Rh(III)-Catalyzed imidoyl C-H carbamylation and cyclization to bicyclic [1,3,5]triazinones

Bicyclic [1,3,5]Triazinones

Letter

Rh(III)-Catalyzed Imidoyl C−H Carbamylation and Cyclization to

Danielle N. Confair, Nathaniel S. Greenwood, Brandon Q. Mercado, and Jonathan A. Ellman*

∇

Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03393

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sı Supporting Information

ABSTRACT: A Rh(III)-catalyzed synthesis of bicyclic [1,3,5]-

triazinones from a diverse array of imines coupled with ethyl

(

[

pivaloyloxy)carbamate is reported. The preparation of [5,6]- and

6,6]-bicyclic heterocycles substituted with aryl, alkyl, and alkoxy

groups demonstrated a broad reaction scope. The eﬃciency of this

approach was further enhanced with the development of a three-

component variant featuring in situ imine formation. X-ray

crystallographic characterization of a rhodacycle formed by imidoyl

C−H activation provides support for the proposed mechanism.

used heterocycles with ring-junction nitrogens occur in

many approved drugs and clinical candidates, and we

rhodacycle formed by imidoyl C−H activation, and demon-

stration of its catalytic competence, provide support for our

proposed catalytic cycle.

have developed catalytic imidoyl C−H functionalization/

annulation as a general approach for their preparation. This

strategy enables the preparation of heterocycles displaying

diverse functionality because the condensation of abundant

aldehydes and amines provides straightforward access to an

enormous number of imines that can undergo annulation with

diﬀerent types of coupling partners. We have previously

reported the synthesis of N-fused [5,6]- and [6,6]-bicyclic

heterocycles via Rh-catalyzed imidoyl C−C bond formation

using alkynes, diazoesters, and sulfoxonium ylides as coupling

After a thorough study of reaction parameters for the

annulation of imine 1a to give 3a, we selected ethyl

(pivaloyloxy)carbamate, 2, as the carbamylation reagent, the

commercially available and air-stable cationic catalyst [Cp*Rh-

(MeCN) ][SbF ] , pivalic acid (PivOH) as an additive, and

6 2

1,2-dichloroethane (DCE) as the solvent at 60 °C for 20 h

(

Table 1, entry 1). Other (pivaloyloxy)carbamate derivatives,

ethyl N-chlorocarbamate and ethyl azidoformate were

evaluated, but proved to be less eﬀective (see Tables S1 and

S2 in the Supporting Information). The corresponding cationic

Cp*Ir and Cp*Co catalysts and di ﬀ erent Cp*Rh complexes

also gave reduced yields (see Table S3 in the Supporting

Information). Switching to an electron-deﬁcient Rh catalyst

has been shown to be eﬀective for other Rh(III)-catalyzed C−

partners (Scheme 1A). Although less explored, we have also

shown that catalytic imidoyl C−N bond formation is viable for

the construction of azolo[1,3,5]triazines using dioxazolones as

coupling partners (Scheme 1B).

To broaden the scope of nitrogen heterocycles readily

accessible via imidoyl C−H functionalization, we sought to

further explore this strategy with other coupling partners.

Herein, we report a rapid, new entry to fused bicyclic

H functionalization reactions, but gave almost no desired

product (Table 1, entry 2). Lowering the catalyst loading

resulted in a reduced yield (Table 1, entry 3) and, as expected,

no desired product was observed in the absence of Rh (Table

6,7

[

1,3,5]triazinones 3 using ethyl (pivaloyloxy)carbamate, 2,

as a coupling partner with imines 1 derived from diverse and

commercially available aldehydes and aminopyridines or

aminoimidazoles (Scheme 1C). Imine carbamylation and

cyclization proceeded with a broad scope, with respect to

steric and electronic modiﬁcation and functional group

compatibility. Moreover, to further increase the eﬃciency of

this method, a one-pot three-component protocol was

developed in which imine formation occurs in situ from

aldehydes 4 and amines 5. This three-component approach

also expands scope to include annulations via in situ

preparation and reaction of imines derived from enolizable

aliphatic aldehydes. X-ray crystallographic characterization of a

, entry 4). When the reaction was performed with a catalytic

amount of PivOH (Table 1, entry 5), or without (Table 1,

entry 6) PivOH, only modest decreases in yield were observed.

