Rh(III)-Catalyzed Coupling of N-Chloroimines with α-Diazo-α-phosphonoacetates for the Synthesis of 2 H-Isoindoles

Article abstract of DOI:10.1021/acs.orglett.9b02501

We report herein the first use of N-chloroimines as effective synthons for directed C-H functionalization. Rh(III)-catalyzed coupling of N-chloroimines with α-diazo-α-phosphonoacetates allows for efficient dechlorinative/dephosphonative access to 2H-isoindoles. Further deesterification under Ni(II) catalysis enables the complete elimination of reactivity-assisting groups and full exposure of reactivity of C3 and N2 ring atoms for attaching structurally distinct appendages.

Full text of DOI:10.1021/acs.orglett.9b02501

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rh(III)-Catalyzed Coupling of N‑Chloroimines with α‑Diazo-α-
phosphonoacetates for the Synthesis of 2H‑Isoindoles
Bing Qi, Lei Li, Qi Wang, Wenjing Zhang, Lili Fang, and Jin Zhu*
Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering, State Key Laboratory of
Coordination Chemistry, Nanjing National Laboratory of Microstructures, Collaborative Innovation Center of Chemistry for Life
Sciences, Nanjing University, Nanjing 210093, China
S
* Supporting Information
ABSTRACT: We report herein the first use of N-
chloroimines as effective synthons for directed C−H
functionalization. Rh(III)-catalyzed coupling of N-chloroi-
mines with α-diazo-α-phosphonoacetates allows for efficient
dechlorinative/dephosphonative access to 2H-isoindoles.
Further deesterification under Ni(II) catalysis enables the
complete elimination of reactivity-assisting groups and full
exposure of reactivity of C3 and N2 ring atoms for attaching structurally distinct appendages.
ransition-metal-catalyzed directed C−H functionalization
Isoindoles are important structural moieties in biologically
active molecules (e.g., lenalidomide4 as a drug against multiple
myeloma). Although various methods have been developed for
the synthesis of isoindoles,5−8 their drawbacks are apparent,
including complicated synthetic procedures, harsh reaction
conditions, limited substrate scope, etc. Rh(III)-9 and Ru(II)-
catalyzed10 C−H activation has been recently explored as an
alternative strategy to address these issues. Despite the
effectiveness, all these protocols employ acrylates for ring
closure, thus inevitably leaving carboxylate ester groups that
are recalcitrant for complete removal, due to extra carbon
atoms between the isoindole skeleton and ester groups.
T
has recently emerged as a promising step-economic
strategy for the synthesis of a diverse range of structures.1
Heterocycles, as privileged molecular skeletons for pharma-
ceutical applications, have been the center of focus in this
nascent field.2 In this regard, an important driving force for
innovations in synthetic protocols is the development of new
directing groups. Herein, we report the first use of N-
chloroimines for directed C−H functionalization (Scheme 1).3
Scheme 1. Rh(III)-Catalyzed, N-Chloroimine and α-Diazo-
α-Phosphonoacetate Coupling for Access to 2H-Isoindoles
We initiated the reaction development by screening
experimental conditions for the coupling of N-chloro-1-
phenylethan-1-imine (1a) with ethyl 2-diazo-2-(diethoxy-
phosphoryl)acetate (2a) (Supporting Information). Initial
examination of the reaction in dichloroethane (DCE) at 80
°C under the catalysis of [RhCp*Cl2]2 (2 mol %)/AgSbF6 (8
mol %) shows that NaOAc (1 equiv) is the best additive for
transformation into an expected dechlorinative/dephosphona-
tive product, ethyl 3-methyl-2H-isoindole-1-carboxylate (3aa,
64% yield after 12 h). Virtually no conversion can be observed
in the absence of either AgSbF6 or NaOAc. A decrease or
increase of the NaOAc quantity to 0.5 or 2 equiv substantially
retards the reaction. A switching of the solvent to MeOH,
trifluoroethanol (TFE), MeCN, 1,4-dioxane, or THF is not
beneficial. The generation of a cationic Rh(III) catalyst is
essential for the transformation; the reaction does not occur
under [RhCp*(OAc)2]2 (2 mol %) but proceeds to afford a
79% yield of 3aa utilizing [RhCp*(MeCN)3](SbF6)2 (4 mol
%). The replacement of AgSbF6 with either AgO2CCF3 or
AgBF4 identifies AgBF4 as an even better halide abstraction
In particular, in coupling with α-diazo-α-phosphonoacetates
under Rh(III) catalysis, regiochemically allowed, polarity-
matched reaction between N(δ+)−Cl(δ−) and C(δ−)−
P(δ+) bonds allows for dechlorinative/dephosphonative syn-
thesis of 2H-isoindoles. Further deesterification under Ni(II)
catalysis enables the complete elimination of reactivity-assisting
groups and full exposure of reactivity of C3 (electrophilic
substitution: e.g., dimethylaminomethylidene derivatization
and formylation, azo derivatization) and N2 (nucleophilic
reaction: e.g., methylation) ring atoms for attaching structur-
ally distinct appendages.
