Modular Entry to Functionalized Tetrahydrobenzo[ b]azepines via the Palladium/Norbornene Cooperative Catalysis Enabled by a C7-Modified Norbornene

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Modular Entry to Functionalized Tetrahydrobenzo[b]azepines via

the Palladium/Norbornene Cooperative Catalysis Enabled by a C7-

Modi ﬁ ed Norbornene

Xin Liu, Jianchun Wang,* and Guangbin Dong*

Cite This: J. Am. Chem. Soc. 2021, 143, 9991 −10004

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sı Supporting Information

ABSTRACT: Tetrahydrobenzo[b]azepines (THBAs) are com-

monly found in many bioactive compounds; however, the modular

preparation of functionalized THBAs remains challenging to date.

Here, we report a straightforward method to synthesize THBAs

directly from simple aryl iodides via palladium/norbornene (Pd/

NBE) cooperative catalysis. Capitalizing on an oleﬁn-tethered

electrophilic amine reagent, an ortho amination followed by 7-exo-

trig Heck cyclization furnishes the seven-membered heterocycle.

To overcome the diﬃculty with ortho-unsubstituted aryl iodide

substrates, we discovered a unique C7-bromo-substituted NBE

(

N1) to oﬀer the desired reactivity and selectivity. In addition to

THBAs, synthesis of other benzo-seven-membered ring com-

pounds can also be promoted by N1. Combined experimental and

computational studies show that the C7-bromo group in N1 plays an important and versatile role in this catalysis, including

promoting β-carbon elimination, suppressing benzocyclobutene formation, and stabilizing reaction intermediates. The mechanistic

insights gained could guide future catalyst design. The synthetic utility has been demonstrated in a streamlined synthesis of tolvaptan

and forming diverse pharmaceutically relevant THBA derivatives. Finally, a complementary and general catalytic condition to access

C6-substituted THBAs from ortho-substituted aryl iodides has also been developed.

INTRODUCTION

Recently, the palladium/norbornene (Pd/NBE) cooperative

■

catalysis, originally discovered by Catellani, has emerged as a

Seven-membered nitrogen-containing heterocycles represent an

important class of pharmacophores and exhibit a broad

spectrum of biological activities. In particular, the

useful tool for modular arene synthesis. Through forming a

unique aryl-norbornyl-palladacycle (ANP) intermediate, simul-

taneous functionalizations of ortho and ipso positions of aryl

halides can take place through selective coupling with an

electrophile and a nucleophile, respectively. In particular,

Lautens has pioneered the demonstration of fused-ring

construction using electrophile/nucleophile-tethered re-

tetrahydrobenzo[b]azepine (THBA) ring system has been

found in a number of marketed drugs, such as tolvaptan and

benazepril, and other bioactive compounds (Figure 1).

However, compared to their six- or ﬁve-membered counter-

partstetrahydroquinolines and indolinessynthesis of func-

tionalized THBAs still represents a substantial challenge because

of limited approaches to accessing medium-sized heterocycles in

an eﬃcient and modular manner.

agents. Complementary to the C−C bond-forming C−H

functionalization approaches, the Pd/NBE-catalyzed tandem

ortho C−H amination followed by an intramolecular ipso

Heck cyclization can provide a straightforward and modular

strategy to access diverse THBAs (Scheme 1, bottom).

Conventional methods of preparing THBAs, including

annulation, ring expansion, and aryne strategies, usually

take a multistep sequence and/or have limited scopes (Scheme

Although this direct annulation approach to constructing

THBAs may seem to be straightforward, a number of key issues

remain to be addressed (Scheme 2). First, almost all the Pd/

, top). In addition, vicinal difunctionalized arenes are needed

with these methods. For comparison, the use of intramolecular

C−H functionalization to construct the C−C bond in THBAs,

Received: May 2, 2021

Published: June 23, 2021

9,10

via either Friedel−Crafts or transition-metal catalysis,

avoids complex arene precursors and simpliﬁes the synthesis

Scheme 1, middle). Although they clearly represent more

(

attractive strategies to access THBAs, the availability of the

corresponding elaborated aniline substrates cannot be ignored.

2021 American Chemical Society

J. Am. Chem. Soc. 2021, 143, 9991−10004

991

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Figure 1. Examples of tetrahydrobenzo[b]azepine (THBA)-based bioactive compounds.

Scheme 1. Synthetic Strategies toward THBAs

PG, protecting group; FG, functional group.

NBE-catalyzed annulations require the presence of an ortho

so-called “ortho constraint” represents a major limitation to

this method, as such ortho substituents are unnecessary in most

bioactive THBAs (e.g., in Figure 1). Second, most ortho

substituent on the aryl iodide substrate in order to promote

the desired NBE extrusion. Without ortho substituents, di-ortho

amination and formation of NBE-attached side-products can

14,18

aminations employ cyclic amine electrophiles;

acyclic ones (i.e., those needed for THBA synthesis) are

in contrast,

dominate, leading to low yield and low selectivity. Thus, this

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Scheme 2. Challenges of Synthesizing THBAs from Ortho-Unsubstituted Aryl Iodides

relatively bulkier and generally less reactive because of the steric

requirement when reacting with ANP. The slow reaction

between ANP and the electrophile can lead to competing ANP

reductive elimination to generate the benzocyclobutene side

product. Third, comparing to ﬁve- or six-membered ring

formation, it is uncommon to use the tethered electrophile/

nucleophile approach to construct medium-sized rings via the

Pd/NBE catalysis. This issue could be more prominent for the

ortho-unsubstituted substrates, as the enhanced barrier of the

NBE exclusion step can further hinder the kinetically less

favorable ipso-cyclization. As NBE is involved in all the key

intermediates, it is therefore expected to play a critical role in

overcoming the above diﬃculties. Thus, the “ideal NBE”

cocatalyst in this scenario needs to eﬃciently promote the β-

carbon elimination to address the “ortho constraint”, inhibit

ANP reductive elimination to avoid the benzocyclobutene side-

product, and not hinder the reaction between ANP and the

bulky amine electrophile. To the best of our knowledge, a NBE

cocatalyst exhibiting all these features has not been reported. In

this article, we describe a full story of discovering a unique C7-

bromo-substituted NBE (N1) that eﬀectively addresses the

aforementioned three challenges to realize general THBA

synthesis. The unique and versatile roles of the bromo

substituent of N1 in this catalysis have also been disclosed in

this study.

