Reactions of α-boranophosphorus compounds with electrophiles: Alkylation, acylation, and other reactions

Article abstract of DOI:10.1021/jo900300c

(Chemical Equation Presented) The homologation of phosphorus carbenoids with organoboranes leads to α-boranophosphorus compounds, which can be further functionalized through reactions with various electrophiles, either directly or after activation to the

Full text of DOI:10.1021/jo900300c

Reactions of r-Boranophosphorus Compounds with Electrophiles:
Alkylation, Acylation, and other Reactions
Monika I. Antczak and Jean-Luc Montchamp*
Department of Chemistry, Box 298860, Texas Christian UniVersity, Fort Worth, Texas 76129
j.montchamp@tcu.edu
ReceiVed February 11, 2009
The homologation of phosphorus carbenoids with organoboranes leads to R-boranophosphorus compounds,
which can be further functionalized through reactions with various electrophiles, either directly or after
activation to the corresponding borate. A variety of substituted organophosphorus compounds can be
obtained in one pot via reaction with many electrophiles. Complex structures are prepared in a single
step using simple building blocks.
SCHEME 1. Homologation of Phosphorus Carbenoids and
Electrophilic Trapping
Introduction
Organophosphorus compounds, especially phosphonates,
continue to be the object of significant scrutiny due to their
importance in various applications, both as final products and
as synthetic intermediates.1 Simple methods readily delivering
complex structures are particularly desirable and valuable.
Recently, we disclosed a general approach based on the
homologation of phosphorus carbenoids 1 with organoboranes
2 followed by electrophilic reactions with water (H2O or D2O),
iodine, or phosphorus electrophiles to form compounds 5 in one
pot (Scheme 1).2,3 While the hydrolysis or iodinolysis of
intermediates 3 occurred readily,2 in the case of phosphorus
electrophiles3 activation of 3 to the corresponding borate 4 was
necessary. Noteworthy was the fact that phosphorus carbenoids
derived from phosphonates, thiophosphonates, phosphinates,
boranophosphonites, and boranophosphines all reacted success-
fully to form intermediate 3.3 In addition, the selective transfer
of one group in the organoborane could be achieved in some
cases using 9-borabicyclononane (9-BBN) derivatives.2 Based
on these promising results, we have investigated the reactions
of the R-boranophosphorus intermediates 3 and the correspond-
ing borates 4 with a variety of other electrophiles, and we now
report the scope and limitations of the method for the synthesis
of a range of organophosphorus compounds.
SCHEME 2. The Carbon Analogy: Formation of Enol
Borinates from Carbonyl-Containing Carbenoids
Results and Discussion
Since a wide variety of R-boranophosphorus intermediates 3
could be prepared, the reactivity of these novel species could
be probed. It is well-known that the analogous homologation
of carbonyl-containing carbenoids 6 leads to R-boranocarbonyl
intermediates 7 which tautomerize to the enol borinates 8
(Scheme 2).4 These enol borinates are readily hydrolyzed or
can further undergo various reactions, particularly aldol-type
condensations. In the case of our phosphorus intermediates 3,
it was thus expected that reactivity would lie somewhere
between that of the enol borinates 8 and unactivated boranes 2.
Indeed, unlike with boranes 2, hydrolysis and iodinolysis of 3
readily take place.2
* Phone: (+1)-817-257-6201. Fax: (+1)-817-257-5851.
(1) (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.
(2) Antczak, M. I.; Montchamp, J.-L. Org. Lett. 2008, 10, 977.
(3) Antczak, M. I.; Montchamp, J.-L. Tetrahedron Lett. 2008, 49, 5909.
On the other hand, tautomerization of intermediate 3 into 9
(Scheme 3) might not occur readily even if silicon analogues
3758 J. Org. Chem. 2009, 74, 3758–3766
10.1021/jo900300c CCC: $40.75 2009 American Chemical Society
Published on Web 04/14/2009

Reactions of R-Boranophosphorus Compounds
SCHEME 3. r-Boranophosphorus Intermediates
1. As expected, the butyl group from BuLi is not incorporated
into the products. One group comes from the organoborane
(in our case Bu3B or n-heptyl3B) and the other from the alkyl
halide (MeI, BnBr, AllBr, OctI). Both phosphonate (entries
1 and 2) and boranephosphonite (entries 3 and 4) reacted
satisfactorily. Additionally, even a simple alkyl iodide reacted
smoothly to deliver the alkylated product (entry 4). Thus,
alkylation to functional organophosphorus compounds can
be achieved to deliver substituted organophosphorus species
in a single pot.
Although not directly related to the sequence shown in
Scheme 1, the direct nonhomologative alkylation of borane-
phosphonite complexes was briefly investigated (Table 2).
Alkylation of phosphonate anions is well-known but in general
not always efficient.1b,9 Since boranophosphonites can be
prepared through either homologation or alkylation of
(RO)2P(BH3)H as we previously reported,9 it was of interest to
examine their alkylation in order to compare with the present
one-pot methodology. Interestingly, the chloromethylphospho-
nite borane complex was deprotonated efficiently with n-BuLi
(entries 1 and 2), whereas octylphosphonite borane complex
required s-BuLi instead (entries 3 and 4). In both cases, excellent
yields of alkylated products were obtained. Entries 1 and 2 show
products which can be employed as precursors to the homolo-
gation reaction described above.
