Modular asymmetric synthesis of P-chirogenic β-amino phosphine boranes

Article abstract of DOI:10.1021/jo800672b

(Chemical Equation Presented) A short concise route to β- aminophosphine boranes is presented via the desymmetrization of prochiral phosphine boranes, forming P-chirogenic aldehydes that are rapidly transformed to the target compounds employing reductive

Full text of DOI:10.1021/jo800672b

Modular Asymmetric Synthesis of P-Chirogenic ꢀ-Amino Phosphine
Boranes
Magnus J. Johansson,* Kristian H. O. Andersson, and Nina Kann*
Organic Chemistry, Department of Chemical and Biological Engineering, Chalmers UniVersity of
Technology, SE-41296 Göteborg, Sweden
magjo@chembio.chalmers.se; kann@chalmers.se
ReceiVed August 29, 2007
A short concise route to ꢀ-aminophosphine boranes is presented via the desymmetrization of prochiral
phosphine boranes, forming P-chirogenic aldehydes that are rapidly transformed to the target compounds
employing reductive amination under microwave irradiation. This sequence provides a modular route to
P-chirogenic P,N ligands, and in addition, the intermediate aldehydes are versatile P-chiral building blocks
for ligand design in general. An alternative pathway via the corresponding R-carboxyphosphines is also
described. The ligands were subsequently evalutated in the asymmetric conjugate addition of diethylzinc
to trans-ꢀ-nitrostyrene.
Introduction
of tertiary phosphine boranes have been developed, metal-
mediated as well as biocatalytic.
4
In recent years, P-chirogenic ligands have become an
important alternative to phosphorus ligands with the chirality
residing on the surrounding carbon skeleton. Presumably, it
would be interesting to investigate P-chirogenic ligands in more
detail as the chiral center is moved closer toward the metal upon
coordination, and the electronic properties of the phosphorus
part of the ligand can be altered more freely. However, practical
methods for attaining chirality on phosphorus without traditional
resolution are limited. The most commonly employed techniques
are the diastereoselective opening of oxazaphospholidine bo-
The pharmaceutical and fine chemicals industry are reliant
on both enantiomers of chiral ligands for use in asymmetric
catalysis. Therefore, it is surprising to see that many ligands
are still only available in one enantiomeric form. To overcome
this obstacle, we have recently reported on the use of (+)-
sparteine surrogates to achieve the synthesis of both enantiomers
of P-chirogenic phosphine boranes independently via enanti-
1
5
oselective deprotonation. By extending this methodology to
the preparation of mixed bidentate ligands, one would get access
to ligands where the coordinating atoms have different binding
properties to the metal.
To achieve this target, we thus embarked upon the preparation
of a diverse set of P-chirogenic ꢀ-aminophosphine boranes.
Although numerous exmples of chiral P,N-ligands have been
2
ranes, a methodology developed by Gen eˆ t and Jug e´ , and the
asymmetric deprotonation of prochiral aryl dimethyl phosphine
boranes as described by Evans and co-workers. More recently,
catalytic methods allowing the direct enantioselective synthesis
3
(
1) For reviews on P-chirogenic phosphines, see: (a) Ohff, M.; Holz, J.;
Quirmbach, M.; B o¨ rner, A. Synthesis 1998, 1391–1415. (b) Cr e´ py, K. V. L.;
Imamoto, T. AdV. Synth. Catal. 2003, 345, 79–101. (c) Cr e´ py, K. V. L. Imamoto,
T. Top. Curr. Chem. 2003, 229, 1–40. (d) Johansson, M. J.; Kann, N. C. Mini-
ReV. Org. Chem. 2004, 1, 233–247. (e) Grabulosa, A.; Granell, J.; Muller, G.
Coord. Chem. ReV. 2007, 251, 25–90.
(4) (a) Chan, V. S.; Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem.
Soc. 2006, 128, 2786–2787. (b) Scriban, C.; Glueck, D. S. J. Am. Chem. Soc.
2006, 128, 2788–2789. (c) Wiktelius, D.; Johansson, M. J.; Luthman, K.; Kann,
N. Org. Lett. 2005, 7, 4991–4994. (d) Kiełbasi n˜ ski, P.; Albrycht, M.; Z
˙
urawi n˜ ski,
(
2) Jug e´ , S.; Stephan, M.; Laffitte, J. A.; Gen eˆ t, J. P. Tetrahedron Lett. 1990,
R.; Mikołajczyk, M. J. Mol. Catal. B-Enzym. 2006, 39, 45–49.
3
1, 6357–6360.
(5) (a) Johansson, M. J.; Schwartz, L. O.; Amedjkouh, M.; Kann, N. C. Eur.
J. Org. Chem. 2004, 1894–1896. (b) Johansson, M. J.; Schwartz, L.; Amedjkouh,
M.; Kann, N. Tetrahedron: Asymmetry 2004, 15, 3531–3538. (c) McGrath, M. J.;
O’Brien, P. J. Am. Chem. Soc. 2005, 127, 16378–16379.
(
3) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995, 117,
1
9
075–9076. H NMR data were in accordance to published data for this
compound.
4
458 J. Org. Chem. 2008, 73, 4458–4463
10.1021/jo800672b CCC: $40.75  2008 American Chemical Society
Published on Web 05/20/2008

P-Chirogenic ꢀ-Amino Phosphine Boranes
SCHEME 1. Versatile r-Formyl Phosphine Intermediate
SCHEME 3. Synthesis of a PAMP-Derived
r-Formylphosphine Borane
using a formyl source like DMF or formyl-piperidine, using a
9
modified Beak procedure.
