Copper-Catalyzed borylative cyclization of substituted N -(2-Vinylaryl)benzaldimines

Article abstract of DOI:10.1021/acs.orglett.8b00213

A t-BuOCu-initiated reaction sequence of styrene borometalation and intramolecular imine addition has been achieved using a Cu(OTf)₂/dppf combination as catalyst. The product of this reaction cascade is a useful 2,3-disubstituted indoline beari

Full text of DOI:10.1021/acs.orglett.8b00213

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Copper-Catalyzed Borylative Cyclization of Substituted N‑(2-
Vinylaryl)benzaldimines
He-Min Wang, Hao Zhou, Qing-Song Xu, Tai-Shang Liu, Chen-Lu Zhuang, Mei-Hua Shen,*
and Hua-Dong Xu*
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Pharmaceutical Engineering & Life Science,
Changzhou University, Changzhou 213164, P. R. China
*
S Supporting Information
ABSTRACT: A t-BuOCu-initiated reaction sequence of styrene borometalation and intramolecular imine addition has been
achieved using a Cu(OTf) /dppf combination as catalyst. The product of this reaction cascade is a useful 2,3-disubstituted
2
indoline bearing a versatile boryl moiety and is formed with sole cis-selectivity. To account for the observation of the exclusive
formation of cis-stereoisomers, a transition state featuring copper−imine coordination is suggested. The application to the
synthesis of antioxidant tetrahydroindenoindoles is described.
ecently, 1,2-carboboration of π-bonds has received
attention, as these are transformations that could convert
readily available alkenes, alkynes, or allenes into valuable,
the double or triple bond in 3 forms the key organocopper
intermediate III which couples with the carbon electrophile 4 to
give IV and the carboboration product 5 with concomitant
regeneration of complex I which continues the catalytic cycle.
Carbon electrophiles that can trap the organocopper inter-
R
diversely functionalized organic boronates through concurrent
1
,2
construction of C−B and C−C bonds. The C−B motif formed
8
9
in such reactions can serve as a facile point for further chemical
mediate III include alkyl halides or sulfonates, aryl halides, alkyl
3
4
10 11
manipulation. Carboboration of unsaturated bonds initiated by
carbonates/phosphates, α,β-enonates, and carbonyl
5
12
borylcopper has emerged as a practical means for this purpose
groups. Herein, we report an intramolecular carboboration
because these reactions can proceed in a chemo-, regio-, and
stereocontrolled manner by the use of properly ligated metal
reaction of aryl alkenes with an imino group to give N-
heterocycles containing a C−B group.
6
,7
catalysts derived from readily available copper reagents. As
outlined briefly in Scheme 1, the catalytic cycle generally begins
with the formation in situ of a copper alkoxide, typically copper
tert-butoxide I, which undergoes transmetalation with boron
compounds, such as 1 giving rise to the nucleophilic borylcopper
species II. Subsequent chemoselective migratory insertion into
We became interested in carboboration of alkenes with imino
carbon electrophiles as a result of the utility of the boronated
alkylamines. To our knowledge, there are only a few related
published examples, and no intramolecular precedent has been
13
reported. On the other hand, Buchwald et al. in 2015 reported a
CuH-catalyzed asymmetric intramolecular hydrocarbonation of
14
alkenes with aldmines. The model substrate N-(vinylphenyl)-
aldimine 6a reacting with B (pin) was taken as a proof of
Scheme 1. General Mechanism for Carboboration of Multiple
2
2
Carbon−Carbon Bonds
concept and was used to optimize the reaction conditions. On
the basis of earlier work, cuprous triflate Cu(OTf) was quickly
2
identified as a superior catalyst and t-BuOLi/t-BuOH as an
optimal choice of base/proton source combination. Phosphorus
ligands were found to be necessary for the reaction to proceed
smoothly, giving 3-(borylmethyl)-2-phenylindoline 7a. The
stereochemistry of 7a was established by NMR spectroscopy,
1
1
which revealed a considerable H− H NOESY correlation, as
shown between the methylene protons and benzyl protons.
Experiments aimed at screening the reaction conditions are
summarized in Table 1. In the absence of a phosphorus-
containing ligand, the imine 6a fails to react with B (pin) (1.1
2
2
Received: January 26, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00213
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Condition Optimization for Intramolecular
Carboboration of o-Iminostyrene
observed with further increase up to a factor of 3 in the base
loading (Table 1, entry 15). The reaction also proceeds in
MeCN, MTBE, and toluene but is less efficient (Table 1, entries
a
1
6−18).
