Do more electrophilic aldehydes/ketones exhibit higher reactivity toward nucleophiles in the presence of Lewis acids?

Article abstract of DOI:10.1002/1521-3773(20010903)40:17<3206::AID-ANIE3206>3.0.CO;2-5

A crucial role in the chemoselective synthesis of primary, secondary, and homoallylic alcohols and of Diels-Alder adducts is played by Lewis acids (LA) in the addition of nucleophiles (Nu) to carbonyl compounds (see scheme; EWG = electron-withdrawing group, EDG = electron-donating group).

Full text of DOI:10.1002/1521-3773(20010903)40:17<3206::AID-ANIE3206>3.0.CO;2-5

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groups were protected with a thioalkyl linker. The oligonucleotides were
deprotected with DTT immediately before reaction with 2Py-SS-CLIO.
Do More Electrophilic Aldehydes/Ketones
Exhibit Higher Reactivity toward Nucleophiles
in the Presence of Lewis Acids?
[
11]
Synthesis of magnetic oligonucleotide nanoparticles: Complementary
5
'
3'
(
(
TAC-GAG-TTG-AGA-ATC-CTG-AAT-GCG ), half-complementary
5
'
3'
TAC-GAG-TTG-AGA-GAG-TGC-CCA-CAT ), and noncomplemen-
Naoki Asao, Toru Asano, and Yoshinori Yamamoto*
5
'
3'
tary ( ATG-CTA-AAT-GAC-GAC-TGC-CCA-CAT ) oligonucleotides
were synthesized using standard phosphoramidite chemistry (underlined
bases will hybridize). Either 5'- or 3'-alkanethio-oligonucleotide (550 mg)
was added to of 2Py-SS-CLIO (1.1 mL; 3 mg of Fe in 0.1m phosphate
buffer, pH 8.0), and the mixture incubated overnight at room temperature.
The mixture was purified using an LS ‡ high-gradient magnetic separation
column (Miltenyi Biotec, Auburn, CA) equilibrated with 0.1m phosphate
buffer, pH 7.5. The number of oligonucleotides attached per particle was
determined by treatment with DTT, followed by separation of the iron and
oligonucleotide using a microconcentrator as described.[ The oligonu-
cleotide concentration was then determined from absorbance spectroscopy
Lewis acid mediated electrophilic reactions of carbonyl
compounds are among the most fundamental and important
[1]
reactions in modern organic synthesis. It is well known that
the coordination of carbonyl groups to Lewis acids exerts a
dramatic effect on the rates and selectivities of reactions at the
carbonyl centers. While much research into the Lewis acid
mediated stereoselective or regioselective reactions has been
carried out, less attention has been paid to the chemoselective
reactions in the presence of Lewis acids.[ It is evident for
organic chemists that more electrophilic aldehydes and
6]
5
� 1
� 1
at 260 nm using an extinction coefficient of 1.2 Â 10 m cm . The probes
are denoted P1 (CLIO-SS-(CH -CGC-ATT-CAG-GAT) and P2 (TCT-
CAA-CTC-GTA-(CH -SS-CLIO).
Hybridization: For Figure 1 equal volumes (25 mL) of P1 and P2 (both at
2±4]
2 6
)
2 3
)
�
ketones 1 react with nucleophiles (Nu ) much faster than
�
1
less electrophilic analogues
5
50 mg FemL ) were mixed with a solution of 1m NaCl and 0.1m phosphate
fast
slow
at pH 7.5 (14 mL). Various oligonucleotides (2 mL, 400 ng) were then added.
The mixture was heated to 508C for 5 min and allowed to react at room
temperature overnight. The precipitate shown in Figure 2B was obtained
after overnight incubation of P1/P2 with complementary oligonucleotide;
the precipitate was washed with 0.1m NaCl and 0.1m phosphate buffer, and
re-suspended in the same buffer (300 mL). The sample was split into two
portions (15 mL) and examined by electrophoresis without DTT (lane 1) or
with 4 mm DTT (lane 2) under nondenaturing conditions (Figure 2A) or
denaturing conditions (Figure 2B).
2. We found that the reverse
is the case in the Lewis acid
mediated reactions: more
electrophilic aldehydes and
ketones 1 react much slower
than the less electrophilic
analogues 2 in the presence
of Lewis acids (Scheme 1),
with a chemoselectivity that
is not attainable under ordi-
nary conditions.
Nu
EWG
EDG
R
C
R
O
C O
1
2
Nu / LA
slow
fast
Gel electrophoresis: Nondenaturing gels (10% polyacrylamide) and
denaturing gels (20% polyacrylamide) were used. Gels were stained with
SYBR Gold dye (Molecular Probes,Eugene OR).
