Stereoselective synthesis of Baylis-Hillman-type adducts via allenolates generated by acyl migration

Article abstract of DOI:10.1021/ol0483908

(Chemical Equation Presented) The rearrangement of the carbamoyl group in allenyl carbamate 1 in the presence of n-BuLi in situ generates the allenolate 3, which is subsequently intercepted with aromatic aldehydes furnishing (Z)- or (E)-configured Baylis-

Full text of DOI:10.1021/ol0483908

ORGANIC
LETTERS
2004
Vol. 6, No. 22
4005-4008
Stereoselective Synthesis of
Baylis Hillman-Type Adducts via
Allenolates Generated by Acyl Migration
−
Nagaraju Gudimalla, Roland Fro1
hlich,† and Dieter Hoppe*
Organisch-Chemisches Institut, Westfa¨lische Wilhelms-UniVersita¨t Mu¨nster,
Corrensstrasse 40, D-48149 Mu¨nster, Germany
dhoppe@uni-muenster.de
Received August 13, 2004
ABSTRACT
The rearrangement of the carbamoyl group in allenyl carbamate 1 in the presence of n-BuLi in situ generates the allenolate 3, which is
subsequently intercepted with aromatic aldehydes furnishing (Z)- or (E)-configured Baylis−Hillman-type adducts 4 or 5. The double bond
isomers can be interconverted by a retro aldol-type reaction.
Allenes are important building blocks for the synthesis of
various complex compounds.1 As a consequence, there is a
growing demand in exploring their application. Among them
are Baylis-Hillman-type adducts that have found application
for a wide variety of chemical and biological purposes2 and
thus have attracted interest in the recent past. Although some
of these compounds can be synthesized by the Baylis-
Hillman reaction,2 there exist alternative methods via the
intermediacy of allenolates, which are subsequently trapped
with aldehydes and ketones to result in Baylis-Hillman-
type adducts. There are in principle three general methods
to arrive at allenolates: (a) 1,4-addition to unsaturated
conjugated propargyl systems,3 (b) Brook4 and retro Brook5
rearrangement, and (c) desilylation of R-silyl enones.6
Our research group has been involved in the synthesis of
allenes and their applications in organic synthesis for some
time.7 Recently, we have reported a concise approach for
the synthesis of enantioenriched cyclopentenones from
enantioenriched allenes by a modified Nazarov cyclization
reaction via allenolates.7f Herein we report a novel approach
for the synthesis of Baylis-Hillman-type adducts by an in
situ generation of allenolates from allenes. The working
hypothesis for our approach is as follows: If the allenyl
carbamate 1 is treated with a base, it forms the alkoxide 2,
which upon warming undergoes an intramolecular nucleo-
* To whom correspondence should be addressed. Fax: (+49)251/
8336531.
† To whom correspondence regarding X-ray analysis should be addressed.
(1) (a) Hoffmann-Ro¨der, A.; Krause. N. (a) Angew. Chem. 2004, 116,
1216; Angew. Chem., Int. Ed. Engl. 2004, 43, 1196. (b) Zimmer, R. Synthesis
1993, 165. (c) Patai, S. The Chemistry of Ketenes, Allenes, and Related
Compounds; John Wiley & Sons: Chichester, 1980. (d) Schuster, H. F.;
Coppola, G. M. Allenes in Organic Synthesis; John Wiley & Sons: New
York, 1984. (e) Landor, S. R. The Chemistry of the Allenes; Academic
Press: New York, 1982.
(2) Reviews: (a) Basavaiah, D.; Jaganmohan Rao, A.; Satyanarayana,
T. Chem. ReV. 2003, 103, 811. (b) Ciganek, E. Org. React. 1997, 51, 201.
(c) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001.
(d) Langer, P. Angew. Chem. 2000, 112, 3177; Angew. Chem., Int. Ed. 2000,
39, 3049.
(3) (a) Li, G.; Wei, H.-X.; Phelps, B. S.; Purkiss, D. W.; Kim, S. H.
Org. Lett. 2001, 3, 823. (b) Cheon, S. H.; Christ, W. J.; Hawkins, L. D.;
Jin, H. L.; Kishi, Y.; Taniguchi, M. Tetrahedron Lett. 1986, 39, 4759. (c)
Taniguchi, M.; Kobayashi, S.; Nakagawa, M.; Hino, T.; Kishi, Y.
Tetrahedron Lett. 1986, 39, 4763. (d) Taniguchi, M.; Hino, T.; Kishi, Y.
Tetrahedron Lett. 1986, 39, 4767. (e) Wei, H. X.; Caputo, T. D.; Purkiss,
D. W.; Li, G. Tetrahedron Lett. 2000, 56, 2397. (f) Deng, G.-H.; Hu, H.;
Wei, H.-X.; Pa´re, P. W. HelV. Chim. Acta 2003, 86, 3510.
