Asymmetric Synthesis of Fluorinated Isoindolinones through Palladium-Catalyzed Carbonylative Amination of Enantioenriched Benzylic Carbamates

Article abstract of DOI:10.1002/chem.201500773

The asymmetric synthesis of fluorinated isoindolinones has been achieved by a palladium-catalyzed aminocarbonylation reaction of the corresponding α-fluoroalkyl o-iodobenzylamines. A base-mediated anti β-hydride elimination process was suggested to explain the partial erosion of the optical purity observed in some cases. This mechanistic rationale enabled the minimization of this partial racemization by fine-tuning the pK_a of the base.

Full text of DOI:10.1002/chem.201500773

DOI: 10.1002/chem.201500773
Full Paper
&
Asymmetric Synthesis
Asymmetric Synthesis of Fluorinated Isoindolinones through
Palladium-Catalyzed Carbonylative Amination of Enantioenriched
Benzylic Carbamates
Pablo Barrio,*[a] Ignacio IbµÇez,[b] Lidia Herrera,[a] Raquel Romµn,[a] Silvia Catalµn,*[b] and
Santos Fustero*[a, b]
Abstract: The asymmetric synthesis of fluorinated isoindoli-
nones has been achieved by a palladium-catalyzed amino-
carbonylation reaction of the corresponding a-fluoroalkyl o-
iodobenzylamines. A base-mediated anti b-hydride elimina-
tion process was suggested to explain the partial erosion of
the optical purity observed in some cases. This mechanistic
rationale enabled the minimization of this partial racemiza-
tion by fine-tuning the pKa of the base.
Introduction
The isoindolinone ring system constitutes an important motif
found in numerous bioactive molecules, pharmaceuticals and
natural products with interesting therapeutic activities.[1] They
are considered to be privileged structures because of their
widespread use as building blocks in total synthesis of natural
products as well as a common motif for drug-discovery. In par-
ticular, the chiral 3-substituted isoindolinone scaffold has
emerged as an attractive lead in medicinal chemistry. Examples
containing this benzolactam system are (S)-pagoclone,[2a,b] (R)-
pazinaclone (anxiolytic agents),[2c,d] or (+)-lennoxamine,[2e] a nat-
ural isoindolobenzazepine alkaloid (Figure 1).
Figure 1. Representative 3-substituted isoindolinone natural products and
pharmaceuticals.
Although the synthesis of racemic 3-alkylisoindolinones has
been thoroughly explored,[3] only a few enantioselective ap-
proaches have been described, mainly including diastereose-
lective reactions by using: 1) chiral auxiliaries,[4] including N-
tert-butanesulfinyl imines,[4c] 2) catalytic asymmetric process-
es,[5] or 3) organocatalytic approaches.[6] Surprisingly, only
a few examples of racemic fluorinated isoindolinones have
been reported,[7] despite the fact that the inclusion of fluorinat-
ed fragments, such as the trifluoromethyl group, in organic
molecules has contributed significantly to the development of
new drugs.[8] To the best of our knowledge, there has been no
report on enantiomerically pure fluorinated analogues.
Previously, we reported, within the context of diversity-ori-
ented synthesis (DOS), the use of ortho-substituted aromatic
tert-butylsulfinyl imines for the asymmetric synthesis of a varie-
ty of benzo-fused carbo- and heterocycles such as fluorinated
and non-fluorinated isoindolines and isoquinolines,[9a–c] indano-
nes[9d] or, more recently, the antidepressant sertraline[9e] and
aminoesteroid derivatives[9g] (Scheme 1). We have now extend-
ed our work based on DOS to the preparation of enantiomeri-
cally pure fluorinated g-lactam derivatives by using palladium-
catalyzed carbonylative amination as the key step.[10] In this
case, carbon monoxide was used as an inexpensive and readily
available C1 source.
