Regio- and diastereoselective crotylboration of vic-tricarbonyl compounds

Article abstract of DOI:10.1002/ejoc.201201517

Crotylboration of vic-diketoamides and vic-diketo esters was achieved with high diastereoselectivity and complementary regioselectivity. Whereas (E)-crotylboration of α,β-diketoamides resulted in high yields (91-99 %) of β-crotylated products obtained as a single diastereomer (anti), Lewis acid promoted crotylboration of α,β-diketo esters yielded the α-crotylated species with the anti product as main diastereomer. (E)-Crotylboration of α,β-diketoamides resulted in high yields (91-99 %) of β-crotylated products obtained as a single diastereomer (anti). Lewis acid promoted crotylboration of α,β-diketo esters yielded the α-crotylated species with the anti product as main diastereomer. Copyright

Full text of DOI:10.1002/ejoc.201201517

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201517
Regio- and Diastereoselective Crotylboration of vic-Tricarbonyl Compounds
[a]
[a]
[a]
[a]
Jan Roßbach, Julia Baumeister, Klaus Harms, and Ulrich Koert*
Keywords: Synthetic methods / vic-Tricarbonyl compounds / Crotylboration / Regioselectivity / Diastereoselectivity
Crotylboration of vic-diketoamides and vic-diketo esters was
achieved with high diastereoselectivity and complementary
regioselectivity. Whereas (E)-crotylboration of α,β-diketo-
amides resulted in high yields (91–99%) of β-crotylated prod-
ucts obtained as a single diastereomer (anti), Lewis acid pro-
moted crotylboration of α,β-diketo esters yielded the α-crotyl-
ated species with the anti product as main diastereomer.
Introduction
Results and Discussion
The synthesis of vic-tricarbonyl compounds 1 and 4 ide-
ally uses the corresponding β-ketoamide 7 or β-keto ester 9
Vicinal tricarbonyl compounds offer the chance for
multifunctionalization and have considerable potential as
synthetic building blocks, if a regioselective functionaliza-
tion can be achieved. For unsymmetrical vic-tricarbonyl
compounds such as diketoamides 1 or diketo esters 4, two
regioisomers can be formed upon attack of a C-nucleophile:
α adducts 2/5 or β adducts 3/6 (Scheme 1). Considering the
central carbonyl group most activated by the adjacent carb-
onyl groups, one may predict α adduct 2/5 as the main re-
gioisomer. Here we report that both regioisomers can be
obtained selectively depending on the nature of the carbox-
ylic acid derivative (amide 1 or ester 4).
[
1,2]
as starting material (Scheme 2).
Reliable procedures for
the conversion into tricarbonyl compounds include oxidat-
[
9,10]
ive cleavage of α-methylene derivatives,
dation,
direct oxi-
[
11]
[12]
and the use of α-diazo-β-dicarbonyls.
In our
hands, the latter method gave the best results (for details
see Supporting Information). For diketoamides 1a–f, Regitz
diazo transfer (7 Ǟ 8) and subsequent treatment with tert-
butyl hypochlorite in formic acid led, upon distillation or
precipitation, to the tricarbonyl compound. For diketo es-
ters 4a–e, α-diazo-β-keto ester 10 was treated with tert-butyl
hypochlorite in ethyl acetate/water to produce hydrate 11,
which was converted into diketo ester 4 prior to its further
use. Storage of hydrate 11 was unproblematic, while storage
of vic-tricarbonyl 4, even at –30 °C, led to extensive decom-
position due to self condensation.
Scheme 1. Regioselectivity in the addition of C-nucleophiles to un-
symmetrical vic-tricarbonyl compounds.
The addition of nucleophiles to unsymmetrical acyclic
vic-tricarbonyl compounds has been limited so far to O-
and N-nucleophiles.[
1,2]
Stereoselective C-nucleophile ad-
ditions have been investigated with symmetrical vic-tri- Scheme 2. Synthesis of vic-diketoamides 1 and diketo esters 4.
[
3–7]
carbonyl compounds in particular diethyl ketomalonate
Allyl and crotyl boronates were selected as C-nucleo-
philes because of the firm fundament of knowledge (reac-
tivity, stereoselectivity) available for this transformation.
