Direct, Catalytic α-Alkylation of N-Heterocycles by Hydroaminoalkylation: Substrate Effects for Regiodivergent Product Formation

Rebecca C. DiPucchio, Karst E. Lenzen, Pargol Daneshmand, Maria B. Ezhova, and Laurel L. Schafer*

Article

Direct, Catalytic α‑Alkylation of N‑Heterocycles by

Hydroaminoalkylation: Substrate Eﬀects for Regiodivergent Product

Formation

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ABSTRACT: Saturated N-heterocycles are prevalent in pharmaceutical

and agrochemical industries, yet remain challenging to catalytically

alkylate. Most strategies for C−H activation of these challenging

substrates use protected amines or high loadings of precious metal

catalysts. We report an early transition-metal system for the broad,

robust, and direct alkylation of unprotected amine heterocycles with

simple alkenes. Short reaction times are achieved using an in situ

generated tantalum catalyst that avoids the use of bases, excess substrate,

or additives. In most cases, this catalyst system is selective for the branched reaction product, including examples of products that are

generated with excellent diastereoselectivity. Alkene electronic properties can be exploited for substrate-modiﬁed regioselectivity to

access the alternative linear amine alkylation product with a group 5 catalyst. This method allows for the facile isolation of

unprotected N-heterocyclic products, as useful substrates for further reactivity.

INTRODUCTION

combination with Michael acceptors to generate the linear

■

4−19

alkylation product.

Established late transition-metal

N-Heterocycles are privileged scaﬀolds in drug development,

hydroaminoalkylation strategies for protected heterocycle

representing 59% of recently approved small-molecule treat-

20,21

alkylation

beneﬁt from good functional group tolerance

ments. Saturated heterocycles such as piperidine, azepane, and

and dominant regioselectivity for the linear reaction product

tetrahydroquinoline are particularly prevalent yet remain some

of the most challenging heterocycles to directly and selectively

functionalize. The ability to selectively C−H functionalize N-

heterocycles allows for the rapid generation of complex amine

products from simple starting materials in one catalytic step.

According to a recent minireview of catalytic C−H

functionalization of heterocycles, less than 8% of reports

disclose the ability to C−H functionalize saturated N-

heterocycles and most demand the use of protected amine

21−32

with modest diastereoselectivity (Figure 1b).

Early

transition-metal hydroaminoalkylation accesses the comple-

mentary branched α-alkylation product with a variety of

secondary aryl and alkyl amines without the need for

protecting/directing groups or cocatalysts/additives (Figure

33−36

c).

Group 5 hydroaminoalkylation uses free amines as substrates

for addition to unactivated alkenes. To date, early transition-

metal-catalyzed hydroaminoalkylation of unprotected N-

heterocycles has remained largely unexplored. The only report

focused on this transformation uses piperidine at high reaction

substrates. Current literature to react saturated amine

3−5

heterocycles is dominated by Csp −Csp arylation

6,7

Csp −Csp cyanation/alkynylation.

Photocatalytic cross-

temperatures (165 °C), with long reaction times (143 h) and

coupling can realize the α-C−H alkylation of protected

37,38

high catalyst loadings (10 mol %).

This previous work

saturated amines with activated electrophiles, such as

required an isolated tantalum amidate precatalyst and an excess

of unactivated alkene, such as 1-octene, to give only the

branched reaction products. All products were protected and

−11

aldehydes or alkyl halides,

alkylation of unprotected N-heterocycles can be achieved by

or the stoichiometric α-

the addition of organometallic nucleophiles to transiently

isolated as N-tosylates to facilitate isolation and character-

2,13

generated imines.

These methods require activated

37,39

ization.

This latter protection step negates the potential

alkylating agents that result in the generation of stoichiometric

amounts of waste. An atom-economic alternative is to use

alkenes as reagents for the catalytic alkylation of N-hetero-

cycles by hydroaminoalkylation.

