Decarboxylative Cross-Electrophile Coupling of N-Hydroxyphthalimide Esters with Aryl Iodides

Article abstract of DOI:10.1021/jacs.6b01533

A new method for the decarboxylative coupling of alkyl N-hydroxyphthalimide esters (NHP esters) with aryl iodides is presented. In contrast to previous studies that form alkyl radicals from carboxylic acid derivatives, no photocatalyst, light, or arylmetal reagent is needed, only nickel and a reducing agent (Zn). Methyl, primary, and secondary alkyl groups can all be coupled in good yield (77% ave yield). One coupling with an acid chloride is also presented. Stoichiometric reactions of (dtbbpy)Ni(2-tolyl)I with an NHP ester show for the first time that arylnickel(II) complexes can directly react with NHP esters to form alkylated arenes.

Full text of DOI:10.1021/jacs.6b01533

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Communication
Decarboxylative Cross-Electrophile Coupling of
N-Hydroxyphthalimide Esters with Aryl Iodides
Kierra M. M. Huihui, Jill A. Caputo, Zulema Melchor, Astrid M. Olivares, Amanda M. Spiewak,
Keywan A. Johnson, Tarah DiBenedetto, Seoyoung Kim, Laura K. G. Ackerman, and Daniel J. Weix
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01533 • Publication Date (Web): 30 Mar 2016
Downloaded from http://pubs.acs.org on March 31, 2016
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Decarboxylative Cross-Electrophile Coupling of N-
Hydroxyphthalimide Esters with Aryl Iodides
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Kierra M. M. Huihui,‡ Jill A. Caputo,‡ Zulema Melchor, Astrid M. Olivares, Amanda M. Spiewak, Keywan A.
Johnson, Tarah A. DiBenedetto, Seoyoung Kim, Laura K. G. Ackerman,† and Daniel J. Weix*
University of Rochester, Rochester, NY USA 14627-0216
Supporting Information Placeholder
11
bipyridine nickel complex as a catalyst. By comparison of
reduction potentials, it appeared to us that nickel-mediated
reduction of an NHP ester to form an alkyl radical, CO2, and
phthalimide should be possible without the need for photo-
ABSTRACT: A new method for the decarboxylative coupling
of alkyl N-hydroxyphthalimide esters (NHP esters) with aryl
iodides is presented. In contrast to previous studies that form
alkyl radicals from carboxylic acid derivatives, no photocata-
lyst, light, or arylmetal reagent is needed, only nickel and a
reducing agent (Zn). Methyl, primary and secondary alkyl
groups can all be coupled in good yield (77% ave yield). One
coupling with an acid chloride is also presented. Stoichio-
metric reactions of (dtbbpy)Ni(2-tolyl)I with an NHP ester
show for the first time that arylnickel(II) complexes can di-
rectly react with NHP esters to form alkylated arenes.
12, 13, 14, 15
chemistry.
Concurrent with our study, Baran found that NHP esters
could be coupled with an excess of an arylzinc reagent. The-
se two approaches are complementary: we use aryl iodides in
place of arylzinc reagents and while we can couple methyl,
primary, and secondary radicals, the Baran chemistry uses
arylzinc reagents and works with secondary radicals.
16
Scheme 1. Conversion of alkanoic acids to radicals.
Previous studies - visible-light photocatalysis
The formation of Csp2-Csp3 bonds by cross-coupling has
Ir(F-ppy)2(dtbbpy)
1
advanced rapidly in recent years, but remains less advanced
visible light
(oxidation)
(dtbbpy)Ni
Ar-Br
O
O
than the synthesis of Csp2-Csp2 bonds. One challenge for
these cross-coupling reactions is the lower availability of alkyl
Doyle &
MacMillan
R-Ar
ꢀ,
-CO2
R
O-
O
2
coupling reagents compared to aryl coupling reagents. As a
Ru(bpy)3Cl2
visible light
(reduction)
ꢁ,
or
potential solution, alkanoic acids are much more abundant
than alkyl halides, making them attractive coupling partners.
