Allenyl ketones as versatile Michael acceptors for the addition of chelated enolates

Article abstract of DOI:10.1055/s-2005-923591

Chelated amino acid ester enolates undergo clean 1,4-addition towards allenyl ketones 9, giving rise to unsaturated δ-keto amino acid esters 12 at low temperature. If the reaction is allowed to warm to room temperature, the enolate intermediates A undergo

Full text of DOI:10.1055/s-2005-923591

LETTER
255
Allenyl Ketones as Versatile Michael Acceptors for the Addition of Chelated
Enolates
A
S
llenyl
K
eton
i
es as
V
m
ersatile Michae
l
A
c
o
ceptors n Lucas, Uli Kazmaier*
Institut für Organische Chemie, Universität des Saarlandes, 66123 Saarbrücken, Germany
Fax +49(681)3022409; E-mail: u.kazmaier@mx.uni-saarland.de
Received 17 November 2005
Abstract: Chelated amino acid ester enolates undergo clean 1,4-ad-
dition towards allenyl ketones 9, giving rise to unsaturated d-keto
amino acid esters 12 at low temperature. If the reaction is allowed
to warm to room temperature, the enolate intermediates A undergo
cyclization towards the corresponding a-pyrones 13.
Key words: amino acids, chelates, enolates, Michael addition,
MIRC
Michael additions belong to the most popular C–C-cou-
pling reactions, especially because of the wide range of
nucleophiles and Michael acceptors which can be coupled
1
by this protocol. Besides a,b-unsaturated esters and ke-
tones, also allenes bearing electron-withdrawing groups
2
3
4
such as allenyl ketones, sulfones or nitriles can be
5
used. In principle, the 1,4-addition towards a,b-unsatur- Scheme 1 Michael addition induced ring-closure of allenic ketones.
ated ketones has to compete with the 1,2-aldol addition.
Both processes are reversible, and therefore it is some-
allenyl ketones, and if the enolate intermediates formed
times advantageous to remove some of the intermediates
might undergo cyclization according to Ma et al.
by subsequent reactions, such as cyclizations from the
(
Scheme 1).
equilibrium. These so-called ‘Michael addition induced
ring-closing’ (MIRC) reactions became very popular over
the last years. Herein, also allenyl ketones can be used
and several applications towards the synthesis of hetero-
cycles are reported so far. For example, Knight et al. re-
For this purpose we synthesized several allenyl ketones 9
12
6
(Scheme 3). The ketones 9a and 9b were obtained from
the corresponding aldehyde and propargyl bromide in a
Barbier-type reaction,13 followed by a Dess–Martin
periodinane oxidation. During the chromatographical
purification the primary formed propargylic ketone
ported on a 1,4-addition of Me CuLi towards allene 1,
2
followed by a subsequent lactonization giving rise to lac-
14
7
isomerized to the required allenyl ketone. Ketone 9c was
tone 2 (Scheme 1). Ma et al. were able to show, that ac-
1
5
obtained from the corresponding allenylalcohol via
ceptor-substituted ester enolates undergo Michael
addition towards allenyl ketones 3. Subsequent isomeriza-
tion–cyclization of the intermediary enolates provides a-
pyrones 4 in good to excellent yields, depending on the
reaction parameters and the coupling partners used.8
oxidation with SIBX.16
Our group is involved in amino acid synthesis, investigat-
9
ing reactions of chelated amino acid ester enolates. These
stabilized enolates are also versatile nucleophiles for 1,4-
1
0
11
additions or MIRC reactions. For example, Michael
addition of trifluoroacetylated (TFA-) glycinate towards
a,b-unsaturated esters 5 bearing a carbonate functionality
gives rise to cyclic glutamate derivative 6, while with the
corresponding phosphonate 7 the cyclopropyl amino acid
ester 8 was formed (Scheme 2). Therefore, we were inter-
ested to see, if our chelated enolates would react also with
Scheme 2 Michael addition induced ring-closure of chelated
enolates.
SYNLETT 2006, No. 2, pp 0255–0258
0
1.
0
2.