Figure 2. Kinetic proﬁles for the model reaction and ratio of products

over time.

unsubstituted aryl halides with unhindered electrophiles, was

found to be ineﬀective, with the formation of a large amount of

the benzocyclobutene side product (for detailed discussions, see

the Study of the NBE Eﬀect and Scheme 5). After an extensive

screening of various structurally modiﬁed NBEs, to our

surprise, 7-bromosubstituted NBE (N1) proved to be optimal

and eﬃcient for this challenging THBA synthesis (Table 1, entry

). For comparison, NBEs with substitutions at other positions

RESULTS AND DISCUSSION

■

(

N3−N9) all gave low yield and low selectivity (vide infra) in

To explore this strategy, we chose as 1-chloro-3-iodobenzene

1a) as the initial substrate because of its relevance to the

this reaction (entry 2). Notably, C7-substituted NBEs have not

been used as the optimal NBE in any previous Catellani-type

reactions, likely due to the concern of the C7 sterics on the NBE

exo-face where the Pd migratory insertion normally takes place.

The bromine group also appears to be important, as replacing Br

with an alkoxy group (N10), an iodo group (N11), or a chloro

group (N12) led to a signiﬁcant drop of the yield (vide infra).

The anti-7-bromonorbornene (N13) also gave a much inferior

result, which indicated that the inductive eﬀect of the Br may not

be responsible for the high eﬃciency of N1. The less sterically

(

synthesis of drug tolvaptan (vide infra, Scheme 3). O-Benzoyl

hydroxylamine 2a containing a terminal alkene was prepared in

two steps from commercially available chemicals and employed

as the initial coupling reagent; para-methoxylbenzyl (PMB) was

used as the nitrogen-protecting group because of the ease of its

removal. Not surprisingly, the initial trials with simple NBE

N2) only aﬀorded a complex mixture with NBE-containing side

products (see the Supporting Information ). The C1-substituted

NBE, known to enable mono ortho functionalization of ortho-

(

hindered and more π-acidic phosphaﬂuorene (L1) was found

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Table 1. Control Experiments

Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), Pd(cod)Cl (0.01 mmol), ligand (0.025 mmol), NBE (0.1 mmol), and Cs CO (0.25 mmol)

in 1,4-dioxane (1 mL), 100 °C, 12 h. Yields (3a + 3a’) and ratios were determined by crude H NMR analysis using pyrazine as the internal

standard.

14a

to be the best ligand. A survey of the phosphine eﬀect (entry 3

and the Supporting Information ) shows that, in general,

electron-deﬁcient ligands worked better than electron-rich

ones; for example, P(4-CF C H ) (L4) gave higher yield

ligand for ortho amination (entry 3).

As expected, the

palladium catalyst, phosphine ligand, and NBE were all essential

for this transformation (entries 4−6). Similar to our previous

ﬁndings, Pd(OAc) is a worse precatalyst in the context of

4 3

than P(4-OMeC H ) (L3), which was the previously optimal

“ortho constraint” than Pd(cod)Cl₂(entry 7). This is

4 3

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Table 2. Substrate Scope with Ortho-Unsubstituted Aryl Iodides

Reaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), Pd(cod)Cl (0.01 mmol), L1 (0.025 mmol), N1 (0.1 mmol), and Cs CO (0.25 mmol) in 1,4-

dioxane (1 mL), 100 °C, 12 h. All yields are combined isolated yields of the products. The ratios were determined by H NMR analysis of crude

samples using pyrazine as the internal standard.

presumably due to the noninnocent role of acetate anion in

facilitating undesired C−H activation, as the use of cesium

acetate as the base almost shut down the reaction (entry 8). In

addition, cesium carbonate proved to be a much better base than

potassium carbonate (entry 9). Reducing the N1 NBE loading

to 50 and 25 mol % diminished the yield from 72 to 55 and 49%,

respectively (entries 10 and 11), though turnover of N1 can be

observed. It is worth mentioning that 71% of N1 can be

recovered under the standard condition. The reaction is

regioselective with the annulation only at the C3 and C4

positions (3a). The alkene-isomerized product (3a′) was

formed as a minor product, which can be separated from the

main product. The kinetic monitoring of the reaction (Figure 2)

shows that 3a′ was generated at the beginning of the reaction

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Scheme 3. Synthetic Applications

NMO: N-methylmorpholine-N-oxide.

and the ratio between 3a and 3a′ did not change much

throughout the reaction. It is likely that the lack of the ortho

substituent allows the Pd-hydride reinsertion to generate a

tertiary alkyl-Pd(II) species, which can undergo inward β-

hydrogen elimination to give trisubstituted alkene 3a′; in sharp

contrast, such alkene isomers were not observed with ortho-

substituted aryl iodides (vide infra, Table 3), highlighting

another challenge with ortho-unsubstituted substrates.

