Direct carbon - Carbon bond formation via soft enolization: A facile and efficient synthesis of 1,3-diketones

Article abstract of DOI:10.1021/ol701599v

Ketones undergo soft enolate formation and acylation on treatment with MgBr₂·OEt₂, i-Pr₂NEt, and various acylating agents to give 1,3-diketones. The process is particularly efficient for N-acylbenzotriazoles and O-Pfp esters, and, in these cases, is conducted with untreated, reagent-grade CH₂Cl₂ open to the air, thus providing an exceptionally simple approach to the synthesis of this important class of compounds.

Full text of DOI:10.1021/ol701599v

ORGANIC
LETTERS
2
007
Vol. 9, No. 21
139-4142
Direct Carbon−Carbon Bond Formation
via Soft Enolization: A Facile and
Efficient Synthesis of 1,3-Diketones
4
Daniel Lim, Fang Fang, Guoqiang Zhou, and Don M. Coltart*
Department of Chemistry, Duke UniVersity, Durham, North Carolina 27708
don.coltart@duke.edu
Received July 7, 2007
ABSTRACT
2 2 2
Ketones undergo soft enolate formation and acylation on treatment with MgBr ‚OEt , i-Pr NEt, and various acylating agents to give 1,3-
diketones. The process is particularly efficient for N-acylbenzotriazoles and O-Pfp esters, and, in these cases, is conducted with untreated,
reagent-grade CH
2
Cl
2
open to the air, thus providing an exceptionally simple approach to the synthesis of this important class of compounds.
1
1
,3-Diketones are important compounds in synthetic organic
diketones. The classic procedure, which is a modification
1,2
3
chemistry. They are widely represented in natural products,
pharmaceuticals, and other biologically relevant compounds,
or are key intermediates en route to such species. Indeed,
their interesting and at times unusual chemical properties
are often used to facilitate other synthetic methods, including
the preparation of heterocycles and other aromatic com-
pounds. Many naturally occurring 1,3-diketones exhibit
biological activity including antioxidant, antitumor, anti-
microbial, antiviral, and antifungal activity. Despite their
prevalence, the synthesis of 1,3-diketones remains problem-
atic. As part of an ongoing program aimed at developing
operationally simple approaches to key carbon-carbon bond-
forming reactions via soft enolization, we have developed a
method for 1,3-diketone synthesis that resolves the long-
standing problems associated with their preparation. In our
approach, a ketone and either an N-acylbenzotriazole or
of the well-known Claisen condensation, involves acylation
of a ketone by an ester in the presence of an alkoxide base.1
This method has limited substrate scope, gives only modest
to good yield, requires a large excess of the acylating agent,
and often requires elevated temperatures and/or removal of
the alcohol produced. Coupling yields are generally improved
through the use of at least 2 equiv of sodium or lithium
hydride in place of the alkoxide, but this approach is not
applicable to substrates having even weakly acidic function-
ality elsewhere in the reactants. The current procedure of
choice for 1,3-diketone synthesis uses a strong, non-
nucleophilic base such as LDA to preform the required
enolate, which is followed by addition of the acylating agent,
typically as an acid chloride. Yields generally improve under
these conditions, but the presence of acidic functionality
elsewhere in the reactants remains an issue. Furthermore,
1
2
1
3
O-Pfp ester are combined with MgBr
2
‚OEt
2
and i-Pr
2
NEt in
competing O-acylation and bis-acylation are common. The
untreated, reagent-grade CH Cl open to the air. Prior enolate
2
2
major drawback of this method is that at least 2-3 equiv of
the enolate are required, making it inherently inefficient.3
This stems primarily from the fact that the 1,3-diketone
formation and the use of a large excess of enolate and
acylating agent are avoided, making the method both facile
and efficient compared to conventional approaches.
Considerable research has been conducted over the years
on the development of methods for the synthesis of 1,3-
product is significantly more acidic (pK
ketone (pK
≈ 20), so, as it forms, it protonates the unreacted
ketone enolate preventing acylation.
a
≈ 9) than the parent
a
(
3) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry:
(
1) Kel’in, A. V. Curr. Org. Chem. 2003, 7, 1691-1711.
Reactions, Mechanisms, and Structure, 6th ed.; Wiley & Sons: Hoboken,
NJ, 2007; Chapter 16.
(2) Kel’in, A. V.; Maioli, A. Curr. Org. Chem. 2003, 7, 1855-1886.
1
0.1021/ol701599v CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/18/2007