2
0
0
6
Advanced online publication: 23.12.2005
DOI: 10.1055/s-2005-923591; Art ID: G36605ST
©
Georg Thieme Verlag Stuttgart · New York

2
56
S. Lucas, U. Kazmaier
LETTER
some starting material left (16%). This slow Michael ad-
dition might explain why the aldol product from the rather
unreactive ketone was obtained. Warming the reaction
mixture to room temperature did not increase the yield
either, but resulted in the formation of the lactone 13a as
sole product (entry 3). No aldol product could be observed
under these conditions.18
This suggests that the aldol reaction is reversible, what
might be also the case for the Michael addition. To in-
crease the reaction rate and the tendency for cyclization
Scheme 3 Synthesis of allenylketones 9.
In principle, several possibilities have to be considered. we decided to switch to the sterically less hindered methyl
The enolate obtained from 10 can either undergo an aldol ester 10b (entries 4–10). And indeed, no aldol reaction
reaction with ketone 9 giving rise to allenyl b-hydroxy was observed anymore, and the yield was significantly in-
amino acid ester 11, or it can undergo the desired 1,4-ad- creased, especially with a slight excess of nucleophile (en-
dition, forming intermediate A (Scheme 4). Protonation tries 4 and 5). The reaction was complete after three hours
should provide d-keto amino acid derivative 12 or a deriv- at –78 °C, and the linear Michael adduct 12ab could be
ative with an isomerized double bond (12¢). On the other obtained in high yield by quenching the reaction at this
hand, if cyclization occurs, one might expect 13 as a major temperature (entry 6). On the other hand, warming the
product, also with an isomerized double bond. Isomeriza- reaction mixture to room temperature resulted in a clean
tion of the external double bond to a thermodynamically cyclization–isomerization giving rise to a-pyrone 13a.
more stable one has to be considered under these basic Prolonging the reaction time at low temperature does not
conditions on any stage.
increase the yield but favors decomposition reactions.
Changing the chelated metal salt does also give no im-
provement. For example, with TiCl(Oi-Pr) the yield
3
dropped to 26%. Therefore, we applied these optimized
conditions also for the other allenic substrates 9b and 9c
(
entries 7–10). And again, the Michael adducts 12 were
obtained exclusively at –78 °C, and the a-pyrones 13 by
warming to room temperature.19 The yields were repro-
ducible in the range of 54–84% for the Michael adducts
and 61–70% for the a-pyrones.
In conclusion, we have shown that chelated enolates of
amino acid esters can be used as nucleophiles in Michael
additions towards allenylketones, and that the Michael
adducts undergo clean cyclization–isomerization to a-py-
rones by warming the reaction mixture to room tempera-
ture. Applications of this protocol for the synthesis of
even more complex amino acids and derivatives are cur-
rently under investigation.
Scheme 4 Possible reaction pathways.
Acknowledgment
For our first investigations we chose the tert-butyl ester
Financial support by the Deutsche Forschungsgemeinschaft as well
as the Fonds der Chemischen Industrie is gratefully acknowledged.
(
R¢ = t-Bu) of 10 (10a), because this nucleophile gave the
best results in several other reactions, including the
1
1
MIRC. We hoped that with the sterically demanding es-
ter the cyclization step can be suppressed and to obtain the
linear amino acid derivative 12. And indeed, if the reac-
tion with ketone 9a was kept at –78 °C and quenched at
this temperature, the linear product 12aa was obtained
preferentially, together with aldol product 11aa17 as the
minor compound (Table 1, entry 1). Unfortunately, the
Michael addition at this temperature was rather sluggish
and no complete consumption of the allenyl ketone could
be observed. Therefore, the yield was only moderate
References and Notes
(
1) (a) Yamamoto, Y. Stereoselective Synthesis, In Houben–
Weyl: Methoden der organischen Chemie; Helmchen, G.;
Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds.; Thieme:
Stuttgart, New York, 1996, 2041–2067. (b) Feringa, B. L.;
Jansen, J. F. G. A. Stereoselective Synthesis, In Houben–
Weyl: Methoden der organischen Chemie; Helmchen, G.;
Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds.; Thieme:
Stuttgart, New York, 1996, 2104–2156.