While the addition to isolated carbonyls (aldehydes and
or for an intramolecular aldol reaction[ only.
8]
[
a] Fachbereich Chemie, Philipps-Universität Marburg
Hans-Meerwein-Straße 4, 35043 Marburg, Germany
Fax: +49-6421-2825677
[
13]
ketones) is well established,
carbonyl compounds is less developed. The regioselectiv-
the reaction with vic-di-
E-mail: koert@chemie.uni-marburg.de
[14]
Homepage: www.uni-marburg.de/fb15/ag-koert
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201517.
ity and diastereoselectivity of the allylboration of vic-tri-
[
6,7]
carbonyl compounds are unexplored.
662
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 662–665

Crotylboration of vic-Tricarbonyl Compounds
The reaction of diketoamides 1 with (E)-crotyl boronate gave equal amounts of α- and β-attack. Addition of Lewis
[
17]
1
2 at room temperature resulted exclusively in β-attack acids had a pronounced effect on the regioselectivity α/β
(Scheme 3). Out of the two possible diastereomeric β ad- [Cu(OTf)2 74:26, Mg(OTf)2 57:43, La(OTf)3 39:61,
ducts 13 (anti) and 14 (syn), anti product 13 was formed Sc(OTf)3 Ͼ99:1, BF ·OEt2 Ͼ99:1]. Having identified
3
with complete diastereoselectivity (Ͼ20:1). The regio- and BF ·OEt as the Lewis acid that exclusively results in an α-
3
2
diastereoselectivity were assigned by a combination of attack of the boronate reagent, the diastereoselectivity was
[
15]
NMR spectroscopic and X-ray structural analysis of 13c.
investigated for this case next (Scheme 5). vic-Tricarbonyl
The scope of the reaction was shown for diketoamides 1a– compound 4 was prepared in situ from the corresponding
d. Adducts to diketo Weinreb amide 1e and N-diketoacylox- diazo precursor 10. Hydrate 11 formed in the tert-butyl hy-
azolidinone 1f could also be obtained with the same high pochlorite oxidation was converted into the diketo ester by
degree of regio- and diastereoselectivity.
using excess BF ·OEt . In the reaction with (E)-crotyl
3 2
boronate 12, out of the two possible diastereomeric α ad-
ducts 16 (anti) and 17 (syn), anti product 16 was formed as
main stereoisomer. The regio- and diastereoselectivity were
assigned by a combination of NMR spectroscopic and X-
ray structural analysis of the 1,4-dinitrophenylhydrazone
[
15]
obtained from ketone 16a.
Scheme 3. Regio- and diastereoselective addition of (E)-crotyl
boronate 12 to vic-diketoamides 1 with selective formation of anti
adduct 13.
With the goal to investigate the diastereospecificity of the
crotyl boronate addition, which was shown for aldehydes
[
16]
first,
the reaction of diketoamides 1 with (Z)-crotyl
boronate 15 was investigated next (Scheme 4). This reaction
proceeded very slowly at room temperature and resulted in
the regioselective formation of the β adduct. Only a very
moderate diastereoselectivity for syn product 14 was ob-
served. The regio- and diastereoselectivity were assigned by
a combination of NMR spectroscopic and X-ray structural
[
15]
analysis of 14e.
Scheme 5. Lewis acid catalyzed regio- and diastereoselective ad-
dition of (E)-crotyl boronate 12 to vic-diketo ester 4 with favored
formation of anti adduct 16.
Use of (Z)-crotyl boronate 15 in the BF ·OEt -catalyzed
3
2
crotylboration of diketo esters 4 showed complete regiose-
lectivity (α-attack) but no diastereoselectivity.
A hint for a rationale of the β-regioselectivity found for
diketoamides 1 comes from an X-ray structure of com-
[
15]
pound 1b (Scheme 6). The amide group adopts a confor-
mation orthogonal to the diketo plane, which disfavors an
α-attack sterically but cannot favor it electronically. The ob-
served diastereoselectivity for the (E)-crotylboration of the
diketoamides (1 + 12 Ǟ 13) can be explained by a cyclic
transition state 17 with an equatorial position of the bulky
Scheme 4. Addition of (Z)-crotyl boronate 15 to vic-diketo-
amides 1.
