Kinetic resolution of P-stereogenic phosphine boranes via deprotonation using s-butyllithium/(-)-sparteine

Article abstract of DOI:10.1016/j.tetasy.2009.10.026

The attempted kinetic resolution of racemic secondary phosphine boranes [t-BuPhP(BH₃)H and t-BuMeP(BH₃)H] by P-H deprotonation using 0.5 equiv of s-BuLi and (-)-sparteine was unsuccessful and generated racemic benzyl bromide-trapped

Full text of DOI:10.1016/j.tetasy.2009.10.026

Tetrahedron: Asymmetry 20 (2009) 2432–2434
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Kinetic resolution of P-stereogenic phosphine boranes via deprotonation
using s-butyllithium/(À)-sparteine
b
Johan Granander a, Francesco Secci a, Peter O’Brien a, , Brian Kelly
*
a Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
b Celtic Catalysts Ltd, Nova Centre, Belfield Innovation Park, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
The attempted kinetic resolution of racemic secondary phosphine boranes [t-BuPhP(BH3)H and
t-BuMeP(BH3)H] by P–H deprotonation using 0.5 equiv of s-BuLi and (À)-sparteine was unsuccessful
and generated racemic benzyl bromide-trapped adducts in 42–49% yield. In contrast, an efficient kinetic
resolution was observed with racemic tertiary phosphine boranes [t-BuPhP(BH3)Me and t-BuEtP(BH3)Me]
by C–H deprotonation on the P–Me group using 0.5 or 0.6 equiv of s-BuLi and (À)-sparteine. For example,
the use of 0.6 equiv of s-BuLi/(À)-sparteine with t-BuEtP(BH3)Me and trapping with DMF gave the
(R)-aldehyde adduct in 37% yield and 83:17 er together with recovered (R)-t-BuEtP(BH3)Me in 44% yield
and 74:26 er. These are the first examples of kinetic resolution of P-stereogenic phosphine boranes via
deprotonation using s-BuLi/(À)-sparteine.
Received 23 September 2009
Accepted 23 October 2009
Available online 24 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
An increasing number of useful P-stereogenic bisphosphine
ligands1 are being synthesised using n-BuLi or s-BuLi and (À)-spar-
1. sBuLi, (—)-sparteine
Et2O, —78 ºC
BH3
P
BH3 OH
P
2
*
teine chiral base methodology (e.g., Imamoto’s BisP , Mini-
PHOS2b,3 and QuinoxP4, and Zhang’s Tangphos5). Most of the
chiral base routes utilise Evans’ asymmetric desymmetrisation of
dimethylphosphine boranes as the key step.6 For example, lithia-
tion of phosphine borane 1 using s-BuLi/(À)-sparteine and trapping
with benzophenone gave P-stereogenic phosphine borane (S)-2 in
79% ee (Scheme 1). A limitation of this approach is that a methyl
group will inevitably be one of the substituents in the product.
Subsequently, Livinghouse reported a different (À)-sparteine
approach to P-stereogenic phosphines in which a dynamic thermo-
dynamic resolution of a lithiated secondary phosphine borane was
utilised.7 Thus, racemic lithiated 3 was formed and equilibrated in
the presence of (À)-sparteine at 25 °C (a temperature at which lith-
iated 3 is configurationally unstable) and then trapped at À78 °C
with methyl iodide to give (R)-4 in 93% ee (Scheme 1). Since the
equilibration is driven by precipitation, attempts to extend the Liv-
inghouse method to other substituents have met with limited suc-
cess.8,9 In order to address the limitations of these two methods,
we reasoned that it should be possible to carry out each of these
two processes in a kinetic resolution manifold. Thus, we planned
to use 0.5 equiv of n-BuLi or s-BuLi and (À)-sparteine followed by
electrophilic trapping (with E+) to carry out the kinetic resolution
Me
Ph
Ph
Ph
Ph
2. Ph2CO
Me
Me
H
1
(S)-2 (79% ee)
N
(—)-sparteine
N
H
1. nBuLi, (—)-sparteine
Et2O, 25 ºC
BH3
BH3
P
P
H
tBu
Ph
Me
Ph
2. —78 ºC, MeI
tBu
(R)-4 (93% ee)
rac-3
Scheme 1. Asymmetric synthesis of P-stereogenic phosphines via organolithium
reagents and (À)-sparteine.
of secondary phosphine boranes rac-5 (non-racemic 6 and 5) by
deprotonation of the PH proton and of tertiary phosphine boranes
rac-7 (non-racemic 8 and 7) by deprotonation of a proton on the
PMe group (Scheme 2). To the best of our knowledge, this strategy
has not previously been reported but, if successful, it could consti-
tute a general route to P-stereogenic phosphines such as 5–8
equipped with any R1 and R2 groups. Herein, we report our preli-
minary investigations.
