Intra- and intermolecular alkylation of N, O-acetals and π-activated alcohols catalyzed by in situ generated acid

Article abstract of DOI:10.1021/jo4015886

Intramolecular and intermolecular alkylations of carbocation precursors of limited ionization ability, principally N,O-acetals, without the use of an exogenous reagent have been developed. The reactions are carried out in 1,1,2,2-tetrachloroethane (TCE) a

Full text of DOI:10.1021/jo4015886

Article
pubs.acs.org/joc
Intra- and Intermolecular Alkylation of N,O‑Acetals and π‑Activated
Alcohols Catalyzed by in Situ Generated Acid
Melanie Hamon,† Niall Dickinson,‡ Alice Devineau,† David Bolien,§ Marie-Jose Tranchant,†
́
́
Catherine Taillier,† Ivan Jabin,∥ David C. Harrowven,§ Richard J. Whitby,§ A. Ganesan,‡
and Vincent Dalla*,†
†Unite
́ ́ ́ ́
de Recherche en Chimie Organique et Macromoleculaire, Faculte des Sciences et Techniques de l’Universite du Havre, EA
3221, FR CNRS 3038, 25 rue Philippe Lebon, BP 540, 76058 Le Havre cedex, France
‡School of Pharmacy, University of East Anglia, Norwich NR4 7TJ, United Kingdom
§Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, United Kingdom
∥Laboratoire de Chimie Organique, Universite
Belgium
́
Libre de Bruxelles (ULB), Av. F. D. Roosevelt 50, CP160/06, B-1050 Brussels,
S
* Supporting Information
ABSTRACT: Intramolecular and intermolecular alkylations of carboca-
tion precursors of limited ionization ability, principally N,O-acetals,
without the use of an exogenous reagent have been developed. The
reactions are carried out in 1,1,2,2-tetrachloroethane (TCE) and take
advantage of the ability of this solvent to continuously release small
amounts of HCl by thermolytic elimination. A study of the reaction led to
several improved protocols such as (1) preheated TCE, (2) microwave-
assisted reactions, and (3) flow or sealed-tube conditions, which allow
significant reaction rate enhancements and made possible some
challenging reactions such as the α-amidoalkylation of ketones. Studies using flow chemistry confirmed not only that very
low concentrations of HCl generated from the solvent were responsible for the reactivity but also that TCE had additional
beneficial properties in comparison to other chlorinated solvents such as dichloroethane. The method can easily be extended to
the alkylation using proelectrophiles such as π-activated alcohols, which are normally unreactive toward HCl catalysis. This work
represents the first successful use of HCl, the simplest strong Brønsted acid, as an efficient alkylation catalyst.
provide useful α-functionalized amino compounds.8 Despite
INTRODUCTION
■
their widespread use and many synthetic applications, it is
remarkable to note that catalytic N-acyliminium ion chemistry
has been rather neglected, and the use of stoichiometric or even
an excess amount of an acidic reagent is routine. In this context,
the best combination of promoter and solvent for a particular
reaction often has to be screened in a time-consuming manner.
As far as (super)stoichiometric amounts of strong Lewis acids
(TMSOTf, BF3·OEt2, TiCl4, SnCl4, ...) are concerned, the
quality of these air- and moisture-sensitive reagents also
becomes critical, and it is frequently required to distill them
just prior to use. It is also worth noting that these methods
generate a large aqueous waste stream during workup. Recently,
we have reported that such reactions can nevertheless be
achieved with very high catalytic and chemical efficiencies using
superacidic reagents,9−11 such as Sn(NTf2)4.9d,12
Carbocations are ubiquitous reactive intermediates in organic
synthesis that readily participate in SN1-type alkylation
reactions.1 One common method for the generation of
carbocations is by loss of a leaving group attached to carbon,
and this can be assisted by protonation or metalation as in the
case of alcohols and their derivatives. Over the past decade,
many different catalytic systems based on the use of Lewis and
Brønsted acids for this activation mode have been reported,
therefore considerably improving the value of cationic
chemistry.2,3 While highly stabilized carbenium ions4 can be
generated under extremely mild conditions, for example simply
using hot water5 or fluorinated alcohols as both solvents and
promoters,6,7 highly reactive carbocations4 need to be
generated from alcohol derivatives with markedly reduced
polarizability, and therefore much stronger acidic promoters
(and/or greater amounts of them) are required. This trend
generally follows Mayr’s scale: i.e., the strength and/or load of
the catalyst grow as the E parameter of the cations increases. N-
Acyliminium ions are prototypical examples of such highly
reactive carbocations. Their C−C bond forming reactions with
carbon nucleophiles upon acidic activation of N,O-acetals
represent an important field of research in organic chemistry to
The aim of this study was to develop an experimentally
simple and robust protocol for performing α-amidoalkylation of
diverse carbon nucleophiles with the hope of extension to the
Received: August 2, 2013
Published: February 17, 2014
© 2014 American Chemical Society
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Scheme 1. Two Typical Approaches for the α-Amidoalkylation of Weak Carbon Nucleophiles and Our New Method
alkylation of related proelectrophiles such as, for example, π-
activated alcohols.2
Table 1. Thermal Cyclization of N,O-Acetals Tethered to an
Arene Nucleus in TCE
Our procedure is based on the use of 1,1,2,2-tetrachloro-
ethane (TCE) as a solvent, which serves to generate trace
amounts of HCl by thermolytic elimination. The mechanisms
and kinetics of decomposition of TCE to generate HCl were
investigated by Barton at temperatures above 263 °C.13 We
reasoned that release should still occur at significantly lower
temperatures and provide very low levels of anhydrous HCl in
the reaction solution. As opposed to the commercially available
solutions of HCl which are supplied in hydrogen-bond acceptor
solvents,14 this in situ generated “free” HCl is expected to be
significantly more active, while avoiding the need for dealing
with gaseous HCl15 and also preserving compatibility with the
range of neutral carbon nucleophiles commonly used in
alkylative chemistry.2−11 If these assumptions were confirmed,
efficient catalytic alkylation methods could be developed
through successful use of one of the simplest acid catalysts,
HCl. To the best of our knowledge, HCl has not been
demonstrated as an efficient catalyst in SN1-type alkylation
involving N-acyliminium ions, while other common Brønsted
acids such as PTSA and TFA are typically used in super-
stoichiometric amounts for such reactions.
Herein we report the efficient SN1 alkylation of N-
acyliminium ions and other relatively electrophilic π-stabilized
cations in TCE solvent in the absence of exogenous acidic
activators. We acknowledge the toxicity associated with this
solvent16 but believe this can be compensated by the
advantages of the method (Scheme 1).
RESULTS AND DISCUSSION
■
The intramolecular Friedel−Crafts type cyclization of N,O-
acetals tethered to an arene nucleus is a major subtheme in N-
acyliminium ion chemistry, and some efficient catalytic
examples have been recently reported.8a,b,9c,d,10d,e,11a,c We
therefore decided to focus our initial effort on this reaction
type (Table 1). We were delighted that our working hypothesis
was immediately rewarded with the observation of a fast and
clean reaction of the model substrate 1A in refluxing TCE
(entry 1). For comparison, thermal reactions in other high-
boiling-point solvents such as xylene and dioxane, which are not
able to generate HCl, expectedly gave much slower kinetics for
substrate 1A (see footnote a in Table 1) and either
decomposition or no conversion particularly when the less
favorable cyclizations were attempted (viz. 1C and 1H).
a
The cyclization of IA was completed in 4 h and gave >95% yield when
b
carried out in xylene at 138 °C. No cyclization took place in boiling
xylene. A single stereoisomer was isolated.
c
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Delightfully, the less activated iminoacyl cation precursor
hydroxy lactam IB bearing only one methoxy substituent on the
nucleophilic aryl group could also be converted to the product
in good yield in refluxing TCE (entry 2). The facile cyclization
of the less robust succinimide derivative IC in comparison to
phthalimide nicely exemplifies the synthetic applicability of the
method (entry 3).
Table 2. Thermal Intermolecular α-Amidoalkylation of
Neutral C-Nucleophiles with 2-Acetoxy Lactams IIIA−IIIG
Careful monitoring of this reaction by 1H NMR spectroscopy
revealed that the transformation was a dehydrative process
which produced the α,β-unsaturated pyrrolidinone A (Scheme
2) as the first detectable species, which presumably arises from
Scheme 2. Dehydrative Cyclization Pathway of Succinimide
Hydroxy Lactam IC
isomerization of enamide B, in turn generated by proton loss
from the reactive N-acyliminium ion C.17 Under our reaction
conditions A−C are in equilibrium via an acid-catalyzed
process, with C cyclizing to the product IIC.13,18
The ability of the TCE method to further activate and
alkylate the α,β-unsaturated pyrrolidone may offer a practical
solution for certain amidoalkylation reactions which stop at the
stage of the α,β-unsaturated pyrrolidinone under an ordinary
catalytic regime.10e The homologous substrate ID with a propyl
linker performed nicely in this cyclization to give the desired
seven-membered-ring tricyclic product IID in high yield (Table
1, entry 4). These thermal conditions can also accommodate
stereogenicity close to the reaction center, as exemplified by the
successful amidoalkylation of IE, producing IIE in high yield and
with complete stereocontrol (entry 5). The reaction scope of
the method was further broadened with the cyclization of the
tertiary hydroxyl lactams IF−IH (entries 6−8). Cyclization of
the methyl-substituted substrate IH was shown to proceed by a
dehydrative pathway similarly to the cyclization of Ic with, first,
generation of a transient exocyclic enamide intermediate which
then underwent acid-catalyzed cyclization. Furthermore, this
cyclization protocol was also efficient for substrates II and IJ
with a thiophene nucleophile (entries 9 and 10).
With these excellent preliminary results in hand, we next
queried whether an effective intermolecular α-amidoalkylation
variant could be implemented as well. As Table 2 shows
(entries 1−7), using the optimized conditions allowed
incorporation of a range of neutral nucleophiles NuH with
the model N-allyl acetate IIIA. In this intermolecular variant,
IIIA was much more reactive than the parent hydroxy lactam,
which reacted sluggishly with acetylacetone to give after 60 h in
refluxing TCE compound IVA with incomplete conversion and
an isolated 77% yield (result not shown). Acetylacetone
appeared to be more reactive than dibenzoylmethane under
these thermal conditions (entry 1 vs 2), an observation which
a
b
Isolated as a 1:1 ratio of stereoisomers. 3 equiv of cyclohexanone
c
d
was used. Isolated as a 2:1 ratio of stereoisomers. 1.5 equiv of
nucleophile was used.
