One-pot hydroxy group activation/carbon-carbon bond forming sequence using a Bronsted base/bronsted acid system

Article abstract of DOI:10.1002/adsc.201000602

A new sequential two-step multicatalytic strategy is presented consisting in the efficient DBU-catalysed trichloroacetimidation of an alcohol followed by a ditriflylamine (Tf₂NH)-catalysed intermolecular alkylation by silicon-based nucleophiles and C-H nucleophiles. The distinct feature of the trichloroacetimidate group allows use of weaker acid catalysts such as 1,1′-bi-2-naphthol (BINOL)-derived phosphoric acid, pointing out the possible development of an enantioselective variant. This unprecedented sequential one-pot Bronsted base-Bronsted acid catalysis further expands the synthetic scope of the trichloroacetimidate group. Copyright

Full text of DOI:10.1002/adsc.201000602

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DOI: 10.1002/adsc.201000602
One-Pot Hydroxy Group Activation/Carbon-Carbon Bond
Forming Sequence Using a Brønsted Base/Brønsted Acid System
Alice Devineau,a Guillaume Pousse,b Catherine Taillier,a Jꢀrꢁme Blanchet,b
Jacques Rouden,b and Vincent Dallaa,*
a
URCOM, EA 3221, FR3038, Universitꢀ du Havre, 25 rue Philippe Lebon, BP 540, 76058 Le Havre, France
Fax : (+33)-2-3274-4391; phone: (+33)-2-3274-4401; e-mail: vincent.dalla@univ-lehavre.fr
Laboratoire de Chimie Molꢀculaire et Thio-organique, ENSICAEN, Universitꢀ de Caen Basse-Normandie UMR 6507,
b
CNRS-INC3M FR3038; 6 boulevard du Marꢀchal Juin, 14050 Caen, France
Received: July 28, 2010; Published online: November 9, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000602.
Abstract: A new sequential two-step multicatalytic
strategy is presented consisting in the efficient
DBU-catalysed trichloroacetimidation of an alcohol
followed by a ditriflylamine (Tf2NH)-catalysed in-
termolecular alkylation by silicon-based nucleo-
electrophilic acetate derivatives, the latter constitute
the common alternative to circumvent the problemat-
ic catalytic alkylation of silicon-based nucleophiles.
However, the two acylative and alkylative processes
are always performed sequentially.[2] Instead, the de-
velopment of an efficient and reliable tandem reac-
tion sequence combining the installation of a leaving
group and its subsequent displacement in a one-pot
operation would obviously provide a useful and
straightforward novel solution in catalytic alkylative
chemistry.
Hydroxy lactams derived from phthalimide and
benzhydrol are typical examples of such weakly reac-
tive alcohols in acid-catalysed alkylation with silicon-
based nucleophiles.[3] We report herein the efficient
alkylation of these model substrates by means of a
one-pot homogeneous Brønsted base/Brønsted acid
(BB/BA) organocatalytic sequence. According to our
strategy, the OH group needs to be in situ activated
as a transient good leaving group under conditions
compatible with the subsequent one-pot catalytic al-
À
philes and C H nucleophiles. The distinct feature
of the trichloroacetimidate group allows use of
weaker acid catalysts such as 1,1’-bi-2-naphthol
(BINOL)-derived phosphoric acid, pointing out the
possible development of an enantioselective var-
iant. This unprecedented sequential one-pot Brønst-
ed base-Brønsted acid catalysis further expands the
synthetic scope of the trichloroacetimidate group.
Keywords: N-acyliminium; alkylation; electrophilic
alcohols; sequential organocatalysis; trichloroacet-
ACHTUNGTRENNUNGimidates
Due to some specific attributes including good availa- kylation step (Scheme 1).[4]
bility and minimum side-products, p-alcohols are
ideal electrophilic reagents in modern acid-catalysed
alkylative chemistry. Therefore, considerable advan-
ces in their Lewis and Brønsted acid-catalysed direct
alkylation with carbon nucleophiles have been recent-
ly achieved.[1] Because of the poor leaving group abili-
ty of the hydroxy group, sometimes even under acid-
catalysed conditions, high temperatures and/or long
reaction times are frequently required to achieve
these reactions with good efficiency. This makes par-
ticularly challenging the alkylation of sensitive nucle-
ophiles such as enoxysilanes and ketene silyl acetals,
which do not survive under these drastic reaction con-
ditions. Given the greater catalytic activities generally
Scheme 1. Objective: sequential one-pot Brønsted base-cata-
lysed hydroxy group activation/Brønsted acid-catalysed nu-
observed in the acid-catalysed alkylation of the more cleophilic displacement.
