Tin-free enantioselective radical reactions using silanes

Article abstract of DOI:10.1021/ol802154d

(Chemical Equation Presented) Readily available hexyl silane is an excellent choice as a H-atom donor and a chain carrier in Lewis acid mediated enantioselective radical reactions. Conjugate radical additions to α,β-unsaturated imides at room temperature proceed in good yields and excellent enantioselectivities.

Full text of DOI:10.1021/ol802154d

ORGANIC
LETTERS
2008
Vol. 10, No. 23
5349-5352
Tin-Free Enantioselective Radical
Reactions Using Silanes
Mukund P. Sibi,* Yong-Hua Yang, and Sunggi Lee
Department of Chemistry, North Dakota State UniVersity, Fargo, North Dakota 58105
mukund.sibi@ndsu.edu
Received September 15, 2008
ABSTRACT
Readily available hexyl silane is an excellent choice as a H-atom donor and a chain carrier in Lewis acid mediated enantioselective radical
reactions. Conjugate radical additions to r,ꢀ-unsaturated imides at room temperature proceed in good yields and excellent enantioselectivities.
Organotin reagents play a significant role in radical reac-
tions.1 Due to the nature of the weak Sn-H bond, tin hydride
reagents have been and continue to be reagents of choice to
carry out chain radical reactions. Although very popular and
highly useful for the successful execution of radical reactions,
tin reagents have significant drawbacks.2 Organotin reagents
are toxic, and the tin byproducts from radical reactions often
prove to be very difficult to remove. To overcome these
significant liabilities, several alternatives to tin reagents3 have
been put forward in the literature. Of these, silicon,4
phosphorus,5 sulfur,6 indium,7 Lewis acid activated water,8
and cyclohexadiene9 based reagents have shown the most
promise (Figure 1).
(1) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, 2001; Vols. 1 and 2.
(2) For general reviews on alternate reagents to tin, see: (a) Baguley,
P. A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072–3082. (b) Studer,
A.; Amrein, S. Synthesis 2002, 835–849. (c) Walton, J. C.; Studer, A. Acc.
Chem. Res. 2005, 38, 794–802. (d) Studer, A.; Amrein, S. Angew. Chem.,
Int. Ed. 2000, 39, 3080–3082. (e) Parsons, A. Chem. Br. 2002, 38, 42–44.
(3) Fluorous tin hydrides: (a) Curran, D. P.; Hadida, S.; Kim, S-Y.; Luo,
Z. J. Am. Chem. Soc. 1999, 121, 6607–6615. (b) Curran, D. P.; Hadida, S.
J. Am. Chem. Soc. 1996, 118, 2531–2532.
Figure 1. Alternate reagents for radical reactions.
(4) Oragnosilanes: (a) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188–
194. (b) Chatgilialoglu, C. Chem. Eur. J. 2008, 14, 2310–2320. (c)
Chatgilialoglu, C. Organosilanes in Radical Chemistry; Wiley: Chichester,
2004.
