Rhodium(i)-catalyzed N-CN bond cleavage: Intramolecular β-cyanation of styrenes

Article abstract of DOI:10.1039/c3cc43597k

We report herein the first example of intramolecular cyanation of a styrene by a rhodium(i)-catalyzed N-CN cleavage reaction. Substituents on the arenes or the styrene alpha-position are tolerated. Our results demonstrate that alkene cyanation can indeed be atom economical.

Full text of DOI:10.1039/c3cc43597k

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Rhodium(I)-catalyzed N–CN bond cleavage:
intramolecular b-cyanation of styrenes†
Cite this: Chem. Commun., 2013,
49, 6516
Rui Wang* and John R. Falck
Received 14th May 2013,
Accepted 28th May 2013
DOI: 10.1039/c3cc43597k
www.rsc.org/chemcomm
We report herein the first example of intramolecular cyanation of a of stoichiometric metal-cyano reagents and pre-activated (sub-
styrene by a rhodium(I)-catalyzed N–CN cleavage reaction. Substi- stituted) alkenes (X = Br, Cl, I, OTf, etc.) in the presence of a
tuents on the arenes or the styrene alpha-position are tolerated. transition metal catalyst (Scheme 1, eqn (1)).17 Alternatively,
Our results demonstrate that alkene cyanation can indeed be atom there has been considerable progress towards synthesis of
economical.
3-arylacrylonitriles from boronic acids.9a,18 In 2006, Liebeskind
reported the palladium-catalyzed, copper(I)-mediated coupling
Transition metal catalyzed activation of traditionally inert of boronic acids and benzyl thiocyanate to provide alkenyl
bonds such as unactivated C–H, C–C and C–O not only make nitriles.18a Later, Hartwig disclosed an iridium-catalyzed bor-
synthetic routes simpler but also more efficient and, conse- ylation of arene C–H bonds followed by a copper-mediated
quently, this field has attracted enormous attention recently.1 cyanation of the formed arylboronate esters using Zn(CN)2 to
Of particular interest is C–C activation given the central role of access 3-arylacrylonitriles.18b Recently, Hu and Cheng et al.
this bond in organic chemistry and the challenge of selective reported a simple copper(I)-mediated procedure for the cyana-
manipulation. An important variant of C–C bond activation, tion of boronic acids with CuCN and TMSCN.18c Additionally,
i.e., C–CN activation,2 has already been demonstrated in the Yamamoto and co-workers reported a copper-catalyzed stereo-
DuPont’s adiponitrile process using catalytic nickel. The first selective hydroarylation of 3-aryl-2-propynenitriles with aryl-
example of carbocyanation reaction was realized in 2004 by boronic acid, which provided
a different route for the
Hiyama and co-workers. Subsequently, Chatani, Hiyama and synthesis of 3,3-diarylacrylonitriles (Scheme 1, eqn (2)).18e,19
Jacobsen et al. reported several key results for the generation of Most recently, Jiao and co-workers reported a strategy which
C–H,3 C–Si,4 C–C4b,5 and C–B6 bonds via activation of the C–CN relies upon activated C(sp3)–N coupling reactions, i.e., trans-
bond following Hiyama’s precedent.5b Generally, metals such formation of alkyl arenes or alkenes with TMSN3 to the corres-
as Fe and Rh are utilized in tactical combination with organic ponding alkenyl nitriles catalyzed by inexpensive and nontoxic
silicon reagents or metal-Lewis acid bifunctional catalysis.5g,7 iron(II) chloride (Scheme 1, eqn (3)).20 All of these methods
Only a few cases involving O–CN8 activation have been realized exploited pre-activated precursors for high atom economy.21
recently while N–CN9 cleavage is even more rare. Herein, we
report that Rh(I) can activate the N–CN bond under mild
conditions and the resultant intermediate is utilized in the
intramolecular cyanation of styrenes to give 3-arylacrylonitriles
(cinnamonitriles) in good yields. 3-Arylacrylonitriles find
numerous applications in the preparation of pharmaceutical,
agrochemical, and material science/optoelectronic com-
pounds.10 The conjugated alkene is readily functionalized11–15
whereas the nitrile16 is a useful precursor for a wide range of
functionalities, e.g., aldehydes, acids, amides, amines and so
on. 3-Arylacrylonitriles are commonly prepared by the reaction
UT Southwestern Medical Center, Biochemistry, 5323 Harry Hines Blvd., Dallas,
TX, USA. E-mail: Rui.Wang@utsouthwestern.edu, shairwang@gmail.com
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Strategies for the synthesis of 3-arylacrylonitriles.
c3cc43597k
c
6516 Chem. Commun., 2013, 49, 6516--6518
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However, one of the most straightforward approaches to from 5 mol% to 10 mol%, the reaction temperature from 90 1C to
3-arylacrylonitrile synthesis, i.e., transition metal catalyzed 120 1C and the reaction time from 12 h to 48 h (Table 1, entry 12).
cyanation of unactivated styrenes, has received scant attention
With optimised conditions in hand, we examined the scope
(Scheme 1, eqn (4)).22 Due to the high affinity of many metals for of cyanation of styrenes (Table 2). Alkyl substituents in the
cyano ligands and the moderate nucleophilic nature of cyanide, olefinic alpha position led to acrylonitriles 2b–5b in good yields
transition metal mediated insertion or addition of cyanide to (Table 2, entries 1–4), although the influence of the increasing
alkenes is quite challenging.23 Considering these difficulties, we steric bulk was evident in somewhat decreased yields. With