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contrasts with the usual trend observed in acid-catalyzed
alkylative chemistry.19
obtained in every case (entries 8−18). Unfortunately, such an
effect was not observed with lower boiling chlorinated solvents,
since no conversion could be seen when IB was exposed at 80
°C in preheated dichloroethane (DCE) and chloroform.
Similarly, the reactivity profile and reaction scope of the
intermolecular couplings were significantly broadened, both in
terms of reaction rate and yield, using both preheated TCE and
microwave irradiation (Table 4), the latter method particularly
Successful creation of a quaternary center (Table 2, entry 3)
and achievement of a challenging direct alkylation of cyclo-
hexanone (entry 4) under these TCE conditions demonstrate
the remarkable effectiveness of our method. Highly nucleophilic
π-heteroaromatics gave products IVE and IVF rapidly in good
yields (entries 5 and 6), while the rather sensitive 2-
methylfuran gave IVG in a moderate yield probably due to
decomposition (entry 7). A variety of alkyl groups on the
nitrogen, including unsaturated cases, were well tolerated in this
new α-amidoalkylation protocol, producing the desired adducts
VA−VG in high yields (entries 8−14).
Table 4. Preheating of TCE and Microwave Irradiation as
b
Tools for Efficient Intermolecular Alkylation
Given the hypothesis that HCl generated by the decom-
position of the solvent was the active catalyst, we attempted the
cyclization of IA using preheated (overnight) TCE. Under those
conditions, IIA was formed in about 5 min and isolated in 88%
yield (Table 3, entry 2), while 1 h was originally required to
Table 3. Preheating of TCE and Microwave Irradiation as
a
Tools for Efficient Intramolecular Alkylation
b
c
entry
substrate
method
time
product
yield (%)
1
IA
standard
1 h
IIA
99
88
a
b
2
A
5 min
30 min
4 h
Isolated yield. Definition of methods: standard, TCE, 147 °C; A,
3
B
>99
76
preheated TCE, 147 °C; B, TCE, 147 °C, microwave 300 W.
4
IB
standard
A
IIB
5
5 min
14 h
79
d
giving spectacular improvements (entries 4 and 7). The
reactions of IIIA and its parent hydroxyl IIIA′ with cyclo-
hexanone and acetylacetone are given here as representative
examples. These outstanding effects exhibited by either method
even enabled implementation of the more atom-economical yet
challenging intermolecular α-amidoalkylation of hydroxy
lactams,22 which were beyond our reach with the initial
protocol (Table 2). The yields of products for the couplings
performed throughout this study are globally very high and, as
far as we can compare, quite similar to those we previously
obtained by using Brønsted and Lewis superacid catalysts,9b,d
and this attests to the value of our TCE method.
A series of control experiments using optically pure
substrates were run to demonstrate if a cationic (SN1) type
mechanism proceeding via generation of an N-acyliminium ion
intermediate is involved as anticipated. In order to check this
mechanistic hypothesis, we tested reactions using optically
active hydroxy lactams (S)-IIIA′ and (S)-IA, which were
obtained by chiral semipreparative HPLC.23 When intra- and
intermolecular reactions using these enantiopure hydroxy
lactams (S)-IIIA′ and (S)-IA were performed under the standard
conditions (TCE, 147 °C), only racemic products were
obtained, unambiguously supporting a SN1-type mechanism
for both intramolecular and intermolecular reactions (Scheme
3).
6
A
90
7
B
55 min
72 h
>99
65
8
IH
IC
ID
standard
IIH
IIC
IID
9
A
2 h
>99
84
10
11
12
13
14
15
16
17
18
standard
2 h
B
40 min
1 h 45 min
25 min
1 h
>99
96
standard
A
96
B
97
II
standard
1 h
III
>99
>99
90
B
35 min
1 h
IE
standard
B
IIE
35 min
>99
a
Definitions of methods: standard, TCE, 147 °C; A, preheated TCE,
147 °C; B, TCE, 147 °C, microwave 300 W. The structures of
substrates IA‑E and products IIA‑E can be seen in Table 1. Isolated
yield. Reaction conducted at 80 °C.
b
c
d
reach full conversion (entry 1). With the aim of improving our
original protocol, we have also developed conditions using
microwave irradiation (entry 3), providing cyclized product IIA
within 30 min in quantitative manner.
Reduced reaction times were also observed for cyclization of
the monomethoxy analogue IB (Table 3, entries 4−7) using any
of these improved procedures. Remarkably, it was also shown
that successful cyclization of IB could be performed at
temperatures as low as 80 °C (entry 6).20,21 A number of the
cyclizations that proceeded with slow rates under the standard
protocol were then repeated using these methods, and a
significant and uniform diminution of the reaction times was
Flow chemistry represents a tremendous technological
advancement in contemporary organic synthesis.24 In partic-
ular, high temperatures and pressures are easily handled, and we
surmised there could be some opportunities to extend this TCE
chemistry by flow.25 We have then briefly investigated the
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temperatures (Figure 1), which demonstrated a rapid increase
in conversion with temperature. Preheating part of the solvent
(170 °C, 40 min) before combining with the reaction solution
dramatically increased the rate of reaction, e.g. complete
conversion at 100 °C versus almost no conversion without
(Figure 1), confirming the importance of catalyst generation
from the solvent.
Scheme 3. Control Experiments using Optically Active
Hydroxy Lactams (S)-IIIA′ and (S)-IA
We next wished to quantify the amount of HCl generated.
For this purpose, TCE was passed through a stainless steel
column at various temperatures with a 10 min reaction time
and then directly transferred into a solution of KCl in deionized
water and the resulting decrease in pH was measured. The
result allowed us to calculate the concentration of H+ generated
in the TCE at each temperature, and a plot of −log [H+] vs
temperature is given in Figure 2. It should be noted that at
thermal cyclization of IA under flow chemistry conditions. We
were delighted to observe clean and rapid formation of IIA at
160 °C with a 10 min reaction time, in a perfluoroalkyloxy
polymer (PFA) column, as evidenced by inspection of the
1
crude product mixtures by H NMR spectroscopy and good
isolated yield (94%) on a 0.1 g scale. Under flow conditions the
reaction is significantly faster than the regular thermal reaction
at the same temperature: for example, on occasion (see below)
90% conversion was reached at 120 °C after 30 min, whereas
the regular thermal reaction gave little product. A similar effect
was observed in the microwave experiments (see Tables 3 and
4). A reasonable explanation is that in our initial TCE reactions
at reflux much of the HCl formed is likely to be driven out of
the reaction mixture, whereas under flow and microwave
conditions it is retained in the reaction vessel.26
Apart from its interest for implementing clean chemistry,
flow chemistry also represents a practical means for optimizing
reactions and performing kinetic studies. With a fixed reaction
time of 20 min we measured conversions of IA at various
Figure 2. Concentration of HCl generated by heating TCE at various
temperatures for 10 min under flow conditions.
higher temperatures (>170 °C) there was evidence for attack
on the stainless steel columnthe emitted TCE was yellow,
and significant amounts of a brown product were emitted from
the column on subsequent aqueous washing. We repeated the
runs up to 170 °C using a PFA reactor and obtained very
Figure 1. Conversion of IA to IIA with and without preheating of solvent.
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Figure 3. Catalysis of cyclization of IA to IIA using added HCl in TCE and DCE at 100 °C for 20 min under flow conditions.
similar results, indicating that catalysis by iron salts is
unimportant, at least up to this temperature. A notable feature
of the HCl generation from TCE is the exponential increase in
rate with temperature, as indicated by the approximately linear
relationship between temperature and the logarithm of the
amount of H+ formed. In comparison, Barton observed first-
order kinetics, after an induction period, in the temperature
range 263−382 °C for this decomposition.13 The extent of HCl
formation we observe after 10 min at 250 °C is approximately
half that expected from the kinetic data Barton reported at 263
°C, which is in reasonable agreement. The particular success of
the microwave procedures may be related to the formation of
locally superheated hot spots and hence rapid HCl generation.
For reaction under flow at 160 °C with a 20 min reaction time
(Figure 1), we can estimate the average concentration of HCl
generated as 2.6 × 10−6 M, corresponding to approximately
0.023 mol %. For the reactions reported in Tables 1−3 (147
°C) we can estimate the [HCl] generated after 1 h to be 5.5 ×
10−6 M, corresponding to about 0.005 mol %, if we assume that
all remains in solution. For the “preheated” TCE experiments
under flow conditions (Figure 1) we can estimate that the
concentration of HCl generated is 11 × 10−6 M and
corresponds to nearly 0.20 mol %, a sufficient level to enable
complete conversion in 20 min at 100 °C (Figure 1). To
confirm that the effect was due to HCl generation, we prepared
solutions with known concentrations of HCl in TCE and 1,2-
dichloroethane (DCE) and examined the effect on conversion
of IA to IIA at 100 °C (Figure 3). The results show that 6 μM
HCl in TCE (corresponding to 0.05 mol % of HCl in these
experiments) is sufficient to give complete conversion at 100
°Ca concentration similar to that which we calculated was
generated by preheating the TCE above, supporting that HCl is
the catalyst. At this juncture, it is worth pointing out that the
catalytic efficiency of this TCE method is outstanding. HCl in
DCE catalyzes the cyclization, but only 50% conversion is
reached using a 6 μM concentration of HCl, in comparison to
almost complete conversion in TCE, showing that DCE is a
less efficient solvent than TCE when the concentrations of HCl
are the same. Note that at 100 °C we would not expect
significant HCl generation from TCE.
