Smooth isoindolinone formation from isopropyl carbamates via bischler-napieralski-type cyclization

Article abstract of DOI:10.1021/ol403142d

Isopropyl carbamates derived from benzylamines provide isoindolinones by treatment with phosphorus pentoxide at room temperature. Utility of this Bischler-Napieralski-type cyclization and a new mechanism involving a carbamoyl cation for rationalization of this smooth conversion are discussed.

Full text of DOI:10.1021/ol403142d

Letter
pubs.acs.org/OrgLett
Smooth Isoindolinone Formation from Isopropyl Carbamates via
Bischler−Napieralski-Type Cyclization
Satoshi Adachi, Masao Onozuka, Yuko Yoshida, Mitsuaki Ide, Yoko Saikawa,* and Masaya Nakata*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama
223-8522, Japan
S
* Supporting Information
ABSTRACT: Isopropyl carbamates derived from benzylamines provide
isoindolinones by treatment with phosphorus pentoxide at room
temperature. Utility of this Bischler−Napieralski-type cyclization and a
new mechanism involving a carbamoyl cation for rationalization of this
smooth conversion are discussed.
Scheme 1. Discovery of Mild Conditions for the
Isoindolinone Construction using Isopropyl Carbamates
soindolinone skeletons are frequently found in bioactive
Inatural products and pharmaceuticals, e.g., indoprofen (anti-
inflammatory),1 lactonamycin (antibacterial),2 and hericenone
B (platelet aggregation inhibitory)3 (Figure 1).
Figure 1. Natural and synthetic isoindolinones.
A variety of synthetic methods for simple and stable
isoindolinones4 have been employed: lactamization of o-
(aminomethyl)benzoic acids, lithiation/cyclization of o-halo-
benzylcarbamates, metal-catalyzed cyclization via CO insertion
of o-halobenzylamines, and monoreduction of phthalimides.
However, for the synthesis of structurally complex isoindoli-
nones, an ingenious strategy is needed due to the intractable
properties of the isoindolinone skeleton. Staurosporines and
lactonamycins, bioactive natural isoindolinones, are compounds
that have challenged synthetic chemists due to air oxidation of
the isoindolinones to the phthalimides and solubility issues.5
Several direct cyclizations of isocyanates6 and benzylamine
derivatives, such as carbamoylxanthates7 and nitrophenylureas,8
as well as in situ metalation/carbonylation/lactamization,9 have
the potential to simplify the synthesis of complex molecules,
though these reactions require strong acids and/or heating. As a
representative example of simple direct cyclization, we have
recently found that treatment of methyl carbamate 1a with
P2O5 in CH2Cl2 at 40 °C for 3 d provided isoindolinone 2 via a
Bischler−Napieralski-type cyclization (Scheme 1).10 Addition-
ally, the corresponding isopropyl carbamate 1b was much more
smoothly converted into 2 even at room temperature for 1 h.
This cyclization was successfully applied to the highly complex
molecule 3, giving the desired isoindolinone 4, a synthetic
precursor of lactonamycins. The late-stage construction of the
isoindolinone moiety of lactonamycins demonstrated utility of
the isopropoxycarbonyl group, which is the best trigger for this
cyclization as well as a convenient amino protecting group
tolerant to various reaction conditions.10
The Bischler−Napieralski cyclization was originally reported
in 1893 as a method for synthesizing 3,4-dihydroisoquinolines
from N-acetylphenethylamines in the presence of P2O5.11
Three years later, Pictet and Hubert applied this reaction to the
synthesis of phenanthridinone from 2-ethoxycarbonylaminobi-
phenyl using zinc chloride.12 The method was soon applied to
other 3,4-dihydroisoquinolinones synthesized from N-alkox-
ycarbonylphenethylamines with various dehydrating agents,13
along with the original 3,4-dihydroisoquinoline synthesis from
N-acylphenethylamines.14 Mechanistic studies of this series of
cyclizations mainly focused on the N-acyl type;15 cyclization
reaction of N-acylphenethylamines using PCl5 or POCl3
involves the nitrilium ion, whereas N-acyl-N-alkylphenethyl-
Received: November 1, 2013
© XXXX American Chemical Society
A
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Letter
amines are said to cyclize via imidoyl chlorides or related
species. These mechanisms are also believed to be applicable in
the case of the N-alkoxycarbonyl type.13f The mechanism
involving an imidoyl chloride, the most promising intermediate
of the N-alkoxycarbonyl type cyclization, explains why
isoindolinone synthesis with this kind of approach has not
been examined closely. In the five-membered ring formation,
one can expect that the corresponding intermediate is
constrained by a disfavored angle that prevents attack by the
aromatic ring.16 Our recent success10 suggests the possibility of
a new mechanism to explain the smooth γ-lactam formation
from the isopropyl carbamates. Herein, we demonstrate the
utility of this reaction to synthesize a variety of lactams and
discuss the mechanistic interpretation.
and 26 were poor and significant amounts of side products 29
and 30 were obtained. N-H-Carbamate 15b and N-
acetylcarbamate 16b were not suitable for this cyclization to
give no isoindolinones 27 and 28. These results, especially
unexpected formation of the side products 29 and 30,
suggested a new reasonable reaction mechanism (Scheme 3).
