(5S)-1,3-Diaza-2-imino-3-phenylbicyclo[3.3.0]octane: first example of guanidine based in situ recyclable chiral catalytic source for borane-mediated asymmetric reduction of prochiral ketones

Article abstract of DOI:10.1016/j.tetasy.2006.03.020

(5S)-1,3-Diaza-2-imino-3-phenylbicyclo[3.3.0]octane has been synthesized and successfully employed, for the first time, as a chiral catalytic source for the borane-mediated asymmetric reduction of prochiral α-halo ketones to provide the corresponding secondary alcohols in high enantiomeric purity. The potential of this guanidine as an in situ recyclable chiral catalytic source for the borane-mediated chiral reduction processes has also been demonstrated.

Full text of DOI:10.1016/j.tetasy.2006.03.020

Tetrahedron: Asymmetry 17 (2006) 1036–1040
(5S)-1,3-Diaza-2-imino-3-phenylbicyclo[3.3.0]octane: first example
of guanidine based in situ recyclable chiral catalytic source for
borane-mediated asymmetric reduction of prochiral ketones
Deevi Basavaiah,* Kalapala Venkateswara Rao and Bhavanam Sekhara Reddy
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Received 16 March 2006; accepted 23 March 2006
Available online 21 April 2006
Abstract—(5S)-1,3-Diaza-2-imino-3-phenylbicyclo[3.3.0]octane has been synthesized and successfully employed, for the first time, as a
chiral catalytic source for the borane-mediated asymmetric reduction of prochiral a-halo ketones to provide the corresponding secondary
alcohols in high enantiomeric purity. The potential of this guanidine as an in situ recyclable chiral catalytic source for the borane-med-
iated chiral reduction processes has also been demonstrated.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
We have been working for the last few years on the develop-
ment of useful chiral catalysts containing the N–P@O struc-
tural framework for the borane-mediated asymmetric
reduction of prochiral ketones,15–19 actually inspired by the
elegant work of Wills and co-workers.12–14 In this direction,
we have designed and synthesized a number of chiral cata-
lysts having N–P@O structural framework built mainly
on (5S)-1,3-diaza-2-phospha-2-oxo-3-phenylbicyclo[3.3.0]-
octane framework I and examined their applications.15–19
The development of useful and practical chiral catalysts for
the borane-mediated asymmetric reduction of prochiral
ketones for obtaining enantiomerically pure (enriched)
secondary alcohols has been, and continues to be, an area
of interest in chiral chemistry because of the challenges
involved in such endeavors and also due to the applications
of homochiral secondary alcohols in organic and medicinal
chemistry.1–6 In fact, after ingenious utilization of oxaza-
borolidines, by Corey et al.,6,7 as chiral catalysts for the
borane-mediated asymmetric reduction of prochiral
ketones, there has been much activity in designing and
developing various kinds of oxazaborolidine-based chiral
catalysts. Several efforts have also been made in developing
chiral catalysts based on titanium,8,9 sulfonamide,10,11 and
phosphorus12–14 derivatives for this purpose. To the best of
our knowledge, there is no report in the literature on the
application of chiral guanidine as a chiral catalyst/catalytic
source for the borane-mediated asymmetric reduction of
prochiral ketones. We herein report (5S)-1,3-diaza-2-imino-
3-phenylbicyclo[3.3.0]octane as the first example of guani-
dine based in situ recyclable chiral catalytic source for
the borane-mediated asymmetric reduction of representa-
tive prochiral ketones.
