Gold-catalyzed intramolecular hydroamination of o-alkynylbenzyl carbamates: A route to chiral fluorinated isoindoline and isoquinoline derivatives

Article abstract of DOI:10.1021/ol3035142

Enantiomerically pure fluorinated isoindoline and dihydroisoquinoline scaffolds have been prepared through a diastereoselective addition of fluorinated nucleophiles to Ellman's N-(tert-butanesulfinyl)imines followed by a sequence of Sonogashira cross-coupling/gold(I)-catalyzed cycloisomerization of the corresponding carbamate. A more favored 5-exo-dig mechanism was observed mainly due to an electronic effect of the fluorinated group.

Full text of DOI:10.1021/ol3035142

ORGANIC
LETTERS
2013
Vol. 15, No. 4
832–835
Gold-Catalyzed Intramolecular
Hydroamination of o‑Alkynylbenzyl
Carbamates: A Route to Chiral Fluorinated
Isoindoline and Isoquinoline Derivatives
†
†
§,
Santos Fustero,*,†,‡ Ignacio Ibanez, Pablo Barrio, Miguel A. Maestro, and
ꢀ
Silvia Catalan*
ꢀ~
,†,‡
´
Departamento de Quımica Organica, Universidad de Valencia, E-46100 Burjassot,
Spain, Laboratorio de Moleculas Organicas, Centro de Investigacion Prıncipe Felipe,
ꢀ
ꢀ
ꢀ
ꢀ
´
´
E-46012 Valencia, Spain, and Laboratorio de Quımica Fundamental, Universidade da
~ ~
Coruna, 15071, A Coruna, Spain
santos.fustero@uv.es; silvia.catalan@uv.es
Received December 22, 2012
ABSTRACT
Enantiomerically pure fluorinated isoindoline and dihydroisoquinoline scaffolds have been prepared through a diastereoselective addition of
fluorinated nucleophiles to Ellman’s N-(tert-butanesulfinyl)imines followed by a sequence of Sonogashira cross-coupling/gold(I)-catalyzed
cycloisomerization of the corresponding carbamate. A more favored 5-exo-dig mechanism was observed mainly due to an electronic effect of the
fluorinated group.
Isoindoline and isoquinoline ring systems are wide-
spread in the alkaloid family and other natural products
displaying a wide range of interesting biological properties.1
They are considered “privileged structures” owing to their
general use as building blocks in the total synthesis of
natural products but also a common motif in the design
of new drugs.2 On the other hand, selective introduction of
fluorine atoms into organic molecules has become one of
the most efficient methods for modulation of their biolo-
gical properties.3 Thus, preparation of both fluorinated
isoindoline and isoquinoline derivatives has received much
attention in industry, especially with regard to efforts directed
at asymmetric synthesis.
† Universidad de Valencia.
‡
ꢀ
ꢀ
Centro de Investigacion Prıncipe Felipe.
§
~
Universidade da Coruna.
Author to whom correspondence regarding X-ray analysis should be
addressed.
(1) For a comprehensive review of isoindolines, see: (a) Portevin, B.;
Tordjman, C.; Pastoureau, P.; Bonnet, J.; De Nanteuil, G. J. Med.
Chem. 2000, 43, 4582. (b) Stuk, C. L.; Assink, B. K.; Bates, R. C.;
Erdman, B. T.; Fedij, V.; Jennings, S. M.; Lassig, J. A.; Smith, R. J.;
Smith, T. L. Org. Process Res. Dev. 2003, 7, 851. For isoquinolines: (c)
Bentley, K. W. Nat. Prod. Rep. 2006, 23, 444. (d) Vincent, G.; Williams,
R. M. Angew. Chem., Int. Ed. 2007, 46, 1517. (r) Bhadra, K.; Kumar, S.
Med. Res. Rev. 2011, 31, 821.
Among the different methods to access these nitrogen-
containing heterocycles, transition-metal-catalyzed intra-
molecular hydroamination reactions are of particular
(2) The concept of “privileged structures”was first introduced by
Evans and was recently updated by Patchett and Nargund. (a) Evans,
B. E.; Rittle, K. E.; Bock, M. G.; Dipardo, R. M.; Freidinger, R. M.;
Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang,
R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel,
K. A.; Springer, J. P.; Hirschfield, J. J. J. Med. Chem. 1988, 31, 2235. (b)
Patchett, A. A.; Nargund, R. P. Annu. Rep. Med. Chem. 2000, 35, 289.