Scheme 3. Plausible Mechanism for Bischler−Napieralski-
Type Cyclization
First, various isopropyl carbamates were subjected to the
Bischler−Napieralski-type cyclization. The results of each
isopropyl carbamate under our optimized conditions are
summarized in Scheme 2.17
Scheme 2. Bischler−Napieralski-Type Cyclizations from
Various Isopropyl Carbamates
First, P2O5 (actual formula is P4O10) bonds to the carbonyl
of the carbamate on the basis of the common mechanism for
general Friedel−Clafts-type cyclizations to give intermediate A,
an imidoyl phosphate. The imidoyl phosphate derived from
phenethylcarbamate would be appropriate for dihydroisoqui-
nolinone formation, but intermediate A is unfit for
isoindolinone formation. Hydrogen abstraction from the
isopropyl group causes elimination of propene to give a new
intermediate, carbamoyl cation B, which allows smooth
cyclization to give the γ-lactam. Electron-withdrawing groups
(R = Br and CO2Me), however, retard the cyclization. Instead,
liberated propene can attack the carbonyl center via a
carbonyl−ene reaction, giving alkene adducts such as 29 and
30. Similar observation that treatment of the Boc-protected
homobenzylamine with Tf2O afforded a neutral isocyanate
intermediate through release of isobutene would support this
unprecedented carbamoyl cation formation.18
To assess the credibility of the proposed mechanism, various
alkoxy groups in the carbamates were investigated under two
different reaction conditions: method A, 1,2-dichloroethane, 84
°C, 1 d; and method B, dichloromethane, room temperature, 1
h (Table 1). Methyl carbamate 1a was converted to
isoindolinone 2 in 57% yield along with recovery of 1a
(31%) in method A, whereas almost no reaction occurred in
method B (entries 1 and 3). Cyclization of isopropyl carbamate
1b afforded 2 in high yield with both methods A and B (entries
4 and 6). n-Propyl carbamate 1c and isobutyl carbamate 1d
yielded similar results as 1b in method A (entries 8 and 11).
Compounds 1b−d are able to eliminate propene or isobutene
via an imidoyl phosphate corresponding to intermediate A,
producing intermediate B. The results of method B on 1b−d
indicate that ease of formation of intermediate B influences the
cyclization rate (entries 6, 10, and 12). On the other hand, tert-
butyl carbamate 1e, expected as a rapid carbamoyl cation
generator, was not suitable for this cyclization due to partial
decomposition of 1e (entries 13 and 14).19 For comparison,
treatment of 1e with Tf2O and DMAP18a resulted in
decomposition whereas the same reaction using isopropyl
carbamate 1b afforded the desired isoindolinone in only 27%
Cyclization of various isopropyl carbamates (5b−8b) having
the ortho- and/or meta-substituted benzyl groups proceeded
smoothly to afford 17−20. in particular, the multisubstituted
carbamate 8b was relatively sensitive, and cyclization of the
corresponding methyl carbamate 8a resulted in low yield of 20
concomitant with decomposition. Isoquinolinone 21 and the
aliphatic lactam 22 were also obtained in good yield from 9b
and 10b. On the other hand, para-substituted substrates were
occasionally fractious (compounds 23−26). p-Methoxybenzyl-
carbamate 11b was readily decomposed presumably due to the
formation of the unstable p-quinone methide intermediate,
whereas benzodioxole 12b smoothly provided the correspond-
ing isoindolinone 24. In contrast, in the case of the electron-
withdrawing para-substituents (13b and 14b), the yields of 25
B
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Letter
method A (entries 15 and 20). Formation of carbonyl−ene
adducts implied formation of intermediate B, which has an
extremely electrophilic center.22 These results clearly indicate
that the formation of intermediate B is a key step for this γ-
lactam formation under such mild conditions. Thus, we reached
to other useful carbamates containing an alkoxy group with an
acidic β-hydrogen and without a γ-hydrogen, for the effective
construction of isoindolinones with electron-poor aromatic
groups. The 9-fluorenylmethyl, phenethyl, and homoallyl
groups satisfied these requirements, and we selected the
Fmoc-protected benzylmethylamines (9-fluorenylmethyl carba-
mate of benzylmethylamine) due to their easy preparation and
reactivity in cyclization.17 Thus, Fmoc-amine 13g, which
releases dibenzofulvene by treatment of P2O5, was transformed
into isoindolinone 25 in 85% yield without any side products
(Scheme 4). Furthermore, (p-methoxycarbonyl)-
benzylcarbamate 14g provided isoindolinone 26 in better
yield than the 14b case (Scheme 2).