The highly efficient formation of 7a is remarkable given the
unfavorable 5-endo-trig cyclization step that forms the indoline
ring. With the optimal conditions in hand, the substrate scope
was examined with 2-vinylanilinylaldimines 6b−q derived from
the appropriate aromatic aldehydes (Scheme 2). Generally, the
Scheme 2. Substrate Scope Imines Derived from Various Aryl
,
a b
Aldehydes
a
Reactions were conducted out on a 0.25 mmol scale in 2 mL of THF.
Isolated yields are reported.
b
reaction affords 2,3-disubstituted borylindolines with good to
excellent yields. In all cases, the cis-diastereomers are observed
exclusively. Aryl halides and aryl cyanide are well tolerated with
this transition-metal-catalyzed process as is exhibited by good
yields in the case of 6b−e, which produces 7b−e in 57−72%
yield. Substrates with 4-CF , 4-Me, or 4-t-Bu at the C4 position
3
give comparable yields (7f−g, 7i: 62−71%), while a methyloxyl
group at this position produces a higher yield (7h: 81%).
Substitution at the meta position has little effect on the outcomes
of this transformation (7j,k: 55% and 60%), but interestingly,
ortho-substitution of this ring increases the yield to approx-
imately 80% (7l,m). Aromatic groups other than the phenyl ring
are also viable in this reaction, and 2-naphthyl-, 2-pyridyl-, 2-
thiophene-yl-, and 2-furanylindolines 7n−q are formed with
satisfactory yields (50−64%). Unfortunately, o-iminopropenyl-
benzene 6r fails undergo this transformation, probably because
the borocupration step encounters increased steric problems.
Substrates with substituents in the styrene moiety were
examined (Scheme 3). (E)-N-Benzylidene-2-vinylanilines 8a−c
with 4-F, 4-Cl, or 4-Br at the C4 position were converted to the
a
Reactions were conducted on a 0.25 mmol scale in 2 mL of solvent at
b
rt. Isolated yields are reported. NR: no reaction.
equiv) at rt for 12 h (Table 1, entry 1), but a trace amount of 7a is
formed after introduction of 10 mol % of a bidentate phosphorus
ligand such as dppm, dppe, or dppp (Table 1, entries 2−4). The
yield increases dramatically to ∼33% when dppb or XantPhos is
used as the ligand (Table 1, entries 5 and 6) and is further
increased to 51% when dppf is used (Table 1, entry 7). While the
monodentate ligands XPhos, JohnPhos, and PCy are ineffective
in this transformation (Table 1, entries 8−10), SPhos and
DavePhos provide much improved outcomes (Table 1, entries
3
1
1 and 12). A detectable side reaction involves alkene
related boryl indolines 9a−c in yields of 58−70%. With a CH at
3
hydroboration, which leads to the product from the protonation
C4, 9d is produced in 65% yield, whereas 9e with a 4-t-Bu
substituent is formed in only 40% yield from 8e. A strongly
electron-donating methoxyl group at the para positon has little
effect on the reaction, as demonstrated by a 58% yield obtained
for 9f. A 4-phenyl group also has little influence on the reaction
yield, and 9g is isolated in 61% yield. Carboxylate and nitrile
groups vulnerable to nucleophiles are compatible with the
borocupration−aldimine addition cascade and good yields are
observed for 9h (70%) and 9i (64%). While the reaction of the
of the related copper intermediate III.
It is reasonable to predict that an increase in the t-BuOLi/t-
BuOH ratio should slow the C-protonation side process and thus
favor the imine addition event, which produces the desired
intermediate IV. Indeed, doubling the amount of the base results
in a 20% enhancement of the yield and 2.5 times the amount of t-
BuOLi gives the highest yield of 83% (Table 1, entries 13 and
1
4). However, a drastic decrease in the yield, to 58%, was
B
DOI: 10.1021/acs.orglett.8b00213
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope-Iminostyrenes Derived from
Various 2-Vinylanilines
the synthesis of 2,3-disubstituted indolines by hydrocarbora-
tion.
a
,
b
14
To show the usefulness of this reaction, product 7m was
submitted to a Suzuki reaction to test whether intramolecular
coupling could take place (Table 2). In this case, the desired
a
Table 2. Intramolecular Suzuki Coupling of Boryl Indolines
a
Reactions were conducted on a 0.25 mmol scale in 2 mL of THF.