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anhydrous THF at 90 °C (eq 1 ). Crystals suitable for X-ray

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Scheme 4. Extension of the Reaction Scope to Other Types of Ortho Functionalization

With the optimized conditions in hand, the scope of the

THBA formation with ortho-unsubstituted aryl iodides was then

examined (Table 2). Both electron-deﬁcient and -rich aryl

iodides are competent coupling partners (3a−3l), though the

electron-deﬁcient aryl iodides gave slightly better yields. Besides

meta-substituted aryl iodides, meta-, para-disubstituted ones

also reacted smoothly (3m−3r). The reaction conditions can

tolerate a wide range of functional groups, including chloro (3a),

bromo (3b), nitro (3c), triﬂuoromethyl (3d), ester (3e), nitrile

tile role of the alkene moiety for potential medicinal chemistry

applications. Finally, under acidic conditions, the mixture of exo-

and endo-cyclic products could be isomerized into the

thermodynamically more stable internal oleﬁn in nearly

quantitative yield (Scheme 3C).

To explore the generality of N1 in promoting seven-

membered-ring formation with ortho-unsubstituted iodoarenes,

we examined two other ortho functionalization tactics (Scheme

4). To our delight, besides ortho amination, preliminary success

has been achieved with Catellani annulations via ortho

(3f), terminal alkene (3k), and silyl ether (3l). Other alkene-

tethered O-benzoyl hydroxylamines 2 were explored next. When

substituted amination reagents were employed, 3-substituted

THBAs (3s−3t) can still be aﬀorded in good yields. Besides the

PMB protecting group, simple benzyl can be introduced in even

higher yield (3u). When using the styrene-tethered reagent,

complete selectivity of a single alkene geometrical isomer (3v)

was observed. It is likely that the conjugation and/or the

increased sterics inhibited the alkene isomerization. Finally,

ortho-unsubstituted aryl iodides derived from naphthalene (3w),

ﬂuorenone (3x), quinoline (3y), estrone (3z), and loratadine

alkylation and ortho aminocarbonylation to give benzoan-

nulene and benzoazepin-1-one products, respectively. In

contrast, unsubstituted NBE (N2) gave much inferior results

along with forming a signiﬁcant amount of NBE-containing side-

products, further conﬁrming that the C7-bromo group is critical

to addressing the “ortho constraint” and inhibiting undesired

pathways.

X-ray Crystal Structure of Complex 11. The unique

property of the C7-bromo NBE (N1) prompted us to investigate

its exact role in the catalysis. Migratory insertion with NBEs

typically occurs in a cis, exo manner because of the predistortion

(3aa) all delivered the desired THBAs in moderate to good

12a,27

of the NBE π bond.

However, one cannot assume, a priori,

yields. These polycyclic ring-fused azepines with diverse

functional groups could be challenging to access via conven-

tional approaches.

that N1 should maintain the exo selectivity because of the

potential steric repulsion between the C7 substituent with the

Pd during the migratory insertion process. To conﬁrm the

alkene facial selectivity of the migratory insertion step, we

synthesized pure palladium complex 11 in good yield by reacting

Synthetic applications. The utility of this method was then

evaluated. Tolvaptan, an aquaretic drug that functions as an

orally active vasopressin receptor 2 antagonist, has been used to

treat hyponatremia and autosomal dominant polycystic kidney

disease. The ketone intermediate 5 was previously prepared in

-iodoanisole with N1 and stoichiometric Pd(PPh₃)₄in

seven steps; for comparison, it can now be accessed in two steps

from THBA 3a (Scheme 3 A). Note that the PMB protecting

group can be removed in high yield by treatment with TFA. Due

to the modularity of the synthesis, this approach could be

beneﬁcial for preparing diverse tolvaptan analogues from readily

available substituted aryl iodides. In addition, the chloro group

on THBA 3a can serve as a handle to conveniently introduce

other functional groups, e.g., an aryl group (6a), via cross

couplings (Scheme 3 B); it can also be deleted through

analysis were obtained from dissolving 11 in CH Cl followed by

the addition of MeOH.The X-ray structure of complex 11 clearly

shows that the aryl ring and the palladium still remain positioned

reduction (6b). Moreover, the alkene moiety in THBA

products can undergo dihydroxylation, hydroboration−oxida-

tion, and Simmons−Smith reaction to install vicinal diol (6c),

primary alcohol (6d), and cyclopropane (6e), respectively.

Furthermore, under the Mukaiyama hydration conditions, the

alkene was converted into a tertiary alcohol (6f) and an

interesting oxa-bridged benzazepine (6f′). It is noteworthy that

these derivatizations could ﬁnd their relevance in a number of

cis and exo to the norbornyl group (Figure 3, left). Interestingly,

the d Pd center possesses a square-planar geometry with PPh ,

iodide, norbornyl group, and the bromo substituent. This is in

contrast with the literature reported analogue (complex 12)

with simple NBE, where the η coordination with the C(5)−

C(6) π bond occupies one of the four coordination sites (Figure

3, right). Other bond lengths, such as Pd(1)−I(2), Pd(1)−

C(3), and Pd(1)−P(4) bonds, remain largely unchanged. Such

THBA-containing bioactive compounds, implying the versa-

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a weakly coordinating bromo substituent can be considered as a

built-in” L-type ligand into NBE, which may have some

“

implications in catalysis (vide infra).

Study of the NBE Eﬀect. To understand the speciﬁc role of

the C7-bromo substituent, it would be important to ﬁrst

recognize the reactivity diﬀerences between diﬀerent NBEs. As

such, side products of the model reactions with four

representative NBEs have been carefully characterized and

analyzed (Scheme 5). In contrast to the result with N1,

benzocyclobutene 15 was the major isolated side-product when

simple NBE N2 was employed. Comparing to the standard

14a

ortho amination with cyclic amine electrophiles, it is likely

that the bulkiness of electrophile 2a or the coordination of the

alkene moiety hindered amination with the ANP intermediate.

