Selective methylation of NH-containing heterocycles and sulfonamides using n, N -dimethylformamide dimethylacetal based on calculated pKa Measurements

Article abstract of DOI:10.1055/s-0032-1318315

The use of N,N-dimethylformamide dimethylacetal (DMF-DMA) as a suitable methylating agent for the methylation of NH-containing groups and heterocycles has been investigated. Use of ReactArray and calculated pK_a measurements have allowed additional helpful information to be collated to determine optimum reaction conditions for a variety of substrates.

Full text of DOI:10.1055/s-0032-1318315

570▌
LETTER
lSeteterlective Methylation of NH-Containing Heterocycles and Sulfonamides Using
N,N-Dimethylformamide Dimethylacetal Based on Calculated pKa Measure-
ments
DMF-DMA Methylation
Gary Fairley,* Catherine Hall, Ryan Greenwood
Astrazeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
Fax +44(1625)513253; E-mail: Gary.Fairley@astrazeneca.com
Received: 02.01.2013; Accepted after revision: 06.02.2013
site for formylation
Abstract: The use of N,N-dimethylformamide dimethylacetal
(DMF-DMA) as a suitable methylating agent for the methylation of
Δ
N+
N
O
NH-containing groups and heterocycles has been investigated. Use
of ReactArray and calculated pKa measurements have allowed ad-
ditional helpful information to be collated to determine optimum re-
action conditions for a variety of substrates.
O–
••
+
O
O
Key words: methylation, N,N-dimethylformamide dimethylacetal,
heterocycles, sulfonamides, pKa
site for methylation
Scheme 1 Electrophilic sites for methylation and formylation
Methylation of NH-containing heterocycles is a widely
performed transformation within synthetic chemistry.
Traditional reagents such as methyl iodide and dimethyl-
sulfate are widely used, however, these have undesirable
safety aspects mainly associated with their carcinogenic
properties. Practical issues include difficulty of handling
these reagents on small scale, over methylation due to
their reactive nature and regioselectivity, such as when
oxygen and sulfur are also present in the structure.
and 3-phenyl-1H-indole (13) were chosen as suitable sub-
strates for investigation based on ease of synthesis or
availability in our local building-block collection (Figure
1). Crucially, they all have blocking groups at C3 to avoid
the formylation reaction pathway.
Br
Ph
Ph
N
The use of DMF-DMA as a suitable methylating agent has
been widely reported in the literature for the synthesis of
esters from carboxylic acids,1 ethers from phenols,2 and
thioethers from aromatic thiols.3 However, methylation of
NH-containing heterocycles has been less widely report-
ed, these have mainly included amidic-based structures
such as uracil derivatives.4 A notable exception was by B.
Stanovnik et al.5 who reported methylation of a number of
heterocycles bearing SH, NH, and/or OH groups.
N
N
N
N
H
H
H
6
11
13
Figure 1 Substrates chosen for investigation
To determine the temperature required for methylation to
occur with the three chosen substrates as well as confirm-
ing alkylation on N1 for substrates 6 and 11, a small scale
trial was carried out utilizing DMF-DMA in DMF as the
reaction solvent. Results of this are shown in Table 1.
The ReactArray optimizer6,7 was chosen as a suitable au-
tomation platform to aid further investigation of this reac-
tion. It was decided that the main benefits of the reaction
were its simplistic nature, therefore the two main parame-
ters to be investigated were time and temperature. Sam-
ples for LC–MS analysis were automatically taken at
three hour time points during a 24 hour time period for
LC–MS analysis and the following graphs plotted for ease
of analysis of data (Figure 2).
DMF-DMA can react via two different pathways, one
leading to methylation and the other leading to condensa-
tion products such as N,N-dimethyl enaminones (protect-
ed formyl group, Scheme 1). Depending on the choice of
substrate, the benefits of the reaction are that DMF-DMA
generates its own base (methoxide) and the byproducts are
easily removed by standard evaporation techniques.
Recent work within our group had shown indole and relat-
