Transition-metal free umpolung carbon-nitrogen versus carbon-chlorine bond formation

Article abstract of DOI:10.1016/j.tetlet.2015.08.053

The formation of carbon-nitrogen (C-N) bonds via an umpolung substitution reaction has been achieved at -78 °C without the need for catalysts, ligands, or additives. The scope is limited to aryl Grignard reagents with N-chloroamines. The findings in this manuscript serve as a reference point for all C-N bond formations involving N-chloroamines and organometallic reagents. Knowing the yields of uncatalyzed reactions will be useful when determining the success of future catalytic methods.

Full text of DOI:10.1016/j.tetlet.2015.08.053

Tetrahedron Letters 56 (2015) 5610–5612
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Transition-metal free umpolung carbon–nitrogen versus
carbon–chlorine bond formation
⇑
John J. Sirois, Brenton DeBoef
Department of Chemistry, University of Rhode Island, Kingston, RI 02881, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The formation of carbon–nitrogen (C–N) bonds via an umpolung substitution reaction has been achieved
at À78 °C without the need for catalysts, ligands, or additives. The scope is limited to aryl Grignard
reagents with N-chloroamines. The findings in this manuscript serve as a reference point for all C–N bond
formations involving N-chloroamines and organometallic reagents. Knowing the yields of uncatalyzed
reactions will be useful when determining the success of future catalytic methods.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 22 July 2015
Revised 12 August 2015
Accepted 20 August 2015
Available online 21 August 2015
Keywords:
Metal-free
Grignard reagent
Chloroamine
Amination
The formation of C–N bonds is essential for the synthesis of
highly desirable pharmaceutical and biologically active targets.
Current methods rely on transition metals such as palladium1
and rhodium.2 More recently the focus has shifted toward catalysts
that are more environmentally friendly and affordable catalysts
like cobalt,3 copper,4–6 and nickel.7–9 Recent advances have discov-
ered transition metal free methods that also result in C–N bond
formation.10 We report herein a fast and easy method for the for-
mation of C–N bonds resulting in arylated tertiary amines.
Cl
N
Ph
N
Catalyst
Temp.
Additive
+
PhMgBr
2
+
Ph-Cl
4
+
Ph-Ph
5
O
2-MeTHF
O
1a
3a
Scheme 1. Initial optimization outline.
Considering our recent work involving iron catalysts and Grig-
nard reagents to directly form carbon–carbon (C–C) bonds via
directed C–H functionalization on aromatic heterocycles,11 and
the success of other earth-abundant transition metals accomplish-
ing reactions of this type for the formation of both C–C and C–N
bonds, we envisioned that iron-catalyzed reactions could play a
role in amination reactions as well. When we began this investiga-
tion Bolm and Correa had already demonstrated that iron could
efficiently catalyze the formation of Csp2–N bonds from aryl iodides
and nucleophilic nitrogen sources.12 Our initial optimization
focused on the coupling of N-chloroamines with phenylmagnesium
bromide in an effort to form similar Csp2–N bonds in an umpolung
fashion (Scheme 1). The variables investigated included the screen-
ing of iron catalysts, nitrogen and phosphine ligands, several addi-
tives, and a range of temperatures (see Table 1).
Our initial efforts to use iron catalysts appeared successful. Sev-
eral iron salts were shown to produce the expected product (3a) in
reasonable yields (entries 1–8).
Inorganic salts had been shown to promote the presumed trans-
metalation step.13 In our studies, LiCl was detrimental to the yield
(entry 9), and MgBr2 completely shut down the reaction (entry 10).
Contrary to other’s reports,10 formation of the desired C–N product
dominated over chlorobenzene formation at À40 °C. This could be
detected by GCMS along with small amounts of biphenyl, presum-
ably arising from homocoupling of the Grignard reagent. In an
attempt to minimize these side reactions, we lowered the temper-
ature and varied the equivalents of Grignard reagent used (entries
11–13). We found that with 1.5 equiv of Grignard reagent at
À78 °C the reaction afforded a 75% isolated yield (entry 13). With
these optimized conditions, we attempted to investigate and
expand the substrate scope. Unfortunately the Fe(acac)2 catalyzed
reactions performed on other substrates showed a significant
decrease in yield, and other metals, CoBr2, and Cu(OTf)2, were
detrimental.
⇑
Corresponding author. Tel.: +1 401 874 9480; fax: +1 401 874 5072.
E-mail address: bdeboef@chm.uri.edu (B. DeBoef).
http://dx.doi.org/10.1016/j.tetlet.2015.08.053
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