(4) Reich, H. J.; Eisenhart, E. K.; Olson, R. E.; Kelly, M. J. J. Am. Chem.
Soc. 1986, 108, 7791.
(5) (a) Tius, M. A.; Hu, H. Tetrahedron Lett. 1998, 39, 5937. (b)
Stergiades, I. A.; Tius, M. A. J. Org. Chem. 1999, 64, 7547.
(6) Matsumoto, K.; Oshima, K.; Utimoto, K. Chem. Lett. 1994, 1211.
10.1021/ol0483908 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/01/2004

philic attack at the carbamoyl group7i resulting in the
allenolate 3, which is trapped with aldehydes, achieving
Baylis-Hillman-type adducts (Z)-4 or (E)-5 (Scheme 1).
mixture had been warmed to room temperature following
the addition of the aldehyde, Baylis-Hillman-type adducts
11a-11j with (E) double bond geometry along with a minor
amount (<3%) of ketone (E)-12 were isolated (Scheme 3).8
Scheme 1. In Situ Generation of Allenolate
Scheme 3. Synthesis of Baylis-Hillman-Type Adducts
The results with various aromatic aldehydes are shown in
Table 1. Thus, the geometry of the double bond can be
controlled by the temperature at which the reaction is
performed.
The starting points for our investigation are the allenyl
carbamates 8a and 8b, which are prepared in a two-step
sequence from the corresponding 2-alkynyl carbamates 6a
and 6b in overall yields of 86% and 61% (Scheme 2).7b
Table 1. Stereoselective Synthesis of (Z) and (E)
Baylis-Hillman-Type Adducts 10a-j and 11a-j
entry
Ar
yield (%) (-40 °C)
yield (%) (rt)
1
2
3
4
5
6
7
8
Ph
p-Br-Ph
p-NO2-Ph
p-MeO-Ph
o-Me-Ph
2-Naphthyl
p-Cl-Ph
furyl11
79 (Z)-10a
69 (Z)-10b
83 (Z)-10c
91 (Z)-10d
67 (Z)-10e
82 (Z)-10f
82 (Z)-10g
54 (Z)-10h
79 (Z)-10i
78 (Z)-10j
72 (E)-11a
63 (E)-11b
60 (E)-11c
60 (E)-11d
63 (E)-11e
76 (E)-11f
50 (E)-11g
62 (Z)-11h
68 (E)-11i
71 (E)-11j
Scheme 2. Synthesis of Allenyl Carbamates 8a and 8b
9
10
2,4,6-MeO-Ph
(E)-Me-CdCH-Ph
The assignment of the configuration of the double bond
was performed on the basis of extensive NOE experiments.9
(7) (a) Hoppe, D.; Riemenschneider, C. Angew. Chem. 1983, 95, 64;
Angew. Chem., Int. Ed. Engl. 1983, 22, 54. (b) Schultz-Fademrecht, C.;
Wibbeling, B.; Fro¨hlich, R.; Hoppe, D. Org. Lett. 2001, 8, 1221. (c) Hoppe,
D.; Gonschorrek, C.; Egert, E.; Schmidt, D. Angew. Chem. 1985, 97, 706;
Angew. Chem., Int. Ed. Engl. 1985, 24, 700. (d) Egert, E.; Beck, H.; Schmidt,
D.; Gonschorrek, C.; Hoppe, D. Tetrahedron Lett. 1987, 28, 789. (e)
Behrens, U.; Wolff, C.; Hoppe, D. Synthesis 1991, 644. (f) Schultz-
Fademrecht, C.; Tius, M. A.; Grimme, S.; Wibbeling, B.; Hoppe, D. Angew.
Chem. 2002, 114, 1610; Angew. Chem., Int. Ed. 2002, 41, 1531. (g) Schultz-
Fademrecht, C.; Zimmermann, M.; Fro¨hlich, R.; Hoppe, D. Synlett 2003,
1969. (h) Zimmermann, M.; Wibbeling, B.; Hoppe, D. Synthesis 2004, 765.
(i) Behrens, U. Ph.D. Thesis, Universita¨t Kiel, 1990.
(8) In some examples, enone (E)-12 and (Z)-adducts (<2%) were isolated
after aqueous workup.
(9) In the (E)-configured adducts a NOE between the olefinic proton
and the methyl groups adjacent to the carbamate group is present, whereas
in the (Z)-configured adducts a NOE between the olefinic proton and the
benzyl proton is observed.
