Mild cobalt-catalyzed hydrocyanation of olefins with tosyl cyanide

Article abstract of DOI:10.1002/anie.200700575

Mild-mannered and well-behaved: A conceptually new hydrocyanation reaction for non-activated olefins provides secondary and tertiary nitriles in good yields under mild conditions. Salient features of this process include broad functional-group tolerance, readily available starting materials, and ease of execution.

Full text of DOI:10.1002/anie.200700575

Angewandte
Chemie
DOI: 10.1002/anie.200700575
Alkene Hydrocyanation
Mild Cobalt-Catalyzed Hydrocyanation of Olefins with Tosyl
Cyanide**
Boris Gaspar and Erick M. Carreira*
Dedicated to Professor Miguel Yus on the occasion of his 60th birthday
The diverse transformations in which nitriles participate[1]
(for example, RCHO,
RCN!RCO2H, RCONH2,
the alkene substrate is often used in excess (up to 2 equiv).
Recently, a low-temperature protocol for the asymmetric
RCH2NH2, and RCN4, as well as Pinner and Ritter reactions)
place them among the most versatile intermediates in organic
chemistry. Although the displacement reactions of leaving
groups by cyanide constitute the most common access routes
to these, direct olefin hydrocyanation is an attractive alter-
native. In our continuing interest in the development of
functionalization reactions of olefins, we have discovered a
hydrocyanation reaction that is conceptually different from
the existing methods that are available. Herein, we report the
cobalt-catalyzed hydrocyanation of non-activated olefins
using p-toluenesulfonyl cyanide (TsCN) and phenylsilane in
ethanol at room temperature [Eq. (1)].
hydrocyanation has been documented albeit for 1,3-dienes
only.[8]
We have recently documented that simple cobalt com-
=
plexes effect the hydrohydrazination (RO2CN NCO2R +
alkene!N-alkyl hydrazine)[9] and hydroazidation (TsN3
+
alkene!alkyl azide)[10] reactions of olefins. The methods
display broad substrate scope for a wide range of alkenes.[11]
We have been keen in investigating whether similar protocols
ꢀ
could be developed for C C bond-forming processes, which
would considerably expand the reaction and product space
accessible from olefins. We decided to test our hypothesis in
the context of the olefin hydrocyanation reaction, because
such a process would not only perhaps exhibit complementary
substrate scope to that observed with Ni catalysts, but it would
also open up new possibilities for the synthesis of useful
building blocks.
At the outset of our investigations tert-butyl-(2-methyl-
allyloxy)diphenyl silane (1) was employed as a test substrate
in combination with TsCN[12] as reagent [Eq. (2)]. We
The conversion of an olefin into a nitrile by hydro-
cyanation has long been recognized to be important, because
of the useful, simple building blocks that would be accessible.
Additionally, a mild and versatile procedure for such a
process would facilitate novel strategic approaches for the
synthesis of complex molecules. The most notable advance in
olefin hydrocyanation stems from the discovery that certain
nickel complexes catalyze the addition of hydrogen cyanide to
alkenes,[2] a reaction that has been studied in mechanistic
detail.[3] For the reported system, aryl alkenes[4] and dienes[5]
have been shown to react well at elevated temperatures,
whereas non-activated olefins[6] require the addition of Lewis
acid activators such as AlCl3. The enantioselective version has
also been documented, primarily for aryl-substituted alke-
nes.[4b,7] A typical reaction is commonly run at 60–1208C, and
proceeded to screen and examine complexes of cobalt that
had proven successful in previous investigations involving
olefin heterofunctionalization (Figure 1).