Next, a set of batch experiments was carried out to further
characterize the method (Table 5). Carrying out the intra-
Table 5. Intra- and Intermolecular Alkylations of Hydroxy
Lactams IB and IIIA′ in Sealed Tubes
a
entry substrate
method
product/substrate ratio
b
1
IB
147 °C, 4 h, open air
147 °C, 1 h, open air
147 °C, 1 h, open air
147 °C, 1 h, sealed tube
147 °C, 1 h, sealed tube
147 °C, 55 min, microwave
147 °C, 60 h, open air
147 °C, 6 h, sealed tube
147 °C, 17 h, sealed tube
147 °C, 0.5 h, microwave
IIB/IB > 99/1 (76)
2
IIB/IB 40/60
IIB/IB 40/60
IIB/IB > 99/1
IIB/IB > 99/1
IIB/IB > 99/1
c
3
4
c
5
6
b
7
IIIA′
IVA/IIIA′ 85/15 (77)
IVA/IIIA′ 62/38
8
9
IVA/IIIA′ > 99/1
10
IVA/IIIA′ > 99/1
a
1
The product/substrate ratio was determined by H NMR spectros-
b
copy on the crude reaction mixture. Isolated yields are given in
parentheses. Reaction done in the presence of 1 equiv of water added
c
on purpose.
molecular Friedel−Crafts reaction of IB in sealed tubes27 gave
much faster reactions than their open-air variants (entry 4 vs 2),
confirming that HCl escape from the latter conditions slows the
reaction. The effect of using a sealed tube was also apparent in
the intermolecular coupling affording IVA (entry 7 vs 8), but in
contrast to the cyclization of IB, the net result was inferior to
the microwave experiment (entry 8 vs 10). However,
prolonging the reaction as depicted in entry 9 allowed the
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reaction to reach completion in a reasonable (nonoptimized)
period of time. The sealed-tube conditions thus provide a
convenient way to carry out the reactions (or to improve their
performances) when microwave or flow equipment is not
available. Water is continuously released in the medium as the
reaction is progressing, and it was interesting to investigate its
effect on the reaction outcome. Reactions started in the
presence of 1 equiv of water led to results identical with those
of anhydrous reactions in either open or sealed systems (Table
5, entries 3 and 5), demonstrating that water does not affect the
cyclization.
Given that HCl is usually recognized as a poor alkylation
catalyst in SN1 reactions, the excellent catalytic performance
systematically observed throughout this study is probably due
to the constant in situ generation of anhydrous HCl together
with the particular benefits of TCE as a medium for efficient
electrophilic catalysis.28 To gain a better understanding of the
different roles played by TCE (and particularly as a reaction
medium), use of a commercially available 4 N solution of dry
HCl in dioxane to catalyze either cyclization of hydroxy lactam
IB or alkylation of acetoxy lactam IIIA with acetylacetone in
refluxing xylene and TCE was examined (Table 6).
provider of dry HCl and has a very important impact on this
alkylative method. The fact that a similar reaction executed in
DCE (80 °C, 14 h) remained far from completion (63%
conversion) is consistent with observations under flow
conditions (Figure 3) and further reinforces the particular
advantage of TCE.
Use of exogenous HCl also demonstrated limited efficacy in
the intermolecular coupling of IIIA with 2,4-pentanedione. The
alkylation failed in boiling xylene whatever the amount of HCl
used, and the parent phthalimide, presumably formed from IIIA
following a hydrolysis/dehydrogenation sequence, was returned
as the major product. Repeating this reaction in refluxing TCE
(5 mol % HCl) for 7 h also turned out to be beneficial and
returned the desired product IVA cleanly in excellent
conversion (90%), again mimicking the conditions of the
TCE method (but once more in a less efficient manner). In
addition to lending additional credence to the benefits of TCE
as a solvent, these results demonstrate that the combination of
HCl in boiling xylene, but not the source of HCl employed
herein, is responsible for the decomposition of IIIA into
phthalimide.
Overall, these comparative experiments exemplify that
heating TCE is a useful way of continuously generating trace
amounts of a “highly active” source of HCl. In addition, they
show that the superiority of the TCE reactions also results from
its particular features as a solvent. At this stage, the exact nature
of such effects remained to be ascertained, but N-acyliminium
stabilization by the inherent Lewis basicity of the solvent
chlorine atoms could possibly be one explanation. Chloride
abstraction, very well-known in cationic chemistry performed in
chlorinated solvents, might even be involved.30 This would lead
to a transient α-chloro lactam which is known to be highly
prone to ionization.11a,b In this context, the apparent superiority
of TCE over DCE in reactions that were supposed to perform
equally well in either solvent (see Figure 3 and Table 6) is
noteworthy.
Table 6. Use of Exogenous HCl
As many organic reactions are promoted by Brønsted acid
catalysis, this method is expected to have utility in many more
situations beyond the iminium ion chemistry reported here. As
a preliminary effort into this direction, we questioned whether
our methodology could also encompass π-activated alco-
hols.2−4,6 We were delighted to observe that the alcohols
VIA−VID reacted successfully with β-diketones in our thermal
alkylative method, giving the desired alkylated products in
excellent yields (Table 7).
To summarize, we have described a novel and highly efficient
α-amidoalkylation catalyzed by very low levels of HCl
generated in situ from the solvent 1,1,2,2-tetrachloroethane.
Recognition of the importance of in situ generated acid led to
markedly improved protocols, which allowed both considerable
rate enhancements and higher applicability. The reaction works
in both an intramolecular and intermolecular fashion with
broad scope in terms of nucleophilic partners, and its
mechanism has been demonstrated to be SN1 under all
circumstances. The known toxicity of TCE is a disadvantage we
acknowledge, but its exquisite reactivity and simplicity of
reaction procedure make its use worthwhile, particularly for
small-scale reactions. This work represents the first successful
use of HCl, the simplest strong Brønsted acid, as an alkylation
catalyst and suggests an interesting new direction in cationic
chemistry.31 It can be applied to π-activated alcohol derivatives
and might be easily extended to other robust N,O-acetal
The intramolecular reaction in xylene gave poor yields after 4
h
29 (≤22% due to lack of conversion at catalyst loadings up to 5
mol % or extensive decomposition when 10−40 mol % of HCl
was used).
Repeating the experiment at 5 mol % loading in a sealed tube
proved beneficial, as already indicated (see Table 5), with about
50% conversion and little decomposition observed; however,
the performance of this reaction remained far below that of the
reaction in TCE (see results in Tables 1, 3, and 5 for
comparison), although the latter contains a much smaller
amount of HCl (see Figures 2 and 3 and comments thereof).
On simple replacement of xylene by TCE, the reaction
proceeded cleanly and gave 50% conversion within 5 min at
147 °C and, as previously noted using preheated TCE, reached
completion after 14 h at 80 °C (compare with entries 5 and 6 in
Table 3, respectively). This set of comparative results
demonstrates that 5 mol % exogenous HCl in solution is an
acceptable mimic of preheated TCE but, more importantly,
provides compelling evidence that TCE is more than a simple
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Table 7. Extension of the Thermal Alkylation Approach to the Alkylation of π Alcohols
residue was purified by column chromatography on silica gel to afford
the corresponding cyclized product.
systems and to any acid-catalyzed transformation beyond
iminium ion chemistry.
2,3-Dimethoxy-5,6-dihydroisoindolo[1,2-a]isoquinolin-8(12bH)-
one (IIA). Prepared from hydroxy lactam IA following the general
procedure (reaction time 1 h). Purification by flash chromatography
on silica gel (eluting with DCM/AcOEt 9/1) to give the title
compound as a white solid (88% yield). 1H NMR (300 MHz, CDCl3,
293 K): δ 7.86 (d, J = 12.6 Hz, 1H), 7.83 (d, J = 12.6 Hz, 1H), 7.60 (t,
J = 7.2 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.11 (s, 1H), 6.65 (s, 1H),
5.62 (s, 1H), 4.52−4.44 (m, 1H), 3.92 (s, 3H), 3.84 (s, 3H), 3.46−
3.37 (m, 1H), 3.05 (m, 1H), 2.84 (dt, J = 15.6 Hz, 3.9 Hz, 1H). Data
are in accordance with previously reported results.32
EXPERIMENTAL SECTION
■
All reactions were carried out in an air atmosphere in oven-dried
glassware with magnetic stirring except where stated. Xylene and
toluene were distilled over CaH2. Analytical grade 1,1,2,2-tetrachloro-
ethane and dichloroethane were used without distillation in the flow
experiments, and dichloroethane was distilled over CaH2 prior to use
in the batch reactions. 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 staining
with a solution of p-anisaldehyde, followed by heat. Flash column
chromatography was performed using silica gel 60 (particle size
0.040−0.063 mm). 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 broad-band proton
decoupling, and chemical shifts are reported in ppm using residual
solvent peaks as reference (CHCl3: δ 77.20). Carbon multiplicities
were assigned by DEPT techniques. High-resolution mass spectra were
recorded on a Q-TOF instrument, which was operated under the
following conditions: ion source ESI+ or APCI, both in positive
ionization mode. Melting points were measured using open capillary
tubes and are uncorrected. GC-MS measurements were recorded on a
mass spectrometer coupled with a gas chromatograph. Enantiomeric
excesses were determined on an analytical HPLC using Daicel
Chiralpak IA, IB, or IC columns. Microwave reactions were performed
using 10 mL reaction vessels, and the reaction mixture temperatures
were measured with an external heating sensor. The reactions were
carried out at a constant temperature of 147 °C, which was reached
within 1 min. Flow chemistry was performed in a Vaportec R2/R4+
reaction system. All of the known products were confirmed by
3-Methoxy-5,6-dihydroisoindolo[1,2-a]isoquinolin-8(12bH)-one
(IIB). Prepared from hydroxy lactam IB following the general procedure
(reaction time 4 h). Purification by flash chromatography on silica gel
(eluting with DCM/AcOEt 95/5) to give the title compound as a
1
white solid (76% yield). H NMR (300 MHz, CDCl3, 293 K): δ 7.85
(d, J = 7.5 Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.62−7.45 (m, 3H), 6.82
(dd, J = 8.2 Hz, 2.1 Hz, 1H), 6.72 (d, J = 1.8 Hz, 1H), 5.61 (s, 1H),
4.40 (ddd, J = 12.6 Hz, 10.2 and 5.1 Hz, 1H), 3.75 (s, 3H), 3.46 (ddd,
J = 13.5 Hz, 9.6 and 4.8 Hz, 1H), 3.03 (ddd, J = 15.3 Hz, 9.0 and 6.0
Hz, 1H), 2.84 (dt, J = 15.9 Hz, 4.5 Hz, 1H). Data are in accordance
with previously reported results.9d
8,9-Dimethoxy-1,5,6,10b-tetrahydropyrrolo[2,1-a]isoquinolin-
3(2H)-one (IIC). Prepared from hydroxy lactam IC following the general
procedure (reaction time 2 h). Purification by flash chromatography
on silica gel (eluting with AcOEt) to give the title compound as a
1
white solid (89% yield). H NMR (300 MHz, CDCl3, 293 K): δ 6.62
(s, 1H), 6.57 (s, 1H), 4.73 (t, J = 7.5 Hz, 1H), 4.32 (m, 1H), 3.87 (s,
3H), 3.86 (s, 3H), 3.06−2.81 (m, 2H), 2.71−2.42 (m, 4H), 1.85 (m,
1H). Data are in accordance with previously reported results.33
2,3-Dimethoxy-6,7-dihydro-5H-benzo[3,4]azepino[2,1-a]-
isoindol-9(13bH)-one (IID). Prepared from hydroxy lactam ID
following the general procedure (reaction time 1 h 45 min).
