Triethylsiloxymethyl-N,N-dimethylamine, Et3SiOCH2NMe2: A Dimethylaminomethylation (Mannich) Reagent for O–H, S–H, P–H and Aromatic C–H Systems

Article abstract of DOI:10.1002/ejoc.201700902

Triethylsiloxymethylamine, Et₃SiOCH₂NMe₂, readily synthesized in high yield by the hydrosilylation reaction between Et₃SiH and DMF, is an excellent (N,N-dimethylamino)methyl transfer agent to a representative range of aliphatic alcohols, thiols, and Ph₂PH (E–H) materials. The reactions are almost instantaneous at room temperature in inert solvents and require no activating agents to produce E–CH₂NMe₂ products in high yields and illustrate the title compound as an excellent addition to the family of organic reagents. For aromatic alcohols, electrophilic substitution of the aromatic ring occurs in high yield. Crystal structures of new materials such as the cholestero–CH₂NMe₂ derivative, 2–4-[bis(N,N-dimethylamino)methyl]-1-naphthol, and the phosphine oxide derived from Ph₂PCH₂NMe₂ are reported.

Full text of DOI:10.1002/ejoc.201700902

A Journal of
Accepted Article
Title: Triethylsiloxymethyl-N-N-dimethylamine, Et3SiOCH2NMe2: A
new dimethylaminomethylation (Mannich) reagent for O-H, S-H,
P-H and aromatic C-H systems
Authors: Keith H. Pannell, Paulina E Gonzalez, Hemant Sharma,
Sanchita Chakrabarty, and Alejandro Metta-Magaña
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700902
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
Triethylsiloxymethyl-N-N-dimethylamine, Et3SiOCH2NMe2: A new
dimethylaminomethylation (Mannich) reagent for O-H, S-H, P-H and
aromatic C-H systems
Paulina E. Gonzalez, Hemant K. Sharma, Sanchita Chakrabarty, Alejandro Metta-Magaña, Keith
H. Pannell*
The Department of Chemistry, University of Texas at El Paso, El Paso, TX. 79968-0513, USA
Keywords: Siloxymethylamine; Amination; Mannich; imminium
Abstract
Triethylsiloxymethylamine, Et3SiOCH2NMe2, readily synthesized in high yield by the hydrosilylation reaction
between Et3SiH and DMF, is an excellent (N,N-dimethylamino)methyl transfer agent to a representative range of
aliphatic alcohol, thiol and Ph2PH (E-H) materials. The reactions are almost instantaneous at room temperature in
inert solvents and require no activating agents to produce E-CH2NMe2 products in high yield and illustrate the title
compound as an excellent addition to the family of organic reagents. For aromatic alcohols electrophilic substitution
of the aromatic ring occurs in high yield. Crystal structures of new materials such as the cholesteryl –CH2NMe2
derivative, 2-4-[bis(N,N-dimethylamino)methyl]-1-naphthol, and the phosphine oxide derived from Ph2PCH2NMe2
are reported.
Introduction
We recently reported that when catalyzed by (Me3N)Mo(CO)5 (M), the organosilane
(R3SiH) reduction of amides,1 (leading to the formation of Me3N and the corresponding
disiloxane),2,3 involved the intermediacy of siloxymethyldimethylamines, R3SiOCH2NMe2, 1, eq.
1, R = Et (1a).4
1
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
Me
N
Me
[M]
[M]
OSiEt3
Me3N + Et3SiOSiEt3
(1)
+ Et3SiH
H
N
C
C
O
Me
Me
A
B
H
H
We were able to observe, isolate in good yield, characterize, and study the chemistry of
these intermediates.4 The degree to which this is a generally applicable mechanism is, however,
unclear and probably, depending upon both catalyst and substrate, other reaction pathways are
operative.5
The discovery that 1a could undergo a facile reaction with the active R3Siδ+-Hδ- and R3Siδ+-
Clδ- bonds, resulting in the formation of Me3N (or ClCH2NMe2) and R3SiOSiR3,6,7 respectively,
suggests that 1, which can be termed O-silylated aminol ethers, are masked analogs of
Eschenmoser’s salt,8 eq. 2, and thereby act as aminomethyl transfer agents (Mannich reagents).
