Tripyrrolidinophosphoric acid triamide as an activator in samarium diiodide reductions

Article abstract of DOI:10.1021/ol102040s

The electrochemical and spectrophotometric characterization of the complex formed from samarium diiodide and 4 equiv of tripyrrolidinophosphoric acid triamide (TPPA) is presented. Kinetic studies indicate that the SmI ₂/TPPA complex possesses reactivity greater than the complex formed between samarium diiodide and 4 equiv of HMPA. Examples of the use of SmI ₂/TPPA in synthesis are presented.

Full text of DOI:10.1021/ol102040s

ORGANIC
LETTERS
2
010
Vol. 12, No. 22
178-5181
Tripyrrolidinophosphoric Acid Triamide
as an Activator in Samarium Diiodide
Reductions
5
Chriss E. McDonald,* Jeremy D. Ramsey, David G. Sampsell, Julie A. Butler, and
Michael R. Cecchini
Department of Chemistry, Lycoming College, Williamsport,
PennsylVania 17701, United States
mcdonald@lycoming.edu
Received September 15, 2010
ABSTRACT
The electrochemical and spectrophotometric characterization of the complex formed from samarium diiodide and 4 equiv of tripyrrolidino-
phosphoric acid triamide (TPPA) is presented. Kinetic studies indicate that the SmI /TPPA complex possesses reactivity greater than the
complex formed between samarium diiodide and 4 equiv of HMPA. Examples of the use of SmI /TPPA in synthesis are presented.
2
2
7,8
Samarium diiodide is a useful reagent for a broad range
of organic reductions. Inanaga reported that the addition
HMPA inhalation (50 ppb for one year). Various additives
have therefore been used in place of HMPA in SmI
1
2
of the electron-rich cosolvent HMPA greatly accelerates
reactions. N,N′-Dimethylpropyleneurea (DMPU) is the most
2
9
the reduction of alkyl halides by SmI
HMPA to a deep blue THF solution of SmI
2
.
Addition of
results in
commonly used alternative cosolvent for samarium diiodide.
Other electron-rich compounds such as 1,1,3,3-tetrameth-
ylguanidine (TMG), 1,8-diazabicyclo[5.4.0]undec-7-ene
2
the formation of a purple soluble complex. X-ray analysis
reveals the structure of the complex to possess four HMPA
1
0
11
(DBU), and hexamethyldisilazide have been used with
some success. We recently reported on the effectiveness of
the dehydro dimer of HMPA (diHMPA) as an alternative to
2
+
molecules bound to a central Sm and two exceptionally
3
long Sm-I bonds. Conductivity measurements suggest
1
2
that in solution the two iodides are displaced to the outer
HMPA. None of these substitutes appears to lead to
sphere by solvent, resulting in an ionic complex thought
2
+
-
4,5
to be [Sm(HMPA)
tails numerous SmI
4
(THF)
2
] 2I . Current literature de-
(5) For a review of mechanistic work done on various SmI reductions,
2
6
see: Flowers, R. A., II Synlett 2008, 1427–1439
.
2
reductions promoted by HMPA.
(
6) For current examples of the use of SmI /HMPA in the development
2
Unfortunately, HMPA has deleterious biological effects.
It is reported to be both antispermatogenic (oral administra-
tion) and mutagenic, with rats developing nasal tumors from
of new synthetic methods, see: (a) Sch o¨ ttner, E.; Wiechoczek, M.; Jones,
P.; Lindel, T. Org. Lett. 2010, 12, 784–787. (b) Beemelmanns, C.; Reissig,
H.-U. Org. Biomol. Chem. 2009, 7, 4475–4480. (c) Lam, K.; Mark o´ , I.
Org. Lett. 2008, 10, 2773–2776
.
(
7) Jackson, H.; Jones, A.; Cooper, E. J. Reprod. Fert. 1969, 20, 263–
2 .
69
(8) Kimbrough, R.; Gaines, T. Bull. EnViron. Contam. Toxicol. 1973,
10, 225–226
(
1) Procter, D. J.; Flowers, R. A., II; Skrydstrup, T. Organic Synthesis
Using Samarium Diiodide: A Practical Guide; Royal Society of Chemistry
.
Publishing: UK, 2010.
(9) Hasegawa, E.; Curran, D. P. J. Org. Chem. 1993, 58, 5008–5010.
(10) Cabri, W.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi, A.
Tetrahedron Lett. 1995, 36, 949–952.
