General method for nucleophilic aromatic substitution of aryl fluorides and chlorides with dimethylamine using hydroxide-assisted decomposition of N,N-dimethylforamide

Article abstract of DOI:10.1080/00397911.2016.1147051

A practical and convenient procedure for the nucleophilic aromatic substitution of aryl fluorides and chlorides with dimethylamine was developed using a hydroxide-assisted thermal decomposition of N,N-dimethylforamide. These conditions are tolerant of nitro, nitrile, aldehyde, ketone, and amide groups but will undergo acyl substitution to form amides for methyl esters and acyl chlorides. Isolated yields of the products range from 44% to 98%, with the majority being greater than 70% for 17 examples.

Full text of DOI:10.1080/00397911.2016.1147051

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A general method for nucleophilic aromatic
substitution of aryl fluorides and chlorides
with dimethylamine using hydroxide-assisted
decomposition of N,N-dimethylforamide
Juana Garcia, Jacob Sorrentino, Emily J. Diller, Daniel Chapman & Zachary R.
Woydziak
To cite this article: Juana Garcia, Jacob Sorrentino, Emily J. Diller, Daniel Chapman &
Zachary R. Woydziak (2016): A general method for nucleophilic aromatic substitution of aryl
fluorides and chlorides with dimethylamine using hydroxide-assisted decomposition of N,N-
dimethylforamide, Synthetic Communications, DOI: 10.1080/00397911.2016.1147051
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1147051
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Date: 01 March 2016, At: 06:16

A general method for nucleophilic aromatic substitution of aryl fluorides and
chlorides with dimethylamine using hydroxide-assisted decomposition of N,N-
dimethylforamide
1
1
1
1
Juana Garcia , Jacob Sorrentino , Emily J. Diller , Daniel Chapman , Zachary R.
1
Woydziak
1
Department of Physical and Life Sciences, Nevada State College, Henderson, NV 89002
Supplemental data for this article can be accessed on the publisher’s website.
Abstract
A practical and convenient procedure for the nucleophilic aromatic substitution of aryl
fluorides and chlorides with dimethylamine was developed using a hydroxide assisted,
thermal decomposition of N,N-dimethylforamide. These conditions are tolerant of nitro,
nitrile, aldehyde, ketone, and amide groups but will undergo acyl substitution to form
amides for methyl esters and acyl chlorides. Isolated yields of the products range from
4
4 – 98%, with the majority being greater than 70% for seventeen examples.
KEYWORDS: Nucleophilic Aromatic Substitution, dimethylamine, aryl halides, aniline
derivatives, DMF decomposition
INTRODUCTION
Aromatic compounds substituted with a dimethylamino group compose an important
class of molecules that possess a range of biological activities including central nervous
[
1]
[2]
[3,4]
[5]
system stimulant, antimicrobial, anti-cancer,
anti-HIV, AT2 receptor
[
6-8]
[9,10]
[11]
antagonist,
progesterone receptor modulator,
and rho kinase antagonists.
Additionally, numerous aromatic natural products are substituted with a dimethylamino
[
2]
[12]
group with some notable examples being Tigecycline, Minocycline,
1

[
13]
[14]
Orthoformimycin, and Dendrodione.
While installation of the dimethylamino
group can be carried out by nucleophilic aromatic substitution (S Ar), the dimethylamine
N
[
15-17]
nucleophile often requires high temperatures and reaction times
to install, which can
be challenging when using premade solutions given dimethylamine’s volatility. Sealed
tubes can be used to contain the dimethyamine gas, but the build-up of pressure can
create a potentially dangerous environment and the scalability of the reaction is limited.
To circumvent these issues, several procedures have been developed which involve the
thermal decomposition of N,N-dimethylamine (DMF) to slowly and safely liberate
[
18]
dimethylamine.
To avoid high temperature reaction conditions, the decomposition is
[
19,20]
[21-26]
generally catalyzed by acidic
or basic conditions,
however, the scope of these
reactions are limited, and temperatures greater than 100 ˚C are still required or
specialized microwave reactors are utilized to obtain good yields. Herein, we report a
general procedure for the S Ar of halides with dimethylamine using hydroxide assisted
N
decomposition of DMF. This procedure can be performed using common laboratory
equipment, is safe and scalable, and can be run using only DMF, and aqueous hydroxide
solution.
RESULTS AND DISCUSSION
To better understand the scope of acids and bases that can facilitate DMF decomposition
and the desired S Ar reaction, a range of additives were tested to estimate relative rates
N
of conversion of 4-fluorobenzaldehyde to 4-(dimethylamino)benzaldehyde at various
temperatures for a reaction time of an hour (Table 1). Trifluoroacetic acid (TFA, entry
1
) did not demonstrate any detectable conversion and similarly aqueous ammonia and
2