The reaction of 1.5 equiv of TsCN together with 1 equiv of
phenylsilane in the presence of Co complex 3 afforded nitrile
2 in 29% yield [Eq. (2)]. Complex 4, prepared in situ, with
1 equiv of tetramethyldisiloxane (TMDSO) provided the
hydrocyanation product 2, albeit in a meager 19% yield; and
the same reaction with [Mn(dpm)3][13] resulted in no con-
version at all. We then turned our attention to the inves-
tigation of Co complexes incorporating salen ligands.[14] We
were pleased to see that CoIII catalyst (ꢁ )-5a displayed good
activity, leading to isolation of nitrile 2 in 81% yield after 3 h.
As tBuOOH is known to facilitate the initiation period in
reactions we have studied with these catalysts,[10,15] its effect
on the reaction at hand was tested next. Indeed, addition of
30 mol% of tBuOOH shortened the reaction time to 2 h and
increased the yield to 88%. In subsequent studies, we
observed that the sterically less hindered catalysts 5b and
6b[16] were less active; consequently, we prepared and
[*] B. Gaspar, Prof. Dr. E. M. Carreira
Laboratorium für Organische Chemie
ETH Hönggerberg, HCI G336
8093 Zürich (Switzerland)
Fax: (+41)44-632-1328
E-mail: carreira@org.chem.ethz.ch
[**] This research was supported by a grant from the Swiss National
Science Foundation.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Hydrocyanation reaction of olefins.
Entry
Alkene
Product
Yield [%]
5a[a] 6a[b]
1
2
3
99
95
84
99
99
95
4
5
88
82
99
89
Figure 1. Catalysts screened in the hydrocyanation reaction.
6
7
99
86
96
87
examined the tetramethyl-substituted salen ligand[17] and its
corresponding cobalt complex 6a. When 1 mol% of 6a was
mixed with alkene 1, 1.5 equiv of TsCN, and 1 equiv of PhSiH3
in EtOH at room temperature, nitrile 2 was isolated in 99%
yield within 1 h. Importantly, the addition of tBuOOH was
not necessary, and furthermore, we were able to decrease the
amount of TsCN to 1.2 equiv without influencing the yield.
The effect of other silanes on the reaction was tested next.
Et3SiH was not active at all, and 3 equiv of Ph2MeSiH gave
only 51% of the nitrile 2 after 19 h. Me2PhSiH (3 equiv) and
TMDSO (2 equiv) provided the desired product 2 in yields of
83% and 87%, respectively. These two silanes, however,
required longer reaction times (4–6 h).
The scope of the hydrocyanation reaction employing both
protocols with catalysts 5a and 6a (Table 1) was next
examined. In general, catalyst 6a is more active, giving
equal or higher yields and shorter reaction times than 5a. All
of the monosubstituted, 1,1-disubstituted, and trisubstituted
olefins showed excellent Markovnikov selectivity as linear
nitriles were never observed. In the case of 1,2-disubstituted
alkenes conjugated to an aromatic ring (entries 12 and 13,
Table 1), cyanation occurred only at the benzylic position.
Simple alkenes, protected alcohols, esters and amides
(entries 1–7, Table 1) are well tolerated for the reaction,
with both catalysts performing equally well. In the presence of
an aldehyde or keto functionality the difference between the
two catalytic systems becomes apparent (entries 8 and 9,
Table 1), with 6a being more effective and providing the
corresponding products in higher yields. A similar trend was
observed with a trisubstituted olefin (entry 10, Table 1).
Styrene derivatives (entries 12 and 13, Table 1) provided
benzylic nitriles in moderate yields. Interestingly these
substrates proved excellent in the hydrohydrazination[9] but
failed in the hydroazidation[10,11b] reaction. a,b-Unsaturated
esters and unactivated 1,2-disubstituted cyclic olefins such as
cyclohexene failed to provide the product of hydrocyanation,
thus representing the limitations of this process. Compounds
with an exocyclic double bond (entries 14 and 15, Table 1),
however, are good substrates for the reaction. It is worth
noting that the recent advances in enantioselective biotrans-
formations of nitriles, involving hydratases, nitrilases, and
amidases, provide powerful approaches for the preparation of
8
64
81
9
10
11
12
13
40
48
73
45
63
91
92
71
55
64
14
15
88[c]
74[d]
60[c]
81[e]
[a] Conditions: catalyst 5a (1 mol%), alkene (0.5 mmol), TsCN
(0.75 mmol), tBuOOH (30 mol%), PhSiH3 (0.5 mmol), EtOH (3 mL),
argon, 238C. [b] Conditions: catalyst 6a (1 mol%), alkene (0.5 mmol),
TsCN (0.6 mmol), PhSiH3 (0.5 mmol), EtOH (2.5 mL), argon, 238C.