The P-H, O-H, and C-H bonds are comparatively much
stronger than the Sn-H bond. Thus it is much more difficult
to carry out chain reactions with these reagents at low
temperatures, a condition required for optimal organization
of the complex that provides face selectivity in chiral Lewis
acid mediated reactions. At the present time there are only
a handful of examples in the literature that do not utilize tin
reagents for execution of enantioselective radical reactions.10
(5) (a) Hypophosphorous acid: Barton, D. H. R.; Jang, D. O.; Jaszber-
enyi, J. Cs. Tetrahedron Lett. 1992, 33, 5709. (b) EPHP: Jang, D. O.; Cho,
D. H. Synlett 2002, 1523–1525. Francisco, C. G.; Gonzalez, C. C.; Herrera,
A. J.; Paz, N. R.; Suarez, E. Tetrahedron Lett. 2006, 47, 9057–9060. (c)
DEPO: Khan, T. A.; Tripoli, R.; Crawford, J. J.; Martin, C. G.; Murphy,
J. A. Org. Lett. 2003, 5, 2971–2974. (d) Murphy, J. A.; Tripoli, R.; Khan,
T. A.; Mali, U. W. Org. Lett. 2005, 7, 3287–3289.
10.1021/ol802154d CCC: $40.75
Published on Web 11/06/2008
2008 American Chemical Society

Recently, radical reactions mediated by organocatalysts have
been reported.11 Over the past several years, we have been
very interested in the development of tin-free enantioselective
radical reactions using silanes or phosphorus acids. The lower
reactivity of the silicon and phosphorus based reagents
necessitates the need to generally carry out reactions at room
temperature or higher. Thus it is necessary to have a
substrate-chiral catalyst complex that can provide reactivity
enhancements to allow for reactions with the less efficient
Si-H and P-H reagents and at the same time provide high
selectivity. In this work we demonstrate that readily available
silanes are effective as hydrogen atom donors and chain
carriers in chiral Lewis acid medidated enantioselective
radical conjugate additions.12
silanes are excellent alternatives to tributyltin hydride in
enantioselective radical reactions. Of the two most effective
silanes examined in this study, tristrimethylsilyl silane is less
atom economical (1H atom for a molecular weight of 252).
However, it is more effective than hexyl silane (vide infra).
Having established that silanes are effective mediators in
enantioselective radical reactions, we next examined conju-
gate additions to crotonates attached to two different well-
established achiral templates. Isopropyl radical addition to
oxazolidinone crotonate 4 was carried out using two different
chiral Lewis acids and the two most promising silanes (Table
2). Reaction using TTMSS and Mg(NTf2)2/ligand 2 gave 5
We began our work with the goal of identifying an optimal
silane for conjugate radical addition, and these results are
presented in Table 1. For our initial work, we chose the imide
Table 2. Investigation of Oxazolidinone-Derived Crotonatea
Table 1. Identification of Optimal Silane for Conjugate Radical
Additions
entry
silane
Lewis acid yieldb prod:ethylc ee, %d
1
2
3
4
(TMS)3SiH Mg(NTf2)2
87
54
55
20e
12:1
15:1
20:1
10:1
20
11
8
hexylSiH3 Mg(NTf2)2
(TMS)3SiH Zn(OTf)2
hexylSiH3 Zn(OTf)2
7
a For experimental details see Supporting Information. b Isolated yields.
c Determined by 1H NMR. d Determined by chiral HPLC. e 62% of the
starting material was recovered.
yield, %b
prod:ethylc
ee, %d
in high yield and low ee (entry 1). An idential reaction except
using hexyl silane also gave the product in modest yield and
low ee (entry 2). Reactions using a chiral Lewis acid derived
from Zn(NTf2)2/ligand 2 were not highly effective with either
of the silanes (entries 3 and 4).
We have previously shown that pyrazolidinones are very
effective as achiral templates and provide enantioselectivity
enhancements in a variety of reactions including conjugate
radical additions.15 Isopropyl radical addition to 6 using
TTMSS (entry 1, Table 3) or hexyl silane (entry 2) were
not very effective with respect to both chemical efficiency
or selectivity. As a comparison experiment, reaction using
entry
silane
1
2
3
4
5
6
7
(TMS)3SiH
Ph2SiH2
Et3SiH
Et2SiH2
PhSiH3
91
86
31
53
75
76
29
30:1
15:1
12:1
12:1
12:1
30:1
30:1
81
78
80
80
79
80
hexylSiH3
a For experimental details see Supporting Information. b Isolated yields.
Determined by H NMR. d Determined by chiral HPLC.
c
1
1 as a substrate because of its relatively high reactivity, and
we used the chiral Lewis acid derived from magnesium
triflimide and bisoxazoline 2.13 The reactions were carried
out at room temperature using triethylborane/oxygen as an
initiator. Tristrimethylsilylsilane (TTMSS), the most well-
known alternative to tinhydride, was evaluated first. The
reaction gave the isopropyl addition product 3 in high yield
and excellent enantioslectivity (entry 1). A minor amount
of the ethyl radical addition product was also formed. Other
commercially available silanes were also evaluated (entries
2-6). Of these, diphenyl silane (entry 2), phenyl silane (entry
5), and hexyl silane (entry 6) gave the product in good yield
and nearly identical selectivity. In contrast to other silanes
(entries 2-5), hexyl silane gave minor amounts of ethyl
addition product (entry 6). A control experiment in the
absence of hexyl silane gave the radical adduct in low yield
(entry 7).14 These experiments demonstrate that eco-friendly
Table 3. Investigation of Pyrazolidinone-Derived Crotonatea
entry
H-donor
Lewis acid
yield, % (SM)b
ee, %c
1
(TMS)3SiH
hexylSiH3
Bu3SnH
Mg(NTf2)2
Mg(NTf2)2
Cu(OTf)2
56
33
80
51
54
95
2
3d
a For experimental details see Supporting Information. b Isolated yields.
c Determined by chiral HPLC. d Reaction at -78 °C (data from ref 15b).