Received: May 28, 2021

Published: July 19, 2021

Various catalytic approaches exist to address the challenge of

directly alkylating saturated N-heterocycles by hydroaminoal-

kylation (Figure 1). Recently developed photocatalytic

strategies (Figure 1a) employ protected N-heterocycles in

2021 American Chemical Society

Journal of the American Chemical Society

J. Am. Chem. Soc. 2021, 143, 11243−11250

1243

Article

RESULTS AND DISCUSSION

Ligand Design and Reaction Optimization. Initial

■

reaction development eﬀorts began by investigating the

reaction between piperidine and 1-octene as benchmark

substrates for N-heterocycle reactivity. Here, 5 mol % catalyst

loading (equimolar amounts of Ta precursor and ligand salt)

was used with a 1:1 mixture of the substrates at 150 °C for 6 h

Figure 2 a). Both substrates are inexpensive, commercially

Figure 1. (a) Photocatalytic C−H alkylation of protected amines. (b)

Late transition-metal-catalyzed hydroaminoalkylation of protected

amines. (c) This work: A tantalum catalyst system for reactions of

unprotected amines with unactivated alkene substrates.

advantage of preparing free amine products that are ready for

36,37,39−43

further reactivity.

Some other early transition-metal

catalysts have been reported for hydroaminoalkylation with

speciﬁcally tetrahydroquinoline or tetrahydroisoquino-

9,44,45

line.

However, due to the fused aryl ring, these are

activated heterocycles and these same catalysts cannot be used

39,44,45

with unactivated piperidines.

Figure 2. Screening ureate ligand salts for hydroaminoalkylation with

piperidine and (a) 1-octene and (b) styrene.

Our group recently showed that highly active tantalum and

titanium ureate hydroaminoalkylation catalysts can be

prepared in situ for the eﬃcient alkylation of both aryl and

46−48

alkyl N-methylated secondary amines.

Although reactivity

available, and represent challenging unactivated feedstocks.

with N-heterocycles was not achieved, this earlier work

showcased the tunable nature of ureate ligand salts to improve

catalytic activity and enhance substrate scope. Here, we report

a tantalum ureate catalyst for the rapid α-C−H alkylation of

saturated N-heterocycles with activated and unactivated alkene

coupling partners (Figure 1c). A simple protocol for in situ

catalyst assembly is featured. Complete precatalyst character-

ization and catalytic evaluation is also presented. We show that

this new catalyst system can be used at 5 mol % loading to give

isolable, unprotected α-alkylated six- and seven-membered ring

N-heterocycles. Investigations into alkene substrate scope

revealed steric and electronic eﬀects on regioisomeric control,

with branched products being favored for unactivated alkenes,

while activated styrene derivatives could be used for substrate-

controlled linear regioisomer formation. This is the ﬁrst early

transition-metal-catalyst system that displays this shift from

branched to linear products with these unactivated saturated

N-heterocycles, providing insights that guide the development

of further early transition-metal catalysts to access linear

products.

Attempts to achieve this transformation with the known simple

36,39,49

tantalum complex Ta(NMe₂)₅

were unsuccessful under

any reaction conditions. Using a known organometallic

46,47

tantalum starting material, Ta(CH SiMe ) Cl ,

the bench-

3 3

mark reaction with piperidine over 24 h at 165 °C gave only

% conversion, as determined by H NMR spectroscopy.

None of the established amidate, pyridonate ligand salts (L12,

L13) could be used for any reactivity with this challenging N-

39,44,51

heterocycle substrate.

Only starting material remained

by NMR spectroscopy after heating. However, when Ta-

(CH SiMe ) Cl was combined with various acyclic N,O-

3 3

chelating ureate salts, seven very active catalyst combinations

resulted (Figure 2; ligands L1, L2, L4, L6, L8−L10). This

reaction did not generate any observable side products, as

measured by NMR spectroscopy and GC−MS of the reaction

mixture (See SI). These reactions achieved full conversion

after only 6 h of reaction time at 150 °C. The branched

product was formed exclusively, in all cases, and a diagnostic

doublet of the new methyl substituent was observed at 0.84

ppm in the H NMR spectrum. All reactions also oﬀered

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Article

excellent diastereoselectivity for the major isomer indicated

(

>10:1).