(
2) Inanaga, J.; Ishikawa, M.; Yamaguchi, M. Chem. Lett. 1987, 1485–
1
486.
(
3) Hou, Z.; Wakatsuki, Y. J. Chem. Soc., Chem. Commun. 1994, 149–
(11) Prasad, E.; Knettle, B.; Flowers, R. A. II. J. Am. Chem. Soc. 2002,
124, 14663–14667.
1
53.
(
4) Enemærke, R.; Hertz, T.; Skrydstrup, T.; Daasbjberg, K. Chem.sEur.
(12) McDonald, C.; Ramsey, J.; Grant, J.; Howerter, K. Tetrahedron
Lett. 2009, 50, 5308–5310.
J. 2000, 3747–3754
.
10.1021/ol102040s  2010 American Chemical Society
Published on Web 10/27/2010

complexes that can match the reactivity of the SmI
combination.
2
/HMPA
using the HEPA complex. The rapidity and yield of the SmI
2
/
1
3,14
TPPA reduction is functionally equivalent to the results
2
,23
obtained by Inanaga with SmI
The reactivities of the SmI
2
/HMPA.
complexes with HMPA,
It is interesting to note that the ethyl analogue of HMPA,
hexaethylphosphoric acid triamide (HEPA, Figure 1), is not
2
HEPA, and TPPA were determined by measuring the rate
constant during the reduction of 1-bromodecane. In each
case, 1-bromodecane was added to a stirred 0.010 M solution
of SmI
2
containing the indicated amounts of each ligand,
-butanol and tetradecane. Sufficient quantities of SmI and
-butanol were included to ensure pseudofirst-order condi-
1
1
2
tions. Aliquots were removed and immediately quenched
with I . Gas chromatographic analyses of the resultant
2
2
4
mixtures were performed. Linear plots of reaction time vs
ln[1-bromodecane] were obtained in the HMPA and TPPA
cases allowing for the calculation of rate constants. The
HEPA kinetic analysis revealed no diminution of the
1-bromodecane nor measurable formation of decane, so a
Figure 1
.
2
Phosphoramides investigated in SmI reductions.
7
antispermatogenic. HEPA is 300 times less mutagenic than
1
5
HMPA in Drosophila melanogaster. Although it has not
been studied in detail, there is no evidence for toxicity or
mutagenicity for the tricyclic analogue of HEPA, tripyrro-
lidinophosphoric acid triamide (TPPA). We therefore inves-
tigated the synthetic utility of complexes formed between
SmI and the two phosphoramides HEPA and TPPA.
2
TPPA is particularly intriguing as a ligand because it is
known to be an excellent Lewis base. This ligand has a
2
rate constant could not be determined (Table 1). The SmI /
Table 1. Pseuofirst-Order Kinetic Study on the Effect of Ligand
on the Reduction of 1-Bromodecane at 21 °C
1
6,17
entry
ligand
k
obs (s-1)a
-
4
-4
-3
1
2
3
HMPA
TPPA
HEPA
7.0 × 10 ( 0.3 × 10
-3
2.0 × 10 ( 0.3 × 10
substantially higher exothermic heat of reaction with BF
than all of the other phosphoramides examined, including
3
-
a
1
8
[1-bromodecane] ) 0.0015 M, [SmI
M, [1-butanol] ) 0.020 M.
2
] ) 0.010 M, [ligand] ) 0.040
HMPA. TPPA also has a higher dipole moment than all
1
9
of the phosphoramides examined, including HMPA.
Both HEPA and TPPA are readily accessible. The
synthesis of TPPA can be accomplished in high yield by
TPPA complex is approximately three times more reactive
than the corresponding SmI /HMPA complex. This is
2
0
treating POCl
3
with excess pyrrolidine in ether. HEPA is
2
prepared by the oxidation of tris(diethylamino)phosphine
noteworthy because there is no previously reported evidence
2
1
with H
Initial experiments to probe the reactivity of the SmI
HEPA and SmI /TPPA complexes were executed as follows.
Purple soluble complexes were formed from SmI and 4
equiv of each ligand. Ten minutes after the addition of
2 2
O .
of an organic ligand which activates SmI toward the
2
reduction of alkyl halides to a greater extent than HMPA.
2
/
2
The low reactivity of the SmI /HEPA complex indicates that
2
HEPA does not activate SmI
value.