SCHEME 2. Precursors to P-Chirogenic Aminophosphines
Results and Discussion
A diverse set of prochiral phosphine boranes, containing
phenyl-, ferrocenyl- or tert-butyl- as substituents on phosphorus,
were selected for the study. Both ferrocenyl dimethylphosphine
borane as well as phenyldimethylphosphine borane were
subjected to asymmetric deprotonation using (-)-sparteine/sec-
BuLi. We were delighted to find that N,N-dimethylformamide
was a very effective electrophile in the desymmetrization of
prochiral phosphine boranes, affording the corresponding chiral
aldehydes in good yields (eq 1).
6
reported, only a very limited number of these have the chirality
7
residing on the phosphorus atom. Also, the methodologies
described do not allow for facile variation of the substitution
pattern on both phosphorus and nitrogen, allowing fine-tuning
of the electronic and steric properties of the ligands. The most
appealing route would preferably render P-chirogenic phosphine
boranes functionalized with an R-formyl moiety, a useful
building block for reductive amination, but also for other types
8
of diversifying transformations (Scheme 1).
We envisioned that an asymmetric deprotonation of a
prochiral phosphine borane or a diastereoselective opening of
an oxazaphospholidine borane would give access to P-chirogenic
ligands with the desired modular structural properties (Scheme
2
). The asymmetric deprotonation gives easy access to both
Because P,P-diaryl substituted R-formylphosphines cannot be
synthesized via asymmetric deprotonation, the stereoselective
ring-opening of an oxazaphospholidine borane complex proved
to be the best alternative route to introduce two different aryl-
substituent onto phosphorus. Borane-protected PAMP (o-anisyl
enantiomers of the desired phosphine borane using either (-)-
sparteine or a (+)-sparteine surrogate. In the diastereselective
opening of the oxazaphospholidine, both enantiomers of the
desired phosphine borane can also be accessed by reversing the
2
order of addition of the aryl/alkyl lithium.
2
methyl phenyl phosphine) was synthesized in three steps,
Both of the above-mentioned routes will provide methyl
substituted phosphine boranes that can be further elaborated into
aldehydes by asymmetric deprotonation and subsequent trapping
followed by deprotonation with sec-BuLi. The lithiated
PAMP·BH3 was subsequently quenched with DMF to give the
P-diaryl R-formylphosphine borane in good yield and excellent
optical purity (Scheme 3). It should be emphasized that this
route can be used to introduce a variety of substituents other
than anisyl, although it is somewhat longer than the asymmetric
deprotonation sequence.
(
6) For a recent review on P,N-ligands, see: Guiry, P. J.; Saunders, C. P.
AdV. Synth. Cat. 2004, 346, 497–537.
7) (a) Bianchini, C.; Cicci, S.; Peruzzini, M.; Pietrusiewicz, K. M.; Brandi,
A. J. Chem. Soc., Chem. Commun. 1995, 833–834. (b) Peer, M.; de Jong, J. C.;
Kiefer, M.; Langer, T.; Rieck, H.; Schell, H.; Sennhenn, P.; Sprinz, J.; Steinhagen,
H.; Wiese, B.; Helmchen, G. Tetrahedron 1996, 52, 7547–7583. (c) Yang, H.;
Lugan, N.; Mathieu, R. Organometallics 1997, 16, 2089–2095. (d) Kudis, S.;
Helmchen, G. Angew. Chem., Int. Ed. 1998, 37, 3047–3050. (e) Gilbertson, S. R.;
Genov, D. G.; Rheingold, A. L. Org. Lett. 2000, 2, 2885–2888. (f) Maj, A. M.;
Pietrusiewicz, K. M.; Suisse, I.; Agbossou, F.; Mortreux, A. J. Organomet. Chem.
(
The P-chirogenic aldehydes synthesized were then subjected
to a reductive amination, treating the aldehyde with sodium
triacetoxyborohydride and different amines in dichloroethane,
10
following a protocol reported by Abdel-Magid and co-workers.
2001, 626, 157–160. (g) Camus, J.-M.; Andrieu, J.; Richard, P.; Poli, R.; Darcel,
The amines chosen for the study were anisidine, morpholine,
as well as both enantiomers of R-methylbenzyl amine, selected
to provide a diverse set of amines with different binding
properties to a potential metal center (Figure 1).
Initial attempts were carried out on the crude aldehydes at
room temperature. Reaction progress was slow, and the desired
C.; Jug e´ , S. Tetrahedron: Asymmetry 2004, 15, 2061–2065. (h) Cheng, X. H.;
Horton, P. N.; Hursthouse, M. B.; Hii, K. K. Tetrahedron: Asymmetry 2004,
1
5, 2241–2246. (i) Lam, H.; Horton, P. N.; Hursthouse, M. B.; Aldous, D. J.;
Hi, K. K. Tetrahedron Lett. 2005, 46, 8145–8148. (j) Sun, X.-M.; Koizumi, M.;
Manabe, K.; Kobayashi, S. AdV. Synth. Cat. 2005, 347, 1893–1898. (k) Oliana,
M.; King, F.; Horton, P. N.; Hursthouse, M. B.; Hii, K. K. J. Org. Chem. 2006,
7
1, 2472–2479.
(
8) For examples of non-chiral/racemic R-formylphosphines and phosphine
boranes, see: (a) Pellon, P. Tetrahedron Lett. 1992, 33, 4451–4452. (b) Mathey,
F.; Mercier, F. J. Organomet. Chem. 1979, 177, 255–263. The latter reference
indicates an alternative method for the preparation of P-chirogenic R-formylphos-
phines via the corresponding phosphine sulfide, although this was not carried
out in practice for the R-formyl example.