Purification by flash chromatography on silica gel (eluting with
DCM/MeOH 98/2) to give the title compound as a yellow oil (96%
1
comparison of their H NMR spectral data reported in the literature.
1
yield). H NMR (300 MHz, CDCl3, 293 K): δ 7.90 (d, J = 7.6 Hz,
General Experimental Procedure for Thermal Intramolecu-
lar α-Amidoalkylation of Hydroxyl Lactams IA−IK. In a round-
bottomed flask equipped with a reflux condenser and a magnetic stirrer
were added one of the hydroxy lactams IA−IK (83 μmol) and
tetrachloroethane (750 μL). The reaction mixture was stirred at reflux
(see reaction time specified for each compound), and complete
1H), 7.65−7.40 (m, 3H), 6.81 (s, 1H), 6.64 (s, 1H), 5.68 (s, 1H), 4.35
(ddd, J = 14.3 Hz, 6.7 and 1.9 Hz, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.36
(ddd, J = 14.3 Hz, 10.5 and 5.7 Hz, 1H), 2.67 (t, J = 6.2 Hz, 2H), 2.16
(m, 1H), 1.92 (m, 1H). 13C NMR (75 MHz, CDCl3, 293 K): δ 168.9,
148.4, 147.4, 144.2, 132.5, 132.3, 131.4, 128.4, 126.8, 123.9, 123.1,
113.9, 111.4, 65.5, 56.2, 55.9, 41.0, 31.1, 25.6. IR (CHCl3): ν 2938,
2360, 2340, 1687, 1610 cm−1. LRMS (ESI): m/z 310 [M + H]+.
1
conversion of the starting material was monitored by TLC and/or H
NMR. The solvent was removed under reduced pressure, and the
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HRMS (ESI): calcd for C19H19NO3 [M + Na+], 332.1263; found,
332.1268.
silica gel (eluting with dichloromethane/MeOH 98/2) to give the title
compound as a brown solid (92% yield). Mp: 72−74 °C. H NMR
1
2,3-Dimethoxy-5,6,8a,9,12,12a-hexahydro-9,12-methanoiso-
indolo[1,2-a]isoquinolin-8(12bH)-one (IIE). Prepared from hydroxy
lactam IE following the general procedure (reaction time 1 h 30 min).
Purification by flash chromatography on silica gel (eluting with DCM/
MeOH 98/2) to give the title compound as a white solid (90% yield as
a single diastereoisomer). Mp: 127 °C dec. 1H NMR (300 MHz,
CDCl3, 293 K): δ 6.66 (s, 1H), 6.56 (s, 1H), 6.33 (m, 1H), 6.25 (m,
1H), 4.23 (m, 1H), 4.05 (d, J = 1.9 Hz, 1H), 3.91 (s, 3H), 3.85 (s,
3H), 3.30 (br s, 2H), 3.13 (dd, J = 9.5 Hz, 4.8 Hz, 1H), 2.98−2.77 (m,
3H), 2.54 (d, J = 12.4 Hz, 1H), 1.70 (d, J = 8.6 Hz, 1H), 1.49 (d, J =
8.6 Hz, 1H). 13C NMR (75 MHz, CDCl3, 293 K): δ 173.6, 148.1,
147.9, 137.0, 134.3, 130.1, 125.6, 111.7, 107.7, 59.7, 56.2, 55.9, 51.4,
51.3, 46.5, 45.8, 44.6, 37.4, 27.8. IR (CHCl3): ν 2963. 2360. 1669.
1516 cm−1. HRMS (ESI): calcd for C19H21NO3 [M + Na+], 334.1414;
found 334.1428.
(300 MHz, CDCl3, 293 K): δ 7.18 (d, J = 4.8 Hz, 1H), 6.81 (d, J = 4.8
Hz, 1H), 4.85−4.63 (m, 1H), 4.48 (dd, J = 13.4 Hz, 4.8 Hz, 1H),
3.09−2.75 (m, 3H), 2.67−2.34 (m, 3H), 1.79 (m, 1H). 13C NMR (75
MHz, CDCl3, 293 K): δ 173.6, 135.9, 133.0, 124.1, 123.4, 56.3, 37.2,
31.6, 26.7, 24.6. IR (CHCl3): ν 3099, 2924, 2849, 1683 cm−1. HRMS
(ESI): calcd for C10H11NOS [M + Na+], 216.0459; found, 216.0459.
General Experimental Procedure for Thermal Intermolecu-
lar α-Amidoalkylation of Neutral C-Nucleophiles with Acetoxy
Lactams IIIA−IIIG. In a round-bottomed flask equipped with a reflux
condenser and a magnetic stirrer were added on eof the acetoxy
lactams IIIA−IIIG (88.5 μmol), a C-nucleophile (1−3 equiv), and
tetrachloroethane (500 μL). The reaction was stirred at reflux (see
reaction time specified for each compound), and complete conversion
of the starting material was monitored by TLC. The solvent was
removed under reduced pressure, and the residue was purified by
column chromatography on silica gel to afford the corresponding
alkylated product.
3-(2-Allyl-3-oxoisoindolin-1-yl)pentane-2,4-dione (IVA). Prepared
from acetoxy lactam IIIA following the general procedure with
acetylacetone (1 equiv) as nucleophile (reaction time 7 h 30 min).
Purification by flash chromatography on silica gel (eluting with
cyclohexane/AcOEt 70/30) to give the title compound (mixture
ketone/enol form 1/19) as a colorless oil (100% yield). 1H NMR (300
MHz, CDCl3, 293 K): δ 7.90 (d, J = 7.5 Hz, 1H, enol form), 7.84 (d, J
= 7.5 Hz, 1H, ketone form), 7.60 (t, J = 7.5 Hz, 2H, ketone and enol
form), 7.51 (t, J = 7.5 Hz, 2H, ketone and enol form), 7.44 (d, J = 7.5
Hz, 1H, ketone form), 7.36 (d, J = 7.5 Hz, 1H, enol form), 5.68 (s, 1H,
enol form), 5.46 (d, J = 3 Hz, 1H, ketone form), 5.16 (s, 1H, ketone
form), 4.84 (dd, J = 17.7 Hz, 2.4 Hz, 1H, enol form), 4.69 (dd, J = 18.0
Hz, 2.4 Hz, 1H, ketone form), 4.46 (d, J = 3.3 Hz, 1H, ketone form),
4.17 (dd, J = 17.7 Hz, 2.4 Hz, 1H, ketone form), 3.80 (dd, J = 17.7 Hz,
2.4 Hz, 1H, enol form), 2.51 (s, 3H, enol form), 2.31 (t, J = 2.4 Hz,
1H, ketone form), 2.27 (t, J = 2.4 Hz, 1H, enol form), 2.18 (s, 3H,
ketone form), 1.93 (s, 3H, ketone form), 1.36 (s, 3H, enol form). Data
are in accordance with previously reported results.9d
2,3-Dimethoxy-12b-phenyl-5,6-dihydroisoindolo[1,2-a]-
isoquinolin-8(12bH)-one (IIF). Prepared from hydroxy lactam IF
following the general procedure (reaction time 14 h). Purification by
flash chromatography on silica gel (eluting with cyclohexane/AcOEt
60/40) to give the title compound as a white solid (85% yield). Mp:
1
201 °C. H NMR (300 MHz, CDCl3, 293 K): δ 7.91 (d, J = 7.5 Hz,
1H), 7.57−5.70 (m, 3H), 7.25−7.23 (m, 3H), 7.11 (s, 1H), 6.98−6.96
(m, 2H), 6.70 (s, 1H), 4.25 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.27
(m, 1H), 3.02 (m, 1H), 2.67 (m, 1H). 13C NMR (75 MHz, CDCl3,
293 K): δ 167.8, 150.0, 148.6, 147.6, 141.9, 131.8, 129.9, 128.5, 128.4,
127.9, 127.8, 127.3, 124.0, 123.9, 111.9, 110.9, 69.8, 56.2, 55.9, 35.7,
28.2. IR (CHCl3): ν 3054, 1686, 1265, 909, 736 cm−1. LRMS (EI, 70
eV): m/z 355 (M•+ − CH3, 9), 281 (23), 221 (57), 207 (41), 147
(61), 73 (100). HRMS (ESI): calcd for C24H21NO3 [M + Na+],
394.1414; found, 394.1409.