[a] Dr. P. Barrio, L. Herrera, Dr. R. Romµn, Prof. Dr. S. Fustero
Departmento de Química Orgµnica
Universidad de Valencia, 46100 Burjassot, Spain
E-mail: pablo.barrio@uv.es
Results and Discussion
santos.fustero@uv.es
Preliminary results
[b] I. IbµÇez, Dr. S. Catalµn, Prof. Dr. S. Fustero
Laboratorio de MolØculas Orgµnicas
Centro de Investigación Príncipe Felipe, 46012 Valencia (Spain)
E-mail: silvia.catalan@uv.es
First, condensation with Ellman’s reagent[11] and then diastereo-
selective nucleophilic addition of the Ruppert–Prakash re-
agents[12] (CF3TMS, C2F5TMS) proceeded uneventfully, consis-
tent with previous results.[9a] In a first approach, the carbonyla-
tive amination reaction was performed on the starting sulfinyl
santos.fustero@uv.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500733.
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yield; e.r. 92:8; Table 2, entry 8). We further explored different
catalytic systems (Table 2, entries 9–13) consisting of [Pd(OAc)2]
or [PdCl2(PPh3)2] and phosphine-based ligands (PPh3, 1,4-bis(di-
phenylphosphino)butane (dppb), 4,5-bis(diphenylphosphino)-
9,9-dimethylxanthene (XantPhos)) but none was as good as
[Pd(PPh3)4] (10 mol%). Toluene turned out to be the best sol-
vent, whereas the use of other solvents such as MeCN, DMF, or
dioxane led to unfavorable results (Table 2, entries 14–16). To
minimize the racemization, the reaction was carried out at
lower temperature (508C, Table 2, entry 17), but very low con-
version was achieved. Conversion at this temperature could be
improved by increasing the pressure of CO to 10 atm (Table 2,
entry 18); however, under these conditions epimerization took
place to a slightly higher extent than when using 1 atm of CO
at 908C (Table 2, entry 18 vs. entry 8). Finally, the reaction con-
ditions shown in entry 8 (CO (1 atm), [Pd(PPh3)4] (10 mol%),
908C, toluene, Et3N (4 equiv)) were selected for studying the
scope and limitations of this transformation.
Scheme 1. Diversity-oriented synthesis (DOS) strategy on 2-halobenzalde-
hyde.
amine 1a/1’a (X=I, Br), being unsuccessful under different re-
action conditions (Table 1, entries 1 and 2). In contrast, we
found that subjecting unprotected ortho-iodo derivative 2a to
the carbonylation protocol provided the desired isoindolinone
scaffold 3a in good yield but with partial erosion of optical
purity (Table 1, entry 3). Surprisingly, no reaction was obtained
with the unprotected ortho-bromo derivative 2’a (Table 1,
entry 4).[9a]
Table 2. Optimization of the reaction conditions for the intramolecular
aminocarbonylation.
Entry
[Pd]/L
Base
Solvent
3a [%][a] e.r.[b]
Table 1. Preliminary results.
1
2
3
4
5
6
7
8
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
Pd(PPh3)4
[Pd(PPh3)4]
[Pd(PPh3)4]
[(Ph3P)2PdCl2]/PPh3
K3PO4
tBuOK
DBU
Li2CO3
K2CO3
TolH
TolH
TolH
TolH
TolH
67
83:17
–
–
c.m.
c.m.
21
42
30
53
85
n.r.
74
63
83:17
94:6
92:8
93:7
92:8
–
75:25
60:40
80:20
88:12
80:20
65:35
78:22
n.d.
Cs2CO3 TolH
AcOK
Et3N
Et3N
TolH
TolH
TolH
TolH
TolH
TolH
TolH
MeCN
DMF
9
10
11
12
13
14
15
16
17[c]
18[c,d]
[Pd(OAc)2]/XantPhos Et3N
Entry
Compound
(e.r.)
Compound
([%])[a]
e.r.[b]
[Pd(OAc)2]/PPh3
[Pd(OAc)2]/dppb
[Pd(OAc)2]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
37
26
50
90
1
2
3
4
1a
1’a
2a (98:2)
2’a
n.r.[c]
n.r.[c]
3a (67)
n.r.[c]
83:17
1,4-dioxane 73
TolH
TolH
28
67
88:12
[a] Yield of the isolated product. [b] Determined by chiral HPLC analysis.