We reasoned that the inefficiency of these conventional
methods could be overcome if the required enolates were
formed under soft rather than hard conditions. In hard
enolization the required enolates are preformed by treatment
with a strong, non-nucleophilic base such as LDA (Scheme
provide the basis for workable solutions to the aforemen-
tioned problems associated with the synthesis of 1,3-
diketones.
To explore the use of soft enolization in 1,3-diketone
synthesis, acetophenone (6) was combined with benzoyl
chloride (7), MgBr
2
‚OEt
2 2 2 2
, and i-Pr NEt in CH Cl (Scheme
1). While effective, these stepwise procedures are time-
2
). The desired 1,3-diketone (8) was indeed isolated from
Scheme 1. Hard and Soft Enolate Formation
Scheme 2. MgBr
2
2
‚OEt -Promoted Direct Acylation of
Acetophenone and Representative Acid Chlorides
this reaction in very good yield (83%) after only 1 h. A
control experiment was carried out in which acetophenone
and benzoyl chloride were combined in CH
presence of i-Pr NEt but in the absence of MgBr
no coupled product observed after 24 h, thus confirming the
essential nature of the Lewis acid in enolization. Encouraged
2
Cl
‚OEt
2
in the
2
, with
consuming, particularly if enolate trapping is involved, and
require that all manipulations be conducted under anhydrous
conditions and, when strong bases are used, at low temper-
atures. An alternative is soft enolization (Scheme 1), which
does not employ a strong base and, consequently, can be
conducted under less stringent conditions (e.g., open to the
2
2
by the result with MgBr
2 2
‚OEt , we conducted a similar
reaction with the aliphatic system, 3,3-dimethylbutanoyl
chloride (9). In this case the desired product (10) was also
obtained, but in a somewhat lower yield (65%). Use of
pentanoyl chloride (11) as the acylating agent also gave the
desired â-diketone (12), albeit in a much lower yield (30%)
due to formation of the R,R-bis-acylation byproduct (13),
as is typical when acid chlorides are used in enolate
acylations. None of the reactions showed any improvement
in yield when left for greater than 1 h.
4
air, untreated solvent, rt) than are required of hard enoliza-
tion. In soft enolization, a weak base and a Lewis acid act
in concert to effect deprotonation reversibly. Here, the Lewis
acid interacts with the carbonyl oxygen to polarize it beyond
its normal state, resulting in a substantial increase in the
acidity of the R-proton, to the extent that it can be removed
appreciably by the weak base. Since enolization in this case
is reversible, it is conducted in a direct fashion in the presence
of the electrophilic species, further simplifying the procedure.
In addition, when applied in acylation reactions the â-di-
Significantly, in the two reactions involving 9 and 11, no
products were detected corresponding to self-acylation of the
acid chloride (14 or 15, respectively, Scheme 3). This is
2
carbonyl product (3, E ) COR , Y ) alkyl/aryl, Scheme 1)
that forms would not be expected to interfere in a detrimental
way, as in situations employing hard enolization. Deproto-
nation of this species by the ketone enolate (cf. 5, Y ) alkyl/
aryl) would undoubtedly occur, but in a reversible sense such
that the intended ketone enolate could reform and eventually
undergo the desired acylation. Given the relatively weak
nucleophilic nature of the dicarbonyl enolate, bis-acylation
should not occur with appropriate choice of acylating agent.
Scheme 3. Mechanistic Considerations in the
‚OEt -Promoted Direct Acylation with Acid Chlorides
2
MgBr
2
We recently reported the initial stages of development of
an efficient MgBr
simple thioesters based on soft enolization. The reaction is
conducted with inexpensive MgBr ‚OEt in untreated, reagent-
grade solvent open to the air, and produces innocuous
byproducts on workup. Given the efficiency, mildness, and
operational simplicity of this reaction, we felt that it might
2
‚OEt
2
-promoted direct aldol addition of
understandable if it is assumed that the reaction is facilitated
by coordination of Mg to the carbonyl oxygen (1 f 16),
4
2+
followed by deprotonation to form the enolate (16 f 17),
rather than on the basis of R-proton acidity alone. In such a
case, despite greater acidity predicted for the acid chloride
R-protons (1, Y ) Cl) compared to the ketone (1, Y ) alkyl/
aryl), its relatively electron deficient carbonyl oxygen would
be less prone to coordination to the electrophilic metal salt
(1 f 16, Y ) Cl) and, correspondingly, enolate formation,
2
2
(
4) Zhou, G.; Yost, J. M.; Coltart, D. M. Synthesis 2007, 478-482. Yost,
J. M.; Zhou, G.; Coltart, D. M. Org. Lett. 2006, 8, 1503-1506.
4140
Org. Lett., Vol. 9, No. 21, 2007

