Carboiodination Catalyzed by Nickel

Article abstract of DOI:10.1021/jacs.8b06966

A novel nickel-catalyzed cycloisomerization reaction forming a new carbon-carbon bond while preserving the carbon-halogen bond has been developed. A cheap and readily available Ni-catalyst is employed to generate nitrogen containing heterocycles in good t

Full text of DOI:10.1021/jacs.8b06966

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Carboiodination Catalyzed by Nickel
Hyung Yoon,† Austin D. Marchese,† and Mark Lautens*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
Scheme 1. Previous Work on the Ni-Catalyzed
Arylcyanation and Pd-Catalyzed Carbohalogenation
Reaction
ABSTRACT: A novel nickel-catalyzed cycloisomeriza-
tion reaction forming a new carbon−carbon bond while
preserving the carbon−halogen bond has been developed.
A cheap and readily available Ni-catalyst is employed to
generate nitrogen containing heterocycles in good to
excellent yields and the procedure is readily scalable. The
more readily available aryl bromides were also cyclized
with the addition of potassium iodide to generate the
respective alkyl iodides. A rare dual ligand system
employing a bisphosphine and bisphosphine monoxide
was used to achieve enantioenriched products.
ickel-catalyzed processes continue to be of interest from
N
researchers in academia and industry due to their low
cost and diverse reactions.1 In particular, advances in Ni-
catalyzed cross coupling reactions in the formation of new
carbon−carbon and carbon−heteroatom bonds have been
achieved1−4 though the preinstalled coupling moiety dis-
appears in the process. Despite the remarkable progress made,
highly atom economical methodologies remain scarce.5 We
envisioned that a cycloisomerization reaction would represent
an ideal platform for the development of a novel, perfectly
atom economical Ni-catalyzed transformation. Notably in
2008, the Jacobsen6 and Hiyama7 groups concurrently
disclosed the intramolecular Ni- and Lewis acid cocatalyzed
arylcyanation reaction of arylnitriles to generate the respective
alkylnitriles (Scheme 1A). However, the isomerization reaction
of organic halides via Ni-catalysis remains unprecedented.
Transition-metal catalyzed synthesis of halogenated com-
pounds have also attracted tremendous attention as organic
halides are found in various natural products, bioactive
molecules and undoubtedly represent valuable and versatile
synthetic precursors.8−10 In 2010 and 2011, our group
described the first Pd-catalyzed reactions based on reversible
oxidative addition of C−X bonds. A particular focus was on the
cycloisomerization (carbohalogenation) reaction forming
heterocycles wherein the carbon−iodine bond was regenerated
at the end of the catalytic cycle (Scheme 1B).11 We showed
that the use of an exceptionally bulky and electron rich
phosphine ligand such as QPhos or P(tBu)3 facilitated
reversible oxidative addition. The Tong group also independ-
ently described the Pd-catalyzed carboiodination reaction
utilizing vinyl iodides at higher temperatures in the presence
of excess dppf to generate 1,2,3,6-tetrahydropyridines.12
Following these seminal reports, several related methodologies
were reported13 including the reductive elimination of C−Br
and C−Cl bonds,14 highly diastereoselective transformations,15
as well as the use of HX salts as external halogen sources.16 As
part of our ongoing research interest and aim to advance the
carbohalogenation reaction, we sought to employ nickel, a
cheaper, base metal equivalent, to provide a new perspective in
generating the respective alkyl halides.
Herein, we describe the first Ni-catalyzed intramolecular
carbohalogenation reaction, using an inexpensive and easily
accessible catalyst, to generate valuable halogenated 3,3-
disubstituted heterocycles in good to excellent yield (Scheme
1C). Inexpensive, readily available phosphine and phosphite
ligands can be used in place of the sterically bulky ligands
typically required for the analogous Pd process. In addition to
the cycloisomerization reaction, the synthesis of alkyl iodides
from the respective aryl bromide and additional potassium
iodide is reported. Moreover, a significant limitation in the Pd-
catalyzed carboiodination reaction was the lack of an
asymmetric variant. We discovered that using an unusual
dual ligand system combining a bisphosphine and bi-
sphosphine monoxide, generated the respective chiral iodi-
nated oxindoles that were previously inaccessible.
