Building functionality through sequential C-B and C-F bond formation

Article abstract of DOI:10.1002/adsc.201300282

α′-Fluoro β-boryl ketones can be efficiently synthesised from a sequential organocatalytic β-boration pathway and consecutive electrophilic fluorination reaction in an acidic medium. Alternatively, the regioisomers of α-fluoro β-boryl ketones can be diastereoselectively obtained from Cu(I)-mediated β-boration followed by in situ fluorination of the boron enolate. Enantioenriched mixtures of the major anti-diastereomer of vicinal C-B and C-F bonds are found in the presence of the chiral ligand QuinoxP . Copyright

Full text of DOI:10.1002/adsc.201300282

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DOI: 10.1002/adsc.201300282
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Building Functionality through Sequential C B and C F Bond
Formation
Gerard Palau-Llucha and Elena Fernꢀndeza,*
a
Department Quꢁmica Fꢁsica i Inorgꢂnica, University Rovira i Virgili, C/Marcel·lꢁ Domingo s/n, 43007 Tarragona, Spain
Fax : (+34)-977-559-563; e-mail: mariaelena.fernandez@urv.cat (homepage:
http://www.quimica.urv.cat/tecat/catalytic_organoborane_chemistry.php)
Received: April 4, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300282.
Abstract: a’-Fluoro b-boryl ketones can be effi-
ciently synthesised from a sequential organocatalyt-
ic b-boration pathway and consecutive electrophilic
fluorination reaction in an acidic medium. Alterna-
tively, the regioisomers of a-fluoro b-boryl ketones
can be diastereoselectively obtained from Cu(I)-
mediated b-boration followed by in situ fluorination
of the boron enolate. Enantioenriched mixtures of
tion steps, has led to the generation of molecular
complexity in a concise fashion.[1,2] The benefits are
based on reduced time, costs, and waste generation,
but compatibility and reliability must be circumvented
to become attractive for industrial purposes.[1] In this
context, the combination of the fluorination reaction
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with reported C B bond forming reactions has in-
creased the utility of organoboranes in the synthesis
of organofluorides. One-pot strategies combining hy-
droboration or diboration of alkynes followed by fluo-
rination of the alkenyl-monoborated or diborated in-
termediates, afforded efficient routes to polyfunc-
tional compounds without intermediate purification
steps (Scheme 1).[3,4] These strategies precisely trans-
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the major anti-diastereomer of vicinal C B and C
F bonds are found in the presence of the chiral
ligand QuinoxP*.
Keywords: b-boration; copper catalysts; a-fluorina-
tion; organocatalysis; regioselectivity
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form the C-boryl moiety into a C F bond. Here we
address a new synthetic target by developing a one-
pot transformation of a,b-unsaturated ketones into a-
fluoro b-boryl ketones or a’-fluoro b-boryl ketones,
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Current emphasis on the development of multiple via a very selective C B and C F sequential bond
chemical transformations sequentially performed in formation (Scheme 2).
a single reaction vessel, without intermediary purifica-
Scheme 1. One-pot strategies of fluorination of alkenylboronate intermediates.
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Scheme 2. Regioselective one-pot nucleophilic b-boration/electrophilic fluorination studied in this work.
Our aim is to preserve both functionalities during Therefore, the organocatalytic b-boration followed by
the sequential reaction to provide a new palette of the addition of 1 equiv. of F-TEDA-BF4 and H2SO4
polyfunctional molecules, in a highly regioselective (10 mol%) transformed 1 into the corresponding a’-
way. To achieve this goal we suggest the strategy fluoro b-(pinacol)boryl ketone (3a) with a conversion
based on nucleophilic b-boration of activated olefins of 29% (Table 1, entry 2). The need for an excess of
followed by electrophilic fluorination. To guarantee fluorinating reagent was justified by the higher con-
the most condition-tolerant method for the sequential version observed on 3a, when 2 equiv. of F-TEDA-
functionalisation, we explored two approaches to- BF4 were used (60% isolated yield, Table 1, entry 3).
