Selective addition of organolithium reagents to BF2-chelates of β-ketoesters

Article abstract of DOI:10.1021/ol100620j

A short, mild, and highly chemoselective addition of organolithium reagents to a BF₂ complex of 3-oxopropanoates has been developed. The methodology allows straightforward preparation of various 1,3-dioxa-BF ₂ complexes and subsequently leads to the formation of 1,3-diketones starting from the corresponding 3-oxopropanoates.

Full text of DOI:10.1021/ol100620j

ORGANIC
LETTERS
2010
Vol. 12, No. 13
2900-2903
Selective Addition of Organolithium
Reagents to BF2-Chelates of ꢀ-Ketoesters
ˇ
Bogdan Stefane*
Faculty of Chemistry and Chemical Technology, UniVersity of Ljubljana, AsˇkercˇeVa 5,
SI-1000 Ljubljana, SloVenia
bogdan.stefane@fkkt.uni-lj.si
Received March 16, 2010
ABSTRACT
A short, mild, and highly chemoselective addition of organolithium reagents to a BF2 complex of 3-oxopropanoates has been developed. The
methodology allows straightforward preparation of various 1,3-dioxa-BF2 complexes and subsequently leads to the formation of 1,3-diketones
starting from the corresponding 3-oxopropanoates.
Carbon-carbon bond formation is one of the foremost topics
in organic synthesis. There have been numerous methods
developed to date, each of them having their own advantages
and disadvantages. Among these methods, ones characterized
by high functional group tolerance are most desired. It has
been known for many years that coordination of the Lewis
basic carbonyl group by Lewis acids enhances the electro-
philic character of the carbonyl carbon. This phenomenon
has played a crucial role in the development of mild
nucleophilic reagents for carbon-carbon bond formation.1
In the 1970s, Smith and Spencer described the formation of
2-alkylidene ketones employing BF2 complexes of 2-formyl
ketones and organometallic reagents.2 In the past few years,
we have been interested in the reactivity of ꢀ-diketonatoboron
difluorides and their applications as a starting materials for
the regioselective enamine formation3 as well as construction
of several heterocycles.4 Additionally, Christoffers et al.
demonstrated regioselective enamine formation from oxonia-
boranuida-betaines and their application in the asymmetric
Michael reaction.5 Garcia-Garibay et al. used difluorodiox-
aborinines as a tool for the enantiomerically pure synthesis
of natural products (+)- and (-)-R-cuparanone.6 Recently,
different 1,3-dioxa-BF2-chelate systems have been shown to
be remarkably efficient probes for tumor hypoxia imaging7
and as near-infrared probes for in vivo detection of amiloid-ꢀ
deposites.8 Additionally, materials with the 1,3-dioxa-BF2-
chelate functionality possess n-type semiconducting proper-
ties, recently discovered by Ono et al.9
The long-known and readily prepared boron difluoride
complexes of alkyl and aryl 3-oxopropanoates (e.g., 2)
seemed to offer an attractive alternative method for the
synthesis of asymmetrically substituted 1,3-diketonatoboron
difluorides if the electrophilicity at the ester moiety of the
ˇ
ˇ
(4) (a) Stefane, B.; Polanc, S. Synlett 2004, 698–702. (b) Stefane, B.;
ˇ
Polanc, S. Tetrahedron 2007, 63, 10902–10913. (c) Stefane, B.; Polanc, S.
Tetrahedron 2009, 65, 2339–2343.
(5) Christoffers, J.; Kreidler, B.; Unger, S.; Frey, W. Eur. J. Org. Chem.
2003, 2845–2853.
(1) For reviews, see: (a) Corma, A.; Garc´ıa, H. Chem. ReV. 2003, 103,
4307–4365. (b) Ishihara, K.; Yamamoto, H. Eur. J. Org. Chem. 1999, 527–
538. (c) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-
VCH: Weinheim, 2000. (d) Modern Carbonyl Chemistry; Otera, J., Ed.;
Wiley-VCH: Weinheim, 2001. For recent examples, see: (e) Abraham, C. J.;
Paull, D. H.; Bekele, T.; Scerba, M. T.; Dudding, T.; Lectka, T. J. Am.
Chem. Soc. 2008, 130, 17085–17094. (f) Fu, G. C. J. Org. Chem. 2004,
69, 3245–3249. (g) Morrison, D. J.; Piers, W. E. Org. Lett. 2003, 5, 2857–
2860.
(6) Natarajan, A.; Ng, D.; Yang, Z.; Garcia-Garibay, M. A. Angew.
Chem., Int. Ed. 2007, 46, 6485–6487.
(7) Zhang, G.; Palmer, G. M.; Dewhirst, M. W.; Fraser, C. L. Nat. Mater.
2009, 8, 747–751.
(8) Ran, C.; Xu, X.; Raymond, S. B.; Ferrara, B. J.; Neal, K.; Bacskai,
B. J.; Medarova, Z.; Moore, A. J. Am. Chem. Soc. 2009, 131, 15257–15261.
(9) (a) Ono, K.; Yamaguchi, H.; Taga, K.; Saito, K.; Nishida, J.;
Yamashita, Y. Org. Lett. 2009, 11, 149–152. (b) Ono, K.; Hashizume, J.;
Yamaguchi, H.; Tomura, M.; Nishida, J.; Yamashita, Y. Org. Lett. 2009,
11, 4326–4329.
(2) Smith, R. A. J; Spencer, T. A. J. Org. Chem. 1970, 35, 3220–3223.
ˇ
(3) Stefane, B.; Polanc, S. New J. Chem. 2002, 26, 28–32.
10.1021/ol100620j  2010 American Chemical Society
Published on Web 06/11/2010

