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Cooperative palladium/Lewis acid-catalyzed transfer hydro-cyanation of alkenes and alkynes using 1-methylcyclohexa-2,5-diene-1-carbonitrile Anup Bhunia, Klaus Bergander, and Armido Studer J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 04 Nov 2018 Downloaded from http://pubs.acs.org on November 4, 2018
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Journal of the American Chemical Society
Cooperative palladium/Lewis acid-catalyzed transfer hydrocyanation of alkenes and alkynes using 1methylcyclohexa-2,5-diene-1-carbonitrile Anup Bhunia,a Klaus Bergandera and Armido Studer*a aOrganisch-Chemisches
Institut, Westfalische Wilhelms-Universität, Corrensstraβe 40, 48149 Münster, Germany
Supporting Information Placeholder ABSTRACT: The catalytic transfer hydrocyanation represents a clean and safe alternative to hydrocyanation processes using the toxic HCN gas. Such reactions provide access to pharmaceutically important nitrile derivatives starting with alkenes and alkynes. Herein, an efficient and practical cooperative palladium/Lewis acid catalyzed transfer hydrocyanation of alkenes and alkynes is presented using 1-methylcyclohexa-2,5-diene-1-carbonitrile as a benign and readily available HCN source. A large set of nitrile derivatives (> 50 examples) are prepared from both aliphatic and aromatic alkenes with good to excellent anti-Markovnikov selectivity. A range of aliphatic alkenes engage in selective hydrocyanation to provide the corresponding nitriles. The introduced method is useful for chain walking hydrocyanation of internal alkenes to afford terminal nitriles in good regioselectivities. This protocol is also applicable to late stage modification of bioactive molecules.
INTRODUCTION The development of practically applicable catalytic transfer processes that enable in situ transfer of an atom or a functional group from one molecule to another, which is also relevant in biological systems, is of great importance in organic synthesis.1 Transfer hydrogenation using 1,4cyclohexadiene (CHD) or alcohols as H2-equivalents has been used widely for reduction of -systems.2 Along with the “simple” H2-transfer, the conceptual approach is also applicable to the transfer of functional moieties. In such processes, two distinct compounds undergo facile defunctionalization/functionalization through a transmitting functional group.3 The successful realization of the transfer functionalization strategy relies on several key factors: i) the nature of the interchanging functional group; ii) the stability of the residual part of the donor, which provides the thermal driving force; iii) the nature of the acceptor compound, and the thermodynamic as well as kinetic stability of the resulting product. Importantly, transfer or shuttle catalysis helps avoiding the use of gaseous/hazardous and/or unstable starting materials. In this context, the cyclohexadiene core structure has proved to be a highly efficient platform for the design of donors in such functional group transfer processes. Compounds comprising the CHD core (Scheme 1) act as pro-aromatic compounds and upon transfer defunctionalization they gain 33-36 kcal/mol arene resonance stabilization energy, that is harvested to drive the targeted transfer reaction.4 In 1995, Walton, Cardellini and co-workers demonstrated the radical alkene hydroalkylation using cyclohexa-2,5-diene-1-carboxylates as reagents with di-tert-butylperoxide as a radical initiator (Scheme 1a).5 Building on this seminal study our laboratory
has introduced silylated CHD reagents, which have been successfully used in radical transfer hydrosilylations (Scheme 1b).6b-c Notably, these reagents have also found application in tin-free radical dehalogenations, deselanations and deoxygenations.6a The same conceptual approach has later been successfully applied to the radical transfer hydroamidation using aminated CHDs as reagents.7 These cascades proceed via cyclohexadienyl radical intermediates A and B. Scheme 1. 1-Susbtituted cyclohexa-2,5-dienes reagents for functional group transfer reactions
as
a. Cardellini, Walton & co-workers R CO2R1
R CO2R1
R radical initiator
+
+
H
-CO2
CN H H pro-aromatic
R1 A intermediate
CN driving force aromatization
b. Studer & co-workers R FG
