Atom-Economic Catalytic Direct Substitution of N,O-Acetals with Simple Ketones

Article abstract of DOI:10.1002/ejoc.201700530

A general and powerful catalytic protocol for the direct amidoalkylation of simple enolizable ketones is described, with use of the Lewis superacid Sn(NTf₂)₄ as a catalyst under thermal conditions. A complete and rational study direc

Full text of DOI:10.1002/ejoc.201700530

A Journal of
Accepted Article
Title: Atom Economical Catalytic Direct Substitution of N,O-Acetals
with Simple Ketones
Authors: Vincent Dalla, Bahria Touati, Mohamed Salah Azizi,
Abderrhamane el Bouakher, Catherine Taillier, Sylvain
Antoniotti, Elisabet Dunach, Malika Trabelsi-Ayadi, and Raja
Ben Othman
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700530
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10.1002/ejoc.201700530
European Journal of Organic Chemistry
FULL PAPER
Atom Economical Catalytic Direct Substitution of N,O-Acetals
with Simple Ketones
Bahria Touati,[a,c]Abderrahman El Bouakher,[a] Mohamed Salah Azizi,[a,c] CatherineTaillier,[a] Raja Ben
Othman,[b]Malika Trabelsi-Ayadi,[c] Sylvain Antoniotti,[d] Elisabet Duñach[d] and Vincent Dalla*[a]
Abstract: A general and powerful catalytic protocol for the direct
amidoalkylation of simple enolisable ketones is described using the
super Lewis acid Sn(NTf2)4 as catalyst under thermal conditions. A
complete and rational study directed towards the development of
efficient conditions for the coupling of a wide range of reaction
partner combinations, including the most recalcitrant, is presented.
The synthetic potential of the reaction is demonstrated through the
use of a large set of both carbonyl and N,O-acetalic substrates,
providing the corresponding amidoalkylated ketones in 49-99%
yields, using very low catalyst loadings (≤ 1 mol %).
character of the carbonyl partner was found to be essential to
reach high efficiency and/or selectivity.[5-8] Until recently, only
scarce examples of similar reactions involving more reactive
carbocations have been described in the literature. [12-15]
In connection with our long-standing interest in catalytic N-
acyliminium ion chemistry,[16] we have recently started to
demonstrate the excellent potential of metallic triflimide-type
Lewis superacids,[17] and more particularly of tin(IV) triflimide
Sn(NTf2)4, to promote nucleophilic substitutions of N,O-acetals
with
a
wide range of carbon nucleophiles, including
allyltrimethylsilane, silyl enol ethers, active methylene
derivatives, and arenes under a remarkably efficient catalytic
regime generally requiring ≤ 1 mol % catalyst loading.[16b]
Rewardingly, the process was extended even to the most
challenging enolisable ketones, which were shown to be suitable
nucleophilic partners as illustrated by our description of the first
few examples of high temperature (60-70 °C) experiments that
were restricted to random combinations of isoindolic
hemiaminals and a small set of ketones.
Introduction
The direct catalytic amidoalkylation of non pre-activated carbon
nucleophiles has been relatively unexplored, mostly with
intramolecular arylation (Friedel-Crafts type) reactions and
intermolecular couplings with -keto-esters or -diketones.[1,2]
Besides their synthetic potential for further functionalization,
carbonyl motifs are also often encountered in the structure of
biologically active compounds. As the need for greener chemical
processes increases continuously, the development of efficient,
versatile, direct couplings using simple enolisable carbonyl
derivatives continues to present a significant synthetic interest.
Though major advances have been achieved in recent years for
the development of direct catalytic alkylation reactions of
ketones and aldehydes,[3-15] most of the contributions that
involve racemic or stereoselective SN1-type processes made
use of precursors of highly stabilized carbocations (alcohols or
their acetate derivatives or alkyl halides) of carbenium type (e.g.
benzyl, allyl, indenyl).[5-6] In a number of cases, the use of
synergistic catalytic systems intended to promote carbocation
formation while simultaneously boosting the nucleophilic
[a]
B. Touati, Dr A. El Bouakher, M. S. Azizi, Dr C.Taillier, Dr Pr. V. Dalla,
UNIHAVRE, FR 3032 CNRS, URCOM EA3221, 76600 Le Havre,
France
25, Rue Philippe Lebon, BP 540, 76058-F. Le Havre (France).
Fax: (+33)2-32-74-43-91
E-mail: vincent.dalla@univ-lehavre.fr
[b]
[c]
Dr R. Ben Othman,
Ecole supérieure des sciences et de technologie de Hammam Sousse,
Rue Lamine Abassi 4011 H. Sousse (Tunisie)
B. Touati, M. S. Azizi, Dr Pr Malika Trabelsi-Ayadi,
Laboratoire d’Application de la Chimie aux Ressources et Substances
Naturelles et à l’Environnement-LACReSNE-Faculté des Sciences de
Bizerte- 7021, Bizerte
Scheme 1. Sn(NTf2)4-catalyzed direct α-amidoalkylation reaction of ketones.
We then pursued this study by undertaking a rational design
of this transformation at room temperature (rt). This in-depth
survey of the reaction under mild reaction conditions was
made by a careful individual evaluation of both families of
reaction partners, and resulted in the establishment of two
orthogonal empirical scales of reactivity, which in turn have
Université de Carthage–Tunisie
Dr S. Antoniotti, Dr E. Duñach
Université Côte d’Azur, C.N.R.S., Institut de Chimie de Nice, Parc
Valrose, 06108 - Nice cedex 2, France.
Supporting information for this article is given via a link at the end of the
document.
[d]
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10.1002/ejoc.201700530
European Journal of Organic Chemistry
FULL PAPER
proven to be extremely useful and valuable platforms to develop
the reaction in a rational manner (Scheme 1).[16g,18] Considerable
advances were thus made during the development of this mild
variant of Sn(NTf2)4-catalyzed direct Mannich-type reaction, not
only in terms of selection of the adequate leaving groups to be
used inside the various categories of the N,O-acetal substrates,
but also in terms of synthetic usefulness. It was indeed found
catalyst, what consequently resulted in significant decrease in
reaction output,16g rather similar reaction rates were measured in
this thermal variant, as shown in Table 1, even with the less
reactive substrates 1c-1e (entries 3-5). In all the cases, every
reaction went to completion within 2.5 to
4 h and the
corresponding amidoalkylated products 4aa-4ea were isolated in
good to excellent yields (58%-99%) with, in general, either no or
modest diastereocontrol.[19]
that the reaction had
a
large number of successful
electrophile/nucleophile combinations that could assemble in an
efficient way by using only 0.5-2 mol% of catalyst. However,
some limitations remained, in particular when dealing with less
reactive ketones such as acyclic ones (see reactivity scale in the
SI), which were systematically unable to undergo
amidoalkylation efficiently. The same held true for the less
reactive N,O-acetals, a representative example of which being
shown in Scheme 1. Moreover, it is worth reminding that only a
few atom-economical Mannich couplings making use of
hydroxylactams as the electrophilic substrates were effective.
This is also a current limitation of the rt protocol that is an
additional reason for seeking to improve this tin(IV) triflimidate-
based methodology.
Capitalizing on the valuable information accumulated during our
initial study,[16g] we next concentrated on the development of a
versatile and powerful direct amidoalkylation protocol, by
specifically harnessing the limitations mentioned above, which in
turn was expected to push the current limits of the method, i.e.
ketonic C-nucleophiles of low reactivity and non-activated N-
acyliminium ion precursors such as hydroxy lactams. We here
report the details of the evaluation of a variant of the Sn(NTf2)4-
catalyzed reaction performed under heating that fully fulfilled our
expectations. The wide scope of this thermal variant and the
complementarity of the two methods were, therefore, firmly
established.
Table 1. Scope of N-protected isoindolinic substrates (from good to low
reactivity) in the thermal Sn(NTf2)4-catalyzed amidoalkylation of
cyclohexanone 3a.
[b]
Entry
Substrate
R1
Product
4aa
Time
2.5h
4h
Yield[a]
98%
d.r.
. More reactive substrates[b]
1
2
1a
64:36
54:46
1b
4ba
99%
. Less reactive substrates[b]
3
4
5
6
1c
4ca
4da
4ea
“
2.5h
2.5h
2.5h
6h
79%[c]
58%[c]
88%
62:38
52:48
61:39
60:40
1d
1e
“
“
72%[d]
Results and Discussion
[a] Isolated yields. [b] Based on the reactivity scale established in the room
temperature Sn(NTf2)4-catalyzed amidoalkylation of acetoxy lactam derived
from 1b.[16g] [c] Conversion determined by 1H NMR analysis of the crude.
[d] Reaction run with 0.1 mol% of Sn(NTf2)4 on a 700 mg scale of 1e.
We started the evaluation of some combinations of reactive
partners which were initially found unproductive under mild
conditions (Scheme 1).[16g]
Interestingly, it proved possible to run the reaction with
hydroxylactam 1e on a 700 mg scale, using only 0.1 mol % of
catalyst with slightly less erosion of the chemical efficiency and
the alkylated cyclohexanone 4ea was isolated in 72% yield, after
6 h of reaction (entry 6). Since significant differences in ketone
reactivity were observed at rt, as anticipated from their
respective propensity to equilibrate with their enol form, a set of
ketones was next evaluated in the reaction with hydroxylactam
1b (Table 2). A representative set of results is presented in
Table 2.[20]
Ketones with a nucleophilicity close to that of cyclohexanone 3a
were first considered, including the slightly more reactive 1-
indanone 3b or 2-phenylacetophenone 3c, as well as others
slightly weaker ones, such as cyclopentanone 3d, 2-
methoxyacetophenone 1e and (E)-4-phenylbut-3-en-2-one 3f.
All of them gave fast reactions with the corresponding products
The perfect atom-economical -amidoalkylation of isoindolinic
hemiaminals was only possible with 2-indanone and 2-tetralone
which appeared outstanding nucleophilic components in our mild
variant.[16g,18] Accordingly, we evaluated the same types of ideal
coupling with ketones of lower reactivity, paying particular
attention to the subunits carried by the nitrogen atom that had
shown a propensity to slow down the alkylation process. We
started with the amidoalkylation of our model nucleophile
cyclohexanone 3a, which was first examined in refluxing
acetonitrile with a range of N-substituted isoindolinic hydroxyl
lactams 1a-e of variable reactivities (based on the reactivity
trend observed for their acetoxy analogs 2 at rt). Whereas a
strong influence of the nitrogen substituent was observed in the
reactions at rt, in particular because of the likely interactions of
the more metallophilic/Lewis basic of them (e.g. isoprenyl,
propargyl, 3,4-dimethoxy benzyl, methallyl) with the acidic
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10.1002/ejoc.201700530
European Journal of Organic Chemistry
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4bb-4bf being obtained in yields from 68% to 94% irrespective
of their intrinsic reactivity (entries 1-5).
case, the formation of a small portion (10%) of the acetamide
derived from 1b, resulting from a Ritter side-reaction with
acetonitrile, was also observed.[22] Switching the solvent to
toluene was, as expected, found suitable to avoid formation of
this side-product, and gave the coupled product in an excellent
92% yield (entry 9).[23] Importantly, this protocol was also
successfully applied to the half gram-scale coupling with 3i
under the catalytic influence of only 0.1 mol % of Sn(NTf2)4 (72
h, 80% isolated yield, entry 10), as a remarkable illustration of
the potency of this catalytic direct amidoalkylation methodology.
From this result, we expanded the scope of the reaction to other
poorly reactive α-substituted acyclic ketones. To understand the
influence of reaction condition parameters on both the efficiency
and regiocontrol of the reaction, the catalytic amidoalkylation of
2-chloroacetone 3j was studied in detail with the model
hydroxylactam 1b. To get a clear comparison, attempts were
made over 2 h using 1 mol% of Sn(NTf2)4. After work-up,
Table 2. Scope of ketones (from good to low reactivity) in the thermal
Sn(NTf2)4-catalyzed amidoalkylation with hydroxy lactam 1b.
Entry
Ketone
Product
Time
2.5 h
Yield[a]
92%
d.r.
.Ketones with good reactivity[b]
1
4bb
4bc
60:40
1
68%[c]
68:32
conversions and regioselectivities were estimated from H NMR
2
3 h
analyses of the crude mixtures by measuring the ratios of adduct
formed[24]/1b and the proportion of linear and branched
regioisomers 4bj and 5bj, respectively. As shown in Table 3
(entries 1-5), increasing the temperature from 70 to 90 °C
strongly impacted the reaction rate with only a slight influence on
the regioselectivity. Conversely, only minor differences were
observed when changing the stoichiometry of the ketone from 3
to 2 equivalents.[25] Using the best conditions (3 equiv of ketone
3j, CH3CN, heating at 90 °C), only 5 h of reaction time were
found necessary to achieve full conversion of the hydroxy lactam
1b affording the amidoalkylated adducts 4bj and 5bj albeit with
a slightly lower regioselectivity (ratio 4bj/5bj = 6:1, entry 6). As
anticipated, running the reaction in toluene at 110 °C was found
to increase the rate of the reaction, which went to completion
within only 4 h (entry 7). However, a drop in regiocontrol was
again observed, the product being isolated in 91% yield as a 3:1
mixture of regioisomers. We next demonstrated that the
alkylation of butan-2-one 3k and 2-methoxyacetone 3l was also
possible applying these thermal conditions to hydroxy lactam 1b.
Although longer reaction times were required, especially with
butan-2-one 3k, these two reactions led to the formation of the
corresponding alkylation products, as mixtures of branched and
linear regioisomers 4bj-4bl and 5bj-5bl, with a good efficiency
and combined isolated yields greater than 85% (entries 8-9). It
should be noted that the reaction with ketone 3l was run at
70 °C with the goal of favoring the formation of the branched
regiosiomer 4bl. A poor regioselectivity of 2.8:1 was however
obtained. We interpret this result by a specific and unusual
stabilization of the less substituted enol form by H-bonding with
the methoxy group. This feature likely contributes in decreasing
.Ketones with moderate reactivity[b]
3
4
4bd
2.5 h
3 h
94%
81%
60:40
56:44
4be
4bf
5
6 h
93%
.Ketones with low reactivity[b]
6
7
4bg
1.5 h
4 h
92%
95%
4bh
4bi
8
9 h
89%[d],[e]
9
“
“
“
“
16 h
72 h
92%[d],[f]
80%[f],[g]
10
[a] Isolated yield. [b] Based on the reactivity scale established in the room
temperature Sn(NTf2)4-catalyzed amidoalkylation of acetoxy lactam derived
from 1b.[16g] [c] 2 equivalents of ketone 3c were used. [d] 10 equivalents of
acetone 3i were used to anticipate possible volatility issue. [e] The formation
of 10% of the acetamide resulting from a Ritter reaction, was also observed.[21]
[f] The reaction was run in toluene. [g] The reaction was run on a half-gram
scale of 1b, in the presence of 0.1 mol% of Sn(NTf2)4 and 10 equivalents of
acetone 3i.
Gratifyingly, poorly reactive ketones 3g-3i also underwent
smooth reactions affording the coupling product 4bg-4bi in high
yields within short reaction times too (entries 6-8). Even the less
reactive acetone 3i was efficiently amidoalkylated with
hydroxylactam 1b when a longer but still reasonable reaction
time (9 h) was applied in the presence of 10 equivalents of
acetone, (entry 8).[21] It is worth noting that, in this less favorable
Scheme 2. Proposed rationale of the regiochemical outcome of acyclic
ketones as a consequence of the distribution of enol forms.
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10.1002/ejoc.201700530
European Journal of Organic Chemistry
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the energetic gap with the intrinsically more stable trisubstituted
Conversely and much to our satisfaction, excellent results in
enol regioisomer, and thus in influencing the equilibrium position, terms of reaction rates and yields were obtained when the
with, as consequence, delivery of an increased proportion of the
linear regioisomer product 5bl compared with the traditional
cases (Scheme 2). To test the limit of the reaction, other
challenging transformations also previously beyond our reach
were next examined. Scheme 3 outlines a representative
selection of results demonstrating the broad applicability and
generality of the transformation. We initiated this effort by
reinvestigating the reactions of ketones 3m-3p.
hemiaminal substrates 1a or 1b were engaged with
cycloheptanone 3o and methylcyclopropyl ketone 3p in refluxing
toluene (conditions B), which constitutes a more appealing
atom-economical transformation.