7
8
6
O
P
5
N
1
H
2
4
N
3
Ph
I
2. Results and discussion
During these studies we have also, to some extent,
established that the group on the phosphorus in (5S)-1,3-
diaza-2-phospha-2-oxo-3-phenylbicyclo[3.3.0]octane skel-
eton I has no significant role to play in chiral induction
process18 and also the stereochemistry on the phosphorus
stereogenic center does not play any role in directing the
*
Corresponding author. Tel.: +91 40 23134812; fax: +91 40 23012460;
e-mail: dbsc@uohyd.ernet.in
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.020

D. Basavaiah et al. / Tetrahedron: Asymmetry 17 (2006) 1036–1040
1037
stereoselectivity of the reduction process.19 On the basis of
these results, it appeared to us that real chiral director in all
these studies is the chiral diamine (2S)-2-anilinomethyl-
pyrrolidine II from which actually all our catalysts were de-
rived. It, therefore, occurred to us that guanidine derivative
1, derived from this wonderful diamine II, might provide
some interesting guidelines/directions so as to understand
the applicability of molecules, containing chiral guanidine
framework as possible chiral catalysts or catalytic sources
for the borane-mediated asymmetric reduction of prochiral
ketones. Accordingly, we have synthesized the desired (5S)-
1,3-diaza-2-imino-3-phenylbicyclo[3.3.0]octane 120 via the
reaction of the chiral diamine II with cyanogen bromide
according to the general literature procedure (Eq. 1).21
The structure of this compound was also established by
the single crystal X-ray data (Fig. 1).22
Figure 1. ORTEP diagram of 1 (Hydrogen atoms were omitted for clarity).
2.1. Towards understanding catalytic process
H
With a view to understand the nature of the actual chiral
catalyst/catalytic source, we carried out the following
experiments: (i) We performed the reaction between guani-
dine derivative 1 (0.25 mM) and BH3ÆSMe2 (5 mM, 5 mL,
1 M solution in toluene) in refluxing toluene (25 mL) for
15 min (in the ratio of 1:20 as in the case of reaction con-
H
EtOH
N
BrCN
+
N
0 oC to rt
N
H
HN
II
HN
62 %
1
ð1Þ
1
11
ditions), and recorded the H, 13C, B NMR27 spectra of
this crude mixture (after removal of excess BH3ÆSMe2
1
and toluene under vacuum). Although H and 13C NMR
We first examined the reduction of phenacyl bromide 2a
with different catalytic amounts of guanidine derivative 1
(Table 1, Eq. 2). The best results were obtained when
phenacyl bromide 2a was subjected to the borane-mediated
chiral reduction under the influence of 1 (5 mol %) in
refluxing toluene for 15 min, thus providing the desired
alcohol (S)-2-bromo-1-phenylethanol 3a in 81% yield with
83% enantiomeric excess (Table 1, entry 3).23
spectral data did not provide any indication about the
exact structure of the actual catalyst, the presence of a peak
at d 85.02 ppm (along with other peaks) and also the
absence of a peak at d 161.69 ppm (present in spectrum
of original guanidine 1) in the 13C NMR spectrum indicate
the possible reduction of C@N of the guanidine, probably
leading to the formation of compound III (possibly com-
plexing with borane) having CH attached to three different
nitrogens (Scheme 1).
Table 1. Asymmetric reduction of phenacyl bromide 2a at 110 ꢁCa
OH
O
(ii) With a view to understand the stability of guanidine
moiety in the presence of BH3ÆSMe2 at room tempera-
ture, we have treated guanidine derivative 1 (0.25 mM)
and BH3ÆSMe2 (5 mM, 5 mL, 1 M solution in toluene)
in toluene (25 mL) at room temperature (ꢀ30 ꢁC) for
15 min (in the ratio of 1:20 as in the case of reaction con-
Br
Br
1.0 eq. BH3.SMe2 / 1 (cat.)
Toluene, 110 oC, 15 min
3a
2a
ð2Þ
ditions) and recorded H, 13C, B NMR28 spectra of this
crude compound (after removal of excess BH3ÆSMe2 and
toluene under vacuum). 13C NMR spectrum indicated
that the guanidine moiety is more or less intact as evi-
denced by the absence of any peak in the region d 70–
110 ppm (due to the absence of carbon attached to three
nitrogens) and the presence of a peak at d 161.02 ppm (as
there is no reduction of C@N). The 13C NMR spectrum
also showed the presence of all the peaks that are origi-
nally present in starting guanidine 1 (with little difference
in the chemical shift values) along with the minor peaks
(probably arising due to the complexation with borane).