[R3SiO]- [CH2=NMe2]+
R3SiO-CH2NMe2
(2)
Aminol ethers and aminals are reported to function best in the presence of an activating
species, e.g. SO2, chlorosilanes, acetyl chloride, trifluoroacetic acid, trimethylamine oxide etc.,
and thus facilitating the Mannich reaction in convenient non-protic solvents is a useful new
synthetic tool.9 We previously reported the utility of 1a to react with amines, R2NH, in benzene,
to form new diaminomethanes, R2NCH2NMe2, and bis-(dimethylamino)amines (Me2NCH2)2NPh
which possess interesting lability properties.10 We now report the reactions of 1a with a
representative group of element-hydrogen bonds, E-H (E = O, S, N, P), and aromatic C-H bonds,
which illustrate that 1a is a general, useful and reliable [CH2NMe2] transfer reagent requiring no
activating co-reactants, occurs at room temperature and gives high yields.
Results and Discussion
2
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
It is well-established that Mannich reagents can react with E-H (E = O, S) bonded
compounds;9a thus, our initial studies concentrated upon the reactions of 1a with simple alcohols
and thiols to form the corresponding E-CH2NMe2 products. In each case there is a very rapid
reaction involving transfer the aminomethyl group with concomitant formation of R3SiOH. As
previously known, the Mannich reaction products with alcohols depend upon the nature of the R
group attached to O, aliphatic or aromatic;9 this is not the case for thio-alcohols.11 For the aliphatic
alcohols studied, MeOH, EtOH, iPrOH and cholesterol, the products are the corresponding aminol
ethers, Me2NCH2OR’,2, formed in good yields, Scheme 1 (routes A and B). Similar chemistry
was observed for the reactions with both aliphatic and aromatic thiols, Scheme 1 (routes C-F).
C8H
17
Me
Me
CH2
Me2N
O
2d
B
Cholesterol
CH2
R'
Me2N
O
CH2
R"
Me2N
S
R'OH
Me
N
R"SH
2a-2c
3a-3c
A
C
OSiEt3
C
Me
H
H
2,6-Me2C6H3SH
Me2N
C6H5SH
F
Me
S
D
E
C10H7-2-SH
CH2
CH2
S
Me2N
Me
4c
4a
CH2
S
Me2N
4b
Scheme 1. Reactions of 1a with aliphatic alcohols (route A, R’ = Me (2a), Et (2b), iPr (2c)), -thiols
(route C, R” = Et (3a), Pr (3b), Bu (3c)), aromatic thiols (routes D-F), and cholesterol (route B).
The structure of the aminomethyl cholesterol derivative, a previously unknown material,
is illustrated in Figure 1.
3
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
Figure 1: Structure of cholesteromethyl(dimethyl)amine, 2d, CCDC # 1428932
With respect to the structure, the most reported cholesterol derivatives are those with
modifications in the aliphatic chain;12a however, there are also some with the alcohol
functionalized.12b The substitution of the alcohol in the compound 2d has no effect in the C-O bond
distance, neither on the cholesterol conformation.
For the aromatic alcohols investigated, phenol, 2,6-dimethylphenol, and α- and β-
naphthol, simple aromatic electrophilic substitution reactions take preference,9f with no indication
of substitution of the OH group, Scheme 2.9b O-aminomethylphenols, e.g. 5, have recently been
used for o-quinone methide synthesis, species with an important and interesting chemistry.9e
Me2N
Me2N
CH2
PhOH
CH2
5
OH
Me
N
2,6-Me2C6H3OH
OSiEt3
C
Me
Me
Me
H
H
OH
2-NpOH
6
OH
CH2
NMe2
7
Scheme 2. Reactions of 1a with aromatic alcohols.
4
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
The initial substitution is very selective and always ortho with respect to the OH group on the
aromatic core when possible, as is well-established.9b However, if this position is blocked, as in
2,6-dimethylphenol, para substitution occurs. The same ortho-(N,N-dimethylamino)methylation
of phenol has been achieved using both Eschenmoser’s salt9g and bis-(N,N-
dimethylamino)methane;9d however, the experimental conditions involved required an activation
system involving two or more equivalents of MgCl2-Et3N or SO2, respectively.
The structures of 4-[(N,N-dimethylamino)methyl]-2,6-dimethyl-phenol, 6, and 1-[(N,N-
dimethylamino)methyl]-2--naphthalenol, 7, are illustrated in Figure 2. For 7, the anticipated
formation of an intramolecular HB [r(OH∙∙∙N) = 1.56(3)] can be observed, which is statistically
similar
to
the
interaction
and
found
and
studied
for
4,5-dimethyl-2-[(N,N-
dimethylaminomethyl)phenol
3,5,6-trimethyl-2-(N,N-dimethylamino)methyl]phenol
[r(OH∙∙∙N) = 1.73(6) and 1.73(3) Å respectively.13a
Figure 2: Structure of 1-[N,N-dimethylamino)methyl-2--naphthalenol. 7, CCDC # 1428933; and 2,5-
dimethyl-4-(N,N-dimethylamino)methyl]-phenol, 6, CCDC # 1428937.