To boost the reactivity of the reaction partners and thus the
efficacy of the coupling, the development of more efficient
conditions proved in some cases to be essential. On the one
hand, the alkylation of the poorly reactive ketones 3m and 3n
was shown to proceed with good efficiencies, provided that the
acetoxylactam 2b was used (conditions A) instead of its parent
heminaminal 1b, which itself was recognized to be clearly less
reactive under general (Brønsted- and Lewis) acid catalysis. The
failure of the coupling when using hemiaminal 1b is somewhat
surprising and the reason still remains unclear, given that 1b
gave good results in the reaction with poorly reactive acyclic
ketones (see Table 2, entry 8 and Table 3).
Table 3. Sn(NTf2)4-catalyzed amidoalkylation of poorly reactive α-substituted
acyclic ketones with hydroxy lactam 1b.
Entry
n
T (°C)[a]
Time
X
Conversion[b]
Ratio
4/5[b]
1
3
2
3
2
3
3
3
3
3
70
80
80
90
90
90
110
90
70
2h
Cl (3j→4bj)
30%[c]
14/1
2
2h
Cl
38% [c]
12/1
3
2h
Cl
47% [c]
11/1
4
2h
Cl
67% [c]
10/1
5
2h
Cl
71% [c]
11/1
Scheme 3. Challenging α-amidoalkylation reactions.
6
5h
Cl
100% (>99%)
100% (91%)[e]
100% (86%)[e]
100% (98%)[e]
6/1[f],[g]
3.1/1[f]
7.6/1[f],[h]
2.8/1[f],[i]
7[d]
8
4h
Cl
Phthalimide-derived acetoxy lactams 2f and 2g bearing a 3,4-
18h
16h
Me (3k→4bk)
OMe (3l→4bl)
dimethoxyphenylmethyl
and
a
but-1-ynyl
substituent,
respectively, featuring the weakest reactivities in standard
conditions at room temperature, were also found to be of
mandatory use to give coupling products 4fa and 4ga with
cyclohexanone 3a, within short reaction times and in satisfactory
yields (2.5 h, 55-78% yields, conditions A). Noticeably, the
combination of reaction partners displaying both a low reactivity
was also found possible as exemplified by the formation of the
alkylated ketones resulting from reactions of ketones 3f and 3i
and N,O-acetals 1e or 2d-2g. According to the earlier results
discussed above, most of these reactions proceeded
satisfactorily under conditions A to provide the corresponding
9
[a] Oil bath temperature. [b] Determined by 1H NMR analysis of the crude
product unless otherwise stated. [c] The crude reaction mixture was not
purified. [d] Reaction run in toluene. [e] Combined isolated yields.
[f] Determined from isolated yields of both regioisomers - the ratio 4/5 on the
crude reaction mixtures were not measured. [g] The branched regioisomer
was obtained as a mixture of diastereoisomer d1/d2 = 72:28. [h] The branched
regioisomer was obtained as a mixture of diastereoisomer d1/d2 = 66:34. [i]
The branched regioisomer was obtained as a mixture of diastereoisomer d1/d2
= 55:45.
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Mannich adducts 4gf, 4ef and 4fi in short reaction times (< 2 h).
As anticipated, the alkylation of acetone 3i with acetate 2d
bearing the "worse" N-isoprenyl subunit proved to be even more
First, the alkylations of cyclohexanone 3a with N-Cbz and N-Ts
substituted N,O-acetals 6a and 6b derived from pyrrolidin-2-one,
as well as the succinimidic N-PMB N,O-acetal 8 were examined.
challenging requiring several days to reach completion. However, These substrates are typical examples where alkoxy aminals are
running the reaction in refluxing toluene (condition C) turned out
to be beneficial with a marked increase in the reaction rate (8 h
versus 3 d) being observed.
Encouraged by these results, we considered testing whether
heteroaromatic
amidoalkylation in these catalytic conditions.
methyl
ketones
could
also
undergo
set of
A
heteroaromatic methyl ketones 3q-u was then evaluated in the
Sn(NTf2)4-catalyzed alkylation of N-benzyl phtalimidic hydroxy
and acetoxy substrates 1a and 2a. Ketones used appeared to
be efficient nucleophiles in the reaction affording the
corresponding alkylation products 4aq-4au in high yields
(greater than 73%). Significant differences in reaction rates were
however observed, depending on the electronic character of the
heteroaromatic ring.
When furane- and thiophene-containing ketones 3q-3s were
used, full conversions of the substrates were obtained in 4 to 5 h,
while 48 h and 24 h were respectively required in reactions with
the pyridine and pyridazine-derived methylketones 3t and 3u.
The latter two positive results are quite remarkable and are
undoubtedly beyond our expectation, considering the potentially
strong coordinating ability of the pyridine and pyridazine rings
towards the tin catalyst, with risks of catalyst inhibition. In the
coupling of these two ketones 3t-3u, we observed a counter-
intuitive superiority of the N-benzyl hydroxylactam 1a over the
generally more reactive acetate 2a, the latter leading to
incomplete conversion whatever the reaction conditions applied,
as depicted in Scheme 3.
Besides their increased reactivity towards alkylation, ketones 3q
and 3r can also undergo competitive Friedel-Crafts (FC)
reactions (π-nucleophilic properties of the heteroaromatic ring).
No such side-reaction was observed in the thiophene series (as
for 3r) but small proportions of the FC product were repeatedly
obtained with 2-acetylfurane 3q. Optimization (temperature,
solvent, substrate, stoichiometry) demonstrated that using
conditions A led to an acceptable compromise between α-
amidoalkylation and the competitive FC reaction (1:0.16 ratio of
alkylated and FC adducts). These results suggest that the FC
products increase with the increasing π-nucleophilic properties
of the heteroaromatic moiety. Accordingly, when similar
reactions were run with 3-acetylindole and 2-acetyl 1-methyl-
pyrrole, a poor ketone chemoselectivity was obtained and either
formation of a significant amount (the case of NH indole) or
formation of the FC product alone (N-Methyl-pyrrole, 88%
isolated yield) were respectively observed.[26]
To further evaluate the general applicability of the reaction, we
investigated the coupling of non-iso-indolinic N,O-acetals. In this
context, we tried to optimize the coupling involving hemiaminal
substrates (hydroxylactams/carbamates) so as to achieve the
most atom-economical transformation. In some cases, alkoxy
aminals (instead of their hydroxy precursors) were found to be
necessary to give a more efficient transformation. Our results
are summarized in Scheme 4.
Scheme 4. Generalization to other N,O-acetals.
superior to their hydroxy counterparts. Although known to be
reactive, this class of N-acyliminium precursors was also found
to be far less robust than phthalimide derivatives due to their
propensity for β-proton loss (E1 elimination). Consequently,
reactions under mild conditions (CH3CN, rt) were initially run
furnishing the corresponding coupled products in variable yields
(41-86%).[16g] Interestingly, heating the reactions at 90 °C (for
substrate 6a) and at 60 °C (for substrates 6b and 8) was found
to increase either the efficiency or the reaction rates of all these
reactions without favoring any degradation or side-reaction.
Synthetically useful yields ranging from 60% to 80 % were thus
obtained within decent reaction times (2.5 h to 8 h). In contrast,
most likeky due to a fast -proton loss in the N-acyliminium
intermediate, piperidine analogs of 7aa and 9a were found to be
more difficult substrates (results not shown).[27]
Having found that substrates equipped with a sulfonyl group, as
exemplified with the N-tosyl pyrrolidine derivative 6b, were
tolerated
in
this
tin(IV)
triflimidate-catalyzed
direct
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10.1002/ejoc.201700530
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amidoalkylation of ketones, we next queried whether the method
could also encompass sultam-containing substrates. This was
examined by replacing the carbonyl moiety of lactams by a
sulfonyl group, giving the opportunity to access a class of
to circumvent the low reactivity of the electrophilic partners, the
use of highly reactive ketones such as 2-indanone 3v and 2-
tetralone 3w was found to be decisive to afford the
corresponding adducts in 72-82% yields. The results presented
valuable products with the sultam pattern in the saccharin series. in this report, and in particular the latter, highlight the
To our satisfaction, the N-propargyl hydroxy sulfonamide 10a
displayed a similar reactivity to its phthalimide analog 1e, with
the reaction of cyclohexanone 3a being completed in 4 h in
refluxing acetonitrile. However, despite full conversion and a
complementarity of the thermal alkylative procedure with the
previously described mild variant.[16g] We must point out,
however, that very challenging transformations continue to resist
our method. This is illustrated by the complete lack of reactivity
that was observed when combining the two N,O-acetal
carbamates 14a and 14b with less reactive ketones such as
cyclohexanone and phenylacetone, or when running the reaction
with the pyrrolidinone analog 16 (the least reactive substrate in
our collection), whatever the ketones used (see scheme 4).
1
clean reaction profile, as confirmed by H-NMR analysis of the
crude reaction mixture, only 61% of the coupled product 11aa
was obtained after treatment and purification by flash
chromatography. We suspect that either the volatility or
instability of compound 11aa accounted for this loss of material.
The high reactivity of this class of saccharin derivatives was also
demonstrated by the alkylations of substrates10b and 10c with
the less reactive acetone 3i, which proceeded similarly to their
phthalimidic analogues (see Table 2 and Scheme 3) in toluene
at reflux, to give the corresponding products 11bi and 11ci in up
to 84 % yields. Satisfyingly, the formation of compound 11ci was
achieved on a 2.5 mmol scale using only 0.1 mol% of the super
Lewis acid catalyst, without erosion of the chemical yield.[21]
To push the limit of the reaction further, less reactive N,O-
acetals as compared to phthalimide-derived substrates were
evaluated. The first candidates tested were acetoxy and hydroxy
tetrahydrophthalimide derivatives which previously completely
failed to react at room temperature with 3 equivalents of
cyclohexanone in the presence of 1 mol % of Sn(NTf2)4.[28]
Although the reaction rates were, as anticipated, significantly
slower in comparison to the isolindolinic series, this substrate
class was adequately tolerated, and even atom-economical
reactions of the hemi-aminal substrate 12 provided high yields of
the coupling products 12a and 12d with cyclohexanone 3a or
cyclopentanone 3d after 24 h of reaction in refluxing acetonitrile.
Having established the feasibility of the reaction with ketones of
intermediate reactivity,[18] we continued exploring the scope by
varying the carbonyl nucleophile and by choosing some
representative examples of poorly reactive partners. The
couplings of the tetrahydrophthalimide hemiaminal 12 with 2-
methoxyacetophenone 3e, trans-4-phenylbut-2-en-3-one 3f and
acetone 3i were all found effective when performed in refluxing
toluene and the coupled products were isolated in 49% to 83%
yield. It should be noted that in the case of -methoxy
acetophenone 3e, the isolated product was determined to be the
conjugated dienone 13’e resulting from elimination of the
methoxy group. However, isolation of the expected coupled
product 13e was shown to be possible when the reaction was
run under milder conditions (CH3CN, 50°C) from the acetoxy
lactam 2b derived from 1b. Under these conditions, 13e was
isolated in 50% yield.
Conclusions
To summarize, this complete study started from an initial
report that presented a few examples of a direct Mannich
reaction resulting from the union of a random choice of
hydroxylactams and enolisable ketones under Lewis super acid
Sn(NTf2)4 catalysis (1 mol %) in thermal conditions.[16b] Further
by going through a comprehensive and rational study of the
individual reactivity of each family of reaction partners in mild
conditions (at room temperature),[16g] the present paper
describes the development of conditions where the combination
of Lewis acid catalysis and thermal activation allowed for the
effective Mannich coupling of ketones and N,O-acetals
previously identified as unreactive. The structural requirements
of the N,O-acetals (notably the nature of the leaving group being
either OAc, OAlkyl or OH) for achieving effective couplings, as
well as the best experimental conditions for certain specific and
delicate transformations, were determined at catalyst loadings
not exceeding 1 mol %. The synthetic benefit of the in-depth
study of this direct Mannich-type reaction is a significant
increase of an already promising scope, which now
accommodates a very wide range of cyclic N-acyliminium ion
precursors and various ketones with very few limitations. The
most prominent results of this study are the execution of highly
efficient and atom-economical couplings, with a catalyst loading
of only 0.1 mol %, of ketones such as acetone, identified as
poorly reactive in our model study[16g] on the one hand, as well
as couplings of strongly deactivated N,O-acetals by the
presence of two electron-withdrawing ester groups nearby to the
N,O-acetalic center, on the other hand. The catalytic direct
Mannich reactions of N,O-acetals is now well understood, and
the potential of the fascinating and easily available Sn(NTf2)4
Lewis superacid catalyst is also broadened.[30]
To complete this investigation and to further highlight the
attractive feature of thermal conditions for alkylation, we
selected the N,O-acetal carbamates 14a and 14b, some of the
less reactive class of N,O-acetals at our disposal. We were
delighted to observe that conditions A allowed efficient alkylation
of the N,O-acetal carbamates 14a and 14b that are equipped
with two neighboring and deactivating ester groups.[29] However,
Experimental Section
I.
General remarks
All reactions were carried out under argon atmosphere in oven-dried
glassware with magnetic stirring. Commercially available compounds
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700530
European Journal of Organic Chemistry
FULL PAPER
were used without further purification. Solvents were distilled prior to use,
taking precaution to exclude moisture by refluxing over CaH2 (CH3CN,
CH2Cl2) under inert atmosphere. The tin triflimidate salts were prepared
as previously reported[31] and used as such, as solvates. Sn(NTf2)4 was
then used in the form Sn(NTf2)4.4DMSO or Sn(NTf2)4.8DMSO.[32]
Analytical thin-layer chromatography (TLC) was performed on silica gel
60 with fluorescent indicator UV254 TLC plates. The spots were
visualized with UV light (254 nm) and stained with a solution of p-
anisaldehyde, followed by heating. Flash column chromatography was
performed using silica gel 60 (particle size 0.040-0.063 mm) typically
using a cyclohexane/ethyl acetate eluent system. FT-IR spectra were
recorded with a Perkin-Elmer Frontier. NMR spectra were measured at
room temperature on a Bruker Avance 300 spectrometer. 1H NMR
spectra were recorded at 300 MHz. Chemical shifts (δ) are reported in
ppm using residual solvent peaks as reference (CHCl3: δ 7.26). Data are
reported as follows: chemical shift, multiplicity (s: singlet, d: doublet, t:
triplet, q: quartet, qui: quintuplet, m: multiplet), coupling constant (J in Hz)
and integration. 13C NMR spectra were recorded at 75 MHz using
broadband proton decoupling and chemical shifts are reported in ppm
1.89 (m, 4.46H), 1.98-2.16 (m, 1H), 2.24-2.46 (m, 1H), 2.50-2.66 (m, 1H),
2.82 (m, 0.46H, 1H d1), 3.01 (m, 0.54H, 1H d2), 3.72 (dd, J = 5.9 and 15.7
Hz, 0.46H, 1H d1), 3.81 (dd, J = 7.0 and 15.8 Hz, 0.54H, 1H d2), 4.45 (dd,
J = 6.0 and 15.3 Hz, 0.46 H, 1H d1), 4.57 (dd, J = 5.2 and 15.7 Hz, 0.54H,
1H d2), 5.08-5.34 (m, 2.54H), 5.47 (s, 0.46H, 1H d1), 5.78-6.00 (m, 1H),
7.30-7.59 (m, 3H), 7.79-7.88 (m, 1H); 13C NMR (75 MHz, CDCl3, 20°C)
mixture of diastereoisomers δ 24.3, 24.4, 24.5, 25.2, 26.1, 26.5, 26.9,
41.8, 42.2, 43.1, 44.4, 50.1, 53.9, 57.1, 58.6, 117.7, 118.0, 121.3, 123.5,
123.7, 124.5, 128.2, 128.3, 131.6, 131.7, 132.7, 133.0, 133.2, 143.6,
145.1, 169.2, 169.3, 209.5, 210.7; Data analyses were identical in all
respects with our previously reported data.[33]
2-(2-Methylallyl)-3-(2-oxocyclohexyl)isoindolin-1-one (4ca): Prepared
from hydroxy lactam 1c (0.25 mmol) and cyclohexanone 3a (3 equiv)
following the general procedure at 90°C in acetonitrile with 1 mol % of
Sn(NTf2)4.4DMSO. Reaction time: 2.5 h. The product was isolated after
purification by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 70:30) as a colorless viscous oil. Yield: 79% (56
mg, mixture of diastereoisomers d1/d2 = 62:38). Rf
0.45
=
(cyclohexane/EtOAc : 70/30); 1H NMR (300 MHz, CDCl3, 20°C) mixture
of diastereoisomers δ 0.66 (m, 0.38H, 1H d2), 1.08-2.60 (m, 7.62H),1.61
(s, 1.14H, 3H d2), 1.68 (s, 1.86H, 3H d1), 2.75 (m, 0.62H, 1H d1), 2.92 (m,
0.38H, 1H d2), 3.38 (d, J = 15.8 Hz, 0.62H, 1H d1), 3.51 (d, J = 15.4 Hz,
0.38H, 1H d2), 4.41 (d, J = 15.8 Hz, 0.62H, 1H d1), 4.56 (d, J = 15.4 Hz,
0.38H, 1H d2), 4.59 (s, 0.38H, 1H d2), 4.77 (s, 0.62H, 1H d1), 4.81 (s,
0.62H, 1H d1), 4.84 (s, 0.38H, 1H d2), 5.17 (s, 0.38H, 1H d2), 5.36 (s,
0.62H, 1H d1), 7.36-7.91 (m, 4H); 13C NMR (75 MHz, CDCl3, 20°C)
mixture of diastereoisomers δ 19.9, 20.6, 24.3, 24.5, 24.7, 25.3, 26.1,
26.4, 41.7, 42.1, 46.2, 47.1, 50.0, 53.9, 57.1, 58.1, 111.6, 113.4, 121.3,
123.6, 123.7, 124.5, 128.1, 128.2, 131.5, 131.7, 132.5, 132.6, 140.5,
140.9, 143.5, 145.1, 168.8, 169.3, 209.1, 210.5; Data analyses were
identical in all respects with our previously reported data.[16g]
using residual solvent peaks as reference (CHCl3:
δ 77.0). High
resolution mass spectra were recorded on a 6530 Q-TOF (Agilent
Technologies). The Q-TOF MS instrument was operated under the
following condition: Ion source ESI+ Agilent Jet Stream or APCI both in
positive ionization mode. Melting points were measured using open
capillary tubes on a Stuart Scientific analyzer and are uncorrected.