(9) Beak, P.; Kerrick, S. T.; Wu, S. D.; Chu, J. X. J. Am. Chem. Soc. 1994,
116, 3231–3239.
(10) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849–3862.
J. Org. Chem. Vol. 73, No. 12, 2008 4459

Johansson et al.
SCHEME 4. Alternative Strategy for the Synthesis of
Alkyl-Substitued ꢀ-Aminophosphines
FIGURE 1. Set of amines used for the reductive amination.
TABLE 1. Microwave-Assisted Reductive Amination
R1
R2
product
a
yield
b
entry
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Fc
Fc
Fc
Fc
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
o-An
o-An
o-An
o-An
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
88
88
98
90
95
71
88
83
84
89
96
90
TABLE 2. Preparation of Dialkyl-Substituted Aminophosphines
a
c
b
d
entry
prod.
yield
entry
prod.
yield
1
2
3
4
7a
7b
7c
7d
92
89
88
71
5
6
7
8
8a
8b
8c
8d
87
95
71
77
a
b
c
See Scheme 5. See Figure 1 for amino-structures a-d. Crude
10
11
12
d
yield. Yield of pure product.
SCHEME 5. Preparation of Tetradentate P,N-Ligands
a
b
See Figure 1 for amino-structures a-d. Isolated yields after SCX-2
purification, eluting with NH3 in MeOH.
product amines were difficult to purify, affording isolated
product in general in yields of 6-22%. Purification of the
precursor aldehydes in conjunction with the use of microwave
1
1
heating gave substantially better results. After 6 min under
microwave irradiation at 120 °C, the desired amino-substituted
phosphine boranes could be isolated in high purity and good
yields by simple cation exchange chromatography, eluting the
product with NH3 in MeOH (Table 1).
Attempted preparation of tert-butyldimethylphosphine borane
derivatives using the desymmetrization strategy afforded only
small amounts of product upon quenching and isolation,
although the crude material contained substantial quantities of
the desired compound. Purification by chromatography on either
deactivated silica gel or neutral/basic alumina resulted in
degradation of the product. Reductive amination of the crude
aldehyde gave desired products but in low yields. These
derivatives were thus prepared via an alternative route involving
the formation of R-carboxyphosphine-boranes using (-)-
sparteine/sec-BuLi and carbon dioxide, followed by amide bond
formation using 1-(3-dimethylaminpropyl)-3-ethylcarbodiimide
hydrochloride (EDCI) and 1-hydroxybenzotriazole hydrate
Two tetradentate C2-symmetric P,N,N,P-ligands were also
prepared starting from the chiral diamines 2,2′-diaminobinaphtha-
12
lene and 1,2-diphenylethylenediamine respectively (Scheme 5).
Reductive amination with R-formyl phosphine borane 1 at
ambient temperature afforded, after preparative HPLC, the
desired tetradentate ligands 9 and 10 in moderate yields but
excellent optical purity.
To evaluate the ligands in catalytic asymmetric synthesis, they
were applied in the copper-catalyzed conjugate addition of
1
3–15
diethylzinc to trans-ꢀ-nitrostyrene.
Jug e´ and co-workers
have shown that borane-protected phosphines can be applied
directly in several types of metal-catalyzed transformations
(
HOBt) (Scheme 4).
The resulting amides 7 were then reduced with BH3 ·THF at
elevated temperature to furnish the ꢀ-aminophosphines 8 in
respectable yields (Table 2). After BH3 mediated reduction, the
(12) See: Widhalm, M.; Wimmer, P.; Klintschar, G. J. Organomet. Chem.
1
996, 523, 167–178, for a related macrocyclic ligand.
13) For the first example of the conjugate addition of diethylzinc to a
nitroolefin, see: (a) Alexakis, A.; Vastra, J.; Mangeney, P. Tetrahedron Lett.
997, 38, 7745–7748. For a review on asymmetric copper-catalyzed conjugate
addition, see: (b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221–
236.
(14) For other examples of asymmetric conjugate addition to nitroolefins,
ꢀ
-aminophosphines were protected with borane on phosphorus
(
and partially on nitrogen. Selective deprotection has earlier been
reported using 1 equivalent of 1,4-diazabicyclo[2.2.2]octane
1
(
DABCO). However, we instead applied a strong cationic ion-
3
exchange resin (SCX-2) to selectively remove borane from
nitrogen.
see: (a) Alexakis, A.; Benhaim, C. Org. Lett. 2000, 2, 2579–2581. (phosphora-
midite ligands). (b) Ongeri, S.; Piarulli, U.; Jackson, R. F. W.; Gennari, C. Eur.
J. Org. Chem. 2001, 803–807. (sulfonamide-based ligands)
(15) For other examples of the use of P-chirogenic ligands in the copper-
catalyzed asymmetric conjugate addition reaction, see: (a) Takahashi, Y.;
Yamamoto, Y.; Katagiri, K.; Danjo, H.; Yamaguchi, K.; Imamoto, T. J. Org.
Chem. 2005, 70, 9009–9012. (b) Duncan, A. P.; Leighton, J. L. Org. Lett. 2004,
6, 4117–4119.
(
11) For some other examples of microwave-assisted reductive amination,
using slightly different reaction conditions, see: (a) Bailey, H. V.; Heaton, W.;
Vicker, N.; Potter, B. V. L. Synlett 2006, 2444–2448. (b) Anderluh, M.
Tetrahedron Lett. 2006, 47, 9203–9206. (c) Varma, R. S.; Dahiya, R. Tetrahedron
1
998, 54, 6293–6298.
