Proximal ester assistance vsstereoelectronic prohibition in catalytic N -acyliminium ion reactions: Stereoselective formation of aza-heterocycles with two contiguous quaternary-tertiary stereocenters

Article abstract of DOI:10.1055/s-0030-1260311

The catalytic intramolecular and intermolecular -amidoalkylation of deactivated N,O-acetals equipped with either two ester groups or both an ester and a cyano groups to the reactive center has been developed. Reactions in the cyano ester series proceeded

Full text of DOI:10.1055/s-0030-1260311

LETTER
2425
Proximal Ester Assistance vs. Stereoelectronic Prohibition in Catalytic
N-Acyliminium Ion Reactions: Stereoselective Formation of Aza-Heterocycles
with Two Contiguous Quaternary-Tertiary Stereocenters
Stereoselective
Format
o
ion of
A
za-H
u
eterocyclesssa Saber, Sébastien Comesse,* Vincent Dalla,* Pierre Netchitaïlo, Adam Daïch
Laboratoire de Chimie, URCOM, EA 3221, CNRS-INC3M FR3038, UFR des Sciences et Techniques, Université du Havre,
BP: 540, 25 Rue Philipe Lebon, 76058 Le Havre Cedex, France
Fax +33(2)32744391; E-mail: sebastien.comesse@univ-lehavre.fr; E-mail: vincent.dalla@univ-lehavre.fr
Received 16 June 2011
fore, one of the privileged directions in this field aims at
Abstract: The catalytic intramolecular and intermolecular a-ami-
evaluating new challenging substrates. We realized that
this exercise might be addressed through the use of the ge-
neric substrates 1 represented in Scheme 1. With a quater-
doalkylation of deactivated N,O-acetals equipped with either two
ester groups or both an ester and a cyano groups a to the reactive
center has been developed. Reactions in the cyano ester series pro-
ceeded under harsher reaction conditions than those in the diester nary center flanked by two electron-withdrawing groups
series, but furnished products with two contiguous quaternary and
(EWG = CO2R, CN) resident to the N,O-acetalic carbon,
this novel and readily available substrate class8 is at first
tertiary stereocenters with high to complete diastereocontrol. The
reactivity trends and stereoselectivity profiles exhibited by these re-
glance regarded as stereoelectronically deactivated to-
actions may be consistent with a relay mode exerted by the ester
wards electrophilic catalysis and therefore represents a
suitable model for our preliminary study.
arm(s), which might possibly direct the catalyst delivery and/or sta-
bilize the raising carbenium ion through anchimeric bridging.
Likewise, several groups have recently shown that, in the
presence of superacidic reagents such as triflic acid and
Sn(NTf2)4, the electrophilic activation of an alkene to pro-
duce a transient carbocation intermediate could be relayed
by a proximal ester function owing to the intrinsic basicity
and nucleophilicity of the ester carbonyl.9
Key words: catalysis, bistrifluoromethanesulfonimide, N-acyl-
iminium, directing effect and relay mode, diastereocontrol
Amongst common methods that readily generate N-
acyliminium ions,1 the acid-promoted activation of N,O-
acetals is cornerstone.2 Our group and others have recent-
ly documented novel catalytic systems for related a-ami-
doalkylation reactions.3–7 In most cases, structurally
simple, and then relatively reactive N,O-acetals were
used. Catalytic N-acyliminium ion chemistry let the chal-
lenge of using substrates with high density of steric and
electronic deactivating elements largely unmet. There-
We then questioned whether this paradigm might also be
effective for generating N-acyliminium ions from com-
pounds 1 as well as carbenium ions from related alcohol
derivatives in a more general prospect.10 This would per-
mit overcoming the inherent stereoelectronic deactivation
exerted by the two proximal EWG groups and make sub-
strates 1 amenable to a challenging catalytic N-acylimini-
a chemical relay for
cation formation?
EWG
EWG
EWG
CO2R
CO2R
Nu
CO2R
Nu
Nu
OR1
Nu
O
O
N
N+
R2
O
H+/M+ (cat.)