2
sufficiently to be of synthetic
2
To assist in the characterization of the reactivity of the
1
-bromodecane and tetradecane (internal standard), an aliquot
2
2
SmI /phosphoramide complexes, cyclic voltammetry was
2
was removed and quenched with I
2
.
Gas chromatographic
/TPPA
95%) were obtained. At 30 min of reaction time, the same
process indicated a chromatographic yield of 98% decane
utilized. Previously, addition of up to 3 equiv of HMPA to
2 2
yields of decane for SmI /HEPA (41%) and for SmI
4,25
2
SmI caused a negative shift in standard potential. A much
(
larger decrease was observed for 4 equiv of HMPA (0.72
V), which greatly increases its ability to perform reductions.
Because large excesses of HMPA (10 equiv) did not result
in further decreases in standard potential, it was concluded
(
(
(
13) Dahl e´ n, A.; Hilmersson, G. Eur. J. Inorg. Chem. 2004, 3393–3403
14) Kagan, H.; Namy, J. Top. Organomet. Chem. 1999, 2, 155–197
15) Zijlstra, J.; Brussee, J.; van der Gen, A.; Vogel, E. Mutat. Res.
.
.
that the species present under these conditions, [Sm(H-
1
989, 212, 193–211.
2+ 3,4
6
MPA) ] , exhibits reactivity toward organic functional
(
16) A recent report on the use of TPPA to improve a SmI -mediated
2
2
+
5
4 2
groups similar to [Sm(HMPA) (THF) ] . Recently, we
reductive cyanation has appeared: Ankner, T.; Friden-Saxin, M.; Pemberton,
N.; Seifert, T.; Grøtli, M.; Luthman, K.; Hilmersson, G. Org. Lett. 2010,
observed that 2 equiv of diHMPA produced a decrease in
1
2, 2210–2213
(
.
12
standard potential of 0.68 V.
17) Molander has previously reported the use of the related phosphora-
mide, tripiperidinophosphoric acid triamide: Molander, G. A.; McKie, J. A.
J. Org. Chem. 1993, 58, 7216–7227
Table 2 shows the standard potential of a series of SmI
2
/
.
HEPA complexes with varying equivalents of cosolvent. As
(
(
18) Maria, P.; Gal., J. J. Phys. Chem. 1985, 89, 1296–1304.
19) Ozari, Y.; Jagur-Grodzinski, J. J. Chem. Soc., Chem. Commun.
1
974, 295–296.
(23) In the absence of phosphoramide ligands, SmI
decane to decane in 4% yield after 10 min.
2
reduces 1-bromo-
(
20) Wilson, S.; Misra, R.; Georgiadis, G. J. Org. Chem. 1980, 45, 2460–
2
468.
(24) Fuh, M.; Lin, T.; Chang, S. Talanta 1998, 46, 861–866.
(
(
21) Stuebe, C.; Lankelma, H. J. Am. Chem. Soc. 1956, 78, 976–977.
22) Dahl e´ n, A.; Hilmersson, G. Chem.sEur. J. 2003, 9, 1123–1128.
(25) Shabangi, M.; Flowers, R. A.II. Tetrahedron Lett. 1997, 38, 1137–
1140
.
Org. Lett., Vol. 12, No. 22, 2010
5179

4,25,26
previously observed for SmI
SmI is saturated with four TPPA molecules.
The SmI /TPPA complex was also characterized by
visible spectroscopy. A 5 mM solution of SmI in THF
2
/HMPA.
This suggests that
2
a
Table 2. Effect of HEPA on the Standard Potential of SmI
2
2
[
ligand] to
standard potential ∆E relative
2
entry
2
[SmI ] ratio
(V vs Ag/AgNO
3
)
to SmI
2
(V)
with 4 equiv of TPPA affords a peak at 540 nm, which is
SmI
2
2
2
2
2
2
2
:HEPA
0
1
2
3
4
10
4
-1.329 ( 0.005
-1.39 ( 0.02
-1.46 ( 0.05
-1.68 ( 0.02
-1.53 ( 0.04
-1.65 ( 0.08
-2.07 ( 0.01
0.00
0.06
0.13
0.35
0.20
0.32
0.74
identical to the λmax that was previously observed for
SmI
SmI
SmI
SmI
SmI
SmI
a
:HEPA
:HEPA
:HEPA
:HEPA
:HEPA
:HMPA
2+
-
4
[
Sm(HMPA)
similar over the range of the analysis (300 to 800 nm).