ꢁ
ꢀ
(3) (a) Begue, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal
Chemistry of Fluorine; Wiley: Hoboken, NJ, 2008. (b) M€uller, K.; Faeh, C.;
Diederich, F. Science 2007, 317, 1881. (c) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (d)
O’Hagan, D. J. Fluorine Chem. 2010, 131, 1071.
r
10.1021/ol3035142
Published on Web 01/29/2013
2013 American Chemical Society

value.4 This process relies on the catalytic activation of the
CÀC triple bond followed by an attack of an internal
nucleophile. In the past few years, gold complexes have
emerged as powerful catalysts for this purpose.5
Table 1. Obtention of Enantiomerically Pure Fluorinated
2-Iodobenzyl Carbamates 3
To the best of our knowledge, most cycloisomerizations
catalyzed by gold lead to the formation of the isoquinoline
skeleton as a result of a favored 6-endo-dig cyclization.6 In
these cases, the corresponding 5-exo-dig product was not
isolated due to either its instability or its nonformation.6b,c
However, we have found that the gold-catalyzed cyclo-
isomerization of fluorinated o-alkynylaryl carbamates
evolves preferably toward the isoindoline formation, as
opposed to our expectations.
Given our group’s interest in organofluorine chemistry,
we have recently reported a stereoselective synthesis of
fluorinated 1,3-disubstituted isoindolines based on a nucleo-
philic addition/intramolecular aza-Michael reaction tandem
process.7 The choice of Ellman’s (R)-N-(tert-butanesulfinyl)-
imines as chiral auxiliaries was crucial in the achievement
of excellent diastereoselectivities.8 Building on these results,
we envisioned an alternative and more direct route toward
enantioenriched fluorinated isoindoline 5 and isoquinoline 6
scaffolds through a gold(I)-catalyzed intramolecular hydro-
amination reaction as the key step.
Our strategy implies the use of an appropriate building
block to introduce chirality and the fluorinated group into
the molecule at the beginning. Hence, 2-iodobenzyl carba-
mate 3 was regarded as the fluorinated building block of
choice in a first approach.
Starting from Ellman’s (R)-N-(tert-butanesulfinyl)imines
1, selective addition of different fluorinated nucleophiles
(CF3TMS, CF3CF2TMS, PhSO2CF2H, PhSO2CH2F) led
to the expected sulfinyl amines 2 in good yields as single
diastereoisomers (Table 1).9,10
In view of the fact that the stereochemistry of the chiral
auxiliary is known (RS), the absolute configuration of
the newly created stereocenter was determined to be S
entry
2
% yielda
RF
X
Y
3
% yielda (er)b
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
80
70
71
77
71
83
92
88d
CF3
H
H
H
H
H
3a
3b
3c
3d
3e
3f
80 (<99:1)
74 (97:3)
82c
CF3
F
CF3
CF3
OMe
CF3
75 (97:3)
80 (98:2)
60 (99:1)
75c
CF3
OÀCH2ÀO
C2F5
CF2R
CFHR
H
H
H
H
2g
2h
H
H
3g
3h
88d
a Isolatedyield. b Determined bychiralHPLC analysis. c Incompletely
separated enantiomeric mixture. d Obtained as a diastereomeric mixture
(1:2), determined by 19F NMR analysis of crude reaction mixture. R =
SO2Ph.
according to previous reports7,11 and definitely confirmed
by X-ray analysis.12 Since we proved that the cycloisome-
rization did not take place in the presence of the tert-
butanesulfinyl group (t-BuSO), the conversion of t-BuSO
into another nitrogen-protecting group compatible with
the intramolecular hydroamination was required. With
this purpose, chiral intermediates 2 were treated with
4 M HCl in dioxane yielding the corresponding free amines
after basification. Unisolated amines were then protected
ascarbamatesunder standardconditions, giving the fluori-
nated building blocks 3 in good to excellent yields and
enantioselectivities (Table 1).
Next, the functionalization of synthon 3 with selected
terminal acetylenes by means of a typical Sonogashira
cross-coupling reaction afforded alkynyl carbamates 4 in
excellent yields (Table 2). To our delight, the enantioselec-
tivity was well preserved during the process.
According to our synthetic plan, the next step would
be the intramolecular hydroamination reaction catalyzed
by a transition metal complex. In order to find optimum
conditions, alkynyl carbamate (()-4a was subjected to the
intramolecular protocol in the presence of different Lewis
acid catalysts.