Since we have already demonstrated the transformations
of boranophosphonite complexes into either H-phosphinic
esters or disubstituted phosphinic acids,2,3,10 the formation
of boranophosphonites through homologative or direct alky-
lations represents a powerful methodology to prepare phos-
phinic acids.
Unfortunately, attempts at the palladium- or nickel-catalyzed
(Pd(PPh3)4, PdCl2(dppf), NiCl2(PPh3)2, NiCl2(dppf)) Suzuki-
type cross-coupling8c,11 of intermediates 3 or 4 with aryl halides
(PhI, PhBr) were unsuccessful under several conditions, even
though the coupling of organoborates with aryl halides is well-
precedented.11 While more work would be necessary before
dismissing this approach altogether, the hydrolysis of 3 or 4
was observed instead of the desired C-C bond formation.
Another failed reaction was the radical addition of the R-bo-
ranophosphorus intermediate under free radical conditions.12
Thus, one attempt at adding intermediate 3 to 1-octene under
air gave only the hydrolyzed diethyl pentylphosphonate. This
reaction was not investigated further.
of 9 have been postulated.5 Scheme 3 shows the possible
structures, including resonance forms, for species derived from
phosphonates or phosphine oxides. Resonance forms containing
P(+)-O(-) are better representations than the PdO form even
if the latter formalism is still most commonly employed.
Activation of 3 and 9 with butyllithium would result in the
organoborate intermediates, which could either react directly
with electrophiles or lose the organoborane moiety forming
reactive carbanions.6 All attempts at spectroscopic detection of
some of these species were unsuccessful, as was derivatization
with trialkylsilyl trifluoromethanesulfonates.7 No matter the
actual species involved, it is clear that borates 4 and 10 and/or
phosphorus anion 11 will be significantly more reactive than 3,
a fact previously illustrated with the successful reactions of 4
with phosphorus electrophiles.3 Our latter work indicated that
the reactivity of R-boranophosphorus compounds with electro-
philes needed to be investigated, both directly and after in situ
activation with BuLi. Since many transformations of organobo-
ranes8 and organoborates6 are well-precedented, useful func-
tionalizations from intermediates 3 and 4, respectively, were
expected and thus examined.
1. Carbon-Carbon Bond-Forming Reactions. Alkyla-
tion. Since carbon-carbon bond formation remains a major
goal in organic synthesis, the reactivity of intermediates 3
was investigated with alkyl halides. However, perhaps not
surprisingly, no alkylation took place directly. Fortunately,
in situ activation with BuLi was sufficient to deliver good
yields of alkylated products. The results are shown in Table
Acylation. Next the acylation of intermediates 3 with acyl
chlorides was investigated. The acylation of phosphonate anions
has been reported by Savignac, but transmetalation to an
organocopper species was necessary (eq 1).13 The acylation of
organoboron compounds has also been reported using palladium
catalysis.14
(4) Representative examples: (a) Brown, H. C.; Rogic, M. M.; Rathke, M. W.
J. Am. Chem. Soc. 1968, 90, 6218. (b) Brown, H. C.; Rogic, M. M.; Rathke,
M. W.; Kabalka, G. W. J. Am. Chem. Soc. 1968, 90, 1911. (c) See also
ref 14.
(5) De, B.; Corey, E. J. Tetrahedron Lett. 1990, 31, 4831.
(6) Negishi, E.; Idacavage, M. J. Org. React. 1985, 33, 1.
(7) 31P NMR analysis of the crude reaction mixture (at room temperature)
obtained from diethyl (chloromethyl)phosphonate and Bu3B showed a very broad
signal centered at 50 ppm (95%) and a sharp singlet at 55 ppm (5%). Hydrolysis
of the mixture at this stage gives a sharp singlet at 34 ppm (100%) corresponding
to diethyl pentylphosphonate. No attempt at variable-temperature NMR was made.
(8) (a) Brown, H. C. Organic Synthesis Via Boranes; Wiley: New York, 1975;
Vol. 1. (b) Brown, H. C., Zaidlewicz, M. Organic Synthesis Via Boranes: Recent
DeVelopments; Wiley: New York, 2001; Vol. 2. (c) Suzuki, A., Brown, H. C.
Organic Synthesis Via Boranes: Suzuki Coupling; Wiley: New York, 2003; Vol.
3.
(9) (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.
(10) Belabassi, Y.; Antczak, M. I.; Tellez, J.; Montchamp, J.-L. Tetrahedron
2008, 64, 9181.
J. Org. Chem. Vol. 74, No. 10, 2009 3759

Antczak and Montchamp
TABLE 1. One-Pot Phosphorus Carbenoid/Alkylation Sequence via In Situ Activation with BuLi
TABLE 2. Alkylation of Boranophosphonites
a n-BuLi was used. b s-BuLi was used.