Adv. Synth. Catal. 2010, 352, 2881 – 2886
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The trichloroacetimidate group, which is readily dation of a hydroxy group.[10] The subsequent alkyla-
generated through the base-catalysed reaction of tive step was then undertaken in the same reaction
commercially available trichloroacetonitrile and an al- vessel. Consecutive addition of trimethylsilyl enol
cohol, is a widely used leaving group in cationic ether derived from acetophenone and only 3 mol% of
chemistry. This chemical group was introduced by Tf2NH[11] readily accomplished the alkylation furnish-
Schmidt and co-workers in sugar chemistry and has ing the desired Mannich adduct 2a in yields exceeding
been found very useful for the development of stereo- 90%. A loading of 3 mol% Tf2NH was introduced
selective glycosylations under unprecedented mild here to ensure entire DBU neutralisation.[12] Careful
TMSOTf-catalysed conditions.[5] The unique ability of monitoring of the alkylation step revealed a complete
a sugar-derived trichloroacetimidate to undergo effi- conversion within less than 15 min, confirming the ex-
cient glycosylation processes under mild acidic condi- cellent potential of Tf2NH as pre-catalyst in the cata-
tions is obviously due to its specific feature to release lytic alkylative reactions of silyl enol ethers
neutral trichloroacetamide, which does not interfere
with the subsequent catalytic glycosylation. The tri-
chloroacetimidate method has also been useful in
Table 1. Scope of the one-pot BB/BA-catalysed a-amidoal-
carbon-carbon bond forming reactions, with some
recent applications to the catalytic alkylation of hy-
droxy lactams,[6] hydroxymethylimides[7] and benzylic/
propargylic type alcohols.[8] However, a two step-two
stage protocol was systematically followed in these
approaches. Due to its unique features we believe
that this trichloroacetimidate chemistry holds the po-
tential for implementing our required BB/BA alkyla-
tive organocatalytic sequence.
kylation with N-protected hydroxy lactams and trimethyl-
silyl enol ether 3a.[a]
Recognising that the trichloroacetimidation of alco-
hols generally requires sub-stoichiometric amounts of
base (frequently 0.5 equiv. DBU or NaH) and/or
large excess (5–10 equiv.) of trichloroacetonitrile, our
studies started with the search for optimal catalytic
trichloroacetimidation conditions. Starting with com-
pound 1a (R=allyl), this was efficiently achieved
using only 1 mol% DBU and 1.2 equiv. of trichloro-
Entry Substrate
Product
Yield
4 n=1 82%
5 n=2 100%
1
ACHTUNGTRENNUNGacetonitrile in either acetonitrile, dichloromethane or
toluene (Scheme 2).[9]
We believe that this careful optimisation not only
was crucial for the success of the subsequent acid-cat-
alysed alkylation, but also constitutes the most effi-
cient protocol so far reported for the trichloroacetimi-
2
3
4
6
90%
7 n=1 98%
8 n=2 91%
9
97%
98%
5
10
Scheme 2. Optimisation of the sequential one-pot Brønsted
base-catalysed hydroxy trichloroacetimidation/Tf2NH-cata-
lysed nucleophilic displacement.
[a]
Experimental details are given in the Supporting Infor-
mation.
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One-Pot Hydroxy Group Activation/Carbon-Carbon Bond Forming Sequence
Table 2. Scope of the one-pot BB/BA-catalysed a-amidoal-
kylation of hydroxy lactam 1a with various nucleophiles.[a]
Table 2. (Continued)
Entry Nucleophile
Product
Yield
9
2j[d] 55%[b,e]
Entry Nucleophile
Product
Yield
76%
[a]
Experimental details are given in the Supporting Infor-
mation.
1
2b
[b]
[c]
Reaction carried out in CH3CN.