[c] n.r. = no reaction.
[a] Yields of the isolated products (c.m.=complex mixture; n.d.=not de-
termined; n.r.=no reaction). [b] Determined by chiral HPLC. [c] Reaction
conducted at 508C. [d] Reaction conducted under 10 atm of CO.
Optimization
Scope and limitations
In view of these results, we first evaluated the influence of the
base (Table 2, entries 2–8), employing [Pd(PPh3)4] as the cata-
lyst (10 mol%)[13] at 908C. Whereas strong bases such as tBuOK
or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave complex mix-
tures and decomposition of the starting material (Table 2, en-
tries 2 and 3), milder bases such as Li2CO3, K2CO3, Cs2CO3, or
AcOK provided high enantioselectivity (an enantiomeric ratio
(e.r.) of up to 94:6) to the detriment of chemical yield (21–
53%; Table 2, entries 4–7). Finally, Et3N was mild enough to
give a good yield and preserve the enantioselectivity (85%
With the optimized reaction conditions in hand (Table 2,
entry 8), the scope of this transformation was studied next
(Scheme 2). Unfortunately, a noticeable loss of optical purity
was observed in all cases during carbonylation, this behavior
being particularly pronounced for substrates bearing electron-
withdrawing groups, such as F or CF3, at the aromatic ring
(Scheme 2, 3b,c). Actually, complete racemization was ob-
served for the CF3 derivative 3c (Scheme 2, 3c). It should also
be mentioned that the non-fluorinated substrate 2w (X=H,
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Scheme 2. Intramolecular aminocarbonylation on unprotected benzylamines
2.
R=allyl) did not undergo racemization under the reaction con-
ditions (Scheme 2, 3w).[14]
In view of the observed loss of optical purity, we shifted our
attention to N-protected derivatives, in particular, ortho-iodo-
benzyl carbamates 4, as the fluorinated building block of
choice (Scheme 3). To our delight, tert-butoxycarbonyl (Boc)-
protected substrate 4a was successfully cyclized under the es-
tablished conditions with no racemization, apart from certain
substrates, especially those containing strong electron-with-
drawing groups at the aromatic ring (Scheme 3, 5b,c). In addi-
tion to trifluoromethyl analogues, products bearing higher or
lower fluorine loading at the substituent at position 3 could
also be synthesized (Scheme 3, 5i,j). These latter results are re-
markable, since they allow fine tuning important physicochem-
ical properties of potential drugs such as pKa, lipophilicity, or
shape. The benzyloxycarbonyl (Cbz) group can be used as al-
ternative nitrogen protecting group, providing comparable re-
sults (Scheme 3, 5k–o).
Scheme 3. Intramolecular aminocarbonylation on carbamate protected ben-
zylamines 4.
Mechanistic studies
Scheme 4. Studies on the epimerization.
At this point, the question about the partial erosion of optical
purity upon carbonylation remained obscure. Racemization
might take place by the formation of a flat carbon–nitrogen
double bond. To shed some light on this issue, a few experi-
ments were carried out to determine the step when the race-
mization occurs. In a first set of experiments, the protected
and unprotected final products were subjected to the reaction
conditions to check their configurational stability. Hence, par-
tial racemization was observed when the free NH isoindolinone
3a was treated with [Pd(PPh3)4] and Et3N under the reaction
conditions. As expected, racemization was much faster for 3c,
which completely racemizes in just half an hour (Scheme 4).