Moreover, a stoichiometric amount of other additives, such as

Received: October 10, 2020

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Scheme 1. Heterocycle Synthesis via Imidoyl C−C and C−

N Bond Formation

the temperature lowered the yield (Table 1, entry 10),

presumably because of competitive decomposition of the

carbamylating reagent. When dioxane was used in place of

DCE, only a small decrease in the yield was observed (Table 1,

entry 11). For protic solvents, alcohol acidity had a

pronounced eﬀect on the reaction performance. While

MeOH resulted in a signiﬁcantly lower yield (Table 1, entry

12), only a slight decrease in yield was observed with TFE

(

Table 1, entry 13). In addition, either increasing or decreasing

the reaction concentration had relatively little eﬀect on the

reaction outcome (Table 1, entries 14 and 15).

Having established the optimal reaction conditions, we set

out to explore the scope and generality of this transformation.

We began by investigating imines 1 prepared from diverse

aldehydes (Scheme 2). In addition to the benzaldehyde-

derived imine (1a), the reaction proceeded eﬃciently with

substrates that were either electron-rich (3b) or electron-

deﬁcient (3c and 3d). Imines derived from aromatic aldehydes

substituted with halogens at either the meta (3e) or ortho

Scheme 2. Scope of the R-Substituent in Imine 1

Table 1. Reaction Parameters for Annulation to 3a

entry

variation

yield (%)

none

76 (76)

[Cp RhCl ] (5 mol %) + AgSbF (20 mol %)

5 mol % of Rh

no Rh

PivOH (0.1 equiv)

no PivOH

AcOH instead of PivOH

NaOAc instead of PivOH

PivOH + NaOAc

80 °C

dioxane as solvent

MeOH as solvent

TFE as solvent

0.4 M

0.1 M

Conditions: 1a (0.10 mmol), 2 (0.15 mmol). Yields determined by

H integration, relative to trimethyl(phenyl)silane as a external

standard. Isolated yield at 0.2 mmol scale of limiting reagent 1a.

AcOH (Table 1, entry 7) or NaOAc (Table 1, entry 8), instead

of PivOH, were also eﬀective. When both PivOH and NaOAc

were added, a slight increase in yield was observed (Table 1,

entry 9). For operational simplicity, only PivOH was used as

an additive when evaluating reaction scope, although, for some

imines, NaOAc was also found to provide a signiﬁcant

improvement in the reaction outcome (vide infra). Increasing

Standard conditions: 1 (0.20 mmol), 2 (0.30 mmol). Reaction

performed at 80 °C. NaOAc (1 equiv) was used. Reaction

performed with TFE as solvent. Isolated yields are reported.

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

positions (3f and 3g) successfully underwent carbamylation,

despite the potential for steric hindrance. With 2,6-dichloro

substitution (3h), incomplete cyclization was observed after

carbamylation, and a higher reaction temperature was

necessary to drive cyclization to completion. A reaction

temperature of 80 °C was also necessary to obtain high yields

for imines featuring 5- and 6-membered basic nitrogen

heterocycles, including pyridyl (3i), chloropyridyl (3j), and

pyrazyl (3k) functionalities. Imines derived from furan (3l)

and thiophene (3m) carboxaldehydes also coupled eﬃciently.

Broad functional group compatibility was observed with high

yields obtained for bromo and chloro substituents (3e−3h and

After demonstrating reaction scope for imidoyl carbamyla-

tion and cyclization, we decided to pursue a three-component

approach with in situ imine formation. This approach would

enhance step-economy and potentially broaden scope by

circumventing the need for isolation of potentially unstable

imines, such as those derived from enolizable alkyl aldehydes.