Interestingly, the use of a cyclic ureate ligand salt, which has

shown excellent reactivity with dialkyl amines, was less

eﬀective when used with piperidine, even at longer reactions

times of 12 h (L11). Known amidate and pyridonate

7,39,44,53,54

ligands,

which have been used in hydroaminoalky-

lation catalysis with secondary amines (L12 and L13), both

showed no reaction with piperidine within 24 h. A comparison

of results using the diﬀerent acyclic ureate ligands showed that

small structural changes resulted in unpredictable changes in

reactivity (e.g., L5 vs L6). Entries L4 and L8−L10 were tested

to explore electronic eﬀects on catalysis, but no changes could

be noted with these varied N-aryl substituents.

Styrene is an activated alkene substrate that is typically more

reactive than octene, but was previously unknown for addition

to piperidine due to unwanted polymerization at the elevated

temperatures required. Previous work from our group and

others could not realize the alkylation of piperidine with

styrene, regardless of reaction conditions. Here, we can use in

situ generated Ta ureate mixtures to accomplish this

challenging reaction. As shown in Figure 2b, entries L1, L2,

L4, and L6 show that the best catalysts for reactivity with 1-

octene all display impressive reactivity with styrene, although

longer reaction times of 20 h are required. Again, equivalent

amounts of amine and styrene are used, and competing

polymerization is not problematic. Further, these are the ﬁrst

examples of a group 5 hydroaminoalkylation catalyst that can

access linear regioisomers with styrene substrate, as L1, L2, L4,

and L6 all generated signiﬁcant amounts of this previously

unobserved product. The diastereoselective formation of the

branched product is retained with styrene substrates (vide

infra).

Figure 3. Solid-state molecular structure of precatalyst 1 determined

by X-ray crystallography. Ellipsoids plotted at 50% probability, and H

atoms omitted. Selected bond lengths (Å) and angles (deg): Ta−O1:

.164(2), C1−N2: 1.338(4), C1−O1: 1.305(4), Ta−N1: 2.155(3),

C1−N1: 1.341(4), O1−Ta−N1: 60.29(9), N1−Ta−C4:99.672.

electrostatic interaction with the electrophilic metal center.

We propose that this bonding environment enhances ionic

character in these complexes, thereby increasing the

polarized bonding in these early transition metal catalysts for

enhanced hydroaminoalkylation reactivity.

The catalytic activity of isolated precatalyst 1 was compared

with in situ reactivity to ensure that the isolated material was

representative of the catalyst system assembled in situ. Both

experiments provided complete conversion to the branched

product using optimized reaction conditions (20 h, 150 °C, 5

To further develop and mechanistically explore this N-

heterocycle reactivity, we continued experiments with the

mol %). Furthermore, the H NMR spectrum of isolated 1

matches that of the corresponding in situ generated mixture,

known ligand salt L4, as the corresponding proteoligand can

be easily synthesized and puriﬁed in large batches (up to 10 g)

in excellent yield (86%) of recrystallized product. Further, the

sodium salt of this ligand is soluble in toluene, facilitating stock

solution preparation (vide infra) and in situ catalyst preparation

and reaction setup. Although this ligand is chiral, previous

work has shown that the incorporation of a remote

stereocenter into the ligand is not useful for enantioselective

further conﬁrming 1 is the dominant species prepared in

solution. All further reactions in this work have been done

using in situ precatalyst generation to simplify the synthetic

protocol.

Substrate Scope and Reaction Mechanism. The

substrate scope featured in this paper highlights not only

functional group tolerance but also regioselectivity shifts that

can be realized with electronically biased substrates. These

results contrast with previous catalyst development work

featuring Ta that largely gave branched products uniquely.

This report that discloses a shift from branched product to

linear product formation is complementary to a recent late

transition-metal hydroaminoalkylation contribution that cele-

brates being able to access branched regioisomers in speciﬁc

hydroaminoalkylation. Thus, all work here was done using

the racemic ureate ligand.