On the other hand, Boc-protected product 5a maintained its
optical purity even after prolonged periods (24 h) under the re-
action conditions (Scheme 4).
of an acidic NH. This reaction pathway would be completely
suppressed for Boc-protected isoindolines. However, a noticea-
ble loss of enantiomeric purity was still observed for some pro-
tected amines (Scheme 3, 5b,c,k,l). In this case, racemization
on the final product was ruled out and, therefore, we exam-
ined the configurational stability of the starting carbamate 4 as
it contains an NH of similar pKa of those unprotected isoindoli-
nones 3 and thus, susceptible to deprotonation. To this end,
we used the Boc-protected 5-trifluoromethyl-2-bromobenzal-
dehyde derivative 4’c (X=Br), which does not give rise to car-
bonylation under our reaction conditions. Thus, the e.r. of the
starting material was monitored upon heating under the reac-
tion conditions. To our surprise, no erosion of the optical
purity was observed even after 24 h (Scheme 5).
From these experiments, we suggest that the origin of the
partial racemization observed upon aminocarbonylation of un-
protected benzylamines might be attributed to the presence
All these data suggest that for the unprotected amines 2,
the partial racemization observed may be explained by the
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Scheme 5. Studies on the epimerization.
configurational instability of the final products under the reac-
tion conditions; whereas for the carbamate-protected deriva-
tives 4, racemization occurs neither on the final product nor
on the starting material. Therefore, we suggest that this partial
racemization takes place by reversible b-hydride elimination
(b-HE)/hydropalladation (HP) on one of the intermediates after
oxidative addition (Scheme 6).
Scheme 7. Aminocarbonylation reaction on deuterium-labeled derivatives D-
4b and ND-4c.
Table 3. Dependence of the e.r. with the pKa of the base.
Entry
Base
pKa
5c [%][a]
e.r.[b]
1
2
3
4
Et3N
10.75
7.4
5.96
4.76
85
88
95
70
71:29
76:24
90:10
98:2
collidine
NH2OH
AcONa
[a] Yield of the isolated product. [b] Determined by chiral HPLC analysis.
Scheme 6. Mechanistic proposal for the epimerization.
entries 1–4).[19] In this way, the use of a milder base, such as
AcONa, allowed us to obtain product 5c with complete preser-
vation of the optical purity (Table 3, entry 4). A few features de-
serve mentioning: 1) To date, most examples of anti b-hydride
elimination mechanisms have been reported on Heck or allylic
acetate elimination reactions;[16] 2) In most of those examples,
isomerization of the palladium intermediate to one featuring
hydrogen in a syn disposition cannot be excluded,[20] therefore,
they would only be formally anti; 3) To the best of our knowl-
edge, this is the first report on erosion of optical purity by a re-
versible anti b-hydride elimination/hydrometalation mecha-
nism; 4) Identification of such undesired reaction pathway has
allowed us to suppress the racemization by fine-tuning the pKa
of the base used.
The geometrical restrictions imposed by the cyclic structure
of intermediate A[15] (the same argument may be applied to in-
termediate C) require the b-hydride elimination step to take
place in an anti-fashion rendering planar intermediate B
(Scheme 6). Although several authors have proposed processes
of this kind, little mechanistic support has been reported to
date.[16,17] Again, this proposal would explain the greater exten-
sion of the racemization when electro-withdrawing substitu-
ents are present by increasing the acidity of the benzylic
proton.
In a further effort to find experimental support for the intra-
molecular nature of the racemization process, the aminocarbo-
nylation reaction was tested on deuterium-labeled derivatives
D-4b and ND-4c (Scheme 7). In agreement with our hypothe-
sis, neither H- nor D-incorporation was observed upon amino-
carbonylation of D-4b and ND-4c, respectively (Scheme 7).
The lack of H/D scrambling seems to rule out that a simple
acid–base reaction is responsible for the observed partial epi-
merization.
With the optimal base (AcONa, Table 3, entry 4), other reac-
tions for which a higher degree of racemization was observed
under our initial reaction conditions were repeated (Scheme 8).
As expected, carbamate derivative 4b underwent smooth ami-
nocarbonylation with complete preservation of optical purity.
