Mild synthesis of organophosphorus compounds: Reaction of phosphorus-containing carbenoids with organoboranes

Article abstract of DOI:10.1021/ol800085u

Organoboranes react with phosphorus-containing carbenoids to produce a variety of functionalized organophosphorus compounds under mild conditions. In some cases, selective migration of one group atached to boron can be observed. Phosphonite-borane complexes are introduced as novel synthons for the synthesis of phosphinic esters.

Full text of DOI:10.1021/ol800085u

ORGANIC
LETTERS
2008
Vol. 10, No. 5
977-980
Mild Synthesis of Organophosphorus
Compounds: Reaction of
Phosphorus-Containing Carbenoids with
Organoboranes
Monika I. Antczak and Jean-Luc Montchamp*
Department of Chemistry, Box 298860, Texas Christian UniVersity,
Fort Worth, Texas 76129
j.montchamp@tcu.edu
Received January 14, 2008
ABSTRACT
Organoboranes react with phosphorus-containing carbenoids to produce a variety of functionalized organophosphorus compounds under
mild conditions. In some cases, selective migration of one group attached to boron can be observed. Phosphonite
−borane complexes are
introduced as novel synthons for the synthesis of phosphinic esters.
Organoboranes have often been homologated to various
functional groups using carbenoids.1 However, as far as we
could determine, application of this general reactivity pattern
has surprisingly not been implemented in organophosphorus
chemistry. Herein we describe studies aiming at the func-
tionalization of a C-B bond 1 into a C-C-P 3 motif using
various organophosphorus carbenoids (Scheme 1).
Based on the extensive precedent for reaction of orga-
noboranes with halocarbonyl anions and diazocarbonyl
compounds, the feasibility of the analogous reaction of
phosphorus-containing reagents appeared reasonable. One
likely difference concerns the reactivity of the R-boron-
substituted intermediate phosphorus species 2. The synthetic
strategy outlined below provides various organophosphorus
compounds under mild conditions.
To test the possibility of the reaction depicted in Scheme
1, the reaction of dimethyl (diazomethyl)phosphonate (Sey-
ferth/Gilbert reagent, 4a)2 with tributylborane was investi-
gated. Treatment of 4a with Bu3B at room temperature in
THF, resulted in the instantaneous evolution of N2 and
formation of 2a which was hydrolyzed with water or D2O
(1) Representative examples: (a) Blakemore, P. R.; Burge, M. S. J. Am.
Chem. Soc. 2007, 129, 3068. (b) Blakemore, P. R.; Marsden, S. P.; Vater,
H. D. Org. Lett. 2006, 8, 773. (c) Goddard, J.-P.; Le Gall, T.; Mioskowski,
C. Org. Lett. 2000, 2, 1455. (d) Matteson, D. S. Acc. Chem. Res. 1988, 21,
294. (e) Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687. (f)
Larson, G. L.; Argu¨elles, R.; Rosario, O.; Sandoval, S. J. Organomet. Chem.
1980, 198, 15. (g) Matteson, D. S.; Majumdar, D. Organometallics 1983,
2, 230. (h) Hooz, J.; Linke, S. J. Am. Chem. Soc. 1968, 90, 5936. (i) Hooz,
J.; Linke, S. J. Am. Chem. Soc. 1968, 90, 6891. (j) Hooz, J.; Morrison, G.
F. Can. J. Chem. 1970, 48, 868. (k) Negishi, E.; Yoshida, T.; Silveira, A.,
Jr.; Chiou, B. L. J. Org. Chem. 1975, 40, 814. (l) Brown, H. C.; Rogic, M.
M.; Rathke, M. W.; Kabalka, G. W. J. Am. Chem. Soc. 1968, 90, 818. (m)
Brown, H. C.; Rogic, M. M.; Rathke, M. W. J. Am. Chem. Soc. 1968, 90,
6218. (n) Brown, H. C.; Rogic, M. M.; Rathke, M. W.; Kabalka, G. W. J.
Am. Chem. Soc. 1968, 90, 1911.
Scheme 1. Homologation of Phosphorus Carbenoids with
Organoboranes
10.1021/ol800085u CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/06/2008