ed azaindole-based scaffolds to be suitable substrates for
the NH methylation with DMF-DMA. This led us to fur-
ther investigate this reaction.
The data obtained from these experiments showed that
complete reaction occurred as long as the temperature was
of the required level. Failure to reach this temperature re-
sulted in incomplete reaction presumably due to either
degradation of reagent or gradual loss through evapora-
tion from the vessel. An additional ReactArray experi-
ment using 6 which investigated time vs. the number of
equivalents of DMF-DMA also showed the reaction pro-
The following (aza)-indoles, 3-bromo-1H-pyrrolo[2,3-
b]pyridine (6), 3-phenyl-1H-pyrrolo[2,3-c]pyridine (11),
SYNLETT 2013, 24, 0570–0574
Advanced online publication: 25.02.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318315; Art ID: ST-2013-D0004-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
DMF-DMA Methylation
571
Figure 3 ReactArray data plot, time vs. product (%) at 100 °C with
two, three, and four equivalents of DMF-DMA
temperature required for methylation to take place. Based
on this data a small selection of heterocycles were subject-
ed to DMF-DMA at a temperature determined based on
the calculated pKa of the NH to be methylated. Results are
shown in Table 1.
This showed some interesting results, all heterocycles
gave moderate to good yields – carried out at a tempera-
ture based on purely calculated pKa.8 With regards to entry
6 and 11 (Table 1), no methylation was observed on pyri-
dine-ring nitrogens, N7 and N6, respectively. Most nota-
ble were entries 1 and 12 (Table 1) whereby regioselective
methylation could be obtained with methylation occurring
at 60 °C on the more acidic sulfonamide NH in excellent
yield, dimethylation can be obtained by simply raising the
temperature, in this case 110 °C was chosen based on pKa
calculations. Acyclic amides did not methylate under the
conditions chosen but this could be used to an advantage
as selective methylation can occur on additional NH sites.
Entries 3 and 7 (Table 1) show methylation on sulfon-
amide and indole NH, respectively, in good yield. Entries
5 and 9 (Table 1) gave mixtures of N1 and N2 methylation
which were separated showing a 5:4 ratio in favor of N2
methylation for entry 5 and a 2:1 ratio of N1 methylation
for entry 9. Unfortunately, Boc-protected amines (Table
1, entry 14) did not undergo methylation presumably due
to sterics, and increase of temperature gave an unwanted
methylcarbamate side product. This may well have
formed via base-mediated isocyanate formation and sub-
sequent attack by methanol or methoxide.9 Cyclic ureas
underwent methylation in good yields with no O-methyl-
ation observed (Table 1, entry 4).
Figure 2 ReactArray data plots, time vs. product (%) at a variety of
temperatures over a 24 hour time period
gressed to completion with only a twofold excess of re-
agent (Figure 3).
With this data in hand, it was deemed that there may be a
correlation between pKa of NH that was to be methylated
and temperature required for methylation to proceed to
completion. In general, the lower the pKa, the lower the
Table 1 Methylations Using DMF-DMA (5 equiv) in DMF at a Specific Temperature Based on Calculated pKa
Entry
1
Heterocycle
Product
Calcd pKa (+/– 0.5) Temp (°C) Yield (%)a
Me
Cl
Cl
H
N
O
O
8.6 (NHSO2Me)
N
60
60
83
62
S
S
15.9 (indole NH)
O
O
Me
Me
N
N
Me
H
N
N
N
N
2
10.3
N
N
Cl
Cl
© Georg Thieme Verlag Stuttgart · New York
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G. Fairley et al.
LETTER
Table 1 Methylations Using DMF-DMA (5 equiv) in DMF at a Specific Temperature Based on Calculated pKa (continued)
Entry
Heterocycle
Product
Calcd pKa (+/– 0.5) Temp (°C) Yield (%)a
N
N
O
O
60b
H
N
3
5.1
60
Me
N
S
S
S
S
O
O
O
O
N
N
N
N
O
O
410
9.5
8.3
70
70
78
39
N
N
H
Me
N
N
N
N
MeO
MeO
N
N
MeO
MeO
N
N
N
N
5
Me
H
5a
MeO
MeO
N
N
Me
50
76
N
5b
Br
Br
6
7
12.2
15.1
80
80
N
N
N
N
Me
H
Me
HN
Me
HN
O
O
O
O
87
N
N
H
Me
O
O
S
O
O
S
810
10.9
13.1
80
90
92
43
N
N
Me
Me
H
Me
Br
Br
Br
Br
N
N
N
9
N
Me
H
9a
9b
Br
N
Me
27c
41
73
N
10
13.9
14.4
90
N
N
N
N
N
H
Me
Ph
Ph
1110
100
N
N
N
H
Me
Synlett 2013, 24, 570–574
© Georg Thieme Verlag Stuttgart · New York