On the other hand, the most challenging substrate, the unpro-
tected 5-CF3 derivative 2c, led to complete racemization be-
cause of the configurational instability of the free NH isoindoli-
none under the reaction conditions. However, the correspond-
ing product 3c was achieved in excellent optical purity by tri-
fluoroacetic acid (TFA) deprotection of 5c (see below).
Assuming that the anti b-hydride elimination is a base-pro-
moted E2-type process,[18] the degree of epimerization should
display a pronounced dependence on the pKa of the base.
Therefore, fine-tuning of the basicity made it possible to over-
come the partial racemization on substrates bearing fluorinat-
ed residues at the aromatic ring (Table 3).
Deprotection
From Table 3, a nice correlation between the pKa of the base
and the e.r. of the final products may be inferred: the weaker
the base, the higher the optical purity of the product (Table 3,
Finally, free NH isoindolines 3 may be obtained in high optical
purity by TFA deprotection of the corresponding NBoc deriva-
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for their financial support. S.C. expresses her thanks for a Juan
de la Cierva contract and L.H. for a predoctoral fellowship.
Keywords: asymmetric synthesis · carbonylation · fluorine ·
heterocycles · palladium
Scheme 8. Application of the re-optimized reaction conditions to other chal-
lenging substrates.
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Conclusion
We have described a palladium-catalyzed aminocarbonylation
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General procedure for the intramolecular aminocarbonyla-
tion
CO was bubbled for 10 min into a suspension of the correspond-
ing free amine 2 or carbamate 4, [Pd(PPh3)4] (10 mol%) and the ap-
propriate base (4 equiv) in toluene (0.1m). Then, the reaction mix-
ture was heated at 908C under an atmosphere of CO (1 atm) until
TLC revealed disappearance of the starting material. The reaction
mixture was filtered through a short pad of Celite, concentrated
under reduced pressure, and purified by means of column chroma-
tography on silica gel using mixtures of hexane and ethyl acetate
as eluent.
Acknowledgements
[12] For seminal reports on the diastereoselective addition of the Ruppert–
Prakash reagent to tert-butylsulfinimines, see: a) G. K. S. Prakash, M.
Mandal, G. A. Olah, Angew. Chem. Int. Ed. 2001, 40, 589; Angew. Chem.
The authors are grateful to the Spanish MINECO (CTQ2013-
43310-P) and Generalitat Valenciana (PROMETEOII/2014/073)
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[13] Lower catalyst loadings (5 mol%) led to poor conversions.
[14] This compound has previously been described by means of different
approaches: a) see ref. [4b] and [4c]; b) S. Dhanasekaran, V. Bisai, R. A.
Unhale, A. Suneja, V. K. Singh, Org. Lett. 2014, 16, 6068.
[15] Closely structurally related palladacycles have been isolated and charac-
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Angew. Chem. Int. Ed. 2001, 40, 1439; Angew. Chem. 2001, 113, 1485;
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la, M. Martínez, E. P. Urriolabeitia, Chem. Eur. J. 2013, 19, 17398.
[16] For “synthetic” reports in which an anti b-hydride elimination process is
suggested without any further experimental evidence, see: a) K. M.
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a review on Heck reactions involving a “formal” anti b-hydride elimina-
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Bialy, T. Yakura, Heterocycles 1999, 51, 1957.
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[18] At this stage an alternative E1cb reaction pathway cannot be ruled out.
[19] Other bases such as pyridine, 2,4,6-trimethylpyridine, 2,6-di-tert-butyl-4-
methylpyridine, imidazole, aniline, NaHCO3, NaN3, have also been used
but less efficient results have been obtained; for details, see the Sup-
porting Information.
[20] See, for instance: a) H. Kurosawa, S. Ogoshi, N. Chatani, Y. Kawasaki, S.
Murai, I. Ikeda, Chem. Lett. 1990, 19, 1745; b) S. Ogoshi, H. Kurosawa, Or-
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Received: February 23, 2015
Revised: May 13, 2015
Published online on June 29, 2015
Chem. Eur. J. 2015, 21, 11579 – 11584
www.chemeurj.org
11584
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