* Corresponding author. Tel.: +44 (0) 1904 432535; fax: +44 (0) 1904 432516.
E-mail address: paob1@york.ac.uk (P. O’Brien).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.10.026

J. Granander et al. / Tetrahedron: Asymmetry 20 (2009) 2432–2434
2433
1. 0.5 equiv. RLi/
BH3
P
BH3
BH3
P
(—)-sparteine
P
+
R1
R2
H
H
R1
E
R2
Et2O, —78 °C, 3 h
2. E+
R2
R1
rac-5
6
5
1. 0.5 equiv. RLi/
(—)-sparteine
BH3
P
BH3
P
BH3
P
+
E
R1
R2
Me
R1
R2
Et2O, —78 ºC, 3 h
2. E+
Me
R2
R1
rac-7
8
7
Scheme 2. Proposed kinetic resolution strategy for the synthesis of secondary and tertiary P-stereogenic phosphine boranes.
2. Results and discussion
1. 0.5 equiv. RLi/
(—)-sparteine
BH3
P
BH3
P
Et2O, —78 ºC, 3 h
To start with, we prepared secondary phosphine boranes rac-3
(from the one-pot reaction of PhPCl2 with t-BuMgBr, LiAlH4 and
BH3ÁMe2S) and the volatile rac-10 (from the one-pot reaction of t-
BuPCl2 with MeMgBr, LiAlH4 and BH3ÁMe2S). Next, we attempted
to carry out the kinetic resolution of phosphine boranes rac-3 and
rac-10 via deprotonation using 0.5 equiv of organolithium reagents
and (À)-sparteine in Et2O at –78 °C and subsequently trapping with
benzyl bromide. The use of s-BuLi and n-BuLi was investigated under
three different procedures: (i) addition of a pre-mixed organolith-
ium reagent/(À)-sparteine to the phosphine borane; (ii) addition
of the phosphine borane to pre-mixed organolithium reagent/(À)-
sparteine and (iii) addition of organolithium reagents to phosphine
borane and (À)-sparteine. Under all these conditions, we isolated
42–49% yields of benzylated adducts rac-9 and rac-11 as shown by
chiral HPLC (Scheme 3). No kinetic resolution was observed.
Ph
H
R
R
tBu
t Bu
rac-9: R = Ph
2. BnBr
42-49%
rac-3: R = Ph
rac-10: R = Me
rac-11: R = Me
Scheme 3. Attempted kinetic resolution of secondary phosphine boranes.
In order to improve the conversion to product, we increased the
amount of reagent to 0.6 equiv of s-BuLi/(À)-sparteine and trap-
ping with a different electrophile (DMF) to allow recovery of the
enantioenriched starting phosphine boranes. Thus, kinetic resolu-
tion of phosphine borane rac-4 using 0.6 equiv of s-BuLi/(À)-spar-
teine followed by DMF trapping gave aldehyde (R)-15 (36%, 70:30
er) and recovered phosphine borane (S)-4 (52%, 65:35 er). In this
example, it was possible to isolate both the product and recovered
starting material after chromatography. Even better results were
obtained with phosphine borane rac-12, which gave (R)-16 in
37% yield and 83:17 er together with recovered phosphine borane
(R)-12 in 44% yield and 74:26 er (Scheme 5).11 In order to deter-
mine the ers of (R)-15, (S)-4, (R)-16 and (R)-12, a range of subse-
quent transformations was required. The er of (R)-15 was
determined by chiral HPLC of the corresponding alcohol (obtained
by NaBH4 reduction). To obtain the er of (R)-16, it was reduced to
the primary alcohol using NaBH4 and converted into a hydroxy
phosphine sulfide (by reaction with DABCO and sulfur in toluene
at 80 °C12) which was suitable for chiral HPLC analysis. The ers of
(S)-4 and (R)-12 were obtained by chiral HPLC analysis of (S)-13
and (S)-14, respectively (which were formed from (S)-4 and (R)-
12 by racemic lithiation/benzophenone trapping).