At the outset of our investigation, we selected substrate 1a
for the optimization of the conditions for the nickel-catalyzed
carboiodination reaction. Utilizing the bulky QPhos ligand
previously employed for the Pd-catalyzed variant, 1a was
subjected to NiBr·glyme, ligand and manganese as the
reducing agent to give 2a in 45% yield (Scheme 2). The
Received: July 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b06966
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Journal of the American Chemical Society
Communication
Having established the optimized reaction conditions, we
investigated the substrate scope of this reaction (Scheme 3).
Scheme 2. Initial Hit
Scheme 3. Ni-Catalyzed Carboiodination*
structure of 2a was unambiguously determined by spectro-
scopic analysis and single crystal X-ray crystallography. After
screening of the reaction parameters, the optimal conditions
were found to be NiI2(PPh3)2 as the precatalyst and
manganese as the reducing agent in toluene at 100 °C for 24
h (90% yield). A series of variations from the standard reaction
conditions were performed to examine their effects on the
efficiency of the transformation (Table 1).
Table 1. Ni-Catalyzed Carboiodination: Variation from the
Standard Reaction Conditions
a,b
Entry
Variation from “standard conditions”
None
Yield 2a (%)
1
2
3
4
5
(90)
79
NiBr2(PPh3)2 instead of NiI2(PPh3)2
NiCl2(PPh3)2 instead of NiI2(PPh3)2
*
a
N.R.
N.R.
N.R.
N.R.
81
36
80
50
Reactions were run on 0.2 mmol scale. Isolated yields. Reaction was
b
c
c
d
run on 2.75 mmol scale. Reaction was run for 48 h. Reaction was
heated to 120 °C. NiI2 (10 mol %) and P(OiPr)3 (20 mol %) was
used at 80 °C.
NiI2 and Phen instead of NiI2(PPh3)2
d
e
No Ni catalyst
No Mn
Ni(COD)2 and PPh3 instead of NiI2(PPh3)2
Zn instead of Mn
Dioxane instead of PhMe
5 mol % instead of 10 mol %
6
7
f
8
9
10
The weakly electron-rich acrylamides 1b and 1c provided 2b
and 2c in good yield to excellent yields (85% and 92% yield,
respectively). Other halogens such as chloride and fluoride
were tolerated in the isomerization reaction (2d and 2e, 82%
yield). The trifluoromethylated acrylamide 1f was found to be
less reactive under the reaction conditions and required
elevated temperature and longer reaction time to attain 2f in
moderate yield (120 °C and 48 h). Removable N-protecting
groups such as −MOM and −Bn afforded the corresponding
products in moderate to excellent yields. However, both
reactions required additional time to reach full conversion (2g
and 2h, 68 and 91% yield respectively). Introduction of a 2-
methylated pendant aromatic group afforded 2i in diminished
yield, suggesting that steric encumbrance impacts the efficiency
of the cyclization (38% yield). The fluorinated pendant
aromatic ring was well tolerated (2j, 76% yield). Upon
changing the substituent on the alkene from an aromatic group
to an alkyl group, a different catalyst system was required to
give the corresponding halogenated oxindoles. The combina-
tion of NiI2 and P(OiPr)3 gave the desired cycloisomerized
product in higher yields. Methyl- and benzylacrylamides 1k
and 1l cyclized in good yields (78% and 75%, respectively).17
In contrast to 2i, bulkier substituent such as isopropyl afforded
2m in 72% yield. The n-butyl substituted substrate 1n required
longer reaction times to reach full conversion (48 h and 58%
yield). Finally, to test the scalability of this protocol, model
acrylamide 1a was cyclized on gram scale to provide 2a in 86%
yield. Unfortunately, unprotected acrylamides and monosub-
g
11
80 °C instead of 100 °C
54
a
1
Determined by H NMR analysis of the crude reaction mixtures
using 1,3,5-trimethoxybenzene as internal standard. Isolated yields in
parentheses. 10 mol % of NiI2 was used. Phen = 1,10-
phenanthroline. 20 mol % of PPh3 was added. No Mn was added
and 40 mol % of PPh3 was added. Reaction was run at 0.4 M. N.R. =
no reaction observed.