After several optimization experiments, it was found that
the ideal base and solvent to effect the complete migration
of the carbamoyl group in the allenyl carbamate 8a are
n-BuLi and THF. Upon treatment with 1.1 equiv of n-BuLi
at -78 °C followed by rapid warming of the reaction mixture
to -40 °C, the allenyl carbamate 8a generated the allenolate
9, which underwent addition to different aromatic aldehydes,
resulting in the Baylis-Hillman-type adducts 10a-10j with
exclusively (Z) double bond geometry. After the reaction
4006
Org. Lett., Vol. 6, No. 22, 2004

min, followed by warming the reaction mixture to room
temperature, led to the formation of the double bond isomer
(E)-11a (46%) along with the enone (E)-12 (30%), which
arises from the protonation of the allenolate 9 (Scheme 4).
Scheme 4. retro Aldol Mechanism
Figure 1. Crystal structure analysis of rac-(E)-11f.10b
Further solid evidence for the configuration of the double
bond in the Baylis-Hillman-type adducts is drawn from the
X-ray crystal structure analysis10 of the products (E)-11f and
(Z)-10d (Figures 1 and 2).
Likewise, (Z)-10a was treated with n-BuLi at -78 °C, and
after 20 min, 3.0 equiv of 2-methylbenzaldehyde was added.
The reaction mixture was rapidly warmed to room temper-
ature, furnishing Baylis-Hillman-type adducts (E)-11a
(30%), (E)-11e (38%, which results from the addition of
2-methylbenzaldehyde), and enone (E)-12 (10%), respec-
tively (Scheme 4). The above results shed an insight on the
course of the reaction, which can be interpreted as follows:
Upon treatment with n-BuLi at -78 °C, the hydroxy proton
of (Z)-10a is abstracted to form the alcoholate (Z)-13, which
undergoes a retro aldol-type reaction12 to generate the
allenolate 9 and benzaldehyde.
Upon warming of the reaction mixture to room temper-
ature, the allenolate 9 positions itself in such a manner that
the bulky tert-butyl group and the ketone side chain are
displaced to remote positions from each other. Under these
circumstances, the allenolate 9 has equal opportunity to
undergo addition to benzaldehyde or 2-methylbenzaldehyde.
Hence, it adds to both aldehydes to furnish (E)-11a and (E)-
11e in 30% and 38% yields, respectively.
Figure 2. Crystal structure analysis of rac-(Z)-10d.10c
During these investigations an interesting observation was
made. Treatment of (Z)-10a with n-BuLi at -78 °C for 20
(10) (a) Crystals suitable for X-ray diffraction analysis were grown by
slow evaporation of an ethereal solution. (b) X-ray crystal structure analysis
of rac-(E)-11f: formula C28H39NO4, M ) 453.60, colorless crystal 0.40 ×
0.30 × 0.20 mm3; a ) 8.660(1), b ) 13.115(1), c ) 23.230(1) Å, V )
2638.4(4) Å3; Fcalc ) 1.142 g cm-3, µ ) 5.96 cm-1, empirical absorption
correction (0.796 e T e 0.890), Z ) 4, orthorhombic, space group P212121
(No. 19), λ ) 1.54178 Å, T ) 223(2) K, ω and æ scans, 10241 reflections
collected ((h, (k, (l), [(sin θ)/λ] ) 0.59 Å-1, 4027 independent (Rint
)
0.026) and 3280 observed reflections [I g 2σ(I)], 309 refined parameters,
R ) 0.056, wR2 ) 0.141, Flack parameter 0.0(4), max residual electron
density 0.40 (-0.26) e Å-3, hydrogens calculated and refined as riding
atoms. (c) X-ray crystal structure analysis of rac-(Z)-10d: formula C25H39-
NO5, M ) 433.57, colourless crystal 0.40 × 0.20 × 0.15 mm3, a ) 8.395-
(1), b ) 16.627(1), c ) 17.977(1) Å, â ) 92.14 (1)°, V ) 2507.5(4) Å3;
Moreover unreacted allenolate 9 is protonated to result in
the ketone (E)-12 in 10% yield. It can be said that there exists
a dynamic equilibrium between the allenolate 9 and aldehyde
on one side and the Baylis-Hillman-type adducts on the
other side. This led us to consider the (Z) Baylis-Hillman-
type adducts as kinetically controlled products and the (E)
F
calc ) 1.148 g cm-3, µ ) 6.33 cm-1, empirical absorption correction (0.786
e T e 0.911), Z ) 4, monoclinic, space group P21/c (No. 14), λ ) 1.54178
Å, T ) 223(2) K, ω and æ scans, 16787 reflections collected ((h, (k, (l),
[(sin θ)/λ] ) 0.59 Å-1, 4179 independent (Rint ) 0.037) and 3286 observed
reflections [I g 2σ(I)], 291 refined parameters, R ) 0.042, wR2 ) 0.131,
max residual electron density 0.33 (-0.17) e Å-3, hydrogens calculated
and refined as riding atoms. Data sets were collected with a Nonius
KappaCCD diffractometer. Programs used: data collection COLLECT
(Nonius B.V., 1998), data reduction Denzo-SMN (Otwinowski, Z.; Minor,
W. Methods Enzymol. 1997, 276, 307), absorption correction SORTAV
(Blessing, R. H. Acta Crystallogr. 1995, A51, 33. Blessing, R. H. J. Appl.
