Palladium and Lewis-Acid-Catalyzed Intramolecular Aminocyanation of Alkenes: Scope, Mechanism, and Stereoselective Alkene Difunctionalizations

Article abstract of DOI:10.1021/jacs.8b01330

An expansion of methodologies aimed at the formation of versatile organonitriles, via the intramolecular aminocyanation of unactivated alkenes, is herein reported. Importantly, the need for a rigid tether in these reactions has been obviated. The ease-of-synthesis and viability of substrates bearing flexible backbones has permitted for diastereoselective variants as well. We demonstrated the utility of this methodology with the formation of pyrrolidones, piperidinones, isoindolinones, and sultams. Furthermore, subsequent transformation of these motifs into medicinally relevant molecules is also demonstrated. A double crossover ¹³C-labeling experiment is consistent with a fully intramolecular cyclization mechanism. Deuterium labeling experiments support a mechanism involving syn-addition across the alkene.

Full text of DOI:10.1021/jacs.8b01330

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Palladium and Lewis-Acid-Catalyzed Intramolecular Aminocyanation
of Alkenes: Scope, Mechanism, and Stereoselective Alkene
Difunctionalizations
Zhongda Pan,† Shengyang Wang,† Jason T. Brethorst, and Christopher J. Douglas*
Department of Chemistry, University of MinnesotaTwin Cities, 207 Pleasant St. SE, Minneapolis, Minnesota 55455, United States
S
* Supporting Information
ABSTRACT: An expansion of methodologies aimed at the
formation of versatile organonitriles, via the intramolecular
aminocyanation of unactivated alkenes, is herein reported.
Importantly, the need for a rigid tether in these reactions has
been obviated. The ease-of-synthesis and viability of substrates
bearing flexible backbones has permitted for diastereoselective
variants as well. We demonstrated the utility of this
methodology with the formation of pyrrolidones, piperidi-
nones, isoindolinones, and sultams. Furthermore, subsequent transformation of these motifs into medicinally relevant molecules
is also demonstrated. A double crossover 13C-labeling experiment is consistent with a fully intramolecular cyclization mechanism.
Deuterium labeling experiments support a mechanism involving syn-addition across the alkene.
Scheme 1. Synthesis of Lactams and Sultams by N−CN
Bond Activation and Aminocyanation of Alkenes
1. INTRODUCTION
Nitriles are versatile building blocks in organic chemistry found
in pharmaceuticals, cosmetics, and organic materials.1 Recent
advances in cyanation reactions using nonmetallic cyanating
agents hold promise for minimizing the environmental
concerns associated with metal cyanides.2 The DuPont
adiponitrile process represents a classic industrial application
of the catalytic hydrocyanation reaction of alkenes.3 However,
compared with the well-established cyanide addition reactions
to polar functional groups,4 cyanide addition reactions to
nonpolar C−C multiple bonds, such as alkenes and alkynes, are
substantially more challenging.5
Recently, new catalytic approaches for accessing function-
alized nitriles by cyanofunctionalization reactions of alkenes (or
alkynes) have been discovered. The addition of a C−CN or
heteroatom−CN σ-bond across a nonpolar C−C π-bond
installs new C−CN bonds in conjunction with vicinal C−C,6
C−B,7 C−Si,8 C−Ge,9 C−Sn,10 C−Br,11 C−S,12 C−O,13 or
C−N14,15 bonds in a single operation. Nakao’s group reported
palladium/Lewis-acid-catalyzed intramolecular oxycyanation13a
and aminocyanation14a of alkenes through the activation of O−
CN bonds of cyanates and N−CN bonds of cyanamides,
respectively. These transformations, including a preliminary
enantioselective variant, enable rapid construction of sub-
stituted dihydrobenzofuranes, indolines, and pyrrolidines. We
independently discovered Rh(I)/BPh3-catalyzed and B(C6F5)3-
catalyzed aminocyanation of alkenes to access indolines and
tetrahydroquinolines (Scheme 1, part a).14b For our metal free
process, a recent computational study postulated a concerted
asynchronous alkene addition mechanism.14c Very recently, Shi
and co-workers demonstrated an oxycyanation of methylene-
cyclopropanes triggered by N−CN bond cleavage, leading to
the formation of benzo[d][1,3]oxazines.13b
Despite these advances, current aminocyanation methods are
typically restricted to constructing heterocycles containing rigid
aromatic backbones (e.g., indolines and tetrahydroquinolines)
or requiring activated alkenes (e.g., methylenecyclopropanes).