In addition, a minor side product 16 containing the norbornyl

group at the ipso position was also isolated, and such a C−H

reductive elimination product was not observed when N1 was

used. These results indicated that the bromo substituent in N1

should also promote β-carbon elimination or prevent C−H

reductive elimination. As a comparison, although the sterics of

Figure 3. Structures of complex 11 and 12 (ref 28) as determined by X-

ray crystallography.

the C2-substituted NBE (N6) can eﬀectively inhibit the

benzocyclobutene formation, it led to NBE-attached side-

product 17 and bis ortho-amination side-product 14. The

Scheme 5. Isolation of Side Products with Diﬀerent NBEs

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Figure 4. Comparison of the β-carbon elimination and subsequent 7-exo-trig between NBEs N1 and N2. All energies are in kcal/mol. Calculations

were performed at the B3LYP-D3/SDD-6-311+G(d,p)-SMD(1,4-dioxane)//B3LYP/LANL2DZ-6-31G(d) level of theory.

formation of 17 is possibly due to the lability of the Pd-enolate

intermediate that can undergo protonation or β-hydrogen

elimination via the “face switch”. The formation of 14

indicates that N6 cannot eﬃciently suppress the “ortho

constraint”. On the other hand, with the C1-substituted NBE

slightly higher barrier than the β-carbon elimination in this

reaction, NBE extrusion can be regarded as a pre-equilibrium.

The steric repulsion between the bromo substituent and the

ortho C−H bond (H···Br distance is 2.66 Å) is expected to

account for the faster 7-exo-trig (22.6 with N1 vs 25.3 kcal/mol

with N2) by driving the NBE extrusion pre-equilibrium.

Another feature of the bromo-substituted NBE is the weak

coordination between the Pd and the Br, which was also

observed in the X-ray structure of complex 11. Such weak

coordination could stabilize intermediate INT1 and prevent

competing side reactions (e.g., C−H reductive elimination,

protonation or β-H elimination). On the other hand, even from

a relatively stable intermediate (INT1), the β-carbon elimi-

nation with N1 still takes place with a relatively low kinetic

barrier. Analysis of the transition state TS1 (with N1) revealed

that a weak interaction between the Pd and the Br still exists

(Pd···Br distance is 3.34 Å) during the β-carbon elimination

transition state. Thus, the kinetic barrier of the β-carbon

elimination remains very similar to simple NBE N2 (21.7 vs 20.6

kcal/mol). As a result, the DFT study implies that the overall

NBE extrusion and subsequent Heck cyclization process is more

favorable with N1.

(N3), no ortho difunctionalized products (like 14) were

observed, showing that N3 is indeed eﬀective to minimize the

second ortho C−H activation. However, direct reductive

elimination of ANP became the major side reaction, resulting

in undesired benzocyclobutene 18; compared to N1, the

increased sterics in the N3-derived ANP intermediate renders

it less reactive with the bulky electrophile. With N1 as the

cocatalyst, side products (13 and 14) were observed with only

5% yields; therefore, the beneﬁts of using the C7-bromo NBE

(N1) include suppressing ANP reductive elimination, promot-

ing NBE exclusion, and/or inhibiting the second ortho C−H

activation without signiﬁcantly interfering with the reaction

between the ANP and the electrophile.

To further elucidate the detailed roles of the bromo moiety of

N1 in this reaction, DFT calculation was conducted. First, the

eﬀect of N1 on the β-carbon elimination and subsequent 7-exo-

trig processes was examined (Figure 4). As the 7-exo-trig has a

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Figure 5. Comparison of reductive elimination from INT3 between NBE N1 and N2. All energies are in kcal/mol.

Meanwhile, the reactivity diﬀerences between N1- and N2-

derived ANPs (INT3) have also been studied computationally

As a summary of the NBE eﬀect, the C7-bromo-substituted

N1 indeed exhibits a range of unique and versatile features. First,

the bromo atom can serve as a built-in L ligand to stabilize

reaction intermediates to minimize side reactions. In addition, it

can promote NBE extrusion through stabilizing the β-carbon

elimination transition state, therefore addressing the “ortho

constraint” challenge. Moreover, the electronegative Br

substituent can suppress ANP reductive elimination because

of charge repulsion with the metalated arene. Finally, the lack of

steric bulkiness of the Br substituent retains good reactivity of

the ANP with the electrophile. Altogether, the C7-bromo-

substituted N1 is well suited for the challenging medium-sized-

ring formation with ortho-unsubstituted aryl iodides.

(Figure 5). The benzocyclobutene side products (e.g., 15 and

8) have been previously found to come from reductive

elimination of the anionic ANP intermediate (INT3).

Through the DFT calculation, the presence of the electro-

negative bromo substituent in N1-derived ANP was found to

disfavor the reductive elimination by 4.3 kcal/mol relative to the

one derived from N2. The increased kinetic barrier was

presumably due to the repulsive interaction between the

negatively charged Br atom with the arene π electrons in TS3.

This is evidenced by the shortest C···Br bond distance of 3.40 Å

(

the sum of their van der Waals radii is 3.55 Å) in the required

Scope of the Ortho-Substituted Aryl Iodides. Finally, to

complete the method development for the Pd/NBE-catalyzed

THBA synthesis, we also investigated the scope of using ortho-

substituted aryl iodides (Table 3). Aided by the ortho

substituents, this reaction can now be achieved in good yields

by several NBEs (see the Supporting Information for details),

transition state. On the other hand, INT3 derived from N1 has a

very similar oxidative addition barrier with 2a to that of N2,

indicating its reactivity with electrophiles is not aﬀected by the

bromo substituent. This could be explained by the fact that the

bromo substituent does not have signiﬁcant steric repulsion with

the electrophile during the transition state TS4 (N1) (the

shortest H···Br distance is over 4 Å). Thus, the DFT study also

supports that NBE N1 can inhibit the ANP reductive

elimination without compromising the reaction with the

electrophile.