5
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European Journal of Organic Chemistry
When the stoichiometry of the phenol + 1a reaction is changed from 1:1 to 1:2 the reaction
leads to the di-substituted product, 2,6-bis-[(N,N-dimethylamino)methyl]phenol, 5a, via the
intermediacy of 5; however, at that stoichiometry a mixture of the two products was obtained.
With a larger excess of 1a (1:4 equivalents) product 5a can be obtained pure when the reaction
is performed at room temperature. Using at least a 1:3 ratio of reactants, the tri-substituted material
2,4,6-tris-[(N,N-dimethylamino)methyl)]phenol, 5b, can be readily formed in high yield when the
reaction is performed at 80 oC, eq. 3a. Thus 1a is a simple and effective reagent to form all three
(N,N-dimethylamino)methyl in high yields under the appropriate conditions. It is of interest that
the reported reaction of phenol with Me2NCH2NMe2, using SO2 as an activator, produced
primarily 5 and smaller amounts of the 2,4-bis[(N,N-dimethylamino)methyl]phenol, a product we
did not observe.9d Both the bis-and tris-[(N,N-dimethylamino)methyl]phenols are well-established
materials;13c 13C and 1H NMR spectra were in accord with expectation.13d
Similar chemistry occurs during the reaction of 1a with α-naphthol; initial rapid formation
of the ortho-substituion product with a slower secondary reaction leading to the di-substituted
ortho and para product, eq. 3b.
CH
Me2N
2
90 o
C
(3a)
1a
1a
1a
Me2NCH2
Me2NCH2
Me2NCH2
CH2NMe2
5a
CH2NMe2
5b
OH
5
OH
OH
OH
NMe2
CH2
NMe2
CH2
OH
OH
OH
(3b)
1a
1a
CH2
8
9
Me2N
We could find only a single previous report on 9 in the literature, and its single crystal
structure is presented in Figure 3.13b
6
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
Figure 3. Structure of 2,4-dimethylaminomethyl-1-naphthol, 9, CCDC # 1535575
As expected, the crystal structure involves formation of an intramolecular HB between the
amino and the alcohol function as in 7, [r(OH∙∙∙N) = 1.83(2)]. This HB is longer in 9 because of
the introduction of a second amino group, and results in a the less dense packing, 1.172 g/cm3 for
9 vs 1.215 g/cm3 for 7.
Initial studies on the reaction between 1a and Ph2PH illustrated that no reaction was
occurring, even at temperatures considerably elevated compared to those of the OH and SH
reactions reported above (70 °C cf. 25 °C) and the reactions with NH compounds.10 However,
addition of ~5% of (ƞ5-C5H5)Mo(CO)3Me to a reaction mixture in C6D6 at 30 °C, resulted in a
transformation to the expected dimethylaminomethyl transfer species, Ph2PCH2NMe2 (10). This
is a previously reported species, obtained from the reaction of Ph2PLi and ClCH2NMe2,14a or from
the acid catalyzed reaction of Ph2PH with tetramethyldiaminomethane.14b The 31P NMR chemical
shift of our product appears at -26.6 ppm, consistent with the 31P NMR chemical shift reported for
diphenylphosphino group of diphenylphosphino(dimethylphoshino)methane, Ph2PCH2PMe2, at ~
-22.8 ppm.15 However, our value is significantly at variance with a reported literature value of
7
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
27.5 ppm ppm,14b but in accord with another literature value of -25.3 ppm.14c Studies on our
sample illustrated that upon mild exposure to air it rapidly transforms to the corresponding
phosphine oxide, Ph2P(O)CH2NMe2 (11) which indeed exhibits a 31P NMR resonance at 26.9 ppm!
This latter value is comparable with the 31P NMR chemical shift of the Ph2P=O group of
Ph2P(O)CH2PPh2 at 27.6 ppm,16 thus we conclude that one of the original reports of Ph2CH2NMe2
resulted in the isolation of the phosphine oxide derivative 11.14b This is a crystalline material and
we have been able to determine its single crystal structure, Figure 4, hence proving the suggested
formulation.