LETTER
DMF-DMA Methylation
573
Table 1 Methylations Using DMF-DMA (5 equiv) in DMF at a Specific Temperature Based on Calculated pKa (continued)
Entry
12
Heterocycle
Product
Calcd pKa (+/– 0.5) Temp (°C) Yield (%)a
H
Me
Cl
Cl
O
O
N
N
8.6 (NHSO2Me)
15.9 (indole NH)
S
S
110
52
O
O
Me
Me
N
N
H
Me
Ph
Ph
1310
16.7
13.9
120
120
87
0
N
H
N
Me
Me
H
N
O
N
O
14
O
O
a Isolated yield.
b 21% starting material remained after 2 d at 60 °C.
c Product inseparable from remaining starting material, yield based on 1HNMR analysis showing purity of 58%.
In summary, DMF-DMA is an excellent methylating
agent for NH-containing heterocycles as well as sulfon-
amides. Using calculated pKa values allowed a rough pre-
diction of temperature required for methylation to occur
enabling a right first-time approach.
Acknowledgment
The author would like to thank Paul Kemmitt for his help in using
the ReactArray and to Darren McKerrecher, Mark Graham for help
in revising the manuscript.
This pKa–temperature correlation (Table 2) allows the po-
tential for regioselective methylations to take place which
may have added benefits over traditional methylating con-
ditions. The possibility of two different reaction pathways
is key to choosing whether the substrate may be accept-
able for methylation. The simplistic nature of the reaction
is one of the true benefits as it is very straightforward to
perform on both small scale and large scale with an easy-
to-handle reagent and simple workup procedures.
References and Notes
(1) Vorbruggen, H. Angew. Chem., Int. Ed. Engl. 1963, 2, 211.
(2) Priefer, R. Tetrahedron Lett. 2011, 52, 2776.
(3) Abdulla, R. F.; Brinkmeyer, R. S. Tetrahedron 1979, 35,
1675.
(4) Watanabe, K. J. Heterocycl. Chem. 1977, 14, 537.
(5) Stanovnik, B. Aust. J. Chem. 1981, 34, 1729.
(6) http://www.alphamultiservicesinc.com/page/442725626.
(7) Emiabata-Smith, D. F.; Crookes, D. L.; Owen, M. R. Org.
Process Res. Dev. 1999, 3, 281.
(8) http://www.acdlabs.com/products/percepta/predictors/pka.
(9) Knölker, H.-J.; Braxmeier, T. Tetrahedron Lett. 1996, 37,
5861.
Table 2 Approximate Temperature to Trial for DMF-DMA Methyl-
ation Based on Calculated pKa
(10) General Procedure:
Calcd pKa
Temp (°C)
To a stirred solution of substrate in dry DMF was added
DMF-DMA (5 equiv) in one portion at r.t. The resulting
mixture was heated at a temperature (60–120 °C) based on
calculated pKa (Table 2) for approximately 18 h and allowed
to cool to r.t. The reaction mixture was evaporated to dryness
and purified by flash silica chromatography.
8
9
50
60
10
11
12
13
14
15
16
17
70
2-Methyl-4-phenyl-1,2,4-triazol-3-one (4)
80
Temp 70 °C; yield 78%; white solid; MS (ES+): m/z [M +
H]+ = 176.33; HPLC: tR= 1.02 min. 1H NMR (700 MHz,
DMSO): δ = 8.43 (s, 1 H), 7.67 (dt, J = 8.7, 1.7 Hz, 2 H),
90
7.48–7.52 (m, 2 H), 7.35–7.38 (m, 1 H), 3.38 (s, 3 H). 13
NMR (176 MHz, DMSO): δ = 151.31, 134.59, 134.11,
129.32, 127.00, 121.48, 32.10.
C
100
110
120
130
140
3-Bromo-N,N-dimethyl-benzenesulfonamide (8)
Temp 80 °C; yield 92%; white solid; HRMS: m/z [M + H]+
calcd for C8H10BrNO2S: 263.96939; found: 263.96875. 1H
NMR (400 MHz, CDCl3): δ = 7.86 (t, J = 1.8 Hz, 1 H), 7.62–
7.69 (m, 2 H), 7.35 (t, J = 7.9 Hz, 1 H), 2.67 (s, 6 H).
1-Methyl-3-phenyl-1H-pyrrolo[2,3-c]pyridine (11)
Temp 100 °C; yield 73%; beige solid; MS (ES+): m/z [M +
© Georg Thieme Verlag Stuttgart · New York
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574
G. Fairley et al.
LETTER
H]+ = 209.41. HPLC: tR = 2.13 min. 1H NMR (400 MHz,
DMSO): δ = 8.90 (s, 1 H), 8.23 (d, J = 5.6 Hz, 1 H), 7.95 (s,
1 H), 7.83 (dd, J = 5.6, 1.0 Hz, 1 H), 7.69 (dd, J = 8.3, 1.2
Hz, 2 H), 7.46 (t, J = 7.8 Hz, 2 H), 7.27 (t, J = 7.4 Hz, 1 H),
3.97 (s, 3 H). 13C NMR (101 MHz, DMSO, 30 °C): δ =
138.71, 134.37, 134.12, 133.72, 131.18, 129.26, 128.87,
126.21, 125.70, 114.23, 113.58, 32.79.
1-Methyl-3-phenylindole (13)
Temp 120 °C; yield 87%; colorless gum; HRMS: m/z [M +
H]+ calcd for C15H13N: 207.1048; found: 207.1027. 1H NMR
(400 MHz, DMSO): δ = 7.88 (d, J = 8.0 Hz, 1 H), 7.64–7.7
(m, 3 H), 7.50 (d, J = 8.2 Hz, 1 H), 7.40–7.47 (m, 2 H), 7.20–
7.27 (m, 2 H), 7.11–7.17 (m, 1 H), 3.85 (s, 3 H).
Synlett 2013, 24, 570–574
© Georg Thieme Verlag Stuttgart · New York

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