Pronounced solvent effect on the hydrostannylation of propargylic alcohol derivatives with nBu3SnH/Et3B at room temperature

Article abstract of DOI:10.1002/chem.201203405

The solvent is key: A general protocol is described for the hydrostannylation of propargyl alcohol derivatives at room temperature using Et₃B/O₂ as the promoter (see scheme). Rate and mechanistic studies point to a different autoxidation product of Et₃B in THF than is observed in benzene, the typical solvent. Copyright

Full text of DOI:10.1002/chem.201203405

COMMUNICATION
DOI: 10.1002/chem.201203405
Pronounced Solvent Effect on the Hydrostannylation of Propargylic Alcohol
Derivatives with nBu3SnH/Et3B at Room Temperature
Martins S. Oderinde and Michael G. Organ*[a]
Alkenylstannanes have been used in a wide array of trans-
formations including Stille–Migita cross-coupling, metal–hal-
ogen exchange, and transmetallation reactions.[1] One of the
most efficacious approaches to alkenylstannanes is the
direct hydrometallation of alkynes. Stereo-defined alkenyl-
stannanes have been prepared from both internal and termi-
nal alkynes by using Pd-catalysed [nBu3SnH-Pd0],[2] Cu-
mediated [nBu3Sn(R)CuCNLi2][3]
, and radical protocols
Scheme 1. Hydrostannylation of 1 using Et3B/O2 as mediators.[5]
with either AIBN [nBu3SnH-AIBN], or Et3B/O2 [nBu3SnH-
Et3B/O2 or Ph3SnH-Et3B/O2] as mediators (AIBN=azobis-
ACHTUNGTRENNUNGisoACHTUNGTRENNUNG
butyronitrile).[4] Of course, of equal merit is the ability to
prepare alkenylstannanes of a single regiochemistry, which
is especially challenging when the alkyne precursor is inter-
nal. Here, propargylic alcohols and their derivatives have
shown a strong preference to place the tin moiety on the
proximal carbon of the alkyne (i.e., b to oxygen).[4a,d–f]
Taken together, the ability to carry out radical hydrostannyl-
nBu3Sn derivatives, makes the use of Ph3SnH impractical
and less attractive.[2e] Furthermore, while stereospecific tin/
halogen exchange of the tributylstannyl moiety proceeds re-
liably to give the alkenylhalide, sides reactions in phenylhal-
ogen exchange plague the corresponding triphenylstannyl
moiety.[4f] Consequently, the development of a hydrostannyl-
A
ACHTUNGTRENaNGNU tion method using nBu3SnH that proceeds efficiently under
A
mild and environmentally friendly conditions is a priority.
Free-radical-mediated hydrostannylation is invariably re-
ported in benzene or toluene, primarily for solvent compati-
bility reasons. When the rate of hydrostannylation with
nBu3SnH was followed in benzene, it is clear that the reac-
tion is very slow (Figure 1). This cannot be an issue of radi-
cal initiation, as the autoxidation of Et3B is instantaneous in
the presence of trace oxygen, even at or below 08C.[4b] De-
spite the general belief that radical processes should not
show a significant rate change in more polar solvents, there
is precedent for significant increases (and decreases) in rate,
when a more polar solvent is substituted for those conven-
tionally used in radical reactions (e.g., CCl4, benzene, alka-
nes).[6] Changing the solvent to THF resulted in a remarka-
ble increase in the rate of hydrostannylation using nBu3SnH
(Figure 1). The ability to carry out the reaction at room tem-
perature in THF offers several advantages. The stereoselec-
tivity of the radical addition can be better controlled, since
the isomerisation of the kinetically formed Z product to the
thermodynamic E product is promoted at higher tempera-
ture.[4a] Furthermore, given that hydrostannylation is con-
ducted on a large scale in industry,[7] the replacement of
benzene for THF and a vast reduction in the equivalents of
tin reagent required will impact significantly on safety and
the environment.
important and necessitates a solid mechanistic understand-
ing of the process.
