Synthesis, reactivity, and resolution of a C 2-symmetric, P-stereogenic benzodiphosphetane, a building block for chiral bis(phosphines)

Article abstract of DOI:10.1021/ol301935q

Although the pyramidal inversion barriers in diphosphines (R ₂P-PR₂) are similar to those in phosphines (PR ₃), P-stereogenic chiral diphosphines have rarely been exploited as building blocks in asymmetric synthesis. The synthesis, reactivity, and resolution of the benzodiphosphetane trans-1,2-(P(t-Bu))₂C ₆H₄ are reported. Alkylation with MeOTf followed by addition of a nucleophile gave the useful C₂-symmetric P-stereogenic ligand BenzP* and novel analogues.

Full text of DOI:10.1021/ol301935q

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Synthesis, Reactivity, and Resolution of a
C2ꢀSymmetric, PꢀStereogenic
Benzodiphosphetane, a Building Block for
Chiral Bis(phosphines)
Samantha C. Reynolds,† Russell P. Hughes,† David S. Glueck,*,† and Arnold L. Rheingold‡
6128 Burke Laboratory, Department of Chemistry, Dartmouth College, Hanover,
New Hampshire 03755, United States, and Department of Chemistry,
University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093
Glueck@dartmouth.edu
Received July 12, 2012
ABSTRACT
Although the pyramidal inversion barriers in diphosphines (R2PꢀPR2) are similar to those in phosphines (PR3), P-stereogenic chiral diphosphines
have rarely been exploited as building blocks in asymmetric synthesis. The synthesis, reactivity, and resolution of the benzodiphosphetane trans-
1,2-(P(t-Bu))2C6H4 are reported. Alkylation with MeOTf followed by addition of a nucleophile gave the useful C2-symmetric P-stereogenic ligand
BenzP* and novel analogues.
P-Stereogenic phosphines such as DiPAMP1 are valu-
able ligands in asymmetric catalysis.2 The barrier to pyr-
amidal inversion in the diphosphines R2PꢀPR2 (22ꢀ
26 kcal/mol)3 is similar to that in phosphines PR3
(29ꢀ36 kcal/mol),4 but chiral diphosphines have received
little attention in asymmetric synthesis. The reactive PꢀP
bond makes these compounds potentially useful building
blocks in the synthesis of chiral phosphines.5 For example,
enantiomerically pure diphosphine 1 was recently used to
prepare P-stereogenic Josiphos ligands.6 However, isolat-
ing C2-symmetric menthyl-substituted diphosphine 2 re-
quired separation of a 1:3 mixture of C2- and meso-2, and
C2-2 rapidly epimerized in solution below room tempera-
ture (Figure 1).7
† Dartmouth College.
‡ University of California.
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Figure 1. P-Stereogenic chiral diphosphines.
€
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r
10.1021/ol301935q
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These examples suggest that chiral diphosphines such as
2 might be useful synthons if the C2-symmetric isomer
could be prepared selectively and if the P-inversion barrier
was high enough to enable routine manipulations. There-
fore, we investigated a rare class of heterocycles, the
benzodiphosphetanes, in which steric effects make the
meso-isomer less stable than the C2 one and should also
increase the P-inversion barrier (Figure 2).
available 10 with t-BuMgCl (Scheme 1).16 Treatment of
9 withexcess t-BuMgCl also generated 8. This reaction had
been reported in 1986 by Kyba and co-workers, who
observed benzodiphosphetane 8 by 31P NMR spectro-
scopy but were not able to identify or isolate it.16
Scheme 1. Synthesis of Benzodiphosphetane 8
Figure 2. Benzodiphosphetanes and analogous dicarbaborane
derivatives.
Although the all-carbon analogues (cyclobutarenes)8
have been intensively studied, and silicon9 and sulfur
derivatives are known,10 very few benzodiphosphetanes
have been prepared. After unsuccessful attempts to make
3, which gave its dimer 4 in <1% yield,11 the sterically
protected 5 (Mes* = 2,4,6-(t-Bu)3C6H2) was reported,12
and the parent compound 6 was observed as a reaction
intermediate (Figure 2).13 More recently, the synthesis and
structures of analogous carbaborane derivatives 7aꢀb
were reported,14 but little is known about the reactivity
and possible applications of the PꢀP bond in these
compounds.
Here we report a simple synthesis of trans-1,2-(P(t-Bu))2
C6H4 (8), studies of its reactivity, its resolution using a Pd