sodium carbonate solutions (entries 2 and 3) produced very little conversion at 95 ˚C.
Using aqueous solutions of potassium hydroxide as an additive, however, generated
considerably more substitution product (entry 4), which improved by increasing the
reaction temperature (entries 5 and 6). A relatively high concentration of potassium
hydroxide is required for a timely reaction as decreasing the concentration of hydroxide
resulted in lower conversion (entry 7). Interestingly, no hydroxide substituted side
products were detected by HPLC analysis. The conversion was optimized further by
adding the potassium hydroxide solution in two aliquots (entry 8), resulting in a complete
conversion. The portion-wise hydroxide addition produced two DMF decomposition
cycles providing a more steady concentration of dimethylamine, which improved the
overall yield.
In applying the optimized reaction conditions to a range of substrates, typical S Ar trends
N
were observed (Table 2). Fluorine served as the best leaving group and underwent
conversion notably faster than chlorine. Substitution of bromine does not occur readily
and is relatively inert using these reaction conditions (a conversion was not detected after
a 72 h reaction time). The S Ar reaction occurred most rapidly for 1-fluoro-2,4-
N
dinitrobenzene (entry 1), in which the reaction was completed within three minutes of
introducing the substrate to provide the product as pure yellow crystals in 81% yield.
Similarly, p-fluoronitrobenzene and p-chloronitrobenzene (entries 2 and 3) reacted
readily in high yields generating pure crystals that were washed and filtered directly from
the reaction mixture. Chlorinated and fluorinated benzonitriles (entries 4-6) possessed
similar reaction times as the corresponding nitrobenzene examples, however, the yields
3

for all of the substrates were lower. Fluorinated aldehydes (entries 7-9) reacted smoothly
in moderate to excellent yields. Entry 8 illustrates a disubstitution reaction, in which
dimethylamine replaces fluorine atoms situated at positions ortho and para to the nitrile
electronwithdrawing group. The addition of the first equivalent of dimethylamine,
however, substantially decreases the reaction rate of the second addition, and therefore
required 24 h for the reaction to complete. In exploiting the unreactive nature of bromine
in this reaction, it is possible to replace a fluorine atom and retain a bromine atom in very
good yield as demonstrated in entry 9. Ortho and para substituted acetophenones and
benzamides (entries 10 – 12) generally result in good to excellent yields in 1-6 h reaction
times, with the exception of para-chloroacetophenone (entry 11) which required a
reaction time of 24 h to obtain a 45% yield of dimethyl-substituted acetophenone. Using
these conditions, it is also possible to perform an acyl substitution in addition to the S Ar
N
reaction, as demonstrated in entries 13 and 14. However, the acyl chloride (entry 13)
reaction completed in significantly less time and in substantially higher yield than the
corresponding methyl ester (entry 14). Substituted heterocyclic compounds (entries 15-
1
7) also readily undergo S Ar using the optimized conditions to provide dimethylamino
N
substituted products in good yields. Pyridine analogs, 2-fluoropyridine and 2-chloro-3-
nitropyridine reacted in the highest yields of all the substrates tested in the study (95 and
9
8% respectively) with reaction times of an hour or less. Purine derivative, 2-amino-6-
chloropurine, also smoothly converted the amino substituted product in an 81% yield.
Interestingly, the purine product was crystallized directly from the reaction mixture also
providing a simplified method of purification than previously reported for this
2
6
compound.
4

CONCLUSION
In summary, a method for installing dimethylamine groups via S Ar of aryl fluorides and
N
chlorides using the thermal decomposition of DMF in the presence of KOH is discribed.
This method uses relatively mild reaction temperatures (95 ˚C), is tolerant of nitro, nitrile,
aldehyde, ketone, and amide functional groups, and the reactions can be scaled up to
gram quantities without a significant change in yield. The reaction conditions can also be
used in a chemoselective fashion to substitute fluorine in the presence and without
substution of bromine groups. Multiple substitutions on a single molecule can also occur
in the same reaction pot.
EXPERIMENTAL
All of the solvents and chemicals used were purchased from commercial suppliers and
were used without any further purification. Thin layer chromatography (TLC) analysis
was performed using P254 silica gel 60 aluminum backed plates and column
chromatography purification was accomplished using BDH silica gel (230 – 400 mesh).
Melting point ranges were acquired with a Bibby scientific SMP10 melting point
apparatus and are uncorrected. FT-IR measurements were obtained using a Shimadzu
GladiATR 10 Single Reflection ATR accessory and UV-Vis measurements were
obtained by using a Beckman Coulter DU 800 Spectrophotometer. HPLC analysis was
performed using a Beckman Coulter System Gold unit equipped with UV-Vis detection.
1
H (400 MHz) NMR spectra was acquired on Varian VNMRS-400 instrument using
5