Received: July 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02501
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
t
reagent (84% 3aa yield). A negative control experiment under
AgBF4/NaOAc evidences the critical role played by
[RhCp*Cl2]2. Further optimization of the [RhCp*Cl2]2/
AgBF4 quantity indicates that 1 mol %/4 mol % gives the
best 3aa yield (91%).
Under the previous optimized reaction conditions, we then
undertook an extensive survey of the substrate scope (Scheme
2). By fixing 2a as the coupling partner, the substrate scope of
substituents (Me, 2b; Bu, 2c; Ph, 2d). With Ph as both the
imino C-substituent (1w) and acetate substituent (2d), the
reaction proceeds to a comparable extent to that with either
1w and 2a or 1a and 2d as the reactants.
With the substrate scope inspected, we then proceeded to
the mechanistic studies. A H/D scrambling experiment on 1a
shows 14% N-chloroimine-ortho D labeling (Supporting
Information). An intermolecular competition experiment
(between either 1b/1g or 1f/1g and 2a) reveals no significant
electronic preference (3ba/3ga = 1.4, 3fa/3ga = 1.4). A kinetic
isotope effect (KIE) experiment (between 1a/1a-d5 and 2a)
furnishes a kH/kD value of 3.0. These observations support a
concerted metalation−deprotonation (CMD), turnover-limit-
ing C−H activation pathway.
Scheme 2. Substrate Scope for the Synthesis of 2H-
a b
,
Isoindoles
We further sought to delineate the reaction pathway by
examining the reactivity of five-membered rhodacycles. A
reaction between [RhCp*(MeCN)3](SbF6)2 and 1g under
NaOAc in DCE, dichloromethane (DCM), or CHCl3 at room
temperature (rt) affords the rhodacycle 1g-Rh-Cl (Scheme 3).
Scheme 3. Mechanistic Studies Involving 1g-Rh-Cl
a
Conditions: N-chloroimine (0.2 mmol), α-diazo-α-phosphono-
b
acetate (0.3 mmol), DCE (2 mL). Yield of isolated product.
c
d
[RhCp*Cl2]2 (2 mol %), AgBF4 (8 mol %). AgSbF6 instead of
AgBF4.