compared to the ketone. This model is also consistent with
the lack of reactivity observed in the control experiment
Table 2. MgBr
Solvent Open to the Air
2
2
‚OEt -Promoted Coupling with Untreated
2 2
described above, in which MgBr ‚OEt was omitted for the
reaction.
To improve the yield for the aliphatic systems, we
undertook an investigation into the effect of the acylating
component on the outcome of the reaction. To do this we
screened a variety of known acylating agents both with and
5
without added DMAP as a nucleophilic acylation catalyst.
The results are summarized in Table 1. Addition of DMAP
Table 1. Effect of the Acylating Agent on the
MgBr
2
‚OEt
2
-Promoted Synthesis of 1,3-Diketones
nucleophilic
time yield
entry
acylating agent
9, X ) Cl
acylation catalyst (h)
(%)
1
2
3
4
5
6
7
8
9
1
1
63
65
NR
40
39
79
80
92
96
92
2 2
dry CH Cl and an Ar atmosphere (see Table 2, entry 1).
As such, this protocol was employed for the remainder of
our work.
9, X ) Cl
DMAP
18, X ) O-succinimide
19, X ) SC6H4-4-NO2
19, X ) SC6H4-4-NO2
20, X ) OC6F5
20, X ) OC6F5
20, X ) OC6F5
24
24
12
12
24
3
DMAP
DMAP
Having secured a mild and straightforward method for the
synthesis of â-diketone 10, we determined the scope of the
method with respect to other N-acylbenzotriazoles and O-Pfp
esters (see Table 2). In general, the N-acylbenzotriazoles
outperformed the O-Pfp esters in terms of both reaction time
and yield. The isolated yields were typically excellent when
N-acylbenzotriazoles were used. Significantly, the coupling
reaction could be carried out in the presence of an acidic
urethane nitrogen protecting group (entry 11), and also in
the presence of an enone (entry 14), without detrimental
results, as would be expected in the corresponding hard
enolization processes.
21, X ) benzotriazole
21, X ) benzotriazole
1
0
DMAP
3
was uniformly of no benefit with regard to either the time
required for the reaction or the yield produced (entries 2, 5,
7, and 10). O-Succinimide ester 18 failed to react altogether,
and while thioester 19 did produce the desired product, yields
were lower than for the corresponding acid chloride (9).
O-Pfp ester 20 proved to be a suitable acylating agent, giving
We next explored the scope of the coupling reaction using
a variety of ketones with various N-acylbenzotriazoles and
O-Pfp esters (see Table 3). Once again, in all cases the
desired 1,3-diketone was obtained in good to excellent yield.
Notably, the coupling could be conducted with cyclohex-
anone as the nucleophile to give the corresponding mono-
substituted 1,3-diketone (33) in excellent yield (entry 13).
Entries 11 and 12 reveal that the process is even compatible
with the presence of phenolic functionality. Such a substrate
would not be amenable to traditional coupling methods
without prior incorporation of a phenol protecting group. A
significant result is shown in entry 18 where 1-[(E)-
cinnamoyl]-1H-benzotriazole and 3-pentanone were coupled
to give the desired 1,3-dicarbonyl (35) without subsequent
cyclization to the corresponding 1,3-cyclohexanedione (36),
79% yield of the â-diketone within 12 h and 92% within 24
h. Even better yields and shorter reaction times resulted from
6
the use of N-acylbenzotriazole 21. Thus, both O-Pfp esters
and N-acylbenzotriazoles were investigated in our subsequent
studies.
Another compelling reason for the use of O-Pfp esters and
N-acylbenzotriazoles in this reaction is that, unlike acid
chlorides, they are relatively insensitive to moisture. This
trait would potentially allow us to conduct the coupling
reactions open to the air using untreated, reagent-grade CH
Cl , resulting in even greater simplification of the procedure.
To test this, N-acylbenzotriazole 21 and O-Pfp ester 20 were
each combined with acetophenone, MgBr ‚OEt , and i-Pr
NEt with use of untreated, reagent-grade CH Cl open to
2
-
2
2
2
2
-
2
2
1
as is typical of such systems. To further explore the
the air. Under these conditions the desired 1,3-dicarbonyl
product (10) was obtained with no change in either the
isolated yield or reaction time, in comparison to the use of
versatility of our method, we undertook the synthesis of 23
in an inverse sense by switching the respective ketone and
acylbenzotriazole. Thus, methyl ketone 37 was prepared
7
according to known procedures and was subjected to the
(
5) Scriven, E. F. V. Chem. Soc. ReV. 1983, 12, 129-161. Spivey, A.
C.; Arseniyadis, S. Angew. Chem., Int. Ed. 2004, 43, 5436-5441.
coupling with 1-benzoylbenzotriazole. â-Diketone 23 was
(
6) The pentafluoro phenol (pKa ≈ 5) produced in the coupling reaction
can be recovered by extraction into saturated aqueous NaHCO3, followed
by neutralization (10% HCl) and back extraction (EtOAc).
(7) Vries, E. F. S.; Steenwinkel, P. J. Org. Chem. 1993, 58, 4315-4325.
Org. Lett., Vol. 9, No. 21, 2007
4141