Received: February 2, 2018
© XXXX American Chemical Society
A
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Table 1. Optimization of Aminocyanation Conditions
a
entry
palladium
ligand
Lewis acid (equiv)
T (°C)
yield of 2a (%)
b
b
c
1
BPh3 (0.5)
B(C6F5)3 (0.5)
AlCl3 (0.5)
BPh3 (0.5)
BPh3 (0.5)
BPh3 (0.5)
BPh3 (0.5)
BPh3 (0.4)
BPh3 (0.4)
BPh3 (0.4)
BPh3 (0.4)
BPh3 (0.4)
BPh3 (0.4)
BPh3 (0.4)
100
80
80
90
90
90
90
80
80
80
80
80
80
80
80
80
80
0
0
0
2
3
4
CpPd(1-phenylallyl)
Pd(PPh3)4
Xantphos
87
81
67
69
5
6
Pd(OAc)2
Xantphos
Xantphos
7
Pd2dba3
d
b
8
CpPd(1-phenylallyl)
CpPd(1-phenylallyl)
CpPd(1-phenylallyl)
CpPd(1-phenylallyl)
CpPd(1-phenylallyl)
CpPd(1-phenylallyl)
CpPd(1-phenylallyl)
CpPd(1-phenylallyl)
CpPd(1-phenylallyl)
CpPd(1-phenylallyl)
dppe
0
9
dppp
23
49
72
93
81
10
11
12
13
14
15
dppb
DPEphos
Xantphos
Nixantphos
DBFphos
Xantphos
Xantphos
Xantphos
b
0
e
<20
g
f
16
BPh3 (0.4)
89
g
f
17
BEt3 (0.4)
99
a
b
1
Determined by H NMR analysis using p-methoxyacetophenone as the internal standard. Only 1a and 1a′ detected by NMR spectroscopy.
c
d
Decomposition of 1a. Bite-angle values obtained from ref 21: dppe 85°; dppp 91°; dppb 98°; DPEphos 102°; Xantphos 111°; Nixantphos 114°;
e
f
g
DBFphos 131°. Complex reaction mixture. Yield after column chromatography. Conditions applied to further substrate scope study. dppe = 1,2-
bis(diphenylphosphino)ethane; dppp = 1,3-bis(diphenylphosphino)propane; dppb = 1,4-bis(diphenylphosphino)butane; DPEphos = bis[(2-
diphenylphosphino)phenyl] ether; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Nixantphos = 4,6-bis(diphenylphosphino)-10H-
phenoxazine; DBFphos = 4,6-Bis(diphenylphosphino)dibenzofuran.
We envisioned that the cleavage of N−CN bonds of N-acyl and
N-sulfonyl cyanamides (1), followed by subsequent addition
across an unactivated alkene could take place without the
templating effect of an aromatic ring. Further, the N-acyl or N-
sulfonyl group, if placed in the forming ring, would enable the
synthesis of substituted lactams or sultams bearing a nitrogen-
substituted quaternary stereocenter (2, Scheme 1b).16 Unex-
plored in previous studies, these heterocycles are valuable
synthetic targets found in medicinally relevant molecules, such
as isoindolinone JM-1232 (a sedative drug)17a and isoindoli-
none 8 (a renin inhibitor),17b as well as sultam 9, a tumor
necrosis factor-α converting enzyme (TACE) inhibitor
(Scheme 1c).17c Furthermore, a pre-existing stereocenter on
the alkyl tether offers the potential for stereoselective
cyanofunctionalization, which has been rarely examined.
and Xantphos (10 mol %) afforded γ-lactam 2a in 87% yield
alongside a small amount of 1a′ (entry 4). This result showed
that the palladium/Lewis acid strategy developed by Nakao’s
group was also applicable to an alkyl-tethered cyanamide
substrate.14a Remarkably, a reaction using Pd(PPh3)4 and BPh3
afforded a slightly lower yield of 2a than the Xantphos/
CpPd(1-phenylallyl) system (81% versus 87%), offering a
simple and affordable alternative catalytic system (entry 5).