N-chloroimines was first investigated. The reaction proceeds
well for N-chloroimines bearing both electron-donating (Me,
1b; Et, 1c; nAm, 1d; Ph, 1e; OMe, 1f) and electron-
withdrawing (F, 1g; Cl, 1h; Br, 1i; I, 1j; CF3, 1k; CN, 1l)
groups at the para position of the phenyl ring. The yields of
3ba, 3ea, and 3ga reach the impressive 98%, 95%, and 95%,
respectively. A single-crystal X-ray diffraction of 3ga
unambiguously confirms the 2H-isoindole structure. Meta
substitution, irrespective of its electronic character (Me, 1m;
OMe, 1n; F, 1o; Cl, 1p; Br, 1q; CF3, 1r), can be tolerated in
general. Regiospecific coupling is exclusively observed for
sterically more demanding substituents (1m, 1p, 1q, 1r)
whereas regioisomers are identified for sterically less bulky
ones (1n, 1o). Ortho substitution is also synthetically
compatible (F, 1s), albeit with a slightly lower yield compared
to the para and meta counterparts. Disubstitution (1t) further
hinders the reactivity. The alteration of the imino C-Me group
to either C-Et (1u), C-nPr (1v), or C-Ph (1w) group results in
a diminished yield, suggestive of a steric effect. The steric effect
is more pronounced for a fused ring system (1x). Preliminary
examination of the substrate scope for α-diazo-α-phosphonoa-
cetates shows largely preserved reactivity for different acetate
In this case, rhodacycle-stabilizing ligand Cl− comes from
DCE, DCM, or CHCl3. A switching of the solvent to either
MeOH or THF mandates the addition of Cl− (e.g., from
NaCl) for acquiring 1g-Rh-Cl. Further comprehensive experi-
ments offer the following observations: (1) initial attempt at
the stoichiometric reaction between 1g-Rh-Cl and 2a fails to
deliver 3ga (eq 1); (2) neither HOAc nor 1g is capable of
changing the reaction outcome for 1g-Rh-Cl and 2a when
added at the postreaction stage (eqs 2 and 3); (3) the reaction
between 1g-Rh-Cl and 2a can proceed to the 3ga stage with
the additional participation of 1g (eq 4); (4) a reaction for 1g-
B
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Rh-Cl, 1a, and 2a gives a mixture of 3ga and 3aa (eq 5); (5)
although 1-phenylethan-1-one oxime (1y) does not react with
2a, it can effect the reaction between 1g-Rh-Cl and 2a (eq 6);
(6) 1g-Rh-Cl can efficiently catalyze the reaction between 1g
and 2a as well as between 1a and 2a (eqs 7 and 8); (7) neither
the stoichiometric reaction nor the catalytic reaction involving
1g-Rh-Cl (as well as 2a and 1g) can proceed without NaOAc
(eqs 9 and 10); (8) the rhodacycle 1h′-Rh-Cl (synthesized
from [RhCp*Cl2]2 and 1h under NaOAc in DCE at 45 °C)
(Scheme 4), with the Cl portion of the N-chloroimine group
Scheme 5. Proposed Reaction Mechanism
Scheme 4. Mechanistic Studies Involving 1h′-Rh-Cl
(3ha′), under HOAc (eq 18). The same type of isoquinolin-
3(2H)-one derivative (3ga′) can be acquired starting from 1g-
Rh-Cl (with 2a) (eq 12). Reexamination of the reaction either
between 1h and 2a or between 1g and 2a shows the Rh(III)-
catalyzed transformation to the respective target product (3ha′
or 3ga′) utilizing HOAc (eqs 19 and 20). In addition, 1h′-Rh-
Cl also allows catalytic access to 3ha′ from 1h and 2a only
using HOAc (eq 21). Essentially, the NaOAc and HOAc
processes are in direct competition with each other (eqs 13
and 14): basic conditions favor a late-stage N−Cl cleavage
pathway, whereas acidic conditions bias the reaction for an
early stage N−Cl cleavage pathway.