We then performed the asymmetric reduction of phenacyl
bromide under the influence of 1 (5 mol %) at room tem-
perature (ꢀ30 ꢁC) in order to understand its efficiency as
a catalyst. The resulting secondary alcohol was obtained
with 32% enantiomeric excess, and more interestingly
with an (R)-configuration (opposite to the configura-
tion of the alcohol obtained under reflux conditions).
Although enantioselectivity is low, this interested us
1
11
Entry
Catalyst 1 (mol %)
Yieldb (%) 3a
Enantiomeric
excessc (%) 3a
1
2
3
4
5
6
2
4
5
82
84
81
86
88
80
74
81
83
79
78
80
6
8
10
a All reactions were carried out on a 1 mM scale of phenacyl bromide with
1 mM of BH3ÆSMe2 in the presence of 1 in toluene for 15 min at 110 ꢁC.
b Isolated yields of alcohol after purification by column chromatography
(silica gel, 5% ethyl acetate in hexanes).
c Determined by HPLC analysis using the chiral column, Chiralcel-OD-H.
Encouraged by this result and also with a view to under-
stand the generality, we extended this methodology to a
representative prochiral a-halo ketones 2b–h. The resulting
secondary alcohols 3b–h were obtained in 72–83% enantio-
meric excesses (Table 2, Eq. 3).

1038
D. Basavaiah et al. / Tetrahedron: Asymmetry 17 (2006) 1036–1040
Table 2. Asymmetric reduction of prochiral a-halo ketonesa
O
OH
1 (5 mol%)
/
1.0 eq. BH3.SMe2
X
X
Ar
Ar
Toluene, 110 oC, 15 min
ð3Þ
2a-h
3a-h
X = Br, Cl
Ar = Ph, 4-MePh, 4-BrPh, 4-ClPh, 4-NO2Ph, Naphth-2-yl
25
Substrate
Ar
X
Product
Yieldb (%)
½aꢁD
Conf.c
ee (%)
2a
2b
2c
2d
2e
2f
Phenyl
Phenyl
Br
Cl
Br
Cl
Br
Br
Br
Br
3a
3b
3c
3d
3e
3f
81
80
85
82
78
89
84
86
+36.5 (c 1.1, CHCl3)
S24
S24
S15
S15
S25
S15
S16
S26
83d
81d
82d
83d
81e
83e
78f
72e
+40.7 (c 1.3, C6H12
)
4-Methylphenyl
4-Methylphenyl
4-Bromophenyl
4-Chlorophenyl
4-Nitrophenyl
Naphth-2-yl
+35.3 (c 1.2, CHCl3)
+42.0 (c 1.1, CHCl3)
+27.7 (c 1.1, CHCl3)
+37.4 (c 1.2, CHCl3)
+26.5 (c 1.2, CHCl3)
+21.6 (c 1.0, EtOH)
2g
2h
3g
3h
a All reactions were carried out on 1 mM scale of a-halo ketone with 1 mM of BH3ÆSMe2 in the presence of 1 (5 mol %) in toluene for 15 min at 110 ꢁC.
b Isolated yields of alcohols after purification by column chromatography (silica gel, 5% ethyl acetate in hexanes).
c Absolute configuration was assigned by comparison of the sign of the specific rotation with that of reported molecules.
d Determined by HPLC analyses using the chiral column, Chiralcel-OD-H.
e Determined by HPLC analyses using the chiral column, Chiralcel-OJ-H.
f Determined by HPLC analysis of the corresponding acetate using the chiral column, Chiralcel-OD-H.
H
H
N
Toluene
110 oC, 15 min
Toluene
N
+
BH3.SMe2
N
Guanidine moiety
is intact
N
rt, 15 min
N
HN
III
1
Scheme 1.
because of the reversal of stereoselection from room
temperature to 110 ꢁC. Thus the same catalytic source
operates in two different stereodirections in the reduction
of phenacyl bromide, providing the resulting alcohol with
opposite configurations at room temperature and high
temperature (110 ꢁC) due to two different catalytic species
actually involved in the reduction pathway. We also
carried out the same reaction with different catalytic
amounts in order to study the influence of the amount
of catalyst on the asymmetric induction at room tempera-
ture (Table 3, Eq. 4).