General procedure for the Sn(NTf2)4-Catalyzed direct -
amidoalkylation reactions of ketones: To a solution of N,O-acetal in
dry solvent (2 mL/mmol of substrate) were successively added a ketone
(3 equiv) and Sn(NTf2)4.xDMSO (x = 4 or 8, 0.1 to 1 mol %) under argon
atmosphere. The reaction mixture was then heated at the indicated
temperature (see also reaction time specified for each compound). The
reaction mixture was next allowed to cool to room temperature and
directly purified by flash-column chromatography on silica gel, eluting
with cyclohexane and ethyl acetate, to afford the corresponding -
amidoalkylated ketone.
2-(3-Methylbut-2-enyl)-3-(2-oxocyclohexyl)isoindolin-1-one
(4da):
Prepared from hydroxy lactam 1d (0.25 mmol) and cyclohexanone 3a (3
equiv) following the general procedure at 90°C in acetonitrile with 1
mol % of Sn(NTf2)4.4 DMSO. Reaction time: 2.5 h. The product was
isolated after purification by flash chromatography on silica gel (eluting
with Cyclohexane/EtOAc = 70:30) as a colorless viscous oil. Yield: 58%
2-Benzyl-3-(2-oxocyclohexyl)isoindolin-1-one (4aa): Prepared from
hydroxy lactam 1a (0.25 mmol) and cyclohexanone 3a (3 equiv) following
the general procedure at 90°C in acetonitrile with
1
mol
%
of
(43 mg, mixture of diastereoisomers d1/d2 = 52:48). Rf = 0.37
Sn(NTf2)4.4DMSO. Reaction time: 2.5 h. The product was isolated after
purification by flash chromatography on silica gel (eluting with
Cyclo/EtOAc = 70:30) as a white solid. Yield: 98% (78 mg, mixture of
diastereoisomers d1/d2 = 64:36). Rf = 0.34 (cyclohexane/EtOAc = 70/30);
1H NMR (300 MHz, CDCl3, 20°C) δ 0.66 (m, 0.64H, 1H d1), 0.99-2.06 (m,
5.36H), 2.13-2.54 (m, 2H), 2.73 (m, 0.36H, 1H d2), 2.88 (m, 0.64H, 1H d1),
4.43 (d, J = 15.3 Hz, 0.64H, 1H d1), 4.47 (d, J = 14.7 Hz, 0.36H, 1H d2),
4.84 (d, J =14.7 Hz, 0.36H, 1H d2), 5.03 (d, J = 15.3 Hz, 0.64H, 1H d1),
5.18 (s, 0.64H, 1H d1), 5.43 (s, 0.36H, 1H d2), 7.15-7.56 (m, 8H), 7.80-
7.92 (m, 1H); 13C NMR (75 MHz, CDCl3, 20°C) mixture of
diastereoisomers δ 24.2, 24.2, 25.3, 25.4, 26.4, 41.6, 42.1, 44.5, 46.0,
50.3, 53.8, 57.9, 58.8, 121.2, 123.6, 123.8, 124.5, 127.3, 127.7, 127.9,
128.2, 128.2, 128.3, 128.8, 128.9, 131.6, 131.8, 132.6, 137.0, 137.7,
143.6, 145.2, 169.0, 169.9, 209.4, 210.6; Data analyses were identical in
all respects with our previously reported data.[16g]
(cyclohexane/EtOAc : 70/30); 1H NMR (300 MHz, CDCl3, 20°C) mixture
of diastereoisomers δ 0.74 (m, 0.48H, 1H d2), 1.22-1.95 (m, 4.52H), 1.72
(s, 1.44H, 6H d2), 1.75 (s, 1.56H, 6H d1), 2.01-2.14 (m, 1H), 2.30-2.47 (m,
1H), 2.52-2.64 (m, 1H), 2.80 (dd, J = 7.2 and 11.5 Hz, 0.52H, 1H d1),
2.98 (m, 0.48H, 1H d2), 3.71 (dd, J = 4.6 and 15.4 Hz, 0.52H, 1H d1),
3.80 (dd, J = 7.1 and 15.4 Hz, 0.48H, 1H d2), 4.43 (dd, J = 7.7 and 15.4
Hz, 0.52H, 1H d1), 4.53 (dd, J = 7.1 and 15.4 Hz, 0.48H, 1H d2), 5.24 (t,
J = 7.0 Hz, 0.48H, 1H d2), 5.30 (d, J = 2.6 Hz, 0.48H, 1H d2), 5.35 (m,
0.52H, 1H d1), 5.47 (s, 0.52H, 1H d1), 7.30-7.64 (m, 3H), 7.77-7.86 (m,
1H); 13C NMR (75 MHz, CDCl3, 20°C) mixture of diastereoisomers δ 18.0,
18.1, 24.4, 24.4, 25.4, 25.7, 25.8, 25.8, 26.5, 38.1, 40.1, 41.6, 42.2, 50.4,
53.7, 57.4, 58.4, 119.1, 119.8, 121.1, 123.4, 123.5, 124.4, 128.0, 128.1,
131.3, 131.4, 133.0, 133.1, 135.5, 136.6, 143.5, 145.1, 168.4, 169.0,
209.0, 210.7; Data analyses were identical in all respects with our
previously reported data.[16g]
2-Allyl-3-(2-oxocyclohexyl)isoindolin-1-one (4ba): Prepared from
hydroxy lactam 1b (0.25 mmol) and cyclohexanone 3a (3 equiv) following
the general procedure at 90°C in acetonitrile with 1 mol % of Sn(NTf2)4.4
DMSO. Reaction time: 4 h. The product was isolated after purification by
flash chromatography on silica gel (eluting with Cyclohexane/EtOAc =
70:30) as a white solid. Yield: 99% (67 mg, mixture of diastereoisomers
d1/d2 = 46:54). Rf = 0.21 (cyclohexane/EtOAc: 70/30); 1H NMR (300 MHz,
CDCl3, 20°C) mixture of diastereoisomers δ 0.76 (m, 0.54H, 1H d2), 1.20-
3-(2-Oxocyclohexyl)-2-(prop-2-ynyl)isoindolin-1-one (4ea): Prepared
from hydroxy lactam 1e (0.25 mmol) and cyclohexanone 3a (3 equiv)
following the general procedure at 90°C in acetonitrile with 1 mol % of
Sn(NTf2)4.4 DMSO. Reaction time: 2.5 h. The product was isolated after
purification by flash chromatography on silica gel (eluting with
Cycloehxane/EtOAc = 70:30) as a yellow viscous oil. Yield: 88% (59 mg,
mixture
of
diastereoisomers
d1/d2 = 61:39).
Rf
=
0.18
(cyclohexane/EtOAc : 70/30); 1H NMR (300 MHz, CDCl3, 20°C) mixture
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700530
European Journal of Organic Chemistry
FULL PAPER
of diastereoisomers δ 0.76 (m, 0.61H, 1H d1), 1.21-2.72 (m, 8.39H), 2.88
(m, 0.39H, 1H d2), 3.23 (m, 0.61H, 1H d1), 4.18 (d, J = 17.9 Hz, 0.61H,
1H d1), 4.3 (d, J = 17.9 Hz, 0.39H, 1H d2), 4.37 (d, J = 17.9 Hz, 0.39H,
1H d2), 4.61 (d, J = 17.9 Hz, 0.61H, 1H d1), 5.48 (s, 1H), 7.32-7.98 (m,
4H); 13C NMR (75 MHz, CDCl3, 20°C) mixture of diastereoisomers δ 24.1,
24.5, 25.5, 25.9, 26.5, 26.8, 30.0, 32.2, 41.6, 42.1, 50.3, 53.8, 58.3, 59.0,
71.7, 72.3, 77.8, 79.5, 121.2, 123.5, 123.8, 124.5, 128.2, 128.2, 131.8,
132.0, 132.1, 143.4, 145.0, 168.1, 169.0, 209.4, 210.4; Data analyses
were identical in all respects with our previously reported data.[16g]
(cyclohexane/EtOAc : 70:30); 1H NMR (300 MHz, CDCl3, 20°C) mixture
of diastereoisomers δ 0.96 (m, 0.60H, 1H d1), 1.37-2.55 (m, 5.40H), 2.73
(t, J = 10.4 Hz, 0.40H, 1H d2), 2.98 (m, 0.60H, 1H d1), 3.44 (dd, J = 6.2
and 15.6 Hz, 0.40H, 1H d2), 3.75 (dd, J = 7.2 and 15.7 Hz, 0.60H, 1H d1),
4.54 (dd, J = 5.7 and 15.6 Hz, 0.40H, 1H d2), 4.70 (dd, J = 4.9 and 15.6
Hz, 0.60H, 1H d1), 5.13-5.33 (m, 3H), 5.72-5.99 (m, 1H), 7.20 (m, 0.60H,
1H d1), 7.36-7.63 (m, 2.40H), 7.85-7.93 (m, 1H); 13C NMR (75 MHz,
CDCl3, 20°C) mixture of diastereoisomers δ 20.1, 20.2, 21.8, 22.7, 38.4,
39.6, 42.9, 44.0, 49.9, 52.8, 57.7, 58.9, 118.2, 118.3, 121.4, 122.9, 123.8,
128.4, 128.6, 131.7, 131.9, 132.3, 132.9, 142.6, 145.1, 167.9, 169.1,
218.0, 219.0; Data analyses were identical in all respects with our
previously reported data.[16g]
2-Allyl-3-(2,3-dihydro-1-oxo-1H-inden-2-yl)isoindolin-1-one
(4bb):
Prepared from hydroxy lactam 1b (0.25 mmol) and 1-indanone 3b (3
equiv) following the general procedure at 90°C in acetonitrile with 1
mol % of Sn(NTf2)4.4 DMSO. Reaction time: 2.5 h. The product was
isolated after purification by flash chromatography on silica gel (eluting
with Cyclohexane/EtOAc = 70:30) as a colorless viscous oil. Yield: 92%
2-Allyl-3-(1-methoxy-2-oxo-2-phenylethyl)isoindolin-1-one
(4be):
Prepared from hydroxy lactam 1b (0.25 mmol) and 2-
methoxyacetophenone 3e (3 equiv) following the general procedure at
90°C in acetonitrile with 1 mol % of Sn(NTf2)4.4 DMSO. Reaction time: 3
h. The product was isolated after purification by flash chromatography on
silica gel (eluting with Cyclohexane/EtOAc = 70:30) as a colorless
viscous oil. Yield: 81% (65 mg, mixture of diastereoisomers
(70 mg, mixture of diastereoisomers d1/d2 = 60:40). Rf
= 0.35
(cyclohexane/EtOAc : 70:30); 1H NMR (300 MHz, CDCl3, 20°C) mixture
of diastereoisomers δ 2.07 (dd, J = 4.4 and 17.7 Hz, 0.60H, 1H d1), 2.48
(dd, J = 4.8 and 17.7 Hz, 0.40 H, 1H d2), 2.76 (dd, J = 8.0 and 17.7 Hz,
0.40H, 1H d2), 2.93 (dd, J = 8.0 and 17.7 Hz, 0.60H, 1H d1), 3.20 (dd, J =
6.6 and 15.8 Hz, 0.40H, 1H d2), 3.36 (m, 0.40H, 1H d2), 3.52 (m, 0.60H,
1H d1), 3.96 (dd, J = 6.6 and 15.6 Hz, 0.60H, 1H d1), 4.35 (dd, J = 5.4
and 15.6 Hz, 0.40H, 1H d2), 4.65 (dd, J = 5.4 and 15.6 Hz, 0.60H, 1H d1),
4.95-5.07 (m, 1H), 5.25-5.49 (m, 2H), 5.61 (m, 0.40H, 1H d2), 5.93 (m,
0.60H, 1H d1), 7.00 (d, J = 7.2 Hz, 0.60H, 1H d1), 7.21-7.90 (m, 7.40H);
13C NMR (75 MHz, CDCl3, 20°C) mixture of diastereoisomers δ 25.5,
26.7, 43.2, 43.9, 47.8, 50.5, 58.6, 59.9, 118.1, 118.4, 121.8, 122.7, 123.4,
123.6, 123.8, 123.9, 123.9, 126.6, 126.8, 127.6, 127.8, 128.5, 128.6,
131.6, 131.8, 132.0, 132.0, 132.7, 132.9, 135.2, 135.4, 136.2, 136.9,
141.5, 144.7, 153.4, 153.7, 168.1, 169.0, 205.2, 205.7; Data analyses
were identical in all respects with our previously reported data.[16g]
1
d1/d2 = 56:44). Rf = 0.38 (cyclohexane/EtOAc : 50:50); H NMR (300 MHz,
CDCl3, 20°C) mixture of diastereoisomers δ 3.36 (s, 1.32H, 3H d2), 3.39
(s, 1.68H, 3H d1), 3.83-4.02 (m, 1H), 4.08 (m, 0.44H, 1H d2), 4.65-4.83 (m,
1.56H), 5.02-5.39 (m, 3H), 5.71-5.97 (m, 1H), 7.16-7.68 (m, 6H); 7.69-
7.98 (m, 3H); 13C NMR (75 MHz, CDCl3, 20°C) mixture of
diastereoisomers δ 43.5, 44.4, 58.7, 58.8, 60.6, 61.1, 76.6, 76.7, 77.0,
77.2, 77.4, 82.5, 85.6, 117.8, 118.1, 123.2, 123.6, 127.5, 128.3, 128.4,
128.5, 128.6, 128.7, 128.8, 129.5, 130.3, 131.3, 131.3, 132.3, 132.5,
132.9, 133.5, 133.7, 133.8, 133.8, 133.9, 135.8, 136.1, 140.9, 141.3,
168.5, 198.0; Data analyses were identical in all respects with our
previously reported data.[16g]
(E)-2-Allyl-3-(2-oxo-4-phenylbut-3-en-1-yl)isoindolin-1-one
(4bf):
2-Allyl-3-(2-oxo-1,2-diphenylethyl)isoindolin-1-one (4bc): Prepared
from hydroxy lactam 1b (0.25 mmol) and 2-phenylacetophenone 3c (2
equiv) following the general procedure at 90°C in acetonitrile with 1
mol % of Sn(NTf2)4.4 DMSO. Reaction time: 3 h. The product was
isolated after purification by flash chromatography on silica gel (eluting
Prepared from hydroxy lactam 1b (0.25 mmol) and (E)-4-phenylbut-3-en-
2-one 3f (3 equiv) following the general procedure at 90°C in acetonitrile
with 1 mol % of Sn(NTf2)4.4 DMSO. Reaction time: 6 h. The product was
isolated after purification by flash chromatography on silica gel (eluting
with Cyclohexane/EtOAc = 60:40) as a white solid. Yield: 93% (74 mg).