complex, and its use as a building block for synthesis of
P-stereogenic bis(phosphines) of known and potential utility
in asymmetric catalysis.
Benzodiphosphetane 8 was prepared in 78% yield by
reduction of the known chlorophosphine 9 with Mg;14,15
this reaction may be carried out in one pot without
isolation of 9 after its generation from commercially
Alternatively, a copper-catalyzed reaction of bis-
(secondary phosphine)16 11 with 2 equiv of NaOSiMe3
and dibromoethane gave 8.17 Similarly, treatment of 11
with 2 equiv of n-BuLi gave dianion 12; quenching with
dibromoethane gave 8 as the major product. More surpris-
ingly, treatment of 12withbenzyl bromide or chloride gave
8 in a mixture with the expected product, bis(tertiary
benzylphosphine) 13. The 8/13 product ratios (5:1 for Br,
1.2:1 for Cl) were consistent with formation of 8 via attack
of the phosphido nucleophile at a halide instead of carbon,
or an electron transfer process (Scheme 1).18
Despite the strained ring system, 8 distilled without
decomposition under vacuum at 110 °C. It was air-stable
for several days, even in solution. The volatility of 8 was
consistent with its formulation as a monomer, not a dimer
such as 4, as were 1H NMR DOSY studies, using 11 as an
internal standard.19 DFT calculations on 8 predicted a
PꢀP bond length (2.292 A) in the normal range20 and the
˚
expected acute CPC angle (75.9°, Figure 3). C2-Symmetric
8, the only isomer observed, was calculated to be 12 kcal/mol
more stable than its meso isomer. The computed bar-
rier to pyramidal inversion in 8 (35 kcal/mol) was, as
(8) (a) Sadana, A. K.; Saini, R. K.; Billups, W. E. Chem. Rev. 2003,
103, 1539–1602. (b) Stanger, A. In The Chemistry of Cyclobutanes;
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Cain, M. F.; Reynolds, S. C.; Anderson, B. J.; Glueck, D. S.; Golen,
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(20) Average P-P distance in diphosphines = 2.221 ( 0.11 A
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B
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expected, higher thanusualfor diphosphinesand similar to
values calculated for carbaborane 7a.14
Scheme 2. Reactions of 8
Scheme 3. Reaction of Cation 19 with Nucleophiles
Figure 3. Computed structure (B3LYP/LACV3P**þþ) of ben-
˚
zodiphosphetane 8 with selected bond lengths (A, red) and
angles (deg, blue).
Diphosphetane 8 formed BH3 adduct 14, which readily
lost borane on attempted chromatography or aqueous
workup; bis(phosphine sulfide) 15 also could not be ob-
tained in pure form (Scheme 2). Addition of I2 across the
PꢀP bond gave the diiodophosphine 16, which was also
formed from diiodoethane.5,14 Reaction of 1 equiv of MeI
with 8 yielded cation 18 and unreacted 8; methylation of
the (unobserved) presumed initial product 17 was appar-
ently faster than its formation. Excess MeI gave full
conversion to 18.5 In contrast, 8 reacted with methyl
triflate to form phosphonium salt 19 (JPP = 175 Hz),
which retained the PꢀP bond.6a,21
Scheme 4. Resolution of 8
Reaction of 19 with nucleophiles resulted in PꢀP clea-
vage to form bis(phosphines) with high diastereoselectivity
(Scheme 3).6a,21 Thus, MeMgBr gave C2-symmetric
BenzP* (20),22 while PhMgBr yielded 21. However, t-
BuMgCl transferred a hydride instead of a t-Bu group to
yield, as the major product, the mixed tertiary/secondary
phosphine 22 (2:1 dr), which could also be formed using
borohydrides such as LiEt3BH.23 Reaction of 19 with
NEt3/H2O gave the analogous secondary phosphine oxide
(SPO) 23 as a single isomer, presumably via tautomeriza-
tion of the PꢀOH intermediate.24 The structure of second-
ary phosphine 22 was confirmed by its oxidation to
SPO 23.
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Harris, S. E.; Lange, H.; Orpen, A. G.; Taylor, P. N. J. Chem. Soc.,
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Yamaguchi, K. Org. Lett. 2006, 8, 6103–6106. (c) Imamoto, T.; Tamura,
K.; Zhang, Z.; Horiuchi, Y.; Sugiya, M.; Yoshida, K.; Yanagisawa, A.;
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Treatment of 8 with 2 equiv of chiral Pd complex 24
gave dinuclear 25 (Scheme 4).25 Recrystallization from
Org. Lett., Vol. XX, No. XX, XXXX
C