(
2) (a) Chinkov, N.; Morlender-Vais, N.; Marek, I. Tetrahedron
Lett. 2002, 43, 6009. (b) Lu, C.; Lu, X. Org. Lett. 2002, 4,
4677.
(
48%). It could be slightly increased by increasing the
amount of nucleophile used (entry 2), but still there was
Synlett 2006, No. 2, 255–258 © Thieme Stuttgart · New York

LETTER
Allenyl Ketones as Versatile Michael Acceptors
257
Table 1 Addition of Chelated Enolates towards Allenylketones 9
Entry
Ketone
R
TFA-Gly-OR¢
Reaction conditions
Yield
(%)
9
10
R¢
Equiv
11
(%)
13
12
13
(%)
–
1
2
3
4
5
6
7
8
9
9a
9a
9a
9a
9a
9a
9b
9b
9c
9c
Bn
Bn
Bn
Bn
Bn
Bn
Ph
Ph
10a
10a
10a
10b
10b
10b
10b
10b
10b
10b
t-Bu
t-Bu
t–Bu
Me
Me
Me
Me
Me
Me
Me
0.95
1.25
0.95
0.95
1.25
1.25
1.25
1.25
1.25
1.25
THF, –78 °C, 24 h
11aa
11aa
12aa 48
12aa 54
THF, –78 °C, 24 h
14
–
THF, –78 °C to r.t., 12 h
THF, –78 °C to r.t., 12 h
THF, –78 °C to r.t., 12 h
THF, –78 °C, 3 h
13a
13a
13a
44
63
70
12ab 84
12bb 69
THF, –78 °C, 3 h
THF, –78 °C to r.t., 12 h
THF, –78 °C, 3 h
13b
13c
66
61
2–BrC H
12cb 70
6
4
4
10
2–BrC H
THF, –78 °C to r.t., 12 h
6
(
3) (a) Padwa, A.; Yeske, P. E. J. Am. Chem. Soc. 1988, 110,
7.23 (m, 1 H, 8-H), 7.51 (m, 1 H, 7-H), 7.45 (m, 1 H, 9-H),
1
3
1617. (b) Hayakawa, K.; Takewaki, M.; Fujimoto, I.;
7.54 (m, 1 H, 6-H). C NMR (125 MHz, CDCl ): d = 79.9
3
Kanematsu, K. J. Org. Chem. 1986, 51, 5100. (c) Back, T.
G.; Lai, E. K. Y.; Muralidharan, K. R. J. Org. Chem. 1990,
(t, C-1), 96.8 (d, C-3), 119.0 (s, C-10), 126.9 (d, C-8), 128.7
(d, C-6), 131.1 (d, C-7), 133.1 (d, C-9), 140.5 (s, C-5), 194.4
(s, C-4), 218.8 (s, C-2).
5
5
5, 4595. (d) Padwa, A.; Yeske, P. E. J. Org. Chem. 1991,
6, 6386.
(13) Wu, W.-L.; Yao, Z.-J.; Li, Y.-L.; Li, J.-C.; Xia, Y.; Wu, Y.-
L. J. Org. Chem. 1995, 60, 3257.
(
(
4) Yoneda, R.; Inagaki, N.; Harusawa, S.; Kurihara, T.;
Takushi, T. Chem. Pharm. Bull. 1992, 40, 21.
5) (a) Allenes in Organic Synthesis; Schuster, H. F.; Copolla,
G. M., Eds.; Wiley: New York, 1984. (b) Modern Allene
Chemistry; Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004.
(14) (a) Hashmi, A. S. K.; Ruppert, T. L.; Knöfel, T.; Bats, J. W.
J. Org. Chem. 1997, 62, 7295. (b) Hashmi, A. S. K.;
Schwarz, L.; Bolte, M. Eur. J. Org. Chem. 2004, 1923.
(15) Kazmaier, U.; Lucas, S.; Klein, M. Adv. Synth. Catal. 2005,
submitted.
(
6) (a) Little, R. D.; Dawson, J. R. Tetrahedron Lett. 1980, 21,
(16) Ozanne, A.; Pouységu, L.; Depernet, D.; François, B.;
Quideau, S. Org. Lett. 2003, 5, 2903.
2609. (b) Prempree, P.; Radviroongit, S.; Thebtaranonth, Y.