Rf = 0.34 (cyclohexane/EtOAc : 60/40); 1H NMR (300 MHz, CDCl3, 20°C)
δ 2.95 (dd, J = 7.5 and 17.1 Hz, 1H), 3.30 (dd, J = 5.1 and 17.1 Hz, 1H),
3.91 (dd, J = 6.4 and 15.8 Hz, 1H), 4.56 (dd, J = 5.1 and 15.8 Hz, 1H),
5.20-5.28 (m, 3H), 5.81-5.94 (dddd, J = 5.1, 6.4, 10.6 and 16.8 Hz, 1H),
with Cyclohexane/EtOAc
=
70:30). Yield: 67% (61.5 mg, two
diastereoisomers d1/d2 = 68:32). Major diastereoisomer d1 (62 mg, 68%),
white solid; mp = 134°C, Rf = 0.27 (cyclohexane/EtOAc : 70:30); 1H NMR
(300 MHz, CDCl3, 20°C) δ 2.57 (dd, J = 7.6 and 15.7 Hz, 1H), 4.50 (m,
1H), 4.74 (d, J = 8.4 Hz, 1H), 4.85 (d, J = 17.4 Hz, 1H), 5.08 (d, J = 9.9
Hz, 1H), 5.50 (d, J = 8.4 Hz, 1H), 5.59 (m, 1H), 7.21-7.54 (m, 11H), 7.84-
7.96 (m, 3H); 13C NMR (75 MHz, CDCl3, 20°C) δ 44.5, 59.2, 61.2, 117.7,
123.3, 123.9, 128.4, 128.5, 128.7, 128.7, 129.3, 131.7, 132.0, 132.9,
133.5, 135.1, 136.2, 145.5, 169.6, 198.1; Minor diastereoisomer d2 (29
mg, 32%), white solid; mp = 156°C, Rf = 0.48 (cyclohexane/EtOAc :
70:30); 1H NMR (300 MHz, CDCl3, 20°C) δ 3.85 (dd, J = 6.4 and 15.8 Hz,
1H), 4.72 (m, 1H), 4.80 (d, J = 6.4 Hz, 1H), 5.12-5.24 (m, 2H), 5.55 (d, J
= 6.4 Hz, 1H), 5.84 (m, 1H), 6.64 (d, J = 7.6 Hz, 1H), 7.03-7.56 (m, 11H),
7.93-7.99 (m, 2H); 13C NMR (75 MHz, CDCl3, 20°C) δ 43.8, 56.9, 60.8,
62.6, 117.9, 123.3, 125.0, 128.1, 128.2, 128.8, 128.8, 128.9, 129.3,
129.3, 129.5, 130.7, 132.4, 132.8, 133.5, 134.2, 135.8, 143.4, 143.7,
197.7, 214.7; Data analyses were identical in all respects with our
previously reported data.[16g]
6.77 (d, J = 16.2 Hz, 1H), 7.42-7.62 (m, 9H), 7.88 (d, J = 6.9 Hz, 1H); 13
C
NMR (75 MHz, CDCl3, 20°C) δ43.3, 43.9, 55.8, 117.9, 122.8, 123.8,
125.7, 128.4, 128.5, 129.1, 129.1, 131.0, 131.0, 131.7, 131.8, 133.1,
133.9, 144.0, 145.7, 168.1, 196.9; Data analyses were identical in all
respects with previously reported data.[16b]
2-Allyl-3-(2-oxo-2-phenylethyl)isoindolin-1-one (4bg): Prepared from
hydroxy lactam 1b (0.25 mmol) and acetophenone 3g (3 equiv) following
the general procedure at 90°C in acetonitrile with 1 mol % of Sn(NTf2)4.4
DMSO. Reaction time: 1.5 h. The product was isolated after purification
by flash chromatography on silica gel (eluting with Cyclohexane/EtOAc =
60:40) as
a
colorless oil. Yield: 92% (67 mg). Rf = 0.27
(cyclohexane/EtOAc: 60/40); 1H NMR (300 MHz, CDCl3, 20°C) δ 3.22 (dd,
J = 7.8 and 17.2 Hz, 1H), 3.60 (dd, J = 5.4 and 17.2 Hz, 1H), 3.92 (dd, J
= 6.3 Hz, 16.4 Hz, 1H), 4.55 (dd, J = 4.7 Hz, 16.4 Hz, 1H), 5.10-5.20 (m,
2H), 5.30-5.35 (m, 1H), 5.70-5.95 (m, 1H), 7.40-7.65 (m, 6H), 7.85-7.95
(m, 3H); 13C NMR (75 MHz, CDCl3, 20°C) δ 42.3, 43.6, 56.1, 118.1,
123.2, 134.1, 136.6, 146.1, 168.4, 197.5; Data analyses were identical in
all respects with our previously reported data.[33]
2-Allyl-3-(2-oxocyclopentyl)isoindolin-1-one (4bd): Prepared from
hydroxy lactam 1b (0.25 mmol) and cyclopentanone 3d (3 equiv)
following the general procedure at 90°C in acetonitrile with 1 mol % of
Sn(NTf2)4.4 DMSO. Reaction time: 2.5 h. The product was isolated after
purification by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 70:30) as a yellow viscous oil. Yield: 94% (60 mg,
2-Allyl-3-(2-oxobut-3-yn-1-yl)isoindolin-1-one (4bh): Prepared from
hydroxy lactam 1b (0.25 mmol) and but-3-yn-2-one 3h (3 equiv) following
mixture
of
diastereoisomers
d1/d2 = 60:40).
Rf
=
0.27
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10.1002/ejoc.201700530
European Journal of Organic Chemistry
FULL PAPER
the general procedure at 90°C in acetonitrile with 1 mol % of Sn(NTf2)4.4
DMSO. Reaction time: 4 h. The product was isolated after purification by
flash chromatography on silica gel (eluting with Cyclohexane/EtOAc =
Reaction time: 18 h. The product was isolated after purification by flash
chromatography on silica gel (eluting with Cyclohexane/EtOAc = 70:30)
as an inseparable mixture of branched and linear regiosiomers (ratio
4bk/ 5bk = 7.3 : 1). Colorless oil. Global Yield: 86% (52 mg, mixture of
regioisomers 4bk (as a mixture of diastereoisomers d1/d2 = 66:34) and
5bk (ratio 4bk/5bk = 7.3 : 1). Rf = 0.27 (cyclohexane/EtOAc: 70/30); IR
(CHCl3)  1704, 1676 cm-1; 1H NMR (300 MHz, CDCl3, 20°C) mixture of
regioisomers and diastereoisomers δ 0.66 (d, J = 7.4 Hz, 1.56H, 3H d1
4bk), 0.86 (d, J = 7.2 Hz, 0.90H, 3H d2 4bk), 1.08 (t, J = 7.3 Hz, 0.33H,
3H 5bk), 2.22 (s, 0.90H, 3H d2 4bk), 2.30 (s, 1.56H, 3H d1 4bk), 2.38-
2.50 (m, 0.22H, 2H 5bk), 2.68 (dd, J = 7.4 and 17.5 Hz, 0.11H, 1H 5bk),
2.96-3.10 (m, 0.41 H, 1H d2 4bk + 1H 5bk), 3.15 (qd, J = 2.9 and 7.2 Hz,
0.52H, 1H d1 4bk), 3.56 (dd, J = 6.9 and 15.7 Hz, 0.30H, 1H d2 4bk), 3.70
(dd, J = 7.4 and 15.7 Hz, 0.52H, 1H d1 4bk), 3.88 (m, 0.11H, 1H 5bk),
4.43 (m, 0.11H, 1H 5bk), 4.56-4.73 (m, 0.82H, 1H 4bk), 5.06-5.32 (m,
3H), 5.72-5.93 (m, 1H), 7.25-7.62 (m, 3H), 7.68-7.86 (m, 1H); 13C NMR
(75 MHz, CDCl3, 20°C) mixture of regioisomers and diastereoisomers δ
7.6, 8.6, 9.1, 28.6, 29.0, 36.7, 42.9, 43.3, 43.5, 45.4, 46.7, 49.9, 55.5,
59.1, 59.3, 117.6, 117.9, 118.3, 121.8, 122.5, 123.6, 123.7, 123.8, 128.4,
128.4, 128.5, 131.5, 131.7, 131.8, 132.4, 132.8, 132.9, 133.1, 133.2,
142.5, 144.4, 145.6, 168.0, 168.4, 168.8, 208.4, 208.6, 209.1; HRMS
(ESI) m/z: calculated for C15H17NaNO2 [M+Na]+: 266.1157, found:
266.1156.
60:40) as
a
white solid. Yield: 95% (57 mg). Rf
= 0.45
(cyclohexane/EtOAc: 60/40); mp = 88°C; 1H NMR (300 MHz, CDCl3,
20°C) δ 2.90 (dd, J = 7.0 and 17.6 Hz, 1H), 3.20 (dd, J = 4.7 and 17.6 Hz,
1H), 3.35 (s, 1H), 3.87 (dd, J = 6.2 and 16.4 Hz, 1H), 4.50 (dd, J = 5.4
and 16.4 Hz, 1H), 5.00 (t, J = 6.2 Hz, 1H), 5.15-5.25 (m, 2H), 5.70-5.90
(m, 1H), 7.03-7.50 (m, 3H), 7.80 (d, J = 7.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3, 20°C) δ 43.5, 48.4, 55.3, 81.2, 118.4, 122.8, 124.1, 128.9, 132.1,
133.1, 144.8, 168.2, 183.8; Data analyses were identical in all respects
with our previously reported data.[33]
2-Allyl-3-(2-oxopropyl)isoindolin-1-one (4bi): Prepared from hydroxy
lactam 1b (0.25 mmol) and propan-2-one 3i (10 equiv) following the
general procedure at 90°C in acetonitrile with
1
mol
% of
Sn(NTf2)4.4DMSO. Reaction time: 9 h. The product was isolated after
purification by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 70:30) as a colorless oil. Yield: 89% (51 mg). Rf
= 0.15 (cyclohexane/EtOAc: 70/30); IR (neat)  1625, 1617, 1404, 1353,
1161, 755 cm-1; 1H NMR (300 MHz, CDCl3, 20°C) δ 2.18 (s, 3H), 2.72 (dd,
J = 7.3 and 17.8 Hz, 1H), 3.05 (dd, J = 5.1 and 17.9 Hz, 1H), 3.89 (dd, J
= 6.2 and 15.9 Hz, 1H), 4.43 (dd, J = 5.2 and 15.9 Hz, 1H), 5.07 (t, J =
5.8 Hz, 1H), 5.17 (d, J = 12.6 Hz, 2H), 5.67-5.94 (m, 1H), 7.37-7.53 (m,
3H), 7.82 (d, J = 7.3 Hz, 1H); 13C NMR (75 MHz, CDCl3, 20°C) δ 30.7,
43.3, 46.4, 55.5, 117.7, 122.6, 123.7, 128.4, 131.6, 131.8, 133.1, 145.5,
168.2, 205.8; HRMS (ESI) m/z calculated for C14H16NO2 [M+H]+:
230.1181, found: 230.1183.
2-Allyl-3-(1-methoxy-2-oxopropyl)isoindolin-1-one (4bl) and 2-Allyl-
3-(3-methoxy-2-oxopropyl)isoindolin-1-one (5bl): Prepared from
hydroxy lactam 1b (0.25 mmol) and 1-methoxypropan-2-one 3l (3 equiv)
following the general procedure at 70°C in acetonitrile with 1 mol % of
Sn(NTf2)4.4 DMSO. Reaction time: 16 h. The product was isolated after
purification by flash chromatography on silica gel (eluting with
2-Allyl-3-(1-chloro-2-oxopropyl)isoindolin-1-one (4bj) and 2-Allyl-3-
(3-chloro-2-oxopropyl)isoindolin-1-one (5bj): Prepared from hydroxy
lactam 1b (0.25 mmol) and 1-chloropropan-2-one 3j (3 equiv) following
the general procedure at 90°C in acetonitrile with 1 mol % of Sn(NTf2)4.4
DMSO. Reaction time: 5 h. The product was isolated after purification by
flash chromatography on silica gel (eluting with Cyclohexane/EtOAc =
70:30) as a separable mixture of branched and linear regioisomers (ratio
4bj/5bj = 6 : 1). Combined isolated yield: 100%. Branched regioisomer
4bj (57 mg, 86%, mixture of diastereoisomers d1/d2 = 72:28), yellow
viscous oil; Rf = 0.32 (cyclohexane/EtOAc: 50/50); IR (CHCl3)  1728,
1670 cm-1; 1H NMR (300 MHz, CDCl3, 20°C) mixture of diastereoisomers
δ 2.16 (s, 0.84H, 3H d2), 2.39 (s, 2.16H, 3H d1), 3.63 (dd, J = 6.8 and
15.8 Hz, 0.28H, 1H d2), 3.72 (dd, J = 7.4 and 16.0 Hz, 0.72H, 1H d1),
4.51-4.68 (m, 1.28H), 4.77 (m, 0.72H), 5.09-5.34 (m, 3H), 5.66-5.90 (m,
1H), 7.08-7.19 (m, 0.72 H), 7.40-7.58 (m, 2.28H), 7.77-7.85 (m, 1H); 13C
NMR (75 MHz, CDCl3, 20°C) mixture of diastereoisomers δ 28.0, 29.2,
43.0, 43.7, 60.1, 60.4, 63.1, 64.2, 118.4, 118.6, 122.3, 122.9, 123.4,
123.8, 124.0, 129.1, 129.2, 131.7, 131.9, 132.5, 132.8, 133.1, 134.2,
140.3, 141.7, 168.2, 168.4, 201.6, 203.5; HRMS (ESI) m/z: calculated for
C14H15NO2Cl [M+H]+: 264.0786, found: 264.0782. Linear regioisomer
5bj (9 mg, 14%), yellow viscous oil; Rf = 0.17 (cyclohexane/EtOAc:
50/50); IR (CHCl3)  1732, 1668 cm-1; 1H NMR (300 MHz, CDCl3, 20°C)
δ 2.92 (dd, J = 7.1 and 18.0 Hz, 1H), 3.25 (dd, J = 5.2 and 18.1 Hz, 1H),
3.96 (dd, J = 6.3 and 15.9 Hz, 1H), 4.09 (s, 2H), 4.46 (dd, J = 5.4 and
16.0 Hz, 1H), 5.12 (dd, J = 5.3 and 7.1 Hz, 1H), 5.18-5.27 (m, 2H), 5.86
(m, 1H), 7.40 (d, J = 7.3 Hz, 1H), 7.46-7.61 (m, 2H), 7.88 (d, J = 7.2 Hz,
1H); 13C NMR (75 MHz, CDCl3, 20°C) δ 41.6, 48.2, 55.2, 81.3, 118.0,
122.4, 123.4, 124.0, 129.9, 131.4, 132.3, 132.7, 143.8, 167.1, 208.3;
HRMS (ESI) m/z: calculated for C14H15NO2Cl [M+H]+: 264.0786, found:
264.0784.
Cyclohexane/EtOAc
(d1/d2 = 55:45) and linear regioisomers (ratio 4bl/ 5bl
=
50:50) as
a
separable mixture of branched
2.8 1).