Scheme 1. Chemoselective reac-
tions of equimolar mixtures of 1
and 2. EWG ˆ electron-withdraw-
ing group, EDG ˆ electron-donat-
ing group.
Determination of proton relaxation times: Relaxation time measurements
were performed at 0.47 T and 408C or 808C (Bruker NMR Minispec,
Billerica, MA). To determine the effect of hybridization on the T2 values of
water, equal amounts of P1 and P2 (5 mL) were diluted in a solution of 1m
NaCl and 0.1m phosphate buffer at pH 7.5 (1 mL) to give a total iron
For many years, we have
researched the Lewis acid
mediated reaction of allyl stannanes and related organo-
metallic compounds.[ An interesting observation was made
in the reaction of allyltributylstannane with aldehydes. The
reaction of a 1:1 mixture of p-tolualdehyde (3) and a,a,a-
trifluoro-p-tolualdehyde (4) with one equivalent of allylstan-
nane at 1208C gave the homoallylic alcohol 6 derived from 4,
in 64% yield, along with trace amounts of the homoallylic
alcohol 5 derived from 3 [Eq. (1)]. This is an expected result,
5]
�
1
content of 10 mgmL . T2 values were obtained before and after addition of
mL (390 ng) of complementary, half-complementary, or noncomplemen-
1
tary oligonucleotides and plotted as a function of time. The relaxivity was
determined by plotting 1/T2 and 1/T1 values of water as a function of the
iron concentration. The size of the conjugates was determined by light
scattering (Coulter N4, Hialeah, FL).
Received: February 16, 2001
Revised: June 8, 2001 [Z16627]
[
[
1] J. J. Li, R. Geyer, W. Tan, Nucleic Acids Res. 2000, 28, E52.
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[
[
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2000, 122, 3795.
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Magn. Reson. Med. 1993, 29, 599.
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Scadden, R. Weissleder, Nat. Biotechnol. 2000, 18, 410.
[
*] Prof. Dr. Y. Yamamoto, Dr. N. Asao, T. Asano
Department of Chemistry, Graduate School of Science
Tohoku University, Sendai 980-8578 (Japan)
Fax : (‡81)22-217-6784
[
[
10] R. Weissleder, A. Moore, U. Mahmood, R. Bhorade, H. Benveniste,
E. A. Chiocca, J. P. Basilion, Nat. Med. 2000, 6, 351.
E-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
11] J. J. Storhoff, R. Elghanian, R. C. Mucic, C. A. Mirkin, R. L. Letsinger,
J. Am. Chem. Soc. 1998, 120, 1959.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
3206
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since 4 is more electrophilic than 3 as a result of an electron-
BF ´ OEt , and only the original peak of 14 was observed
3
2
withdrawing CF group at the para position. On the other
(Scheme 2). Next, the equilibrium study of an equimolar
3
hand, the BF ´ OEt -mediated reaction at � 1008C gave 5 in
mixture of 13 and 14 with one equivalent of BF ´ OEt was
carried out. As expected, complex 16 was not observed, and
3
2
3
2
6
3% yield together with 21% of 6. This was an unexpected
result for us. A similar observation was also made in a Diels ±
Alder reaction. The thermal reaction of a 1:1 mixture of 7 and
8
with cyclopentadiene at 408C afforded the [4‡2] cyclo-
adduct 10 derived from 8 in 90% yield, along with a small
amount (8%) of 9 derived from 7 [Eq. (2)]. This is also an
Scheme 2. 13C NMR chemical shifts of 13 ± 15 at � 788C in CD
2
2
Cl .
expected result, since 8, which has an electron-withdrawing
CF3 group, is a better dienophile than 7. However, the
BF ´ OEt -mediated reaction at � 788C gave 9 as the sole
the peak for the carbonyl carbon atom of 15 appeared at d ˆ
14.65 (13:15 3.0:1). Even when an additional amount of
2
3
2
BF ´ OEt2 (two equivalents in total) was added to this
[
6]
3
product in 49% yield.
mixture, the complex 16 was not formed and only an
enhancement of the ratio of 15 (13:15 1.8:1) was observed.
These results clearly imply that a carbonyl compound bearing
an electron-donating group can form the complex 12 with a
Lewis acid much more readily and can also be activated
selectively.
The dramatic reversal of the chemoselectivity in the
thermal and Lewis acid mediated reactions is understandable
if the coordination ability of more electrophilic carbonyl
groups to Lewis acids 11 is weaker than that of less electro-
philic analogues 12. This means that the observed chemo-
selectivities would be ascribed
The aldehydes and ketones were reduced chemoselectively
based on the above concept. The reduction of a 1:1 mixture of
LA
LA
to a higher equilibrium con-
stant for the formation of com-
plex 12 rather than 11.