Precatalyst Characterization. Isolation of Ta acyclic

6,47

ureate complexes has proven challenging.

Here, the

isolation, puriﬁcation, and crystallographic characterization of

the N,O-chelated complex resulting from the 1:1 reaction of

ligand salt to Ta(CH SiMe ) Cl was achieved (Figure 3, 1).

3 3

cases, rather than the more typical linear products. A key

diﬀerence between these complementary early and late

transition metal advances in regiochemical control is the fact

that here we show that early transition metal catalyst

development can alter regiochemical outcomes, while late

transition metal strategies focus on a N-protecting/directing

group design to modify product ratios.

This is the ﬁrst example of a structurally characterized acyclic

ureate-ligated Ta hydroaminoalkylation catalyst. Precatalyst 1

is monoligated with bond metrics that diﬀer from those of a

recently published group 5 N,O-chelated precatalyst with a

cyclic ureate ligand. For example, the Ta−N length in 1 of

.155(3) Å is signiﬁcantly longer than in the published cyclic

ureate precatalyst (2.0694(15) Å). This longer Ta−N bond

The lack of additives and excess substrates in early

transition-metal-catalyzed hydroaminoalkylation allows for

the isolation of the free N−H heterocyclic products directly

(see SI ), and N-tosylation for puriﬁcation can be avoided.

However, these unprotected secondary amine heterocyclic

products are challenging to isolate and purify by column

can be attributed to the bulky N-dimethylphenyl substituent in

. Overall, ureate ligands are bound much closer to the Ta

metal center than related N,O-chelating amidate or pyridonate

ligand scaﬀolds (e.g., Ta−N lengths of 2.447(3) and 2.307(1)

3,55

Å, respectively),

indicating that ureate ligands are better

37,38

able to stabilize negative charge and have a stronger

chromatography.

As a representative example, the hydro-

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aminoalkylation of p-chlorostyrene with piperidine gave

Table 1. Amine Heterocycle Scope for C−H Alkylation

branched and linear regioisomers in 54 and 46% yield

respectively (22/23, Table 2), as determined by H NMR

spectroscopy, using 1,3,5-trimethoxybenzene as an internal

standard, and GC−MS. These compounds were then

separated and puriﬁed by column chromatography in the

reduced yields of 35 and 22%, respectively. Basiﬁed silica,

alumina, or running manual vs automated columns did not

improve the isolated yields. Also, it should be noted that

diastereoenrichment may be observed upon puriﬁcation on

silica. In this case, the major diastereoisomer of the branched

product (22) was obtained as one pure product (see SI).

Furthermore, this same reaction was carried out on gram scale

(

over 1.5 g (25 mmol) of each starting material), to conﬁrm

that yields and product ratios are independent of reaction

scale.

An alternative approach for optimizing yields features the

37,38

use of a protecting group

installed after the reaction to

ensure that products can be readily puriﬁed by chromatog-

raphy. However, considering that unprotected N-heterocyclic

products are directly amenable to further chemical modiﬁca-

tion, as has been shown in other hydroaminoalkylation/N-

40,41,5

functionalization reaction sequences,

this protection step

All amines were reacted and puriﬁed as free amine substrates.

eliminates the synthetic opportunity aﬀorded by early

transition-metal-catalyzed hydroaminoalkylation. Thus, all the

reported yields in Tables 1 and 2 are NMR yields. To conﬁrm

that unprotected products can indeed be isolated, column

chromatography was used in each case to obtain pure materials

for rigorous characterization. Relative stereochemistry was

Reaction conditions: amine (1 mmol), alkene (1 mmol), Ta-

(

CH SiMe ) Cl (0.05 mmol), ligand salt (L4, 0.05 mmol), d₈-

2 3 3 2

toluene (0.6 g). NMR yields were determined using 1,3,5-

trimethoxybenzene as an internal standard. Diastereoselectivity values

are displayed as ratios, with the major diastereomer drawn and the

ratio determined by GC−MS analysis.

determined by comparing data from previous work with 1D/

D NOESY experiments (see SI ).