90% corrected yield (calculated from recovered hydroxy
lactam).
[d]
[e]
Isolated with minor by-products as an inseparable mix-
ture.
Estimated yield.
2
3
2c
62%
(Scheme 2).[11] To the best of our knowledge, this se-
quence is the first example of two consecutive chemi-
cal transformations distinctly catalysed by a Brønsted
2d
100%
base and
a Brønsted acid in a homogeneous
manner.[13]
The substrate scope of this sequential BB/BA reac-
tion was first examined with silylated enol ether 3a
using a variety of nitrogen substituents on the hy-
droxy lactam partner (Table 1). In all cases, the reac-
tions proceeded smoothly providing the correspond-
ing alkylation products 4–10 in high yields (up to
100%). Reaction producing 8 is noteworthy since the
product arising from the potentially undesirable intra-
molecular Friedel–Crafts reaction was not formed.[14]
In order to further demonstrate the versatility of
this methodology, a series of nucleophiles was tested
in the alkylation of hydroxy lactam 1a using the opti-
mal conditions described above (Table 2).
4
5
2e
2f
96%
76%[b]
Most of these reactions were carried out in CH2Cl2,
but some examples are described in CH3CN simply to
demonstrate that the process tolerates either solvent.
When allyltrimethylsilane or silyl enolates derived
from pivalone, methyl acetate and methyl 2-methyl-
propionate were used, the resulting alkylated prod-
ucts 2b–e were isolated in good to excellent yields
(Table 2, entries 1–4).[15] As anticipated from their
high reactivity in direct alkylation with hydroxy lac-
6
7
2g
2h
92%[b]
100%[b]
tams,[16] typical C H nucleophiles such as pyrrole and
À
indole were found to be efficient partners in this BB/
BA tandem alkylation furnishing adducts 2g (one re-
gioisomer) and 2h in high yields (entries 5–7). A
major significance of this trichloroacetimidation-
based methodology was next demonstrated using less
reactive dibenzoylmethane, 1,2-dimethoxybenzene
and anisole. Indeed, we were particularly pleased to
observe formation of the corresponding Friedel–
Crafts adducts 2f (76%), 2i (58%) and 2j (55%)[17]
8
2i
58%[c]
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find that rac-BINOL-derived phosphoric acid PAI[[2109]]
or its slightly more acidic dithio analogue PAII
(3 mol%) were effective catalysts for the process
(Table 4), with PAI performing better than the thio
analogue PAII (entries 1–3). These are the first exam-
ples documenting the use of phosphoric acid catalysts
for the nucleophilic substitution of cyclic N,O-ace-
tals.[21] When the sequential trichloroacetimidation
method was performed with Yamamotoꢃs more acidic
N-triflylphosphoramide catalyst PAIII,[22] the resulting
alkylated product 2a was isolated in high yields using
either CH3CN or CH2Cl2, (entries 4 and 5). CH2Cl2
being a suitable solvent for catalytic enantioselective
ion-pairing approaches, we believe that this last find-
ing provides the foundation for the design of a cata-
lytic enantioselective a-amidoalkylation between hy-
droxy lactams and silyl enol ethers. The efficiency of
our trichloroacetimidation-based method was further
highlighted by comparison with the direct Mannich
reaction starting from the acetoxy lactam derivatives
18.[23] Whereas use of PAI and PAII completely failed
to produce the desired alkylated product (entries 6
and 7), PAIII-catalyzed reaction proceeded with high
efficiency but only in CH3CN (entry 8).[24] Indeed,
when the reaction was performed in CH2Cl2, no reac-
tivity was observed (entry 9).
Table 3. One-pot BB/BA-catalysed alkylation of benzhydrol
17.[a]
Entry
1
NuSiR3
Product
Yield[b]
100%
17a
17b
17c
2
3
84%
87%
4
5
17d
17e
96%
97%
6
17f
98%
The development of an asymmetric approach using
a trichloroacetimidate intermediate is now being in-
vestigated and results will be reported in due course.
To summarise, we have developed an original ho-
mogeneous nucleophilic substitution using Brønsted
base/Brønsted acid (BB/BA) multicatalytic sequence.
[a]
Experimental details are given in the Supporting Infor-
mation.