Because SmI is also very useful in various reductions of
carbonyl compounds, kinetic analyses of SmI /HMPA and
SmI /TPPA reactions with 2-octanone were undertaken
Table 4). These experiments were executed in essentially
4 2
(THF) ] 2I . The spectra are qualitatively
2
2
Cyclic voltammograms were recorded at 5 mM SmI
0.100 M) and n-Bu NI (0.020 M) at 100 mV/s.
2
with n-Bu
4
NPF
6
2
(
4
(
4
,25
was observed with HMPA,
quantities of cosolvent results in a decreased standard
potential for the complex. In all voltammograms of SmI
HEPA complexes, quasi-reversible electron transfer is ob-
served with ∆E g 1000 mV. For HEPA, the standard
addition of even small
Table 4. Pseudofirst-Order Kinetics Study on the Effect of
Ligard on the Reduction of 2-Octanone at 21 °C
2
/
entry
ligand
k
obs (s-1)a
p
-
4
-4
-3
1
2
HMPA
TPPA
3.7 × 10 ( 0.3 × 10
-3
potential decreases until 3 equiv haas been added and then
remains constant at approximately -1.6 V vs Ag/Ag or
+
5.4 × 10 ( 0.6 × 10
] ) 0.010 M, [phosphoramide] )
a
[
2-octanone] ) 0.0015 M, [SmI
.040 M, [1-butanol] ) 0.020 M.
2
-
2
0.3 V relative to uncomplexed SmI , even when 10 equiv
0
of HEPA is utilized. Because the potential does not decrease
substantially when more than 3 equiv of HEPA is utilized,
2
it appears that SmI is saturated with only three HEPA
molecules. The standard potential of this complex is signifi-
cantly more positive than that observed for HMPA and
the same fashion as the 1-bromodecane kinetic analyses, and
linear plots of reaction time vs ln[2-octanone] were obtained
in both cases. The SmI
reactive (by an order of magnitude) than the SmI
complex. There is no previously reported evidence of an
organic ligand that activates SmI for carbonyl reduction to
2
/TPPA complex is substantially more
2
indicates that the reducing power of saturated SmI /HEPA
2
/HMPA
2
+
is much lower than that of [Sm(HMPA)
4
(THF)
2
] /[Sm(H-
2
+
MPA)
6
] . This is consistent with the observation that the
2
use of HEPA as a cosolvent did not result in production of
decane under the dilute conditions of the kinetic analysis.
TPPA, however, has electrochemical characteristics that
are similar to those observed for HMPA. Table 3 contains
2
7
a greater extent than HMPA.
Three examples of the synthetic utility of the SmI
complex are shown, with explicit comparisons to both SmI
HMPA and SmI /DMPU. Samarium diiodide was added to
a mixture of ketone 1, styrene, and t-BuOH in the presence
2
/TPPA
2
/
2
2
8
of various activating ligands (Table 5). Both HMPA and
a
2
Table 3. Effect of TPPA on the Standard Potential of SmI
[
ligand] to
standard potential ∆E relative
entry
[SmI
2
] ratio
(V vs Ag/AgNO
3
)
to SmI
2
(V)
Table 5. Effect of Ligand Choice on the SmI
Addition of 4-Phenylbutanone to Styrene
2
-Mediated
SmI
2
2
2
2
2
2
2
:TPPA
0
1
2
3
4
-1.329 ( 0.005
-1.40 ( 0.01
-1.41 ( 0.02
-1.6 ( 0.2
-1.94 ( 0.05
-2.05 ( 0.09
-2.07 ( 0.01
0.00
0.07
0.08
0.27
0.61
0.72
0.74
SmI
SmI
SmI
SmI
SmI
SmI
a
:TPPA
:TPPA
:TPPA
:TPPA
:TPPA
:HMPA
10
4
a
Cyclic voltammograms were recorded at 5 mM SmI
0.100 M) and n-Bu NI (0.020 M) at 100 mV/s.
2
with n-Bu
4
NPF
6
entry
ligand
yield (%)
(
4
b
1
2
3
HMPA
TPPA
DMPU
97
89
52
the measured standard potentials when varying equivalents
of TPPA were complexed with SmI . The standard potential
decreased significantly upon addition of 4 equiv of TPPA
-0.61 V) and was similar even when a large excess of
TPPA was utilized (-0.72 V). At 4 equiv of TPPA and
above, the voltammograms exhibited quasi-reversible elec-
a
b
Isolated yield. Ref 28.