8,26 which didnot epimerizeonheating to105 °C intoluene
for 18 h, consistent with the high computed barrier to
inversion. Repeating the chemistry of Scheme 3 with
nonracemic 8 gave enantiomerically enriched BenzP* with
efficient chirality transfer (Scheme 5), with similar results
for the synthesis of SPO 23.
Scheme 5. Synthesis of Nonracemic BenzP* from Enriched 8
In conclusion, we report the synthesis and resolu-
tion of a chiral benzodiphosphetane, whose struc-
ture was designed to avoid formation of the unwanted
meso diastereomer and to increase the pyramidal in-
version barrier at phosphorus. Sequential electro-
philic and nucleophilic alkylation gave Imamoto’s
valuable C2-symmetric P-stereogenic bis(phosphine)
BenzP* (20) and novel analogues 21ꢀ22. These results
establish chiral benzodiphosphetanes, and, more
generally, diphosphines, as potentially useful build-
ing blocks in the synthesis of chiral phosphines.
Such processes would be more practical if they used
cheaper resolving agents or exploited (catalytic) asym-
metric synthesis;27 we are now investigating these
possibilities.28
CH2Cl2/pentane effected separation of diastereomers 25,
giving the less soluble (RP,RP) isomer in >100:1 dr, and
(SP,SP)-25 in 14:1 dr. In the crystal structure of (RP,RP)-
25, the cyclometalated Pd-naphthyl moieties occupied
inequivalent positions (Scheme 4). This structure was
maintained in solution for both diastereomers (AB 31P
NMR spectra), as confirmed for (RP,RP)-25 by NOESY
studies.
Separate treatment of enriched samples of diaster-
eomers 25 with the bidentate bis(phosphine) dppe
(Ph2PCH2CH2PPh2) liberated enantiomerically enriched
(25) Wild, S. B. Coord. Chem. Rev. 1997, 166, 291–311.
(26) Albert, J.; Cadena, J. M.; Granell, J.; Muller, G.; Ordinas, J. I.;
Acknowledgment. D.S.G. thanks the National Science
Foundation for support and Amnon Stanger (Technion,
Israel) for helpful discussions; R.P.H. thanks the National
Science Foundation for support.
~
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18, 3511–3518.
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Glueck, D. S. Chem.;Eur. J. 2008, 14, 7108–7117. (c) Glueck, D. S.
Coord. Chem. Rev. 2008, 252, 2171–2179. (d) Glueck, D. S. Synlett 2007,
2627–2634. (e) Harvey, J. S.; Gouverneur, V. Chem. Commun. 2010, 46,
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2010, 3037–3062.
(28) Although deprotonation of 11 with n-BuLi/(ꢀ)-sparteine gave
predominantly one bis(phosphido) dianion, whose simple 31P and 7Li
NMR spectra were consistent with C2 symmetry (Hitchcock, P. B.;
Lappert, M. F.; Leung, W.-P.; Yin, P. J. Chem. Soc., Dalton Trans. 1995,
3925–3932), PꢀP bond formation occurred without any enantioenrichment.
Supporting Information Available. Experimental pro-
cedures and crystallographic, computational, and char-
acterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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