While the use of carboxylic acid derivatives as acyl equiva-
R-H
Okada
ꢀ,
N
R-Alkyl
Overman
-CO2
radical
acceptor
R
O
-phthalimide
O
3
lents in cross-coupling is well known, few decarboxylative
This study - non-photocatalytic cross-coupling with aryl iodides
4
couplings of alkanoic acid derivatives have been reported.
O
(dtbbpy)NiBr2
O
Ph
Recently, Doyle and MacMillan reported a method that
forms alkylated arenes from α-heteroatom substituted car-
Zn powder
N
+
Ph-I
O
-CO2
-phthalimide
5, 6
O
boxylates and aryl halides (Scheme 1). The process pro-
1a
2a
3a
ceeds by photooxidation of the carboxylate to form an alkyl
radical. We show here a complementary approach: coupling
of NHP esters with aryl iodides to form alkylated arenes
without the need for a co-catalyst or light (Scheme 1).
entry change from standard conditions
1 (%)b 3a (%)b
1
2
3
4
5
6
nonea
0
0
60
62
0
reaction run in the dark
Ni(diglyme)Br2 as catalyst
no nickel or ligand
no zinc
In searching for a general method to utilize alkanoic acids
0
in cross-electrophile coupling, we found the studies of
7
Overman and Okada particularly interesting. Reduction of
84
85
81
0
N-hydroxyphthalimide esters by a strong photogenerated
reductant (Ru(bpy)3Cl2) formed alkyl radicals that could be
used in a number of transformations. We had recently
demonstrated that alkyl radicals generated from alkyl hal-
0
NHS ester in place of NHP esterc
0
a
Reactions run with 10 mol% of (dtbbpy)NiBr2 and Zn0 (2
8
9
10
equiv) in DMA (0.8 M) for 20 h. dtbbpy = 4,4’-di-tert-butyl-
ides, benzyl mesylates, and epoxides could all be coupled
b
c
2,2’-bipyridine.
GC yield, uncorrected.
N-
with aryl halides under reducing conditions using a simple
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19
hydroxysuccinimide ester of 4-phenyl butanoic acid was used in
place of NHP ester 1a, along with 20 mol% DMAP.
lower yields and that currently aryl iodides are required for
1
2
3
4
5
6
7
8
high yields. Reactions of less reactive substrates (Ar-Br, Ar-
Cl) result in consumption of NHP ester but not aryl halide.
Finally, for substrates that provided moderate yield, a slight
excess of the NHP ester usually provided a higher yield
(Scheme 2).
The adaptation of NHP esters to cross-electrophile cou-
pling required very little adjustment of our previously pub-
lished conditions (Scheme 1). Consistent with our hypothe-
sis, nickel and zinc were required for activation of the NHP
ester (entries 4 and 5), the reaction proceeded equally well in
the dark (entries 1 and 2), and a less-easily reduced NHS
Overall, NHP esters perform equal to or better than cou-
plings with alkyl iodides and bromides. For example, a pri-
mary alkanoic ester provided near-quantitative yields (3b
and 3f), even when the substrates were reacted in a 1:1 ratio.
A more hindered neopentyl group could be coupled in a bet-
ter yield (3a) than that reported using neopentyl iodide
(38%). Although these reactions were set up in a glovebox
for convenience, the chemistry could be run on preparative
scale (4 mmol PhI) without the need for strict exclusion of
moisture and air. Similarly, cyclopentyl (3c) and piperidine
8
9
17
ester did not react (entry 6).
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Scheme 2. Coupling of alkyl NHP esters with ArI.a
O
7 mol%
(dtbbpy)NiBr2
R'
R'
R
I
O
8a
+
N
Zn0 (2 equiv)
O
R
O
DMA, rt, 5-12 h
1
2
3
20
3a, 87% yield in glovebox
3a, 81% yield on benchtopb
1.5 equiv 1a
(3d) groups were coupled in yields competitive to the best
reported with alkyl halides.
10
3b, 97% yield
1 equiv 1b
While 2-halopyrrolidines are not easily accessible starting
materials, the NHP ester of proline (1e) was coupled in good
yield with iodobenzene to form 3e. This result compares
favorably with similar couplings reported using
Cbz
N
EtO2C
N
Boc
16
Ni/Ir/photoredox5a and with arylzinc reagents.