2
(
TPPA facilitate the formation of alcohol 2 in an efficient
manner. With DMPU a sluggish reaction occurs (as evi-
tron transfer, while at lesser quantities of TPPA the reverse
+
wave for the reduction of SmI
2
/TPPA was diminished and
(26) Shabangi, M.; Kuhlman, M. L.; Flowers, R. A., II Org. Lett. 1999,
1
, 2133–2135.
the systems displayed characteristics of irreversible electron
transfer. Both of these behaviors are similar to those
(
27) Mixtures of water and various amines have been shown to greatly
accelerate SmI reductions of carbonyls; see ref 22.
2
5180
Org. Lett., Vol. 12, No. 22, 2010

denced by the slow rate of decolorization) to afford a modest
2
9
yield of the product.
Organosamarium species derived from radical cyclizations
can be trapped with appropriate electrophiles. The SmI -
2
Table 7. Effect of Ligand Choice on the Reduction of
1
-Chlorodecane
3
0
mediated cyclization of O-allyl-2-iodophenol followed by
the addition of 2-octanone and an aqueous quench provides
alcohol 4. This reaction (Table 6) works very well with both
a
entry
ligand
yield (%)
Table 6. Effect of Ligand Choice on the SmI
Cyclization and Trapping of O-Allyl-2-iodophenol
2
-Mediated
1
2
3
HMPA
TPPA
DMPU
4
16
0
a
GC yield.
2
SmI . In contrast to HMPA, there is no evidence of
untoward biological effects with TPPA. Spectral and
electrochemical evidence suggests the complex formed
a
entry
ligand
yield (%)
b
1
2
3
HMPA
TPPA
DMPU
80
76
30
between SmI
to [Sm(HMPA)
has been shown to react more rapidly than the SmI
complex with an alkyl bromide, an alkyl chloride, and a
ketone. Synthetically, the SmI /TPPA complex appears to
be equivalent to [Sm(HMPA)
2
and 4 equiv of TPPA is structurally similar
2+
-
4
(THF)
2
] 2I . The SmI
2
/TPPA complex
/HMPA
a
b
Isolated yield. Ref 30.
2
2
SmI
2
/HMPA and SmI
2
2
/TPPA. In contrast, SmI /DMPU
produced a 30% yield of alcohol 4 with 55% recovered
2
+
-
4
2
(THF) ] 2I and clearly
superior to the most common HMPA surrogate, DMPU.
Hexaethylphosphoric acid triamide, however, is not a
suitable replacement for HMPA. The electrochemical
evidence presented here suggests that only three HEPA
starting material.
2
Finally, alkyl chlorides are reluctant substrates for SmI /
HMPA-mediated reductions. The reduction of 1-chloro-
dodecane (2.5 equiv of SmI in THF with 5% HMPA)
3
1
2
requires 8 h at 60 °C, whereas the corresponding alkyl
2
ligands coordinate to the SmI . We believe that three
bromide is reduced in 5 min at room temperature with the
HEPA ligands do not provide sufficient electron density
at the samarium center to lower the standard potential to
the level observed for HMPA and TPPA.
2
same reagents. It is of interest to determine if the SmI
2
/
TPPA complex exhibits greater reactivity than SmI
toward a typical alkyl chloride such as 1-chlorodecane. As
can be seen in Table 7, The SmI /TPPA complex is again
significantly more reactive than the SmI /HMPA complex.
The use of SmI /DMPU did not result in detectable formation
2
/HMPA
2
Acknowledgment. D.G.S. would like to thank the Ly-
coming College Chemistry Research Endowed Fund for
summer stipends. The authors are indebted to Holly Bendorf
of Lycoming College and Joseph Keane of Muhlenberg
College for helpful discussions.
2
2
of decane at the 10 min mark.
In conclusion, tripyrrolidinophosphoric acid triamide is
an excellent alternative to HMPA for the activation of
Supporting Information Available: Contains experimen-
tal procedures and NMR spectra for all compounds, all cyclic
voltammograms, and the UV/Visible spectrum. This material
is available free of charge via the Internet at http://pubs.acs.org.
(
28) Ujikawa, O.; Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1989,
0, 2837–2840.
29) A small percentage of alcohol 2 is formed in a complex mixture
when HEPA is used as the ligand.
3
(
(
(
30) Curran, D.; Totleben, M. J. Am. Chem. Soc. 1992, 114, 6050–6058.
31) Girard, P.; Namy, J.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102,
2
693–2698.
OL102040S
Org. Lett., Vol. 12, No. 22, 2010
5181