In our case, as in the alkylation reaction, the formation of a
borate intermediate via in situ addition of n-BuLi was necessary
to achieve the desired acylation. Nonetheless, successful acy-
lation was achieved in a variety of cases summarized in Table
3. Acylation with pivaloyl chloride takes place in good to
excellent yields, using phosphonates, thiophosphonates, and
boranophosphonites. Additionally, the formation of a quaternary
carbon was observed in entry 2, while the selective migration
of a benzyl group is illustrated in entry 6.
The reaction with benzoyl chloride was more complicated
(Table 4) in part because of the competing formation of an
enol benzoate. However and as expected, a substrate for
which enolization is not possible, or the methanolysis of the
reaction mixture during workup, provided the ꢀ-ketophos-
phonate in good yield (Table 5, entry 1 and 2, respec-
tively).
Since ꢀ-ketophosphonates are well-known precursors to
the Wadsworth-Horner-Emmons olefination, one example
of a one-pot homologation/acylation/olefination process was
investigated (eq 2). The trisubstituted alkene was obtained
(11) (a) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633.
(b) Zou, G.; Falck, J. R. Tetrahedron Lett. 2001, 42, 5817. (c) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147. (d) Miyaura, N.; Suzuki, A. Chem. ReV.
1995, 95, 2457.
(12) Ollivier, C.; Renaud, P. Chem. ReV. 2001, 101, 3415.
(13) (a) Coutrot, P.; Savignac, P. Synthesis 1978, 36. (b) Mathey, F.; Savignac,
P. Tetrahedron 1978, 34, 649. (c) See also ref 1b, Chapter 7.
3760 J. Org. Chem. Vol. 74, No. 10, 2009

Reactions of R-Boranophosphorus Compounds
TABLE 3. Acylation of Organoborates 4 with Pivaloyl Chloride
TABLE 4. Acylation of Organoborates 4 with Benzoyl Chloride
a
31P NMR yield. b Isolated yield.
as a 10:1 E/Z isomeric ratio in this particular case. The
stereochemical assignment was conducted by 1D-NOE
experiments, which showed NOEs between the vinylic
hydrogen and the t-butyl group, as well as the allylic
methylene and the phenyl group. The reaction illustrates a
one-pot sequence of transformations leading to an unsaturated
ketone in good yield. Because the process involves multiple
components (organophosphorus carbenoid precursor, orga-
noborane, acid halide, and carbonyl compound), an applica-
tion to combinatorial synthesis can be readily envisioned.
J. Org. Chem. Vol. 74, No. 10, 2009 3761

Antczak and Montchamp
This might be surprising since enol borinates can be brominated
with N-bromosuccinimide,18 but since iodides are probably more
desirable, these reactions were not investigated further. Because
R-fluorophosphonates19 have been considered as potential
pharmacophores, we decided to investigate fluorination instead.
Unfortunately, in spite of the many reagents and conditions
investigated (Selectfluor, 1-fluoropyridinium triflate, N-benze-
nesulfonimide, 1-fluoropyridinium tetrafluoroborate, DAST, and
xenon difluoride) with or without prior formation of an
organoborate, none of the attempts yielded the desired product
in any significant amount, if at all. In general, R-monofluoro-
phosphonates are prepared in the literature from the correspond-
ing R-hydroxyphosphonate using DAST. Thus, because R-hy-
droxyphosphorus compounds appear to be very important
intermediates, the conversion of 3 and/or 4 was then investigated.
Hydroxylation (Table 6, Entry 6). The conversion of a
carbon-boron bond into the corresponding alcohol, the
cornerstone of the famous hydroboration-oxidation sequence,
is one of the most well-known and useful transformation of
organoboranes. Additionally, because R-hydroxyphosphonates
are proven intermediates for the preparation of many
compounds, this transformation appeared particularly im-
portant. Treatment of intermediate 3 using classic oxidation
conditions (H2O2/NaOH, or the milder H2O2/AcONa) only
gave the corresponding hydrolysis in high yield. This might
be surprising since the oxidation of an R-boranophosphonate
has been reported.20 In our hands, aqueous conditions appear
incompatible with the conversion of 3 into anything other
than the protonated or deuterated compounds (we have not
investigated tritiation, although this would be expected to
be a valuable route to radiolabeled phosphorus compounds),
nonaqueous oxidants were then examined. Treatment with
PCC resulted in the formation of the corresponding alcohol
in moderate yield (quantitative by 31P NMR analysis). In
standard organoborane oxidations with PCC, a ketone is
normally obtained from overoxidation of the intermediate
alcohol. It should be noted that simple R-hydroxyphospho-
nates are more easily and cheaply prepared from an aldehyde
(or ketone) and an H-phosphonate.
2. Other Reactions of r-Boranophosphorus Intermedi-
ates 3 or 4 with Electrophiles. Based on the successful
electrophilic trapping of intermediates 3 or 4, other reactions
were investigated (Table 6).
Aldol-like Condensations (Table 6, Entries 1-3). Based
on the enol borinate 8 precedent,15 C-C bond formation through
aldol-like condensation was examined next. In this case, direct
addition to benzaldehyde took place without prior activation as
the borate ion. However, no diastereoselectivity was observed
in the condensation process, unlike what has been observed with
enolborinates. The tetrahedral nature of the phosphorus atom
is no doubt the origin of this difference. On the other hand,
acetone was completely unreactive. Because ꢀ-hydroxyphos-
phonates have been converted into olefins using fluoride ion,16
these intermediates synthesized could also provide an approach
to phosphorus-free olefins. Similar to the aldol-like condensa-
tion, dimethyl(methylene)ammonium iodide salt reacted suc-
cessfully, and without addition of BuLi (entry 3).17 Thus,
ꢀ-aminophosphonates appear to be easily accessible.