=
:
Combined isolated yield: 98%. Branched regioisomer 4bl (42 mg,
74%), colorless viscous oil; Rf = 0.30 (cyclohexane/EtOAc: 50/50); IR
(CHCl3)  1692, 1616 cm-1; 1H NMR (300 MHz, CDCl3, 20°C) mixture of
diastereoisomers δ 1.85 (s, 1.65H, 3H d1), 2.07 (s, 1.35H, 3H d2), 3.35 (s,
1.35H, 3H d2), 3.41 (s, 1.65H, 3H d1), 3.75 (dd, J = 7.7 and 15.8 Hz,
0.55H, 1H d1), 3.79 (dd, J = 7.3 and 15.6 Hz, 0.45H, 1H d2), 4.07 (d,
J = 4.3 Hz, 0.55H, 1H d1), 4.09 (d, J = 2.7 Hz, 0.45H, 1H d2), 4.68 (dd, J
= 4.7 and 15.6 Hz, 0.45H, 1H d2), 4.80 (m, 1H), 4.95 (d, J = 4.3 Hz,
0.55H, 1H d1), 4.96 (d, J = 2.6 Hz, 0.45H, 1H d2), 5.15-5.36 (m, 2H),
5.74-5.92 (m, 1H), 7.22 (m, 1H d2), 7.38-7.89 (m, 4.55H); 13C NMR (75
MHz, CDCl3, 20°C) mixture of diastereoisomers δ 27.0, 27.9, 39.6, 43.6,
43.6, 46.1, 49.1, 59.3, 59.7, 59.9, 61.1, 85.7, 85.8, 118.3, 122.5, 123.4,
123.8, 123.8, 123.9, 128.7, 128.9, 131.5, 131.6, 132.3, 132.6, 132.8,
132.9, 134.2, 141.1, 142.0, 168.3, 168.7, 207.6, 208.7; HRMS (ESI) m/z:
calculated for C15H17NaNO3 [M+Na]+: 282.1106, found: 282.1108. Linear
regioisomer 5bl (14 mg, 25%), colorless viscous oil; Rf = 0.17
(cyclohexane/EtOAc: 50/50); IR (CHCl3)  1715, 1687 cm-1; 1H NMR
(300 MHz, CDCl3, 20°C) δ 2.70 (dd, J = 7.4 and 17.9 Hz, 1H), 3.05 (dd, J
= 5.1 and 18.0 Hz, 1H), 3.33 (s, 3H), 3.83 (dd, J = 6.5 and 15.9 Hz, 1H),
3.92 (s, 2H), 4.44 (dd, J = 5.2 and 15.9 Hz, 1H), 5.05 (dd, J = 5.1 and 7.4
Hz, 1H), 5.10-5.18 (m, 2H), 5.77 (m, 1H), 7.27-7.50 (m, 3H), 7.79 (d, J =
7.2 Hz, 1H); 13C NMR (75 MHz, CDCl3, 20°C) δ 42.2, 43.4, 55.2, 59.4,
117.8, 122.6, 123.9, 128.6, 131.9, 133.1, 145.4, 206.1; HRMS (ESI) m/z:
calculated for C15H17NaNO3 [M+Na]+: 282.1106, found: 282.1107.
2-Allyl-3-(2-oxocyclohex-3-en-1-yl)isoindolin-1-one (4bm): Prepared
from acetoxy lactam 2b (0.25 mmol) and cyclohex-2-enone 3m following
the general procedure at 90°C with 1 mol % of Sn(NTf2)4.4 DMSO.
Reaction time: 1 h. The product was isolated after purification by flash
chromatography on silica gel (eluting with Cyclohexane/EtOAc = 60:40)
as a colorless oil. Yield: 79% (53 mg, mixture of diastereoisomers
d1/d2 = 50:50). Rf = 0.37 (d1) and 0.30 (d2) (cyclohexane/EtOAc: 70/30);
2-Allyl-3-(3-oxobutan-2-yl)isoindolin-1-one (4bk) and 2-Allyl-3-(2-
oxobutyl)isoindolin-1-one (5bk): Prepared from hydroxy lactam 1b
(0.25 mmol) and butan-2-one 3k (3 equiv) following the general
procedure at 110°C in toluene with 1 mol % of Sn(NTf2)4.4 DMSO.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700530
European Journal of Organic Chemistry
FULL PAPER
1H NMR (300 MHz, CDCl3, 20°C) mixture of diastereoisomers δ 1.02
(ddd, J = 5.8, 10.9 and 13.6 Hz, 0.50H, 1H, d1), 1.40-1.60 (m, 1H), 1.95
(m, 0.50H, 1H d2), 2.10-2.35 (m, 2H), 2.77 (dd, J = 4.0 and 14.1 Hz,
0.50H, 1H d1), 3.0 (ddd, J = 3.0, 3.9 and 14.0 Hz, 0.50H, 1H d2), 3.41 (dd,
J = 5.6 and 15.5 Hz, 0.50H, 1H, d1), 3.75 (dd, J = 7.0 and 15.6 Hz, 0.50H,
1H d2), 4.38 (dd, J = 6.0 and 15.5 Hz, 0.50H, 1H d1), 4.51 (dd, J = 5.3
and 15.6 Hz, 0.50H, 1H d2), 5.05-5.35 (m, 2H), 5.46 (d, J = 3.0 Hz, 0.50H,
1H d2), 5.57 (s, 0.50H, 1H d1), 5.70-5.90 (m, 1H), 6.09 (dd, J = 3.0 and
10.0 Hz, 1H), 6.9-7.02 (m, 1H), 7.30-7.55 (m, 3H), 7.78 (m, 1H); 13C
NMR (75 MHz, CDCl3, 20°C) mixture of diastereoisomers δ20.3, 20.8,
25.3, 25.6, 43.1, 44, 46.7, 50.1, 57.1, 58.6, 117.9, 118.2, 121.3, 123.5,
123.6, 123.7, 128.3, 129.6, 130.0, 131.6, 131.8, 132.2, 132.7, 132.7,
132.7, 133.0, 143.1, 144.9, 151.1, 151.2, 168.5, 169, 197.4, 198.7; Data
analyses were identical in all respects with our previously reported
data.[16b]
3.01 (m, 0.80H, 1H d1), 4.31 (d, J = 15 Hz, 0.20H, 1H d2), 4.61 (m,
J = 15.2 Hz, 0.80H, 1H d1), 4.91 (m, J = 15.2 Hz, 0.80H, 1H d1), 4.97 (d,
J = 15 Hz, 0.20H, 1H d2), 5.14 (bs, 0.80H, 1H d1), 5.25 (bs, 0.20H, 1H d2),
7.20-7.40 (m, 6H), 7.41-7.62 (m, 2H), 7.86-7.95 (m, 1H); 13C NMR (75
MHz, CDCl3, 20°C) mixture of diastereoisomers δ 23.1, 23.4, 24.1, 24.3,
29.3, 30.3, 30.4, 30.7, 44.2, 44.9, 44.9, 45.8, 52.2, 55.8, 60.4, 61.2,
121.6, 123.7, 123.9, 123.9, 127.4, 127.7, 128.1, 128.3, 128.4, 128.5,
128.9, 131.5, 131.8, 132.8, 137.3, 137.4, 143.3, 169.2, 213.2, 214.3;
LRMS (ESI) m/z 333 (M+•, 10), 242 (42), 222 (100); HRMS (ESI) m/z:
calculated for C22H23NaNO2 [M+Na]+: 356.1626, found: 356.1622.
2-Benzyl-3-(2-cyclopropyl-2-oxoethyl)isoindolin-1-one
(4ap):
Prepared from hydroxy lactam 2a (0.25 mmol) and cyclopropylethanone
3p (3 equiv) in toluene following the general procedure at 110°C with 1
mol % of Sn(NTf2)4.8DMSO. Reaction time: 4 h. The crude material was
purified by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 60:40) to give the title compound as a white solid.
Yield: 61% (46 mg). Rf = 0.37 (cyclohexane/EtOAc: 60/40); mp = 119°C;
IR (neat)  1679, 1646, 1411, 1296, 985, 723 cm-1; 1H NMR (300 MHz,
CDCl3, 20°C) δ 0.81-0.94 (m, 2H), 1.01-1.07 (m, 2H), 1.71-1.79 (m, 1H),
2.85 (dd, J = 7.1 and 17.3Hz, 1H), 3.12 (dd, J = 5.2 and 17.3 Hz, 1H),
4.48 (d, J = 15.4 Hz, 1H), 5.02 (dd, J = 5.5 and 6.8 Hz, 1H), 5.11 (d, J =
15.4 Hz, 1H), 7.26-7.38 (m, 6H), 7.47-7.57 (m, 2H), 7.92 (dd, J = 1.8 and
6.3 Hz, 1H); 13C NMR (75 MHz, CDCl3, 20°C) δ 11.4, 11.6, 21.2, 44.5,
46.3, 55.6, 122.6, 123.9, 127.5, 127.9, 128.4, 128.7, 131.8, 137.2, 145.7,
168.5, 207.7; HRMS (ESI) m/z: calculated for C20H20NO2 [M+H]+:
306.1503, found: 306.1503.
2-Allyl-3-(2-(4-methoxyphenyl)-2-oxoethyl)isoindolin-1-one
(4bn):
Prepared from acetoxy lactam 2b (0.25 mmol) and p-
methoxyacetophenone 3n (2 equiv) in toluene following the general
procedure at 90°C with 1 mol % of Sn(NTf2)4.8DMSO. Reaction time: 6 h.
The crude material was purified by flash chromatography on silica gel
(eluting with Cyclohexane/EtOAc = 70:30) as a colorless oil. Yield: 88 %
(71 mg). Rf = 0.21 (cyclohexane/EtOAc: 60/40); IR (CHCl3)  1681, 1600,
755 cm-1; 1H NMR (300 MHz, CDCl3, 20°C) δ 3.22 (dd, J = 7.5 and 17.4
Hz, 1H), 3.51 (dd, J = 5.1 and 17.4 Hz, 1H), 3.90 (s, 3H), 3.91 (dd, J =
6.6 and 15.9 Hz, 1H), 4.51 (dd, J = 4.8 and 15.9 Hz, 1H), 5,15-5,22 (m,
2H), 5.33-5.37 (m, 1H), 5.85 (m, 1H), 6.97 (d, J = 8.7 Hz, 2H), 7.49-7.51
(m, 3H), 7.85-8.08 (m, 3H); 13C NMR (75 MHz, CDCl3, 20°C) δ 41.6, 43.3,
55.5, 56.0, 113.9, 117.7, 122.9, 123.7, 128.3, 129.5, 130.4, 131.7, 131.8,
133.1, 146.0, 164.0, 168.1, 195.6; LRMS (ESI) m/z 321 (M+•, 2), 280 (97),
158 (100); HRMS (ESI) m/z: calculated for C20H20NO3 [M+H]+: 322.1443,
found: 322.1441.
2-(3,4-Dimethoxybenzyl)-3-(2-oxocyclohexyl)isoindolin-1-one (4fa):
Prepared from acetoxy lactam 2f (0.25 mmol) and cyclohexanone 3a (3
equiv) in acetonitrile following the general procedure at 90°C with 1
mol % of Sn(NTf2)4.4 DMSO. Reaction time: 2.5 h. The crude material
was purified by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 60:40) to give the title compound as a yellow
2-Allyl-3-(2-oxocycloheptyl)isoindolin-1-one (4bo): Prepared from
hydroxy lactam 2b (0.25 mmol) and cycloheptanone 3o (3 equiv) in
toluene following the general procedure at 110°C with 1 mol % of
Sn(NTf2)4.8DMSO. Reaction time: 2 h. The crude material was purified
by flash chromatography on silica gel (eluting with Cyclohexane/EtOAc =
70:30) to give the title compound as colorless viscous oil. Yield: 96 % (68
viscous oil. Yield: 78% (74 mg, mixture of diastereosiomers d1/d2
=
72:28). Rf = 0.25 (cyclohexane/EtOAc: 60/40); 1H NMR (300 MHz, CDCl3,
20°C) mixture of diastereoisomers δ 0.69 (m, 0.72H, 1H d1), 1.02-1.74 (m,
3.28H), 1.82-2.10 (m, 2H), 2.22-2.37 (m, 1H), 2.44-2.55 (m, 1H), 2.77 (dd,
J = 6.1 and 12.5 Hz, 0.28H, 1H d2), 2.94 (m, 0.72H, 1H d1), 3.83 (s,
2.16H, 3H d1), 3.85 (s, 0.84H, 3H d2), 3.86 (s, 2.16H, 3H d1), 3.88 (s,
0.84H, 3H d2), 4.40 (d, J = 15.1 Hz, 0.72H, 1H d1), 4.43 (d, J = 14.3 Hz,
0.28H, 1H d2), 4.77 (d, J = 14.3 Hz, 0.28H, 1H d2), 4.97 (d, J = 15.1 Hz,
0.72H, 1H d1), 5.21 (s, 0.72H, 1H d1), 5.45 (s, 0.28H, 1H d2), 6.74-7.14
(m, 3H), 7.29-7.57 (m, 3H), 7.82-7.90 (m, 1H); 13C NMR (75 MHz, CDCl3,
20°C) mixture of diastereoisomers δ 22.3, 22.7, 24.2, 24.2, 24.2, 24.8,
25.2, 25.3, 25.5, 26.4, 27.2, 27.6, 29.6, 31.8, 41.7, 42.0, 44.3, 45.6, 50.3,
53.9, 55.8, 55.8, 55.9, 57.8, 58.7, 58.8, 76.6, 77.0, 77.0, 77.2, 77.4,
110.6, 110.9, 111.0, 112.4, 120.1, 121.2, 121.4, 123.5, 123.6, 124.4,
128.1, 128.1, 129.5, 130.4, 131.5, 131.7, 132.6, 143.6, 145.2, 148.2,
148.5, 148.7, 149.3, 168.9, 169.7, 209.5, 210.5; Data analyses were
identical in all respects with our previously reported data.[16g]
mg, mixture of diastereoisomers d1/d2
=
60:40). Rf
=
0.27
(cyclohexane/EtOAc: 70:30); IR (CHCl3)  1772, 1615 cm-1
;
1H NMR
(300 MHz, CDCl3, 20°C) mixture of diastereoisomers δ 0.60-2.76 (m,
10H), 2.82 (d, J = 10.6 Hz, 0.40H, 1Hd2), 3.03 (d, J = 10.6 Hz, 0.60H,
1Hd1), 3.49 (dd, J = 6.0 and 15.5 Hz, 0.40H, 1Hd2), 3.76 (dd, J = 6.8 and
15.8 Hz, 0.60H, 1Hd1), 4.36-4.52 (m, 1 H), 5.00-5.27 (m, 3H), 5.67-5.87
(m, 1H), 7.18-7.58 (m, 2.60H), 7.61-7.86 (m, 1.40H); 13C NMR (75 MHz,
CDCl3, 20°C) mixture of diastereoisomers δ 21.9, 22.2, 23.2, 23.4, 28.6,
29.2, 29.5, 29.7, 42.3, 43.2, 43.3, 43.9, 51.1, 54.7, 58.9, 59.6, 75.6, 76.1,
76.3, 76.5, 116.6, 117.1, 120.6, 122.4, 122.6, 122.7, 122.8, 127.3, 127.3,
130.5, 130.8, 131.7, 131.8, 131.8, 132.2, 133.1, 142.2, 144.0, 167.8,
168.1, 212.3, 213.3; LRMS (ESI) m/z 283 (M+•, 0.7 ), 242 (48), 172 (100);
HRMS (ESI) m/z: calculated for C18H21NaNO2 [M+Na]+: 306.1470, found:
306.1464.