with the C2-substituted NBE N14 being optimal. In

addition, without the challenge of the “ortho constraint”, the

use of acetate salts (e.g., CsOAc and Pd(OAc) ) was beneﬁcial,

possibly through promoting the concerted metalation deproto-

nation during the C−H activation step. The reaction can also

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Table 3. Substrate Scope of the Ortho-Substituted Aryl Iodides

Reaction conditions: 19 (0.1 mmol), 2 (0.2 mmol), Pd(OAc) (0.01 mmol), P(2-furyl) (0.025 mmol), N14 (0.1 mmol), CsOAc (0.25 mmol) in

,4-dioxane (1 mL), 55 °C, 45 h. 70 °C, 18 h. 100 °C, 12 h.

proceed at a lower temperature. No obvious alkene isomer-

ization was observed (vide supra). It is likely that the bulkiness of

the ortho substituents inhibits the palladium-hydride reinser-

tion. Moreover, a number of diﬀerent ortho substituents with

various steric and electronic properties were tolerated. Similarly,

the high chemoselectivity and broad functional group/linker

compatibility make this method generally able to access diverse

C6-substituted THBAs.

CONCLUSION

■

In summary, a unique C7-bromo-substituted NBE N1 has been

identiﬁed to be an “ideal” cocatalyst in promoting THBA and

other seven-membered ring synthesis from ortho-unsubstituted

aryl iodides. The broad substrate scope, the high functional

group tolerance, and the synthetic versatility of the alkene

functionality should make this method attractive for modular

preparation of substituted THBAs. The knowledge gained on

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Nakaya, K.; Kitano, K.; Yamamura, Y.; Nakamura, S.; Onogawa, T.;

Article

the distinct and versatile roles of the C7-bromo group in N1

could have implications on new catalyst design. Further

investigations of N1 (and its analogues) in promoting other

challenging Catellani-type transformations are ongoing.

(2) Kondo, K.; Ogawa, H.; Yamashita, H.; Miyamoto, H.; Tanaka, M.;

et al. 7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)

benzoyl]-2, 3, 4, 5-tetrahydro-1H-1-benzazepine (OPC-41061): a

Potent, Orally Active Nonpeptide Arginine Vasopressin V2 Receptor

Antagonist. Bioorg. Med. Chem. 1999, 7, 1743−1754.

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/jacs.1c04575.

■

(3) Hou, F. F.; Zhang, X.; Zhang, G. H.; Xie, D.; Chen, P. Y.; Zhang,

W. R.; Jiang, J. P.; Liang, M.; Wang, G. B.; Liu, Z. R.; Geng, R. W.

Efficacy and Safety of Benazepril for Advanced Chronic Renal

Insufficiency. N. Engl. J. Med. 2006, 354, 131−140.

(4) (a) Laponogov, I.; Pan, X.-S.; Veselkov, D. A.; Cirz, R. T.;

Wagman, A.; Moser, H. E.; Fisher, L. M.; Sanderson, M. R. Exploring

the Active Site of the Streptococcus Pneumoniae Topoisomerase IV-

DNA Cleavage Complex with Novel 7, 8-Bridged Fluoroquinolones.

Open Biol. 2016 , 6 , 160157. (b) Lean, I. J.; Thompson, J. M.; Dunshea,

F. R. A Meta-Analysis of Zilpaterol and Ractopamine Effects on Feedlot

Performance, Carcass Traits and Shear Strength of Meat in Cattle. PLoS

One 2014, 9, No. e115904. (c) Seto, M.; Aramaki, Y.; Okawa, T.;

Miyamoto, N.; Aikawa, K.; Kanzaki, N.; Niwa, S.-i.; Iizawa, Y.; Baba, M.;

Shiraishi, M. Orally Active CCR5 Antagonists As Anti-HIV-1 Agents:

Synthesis and Biological Activity of 1-Benzothiepine 1, 1-Dioxide and

Detailed experimental procedure, H NMR and C NMR

spectra, and DFT studies (PDF )

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-Benzazepine Derivatives Containing a Tertiary Amine Moiety. Chem.

AUTHOR INFORMATION

Corresponding Authors

Guangbin Dong − Department of Chemistry, University of

Chicago, Chicago, Illinois 60637, United States; orcid.org/

■

Pharm. Bull. 2004 , 52 , 577 −590. (d) Mantlo, N. B.; Escribano, A.

Update on The Discovery and Development of Cholesteryl Ester

Transfer Protein Inhibitors for Reducing Residual Cardiovascular Risk.

J. Med. Chem. 2014, 57, 1−17. (e) Cao, G.; Beyer, T. P.; Zhang, Y.;

Schmidt, R. J.; Chen, Y. Q.; Cockerham, S. L.; Zimmerman, K. M.;

Karathanasis, S. K.; Cannady, E. A.; Fields, T.; Mantlo, N. B.

Evacetrapib Is A Novel, Potent, and Selective Inhibitor of Cholesteryl

Ester Transfer Protein that Elevates HDL Cholesterol Without

Inducing Aldosterone Or Increasing Blood Pressure. J. Lipid Res.

000-0003-1331-6015 ; Email: gbdong@uchicago.edu

Jianchun Wang − Department of Chemistry, University of

Chicago, Chicago, Illinois 60637, United States; Division of

Chemistry and Chemical Engineering, California Institute of

Technology, Pasadena, California 91125, United States;

orcid.org/0000-0002-3998-8699; Email: jcwang.chem@

gmail.com

011, 52, 2169−2176. (f) Das, J.; Floyd, D. M.; Kimball, S. D.; Duff, K.