3c, 89% yielda
1.5 equiv 1c
3d, 64% yieldc
1 equiv 1d
3e, 65% yieldc, d
1.5 equiv 1e
Electron-rich and electron-poor iodoarenes coupled effi-
ciently (3f and 3g) and some steric hindrance on the io-
21
doarene was tolerated (3h). Finally, functional-group com-
patibility is promising, tolerating ketones (3g and 3i), esters
(3c), protected nitrogen (3d, 3e, 3f, 3k, 3l), a boronic acid
pinacol ester (3j), and unprotected alcohols (3m).
N
3f, 89% yield
1.5 equiv 1b
3g, 71% yield
1.5 equiv 1b
O
O
Several of the substrates demonstrate the value of starting
with alkanoic acids because the corresponding alkyl halides
are not commercially available or fail to couple. For example,
the methylation with O-acetyl N-hydroxyphthalimide repre-
sents the first cross-electrophile methylation of an aryl hal-
CH3
O
(pin)B
3h, 91% yield
1 equiv 1b
3i, 70% yield
1.5 equiv 1f
3j, 41% yield
1.5 equiv 1g
22
ide. Similarly, the NHP esters of aspartic acid and glutamic
OH
H
CO2t-Bu
NHBoc
3k, 58% yield
1.5 equiv 1h
acid both coupled in high yield without racemization, provid-
23
ing a new route to valuable phenylalanine and homo-
24
phenylalanine derivatives. Finally, unprotected cholic acid
H
H
NHP ester could be coupled in high yield, even with three
HO
OH
CO2t-Bu
H
25
unprotected alcohols.
NHBoc
3m, 97% yielde
We could also extend this chemistry to the coupling of
NHP ester 1b with acid chloride 4 to form dialkyl ketone 5
3l, 75% yield
1.5 equiv 1i
1.3 equiv ester 1j
26
(eq 1), suggesting broad generality for NHP esters in cross-
a
Reactions were run on 0.8 mmol scale in 1 mL of DMA.
Yields are after isolation and purification. See Supporting In-
electrophile coupling reactions.
O
b
formation. Reaction was set up on the benchtop in a round-
7 mol%
(dtbbpy)NiBr2
Cl
bottom flask. c 12 mol% of catalyst was used on a 0.4 mmol scale
reaction. d Yield of 3e adjusted to account for 4 wt% N-Boc pyr-
rolidine in sample. e Yield of 3m adjusted to account for 14 wt%
of phthalimide and diisopropyl urea that we were unable to
separate by chromatography.
EtO
3 equiv 4
O
Ph
(1)
O
EtO
+
Zn0 (2 equiv)
DMA, rt, 1 h
O
O
O
5, 84% yield
N
Ph
O
1b
O
Reactions conducted without added ligand did not pro-
duce coupled product, but did consume NHP ester (Scheme
1, entry 3). We found that impure NHP esters resulted in
18
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Although we have not yet studied the reaction mechanism
formation by reduction of 6 or 1b, but these results are not
conclusive. Further study of the elementary steps is ongoing.
1
2
3
4
5
6
7
8
in detail, it is reasonable to assume that the NHP ester is re-
duced to form an alkyl radical, CO2, and phthalimide accord-
ing to the accepted mechanism in the photoreduction chem-
We also sought to identify the nickel product of these reac-
tions, with only partial success. Reaction of isolated 6 with
1b in DMF-d7 at rt overnight resulted in consumption of the
diamagnetic 6 and formation of new, paramagnetic species
(eq 5). These new species are EPR silent, consistent with
integer-spin complexes. We tentatively assign these species as
7
istry. Consistent with this hypothesis, we observed the for-
mation of phthalimide and gas in reactions. We had previous-
ly shown how alkyl radicals are a key part of the cross-
27, 28
electrophile coupling of aryl iodides with alkyl iodides.
a
mixture
of
(dtbbpy)NiII(phthalimide)I,
However, there were no reports of the stoichiometric reactiv-
ity of any organonickel complex with an NHP ester.