5350
Org. Lett., Vol. 10, No. 23, 2008

tributyltin hydride as the H-atom donor gave 7 in high yield
and selectivity (entry 5).15b Thus of the three different achiral
templates investigated, only the most reactive imides were
effective using silanes as H-atom donors.
addition: the less nucleophilic ethyl radical adds less ef-
ficiently at lower temperatures (entry 12).
We have evaluated the scope of the radical precursor as
well as the ꢀ-substituent in conjugate radical additions using
hexyl silane and a chiral Lewis acid derived from Mg(NTf2)2/
ligand 2, and these results are shown in Table 5. Addition
In an effort to improve reactivity and/or selectivity, we
examined the effect of the imide substituent on conjugate
radical addition, and these results are shown in Table 4. As
Table 5. Breadth and Scope Studiesa
Table 4. Optimization of the Imide Substituent
entry
R
silane
yield, %b prod:ethylc ee (%)d
1
2
3
4
C6H5
C6H5
(TMS)3SiH
hexylSiH3
91
76
93
62
83
70
70
76
70
70
72
56
30:1
30:1
10:1
6:1
>50:1
5:1
4:1
10:1
5:1
81
80
78
77
83
82
81
83
82
81
87
90
p-ClC6H4 (TMS)3SiH
p-ClC6H4 hexylSiH3
5
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
(TMS)3SiH
(TMS)3SiH
(TMS)3SiH
hexylSiH3
hexylSiH3
hexylSiH3
hexylSiH3
hexylSiH3
6e
7f
8
a For experimental details see Supporting Information. b Isolated yields.
9e
10f
11g
12h
c
Determined by H NMR. d Determined by chiral HPLC.
1
3:1
15:1
20:1
of ethyl radical to 1 was feasible, but the enantioselectivity
was only modest (entry 1). As noted earlier, isopropyl radical
adds efficiently to provide 3 in good yield and selectivity
(entry 2). The bulky and more nucleophilic tert-butyl radical
gave the conjugate addition product in high yield and
a For experimental details see Supporting Information. b Isolated yields.
c
Determined by H NMR. d Determined by chiral HPLC. e Reaction with
1
5 equiv of i-PrI. f Reaction with 3 eq of i-PrI. g Reaction at 0 °C. h Reaction
at -30 °C.
discussed earlier, reactions with 1 with a phenyl imide
substituent proceeds in good yield and selectivity (entries 1
and 2). Reaction with substrate 8 containing a 4-Cl-phenyl
substitutent using TTMSS gave 10 in high yield (entry 3).
However, there was an increase in the amount of ethyl
addition product (compare entry 3 with 1). The same trend
was observed with hexyl silane along with a lowering of
the yield (compare entry 4 with 2). A tert-butyl imide
substituent, 9, was very effective in reaction using TTMSS
(entry 5). Lowering the amount of radical precursor from
10 equiv (entry 1) to 5 equiv (entry 6) to 3 equiv (entry 7)
did not have a significant impact on yield or selectivity.
However, a significant increase in ethyl addition was
observed while using lower amounts of the radical precusor.
Isopropyl radical addition to 9 using hexyl silane was slightly
less efficient than that with TTMSS (compare entry 8 with
entry 5). Reactions with hexyl silane using lower amounts
of the radical precursor (entries 9 and 10) displayed a trend
similar to that observed with TTMSS. Lowering reaction
temperature had a positive impact on enantioselectivity
(entries 11 and 12) reaching a high of 90%, but chemical
yields suffered. Additionally, reaction at -30 °C showed a
better discrimination between isopropyl and ethyl radical
(6) Thiols: (a) Cai, Y.; Roberts, B. P.; Tocher, D. A. J. Chem. Soc.,
Perkin Trans. 1 2002, 137, 6–1386. (b) Dang, H-S.; Franchi, P.; Roberts,
B. P. Chem. Commun. 2000, 499–500. (c) Roberts, B. P. Chem. Soc. ReV.
1999, 28, 25–35. (d) Beaufils, F.; Denes, F.; Renaud, P. Org. Lett. 2004, 6,
2563–2566.