approximately 0.3 M solutions. High resolution electrospray mass spectrum (ESI
HRMS) analysis was conducted at the University of California, Irvine.
General Procedure.
A mixture of DMF (2.00 mL, 25.8 mmol) and 10 M KOH (0.500 mL, 5.00 mmol) were
heated at reflux for 5 min. The corresponding aryl halide (1.00 mmol) was added and the
resulting mixture was heated for 0.5 h at 95 ˚C. The mixture was treated with additional
1
0 M KOH (0.500 mL, 5.00 mmol) and heated for an additional 0.5 h. The reaction was
monitored by TLC and additional portions 10M KOH (0.500 mL, 5.00 mmol) were added
in 0.5 h intervals until completion was evident. The reaction mixture was then cooled,
diluted with water and vacuum filtered (for solid products) or extracted (for product oils)
with Et O (3x). For reaction products that were extracted, the organic fractions were
2
combined, dried over anhydrous Na SO , and concentrated under reduced pressure to
2
4
give the final product.
Selected Spectral Data.
1
2
9
1
1
2
2
,4-bis(dimethylamino)-5-fluorobenzaldehyde (Entry 8): H NMR (CDCl , 400 MHz) δ
3
.93 (d, J = 2.8 Hz, 1H), 7.27 (d, J = 14.5 Hz, 1H), 6.18 (d, J = 7.7 Hz, 1H), 2.92 (d, J =
13
.9 Hz, 6H), 2.76 (s, 6H); C NMR (101 MHz, CDCl ) δ 188.24 (d, J = 1.8 Hz), 154.34 ,
3
48.37 (d, J = 239.7 Hz), 145.43 (d, J = 9.2 Hz), 118.26 (d, J = 5.3 Hz), 116.53 (d, J =
2.5 Hz), 104.97 (d, J = 3.7 Hz), 41.87 (d, J = 6.1 Hz); IR (thin film) 3248, 3069, 2972,
-1
933, 2876, 1628, 1614, 1547, 1445, 1219, 758 cm ; HRMS (ESI) m/z 233.1066
+
(
M+Na , C H FN ONa requires 233.1061).
1
1
15
2
6

1
2
4
6
1
2
-bromo-4-(dimethylamino) benzaldehyde (Entry 9): mp = 87-90 ˚C; H NMR (CDCl ,
3
00 MHz) δ 10.08 (d, J = 0.8 Hz, 1H), 7.79 (d, J = 8.9 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H),
1
3
.63 (ddd, J = 8.9, 2.5, 0.8 Hz, 1H), 3.07 (s, 1H); C NMR (101 MHz, CDCl ) δ 190.23,
3
54.47, 131.05, 129.70, 122.06, 114.84, 110.58, 77.32, 77.00, 76.69, 40.08; IR (thin film)
-1
893, 2833, 2755, 1659, 1587, 1520, 1327, 1258, 804 cm ; HRMS (ESI) m/z 249.9839
+
79
(
M+Na , C H BrNONa requires 249.9843).
9 10
ACKNOWLEDGEMENTS
We would like to thank the National Center for Research Resources (5P20RR016464-11)
and the National Institute of General Medical Sciences (8 P20 GM103440-11) from the
National Institutes of Health and the National Science Foundation (IIA-1301726) for
1
their generous funding, as well as Mr. Jungjae Koh for his help in acquiring 400 MHz H
NMR spectra and Dr. John Greaves for aquiring ESI HRMS.
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9

Table 1. Optimization of Decomposition of DMF-S Ar Conditions for 4-
N
(dimethylamino)-benzaldehyde.
OHC
DMF
OHC
Additive
F
NMe2
1h
a
Entry Additive
Temp
Conversion
b
(˚C)
(%)
c
1
2
3
4
5
6
7
TFA (0.5 M)
95
95
95
65
80
95
0
c
c
NH (aq., 7.3
< 5
< 5
59
68
78
3
Na CO (aq.,
2
3
KOH (aq., 5
KOH (aq., 5
KOH (aq., 5
KOH (aq., 0.5 95
KOH (aq., 5 95
23 d
8
100
a
Final concentration after mixing with equal volumes of DMF.
b
Conversion determined by HPLC.
c
Reaction temperatures were also examined at 25 ˚C, 45 ˚C, and 65 ˚C but a conversion
was not detected.
d
KOH solution was added in two separate portions separated by 0.5 h.
1
0

Table 2. Dimethylamine S Ar of Aryl Fluorides/Chlorides Using the Optimized DMF-
N
KOH Conditions.
a
Entry Reactant
Product
Time (h) Yield (%)
O N
NO2
F
O N
NO2
2
2
1
2
3
4
5
6
7
8
9
0.05
81
90
93
78
72
70
89
64
88
NMe2
O N
O2N
2
1
F
NMe2
NMe2
NMe2
NMe2
O N
O N
2
2
2
Cl
NC
NC
NC
NC
1
F
6
Cl
CN
F
CN
NMe2
1
OHC
OHC
6
F
NMe2
F
F
CHO
F
F
CHO
24
0.6
Me N
NMe2
2
Br
Br
OHC
O
OHC
O
F
NMe2
NMe2
NMe2
1
1
0
1
6
91
45
F
O
O
24
Cl
1
1

O
O
1
1
1
2
3
4
1
1
5
70
76
44
iPrNH
iPrNH
F
NMe2
O
O
Cl
NMe2
F
NMe2
O
O
OMe
NMe2
F
NMe2
1
1
5
6
1
95
98
N
N
F
N
N
NMe2
NO2
Cl
NO2
0.5
NMe2
Cl
N
NMe2
N
1
7
2
81
N
N
N
N
N
H
N
H
H2N
H2N
a
Isolated Yields after purification.
1
2