wards b-boration: the metal-mediated b-boration of
To highlight the efficiency of the one-pot sequence,
activated olefins,[5–13] and the organocatalytic b-bora- we performed a parallel study in which 2 equiv. of F-
tion.[14–18] It was proved that the reagents were com- TEDA-BF4 were added to an isolated b-borated
patible during the sequential reactions and that the ketone 2a. Under identical conditions, the electrophil-
methodology could be used in a series of substrates. ic fluorination transformed 2a into 3a with slightly
To the best of our knowledge, this is the first attempt higher conversion (74% isolated yield, Table 1,
to prepare and isolate organofluroboryl ketones, de- entry 4). The amount of sulphuric acid was also opti-
spite their inherent interest for biomedical applica- mised to 10 mol% because greater amounts of the
tions.[19]
acid catalyst did not significantly improve the yield
We started by considering the simplest described (Table 1, entries 5 and 6) and lower amounts de-
method to activate the diboron source B2pin2 with creased the reaction outcome (Table 1, entry 7). The
MeOH/base, and forming the Lewis base MeOꢀ! application of other acid catalysts, such as HNO3
bis(pinacolato)diboron adduct (A).[16,20] The mixture (Table 1, entry 8), HCOOH and CF3COOH was less
of A with 4-hexen-3-one (1), as the model substrate efficient in this direct electrophilic fluorination. Alter-
selected, favoured the nucleophilic attack[21] of the sp2 native fluorinating reagents,[22] such as N-fluorobenze-
boryl moiety at the b-position of the activated ketone. nesulfonimide (NFSI) and 1-fluoro-2,4,6-trimethylpyr-
Within 2 h, at 708C, total conversion of the substrate idinium tetrafluoroborate (1-F-2,4,6-Me3PyBF4), were
into the corresponding b-borated product, 5-(pinacol)- inefficient under optimised reaction conditions. The
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borylhexen-3-one (2a) was achieved (Table 1). Fur- sequential Cb B and Ca’ F bond formation was also
ther reactivity was explored without isolation of 2a, extended to the use of other diboron reagents. When
by addition of F-TEDA-BF4 as the electrophilic fluo- bis(neopenthylglycolato)diboron (B2neop2) or bis-
rinated reagent in the presence of pyrrolidine.[22,23]
ACHTUNGTRNEN(UNG hexyleneglycolato)diboron (B2hex2) were used in-
However, the reaction did not proceed to the forma- stead of B2pin2, substrate 1 was quantitatively b-borat-
tion of any major product and only 4% of the sub- ed and consecutive electrophilic fluorination, led to
strate was converted into a’-fluorinated b-borated the formation of the corresponding a’-fluoro b-boryl
ketone (Table 1, entry 1). The characterisation of ketones 3b and 3c, respectively (Table 2, entries 1 and
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product 3a reveals that the new C F bond was exclu- 2). It should be pointed out that the one-pot synthesis
sively formed in the Ca’ of the ketone.
of a’-fluoro b-boryl ketones 3a, 3b and 3c was carried
We then turned our attention to an alternative elec- out with total regioselectivity but as a 1:1 mixture of
trophilic fluorination protocol via in situ formation of diastereoisomers. The substrate scope included other
a nucleophilic enol intermediate under acidic condi- a,b-unsaturated ketones, such as 1-penten-3-one (4)
tions. The efficiency of this direct electrophilic fluori- and 5-methyl 2-hepten-4-one (6). Under optimised re-
nation of ketones has recently been demonstrated by action conditions, terminal substrate 4 was totally b-
Batey and co-workers.[24] Since this reaction has been borated with B2pin2 within 2 h, and subsequent fluori-
reported to proceed most efficiently in MeOH, we nation led to the a’-fluoro b-(pinacol)boryl ketone 5
found a principle of compatibility with the organoca- with a conversion of up to 68% (Table 2, entry 3).
talytic b-boration carried out in MeOH as solvent. The more hindered substrate 6 was also efficiently b-
2
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Building Functionality through Sequential C B and C F Bond Formation
Table 1. One-pot organocatalytic nucleophilic b-boration/electrophilic fluorination of 4-hexen-3-one.[a]
Entry
Substrate
Acid or basic catalyst
Conversion [%][b]
Isolated Yield of 3a [%]
1
1
1
1
2a
1
2a
1
1
pyrrolidine (1 equiv.)