complex 2 is dominated over the other functionalities present.
Furthermore, formed 1,3-diketonatoboron difluorides 3 can
be subsequently transformed into the corresponding 1,3-
diketones and other amino derivatives under mild reaction
conditions.4-6 Accordingly, an investigation of the reactions
of the BF2 complex of type 2 with selected organometallic
reagents was undertaken (Scheme 1, Table 1).
As is evident from Table 1, a BF2 complex of 1,3-
diketoesters favors the addition of organolithium reagents
to ester functionality, affording the corresponding asymmetric
1,3-diketonatoboron difluorides (Scheme 1).
BF2 complexes of 1,3-diketoesters. Limiting the organolith-
ium reagent to 1.1 equiv, control of the reaction temperature
and lower reactivity of the products seems to prevent the
reaction yielding the overaddition products.
Table 1. Reaction of 2a with R2M at Different Reaction
Conditions
yield
entry
R2M (equiv)
n-BuLi (1.1)
n-BuMgCl (1.1)
n-Bu2Zn (1.1)
solvent temp (°C) of 3a (%)
1
2
3
4
5
6
7
8
9
THF
THF
THF
-78
-78
-78
73
9
NOb
NOb
43
(n-Bu)2Cu(CN)Li2 (1.1) THF
-78
Scheme 1. Reaction of BF2 Complex of Ethyl
3-Oxopropanoates with Organometallic Reagents
n-BuLi (1.1)
n-BuLi (1.1)
n-BuLi (1.5)
n-BuLi (1.1)
n-BuLi (1.5)
Et2O
PhMe
THF
THF
THF
-78
-78
-78
-78 to 25
-78 to 25
21
71
70
43
a Isolated yields are given, b NO (not observed), ethyl 3-phenyl-3-
oxopropanoate was isolated instead.
With our optimized reaction conditions in hand, the scope
of organolithium reagent addition to several difluoroboron
complexes 2 was investigated. In general, the yields of the
reaction were good (40-97%). t-BuLi also underwent
successful addition albeit with modest yield, which can be
attributed to its steric hindrance and rather strong basicity.
Phenyllithium was also found to undergo successful trans-
formation in good yield subsequently broadening the scope
of the transformation. In addition to alkyl- and aryllithiums,
the applicability of more challenging and synthetically useful
alkynyl and heteroarylorganolithiums was examined (Table
2, entries e-g,l,m).
Initially, we chose derivative 2a as the model substrate
for surveying reaction parameters in the model reaction
(Table 1). The initial screening of several n-Bu-orga-
nomethalic reagents revealed that only n-BuLi adds success-
fully to the activated carboxylic group in complex 2a deriving
the desired product 3a in very promising yield (Table 1, entry
1). On the other hand, analogue organozinc and higher order
organocuprates10 (Table 1, entries 3 and 4) did not lead to
the formation of the desired product. Instead, in both cases,
ethyl 3-phenyl-3-oxopropanoate was isolated almost quan-
titatively. The result suggests that most likely softer orga-
nometallic reagents react on the boron moiety of the complex
2a, via the ate complex, thus deriving the corresponding 1,3-
ketoester. However, when n-BuMgCl was used as a reagent
under the same reaction conditions, the desired product in
low yield (9%) together with ethyl 3-phenyl-3-oxopropanoate
was obtained.
Next, a variety of experimental variables, such as reaction
temperature, choice of solvent, and reagent (n-BuLi) loading
were systematically examined. After thorough investigation,
we found that the best results were accomplished using 1.1
equiv of the organolithium reagents at -78 °C in THF
followed by quenching of the reaction mixture at the same
temperature and subsequent extraction of the product into
dichloromethane (see Table 1). Reacting 3a at -78 °C in
THF with phenyllithium for 30 min followed by quenching
of the reaction mixture at the same temperature resulted in
recovery of the starting material 3a in 87% yield together
with 4% of the mixture of corresponding alcohols. This result
indicates that ꢀ-diketonatoboron difluorides are less reactive
under the applied reaction conditions comparing to analogous
As is evident from Table 2, 2-furyl- and 2-thioazolyl-
lithium prepared according to the literature procedures11 gave
Table 2. Reaction of 2 with R2Li Reagents
starting
material 2
yield
of 3a (%)
R1
R2
a
b
c
d
e
f
g
h
i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
3a (97)
3b (73)
3c (39)
3d (82)
3e (98)
3f (69)
3g (74)
3h (55)b
3i (43)b
3j (41)b
3k (61)
3l (81)
n-Bu
t-Bu
Ph
PhCt
C
2-furyl
2-thiazolyl
Ph
Me
n-Bu
Ph
4-methoxyphenyl
3-furyl
3-furyl
3-furyl
3-furyl
j
k
l
PhCt C
m
n
3-furyl
3-furyl
2-furyl
2-thiazolyl
3m (77)
3n (69)b
a Isolated yields are given, b 5-10% of the corresponding 1,3-diketone
was isolated.
(10) Organocopper Reagents: A Practical Approach; Taylor, R. J. K.,
Ed.; Oxford University Press: Oxford, 1994.
Org. Lett., Vol. 12, No. 13, 2010
2901