(4) (a) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (b)
Kirsch, S. F. Synthesis 2008, 20, 3183. (c) Weibel, J.-M.; Blanc, A.; Pale,
ꢀ
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P. Chem. Rev. 2008, 108, 3149. (d) Alvarez-Corral, M.; Munoz-Dorado,
M.; Rodrıguez-Garcıa, I. Chem. Rev. 2008, 108, 3174. (e) Gilmore, K.;
Alabugin, I. V. Chem. Rev. 2011, 111, 6513.
(5) (a) Zigang, L.; Brouwer, Ch.; He, Ch. Chem. Rev. 2008, 108, 3239.
ꢀ
~
(b) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326.
€
(c) Muller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem.
ꢀ
Rev. 2008, 108, 3795. (d) Corma, A.; Leyva-Perez, A.; Sabater, M. J.
Chem. Rev. 2011, 111, 1657.
(6) (a) Obika, S.; Kono, H.; Yasui, Y.; Yanada, R.; Takemoto, Y.
J. Org. Chem. 2007, 72, 4462. (b) Enomoto, T.; Obika, S.; Yasui, Y.;
Takemoto, Y. Synlett 2008, 11, 1647. (c) Enomoto, T.; Girard, A.-L.;
Obika, S.; Yasui, Y.; Takemoto, Y. J. Org. Chem. 2009, 74, 9158. (d)
Patil, N. T.; Mutyala, A. K.; Lakshmi, P. G. V. V; Raju, P. V. K.;
Sridhar, B. Eur. J. Org. Chem. 2010, 1999.
ꢀ
ꢀ
ꢀ
(7) (a) Fustero, S.; Moscardo, J.; Sanchez-Rosello, M.; Rodrıguez,
E.; Barrio, P. Org. Lett. 2010, 12, 5494. (b) Fustero, S.; Rodrıguez, E.;
Herrera, L.; Asensio, A.; Maestro, M. A.; Barrio, P. Org. Lett. 2011, 13,
6564.
When the model substrate 4a was treated with CuI,
Pd(OAc)2, or AuCl3, cyclization products were not detected
even after prolonged reaction times (2À3 days).13 Although
(8) For a recent and exhaustive review on tert-butanesulfinamide and
its use in synthesis, see: Robak, M. T.; Herbage, M. A.; Ellman, J. A.
Chem. Rev. 2010, 110, 3600.
(9) For the asymmetric synthesis of fluoroalkyl amines, see also:
Soloshonok, V. A.; Ono, T. J. Org. Chem. 1997, 62, 3030 and references
cited therein.
(10) Racemic mixtures were prepared in a similar manner starting
from (()-N-(tert-butanesulfinyl)imines 1. For experimental details, see
the Supporting Information.
(11) Krishnamurti, R.; Bellew, B. R.; Prakash, G. K. S. J. Org. Chem.
1991, 56, 984.
(12) Suitable crystals of products 7 (CCDC 916244) and 10 (CCDC
916245) were obtained for X-ray diffracction analysis. For details, see
the Supporting Information.
(13) An in-depth investigation on the reaction conditions was carried
out. See the Supporting Information for a detailed study.
Org. Lett., Vol. 15, No. 4, 2013
833

Table 2. Sonogashira Cross-Coupling Reaction/Gold(I)-Catalyzed Intramolecular Hydroamination Sequence
entry
4
% yielda (er)b
RF
X
Y
R2
[5:6]
4:1
5
% yielda (er)b
6
% yielda (er)b
1
4a
4b
4c
4d
4e
4f
94 (99:1)
93 (98:2)
97 (98:2)
99 (>99:1)
91 (96:4)
90 (95:5)
60 (97:3)
88 (96:4)
45d (99:1)
94 (97:3)
68f
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
C2F5
CF2H
CH2F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
5a
5b
5c
5d
5e
5f
80 (97:3)
26 (99:1)
54 (93:7)
60 (96:4)
70 (96:4)
80 (93:7)
80 (97:3)
85 (95:5)
>99 (98:2)
50 (94:6)
n.r.
6a
6b
6c
6d
6e
6f
20 (97:3)
74 (98:2)
43 (95:5)
20 (97:3)
18e (98:2)
n.d.
2
H
4-MeOC6H4
4-MeC6H4
4-FC6H4
3-MeOC6H4
3-CF3C6H4
3,5-diMeOC6H3
3,5-diFC6H3
3,5-diCF3C6H3
n-Hex
1:3
3
H
1:1
4
H
3:1
5
H
5:1
6
H
>30:1c
12:1
>30:1c
>30:1c
3:1
7
4g
4h
4i
H
5g
5h
5i
6g
6h
6i
n.d.