Isolated yields are reported. Starting materials were recovered.
b
c
4
4
,5-dichlorinated imine 8j gives rise to 9j in low yield (38%), the
-CN-5-CF -substituted imine 8k is an excellent substrate for the
3
reaction and affords 9k in 87% yield. The 6-fluorinated imine 8l
undergoes this reaction smoothly, affording the 6-F-indoline 9l
in 62% yield, while a marked decrease to 30% in the yield in the
formation of 9m occurs and is due possibly to the steric impact of
the 6-methyl group on this reaction. In comparison with 6-
substituted imines 8l and 8m, 3-substitution has a more obvious
steric effect on the reaction and no reaction is observed with 8o
and 8p. It seems that electron-withdrawing groups on the styrene
benefit the reaction, probably because the initial borolcuperation
step is favorable for electron-deficient styrene. A satisfactory
crystalline sample of 9b was obtained, and its X-ray crystallo-
graphic analysis confirmed the validity of previous assignment of
cis-stereochemistry of the products (Scheme 3).
a
Conditions for Suzuki coupling: 7 or 13a−e (1.0 equiv), Pd(OAc)
2
(
(
10 mol %), Sphos (20 mol %), t-BuOK (3.0 equiv), toluene/H O
10:1, 0.1 M), 80 °C, 24 h. Isolated yields.
2
b
We envisioned that the exclusive formation of cis-2,3-
disubstituted indolines 7 and 9 should arise from the
stereoselective cyclization step, which converts the organocopper
intermediate 10 into the indolyl copper 11 (Scheme 4).
tetracyclic product 14m is obtained in 92% yield when a
Pd(OAc) /Sphos catalyst system is used. Many molecules with
cis-tetrahydroindenoindole scaffolds have been reported for their
15
2
Scheme 4. Suggested Explanation for the Cis-Selectivity
16
antioxidation activities in biological systems. Our two-step
protocol provides a facile access to this class of compounds, and
additional examples are provided in Table 2. Through this two-
step protocol, facile o-iminostyrenes 12a−e can be converted
into antioxidants 14a−e bearing various substituents in both
aromatic rings in 48−88% yields.
In summary, we reported a borometalation−imine addition
cascade, which has been developed into an efficient protocol for
synthesis of 2,3-disubstituted indolines. This reaction features
exclusive diastereoselectivity and cis-2,3-disubstituted indolines
carrying a boronate group can be accessed. The readily accessible
copper salt used as a precatalyst causes this protocol to be
extremely useful for potential applications. The products with
preinstalled o-bromides can participate in an intramolecular
Suzuki reaction to give valuable cis-tetrahydroindenoindoles,
demonstrating the potential applications of this chemistry.
Coordination of the copper atom with the π-orbital of the (E)-
imine group in the hypothetical transition states (trans-TS vs cis-
TS) would force group R to protrude toward the imine moiety
and group R′ to point away from it. Accordingly, the steric
repulsion between group R and the imine hydrogen would be the
singular factor that could dictate the relative energetic levels of
the two transition states. Cis-TS with the H atom oriented inward
is more favored than its counterpart trans-TS, and this results in
the observation of exclusive cis-selectivity. We suspect this might
also account for the cis-selectivity reported by Buchwald et al. in
C
DOI: 10.1021/acs.orglett.8b00213
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Accession Codes
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CCDC 1585427 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 Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
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AUTHOR INFORMATION
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(8) (a) Kageyuki, I.; Osaka, I.; Takaki, K.; Yoshida, H. Org. Lett. 2017,
Corresponding Authors
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9, 830. (b) Kubota, K.; Iwamoto, H.; Yamamoto, E.; Ito, H. Org. Lett.
*
E-mail: shenmh@cczu.edu.cn.
E-mail: hdxu@cczu.edu.cn.
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015, 17, 620. (c) Bidal, Y. D.; Lazreg, F.; Cazin, C. S. J. ACS Catal.
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2014, 4, 1564. (d) Zhou, Y.; You, W.; Smith, K. B.; Brown, M. K. Angew.
Chem., Int. Ed. 2014, 53, 3475. (e) Kubota, K.; Yamamoto, E.; Ito, H. J.
Am. Chem. Soc. 2013, 135, 2635. (f) Yoshida, H.; Kageyuki, I.; Takaki, K.
Org. Lett. 2013, 15, 952. (g) Alfaro, R.; Parra, A.; Aleman, J.; Garcia
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Toyoda, T.; Sawamura, M. J. Am. Chem. Soc. 2010, 132, 5990.
ORCID
Hua-Dong Xu: 0000-0002-4510-3754
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
(
We thank Prof. W. J. Tang for his generous donation of
phosphorus ligands. We thank the National Natural Science
Foundation of China (NSFC 21402014 and 21672027),
QingLan Project of Jiangsu Province (2016), and Six-Talent-
Peaks Program of Jiangsu (2016) for financial support.
2
015, 54, 5228. (e) Semba, K.; Nakao, Y. J. Am. Chem. Soc. 2014, 136,
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Org. Lett. XXXX, XXX, XXX−XXX