Mechanistic insight into the anomalous syn-selectivity observed during the addition of allenylboronates to aromatic aldehydes

Article abstract of DOI:10.1246/cl.2011.1044

The reaction of enantioenriched allenylboronate 3a (98%ee) with benzaldehyde gave homopropargylic alcohol syn- and anti- 4b with anomalous syn addition selectivity (anti:syn = 29:71) and high ee (98% and 97%, respectively). The stereochemical outcome in terms of the absolute configuration shows that this reaction proceeds through a cyclic transition state. Density functional theoretical (DFT) calculations were carried out to elucidate the mechanism of this anomalous syn-selectivity.

Full text of DOI:10.1246/cl.2011.1044

doi:10.1246/cl.2011.1044
1044
Published on the web September 5, 2011
Mechanistic Insight into the Anomalous syn-Selectivity Observed during the Addition
of Allenylboronates to Aromatic Aldehydes
Yusuke Sasaki,1 Masaya Sawamura,1 and Hajime Ito*2
1Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Hokkaido 060-0810
2Division of Chemical Process Engineering, Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628
(Received June 13, 2011; CL-110492; E-mail: hajito@eng.hokudai.ac.jp)
R2
C C
R1
H
The reaction of enantioenriched allenylboronate 3a (98% ee)
with benzaldehyde gave homopropargylic alcohol syn- and anti-
4b with anomalous syn addition selectivity (anti:syn = 29:71)
and high ee (98% and 97%, respectively). The stereochemical
outcome in terms of the absolute configuration shows that this
reaction proceeds through a cyclic transition state. Density
functional theoretical (DFT) calculations were carried out to
elucidate the mechanism of this anomalous syn-selectivity.
M = SiR3, SnR3
/ Lewis acid
M = BR2, SiCl3,
Ti(OR)3, ZnX,
C
R3CHO
R3CHO
M
H
C
R2
C
M
R1
C
O
C
O
L.A.
R3
R2
H
R1
H
H
R3
C
C C
C
M
open transition state
A
cyclic transition state
B
R1
R1
R3
1,2-anti
R2
R3
1,2-syn
R2
The stereoselective reaction of allenylmetal reagents with
carbonyl compounds is the most attractive method available for
the synthesis of sterically defined homopropargylic alcohols.1
The product profiles generated depend mainly on the Lewis
acidity of the metal substituents on the allenylmetal reagent used
(Scheme 1). For example, non-Lewis acidic allenylmetal re-
agents, such as allenyl(trialkyl)silanes or allenyl(trialkyl)stan-
nanes, add to aldehydes in the presence of additional Lewis acid
catalyst through an acyclic, open structure transition state where
the R1 and R3 groups adopt an anti-periplanar conformation.
This results in the corresponding 1,2-syn-product (A) when £-
monosubstituted allenylmetal reagents are used.1 On the other
hand, allenylmetals that contain a Lewis acidic metal center,
such as -B(OR)2, -SiCl3, or -ZnX, add to aldehydes through a
cyclic transition state, in the presence or absence of an external
Lewis acid, leading to the 1,2-anti-product (B).2
During the course of our studies on a copper(I)-catalyzed
route to multisubstituted allenylboronates, and their aldehyde
addition reactions,3 we encountered an unusual 1,2-syn type
product during the addition of an allenylboronate to an aromatic
aldehyde (Scheme 2). A cyclic or open transition state can be
proposed for this reaction. It seems likely, however, that a cyclic
transition state would suffer from steric congestion between the
cyclohexyl group and the phenyl group, while an open transition
state is uncommon for Lewis acidic allenylmetal reagents such
as allenylboronates. Similar anomalous syn preferences have
been reported previously for Lewis acidic allenylmetal additions
to aromatic aldehydes; however, no reports have addressed the
origin of this anomalous selectivity in detail.4
OH
OH
Scheme 1. Open and cyclic transition states in the reaction of
allenylmetal reagents.