J. Org. Chem. 1983, 48, 3553.
7) Knight, J. G.; Ainge, S. W.; Eastman, T. P.; Harwood, S. J.
J. Chem. Soc., Perkin Trans. 1 2000, 3188.
8) (a) Ma, S.; Yin, S.; Tao, F. Org. Lett. 2002, 4, 505. (b) Ma,
S.; Yu, S.; Yin, S. J. Org. Chem. 2003, 68, 8996.
9) Reviews: (a) Kazmaier, U. Amino Acids 1996, 11, 283.
(17) NMR Spectroscopic Data of Aldol Product 11aa.
1
(
(
(
H NMR (500 MHz, CDCl ): d = 1.54 (s, 9 H, 15-H), 2.74
3
2
(s, 1 H, OH), 2.96 (d, J = 13.6 Hz, 1 H, 8-H), 3.12 (d,
J8¢,8 = 13.6 Hz, 1 H, 8¢-H), 4.58 (d, J
H), 4.75 (dd, J = 11.4 Hz, J = 6.6 Hz, 1 H, 7-H), 4.89
(dd, J = 11.4 Hz, J = 6.9 Hz, 1 H, 7¢-H), 5.17 (dd,
8
,8¢
2
3
= 9.2 Hz, 1 H, 3-
3,NH
2
4
7
,7¢
7,5
2
4
7¢,7
7¢,5
4
4
3
(b) Kazmaier, U. Liebigs Ann./Recl. 1997, 285.
J5,7 = 6.6 Hz, J = 6.9 Hz, 1 H, 5-H), 7.00 (d, J
= 9.2
5,7¢
NH,3
1
3
(c) Kazmaier, U. Recent Res. Dev. Org. Chem. 1998, 2, 351.
Hz, 1 H, NH), 7.17–7.32 (m, 5 H, 10-H, 11-H, 12-H). C
(
10) (a) Mendler, B.; Kazmaier, U. Org. Lett. 2005, 7, 1715.
b) Mendler, B.; Kazmaier, U. Synthesis 2005, 2239.
11) (a) Pohlman, M.; Kazmaier, U. Org. Lett. 2003, 5, 2631.
b) Mendler, B.; Kazmaier, U.; Huch, V.; Veith, M. Org.
NMR (125 MHz, CDCl ): d = 28.0 (q, C-15), 44.4 (t, C-8),
3
(
58.8 (d, C-3), 75.2 (t, C-7), 80.2 (s, C-14), 84.3 (s, C-4), 94.8
(d, C-5), 127.1 (d, C-12), 128.2 (d, C-11), 130.9 (d, C-10),
135.0 (s, C-9), 167.7 (s, C-13), 206.3 (s, C-6). Signals of the
TFA protecting group are not detectable.
(
(
Lett. 2005, 7, 2643.
(
12) NMR Spectroscopic Data of Allenylketones 9.
(18) General Procedure for Michael Additions of Chelated
Enolates.
1
Compound 9a: H NMR (500 MHz, CDCl ): d = 3.90 (s, 2
3
4
4
H, 5-H), 5.27 (d, J = 6.6 Hz, 2 H, 1-H), 5.81 (t, J = 6.6
Hexamethyldisilazane (280 mg, 1.73 mmol) was diluted in a
Schlenk tube under argon with THF (1.5 mL). The solution
was cooled to –20 °C before a solution of n-BuLi (1 mL, 1.6
M, 1.6 mmol) was added slowly. Stirring was continued for
further 20 min, before the cooling bath was removed and the
mixture allowed to warm to r.t. In another Schlenk flask a
solution of the protected amino acid ester (0.63 mmol) in
THF (3 mL) was cooled to –78 °C, before the fresh prepared
LHMDS solution was added slowly via syringe. After
1
,3
3,1
1
3
Hz, 1 H, 3-H), 7.21–7.32 (m, 5 H, 7-H, 8-H, 9-H). C NMR
125 MHz, CDCl ): d = 45.9 (t, C-5), 79.8 (t, C-1), 95.4 (d,
(
3
C-3), 126.8 (d, C-9), 128.4 (d, C-7), 129.4 (d, C-8), 134.5 (s,
C-6), 197.5 (s, C-4), 217.1 (s, C-2).