[c] d.r. could not be determined. [d] d.r. =17:1. [e] d.r.=3:1
optically active acids in industrial processes. Thus we envision
that a particular advantage of the method we describe to
provide access to nitriles will result when its use is coupled to
enzymatic resolution. This effectively amalgamates a con-
venient chemical transformation that is outside the realm of
enzyme-mediated reactions (olefin hydrocyanation) with
what is, by contrast, a process that is mainstream for enzymes
(RCN!RCO2H).[1d,18]
To establish the practicality of the process we scaled up
the reaction tenfold. Using only 1 mol% of catalyst 6a and 4-
phenylbutene (7) as substrate, the hydrocyanation product
was obtained in 93% yield [Eq. (3)]. Thus, the protocol
represents a convenient means to rapidly access nitriles from
olefins without recourse to specialized techniques that would
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Chemie
Chem. 2005, 452 – 456; h) A. Sharifi, F. Mohsenzadeh, M. M.
Mojtahedi, M. R. Saidi, S. Balalaie, Synth. Commun. 2001, 31,
431 – 434; i) S. Caddick, D. B. Judd, A. K. de K. Lewis, M. T.
Reich, M. R. V. Williams, Tetrahedron 2003, 59, 5417 – 5423;
j) G. Jayachitra, N. Yasmeen, K. S. Rao, S. L. Ralte, R. Sriniva-
san, A. K. Singh, Synth. Commun. 2003, 33, 3461 – 3466; k) F. Xi,
F. Kamal, M. A. Schenerman, Tetrahedron Lett. 2002, 43, 1395 –
1396; l) Z. P. Demko, K. B. Sharpless, Angew. Chem. Int. Ed.
2002, 41, 2113 – 2116; m) B. Davis, T. W. Brandstetter, C. Smith,
L. Hackett, B. G. Winchester, G. W. J. Fleet, Tetrahedron Lett.
1995, 36, 7507 – 7510.
require handling HCN or elevated pressures and temper-
atures.[19] Moreover, once the reaction has reached comple-
tion, simple removal of solvent followed by chromatography
on silica gel furnishes the desired nitrile product.
[2] a) E. S. Brown, E. A. Rick, Chem. Commun. 1969, 112; b) B. W.
Taylor, H. E. Swift, J. Catal. 1972, 26, 254 – 260; c) J. Podlech,
Science of Synthesis, Vol. 19, Georg Thieme, Stuttgart, 2004,
pp. 333 – 344.
[3] a) J.-E. Bꢀckvall, O. S. Andell, J. Chem. Soc. Chem. Commun.
1984, 260 – 261; b) C. A. Tolman, W. C. Seidel, J. D. Druliner,
P. J. Domaille, Organometallics 1984, 3, 33 – 38.
[4] a) W. A. Nugent, R. J. McKinney, J. Org. Chem. 1985, 50, 5370 –
5372; b) A. L. Casalnuovo, T. V. RajanBabu, T. A. Ayers, T. H.
Warren, J. Am. Chem. Soc. 1994, 116, 9869 – 9882; c) M.
Kranenburg, P. C. J. Kamer, P. W. N. M. van Leeuwen, D. Vogt,
W. Keim, J. Chem. Soc. Chem. Commun. 1995, 2177 – 2178.
[5] W. Keim, A. Behr, H.-O. Lꢁhr, J. Weisser, J. Catal. 1982, 78, 209 –
216.