N
R2
R2
( )-1
( )-2
RO
OR
O+
OR
O
EWG
EWG
and/or
O+
Nu
O
H/M
N
O
O
O
N
EWG
Nu
O+ H/M
R1
N
R2
R2
R1
Nu
R2
lit. 9
Scheme 1 Ester-assisted vs. stereoelectronic prohibition of N-acyliminium ion formation–trapping under catalytic activation mode
SYNLETT 2011, No. 16, pp 2425–2429
x
x
.x
x
.2
0
1
1
Advanced online publication: 13.09.2011
DOI: 10.1055/s-0030-1260311; Art ID: B11011ST
© Georg Thieme Verlag Stuttgart · New York

2426
M. Saber et al.
LETTER
um ion alkylation to produce compounds 2, as illustrated
in Scheme 1.
Table 1 Catalytic Intramolecular a-Amidoalkylations of Substrates
3a–d
EWG1
EWG2
EWG1
EWG2
Such an operation would be an elegant challenge in its
own right, yet pointing out new vistas in alkylative chem-
istry. Moreover, it is also worth mentioning that these
novel reactions would furnish Mannich-type adducts that
bear two contiguous quaternary and tertiary stereocenters.
We advance herein our preliminary efforts towards estab-
lishing this endeavor, with a highly efficient Tf2NH-cata-
lyzed intramolecular and intermolecular a-amido-
alkylation of these novel N,O-acetals.
OMe
Tf2NH (5 mol%)
OEt
O
O
N
N
conditions
OMe
OMe
( )-4a–d
OMe
( )-3a–d
Entry EWG1, EWG2
Conditions
Yield (%)a
4a 90
4b 93
4b 95
0
1b
2
3a H, H
CH2Cl2, r.t., 1 h
MeCN, r.t., 36 h
The requisite substrates (see compounds 3a–d in Table 1,
5a–c in Table 2, and 11a–c in Scheme 2) were readily pre-
pared according to our previously reported, unprecedent-
ed, and completely stereoselective formal [3+2]-
cycloaddition protocol.8,11 With a set of functionalized
and novel subunits in hand, we embarked in the catalytic
studies. The unique ability of Tf2NH in catalytic N-
acyliminium ion chemistry4 prompted us to use this super-
acid for the present study. The capacity of these substrates
to undergo an efficient yet challenging alkylation process
was initially examined with the intramolecular Friedel–
Crafts-type a-amidoalkylation of the substrates 3b–d ac-
tivated with an electron-rich aromatic nucleus (Table 1).
While the presence of two ester substituents in substrate
3b markedly retarded the cyclization to 4b in comparison
3b CO2Et, CO2Et
3b CO2Et, CO2Et
3c CN, CN
3c
4
toluene, 110 °C, 20 min
MeCN, 82 °C, 24 h
toluene, 110 °C, 24 h
MeCN, r.t,. 48 h
5d
6
3c CN, CN
4c 80
0
3d CO2Et, CN
3d CO2Et, CN
3d CO2Et, CN
3d CO2Et, CN
7
MeCN, 82 °C, 40 min
toluene, 110 °C, 20 min
toluene, 60 °C, 15 hf
4d 94e
4d 95e
4d 96e
8c
9
a Isolated yields are given.
b Compound 3a is a methoxyaminal.
to that of the succinimide analogue 3a (Table 1, entry 1 c 1 mol% Tf2NH was used.
d The reaction was incomplete and the remaining 3c was recovered.
e Compound 4d was obtained as a mixture of two diastereomers in a
95:5 ratio.