Table 3. Asymmetric reduction of phenacyl bromide 2a at room
temperaturea
OH
O
Br
Br
1.0 eq. BH3.SMe2 / 1 (cat.)
Toluene, rt, 15 min
3a
2a
ð4Þ
Entry
Catalyst 1
Yieldb
(%) 3a
Enantiomeric
excessc (%) 3a
Configurationd
(iii) With a view to understand the stereoselection of re-
duced catalytic species III, at room temperature, we carried
out the reduction of phenacyl bromide under the influence
of catalytic species III (5 mol %) (generated in situ by the
reaction of guanidine moiety 1 with BH3ÆSMe2 at 110 ꢁC
and cooling back to room temperature) for 30 min at room
temperature and obtained the corresponding (S)-2-bromo-
1-phenylethanol in 44% ee (Scheme 2).
(mol %)
1
2
3
4
5
5
6
8
10
15
87
85
85
84
83
32
31
36
36
37
R
R
R
R
R
a All reactions were carried out on a 1 mM scale of phenacyl bromide with
1 mM of BH3ÆSMe2 in the presence of 1 in toluene for 15 min at ꢀ30 ꢁC.
b Isolated yields of alcohol after purification by column chromatography
(silica gel, 5% ethyl acetate in hexanes).
c Determined by HPLC analysis using the chiral column, Chiralcel-OD-H.
d Absolute configuration was assigned by comparison of the sign of the
specific rotation with that in the literature.24
This study demonstrates that there is a remarkable differ-
ence in the levels of stereoselectivity from the same catalytic
species from 110 ꢁC to room temperature probably due to
two different pathways of reduction processes.

D. Basavaiah et al. / Tetrahedron: Asymmetry 17 (2006) 1036–1040
1039
O
Br
(1 mM)
H
Ph
OH
(in toluene)
N
Toluene
Br
+
BH3.SMe2
1 mM
Ph
N
110 oC, 15 min
rt, 30 min
80%
HN
3a
0.05 mM
44% ee
1
Scheme 2.
2.2. Recyclable potential of in situ generated catalyst/
catalytic species
tive as a chiral catalytic source. Work towards this direc-
tion is underway in our laboratory.
With a view to examine the in situ recyclable potential of
the catalytic species III, we first carried out the reduction
of phenacyl bromide (1 mM) in a usual way at 110 ꢁC
(run 1). BH3ÆSMe2 (1 mM) (for run 2) was added to this
reaction flask (without work-up) and heated at 110 ꢁC for
15 min, and then a solution of phenacyl bromide (1 mM)
in toluene was slowly added drop-wise and stirring was
continued at 110 ꢁC for further 15 min as usual (run 2).
We were pleased to obtain the resulting secondary alcohol
(after work-up and purification as usual) in almost the
same enantioselectivity. In a similar way, we have also
examined the recyclability of this catalytic species for a
further two times (total four times); the enantioselectivity
remained almost the same (Table 4).
Acknowledgments
We thank CSIR (New Delhi) for funding this project. We
thank UGC (New Delhi) for recognizing our University
of Hyderabad as ‘University with Potential for Excellence
(UPE)’ and also recognizing the School of Chemistry as a
‘Center for Advanced Studies in Chemistry’ and providing
some instrumental facilities. K.V.R. and B.S.R. thank
CSIR (New Delhi) for their research fellowships. We also
thank the National Single Crystal X-ray Facility in our
School of Chemistry funded by the DST (New Delhi).
We thank Professor M. V. Rajasekharan and Professor
Samudranil Pal for helpful discussions regarding the
X-ray crystal structure.
Table 4. Recyclable ability of catalytic species III in the asymmetric
reduction of phenacyl bromide 2a
References
Number of runs
Enantiomeric excessa (%) 3a
1. Brown, H. C.; Jadhav, P. K.; Singaram, B. In Modern
Synthetic Methods; Scheffold, R., Ed.; Springer: Heidelberg,
1986; Vol. 4, pp 307–356.
2. Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res. 1992,
25, 16–24.
1
2
3
4
83
79
78
79
3. Singh, V. K. Synthesis 1992, 605–617.
4. Wallbaum, S.; Martens, J. Tetrahedron: Asymmetry 1992, 3,
1475–1504.
a Determined by HPLC analysis using the chiral column, Chiralcel-OD-H.