While the Et3B/O2-mediated hydrostannylation of propar-
gylic alcohols and their derivatives using nBu3SnH proceeds
well at 808C, the transformation is poor at room tempera-
ture requiring three days to reach completion and a large
excess of tin hydride (at least 5.0 equiv).[4] Furthermore, hin-
dered substrates react much slower in the solvents that are
typically used for this transformation (e.g., benzene, tol-
uene). We have reported that hydrostannylation with
nBu3SnH (2.0 equiv)/Et3B at 808C proceeds with excellent
stereoselectively (trans addition to produce the Z isomer)
within 3 h (Scheme 1).[5] However, the transformation must
be monitored carefully for beyond 3 h reaction time, isomer-
isation to the E isomer begins. Conversely, hydrostannyla-
tion with Ph3SnH (1.5–2.0 equiv) is known to proceed well
at room temperature in benzene or toluene.[4d–f] However,
poor reproducibility with regard to regioselectivity and
yield, coupled with difficulty in product isolation relative to
[a] M. S. Oderinde, Prof. M. G. Organ
Department of Chemistry, York University
4700 Keele Street, Toronto, Ontario M3J 1P3 (Canada)
Fax : (+1)416-736-5936
In light of this result, the transformation was further opti-
mised and other polar solvents evaluated (Table 1). Increas-
ing the amount of Et3B from 0.2 to 0.5 equivalents improved
E-mail: organ@yorku.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203405.
Chem. Eur. J. 2013, 19, 2615 – 2618
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2615

2(1H)-pyrimidinone (DMPU; entries 8 and 9). The reaction
also proceeded satisfactorily in isobutyronitrile as the sol-
vent (entry 10). In general, polar solvents accelerate hydro-
stannylation, leading to greater percent conversion. It is
very important to note that a limited amount of molecular
oxygen is required for the hydrostannylation of propargylic
alcohol derivatives reported here to proceed, irrespective of
the solvent and radical initiator employed. If too much
oxygen is present, hydrostannylation fails to proceed (vide
infra). While the reactions carried out in DMI and DMPU
gave slightly higher yields than in THF, they are often diffi-
cult to remove during workup, thus we moved forward using
THF.
To probe the generality of the nBu3SnH/Et3B/THF/room
temperature protocol, we embarked on a scope study that
included different functional groups (Table 2) and found
that a variety of substituents on the propargylic alcohol
were readily tolerated (e.g., OAc: , OTBS, and TIPS: 6a–c).
Also impressive, the secondary propargylic silyl ether (5h),
which did not hydrostannylate well in benzene at 808C, was
Figure 1. The rate of hydrostannylation of 3 using Et3B/O2.
Table 2. Scope studies for Et3B/O2-mediated hydrostannylation in THF
at room temperature.[a,b]
Table 1. Et3B/O2-mediated nBu3SnH addition to 3 in polar solvents.[a]
Entry
Solvent
Et3B
[equiv]
nBu3SnH
[equiv]
Conversion of (Z)-4
[% ][b]
1
2
3
4
5
6
7
8
9
benzene
THF
THF
0.2
0.2
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.5
1.5
1.5
2
2
2
2
22
2
5
22
60
THF
82[d]
50
acetone
DMF
80
THF+H2O[c]
DMI
75
86[d]
87[d]
DMPU
10
0.5
2
78
[a] Reactions were quenched at 90 min by passing them through a pad of
1
silica gel. [b] Percent conversion was determined by H NMR spectrosco-
py of the crude mixture. [c] Five equivalents of water were added to the
reaction solution in anhydrous THF. [d] The reaction went to full conver-
sion within 3 h.
conversion (entries 2 and 3), as did increasing the number of
equivalents of nBu3SnH from 1.5 to 2.0 (entries 3 and 4).
While the conversion was lower in acetone (entry 5), satis-
factory conversion was obtained in DMF (entry 6). Impor-
tantly, the presence of water has little effect on hydro-
ACHTUNGTRENNUNGstannylACHTUNGTRENNUNGation (entry 7). Interestingly, the reaction gave the
best conversion in the highly polar solvents 1,3-dimethyl-2-
imidazolidinone (DMI) and 1,3-dimethyl-3,4,5,6-tetrahydro-
[a] Isomeric ratios were determined by 1H NMR spectroscopy of the
crude reaction mixture. [b] Yields were determined after purification by
silica gel chromatography. For selectivities reported at >99:1, we do not
see any of the E isomer. [c] Alkyne (0.5m in THF) and Et3B (0.5 equiv),
nBu3SnH (2 equiv), 3 h. [d] Alkyne (0.5m in THF), nBu3SnH (2 equiv),
Et3B (1.0 equiv), 12–18 h.