8
H
n.d.
9
H
n.d.
37e,g
10
11
12
13
14
15
16
17
18
4j
H
5j
6j
4k
4l
H
t-Bu
5k
5l
6k
6l
n.r.
88 (97:3)
86g
F
Ph
2:1
62 (97:3)
47 (92:8)
70 (91:9)
75 (95:5)
81 (>99:1)
51 (n.d.)i
36 (n.d.)i
36 (97:3)
41 (92:8)
24e (96:4)
n.d.
4m
4n
4o
4p
4q
4r
CF3
Ph
1:1
5m
5n
5o
5p
5q
5r
6m
6n
6o
6p
6q
6r
83 (96:4)
86 (98:2)
80 (>99:1)
58h,g
OMe
Ph
3:1
OÀCH2ÀO
Ph
17:1
4:1
H
H
H
H
H
H
Ph
19 (>99:1)
<5
Ph
7:1
49h,g
Ph
1:1.5
54 (98:2)
a Isolated yield. b Determined by chiral HPLC analysis. c The other isomer was not observed on 1H and 19F NMR spectra. d 50% conversion. e The
yield refers to an inseparable mixture of (E)-5 isomer and 6. f Only the racemic mixture was prepared. g Incompletely separated enantiomeric mixture.
h Overall yield after two steps: Sonogashira cross-coupling/desulfonation reaction. i Not stable enough to be determined. n.r. = no reaction; n.d. = not
determined.
the cationic gold(I) complex generated in situ from
Ph3PAuCl and AgNTf2 was not very effective by itself
either, the addition of protic additives (5 equiv EtOH)
promoted the cyclization at room temperature,6b,c,14 fur-
nishing the 5-exo-dig product (()-5a and 6-endo-dig prod-
uct (()-6a in 60:40 ratio and moderate conversion (62%
after 48 h).13 To our delight, a slight increase in temperature
(40 °C) accelerated the process significantly, reaching com-
pletion in 3 h and improving the yield up to 90% (50:50
ratio).13
We also evaluated the influence of the nitrogen-protecting
group on the process (Boc, Cbz, t-BuSO, t-BuSO2, H),
and the tert-butyloxycarbonyl (Boc) group was eventually
chosen to be the best protecting group.
Additionally, various silver salts were screened to test
the influence of the counterion, the softer, less-coordinat-
ing bis(trifluoromethanesulfonyl)imidate (NTf2) being
the anion of choice. DCE was the best solvent, while the
useofothersolventssuchasTHF, MeCN, ortoluene ledto
unfavorable results.
AuSPhosNTf2 was confirmed as the most promising
catalyst, providing excellent yield and regioselectivity
(Table 2, entry 1).15
Encouraged by these results, we further explored the
scope of this reaction. Thus, chiral intermediates 4 under-
went a gold(I)-catalyzed cycloisomerization reaction un-
der the established conditions (Table 2). In most cases, the
cooperative catalysis between AuSPhosNTf2 and EtOH
generated mixtures of regioisomers (5:6).16
Electron-donating alkyne substitution led preferably to
6-endo-dig cyclization (entries 2 and 3), while an electron-
withdrawing effect favored isoindoline formation (entry
4).14b,17 It should be noted that when p-MeOC6H4 (4b) was
changed tom-MeOC6H4 (4e), isoindoline 5ewas formedas
the main product versus 6e (entry 5). Interestingly, exclu-
sive 5-exo-dig cyclization was observed with alkynyl 4fÀi,
furnishing isoindolines 5fÀi as the only product (entries
7À9). However, the reaction of 4k (R2 = t-Bu, entry 11)
did not take place at all, and the starting material was
We further optimized the reaction conditions for alkyne 4a
using gold(I) catalysts bearing bulkier biarylphosphine
ligands (SPhos, XPhos, JhonPhos) in order to evaluate
their effect on the regioselectivity. Preformed air-stable
(15) Interestingly, the absence of AgCl in the medium improved the
catalytic activity: Leyva, A.; Corma, A. J. Org. Chem. 2009, 74, 2067.
(16) A parcial racemization of compounds 5 and 6 was observed
probably due to an enantiomer self-disproportionation effect on achiral
silica gel: (a) Soloshonook, V. A. Angew. Chem., Int. Ed. 2006, 45, 766.
~
(b) Sorochinsky, A. E.; Acena, J. L.; Soloshonok, V. D. Synthesis 2013,
45, 141.