5. Deloux, L.; Srebnik, M. Chem. Rev. 1993, 93, 763–784.
6. Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1986–2012.
3. Conclusion
7. Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551–5553.
8. Giffels, G.; Dreisbach, C.; Kragl, U.; Weigerding, M.;
Waldmann, H.; Wandrey, C. Angew. Chem., Int. Ed. Engl.
1995, 34, 2005–2006.
9. Sarvary, I.; Almqvist, F.; Frejd, T. Chem. Eur. J. 2001, 7,
2158–2166.
10. Hu, J.-b.; Zhao, G.; Yang, G.-s.; Ding, Z.-d. J. Org. Chem.
2001, 66, 303–304.
11. Hu, J.-b.; Zhao, G.; Ding, Z.-d. Angew. Chem., Int. Ed. 2001,
40, 1109–1111.
12. Burns, B.; Studley, J. R.; Wills, M. Tetrahedron Lett. 1993,
34, 7105–7106.
13. Gamble, M. P.; Smith, A. R. C.; Wills, M. J. Org. Chem.
1998, 63, 6068–6071.
In conclusion, we have, for the first time, developed a novel
and in situ recyclable chiral catalytic source 1 based on a
guanidine framework for the borane-mediated asymmetric
reduction of prochiral a-halo ketones, thus providing the
secondary alcohols with reasonably high enantiomeric
excesses. Our study also demonstrates a remarkable rever-
sal of stereoselectivity going from room temperature
(ꢀ30 ꢁC) to high temperature (110 ꢁC) during the borane-
mediated reduction of phenacyl bromide using guanidine
1 as a chiral catalytic source, probably due to two different
catalytic species actually involved in the transition state of
the reduction process. We also observed interesting temper-
ature dependant levels of stereoselectivity from the same
catalytic species III, probably due to different pathways
involved in the reduction process. This study also, to some
extent, indicates that it would in principle be possible to
obtain both enantiomers of the secondary alcohols in
homochiral form with appropriate chiral guanidine deriva-
14. Buono, G.; Chiodi, O.; Wills, M. Synlett 1999, 377–388.
15. Basavaiah, D.; Jayapal Reddy, G.; Chandrashekar, V.
Tetrahedron: Asymmetry 2001, 12, 685–689.
16. Basavaiah, D.; Jayapal Reddy, G.; Chandrashekar, V.
Tetrahedron: Asymmetry 2002, 13, 1125–1128.

1040
D. Basavaiah et al. / Tetrahedron: Asymmetry 17 (2006) 1036–1040
17. Basavaiah, D.; Jayapal Reddy, G.; Chandrashekar, V.
Tetrahedron: Asymmetry 2004, 15, 47–52.
18. Basavaiah, D.; Jayapal Reddy, G.; Venkateswara Rao, K.
Tetrahedron: Asymmetry 2004, 15, 1881–1888.
symmetry. For similar literature reports please see: (a) Bats,
J. W.; Grundl, M. A.; Hashmi, A. S. K. Acta Crystallogr.
2001, C57, 208–210; (b) Pradeep, C. P. Acta Crystallogr. 2005,
E61, o3825–o3827.
19. Basavaiah, D.; Chandrashekar, V.; Das, U.; Jayapal Reddy,
G. Tetrahedron: Asymmetry 2005, 16, 3955–3962.
23. Asymmetric reduction of phenacyl bromide 2a: Synthesis of
(S)-2-bromo-1-phenylethanol 3a: Representative procedure:
To a stirred solution of (5S)-1,3-diaza-2-imino-3-phenylbi-
cyclo[3.3.0]octane 1 (0.05 mM, 10.1 mg) in toluene (5 mL)
was added BH3ÆSMe2 (1 mM, 1 mL, 1 M solution in toluene)
at room temperature, and the reaction mixture heated at
110 ꢁC for 15 min. A solution of phenacyl bromide 2a (1 mM,
199 mg) in toluene (2 mL) was added slowly drop-wise and
heating was continued for further 15 min. The reaction
mixture was then cooled to room temperature and quenched
with MeOH. The solvent was removed under reduced
pressure, and the residue thus obtained was purified by
column chromatography (silica gel, 5% ethyl acetate in
hexanes) to provide the desired (S)-2-bromo-1-phenylethanol
3a in 81% (163 mg) yield as a colorless oil.