N-Heterocycle Scope. With an easy to use catalyst system

in hand, further exploration of the N-heterocycle substrate

scope was undertaken. As shown in Table 1, in situ assembled

40,44

compound 1 tolerates fused ring systems,

varied ring sizes,

and substituted N-heterocycles to give exclusively branched

product formation with unactivated alkene substrates. High

yields are observed with most heterocycles (2−9), including a

piperazine derivative that can undergo hydroaminoalkylation in

moderate yield (10), as determined by H NMR spectroscopy.

The tetrahydroisoquinoline substrate (compound 4) shows

good regioselectivity as determined by NMR spectroscopy, in

which the isolated benzylic methylene group α to nitrogen at

.97 ppm remains a singlet in the major product of the crude

reaction mixture. There is no evidence of dialkylation. It is

expected that the benzylic C−H bond of this N-heterocycle

would be electronically favored for C−H activation; however,

this site is sterically inhibited.

The preferred relative stereochemistry of the α,β-stereo-

centers in hydroaminoalkylation products is consistent across

all heterocycles, including a seven-membered ring (Table 1,

compound 5). The excellent diastereoselectivity observed can

be attributed to the metallacyclic intermediates of the

proposed mechanism for early transition-metal-catalyzed

37,58

hydroaminoalkylation (Figure 4).

The catalytically active fused metallaaziridine (C) is formed

via β-H abstraction. This aziridine undergoes facially selective

alkene insertion such that the substituent of the alkene is

oriented to the opposite face of the metallaaziridine ring C

Figure 4. Proposed mechanism for hydroaminoalkylation with

alkyltantalum precursors and saturated N-heterocycles.

37,44,59

from the pyridyl ring.

Thus, alkene insertion into the

fused metallacycle proceeds via transition-state D to give ﬁve-

membered metallacycle E of deﬁned relative stereochemistry.

Then, another molecule of piperidine is involved in

protonolysis, before a subsequent C−H activation releases

the desired product and regenerates the metallaaziridine C.

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Table 2. Alkene Scope for Hydroaminoalkylation with Piperidine Using N-Heterocycles

Reaction conditions: amine (1 mmol), alkene (1 mmol), Ta(CH SiMe ) Cl (0.05 mmol), ligand salt (L4, 0.05 mmol), d -toluene (0.6 g). NMR

yields were determined with 1,3,5-trimethoxybenzene as an internal standard. Diastereoselectivity values are displayed as ratios, with the major

diastereomer drawn and the ratio determined by GC−MS analysis.

The substituted piperazine in compound 10 highlights the

potential for additional heteroatoms being compatible with this

methodology, albeit with a lower yield (48%). Unfortunately,

to obtain complete selectivity for the terminal alkene of a diene

substrate (11). A protected alcohol (12) resulted in the

synthesis of branched product with excellent diastereoselectiv-

ity. Likewise, compound 13 illustrates reactivity with

allyltrimethylsilane to give the branched product with excellent

diastereoselectivity. The diastereoselective generation of the

branched product (compound 15, 11:1 dr as determined by

GC−MS) can be rationalized by the mechanism that places the

steric bulk away from the metal center and locates the

preferred buildup of negative charge α to tantalum (Figure 4).

Next, an evaluation of reactivity with styrene derivatives was

undertaken. As noted in Table 2, all styrenes gave signiﬁcant

amounts of both branched and linear regioisomers. By

modifying the electronic features of the styrenes, substrate-

modiﬁed regioselectivity is realized while maintaining excellent

overall reactivity within 20 h (typically >90% combined yield).

All reactions aﬀorded product mixtures that were analyzed by

quantitative NMR spectroscopy, using internal standard, and

GC−MS was also used to conﬁrm product ratios. As

mentioned earlier, regioisomeric and sometimes diastereo-

meric products could be separated and isolated by column

chromatography for complete characterization. As shown in

entries 14 and 15, the parent styrene gave the branched

product over the linear product in a 1.7:1 ratio. This

unsubstituted case was then compared to styrenes with a

variety of aryl substituents.