2616
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 2615 – 2618

Hydrostannylation of Propargylic Alcohol Derivatives
COMMUNICATION
readily hydrostannylated in THF at room temperature to
give 6h. Excellent yields and absolute regio- and stereocon-
trol were achieved for all cases.
In order to confirm a radical mechanism for Et3B/O2-
mediated hydrostannylation, galvinoxyl (a known radical
scavenger)[4,10] was added to the reaction mixture in benzene
after the autoxidation process was allowed to proceed for
10 min, so as to ensure the formation of the active radical
promoter, and no addition took place. Further, the reaction
between nBu3SnH and Et3B/O2 (1:1) in both benzene and
THF was followed by 119Sn NMR spectroscopy. The spectra
showed the formation of nBu3SnSnBu3 (À79 ppm), which
occurs by the combination of two tin radicals.[4,11] The 119Sn
NMR spectrum of the reaction of nBu3SnH and AIBN (1:1)
in C6D6, which presumably could only be radical mediated,
Our group,[5] and others,[8] have examined the autoxida-
tion of Et3B in benzene and reported that with sufficient
oxygen the first and second autoxidations are rapid at room
temperature, while the third is slow. We have also demon-
strated for the first time that each of these autoxidation
products [Et2BACHTUNGTRENNUNG(OEt), EtBACHNUTRTEGG(NNUN OEt)2 and BACHTNGURTEN(NUGN OEt)3] can individ-
ually mediate hydrostannylation of propargylic alcohol de-
rivatives in air, albeit at very different rates.[5b] In the pres-
ence of oxygen, the first autoxidation product, Et2B
mediates hydrostannylation faster than the second, EtB-
(OEt)2, which is much faster than B(OEt)3. When the autox-
ACHTUNGTRNE(NUNG OEt),
also showed
a prominent peak for nBu3SnSnBu3 at
A
U
À79 ppm.[11]
idation of Et3B (100 mL, 1m in hexane) was conducted in
[D8]THF (0.5 mL) in this study, the first autoxidation to
Since the a-hydrogen of THF is susceptible to radical ab-
straction,[12] we carried out the hydrostannylation of 3 in
[D8]THF to track any hydrogen-atom transfer from the sol-
vent, but only the undeuterated product ((Z)-4) was ob-
tained (Scheme 2a). It has been proposed that H2O can act
Et2B
ACHTUNGTRENNUNG
tion to EtBACHTUNGTRENNUNG
to be fully formed compared with about 5 min in ben-
zene).[9] When the reaction of 3 with nBu3SnH was closely
monitored and deemed to be just complete, the 11B NMR
spectrum of the mixture revealed that EtBACTHNURGTNEUNG(OEt)2 was the
only boron species present. Considering the lifetime of the
autoxidation products, overlaid with the rates of the reaction
in both solvent systems, it would appear that in benzene
EtB
ACHTUNGTRENNUNG
Et2B
ACHTUNGTRENNUNG
and the other polar solvents are stabilising the boron centre
thus extending the lifetime of the more active oxidation
products in solution (i.e., Et2BACTHNUGRTNEUNG(OEt) is longer lived in polar
solvents than apolar solvents), which causes the rate accela-
ration. Although it was difficult for us to synthesise pure
Et2B
ACHTUNGTRENNUNG
commercially available and pure Et2BAHCTUNGTRENNUNG
results as Et3B in THF. In addition to the above, it is con-
ceivable that the higher diffusion/miscibility of molecular
oxygen in polar solvents is playing a crucial-secondary role,
respectively.