In summary, we have documented a conceptually new
hydrocyanation reaction of non-activated olefins that gives
access to secondary and tertiary nitriles. It is a transformation
for which to date few procedures have been available. The
salient features of this process are the broad functional-group
tolerance, mild reaction conditions (room temperature,
EtOH as solvent), readily available starting materials
(TsCN, PhSiH3, catalysts, olefins), and ease of execution.
Moreover, the reaction can be conducted at preparatively
useful scales and essentially no workup is necessary. Further
exploration of the reaction to get deeper insight into this
process is underway, and the results will be reported as they
become available.
[6] W. Goertz, P. C. J. Kamer, P. V. N. M. van Leeuwen, D. Vogt,
Chem. Commun. 1997, 1521 – 1522.
[7] a) M. Hodgson, D. Parker, R. J. Taylor, G. Ferguson, Organo-
metallics 1988, 7, 1761 – 1766; b) T. Horiuchi, E. Shirikawa, K.
Nozaki, H. Takaya, Tetrahedron: Asymmetry 1997, 8, 57 – 63;
c) W. Goertz, P. C. J. Kamer, P. W. N. M. van Leeuwen, D. Vogt,
Chem. Eur. J. 2001, 7, 1614 – 1618; d) T. V. RajanBabu, A. L.
Casalnuovo, Comprehensive Asymmetric Catalysis, Vol. I (Eds.:
E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999,
p. 367; e) J. Wilting, M. Janssen, C. Mꢁller, D. Vogt, J. Am. Chem.
Soc. 2006, 128, 11374 – 11375.
[8] B. Saha, T. V. RajanBabu, Org. Lett. 2006, 8, 4657 – 4659.
[9] a) J. Waser, E. M. Carreira, J. Am. Chem. Soc. 2004, 126, 5676 –
5677; b) J. Waser, E. M. Carreira, Angew. Chem. Int. Ed. 2004,
43, 4099 – 4102.
Experimental Section
General procedure A: Catalyst 5a (3.3 mg, 0.005 mmol, 1 mol%) was
dissolved in EtOH (2 mL; absolute, Merck) at room temperature
under argon. After 2 min alkene (0.5 mmol) was added followed by
TsCN (144 mg, 0.75 mmol, 1.5 equiv; 95% purity, Aldrich,). tBuOOH
(5.5m solution in decane, 25 mL, 0.14 mmol, 0.30 equiv) was added
followed by PhSiH3 (98% ACROS, 62 mL, 0.5 mmol, 1.0 equiv) and
another portion of EtOH (1 mL). The resulting solution was stirred at
room temperature, and the reaction was monitored by TLC. After
completion (1–3 h) the solvent was removed by evaporation, and the
crude mixture purified by flash chromatography to afford the
corresponding nitrile.
General procedure B: Catalyst 6a (3 mg, 0.005 mmol, 1 mol%)
was dissolved in EtOH (2 mL; absolute, Merck) at room temperature
under argon. After 2 min alkene (0.5 mmol) was added to the red
solution followed by TsCN (115 mg, 0.6 mmol, 1.2 equiv; 95% purity,
Aldrich). Finally PhSiH3 (62 mL, 0.5 mmol, 1.0 equiv, 98% purity,
ACROS) was added, and another portion of EtOH (0.5 mL). The
resulting solution was stirred at room temperature, and the reaction
was monitored by TLC. After completion (1–3 h) the solvent was
removed by evaporation and the crude mixture purified by flash
chromatography to afford the corresponding nitrile.
[10] J. Waser, H. Nambu, E. M. Carreira, J. Am. Chem. Soc. 2005,
127, 8294 – 8295.
[11] a) J. Waser, J. C. Gonzꢂlez-Gꢃmez, H. Nambu, P. Huber, E. M.