-methylpiperazine, unprotected piperazine, and morpholine

show only unreacted starting materials remaining after heating.

The incorporation of an aryl substituent, which reduces the

nucleophilic character of the nitrogen of the piperazine, is

important for promoting reactivity. Pyrrolidine was also not

reactive with this catalyst, potentially due to aggregation/

oligomerization. This lack of reactivity contrasts with results

using late transition-metal catalysts that prefer ﬁve-membered

rings over piperidine-based systems.

Table 1 shows that this method can be used to set the

relative stereochemistry of up to three positions in a single,

diastereoselective catalytic step and the substituent at the 3- or

4-position impacts the stereochemical outcome of the reaction.

While 3- or 4-substituted piperidine substrates were highly

reactive, 2-methylpiperidine showed no reactivity, even after 20

h. This is consistent with the lack of dialkylation observed in all

of these reactions. We attribute this observation to the

challenging steric bulk that would need to be incorporated into

metallacyclic species C and/or D or the protonolysis step from

E to F.

Alkene Scope and Control of Regioselectivity. With

various N-heterocycles in hand, next the alkene scope with

piperidine was explored (Table 2). As expected, aliphatic

alkenes (Table 2, compounds 11−13) generate only branched

product with unfunctionalized and functionalized terminal

alkenes, and no reactivity with unactivated internal alkene

substrates can be realized. This trend can be used to advantage

Simple electron-donating alkyl substituents in the para-

position resulted in the preferred formation of the branched

product vs the linear product (2.5:1 for 16:17 and 18:19). The

branched product is formed with excellent diastereoselectivity

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styrenes were compared. Figure 5 depicts the quantitative

Article

in these cases. By employing electron-withdrawing substituents

mol % of a tantalum ureate catalyst, and full conversion can be

realized in as little as 6 h depending on the chosen substrate.

Isolated and in situ versions of our most active catalyst showed

identical reactivity, allowing for the use of an easily assembled

in situ catalyst system for the hydroaminoalkylation of N-

heterocycles. The unprotected, selectively substituted N-

heterocyclic products prepared here are suitable for direct

modiﬁcation. Variously substituted piperidines can be

employed, and good diastereoselectivity was observed to set

the relative stereochemistry of up to three stereocenters in a

single catalytic transformation. The major diastereomer can be

reliably predicted based on the mechanistic understanding of

the key alkene insertion step. Also, by using this unique early

transition metal catalyst, regiodivergent product formation

could be observed with styrene substrates. Changes in

regioselectivity allowed us to better understand the role of

alkene electronic eﬀects, as interpreted by a Hammett study,

on the product distribution and reaction mechanism. This

work shows that the direct C−H alkylation of unprotected N-

heterocycles can be accomplished in an atom-economic

fashion, using common alkene substrates as the alkylating

agent. This early transition-metal-catalyzed approach, which

avoids preactivated and/or protected substrates, oﬀers new

opportunities for assembling a diverse range of substituted N-

heterocycles as precursors to more complex heterocyclic

products.

(

20−33), including the inductively electron-withdrawing

ortho-, meta-, and para-halides, and the triﬂuoromethyl

group, the regioselectivity shifted to give more of the linear

product (e.g., 26:27 gave a 0.63:1 branched:linear ratio).

Excellent diastereoselectivity in the formation of the branched

product remains (∼20:1) except for the sterically demanding

ortho-halide substituents. In these cases, the major diaster-

eomer illustrated is formed in a 5:1 ratio. The impact of this

electronic and steric eﬀect was ampliﬁed in the dichlorosub-

stituted styrene (product 34), whereby only the linear

regioisomer was obtained. The compatibility of our tantalum

catalyst with aryl halides could be used to advantage for

posthydroaminoalkylation cross-coupling.

By taking advantage of these electronic eﬀects upon

regioselectivity, vinyltrimethylsilane (35), as shown previ-

3,61

ously,

furnishes the linear product selectively. This result

can be rationalized by the silyl substituent stabilizing the

buildup of negative charge on the α-carbon in the alkene

61−63

insertion transition state (Figure 4, D′).