J. J. Sirois, B. DeBoef / Tetrahedron Letters 56 (2015) 5610–5612
5611
Table 1
Cl
High
Optimization of reaction conditionsa
Temp.
a
Entry
Catalyst (10 mol %)
Temp (°C)
Additive
Isolated yieldsb
a
b
1
2
3
4
5
6
7
8
FeCl2
0
0
0
0
0
0
0
0
None
None
None
None
None
None
None
None
LiCl
MgBr2
None
None
None
None
dtbpy
bpy
36b
62b
40b
46b
19b
46b
49b
88b
58
MgBr
Cl
N
O
Fe(SO4)3ÁH2O
Fe(C2O4)2Á2H2O
FeF3Á3H2O
Fe(NO3)3Á9H2O
Fe(acac)3
None
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
None
b
N
O
Low
Temp.
Scheme 2. Proposed temperature mediated pathways.
9
0
0
10
11
12
13
14
15
16
17
18
19
20
21
0
À40
À78
À78
À78
À78
À78
À78
À78
À78
À78
À78
79
49c
75
Cl
N
Ar
N
2-MeTHF
74d
77
+
ArMgBr
X
(1.1 equiv.)
75
84
81
74
80
99
X
-78 °C, 5 min
phen
binap
dppbz
phen
None
1a-c
3a-h
X = O, X = CH or X = NCl
2,
None
a
All reactions performed on
reagent.
a 1.00 mmol scale with 1.5 equiv of Grignard
O
N
O
N
O
N
O
N
O
N
b
Yields determined by GC using dodecane as an internal standard.
1.0 equiv Grignard reagent.
2.0 equiv Grignard reagent. dtbpy = ditert-butylbipyridine, bpy = bipyridine,
c
d
CH 3
phen = 1,10-phenanthroline, dppbz = 1,2-bis(diphenylphosphino)benzene.
O
Not satisfied with these results, we screened several ligands
hoping to increase our yield further. Our hypothesis was that the
ligands could coordinate the Mg cation, thus increasing the
nucleophilicity of the Grignard reagents;10 however, we observed
that dinitrogen ligands had a small beneficial effect on the reaction
(entries 15–19). Removing the iron as a control afforded the pro-
duct in near-equal yields (entry 20). This was discouraging; but
we quickly realized that the ligand itself was also not necessary
for the reaction to occur (entry 21). This has been demonstrated
previously by Knochel14 at À45 °C, however only benzylic N-
chloroamines were studied.
3a
99%
3b
21%
25% w/ Fe
0 % w/ Cu
3c
3d
3e
31%
trace
trace
25% w/ Co
N
N
N
N
O
Transition-metal free reactions were performed at several tem-
peratures (Table 2). The decrease in temperature showed a steady
increase in product formation, as well as a decrease in overall
byproducts.
The results of our extensive optimization showed that N-
chloroamines and aryl Grignard reagents readily couple between
À40 and À78 °C with no need for additives or catalysts. The cou-
pling does occur at room temperature, but the biphenyl, the conse-
quence of the homocoupling of the Grignard reagent, as well as
chlorobenzene were present in high amounts. Prolonged reaction
times had no immediate affect and eventually resulted in product
decomposition.
3f
3g
3h
30%
5%
29%
38% w/ Fe
Scheme 3. Reaction scope.
from a renewable source, consequently it is considered to be a
more green solvent. Unfortunately, further attempts to expand
the reaction to other amines beyond morpholine, and a variety of
substituted Grignard reagents, still resulted in low yields
(Scheme 3).
2-Methyl tetrahydrofuran (2-Me-THF) was used as the primary
solvent. The yields achieved from these reactions are comparable
to those performed in THF. We chose 2-Me-THF as it originates
Only the original N-phenylmorpholine product (3a) showed
high yields. Increasing the electron density using 4-methylphenyl
(3b) and 4-methoxyphenyl (3c) Grignard reagents decreased the
yield dramatically. The mesitylmorpholine (3d) and o-methylmor-
pholine (3e) reactions showed only trace amounts of products
detected by NMR spectroscopy. This is presumably due to the
steric hindrance that surrounds the carbon to be functionalized.
The yield of the diarylated product (3f) was respectable since the
reaction must have occurred twice on the dichloroamine substrate.
The metal-free umpolung amination can result in two different
major products depending on the temperature of the reaction
(Scheme 2). At relatively high temperatures (pathway a) the chlo-
ramine acts as an electrophilic source of chlorine; while at lower
Table 2
Effect of temperature on C–N bond formationa
Temp (°C)
Yieldb 3a
Yieldb
4
3a/4
22
0
À21
À41
À78
48
59
77
86
87
55
30
35
36
29
0.9
2.0
2.2
2.4
3.0
a
All reactions performed on a 1.00 mmol scale, in acid-washed oven dried flasks.
Yield determined by GC–MS using dodecane as an internal standard.
b

5612
J. J. Sirois, B. DeBoef / Tetrahedron Letters 56 (2015) 5610–5612
temperatures (pathway b) the same reagent acts as an electrophilic
source of nitrogen. This can be explained by a Curtin–Hammett
relationship, in which both reaction rates are temperature depen-
dent, but one mechanism (pathway a) apparently slows signifi-
cantly more than the competing mechanism as a function of
temperature (pathway b). Alternatively, the higher temperature
could enable a radical-mediated mechanism, as opposed to the
polar mechanism (pathway a) shown in Scheme 2.
Supplementary data
Supplementary data (experimental procedures and characteri-
zation of reported compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2015.08.053.
References and notes
Despite poor yields observed for several substrates, we hypoth-
esize that a systematic optimization of each metal-free reaction
could yield synthetically useful yields. The reactions run smoothly
and are complete upon the drop-wise addition of the Grignard
reagent (<5 min). We hope that this work serves as a cautionary
example to be considered when testing for presumed catalytic
activity in future systems. Future efforts to use other organometal-
lic reagents, such as organolithium or organozinc species, will be
performed as well as the expansion of this reaction to include alkyl
Grignards and amines.
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Acknowledgments
This work was supported by the National Science Foundation
(CAREER 0847222) and the National Institutes of Health (NIGMS,
1R15GM097708-01).