2-Methoxy-12b-phenyl-5,6-dihydroisoindolo[1,2-a]isoquinolin-8-
(12bH)-one (IIG). Prepared from hydroxy lactam IF following the
general procedure (reaction time 24 h). Purification by flash
chromatography on silica gel (eluting with cyclohexane/AcOEt 60/
40) to give the title compound as a white solid (86% yield). Mp: 169
1
°C. H NMR (300 MHz, CDCl3, 293 K): δ 7.92 (d, J = 7.3 Hz, 1H),
2-Allyl-3-(1-benzoyl-2-oxo-2-phenylethyl)-2,3-dihydroisoindol-1-
one (IVB). Prepared from acetoxy lactam IIIA following the general
procedure with dibenzoylmethane (1 equiv) as nucleophile (reaction
time 14 h 30 min). Purification by flash chromatography on silica gel
(eluting with cyclohexane/AcOEt 60/40) to give the title compound
7.60−7.44 (m, 4H), 7.31−7.22 (m, 3H), 7.06−6.96 (m, 4H), 6.85−
6.74 (m, 2H), 4.24 (dt, J = 13.1 and 6.6 Hz, 1H), 3.82 (s, 3H), 3.42
(dt, J = 13.2 and 6.6 Hz, 1H), 3.04 (dt, J = 16.0 and 7.0 Hz, 1H), 2.73
(dt, J = 15.9 and 6.4 Hz, 1H). 13C NMR (75 MHz, CDCl3, 293 K): δ
167.0, 157.9, 148.8, 140.8, 135.8, 130.7, 130.5, 128.4, 128.1, 127.5,
127.3, 127.1, 126.8, 126.4, 125.9, 123.2, 122.8, 113.2, 110.8,68.9, 54.3,
35.0, 27.7. IR (CHCl3): ν 3017, 1679, 1221, 1211 cm−1. HRMS (ESI):
calcd for C23H19NO2 [M + H+], 342.1489; found, 342.1491.
1
as a white solid (77% yield). H NMR (300 MHz, CDCl3, 293 K): δ
7.83 (d, J = 7.4 Hz, 1H), 7.65−7.45 (m, 5H), 7.43−7.30 (m, 7H), 5.88
(dddd, J = 16.7 Hz, 10 Hz, 6.6 and 5.2 Hz, 1H), 5.79 (d, J = 4.8 Hz,
1H), 5.73 (d, J = 4.8 Hz, 1H), 5.17 (dd, J = 10 Hz, 1.2 Hz, 1H), 5.17
(dd, J = 16.7 Hz, 1.2 Hz, 1H), 4.6 (dd, J = 15.8 Hz, 5.2 Hz, 1H), 3.75
(dd, J = 15.8 Hz, 6.6 Hz, 1H). Data are in accordance with previously
reported results.9d
2-Methoxy-12b-phenyl-5,6-dihydroisoindolo[1,2-a]isoquinolin-8-
(12bH)-one (IIH). Prepared from hydroxy lactam IH following the
general procedure (reaction time 72 h). Purification by flash
chromatography on silica gel (eluting with DCM/AcOEt 90/10) to
2-Allyl-3-(1-acetyl-2-oxocyclopentanyl)-2,3-dihydroisoindol-1-
one (IVC). Prepared from acetoxy lactam IIIA following the general
procedure with acetylcyclopentanone (1 equiv) as nucleophile
(reaction time 8 h). Purification by flash chromatography on silica
gel (eluting with cyclohexane/AcOEt 60/40) to give the title
compound (as a mixture of two diastereoisomers, ca. 1:1) as a
1
give the title compound as a beige solid (65% yield). H NMR (300
MHz, CDCl3, 293 K): δ 7.87−7.83 (m, 2H), 7.64 (dt, J = 7.5 and 1.1
Hz, 1H), 7.48 (t, J = 7.4 Hz, 1H), 7.18 (s, 1H), 6.58 (s, 1H), 4.65
(ddd, J = 13.1 Hz, 6.5 and 1.2 Hz, 1H), 3.96 (s, 3H), 3.85 (s, 3H), 3.39
(ddd, J = 13.1 Hz, 11.9 and 4.5 Hz, 1H), 3.04 (ddd, J = 16.0 Hz, 11.9
Hz and 6.5 HZ, 1H), 2.72 (m, 1H), 1.81 (s, 3H). Data are in
accordance with previously reported results.34
4,5-Dihydrothieno[3′,2′:3,4]pyrido[2,1-a]isoindol-7(11bH)-one
(III). Prepared from hydroxy lactam II following the general procedure
(reaction time 1 h). Purification by flash chromatography on silica gel
(eluting with DCM/MeOH 99/1) to give the title compound as a
yellow solid (99% yield). 1H NMR (300 MHz, CDCl3, 293 K): δ 7.90
(d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H),
7.51 (t, J = 7.6 Hz, 1H), 7.33−7.21 (m, 2H), 5.68 (s, 1H), 4.84 (dd, J
= 12.9 Hz, 5.2 Hz, 1H), 3.39 (ddd, J = 13.4 Hz, 11.4 and 5.7 Hz, 1H),
3.13−2.84 (m, 2H). Data are in accordance with previously reported
results.35
1
colorless oil (87% yield). H NMR (300 MHz, CDCl3, 293 K): δ
7.95−7.87 (m, 2H), 7.58−7.48 (m, 4H), 7.31 (m, 1H), 7.05 (m, 1H),
5.88−5.70 (m, 2H), 5.61 (s, 1H), 5.56 (s, 1H), 5.28−5.19 (m, 3H),
5.05 (d, J = 17.3 Hz, 1H), 4.73−4.65 (m, 2H), 3.45 (dd, J = 15.7 Hz,
6.7 Hz, 1H), 3.32 (dd, J = 16.9 Hz, 6 Hz, 1H), 2.56 (s, 3H), 2.53 (s,
3H), 2.48−2.25 (m, 4H), 2.02−1.64 (m, 4H), 1.52−1.10 (m, 4H).
Data are in accordance with previously reported results.9d
2-Allyl-3-(2-oxocyclohexyl)isoindolin-1-one (IVD). Prepared from
acetoxy lactam IIIA following the general procedure with cyclo-
hexanone (3 equiv) as nucleophile (reaction time 14 h). Purification
by flash chromatography on silica gel (eluting with cyclohexane/
AcOEt 70/30) to give the title compound (as a mixture of two
diastereoisomers, ca. 2/1) as a white solid (65% yield). 1H NMR (300
MHz, CDCl3, 293 K): δ 7.84−7.80 (m, 2H), 7.61−7.30 (m, 6H),
5.95−5.78 (m, 2H), 5.40 (s, 1H), 5.35−5.09 (m, 3H), 4.54 (dd, J =
4,5,9,9a-Tetrahydrothieno[2,3-g]indolizin-7(8H)-one (IIJ). Pre-
pared from hydroxy lactam IJ following the general procedure
(reaction time 3 h 30 min). Purification by flash chromatography on
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15.7 Hz, 5.3 Hz, 1H), 4.43 (dd, J = 15.3 Hz, 6.4 Hz, 1H), 3.86−3.65
(m, 2H), 3.03−2.86 (m, 2H), 2.81 (dd, J = 11.6 Hz, 7.0 Hz, 1H),
2.61−2.52 (m, 2H), 2.44−2.29 (m, 2H), 2.08−2.02 (m, 2H), 1.83−
1.23 (m, 10H). Data are in accordance with previously reported
results.9d
2-Allyl-3-(1H-pyrrol-2-yl)isoindolin-1-one (IVE). Prepared from
acetoxy lactam IIIA following the general procedure with pyrrole
(1.5 equiv) as nucleophile (reaction time 2 h 30). Purification by flash
chromatography on silica gel (eluting with cyclohexane/AcOEt 70/30)
to give the title compound as a white solid (79% yield). 1H NMR (300
MHz, CDCl3, 293 K): δ 8.57 (br s, 1H), 7.40 (d, J = 7.6 Hz, 1H),
7.54−7.39 (m, 2H), 7.31 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 1.0 Hz, 1H),
6.40 (s, 1H), 6.19 (d, J = 2.7 Hz, 1H), 5.76 (m, 1H), 5.62 (s, 1H),
5.19−5.09 (m, 2H), 4.47 (dt, J = 15.4 Hz, 2.0 Hz, 1H), 3.41 (dd, J =
15.4 Hz, 7.5 Hz, 1H). Data are in accordance with previously reported
results.9b
2-Allyl-3-methylisoindolin-1-one (IVF). Prepared from acetoxy
lactam IIIA following the general procedure with indole (1.5 equiv)
as nucleophile (reaction time 2 h). Purification by flash chromatog-
raphy on silica gel (eluting with cyclohexane/AcOEt 60/40) to give
the title compound as a white solid (81% yield). 1H NMR (300 MHz,
CDCl3, 293 K): δ 8.41 (br s, 1H), 7.98 (d, J = 6.9 Hz, 1H), 7.54−7.48
(m, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.30−7.27 (m, 2H), 7.18 (t, J = 8.0
Hz, 1H), 6.97−6.92 (m, 2H), 5.90−5.77 (m, 2H), 5.19−5.07 (m, 2H),
4.66 (dt, J = 15.6 Hz, 2.0 Hz, 1H), 3.44 (dd, J = 15.6 Hz, 7.4 Hz, 1H).
Data are in accordance with previously reported results.9b
form), 7.32 (d, J = 7.4 Hz, 1H, enol form), 5.77 (s, 1H, enol form),
5.55 (s, 1H, ketone form), 4.38 (d, J = 1.9 Hz, 1H, ketone form),
4.30−4.21 (m, 1H, ketone form), 3.97−3.89 (m, 1H, enol form),
3.31−3.19 (m, 2H), 2.83−2.69 (m, 1H), 2.60 (t, J = 5.4 Hz, 1H,
ketone form), 2.55−2.48 (m, 4H), 2.06 (s, 3H, ketone form), 1.93 (s,
3H, ketone form), 1.35 (s, 3H, enol form). 13C NMR (75 MHz,
CDCl3, 293 K): δ 202.7, 202.5, 198.3, 189.7, 168.8, 168.5, 145.4,
143.0, 132.5, 132.4, 132.2, 132.0, 129.2, 128.9, 124.1, 124.0, 123.9,
122.4, 105.4, 82.1, 81.6, 70.6, 70.5, 67.3, 59.8, 57.4, 39.5, 39.3, 31.1,
24.6, 23.1, 18.4, 18.3. IR (KBr/neat): ν 1686 cm−1. LRMS (EI, 70 eV):
m/z 240 (M•+ − CH3CO, 18), 197 (M•+ − (2 × CH3CO), 10), 188
(M•+ − Nu, 8), 173 (100), 77 (20). HRMS (ESI): calcd for
C17H17NO3 [M + H+], 284.1281; found, 284.1289.