4
460 J. Org. Chem. Vol. 73, No. 12, 2008

P-Chirogenic ꢀ-Amino Phosphine Boranes
TABLE 3. Optimization of Conditions for the Asymmetric
Copper-Catalyzed Conjugate Addition of Diethylzinc to
trans-ꢀ-Nitrostyrene, Using Ligand 5a
TABLE 4. Results from the Asymmetric Copper-Catalyzed
Conjugate Addition of Diethylzinc to trans-ꢀ-Nitrostyrene Using the
P-Chirogenic Ligands
a
a
b
entry [Cu]:L temp. (°C) solvent time (h) yield (%) ee (%)
entry
ligand
yield
ee (%)
1
2
3
4
5
6
7
8
9
1
1
1:2
1:2
1:2
1:1
1:1
1:2
1:2
1:2
1:2
1:2
1:2
0
-78
25
25
25
25
0
25
25
0
toluene
toluene
toluene
toluene
toluene
CH2Cl2
Et2O
CH2Cl2
CH2Cl2
toluene
CH2Cl2
12
24
12
12
18
20
24
20
20
12
20
35
35
70
45
n.r.
69
15
30
10
33
47
19
14
17
16
n.a.
16
5
10
20
14
13
1
2
3
4
5
6
7
8
9
10
11
1
1
1
1
1
1
1
4a
4b
4c
4d
5a
5b
5c
5d
6a
6b
6c
6d
8a
8b
8c
8d
9
39
47
47
22
70
56
22
59
58
18
20
49
57
56
63
53
30
44
16 (S)
21 (S)
0
0
b
17 (R)
10 (R)
10 (R)
12 (R)
0
37 (S)
9 (S)
14 (S)
6 (S)
14 (S)
5 (S)
28 (S)
2 (R)
16 (S)
c
d
e
f
f
0
1
25
2
3
4
5
6
7
8
a
Measured by chiral HPLC, see Experimental Section for details.
b
d
c
Trimethylsilyl iodide added. Deprotection step performed in toluene.
CuOTf used. Deprotection with HBF4. Cu(acac) used. Deprotection
with HBF4. 5b used instead of 5a.
e
f
10
1
6,17
without the need for prior deprotection of the phosphine.
a
b
[
Cu]:L ratio 1:2. Measured by chiral HPLC, see Experimental
Section for details.
The metal salt is reduced by borane and the phosphine ligand
is simultaneously deprotected, thus affording a practical and
direct method for the formation of the phosphine-metal complex.
To ascertain that this method could be applied in our case, ligand
a was treated with Cu(OTf)2 in a 1:1 ratio in different solvents
CH2Cl2, THF, toluene) at room temperature and at 50 °C. No
deprotection occurred at ambient temperature, whereas full
conversion of the 5a to the corresponding free phosphine could
be achieved in dichloromethane and in toluene at the higher
temperature. We then focused on the conditions for the conjugate
addition reaction. As monodentate, bidentate, and also bridging
structures could be envisaged with the P-chirogenic amino-
phosphine ligands, a metal to ligand ratio of both 1:2 and 1:1
was tested. Results of the trial reactions, including variation of
the solvent, reaction temperature, and decomplexation method,
are shown in Table 3.
not offer any improvement (entry 8). The latter reaction was
also performed using copper(I) acetylacetonate (entry 9).
Although the enantioselectivity was somewhat improved (20%
ee), the yield was low in this case. To see if the modest
enantioselectivities were due to a mismatched situation, con-
sidering that ligand 5a contains two chiral centers, two reactions
were also performed with ligand 5b, with the opposite stereo-
chemistry on the amine moiety. A slightly lower enantioselec-
tivity was obtained, but no great difference could be seen.
We then turned to the screening of the ligand library to study
the effect of different substituents on phosphorus (Table 4).
Following the optimization studies described earlier, a metal to
ligand ratio of 1:2 was selected together with toluene as the
solvent. The reactions were performed at room temperature with
5
(
Reaction in toluene using two equivalents of ligand to metal
(
entries 1-3) gave slightly higher enantioselectivity and better
2
mol% copper(II) triflate as the catalyst. Methyl phenyl ligands
yield when performed at room temperature than at -78 °C. The
use of a 1:1 metal to ligand ratio (entry 4) gave only a slight
decrease in enantioselectivity, but a markedly lower yield as
compared to the corresponding reaction with more ligand added
4
a-b gave enantioselectivities of 16 and 21% respectively, both
affording the same enantiomer of the product (S), indicating
that the phosphine part of the ligand determines the stereo-
chemical outcome (entries 1 and 2). Ligands 4c and 4d
somewhat surprisingly afforded racemic product (entries 3 and
(
entry 3). Addition of trimethylsilyl iodide was found to be
detrimental to the reaction and no product was isolated in this
case (entry 5). Performing the reaction in dichloromethane
instead gave nearly identical results in terms of yield and
enantioselectivity as compared to reaction in toluene (entry 6),
whereas the use of diethyl ether (deprotection step performed
in toluene) gave poor results (entry 7). The use of copper(I)
4
). Ferrocenyl methyl phosphine ligands 5a-d all gave enan-
tioselectivities in the range of 10-17% and product with
R-configuration (entries 5-8). Ligands 6a-d, based on a
PAMP-structure, gave more interesting results. Ligand 6a
afforded racemic product, while switching to the opposite
enantiomer of the amine component of the ligand gave an
enantiomeric excess of 37%, indicating a mismatched situation
in the first case (entries 9 and 10). Ligands 6c and 6d gave
more modest selectivities (entries 11 and 12). For the tert-butyl
methyl phosphine ligands 8a-d (entries 13-16), the morpholine
substituted ligands gave best results (28% ee). Tetradentate
ligands 9 and 10 were also investigated. Ligand 9, based on a
binaphthyl-diamine skeleton, gave nearly racemic product (entry
1
8
triflate, with prior deprotection of the ligand with HBF4, did
(
16) Darcel, C.; Kaloun, E. B.; Merd e` s, R.; Moulin, D.; Riegel, N.;
Thorimberg, S.; Gen eˆ t, J. P.; Jug e´ , S. J. Organomet. Chem. 2001, 624, 333343.