Our hydrostannylation protocol with Et3B involves sealing
the reaction flask in air immediately following the addition
of the last reagent, which means that the oxygen present in
the flask is consumed and not replenished as autoxidation
proceeds. When a large supply of oxygen was used in the re-
action (using an oxygen-filled balloon) at, or above room
temperature, the reaction did not proceed at all in any sol-
vent. This is an indication of a rapid autoxidation to the less
reactive boron species in the presence of excess oxygen. The
solvent dependency of autoxidation coupled with the appa-
rent specificity of which boron species is actually present
and therefore presumably promotes the transformation in a
particular solvent, suggests a delicate balance between the
concentrations of Et3B and O2. That is, enough O2 is re-
quired to reach the necessary species to drive the transfor-
mation in a particular solvent. However, if there is abundant
O2, autoxidation proceeds too far to yield a nonproductive
species. So, having the right balance of Et3B and O2 is para-
mount.
Scheme 2. Deuterium labelling studies for the hydrostannylation of 3.
as a hydrogen donor in reactions mediated by Et3B/O2.[13]
Since the THF protocol that we have developed proceeds in
the presence of water (Table 1, entry 7), five equivalents of
D2O were added to the reaction mixture to see if adventi-
tious water could serve as the hydrogen donor. Again there
was no deuterium label in the product (Scheme 2b). We feel
that this result also casts doubt on proposals that R2BOOH
and R2BOH can be the hydrogen donor in these reactions.
It has been shown by NMR spectroscopy that these protons
are fully exchangeable in D2O and yet there is zero deuteri-
um transfer to the product.[13,14] Finally, we performed the
hydrostannylation with nBu3SnD and the alkenylstannane
showed 100% deuterium incorporation ([D1]-(Z)-4; Sche-
me 2c). The identical outcome was obtained when the reac-
tion was conducted with H2O present.
Chem. Eur. J. 2013, 19, 2615 – 2618
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2617

M. G. Organ and M. S. Oderinde
When we compared the rate of the reaction shown in
Scheme 2c with its non-deuterated counterpart, the transfor-
mation was found to have a primary kinetic isotope effect
(KIE) of 2.33.[11] Presuming that radical initiation is sponta-
neous, this points to the second step of radical chain propa-
gation as being rate-limiting (Figure 2). Although the rate-
[1] a) D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1979, 101, 4992; b) D.
Milstein, J. K. Stille, J. Am. Chem. Soc. 1978, 100, 3636; c) D. A.
Evans, W. C. Black, J. Am. Chem. Soc. 1993, 115, 4497; d) J. R. Beh-
ling, K. A. Babiak, J. S. Ng, A. L. Campbell, R. Moretti, M. Koerner,
B. H. Lipshutz, J. Am. Chem. Soc. 1988, 110, 2641; e) D. Hart, Sci-
ence 1984, 223, 883; f) B. Giese, Angew. Chem. 1985, 97, 555;
Angew. Chem. Int. Ed. Engl. 1985, 24, 553; g) K. W. Kells, J. M.
Chong, J. Am. Chem. Soc. 2004, 126, 15666; h) K. W. Kells, J. M.
Chong, Org. Lett. 2003, 5, 4215; i) E. J. Panek, L. R. Kaiser, G. M.
Whitesides, J. Am. Chem. Soc. 1977, 99, 3708; j) D. Seyferth,
F. G. A. Stone, J. Am. Chem. Soc. 1957, 79, 515; k) J. W. Labadie,
J. K. Stille, J. Am. Chem. Soc. 1983, 105, 6129; l) J. Hibino, S. Metsu-
bara, Y. Morizawa, K. Oshima, H. Nozaki, J. Organomet. Chem.
1985, 285, 163; m) E.-i. Negishi, Organometallics in Organic Synthe-
sis, Wiley, New York, 1980, p. 410.
[2] a) B. M. Trost, Z. T. Ball, Synthesis 2005, 6, 853; b) M. Lautens, J.
Mancuso, Org. Lett. 2000, 2, 671; c) J. A. Marshall, B. M. Bourbeau,
Tetrahedron Lett. 2003, 44, 1087.
[3] a) B. M. Stoltz, T. Kano, E. J. Corey, J. Am. Chem. Soc. 2000, 122,
9044; b) J. F. Betzer, F. Delaloge, B. Muller, A. Pancrazi, J. Prunet,
J. Org. Chem. 1997, 62, 7768; c) E. Piers, J. M. Chong, H. Morton,
Tetrahedron Lett. 1981, 22, 4905.