9
(dtbbpy)NiII(phthalimide)2 and (dtbbpy)NiIII2, in analogy to
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In order to test the reactivity of an organonickel complex
with an NHP ester and its connection to the catalytic reac-
tions, we compared the stoichiometric reactivity of
(dtbbpy)NiII(2-tolyl)I (6) with catalytic reactions in the
same solvent (eq 2-4). The catalytic reaction in DMF pro-
ceeded in lower yield than the reaction in DMA due to the
formation of 1,6-diphenylhexane (eq 2). Stoichiometric reac-
tion of 6 with excess 1b formed cross-product 3h with or
without any added reductant (eq 3 and eq 4). However, the
reaction with added zinc formed cross-product in excellent
yield (eq 4). Importantly, these are the first known reactions of
organonickel intermediates with redox active esters, a key step in
our previous results with alkyl iodides.
complete
consumption of 6
I
(L)Ni
1b (10 equiv)
(5)
DMF-d7
rt, overnight
new paramagnetic
nickel species
Me
6
While these results establish the viability of this step for
nickel-catalyzed couplings of NHP esters, substantial ques-
tions remain. First, the stoichiometric reactions were slower
than the catalytic reaction. If a radical chain mechanism is
8, 27
operating and initiation is slow, this could account for the
differences in rate, but this result could also indicate that a
different, non-chain mechanism is operative. Second, be-
cause zinc alone did not react with an NHP ester (Scheme
1), the higher yield for the stoichiometric reaction of 6 in the
presence of zinc suggests that the reduction of 6, or some
other nickel species, facilitates the coupling. At this time, it is
unclear what this reduced intermediate is, but a nickel(I)
16
both our chemistry and Baran’s arylzinc chemistry.
10 mol%
(dtbbpy)NiBr2
O
Ph
O
(2)
Me
3h, 47% GC yield
1b converted to dimer
N
2-iodotoluene
(1 equiv)
Zn0 (2 equiv)
O
(CH2)3Ph
1b
O
2-iodotoluene remains
16
species is a possiblity. Further studies on the elementary
DMF, rt, 4 h
reactivity of NHP esters with metals and the mechanism of
the present reaction are in progress.
I
Ph
(L)Ni
(L)Ni
1b (10 equiv)
(3)
Me
The utilization of carboxylic acid derivatives as alkyl elec-
trophile equivalents in cross-electrophile coupling has been
demonstrated for the first time. Our cross-electrophile ap-
proach is complementary to photoredox co-catalysis meth-
DMF, rt, 6 h
Me
3h, 47% yield (ave 3 runs)
mostly complete in 2 h
6
I
Ph
1b (10 equiv)
5
ods to couple carboxylic acids with aryl halides because the
(4)
Me
Zn0 (2 equiv)
DMF, rt, 6 h
substrate scope is different and no co-catalysis or light is re-
quired. Furthermore, given this study and Baran’s recent re-
port, the use of NHP esters in nickel-catalyzed cross-
Me
3h, 98% yield (ave 3 runs)
mostly complete in 2 h
6
16
coupling appears to be a general phenomenon. In this con-
The formation of 3h in yields comparable with the catalyt-
ic reaction (eq 2) from reactions that did not contain io-
dotoluene or zinc (eq 3) argues against the intermediacy of
text, our stoichiometric studies establish a mechanistic start-
ing point for further work in this area by showing arylnickel
complexes react with NHP esters to form alkylated arene
product directly. Studies on the mechanism of this transfor-
mation as well as couplings with other electrophiles will be
reported in due course.
16
arylzinc reagents, in contrast with Baran’s work. Further, we
found that a typical aryl iodide, ethyl 3-iodobenzoate, does
not directly react with zinc on the time-scale of catalytic reac-
tions (see Supporting Information).29
Our current hypothesis is that these reactions proceed by a
ASSOCIATED CONTENT
radical-chain mechanism similar to that proposed for the
27
Supporting Information. Detailed experimental procedures,
spectral data, and supplementary optimization data. This mate-
rial is available free of charge via the Internet at
http://pubs.acs.org.
coupling of aryl iodides with alkyl iodides. However, differ-
ences between these studies and our previous studies were
observed. While the reaction without added zinc formed
product (eq 3), the presence of zinc resulted in improved
yields (eq 4). The role of the zinc could be to initiate radical
AUTHOR INFORMATION
Corresponding Author
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Page 4 of 13
*daniel.weix@rochester.edu
‡ These authors contributed equally to this work.