Michael Addition (Table 6, Entry 4). Conjugate addition
was examined next. Unlike the aldol condensation, the R-bo-
ranophosphorus intermediate does not react with 2-cyclohex-
enone directly. Fortunately, conversion to the borate followed
by the addition of the unsaturated ketone in the presence of
TMSCl resulted in the desired conjugate addition.
Halogenation (Table 6, Entry 5). As previously reported,2
the iodination of intermediates 3 takes place readily, with
selective cleavage of the carbon-boron bond next to the
phosphorus atom. This reaction takes place directly through
addition of iodine, in the absence of an external base. R-Io-
dophosphorus are quite scarce in the literature, and typically,
sulfonates derived from the more readily available R-hydroxy
compounds are preferred to create a leaving group at this
position. Thus, the present method offers a rather unique
opportunity at preserving a reactive bond once homologation
has taken place. Since substitution of the iodide can be
conducted, various other substituted compounds can conceivably
be synthesized in two separate steps.
Amination. Although the direct amination of organobo-
ranes is well-known,4 attempts at converting 3 using these
reagents (organic azides, chloroamine, hydroxylamine-O-
sulfonic acid, or O-(mesitylsulfonyl)hydroxylamine) failed
to give the desired amino-substituted product. Similarly, prior
activation to the borate 4 followed by electrophilic amina-
tion21 reagents was not satisfactory. Much like the fluorination
mentioned above, a significant amount of effort was devoted
to this direct transformation since R-aminophosphonates (and
phosphinates) are valuable compounds, which often display
biological activities.22 Thus, we were unable to find a direct,
one-pot method to derivatize the C-B bond into a C-N
bond. Nonetheless, the transformation has some precedent
from other intermediates, such as the R-hydroxyphosphonates.
Chlorination and bromination were also tested briefly.
However, none of these attempts resulted in anything positive.
(14) Acylation of organoboron compounds using palladium catalysis: (a)
Urawa, Y.; Ogura, K. Tetrahedron Lett. 2003, 44, 271. (b) Bumagin, N. A.;
Korolev, D. N. Tetrahedron Lett. 1999, 40, 3057. (c) Haddach, M.; McCarthy,
J. R. Tetrahedron Lett. 1999, 40, 3109.
(15) Enol borinates and aldol: (a) Abiko, A. Acc. Chem. Res. 2004, 37, 387.
(b) Gennari, C. Pure Appl. Chem. 1997, 69, 507. (c) Mukaiyama, T. Org. React.
1982, 28, 203. (d) Brown, H. C.; Dhar, R. K.; Ganesan, K.; Singaram, B. J.
Org. Chem. 1992, 57, 499. (e) Brown, H. C.; Dhar, R. K.; Ganesan, K.; Singaram,
B. J. Org. Chem. 1992, 57, 2716. (f) Brown, H. C.; Ganesan, K.; Dhar, R. K.
J. Org. Chem. 1992, 57, 3767. (g) Brown, H. C.; Ganesan, K.; Dhar, R. K. J.
Org. Chem. 1993, 58, 147. (h) Ganesan, K.; Brown, H. C. J. Org. Chem. 1993,
58, 7162. (i) Mukaiyama, T.; Inomata, K.; Muraki, M. Am. Chem. Soc. 1973,
95, 967.
(16) Kawashima, T.; Ishii, T.; Inamoto, N.; Tokitoh, N.; Okazaki, R. Bull.
Chem. Soc. Jpn. 1998, 71, 209. Olefin geometry is controlled by a stereospecific
syn elimination.
(17) For the Mannich-type reaction of enol borinates, see: (a) Nolen, E. G.;
Aliocco, A.; Broody, M.; Zuppa, A. Tetrahedron Lett. 1991, 32, 73. (b) Nolen,
E. G.; Aliocco, A.; Vitarius, J.; McSorley, K. J. Chem. Soc. Chem. Commun.
1990, 1532.
(18) Hooz, J.; Morrison, G. F. J. Can. Chem. 1972, 50, 2387.
(19) (a) Romanenko, V. D.; Kukhar, V. P. Chem. ReV. 2006, 106, 3868. (b)
See also ref 1b, Chapter 3. For electrophilic fluorination, see: (c) Taylor, S. D.;
Kotoris, C. C.; Hum, G. Tetrahedron 1999, 55, 12431.
(20) Agnel, G.; Negishi, E.-i. J. Am. Chem. Soc. 1991, 113, 7424.
(21) Electrophilic amination reviews: (a) Erdik, E. Tetrahedron 2004, 60,
8747. (b) Erdik, E.; Ay, M. Chem. ReV. 1989, 89, 1947.
(22) (a) Kukhar, V. P.; Hudson, H. R. Aminophosphonic and Aminophos-
phinic Acids; John Wiley & Sons, Inc.: New York, 2000. (b) Ma, J.-A. Chem.