of the synthetic procedures, thus demonstrating that our
method is also compatible with substrates prone to base-
induced epimerization under conventional hard enolization
conditions.
Table 3. MgBr
Solvent Open to the Air
2
2
‚OEt -Promoted Coupling with Untreated
In conclusion, we have developed an efficient direct
coupling reaction between ketones and N-acylbenzotriazoles
or O-Pfp esters, based on soft enolization, that proceeds under
mild conditions to generate 1,3-diketones. The reaction is
2 2
conducted with inexpensive MgBr ‚OEt in untreated, reagent-
grade solvent open to the air, and produces innocuous
byproducts on workup, making it operationally simple.
Furthermore, it is compatible with a range of substrates,
including those having base-epimerizable centers adjacent
to carbonyl groups, as well as those possessing other base-
sensitive functionality. Thus, syntheses employing this
carbon-carbon bond-forming method may well benefit in
the avoidance of protecting groups. Given the importance
of 1,3-dicarbonyl compounds in general, along with the
operational simplicity and mild nature of this reaction, we
expect that it will meet with wide application in synthetic
chemistry.
indeed produced from this reaction, and in a yield (88%)
comparable to that obtained when prepared from acetophe-
none and 38 (91%) (Table 2, entry 7).
Finally, we examined the impact of the coupling reaction
on the stereochemical integrity of the starting materials. As
mentioned above, conventional methods for â-dicarbonyl
synthesis are limited to substrates lacking acidic functionality.
This includes compounds having base epimerizable stereo-
genic centers R to a carbonyl group. To test the effect of
our coupling conditions on such compounds, compound 23,
prepared from 38 and acetophenone and from 37 and
Acknowledgment. D.L. and G.Z. are grateful for Bur-
roughs Wellcome Fellowships from the Duke University
Department of Chemistry. This work was supported, in part,
by the ACS Petrolum Research Fund.
Supporting Information Available: Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1-benzoylbenzotriazole, was compared to the corresponding
racemic material by HPLC using a chiral, nonracemic
stationary phase. No racemization had occurred during either
OL701599V
4142
Org. Lett., Vol. 9, No. 21, 2007