1
2
10 (a) Zhao, Y.; Weix, D. J. J. Am. Chem. Soc. 2014, 136, 48-51; (b) Zhao,
3
4
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6
7
8
9
Y.; Weix, D. J. J. Am. Chem. Soc. 2015, 137, 3237–3240.
Present Addresses
11 Weix, D. J. Acc. Chem. Res. 2015, 48, 1767-1775.
†Department of Chemistry, Princeton University, Princeton, NJ
08544
12
NHP esters are reported to have E1/2 -1.56 to -1.66 V vs. Ag/Ag+ (in
MeCN, references 7a and 12, converted using reference 15) and
(bpy)NiBr2 is reported to have a two-electron E1/2 of -1.52 V vs. Ag/Ag+
(in DMF, reference 14).
ACKNOWLEDGMENT
13
Lackner, G. L.; Quasdorf, K. W.; Pratsch, G.; Overman, L. E. J. Org.
The authors gratefully acknowledge funding from the NIH
NIGMS (R01 GM097243). LKGA acknowledges funding from
the University of Rochester (Elon Huntington Hooker Fellow-
ship). KAJ acknowledges funding from an NSF GRFP award
(DGE-1419118). DJW is a Camille Dreyfus Teacher-Scholar.
Additional funding from Novartis, Pfizer, and Boehringer Ingel-
heim is also gratefully acknowledged. Analytical data were ob-
tained from the CENTC Elemental Analysis Facility at the Uni-
versity of Rochester, funded by NSF CHE-0650456. Prof. Larry
Overman is thanked for suggesting that we look at NHP esters
for cross-electrophile coupling.
Chem. 2015, 80, 6012-6024.
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Mikhaylov, D.; Gryaznova, T.; Dudkina, Y.; Khrizanphorov, M.; Laty-
pov, S.; Kataeva, O.; Vicic, D. A.; Sinyashin, O. G.; Budnikova, Y. Dalton
Trans. 2012, 41, 165-172.
15
Pavlishchuk, V. V.; Addison, A. W. Inorg. Chim. Acta 2000, 298, 97-
102.
16
Cornella, J.; Edwards, J. T.; Qin, T.; Kawamura, S.; Wang, J.; Pan, C.-
M.; Gianatassio, R.; Schmidt, M. A.; Eastgate, M. D.; Baran, P. S. J. Am.
Chem. Soc. 2016, 138, 2174-2177.
17
The NHS ester of acetic acid has an E1/2 of -2.05 V while the NHP es-
ter of acetic acid has an E1/2 of -1.04 V vs. Ag/Ag+ in methanol. See: Horner,
L.; Jordan, M. Justus Liebigs Ann. Chem. 1978, 1978, 1518-1525.
18
A variety of ligands (2,2’-biphenyl, 1,10-phenanthroline, 4,4’-
REFERENCES
dimethoxy-2,2’-biphenyl, bathophenanthroline) and nickel sources
(NiBr2(diglyme), NiBr2•3H2O) were effective.
19
NHP esters synthesized with DIC according to the method of Over-
man7 consistently performed better than esters synthesized with other
g
coupling agents (DCC, EDC). Spiking experiments with possible contami-
nants have not yet revealed the reason for this discrepancy.
1
(a) Frisch, A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674-688;
20
The coupling of alkyl halides with aryl halides has been scaled to mul-
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(c) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417-1492;
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21
Reaction with 2-iodocumene failed to produce the cross-coupled
product, in contrast to reactions with alkyl iodides reported in reference 27.
22
2
Methyl tosylate was reported to methylate alkyl halides and acid chlo-
While 318,496 Ar-Br and 1,000,000 Ar-Cl are listed as commercially
rides, but not aryl halides: Liang, Z.; Xue, W.; Lin, K.; Gong, H. Org. Lett.
available in the eMolecules database (accessed via REAXYS 6/22/2015),
only 9,282 alkyl-Br and 24,746 alkyl-Cl are listed. In contrast, there are
83,315 alkanoic acids commercially available.
2014, 16, 5620-5623.