Isolated yields.
[b]
(entries 8 and 9), while no reactivity was initially ob- This very fast room temperature one-pot two stage
served in direct addition onto hydroxy lactam 1a. protocol proceeds through the activation of a hydroxy
We next investigated whether this sequential BB/ group via a DBU-catalysed trichloroacetimidation
BA catalysis sequence could be extended to common step immediately followed by an acid-catalysed nucle-
p-alcohols which were previously identified as reluc- ophilic displacement of the trichloroacetimidate
tant substrates under mild Tf2NH-catalyzed (1– group. The procedure was established with the nucle-
5 mol%) alkylation mode.[3]
ophilic substitution of hydroxy lactams and benzhy-
Preliminary results using benzhydrol 16 for direct drol, two weakly reactive alcohols in the direct acid-
alkylation with silicon-based nucleophiles are present- catalysed alkylation with silyl enol ethers, and was
ed in Table 3, showing that this kind of alcohol is also carried out with low catalyst loadings. With few ex-
a viable candidate. These results further exemplified ceptions, all the reactions presented in this report did
the synthetic potential of our method since all the al- not proceed if the trichloroacetimidation step was
kylated products were obtained in excellent yields (up omitted. Besides its synthetic utility in catalytic alky-
to 100%).
lative chemistry, this simple reaction adds to the in-
Finally, we were wondering whether this trichloro- creasingly wider repertoire of multicatalytic reactions,
ACHTUNGTRENNUNG
generation of N-acyliminium-chiral phosphate ion
pair.[18]
rac-BINOL-derived Brønsted acids PAIÀIII were
then tested in the Mannich reaction of the trichloro-
Experimental Section
ACHTUNGTRENNUNG
All experimental details are given in the Supporting Infor-
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One-Pot Hydroxy Group Activation/Carbon-Carbon Bond Forming Sequence
Table 4. Weak BINOL-derived acids in the one-pot BB/BA-catalysed alkylation of hydroxy lactams.
Entry
Substrate
Method[a]
Catalyst
Solvent
Time[b]
Yield
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
18
18
18
18
A
A
A
A
PAI
PAI
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
6 h
4 h
6 h
12 h
2 h
12 h
12 h
2 h
74%
61%
59%
79%
90%
0%
PAII
PAIII
PAIII
PAI
PAII
PAIII
PAIII
A
B[c]
B[c]
B
12%[d]
100%
0%
B
12 h
[a]
Method A: 1 mol% DBU and 1.2 equiv Cl3CCN, room temperature, 30 min, then 1.5 equiv. silyl enol ether and 3 mol%
of PAI–III. Method B: 1.5 equiv. silyl enol ether and 2 mol% of PAI–III
Unoptimised reaction time referring to the alkylative step.
5 mol% of the catalyst was used.
.
[b]
[c]
[d]
I
Determined by H NMR on the crude product.
General Procedure for the Sequential One-Pot BB/
BA-Catalysed Intermolecular a-Amidoalkylation of
Hydroxy Lactams
Acknowledgements
We gratefully acknowledge the region Haute-Normandie and
the rꢀseau CRUNCH for a grant to AD and financial sup-
port.
To a room temperature solution of hydroxy lactam 1a–h
(0.16 mmol) in 0.5 mL of dichloromethane or acetonitrile
(as indicated in the text), trichloroacetonitrile (19 mL,
0.19 mmol, 1.2 equiv.) was added dropwise. After 10 min of
stirring, 1 mol% DBU was introduced (6.4 mL). As the tran-
sient trichloroacetimidate entities were found to be labile on
TLC, readily giving back the starting material, the first step
was checked by 1H NMR spectroscopy. Regardless of the
nature of both substituent at nitrogen and solvent, the de-
sired trichloroacetimidates were totally formed within
30 min. At this stage, the nucleophile (1.2 equiv. except for
allyltrimethylsilane and anisole where 2 equiv. and 4 equiv.
are respectively used) and 3 mol% of the acid catalyst
(9.6 mL) were added dropwise at room temperature. The
end of the reaction was monitored by TLC and the product
was purified by flash-column chromatography, eluting with
cyclohexane/EtOAc (80/20).
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