Other palladium sources, such as Pd(OAc)2 and Pd2dba3 were
less effective paired with Xantphos when compared with
CpPd(1-phenylallyl) (entries 6 and 7).20 Examination of
bidentate phosphine ligands correlated the bite angle of ligands
with their efficacy (entries 8−14).21 Thus, ligands with an
increased bite angle generally afforded a higher yield of product,
with Xantphos being optimal (entry 12). Nixantphos, which has
a bite angle (114°) close to that of Xantphos (111°) performed
similarly (entry 13), whereas further increasing the bite angle
shut down the reaction (entry 14). A control reaction without
BPh3 gave a small amount of 2a along with other, unidentified,
byproducts (entry 15). Under the optimized conditions of
heating 1a in toluene at 80 °C in the presence of CpPd(1-
phenylallyl) (10 mol %), Xantphos (10 mol %), and a boron
Lewis acid (40 mol %), product 2a was isolated in 89% and
99% yield with BPh3 and BEt3, respectively (entries 16 and 17).
2.2. Scope of Aminocyanation of N-Acyl Cyanamides
1. We examined the substrate scope of aminocyanation
reactions, starting with cyanamides bearing various aryl
substituents that we prepared from readily available anilines.
(Table 2). N-Phenyl cyanamide 1b and substrates bearing tert-
butyl, fluoro, chloro, methoxy, and acetoxy groups para to the
2. RESULTS AND DISCUSSION
2.1. Reaction Optimization. The cyanamide substrates
employed in previous studies typically required 5−6 steps to
synthesize, including multiple purifications by column
chromatography.14a,b We prepared N-acyl cyanamide 1a from
diphenylacetic acid, β-methallyl chloride, and p-toluidine in just
three total steps.18 Our initial attempt at aminocyanation of 1a
with a boron Lewis acid (BPh3 or B(C6F5)3) alone resulted in
incomplete consumption of 1a and formation of byproduct 1a′,
the product of reductive decyanation (Table 1, entries 1 and
2).19 Attempted aminocyanation of 1a with AlCl3 led to
decomposition (entry 3). Interestingly, aminocyanation reac-
tion with CpPd(1-phenylallyl) (10 mol %), BPh3 (40 mol %),
B
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a
Table 2. Substrate Scope of Aminocyanation Reactions of N-Acyl Cyanamides 1
a
Reaction conditions: CpPd(1-phenylallyl) (10 mol %), Xantphos (10 mol %), BPh3 or BEt3, PhMe (1.0 mL). Reaction time: 30 h (2h, 2m); 36 h
(2u, 2y, 2aa); 48 h (2n, 2s, 2ab, 2ah); 24 h (all other entries). All yields are isolated yields. The structures of 1b−1ak are shown in the Supporting
b
c
d
e
Information. Run with 15 mol % Pd/Xantphos. Run in m-xylene. Run with 20 mol % Pd/Xantphos. Unconsumed staring material. Tol = 4-
methylphenyl, PMP = 4-methoxyphenyl.
cyanamide moiety cyclized into the corresponding pyrrolidones
in good to excellent yields (2b−2g). Substrates containing an
electron-withdrawing aryl substituent (R = Ac, Cl, CF3,
CO2Me; 1h−1k) were more prone to reductive decyanation.
By increasing the amount of Lewis acid and lowering reaction
temperature, we obtained satisfactory yields for 1h−1k (67−
92%). Substrates bearing one or two m-OMe substituents
provide products 2l and 2m in good yield, whereas an o-methyl
substitution resulted in a sluggish reaction and modest yield of
2n, possibly due to steric hindrance. A pendant olefin (1o) or a
pyridine ring (1p) was compatible to the reaction conditions,
demonstrating the compatibility of these typically coordinating
functional groups with aminocyanation.
We then turned our attention to groups α to the acyl
cyanamide carbonyl. We used aminocyanation to prepare
pyrrolidones containing geminal methyl (2q and 2r) and benzyl
groups (2s) α to the carbonyl, as well as spirocyclic products
(2t−2v) in good yield (Table 2). In contrast, complete removal
of the α substituents resulted in a sluggish reaction and poor
yield of product 2w (33%), indicating that the Thorpe-Ingold
effect contributes to chemoselectivity in aminocyanation.