3-(3-Oxo-2-phenethylisoindolin-1-yl)pentane-2,4-dione (VC). Pre-
pared from acetoxy lactam IIID following the general procedure with
acetylacetone (1.1 equiv) as nucleophile (reaction time 7 h 30 min).
Purification by flash chromatography on silica gel (eluting with
cyclohexane/AcOEt 70/30) to give the title compound (mixture
ketone/enol form 1/5.7) as a white solid (99% yield). Mp: 105 °C. 1H
NMR (300 MHz, CDCl3, 293 K): δ 7.91 (d, J = 6.8 Hz, 1H, enol
form), 7.85 (d, J = 7.2 Hz, 1H, ketone form), 7.52 (dq, J = 13.7 Hz, 6.9
Hz, 4H, ketone and enol form), 7.39 (d, J = 7.4 Hz, 1H, ketone form),
7.26−7.16 (m, 11H, ketone form), 5.26 (d, J = 2.5 Hz, 1H, ketone
form), 5.17 (s, 1H, enol form), 4.34−4.25 (m, 1H, ketone form),
4.17−4.07 (m, 1H, enol form), 3.28−2.88 (m, 6H, ketone and enol
form), 1.99 (s, 3H, enol form), 1.95 (d, J = 2.9 Hz, 1H, ketone form),
1.41 (s, 6H, ketone form), 1.31 (s, 3H, enol form). 13C NMR (75
MHz, CDCl3, 293 K): δ 198.1, 189.5, 168.5, 145.2, 139.3, 132.5, 132.3,
129.1, 129.0, 128.9, 126.9, 124.0, 122.3, 105.3, 59.5, 42.3, 34.9, 24.4,
22.3. IR (KBr/neat): ν 1682 cm−1. LRMS (EI, 70 eV): m/z 335 (M•+,
4), 244 (65), 235 (15), 215 (39), 202 (41), 173 (100), 155 (24), 131
(24). HRMS (ESI): calcd for C21H21NO3 [M + H+], 336.1594; found,
336.1593.
3-(2-Benzyl-3-oxoisoindolin-1-yl)pentane-2,4-dione (VD). Pre-
pared from acetoxy lactam IIIE following the general procedure with
acetylacetone (1.1 equiv) as nucleophile (reaction time 9 h).
Purification by flash chromatography on silica gel (eluting with
cyclohexane/AcOEt 70/30) to give the title compound (mixture
ketone/enol form 0/100) as a white solid (96% yield). Mp: 148 °C.
1H NMR (300 MHz, CDCl3, 293 K): δ 7.94 (d, J = 6.9 Hz, 1H),
7.58−7.49 (m, 2H), 7.34−7.21 (m, 6H), 5.44 (d, J = 15.0 Hz, 1H),
5.27 (s, 1H), 3.94 (d, J = 15.0 Hz, 1H), 1.79 (s, 3H), 1.39 (s, 3H). 13C
NMR (75 MHz, CDCl3, 293 K): δ 197.5, 190.5, 168.3, 145.1, 137.0,
132.5, 132.1, 129.1, 128.9, 128.3, 128.0, 124.3, 122.3, 104.9, 57.7, 43.8,
24.2, 22.4. IR (KBr/neat): ν 1686 cm−1. LRMS (EI, 70 eV): m/z 321
(M•+, 4), 236 (22), 230 (100), 221 (27), 188 (99), 170 (20), 131
(11), 91 (33). HRMS (ESI): calcd for C20H19NO3 [M + H+],
322.1438; found, 322.1446.
2-Allyl-3-(1H-pyrrol-2-yl)isoindolin-1-one (IVG). Prepared from
acetoxy lactam IIIA following the general procedure with 2-
methylfuran (1.5 equiv) as nucleophile (reaction time 14 h).
Purification by flash chromatography on silica gel (eluting with
cyclohexane/AcOEt 75/25) to give the title compound as a colorless
1
oil (52% yield). H NMR (300 MHz, CDCl3, 293 K): δ 7.88 (d, J =
7.1 Hz, 1H), 7.50 (q, J = 7.1 Hz, 2H), 7.33 (d, J = 6.9 Hz, 1H), 6.20
(d, J = 2.8 Hz, 1H), 5.93 (s, 1H), 5.82−5.70 (m, 1H), 5.52 (s, 1H),
5.17−5.10 (m, 2H), 4.58 (dd, J = 15.5 Hz, 4.3 Hz, 1H), 3.58 (dd, J =
15.5 Hz, 7.4 Hz, 1H) 2.20 (s, 3H). 13C NMR (75 MHz, CDCl3, 293
K): δ 168.0, 153.5, 147.3, 143.4, 133.0, 132.2, 131.8, 128.8, 123.9,
123.2, 117.9, 110.9, 106.5, 57.8, 43.2, 13.8. LRMS (EI, 70 eV): m/z
253 (100), 239 (6), 145 (23), 122 (18). IR (CHCl3): ν 3017, 1686,
1217, 761 cm−1. HRMS (ESI): calcd for C16H15NO2Na [M + Na+],
276.0995; found, 276.1005.
3-(3-Oxo-2-(prop-2-yn-1-yl)isoindolin-1-yl)pentane-2,4-dione
(VA). Prepared from acetoxy lactam IIIB following the general
procedure with acetylacetone (1.1 equiv) as nucleophile (reaction
time 7 h 30 min). Purification by flash chromatography on silica gel
(eluting with cyclohexane/AcOEt 60/40) to give the title compound
(mixture ketone/enol form 1/7) as a yellow oil (100% yield). 1H
NMR (300 MHz, CDCl3, 293 K): δ 7.90 (d, J = 7.5 Hz, 1H, enol
form), 7.84 (d, J = 7.5 Hz, 1H, ketone form), 7.60 (t, J = 7.5 Hz, 2H,
ketone and enol form), 7.51 (t, J = 7.5 Hz, 2H, ketone and enol form),
7.44 (d, J = 7.5 Hz, 1H, ketone form), 7.36 (d, J = 7.5 Hz, 1H, enol
form), 5.68 (s, 1H, enol form), 5.46 (d, J = 3 Hz, 1H, ketone form),
4.84 (dd, J = 17.7 Hz, 2.4 Hz, 1H, enol form), 4.69 (dd, J = 18.0 Hz,
2.4 Hz, 1H, ketone form), 4.46 (d, J = 3.3 Hz, 1H, ketone form), 4.17
(dd, J = 17.7 Hz, 2.4 Hz, 1H, ketone form), 3.80 (dd, J = 17.7 Hz, 2.4
Hz, 1H, enol form), 2.51 (s, 3H, enol form), 2.31 (t, J = 2.4 Hz, 1H,
ketone form), 2.27 (t, J = 2.4 Hz, 1H, enol form), 2.18 (s, 3H, ketone
form), 1.93 (s, 3H, ketone form), 1.36 (s, 3H, enol form). 13C NMR
(75 MHz, CDCl3, 293 K): δ 203.8, 202.1, 170.2, 147.3, 142.3, 133.8,
132.6, 129.5, 124.6, 124.3, 114.1, 77.6, 66.8, 48.0, 28.8, 28.4. IR (KBr/
neat): ν 1686 cm−1. HRMS (ESI): calcd for C16H15NO3 [M + H+],
270.1128; found, 270.1127.
3-(2-(3-Methylbut-2-en-1-yl)-3-oxoisoindolin-1-yl)pentane-2,4-
dione (VE). Prepared from acetoxy lactam IIIF following the general
procedure with acetylacetone (1.1 equiv) as nucleophile (reaction time
7 h 30 min). Purification by flash chromatography on silica gel (eluting
with cyclohexane/AcOEt 70/30) to give the title compound (mixture
1
ketone/enol form 1/8.3) as a yellow oil (100% yield). H NMR (300
MHz, CDCl3, 293 K): δ 7.87 (d, J = 7.3 Hz, 1H, enol form), 7.81 (d, J
= 6.9 Hz, 1H, ketone form), 7.57−7.45 (m, 4H, ketone and enol
forms), 7.39 (d, J = 7.4 Hz, 1H, ketone form), 7.30−7.26 (m, 1H, enol
form), 5.47 (s, 1H, enol form), 5.28 (s, 1H, ketone form), 5.21−5.15
(m, 2H, ketone and enol forms), 4.63−4.50 (m, 2H, ketone and enol
forms), 4.27 (d, J = 2.9 Hz, 1H, ketone form), 3.79 (dd, J = 15.4 Hz,
7.3 Hz, 1H, ketone form), 3.64 (dd, J = 14.9 Hz, 8.8 Hz, 1H, enol
form), 2.34 (s, 3H, enol form), 2.15 (s, 3H, ketone form), 1.85 (s, 3H,
ketone form), 1.74 (s, 3H, enol form), 1.71 (s, 3H, enol form), 1.65 (s,
3H, ketone form), 1.40 (s, 3H, ketone form), 1.38 (s, 3H, enol form).
13C NMR (75 MHz, CDCl3, 293 K): δ 202.6, 202.3, 197.7, 189.9,
167.8, 145.1, 142.7, 137.2, 132.6, 132.2, 132.1, 129.1, 128.8, 124.4,
124.0, 123.9, 122.2, 119.9, 119.1, 105.5, 67.1, 58.1, 57.3, 38.8, 37.9,
31.4, 30.8, 27.1, 25.9, 24.3, 22.8, 18.2, 17.9. IR (neat): ν 1685 cm−1.
LRMS (EI, 70 eV): m/z 299 (M•+, 39), 256 (34), 231 (91), 200 (60),
3-(2-(But-3-yn-1-yl)-3-oxoisoindolin-1-yl)pentane-2,4-dione (VB).
Prepared from acetoxy lactam IIIC following the general procedure
with acetylacetone (1.1 equiv) as nucleophile (reaction time 5 h).