[4] a) M. Taddei, C. Nativi, J. Org. Chem. 1988, 53, 820; b) K. Nozaki,
K. Oshima, K. Utimoto, Tetrahedron Lett. 1989, 30, 923; c) K.
Nozaki, K. Oshima, K. Utimoto, J. Am. Chem. Soc. 1987, 109, 2547;
d) P. Dimopoulos, J. George, D. A. Tocher, S. Manaviazar, K. Hale,
Org. lett. 2005, 7, 5377; e) P. Dimopoulos, A. Athlan, S. Manaviazar,
J. George, M. Walters, L. Lazarides, A. E. Aliev, K. Hale, Org. Lett.
2005, 7, 5369; f) P. Dimopoulos, A. Athlan, S. Manaviazar, K. Hale,
Org. Lett. 2005, 7, 5373.
[5] a) M. S. Oderinde, H. N. Hunter, M. G. Organ, Chem. Eur. J. 2012,
18, 10817; b) M. S. Oderinde, H. N. Hunter, R. D. J. Froese, M. G.
Organ, Chem. Eur. J. 2012, 18, 10821; c) M. S. Oderinde, M. G.
Organ, Angew. Chem. 2012, 124, 9972; Angew. Chem. Int. Ed. 2012,
51, 9834.
[6] a) O. Ito, M. Matsuda, J. Phys. Chem. 1984, 88, 1002; b) G. A. Rus-
sell, J. Am. Chem. Soc. 1958, 80, 4987; c) J. D. Bacha, J. K. Kochi, J.
Org. Chem. 1965, 30, 3272; d) C. Walling, P. Wagner, J. Am. Chem.
Soc. 1964, 86, 3368.
[7] From private conversations with the Process Chemistry Group at
Sigma–Aldrich, Milwaukee, WI.
Figure 2. Putative alkyne hydrostannylation mechanism with Et3B/
O2.[2a,e,f]
determining and selectivity-determining steps are not neces-
sarily the same, a high transition-state barrier would help
explain why there is such a pronounced kinetic stereoselec-
tivity for the Z olefin, which would be determined in this
step.
In conclusion, we have shed new light on the reactivity of
Et3B/O2-mediated
alkyne
hydrostannylations
using
nBu3SnH as the hydride source. Most importantly, we have
developed new conditions for hydrostannylation at room
temperature in THF, eliminating the need for benzene that
carries with it significant health and environmental con-
cerns.[15] We have also unveiled a rate-accelerating effect of
polar solvents in hydrostannylation and demonstrated
[8] a) Z.-C. Zhang, M. Chung, Macromolecules 2006, 39, 5187; b) C. Ol-
livier, P. Renaud, Chem. Rev. 2001, 101, 3415.
[9] For complete details and spectra of autoxidation studies conducted
in benzene and THF, see the Supporting Information.
C
nBu3SnH as the sole source of H in step 3 of the radical-
[10] G. M. Coppinger, J. Am. Chem. Soc. 1957, 79, 501.
chain process. We believe that this step is rate-limiting in ad-
dition to being the selectivity-determining step in the proc-
ess.
[11] H. R. Kricheldorf, I. Kreiser-Saunders, Polymer 2000, 41, 3957.
[12] T. Yoshimitsu, M. Tsunoda, H. Nagaoka, Chem. Commun. 1999,
1745.
[13] a) D. A. Spiegel, K. B. Wiberg, L. N. Schacherer, M. R. Medeiros,
J. L. Wood, J. Am. Chem. Soc. 2005, 127, 12513; b) G. Villa, G.
Povie, P. Renaud, J. Am. Chem. Soc. 2011, 133, 5913.
Acknowledgements
[14] For experimental details and spectra, see the Supporting Informa-
tion.
This work was supported by NSERC (Canada) and The Ontario Re-
search Fund (ORF).
[15] a) P. T. Anastas, M. M. Kirchhoff, Acc. Chem. Res. 2002, 35, 686;
b) B. M. Trost, Acc. Chem. Res. 2002, 35, 695; c) G. Wulff, Chem.
Rev. 2002, 102, 1; d) D. E. Bergbreiter, Chem. Rev. 2002, 102, 3345.
Keywords: autoxidation
· hydrostannylation · radicals ·
Received: September 23, 2012
solvent effects · stereoselective · triethylborane
Published online: January 10, 2013
2618
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 2615 – 2618