Crystallogr. 1997, 30, 421), structure solution SHELXS-97 (Sheldrick, G.
M. Acta Crystallogr. 1990, A46, 467), structure refinement SHELXL-97
(Sheldrick, G. M. Universita¨t Go¨ttingen, 1997), graphics Diamond (Bran-
denburg, K. Universita¨t Bonn, 1997).
(11) In the case of furfural (entry 8), the (Z) adduct is formed irrespective
of the condition at which the reaction is performed.
(12) (a) Hamelin, O.; Wang, J.; Depre´s, J. P.; Greene, A. E. Angew.
Chem. 2000, 112, 4484; Angew. Chem., Int. Ed. 2000, 39, 4313. (b) Wang,
W.; Digits, C. A.; Hatada, M.; Narula, S.; Rozamus, L. W.; Huestis, C.
M.; Wong, J.; Dalgarno, D.; Holt, D. A. Org. Lett. 1999, 1, 2033.
Org. Lett., Vol. 6, No. 22, 2004
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Baylis-Hillman-type adducts as the thermodynamically
controlled products.
To demonstrate the versatility of this method, methyl-
substituted allenyl carbamate 8b was treated with 1.1 equiv
of n-BuLi at -78 °C in THF and warmed to -40 °C for 4
h, to generate the allenolate 14. Various aromatic aldehydes
were added, and stirring was continued for 1 h at -40 °C
followed by rapid warming to room temperature. To our
surprise, the (Z) Baylis-Hillman-type adducts (Z)-15a-15c
were formed (Scheme 5).
Scheme 5. Methyl-Substituted Baylis-Hillman-Type Adducts
Figure 3. Crystal structure analysis of rac-(Z)-15a.13
logue 8b formed the (Z) isomers. At present, it is not clear
whether the reason for the difference is of thermodynamic
or kinetic origin.
In summary, a novel and simple method for the stereo-
selective synthesis of (Z)- and (E)-configured â-substituted
Baylis-Hillman-type adducts via in situ generated allenolates
has been demonstrated. Moreover, it has been shown that a
retro aldol-type reaction makes the interconversion of the
(Z) isomer to the (E) isomer possible. This method provides
a unique opportunity to prepare Baylis-Hillman-type adducts
that bear a large substituent at the distal end of the alkene
moiety, which are otherwise not achievable by the conven-
tional Baylis-Hillman reaction.
The configuration of the double bond is proven by NOE
experiments and X-ray crystal structure analysis (Figure 3).13
It is amazing to note that under similar reaction conditions,
the tert-butyl-substituted allenyl carbamate 8a formed the
(E) Baylis-Hillman-type adducts, whereas the methyl ana-
Acknowledgment. This work is supported by the Deut-
sche Forschungsgemeinschaft (SFB 424) and the Fonds der
Chemischen Industrie. N.G. gratefully acknowledges a Ph.D.
stipend from the NRW International Graduate School of
Chemistry, Mu¨nster.
(13) X-ray crystal structure analysis of rac-(Z)-15a: formula C25H33-
NO4, M ) 411.52, colourless crystal 0.30 × 0.20 × 0.10 mm3, a )
8.880(1), b ) 18.897(1), c ) 14.191(1) Å, â ) 100.24 (1)°, V ) 2343.4(3)
Å3; Fcalc ) 1.166 g cm-3, µ ) 6.24 cm-1, empirical absorption correction
(0.835 e T e 0.940), Z ) 4, monoclinic, space group P21/n (No. 14), λ )
1.54178 Å, T ) 223(2) K, ω and æ scans, 12808 reflections collected ((h,
(k, (l), [(sin θ)/λ] ) 0.59 Å-1, 3808 independent (Rint ) 0.040) and 2776
observed reflections [I g 2σ(I)], 279 refined parameters, R ) 0.054, wR2
) 0.143, max residual electron density 0.49 (-0.25) e Å-3, hydrogens
calculated and refined as riding atoms.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data for all compounds, and X-ray
crystal data of rac-(Z)-10d, rac-(E)-11f, and rac-(Z)-15a in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0483908
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Org. Lett., Vol. 6, No. 22, 2004