2-(But-3-ynyl)-3-(2-oxocyclohexyl)isoindolin-1-one (4ga): Prepared
from acetoxy lactam 2g (0.25 mmol) and cyclohexanone 3a (3 equiv) in
acetonitrile following the general procedure at 90°C with 1 mol % of
Sn(NTf2)4.4 DMSO. Reaction time: 2.5 h. The crude material was purified
by flash chromatography on silica gel (eluting with Cyclohexane/EtOAc =
70:30) to give the title compound as a yellow viscous oil. Yield: 55% (39
2-Benzyl-3-(2-oxocycloheptyl)isoindolin-1-one (4ao): Prepared from
hydroxy lactam 2a (0.25 mmol) and cycloheptanone 3o (3 equiv) in
toluene following the general procedure at 110°C with 1 mol % of
Sn(NTf2)4.8DMSO. Reaction time: 2 h. The crude material was purified
by flash chromatography on silica gel (eluting with Cyclohexane/EtOAc =
70:30) to give the title compound as a white solid. Yield: 97 % (81 mg,
mg, mixture of diastereosiomers d1/d2
=
50:50). Rf
0.18
=
(cyclohexane/EtOAc : 80/20); 1H NMR (300 MHz, CDCl3, 20°C) mixture
of diastereoisomers δ 0.76 (m, 0.50H, 1H d1), 1.15-1.88 (m, 4.50H), 1.96
(t, J = 2.7 Hz, 0.50H, 1H d1), 2.03 (t, J = 2.7 Hz, 0.50H, 1H d2), 2.03-2.21
(m, 1H), 2.37-2.75 (m, 4H), 2.80-3.01 (m, 1H), 3.10 (m, 0.50H, 1H d2),
3.29 (dt, J = 7.2 and 13.5 Hz, 0.50H, 1H d1), 4.15 (dt, J = 7.2 and 13.5 Hz,
mixture of diastereoisomers d1/d2
=
80:20). Rf
=
0.34
(cyclohexane/EtOAc : 70:30); IR (CHCl3)  1681, 1520 cm-1
;
1H NMR
(300 MHz, CDCl3, 20°C) mixture of diastereoisomers δ 0.64-1.90 (m,
7.6H), 2.18-2.51 (m, 2.4H), 2.52-2.74 (m, 1H), 2.87 (m, 0.20H, 1H d2),
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10.1002/ejoc.201700530
European Journal of Organic Chemistry
FULL PAPER
0.50H, 1H d2), 4.30 (dt, J = 7.7 and 13,5 Hz, 0.50H, 1H d1), 5.47 (s,
0.50H, 1H d1), 5.51 (s, 0.50H, 1H d2), 7.33-7.85 (m, 4H); 13C NMR (75
MHz, CDCl3, 20°C) mixture of diastereoisomers δ 17.6, 18.5, 24.2, 24.4,
24.7, 25.2, 26.4, 39.1, 39.9, 41.7, 42.1, 50.1, 53.8, 56.2, 58.9, 69.7, 70.3,
81.1, 81.4, 121.3, 123.4, 123.7, 124.4, 128.1, 128.2, 131.6, 131.7, 132.4,
132.5, 143.6, 144.8, 169.0, 169.1, 209.8, 210.5; LRMS (ESI) m/z 281
(M+•, 6), 184 (12), 228 (38), 170 (100); Data analyses were identical in all
respects with our previously reported data.[16g]
70:30) to give the title compound as a colorless oil. Yield: 61% (39 mg).
Rf = 0.22 (cyclohexane/EtOAc: 70/30); IR (neat)  1710, 1626, 1396,
1364, 695 cm-1; 1H NMR (300 MHz, CDCl3, 20 °C) δ 1.65 (s, 6H), 2.11 (s,
3H), 2.62 (dd, J = 7.7 and 17.7 Hz, 1H), 2.99 (dd, J = 4.8 and 17.7, 1H),
3.79 (dd, J = 7.0 and 15.4 Hz, 1H), 4.39 (dd, J = 6.6 and 15.5 Hz, 1H),
4.98 (dd, J = 4.9 and 7.5 Hz, 1H), 5.11 (t, J = 6.8 Hz, 1H), 7.31 (d, J = 7.2
Hz, 1H), 7.29-7.43 (m, 2H), 7.76 (d, J = 7.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3, 20°C) δ 18.0, 25.7, 30.8, 38.4, 46.4, 55.2, 119.5, 122.5, 123.7,
128.4, 131.6, 134.1, 136.6, 145.6, 167.9, 205.7; HRMS (ESI) calculated
for C16H20NO2 [M+H]+: 258.1494, found: 258.1499.
(E)-2-(But-3-yn-1-yl)-3-(2-oxo-4-phenylbut-3-en-1-yl)isoindolin-1-one
(4gf): Prepared from acetoxy lactam 2g (0.25 mmol) and (E)-4-
phenylbut-3-en-2-one 3f (3 equiv) in acetonitrile following the general
procedure at 90°C with 1 mol % of Sn(NTf2)4.4 DMSO. Reaction time: 1.5
h. The crude material was purified by flash chromatography on silica gel
(eluting with Cyclohexane/EtOAc = 70:30) to give the title compound as a
yellow viscous oil. Yield: 50% (41 mg). Rf = 0.38 (cyclohexane/EtOAc :
70/30); IR (neat)  1637, 1520 cm-1; 1H NMR (300 MHz, CDCl3, 20°C) δ
2.00 (t, J = 2.7 Hz, 1H), 2.62 (m, 2H), 3.01 (dd, J = 7.3 and 17.3 Hz, 1H),
3.24-3.44 (m, 2H), 4.17 (m, 1H), 5.41 (dd, J = 5.2 and 7.3 Hz, 1H), 6.80
(d, J = 16.2 Hz, 1H), 7.36-7.65 (m, 9H), 7.86 (d, J = 7.2 Hz, 1H); 13C
NMR (75 MHz, CDCl3, 20°C) δ 18.4, 39.4, 44.0, 55.9, 70.3, 81.4, 122.8,
123.7, 125.6, 128.5, 128.5, 129.1, 131.1, 131.6, 131.9, 133.9, 144.2,
145.7, 197.0; LRMS (ESI) m/z 329 (M+·, 5), 251 (21), 160 (100); HRMS
(ESI) calculated for C22H19NaNO2 [M+Na]+: 352.1313, found: 352.1311.
2-Benzyl-3-(2-oxo-2-(thiophen-2-yl)ethyl)isoindolin-1-one
(4aq):
Prepared from hydroxylactam 1a (0.25 mmol) and 2-acetyl-furane 3r (2
equiv) in toluene following the general procedure at 90°C with 1 mol % of
Sn(NTf2)4.8DMSO. Reaction time: 4 h. The crude material was purified
by flash chromatography on silica gel (eluting with Cyclohexane/EtOAc =
60:40) to give an inseparable mixture of the title compound 4aq and the
related Friedel-crafts adduct 4aq’ as a pale solid; Yield: 73 % (61 mg,
ratio 4aq/4aq’ = 82/18). Rf = 0.35 (cyclohexane/EtOAc: 60/40); 1H NMR
(300 MHz, CDCl3, 20°C) δ 2.41 (s, 0.54H, 3H 4aq’), 3.07 (dd, J = 7.0 and
17.0 Hz, 0.82H, 1H 4aq), 3.36 (dd, J = 5.8 and 17.0 Hz, 0.82H, 1H 4aq),
4.19 (d, J = 15.0 Hz, 0.18H, 1H 4aq’), 4.53 (d, J = 15.4 Hz, 0.82H, 1H
4aq), 5.10 (d, J = 15.4 Hz, 0.82H, 1H 4aq), 5.19 (t, J = 6.4 Hz, 0.82H, 1H
4aq), 5.31 (d, J = 15.0 Hz, 0.18H, 1H 4aq’), 5.51 (s, 0.18H, 1H 4aq’),
6.33 (d, J = 3.5 Hz, 0.18H, 1H 4aq’), 6.53 (dd, J = 1.7 and 3.6 Hz, 0.82H,
1H 4aq), 6.98-7.72 (m, 11H), 7.84-8.10 (m, 1H).
(E)-3-(2-Oxo-4-phenylbut-3-en-1-yl)-2-(prop-2-yn-1-yl)isoindolin-1-
one (4ef): Prepared from hydroxy lactam 1e (0.25 mmol) and (E)-4-
phenylbut-3-en-2-one 3f (3 equiv) in toluene following the general
procedure at 110°C with 1 mol % of Sn(NTf2)4.4 DMSO. Reaction time:
2 h. The crude material was purified by flash chromatography on silica
gel (eluting with Cyclohexane/EtOAc = 70:30) to give the title compound
2-Benzyl-3-(2-oxo-2-(thiophen-2-yl)ethyl)isoindolin-1-one
(4ar):
Prepared from hydroxylactam 1a (0.25 mmol) and 2-acetyl-thiophene 3r
(2 equiv) in toluene following the general procedure at 110°C with 1
mol % of Sn(NTf2)4.8DMSO. Reaction time: 5 h. The crude material was
purified by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 60:40) to give the title compound as a white solid.
Yield: 91 % (79 mg). Rf = 0.39 (cyclohexane/EtOAc: 60/40); mp = 129°C;
IR (neat)  1677, 1649, 1410, 721 cm-1; 1H NMR (300 MHz, CDCl3, 20°C)
δ 3.12 (dd, J = 6.9 and 17.0 Hz, 1H), 3.41 (dd, J = 5.8 and 17.0 Hz, 1H),
4.57 (d, J = 15.4 Hz, 1H), 5.06 (d, J = 15.4 Hz, 1H), 5.23 (t, J = 6.3 Hz,
1H), 7.08 (dd, J = 3.9 and 4.9 Hz, 1H), 7.18-7.27 (m, 5H), 7.40-7.43 (m,
1H), 7.46 (dd, J = 1.0 and 3.8 Hz, 1H), 7.50-7.53 (m, 2H), 7.68 (dd, J =
1.0 and 4.9 Hz, 1H), 7.91-7.95 (m, 1H); 13C NMR (75 MHz, CDCl3, 20°C)
δ 42.8, 44.7, 55.9, 122.8, 123.9, 127.5, 128.0, 128.3, 128.5, 128.6, 131.7,
131.9, 132.4, 134.6, 137.0, 143.5, 145.5, 168.5, 189.7; HRMS (ESI) m/z:
calculated for C21H18NO2S [M+H]+: 348.1058, found: 348.1060.
as
a
yellow viscous oil. Yield: 90% (71 mg). Rf
0.54
=
(cyclohexane/EtOAc: 70/30); IR (CHCl3)  1973, 1685 cm-1; 1H NMR
(300 MHz, CDCl3, 20°C) δ 2.15 (bs, 1H), 2.94 (dd, J = 7.3 and 17.3Hz,
1H), 3.36 (dd, J = 5.2 and 17.3Hz, 1H), 4.12 (dd, J = 2.6 and 17.9Hz, 1H),
4.55 (dd, J = 2.6 and 17.8Hz, 1H), 5.28 (t, J = 6.3 Hz, 1H), 6.69 (d, J =
16.1 Hz, 1H), 7.22-7.61 (m, 12H), 7.75 (d, J = 7.4 Hz, 1H); 13C NMR (75
MHz, CDCl3, 20°C) δ 30.4, 43.8, 55.9, 72.4, 78.5, 122.9, 123.8, 125.6,
128.5, 128.5, 129.1, 131.0, 131.3, 132.1, 134.0, 143.9, 145.6, 167.7,
196.7; HRMS (ESI) m/z 315 (M+·, 5), 145 (40), 170 (100); HRMS (ESI)
calculated for C21H17NaNO2 [M+Na]+: 358.1157, found: 338.1157.
2-(3,4-Dimethoxybenzyl)-3-(2-oxopropyl)isoindolin-1-one
(4fi):
Prepared from acetoxy lactam 2f (0.25 mmol) and acetone 3i (3 equiv) in
acetonitrile following the general procedure at 90°C with 1 mol % of
Sn(NTf2)4.8DMSO. Reaction time: 1.5 h. The crude material was purified
by flash chromatography on silica gel (eluting with Cyclohexane/EtOAc =
70:30) to give the title compound as a colorless oil. Yield: 53 % (45 mg).
Rf = 0.15 (cyclohexane/EtOAc: 60/40); IR (neat)  1675, 1615, 1514,
1258, 1024, 755 cm-1; 1H NMR (300 MHz, CDCl3, 20°C) δ 1.99 (s, 3H),
2.71 (dd, J = 6.6 and 17.8 Hz, 1H), 2.94 (dd, J = 5.6 and 17.8Hz, 1H),
3.84 (s, 3H), 3.86 (s, 3H), 4.53 (d, J = 15.1 Hz, 1H), 4.87 (d, J = 15.2 Hz,
1H), 5.03 (t, J = 6.1 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz,
1H), 6.83 (s, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.46-7.56 (m, 2H), 7.90 (dd, J
= 1.1 and 6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3, 20°C) δ 30.6, 44.6,
46.6, 55.6, 55.9, 55.9, 111.0, 111.2, 120.3, 122.4, 123.9, 128.5, 129.7,
131.6, 131.9, 145.6, 148.5, 149.2, 168.5, 205.6; HRMS (ESI) calculated
for C20H21NaNO4 [M+Na]+: 362.1368, found: 362.1364.
2-Benzyl-3-(2-(5-bromothiophen-2-yl)-2-oxoethyl)isoindolin-1-one
(4as): Prepared from hydroxy lactam 1a (0.25 mmol) and 2-acetyl-5-
bromothiophene 3s (2 equiv) in toluene following the general procedure
at 110°C with 1 mol % of Sn(NTf2)4.8DMSO. Reaction time: 5 h. The
crude material was purified by flash chromatography on silica gel (eluting
with Cyclohexane/EtOAc = 70:30) to give the title compound as a white
solid. Yield: 93% (99 mg). Rf = 0.41 (cyclohexane/EtOAc: 60/40); mp =
145°C; IR (neat)  1678, 1646, 1411, 1340, 984, 736 cm-1; 1H NMR (300
MHz, CDCl3, 20°C) δ 3.03 (dd, J = 6.7 and 16.9 Hz, 1H), 3.30 (dd,
J = 5.9 and 16.9 Hz, 1H), 4.61 (d, J = 15.4 Hz, 1H), 4.99 (d, J = 15.4 Hz,
1H), 5.20 (t, J = 6.3 Hz, 1H), 7.03 (d, J = 4.1 Hz, 1H), 7.13 (d, J = 4.1 Hz,
1H), 7.20-7.26 (m, 5H), 7.37-7.34 (m, 1H), 7.48-7.56 (m, 2H), 7.92-7.95
(m, 1H); 13C NMR (75 MHz, CDCl3, 20°C) δ 42.2, 44.8, 55.9, 122.6,
123.9, 124.0, 127.6, 128.0, 128.6, 128.7, 131.4, 131.7, 131.9, 132.5,
137.0, 144.9, 145.3, 168.5, 188.6; HRMS (ESI) m/z: calculated for
C42H32Br2 NaN2O4S2 [2M+Na]+: 875.0036, found: 875.0041.
2-(3-Methylbut-2-enyl)-3-(2-oxopropyl)isoindolin-1-one
(4di):
Prepared from hydroxy lactam 1d (0.25 mmol) and acetone 3i (3 equiv)
in toluene following the general procedure at 110°C with 1 mol % of
Sn(NTf2)4.8DMSO. Reaction time: 8 h. The crude material was purified
by flash chromatography on silica gel (eluting with Cyclohexane/EtOAc =
2-Benzyl-3-(2-oxo-2-(pyridin-2-yl)ethyl)isoindolin-1-one
Prepared from hydroxy lactam 1a (0.25 mmol) and 2-acetylpyridine 3t (2
equiv) in toluene following the general procedure at 110°C with 1 mol %
(4at):
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10.1002/ejoc.201700530
European Journal of Organic Chemistry
FULL PAPER
of Sn(NTf2)4.8DMSO. Reaction time: 48 h. The crude material was
purified by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 70:30) to give the title compound as a white solid.
Yield: 76% (65 mg). Rf = 0.33 (cyclohexane/EtOAc: 60/40); mp = 122°C;
IR (neat)  1682, 1410, 1360, 992, 725 cm-1; 1H NMR (300 MHz, CDCl3,
20°C) δ 3.52 (dd, J = 7.0 and 17.8 Hz, 1H), 3.87 (dd, J = 5.4 and 17.8 Hz,
1H), 4.47 (d, J = 15.4 Hz, 1H), 5.18 (t, J = 6.7 Hz, 1H), 5.23 (d, J = 15.4
Hz, 1H), 7.16-7.28 (m, 5H), 7.41-7.51 (m, 4H), 7.85 (td, J = 1.7 and 7.7
Hz, 1H), 7.91-7.93 (m, 1H), 8.03 (dt, J = 1.0 and 7.9 Hz, 1H), 8.60 (ddd, J
= 0.9, 1.6 and 4.7 Hz, 1H); 13C NMR (75 MHz, CDCl3, 20°C) δ 41.0, 44.4,
55.6, 121.9, 122.8, 123.8, 127.4, 127.5, 128.0, 128.3, 128.6, 131.6,
131.8, 136.9, 137.1, 145.9, 148.9, 152.6, 168.5, 198.8; HRMS (ESI) m/z:
calculated for C22H19N2O2 [M+H]+: 343.1446, found: 343.1444.