Next, we directed our focus to alkene substitution. Substrates
with alkyl substituents other than methyl performed with
comparable yields (2x and 2y). The allylic benzyloxymethyl
group in 1z proved challenging; aminocyanation provided 2z in
much lower yield, even after raising the catalyst loading to 20
mol % of Pd. The cyclization of a styrenyl double bond was
slower, but efficient with slightly higher catalyst loading (2aa,
85% yield, 15 mol % Pd used). We were concerned that
aminocyanation across a monosubstituted alkene would be
challenging due to competitive β-hydride elimination. Despite
our concern, the aminocyanation of such an alkene (1ab)
afforded the corresponding pyrrolidone 2ab in 47% yield.
On the other hand, the N−CN bond of N-alkyl cyanamide
1ac was much more inert toward activation and only 29% yield
of 2ac was obtained. The aminocyanation was smoothly
extended to the construction of isoindolinones from the
cyclization of styrenyl alkenes (2ad−2af, 59−99% yield). The
formation of six-membered lactams 2ag (94% yield) and 2ah
(49% yield) were achieved with a higher catalyst loading. In
addition, we identified several incompatible substrates under
the aminocyanation conditions. Substrates bearing an electron-
deficient alkene (1ai) or an aryl C−Br bond (1aj) failed to
produce any detectable amount of products (2ai or 2aj). An N-
acetyl substituent on the aryl ring (1ak) rendered the N−CN
bond unreactive with our optimized catalyst, even at 120 °C.
2.3. Aminocyanation of N-Sulfonyl Cyanamides 3.
Following our previous success with metal-free aminocyanation
of N-tosyl cyanamides, we prepared N-sulfonyl cyanamide 3a
and examined the reaction conditions to access sultam 4a
(Table 3). We targeted 4a since sultams are biologically active.
Initially, heating 3a with 1.0 equiv of B(C6F5)3 alone in toluene
failed to produce any detectable amount of 4a (Table 3, entry
1). Our attempts with BF3·OEt2 or BPh3 as catalysts were also
unfruitful (entries 2 and 3). In contrast, aminocyanation of 3a
proceeded under palladium/Lewis acid catalysis, affording 4a in
69% yield, along with a small amount of reductive decyanation
byproduct 3a’ (entry 4). A brief screening of palladium sources
(entries 5−7) and reaction temperatures (entries 8−10)
revealed that the catalytic system employing readily available
Pd2dba3 (5 mol %), Xantphos (10 mol %), and BPh3 (40 mol
%) afforded 4a in near quantitative yield (entry 9). A control
C
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an acetal on N-aryl group (4m, 89% yield) were also successful.
However, 2-methoxypyridine-containing substrate 3l only
afforded a trace amount of product (4l) with our optimized
conditions for sultam formation. The mass balance consisted
mainly of 3l. This result contrasts with our successful
preparation of 2p above, also containing a 2-methoxypyridine.
Taken together, aminocyanation when basic heteroatoms are
present is possible, but likely requires additional optimization
on a case-by-case basis. Our results show that a variety of
functional groups are compatible with sultam-forming amino-
cyanation reactions.
Table 3. Aminocyanation of N-Sulfonyl Cyanamide 3a
a
entry
palladium
Lewis acid
T (°C)
yield (%)
b
c
d
1
B(C6F5)3
100
100
100
100
100
100
100
90
0
b
c
d
2
BF3·OEt2
0
b
d
3
BPh3
BPh3
BPh3
BPh3
BPh3
BPh3
BPh3
BPh3
0
2.4. Synthetic Applications. The aminocyanation reaction
could be readily performed on a gram scale (Scheme 2). For
4
Pd(OAc)2
69
63
81
85
95
5
Pd(TFA)2
CpPd(1-phenylallyl)
Pd2dba3
6
a
Scheme 2. Gram-Scale Aminocyanation Reactions
7
8
Pd2dba3
e
9
Pd2dba3
80
99
10
11
Pd2dba3
70
82
d
Pd2dba3
100
0
a
Determined by 1H NMR analysis using DMSO-d6 as the solvent and
b
p-methoxyacetophenone as the internal standard. Without Xantphos.
c
d
e
1.0 equiv. Unconsumed starting material. Yield after column
chromatography.
experiment performed without BPh3 returned only uncon-
sumed starting material (entry 11).