J.; Lago, M. W.; Moquin, R. V.; Lee, V. G.; Gougoutas, J. Z.; Vu Chi

Truc. Benzazepinone Calcium Channel Blockers. 3. Synthesis and

Structure-Activity Studies Of 3-Alkylbenzazepinones. J. Med. Chem.

5) For a review: (a) Mazumdar, W.; Driver, T. G. Recent Advances in

Author

992, 35, 773−780.

Xin Liu − Department of Chemistry, University of Chicago,

Chicago, Illinois 60637, United States

the Development of Catalytic Methods that Construct Medium-Ring

Lactams, Partially Saturated Benzazepines and Their Derivatives.

Synthesis 2021, 53, 1734−1748. For recent examples: (b) Li, D.; Park,

Y.; Yoon, W.; Yun, H.; Yun, J. Asymmetric Synthesis of 1-Benzazepine

Derivatives via Copper-Catalyzed Intramolecular Reductive Cycliza-

tion. Org. Lett. 2019, 21, 9699−9703. (c) Guo, C.; Fleige, M.; Janssen-

Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.1c04575

Author Contributions

All authors have given approval to the ﬁnal version of the

manuscript.

Muller, D.; Daniliuc, C. G.; Glorius, F. Cooperative N-Heterocyclic

Carbene/Palladium-Catalyzed Enantioselective Umpolung Annula-

tions. J. Am. Chem. Soc. 2016, 138 , 7840 −7843. (d) Arnold, J. S.;

Mwenda, E. T.; Nguyen, H. M. Rhodium-Catalyzed Sequential Allylic

Amination and Olefin Hydroacylation Reactions: Enantioselective

Synthesis of Seven-Membered Nitrogen Heterocycles. Angew. Chem.,

Int. Ed. 2014, 53, 3688−3692.

Funding

Financial support from the University of Chicago and NIGMS

(1R01GM124414−01A1) is acknowledged.

Notes

The authors declare no competing ﬁnancial interest.

6) (a) Stockerl, S.; Danelzik, T.; Piekarski, D. G.; García Mancheno,

ACKNOWLEDGMENTS

O. Mild, Metal-Free Oxidative Ring-Expansion Approach for the

■

Synthesis of Benzo[b]azepines. Org. Lett. 2019, 21, 4535 −4539.

Mr. Renhe Li (University of Chicago) is acknowledged for

checking the reproducibility of the experimental procedure. Dr.

Zhao Wu (University of Chicago) is thanked for helpful

discussions. Mr. Shusuke Ochi (University of Chicago) is

acknowledged for X-ray crystallography. We are grateful for the

support of the University of Chicago’s Research Computing

Center for assistance with the calculations carried out in this

work.

(b) Cordero-Vargas, A.; Quiclet-Sire, B.; Zard, S. Z. A Flexible

Approach for the Preparation of Substituted Benzazepines: Application

to the Synthesis of Tolvaptan. Bioorg. Med. Chem. 2006, 14, 6165−

7) Kaldas, S. J.; Kran, E.; Muck-Lichtenfeld, C.; Yudin, A. K.; Studer,

173.

A. Reaction of Vinyl Aziridines with Arynes: Synthesis of Benzazepines

and Branched Allyl Fluorides. Chem. - Eur. J. 2020, 26, 1501−1505.

(8) Vaid, R. K.; Boini, S. K.; Alt, C. A.; Spitler, J. T.; Hadden, C. E.;

Frank, S. A.; Moher, E. D. Synthesis of Methyl 7, 9-Dimethyl-5-oxo-2, 3,

, 5-tetrahydro-1 H -benzo[b ]azepine-1-carboxylate and Its Analogues.

REFERENCES

■

1) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural

Diversity, Substitution Patterns, and Frequency of Nitrogen Hetero-

cycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem.

014, 57, 10257−10274.

Synthesis 2014, 46, 2463−2470.

(9) Wang, G.-W.; Bower, J. F. Modular Access to Azepines by

Directed Carbonylative C-C Bond Activation of Aminocyclopropanes.

J. Am. Chem. Soc. 2018, 140, 2743−2747.

0002

J. Am. Chem. Soc. 2021, 143, 9991−10004

Journal of the American Chemical Society

Article

10) Cui, L.; Zhang, G.; Peng, Y.; Zhang, L. Gold or No Gold: One-

Pot Synthesis of Tetrahydrobenz[b ]azepin-4-ones from Tertiary N -

But-3-ynyl)anilines. Org. Lett. 2009, 11, 1225−1228.

11) Catellani, M.; Frignani, F.; Rangoni, A. A Complex Catalytic

Palladium/Norbornene Cooperative Catalysis to Access Tetrahydro-

naphthalenes and Indanes with a Quaternary Center. ACS Catal. 2018,

8, 4783−4788.

(17) Wang, J.; Li, R.; Dong, Z.; Liu, P.; Dong, G. Complementary Site-

Selectivity in Arene Functionalization Enabled by Overcoming the

ortho Constraint in Palladium/Norbornene Catalysis. Nat. Chem. 2018,

10, 866−872.

(18) For examples of ortho amination using cyclic amine electrophiles,

see: (a) Shi, H.; Babinski, D. J.; Ritter, T. Modular C-H

Functionalization Cascade of Aryl Iodides. J. Am. Chem. Soc. 2015 ,

137 , 3775 −3778. (b) Luo, B.; Gao, J. M.; Lautens, M. Palladium-

Catalyzed Norbornene-Mediated Tandem Amination/Cyanation

Reaction: A Method for the Synthesis of ortho -Aminated Benzonitriles.

Org. Lett. 2016, 18, 4166−4169 and ref 15a.

(19) Qi, X.; Wang, J.; Dong, Z.; Dong, G.; Liu, P. Compatibility Score

for Rational Electrophile Selection in Pd/NBE Cooperative Catalysis.

Chem. 2020, 6, 2810−2825.