Soc. ReV. 2006, 35, 630. (c) Palacios, F.; Alonso, C.; de los Santos, J. M. Chem.
ReV. 2005, 105, 899. (d) Collinsova, M.; Jiracek, J. Curr. Med. Chem. 2000, 7,
629. (e) Fields, S. C. Tetrahedron 1999, 55, 12237.
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Reactions of R-Boranophosphorus Compounds
TABLE 5. Acylation of Organoborates 4 with Benzoyl Chloride
a The reaction mixture was treated with MeONa (4 equiv) before workup.
TABLE 6. Other Electrophilic Reactions
a n-BuLi (1 equiv) was added prior to the electrophile. b Diastereomeric ratio. c Unassigned.
Silylation (Table 6, Entry 7). As mentioned previously,
attempts at trapping any species akin to 9 or 10 through
silylation were not successful. On the other hand, the reaction
of 4 (activation to the borate was required) with N-
J. Org. Chem. Vol. 74, No. 10, 2009 3763

Antczak and Montchamp
SCHEME 4. Reactions Summary
trimethylsilylimidazole23 resulted in the clean formation of
the corresponding organosilicon compound. R-(Trimethylsi-
lyl)phosphonates are well-known reagents for the Peterson
olefination.
methodology provides a most powerful entry into substituted
organophosphorus compounds in a single step. Other useful
transformations such as acylation or chalcogen formation were
demonstrated, even if some other attempted reactions (cross-
coupling, radical addition, fluorination) have failed. While many
combinations of phosphorus reagent, organoborane, and elec-
trophile have yet to be investigated, the present work represents
a useful guideline for possible synthetic applications. Because
of the sheer number of combinations which can be envisioned,
further developments might be possible. Nonetheless, the
homologation/electrophilic trapping sequence described herein
represents a general and flexible one-pot approach toward many
substituted organophosphorus reagents and often offers a useful
alternative to literature synthetic methodologies. At this time,
our laboratory is focusing on the use of chiral auxiliaries.
Sulfur and Selenium (Table 6, Entries 8 and 9). Finally,
the direct conversion of 3 and 4 into sulfur- and selenium-
containing compounds was examined. The preparation of sulfur-
and selenium-substituted phosphonates is well-known in the
literature.24 Typically, these require the formation of a simple
thiomethyl- or selenenylmethylphosphonate (often through
Arbuzov reaction of the halomethylchalcogenide) followed by
deprotonation and alkylation. Diethyl chloromethylphosphonate
was homologated in the usual manner with Bu3B. The resulting
intermediate 3 directly reacted successfully with commercially
available p-nitrophenylsulfenyl chloride to form the correspond-
ing thioether in 65% yield. The use of PhSSPh did not lead to
any C-S bond formation.
A similar reaction with phenylselenenyl chloride resulted in
complete conversion (by 31P NMR monitoring) into the corre-
sponding selenide with an 82% isolated yield. Since selenides
are easily eliminated via oxidation to the corresponding olefins,
a one-pot process was developed for homologation/seleneny-
lation/oxidation into the corresponding unsaturated phosphonate
in outstanding overall yield for this single-pot, four-step process
(eq 3).
Experimental Section
Preparation of the Starting Materials. The starting materials
used in this study were prepared using our previously described
methodologies.2,3 Details are provided in the Supporting Informa-
tion.
General Procedure for the Transformation P-C-B
Complex into P-C-C via Alkylation (Table 1). A flame-dried,
50 mL, three-necked, round-bottomed flask was purged with
nitrogen, charged with diethyl (chloromethyl)phosphonate, or
diethoxy(chloromethyl)phosphine borane (2.50 mmol, 1.0 equiv)
and dry THF (10 mL). The solution was cooled below - 90 °C
(liquid nitrogen/ethanol bath), and n-butyllithium (2.50 mmol, 2.5
M solution in hexane, 1.0 mL, 1.0 equiv) was added slowly by
syringe followed by organoboranes (2.50 mmol, 1.0 equiv) in one
portion. The reaction mixture was warmed slowly to rt and then
was cooled to -78 °C (dry ice/acetone bath), and n-butyllithium
(2.50 mmol, 2.5 M solution in hexane, 1.0 mL, 1.0 equiv) was
added slowly followed by electrophile (3.75 mmol, 1.5 equiv). The
resulting mixture was heated at reflux for 2 h under nitrogen. After
the mixture was cooled to rt, THF was removed in vacuo, the
residue was diluted with EtOAc (20 mL) and washed with water
(30 mL). The aqueous phase was then extracted with EtOAc (2 ×
30 mL), the combined organic fractions were dried with MgSO4,
and the solvent was removed in vacuo. The purification of the crude
product by flash chromatography on silica gel yielded the described
compound.
Conclusion
In conclusion, the reactivity toward a wide range of electro-
philes of R-boranophosphorus intermediates formed during the
homologation of phosphorus-substituted carbenoids with orga-
noboranes was investigated (Scheme 4). The direct alkylation
(23) Other reagents (TMSCl, TIPSCl, TBSOTf, TIPSOTf) did not give
satisfactory results. For the silylation of enol borinates to silyl enol ethers with
N-trimethylsilylimidazole, see: Hooz, J.; Oudenes, J. Tetrahedron Lett. 1983,
24, 5695. For the preparation of R-trimethylsilyl phosphonate, see ref 1b, Chapter
2.