A variety of reaction parameters were evaluated to optimize the

yield in the three-component coupling reaction (see Table S4

in the Supporting Information). The most signiﬁcant

modiﬁcations were the addition of 3 Å molecular sieves and

a switch to HFIP from DCE. The use of 2 equiv of the

aldehyde was also found to be beneﬁcial. With these modiﬁed

conditions, the three-component method aﬀorded 3a (Scheme

j) amenable to further elaboration, as well as electrophilic

ester (3n), acidic phenol (3o) and secondary anilide (3p)

functionalities. With minor modiﬁcations to the reaction

conditions, cyclopropyl (3q) and alkoxy (3r) groups could

also be incorporated directly onto the triazinone core.

We next examined imines derived from diverse hetero-

aromatic amine functionalities (Scheme 3). Methyl groups

) in a comparable yield to that previously observed using

imine 1a (see Scheme 1).

Scheme 4. Three-Component Coupling Scope

Scheme 3. Scope of Heteroaromatic Framework in Imine 1

Standard conditions: 4 (0.4 mmol), 5 (0.2 mmol), 2 (0.3 mmol).

.0 mmol scale using 5 mol % of catalyst. Isolated yields are reported.

Standard conditions: 1 (0.20 mmol), 2 (0.30 mmol). Reaction

performed at 80 °C. NaOAc (1 equiv) was used. Isolated yields are

reported.

Three-component coupling was eﬀective with both electron-

rich (3b) and electron-deﬁcient (3d) aldehydes, and the basic

N-methyl-1H-pyrazole carboxaldehyde also coupled eﬃciently

to provide 3k (see Scheme 4). Five- and six-membered

heterocyclic amines also provided compounds 3y and 3aa in

useful but lower yields than when two-component annulation

of the corresponding imines were performed (see Scheme 3).

Most importantly, the three-component approach proved to

be applicable to a range of aliphatic aldehyde inputs. Using

cyclopropanecarboxaldehyde, 3q was obtained in a comparably

high yield, relative to the two-component reaction (see

Scheme 2). Moreover, propionaldehyde, which is much more

susceptible to tautomerization and resultant side reactions,

provided product 3ab in a synthetically useful yield. Cyclic α-

branched aldehydes featuring ether and Boc-protected amine

functionalities were highly eﬀective, producing 3ac and 3ad,

were used to evaluate substitution at each position on the

pyridine ring. For methyl substituents at the 3-, 4-, and 5-

positions, the products 3s−3u were obtained in good yields.

Even for the sterically congested 6-methyl-derivative, the

methylated product 3v could be obtained in a moderate yield

by performing the reaction at 80 °C with NaOAc as an

additive. A chloro substituent (3w), useful for diversiﬁcation,

and an electron-withdrawing triﬂuoromethyl group (3x) were

compatible with the transformation. In addition, imines formed

from other amino-substituted heterocycles provided diﬀerent

[6,6]- and [5,6]-N-heterocyclic motifs as demonstrated for

those derived from 6-methylpyridazin-3-amine (3y), 1-methyl-

imidazol-2-amine (3z), and 2-amino-1-methylbenzimidazole

(3aa).

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

The Supporting Information is available free of charge at

Letter

respectively, in excellent yields. To demonstrate the scalability

of this three-component procedure, a 1.0 mmol scale reaction

was performed with a reduced catalyst loading of 5 mol % to

give 3ac in 90% yield.

catalyst and carbamate D, which can then cyclize to form

product 3a. The cyclization of carbamate D was shown to

occur with equal eﬃciency in the presence and absence of the

Rh(III) catalyst, indicating that the catalyst does not

participate in this step (see Table S5 in the Supporting

Information).