to produce dimethyl pentylphosphonate 3a (protio 3a-H, or
deuterio 3a-D) in 86% and 80% isolated yields, respectively
(Scheme 2). In the latter case, deuterium incorporation was
Scheme 3. Reaction of Diethyl (Chloromethyl)phosphonate
with Tributylborane
Scheme 2. Reaction of Dimethyl (Diazomethyl)phosphonate
with Tributylborane
be noted that the second butyl group in the product is then
as likely to originate from the added butyllithium (33%
chance) as from the initial Bu3B (Scheme 4). This might
have been true with any combination of BuLi/Bu3B. How-
ever, entry 10 shows that the butyl group came from the
organoborane, and additional results below indicate that the
BuLi used to generate the carbenoid is not incorporated into
the product.
It is important to note that the direct alkylation of
phosphonate anions is often inefficient, so that secondary
phosphonates are not readily available.7 Similarly, the classic
Arbuzov reaction rarely works well to produce secondary
phosphonates.8
higher than 90% D. Encouraged by these two results, we
then undertook a full investigation of the synthetic approach
shown in Scheme 1.
While the synthesis of 4a is relatively straightforward, a
large body of literature is available on the preparation and
reactivity of diethyl (chloromethyl)phosphonate 4b.3 We thus
turned our attention to this phosphonate carbenoid precursor.
Functionalized phosphonates have importance in multiple
fields, particularly as intermediates in the synthesis of
biologically active compounds.4 Initially, Bu3B was selected
as a model reagent to investigate the reactivity of the
presumed intermediate. Deprotonation of 4b and reaction
with Bu3B at -90 °C gave excellent results upon simple
hydrolysis (Scheme 3).5 Diethyl pentylphosphonate 3b-H was
obtained in 96% isolated yield, and deuterated 3b-D was
obtained in 89% (>90% D).
Table 1. Reactions of Carbenoid Precursors with Bu3B, Then
H2Oa
In the next stage, we studied other carbenoid precursors
with Bu3B, and these results are shown in Table 1.
A variety of precursors6 reacted successfully with Bu3B
(Table 1). Yields are good to acceptable, and the lower yield
is observed only when a second migration is involved (entry
3). In this case, a second equivalent of BuLi must be added
prior to hydrolysis to promote the second migration. It should
(2) (a) Seyferth, D.; Marmor, R. S. Tetrahedron Lett. 1970, 2493. (b)
Brown, D. G.; Vethuisen, E. J.; Commerford, J. R.; Brisbois, R. G.; Hoye,
T. R. J. Org. Chem. 1996, 61, 2540.
(3) Waschbu¨sch, R.; Carran, J.; Marinetti, A.; Savignac, P. Chem. ReV.
1997, 97, 3401.
(4) (a) Quin, L. D. A Guide to Organophosphorus Chemistry; Wiley:
New York, 2000. (b) Savignac, P.; Iorga, B. Modern Phosphonate
Chemistry; CRC Press: Boca Raton, 2003.
(5) Typical Experimental Procedure. A flame-dried, 50 mL flask was
purged with nitrogen and charged with diethyl (chloromethyl)phosphonate
4b (4.0 mmol, 746 mg, 1.0 equiv) and dry THF (20 mL). The solution was
cooled below -90 °C (liquid nitrogen/ethanol bath), and n-butyllitium (1.6
M solution in hexane, 2.5 mL, 4.0 mmol, 1.0 equiv) was added slowly by
syringe followed by Bu3B (1.0 M solution in diethyl ether, 4.0 mL, 1.0
equiv) in one portion. The reaction mixture was warmed slowly to room
temperature and was quenched by addition of water. The resulting biphasic
mixture was stirred at reflux for 2 h. After being cooled to room temperature,
the layers were separated, the aqueous phase was extracted with EtOAc
(3×), the combined organic layers were dried with MgSO4, and solvents
were removed in vacuo. Purification of the crude product by flash
chromatography on silica gel (EtOAc/hexane 1:1, v/v) yielded diethyl
pentylphosphonate 3b-H (3.84 mmol, 800 mg, 96%). Additional details
can be found in the Supporting Information.
a Same conditions as in Scheme 3. Details can be found in the Supporting
Information. b An additional 1 equiv of BuLi was added prior to hydrolysis.
c s-BuLi was used in place of n-BuLi.
(6) Detailed procedures for the preparation of the reagents 4 can be found
in the Supporting Information.
978
Org. Lett., Vol. 10, No. 5, 2008