1
Compound 9b: H NMR (500 MHz, CDCl ): d = 5.24 (d,
3
4
4
J1,3 = 6.6 Hz, 2 H, 1-H), 6.43 (t, J = 6.6 Hz, 1 H, 3-H),
3,1
3
7
.44 (m, 2 H, 7-H), 7.54 (m, 1 H, 8-H), 7.88 (dd, J = 8.2
6
,7
4
13
Hz, J6 = 1.3 Hz, 2 H, 6-H). C NMR (125 MHz, CDCl3):
,8
d = 79.2 (t, C-1), 93.2 (d, C-3), 128.6 (d, C-6), 128.7 (d, C-
stirring for 15 min at –78 °C a solution of ZnCl (94 mg, 0.69
2
7
), 132.8 (d, C-8), 137.5 (s, C-5), 191.0 (s, C-4), 217.1 (s, C-
mmol) in THF (1 mL) was added and stirring was continued
for further 45 min, before a solution of the allenyl ketone 9
(0.5 mmol) in THF (1 mL) was added. The progress of the
reaction was monitored by TLC, and after complete
2).
1
Compound 9c: H NMR (500 MHz, CDCl ): d = 5.07 (d,
3
4
4
J1,3 = 6.6 Hz, 2 H, 1-H), 6.13 (t, J = 6.6 Hz, 1 H, 3-H),
3,1
Synlett 2006, No. 2, 255–258 © Thieme Stuttgart · New York

2
58
S. Lucas, U. Kazmaier
LETTER
calcd for C H F NO [M] : 329.0837; found: 329.0856.
+
consumption of the ketone (2–3 h) the reaction mixture was
diluted with Et O and hydrolyzed with 1 N KHSO giving
1
5
14
3
1
4
Compound 12cb: H NMR (500 MHz, CDCl ): d = 3.77 (s,
2
4
3
1
8
2
rise to the expected ketone 12. The aqueous layer was
3 H, 15-H), 3.78 (d, J = 17.8 Hz, 1 H, 5-H), 3.86 (d,
5
,5¢
2
3
extracted twice with CH Cl , the combined organic layers
J5¢,5 = 17.8 Hz, 1 H, 5¢-H), 5.12 (d, J
= 6.7 Hz, 1 H, 3-
2
2
3,NH
were dried (Na SO ) and the solvent was evaporated in
H), 5.32 (s, 1 H, 13-Htrans), 5.46 (s, 1 H, 13-H ), 7.29–7.40
2
4
cis
3
vacuo. The crude product was purified by flash chromato-
(m, 3 H, 9-H, 10-H, 11-H), 7.59 (d, J = 7.9 Hz, 1 H, 8-H),
8
,9
1
9
13
graphy or crystallization. To obtain the a-pyrones 13 the
7.93 (br s, 1 H, NH). C NMR (125 MHz, CDCl ): d = 46.7
(t, C-5), 53.2 (q, C-15), 57.6 (d, C-3), 115.5 (q, J = 287.9
3
1
reaction mixture was allowed to warm to r.t. before work-up.
1
,F
Analytical Data of Michael Addition Products 12.
Hz, C-1), 118.6 (s, C-12), 122.9 (t, C-13), 127.5 (d, C-8),
1
Compound 12aa: H NMR (500 MHz, CDCl ): d = 1.42 (s,
128.7 (d, C-9), 132.2 (d, C-10), 133.8 (d, C-11), 134.6 (s, C-
3
2
2
9
H, 15-H), 3.28 (d, J = 17.0 Hz, 1 H, 5-H), 3.34 (d,
4), 140.5 (s, C-7), 156.7 (q, J = 37.6 Hz, C-2), 169.0 (s,
5
,5¢
2,F
2
J5¢,5 = 17.0 Hz, 1 H, 5¢-H), 3.75 (s, 2 H, 7-H), 4.85 (d,
J3,NH = 6.6 Hz, 1 H, 3-H), 5.10 (s, 1 H, 12-Htrans), 5.34 (s, 1
C-14), 201.9 (s, C-6). HRMS (CI): m/z calcd for
3
79
+
C H BrF NO [M + H] : 408.0074; found: 408.0066.