N-Sulfonyl cyanamides bearing various aryl subsitutents,
including −tBu, −F, −Cl, −OMe, −CF3, and −CO2Me groups
para or meta to the nitrogen atom, all proceeded smoothly to
the corresponding sultams in consistently high yields (Table 4,
4b−4i, 89−95% yield). Aminocyanation reactions that form a
six-membered sultam (4j, 57% yield), aminocyanation with a
OMe substituent para to the sulfonyl group (4k, 76% yield), or
a
Reaction conditions: (a) CpPd(1-phenylallyl) (10 mol %), Xantphos
(10 mol %), BEt3 (40 mol %), PhMe, 80 °C, 24 h; (b) CpPd(1-
phenylallyl) (5 mol %), Xantphos (5 mol %), BEt3 (60 mol %), PhMe,
80 °C, 24 h; (c) CpPd(1-phenylallyl) (8 mol %), Xantphos (8 mol %),
BEt3 (60 mol %), PhMe, 70 °C, 24 h. All yields are isolated yields.
instance, aminocyanation of cyanamides 1d and 1f gave the
corresponding pyrrolidones 2d and 2f in excellent yields.
Cyclizations of 1ad and 1af proceeded smoothly to the
corresponding isoindolinones 2ad and 2af with reduced catalyst
loading (5 mol % and 8 mol % of Pd/Xantphos, respectively).
To demonstrate the versatility of aminocyanation products in
synthesis, we subjected 2ad to various chemical transformations
(Table 5). Isoindolinone 2ad was hydrolyzed under basic
conditions to either carboxylic acid 5a or primary amide 5b in
good yield depending on reaction time. N-tert-Butyl amide 5c
was obtained from 2ad in 88% yield via a Ritter reaction.
Heating 2ad with n-butanol in the presence of p-TsOH gave
ester 5d in 93% yield. A nickel-catalyzed methylation of the
nitrile using AlMe3 provided methyl ketone 5e in 77% yield.22
A palladium-catalyzed arylation reaction with p-tolylboronic
acid quantitatively produced aryl ketone 5f.23 Chemoselective
reduction of the nitrile employing a NaBH4−CoCl2·6H2O
system generated amine 5g or, when combined with (Boc)2O,
the corresponding N-Boc carbamate 5h in good yield.
Dibutyltin oxide-mediated cycloaddition of nitrile 2ad with
trimethylsilyl azide gave tetrazole 5i in 76% yield.24 Chemo-
selective deprotection of the N-PMP group with cerium(IV)
ammonium nitrate afforded free isoindolinone 5j in 71% yield.
Thioamide 5k was obtained in excellent yield by treating 2ad
with Lawesson’s reagent. Chemoselective reduction of the
amide moiety was also achieved with Charette’s procedure,
furnishing isoindoline 5l in 76% yield.25
Table 4. Scope of Aminocyanation of N-Sulfonyl
Cyanamides 3
a
a
Reaction conditions: Pd2dba3 (5 mol %), Xantphos (10 mol %), BPh3
b
(40 mol %), PhMe, 80 °C, 16 h. All yields are isolated yields. Run for
c
24 h. A trace amount of 4l is assigned to minor peaks in the 1H NMR
We also exemplified the transformations of aminocyanation
product 2af by preparing synthetic intermediates and analogues
spectrum of the crude reaction mixture.