23
The coupling of β-iodoalanine or the corresponding organozinc rea-
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Org. Synth. 2005, 81, 77-88; (b) Lu, X.; Yi, J.; Zhang, Z.-Q.; Dai, J.-J.; Liu,
J.-H.; Xiao, B.; Fu, Y.; Liu, L. Chem.–Eur. J. 2014, 20, 15339-15343.
4
The decarbonylative coupling of alkanoic acid derivatives has more
precedent, see the following two examples and references therein: (a)
O'Brien, E. M.; Bercot, E. A.; Rovis, T. J. Am. Chem. Soc. 2003, 125, 10498-
10499; (b) Muto, K.; Yamaguchi, J.; Musaev, D. G.; Itami, K. Nat. Com-
mun. 2015, 6, 7508.
24
Even simple homophenylalanine is an important starting material for
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5
Biotechnol. Adv. 2009, 27, 286-296.
(a) Zuo, Z.; Ahneman, D.; Chu, L.; Terrett, J.; Doyle, A. G.; MacMil-
25
Although the corresponding alkyl iodide is known, it has not been
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MacMillan, D. W. C. J. Am. Chem. Soc. 2015, 137, 624-627; (c) Luo, J.;
Zhang, J. ACS Catalysis 2016, 873-877.
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O.; Michiko, Y.; Shigeo, M.; Mosbach, E. H.; Takahiko, H. Steroids 1992,
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Mater. Chem. 2011, 21, 14693-14705.
6 The coupling of a vinyl bromide with 3 equiv of cyclohexane carboxylic
acid (78% yield) and 5-phenylvaleric acid (11% yield) were reported in
reference 5b.
26
(a) Wotal, A. C.; Weix, D. J. Org. Lett. 2012, 14, 1476-1479; (b) Wu,
7
F.; Lu, W.; Qian, Q.; Ren, Q.; Gong, H. Org. Lett. 2012, 14, 3044-3047; (c)
Yin, H.; Zhao, C.; You, H.; Lin, K.; Gong, H. Chem. Commun. 2012, 48,
7034-7036; (d) Zhao, C.; Jia, X.; Wang, X.; Gong, H. J. Am. Chem. Soc.
2014, 136, 17645-17651; (e) Cherney, A. H.; Kadunce, N. T.; Reisman, S.
E. J. Am. Chem. Soc. 2013, 135, 7442-7445.
(a) Okada, K.; Okamoto, K.; Oda, M. J. Am. Chem. Soc. 1988, 110,
8736-8738; (b) Okada, K.; Okamoto, K.; Oda, M. J. Chem. Soc., Chem.
Commun. 1989, 1636-1637; (c) Okada, K.; Okamoto, K.; Morita, N.;
Okubo, K.; Oda, M. J. Am. Chem. Soc. 1991, 113, 9401-9402; (d) Okada,
K.; Okubo, K.; Morita, N.; Oda, M. Tetrahedron Lett. 1992, 33, 7377-7380;
(e) Okada, K.; Okubo, K.; Morita, N.; Oda, M. Chem. Lett. 1993, 22, 2021-
2024; (f) Schnermann, M. J.; Overman, L. E. Angew. Chem., Int. Ed. 2012,
51, 9576-9580; (g) Pratsch, G.; Lackner, G. L.; Overman, L. E. J. Org.
Chem. 2015, 80, 6025-6036.
27 Biswas, S.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 16192–16197.
28
For related studies suggesting similar mechanisms at play in different
reactions, see: (a) Schley, N. D.; Fu, G. C. J. Am. Chem. Soc. 2014, 136,
16588-16593; (b) Zhao, C.; Jia, X.; Wang, X.; Gong, H. J. Am. Chem. Soc.
2014, 136, 17645-17651.
8
(a) Everson, D. A.; Shrestha, R.; Weix, D. J. J. Am. Chem. Soc. 2010,
29
A reaction conducted with tetrakis(dimethylamino)ethylene in place
132, 920-921; (b) Everson, D. A.; Jones, B. A.; Weix, D. J. J. Am. Chem. Soc.
2012, 134, 6146-6159; (c) Wang, S.; Qian, Q.; Gong, H. Org. Lett. 2012,
14, 3352-3355.
of zinc did not turnover at rt. At elevated temperatures (40-60 °C), reac-
tions run with either TDAE or zinc both resulted in decomposition of the
NHP ester and no consumption of aryl iodide.
