α-Crotyl-α-difluoroboranyloxy-amides: Structure and Reactivity of Isolable Intermediates in Stereospecific α-Ketol Rearrangements

Article abstract of DOI:10.1021/acs.orglett.5b01427

The stereospecific BF₃-mediated α-ketol rearrangement of β-hydroxy-α-ketoamides yields isolable 2-difluoroboranyloxy-3-keto-amides. X-ray and NMR analysis reveal a carbonyl coordination of the boron by the amide not the ketone. The boron complexes are air-stable solids, can be purified by silica gel chromatography, and exhibit novel reactivity in bromination and superior stereoselectivity in dipolar cycloaddition reactions.

Full text of DOI:10.1021/acs.orglett.5b01427

Letter
pubs.acs.org/OrgLett
α‑Crotyl-α-difluoroboranyloxy-amides: Structure and Reactivity of
Isolable Intermediates in Stereospecific α‑Ketol Rearrangements
Jan Roßbach, Klaus Harms, and Ulrich Koert*
Fachbereich Chemie, Philipps-University Marburg, Hans-Meerwein-Strasse 4, D-35043 Marburg, Germany
*
S Supporting Information
ABSTRACT: The stereospecific BF -mediated α-ketol rear-
3
rangement of β-hydroxy-α-ketoamides yields isolable 2-
difluoroboranyloxy-3-keto-amides. X-ray and NMR analysis
reveal a carbonyl coordination of the boron by the amide not
the ketone. The boron complexes are air-stable solids, can be
purified by silica gel chromatography, and exhibit novel
reactivity in bromination and superior stereoselectivity in
dipolar cycloaddition reactions.
4
icinal tricarbonyl compounds are valuable building blocks
tBuOCl-oxidation furnished the vic-diketoamides 1. Crotylbo-
V
in organic synthesis for the construction of complex target
ration of the latter with (E)-crotyl boronate 6 exclusively led to
β-hydroxy-α-ketoamides 7 with high anti-diasteroselectivity
(single diastereomer). The reaction of 1 with (Z)-crotyl
boronate 8 gave β-addition products 9 with syn-diastereose-
molecules such as natural products and potent motifs in
1,2
medicinal chemistry. In the case of unsymmetrical vicinal
tricarbonyl compounds such as vic-diketoamides 1, a
regioselective approach to differentiate the attack of carbon
nucleophiles at one of the two keto functionalities present is
4
lectivity (d.r. 91:9 for Weinreb amide 9f) (Scheme 2).
3
decisive. The allylboration of diketoamides 1 with allylboro-
nates 2 occurs solely with β-regioselectivity and results in the
formation of β-hydroxy-α-ketoamides 3. However, α-allylation
Scheme 2. Stereospecific Access to β-Hydroxy-α-ketoamides
4
product 4 could be attained from β-allylation product 3 by
5
means of α-ketol rearrangement (Scheme 1). Expanding the
Scheme 1. Regioselective Allylation of vic-Diketoamides
Reaction of β-hydroxy-α-ketoamides 7 with stoichiometric
amounts of BF ·OEt2 resulted in the formation of the
3
difluoroalkoxyboranes 10 (Scheme 3). Compounds 10 can be
purified by silica gel chromatography and are bench-stable
solids. For the present case, the amide oxygen acts as a strong
binding ligand to boron and leads to isolable boron complexes
of type 10. A variety of N,N-dialkylamides 7a−e gave the
corresponding difluoroalkoxyboranes 10a−e in very good yield.
The difluoroalkoxyboranes were converted by methanolysis
into the β-hydroxy-α-ketoamides 11 in nearly quantitative yield.
allylboration to a crotylboration allows the study of the
diastereoselectivity/specifity in addition to the regioselectivity
challenge. Here we report on the efficient stereospecific BF3-
mediated α-ketol rearrangement of various β-hydroxy-α-
ketoamides into α-hydroxy-β-ketoamides. Besides structural
characterization of the corresponding difluoroalkoxyborane
intermediates, their synthetic utility was investigated.