H2SO4 (10 mol%)
H2SO4 (10 mol%)
H2SO4 (10 mol%)
H2SO4 (20 mol%)
H2SO4 (20 mol%)
H2SO4 (5 mol%)
HNO3 (10 mol%)
4
2[c]
3
29
63
84
71
86
33
16
60
74
67
75
4
5
6
7
8
[a]
Standard conditions for organocatalytic b-boration: substrate (0.25 mmol), B2pin2 (1.1 equiv.), PCy3 (10 mol%), NaO-t-Bu
(5 mol%), MeOH (2 mL), 708C, 2 h. Standard conditions for electrophilic fluorination of reaction mixture containing 2a:
with pyrrolidine: F-TEDA-BF4 (0.5 mmol), pyrrolidine (0.25 mmol), DMF (1 mL), 15 h; with acid: Selectfluor (0.25 or
0.5 mmol), H2SO4 95% (10 mol%, 0.025 mmol), 508C, 15 h.
Conversion calculated by GC and NMR spectroscopy.
F-TEDA-BF4 (0.25 mmol).
[b]
[c]
borated (>99%) and the electrophilic fluorination gioselective a’-electrophilic fluorination of the b-bo-
also took place regioselectively at the substituted Ca’ rated ketones seems to be controlled by the more
but with lower conversion (Table 2, entry 4). The re- thermodynamically stable enol intermediate.[24]
Table 2. Scope of a’-fluoro b-boryl ketones from a,b-unsaturated ketones.[a]
Entry
Substrate
Diboron Reagent
Product
Conversion [%][b]
Isolated Yield [%]
61
1
70
2
3
73
68
56
4
51
[a]
Standard conditions for organocatalytic b-boration towards >99% of b-borated ketone: substrate (0.25 mmol), B2pin2
(1.1 equiv.), PCy3 (10 mol%), NaO-t-Bu (5 mol%), MeOH (2 mL), 708C, 2 h. Standard conditions for electrophilic fluori-
nation: F-TEDA-BF4 (0.5 mmol), H2SO4 95% (10 mol%, 0.025 mmol), 508C, 15 h.
[b]
Conversion calculated by GC and NMR spectroscopy
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Table 3. Scope of a-fluoro b-boryl ketones from a,b-unsaturated keones.[a]
Entry
1
Substrate
Product
Conversion [%][b]
94
Isolated Yield [%]
30
syn/anti (dr)
23/77
2
3
4
87
75
72
–/–
60
22/78
22/78
5
6
99
99
17[c]
20[c]
20/80
33/67
7
99
99
90
87
40/60
10/90
8
[a]
Standard conditions: CuACHTNURTGNE(UNG CH3CN)4PF6 (0.025 mmol), PCy3 (0.025 mmol) substrate (0.25 mmol), B2pin2 (1.1 equiv.,
0.35 mmol), LiO-t-Bu (0.015 mmol) DMF (2 mL), room temperature, 2 h, after that period F-TEDA-BF4 (0.5 mmol),
room temperature, 16 h.
Conversion calculated by GC and NMR spectroscopy.
[b]
[c]
Isolated as the single minor diastereoisomer.