vs. entry 2), we were delightful to discover that the cata-
lytic room-temperature cyclization was still feasible
(Table 1, entry 2).12 This result highlights the great value
of Tf2NH in N-acyliminium chemistry4 since more than
three equivalents TFA were required for the reaction of 3b
to proceed in refluxing acetonitrile.8 Rewardingly, 4b
could be quantitatively produced within minutes in reflux-
ing toluene in the presence of only 1 mol% Tf2NH
(Table 1, entry 3). Repeating the cyclization with the di-
cyano substrate 3c in refluxing acetonitrile left the starting
material untouched after 24 hours (Table 1, entry 4), thus
firmly establishing a fundamental effect of the ester func-
tion. Remarkably, 4c could be obtained in good yield at
higher temperature (Table 1, entry 5).
f Reaction time nonoptimized.
the temperature and solvent, since ca. 95:5 trans/cis ratios
were consistently obtained over a broad range of temper-
ature (from 60 °C to 110 °C) in either MeCN or toluene
(Table 1, entries 7–9). From this preliminary set of results
a reactivity and stereoselectivity profile, in perfect accor-
dance with our working hypothesis, is clearly observed:
CO2R, CO2R > CO2R, CN (high trans stereoselectivity) >
CN, CN (Scheme 1). Beside the ability of the ester func-
tion located in compounds 3b,c to impart high catalytic
activity and good stereocontrol, the unusual thermal sta-
bility of this N,O-acetals/N-acyliminium ions system is
another remarkable feature that further exemplifies its
synthetic value.
At this juncture we felt that cyano ethyl esters should pro-
vide a good handle to shed more light into the effect exert-
ed by the ester arm and therefore we evaluated their
performance under Tf2NH catalysis. Hence, repeating the
room-temperature protocol using 3d also led to no conver-
sion (Table 1, entry 6), thus showcasing the importance of
the two ester functions for an efficient process to occur
under mild conditions. Pleasingly, conducting the reac-
tion of 3d in refluxing acetonitrile restored an excellent
reaction profile, quantitatively returning 4d with excellent
diastereoselectivity favoring the trans adduct (Table 1,
entry 7); this is in line with the contribution of a bridging
effect from the ester as hypothesized in Scheme 1.13,14 The
trans stereochemistry of 4d was established by X-ray sin-
gle-crystal analysis after selective crystallization of the
major isomer from MeCN–EtOAc (50:50, Figure 1).15 It
has to be noticed that this stereoselectivity is insensitive to
Having clearly established an ester effect in this Friedel–
Crafts-type cyclization, we wondered whether such an ef-
fect could be useful to overcome the even greater difficul-
Figure 1 Ellipsoid model plot of compound 4d. The hydrogen
atoms were omitted for clarity.
Synlett 2011, No. 16, 2425–2429 © Thieme Stuttgart · New York

LETTER
Stereoselective Formation of Aza-Heterocycles
2427
ties associated with an intermolecular a-amidoalkylation
process. The challenging aspect of these reactions was im-
mediately confirmed by the inability of the dicyano sub-
strate 5a to engage an allylation (Table 2, entry 1) or
indoylation (not shown) process under conditions that
permitted an intramolecular cyclization (see entry 5 in
Table 1). In stark contrast, when the dimethyl esters 5b,c
were reacted with an array of C- and O-nucleophiles in the
presence of 5 mol% Tf2NH in toluene, the catalytic cou-
plings were all efficient at only 60 °C (Table 2, entries 2–
6).16
Table 2 Catalytic Intermolecular a-Amidoalkylations of Substrates
5a–c
EWG
EWG
EWG
EWG
Nu (X equiv)
Tf2NH (5 mol%)
Nu
O
OR
O
N
N
P
toluene, 60 °C
P
6–10
5a EWG = CN, R = Et
5b,c EWG = CO2Me, R = Me
Run Substrate 5 (P)a Nu (equiv)
Product 6–10
Yield
(%)b
When the allylation of cyano ester substrates 11a,b was
carried out in refluxing toluene,17 compounds 12 and 13
were isolated in fairly good yields and in this case with a
remarkable >95 de (Scheme 2), which again accounts for
the anchimeric participation of the ester function
(Scheme 1).13 Using a panel of p-nucleophiles a promis-
ing scope and uniformly perfect stereocontrol was found
for this catalytic amidoalkylation (see formation of com-
pounds 14 and 15 in Scheme 2).18 The stereochemistry of
compound 15 was established to be trans by chemical cor-
relation as followed. A Knoevenagel reagent 16 was pre-
pared and engaged with N-benzyl bromoacetamide under
our previously reported11 reaction conditions (Scheme 3).