The starting point for the synthesis of the vic-diketoamides
was the β-ketoamides 5. A Regitz diazo transfer followed by
Received: May 15, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01427
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. BF -Mediated α-Ketol Rearrangement and
Subsequent Methanolysis
Scheme 5. Mechanistic Considerations for the α-Ketol
Rearrangement
3
A priori, coordination of the boron by the amide carbonyl 10
or the ketone carbonyl 13 is conceivable. X-ray crystal
structures revealed the stabilizing and chelating role of the
oxygen of the amide group in the solid state. For all 11
9
difluoroalkoxyboranes described herein, the X-ray crystal
structures exhibit the sole complexation by the amide oxygen
(
Figure 1 and Supporting Information). Whereas the B−F
a
1
b
Single diastereomer as measured by H NMR. Confirmed by X-ray
single crystal structure analysis.
The strict stereospecificity of the rearrangement was
determined by a combination of NMR and X-ray analysis
(
Scheme 4). The anti-β-hydroxy-α-ketoamide 7f gave the anti-
α-hydroxy-β-ketoamide 11f, while the syn compound 9f led to
the syn product 12 exclusively.
Scheme 4. Stereospecifity of the Rearrangement
Figure 1. X-ray crystal structure of rearrangement product 10e.
Hydrogen atoms are omitted for clarity.
bond lengths are similar (B−F1 1.372 to 1.394 Å, average 1.381
Å; B−F2 1.368 to 1.399 Å, average 1.378 Å), different distances
for the covalent B−O bond (1.408 to 1.452 Å, average 1.437 Å)
and the coordinate B−O bond (1.519 to 1.550 Å, average 1.536
Å) are observed. The bonding situation between the boron
substituent and the amide carbonyl group can be described by
II or III.
a
1
b
Single diastereomer as measured by H NMR. Confirmed by X-ray
single crystal structure analysis.
In solution, evidence for the exclusive coordination of the
amide oxygen to the boron center at room temperature was
Mechanistically, the 1,2-migration of the crotyl group from
provided by 13C NMR spectroscopy. F− C-Through-space
coupling was observed for anti-10a−f in all cases at C2, C3, C5,
and C6 (Figure 2a; for numbering of the crystal structure of
19
13
the β- into the α-position can be described as a suprafacial α-
5
ketol rearrangement (Scheme 5). Reaction of α-hydroxy-β-
ketoamide 7 with BF ·OEt leads to intermediate I which is
3
2
TS
transformed by the stereospecific 1,2-crotyl shift into the α-
crotylation product 13. Subsequently, the keto oxygen is
replaced by the more basic amide oxygen (13 → 10, vide infra).
Related rearrangements have been reported for the β-hydroxy-
10e, see Figure 1) with coupling constants in the range of JFC
= 1.3 to 3.8 Hz. Neither quarternary carbon C4 nor amide
carbon C8 shows signal splitting in any case. Therefore, scalar J-
coupling through the chemical bonds can be ruled out as a
6
,7
13
19
13
α-ketoester, but the corresponding difluoroalkoxyboranes
source of the C NMR signal splitting. In all cases, F− C-
8
have not been isolated and characterized before.
through-space coupling resulted in doublet splitting rather than
B
DOI: 10.1021/acs.orglett.5b01427
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
were unsatisfying (ketone reduction with NaBH and NaBH-
4
(
OAc) , nucleophilic addition of a phenyl Grignard reagent,
3
phenyllithium). Oxidative conditions (epoxidation, dihydrox-
ylation) produced complex reaction mixtures and decom-
position of the alkoxyborane. The catalytic hydrogenation of
alkene 10e cleanly gave alkane 14 leaving the borane
functionality untouched (Scheme 7a). In the case of
Scheme 7. Reaction Scope of α-Crotyl-α-
difluoroalkoxyboranyl-amides
Figure 2. a: Illustration of 19F− C-through-space couplings. In the
13
depicted Newman projection, morpholine amide (blue) is omitted for
clarity. b: 19F NMR spectrum (470 MHz, CDCl ) of rearrangement
3
product 10e at room temperature relative to external CFCl3.
doublet−doublet or triplet splitting of the aforementioned 13C
NMR signals. This indicates the absence of rotation around the
covalent O−B bond and points to a firm coordinative O−B
bond of the amide oxygen resulting in a rigid 1,3,2-dioxaborole
structure. With atoms C10, C14, N9, C8, C4, O8, O4, and B1
forming a plane, F1 is located above C5 and C6 on the one side
of the plane and F2 is located above C2 and C3 on the opposite
side. Crystal structure F−C distances range from 3.5 Å (F1−C6
and F2−C2) to 4.0 Å (F1−C5 and F2−C3). Owing to the
configurative inversion at C3, Weinreb analogue syn-10f does
not show 19F− C-through-space coupling at C2 (distance 4.6
13
TS
Å) but at C7 (distance 3.6 Å,
J
FC
= 0.8 to 0.9 Hz).