the desired products in synthetically useful yields. At this
point, it is appropriate to note that in some cases a minor
percentage of the corresponding 1,3-diketone was detected
in the crude reaction product arising from hydrolytic reaction
during reaction workup. The amount of the uncoordinated
1,3-diketone was higher under the basic reaction workup and
prolonged stirring of the workup mixture (30 min).
Interestingly, when TMSCH2Li was employed as a re-
agent, compounds 3a and 7a were isolated as in the case of
using methyllithium. The rationale of this transformation is
depicted in Scheme 2.
dichloromethane at room temperature were determined as
ΦF ) 0.45 and 0.87, respectively.
Scheme 3. Reaction of BF2 Complex of Ethyl 1-Oxo-1,2,3,4-
tetrahydronaphthalene-2-carboxylate (6) with R2Li Reagents
Scheme 2. Reaction of BF2 Complexes 2a and 6 with TMSCH2Li
Detailed optical, electrochemical and the solid-state emis-
sion properties of this and related compounds are currently
under investigation and the results are going to be published
in due course.
The addition of TMSCH2Li to the ester moiety of complex
2a or 6 is most probably followed by the elimination of
Me3SiOEt. The formed intermediate, which was never
isolated or detected in the crude product, must undergo rapid
protonation during the reaction workup resulting in the
formation of final products 3a and 7a (Scheme 2).
We then set out to apply the above-discussed chemistry
to the ethyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxy-
late derivative with representative organolithium reagents.
The starting 1,3-ketoester 5 was synthesized according to
the literature procedure in good yield.12 Treatment of 5 with
2 equiv of BF3·Et2O in toluene at room temperature gave
the desired BF2 complex 6 as a bluish-fluorescence material
(Scheme 3). Treatment of the latter under the optimized
reaction conditions derived the corresponding 1,3-diketobo-
ron difluoride complexes 7a-d in reasonable yields. Interest-
ingly enough, compounds 7c and 7d possess strong fluores-
cence13 for which a solvatochromic effect was observed for
7d (Figure 1). In the fluorescence spectra in dichloromethane,
7c and 7d showed emission maxima at 417 nm (excited at
359 nm) and 540 nm (excited at 401 nm), respectively. The
absolute fluorescence quantum yields of 7c and 7d in
Figure 1. Fluorescence properties of 7c and 7d.
In principle, two mechanistic rationales could be postulated
for the observed transformation of 2 and 6 to 3 and 7. The
first would be the simple nucleophilic attack of C-nucleophile
via the Bu¨rgi-Dunitz trajectory14 and subsequent elimination
of lithium alkoxide. The second, which is in our opinion
more probable, is the initial formation of the ate complex
between Lewis basic borondifluoride center and the Lewis
acidic lithium of organolithium species (most probably
corresponding oligomers) followed by the attack of the
C-centered nucleophile of the organolithium aggregates15 to
the activated ester functionality, forming a tetrahedral
intermediate which subsequently undergoes elimination of
lithium alkoxide, thus yielding the more stable 1,3-diketo-
boron difluoride complex (see Scheme 4).
(11) Dondoni, A.; Junquera, F.; Marchan, F. L.; Merino, P.; Sherramann,
M. C.; Tejero, T. J. Org. Chem. 1997, 62, 5484–5496.
(12) Frew, A. J.; Proctor, G. R. J. Chem. Soc., Perkin Trans. 1 1980,
1245–1250.
In conclusion, we have demonstrated that treatment of
readily accessible and stable borondifluoride complexes of
(13) For recient similar systems, see : (a) Nagai, A.; Kokado, K.; Nagata,
Y.; Arita, M.; Chujo, Y. J. Org. Chem. 2008, 73, 8605–8607. (b) Ono, K.;
Yoshikawa, K.; Tsuji, Y.; Yamaguchi, H.; Uozumi, R.; Tomura, M.; Taga,
K.; Saito, K. Tetrahedron 2007, 63, 9354–9358.
(14) Bu¨rgi, H. B.; Dunitz, J. D.; Shefter, E. J. Am. Chem. Soc. 1973,
95, 5065–5067.
2902
Org. Lett., Vol. 12, No. 13, 2010