10 mol %
Cu(O-t-Bu)
/Xantphos
OCO2Me
Ph2P
PPh2
Bu
O
c-Hex
C
C
C
c-Hex
C
C C
H
H
B2(pin)2 (2)
THF
B(pin)
Bu
(rac)-3a
(rac)-1a
Xantphos
PhCHO(1.0 equiv)
BF3·OEt2 (2.0 equiv)
c-Hex
(rac)-4a, 53%
anti/syn 6:94
Ph
C
C
CH2Cl2,
−70°C, then 0°C
C
(Ref. 2)
Bu
OH
Bu
B(pin)
F3B
H
c-Hex
O
C
C
C
C
H
Ph
Bu
Ph
OR
?
c-Hex
C
C C
O
H
H
B(pin)
Scheme 2. 1,2-syn-Selectivity in a reaction of an allenylboro-
nate with benzaldehyde.
(Scheme 1, B). We have previously reported that the enantioen-
riched allenylboronate (S)-3b reacts with isobutyraldehyde to
afford the corresponding homopropargylic alcohols syn-(3R,4R)-
4b and anti-(3S,4R)-4b with good 1,2-anti-selectivity (Table 1,
Entry 1, 89%, anti/syn = 87:13, 97% ee for syn). These reaction
conditions included an external Lewis acid; however, it is
reasonable to assume a cyclic transition state where the steric
repulsion between the i-Pr and methyl groups is minimized in
the anti-periplanar conformation.2
The reaction of (S)-3a with benzaldehyde gave the
corresponding syn-(1S,2R)-4c and anti-(1R,2R)-4c with a mod-
erate syn-selectivity (Table 1, Entry 2, 94%, anti/syn = 29:71,
97% ee for syn).5,6 The high enantioselectivity was retained even
in the absence of Lewis acid, although the diastereoselectivity
observed was reduced slightly (Entry 3, 97%, anti/syn = 37:63,
97% ee for syn). The absolute configurations of the products,
syn-(1S,2R)-4c and anti-(1R,2R)-4c, were determined by deriva-
tization as ¡-methoxy-¡-trifluoromethylphenylacetate esters,
In this study, we first established that the reaction proceeds
through a cyclic transition state. This was achieved by measur-
ing the absolute configuration of the 1,2-syn-product obtained
from the reaction of the enantioenriched allenylboronate, whose
synthesis in high enantiomeric purity we reported for the first
time in the previous paper.3 Density functional theoretical (DFT)
calculations along the cyclic transition state pathway were also
carried out to investigate the origin of the anomalous syn-
selectivity.
Our first goal was to establish whether the reaction proceeds
through an open (Scheme 1, A) or a cyclic transition state
Chem. Lett. 2011, 40, 1044-1046
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1045
Table 1. Reaction of enantioenriched allenylboronate (S)-3b
and aldehydesa
Me
H
Me H
RCHO
(1.0 equiv)
Bu
H3O+
Me
H
R
C
R
C
C
C
C
+
C
C
BF3·OEt2
(2.0 equiv)
−70 °C
C
C
B(pin)
Bu
Bu
HO
H
H OH
(S)-3b
98% ee
syn-4
anti-4
40−46 h
Entry Aldehyde
1e i-PrCHO
4, Yield/%b anti/sync
ee/%d
4b, 89
4c, 94
4c, 97
87:13 96 (anti), 97 (syn)
29:71 98 (anti), 97 (syn)
37:63 98 (anti), 97 (syn)
36:64 97 (anti), 97 (syn)
39:61 98 (anti), 97 (syn)
2
PhCHO
3f PhCHO
4g,h p-MeOC6H4CHO 4d, 69
5h p-NCC6H4CHO 4e, 78
Figure 1. Three-dimensional structure of TSsyn1 for R = Ph.
Table 2. DFT calculations of the free energy differences
aConditions: (S)-3b (0.21 mmol), CH2Cl2 (0.2 mL), benzalde-
hyde (0.21 mmol), and BF3¢OEt2.(0.42 mmol) at ¹70 °C.
(¦¦G‡) of possible transition state modelsa
c
1
bIsolated yield. Determined by H NMR and HPLC analysis.
1
dDetermined by HPLC analysis using a chiral stationary phase.
5
2 CH3
CH3
4
C
3
C
H3C
H
H3C
H
f
eData was taken from ref. 3. Reaction carried out at room
C
C
C
C
B(OH)2
temperature in the absence of BF3¢OEt2. gReaction carried out
at 0 °C in the absence of BF3¢OEt2. hYield was determined by
1H NMR.
B(OH)2
H
R
R
H
C
O
O
C
6
1
Bu
Me
H
Me H
CH3
R
2
H3C
CH3
H3C
pseudo-
axial
B
C
B
B
B
Me
H
C
C
C
C 3
C
C
C
C
C
O
C
Ph
HO
C
Ph
C
+
C
O
C
C
B(pin)
O
C
C
O
O
R1
R2
4
Bu
Bu
H
H OH
H
H
H
R
H
6
H
CH3
CH3
anti-(1R,2R)-4c
syn-(1S,2R)-4c
H
CH3
CH3
R1=H, R2=Ph (anti)
R1=Ph, R2=H (syn)
H
R
R
5
H
minor
major
TSanti2
TSsyn1
TSsyn2
TSanti1
pseudo-
equatrial
Me
H
Me
H
after isolation from the diastereomeric mixture. The absolute
configuration of the syn-product indicated that the reaction
also proceeded through a cyclic transition state. The electron
density of the phenyl ring did have significant impact on the
diastereoselectivity. The reaction of an aromatic aldehyde with
an electron-donating substituent gave the corresponding
homopropargylic alcohols with moderate diastereoselectivity
(Entry 4, 69%, anti/syn = 36:64, 97% ee for syn). The reaction
of p-cyanobenzaldehyde gave the product with a similar
diastereoselectivity (Entry 5, 78%, anti/syn = 39:61, 97% ee
for syn).
R
C
R
C
C
C
C
C
CH3
CH3
H
OH
HO
H
1,2-syn-product
1,2-anti-product
¹1
Free energy difference/kcal mol
TSanti1 TSanti2 TSsyn1 TSsyn2
Entry
R
Method
1
2
3
4
CH3 B3PW91
CH3 M06-2X
0
0
0
0
3.59
®
6.65
®
0.87
2.19
0.31
5.41
®
6.27
®
Ph
Ph
B3PW91
M06-2X
¹0.69
To gain information regarding the structure and energy
levels of the cyclic transition state, DFT calculations (B3PW91/
6-31G+(d,p)) were performed using model compounds, as
shown in Figure 1.7,8 Gibbs free energies (298.15 K, 1.00 atm)
of four different transition states (TSanti1, TSanti2, TSsyn1, and
TSsyn2) that correspond to the possible reaction pathways with
CH3CHO were calculated, and the energy values were com-
pared. In the most stable transition state (TSanti1, 0.0 kcal mol¹1),
the 5-methyl group of the allenylboronate and the aldehyde
aAll calculations were carried out with the B3PW91/
6-31+G(d,p) or M06-2X/6-31+G(d,p) methods at 298.15 K,
1.00 atm in CH2Cl2 (polarizable continuum model, PCM).
experimental result (Table 1, Entry 1). In the reaction of
benzaldehyde, the most stable transition state calculated using
the B3PW91 DFT method was also found to be TSanti1, with an
¹1
energy difference between TSanti1 and TSsyn1 of 0.31 kcal mol
.
methyl group adopted
a
gauche-conformation (Table 2,
One possible factor in the anomalous 1,2-syn-selectivity
preference may be stabilization due to a CH/³ interaction
between the alkyl group and the phenyl group. The allenylboro-
nate methyl group was found to be in close proximity with the
benzaldehyde phenyl ring in the lowest energy transition state.
The B3PW91 method has been shown to be unable to identify
weak interaction energies, such as CH/³ interactions.9,10 We
Entry 1). The second most stable transition state was TSsyn1
(0.87 kcal mol¹1). The other transition states examined were
¹1
found to have much higher energies (TSanti2, 3.59 kcal mol
;
TSsyn2 5.41 kcal mol¹1) and were therefore omitted from
consideration. In the two stable transition states (TSanti1 and
TSsyn1), the R groups of the aldehyde are in a pseudo-equatorial
conformation, while in the unstable transition states (TSanti2
and TSsyn2) the R groups adopt a pseudo-axial position.
The calculation for CH3CHO reaction is consistent with the
therefore evaluated the two transition states, TSanti1 and TSsyn1
,
for the reaction of benzaldehyde using the alternative method,
M06-2X. This method has been shown to model CH/³
Chem. Lett. 2011, 40, 1044-1046
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1046
interactions with some degree of accuracy.11 In these calcula-
tions, TSanti1 remained the most stable transition state for the
reaction of CH3CHO (Entry 2). However, in the reaction of
benzaldehyde, the TSsyn1 was found to be more stable than
J. Am. Chem. Soc. 2002, 124, 12414. b) J. W. J. Kennedy,
D. G. Hall, J. Am. Chem. Soc. 2002, 124, 11586. c) D. G.
Hall, Synlett 2007, 1644.
H. Ito, Y. Sasaki, M. Sawamura, J. Am. Chem. Soc. 2008,
130, 15774.
3
4
¹1
TSanti1 by ¹0.69 kcal mol (Entry 4).
The transition state structure calculated using the M06-2X
method incorporated the possibility of attractive interactions
between the CH bond and the benzene ring (Figure 1). The
distances between the hydrogen atom and the plane, and the
centroid, of the benzene ring were found to be 2.664 and
2.845 ¡, respectively. These values are less than the sum of the
van der Waals radii of H and C atoms (2.9 ¡), suggesting the
presence of CH/³ interactions between the allenylmetal CH
bond and the benzaldehyde phenyl ring in TSsyn1. No such
interactions were found to be present in TSanti1 for the reaction
of benzaldehyde. The transition state structure TSsyn1 featured a
small dihedral angle for C5-C4-C6-C7 (38.2°), allowing the two
groups to be in close proximity. This facilitates the formation of
CH/³ interactions.
In summary, we have shown experimentally that the
anomalous 1,2-syn-selectivity of the addition reaction of
allenylboronates with aromatic aldehydes originates from a
cyclic transition state, even in the presence of external Lewis
acid. DFT calculations revealed that CH/³ interactions weakly
stabilize the transition state for the 1,2-syn-product. This study
provides compelling evidence for a mechanism that explains
the anomalous 1,2-syn-selectivity of allenylboronates. However,
clarification of the role of these CH/³ interactions warrants
detailed studies that employ improved basis sets and high level
calculations, such as the coupled cluster singles and doubles
(CCSD) method, as well as further investigation of the role of
the external Lewis acid, BF3¢OEt2.12
a) R. Haruta, M. Ishiguro, N. Ikeda, H. Yamamoto, J. Am.
Chem. Soc. 1982, 104, 7667. b) M. Ishiguro, N. Ikeda, H.
Yamamoto, J. Org. Chem. 1982, 47, 2225. c) K. Furuta, M.
Ishiguro, R. Haruta, N. Ikeda, H. Yamamoto, Bull. Chem.
Soc. Jpn. 1984, 57, 2768. d) T. Harada, T. Katsuhira, A.
Osada, K. Iwazaki, K. Maejima, A. Oku, J. Am. Chem. Soc.