At this point we became interested in finding an al- CuACTHNUTRGNE(UNG CH3CN)4PF6 as the copper source and LiO-t-Bu
ternative route for synthesising a-fluoro b-(pinacol)- as the base. When we carried out the copper catalysed
boryl ketone from a wide range of aliphatic cyclic and b-boration reaction of 1 (150 min), followed by the
open chain a,b-unsaturated ketones. To this end, we addition of 2 equiv. of F-TEDA-BF4 (16 h), we ob-
turned our attention to the Cu(I)-mediated b-boration served the quantitative formation of a new regioiso-
of activated olefins[5–7] and we replaced MeOH by mer 8a, in which C F was formed vicinal to the C B
non-protic solvents. Inspired by the work of Shibasaki bond. Substrate 1 was completely transformed and
and co-workers,[7g] who found an efficient copper- only a small percentage of non-fluorinated b-borated
based catalytic system to perform the b-boration of ketone was detected (Table 3, entry 1). In this particu-
a,b-unsaturated ketones in DMF, we selected lar case, the anti diastereoisomer was prefentially
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Building Functionality through Sequential C B and C F Bond Formation
formed versus the syn diastereoisomer (23/77 dr). The
major anti isomer was characterised by comparison
with the reported analogue a-fluoro-b-amino esters
synthesised following a similar strategy of conjugate
addition of lithium amides to a,b-unsaturated esters
and sequential electrophilic fluorination.[25] In our
case, the substrate scope was then investigated under
optimised reaction conditions (Table 3) to establish
ꢀ
the extension of this methodology. In general the Cb
B bond can be quantitatively formed from the conju-
gate B addition in all the substrates studied and the
efficiency of the fluorination step on the copper eno-
Scheme 3. Enantioselective one-pot nucleophilic b-boration/
late, as well as the diastereoselective ratio (dr), seem electrophilic fluorination sequence.
to be dependent on the nature of the substrate. Ter-
minal substrate 4 could be totally b-borated with
B2pin2 within 2 h, and subsequent fluorination led to 72% ee (Scheme 3). Subsequent a-fluorination of the
the a-fluoro b-(pinacol)boryl ketone 9 with a conver- enantioenriched boron enolate produced the a-fluoro
sion of up to 87%, as a single isomer (Table 2, b-(pinacol)boryl ketone 20 with 72% ee as a conse-
entry 2).
quence of the retention of the asymmetric induction
When the long-chain aliphatic ketones 5-methyl-2- (Scheme 3). The advantage of this synthetic method-
hepten-4-one (6) and 3-hepten-2-one (11) were sub- ology is due to the simplicity in the enantioselective
[26]
ꢀ
jected to the sequential b-boration/a-fluorination, the construction of the Csp3 F bond. This synthetic ap-
substrates were converted into the desired products proach represents an alternative to the current efforts
10 and 12 up to 75–87%, with identical diastereoselec- to develop enantioselective aliphatic electrophilic flu-
tivity (22/78 dr) in favour of the anti isomer (Table 3, orinations routes.[3d,27,28]
entries 3 and 4). The more hindered substrate 1-
In conclusion, we have developed two regioselec-
phenyl-2-buten-1-one (13) was quantitatively convert- tive sequential protocols towards a’-fluoro b-boryl ke-
ed into the corresponding a-fluoro b-(pinacol)boryl tones and a-fluoro b-boryl ketones without precedent
ketone 14, with a slight increase in the diastereoselec- in the literature. The a’-fluoro b-boryl ketones were
tivity (20/80 dr). But the more subtle differences in obtained by using a sequential organocatalytic b-bora-
diastereoselectivity were observed in the sequential tion of a,b-unsaturated ketones and a consecutive
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C B and C F bond formation of cylcohexenone 15 electrophilic fluorination reaction in an acidic
and substituted derivatives 17 and 19. Despite the fact medium. Compatibility with different diboron re-
that in all cases the a-fluoro b-boryl ketones were agents has also been demonstrated. Alternatively, a-
quantitatively formed, the lower diastereoselectivity fluoro b-boryl ketones were synthesised in high yields
observed was in the b-boration a-fluorination of 4,4- as an enriched mixture of the anti diastereomer, by
diphenyl-2-cyclohexen-1-one (17) (40/60 dr) (Table 3, copper-mediated b-boration followed by in situ elec-
entry 7). However, the 3-methyl-2-cyclohexen-1-one trophilic fluorination of the boron enolate. When the
(19) provided the higher diastereoselectivity on the conjugate B addition was performed enantioselective-
anti isomer (10/90 dr) (Table 3, entry 8). It is interest- ly, the transient enantioenriched mixture of the boron
ing to note that, to the best of our knowledge, there is enolate reacted with the electrophilic fluorinating re-
ꢀ
only one precedent in the literature in which the cor- agent providing a new asymmetric Csp3 F bond.
