, 69.8, 55.2, 42.9, 28.9; HRMSFAB
calcd for C19H26NO2: [Mþ1] 300.1964, found: 300.1966.
5.3.6. Carbamoylxanthate (45). tert-Butylbenzylamine 44 (1.0 g,
3.34 mmol) was added to a solution at 0ꢀ C of triphosgene (0.39 g,
1.32 mmol) in CH2Cl2 (10.0 mL), and then Et3N (1.57 mL,
11.28 mmol) was added dropwise. The reaction mixture was then
stirred for 10 min at rt, after which the solvent was removed under
reduced pressure to afford the crude carbamoyl chloride. The crude
carbamoyl chloride was dissolved in acetonitrile (5.0 mL), and O-
ethylxanthic acid potassium salt (0.45 g, 2.81 mmol) was added to
the solution. The reaction mixture was stirred for 15 min at rt. The
solvent was then evaporated to dryness and the residue was treated
with distilled water and extracted with CH2Cl2. The organic phase
was dried over Na2SO4 and the solvent was removed under reduced
pressure to afford the crude carbamoylxanthate, which was puri-
fied by column chromatography (hexane/EtOAc, 98:2) to give the
pure carbamoylxanthate 45 (1.12 g, 75%); IR (KBr) nmax/cmꢁ1: 2965,
References and notes
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2930, 2877, 2838, 1685; 1H NMR (200 MHz, CDCl3)
9H), 1.46 (t, 3H), 3.82 (s, 3H), 4.64 (c, 2H), 4.74 (s, 2H), 5.01 (s, 2H),
6.91e7.00 (m, 4H), 7.18e7.35 (m, 4H); 13C NMR (50.3 MHz, CDCl3)
d/ppm: 1.43 (s,
d/
ppm: 207.7, 160.4, 159.5, 155.0, 129.1, 128.8, 128.1, 126.7, 120.9, 120.7,
114.0, 111.6, 70.5, 69.8, 60.4, 55.2, 46.1, 28.1, 13.5; HRMSFAB calcd for
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5.3.7. Isoindolin-1-one (46). The carbamoylxanthate 45 (1.05 g,
2.34 mmol) was dissolved in 1,2-dichloroethane (10 mL) and the
solution was warmed to reflux. DLP (0.10 g, 2.76 mmol) was added in
portions of 0.3 equiv every hour to complete a total of 1.2 equiv After
the addition of peroxide was completed, the solution was cooled and
1,2-dichloroethane was removed under reduced pressure. To pre-
cipitate by-products derived from the DLP, the crude reaction mix-
ture was suspended in acetonitrile (10 mL). The reaction mixture was
then filtered and acetonitrile was removed under reduced pressure.
The residue was purified by column chromatography using hexane/
EtOAc (90:10) as eluent, affording the pure isoindolin-1-one 46
(0.58 g, 78%); IR (solution) nmax/cmꢁ1: 2968, 2929, 2868, 1725, 1681;
€
Guyenne, S.; Hutton, C.; Kallblad, P.; Kemp, S. J.; Kitching, M. S.; Newell, D. R.;
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2H), 5.06 (s, 2H), 6.91e7.04 (m, 4H), 7.33e7.40 (m, 4H); 13C NMR
(75.4 MHz, CDCl3) /ppm: 168.7, 159.6, 153.5, 136.2, 129.3, 129.2,
d/ppm: 1.54 (s, 9H), 3.82 (s, 3H), 4.38 (s,
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(37). Isoindolin-1-one
46
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G. Lopez-Valdez et al. / Tetrahedron 67 (2011) 2693e2701
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