Structural diversification can be envisaged through the
complete elimination of reactivity-assisting groups and
exploitation of the exposed reactivity of ring atoms (Scheme
6). To this end, the ester groups on the C3 site of 2H-
removed, neither exhibits reactivity toward 2a (without or with
the additional participation of 1h) (eqs 15 and 16) nor
catalyzes the reaction between 1h and 2a (eq 17), which
advocates the importance of the Cl moiety of the N-
chloroimine group at the early stage of the reaction pathway
and is consistent with the proposal of P−Cl bond formation as
a late-stage event; and (9) adventitious H2O is excluded as a
necessary component for cleaving the C−P bond based on its
negative effect on the transformation (eq 11). Taken together,
these observations are consistent with the following associative
covalent relay mechanism1a (with 1a and 2a as the illustrative
reactants) (Scheme 5): the reaction between 1a, [RhCp*Cl2]2,
AgBF4, and NaOAc produces C−H-activated intermediate I;11
coordination of I with 2a furnishes Rh(III) carbene species II;
OAc− coordination and 1,1-migratory insertion provide III;
further coordination of III with 1a results in the formation of
coordination site-exchanged species IV; C−H activation of
coordinated 1a under the assistance of OAc− delivers V and
HOAc; proto-demetalation of V with HOAc releases I and
OAc− and simultaneously initiates C−P/N−Cl bond cleavage
and C−N/P−Cl bond formation/ring closure for the
generation of 3aa (via tautomerization). In perspective,
associative relay1a might be a prevalent operating mechanism
in transition metal catalysis, especially for directed C−H
functionalization reactions. It is speculated that many directing
groups, along with the coupling partners, can trap transition
metals in the nonreacting chelating states (e.g., III in Scheme
5); only via competitive binding from the directing group of
the next catalytic cycle, the final turnover steps can occur.
An interesting finding for 1h′-Rh-Cl is its conversion, when
reacting with 2a, to an isoquinolin-3(2H)-one derivative
Scheme 6. Structural Diversification for 2H-Isoindoles
isoindoles should be removed first. For proof-of-concept
demonstration, 3wd was selected and subjected to deester-
ification reaction. The ester group can be removed to afford
target product 4 under Ni(OAc)2/dcype/Ph3SiH catalysis.12
Unlike 3wd, 4 exhibits high reactivity at the C3 site, which also
renders itself an unstable molecule against chromatography.13
However, electrophilic substitution can be performed on 4
without purification. For example, reaction between the crude
product of 4 and Vilsmeier reagent affords a C3-dimethylami-
C
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nomethylidene derivative 5.14 Hydrolysis of 5 in NaOH
generates C3-formyl derivative 6.14 6 can be deprotonated at
the N2 site with NaH and undergo further nucleophilic
methylation with CH3I to produce 7. Collectively, these
transformations have allowed the complete erasure of any trace
of original reactivity-assisting groups and installation of
structually completely unrelated appendages, thus offering an
enabling tool for accessing distinct chemical space. As a second
illustrative example, 4 can also undergo initial azo derivatiza-
tion at the C3 site15 and subsequent methylation at the N2
site, affording 8 and 9, respectively.
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In summary, we have developed herein an efficient strategy
for the synthesis of 2H-isoindoles based on Rh(III)-catalyzed
coupling of N-chloroimines with α-diazo-α-phosphonoace-
tates. The initial dechlorination/dephosphonation and sub-
sequent deesterification allow the full elimination of reactivity-
assisting groups from the 2H-isoindole skeleton. The structural
diversification potential with the exposure of C3 and N2 ring
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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/acs.or-
glett.9b02501.
■
S
Experimental procedures, structural characterization,
mechanistic studies, and copies of the 1H and 13C
NMR spectra of selected products (PDF)
Accession Codes
CCDC 1858032, 1858042, and 1858398 contain 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 Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
(15) Bonnett, R.; North, S. A.; Newton, R. F.; Scopes, D. I. C.
Tetrahedron 1983, 39, 1401.
Corresponding Author
*E-mail: jinz@nju.edu.cn.
ORCID
Jin Zhu: 0000-0003-4681-7895
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Natural
Science Foundation of China (21425415, 21774056), National
Basic Research Program of China (2015CB856303), and
Science and Technology Department of Jiangsu Province
(BRA2017360, BK20181255).
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D
DOI: 10.1021/acs.orglett.9b02501
Org. Lett. XXXX, XXX, XXX−XXX