This led to an expected formal [3+2] lactam cycloadduct
in an excellent yield, the 1H NMR and 13C NMR spectra
of which were identical in all respects with those of com-
pound 15 produced by the N-acyliminium approach as de-
scribed in Scheme 2. Given the trans stereochemical
assignment previously determined for similar cycload-
ducts,11 we assume that the stereochemistry of compound
15 produced by this N-acyliminium ion based catalytic
strategy is trans (i.e., consistent with incorporation of the
nucleophile syn relative to the cyano group). The stereo-
chemistry of compounds 12–14 is proposed by analogy
which is supported by the trans stereoselectivity also dis-
played by the intramolecular approach.
d
1c
5a (Bn)
5b (All)
–
–
TMS
(4.5 equiv)
MeO2C
CO2Me
OTMS
Ph
O
N
2
75
Ph
O
(3 equiv)
6
MeO2C
CO2Me
O
N
3
4
5
5b (All)
93
96
TMS
(2.2 equiv)
7
MeO2C
CO2Me
O
5c (Propar)
N
TMS
(2.2 equiv)
8
MeO2C
CO2Me
O
O
N
5b (All)
>99
HO
The uniform trans stereoselectivity observed herein com-
pares favorably with similar alkylations of 4,5-diacetoxy
pyrrolidin-2-ones, where the stereoselectivity has been
shown to be highly dependent on the nature of the nucleo-
phile.6d,19 This again supports the idea of a bridging stabi-
lization of the ester function in this work. Moreover, the
functional array presented by the coupling products
shown in Table 2 and Scheme 2 is also noteworthy. It of-
fers numerous prospects for further elaboration such as,
for example, ring-closing metathesis (in the case of com-
pounds 7–10 and 12) and intramolecular hydroarylation
(in the case of 14 and 15 and related compounds).
(3.5 equiv)
9
MeO2C
CO2Me
O
O
N
6
5b (All)
>99
HO
(3.5 equiv)
10
a For abbreviations used for P groups, see (a) Bn: benzyl, (b) All: al-
lyl, (c) Propar: propargyl.
b Isolated yields are given.
To summarize, we have demonstrated that stereoelectron-
ically deactivated N,O-acetals bearing two electron-with-
drawing groups in the vicinity of the acetalic carbon
iminium precursors can undergo an acid-catalyzed alkyla-
tion with interesting catalytic activity, provided the resi-
dent quaternary carbon bears at least one ester function.
Based on the general trends and highly stereoselective
profile of this chemistry, a mechanism wherein the ester
carbonyl anchimerically relays the raising cation might
c Reaction conditions: 110 °C over 24 h.
d Compound 5a was completely recovered.
reasonably be postulated. In the case where the substrates
bear two ester functions, preprotonation of one ester
group followed by syn intramolecular H+ delivery to the
alkoxy leaving group might also be involved as an alter-
native synergistic relay mode9 (see Scheme 1). We be-
Synlett 2011, No. 16, 2425–2429 © Thieme Stuttgart · New York

2428
M. Saber et al.
LETTER
EtO2C
EtO2C
References and Notes
CN
CN
Nu
Nu (1.5–4.5 equiv)a
Tf2NH (5 mol%)
(1) (a) For authoritative reviews on N-acyliminium ion
chemistry, see: Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817. (b) Maryanoff, B. E.; Zhang,
H.-C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
Rev. 2004, 104, 1431.
(2) For two recent exhaustive reviews on the intermolecular
amidoalkylation of N,O-acetals, see: (a) Yazici, A.; Pyne, S.
G. Synthesis 2009, 339. (b) Yazici, A.; Pyne, S. G. Synthesis
2009, 513.