1
9
a
Noteworthy is the F NMR of 10e (Figure 2b): It consists
of two sets of signals, one arising from the B species (80%),
the other from the B species (20%). As a result of the
Confirmed by X-ray single crystal structure analysis.
1
1
1
0
bromination, different reactivity was observed for the boron
complex compared to the corresponding α-hydroxy-amide
diastereotopicity of the fluorine atoms, two doublets are
2
observed (Δδ = 0.70 to 1.26 ppm, J = 63 to 70 Hz). These
FBF
(
Scheme 7b). Treatment of compound 10e with bromine led
observations additionally support the existence of a strong
coordinative O−B bond and a rigid 1,3,2-dioxaborole scaffold.
The 2-difluoroboranyloxy-amides were also accessible in
nearly quantitative yield by adding BF ·OEt to a solution of
to dibromide 15 in excellent yield and an 87:13 diastereomeric
ratio. In contrast, the reaction of the free alcohol 11e gave a
mixture of the bromolactones 16 with poor diastereoselectivity
via an intramolecular attack of the amide group at the cyclic
bromonium ion 17.
3
2
the α-hydroxy-amide in methylene chloride at room temper-
ature as shown for the case 11e → 10e in Scheme 6.
The specific chemical reactivity of the novel 2-difluoro-
boranyloxy-amides was investigated next. Compound 10e was
chosen as a trial system for studies with respect to stability and
selective functionalization. Attempts to address the keto
functionality selectively leaving the boron functionality intact
Furthermore, the 1,3-dipolar cycloaddition reaction of
difluoroalkoxyborane 10e with benzonitrile oxide generated
from benzohydroximinoyl chloride 18 gave difluoroalkoxy-
borane isoxazoles 19 in an excellent 91% overall yield with very
good anti-diastereoselectivity (d.r. 91:9). In contrast, the same
reaction conditions applied to the corresponding α-hydroxy-
amide 11e yielded the cycloaddition product 20 in 78% overall
yield with moderate diastereoselectivity (d.r. 72:28) plus 21%
of the double cycloaddition product 21 (Scheme 8). While anti-
Scheme 6. Direct Formation of the 1,3,2-Dioxaborole from
the α-Hydroxy-amide
19 and syn-19 could not be separated chromatographically, Rf -
values of anti-20 and syn-20 differ greatly. BF complexes 19
2
can easily be purified by crystallization.
In summary, we have developed an efficient and high-
yielding stereospecific method for the α-ketol rearrangement of
β-hydroxy-α-ketoamides which provides diastereoselective
access to α-hydroxy-β-ketoamides starting from vicinal
C
DOI: 10.1021/acs.orglett.5b01427
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Scheme 8. 1,3-Dipolar Cycloaddition Reactions
a
Confirmed by X-ray single crystal structure analysis.
tricarbonyl compounds 1 → 3 → 4. The novel class of
difluoroalkoxyborane intermediates of type 10 was studied
structurally by X-ray and NMR analysis revealing an exclusive
amide carbonyl coordination mode. The synthetic utility of
these compounds was proven by novel reactivity in the case of
bromination and superior stereoselectivity for the 1,3-dipolar
cycloaddition. The novel boron functionality could be a useful
protective group for α-hydroxy-amides.
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AUTHOR INFORMATION
■
Corresponding Author
3
Butke, G. P.; Jimenez, M. F.; Michalik, J.; Gorski, R. A.; Rossi, N. F.;
*E-mail: koert@chemie.uni-marburg.de.
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(9) That is anti-10a-f, syn-10f, 14, 15, anti-19, and syn-19.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(
Financial support by the Deutsche Forschungsgemeinschaft
DFG) and Fonds der Chemischen Industrie is gratefully
acknowledged.
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DOI: 10.1021/acs.orglett.5b01427
Org. Lett. XXXX, XXX, XXX−XXX