17) For other examples of application of this methodology, see: (a) Vasse,
J.-L.; Stranne, R.; Zalubovskis, R.; Gayet, C.; Moberg, C. J. Org. Chem. 2003,
8, 3258–3270. (b) Dolhem, F.; Johansson, M. J.; Antonsson, T.; Kann, N.
J. Comb. Chem 2007, 9, 477–486.
18) (a) McKinstry, L.; Livinghouse, T. Tetrahedron 1995, 51, 7655–7666.
b) McKinstry, L.; Overberg, J. J.; Soubra-Ghaouli, C.; Walsh, D. S.; Robins,
K. A.; Tangredi Toto, T.; Toto, J. L. J. Org. Chem. 2000, 65, 2261–2263.
19) The corresponding racemic compound has been prepared earlier, see
ref 8b.
(
6
(
(
17), while the more flexible ligand 10 gave an enantioselectivity
more in line with the earlier results (entry 18). Widhalm and
co-workers have studied similar ligands in other asymmetric
(
J. Org. Chem. Vol. 73, No. 12, 2008 4461

Johansson et al.
2
0
carbon-carbon bond forming reactions such as asymmetric
phosphine borane (0.30 g, 1.15 mmol) in 5 mL of toluene was
added dropwise Via cannula. The reaction was left to stir for 4 h
after which dry N,N-dimethylformamide (0.17 g, 2.30 mmol) was
added dropwise Via cannula. The solution was then heated to 50
allylic substitution and nickel-catalyzed cross-coupling reac-
1
2
tions, and it may be that these are more suitable test reactions
for these two ligands.
°
C for 1 h and subsequently allowed to cool to rt. The reaction
was quenched with sat. NH Cl (aq). The aqueous layer was
extracted three times with diethyl ether. The combined organic
phases were washed three times with sat. KHSO (aq) and once
with brine. The organic layer was dried over Na SO , filtered, and
4
Conclusion
4
In conclusion, we have shown that R-formyl phosphine
boranes can be produced in enantio-enriched form by either
asymmetric deprotonation of prochiral phosphine boranes or by
deprotonation of PAMP ·BH3. This methodology gives access
to a new type of P-chirogenic compounds that are highly
versatile building blocks for the design and construction of new
chiral phosphine ligands. These complementary routes allow
for alkyl,alkyl; aryl,alkyl; and aryl,aryl substituents on phos-
phorus. P,N-ligands are becoming increasingly popular and the
reported approach allows a facile, modular, and efficient
synthesis of such compounds. In addition, a selective N-
deprotection of the diboronated P,N-ligands is reported, employ-
ing a strong cation exchange resin. The ligands were evaluated
in the copper-catalyzed asymmetric conjugate addition of diethyl
zinc to nitrostyrene, employing in situ deprotection of the ligands
by the metal. Noteworthy is the reversal in absolute configu-
ration going from P-phenyl or P-anisyl to P-ferrocenyl.
Although the enantioselectivities were modest, the concept of
in situ deprotection and concomitant complexation to a metal
has proven to be a viable alternative to isolation of the free
phosphine followed by complexation. This allows for easy
screening of ligands in their protected form relying on the metal,
in its higher oxidation state, to cleave the P-B bond. Further
studies in exploring the utility of the obtained R-formyl
phosphine boranes both as ligands in different processes and
as building blocks for ligand development are in progress.
2
4
concentrated in Vacuo. Purification by flash chromatography (30%
ethyl acetate, 70% petroleum ether) yielded the product as a thick
20
brown oil (0.27 g, 82%). Data for 2: [R]
D
) +22.4 (c 1.19 in
1
3 3
CHCl , 88% ee); H NMR (CDCl , 400 MHz) δ 9.61 (t, J ) 12.5
Hz, 1H), 4.58-4.56 (m, 1H), 4.54-4.51 (m, 1H), 4.50-4.48 (m,
1H), 4.31 (s, 5H), 4.30-4.27 (m, 1H), 3.00-2.93 (m, 2H), 1.66
1
3
3
(d, J ) 10.4 Hz), 0.83 (br q, 3H); C NMR (CDCl , 400 MHz) δ
195.3 (d, J ) 4.5 Hz), 72.4 (d, J ) 39.2 Hz), 72.2 (d, J ) 33.2
Hz), 71.9 (d, J ) 6.8 Hz), 69.9 (d, J ) 5.4 Hz), 69.7, 44.3 (d, J )
2
5.7 Hz), 10.5 (d, J ) 37.9 Hz); some signals in the aromatic area
overlap. Anal. Calcd for C13H18BFeOP: C 54.23, H 6.30; Found:
C 54.29, H 6.18. The enantioselectivity was determined by reduction
to the corresponding alcohol and HPLC analysis on a Daicel
Chiralcel OD-H column (n-hexane-i-PrOH).