R
R2 +
R3
R
R2
radical initiator
1
R4
R3 + H
FG = SiR3, NR2
R FG FG R1 B intermediate
R4
H H c. Oestreich & co-workers R FG
R
R2 +
R3
R1 R4
R2
cat. Lewis acid
R3 + H
FG = SiR3, GeR3, H
H H
R4
R FG FG R1
+ C intermediate
d. Present work, transfer hydrocyanation R CN
HCN free nitrile synthesis CN anti-Markonikov selectivity R R broad scope R1 R1 + late stage hydrocyanation H 4 R R4 chain walking cooperative palladium/Lewis acid catalysis R2
3
H H
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cat. Pd(0) cat. Lewis acid
R2
3
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More recently, a significant advance has been achieved by Oestreich and co-workers, who developed Lewis acid (electron-deficient triarylboranes) catalyzed ionic transfer hydrosilylation,8a hydrogermylation8b and hydrogenation8c-d of alkenes using CHD reagents (Scheme 1c). These LA-catalyzed processes proceed through the Wheland intermediate C. In a continuation of our program, we sought to further explore and expand the synthetic utility of CHD-based functional group transfer chemistry. While taking the advantage of pro-aromaticity, we envisaged that 1methylcyclohexa-2,5-diene-1-carbonitrile (2a), that is readily prepared in large scale by reductive Birch methylation of benzonitrile with NH3, Li, and iodomethane (see the Supporting Information, SI), can act as an easily stored, non-toxic HCN donor in transfer hydrocyanation reactions (Scheme 1d). Notably, hydrocyanation of alkenes with zero-valent palladium and nickel complexes are highly attractive from both an industrial and academic perspective.9 However, these reactions currently suffer limitations such as the necessity of using poisonous HCN gas. Considering the generally high reaction temperatures required, volatile reagents like acetone cyanohydrin and (Me)3SiCN applied are also not ideal.10 Moreover, reported methods give mostly the branched alkyl nitriles and the selective synthesis of the linear congeners remains challenging.11 Along these lines, Morandi and co-workers recently developed an elegant Nicatalyzed transfer hydrocyanation of terminal alkenes using alkylnitriles as a HCN donors.12 These Ni-catalyzed transfer hydrocyanations are reversible and the product nitriles can be reverted back to the starting alkenes. This problem was successfully addressed by using isovaleronitrile as the donor leading to the gaseous isobutylene as the side product, which is readily removed from the reaction mixture to drive the equilibrium.
RESULTS AND DISCUSSION To explore the possibility of HCN transfer from 1methylcyclohexa-2,5-diene-1-carbonitrile 2a to -methyl styrene (1a), radical and ionic processes were tested first. Disappointingly, we found that both the radical approach and also Lewis acid (LA) catalysis failed to deliver the targeted transfer hydrocyanation product 3a. However, switching to transition metal catalysis, we realized that cooperative Pd/LA catalysis allows forming the desired nitrile product along with toluene as the by-product. The best result was achieved by using Pd(PPh3)4 (4 mol %)/DPEphos (8 mol%) in combination with BPh3 (20 mol%) as a co-catalyst in dioxane at 110 °C for 20 h to deliver the targeted 3a in 89% yield (Scheme 2). DPEphos has a bite angle of around 105° and other commonly used bisphosphine ligands like dppe, dppp, binap all having smaller bite angles resulted in lower conversions.13 BPh3 can be replaced by B(C6F5)3 but LA-cocatalysis with BF3, AlMe2Cl, AlMe3 and AlCl3 gave worse results. Other sterically and electronically diverse CHDs 2b-2e led to inferior results. Notably, replacing the CHD 2a with isovaleronitrile (2f) as the HCN donor afforded 3a in only
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15% yield, documenting the advantage of the CHD-system over isovaleronitrile in these Pd-catalyzed transfer hydrocyanations. We found that CHD 2a can also be used in combination with Ni-catalysis, albeit with lower efficiency as compared t0 the Pd-mediated process (34% yield, for the detailed optimization study, see SI). Note that activation of nitriles by LA cocatalysis was previously demonstrated by Tolman, Jones, Nakao and Hiyama.14 Scheme 2. Palladium/Lewis acid cocatalyzed transfer hydrocyanation of 1a Pd(PPh3)4 (4 mol%) DPEPhos (8 mol%) BPh3 (20 mol%)