(“boranophosphonates”) 3.9 We were particularly interested
in these intermediates as precursors to H-phosphinate esters.
Conversion of these complexes to phosphinate derivatives
could be achieved easily (Scheme 5). Cleavage to ethyl
Scheme 4. Butyl Group Scrambling in Table 1, Entry 3
Scheme 5. Conversion of Phosphonite-Boranes into
Phosphinate Esters
Aside from phosphonate derivatives (entries 1-5), phos-
phinate (entry 6), phosphonothioate (entry 7), boranophos-
phonates (entries 8 and 9), and phosphine-borane complex
(entry 10) could also be prepared (Table 1). The latter
compounds have obvious potential in the synthesis of ligands
for transition-metal-catalyzed reactions. Our approach there-
fore seemed promising and potentially important as a general
route to produce various organophosphorus compounds.
The next question was to determine the reactivity of other
organoboron compounds, as well as the migratory selectivity
with nonsymmetrical organoboranes (Table 2). As shown
Table 2. Reactions with Other Organoboranesa
H-phosphinate esters 5-8 was readily accomplished with
tetrafluoroboric acid. Under these conditions, no further
hydrolysis of the ester group was observed. Interestingly,
decomplexation to the phosphonite derivative could be
conducted with amines, and subsequent treatment with allyl
bromide, in “one-pot”, led to an Arbuzov reaction with
formation of a disubstituted phosphinate 9. Although more
work must be done to develop and optimize this tandem
decomplexation-Arbuzov reaction, these results are promis-
ing for the preparation of complex phosphinic acid deriva-
tives.
Organoboranes have become routine and ubiquitous
reagents in organic synthesis. One important reason for this
success is the wide variety of functional groups that can be
obtained by transforming a carbon-boron bond.10
Thus, intermediates 2 could potentially be functionalized
beyond simple hydrolysis/deuterolysis using other electro-
a Products were isolated after hydrolysis by column chromatography (see
the Supporting Information for details).
(7) (a) Poindexter, M. K.; Katz, T. J. Tetrahedron Lett. 1988, 29, 1513.
(b) Coutrot, P.; Savignac, P.; Mathey, F. Synthesis 1978, 36. (c) Teulade,
M. P.; Savignac, P.; Abouajouade, E.; Collignon, N. J. Organomet. Chem.
1986, 312, 283. See also ref 4b.
(8) (a) Bhattacharya, A. K.; Thyagarajan, G. Chem. ReV. 1981, 81, 415.
(b) Engel, R.; Cohen, J. I. Synthesis of Carbon-Phosphorus Bonds, 2nd
ed.; CRC Press: Boca Raton, 2003.
in Table 2, a variety of organoboranes could be employed.
Selective transfer of benzyl and octyl groups was observed
(entries 3, 5, 8, and 9). However, the cyclooctyl group
migrated selectively in the case of Alpine borane (entry 4).
The successful reactions with phosphonite-borane 4i
provided a variety of novel phosphonite-borane complexes
(9) For a review on phosphine-borane complexes, see: Brunel, J. M.;
Faure, B.; Maffei, M. Coord. Chem. ReV. 1998, 178-180, 665.
Org. Lett., Vol. 10, No. 5, 2008
979

philes. The reactivity of 2 remains to be fully investigated
at this time, but here we report the successful iodination of
these intermediates to provide highly functional R-iodo
phosphonates (Scheme 6). It is interesting to note that one
nophosphonates and related compounds. Direct amination
of 2 is also a possibility that will be investigated as a route
to R-aminophosphonates.
In conclusion, we have demonstrated a novel synthesis of
organophosphorus compounds using organoboron reagents.
In some cases, selective transfer of one group attached to
the boron atom has been achieved. Reagent 4i was introduced
as a novel precursor of H-phosphinate derivatives. Further
elaboration of the reactive intermediates 2 using various
electrophiles will be reported in due course. Implementation
of an asymmetric version using chiral phosphorus and/or
chiral boron reagents will also be the focus of future
investigations.
Scheme 6. Synthesis of R-Iodophosphonates
Acknowledgment. We thank the Robert A. Welch
Foundation (Grant No. P-1666) and the National Institute
of General Medical Sciences/NIH (1R01 GM067610) for the
financial support of this research. We also thank the
reviewers for helpful suggestions.
C-B bond reacts selectively, as would be expected from a
boron enolate character in 2.11 These iodophosphonates might
also be precursors to valuable compounds12 such as R-ami-
Supporting Information Available: Representative ex-
perimental procedures, preparation of reagents 4, and spec-
troscopic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
(10) (a) Brown, H. C. Organic Syntheses Via Boranes; Wiley: New York,
1975; Vol. 1. (b) Brown, H. C.; Zaidlewicz, M. Organic Syntheses Via
Boranes: Recent DeVelopments; Wiley: New York, 2001; Vol. 2. (c)
Suzuki, A.; Brown, H. C. Organic Syntheses Via Boranes: Suzuki Coupling;
Wiley: New York, 2003; Vol. 3. (d) Negishi, E.; Idacavage, M. J. Org.
React. 1985, 33, 1. (e) Weill-Raynal, J. Synthesis 1976, 633.
(11) For references on the conversion of C-B into C-I, see: (a)
Montchamp, J.-L.; Migaud, M. E.; Frost, J. W. J. Org. Chem. 1993, 58,
7679. (b) Brown, H. C.; Rathke, M. W.; Rogic, M. M.; De Lue, N. R.
Tetrahedron 1988, 44, 2751. (c) Kabalka, G. W.; Gooch, E. E. J. Org.
Chem. 1980, 45, 3578.
OL800085U
(12) For references on the use of secondary R-iodophosphonates, see:
(a) Balczewski, P.; Szadowiak, A.; Bodzioch, A.; Bialas, T.; Wieczorek,
W. M.; Szyrej, M. J. Organomet. Chem. 2007, 692, 997. (b) Balczewski,
P.; Szadowiak, A.; Bialas, T. Heteroatom Chem. 2006, 17, 22. (c) Miryan,
N. I.; Isaev, S. D.; Kovaleva, S. A.; Petukh, N. V.; Dvornikova, E. V.;
Kardakova, E. V.; Yurchenko, A. G. Russ. J. Org. Chem. 1999, 35, 857.
(d) Russell, G. A.; Shi, B. Z.; Jiang, W.; Hu, S.; Kim, B. H.; Baik, W. J.
Am. Chem. Soc. 1995, 117, 3952.
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