(20) (a) Lautens, M.; Paquin, J. F.; Piguel, S.; Dahlmann, M.

Palladium-Catalyzed Sequential Alkylation-Alkenylation Reactions and

Their Application to the Synthesis of Fused Aromatic Rings. J. Org.

Chem. 2001, 66, 8127−8134. (b) Blaszykowski, C.; Aktoudianakis, E.;

Bressy, C.; Alberico, D.; Lautens, M. Preparation of Annulated

Nitrogen-Containing Heterocycles via a One-Pot Palladium-Catalyzed

Alkylation/Direct Arylation Sequence. Org. Lett. 2006, 8, 2043−2045

and ref 13.

(21) Li, R.; Dong, G. Structurally Modified Norbornenes: A Key

Factor to Modulate Reaction Selectivity in the Palladium/Norbornene

Cooperative Catalysis. J. Am. Chem. Soc. 2020, 142, 17859 −17875.

(22) Wang, J.; Dong, Z.; Yang, C.; Dong, G. Modular and

Regioselective Synthesis of All-Carbon Tetrasubstituted Olefins

Enabled by an Alkenyl Catellani Reaction. Nat. Chem. 2019, 11,

1106−1112.

Cycle Leading to a Regioselective Synthesis of o ,o ’-Disubstituted

Vinylarenes. Angew. Chem., Int. Ed. Engl. 1997, 36, 119−122.

(12) For selected reviews, see: (a) Wang, J.; Dong, G. Palladium/

Norbornene Cooperative Catalysis. Chem. Rev. 2019, 119, 7478−7528.

b) Della Ca ’, N.; Fontana, M.; Motti, E.; Catellani, M. Pd/

Norbornene: A Winning Combination for Selective Aromatic

Functionalization via C-H Bond Activation. Acc. Chem. Res. 2016 , 49 ,

389 −1400. (c) Ye, J.; Lautens, M. Palladium-Catalysed Norbornene-

Mediated C-H Functionalization of Arenes. Nat. Chem. 2015 , 7 , 863 −

70. (d) Catellani, M.; Motti, E.; Della Ca ’, N. Catalytic Sequential

Reactions Involving Palladacycle-Directed Aryl Coupling Steps. Acc.

Chem. Res. 2008 , 41 , 1512 −1522. (e) Catellani, M. Catalytic Multistep

Reactions via Palladacycles. Synlett 2003 , 298 −313.

13) Lautens, M.; Piguel, S. A New Route to Fused Aromatic

Compounds by Using a Palladium-Catalyzed Alkylation-Alkenylation

Sequence. Angew. Chem., Int. Ed. 2000, 39, 1045−1046.

(

14) For the ﬁrst report of the Pd/NBE-catalyzed ortho amination,

see: (a) Dong, Z.; Dong, G. Ortho vs Ipso : Site-Selective Pd and

Norbornene-Catalyzed Arene C-H Amination Using Aryl Halides. J.

Am. Chem. Soc. 2013, 135, 18350−18353. (b) For a recent review,

see:Cao, L.; Hua, Y.; Cheng, H.-G.; Zhou, Q. C-H Hetero-

Functionalization of Arenes Through Palladacyclopentane-Type

Intermediates. Org. Chem. Front. 2021, DOI: 10.1039/

D0QO01350A. (c) For recent ortho amination examples, see:

Zhang, B.-S.; Wang, F.; Yang, Y.-H.; Gou, X.-Y.; Qiu, Y.-F.; Wang,

X.-C.; Liang, Y.-M.; Li, Y.; Quan, Z.-J. Synthesis of C4-Substituted

Indoles via a Catellani and C-N Bond Activation Strategy. Org. Lett.

2020, 22, 8267−8271. (d) Zhang, B.-S.; Li, Y.; Zhang, Z.; An, Y.; Wen,

Y.-H.; Gou, X.-Y.; Quan, S.-Q.; Wang, X.-G.; Liang, Y.-M. Synthesis of

C4-Aminated Indoles via a Catellani and Retro-Diels-Alder Strategy. J.

Am. Chem. Soc. 2019 , 141 , 9731 −9738. (e) Li, R.; Liu, F.; Dong, G.

Redox-Neutral ortho Functionalization of Aryl Boroxines via

Palladium/Norbornene Cooperative Catalysis. Chem. 2019, 5 , 929 −

(23) The more challenging simple para-substituted aryl iodides were

not eﬀective substrates under the current conditions, except that 4-

iodobenzotri ﬂ uoride gave 22% of the desired product (see the

Supporting Information).

(24) Ding, T.-H.; Qu, J.-P.; Kang, Y.-B. Visible-Light-Induced, Base-

Promoted Transition-Metal-Free Dehalogenation of Aryl Fluorides,

Chlorides, Bromides, and Iodides. Org. Lett. 2020, 22, 3084−3088.

(25) (a) Roberts, E.; Mittapalli, G. K.; Wang, Y.; Yang, J.; Toussaint,

M.; Habarova, O.; Rosen, H. Modulators of Vasopressin Receptors with

Therapeutic Potential. WO 2014127350, 2014. (b) Ogawa, H.;

Miyamoto, H.; Kondo, K.; Yamashita, H.; Nakaya, K.; Tanaka, M.;

Kitano, K.; Kan, K.; Tominaga, M.; Yabuuchi, Y. Oxytocin antagonist.

WO 1994001113 A1, 1994. (c) Zhong, M.; Peng, E.; Huang, N.;

Huang, Q.; Huq, A.; Lau, M.; Colonno, R.; Li, L. Discovery of Novel

Potent HCV NS5B Polymerase Non-Nucleoside Inhibitors Bearing a

Fused Benzofuran Scaffold. Bioorg. Med. Chem. Lett. 2018, 28, 963−

968.