56.9, 66.6, 127.8, 127.9, 128.4, 128.5, 136.9, 154.8, 155.5, 211.8, 212;
Data analyses were identical in all respects with literature data.[33]
N-(4-Methoxybenzyl)-5-(2-Oxo-cyclohexyl)pyrrolidin-2-one
(9a):
Prepared from methoxy lactam 8 (0.25 mmol) and cyclohexanone 3a (3
equiv) in acetonitrile following the general procedure at 60°C with 1
mol % of Sn(NTf2)4.8DMSO. Reaction time: 8 h. The crude material was
purified by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 20:80) to give the title compound as a colorless oil.
Yield: 60% (45 mg). The adduct was obtained as a mixture of two
diastereoisomers (d1/d2 = 52:48). Rf = 0.26 (d1) and 0.15 (d2)
(cyclohexane/EtOAc: 80/20); IR (CHCl3)  1703, 1667, 1611 cm-1; 1H
NMR (300 MHz, CDCl3, 20°C) mixture of diastereoisomers (deliberately
not separated) δ1.15-2.53 (m, 12H), 2.53-2.77 (m, 1H), 3.80 (s, 1.56H,
3H d1), 3.81 (s, 1.44H, 3H d2), 3.95 (dt, J = 3.4 and 9.6Hz, 0.52 H), 3.99-
4.14 (m, 1.48H), 4.63 (d, J = 14.9 Hz, 0.52H, 1H d1), 4.70 (d, J = 14.9 Hz,
0.48 H, 1H d2), 6.81-6.88 (m, 2H), 7.13-7.24 (m, 2H); 13C NMR (75 MHz,
CDCl3, 20°C) mixture of diastereoisomers δ 20.8, 22.5, 24.5, 25.0, 25.7,
26.9, 27.0, 28.8, 30.3, 30.5, 42.2, 44.2, 45.2, 51.4, 53.2, 55.3, 55.3, 56.3,
57.1, 113.9, 114.1, 128.6, 129.2, 129.3, 129.6, 158.9, 159.1, 175.6,
176.3, 210.2, 210.7; Data analyses were identical in all respects with
previously reported data.[16b]
2-Benzyl-3-(2-oxo-2-(pyrazin-2-yl)ethyl)isoindolin-1-one
(4au):
Prepared from hydroxy lactam 1a (0.25 mmol) and 2-acetylpyrazine 3u
(2 equiv) in toluene following the general procedure at 110°C with 1
mol % of Sn(NTf2)4.8DMSO. Reaction time: 24 h. The crude material was
purified by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 70:30) to give the title compound as a white solid.
Yield: 94% (81 mg). Rf = 0.23 (cyclohexane/EtOAc: 60/40); mp = 163°C;
IR (neat)  1677, 1647, 1411, 985, 736 cm-1; 1H NMR (300 MHz, CDCl3,
20°C) δ 3.45 (dd, J = 6.2 and 18.1 Hz, 1H), 3.80 (dd, J = 6.1 and 18.1 Hz,
1H), 4.65 (d, J = 15.5 Hz, 1H), 5.03 (d, J = 15.5 Hz, 1H), 5.20 (t, J = 6.1
Hz, 1H), 7.06-7.11 (m, 1H), 7.15-7.25 (m, 4H), 7.41-7.45 (m, 1H), 7.47-
7.57 (m, 2H), 7.92-7.95 (m, 1H), 8.52 (dd, J = 1.5 and 2.4 Hz, 1H), 8.74
(d, J = 2.5 Hz, 1H), 9.16 (d, J = 1.4 Hz, 1H); 13C NMR (75 MHz, CDCl3,
20°C) δ 41.2, 44.7, 55.6, 122.6, 124.0, 127.3, 127.9, 128.5, 128.6, 131.7,
131.8, 136.9, 143.4, 143.6, 145.5, 146.7, 148.0, 168.6, 198.1; HRMS
(ESI) m/z: calculated for C21H18N3O2 [M+H]+: 344.1399, found: 344.1397.
2-(1,1-Dioxido-2-(prop-2-yn-1-yl)-2,3-dihydrobenzo[d]isothiazol-3-yl)
cyclohexanone (11aa): Prepared from hydroxy sultam 10a (0.25 mmol)
and cyclohexanone 3a (3 equiv) in acetonitrile following the general
procedure at 90°C with 1 mol % of Sn(NTf2)4.8DMSO. Reaction time: 4 h.
The crude material was purified by flash chromatography on silica gel
(eluting with Cyclohexane/EtOAc = 70:30) to give the title compound as a
white solid. Yield: 61% (46 mg). The adduct was obtained as a mixture of
two diastereoisomers (d1/d2 = 60:40). Rf = 0.34 (Cyclohexane/EtOAc :
60/40), mp = 156°C; IR (CHCl3) 1696 cm-1; 1H NMR (300 MHz, CDCl3,
20°C) mixture of diastereoisomers δ 1.02 (m, 0.6H, 1H d1), 1.21-2.63 (m,
8.4H), 2.81 (m, 0.4H, 1H d2), 3.13 (m, 0.6H, 1H d1), 4.18 (s, 1.2H, 2H d1),
4.27 (s, 1.2H, 2H d2), 5.44 (d, J = 2.0 Hz, 0.6H, 1H d1), 5.48 (bs, 0.4H,
1H d2), 7.37-7.69 (m, 3H), 7.74-7.84 (m, 1H); 13C NMR (75 MHz, CDCl3,
20°C) mixture of diastereoisomers δ 24.6, 24.7, 26.8, 27.1, 27.5, 27.5,
34.1, 36.9, 42.1, 42.3, 53.5, 56.5, 60.0, 60.5, 73.0, 73.8, 77.3, 78.2,
121.3, 121.4, 123.9, 126.3, 129.3, 129.4, 132.9, 133.3, 135.4, 135.5,
136.1, 138.1, 210.4, 211.2; HRMS (ESI) calculated for C16H18NO3S
[M+H+]: 304.1007, found: 304.1007.
N-Tosyl-2-(2-oxocyclohexyl)pyrrolidine (7aa): Prepared from methoxy
compound 6a (0.25 mmol) and cyclohexanone 3a (3 equiv) in acetonitrile
following the general procedure at 90°C with
1
mol
%
of
Sn(NTf2)4.8DMSO. Reaction time: 2.5 h. The crude material was purified
by flash chromatography on silica gel (eluting with Cyclohexane/EtOAc =
80:20) to give the title compound as a white solid. Yield: 80% (64 mg);
The adduct was obtained as
a mixture of two diastereoisomers
(d1/d2 = 54:46). Rf = 0.45 (cyclohexane/EtOAc: 70/30); IR (CHCl3) 1703,
1339, 1155 cm-1; 1H NMR (300 MHz, CDCl3, 20°C) mixture of
diastereomers δ 1.22-1.90 (m, 7H), 1.91-2.16 (m, 2H), 2.21-2.50 (m,
3.46H), 2.43 (s, 3H), 3.09 (s, 0.54H), 3.17-3.44 (m, 2H), 3.98-4.08 (m,
1H), 7.29-7.35 (m, 2H), 7.67-7.74 (m, 2H); 13C NMR (75 MHz, CDCl3,
20°C) mixture of diastereomers δ 21.5, 23.8, 24.6, 24.8, 25.1, 26.5, 27.3,
28.2, 28.2, 30.5, 32.0, 42.2, 43.0, 48.6, 49.8, 54.8, 55.4, 58.6, 60.2,
127.6, 127.7, 129.7, 133.3, 135.0, 143.4, 143.5, 211.9, 212.3; Data
analyses were identical in all respects with our previously reported
data.[16g]
1-(2-Benzyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)propan-2-
one (11bi): Prepared from hydroxy sultam 10b (0.25 mmol) and acetone
3i (3 equiv) in toluene following the general procedure at 110°C with 1
mol % of Sn(NTf2)4.8DMSO. Reaction time: 4 h. The crude material was
purified by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 70:30) to give the title compound as a white solid.
Yield: 79 % (62 mg). Rf = 0.25 (cyclohexane/EtOAc: 70/30); mp = 89°C;
IR (neat)  1716, 1279, 1164, 1135, 1062, 709 cm-1; 1H NMR (300 MHz,
CDCl3, 20°C) δ 1.92 (s, 3H), 2.79 (dd, J = 6.2 and 18.1 Hz, 1H), 2.98 (dd,
J = 5.6 and 18.1 Hz, 1H), 4.44 (d, J = 15.6 Hz, 1H), 4.59 (d, J = 15.6 Hz,
1H), 5.01 (t, J = 5.9 Hz, 1H), 7.28-7.43 (m, 6H), 7.52-7.61 (m, 2H), 7.84
(dd, J = 1.4 and 6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3, 20°C) δ 30.3,
47.2, 48.2, 56.4, 121.3, 124.3, 128.0, 128.5, 128.8, 129.4, 133.0, 134.7,
135.7, 138.1, 205.4; HRMS (ESI) m/z: calculated for C17H18NO3S [M+H]+:
316.1007, found: 316.1005.
N-Benzylcarboxy-2-(2-oxocyclohexyl)pyrrolidine (7ba): Prepared
from methoxy compound 6b (0.25 mmol) and cyclohexanone 3a (3
equiv) in acetonitrile following the general procedure at 60°C with 1
mol % of Sn(NTf2)4.8DMSO. Reaction time: 8 h. The crude material was
purified by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 80:20) to give the title compound as a colorless oil.
Yield: 66% (50 mg). The adduct was obtained as an inseparable mixture
of two diastereoisomers, the ratio of which could not be determined due
to complication of both 1H and 13C NMR spectra by the presence of
rotamers. Rf = 0.20 (cyclohexane/EtOAc : 80/20); 1H NMR (300 MHz,
CDCl3, 20°C) δ 1.19-2.02 (m, 9H), 2.04-2.43 (m, 3H), 2.63-2.74 (m,
0.25H), 2.83-2.97 (m, 0.25H), 3.14-3.58 (m, 2.5H), 3.97-4.37 (m, 1H),
4.93-5.22 (m, 2H), 7.22-7.35 (m, 5H); 13C NMR (50 MHz, CDCl3, 20°C) δ
24.6, 24.9, 26.7, 27.2, 27.9, 29.7, 31.1, 42.1, 42.7, 46.6, 47.1, 51.9, 53.3,
1-(2-Allyl-1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-3-yl)propan-2-
one (11ci): Prepared from hydroxy sultam 10c (2.5 mmol) and acetone
3i (10 equiv) in toluene following the general procedure at 90°C with 0.1
mol % of Sn(NTf2)4.8DMSO. Reaction time: 48 h. The crude material was
purified by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 70:30) to give the title compound as colorless oil.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700530
European Journal of Organic Chemistry
FULL PAPER
Yield: 84 % (557 mg). Rf = 0.25 (cyclohexane/EtOAc: 70/30); IR (neat)
1716, 1455, 1281, 1134, 1062, 709 cm-1; 1H NMR (300 MHz, CDCl3,
20°C) δ 2.22 (s, 3H), 2.90 (dd, J = 6.5 and 17.9 Hz, 1H), 3.18 (dd, J = 5.8
and 17.9 Hz, 1H), 3.91 (ddt, J = 1.1, 7.3 and 15.7 Hz, 1H), 4.04 (ddt, J =
1.4, 5.4 and 15.7 Hz, 1H), 5.06 (t, J = 6.2 Hz, 1H), 5.28 (ddd, J = 1.2, 2.4
and 10.1 Hz, 1H), 5.39 (ddd, J = 1.1, 7.3 and 10.1 Hz, 1H), 5.83-5.95 (m,
1H), 7.37-7.40 (m, 1H), 7.52-7.63 (m, 2H), 7.78-7.81 (m, 1H); 13C NMR
(75 MHz, CDCl3, 20°C) δ 30.7, 47.2, 48.6, 56.2, 119.5, 121.3, 124.4,
129.4, 132.5, 133.0, 135.2, 138.5, 205.7; HRMS (ESI) m/z: calculated for
C13H15NaNO3S [M+Na]+: 288.0671, found: 288.0676.
133.3, 133.4, 136.3, 137.6, 150.0, 172.0, 197.7; HRMS (ESI) m/z:
calculated for C24H26NO3 [M+H]+: 376.1924, found: 376.1926.
2-Benzyl-3-(2-oxo-2-phenylethylidene)-2,3,4,5,6,7-hexahydro-1H-
isoindol-1-one (13e’): Prepared from hydroxy lactam 12 (0.25 mmol)
and 2-methoxyacetophenone 3e (3 equiv) in toluene following the
general procedure at 110°C with 1 mol % of Sn(NTf2)4.8DMSO. Reaction
time: 16 h. The crude material was purified by flash chromatography on
silica gel (eluting with Cyclohexane/EtOAc = 70:30) to give the title
compound as a yellow solid. Yield: 83% (71 mg). The adduct was
obtained as a mixture of two diastereoisomers (E/Z = 62:38). Rf = 0.63
(cyclohexane/EtOAc: 70/30); mp = 101°C; IR (neat)  1698, 1647, 1615,
1222, 767 cm-1; 1H NMR (300 MHz, CDCl3, 20°C) mixture of
diastereoisomers δ 1.67-1.83 (m, 4H), 2.23-2.52 (m, 4H), 4.92 (s, 1.24H,
2H E), 5.14 (s, 0.76H, 2H Z), 6.05 (s, 0.38H, 1H Z), 6.31 (s, 0.62H, 1H E),
6.87-6.90 (m, 7H), 6.95-6.98 (m, 3H); 13C NMR (75 MHz, CDCl3, 20°C)
mixture of diastereoisomers δ 20.5, 21.0, 21.1, 21.2, 21.7, 22.1, 22.5,
25.0, 43.0, 44.2, 103.6, 107.0, 126.8, 127.0, 127.4, 127.5, 128.1, 128.2,
128.4, 128.5, 128.9, 132.7, 132.8, 133.1, 135.7, 136.7, 136.8, 137.9,
138.1, 143.6, 146.1, 146.5, 147.8, 169.9, 171.9, 190.1, 190.8; HRMS
(ESI) m/z: calculated for C23H22NO2 [M+H]+: 344.1652, found: 344.1654.
2-Benzyl-3-(2-oxocyclohexyl)-2,3,4,5,6,7-hexahydro-1H-isoindol-1-
one (13a): Prepared from hydroxy lactam 12 (0.25 mmol) and
cyclohexanone 3a (3 equiv) in acetonitrile following the general
procedure at 90°C with 1 mol % of Sn(NTf2)4.8DMSO. Reaction time: 24
h. The crude material was purified by flash chromatography on silica gel
(eluting with Cyclohexane/EtOAc = 70:30) to give the title compound as
colorless oil. Yield: 87 % (70 mg). The adduct was obtained as a mixture
of two diastereoisomers (d1/d2 = 68:32). Rf = 0.25 (cyclohexane/EtOAc:
70/30); IR (neat)  1728, 1672, 1160 cm-1; 1H NMR (300 MHz, CDCl3,
20°C) mixture of diastereoisomers δ 0.80-2.50 (m, 16.68 H), 2.63 (m,
0.32H, 1H d2), 4.33 (d, J = 15.4 Hz, 0.32H, 1H d2), 4.43 (d, J = 15.0 Hz,
0.68H, 1H d1), 4.58 (d, J = 15.0 Hz, 0.68H, 1H d1), 4.61 (s, 0.32H, 1H d2),
4.81 (s, 0.68H, 1H d1), 4.82 (d, J = 15.4 Hz, 0.32H, 1H d2), 7.18-7.40 (m,
4H); 13C NMR (75 MHz, CDCl3, 20°C) mixture of diastereoisomers δ 20.4,
20.5, 21.7, 21.9, 22.3, 23.1, 23.6, 24.1, 24.2, 25.0, 25.1, 25.6, 26.2, 41.6,
41.8, 44.2, 45.8, 48.8, 50.2, 60.8, 61.0, 127.0, 127.5, 127.8, 128.2, 128.7,
129.0, 132.7, 133.0, 137.8, 138.4, 152.5, 152.5, 172.2, 173.2, 209.6,
209.8; HRMS (ESI) m/z: calculated for C21H25NaNO2 [M+Na]+: 346.1783,
found: 346.1782.