To gain insight into the reaction mechanism, we isolated and

characterized rhodacycle 6 by X-ray crystallography (Scheme

A). We then tested this rhodacycle under our two-

In conclusion, we have developed a Rh(III)-catalyzed

synthesis of [5,6]- and [6,6]-bicyclic [1,3,5]triazinones via

coupling of imines with ethyl (pivaloyloxy)carbamate and

subsequent cyclization. Imines derived from aldehydes of

varying electronic proﬁles reacted eﬃciently, and a diverse set

of functionalities was compatible with the reaction conditions.

A range of diﬀerent N-heterocycles were successfully

incorporated into the bicyclic framework, and aromatic,

aliphatic, and alkoxy groups were all eﬀectively introduced

on the triazinone ring. This method was further developed in a

one-pot three-component procedure. By forming imines in

situ, practicality was enhanced, and the scope was extended to

include enolizable aliphatic aldehydes. X-ray crystallographic

characterization of a rhodacyle corresponding to a likely

catalytic intermediate was also obtained, and a plausible

mechanistic pathway is proposed.

Scheme 5. Isolation and Reaction of Rhodacycle 6

Yield determined by H integration relative to trimethyl(phenyl)-

silane as external standard.

ASSOCIATED CONTENT

■

component reaction conditions to assess its viability as a C−

H activation intermediate. Imine 1a was coupled with 2 in the

sı Supporting Information

presence of rhodacycle 6 (10 mol %) and AgSbF (10 mol %),

https://pubs.acs.org/doi/10.1021/acs.orglett.0c03393.

producing product 3a in 68% yield (Scheme 5B). This result is

consistent with a cationic Rh(III) rhodacycle formed via

imidoyl C−H activation as a plausible intermediate along the

catalytic pathway.

A possible catalytic cycle for the two-component coupling of

model substrate 1a is presented in Scheme 6. Based on the

Procedure details and NMR spectra (PDF)

Accession Codes

CCDC 2035056 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.

Scheme 6. Proposed Reaction Mechanism

AUTHOR INFORMATION

■

Corresponding Author

Jonathan A. Ellman − Department of Chemistry, Yale

University, New Haven, Connecticut 06520, United States;

orcid.org/0000-0001-9320-5512;

Email: jonathan.ellman@yale.edu

Authors

Danielle N. Confair − Department of Chemistry, Yale

University, New Haven, Connecticut 06520, United States

Nathaniel S. Greenwood − Department of Chemistry, Yale

University, New Haven, Connecticut 06520, United States

Brandon Q. Mercado − Department of Chemistry, Yale

University, New Haven, Connecticut 06520, United States

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.0c03393

results shown in Scheme 5, we propose that imine 1a

undergoes a concerted metalation−deprotonation to generate

rhodacycle A. Both the starting imine 1a and heterocyclic

product 3a contain basic nitrogen sites that could serve as the

Author Contributions

^∇These authors contributed equally.

base for this and other steps. Next, coordination of the

carbamylating reagent 2 to the Rh(III) center followed by

insertion and loss of PivOH leads to the formation of

Notes

,13

intermediate C.

Proto-demetalation releases the Rh(III)

The authors declare no competing ﬁnancial interest.

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

see: (a) Albinati, A.; Arz, C.; Pregosin, P. S. Synthesis, Structure and

Letter

(

11) For characterization of rhodacycles obtained by oxidative

ACKNOWLEDGMENTS

■

addition of imines derived from 2-aminopyridine to Rh(I) complexes,

NMR Spectroscopy of Some Rhodium(III) Cyclometallated Schiff ’s

Base Complexes Derived from 2-Benzylidene-3-methylpyridines.

Crystal Structure of [RhHI{2-(3-nitrobenzylidene)-3-methylpyri-

dine}; (PPh ) ]. J. Organomet. Chem. 1987 , 335 , 379 −394.

The NIH (No. R35GM122473) is gratefully acknowledged for

supporting this work.

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