initiated our research using a model compound 1a.
substituted arenes in the olefinic a-position, the cyanation
We initially screened different rhodium complexes along reaction gave 6b–11b in moderate yields (Table 2, entries
with a suitable ligand (Table 1, entries 1–4). It was found that 5–10), whether it contained electron-donating groups or electron-
[RhCl(COD)]2 (COD = cyclooctadiene) combined with the DPE- withdrawing groups. Importantly, we also found that a substituent
phos ligand gave a promising outcome with a 65% isolated in the alpha position of the alkene is necessary for the cyanation to
yield of 1b under unoptimized conditions, and only trace occur. Substrates without an alpha substituent or with a beta-
amount of a double bond isomer was detected. Other Rh(I) position (either electron-rich or poor) substituent failed to give
species such as [RhOH(COD)]2, [RhBF4(COD)]2 or Wilkinson’s acrylonitrile.24 Various arene substituents (12a–15a) were also
catalyst were no better than the original catalyst. Although the examined and, in most cases, afforded moderate yields (Table 2,
conversion of the reaction was almost quantitative, the major entries 11–14); electron-rich arenes (12a and 14a) resulted in
by-product was 1c, derived from simple de-cyanation. Subse- higher yields (Table 2, entries 11 and 13) than electron-deficient
quently optimization attempts via (i) water-exclusion (added 4 Å arenes (13a and 15a) (Table 2, entries 12 and 14). The low yield of
sieves or MgSO4), (ii) alternative metal catalyses (Table 1, 13b might be the consequence of a competitive reaction between
entries 5 and 6) and (iii) different solvents (Table 1, entries 7 the chloro-substituent and the metallic catalyst.25
and 8) proved to be disappointing. Palladium species afforded
To demonstrate the potential synthetic utility of the above
low yields while solvents such as dichloroethane and aceto- styrene cyanation, 1b was transformed into indole 1d in 70%
nitrile afforded no better yields than the original reaction condi-
Table 2 Reaction substrate scopea
tions. We also tried various phosphine ligands. For example,
triphenylphosphine was not effective while dppf gave a high
conversion but relatively low yield compared with the DPEphos
ligand (Table 1, entries 9–11). To seek whether the reaction is
catalyzed by metal or phosphine, 1a was heated to 120 1C in the
absence of the metal (Rh(I)) or the catalyst (DPEphos) for 24 h,
and the starting material was recovered. Also, the Ts group is
necessary for this transformation. Finally, improvements in the
yield of 1b were realized when the catalyst loading was increased
Table 1 Optimization of reaction conditions
Entrya
Catalystb
Ligand
Solventc
Yieldd [%]
1
2
3
4
5
6
7
8
[RhCl(COD)]2
[RhBF4(COD)]2
RhCl(PPh3)3
[RhOH(COD)]2
Pd2(dba)3
PdCl2(dppf)2
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(COD)]2
[RhCl(COD)]2
DPEphos
DPEphos
None
DPEphos
Dppe
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
CH3CN
Toluene
Toluene
Toluene
Toluene
65
51
50
40
31
42
43
44
53
48
60
81
None
DPEphos
DPEphos
PPh3
Dppe
Dppf
9
10
11
12
DPEphos
a
Entries 1–11: Rh catalyst 5 mol%, ligand 10 mol%, 0.1 M 1a, 90 1C,
12 h. Entry 12: Rh catalyst 10 mol%, ligand 10 mol%, 0.1 M 1a, 120 1C,
b
c
a
48 h. Reduced catalyst loadings led to low conversions. All solvents
Conditions: Rh catalyst 10 mol%, ligand 10 mol%, 0.1 M xa, 120 1C,
d
b
were freshly purified. Isolated yield after silica gel flash chromato-
48 h. Xantphos was replaced by DPEphos. DPEphos as a ligand gave
less than 10% yield. Xantphos = 4,5-bis(diphenyl phosphino)-9,9-
dimethylxanthene.
graphy, 1c was isolated in approximately 5% yield. Configuration of 1b
was confirmed using COSY and NOESY, see ESI.
c
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yield (Scheme 2). Given the rapid route for the synthesis of
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To gain an insight into the reaction mechanism, we inves-
tigated the reaction of [D2]-9a (80 carbon atom% D). Under
standard reaction conditions, we obtained N-tosyl aniline ([D2]-
9b) with 68% D content. The result indicated that an intra-
molecular process existed, i.e., the Rh(I) mediated cyano group
transferred from a nitrogen atom to the terminal alkene
(Scheme 3).
In conclusion, we report the first example of intramolecular
cyanation of a styrene by a rhodium(I)-catalyzed N–CN cleavage
reaction. Substituents on the arenes or the styrene alpha-
position are tolerated. Our results demonstrate that alkene
cyanation can indeed be atom economical. Furthermore, the
cyanation product, 1b, underwent an additional intramolecular
C–N coupling to afford 3-Me-2-CN indole 1d. This synthetic
route provides an efficient construction of 3-alkyl/aryl-2-CN
indole derivatives. Current efforts are focused on discovering
intermolecular cyanation and/or with other cascade reactions
to expand the utility of this methodology.
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´
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We thank the NIH (GM31278) and the Robert A. Welch
Foundation (GL625910) for financial support.
Notes and references
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c
6518 Chem. Commun., 2013, 49, 6516--6518
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