In contrast to the diketoamides, the reaction of diketo amide group. The results for the (Z)-crotylboration with 15
esters 4 with allyl and crotyl boronates at room temperature indicate an increasing problem for a defined cyclic transi-
Eur. J. Org. Chem. 2013, 662–665
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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663

J. Roßbach, J. Baumeister, K. Harms, U. Koert
SHORT COMMUNICATION
tion state with reagents of this type. The situation is more (3R*,4R*)-3-Hydroxy-3,4-dimethyl-1-morpholinohex-5-ene-1,2-
dione (13c) as a Representative Procedure: A mixture of diketo-
complicated for the reaction of diketo ester 4 in the pres-
amide (122 mg, 0.66 mmol, 1.00 equiv.), (E)-crotylboronic acid pin-
acol ester (12) (120 mg, 0.66 mmol, 1.00 equiv.), and dichlorometh-
ane (5 drops) was stirred overnight at ambient temperature. The
crude product was purified by flash column chromatography
ence of a Lewis acid. A mechanistic understanding of vic-
diketo ester reactivity will require further studies on the
chelation mode of the Lewis acid and the role of the bor-
[
18]
ation agent.
(
dichloromethane) on silica gel. Compound 13c was obtained as a
colorless solid (159 mg, 0.66 mmol, 99%). TLC (pentane/ethyl acet-
1
ate, 3:1): R
CDCl ): δ = 5.81 (ddd, J = 17.2, 10.3, 8.7 Hz, 1 H, 5-H), 5.12 (ddd,
H, J = 17.2, 1.9, 0.9 Hz, 6-H ), 5.10 (ddd, J = 10.3, 1.9, 0.6 Hz,
H, 6-H ), 3.75–3.60 [m, 6 H, NC + O(CH ], 3.48 3.33 (m,
H, NC ), 3.05 (s, 1 H, OH), 2.90–2.79 (m, 1 H, 4-H), 1.40 (s,
H, 3-CH
f
= 0.24. M.p. 75 °C (diethyl ether). H NMR (300 MHz,
3
1
1
2
3
Z
E
a
H
2
2 2
)
b
H
2
1
3
3
), 1.08 (d, J = 6.9 Hz, 3 H, 4-CH
): δ = 204.0 (C2), 165.3 (C1), 138.8 (C5), 117.7
C6), 80.8 (C3), 66.6 (OC ), 66.7 (OC ), 46.5 (NC ), 45.4
C4), 41.8 (NC ), 23.0 (3-CH ), 14.1 (4-CH ) ppm. HRMS
ESI): calcd. for C12
Na [M + Na]+ 264.1206; found
64.1207. FTIR (neat): ν˜ = 3420 (m), 2968 (w), 2923 (w), 2859 (w),
3
) ppm. C NMR
(
(
(
(
75 MHz, CDCl
3
a
H
2
b
H
2
b 2
H
a
H
2
3
3
H
19NO
4
2
1
1
1
7
714 (m), 1616 (s), 1477 (m), 1446 (m), 1383 (w), 1359 (m),
305 (w), 1273 (m), 1201 (w), 1158 (m), 1109 (s), 1072 (m),
019 (m), 992 (s), 933 (s), 896 (w), 873 (w), 840 (m), 806 (w),
–
1
67 (w), 707 (m), 644 (m), 588 (m), 493 (w), 461 (w), 416 (w) cm .
Scheme 6. X-ray structure of vic-diketoamide 1b and mechanistic
proposal for the (E)-crotylboration of vic-diketoamides 1.
(
2R*,3S*)-Benzyl 2-Acetyl-2-hydroxy-3-methylpent-4-enoate (16e)
as a Representative Procedure: To a solution of the diazo compound
(46 mg, 0.35 mmol, 1.00 equiv.) in ethyl acetate (4 mL) and water
(13 mg, 0.70 mmol, 2.00 equiv.) was added tert-butyl hypochlorite
(42 mg, 0.39 mmol, 1.10 equiv.) at 0 °C. After stirring for 15 min
Conclusions
the reaction mixture was concentrated under reduced pressure. The
crude hydrate was diluted in dichloromethane, and boron trifluor-
ide etherate (0.13 mL, 1.05 mmol, 3.00 equiv.) was added at 0 °C.