Next, we turned our attention to tertiary phosphine boranes
rac-4 and rac-12 which contained a P-methyl group suitable for
deprotonation. Phosphine borane rac-4 was prepared by
a
sequential one-pot reaction of PhPCl2 with t-BuMgCl, MeMgBr
and BH3ÁMe2S whereas rac-12 was prepared from PCl3 by reaction
with t-BuMgCl, EtMgCl, MeMgBr and BH3ÁMe2S. With rac-4 and
rac-12 in hand, the kinetic resolution was attempted by adding
a pre-cooled (À78 °C) solution of 0.5 equiv of s-BuLi/(À)-sparteine
in Et2O to a solution of the phosphine borane rac-4 or rac-12 in
Et2O at –78 °C. After 3 h, benzophenone was added and, after
chromatography, adducts (R)-13 (22%, 91:9 er by chiral HPLC)10
and (R)-14 (19%, 84:16 er by chiral HPLC) were isolated
(Scheme 4). Much lower enantioselectivity was observed using
n-BuLi in place of s-BuLi. The stereochemistry of (R)-13 has been
secured (vide infra) and that of (R)-14 is tentatively assigned by
analogy. Unfortunately, it was not possible to recover the re-
solved starting materials (S)-4 and (R)-12 in pure form and hence
they could not be analysed further (for % yield and er). However,
these results clearly show that a kinetic resolution had occurred
and that this strategy is a viable route to P-stereogenic phosphines.
The absolute configuration of the recovered phosphine borane 4
was assigned as (S) based on a comparison of its specific rotation
{[
a]D = –6.3 (c 1.1, CHCl3); [a]D = +3.0 (c 1.0, MeOH)} with that re-
ported for (R)-4 of 93% ee {[
the stereochemistry of (R)-15 and, by analogy, (R)-13 to be as-
a
]
D = À10 (c 1, MeOH)}.7 This allows
1. 0.5 equiv. sBuLi/
(—)-sparteine
Et2O, —78 ºC, 3 h
BH3
BH3 OH
P
BH3
P
P
tBu
Ph
Ph
Me
R
tBu
+
Me
tBu
2. Ph2CO
R
R
(R)-13 (22%, 91:9 er)
(R)-14 (19%, 84:16 er)
(S)-4
(R)-12
rac-4: R = Ph
rac-12: R = Et
R = Ph
R = Et
Scheme 4. Kinetic resolution of tertiary phosphine boranes.

2434
J. Granander et al. / Tetrahedron: Asymmetry 20 (2009) 2432–2434
1. 0.6 equiv. sBuLi/
(—)-sparteine
BH3
P
O
BH3
P
Et2O, —78 ºC, 3 h
rac-4
or
tBu
R
+
H
Me
rac-12
tBu
2. DMF
R
(R)-15 (36%, 70:30 er)
(R)-16 (37%, 83:17 er)
(S)-4 (52%, 65:35 er)
(R)-12 (44%, 74:26 er)
R = Ph
R = Et
Scheme 5. Kinetic resolution of tertiary phosphine boranes.
126 °C; Rf (19:1 petrol–EtOAc) 0.2; IR (NaCl) 3466, 3016, 2399, 1493, 1448,
1368, 1215, 1057, 753, 700, 669 cmÀ1 1H NMR (400 MHz, CDCl3) d 7.64–7.57
signed. We have also extended our assignment of stereochemistry
to the ethyl-substituted series (R)-14, (R)-16 and (R)-12 (although
these assignments have not been proven unequivocally and are
only tentative at this stage).