diketoborondifluoride analogues. The latter can be simply
transformed to the synthetically valuable asymmetrically
substituted 1,3-diketones. On the other hand, the presented
methodology enables straightforward access to the variety
of attention-grabbing fluorescent dyes. However, to the best
of our knowledge, the presented transformation is herein
discussed for the first time.
Scheme 4. Proposed Reaction Mechanism for the
Transformation of 2 and 6 to 3a-n and 7a-d
Acknowledgment. The Ministry of Higher Education,
Science and Technology of the Republic of Slovenia as well
as the Slovenian Research Agency (P1-0230-0103) are
gratefully acknowledged for their financial support. I thank
ˇ
Dr. D. Zigon and Dr. B. Kralj (Center for Mass Spectroscopy,
“Jozef Stefan” Institute, Ljubljana, Slovenia) for the mass
spectroscopy measurements and N. Brezavsˇcˇek and K. Slanc
(Faculty of Chemistry and chemical Technology, University
of Ljubljana) for laboratory assistance. I also thank J. A. I.
Smith (Department of Chemistry and Biochemistry, Uni-
versity of Maryland) for critical reading of the manuscript.
1,3-ketoesters with a variety of organolithiums at -78 °C
in THF can lead to the formation of the corresponding 1,3-
(15) For organolithium agregates, see : (a) Kottke, T.; Stalke, D. Angew.
Chem., Int. Ed. Engl. 1993, 32, 580–582. (b) Ogle, C. A.; Huckabee, B. K.;
Johnson, H. C.; Sims, P. F.; Winslow, S. D. Organometallics 1993, 12,
1960–1963. (c) Siemeling, U.; Redecker, T.; Neuman, B.; Stammler, H. G.
J. Am. Chem. Soc. 1994, 116, 5507–5508. (d) Qu, B.; Collum, D. B. J. Am.
Chem. Soc. 2006, 128, 9355–9360. For computational examples, see: (e)
Koch, R.; Wiedel, B.; Anders, E. J. Org. Chem. 1996, 61, 2523–2529. (f)
Hoffmann, D.; Collum, D. B. J. Am. Chem. Soc. 1998, 120, 5810–5811.
(g) Kwon, O.; Sevin, F.; McKee, M. L. J. Phys. Chem. A 2001, 105, 913–
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Duin, A. C. T.; Goddard, W. A., III; Lee, H. M. J. Phys. Chem. A 2005,
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Supporting Information Available: Synthesis of the
starting materials, general experimental methods, character-
ization of all new compounds, and copies of 1H and 13C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL100620J
Org. Lett., Vol. 12, No. 13, 2010
2903