15
14
3
4
3
4
H, 12-H ), 7.19 (dd, J = 8.2 Hz, J = 1.3 Hz, 2 H, 9-
H), 7.27 (tt, J1 = 7.3 Hz, J = 1.3 Hz, 1 H, 11-H), 7.33
(
(19) Analytical Data of a-Pyrones 13.
cis
9,10
9,11
3
4
1
Compound 13a: H NMR (500 MHz, CDCl ): d = 2.04 (s, 3
1,10
11,9
3
3
13
m, 2 H, 10-H), 7.87 (d, J
= 6.6 Hz, 1 H, NH). C NMR
H, 13-H), 3.78 (s, 2 H, 8-H), 5.84 (s, 1 H, 6-H), 7.23 (dd,
NH,3
3
3
3
4
(
125 MHz, CDCl ): d = 27.7 (q, C-15), 49.1 (t, C-5), 49.8 (t,
J10,11 = 6.9 Hz, J
= 1.6 Hz, 2 H, 10-H), 7.29 (tt,
= 1.6 Hz, 1 H, 12-H), 7.34 (dd,
= 6.9 Hz, 2 H, 11-H), 8.38 (br s, 1 H,
3
10,12
12,10
11,10
1
4
C-7), 58.1 (d, C-3), 83.6 (s, C-14), 115.7 (q, J1 = 287.9 Hz,
J12,11 = 7.3 Hz, J
,F
4
C-1), 121.6 (t, C-12), 127.3 (d, C-11), 128.9 (d, C-10), 129.4
J11,12 = 7.3 Hz, J
2
13
(
d, C-9), 133.4 (s, C-4), 135.6 (s, C-8), 156.6 (q, J = 38.4
NH). C NMR (125 MHz, CDCl ): d = 19.2 (q, C-13), 39.6
(t, C-8), 107.5 (d, C-6), 115.6 (q, J = 287.9 Hz, C-1),
2
,F
3
1
Hz, C-2), 167.5 (s, C-13), 206.5 (s, C-6). HRMS (CI): m/z
C,F
+
calcd for C H F NO [M + H] : 386.1498; found:
115.9 (s, C-5), 127.6 (d, C-10), 128.9 (d, C-12), 129.2 (d, C-
19
23
3
4
2
3
86.1539.
11), 134.5 (s, C-9), 150.1 (s, C-4), 155.5 (q, J = 37.4 Hz,
C,F
1
Compound 12ab: H NMR (500 MHz, CDCl ): d = 3.28 (d,
C-2), 160.4 (s, C-7), 161.6 (s, C-3). Anal. Calcd for
3
2
2
J5,5¢ = 17.3 Hz, 1 H, 5-H), 3.37 (d, J = 17.3 Hz, 1 H, 5¢-
C H F NO (311.26): C, 57.88; H, 4.50; N, 3.89. Found: C,
5¢,5
15 12
3
3
H), 3.70 (s, 3 H, 14-H), 3.72 (s, 2 H, 7-H), 5.00 (d,
57.53; H, 4.44; N, 3.93. HRMS (CI): m/z calcd for
3
+
J3,NH = 6.6 Hz, 1 H, 3-H), 5.11 (s, 1 H, 12-Htrans), 5.36 (s, 1
C H F NO [M + H] : 312.0774; found: 312.0811.