b
c
d
e
f
g
The use of similar catalysts but with a different halide
counterion (i.e., NiBr2(PPh3)2 and NiCl2(PPh3)2) led to lower
yield or no formation of 2a (entry 2 and 3 respectively). Of
note, no halogen scrambling was observed when NiBr2(PPh3)2
was used. Employing 1,10-phenanthroline (Phen), a bidentate
N,N ligand commonly used in Ni-catalysis, failed to give the
desired reaction (entry 4). Removing the precatalyst or the
reducing agent led to no reaction (entry 5 and 6).
Interestingly, Ni(COD)2 and PPh3 gave the desired product
in slightly lower yield in the absence of manganese (entry 7).
These results suggest that the manganese is exclusively used
as the reducing agent for the in situ generation of the active
catalyst. Another commonly used reducing agent such as zinc
gave the product in reduced yield (entry 8). Dioxane was also
found to be a suitable solvent but provided the product in
lower yield (80% yield, entry 9). Finally, a lower catalyst
loading or lower temperature stunted the formation of 2a
(entry 10 and 11).17
B
DOI: 10.1021/jacs.8b06966
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Journal of the American Chemical Society
Communication
stituted olefins were found to be unsuitable substrates for this
transformation.
Scheme 5. Ni-Catalyzed Halogen Exchange-Induced
Carboiodination*
Of note, in the presence of a second acceptor where a
competing 5-exo-trig cyclization is possible, 1o selectively
cyclized on the methacryl group to yield 2o exclusively
(Scheme 4). Notably, the absence of the carbonyl functionality
Scheme 4. Directed Ni-Catalyzed Carboiodination*
*
a
Reactions were run on 0.2 mmol scale. Isolated yields. NiI2 (10 mol
b
%) and P(OiPr)3 (20 mol %) was used at 80 °C. Reaction was run
for 48 h.
Scheme 6. Enantioselective Ni-Catalyzed Carboiodination*
*
a
Reactions were run on 0.2 mmol scale. Isolated yields. NiI2 (10 mol
%) and P(OiPr)3 (20 mol %) was used at 80 °C.
gave no cycloisomerized product.18 Intrigued by these results,
we sought to determine if an electron poor alkene was essential
for the transformation. We prepared acetamide 1p, which can
cyclize with the tethered methallyl group to generate the
respective indoline. Subjecting 1p to the standard reaction
conditions gave 2p in excellent yield (93% yield). In addition,
replacing the acetyl group with a tosyl group also afforded the
product in good yield (2q, 89% yield).17 These findings
suggest that an oxygen atom may serve as a directing group to
facilitate the oxidative addition step.19 Exploiting the directed
oxidative addition, tetrahydroquinoline 2r was obtained in 65%
yield.
Aryl bromides are cheaper, more readily available, and easily
accessible building blocks in comparison to the corresponding
aryl iodides. However, with this methodology, the generation
of the alkyl bromide from bromoacrylamide 3a proceeded in
low yield.20 We anticipated that in the presence of an external
iodide source, a halogen exchange would occur in situ to
generate the respective alkyl iodide (Scheme 5). Upon adding
2 equivalents of potassium iodide to the standard reaction
conditions, 2a was formed in 83% yield starting from 3a. By
using the second set of optimized conditions, the electron-rich
p-methoxybromoacrylamide 3b cyclized to give the corre-
sponding oxindole 2s in 70% yield. Additionally, the dioxol
bearing oxindole 2t was generated in good yield (84% yield).