responding boron enolate from 3-substituted 2-cyclo-
hexen-1-one, reacted further with benzaldeyde as an
electrophile reagent to generate the corresponding
Experimental Section
aldol product with (6.5/1 dr).[7g] In that precedent,
the enantioselective conjugate boration [using
Cu(CH3CN)4PF6 modified with the chiral ligand
Organocatalytic b-Boration of a,b-Unsaturated
Carbonyl Compounds Followed by Acid-Catalyzed a-
Fluorination
ACHTUNGTRENNUNG
QuinoxP*] provided the tetrasubstituted carbon with
a high level of enantioselectivity which was preserved
during the sequential aldol/oxidation reaction.[7g] With
this elegant precedent in mind, we decided to perform
the copper-catalysed conjugate boration in an asym-
metric way to further react the boron enolate with F-
TEDA-BF4. The substrate 3-methyl-2-cyclohexen-1-
Diboron reagent (1.1 equiv., 0.27 mmol), [normally bis(pina-
colato)diboron], NaO-t-Bu (5 mol%, 0.01 mmol) and PCy3
(10 mol%, 0.025 mmol) were transferred into an oven-dried
Schlenck tube under an argon atmosphere. MeOH (2 mL)
was then added. The mixture was stirred for 10 min at room
temperature before the a,b-unsaturated ketone used as sub-
strate (0.25 mmol) was added to the reaction mixture. The
one (19) was b-borated with CuACHTUNGRTNE(UNG CH3CN)4PF6/Qui-
noxP*[7g] to generate the quaternary Cb B bond with reaction mixture was stirred at 708C for 2 h (unless longer
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Gerard Palau-Lluch and Elena Fernꢀndez
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time is required to complete the b-boration step). After that
period, an aliquot was analysed by GC to determine the
complete b-boration–a-protonation of the substrate. After-
wards, catalytic amounts of H2SO4 95% (10 mol%,
0.02 mmol) and fluorinating reagent (2 equiv., 0.50 mmol)
(normally F-TEDA-BF4) were added and the reaction was
contuinued overnight with heating at 508C. The reaction
mixture was cooled down, the precipitate formed was fil-
tered and the solvent removed by rotary evaporation. After-
wards, EtOAc (4 mL) and water (2 mL) were added to the
dry crude reaction mixture. The organic layer was collected,
dried over MgSO4 and concentrated gently on a rotary evap-
orator at 408C. An aliquot was diluted in deuterated chloro-
[5] For reviews on metal-mediated b-boration, see: a) J. A.
Schiffner, K. Mꢄther, M. Oestreich, Angew. Chem.
2010, 122, 1214; Angew. Chem. Int. Ed. 2010, 49, 1194;
b) E. Hartmann, D. J. Vyas, M. Oestreich, Chem.
Commun. 2011, 47, 7917; c) V. Lillo, A. Bonet, E.
Fernꢀndez, Dalton Trans. 2009, 2899; d) L. Dang, Z.
Lin, T. B. Marder, Chem. Commun. 2009, 3987; e) L.
Mantilli, C. Mazet, ChemCatChem 2010, 2, 501;
f) A. D. J. Calow, A. Whiting, Org. Biomol. Chem.
2012, 10, 5485–5497.
[6] For pioneer works on Cu(I)-catalysed b-boration, see:
a) K. Takahashi, T. Isiyama, N. Miyaura, Chem. Lett.
2000, 982; b) H. Ito, H. Yamanaka, J. Tateiwa, A.
Hosomi, Tetrahedron Lett. 2000, 41, 6821; c) K. Takaha-
shi, T. Isiyama, N. Miyaura, J. Organomet. Chem. 2001,
625, 47.
[7] For Cu(I)-catalysed b-boration, see: a) S. Mun, J.-E.
Lee, J. Yun, Org. Lett. 2006, 8, 4887; b) J.-E. Lee, J.
Yun, Angew. Chem. 2008, 120, 151; Angew. Chem. Int.