Hammett Plot Analysis. With clear electronic trends

observed in the regioselectivity of reactions with diﬀerent

styrene derivatives, a Hammett study was undertaken. The

results of the reactions of piperidine with various p-substituted

ASSOCIATED CONTENT

sı Supporting Information

■

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/jacs.1c05498.

Experimental details and characterization data (PDF)

Accession Codes

CCDC 2086595 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

via www.ccdc.cam.ac.uk/data_request/cif , or by emailing

data_request@ccdc.cam.ac.uk , or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Figure 5. Branched:linear regioisomer ratios from Table 2 as plotted

against Hammett parameters for hydroaminoalkylation reactions with

a series of substituted styrene substrates.

AUTHOR INFORMATION

■

Corresponding Author

dependence of branched:linear regioisomer ratios on the

electronic eﬀect of each styrene, as depicted using Hammett

Laurel L. Schafer − Department of Chemistry, The University

of British Columbia, Vancouver, BC, Canada V6T 1Z1;

orcid.org/0000-0003-0354-2377; Email: schafer@

chem.ubc.ca

64,65

parameters for p-substituted substrates.

Overall, reactions

using styrenes with electron-donating substituents resulted in

more branched product, while styrenes with electron-with-

drawing groups could be used to generate more of the linear

regioisomer. However, this change in regioselectivity is

dependent upon the use of challenging N-heterocycles, as

the reaction of N-methylaniline with styrene with the same

optimized catalyst aﬀords mostly branched product (∼9:1 B:L;

see SI). The increased preference for multiple regioisomers

with piperidine substrates is attributed to the bulky

tantalaaziridine C intermediate amplifying the eﬀects of varied

alkene steric and electronic properties.

Authors

Rebecca C. DiPucchio − Department of Chemistry, The

University of British Columbia, Vancouver, BC, Canada

V6T 1Z1

Karst E. Lenzen − Department of Chemistry, The University

of British Columbia, Vancouver, BC, Canada V6T 1Z1

Pargol Daneshmand − Department of Chemistry, The

University of British Columbia, Vancouver, BC, Canada

V6T 1Z1

CONCLUSIONS

Maria B. Ezhova − Department of Chemistry, The University

■

of British Columbia, Vancouver, BC, Canada V6T 1Z1

In summary, we have developed the ﬁrst eﬃcient catalyst for

hydroaminoalkylation reactivity with a variety of unprotected

N-heterocyclic substrates. Catalysis occurs with a loading of 5

Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.1c05498

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(17) McManus, J. B.; Onuska, N. P. R.; Nicewicz, D. A. Generation

Article

Notes

and Alkylation of α -Carbamyl Radicals via Organic Photoredox

Catalysis. J. Am. Chem. Soc. 2018, 140, 9056−9060.

The authors declare the following competing ﬁnancial

interest(s): The catalyst featured in this work has been

patented: PCT/CA2018/050619.

(

18) McManus, J. B.; Onuska, N. P. R.; Jeffreys, M. S.; Goodwin, N.

C.; Nicewicz, D. A. Site-Selective C − H Alkylation of Piperazine

Substrates via Organic Photoredox Catalysis. Org. Lett. 2020, 22,

ACKNOWLEDGMENTS

19) Leng, L.; Fu, Y.; Liu, P.; Ready, J. M. Regioselective,

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20) Fukuyama, T.; Chatani, N.; Tatsumi, J.; Kakiuchi, F.; Murai, S.

■

R.C.D. thanks NSERC for a CGSD Scholarship and the

CREATE Sustainable Synthesis program for funding. K.E.L.

thanks the University of Bern for travel funding. P.D. thanks

NSERC for funding. L.L.S. thanks NSERC for ﬁnancial

support of this work. This research was undertaken, in part,

thanks to funding from the Canada Research Chairs program.

Ru3(CO)12-Catalyzed Site-Selective Carbonylation Reactions at a C-

H Bond in Aza-Heterocycles. J. Am. Chem. Soc. 1998, 120, 11522−

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