Analogous to the generation of 2j, the formation of the N-
benzylated oxindole 2u required longer reaction times (44%
yield).
*
Reactions were run on 0.2 mmol scale. Isolated yields. e.r. values
were determined by HPLC analysis on a chiral stationary phase.
success was found in achieving high enantioselectivity, with
MonoPhos providing the best yield and e.r. (45% yield and
65:35 e.r.).21 Serendipitously, we discovered that using a dual
ligand system was essential in achieving higher enantioselec-
tivity.22 Utilizing a 9:1 mixture of (S)-TolBINAP:(S)-BINAPO
afforded the model substrate 2a in 50% yield and 89:11 e.r.23
Employing a more electron rich acrylamide 1c gave 2c in
higher yield and good e.r. (57% yield, 89:11 e.r.). In contrast to
the racemic variant that required elevated temperature and
longer reaction time, generation of the trifluoromethylated
oxindole 2f proceeded in good yields and moderate e.r. (84%
yield, 78:22 e.r.). Switching the vinyl aromatic group to an
alkyl group gave moderate yields and lower e.r. (65:35 e.r.).
We propose that the reaction proceeds via an enantioselective
oxidative addition3c,24 or carbometalation. A radical pathway is
unlikely but cannot be ruled out.25 Efforts are underway to
understand the origin of this two ligand effect.
In conclusion, we have reported the first nickel-catalyzed
cycloisomerization reaction involving the regeneration of a
valuable carbon−halogen bond. Two sets of reaction
conditions were found to promote this transformation. Diverse
functional groups were tolerated and the resulting oxindoles
were obtained in good to excellent yields. Additionally, the Ni-
catalyzed halogen-exchange carboiodination reaction is also
reported. An enantioselective variant was identified employing
a dual ligand system to attain good e.r.
To further showcase the benefits of employing nickel in
carboiodination, the enantioselective variant was explored
(Scheme 6). A variety of ligands were screened including
bisphosphines and BINOL-derived chiral phosphites and
phosphoramidites. Within the class of these ligands, limited
C
DOI: 10.1021/jacs.8b06966
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Journal of the American Chemical Society
Communication
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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/jacs.8b06966.
■
S
X-ray data for 2a (CIF)
Experimental procedures, optimization, characterization
and X-ray data (PDF)
AUTHOR INFORMATION
Corresponding Author
*mlautens@chem.utoronto.ca
ORCID
Hyung Yoon: 0000-0003-4573-2160
Mark Lautens: 0000-0002-0179-2914
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T.; Zinn, P. J.; Simmons, S. J.; Sanford, M. S. Organometallics 2009,
■
́
28, 6142. (b) Renz, A. L.; Perez, L. M.; Hall, M. B. Organometallics
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Author Contributions
†H.Y. and A.D.M. contributed equally to this work.
(5) For selected reviews and references therein, see: (a) Yamamoto,
Y. Chem. Rev. 2012, 112, 4736. (b) Chen, F.; Wang, T.; Jiao, N. Chem.
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Notes
The authors declare no competing financial interest.
(6) Watson, M. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130,
12594.
(7) Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.; Ikawa, M.; Ogoshi, S.
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ACKNOWLEDGMENTS
■
We thank the University of Toronto, Alphora Research, Inc.,
and the Natural Sciences and Engineering Research Council
(NSERC) for financial support. H.Y. is the recipient of an
Ontario Graduate Scholarship. We thank Dr. I. Franzoni
(University of Toronto), Y.J. Jang (University of Toronto) and
Professor Sophie Rousseaux (University of Toronto) for
insightful discussion throughout the project. Y. J. Jang and E.
Larin (University of Toronto) are thanked for the preparation
of starting materials 3c, 3d. We thank Dr. Alan Lough
(University of Toronto) for single-crystal X-ray analysis of 2a.
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(25) Preliminary mechanistic studies regarding radical trap additives
such as TEMPO, galvinoxyl, and BHT were performed. Refer to the
SI for the reactions.
E
DOI: 10.1021/jacs.8b06966
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX