Investigation of the active species in a Michael addition promoted by chirally modified tetrahydroborate

Article abstract of DOI:10.1016/j.tet.2005.11.023

For the first time, asymmetric 1,4-addition of various malonates to enones has been carried out using tetrabutylammoniumtetrahydroborate (TBATB) in the presence of a chiral ligand. The Michael adducts were formed in reasonably good yields (61-67%) with mo

Full text of DOI:10.1016/j.tet.2005.11.023

Tetrahedron 62 (2006) 1474–1478
Investigation of the active species in a Michael addition promoted
by chirally modified tetrahydroborate
*
Susan Abraham and G. Sundararajan
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India
Received 6 September 2005; revised 21 October 2005; accepted 10 November 2005
Dedicated to Professor Robert Moss on the occasion of his 65th birthday
Abstract—For the first time, asymmetric 1,4-addition of various malonates to enones has been carried out using tetrabutylammoniumte-
trahydroborate (TBATB) in the presence of a chiral ligand. The Michael adducts were formed in reasonably good yields (61–67%) with
moderate ee’s at 0 8C. 11B NMR spectroscopic studies explain this unexpected reactivity through the predominant formation of an aminodiol
modified borate complex in the presence of a hydride acceptor.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Herein, we give a brief report on the results of Michael
additions promoted by a mixture of TBATB/(R,R)-1 in THF
and attempts to rationalize our observations.
The Michael addition, being one of the most important C–C
bond-forming reactions, has attracted much attention
toward the development of enantioselective catalytic
procedures in recent years.1 The current literature abounds
with many reports on enantioselective Michael addition
catalyzed by chiral complexes of Ru,2a Co,2b Rh,2c Ni,2d
Cu,2e Zn,2f Cd,2g Al2h and other heterobimetallics.3 Thus
far, however, there are not many reports on boron catalyzed
asymmetric Michael reactions.4
Ph
Ph
Ph
OH
N
HO
(R, R)-1
2. Results and discussion
We have earlier shown that chiral aminodiol, (R,R)-1, in
combination with LiAlH4 or lanthanum–sodium, can be
effectively used for asymmetric Michael additions.5 As an
extrapolation of these findings, we decided to investigate the
application of chirally modified borohydrides in promoting
the Michael reaction of a,b-unsaturated ketones. Although
chirally modified boron has been employed to promote
many asymmetric processes6a such as Diels–Alder,6b
allylation6c and aldol6d reactions, little has been reported
on the chirally modified tetrabutylammoniumtetrahydro-
borate (TBATB) system in such reactions. However, it is
known that chirally modified borohydrides are effective in
asymmetric reduction processes7 but, in contrast, to chiral
auxiliaries of lithium aluminum hydrides that promote
asymmetric Michael addition,3c,5 chirally modified
borohydrides are not known to assist such reactions.3c
The required ligand (R,R)-1 was prepared from the reaction
of (R)-styrene oxide with benzylamine.5c First, a control
reaction was performed to study the reduction pattern of
cyclic enone with TBATB in the presence of (R,R)-1. As
expected the products were alcohol and ketone resulting
from an initial 1,4-addition of hydride across the enone to
give the enolate, that converts into the ketone (via the enol)
and gets reduced further. These findings are in agreement
with other literature reports.8
Subsequently, (R,R)-1 in combination with TBATB was
used as a promoter in the Michael addition of cyclic enones
with diethyl malonate9 (Eq. 1). The corresponding Michael
adducts from cyclohexenone and cyclopentenone were
formed in good yields and with moderate enantioselec-
tivities. The reduced products of cyclic enone were also
obtained in minor amounts along with the Michael adduct.
In all these cases the yields of Michael adducts remained
fairly constant. The results are summarized in Table 1.
Keywords: Borohydride; Michael addition; Malonates.
*
Corresponding author. Tel.: C91 44 2257 4213; fax: C91 44 2257 4202;
e-mail: gsundar@iitm.ac.in
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.023

S. Abraham, G. Sundararajan / Tetrahedron 62 (2006) 1474–1478
Table 1. Michael addition of various malonates to cyclic enones
1475
Entry
Enone
Michael donor
Time (h)
Product distribution (%)a
%ee of 4b
4
5
6
1
2
3
2a
2a
2a
3a
3b
3c
7
7
7
4aZ62
4bZ64
4cZ61
5aZ24
5aZ22
5aZ25
6aZ14
6aZ14
6aZ12
4aZ35
4bZ40
4cZ31
5
6
7
2b
2b
2b
3a
3b
3c
7
7
7
4dZ67
4eZ65
4fZ63
5bZ22
5bZ25
5bZ22
6bZ11
6bZ10
6bZ15
4dZ42
4eZ45
4fZ39
a Determined by HPLC.
b %ee was determined by HPLC connected to a Chiracel OD. The absolute configuration in all cases were determined by comparison of optical rotation and
was found to be R.
Table 2. Michael addition of benzylidineacetophenone with malonates
Entry
Enone
Michael donor
Time (h)
Product distribution (%)a
8
9
10
1
2
3
3a
3b
3c
7
7
7
8aZ62
8bZ64
8cZ61
22
22
23
16
14
16
7
a Isolated yields.
In a similar manner benzylidineacetophenone reacts with
malonates to give 1,4-adducts with moderate enantioselec-
tivity, along with minor amounts of reduced products. The
results are summarized in Table 2.
and with 2.1 equiv of cyclohexenone the quintet disap-
peared completely leaving a sharp singlet at K15.7 ppm
(Fig. 1). In the absence of cyclohexenone, a mixture of 1 and
TBATB, showed the quintet persisting in the 11B NMR
spectrum even after an overnight reflux. Thus, the need for a
hydride acceptor to initiate the formation of the tetraalk-
oxyborate becomes clear.
Thus, in the presence of (R,R)-1 and TBATB a mixture of
enone and malonate gives reasonable yields of the Michael
adducts in moderate enantiomeric excess, suggesting the
formation of a chirally modified borohydride, an obser-
vation that warranted further scrutiny.
When the same experiment was performed with
cyclohexanone, the quintet did not disappear completely,
even after addition of many equivalents of the ketone,
indicative of a relatively slow hydride transfer to
cyclohexanone. Nevertheless, the appearance of a sharp
singlet at K15.9 ppm could be seen here as well. Also as
expected, the 11B NMR spectrum of a solution contain-
ing (R,R)-1, TBATB and diethyl malonate in the absence
of cyclohexenone gave no other signal than the quintet.
Not so surprising also was the sudden appearance of the
singlet at K15.5 ppm beside the quintet when a small
amount of cyclohexenone was added to this solution at
To gain better insight into these findings, we chose to study
the reaction by 11B NMR spectroscopy. The 11B NMR
spectrum of a solution containing (R,R)-1 and TBATB in a
2:1 ratio gave a quintet centered at K57.4 ppm indicating
the presence of free borohydride.10 To this mixture, the
addition of cyclohexenone in portions of 0.5 equiv,
promoted the formation of a singlet centered at
K15.7 ppm alongside the quintet that could be attributed
to a free tetraborate anion having a tetrahedral structure,11,6b

1476
S. Abraham, G. Sundararajan / Tetrahedron 62 (2006) 1474–1478
Figure 1. 11B NMR spectra of 1-TBATB and varying equivalents of cyclohexenone (a) 0 equiv (b) 0.5 equiv (c) 1.0 equiv (d) 1.5 equiv (e) 2.0 equiv
(f) 2.1 equiv.
ambient conditions. Thus, the combined role of 1 and
cyclohexenone in the generation of the singlet around
K15 ppm in 11B NMR needs to be appreciated.
major product along with the reduction products of
cyclohexenone (Scheme 2).
i. TBATB, 0 C, 2h
To probe the effect of any interaction of the nitrogen atom
in the backbone of (R,R)-1 with the boron, the
corresponding borate complex was generated from metha-
nol or pentanediol by reacting with TBATB in the
presence of the cyclic enone (Scheme 1). The borate
complexes generated here, were effective in the Michael
addition with product yields hovering around 47–49%,
comparable to the earlier observations with (R,R)-1 as the
chelating ligand, pointing to an unlikely role for the
nitrogen atom in the scaffold of 1. Predictably, the 11B
NMR spectral studies of these systems were highly
reminiscent of the earlier results.
O
ii. Chalcone/
di-tert-butyl malonate.
Ph
5b +
2b +[(R,R)-1]
t
Ph
CH(CO2 Bu)2
yield=68 %
8b
Scheme 2. Use of cyclohexenone as a sacrificial hydride acceptor.
We also examined an alternate possibility for generating the
borate, by reacting the disodiated (R,R)-1 with BCl3, to
promote the Michael reaction involving cyclohexenone and
diethyl malonate which, as expected, gave the Michael
adduct in 87% yield with 49% ee (Scheme 3). It was also not
surprising that the 11B NMR spectrum of sodium
aminodiolate and BCl3 gave a peak at K16 ppm,
implicating strongly the formation of a tetraborate species
as in earlier cases.
O
O
20%TBATB/
MeOH
+
+
5b
+ 3a
COOEt
COOEt
49 %
O
38 %
O
20%TBATB/
1,5-pentanediol
O
i.. NaH, THF
5b
2b + 3a
+
3a
ii.BCl
3
(R, R)-1
COOEt
*
CO2Et
COOEt
47 %
38 %
CO2Et
yield = 87%
ee = 49%
Scheme 1. Michael addition in the presence of achiral alcohols without any
ligating atom in the backbone.
Scheme 3. Asymmetric Michael addition with chiral borate generated from
R,R-1 and BCl3.
In order to confirm the need for a hydride acceptor in the
formation of the active catalyst, we deliberately added
cyclohexenone as a sacrificial hydride acceptor to the (R,R)-
1-TBATB mixture prior to the addition of chalcone as the
actual Michael acceptor. Thus, a solution of TBATB, (R,R)-
1 and cyclohexenone in the ratio 1:2:2 was stirred for a
period of 2 h, to which a mixture of chalcone and malonate
was added. As expected, we could get the Michael adduct
corresponding to chalcone and di-tert-butyl malonate as the
2.1. Suggested mechanism for the chirally modified
borate promoted asymmetric Michael addition
On viewing the above observations collectively, a plausible
mechanism for the enantioselective Michael addition
emerges (Scheme 4). The less acidic (R,R)-1 does not
react with TBATB to form the borate complex upon simple

S. Abraham, G. Sundararajan / Tetrahedron 62 (2006) 1474–1478
1477
O
OBH3
O
OH
Bu4N+BH4-
Ph
Ph
O
Ph
O
N
B
N
R,R-1
Ph
Ph
Ph
N
N
O
O
Ph
O
O
Ph
Ph
Bu4N
Ph
HO
O
H
Bu4N
Ph
BH3
B
H
Bu4N
Ph
Chiral borate 11
Scheme 4. Suggested mechanism for the formation of the chirally modified borate in the asymmetric Michael addition.
mixing. However, when the enone is added, an initial
hydride transfer from TBATB takes place; the enolate so
generated undergoes a protic quench with (R,R)-1 that
converts it to the ketone. Stepwise mediation of boron leads
to the eventual formation of the bischelate complex, the
catalytically active species in the Michael reaction.
3. Conclusion
In conclusion, we have shown for the first time that
chirally modified TBATB–aminodiol is effective in the
Michael addition of a,b-unsaturated ketones with various
Michael donors with moderate enantioselectivity. Evi-
dence from 11B NMR spectroscopic studies and other
experiments support the formation of chiral tetrahedral
borate from aminodiol and borohydride in the presence
of a hydride acceptor.
Clearly, the moderate (but tangible!) enantioselectivities
observed in all these cases suggest probable coordination of
cyclohexenone to a chirally modified borate complex. The
possibilities could then be, either a tetracoordinate boron
with one arm of the aminodiol acting as a detachable tether
or a pentacoordinate hypervalent boron, the half life of
which is very short on the NMR timescale12 (vide
Scheme 5). Further NMR spectroscopic investigations
performed to detect the catalytically active species involved
did not offer positive clues even at low temperatures
(K60 8C) when only signals at K57 and K15 ppm could be
observed. Since we have no clear proof by boron NMR
spectroscopy or otherwise for the occurrence of pentacoor-
dinate boron, we tend to support the former mechanism. The
mechanism also explains the fact that the combined yields
of the reduced products in the reaction equal a stoichio-
metric transfer of four hydrides from the borate (Table 1).
4. Experimental
4.1. General experimental procedures
All operations were carried out under an atmosphere of
dry, oxygen-free nitrogen employing vacuum or Schlenk
line techniques, unless otherwise noted. Nitrogen was
purified by passage through columns of MnO anchored
˚
on silica gel catalyst and 4 A molecular sieves. Solid
organometallic compounds were transferred in an argon-
filled glove bag. All glassware, syringes and needles
were oven dried at 140 8C and cooled to room
temperature under nitrogen before use. Tetrahydrofuran
was freshly distilled from sodium/benzophenone ketyl
under nitrogen atmosphere. Cyclohexenone, di-tert-butyl-
malonate, di-ethylmalonate, di-benzylmalonate and (R)-
styreneoxide were purchased from Lancaster synthesis
and cyclopentenone was purchased from Aldrich and
used as received. Tetrabutylammoniumtetrahydroborate
(TBATB) was prepared from tetrabutylammonium-
hydrogensulphate according to the literature procedure.
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra
were recorded in CDCl3 at ambient temperature with
TMS as the internal standard and 11B NMR (135 MHz)
spectra were recorded with boric acid as an external
standard using AV400 Bruker spectrometer (BF3$Et2O
signal appeared at K19.38 ppm). Analytical HPLC was
performed with Shimadzu LC-8A HPLC instrument
equipped with RI detector and chiralcel OD column.
Optical rotations were measured on a JASCO DIP-370
Polarimeter. Melting points were determined in a
capillary and are uncorrected. Mass spectra were
recorded on a Q-TOF mass spectrometer.
Chiral Borate 11
O
COOEt
+
COOEt
Path 2
X
Path 1
O
O
O
-
O
B
O
O
O
O
B
- CH(CO2Et)2
O
O
O
- CH(CO2Et)2
*
COOEt
COOEt
Scheme 5. Possible modes of activation of enone.

1478
S. Abraham, G. Sundararajan / Tetrahedron 62 (2006) 1474–1478
1973–1981. (e) Duncan, A. P.; Leighton, J. L. Org. Lett. 2004, 6,
4117–4119. (f) Kumagi, N.; Matsunaga, S.; Shibasaki, M. Org.
Lett. 2001, 3, 4251–4254. (g) Saito, M.; Nakajima, M.;
Hashimoto, S. Chem. Commun. 2000, 1851–1852. (h) Taylor,
M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125,
11204–11205.
4.2. General reaction procedure of malonate addition
on conjugate alkenones
To a solution of TBATB (56 mg, 0.214 mmol) in dry THF
(3 mL) was added a solution of aminodiol (150 mg,
0.432 mmol) in THF (3 mL). The mixture was stirred
under moisture free nitrogen atmosphere for 30 min at 0 8C,
then a mixture of a,b-unsaturated ketone (1.06 mmol) and
Michael donor (1.06 mmol) were added. The mixture was
stirred for 7 h. The reaction was then quenched by the
addition of 3% aqueous hydrogen peroxide (2 mL) and 10%
aqueous sodium hydroxide (1 mL). The mixture was stirred
for 2 h, the layers were separated and the aqueous phase was
extracted with CH2Cl2 (2!20 mL). The combined organic
layer was dried over anhydrous sodium sulfate, concen-
trated and the crude product was purified by column
chromatography (silica gel 60–120, acetone/hexane 10:90).
NMR spectra are identical to those previously reported.5
3. (a) Majima, K.; Takita, R.; Okada, A.; Ohshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2003, 125, 15837–15845. (b) Arai, T.;
Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasaki, M.
Chem. Eur. J. 1996, 11, 1368–1372. (c) Arai, T.; Sasai, H.;
Aoe, K.; Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem.,
Int. Ed. 1996, 35, 104–106.
4. (a) Wu, R. T.; Chong, J. M. J. Am. Chem. Soc. 2005, 127,
3244–3245. (b) Cardillo, G.; Gentilucci, L.; Gianotti, M.;
Tolomelli, A. Org. Lett. 2001, 3, 1165–1167.
5. (a) Prabagaran, N.; Abraham, S.; Sundararajan, G. Arkivoc 2002,
212–226. Part vii. (b) Sundararajan, G.; Prabagaran, N. Org. Lett.
2001, 3, 389–392. (c) Manickam, G.; Sundararajan, G.
Tetrahedron: Asymmetry 1997, 8, 2271–2278.
%ee’s were determined by HPLC (Daicel Chiralcel OD,
2.0:98.0, 2-propanol/hexane, flow rateZ0.5 mL/min,
254 nm; For example, 4e had retention times of t1Z28.6
(S), t2Z36.5 (R)). The absolute configuration was
established by comparison to the literature.13
6. (a) Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763–784 and
references cited therein. (b) Ishihara, K.; Kurihara, M.;
Matsumoto, M.; Yamamoto, M. J. Am. Chem. Soc. 1998,
120, 6920–6930. (c) Yamada, K.; Takeda, M.; Iwakuma, T.
J. Chem. Soc., Perkin Trans. 1 1983, 6, 265–270. (d) Roush,
W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985,
107, 8186–8190.
Acknowledgements
7. (a) Suri, J. T.; Vu, T.; Hernandez, A.; Congdon, J.;
Singaram, B. Tetrahedron Lett. 2002, 43, 3639–3652. (b)
Daverio, P.; Zanda, M. Tetrahedron: Asymmetry 2001, 12,
2225–2259. (c) Yatagai, M.; Ohnuki, T. J. Chem. Soc.,
Perkin Trans. 1 1990, 7, 1826–1828.
Financial support from CSIR, (India) is acknowledged
through project (No.: 01(1755)/02/EMR2). S.A. thanks
CSIR for Research Fellowship. Authors also thank Malati
Raghunath for performing initial studies.
8. D’Incan, E.; Loupy, A. Tetrahedron 1981, 37, 1171–1179.
9. Other malonates like tert-butyl, benzyl were also used and
very little variation in the product distribution was discerned.
10. 11B NMR spectrum was recorded with boric acid as the
external reference.
References and notes
11. (a) Matsuo, H.; Miyazaki, Y.; Takemura, H.; Matsuoka, S.;
Sakashita, H.; Yoshimura, K. Polyhedron 2004, 23, 955–961.
(b) Miyazaki, Y.; Yoshimura, K.; Miura, Y.; Sakashita, H.;
Ishimaru, K. Polyhedron 2003, 22, 909–916.
1. (a) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42,
1688–1690. (b) Halland, N.; Aburel, P. S.; Jorgensen, K. A.
Angew. Chem., Int. Ed. 2003, 42, 661–665. (c) Krause, N.;
12. (a) Blackwell, J. M.; Piers, W. M.; Parvez, M. Org. Lett. 2000,
2, 695–698. (b) Maruoka, K.; Ooi, T. Chem. Eur. J. 1999, 5,
829–833. (c) Lee, D. Y.; Martin, J. C. J. Am. Chem. Soc. 1984,
106, 5745–5746.
¨
Hoffmann-Roder, A. Synthesis 2001, 171–196. (d) Sibi, M. P.;
Manyem, S. Tetrahedron 2000, 56, 8033–8061.
2. (a) Guo, R.; Morris, R. H.; Song, D. J. Am. Chem. Soc. 2005, 127,
516–517. (b) de Vries, A. H. M.; Feringa, B. L. Tetrahedron:
Asymmetry 1997, 8, 1377–1378. (c) Mauleon, P.; Carretero, J. C.
Org. Lett. 2004, 6, 3195–3198. (d) Venkatachalam, A.; DiMauro,
E. F.; Caroll, P. J.; Kozlowski, M. C. J. Org. Chem. 2003, 68,
13. (a) Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M.
J. Am. Chem. Soc. 1995, 117, 6194–6198. (b) Yamaguchi, M.;
Shiraishi, A.; Hirama, M. J. Org. Chem. 1996, 61, 3520–3530.