O
C
O
C
3
and 4 with Bu SnH (1.0 equivalent) at room temperature
EWG
EDG
3
gave 18 in 51% yield along with 3% of 17, whereas the
To confirm this proposal, we
carried out the ab initio study
11
12
[11]
reduction with Bu SnH ± BF ´ OEt (1.0 equivalent)
at
3
3
2
�
788C afforded 17 in 68% yield together with 31% of 18
Eq. (3)]. Similarly, the reduction of a 1:1 mixture of 13 and 14
of the BF complexes of acet-
3
[
aldehyde and trifluoroacetaldehyde by using the GAUSSI-
[
7]
AN94 program, and the energies for all possible stable
conformations of each complex were calculated (see Support-
[
8]
ing Information). A large difference in energy between
CF CHO ´ BF and CH CHO ´ BF complexes were calculated
3
3
3
3
at all levels of theory that were employed (3-21G, 6-31G*, and
MP2/6-31G*). At the MP2/6-31G* level of theory, the most
stable conformer of the CF CHO ´ BF complexes was
3
3
�
1
6
.46 kcalmol less stable than the most stable conformer of
the CH CHO ´ BF complexes. In other words, the basicity of
3
3
the oxygen atom of more electrophilic carbonyl groups is
lower than that of less electrophilic analogues, making the
with Bu SnH (1.0 equivalent) in butyronitrile gave 20 in 40%
3
yield as the sole product,[ whereas the reduction with
12]
[
9]
formation of 12 much easier.
The preferred formation of complex 12 rather than of 11
Bu SnH ± BF ´ OEt (1.0 equiv) afforded 19 in 82% yield as
3
3
2
1
3
the sole product [Eq. (4)].
was also supported by the low-temperature C NMR spec-
troscopic experiments of ketones 13 and 14 in the presence of
BF ´ OEt . The original signals of the carbonyl carbon atoms
3
2
of acetophenone 13 and trifluoroacetophenone 14 appeared
at d ˆ 197.94 and 179.59, respectively. When 13 was treated
with one equivalent of BF ´ OEt in CD Cl at � 788C to form
3
2
2
2
complex 15, a significant downfield shift occurred, and the
signal for the carbonyl carbon atom was observed at d ˆ
[
10]
2
14.65; the integration ratio of 13:15 was 3.0:1. In contrast,
no signal for 16 was detected at all when 14 was treated with
Angew. Chem. Int. Ed. 2001, 40, No. 17
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3
It is now clear that the chemoselectivities in the Lewis acid
promoted reactions of certain aldehydes and ketones are
opposite to those in the reactions in the absence of Lewis acid.
By proper choice of the reaction conditions, either by carrying
out the reaction in the presence or in the absence of Lewis
acids, secondary and primary alcohols, homoallylic alcohols,
and Diels ± Alder adducts can be synthesized chemoselective-
ly. A further extension of the above concept is being
investigated in our laboratories.
The Fate of Bis(h -allyl)palladium Complexes
in the Presence of Aldehydes (or Imines) and
Allylic Chlorides: Stille Coupling versus
Allylation of Aldehydes (or Imines)
Hiroyuki Nakamura, Ming Bao, and
Yoshinori Yamamoto*
Palladium-catalyzed Stille coupling between allylic chlor-
ides 1 and allyltributyltin proceeds through bis(h -allyl)palla-
dium intermediates 2 to give the allylic ± allylic 1,5-hexadiene
3
Received: March 20, 2001 [Z16808]
coupling products 3 and 3' in moderate to high yields
(
Scheme 1).[ Recently, we found that 2 (R ˆ H), generated
1]
[
1] For reviews, see: a) Modern Carbonyl Chemistry (Ed.: J. Otera),
Wiley-VCH, Weinheim, 2000; b) Lewis Acids in Organic Synthesis,
Vol. 1 ± 2 (Ed.: H. Yamamoto), Wiley-VCH, Weinheim, 2000;
c) Lewis Acid Reagents (Ed.: H. Yamamoto), Oxford University
Press, New York, 1999; d) R. Mahrwald, Chem. Rev. 1999, 99, 1095 ±
1120; e) A. Mengel, O. Reiser, Chem. Rev. 1999, 99, 1191 ± 1223; f) M.
Santelli, J. M. Pons, Lewis Acids and Selectivity in Organic Synthesis,
CRC, Boca Raton, 1996; g) S. Shambayati, S. L. Schreiber in
Comprehensive Organic Synthesis, Vol. 1 (Eds.: B. M. Trost, I. Flem-
ing), Pergamon, Oxford, 1991, pp. 283 ± 324; h) M. Yamaguchi in
Comprehensive Organic Synthesis, Vol. 1 (Eds.: B. M. Trost, I. Flem-
ing), Pergamon, Oxford, 1991, pp. 325 ± 353.