(3) Pin, F.; Comesse, S.; Garrigues, B.; Marchalin, Š.; Daich, A.
J. Org. Chem. 2007, 72, 1181.
(4) (a) Ben Othman, R.; Bousquet, T.; Othman, M.; Dalla, V.
Org. Lett. 2005, 7, 5335. (b) Tranchant, M. J.; Moine, C.;
Ben Othman, R.; Bousquet, T.; Othman, M.; Dalla, V.
Tetrahedron Lett. 2006, 47, 4477.
(5) Ben Othman, R.; Affani, R.; Tranchant, M. J.; Antoniotti, S.;
Duñach, E.; Dalla, V. Angew. Chem. Int. Ed. 2010, 49, 776.
(6) For some other recent reports on catalytic amidoalkylation
of N,O-acetals: (a) Okitsu, O.; Suzuki, R.; Kobayashi, S.
J. Org. Chem. 2001, 66, 809. (b) Camilo, N. S.; Pilli, R. A.
Tetrahedron Lett. 2004, 45, 2821. (c) de Godoy, L. A. F.;
Camilo, N. S.; Pilli, R. A. Tetrahedron Lett. 2006, 47, 7853.
(d) Ben Othman, R.; Bousquet, T.; Fousse, A.; Othman, M.;
Dalla, V. Org. Lett. 2005, 7, 2825; and references therein.
(e) Kinderman, S. S.; Wekking, M. M. T.; van Maarseveen,
J. H.; Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T.
J. Org. Chem. 2005, 70, 5519.
OEt
O
O
N
N
R
toluene, 110 °C,
overnight
R
( )-11a–c
( )-12–15
11a R = propargyl
11b R = Bn
11c R = allyl
EtO2C
CN
EtO2C
N
CN
O
N
O
Bn
( )-13 89%a
( )-12 98%
EtO2C
CN
EtO2C
CN
OMe
O
O
N
N
NH
OMe
Bn
( )-15 86%
( )-14 83%
Scheme 2 Preliminary scope of the highly stereoselective Tf2NH-
catalyzed amidoalkylation of gem-4-cyanoester 5-ethoxy pyrrolidin-
5-ones. a 4.5 Equiv of allyltrimethylsilane were used; 1.5 equiv of in-
dole and 1,2-dimethoxybenzene were used.
(7) For impressive catalytic enantioselective approaches, see:
(a) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E.
N. J. Am. Chem. Soc. 2007, 129, 13404. (b) Raheem, I. T.;
Thiara, P. S.; Jacobsen, E. N. Org. Lett. 2008, 10, 1577.
(c) Peterson, E. A.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2009, 48, 6328. (d) Muratore, M. C.; Holloway, C. A.;
Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon, D. J. J. Am.
Chem. Soc. 2009, 131, 10796.
(8) Moussa, S.; Comesse, S.; Dalla, V.; Daïch, A.; Sanselme,
M.; Netchitaïlo, P. Synlett 2010, 2197.
(9) (a) Grau, F.; Heumann, A.; Duñach, E. Angew. Chem. Int.
Ed. 2006, 45, 7285. (b) Paz Muñoz, M.; Lloyd-Jones, G. C.
Eur. J. Org. Chem. 2009, 516.
(10) For a recent series of papers reporting diastereoselective
alkylation of chiral alcohol derivatives bearing an adjacent
ester group, see: (a) Rubenbauer, P.; Bach, T. Adv. Synth.
Catal. 2008, 350, 1125. (b) Stadler, D.; Bach, T. J. Org.
Chem. 2009, 74, 4747. (c) Rubenbauer, P.; Bach, T. Chem.
Commun. 2009, 2130. (d) Cozzi, P. G.; Benfatti, F. Angew.
Chem. Int. Ed. 2010, 49, 256.
lieve these findings improve the knowledge of cationic
chemistry and therefore may open new directions in this
field. Further mechanistic work aimed at gaining a deeper
understanding of the reaction mechanism is currently un-
der way in our laboratory.