;
(m, 2H, Ph), 7.51–7.46 (m, 2H, Ph), 7.46–7.40 (m, 1H, Ph), 7.34–7.28 (m, 4H,
Ph), 7.26–7.21 (m, 1H, Ph), 7.17–7.12 (m, 2H, Ph), 6.93–6.86 (m, 3H, Ph), 4.71
(s, 1H, OH), 3.46 (t, JPH = JHH = 14.5 Hz, 1H, PCHAHB), 2.87 (dd, JHH = 14.5,
JPH = 6.5 Hz, 1H, PCHAHB), 1.14 (d, JPH = 14.0 Hz, 9H, CMe3), 1.30–0.30 (m, 3H,
BH3); 13C NMR (100.6 MHz, CDCl3) d 147.9 (d, JPC = 9.0 Hz, ipso-Ph), 144.3 (d,
JPC = 2.0 Hz, ipso-Ph), 133.2 (d, JPC = 8.0 Hz, Ph), 131.0 (d, JPC = 2.5 Hz, Ph), 128.2
(Ph), 128.0 (d, JPC = 9.5 Hz, Ph), 127.3 (Ph), 127.1 (Ph), 126.6 (Ph), 126.4 (d,
JPC = 51.0 Hz, ipso-Ph), 126.3 (Ph), 125.4 (Ph), 77.6 (COH), 33.3 (d, JPC = 28.5 Hz,
PCH2), 30.2 (d, JPC = 34.5 Hz, PCMe3), 25.4 (d, JPC = 2.0 Hz, CMe3); 31P NMR
(161.9 MHz, CDCl3) d 22.2 (br m); HRMS (ESI) m/z calcd for C24H30BOP (M+Na)+
399.2020, found 399.2010; HPLC: Daicel Chiralcel OD, 19:1 v/v hexane–i-PrOH,
0.5 mL minÀ1, 254.4 nm, 10.4 min [(S)-13], 12.2 min [(R)-13]. A sample of (S)-
13 of 65:35 er (formed by lithiation-benzophenone trapping of (S)-4) had
3. Conclusion
In conclusion, we have reported the first examples of the kinetic
resolution of racemic P-stereogenic tertiary phosphine boranes via
deprotonation using s-BuLi/(À)-sparteine. This strategy may prove
useful for the preparation of P-stereogenic compounds that cannot
be accessed by chiral base-mediated desymmetrisation of di-
methyl-substituted phosphine boranes.
[a
]
D = +14.6 (c 1.0, CHCl3).
11.
A
pre-cooled solution of s-BuLi (0.92 mL of a 1.3 M solution in hexanes,
1.20 mmol, 0.6 equiv) and (À)-sparteine (281 mg, 1.20 mmol, 0.5 equiv) in
Et2O (5 mL) at À78 °C was added dropwise to a stirred solution of phosphine
borane rac-12 (292 mg, 2.00 mmol, 1.0 equiv) in Et2O (10 mL) at À78 °C under
Ar. The resulting mixture was stirred at À78 °C for 3 h and then DMF
(292.4 mg, 4.00 mmol, 2.0 equiv) was added dropwise. The resulting mixture
was allowed to warm to rt over 4 h and then stirred at rt for 16 h. 5% HCl(aq)
(10 mL) was added and the two layers were separated. The aqueous layer was
extracted with EtOAc (3 Â 10 mL) and the combined organic layers were
washed with brine (15 mL), dried (MgSO4) and evaporated under reduced
pressure to give the crude product. Purification by flash column chromatography
using 9:1 petrol–EtOAc and then 4:1 petrol–EtOAc as eluent gave phosphine
borane aldehyde (R)-16 (129 mg, 37%, 83:17 er by chiral HPLC of the
corresponding hydroxy phosphine sulfide obtained by reduction with NaBH4
and treatment with DABCO/sulfur) as a colourless oil, Rf (9:1 petrol–EtOAc) 0.1;
IR (NaCl) 2975, 2872, 2742, 2379, 2258, 1719, 1465, 1369, 1194, 1071, 1033,
Acknowledgement
We thank the EU and Celtic Catalysts (Marie-Curie Transfer of
Knowledge grant) for funding.
References
1. (a) Crépy, K. V. L.; Imamoto, T. Adv. Synth. Catal. 2003, 345, 79; (b) Crépy, K. V.
L.; Imamoto, T. Top. Curr. Chem. 2003, 229, 1; (c) Tang, W.; Zhang, X. Chem. Rev.
2003, 103, 3029; (d) Zhang, W.; Chi, Y.; Zhang, X. Acc. Chem. Res. 2007, 40, 1278.
2. (a) Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda, H.; Yamada, H.; Tsuruta, H.;
Matsukawa, S.; Yamaguchi, K. J. Am. Chem. Soc. 1998, 120, 1635; (b) Gridnev, I.
D.; Yamanoi, Y.; Higashi, N.; Tsuruta, H.; Yasutake, M.; Imamoto, T. Adv. Synth.
Catal. 2001, 343, 118.
3. Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999, 64, 2988.