(24) (a) Midura, W. H.; Krysiak, J. A. Tetrahedron 2004, 60, 12217. (b)
Murai, T.; Izumi, C.; Itoh, T.; Shinzi Kato, S. J. Chem. Soc., Perkin Trans. 1
2000, 917. (c) See also ref 1b.
Diethyl 1-methylpentylphosphonate (Table 1, entry 1):25 Yield
74%; 1H NMR (CDCl3, 300 MHz) δ 4.04 - 4.16 (m, 4 H),
3764 J. Org. Chem. Vol. 74, No. 10, 2009

Reactions of R-Boranophosphorus Compounds
1.36-1.79 (m, 7 H) 1.30 (t, J ) 7 Hz, 6 H), 1.17 (dd, JHH ) 7 Hz,
JHP ) 18 Hz, 3 H), 0.90 (t, J ) 7 Hz, 3 H); 13C NMR (CDCl3,
75.45 MHz) δ 61.6 (t, JPOC ) 6 Hz), 30.9 (d, JPC ) 140 Hz), 29.8,
in one portion. The reaction mixture was warmed slowly to rt, and
benzaldehyde (292 mg, 2.75 mmol, 280 µL, 1.1 equiv) was added.
The resulting mixture was heated at reflux for 2 h under nitrogen.
After the mixture was cooled to rt, THF was removed in vacuo,
the residue was diluted with EtOAc (20 mL) and washed with water
(20 mL). The aqueous phase was then extracted with EtOAc (2 ×
30 mL), the combined organic fractions were dried with MgSO4,
and the solvent was removed in vacuo. The purification of the crude
product by flash chromatography on silica gel yielded the described
compounds.
29.6, 22.7, 16.7 (d, JPOCC ) 6 Hz), 14.2, 13.3 (d, JPCC ) 5 Hz); 31
NMR (CDCl3, 121.47 MHz) δ 36.7.
P
General Procedure for the Alkylation of Boranophospho-
nites (Table 2). A flame-dried, 50 mL, three-necked, round-
bottomed flask was purged with nitrogen, charged with diethoxy-
(chloromethyl)phosphine-borane (4.0 mmol, 736 mg, 1.0 equiv) and
dry THF (20 mL). The solution was cooled to - 78 °C, and
n-butyllithium (3.0 mL, 1.6 M solution in hexane, 4.8 mmol, 1.2
equiv) was added slowly via syringe. The reaction mixture was
stirred at - 78 °C for 5 min, and then electrophile (4.8 mmol, 1.2
equiv) was added. The reaction was warmed slowly to rt and was
quenched by addition of H2O (15 mL). The layers were separated,
and the aqueous phase was extracted with EtOAc (3 × 30 mL).
The combined organic layers were dried with MgSO4, and the
solvent was removed in vacuo. The purification of the crude product
by chromatography on silica gel (EtOAc/hexanes 1:99, v/v) yielded
the described compounds.
Diethyl (1-hydroxyphenylmethylpentyl)phosphonate (Table
4, entry 1): Yield 70%; 1H NMR (CDCl3, 300 MHz) δ 7.23-7.40
(m, 5 H), 4.76-5.87 (m, 1 H), 3.82-4.22 (m, 4 H), 2.07-2.19
(m, 1 H), 1.14-1.52 (m, 6 H), 1.36 (t, J ) 7 Hz, 3 H), 1.23 (t, J
) 7 Hz, 3 H), 0.75 (t, J ) 7 Hz, 3 H); 13C NMR (CDCl3, 75.45
MHz) δ 142.3 (d, J ) 13 Hz), 128.5, 128.3, 127.9, 127.0, 126.1,
73.7 (d, JPCC ) 4 Hz), 71.4 (d, JPCC ) 4 Hz), 62.2 (d, JPOC ) 7
Hz), 72.1 (d, JPOC ) 7 Hz), 44.6 (d, JPC ) 134 Hz), 44.3 (d, JPC
)
134 Hz), 31.0 (d, JPCCC ) 6 Hz), 30.1 (d, JPCCC ) 6 Hz), 26.4 (d,
JPCC ) 4 Hz), 22.6, 16.7 (d, JPOCC ) 6 Hz), 16.5 (d, JPOCC ) 6
Hz), 13.9; 31P NMR (CDCl3, 121.47 MHz) δ 34.32 and 34.29;
HRMS calcd for C16H27O4P 314.1647, found 314.1639.