Table 1. Bischler−Napieralski-Type Cyclization of Various
Carbamates and Competition Experiments with 1-Octene
and 1-Hexene
a
b
entry substrate
R1
method additive
results (yield, %)
1
2
1a
methyl
A
2 (57), 1a (31)
A
1-octene 2 (57), 1a (35), 31
(2)
3
B
A
A
B
B
A
A
B
A
B
A
B
A
A
2 (3), 1a (85)
2 (86)
4
1b
isopropyl
5
1-octene 2(75), 31 (1)
2 (85)
6
Scheme 4. Improved Cyclization Using Fmoc-Protected
Benzylmethylamines
7
1-hexene 2 (61), 32 (14)
2 (86)
8
1c
n-propyl
9
1-octene 2 (76), 31 (1)
2 (58), 1c (22)
2 (85)
10
11
12
13
14
15
16
1d
1e
1f
isobutyl
t-butyl
phenyl
2 (58), 1d (25)
2 (30)
2 (63)
2 (51), 1f (30)
1-octene 2 (46), 1f (44), 31
(0)
17
18
19
20
21
13b
isopropyl
B
B
25 (28), 29 (30)
1-hexene 25 (4), 34 (30)
25 (41), 29 (30)
In summary, we discovered a simple and efficient method for
construction of isoindolinones with a new reaction mechanism.
Most isoindolinones could be synthesized by treatment of
isopropyl carbamates of benzylamines with P2O5 under the
mild conditions. Furthermore, consideration of the mechanism
led to the use of Fmoc-benzylamines as a complement to the
construction of isoindolinones with electron-deficient aryl
groups. The simple and versatile method described here
would be applicable to divergent syntheses demanded by recent
pharmaceutical developments and to natural product syntheses,
as exemplified by our previous success of the total syntheses of
lactonamycins.10
c
13c
13f
n-propyl
B
A
A
phenyl
25 (49), 13f (34)
1-octene 25 (11), 13f (59), 33
(0)
a
Method A: carbamate and P2O5 in 1,2-dichloroethane (0.06 M), 84
°C, 1 d. Method B: carbamate and P2O5 in dichloromethane (0.06 M),
rt, 1 h. Alkene (10 mol amounts) was added to the carbamate
b
c
solution prior to addition of P2O5. Reaction time: 1 d.
yield along with detectable amounts of N-methylbenzylamine
and its N-triflate.20 Tf2O reversibly binds to either oxygen or
nitrogen of the carbamate,21 providing the carbamoyl cation
and the N-sulfonyl carbamate, respectively. Each intermediate
can be attacked by DMAP to give the above side products.
Highly oxophilic P2O5 would selectively bind to oxygen to
provide intermediate B via the imidoyl phosphate. Phenyl
carbamate 1f, without an alkyl group to eliminate, produced
isoindolinone 2 with method A (entry 15), suggesting direct
cyclization from imidoyl phosphate without passing inter-
mediate B at higher temperature.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
Similar to the case of 13b (Table 1 entry 17 and Scheme 2),
cyclization of 13c using method B afforded 25 (41%) and 29
(30%) (entry 19). In addition, the presence of excess amounts
of 1-hexene in the 13b reaction mixture caused competitive
addition of 1-hexene over propene, giving 34 in 30% yield
(entry 18). This competitive experiment was applied to other
substrates. Formation of the externally attacked 31 or 32 was
observed in the case of 1a−c (entries 2, 5, 7, and 9), whereas
phenyl carbamates 1f and 13f provided no carbonyl−ene
adducts (entries 16 and 21), despite their sufficient reactivity in
*E-mail: saikawa@applc.keio.ac.jp.
*E-mail: msynktxa@applc.keio.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was partially supported by a “MEXT-Supported
Program for the Strategic Research Foundation at Private
Universities 2012-2016”.
C
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Letter
(20) For detailed experimental procedures and data, see the
Supporting Information.
(21) Falmagne, J.-B.; Escudero, J.; Taleb-Sahraoui, S.; Ghosez, L.
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