15
13
3
3
3
4
1
H, 12-H ), 7.19 (dd, J = 8.2 Hz, J = 1.3 Hz, 2 H, 9-
Compound 13b: H NMR (500 MHz, DMSO-d ): d = 2.14
cis
9,10
9,11
6
3
4
H), 7.28 (tt, J1 = 7.3 Hz, J = 1.3 Hz, 1 H, 11-H), 7.34
m, 2 H, 10-H), 8.01 (d, J
(s, 3 H, 12-H), 7.16 (s, 1 H, 6-H), 7.53 (m, 3 H, 10-H, 11-H),
1,10
11,9
3
13
13
(
= 6.6 Hz, 1 H, NH). C NMR
7.87 (m, 2 H, 9-H), 11.01 (br s, 1 H, NH). C NMR (125
NH,3
(
125 MHz, CDCl ): d = 46.0 (t, C-5), 49.8 (t, C-7), 53.0 (q,
MHz, DMSO-d ): d = 17.8 (q, C-12), 104.9 (d, C-6), 115.8
3
6
1
1
C-14), 57.5 (d, C-3), 115.6 (q, J = 287.9 Hz, C-1), 122.4
(q, J = 287.9 Hz, C-1), 116.8 (s, C-5), 125.5 (d, C-10),
1
,F
1,F
(
1
1
t, C-12), 127.4 (d, C-11), 128.9 (d, C-10), 129.4 (d, C-9),
129.2 (d, C-11), 130.4 (d, C-9), 131.0 (s, C-8), 152.3 (s, C-
2
2
33.2 (s, C-4), 134.9 (s, C-8), 156.7 (q, J = 37.4 Hz, C-2),
4), 155.3 (q, J = 36.5 Hz, C-2), 156.9 (s, C-7), 158.1 (s,
2
,F
2,F
+
69.0 (s, C-13), 206.8 (s, C-6). HRMS (CI): m/z calcd for
C-3). HRMS (CI): m/z calcd for C H F NO [M] :
1
4
10
3
3
+
C H F NO [M + H] : 343.1130; found: 344.1120.
Compound 12bb: H NMR (500 MHz, CDCl ): d = 3.75 (s,
297.0595; found: 297.0604.
16
17
3
4
1
1
Compound 13c: H NMR (500 MHz, DMSO-d ): d = 2.14
3
6
2
3
H, 13-H), 3.82 (d, J = 17.4 Hz, 1 H, 5-H), 3.94 (d,
(s, 3 H, 14-H), 6.76 (s, 1 H, 6-H), 7.47 (m, 1 H, 10-H), 7.54
5
,5¢
2
3
3
4
J5¢,5 = 17.4 Hz, 1 H, 5¢-H), 5.12 (d, J3,NH = 6.4 Hz, 1 H, 3-
(m, 1 H, 11-H), 7.65 (dd, J
= 7.6 Hz, J
= 1.9 Hz, 1
12,11
12,10
3
4
H), 5.29 (s, 1 H, 11-H ), 5.48 (s, 1 H, 11-H ), 7.48 (m, 2
H, 9-H), 7.60 (tt, J = 7.6 Hz, J = 1.2 Hz, 1 H, 10-H),
7
1
5
1
H, 12-H), 7.80 (dd, J = 7.9 Hz, J = 1.0 Hz, 1 H, 9-H),
11.04 (br s, 1 H, NH). C NMR (125 MHz, DMSO-d ):
d = 17.7 (q, C-14), 109.7 (d, C-6), 115.8 (q, J = 287.9 Hz,
trans
cis
9,10
13
9,11
3
4
1
0,9
10,8
6
3
4
1
.95 (dd, J = 8.5 Hz, J = 1.2 Hz, 2 H, 8-H), 8.19 (br s,
8
,9
8,10
1,F
H, NH). 1 C NMR (125 MHz, CDCl ): d = 43.1 (t, C-5),
3
C-1), 117.5 (s, C-5), 121.0 (s, C-13), 128.2 (d, C-10), 131.4
(d, C-9), 132.4 (d, C-12), 132.6 (d, C-11), 133.6 (s, C-8),
151.8 (s, C-4), 157.0 (s, C-7), 158.1 (s, C-3). C-2 was not
3
1
3.1 (q, C-13), 57.9 (d, C-3), 115.6 (q, J1,F = 286.9 Hz, C-
), 122.9 (t, C-11), 128.4 (d, C-8), 128.8 (d, C-9), 133.9 (d,
2
79
+
C-10), 135.4 (s, C-4), 135.9 (s, C-7), 156.8 (q, J = 37.6
detectable. HRMS (CI): m/z calcd for C H BrF NO [M] :
2
,F
15 9 3 3
Hz, C-2), 169.1 (s, C-12), 198.4 (s, C-6). HRMS (CI): m/z
374.9718; found: 374.9709.
Synlett 2006, No. 2, 255–258 © Thieme Stuttgart · New York