Diethoxy(1-chloroethyl)phosphine borane (Table 2, entry
2
1
1): Yield 96%; H NMR (CDCl3, 300 MHz) δ 4.10-4.24 (m, 4
H), 3.93 (q, J ) 7 Hz, 1 H), 1.66 (d, J ) 7 Hz, 3 H), 1.35 (t, J )
7 Hz, 6 H), 0.50 (qd, JBH ) 94 Hz, JPBH ) 16 Hz, 3 H); 13C NMR
Diethyl 1-Phenylselenylpentylphosphonate (Table 6, Entry
9).26 A flame-dried, 100 mL, three-necked, round-bottomed flask
was purged with nitrogen and charged with diethyl (chlorometh-
yl)phosphonate (465 mg, 2.5 mmol, 1.0 equiv) and dry THF (10
mL). The solution was cooled below -90 °C (liquid nitrogen/
ethanol bath), and n-butyllithium (2.5 mmol, 2.5 M solution in
hexane, 1.0 mL, 1.0 equiv) was added slowly by syringe followed
by Bu3B (2.5 mmol, 2.5 mL, 1.0 M solution in Et2O, 1.0 equiv) in
one portion. The reaction mixture was warmed slowly to rt and
then was cooled to -78 °C (dry ice/acetone bath), and a red-brown
solution of phenylselenyl chloride (2.87 mmol, 505 mg, 1.15 equiv)
in 5 mL of dry THF was added slowly. The addition of each drop
was accompanied by the instantaneous discharge of color. After
addition was complete, the resulting yellow reaction mixture was
allowed to warm to rt and then was heated at reflux for 2 h under
nitrogen. After the mixture was cooled to rt, solvent was removed
in vacuo, and the residue was diluted with EtOAc (20 mL) and
washed with water (30 mL). The aqueous phase was then extracted
with EtOAc (2 × 30 mL), the combined organic fractions were
dried with MgSO4, and the solvent was removed in vacuo. The
purification of the crude product by flash chromatography on silica
gel (EtOAc/hexanes 4:6, v/v) gave diethyl 1-phenylselenylpen-
tylphosphonate (746 mg, 2.05 mmol, 82%): 1H NMR (CDCl3, 300
MHz) δ 7.64-7.57 (m, 2 H), 7.26-7.29 (m, 3 H), 4.08-4.23 (m,
4 H), 3.00 (tt, J ) 10 Hz, J ) 4 Hz, 1 H), 1.45-2.05 (m, 6 H),
1.31 (t, J ) 7 Hz, 3 H), 1.30 (t, J ) 7 Hz, 3 H), 0.87 (t, J ) 7 Hz,
3 H); 13C NMR (CDCl3, 75.45 MHz) δ 134.6, 129.6 (d, J ) 3 Hz),
63.2 (d, JPOC ) 7 Hz), 62.7 (d, JPOC ) 7 Hz), 39.0 (d, JPC ) 149
Hz), 30.1 (d, JPCCC ) 11 Hz), 30.0, 22.3, 16.6 (d, JPOCC ) 6 Hz),
16.5 (d, JPOCC ) 6 Hz), 14.0; 31P NMR (CDCl3, 121.47 MHz) δ
28.1; HRMS calcd for C15H25O4PSe 364.0707, found 364.0704.
Diethyl (Z)-1-Pentenylphosphonate (eq 3).27 A flame-dried,
100 mL, three-necked, round-bottomed flask was purged with
nitrogen and charged with diethyl (chloromethyl)phosphonate (933
mg, 5.0 mmol, 1.0 equiv) and dry THF (20 mL). The solution was
cooled below -90 °C (liquid nitrogen/ethanol bath), and n-
butyllithium (5.0 mmol, 2.5 M solution in hexane, 2.0 mL, 1.0
equiv) was added slowly by syringe followed by Bu3B (5.0 mmol,
5.0 mL, 1.0 M solution in Et2O, 1.0 equiv) in one portion. The
reaction mixture was warmed slowly to rt and then was cooled to
(CDCl3, 75.45 MHz) δ 64.6, 37.5 (d, JPC ) 58 Hz), 18.3, 16.5; 31
P
NMR (CDCl3, 121.47 MHz) δ 141.4 (q, JPB ) 75 Hz); 11B NMR
(CDCl3, 28.88 MHz) δ -44.4 (dq, JBP ) 75 Hz, JBH ) 94 Hz);
HRMS calcd for C6H21BClNO2P ([M + NH4]+) 216.1092, found
216.1089.
General Procedure for the Transformation of P-C-B
Complex into P-C-C via Acylation (Tables 3-5). A flame-
dried, 50 mL, three-necked, round-bottomed flask was purged with
nitrogen and charged with diethyl (chloromethyl)phosphonate,
diethyl (1-chloroethyl)phosphonate, diethyl (chloromethyl)phos-
phonothioate, or diethoxy(chloromethyl)phosphine borane (2.50
mmol, 1.0 equiv) and dry THF (10 mL). The solution was cooled
below - 90 °C (liquid nitrogen/ethanol bath), and n-butyllithium
(2.50 mmol, 2.5 M solution in hexane, 1.0 mL, 1.0 equiv) was
added slowly by syringe followed by organoboranes (2.50 mmol,
1.0 equiv) in one portion. The reaction mixture was warmed slowly
to rt and then was cooled to -78 °C (dry ice/acetone bath), and
n-butyllithium (2.50 mmol, 2.5 M solution in hexane, 1.0 mL, 1.0
equiv) was added slowly followed by pivaloyl chloride (see Table
3 for number of equivaletns). The resulting mixture was heated at
reflux for 2 h under nitrogen. After the mixture was cooled to rt,
THF was removed in vacuo, and the residue was diluted with
EtOAc (20 mL) and washed with water (20 mL). The aqueous phase
was then extracted with EtOAc (2 × 30 mL), the combined organic
fractions were dried with MgSO4, and the solvent was removed in
vacuo. The purification of the crude product by flash chromatog-
raphy on silica gel yielded the described compound.