Carreira, Org. Lett. 2005, 7, 4249 – 4252; b) J. Waser, B. Gaspar,
H. Nambu, E. M. Carreira, J. Am. Chem. Soc. 2006, 128, 11693 –
11712.
[12] For radical cyanations using TsCN see: a) S. Kim, H.-J. Song,
Synlett 2002, 2110 – 2112; b) A.-P. Schaffner, V. Darmency, P.
Renaud, Angew. Chem. 2006, 118, 5979 – 5981; Angew. Chem.
Int. Ed. 2006, 45, 5847 – 5849; c) D. H. R. Barton, J. Cs. Jaszber-
enyi, E. A. Theodorakis, Tetrahedron 1992, 48, 2613 – 2626.
[13] dpm = dipivaloylmethanato.
[14] a) T. P. Yoon, E. N. Jacobsen, Scinece 2003, 299, 1691 – 1693;
b) J. F. Larrow, E. N. Jacobsen, Top. Organomet. Chem. 2004, 6,
123 – 152.
Received: February 8, 2007
Published online: May 4, 2007
Keywords: cobalt · cyanides · homogeneous catalysis ·
.
hydrocyanation · silanes
[15] T. Tokuyasu, S. Kunikawa, A. Masuyama, M. Nojima, Org. Lett.
2002, 4, 3595 – 3598.
[16] For the use of the Mn complex of the corresponding tetramethyl-
substituted ligand see: a) J. Du Bois, J. Hong, E. M. Carreira,
M. W. Day, J. Am. Chem. Soc. 1996, 118, 915 – 916; b) J. Du Bois,
C. S. Tomooka, J. Hong, E. M. Carreira, J. Am. Chem. Soc. 1997,
119, 3179 – 3180; c) J. Du Bois, C. S. Tomooka, J. Hong, E. M.
Carreira, Acc. Chem. Res. 1997, 30, 364 – 372.
[1] a) V. Y. Kukushkin, A. J. L. Pombeiro, Chem. Rev. 2002, 102,
1771 – 1802; b) S. J. Collier, P. Langer, Science of Synthesis,
Vol. 19, Georg Thieme, Stuttgart, 2004, pp. 403 – 425; c) V. Y.
Kukushkin, A. J. L. Pombeiro, Inorg. Chim. Acta 2005, 358, 1 –
21; d) M.-X. Wang, Top. Catal. 2005, 35, 117 – 130; e) H. C.
Brown, Y. M. Choi, S. Narasimhan, Synthesis 1981, 605 – 606;
f) R. A. Michelin, M. Mozzon, R. Bertani, Coord. Chem. Rev.
1996, 147, 299 – 338; g) V. K. Yadav, K. G. Babu, Eur. J. Org.
[17] G. A. Morris, H. Zhou, C. L. Stern, S. T. Nguyen, Inorg. Chem.
2001, 40, 3222 – 3227.
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[18] a) C. OꢄReilly, P. D. Turner, J. Appl. Microbiol. 2003, 95, 1161 –
latter is more efficient in the case of the challenging trisubsti-
tuted alkene, ketone, and aldehyde (Table 1, entries 8–10). The
reaction of TsCN with alcohols is known to give sulfinate esters
in the presence of a base such as 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) or 1,4-diazabicyclo[2.2.2]octane (DABCO): D. H. R.
Barton, J. Cs. Jaszberenyi, E. A. Theodorakis, Tetrahedron 1991,
47, 9167 – 9178.
1174; b) H. E. Schoemaker, D. Mink, M. G. Wubbolts, Science
2003, 299, 1694 – 1697.
[19] It is interesting to note that ethyl 4-methylbenzenesulfinate was
isolated as a side product of the reaction. We observed that
TsCN is consumed faster in the reaction with catalyst 5a than in
the reaction employing catalyst 6a. This could explain why the
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