CN
Ph (1.0 equiv)
+ (1.5 equiv)
1a Et CN
dioxane, 110 °C 20 h
2a i-Pr CN
CN Ph
+
3a 89% CN
CN CN
2b (53%)
2c (39%)
2d (22%)
2e (0%)
2f (15%)
To study the scope and limitations of the new hydrocyanation method, various alkenes were reacted with the reagent 2a under the optimized conditions. As shown in table 1, the transfer hydrocyanation can be extended to a range of other -substituted styrenes, giving the corresponding linear nitriles in 59-92% yield (3a-3i). Various substituents at the phenyl ring and at the position were tolerated. Less activated 2-substituted aliphatic alkenes such as (2-methylallyl)benzene and 2-(2methylallyl)naphthalene gave 3j and 3k in reasonable yields. In all these cases, the reaction proceeded with high regioselectivity (linear:branched ≥ 20:1). Styrene derivatives bearing an iodo or a bromo-substituent at the aryl moiety did not work. Transfer hydrocyanation of styrenes lacking the -substituent gave the desired products in high yields with good linear to branched selectivity (3l-3t). The high regioselectivity toward formation of the linear nitriles with aryl alkenes as substrates is worth noting.15 In general, branched nitriles are favored for most reported hydrocyanation processes. Vinyl silane and 9-vinyl-9H-carbazole also afforded the cyanated products 3u and 3v in high yields. However, heteroaryl-alkenes such as 2-vinyl pyridine or 4-vinyl pyridine did not engage in this sequence. The hydrocyanation was also effective for terminal aliphatic alkenes lacking any -substituent. The corresponding linear nitriles were isolated in good to excellent yields (3w-3ag). Notably, the hydrocyanation of 1-hexene and 1-octene afforded the terminal nitriles 3w and 3x with complete regioselectivities in high yields.16 These results were particularly remarkable taking into consideration the low selectivity profiles found in related hydrocyanation processes using existing methodology, specifically employing Ni-catalysis. The significantly improved l/b ratios as compared to those obtained for the complementary Ni-catalyzed transfer hydrocyanations using isovaleronitrile12 is an important point considering the higher cost of the CHD-type reagent 2a. The presence
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Journal of the American Chemical Society of various functional groups did not suppress the reaction and non-conjugated dienes participated in the transfer hydrocyanation (3ah). Table 1. Transfer hydrocyanation of various alkenes and alkynesa A -Substituted alkenes
CN
CN Cl
CN Me
3a 89% (87%)b
CN Ph
3b 80%
CN
CN
CN
CN
Me
3c 86%
3d 92%
3e 81%
3f 87%
3g 78%
3h 59%
B. Styrenesd CN
CN CN 3i 74%c
CN
3j 86%
3l 90% (90:10)
3m 84%
3n 87% (91:9)
Me CN
CN
CN
F 3C
O
3k 90%
Me
Me
Me
Me
CN
F5
3r 75%
3q 90%
3t 95% (90:10)
3s 85% (92:8)
CN
N
Si OMe 3p 82% (89:11)
3o 94% (90:10)
C. Activated alkenes
CN
CN
CN
CN
CN
3u 96%
3v 83%
D. Aliphatic alkenesd Me CN
CN 3w 99%e
CN
CN
3x 80%e
3y 78% (85:15)
3aa 81% (90:10)
3z 88% (94:6)
O O
O
CN O
O
3ac 85% (90:10)
CN
O
CN
3ai 75% (86:14)
CN
O S N O
EtO2C EtO2C CN
3af 77% (90:10)
3ag 86% (90:10)
CN 3ah 68%
f
Ph
CO2Me
Ph
Ph
3aj 73% (78:22)
3ab 84% (90:10)
CN
CN
3ae 90% (90:10)
3ad 93% (92:8)
E. Chain walking hydrocyanation of internal alkenes
Me
N
O
O
CN
CN
CN
CO2Et
Ph
CN
CN
3al 67% (84:16)
3ak 77% (82:18)
CN 3am 70% (80:20)
CN
Ph Ph
3an 68% (85:15)
Ph CN
3ao 79% (90:10)
F. Diastereoselective hydrocyanationd CN CN
tBu
NC
CN
MeO
Me
H tBu
CN
H
Ph
CN
3ap 63% dr 20:1 3aq 91% rr 2:1 dr 20:1
H
H
H
+
CN
OMe
H
H H
O
CN
MeO
H
3ar 84% dr 20:1
3au 73% dr 5:1
3at 78% dr 3:1
3as 90% dr 20:1
3av 66% dr 1:1
G. Alkynes H
H O 3aw 75% dr 1:1
CN
CN
H TMS
5a 87% (96:4)
CN TMS
5b 33%
H
Ph
H
TMS
CN
TMS
5c 62%g
S CN
5d 72%
aStandard
conditions: Pd(PPh3)4 (4 mol %), DPEphos (8 mol%) and BPh3 (20 mol%), dioxane (3.0 mL), 110 °C, 20 h, Isolated yield on a 0.5 mmol scale. bReaction performed in 2.0 mmol scale. cReaction performed in 1.0 mmol scale. dIn parenthesis ratio of linear to branched product and reaction performed with B(C6F5)3 (15 mol%) instead of BPh3. eGC yield reported fReaction performed with B(C6F5)3 (15 mol%) instead of BPh3 and Xantphos in place of DPEphos for 40 h. g15% of the other regioisomer isolated. The highlighted red -bond indicates the former double bond in the substrate alkene.