9
Ackerman, L. K. G.; Anka-Lufford, L. L.; Naodovic, M.; Weix, D. J.
Chem. Sci. 2015, 6, 1115-1119.
ACS Paragon Plus Environment

Page 5 of 13
Journal of the American Chemical Society
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O
Journal of the American Chemical SocietPyage 6 of 13
7 mol%
(dtbbpy)NiBr2
Cl
EtO
O
Ph
3 equiv 4
O
(1)
EtO
1
2
3
4
5
6
7
+
Zn0 (2 equiv)
DMA (1 mL), rt, 1 h
ACS Paragon Plus Environmen5t, 84% yield
Ph
O
O
O
N
O
1b
O

10 mol%
O
Ph
Page 7 of 1J3ournal of the American Chemical Society
O
(dtbbpy)NiBr2
2-iodotoluene
(CH2)3Ph
(2)
Me
N
O
3h, 47% GC yield
1b converted to dimer
2-iodotoluene remains
1
2
3
4
1b
ACS Paragon Plus Environment
(1 equiv)
O
Zn0 (2 equiv)
DMF, rt, 4 h

I
Ph
Journal of the American Chemical SocietPyage 8 of 13
(L)Ni
Me
1
2
1b (10 equiv)
(3)
Me
ACS Paragon Plus Environment
DMF, rt, 6 h
3h, 47% yield (ave 3 runs)
mostly complete in 2 h
6

I
Ph
Page 9 of 1J3ournal of the American Chemical Society
(L)Ni
1b (10 equiv)
(4)
Me
ACS Paragon Plus Environment
Zn0 (2 equiv)
Me
3h, 98% yield (ave 3 runs)
mostly complete in 2 h
DMF, rt, 6 h
1
2
6

complete
I
(L)Ni
Me
1b (10 equiv)
Journal of the American Chemical SociePtayge 10 of 13
consumption of 6
ACS Paragon Plus Environment
(5)
DMF-d7
rt, overnight
new paramagnetic
nickel species
6
1

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ACS Paragon Plus Environment

Previous studies - visible-light photocatalysis
Journal of the American Chemical SociePtyage 12 of 13
Ir(F-ppy)2(dtbbpy)
visible light
(oxidation)
(dtbbpy)Ni
Ar-Br
O
Doyle &
MacMillan
1
R-Ar
R•
-CO2
R
O-
O
2
3
4
5
6
7
Ru(bpy)3Cl2
visible light
(reduction)
H•
or
R-H
Okada
O
R•
N
R-Alkyl
Overman
-CO2
-phthalimide
radical
acceptor
R
O
8
9
O
This study - non-photocatalytic cross-coupling with aryl iodides
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(dtbbpy)NiBr2
O
Zn powder
Ph
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N
+
ACS ParagoPnh-PIlus Environment
O
-CO2
-phthalimide
O
1a
2a
3a

O
7 mol%
(dtbbpy)NiBr2
R'
R'
R
Page 13 ofJ1o3urnal of the American Chemical Society
I
O
+
N
Zn0 (2 equiv)
O
R
1
2
3
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6
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8
9
O
DMA, rt, 5-12 h
1
2
3
3a, 87% yield in glovebox
3a, 81% yield on benchtopb
1.5 equiv 1a
3b, 97% yield
1 equiv 1b
Cbz
N
EtO2C
10
N
11
12
13
14
Boc
3c, 89% yielda
1.5 equiv 1c
3d, 64% yieldc
1 equiv 1d
3e, 65% yieldc, d
1.5 equiv 1e
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N
3f, 89% yield
1.5 equiv 1b
3g, 71% yield
1.5 equiv 1b
O
O
CH3
O
(pin)B
3h, 91% yield
1 equiv 1b
3i, 70% yield
1.5 equiv 1f
3j, 41% yield
1.5 equiv 1g
OH
H
CO2t-Bu
NHBoc
3k, 58% yield
1.5 equiv 1h
H
H
HO
OH
CO2t-Bu
H
ACS Paragon Plus Environment
NHBoc
3m, 97% yielde
1.3 equiv ester 1j
3l, 75% yield
1.5 equiv 1i