In summary, a complementary regioselectivity can be ob-
tained in the (E)-crotylboration of unsymmetrical vic-tri-
carbonyl compounds depending on the nature of the car-
boxylic acid derivative (β-attack for amide 1 and α-attack
for ester 4). For both cases, an anti diastereoselectivity is
achieved. Limitations are observed for (Z)-crotylboration.
These results point to the high potential of allyl boronates
(
1
E)-Crotyl boronic acid pinacol ester (12) (96 mg, 0.53 mmol,
.50 equiv.) was added after 10 min. After the reaction had gone
to completion, the reaction was quenched with water (4 mL). The
aqueous layer was extracted with dichloromethane (2ϫ 4 mL). The
crude product was purified by flash column chromatography (pent-
and other C-nucleophiles in reaction with unsymmetrical ane/diethyl ether, 10:1) to yield 16e as a colorless oil (ds: 90:10;
vic-tricarbonyl compounds and will enable their use for fur- 84 mg, 0.320 mmol, 91%). TLC (pentane/ethyl acetate, 4:1): R
f
=
ther synthetic applications. Chiral Lewis acids could lead to
enantioselective addition reactions.
18 4
H O
Na [M + Na]+ 285.1097;
0
.65. HRMS (ESI): calcd. for C15
found 285.1093. FTIR (neat): ν˜ = 3486 (w, br), 2976 (w), 1717 (s),
1
1
6
456 (w), 1419 (w), 1358 (m), 1257 (m), 1194 (m), 1147 (s),
095 (w), 1027 (w), 997 (m), 972 (m), 925 (m), 746 (m), 699 (m),
–
1
02 (w) cm .
Experimental Section
Analytical data for (2R*,3S*)-Benzyl 2-acetyl-2-hydroxy-3-meth-
1
-Morpholinobutane-1,2,3-trione (1c) as a Representative Procedure:
To a solution of the diazo compound (499 mg, 2.53 mmol,
.00 equiv.) in formic acid (8.4 mL) was added tert-butyl hypo-
1
ylpent-4-enoate (16e): H NMR (300 MHz, CDCl
3
): δ = 7.40–7.30
), 5.70 (ddd, J = 17.3 10.2, 8.6 Hz, 1 H, 4-H), 5.18
), 5.07–4.95 (m, 2 H, 5-H ), 4.11 (s, 1 H, OH), 3.28–
.16 (m, 1 H, 3-H), 2.28 (s, 3 H, 2-CO-CH ), 0.92 (d, J = 6.8 Hz,
) ppm. C NMR (75 MHz, CDCl ): δ = 205.0 (2-CO),
70.4 (C1), 137.4 (C4), 134.9 (Cipso), 128.8, 128.8 (2ϫ Cortho + 2ϫ
meta), 128.6 (Cpara), 117.2 (C5), 87.4 (C2), 68.4 (CH ), 43.7 (C3),
5.7 (2-CO-CH ), 14.2 (3-CH ) ppm.
(
m, 5 H, C
6 5
H
1
(s, 2 H, CH
2
2
chlorite (275 mg, 2.53 mmol, 1.00 equiv.) by syringe at 0 °C. After
the bubbling had ceased, the mixture was warmed to ambient tem-
perature, and the solvent was evaporated under reduced pressure.
The crude product was purified by bulb-to-bulb-distillation. Com-
pound 1c was obtained as a yellow solid (469 mg, 2.53 mmol,
3
3
1
C
2
3
13
H, 3-CH
3
3
2
3
3
quant.). TLC (pentane/ethyl acetate, 1:1): R
500 MHz, CDCl ): δ = 3.76–3.73 (m, 2 H, OC
+ NC ), 3.37–3.33 (m, 2 H, NC
) ppm. 13C NMR (75 MHz, CDCl
): δ = 197.5 (C3), 184.6
), 66.5 (OC ), 46.1 (NC ), 42.0
), 24.5 (C4) ppm. HRMS (ESI): calcd. for C Na
f
= 0.43. 1H NMR
), 3.71–3.65 (m,
(
3
a
H
2
Supporting Information (see footnote on the first page of this arti-
H ), 2.46 (s, 3 H, cle): Experimental procedures, characterization data and copies of
b 2
4
4
H, OC
-H
b
H
2
a
H
2
1
13
19
3
3
the H NMR, C NMR, and F NMR spectra for all compounds.