(E)-2-Benzyl-3-(2-oxo-4-phenylbut-3-enyl)-2,3,4,5,6,7-hexahydro-1H-
isoindol-1-one (13f): Prepared from hydroxy lactam 12 (0.25 mmol) and
(E)-4-phenylbut-3-en-2-one 3f (3 equiv) in toluene following the general
procedure at 110°C with 1 mol % of Sn(NTf2)4.8DMSO. Reaction time: 18
h. The crude material was purified by flash chromatography on silica gel
(eluting with Cyclohexane/EtOAc = 70:30) to give the title compound as a
colorless oil. Yield: 49% (46 mg). Rf = 0.2 (cyclohexane/EtOAc: 70/30);
IR (neat)  1668, 1607, 1089, 730 cm-1; 1H NMR (300 MHz, CDCl3, 20°C)
δ 1.57-1.74 (m, 4H), 2.08-2.29 (m, 4H), 2.73 (dd, J = 6.0 and 16.9 Hz,
1H), 2.87 (dd, J = 6.0 and 16.9 Hz, 1H), 4.42 (d, J = 15.5 Hz, 1H), 4.51
(m, 1H), 4.81 (d, J = 15.4 Hz, 1H), 6.55 (d, J = 16.2 Hz, 1H), 7.11-7.58
(m, 11H); 13C NMR (75 MHz, CDCl3, 20°C) δ 20.4, 21.8, 22.2, 23.6, 41.8,
44.5, 58.6, 125.5, 127.3, 128.0, 128.4, 128.6, 129.0, 130.9, 131.6, 134.0,
137.8, 143.5, 154.0, 171.8, 196.8; HRMS (ESI) m/z: calculated for
C25H26NaNO2 [M+Na]+: 394.1783, found: 394.1782.
2-Benzyl-3-(2-oxocyclopentyl)-2,3,4,5,6,7-hexahydro-1H-isoindol-1-
one (13d): Prepared from hydroxy lactam 12 (0.25 mmol) and
cyclopentanone 3d (3 equiv) in acetonitrile following the general
procedure at 90°C with 1 mol % of Sn(NTf2)4.8DMSO. Reaction time: 24
h. The crude material was purified by flash chromatography on silica gel
(eluting with Cyclohexane/EtOAc = 70:30) to give the title compound as
colorless oil. Yield: 88 % (68 mg). The adduct was obtained as a mixture
of two diastereoisomers (d1/d2 = 52:48). Rf = 0.23 (cyclohexane/EtOAc:
70/30); IR (neat)  1733, 1670, 1408, 1160, 729 cm-1; 1H NMR (300
MHz, CDCl3, 20°C) mixture of diastereoisomers δ 0.88 (m, 0.48H, 1H d2),
1.07-2.44 (m, 11.04H), 2.61 (m, 0.48H, 1H d2), 4.16 (d, J = 8.0 Hz, 0.48H,
1H d2), 4.21 (d, J = 8.1 Hz, 0.52H, 1H d1), 4.35 (bs, 0.52H, 1H d1), 4.45
(bs, 0.48H, 1H d2), 4.60 (d, J = 15.3 Hz, 0.52H, 1H d1), 4.94 (d, J = 15.3
Hz, 0.48H, 1H d2), 7.19-7.35 (m, 5H); 13C NMR (75 MHz, CDCl3, 20°C)
mixture of diastereoisomers δ 20.0, 20.1, 20.3, 20.4, 21.4, 21.7, 21.8,
22.2, 22.2, 23.1, 23.1, 24.9, 38.0, 39.0, 43.9, 45.7, 49.1, 49.9, 61.3, 61.5,
127.2, 127.5, 127.9, 128.4, 128.5, 128.7, 132.2, 133.5, 137.5, 137.8,
151.2, 153.5, 171.5, 173.3, 218.2, 219.0; HRMS (ESI) m/z: calculated for
C20H24NO2 [M+H]+: 310.1813, found: 310.1815.
2-Benzyl-3-(2-oxopropyl)-2,3,4,5,6,7-hexahydro-1H-isoindol-1-one
(13i): Prepared from hydroxy lacatam 12 (0.25 mmol) and acetone 3i (3
equiv) in toluene following the general procedure at 110°C with 1 mol %
of Sn(NTf2)4.8DMSO. Reaction time: 3 h. The crude material was purified
by flash chromatography on silica gel (eluting with Cyclohexane/EtOAc =
70:30) to give the title compound as a white solid. Yield: 73 % (52 mg).
Rf = 0.25 (cyclohexane/EtOAc: 70/30); mp = 90°C; IR (neat)  1719,
1666, 1429, 1407, 737 cm-1; 1H NMR (300 MHz, CDCl3, 20°C) δ 1.60-
1.78 (m, 4H), 1.84 (s, 3H), 2.07-2.17 (m, 2H), 2.22-2.35 (m, 2H), 2.50
(dd, J = 6.3 and 18.2 Hz, 1H), 2.58 (dd, J = 5.6 and 18.0 Hz, 1H), 3.39 (t,
J = 6.0 Hz, 1H), 4.52 (d, J = 15.5 Hz, 1H), 4.64 (d, J = 15.5 Hz, 1H), 7.20-
7.33 (m, 5H); 13C NMR (75 MHz, CDCl3, 20°C) δ 20.3, 21.8, 22.2, 23.3,
30.2, 44.5, 44.6, 58.2, 127.2, 127.9, 128.6, 131.7, 138.1, 153.4, 171.7,
205.5; HRMS (ESI) m/z: calculated for C18H22NO2 [M+H]+: 284.1654,
found: 284.1655.
2-Benzyl-3-(1-methoxy-2-oxo-2-phenylethyl)-2,3,4,5,6,7-hexahydro-
1H-isoindol-1-one (13e): Prepared from hydroxy lactam 12 (0.25 mmol)
and 2-methoxyacetophenone 3e (3 equiv) in acetonitrile following the
general procedure at 50°C with 1 mol % of Sn(NTf2)4.8DMSO. Reaction
time: 5 h. The crude material was purified by flash chromatography on
silica gel (eluting with Cyclohexane/EtOAc = 70:30) to give the title
compound as a colorless oil. Yield: 50 % (47 mg). The adduct was
obtained as a single diastereoisomer. Rf = 0.20 (cyclohexane/EtOAc:
70/30); IR (neat) 1672, 1447, 1416, 1104, 727 cm-1; 1H NMR (300 MHz,
CDCl3, 20°C) δ 1.43-1.85 (m, 8H), 4.24 (t, J = 5.4 Hz, 1H), 4.31 (d,
J = 15.4 Hz, 1H), 4.84 (d, J = 2.3 Hz, 1H), 5.29 (d, J = 15.4 Hz, 1H), 7.30-
7.42 (m, 7H), 7.48-7.55 (m, 3H); 13C NMR (75 MHz, CDCl3, 20°C) δ 20.3,
21.3, 22.0, 24.2, 44.5, 58.7, 63.6, 81.5, 127.6, 127.8, 128.3, 128.8, 128.9,
1-Benzyl
3,3-dimethyl
2-(2-oxo-2,3-dihydro-1H-inden-1-
yl)pyrrolidine-1,3,3-tricarboxylate (15av): Prepared from 1-benzyl 3,3-
dimethyl 2-methoxypyrrolidine-1,3,3-tricarboxylate 14a (0.25 mmol) and
2-indanone 3v (3 equiv) in acetonitrile following the general procedure at
90°C with 1 mol % of Sn(NTf2)4.8DMSO. Reaction time: 6 h. The crude
material was purified by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 70:30) to give the title compound as a colorless oil.
Yield: 82 % (92 mg). The adduct was obtained as an inseparable mixture
of two diastereoisomers, the ratio of which could not be determined due
to complication of both 1H and 13C NMR spectra by the presence of
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700530
European Journal of Organic Chemistry
FULL PAPER
rotamers. Rf = 0.33 (cyclohexane/EtOAc: 70/30); IR (neat)  1734, 1695,
1409, 1265, 1217, 1111, 1070, 730 cm-1; 1H NMR (300 MHz, CDCl3,
20°C) mixture of diastereoisomers δ 2.36-3.18 (m, 3.74H), 3.18-3.90 (m,
9H), 4.47 (d, J = 12.1 Hz, 0.26H), 4.82-5.02 (m, 1H), 5.04-5.19 (m, 1H),
5.21-5.44 (m, 1H), 6.94-7.43 (m, 9H); 13C NMR (75 MHz, CDCl3, 20°C)
mixture of diastereoisomers δ 27.6, 27.8, 29.5, 31.0, 32.2, 37.1, 37.5,
37.8, 43.4, 43.5, 44.0, 44.3, 52.5, 52.7, 52.9, 53.0, 53.1, 53.4, 53.4, 54.2,
54.9, 56.0, 57.3, 61.2, 61.2, 61.7, 62.1, 62.5, 62.7, 63.2, 66.7, 66.9, 67.0,
67.3, 124.7, 124.8, 126.2, 126.5, 127.1, 127.4, 127.5, 127.6, 127.6,
127.7, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.3, 128.4,
128.4, 128.7, 129.5, 130.0, 130.1, 133.7, 133.8, 135.9, 136.6, 137.8,
138.3, 154.2, 154.3, 154.4, 167.5, 167.9, 170.0, 170.2, 210.2, 210.4,
214.4, 214.9; HRMS (ESI) m/z: calculated for C25H26NO7 [M+H]+:
452.1722, found: 452.1722.
[3]
[4]
For reviews and features articles: a) P. Melchiorre, Angew. Chem. Int.
Ed. 2009, 48, 1360; Angew. Chem. 2009, 121, 1386. b) A. Gualandi, P.
G. Cozzi, Synlett, 2013, 281. c) D. M. Hodgson, A. Charlton,
Tetrahedron, 2014, 70, 2207.
For asymmetric organocatalytic SN2 α-alkylations of aldehydes: B. List,
I. Čorić, O. O. Grygorenko, P. S. J. Kaib, I. Komarov, A. Lee, M.
Leutzsch, S. Chandra Pan, A. V. Tymtsunik, M. van Gemmeren, Angew.
Chem. Int. Ed. 2014, 53, 282; Angew. Chem. 2014, 126, 286 and
references cited therein.
[5]
For selected key examples of asymmetric organocatalytic SN1
α-alkylations of aldehydes, see: a) R. R. Shaikh, A. Mazzanti, M. Petrini,
G. Bartoli, P. Melchiorre, Angew. Chem. Int. Ed. 2008, 47, 8707; Angew.
Chem. 2008, 120, 8835. b) P.-G. Cozzi, F. Benfatti, L. Zoli, Angew.
Chem. Int. Ed. 2009, 48, 1313; Angew. Chem. 2009, 121, 1339. c) A.
R. Brown, W.-H. Kuo, E. N. Jacobsen, J. Am. Chem. Soc. 2010, 132,
9286. d) B. Xu, Z. –L. Guo, W.-Y. Jin, Z.-P. Wang, Y.-G. Peng, Q.-X.
Guo,; Angew. Chem. Int. Ed. 2012, 51, 1059; Angew. Chem. 2012, 124,
1083.
Trimethyl
2-(2-oxo-1,2,3,4-tetrahydronaphthalen-1-yl)pyrrolidine-
(15bw): Prepared from trimethyl 2-
1,3,3-tricarboxylate
methoxypyrrolidine-1,3,3-tricarboxylate 14b (0.25 mmol) and 2-tetralone
3w (3 equiv) in acetonitrile following the general procedure at 90°C with 1
mol % of Sn(NTf2)4.8DMSO. Reaction time: 6 h. The crude material was
purified by flash chromatography on silica gel (eluting with
Cyclohexane/EtOAc = 70:30) to give the title compound as colorless oil.
Yield: 72 % (70 mg). The adduct was obtained as an inseparable mixture
of two diastereoisomers, the ratio of which could not be determined due
to complication of both 1H and 13C NMR spectra by the presence of
rotamers. Rf = 0.2 (cyclohexane/EtOAc: 70/30); IR (neat) 1734, 1702,
1449, 1385, 1019, 1176, 729 cm-1; 1H NMR (300 MHz, CDCl3, 20°C)
mixture of diastereoisomers δ 2.11-3.06 (m, 5H), 3.07-3.87 (m, 13H),
5.18 (m, 0.72H), 5.31 (m, 0.28H), 6.94-7.18 (m, 4H); 13C NMR (75 MHz,
CDCl3, 20°C) mixture of diastereoisomers δ 27.6, 27.9, 29.5, 30.1, 31.1,
37.3, 37.5, 37.9, 42.6, 43.4, 43.4, 52.3, 52.5, 52.7, 52.8, 52.9, 53.4, 53.4,
54.5, 56.0, 57.4, 61.1, 61.6, 61.9, 62.0, 62.4, 63.1, 63.4, 100.0, 126.1,
126.2, 126.6, 127.3, 127.6, 127.7, 127.8, 127.9, 128.4, 129.3, 130.0,
130.2, 133.7, 133.8, 137.8, 138.2, 138.9, 154.8, 154.9, 155.4, 167.4,
167.5, 168.0, 170.0, 170.3, 209.8, 210.2, 210.3; HRMS (ESI) m/z:
calculated for C20H23NaNO7 [M+Na]+: 412.1372, found: 412.1380.
[6]
For some examples of asymmetric organocatalytic SN1 α-alkylations of
aldehydes involving stable carbenium ions: a) A. Gualandi, E. Emer,
M. G. Capdevila, P. G. Cozzi, Angew. Chem. Int. Ed. 2011, 50, 7842;
Angew. Chem. 2011, 123, 7988. b) A. Gualandi, D. Petruzziello, E.
Emer, P. G. Cozzi, Chem. Commun. 2012, 3614. For a cascade
reaction including an organocatalytic stereoselective SN1 α-alkylation,
see: c) J. Stiller, A. J. Vorholt, K. A. Ostrowski, A. Behr, M. Christmann,
Chem. Eur. J. 2012, 18, 9496.
[7]
[8]
For selected key examples of asymmetric dual-catalytic α-alkylation of
aldehydes, see: a) A. Gualandi, L. Mengozzi, C. M. Wilson, P. G. Cozzi,
Synthesis 2014, 1321. b) M. G. Capdevila, F. Benfatti, L. Zoli, M. Stenta,
P. G. Cozzi, Chem. Eur. J. 2010, 16, 11237. c) K. Motoyama, M. Ikeda,
Y. Miyake, Y. Nishibayashi, Eur. J. Org. Chem. 2011, 2239.
For selected key examples of dual-catalytic α-allylation of aldehydes
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B.T. and M.S.A. are grateful to the Tunisian government for
scholarships. A. E. B. thanks the University of Le Havre for an
ATER position. Dr Radouane Affani and Ms Nabawia Mechi are
acknowledged for their contribution at the early stage of this
study. We are grateful to Dr Nicolas Hucher and Ms Marie-José
Tranchant for their analytical assistance.
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Keywords: Direct SN1 α-amidoalkylation • Lewis superacid
catalysis • N,O-acetals • Enolisable ketones
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10.1002/ejoc.201700530
European Journal of Organic Chemistry
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[18] Scheme 1 shows simplified pictures of our two reactivity scales which
are fully presented in the SI.
[19] It is worth noting that, for a given combination of substrate and ketone,
no significant differences in terms of diastereoselectivity were observed
between the room-temperature and thermal experiments.
[20] A lot more examples involving more favorable combinations of reaction
partners, that are ketones and phthalimide-derived N,O-acetals
identified as more reactive than the compounds used in table 2 (see
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corresponding coupled products in high yields.
[21] 10 equivalents of acetone were used in this case to prevent incomplete
conversion due to possible loss of acetone by evaporation in refluxing
toluene.
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Lewis superacid catalysis*
B. Touati, A. El Bouakher, M. S. Azizi,
C. Taillier, R. Ben Othman, M. Trabelsi-
Ayadi, S. Antoniotti, E. Duñach, V. Dalla*
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Atom Economical Catalytic Direct
Substitution of N,O-Acetals with
Simple Ketones
A general and powerful catalytic protocol for the direct amidoalkylation of simple enolisable ketones is described using the super
Lewis acid Sn(NTf2)4 as catalyst. The synthetic potential of the reaction was demonstrated through the coupling of a large set of both
carbonyl and N,O-acetalic substrates (mostly the simplest OH-hemi aminals), with very low catalyst loadings (≤ 1 mol%), providing
the corresponding amidoalkylated ketones in high yields (up to 99%).
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