39. (f) Chen, S.; Wang, P.; Cheng, H.-G.; Yang, C.; Zhou, Q. Redox-

Neutral Ortho-C-H Amination of Pinacol Arylborates via Palladium

II)/Norbornene Catalysis for Aniline Synthesis. Chem. Sci. 2019, 10,

384−8389.

15) (a) Chen, Z.-Y.; Ye, C.-Q.; Zhu, H.; Zeng, X.-P.; Yuan, J.-J.

Palladium/Norbornene-Mediated Tandem C-H Amination/C-I Alke-

nylation Reaction of Aryl Iodides with Secondary Cyclic O-Benzoyl

Hydroxylamines and Activated Terminal Olefins. Chem. - Eur. J. 2014,

0, 4237−4241. (b) Gao, Q.; Liu, Z.-S.; Hua, Y.; Li, L.; Cheng, H.-G.;

Cong, H.; Zhou, Q. A Palladium/Norbornene Cooperative Catalysis to

Access N -Containing Bridged Scaffolds. Chem. Commun. 2019, 55,

8816−8819. (c) Li, J.; Yang, Y.; Liu, Y.; Liu, Q.; Zhang, L.; Li, X.; Dong,

Y.; Liu, H. Palladium/Norbornene Catalyzed ortho Amination/

Cyclization of Aryl Iodide: Process to 3-Methyl-indole Derivates and

Controllable Reductive Elimination against the Second Amination. Org.

Lett. 2021 , 23 , 2988 −2993. (d) Rago, A. J.; Dong, G. Synthesis of

C3,C4-Disubstituted Indoles via the Palladium/Norbornene-Catalyzed

ortho -Amination/ipso-Heck Cyclization. Org. Lett. 2021, 23, 3755−

(26) Li, X.; Pan, J.; Song, S.; Jiao, N. Pd-Catalyzed Dehydrogenative

Annulation Approach for the Efficient Synthesis of Phenanthridinones.

Chem. Sci. 2016, 7, 5384−5389.

(27) Lopez, S. A.; Houk, K. N. Alkene Distortion Energies and

Torsional Effects Control Reactivities, and Stereoselectivities of Azide

Cycloadditions to Norbornene and Substituted Norbornenes. J. Org.

Chem. 2013, 78, 1778−1783.

(28) Chai, D. I.; Thansandote, P.; Lautens, M. Mechanistic Studies of

Pd-Catalyzed Regioselective Aryl C-H Bond Functionalization with

Strained Alkenes: Origin of Regioselectivity. Chem. - Eur. J. 2011, 17,

8175−8188.

(29) We hypothesized that the imine or enamine generated from the

reaction of 2a after OBz elimination might serve as the hydride source

for the C-H reductive elimination.

(30) Shen, P.-X.; Wang, X.-C.; Wang, P.; Zhu, R. Y.; Yu, J.-Q. Ligand-

Enabled meta -C-H Alkylation and Arylation using a Modified

Norbornene. J. Am. Chem. Soc. 2015, 137, 11574−11577.

(31) (a) Yang, T.; Kong, C.; Yang, S.; Yang, Z.; Yang, S.; Ehara, M.

Reaction Mechanism, Norbornene and Ligand Effects, and Origins of

Meta-Selectivity of Pd/Norbornene-Catalyzed C-H Activation. Chem.

3760.

(16) For a single report using ortho unsubstituted arenes tethered with

an electrophile and a nucleophile, see: (a) Rudolph, A.; Rackelmann,

N.; Turcotte-Savard, M. O.; Lautens, M. Application of Secondary

Alkyl Halides to a Domino Aryl Alkylation Reaction for the Synthesis of

Aromatic Heterocycles. J. Org. Chem. 2009, 74, 289−297. (b) A report

by Liang shows two electron-deficient meta-substitued aryliodides can

react with 1-tosylaziridine: Liu, C.; Liang, Y.; Zheng, N.; Zhang, B.-S.;

Feng, Y.; Bi, S.; Liang, Y.-M. Synthesis of Indolines via a Palladium/

Norbornene-Catalyzed Reaction of Aziridines with Aryl Iodides. Chem.

Commun. 2018, 54, 3407−3410. A report by Zhou shows two meta-

alkoxyl phenyliodides can react with a electrophile/nucleophile-

tethered reagent, albeit in moderate yields: (c) Liu, Z.-S.; Qian, G.;

Gao, Q.; Wang, P.; Cheng, H.-G.; Wei, Q.; Liu, Q.; Zhou, Q.

0003

J. Am. Chem. Soc. 2021, 143, 9991−10004

Journal of the American Chemical Society

Sci. 2020 , 11 , 113 −125. (b) Wang, J.; Zhou, Y.; Xu, X.; Liu, P.; Dong, G.

Article

Entry to 1,2,3,4-Tetrasubstituted Arenes through Addressing the “Meta

Constraint ” in the Palladium/Norbornene Catalysis. J. Am. Chem. Soc.

32) (a) Culkin, D. A.; Hartwig, J. F. C-C Bond-Forming Reductive

020, 142, 3050−3059.

Elimination of Ketones, Esters, and Amides from Isolated

Arylpalladium(II) Enolates. J. Am. Chem. Soc. 2001, 123, 5816−5817.

(

b) Cámpora, J.; Maya, C. M.; Palma, P.; Carmona, E.; Gutiérrez, E.;

Ruiz, C.; Graiff, C.; Tiripicchio, A. Cyclic Enolates of Ni and Pd:

Equilibrium between C- and O-Bound Tautomers and Reactivity

Studies. Chem. - Eur. J. 2005, 11, 6889−6904.

(33) The C7-bromo NBE N1 can also give good yields with ortho-

substituted aryl iodides. For details, see the Supporting Information.

0004