(
S
p
)-(r-Formylmethyl)-(2-methoxyphenyl)-phenylphos-
phine Borane (3). To a cooled (-78 °C) solution of (S)-
2
PAMP · BH (5.14 mmol, 1.25 g, >98% ee) in 30 mL THF was
3
added sec-BuLi (6.17 mmol) Via cannula. The reaction was left
to stir for 2 h after which dry N,N-dimethylformamide (10.28
mmol, 0.75 g) was added dropwise Via cannula. The reaction
was stirred for 1 h and then quenched with sat. NH Cl (aq).
The aqueous layer was extracted three times with diethyl ether.
The combined organic phases were washed three times with
4
saturated KHSO
4
(aq) and once with brine. The organic layer
SO , filtered, and concentrated in Vacuo.
was dried over Na
Purification by flash chromatography (15% ethyl acetate, 85%
petroleum ether) yielded the product as colorless oil (1.18 g,
2
4
8
4%). The product degraded rapidly upon storage, even when
Experimental Section
stored under argon at -18 °C. Freshly prepared compound and
immediate use in the next step are thus recommended. Data for
1
9
p
(S )-(r-Formylmethyl)-methylphenylphosphine Borane (1). To
1
3
: H NMR (CDCl
3
, 400 MHz) δ 9.70 (t, J ) 3.2 Hz, 1H), 7.82
a cooled (-78 °C) solution of (-)-sparteine (1.70 g, 7.24 mmol)
in 30 mL of diethyl ether was added sec-BuLi (7.24 mmol) Via
cannula. After stirring for 30 min, a solution of dimethylphe-
(
(
ddd, J ) 14.8 Hz, J ) 8.0 Hz, J ) 2.0 Hz, 1H), 7.67-7.62,
m, 2H), 7.57-7.52 (m, 1H), 7.47-7.39 (m, 3H), 7.10-7.06
3
(m, 1H), 6.93 (dd. J ) 8.4 Hz, J ) 3.6 Hz, 1H), 3.75 (s, 3H),
nylphosphine borane (1.00 g, 6.58 mmol) in 20 mL of diethyl
13
3
3
.62-3.45 (m, 2H), 1.60-0.60 (m, 3H); C NMR (CDCl , 100
ether was added dropwise Via cannula. The reaction was left to
stir for 3 h after which dry N,N-dimethylformamide (0.96 g,
MHz) δ 195.5, 161.0, 135.9 (d, J ) 15.2 Hz), 134.5 (d, J ) 1.5
Hz), 131.4 (d, J ) 10.6 Hz), 131.1 (d, J ) 2.3 Hz), 128.6 (d, J
)
1
)
1
3.2 mmol) was added dropwise Via cannula. The reaction was
left to stir for 1 h. The reaction was quenched with sat. NH Cl
aq). The aqueous layer was extracted three times with diethyl
ether. The combined organic phases were washed three times
with KHSO (aq) and once with brine. The organic layer was
dried over Na SO , filtered, and concentrated in Vacuo. Purifica-
58.4 Hz), 128.6 (d, J ) 10.6 Hz), 121.4 (d, J ) 12.9 Hz),
4
14.5 (d, J ) 53.1 Hz), 111.2 (d, J ) 3.8 Hz), 55.4, 40.4 (d, J
(
30.3 Hz).
General Procedure for the Microwave-Assisted Reductive
4
Amination (4a-d, 5a-d, 6a-d). P-chirogenic aldehyde 1, 2, or
3 (1.2 equiv) was solubilized at room temperature in 5 mL of
dichloroethane into a 5 mL microwave vial with a magnetic
stirrer. To this was added an amine (a-d, 1 equiv) followed by
sodium triacetoxyborohydride (1.3 equiv) in one portion. The
2
4
tion by flash chromatography (25% ethyl acetate, 75% petroleum
ether) yielded the product as a pale-yellow oil (1.12 g, 93%).
2
0
1
Data for 1: [R]
D
) +22.3 (c 1.03 in CHCl
, 400 MHz) δ 9.68 (dt, J ) 3.2, 1.6 Hz, 1H), 7.80-7.70
m, 2H), 7.60-7.44 (m, 3H), 3.10 (dq, J ) 12.0, 1.2 Hz, 2H),
3
, 81% ee); H NMR
(
(
CDCl
3
2
vial was then sealed and evacuated before being filled with N .
.71 (d, J ) 10.0 Hz, 3H), 1.87 (br q, 3H); 1 C NMR (CDCl
00 MHz) δ 195.2 (d, J ) 12.4 Hz), 131.9 (d, J ) 3.1 Hz),
31.2 (d, J ) 13.1 Hz), 128.9 (d, J ) 9.9 Hz), 42.4 (d, J ) 26.6
3
,
1
4
1
3
The microwave reaction was performed at 130 °C for 6 min in
a Biotage Series 60 Initiator, where the reaction temperature
was monitored with an IR sensor. Purification was performed
using a cationic ion-exchange resin (IST SCX-2) and washed
with eight column volumes of DCM and eight column volumes
of methanol. The product was eluted with NH /methanol and
concentrated in Vacuo.
Hz), 10.5 (d, J ) 25.7 Hz); two signals in the aromatic area
overlap. Anal. Calcd for C
9
H14BOP: C 60.06, H 7.84; Found: C
5
9.93, H 7.81. The enantioselectivity was determined by
3
reduction to the corresponding alcohol and HPLC analysis on a
Daicel Chiralcel OD-H column (n-hexane-i-PrOH).
p
(S )-Ferrocenyl-(r-formylmethyl)-methylphosphine Borane
(
2). To a cooled (-78 °C) solution of (-)-sparteine (0.30 g, 1.27
(
20) Oohara, N.; Katagiri, K.; Imamoto, T. Tetrahedron: Asymmetry 2003,
mmol) in 5 mL of ether was added sec-BuLi (1.27 mmol) Via
cannula. After stirring for 30 min, a solution of dimethylferrocenyl
1
1
4, 2171–2175. H NMR data were in accordance to published data for this
compound.