(14) (a) Monge, D.; Jensen, K. L.; Franke, P. T.; Lykke, L.; Jørgensen,
K. A. Chem.;Eur. J. 2010, 16, 9478. (b) Lu, D.; Zhou, Y.; Li, Y.; Yan, S.;
Gong, Y. J. Org. Chem. 2011, 76, 8869.
(17) (a) Park, J. H.; Bhilare, S. V.; Youn, S. W. Org. Lett. 2011, 13,
2228. (b) Patil, N. T.; Nijamudheen, A.; Datta, A. J. Org. Chem. 2012,
77, 6179.
834
Org. Lett., Vol. 15, No. 4, 2013

Figure 1. R-Substituent effect on the gold(I)-catalyzed cycloisomerization reaction.
(Figure 1).19 Hence, we can conclude that the regioselec-
tivity between 5-exo-dig 5 and 6-endo-dig 6 did not only
depend on the nature and position of the substituents in R2
but also on the R-substitution of the nitrogen.
Scheme 1. Reduction and Deprotection of 5h and 6b
In order to expand our methodology and make it
synthetically more useful, we carried out the diastereo-
selective hydrogenation of the generated double bond giving
rise to N-Boc-protected derivatives 7 and 9 (Scheme 1).
Next, the Boc protecting group was removed affording the
free NH isoindoline 8 and tetrahydroisoquinoline 10 in
90% and 60% yield, respectively. The absolute configura-
tion was confirmed by X-ray diffraction analysis (see the
Supporting Information). These chiral fluorinated deriva-
tives would potentially be good candidates as ligands in
the design and development of new catalytic species, which
could find applications, for instance, in organocatalysis.20
In summary, we have developed an asymmetric synthe-
sis of fluorinated isoindolines 1 and 1,2-dihydroisoquino-
lines 2 by means of a gold(I)-catalyzed cycloisomerization
as the key step. By tuning the electronic property of the
alkyne moiety, the regioselectivity can be controlled and
directed toward one major product. Also, a significant
effect by the fluorinated group was observed, leading the
cyclization process through a more favored 5-exo-dig
mechanism. Applying the principles of diversity-oriented
synthesis,21 access to new libraries of chiral fluorinated
molecules would be feasible from our small fluorinated
building blocks. Further applications of the new substrates
are underway in our laboratory.
recovered, probably owing to the steric hindrance of the
bulkier t-Bu group. In all cases but 5j,18 (Z)-isomers of
isoindolines were formed stereoselectively. Likewise, we
also explored differently substituted arene rings (Table 2,
entries 12À15). In this case, an electron-rich aromatic ring
strongly favors a nucleophilic attack to afford the 5-exo-dig
product (entry 15) owing to its effect on the polarization of
the triple bond.14b
On the other hand, the replacement of one or more
hydrogen atoms by fluorine in the vicinity of an amine
function results in a lower basicity. Presumably, this fact
has a significant influence on the regioselectivity of the
process. In contrast to published results (Figure 1, A),6b,c
we observed thatthe gradual introduction of fluorine atoms
at the R-position (CH3 < CH2F < CHF2,CF3,C2F5)
promotes the 5-exo-dig mechanism, leading to isoindoline
5 as a major product under the optimized conditions
Acknowledgment. We would like to thank the Spanish
ꢀ
Ministerio de Ciencia e Innovacion (CTQ2010-19774) and
Generalitat Valenciana (PROMETEO/2010/061) for its
financial support. S.C. and P.B. express their thanks for a
Juan de la Cierva contract.
(18) Isoindoline 5j was obtained as a mixture of (E)- and (Z)-isomers
in a 50:50 ratio, determined by 19F NMR of the crude reaction mixture.
Compounds 5e and 5n in 2:98 and 10:90 E/Z ratio, respectively.
(19) Certain instability was noticed in chloride solvents for isoindo-
line analogues particularly, which was successfully circumvented by
increasing the fluorine loading.
Supporting Information Available. Experimental pro-
cedures and NMR spectra for all new compounds, as
well as crystallographical data for compounds 7 and 10,
including their CIF files. This material is available free of
charge via the Internet at http://pubs.acs.org.
(20) (a) List, B. Chem. Commun. 2006, 8, 819. (b) Melchiorre, P.;
Marigo, M.; Carnole, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47,
ꢀ
6138. (c) Palomo, C.; Oiarbide, M.; Lopez, R. Chem. Soc. Rev. 2009, 38,
632.
(21) Spring, D. Org. Biomol. Chem. 2003, 1, 3897.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
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