–
H3N+
CO2
CHO
( )3
NC
CO2Et
NC
(0.05 equiv)
EtOH–H2O
MeO
MeO
+
EtO2C
MeO
OMe
16 95%
Br
O
EtO2C
CN
BnHN
(1.2 equiv)
OMe
O
N
NaH (1.2 equiv)
THF, r.t., 12 h
OMe
(11) For related studies in our group, see: Comesse, S.; Sanselme,
M.; Daïch, A. J. Org. Chem. 2008, 73, 5566.
Bn
( )-15 84%
(12) Typical Procedure for the Preparation of 4a–d
To a solution of an N,O-acetal 3a–d (0.4 mmol) in a freshly
distilled solvent as indicated in Table 1 (1.5 mL) was added
dropwise a 0.5 M CH2Cl2 solution of HNTf2 (40 mL, 0.02
mmol, 0.05 equiv). The reaction was stirred at the temper-
ature indicated in Table 1 and followed by TLC. At the end
of the reaction, the solution was quenched at r.t. by a 5% aq
solution of NaHCO3, and the aqueous phase was extracted
two times with EtOAc (3 mL). The combined organic layers
were dried over MgSO4, the solvent was removed under
vacuum, and the residue was then purified by silica gel
chromatography to provide the desired tricycles 4a–d.
Physical Data for 4b
Scheme 3 Determination of the stereochemistry of compound 15 by
chemical correlation
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We are grateful to the University of Le Havre for the aid ‘ATER po-
sition’, attributed to one from us (M. S.) and to Miss Aurore Grand
for experimental contribution. We thank Dr. Morgane Sanselme for
her generous support in X-ray crystallographic analysis of 4d.
Isolated as white solid (recrystallized from Et2O); mp 157–
159 °C; yield 95% (EtOAc–cyclohexane, 40:60). IR (KBr):
1728, 1691 cm–1. 1H NMR (300 MHz, CDCl3): d = 0.84 (t,
J = 7.0 Hz, 3 H), 1.36 (t, J = 7.0 Hz, 3 H), 2.60 (d, J = 16.4
Synlett 2011, No. 16, 2425–2429 © Thieme Stuttgart · New York

LETTER
Hz, 1 H), 2.79–3.03 (m, 3 H), 3.05 (d, J = 16.4 Hz, 1 H),
Stereoselective Formation of Aza-Heterocycles
2429
Copies of the data can be obtained free of charge at the
following address: http://www.ccdc.cam.ac.uk.
(16) For typical procedure for the preparation of 6–10, see the
Supporting Information.
(17) When these allylations were performed at 60 °C overnight,
around 25% conversion into the desired product was
observed, thus confirming the importance of the two ester
functions for an efficient process under mild conditions in
the intermolecular reactions too.
(18) For typical procedure for the preparation of 12–15, see the
Supporting Information.
(19) For a representative paper, see: Louwrier, S.; Ostendorf, M.;
Boom, A.; Hiemstra, H.; Speckamp, W. N. Tetrahedron
1996, 52, 2603.
3.62–3.84 (m, 2 H), 3.84 (s, 6 H), 4.29–4.50 (m, 3 H), 5.54
(s, 1 H), 6.57 (s, 1 H), 7.30 (s, 1 H). 13C NMR (75 MHz,
CDCl3): d = 13.7, 14.3, 28.6, 37.8, 40.1, 60.9, 62.0, 26.6,
110.8, 110.5, 123.6, 127.9, 147.7, 148.4, 168.9, 169.8,
170.7.
(13) A simple steric bias (ester > cyano) could also be considered
as an alternative or competitive mechanism, in line with ref.
10.
(14) Analytical data and copy of the 1H NMR spectrum for
compound 4d are provided in the Supporting Information.
(15) Full crystallographic data have been deposited at the
Cambridge Crystallographic Data Centre; CCDC reference
number 833548 for the major diastereoisomer of product 4d.
Synlett 2011, No. 16, 2425–2429 © Thieme Stuttgart · New York

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