[
2] For reports of chemoselective aldol reactions mediated by special
3 3 4
Lewis acids, for example, [Eu(dppm) ] and Bu SnClO , see: a) K.
Mikami, M. Terada, T. Nakai, J. Org. Chem. 1991, 56, 5456 ± 5459; b) J.
Chen, J. Otera, Synlett 1997, 29 ± 30; c) J. Chen, J. Otera, Tetrahedron
3
Scheme 1. Different reaction pathways of bis(h -allyl)palladium inter-
mediates 2.
1997, 53, 14275 ± 14286.
[
3] The discrimination between two different carbonyl compounds on the
basis of steric effects has been reported; see: S. Saito, H. Yamamoto in
Modern Carbonyl Chemistry (Ed.: J. Otera), Wiley-VCH, Weinheim,
from allyl chloride and allyltributyltin in the presence of a
palladium catalyst, reacts with aldehydes 4 and imines 5 to
produce the corresponding homoallyl alcohols 6 and amines 7,
2
000, pp. 33 ± 67.
[
4] a-Alkoxy aldehydes can be selectively activated by bidentate Lewis
acids in the presence of other aldehydes as a result of the chelation
effect; see: M. T. Reetz, A. Gansäuer, Tetrahedron 1993, 49, 6025 ±
[2, 3]
respectively, in high yields.
Also, we found that unsym-
3
6
030, and references therein.
metrical bis(h -allyl)palladium complexes 2 can selectively
[
[
5] Y. Yamamoto, N. Asao, Chem. Rev. 1993, 93, 2207 ± 2293.
6] The rather low yield of 9 is a result of the preferential dimerization of
transfer the unsubstituted allyl group to aldehydes and
[4]
imines. Important questions are what factors control the
3 2
cyclopentadiene in the presence of BF ´ OEt .
3
reaction pathways of bis(h -allyl)palladium intermediates 2,
[
7] Gaussian94, M. J. Frisch, G. W. Trucks, H. B. Schlegel, P. M. W. Gill,
B. G. Johnson, M. A. Robb, J. R. Cheesemen, T. A. Keith, J. A.
Petersson, J. A. Montgomery, K. Raghavachari, M. A. Al-Laham,
V. G. Zakrzewski, J. V. Ortiz, J. B. Foresman, J. Cioslowski, B. B.
Stefanov, A. Nanayakkara, M. Challacombe, C. Y. Peng, P. Y. Ayala,
W. Chen, M. W. Wong, J. L. Andres, E. S. Replogle, R. Gomperts,
R. L. Martin, D. J. Fox, J. S. Binkley, D. J. DeFrees, J. Baker, J. J. P.
Stewart, M. Head-Gordon, C. Gonzales, J. A. Pople, Gaussian, Inc.,
Pittsburgh, PA, 1995.
and why does the Stille coupling of 2 cease in the presence of
aldehydes 4 or imines 5?
We now report that phosphine ligands play a key role in this
process; the Stille coupling reaction takes place in the
presence of triphenylphosphine,[ even if aldehydes 4 and
imines 5 are present, whereas the allylation of aldehydes and
imines occurs in the absence of the phosphine, even in the
presence of allylic chlorides 1 (Scheme 2).
5]
[
8] a) B. W. Gung, Tetrahedron Lett. 1991, 32, 2867 ± 2870; b) B. W. Gung,
M. A. Wolf, J. Org. Chem. 1992, 57, 1370 ± 1375.
The palladium-catalyzed reactions of various aldehydes 4
and imines 5 with allylic chlorides were investigated in the
[
9] The results of theoretical calculations of the LUMO in the presence,
and absence, of BF
in a full paper.
3
and transition-state calculations will be published
presence or absence of PPh (Table 1). In the absence of a
3
[
[
[
10] R. J. Gillespie, J. S. Hartman, Can. J. Chem. 1968, 46, 2147 ± 2157.
11] W. P. Neumann, E. Heymann, Justus Liebigs Ann. Chem. 1965, 683, 11.
12] a) A. J. Leusink, H. A. Budding, J. W. Marsman, J. Organomet. Chem.
phosphine ligand, the reaction of 1a and allyltributyltin with
benzaldehyde (4a) gave the homoallyl alcohol 6a in 94%
yield, and cinnamyl chloride 1a was recovered in essentially
1968, 13, 155 ± 162; b) A. J. Leusink, H. A. Budding, W. Drenth, J.
Organomet. Chem. 1968, 13, 163 ± 168.
[*] Prof. Dr. Y. Yamamoto, Dr. H. Nakamura, Dr. M. Bao
Department of Chemistry
Graduate School of Science
Tohoku University
Sendai 980-8578 (Japan)
Fax : (‡81)22-217-6784
E-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
3208
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4017-3208 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 17