(7) Triethylsilane-indium(III) chloride: Hayashi, N.; Shibata, I.; Baba,
A. Org. Lett. 2004, 6, 4981–4983.
(8) Water as a hydrogen atom source: (a) Spiegel, D. A.; Wiberg, K. B.;
Schacherer, L. N.; Medeiros, M. R.; Wood, J. L. J. Am. Chem. Soc. 2005,
127, 12513–12515. (b) Medeiros, M. R.; Schacherer, L. N.; Spiegel, D. A.;
Wood, J. L. Org. Lett. 2007, 9, 4427–4429. (c) Pozzi, D.; Renaud, P. Chimia
2007, 61, 151–154.
(9) (a) Walton, J. C.; Studer, A. Acc. Chem. Res. 2005, 38, 794–802.
(b) Studer, A.; Amrein, S.; Schleth, F.; Schulte, T.; Walton, J. C. J. Am.
Chem. Soc. 2003, 125, 5726–5733.
(10) (a) Cai, Y.; Roberts, B. P.; Tocher, D. A. J. Chem. Soc., Perkin
Trans. 1 2002, 1376–1386. (b) Haque, M. B.; Roberts, B. P.; Tocher, D. A.
J. Chem. Soc., Perkin Trans. 1 1998, 2881–2890. (c) Gansaeuer, A.; Fan,
C-A.; Piestert, F. J. Am. Chem. Soc. 2008, 130, 6916–6917. (d) Sibi, M. P.;
Asano, Y.; Sausker, J. B. Angew. Chem., Int. Ed. 2001, 40, 1293–1296.
(11) (a) Aechtner, T.; Dressel, M.; Bach, T. Angew. Chem., Int. Ed.
2004, 43, 5849. (b) Beeson, T. D.; Mastracchio, A.; Hong, J.-B.; Ashton,
K.; MacMillan, D. W. C. Science 2007, 316, 582. (c) Sibi, M. P.; Hasegawa,
M. J. Am. Chem. Soc. 2007, 129. (d) Jang, H.-Y.; Hong, J.-B.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2007, 129, 7004.
(12) For recent reviews on enantioselective radical reactions, see: (a)
Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. ReV. 2003, 103, 3263. (b)
Zimmerman, J.; Sibi, M. P. Top. Curr. Chem. 2006, 263 (Radicals in
Synthesis 1), 107–162. (c) Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999,
32, 163.
(13) For details on reaction conditions and characterization data, see
Supporting Information.
Org. Lett., Vol. 10, No. 23, 2008
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selectivity with minimal contamination from ethyl radical
addition (entry 3). Interestingly, cyclohexyl radical addition
to 1 proceeded with only modest efficiency (entry 4). The
functionalized tertiary radical gave the product in excellent
yield and selectivity (entry 5). The addition of tert-butyl
radical to different substrates was investigated. Conjugate
addition to cinnamate 12 proceeded well and gave the
product in good yield and excellent selectivity (entry 6). Even
higher yield and selectivity was obtained using 13 as a
substrate (entry 7). The formation of 20 with 94% ee for a
reaction at room temperature is highly noteworthy.
In conclusion, we have developed an efficient tin-free
methodology for enantioselective conjugate radical additions
using readily available silanes. Conjugate additions using an
imide template provides products in good yields and
selectivity for reactions at room temperature. Experiments
are underway to further extend the methodology to other
enantioselctive radical reactions.
Acknowledgment. We thank the NIH (GM-54656) for
(14) Control experiments suggest that the reaction does not proceed
through the formation of a boron enolate to any significant extent. Reaction
using hexyl silane and CD2Cl2 as a solvent showed no deuterium
incorporation in the product. Similarly, quenching the reaction with D2O
also showed no deuterium incorporation.
financial support of this work.
Supporting Information Available: Experimental pro-
cedures, characterization data, and proof of stereochemistry.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(15) For a full account on the use of pyrazolidinones in Diels-Alder
reactions, see: (a) Sibi, M. P.; Stanley, L. M.; Venkatraman, L.; Nie, X.;
Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 2007, 129, 395. For conjujate
radical addition, see: (b) Sibi, M. P.; Prabagaran, N. Synlett 2004, 2421.
OL802154D
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Org. Lett., Vol. 10, No. 23, 2008