1996, 118, 11377. e) J. W. Han, N. Tokunaga, T. Hayashi,
J. Am. Chem. Soc. 2001, 123, 12915.
A representative procedure for the reaction of allenylboro-
nate with aldehydes: to a solution of allenylboronate (S)-3b
(50 mg, 0.21 mmol) in CH2Cl2 (0.2 mL), benzaldehyde (21.6
¯L, 0.21 mmol) was added dropwise at ¹78 °C, followed by
addition of BF3¢OEt2 (50 ¯L, 0.42 mmol). After the reaction
was complete (46 h), aqueous NaHCO3 was added and the
mixture was allowed to warm to room temperature. The
reaction mixture was then extracted with ether and the
combined organic phases were dried over MgSO4 and
filtered. After the removal of solvents in vacuo, the residue
was purified by column chromatography (SiO2, hexane/
diethyl ether = 100:0 to 70:30) to give an anti/syn mixture
of 4c.
5
6
L.-N. Guo, H. Gao, P. Mayer, P. Knochel, Chem.®Eur. J.
2010, 16, 9829.
7
8
A. D. Becke, J. Chem. Phys. 1993, 98, 1372.
All calculations were carried out using the Gaussian 09W
program package. The DFT method was employed, using
B3PW91 and M06-2X. All transition state geometries were
calculated with the 6-31+G(d,p) basis set. The solvent effect
was considered using the PCM model method with ¾ = 8.93
(CH2Cl2). Zero-point energy corrections were obtained from
frequency calculations without scaling. The presence of one
imaginary frequency was checked for all transition state
structures.
This work was supported by a Grant-in-Aid for Scientific
Research (B) (Ministry of Education, Culture, Sports, Science
and Technology), and the Precursory Research for Embryonic
Science and Technology, Japan Science and Technology Agency
(PRESTO, JST). Y.S. thanks the Japan Society for the Promotion
of Science for a fellowship.
9
N. Mohan, K. P. Vijayalakshmi, N. Koga, C. H. Suresh,
J. Comput. Chem. 2010, 31, 2874.
This paper is in celebration of the 2010 Nobel Prize
awarded to Professors Richard F. Heck, Akira Suzuki, and
Ei-ichi Negishi.
10 a) C. Uyeda, E. N. Jacobsen, J. Am. Chem. Soc. 2011, 133,
5062. b) O. Takahashi, Y. Kohno, M. Nishio, Chem. Rev.
2010, 110, 6049. c) O. Takahashi, K. Yamasaki, Y. Kohno,
K. Ueda, H. Suezawa, M. Nishio, Chem.®Asian J. 2006, 1,
852. d) M. Nishio, Tetrahedron 2005, 61, 6923. e) G.
Hattori, K. Sakata, H. Matsuzawa, Y. Tanabe, Y. Miyake, Y.
Nishibayashi, J. Am. Chem. Soc. 2010, 132, 10592. f) G. G.
Melikyan, R. Spencer, Tetrahedron 2010, 66, 5321.
11 a) Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 119, 525.
b) Y. Zhao, D. G. Truhlar, Acc. Chem. Res. 2008, 41, 157.
12 Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
References and Notes
1
For reviews of allenylmetals, see: a) J. A. Marshall, B. W.
Gung, M. L. Grachan, in Modern Allene Chemistry, ed. by
N. Krause, A. S. K. Hashmi, Weinheim, 2004, Vol. 1,
Chap. 9, p. 493. doi:10.1002/9783527619573.ch9. b) N.
Krause, A. Hoffmann-Röder, Tetrahedron 2004, 60, 11671.
c) K. M. Brummond, J. E. DeForrest, Synthesis 2007, 795. d)
J. A. Marshall, J. Org. Chem. 2007, 72, 8153.
2
For Lewis acid-mediated reactions of allylboronates with
aldehydes, see: a) T. Ishiyama, T.-a. Ahiko, N. Miyaura,
Chem. Lett. 2011, 40, 1044-1046
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/