4
462 J. Org. Chem. Vol. 73, No. 12, 2008

P-Chirogenic ꢀ-Amino Phosphine Boranes
Data for Compounds 4a, 5a, and 6a. (S
ꢀ-{(1R)-1-phenethyl}amino]-phosphine Borane (4a). Transparent
p
)-Methylphenyl-
9H); 13C NMR (CDCl
, 100 MHz) δ 165.0, 142.6, 128.6, 127.4,
3
21
[
126.3, 49.8, 30.9 (d, J ) 23.5 Hz), 27.8 (J ) 32.6 Hz), 5.2 (d, J )
2
0
1
oil (88%). [R]
D
) +25.7 (c 0.79 in CHCl
3
); H NMR (CDCl
3
,
33.3 Hz). Anal. Calcd for C15
C, 64.63; H, 9.71.
H27BNOP: C, 64.54; H, 9.75. Found:
4
(
2
00 MHz) δ 7.71-7.65 (m, 2H), 7.52-7.40 (m, 3H), 7.32-7.20
m, 4H), 3.77-3.70 (m, 1H), 2.72-2.62 (m, 2H), 2.12-2.01 (m,
H), 1.89 (br s, 1H), 1.56 (d, J ) 10.2 Hz, 3H), 1.32 (d, J ) 6.6
General procedure for the borane reduction of phosphine
amides 7a-d (formation of 8a-d). Phosphine amide borane 7a-d
2
respectively (1.0 mmol) were dissolved in THF (5 mL) under N .
13
Hz, 3H), 1.20-0.30 (m, 3H); C NMR (CDCl
3
, 400 MHz) δ 144.9
d, J ) 6.1 Hz), 131.5 (dd, J ) 9.2, 3,1 Hz), 129.7, 129.2, 128.7
d, J ) 9.8 Hz), 128.3, 126.9, 126.4, 57.9, 41.7, 28.0 (d, J ) 35.1
25BNP: C
(
(
3
Then BH -DMS (5.0 mmol) was added dropwise at 0 °C, and then
the mixture was stirred at 50 °C for 6 h. The crude mixture was
poured directly onto a cationic ion-exchange resin (IST SCX-2).
The column was washed thoroughly with 8 × 20 mL DCM and 8
× 20 mL MeOH. Finally the product was eluted using methanol
saturated with ammonia. Evaporation of the solvent gave the
corresponding analytically pure ꢀ-aminophosphine boranes 8a-d.
Hz), 24.0, 11.3 (d, J ) 38.7 Hz). Anal. Calcd for C17
1.60, H 8.84; Found: C 71.46, H 8.71.
)-Ferrocenyl-[ꢀ-{(1R)-1-phenethyl}amino]-phenylphos-
H
7
(S
p
2
0
phine Borane (5a). Brown oil (95%). [R]
D
) +2.95 (c 0.61 in
, 400 MHz) δ 7.33-7.19 (m, 5H),
.44-4.39 (m, 4H), 4.27 (s, 5H), 4.26-4.25 (m, 1H), 3.69 (q, J )
.6 Hz, 1H), 2.71-2.55 (m, 2H), 1.91-1.83 (m, 2H), 1.49 (d, J )
1
3 3
CHCl ); H NMR (CDCl
4
6
1
Datafor8a:(S
p
)-tert-Butyl-methyl-[ꢀ-{(1R)-1-phenethyl}amino]-
2
0
phosphine borane (8a). White solid (87%). [R]
D
) +23.4 (c
3 3
1.29 in CHCl ); H NMR (CDCl , 400 MHz) δ 7.34-7.21 (m, 5H),
1
3
1
0.3 Hz, 3H), 1.29 (d, J ) 6.6 Hz, 3H), 1.10-0.30 (m, 3H);
C
NMR (CDCl
3
, 400 MHz) δ 128.4, 126.9, 126.5, 72.2 (d, J ) 13.9
3.77 (q, J ) 6.8 Hz, 1H), 2.80 (m, 1H), 2.75 (m, 1H), 2.0 (broad
s, 1H), 1.82-1.62 (m, 2H), 1.35 (d, J ) 6.8 Hz, 3H), 1.14-1.05
Hz), 71.3 (d, J ) 7.6 Hz), 71.2 (d, J ) 6.2 Hz), 69.7 (d, J ) 6.0
1
3
Hz), 69.5, 69.5, 69.4, 58.0, 41.9, 29.3 (d, J ) 36.2 Hz), 24.0, 11.4
3
(m, 12H), 0.90-0.00 (m, 3H); C NMR (CDCl , 100 MHz) δ
(
d, J ) 40.2 Hz). Anal. Calcd for C21
Found: 63.86, H 7.58.
)-(2-Methoxyphenyl)-[ꢀ-{(1R)-1-phenethyl}amino]-phe-
H
29BFeNP: C 64.16, H 7.44;
128.4, 127.0, 126.5, 58.4, 42.2 (d, J ) 1.5 Hz), 27.2 (d, J ) 34.2
Hz), 24.8 (d, J ) 2.2 Hz), 24.2, 21.9 (d, J ) 31.1 Hz) 5.6 (d, J )
(
S
p
34.2 Hz). Anal. Calcd for C15
C, 67.82; H, 10.96.