20. Chiral guanidine, (5S)-1,3-diaza-2-imino-3-phenylbicyclo-
[3.3.0]octane 1, is a new molecule. This was synthesized
following the general procedure described by Ma and Cheng.21
25
Spectral data for the chiral source 1: mp: 58 ꢁC; ½aꢁD ¼ ꢂ48:7
1
(c 1.1, CHCl3); H NMR (400 MHz/CDCl3): d 1.42–1.54 (m,
1H), 1.84–1.98 (m, 1H), 1.99–2.10 (m, 2H), 3.22–3.29 (m, 1H),
3.50–3.61 (m, 1H), 3.68–3.73 (m, 1H), 3.77–3.86 (m, 1H), 3.91–
3.98 (m, 1H), 5.09 (b, 1H), 7.02–7.10 (m, 1H), 7.32–7.56 (m,
4H); 13C NMR (100 MHz/CDCl3): d 25.92, 31.37, 48.14,
51.60, 57.48, 120.32, 123.09, 129.09, 141.32, 161.69; IR (KBr):
3316, 1630, 1593 cmꢂ1; LCMS (m/z): 202 (M+H)+; Anal.
Calcd for C12H15N3: C, 71.61; H, 7.51; N, 20.88. Found: C,
71.66; H, 7.47; N, 20.86.
21. Ma, D.; Cheng, K. Tetrahedron: Asymmetry 1999, 10, 713–719.
22. Crystal data for (5S)-1,3-diaza-2-imino-3-phenylbicyclo[3.3.0]-
octane 1: The single crystal X-ray structure revealed the
presence of two molecules in the asymmetric unit. For
clarity we have shown one molecule in the ORTEP diagram
(Fig. 1). Empirical formula, C12H15N3; formula weight,
201.27; colorless, rectangular crystals; crystal dimensions,
0.45 · 0.32 · 0.14 mm3; monoclinic, lattice type, primitive;
24. Imuta, M.; Kawai, K. I.; Ziffer, H. J. Org. Chem. 1980, 45,
3352–3355.
25. Hiratake, J.; Inagaki, M.; Nishioka, T.; Oda, J. J. Org. Chem.
1988, 53, 6130–6133.
26. Brown, H. C.; Pai, G. G. J. Org. Chem. 1985, 50, 1384–1394.
27. 11B NMR spectrum showed a broad peak at d 31.7 ppm (in
addition to other peaks in the region d ꢂ32 to 3 ppm),
probably indicating the presence of N–B–N (diazaborolidine
moiety). For similar 11B NMR chemical shifts see: Cruz, A.;
Geniz, E.; Contreras, R. Tetrahedron: Asymmetry 1998, 9,
3991–3996.
˚
˚
˚
a = 9.5937 (13) A, b = 11.6631 (16) A, c = 9.6206 (13) A;
3
˚
a = 90.00; b = 91.683 (2); c = 90.00; V = 1076.0 (3) A ; space
group, P21 (International Table No. 14); Z = 4;
Dcalcd = 1.242 g/cm3; F000 = 432; k(Mo Ka) = 0.71073 A;
28. 11B NMR spectrum did not show any peak in the region d
15–40 ppm, thus indicating the absence of N–B–N and 11B
NMR spectrum showed peaks at d ꢂ20.3, ꢂ21.4, ꢂ29.9 ppm
and a minor peak at d ꢂ11.3 ppm, indicating the presence of
the tetra-coordinated boron (ate complexes). However, it
needs more studies to understand the actual nature of the boron
present in the catalytic cycle.
˚
R(I P 2r1) = 0.0378; wR2 = 0.0923. Detailed X-ray crystallo-
graphic data are available from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK (CCDC No. 299827). Although the sample is enantio-
merically pure, with an (S)-configuration, the asymmetric unit
consists of two molecules related by a pseudo-center of