Purification by flash chromatography on silica gel (eluting with
cyclohexane/AcOEt 60/40) to give the title compound (mixture
1
ketone/enol form 1/3.8) as a yellow oil (99% yield). H NMR (300
MHz, CDCl3, 293 K): δ 7.88 (d, J = 7.4 Hz, 1H, enol form), 7.84 (d, J
= 7.7 Hz, 1H, ketone form), 7.60−7.44 (m, 5H, ketone and enol
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188 (100), 171 (41), 131 (35), 84 (31), 43 (72). HRMS (ESI): calcd
for C18H21NO3 [M + H+], 300.1594; found, 300.1596.
procedure with dibenzoylmethane as nucleophile (reaction time 36 h).
Purification by flash chromatography on silica gel (eluting with
cyclohexane/AcOEt 80/20) to give the title compound as a white solid
(100% yield). 1H NMR (300 MHz, CDCl3, 293 K): δ 7.83 (d, J = 7.5
Hz, 4H), 7.51−7.31 (m, 8H), 7.31−6.92 (m, 5H), 6.78 (d, J = 9.9 Hz,
2H), 6.31 (d, J = 11.7 Hz, 1H), 5.28 (d, J = 11.7 Hz, 1H), 3.67 (s, 3H).
Data are in accordance with previously reported results.36
3-(2-(2-Methylallyl)-3-oxoisoindolin-1-yl)pentane-2,4-dione (VF).
Prepared from acetoxy lactam IIIG following the general procedure
with acetylacetone (1.1 equiv) as nucleophile (reaction time 7 h).
Purification by flash chromatography on silica gel (eluting with
cyclohexane/AcOEt 70/30) to give the title compound (mixture
1
ketone/enol form 1/5.25) as a colorless oil (100% yield). H NMR
(E)-3-(1,3-Diphenylallyl)pentane-2,4-dione (IXA). Prepared from
alcohol VIC following the general procedure with acetylacetone as
nucleophile (reaction time 15 h). Purification by flash chromatography
on silica gel (eluting with cyclohexane/AcOEt 80/20) to give the title
compound as a white solid (85% yield). 1H NMR (300 MHz, CDCl3,
293 K): δ 7.34−7.20 (m, 10H), 6.43 (d, J = 15.8 Hz, 1H), 6.19 (ddd, J
= 15.8 Hz, 5.1 and 2.7 Hz, 1H), 4.34 (m, 2H), 2.25 (s, 3H), 1.92 (s,
3H). Data are in accordance with previously reported results.36
(E)-2-(1,3-Diphenylallyl)-1,3-diphenylpropane-1,3-dione (IXB).
Prepared from alcohol VIC following the general procedure with
dibenzoylmethane as nucleophile (reaction time 15 h). Purification by
flash chromatography on silica gel (eluting with cyclohexane/AcOEt
(300 MHz, CDCl3, 293 K): δ 7.91 (d, J = 7.5 Hz, 1H, enol form), 7.86
(d, J = 10.8 Hz, 1H, ketone form), 7.60−7.42 (m, 5H), 7.33 (d, J = 7.5
Hz, 1H, enol form), 5.43 (s, 1H, enol form), 5.24 (d, J = 3.0 Hz, 1H,
ketone form), 4.94 (s, 2H, ketone and enol form), 4.76 (s, 2H, ketone
and enol form), 4.68 (d, J = 15.6 Hz, 2H, ketone and enol form), 4.27
(d, J = 3.3 Hz, 1H, ketone form), 3.65 (d, J = 15.9 Hz, 1H, ketone
form), 3.39 (d, J = 15.3 Hz, 1H, enol form), 2.34 (s, 3H, enol form),
2.15 (s, 3H, ketone form), 1.88 (s, 3H, ketone form), 1.73 (s, 3H, enol
form), 1.68 (s, 3H, ketone form), 1.37 (s, 3H, enol form). 13C NMR
(75 MHz, CDCl3, 293 K): δ 201.3, 201.1, 196.4, 189.1, 167.6, 167.0,
144.0, 141.5, 140.2, 139.5, 131.2, 131.0, 128.0, 127.7, 123.1, 123.0,
121.2, 112.1, 112.0, 104.0, 65.9, 56.7, 56.0, 45.5, 44.3, 30.1, 29.7, 23.1,
21.8, 19.1, 19.0. IR (neat): ν 1684 cm−1. LRMS (EI, 70 eV): m/z 242
(M•+ − CH3CO, 56), 200 (M•+ − (2 × CH3CO), 49), 188 (100), 186
(M•+ − CH3COCH2COCH3, 60), 147 (58), 77 (40). HRMS (APCI):
calcd for C17H19NO3 [M + H+], 286.1438; found, 285.1446.
1
90/10) to give the title compound as a white solid (94% yield). H
NMR (300 MHz, CDCl3, 293 K): δ 8.04 (d, J = 7.4 Hz, 2H), 7.82 (d, J
= 7.3 Hz, 2H), 7.55−7.09 (m, 16H), 6.37−6.25 (m, 2H), 5.97 (d, J =
10.5 Hz, 1H), 4.80 (dd, J = 9.5 and 6.1 Hz, 1H). Data are in
accordance with previously reported results.37
3-(1H-Indol-3-yl)-2-(prop-2-yn-1-yl)isoindolin-1-one (VG). Pre-
pared from acetoxy lactam IIIB following the general procedure with
indole (1.1 equiv) as nucleophile (reaction time 2 h). Purification by
flash chromatography on silica gel (eluting with cyclohexane/AcOEt
60/40) to give the title compound as a white solid (73% yield). Mp:
111 °C. 1H NMR (300 MHz, CDCl3, 293 K): δ 8.29 (br s, 1H), 8.03−
7.90 (m, 1H), 7.50 (q, J = 6.8 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.34−
7.28 (m, 1H), 7.16 (t, J = 7.7 Hz, 1H), 6.91 (t, J = 7.5 Hz, 1H), 6.00
(s, 1H), 4.88 (dd, J = 17.5 Hz, 2.4 Hz, 1H), 3.50 (dd, J = 17.6 Hz, 2.2
Hz, 1H), 2.22 (t, J = 2.3 Hz, 1H). 13C NMR: (75 MHz, CDCl3, 293
K): δ 167.6, 145.9, 136.8, 132.1, 131.5, 128.4, 125.3, 123.9, 123.7,
123.4, 122.7, 120.2, 119.1, 111.5, 110.2, 78.8, 71.8, 57.3, 29.4. IR
(KBr/neat): ν 2254, 1682 cm−1. LRMS (EI, 70 eV): m/z 286 (M•+,
40), 257 (15), 204 (56), 155 (100), 130 (20), 102 (23). HRMS
(APCI): calcd for C19H14N2O [M + H+], 287.1179; found, 287.1185.
General Procedure for Thermal Intermolecular Alkylation of
Neutral C-Nucleophiles with π-Alcohols VIA−VID. In a round-
bottomed flask equipped with a reflux condenser and a magnetic stirrer
were added one of the π-alcohols VIA−VID (88.5 μmol), acetylacetone
(1 equiv) or dibenzoylmethane (1 equiv), and tetrachloroethane (500
μL). The reaction mixture was stirred at reflux (see reaction time
specified for each compound), and complete conversion of the starting
material was monitored by TLC. The solvent was removed under
reduced pressure, and the residue was purified by column
chromatography on silica gel to afford the corresponding alkylated
product.
3-(1-(4-Methoxyphenyl)-3-phenylprop-2-ynyl)pentane-2,4-dione
(XA). Prepared from alcohol VID following the general procedure with
acetylacetone as nucleophile (reaction time 12 h). Purification by flash
chromatography on silica gel (eluting with cyclohexane/AcOEt 85/15)
1
to give the title compound as a white solid (100% yield). H NMR
(300 MHz, CDCl3, 293 K): δ 7.49−7.26 (m, 7H), 6.86 (d, J = 8.7 Hz,
2H), 4.62 (d, J = 11.0 Hz, 1H), 4.19 (d, J = 11.0 Hz, 1H), 3.79 (s, 3H),
2.38 (s, 3H), 1.94 (s, 3H). Data are in accordance with previously
reported results.38
General Procedure for Thermal α-Amidoalkylation of
Acetoxy or Hydroxy Lactams Using Preheated TCE. TCE was
heated at reflux for 14 h under an inert atmosphere prior to use. After
it was cooled to room temperature, TCE was used as such in general
procedures for thermal intramolecular and intermolecular reactions.
General Procedure for Thermal α-Amidoalkylation of
Hydroxy Lactams using Microwave Irradiation. In a microwave
reaction vessel were added hydroxy lactam VIA (20 mg, 105.7 μmol), a
C-nucleophile (1−3 equiv in the case of intermolecular reactions), and
tetrachloroethane (700 μL). The reaction mixture was stirred at reflux
(300 W) (see reaction time specified for each compound), and
complete conversion of the starting material was monitored by TLC
1
and/or H NMR. The solvent was removed under reduced pressure,
and the residue was purified by column chromatography on silica gel
to afford the corresponding alkylated product.
General Procedure for Thermal Cyclization under Flow
Conditions. 1,1,2,2-Tetrachloroethane (TCE), was stored over base
(K2CO3) and filtered prior to the reaction.
3-(1-(4-Methoxyphenyl)ethyl)pentane-2,4-dione (VIIA). Prepared
from alcohol VIA following the general procedure with acetylacetone
as nucleophile (reaction time 16 h). Purification by flash
chromatography on silica gel (eluting with cyclohexane/AcOEt 90/
10) to give the title compound as a white solid (80% yield). 1H NMR
(300 MHz, CDCl3, 293 K): δ 7.18 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.7
Hz, 2H), 3.99 (d, J = 11.4 Hz, 1H), 3.79 (s, 3H), 3.57 (m, 1H), 2.33
(s, 3H), 1.83 (s, 3H), 1.27 (d, J = 6.9 Hz, 3H).
A solution of 2-(3,4-dimethoxyphenethyl)-3-hydroxyisoindolin-1-
one (0.007 g, 0.022 mmol) in TCE (2 mL) was inserted using an
injection loop into a flow of TCE (0.5 mL/min) and passed through a
10 mL capacity PFA column (1 mm i.d., 20 min reaction time) heated
to the required temperature and then through a back-pressure
regulator (40 psi) and the appropriate fraction collected. This fraction
was washed with an aqueous solution of NaHCO3 (5%) to neutralize
residual traces of HCl, the aqueous layer was extracted with one
volume of dichloromethane, and the organic layer was dried over
MgSO4. Filtration and evaporation of the solvent (14 mbar, 60 °C)
afforded the crude product, which was submitted for 1H NMR
analysis.