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Eur. J. 2009, 15, 1939; d) V. Lillo, A. Prieto, A. Bonet,
M. M. Dꢁaz-Requejo, J. Ramꢁrez, P. J. Pꢅrez, E. Fernꢀn-
dez, Organometallics 2009, 28, 659; e) W. J. Fleming, H.
Mꢄller-Bunz, V. Lillo, E. Fernꢀndez, P. J. Guiry, Org.
Biomol. Chem. 2009, 7, 2520; f) A. Bonet, V. Lillo, J.
Ramꢁrez, M. M. Dꢁaz-Requejo, E. Fernꢀndez, Org.
Biomol. Chem. 2009, 7, 1533; g) I.-H. Chen, L. Yin, W.
Itano, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2009,
131, 11664; h) X. Feng, J. Yun, Chem. Commun. 2009,
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Hong, Chem. Commun. 2010, 46, 7525; k) X. Feng, J.
Yun, Chem. Eur. J. 2010, 16, 13609; l) J. K. Park, H. H.
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Santos, Org. Lett. 2012, 14, 1918.
1
form and analysed by GC and H NMR to determine con-
version.
General Experimental Procedure for the Copper
Catalytic b-Boration–a-Fluorination of a,b-
Unsaturated Ketones
Cu(CH3CN)4PF6
(0.025 mmol),
bis(pinacolato)diboron
(0.35 mmol), LiO-t-Bu (0.015 mmol), PCy3 (0.025 mmol)
were transferred into an oven-dried Schlenck tube under an
argon atmosphere. DMF (2 mL) was then added. The mix-
ture was stirred for 10 min at room temperature before the
a,b-unsaturated ketone used as substrate (0.25 mmol) was
added to the reaction mixture. The reaction mixture was
stirred at room temperature for 2.5 h. Afterwards, the fluori-
nating reagent F-TEDA-BF4 (0.5 mmol) was added to the
reaction mixture and the reaction was continued at room
temperature for 16 h. After 16 h the reaction was quenched
with EtOAc (4 mL) and water ( 2 mL). The organic layer
was collected, dried over MgSO4 and concentrated gently on
a rotary evaporator at 408C. An aliquot was diluted in deu-
1
terated chloroform and analysed by GC and H NMR to de-
termine conversion and selectivity.
[8] For Cu(I)-catalysed b-boration with mixed diboron re-
agents, see: a) M. Gao, S. B. Thorpe, W. L. Santos, Org.
Lett. 2009, 11, 3478; b) S. B. Thorpe, X. Guo, W. L.
Santos, Chem. Commun. 2011, 424; c) M. Gao, S. B.
Thorpe, Ch. Kleeberg, C. Slebodnick, T. B. Marder,
W. L. Santos, J. Org. Chem. 2011, 76, 3997.
Acknowledgements
We thank MEC for funding (CTQ2010-16226) and G. P. is
grateful for an FPI grant
[9] For Cu(II)-catalysed b-boration, see: a) S. Kobayashi,
P. Xu, T. Endo, M. Ueno, T. Kitanosono, Angew. Chem.
Int. Ed. 2012, 51, 1276; b) S. B. Thorpe, J. A. Calderone,
W. L. Santos, Org. Lett. 2012, 14, 1918.
[10] For Pt-catalysed b-boration, see: a) Y. G. Lawson,
M. J. G. Lesley, T. B. Marder, N. C. Norman, C. R. Rice,
Chem. Commun. 1997, 2051; b) H. A. Ali, I. Goldberg,
M. Srebnik, Organometallics 2001, 20, 3962; c) N. J.
Bell, A. J. Cox, N. R. Cameron, J. S. O. Evans, T. B.
Marder, M. A. Duin, C. J. Elservier, X. Baucherel,
A. A. D. Tilloch, R. P. Tooze, Chem. Commun. 2004,
1854.
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Building Functionality through Sequential C B and C F Bond Formation
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COMMUNICATIONS
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8 Building Functionality through Sequential C B and C F
Bond Formation
Adv. Synth. Catal. 2013, 355, 1 – 8
Gerard Palau-Lluch, Elena Fernꢀndez*
8
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Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!