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Interestingly, internal alkenes afforded mainly the terminal nitriles with good selectivities over all other possible branched nitriles under slightly modified conditions (3ai-3ao). Using 5-decene as a starting material, we observed that under the standard conditions the antiMarkovnikov product 1-cyanodecane was obtained with 46:54 (l:b) regioselectivity and the branched nitriles were formed as a mixture of the 4 possible isomers (see SI).17 We found that with Xantphos as the ligand, the linear to branched ratio could be further increased to 86:14 (see the SI). Increased selectivity clearly indicate that Xantphos supports the β-hydride elimination/migratory insertion sequence (metal walking) thereby changing the position of the metal without dissociation of the alkene (chain walking). The sequence is initiated by the reversible hydropalladation of the internal alkene and is driven by the formation of a thermodynamically more stable terminal carbo-palladium intermediate and/or by faster reductive elimination of the primary alkyl-Pd-intermediate over its secondary congeners18 (see also mechanistic discussion below). We next addressed diastereoselective transfer hydrocyanations. Reaction with the strained norbornene worked well to provide the cyanated product 3ap with good yield and very high exo-selectivity. Using cyclic alkene 1q, we found highly diastereoselective equatorial cyanide incorporation with 2:1 regioselectivity (3aq).19 Hydrocyanation also proceeded smoothly on (4methylenecyclohexyl)benzene to furnish 3ar in 80% yield with very good diastereoselectivity (20:1). A high selectivity (20:1) was also noted for the steroid derivative 3as. Late stage functionalization of more complex alkenes derived from O-Me-(-)-isopulegol, estrone and dihydrocarvone gave the corresponding nitriles 3at-3av in moderate diastereoselectivity. Chemoselective hydrocyanation of (S)-(+)-carvone afforded 3aw and the enone functionality remained unreacted. Pleasingly, reaction with aliphatic and aromatic internal alkynes worked to provide alkenyl nitriles 5a-5d in moderate to good yields and high regioselectivities. Whereas the symmetrical non-aromatic alkynes delivered the expected cis-hydrocyanation products 5a and 5b, the aromatic congeners provided the trans-product (see 5c and 5d). We assume that in the latter two cases, the initial cisproduct isomerizes under the reaction conditions to the thermodynamically more stable trans-isomers.12a Notably, Ni-catalyzed transfer hydracyanation of aryl-TMS-alkynes provided the regioisomeric products,12a further documenting the complementary of the herein introduced method over existing methodology. Unfortunately, terminal alkynes did not work under the tested conditions. To shed light on the mechanism of this transfer hydrocyanation, additional experiments were conducted (see Scheme 3). We reacted an equimolecular mixture of the linear and branched nitriles 3x and 3ax with norbornene as the limiting substrate in the absence of reagent 2a under optimized conditions. The branched 3ax (41%) and linear nitrile 3x (44%) were consumed in almost equal amounts (Scheme 3, eq 1).20 This result shows that
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both branched and linear nitriles are active HCN donors.21 Moreover, in this experiment unreacted nitrile 3x (8 C atoms) was not converted to its branched isomer 3x’ and accordingly branched 3ax (9 C atoms) not to its corresponding linear nitrile 3ax’. A similar result was also noted with nitriles 3l and 3l’, where both nitriles were consumed in equal amounts (Scheme 3, eq 2). However, as compared to the reaction with the couple 3ax/3ax’, a higher conversion was achieved in the latter case. To address the reversibility of the hydrocyanation, we reacted in two separate experiments 3ax and 3ax’ under optimized conditions in the absence of 1-nonene. Interestingly, in both cases the starting nitriles could be recovered without formation of the other regioisomer (Scheme 3, eqs 3 and 4). Scheme 3. Mechanistic studies CN
3x (56%)
CN
3ax (59%)
(0.125 mmol) 3x
norbornene
+
CN
+
(1)
optimized conditions
CN (0.125 mmol) 3ax
CN 3x' (0%)
CN (0.125 mmol) 3l
CN
norbornene
+
3ax' (0%)
3l (8%) +
optimized conditions
(2)
3l' (8%)
CN (0.125 mmol) 3l' optimized conditions CN 3ax
CN
optimized conditions
D3C CN +
Ph 1ab
1ab
2a-d3
+
3ax' (0%, A) 3ax' (10%, B)
A: no 1-nonene B: 1 equiv of 1-nonene
3ax'
Ph
CN
A: no 1-nonene B: 1 equiv of 1-nonene
optimized conditions
CN
(3)
3ax (99%, A) 3ax (90%, B)
CN + 3ax' (99%, A) 3ax' (99%, B)
CN
(4)
3ax (0%, A) 3ax (