H29BNP: C, 67.94; H, 11.02. Found:
2
0
nylphosphine Borane (6a). Pale-yellow solid (84%). [R]
D
)
1
General Procedure for the Asymmetric Conjugate Addi-
tion of Diethyl Zinc to trans-ꢀ-Nitrostyrene (Formation of 11).
The desired ligand (8.2 µmol, 4 mol%) was placed in a 5 mL round-
+
14.5 (c 0.83 in CHCl
J ) 14.0 Hz, 7.6, 1H), 7.59 (app. t, J ) 9.6 Hz, 2H), 7.48-7.19
m, 9H), 7.02 (t, J ) 7.2 Hz, 1H), 6.81 (dd, J ) 8.0 Hz, 3.2, 1H),
.85-3.70 (m, 1H), 3.62 (s, 3H), 2.90-2.73 (m, 2H), 2.72-2.48
3 3
); H NMR (CDCl , 400 MHz) δ 7.84 (dd,
(
3
(
(
(
9
4
2
bottom flask together with Cu(OTf) (4.1 µmol, 3 mg, 2 mol%)
1
3
and dry toluene (1.5 mL) under an argon atmosphere. The mixture
was heated to 50 °C, and the deprotection was monitored by TLC.
When no phosphine borane complex could be detected, trans-ꢀ-
nitrostyrene (0.2 mmol, 30 mg) in 0.5 mL toluene was added. After
20 min, the reaction was cooled to 0 °C, and a 1 M solution of
diethylzinc in hexane (0.3 mmol, 0.3 mL) was added. The reaction
was allowed to warm up to room temperature and stirred until no
substrate could be detected by TLC (12-24 h). Quenching with
saturated ammonium chloride was followed by extraction with ether
and washing with saturated sodium bicarbonate and brine. The
combined organic phases were filtered through a short plug of silica
gel, dried with sodium sulfate, and concentrated in Vacuo, affording
essentially pure 1-nitro-2-phenylbutane (11). The enantioselectivity
was determined by HPLC analysis on a Daicel Chiralcel OD-H
column (n-hexane-i-PrOH 95:5, 0.5 mL/min, 230 nm). 1-Nitro-2-
m, 2H), 1.33 (d, J ) 6.8 Hz, 3H), 1.30-0.40 (m, 3H); C NMR
CDCl , 100 MHz) δ 161.2, 136.2 (d, J ) 14.4 Hz), 133.8, 131.4
3
d, J ) 9.1 Hz), 130.4 (d, J ) 3 Hz), 129.7, 128.4, 128.2 (d, J )
.9 Hz), 126.7, 121.1 (d, J ) 12.1 Hz), 115.9, 115.4, 110.9 (d, J )
.5 Hz), 57.9, 55.3, 41.8, 24.0 (d, J ) 38 Hz), 23.6. Anal. Calcd
for C23H29BNOP: C, 73.22; H 7.75. Found: C, 73.08; H, 7.70.
General Procedure for the Amidation of 2-(S
P
)-(tert-butyl-
(
2
9
methyl)phosphino)acetic Acid Borane (Formation of 7a-d).
22
-(S
P
)-(tert-Butyl(methyl)phosphino)-acetic acid borane (1.0 mmol,
. HOBt (2.0 mmol)
4% ee) was dissolved in THF (10 mL) under N
2
and EDCI (1.2 mmol) was added in one portion at 0 °C, then the
mixture was stirred at room temperature for 30 min. An amine (a-
d, 1.2 mmol) was added at 0 °C, and the solution was stirred at
ambient temperature. The reaction was quenched after 16 h by the
addition of 1 M HCl (30 mL) and diluted with CHCl
The layers were separated. Then the combined organic layers were
washed with saturated NaHCO , 2 M NaOH, 2 M HCl and brine.
The organic phase was then dried over Na SO . Filtration and
3
(10 mL).
23
1
phenylbutane: t /min ) 17.8 (R), 23.5 (S). H NMR data were in
R
accordance to published data for this compound.
3
2
4
Acknowledgment. We thank the Swedish Foundation for
Strategic Research, the Swedish Research Council and the Royal
Society of Arts and Sciences in Göteborg for financial support
and Dr. Thomas Antonsson for his interest in this project.
evaporation of the solvent gave crude phosphineamide boranes 7,
of sufficient purity to be used directly in the next step.
Data for 7a: (R
phenylethyl)-acetamide borane (7a). White solid (92%). H NMR
CDCl , 400 MHz) δ 7.34-7.26 (m, 5H), 6.45 (d, J ) 6.8 Hz,
H), 5.07 (q, J ) 6.8 Hz, 1H), 2.58 (d, J ) 11.6 Hz, 2H), 1.52 (d,
J ) 6.8 Hz, 3H), 1.33 (d, J ) 9.6 Hz, 3H), 1.13 (J ) 14.4 Hz,
c p
,S )-2-(tert-Butyl(methyl)phosphanyl)-N-(1-
1
(
1
3
Supporting Information Available: 1H and 13C NMR
spectra for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(
(
21) The corresponding free phosphine has been prepared earlier, see ref 7c.
JO800672B
22) Ohashi, A.; Kikuchi, S.-I.; Yasutake, M.; Imamoto, T. Eur. J. Org. Chem.
1
2
002, 2535–2546. H NMR data were in accordance to published data for this
compound.
(23) Sch a¨ fer, H.; Seebach, D. Tetrahedron 1995, 52, 2305–2324.
J. Org. Chem. Vol. 73, No. 12, 2008 4463