With Preheating of Solvent. A flow of TCE (0.25 mL/min) was
passed through a 10 mL PFA reactor heated to 170 °C and then
combined using a mixing T with a flow of TCE (0.25 mL/min) into
which a solution of the substrate was inserted as above. The combined
flow was passed through a 10 mL PFA column heated to the required
temperature before being collected, worked up, and analyzed as above.
Data are in accordance with previously reported results.36
3-((4-Methoxyphenyl)(phenyl)methyl)pentane-2,4-dione (VIIIA).
Prepared from alcohol VIB following the general procedure with
acetylacetone as nucleophile (reaction time 9 h 30 min). Purification
by flash chromatography on silica gel (eluting with cyclohexane/
AcOEt 90/10) to give the title compound as a white solid (89% yield).
1H NMR (300 MHz, CDCl3, 293 K): δ 7.26−7.16 (m, 8H), 6.80 (d, J
= 8.7 Hz, 2H), 4.76 (d, J = 12.3 Hz, 1H), 4.68 (d, J = 12.3 Hz, 1H,),
3.74 (s, 3H), 2.00 (s, 3H), 1.99 (s, 3H). Data are in accordance with
previously reported results.36
2-((4-Methoxyphenyl)(phenyl)methyl)-1,3-diphenylpropane-1,3-
dione (VIIIB). Prepared from alcohol VIB following the general
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Preparative-Scale Reactions. For preparative-scale reactions a
solution of IA (0.011 M) in TCE was pumped directly from a bottle
through the pump and then the heated column, allowing potentially
continuous production. The crude product was purified by
chromatography on silica using 2% MeOH in DCM as eluent. For
example, a 30 mL aliquot (0.33 mmol of IA) was pumped at 0.5 mL/
min through a 10 mL PFA column held at 160 °C to give 0.092 g of
pure IIA (94%).
racemates by preparative HPLC and Betty Renault for initiating
this work.
REFERENCES
■
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Procedure for Monitoring HCl Formation from TCE under
Flow Conditions. A plug of TCE (5 mL, stored over K2CO3) was
inserted into a flow of toluene (1 mL/min) and pumped through a
stainless steel reactor (10 mL, 1 mm i.d.) at various temperatures. For
temperatures up to 170 °C a PFA column was also used. The reactor
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Procedure for Use of TCE and DCE Containing Known
Amounts of Anhydrous HCl under Flow Conditions. HCl gas
was generated as previously described39 and absorbed into TCE or
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aqueous NaOH, giving HCl concentrations of 0.009 and 0.014 M in
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analyzed as above.
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́
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ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures giving H and 13C spectra for all new compounds and
text and a figure giving a description of results obtained from α-
amidoalkylation reactions carried out in fluorinated alcohols as
solvents. This material is available free of charge via the Internet
at http://pubs.acs.org.
(8) For authoritative reviews on N-acyliminium ion chemistry:
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(b) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J.-H.; Turchi, I. J.;
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G. Synthesis 2009, 339. (d) Yazici, A.; Pyne, S. G. Synthesis 2009, 513.
(9) (a) Ben Othman, R.; Bousquet, T.; Othman, M.; Dalla, V. Org.
Lett. 2005, 7, 5335. (b) Devineau, A.; Pousse, G.; Taillier, C.; Blanchet,
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AUTHOR INFORMATION
Corresponding Author
*E-mail for V.D.: vincent.dalla@univ-lehavre.fr.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.G. and N.D. thank the European Community for financial
support for the project IS:CE-Chem in the framework of
INTERREG IVA France-(Manche)-England (project 4061).
Dunach, E.; Dalla, V. Angew. Chem., Int. Ed. 2010, 49, 776.
̃
(10) For a selection of contributions by others: (a) Okitsu, O.;
Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66, 809. (b) Soares
Camilo, N.; Pilli, R. A. Tetrahedron Lett. 2004, 45, 2821. (c) de Godoy,
L. A. F.; Soares Camilo, N.; Pilli, R. A. Tetrahedron Lett. 2006, 47,
7853. (d) Kinderman, S. S.; Wekking, M. M. T.; van Maarseveen, J. H.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Org. Chem. 2005,
70, 5519. (e) Maity, A. K.; Roy, S. J. Org. Chem. 2012, 77, 2935.
́
M.H., A.D., C.T., and V.D. thank the Region Haute Normandie
(Crunch interregional network) for their financial support.
R.J.W., D.B., and D.C.H. thank the EPSRC for support from
grant EP/G027986/1. We acknowledge Fabien Le Cavelier
(LCMT Caen) for the separation of the hydroxyl lactam
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The Journal of Organic Chemistry
Article
(11) For a selection of impressive catalytic enantioselective
approaches: (a) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404. (b) Peterson, E.
A.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2009, 48, 6328. (c) Muratore,
M. C.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon,
D. J. J. Am. Chem. Soc. 2009, 131, 10796.
limited reactivities were observed. These results are included in the
Supporting Information.
(29) Reaction times required to observe complete conversion of the
starting N,O-acetal using refluxing tetrachloroethane.
(30) For a recent elegant example, see: Sun, J.; Kozmin, S. A. J. Am.
Chem. Soc. 2005, 127, 13512.
(31) As this work was in progress, a paper appeared where the
intramolecular amidoalkylation of a hydroxy lactam related to IA and IB
was achieved; however, the reaction was carried out in the presence of
huge excess amounts of HCl (37% aqueous HCl) at reflux: Castro-
(12) Antoniotti, S.; Dalla, V.; Dunach, E. Angew. Chem., Int. Ed. 2010,
̃
49, 7860.
(13) For seminal papers on the thermal decomposition of chlorinated
solvents and TCE in particular, see: (a) Barton, D. H. R. J. Chem. Soc.,
Chem. Commun. 1949, 148. (b) Barton, D. H. R.; Howlett, K. E. J.
Chem. Soc., Chem. Commun. 1949, 155. (c) Barton, D. H. R.; Howlett,
K. E. J. Chem. Soc., Chem. Commun. 1951, 2033. (d) Kawaguchi, T.;
Suzuki, Y.; Saito, R. Ind. Eng. Chem. 1970, 62, 36.
́ ́ ́
Castillo, V.; Suarez-Rozas, C.; Pabon, A.; Perez, E. G.; Cassels, B. K.;
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(14) HCl is supplied as solutions in organic solvents such as dioxane,
diethyl ether, cyclopentyl methyl ether, and ethyl acetate.
(15) The acidity strength of HCl is inevitably affected in these
solvents due to hydrogen bonding.
(16) Information on the toxicity of 1,1,2,2-tetrachloroethane can be
found on the web. For an example, see: http://ntp.niehs.nih.gov/go/
11901 Home ≫ Study Results & Research Projects ≫ Reports &
Publications ≫ Short-Term Toxicity Reports and Abstracts ≫
Abstract for TOX-49 - 1,1,2,2-Tetrachloroethane (CAS registry no.
79-34-5).
(17) Indeed, after 1 h of reaction time, Ic has been completely
converted, and the conjugated pyrrolidinone A was the major product
1
detectable from the H NMR spectrum along with minor amounts of
the cyclized product IIc.
(18) For similar amidoalkylations of α,β-unsaturated pyrrolidinones
in acidic media, see: (a) Xie, Y.; Zhao, Y.; Qian, B.; Yang, L.; Xia, C.;
Huang, H. Angew. Chem., Int. Ed. 2011, 50, 5682 and references cited
therein. (b) Ascic, E.; Jensen, J. F.; Nielsen, T. E. Angew. Chem., Int. Ed.
2011, 50, 5188. This latter example focused on a sequential one-pot
ring-closing metathesis/alkene isomerization/thermal intramolecular
amidoalkylation. The Hoveyda−Grubbs catalyst was used for meta-
thesis, and we suggest some catalyst decomposition at elevated
temperature to generate HCl might be responsible for the
amidoalkylation.
(19) For a representative example, see: Rueping, M.; Nachtsheim, B.
J.; Kuenkel, A. Org. Lett. 2007, 9, 825.
(20) A control experiment showed that IB remained untouched
under similar conditions without preheating of tetrachloroethane.
(21) This temperature is unoptimized, and it is possible that certain
reactions could be performed at even lower temperatures.
(22) Hydroxy lactams derived from phthalimide are poorly reactive
in room-temperature catalytic intermolecular amidoalkylations even
using superacidic catalysts. For more details see ref 9b.
(23) HPLC conditions used for IIIA′: Chiralpak IC column, 80/20
heptane/-PrOH, 1 mL/min, t1 = 8.3 min, t2 = 11.5 min. HPLC
conditions used for IVA: Chiralpak IB column, 85/15 heptane/i-
PrOH, 1 mL/min, t1 = 7.2 min, t2 = 8.9 min; HPLC conditions used
for IA: Chiralpak IC column, 50/50 heptane/i-PrOH, 1 mL/min, t1 =
8.2 min, t2 = 9.5 min. HPLC conditions used for IIA: Chiralpak IA
column, 80/20 heptane/i-PrOH, 1 mL/min, t1 = 8.3 min, t2 = 11.5
min.
(24) (a) Wegner, J.; Ceylan, S.; Kirschning, A. Adv. Synth. Catal.
2012, 354, 17. (b) Hartman, R. L.; McMullen, J. P.; Jensen, K. F.
Angew. Chem., Int. Ed. 2011, 50, 7502.
(25) Flow chemistry has been demonstrated as a useful tool in the
context of acetal activation for nucleoside synthesis: Sniady, A.;
Bedore, M. W.; Jamison, T. F. Angew. Chem., Int. Ed. 2011, 50, 2155.
(26) We consider a potential pressure effect unlikely, because here
pressures are far too low to have any significant effect on transition
state energies. Any effect must be on the composition of the reaction:
i.e., by keeping volatile components dissolved.
(27) We used easily accessible thick-walled vessels with a Teflon
screw cap.
(28) Some reactions presented in this paper were repeated in
refluxing fluorinated solvents for comparison purposes, and very
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