4. Imamoto, T.; Sugita, K.; Yoshida, K. J. Am. Chem. Soc. 2005, 127, 11934.
5. Tang, W.; Zhang, Z. Angew. Chem., Int. Ed. 2002, 41, 1612.
734 cmÀ1 1H NMR (400 MHz, CDCl3) d 9.74 (dd, J = 3.5, 2.0 Hz, 1H, CHO), 2.82
;
(td, J = 13.0, 3.5 Hz, 1H, PCHAHB), 2.70 (td, J = 13.0, 3.5 Hz, 1H, PCHAHB), 1.76–
1.65 (m, 2H, PCH2Me), 1.21–1.12 (m, 12H, CMe3 + PCH2Me), 0.90–0.05 (m, 3H,
BH3); 13C NMR (100.6 MHz, CDCl3) d 196.9 (d, JPC = 1.0 Hz, CHO), 36.2 (d,
JPC = 20.0 Hz, PCH2CHO), 28.7 (d, JPC = 31.0 Hz, CMe3), 25.2 (d, JPC = 2.0 Hz,
CMe3), 13.9 (d, JPC = 31.5 Hz, PCH2Me), 7.5 (d, JPC = 2.0 Hz, PCH2Me); 31P NMR
(161.9 MHz, CDCl3) d 35.0 (br m); HRMS (ESI) m/z calcd for C8H20BOP (M+H)+
175.1418, found 175.1418 and phosphine borane (R)-12 (129 mg, 44%, 74:26 er
by chiral HPLC of the corresponding hydroxy phosphine borane (S)-14 obtained
6. Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995, 117, 9075.
7. Wolfe, B.; Livinghouse, T. J. Am. Chem. Soc. 1998, 120, 5116.
8. Dearden, M. J.; McGrath, M. J.; O’Brien, P. J. Org. Chem. 2004, 69, 5789.
9. Headley, C. E.; Marsden, S. P. J. Org. Chem. 2007, 72, 7185.
by lithiation-benzophenone trapping) as
D = À8.9 (c 1.05, CHCl3); Rf (29:1 petrol–EtOAc) 0.25; IR (NaCl) 3006, 2975,
2365, 1216, 1071, 1016, 901, 884, 752 cmÀ1 1H NMR (400 MHz, CDCl3) d 1.70–
a white solid, mp 41–42 °C;
10.
A pre-cooled solution of s-BuLi (0.38 mL of a 1.3 M solution in hexanes,
[a]
0.50 mmol, 0.5 equiv) and (À)-sparteine (117 mg, 0.50 mmol, 0.5 equiv) in
Et2O (3 mL) at À78 °C was added dropwise to a stirred solution of phosphine
borane rac-4 (194 mg, 1.00 mmol, 1.0 equiv) in Et2O (6 mL) at À78 °C under Ar.
The resulting mixture was stirred at À78 °C for 3 h and then a solution of
benzophenone (91 mg, 0.50 mmol, 0.5 equiv) in Et2O (2 mL) was added
dropwise. The resulting mixture was allowed to warm to rt over 4 h and
stirred at rt for 16 h. Next, 5% HCl(aq) (10 mL) was added and the two layers
were separated. The aqueous layer was extracted with EtOAc (3 Â 10 mL) and
the combined organic layers were washed with brine (15 mL), dried (MgSO4)
and evaporated under reduced pressure to give the crude product. Purification
by flash column chromatography using 19:1 petrol–EtOAc as eluent gave
phosphine borane (R)-13 (83 mg, 22%, 91:9 er) as a white solid, mp 125–
;
1.50 (m, 2H, PCH2), 1.18 (t, JPH = 7.5 Hz, 3H, PCH2Me), 1.15 (d, JPH = 9.5 Hz, 3H,
PMe), 1.14 (d, JPH = 13.5 Hz, 9H, CMe3), 0.80 to À0.05 (br m, 3H, BH3); 13C NMR
(100.6 MHz, CDCl3) d 27.2 (d, JPC = 34.5 Hz, CMe3), 25.1 (d, JPC = 2.5 Hz, CMe3),
14.2 (d, JPC = 34.0 Hz, PCH2), 7.4 (d, JPC = 2.0 Hz, PCH2Me), 4.4 (d, JPC = 34.5 Hz,
PMe); 31P NMR (161.9 MHz, CDCl3) d 28.2 (br m); HRMS (ESI) m/z calcd for
C7H20BP (M+Na)+ 169.1288, found 169.1295.
12. We have
a number of examples in our group where the conversion of
phosphine boranes into phosphine sulfides using DABCO and sulfur in toluene
at 80 °C proceeds with no loss of er.