(
(
[
C2), 164.2 (C1), 66.7 (OC
NC
a
H
2
b
H
2
a 2
H
H11NO
8 4
b
H
2
+
M + Na] 208.0580; found 208.0578. FTIR (neat): ν˜ = 2972 (w), Acknowledgments
2
1
1
4
923 (w), 2860 (w), 1716 (m), 1640 (s), 1442 (m), 1358 (m),
272 (m), 1231 (w), 1193 (w), 1164 (w), 1111 (s), 1071 (m),
Financial support by the Deutsche Forschungsgemeinschaft
012 (m), 954 (m), 923 (w), 834 (m), 733 (m), 582 (m), 502 (m), (DFG) and Fonds der Chemischen Industrie is gratefully acknowl-
–1
74 (w), 437 (w) cm .
edged.
664
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 662–665

Crotylboration of vic-Tricarbonyl Compounds
[13] H. Lachance, D. G. Hall, Org. React. 2008, 73, 1–573.
[
[
[
1] H. H. Wasserman, J. Parr, Acc. Chem. Res. 2004, 37, 687–701.
2] M. B. Rubin, R. Gleiter, Chem. Rev. 2000, 100, 1121–1164.
3] S. Yao, M. Roberson, F. Reichel, R. Hazell, K. A. Jørgensen,
J. Org. Chem. 1999, 64, 6677–6687.
[14] α-keto carboxylic acids: a) Z. Wang, X.-J. Meng, G. W. Kab-
alka, Tetrahedron Lett. 1991, 32, 5677–5680; α-keto ester: b) R.
Metternich, R. W. Hoffmann, Tetrahedron Lett. 1984, 25,
4095–4096.
[
[
4] C. Bolm, O. Simi c´ , J. Am. Chem. Soc. 2001, 123, 3830–3831.
5] M. Frings, I. Atodiresei, J. Runsink, G. Raabe, C. Bolm, Chem.
Eur. J. 2009, 15, 1566–1569.
[
15] CCDC-902293 (for 13c), -902294 (for 14e), -902291 (for 16a),
and -902292 (for 1b) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[
6] a) M. Wohlfahrt, K. Harms, U. Koert, Angew. Chem. 2011,
123, 8554–8556; Angew. Chem. Int. Ed. 2011, 50, 8404–8406;
b) M. Wohlfahrt, K. Harms, U. Koert, Angew. Chem. 2011,
23, 10945; Angew. Chem. Int. Ed. 2011, 50, 10742.
7] M. Wohlfahrt, K. Harms, U. Koert, Eur. J. Org. Chem. 2012,
260–2265.
8] P. Truong, C. S. Shanahan, M. P. Doyle, Org. Lett. 2012, 14,
608–3611.
[
16] R. W. Hoffmann, Angew. Chem. 1982, 94, 569–580; Angew.
Chem. Int. Ed. Engl. 1982, 21, 555–642.
1
[
[
[17] a) J. W. J. Kennedy, D. G. Hall, J. Am. Chem. Soc. 2002, 124,
2
11586–11587; b) T. Ishiyama, T.-a. Ahiko, N. Miyaura, J. Am.
Chem. Soc. 2002, 124, 12414–12415.
3
[
18] J. W. J. Kennedy, D. G. Hall, Angew. Chem. 2003, 115, 4880–
[9] H. H. Wasserman, Aldrichim. Acta 1987, 20, 63–74.
[10] K. Schank, C. Schuhknecht, Chem. Ber. 1982, 115, 2000–2002.
[11] H.-J. Teuber, J. Hohn, Chem. Ber. 1982, 115, 90–98.
[12] M. Regitz, H.-G. Adolph, Liebigs Ann. Chem. 1969, 723, 47–
4887; Angew. Chem. Int. Ed. 2003, 42, 4732–4739.
Received: November 12, 2012
Published Online: December 21, 2012
60.
Eur. J. Org. Chem. 2013, 662–665
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
665