D
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a
yield as a structural analogue to the anxiolytic drug
pazinaclone.27
Table 5. Transformations of Isoindolinone 2ad
2.5. Mechanistic Considerations. We propose a catalytic
cycle consistent with the Nakao group’s study.14a Lewis-acid-
promoted oxidative addition of the N−CN bond to the Pd(0)
center gave rise to amidopalladium(II) cyanide complex I
(Scheme 4, part a). Intramolecular addition of the N−Pd bond
Scheme 4. Mechanistic Considerations
a
All yields are of isolated material. Reaction conditions: (a) KOH,
EtOH/H2O, 90 °C, 40 h; (b) KOH, MeOH/H2O, 90 °C, 2 h; (c)
H2SO4 (1.2 equiv), tBuOH, 80 °C, 12 h; (d) TsOH·H2O (2 equiv),
nBuOH, 120 °C, 20 h; (e) Ni(acac)2 (10 mol %), AlMe3 (3 equiv),
benzene, 50 °C, 5 h; (f) Pd(OAc)2 (10 mol %), p-tolylboronic acid (2
equiv), 2,2′-bipyridyl (20 mol %), CF3CO2H (10 equiv), THF/H2O,
90 °C, 28 h; (g) NaBH4 (4 equiv), CoCl2·6H2O (1.5 equiv), MeOH, 0
°C, 2 h; (h) (Boc)2O (2.5 equiv), NaBH4 (4 equiv), CoCl2·6H2O (1.5
equiv), MeOH, 0 °C, 3 h; (i) TMSN3 (3 equiv), nBu2Sn(O) (0.5
equiv), PhMe, 100 °C, 48 h; (j) cerium(IV) ammonium nitrate (6
equiv), CH3CN/H2O, rt, 2 h; (k) Lawesson’s reagent (1 equiv),
PhMe, 100 °C, 2.5 h; (l) Tf2O (1.2 equiv), CH2Cl2, 0 °C to rt, 30 min,
then Hantzsch ester (3 equiv), rt, 4 h. acac = acetylacetonyl; PMP = 4-
methoxyphenyl.
of biologically active isoindolinones (Scheme 3). Chemo-
selective reduction of the nitrile, followed by base-mediated
formation of the piperazine ring gave isoindolinone 6 in 73%
yield, which served as an advanced intermediate to PD-172938,
a potent dopamine D4 ligand.26 In addition, a two-step
hydrolysis/amide coupling sequence afforded amide 7 in 82%
Scheme 3. Synthetic Applications of Isoindolinone 2af
across the alkene double bond provides alkylpalladium(II)
cyanide complex II, which, upon C−CN bond-forming
reductive elimination, released the product and regenerated
the active catalyst. The substrate scope study revealed a
pronounced Thorpe-Ingold effect.
We conducted a double crossover experiment to probe
intramolecularity in Pd/Lewis-acid-catalyzed aminocyanation
(Scheme 4, part b. A mixture of 1d and 13C-lableled cyanamide
1r ([13C]1r) were subjected to the aminocyanation conditions,
affording the corresponding noncrossover products 2d and
[13C]2r. The crossover products were not observed. This result
indicated that BEt3 did not facilitate the dissociation of Pd−CN
bond in the proposed catalytic cycle. These results are
consistent with the proposed intermediates I and II in Scheme
4, part a.28
Substrates bearing an existing stereogenic center α to the
carbonyl were prepared by routine alkylation reactions of
enolates, offering a convenient way to examine the diaster-
eoselectivity of the alkene addition step (Scheme 4c). For
E
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instance, cyclization of α-methyl-substituted cyanamide 1al
gave lactams 2al in 59% yield and 9:1 d.r. The syn-relationship
of the two methyl groups was determined by nOe experiments.
Similarly, substrate substituted with a phenyl group α to the
carbonyl (1am) yielded the corresponding lactam 2am in
moderate yield (48%), but with excellent selectivity (>20:1
d.r.). Encouraged by these results, we further extended the
scope of diastereoselective aminocyanation reactions to access
functionalized lactams bearing an all-carbon stereocenter (2an),
an N-phthalimide group (2ao), or a benzyloxy group (2ap) α
to the carbonyl, resulting in generally good yield. The d.r. was
excellent when one of the α-substituents was large, as in 2an
(19:1 d.r.) and 2ao (20:1 d.r.), but lower when both were small
(2ap, 3.2:1). Furthermore, cyclization of an alkene with an
allylic stereogenic center proceeded cleanly to provide densely
substituted lactam 2aq in 92% yield and 4.4:1 d.r.
To gain the further insight into the diastereoselectivity of the
aminocyanation reactions, we studied the stereochemistry of
the alkene addition step. We designed a terminal monodeu-
terated substrate (trans-1ad-d1) to examine how the N−Pd
bond inserts into the alkene. The possible outcomes are syn-
addition, anti-addition, or a mixture of the two. A possible
mode for anti-addition is through ionization of N−Pd bond to
form an alkene complex, followed by attack of nitrogen on the
alkene. This would be consistent with our null observation on
cyano group crossover, if it occurred by the formation of a tight
ion pair. The structures of the possible products (2ad-d1-I and
2ad-d1-II) are shown in Scheme 5.
Figure 1. Optimal geometry of 2ad and nOe results.30
product as 2ad-d1-I, assuming a conformation where the
methyl and nitrile groups are anti. This assumption seemed
reasonable, but we sought additional data to confirm our
assignment.
To bolster our assignment of 2ad-d1, we utilized computa-
tional methods29 to predict the chemical shifts of the
diastereotopic protons in 2ad. Conformational minimization
in silico confirmed our assumptions about the anti-orientation of
the nitrile and methyl group in the dominant conformers. The
diastereotopic protons (labeled as 31 and 13 in Figure 1) were
respectively predicted at δ = 2.80 and 2.62 ppm (Δδ = 0.18
ppm), while the experimental chemical shifts are δ = 2.89, 2.70
ppm (Δδ = 0.19 ppm) in the 1H NMR of 2ad. Compared with
the spectrum of 2ad-d1, the more upfield peak around 2.70
ppm is not observed, confirming that proton 13 is the one
labeled as deuterium. Combined with nOe results, we assign
2ad-d1-I as the diastereomer produced by of aminocyanation of
trans-1ad-d1. These results are consistent with the alkene
addition proceeding via a syn-addition pathway.
Scheme 5. Mechanistic Study of Alkene Addition Step
Based on syn-aminopalladation, we proposed a model
(shown in Scheme 6) to elucidate the origin of the
Scheme 6. Proposed Model for the Diastereoselectivity
Aminocyanation of trans-1ad-d1 yielded a single diaster-
eomer, however, assigning the position of deuterium in 2ad-d1
was challenging due to the exocyclic stereogenic center. The 1H
NMR spectrum of unlabeled 2ad showed the diastereotopic
protons (atom 13 and 31 in Figure 1) as well-resolved signals
(δ = 2.89, 2.70 ppm), showing that the two protons are in
distinct electronic environments. Thus, we hypothesized that
the two diastereotopic protons could be assigned by nOe
experiments. As expected, the downfield diastereotopic proton
in 2ad shows the through-space interactions with aromatic
proton 24 on the isoindoline and 32/35 on the para-
methoxyphenyl group. The upfield diastereotopic proton is
only observed to enhance the signal of proton 32/35 on the
para-methoxyphenyl group. We also ran an nOe experiment for
diastereoselectivity. During the ring-forming step, the molecule
may adopt a chairlike conformation. Meanwhile, the larger
substituent adjacent to the carbonyl prefers to be oriented in a
pseudoaxial position to minimize strain between the R-group
and the carbonyl. Hence, the cyclization reactions afforded the
diastereomers we observed (2al−2ap).
3. CONCLUSION
In summary, we developed an intramolecular aminocyanation
of alkenes by N−CN bond activation of N-acyl and N-sulfonyl
cyanamides, accessing a broad range of nitrogen-containing
heterocycles, including pyrrolidones, piperidinones, isoindoli-
nones, and sultams. The synthetic utility of the method was
1
the only proton alpha to the nitrile (δ = 2.88 ppm) in the H
NMR of 2ad-d1, and we observed nOe for aromatic proton 24
and 32/35. These data support the assignment of our labeled
F
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b01330.
■
S
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Experimental details for the preparation of new
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13C NMR, melting points, MS, and IR), and copies of
NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*cdouglas@umn.edu
ORCID
■
Christopher J. Douglas: 0000-0002-1904-6135
Author Contributions
†Z.P. and S.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank National Institutes of Health for funding this work
(R01 GM095559). We thank Dr. Letitia Yao (UMN) for
assistance with nOe experiments. We thank Mr. Xiao Xiao
(UMN) for discussions regarding NMR chemical shift
prediction.
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