Diethyl 1-(2,2-dimethylpropionyl)pentylphosphonate (Table
1
3, entry 1): Yield 92%; H NMR (CDCl3, 300 MHz) δ 4.05 -
4.21 (m, 4 H), 3.64 (dm, JPH ) 21 Hz, 1 H), 1.78 - 2.00 (m, 2 H),
1.24 - 1.36 (m, 4 H), 1.33 (t, J ) 7 Hz, 6 H), 1.20 (s, 9 H), 0.89
(t, J ) 7 Hz, 3 H); 13C NMR (CDCl3, 75.45 MHz) δ 212.5 (d, J )
6 Hz), 62.7 (t, JPOC ) 7 Hz), 46.5 (d, JPC ) 130 Hz), 45.5, 31.1 (d,
JPCCC ) 13 Hz), 29.2 (d, JPCC ) 6 Hz), 26.8, 22.8, 16.6 (d, JPOCC
) 6 Hz), 14.0; 31P NMR (CDCl3, 121.47 MHz) δ 24.9; HRMS
calcd for C14H29O4P 292.1803, found 292.1802.
General Procedure for the Transformation of P-C-B
Complex into P-C-C via Aldol Reaction. A flame-dried, 50 mL,
three-necked, round-bottomed flask was purged with nitrogen and
charged with diethyl (chloromethyl)phosphonate, or diethoxy(chlo-
romethyl)phosphine borane (2.50 mmol, 1.0 equiv) and dry THF
(10 mL). The solution was cooled below -90 °C (liquid nitrogen/
ethanol bath), and n-butyllithium (2.50 mmol, 2.5 M solution in
hexane, 1.0 mL, 1.0 equiv) was added slowly by syringe followed
by Bu3B (2.50 mmol, 1.0 M solution in Et2O, 2.5 mL, 1.0 equiv)
(25) (a) Villieras, J.; Reliquet, A.; Normant, J. F. J. Organomet. Chem. 1978,
144, 17. (b) Teulade, M. P.; Savignac, P.; Aboujaoude, E. E.; Collignon, N. J.
Organomet. Chem. 1986, 312, 283.
(26) Commaseto, J. V.; Pertagami, N. J. Organomet. Chem. 1978, 152, 295.
(27) (a) Cristau, H.-J.; Yangkou-Mbianda, X.; Beziat, Y.; Gasc, M.-B. J.
Organomet. Chem. 1996, 529, 301. (b) Koizumi, T.; Tanaka, N.; Iweta, M.;
Yosihii, E. Synthesis 1982, 917.
J. Org. Chem. Vol. 74, No. 10, 2009 3765

Antczak and Montchamp
-78 °C (dry ice/acetone bath), and a red-brown solution of
phenylselenyl chloride (5.75 mmol, 1.10 g, 1.15 equiv) in 5 mL of
dry THF was added slowly. The addition of each drop was
accompanied by the instantaneous discharge of color. After addition
was complete, the resulting yellow reaction mixture was allowed
to warm to rt and then was heated at reflux for 2 h under nitrogen.
31P NMR analysis indicated the formation of R-selenophosphonate,
which was converted into diethyl (Z)-1-pentenylphosphonate by the
addition of pyridine (2.37 mg, 30 mmol, 2.40 mL, 6.0 equiv) at
-78 °C (dry ice/acetone bath) followed by 30% H2O2 (30 mmol,
6.0 equiv) and H2O (1:1 by volume) at 0 °C. After warming to rt,
the organic layer was separated and aqueous layer was extracted
with EtOAc (3 × 30 mL). The combined organic fractions were
dried with MgSO4, and the solvent was removed in vacuo. The
purification of the crude product by flash chromatography on silica
gel (EtOAc/Hexanes 1:1, v/v) gave the diethyl (Z)-1-pentenylphos-
phonate (906 mg, 4.40 mmol, 88%): 1H NMR (CDCl3, 300 MHz)
δ 6.80 (ddt, J ) 53 Hz, J ) 13 Hz, J ) 7 Hz, 1 H), 5.52 (tt, J )
19 Hz, J ) 13 Hz, J ) 2 Hz, 1 H), 4.03-4.17 (m, 4 H), 2.18-2.26
(m, 2 H), 1.45 (q, J ) 7 Hz, 2 H), 1.34 (t, J ) 7 Hz, 6 H), 0.95 (t,
J ) 7 Hz, 3 H); 31P NMR (CDCl3, 121.47 MHz) δ 20.0.
Acknowledgment. We thank the Robert A. Welch Founda-
tion (Grant No. P-1666) for financial support of this research.
We also thank Professor David E. Minter for obtaining the NOE
data (eq 2).
Supporting Information Available: Spectral data and ad-
ditional experimental procedures. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO900300C
3766 J. Org. Chem. Vol. 74, No. 10, 2009