Figure 4: Structure of [Ph2P(O)CH2NMe2], 11, CCDC # 1535574
The space group for this molecule is Pbca, a centrosymmetric structure with two orthogonal
H-bonding motifs. One network is associated with the N lone pair and an aromatic para-C-H,
Figure 5 (left). The other, a chain like pattern is formed via three P=O…H bonds, two ortho-C-H
units and a single H-bond with a methylene H atom, Figure 5 (right).
8
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
Figure 5. HB chain of 11 formed by interaction of the amino group with one C-H from
the aromatic ring on the phosphine [2.724 Å], left; and a chain formed by a triple HB
to the phosphine oxygen with the following distances 2.301, 2.312 and 2.473 Å, right.
The sulfur analog, Ph2P(S)CH2NMe2, has been obtained from the Mannich reaction of Ph2P(S)H
with DMF.17
Initial attempts to obtain transition metal derivatives of this bidentate PC1N ligand
Ph2PCH2NMe2, a member of the interesting class of hemilabile ligands, PCnN,18 have not been
successful. Given the ready formation of R’2NCH2NR2 complexes,10 this is surprising, but a search
of the literature reveals a handful of such complexes; a dimeric palladium complex where each
ligand atom binds a separate metal centre;19 and three complexes of bis(tris(N-
piperidinomethyl)phosphine oxide)- with zinc and cadmium dinitrate, and zinc dichloride.20
Conclusions
We have demonstrated that triethylsiloxymethyl-N-N-dimethylamine, Et3SiOCH2NMe2,
1a, readily formed in high yield from the reaction of Et3SiH and DMF, is an excellent new Mannich
reagent and transfers Me2NCH2 group to reactive E-H bonds (E = O, S, N, P, and aromatic C-H)
in high yields. The reagent is soluble in most organic solvents permitting homogeneous reaction
conditions which also involve relatively low temperatures and short reaction times, and, in general
9
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
for E = O, S and N, useful in the absence of any activating reagents or catalysts. Where appropriate
the side product, Et3SiOH, can be readily removed under vacuum at 60 oC, thus facilitating product
purification for all but low boiling materials.
Experimental
All manipulations were carried out under Argon atmosphere using Schlenk or vacuum line
techniques. THF was distilled under nitrogen from benzophenone ketyl prior to use. Other
solvents, hexanes, benzene and toluene were dried over sodium metal and distilled before use. All
alcohols and thiols, were purchased from Sigma-Aldrich. NMR spectra were recorded on either a
JEOL 600 MHz or Bruker 300 MHz spectrometer in either CDCl3 or C6D6 and recorded in ppm.
Column chromatography was performed on small columns (5 x 60 mm) of Silica Gel (Aldrich),
70-230 mesh, 60 Å, Pore Volume 0.75 cm3/g.
Single crystal X-ray diffraction. Crystals of compounds 2d, 6, 7, 9, and 11, were each mounted
on a glass fiber in a random orientation using paratone oil. The X-ray intensity data were collected
with APEX2 suite [APEX2 v2010.7-0 Bruker AXS 2005-2010] on a Bruker APEX CCD
diffractometer with monochromatized MoK radiation (λ = 0.71073 Å) at room temperature.
Synthesis of Et3SiOCH2NMe2, 1a.4b
A 25 mL Schlenk tube with a HI-VAC valve was charged with 3.64 g (31.4 mmol) of Et3SiH,
2.3 g (31.5 mmol) DMF and 2 mole % of the Mo(CO)6 as a catalyst. The tube was sealed under
vacuum and heated at 60 oC for 12 h. The tube was opened under Ar and the catalyst was
removed by repeatedly freezing the tube in liquid N2 and decanting the liquid into another flask.
The crude product was distilled at 60-62 oC at 20 mm/Hg. Yield: 4.45g (76 %). 1H NMR: 0.55
(q, 6 H, CH2), 0.97( t, 9H, CH3), 2.31, (s, 6 H, Me2N), 4.28 (s, 2 H, CH2). 13C NMR: 5.03, 7.15
(Et), 41.1 (Me2N), 82.3 (CH2). 29Si NMR: 15.3 ppm; HRMS(ESI): Calcd. for C9H22SiNO: (M+-
10
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
1): 188.1470, Found 188.1445. Anal. Calcd. for C9H23NOSi: C, 57.1; H, 12.2. Found: C, 55.9;
H, 12.2.
Reactions of Et3SiOCH2NMe2 with alcohols and thiols, 2-3.
In a typical experiment, a Pyrex NMR tube or 15-mL round-bottom flask was charged with a 10%
excess of 1a, and R′EH (E = O, R′ = Me, Et, t-Bu, Ph, 2,6-Me2C6H3, cholesterol; E = S, R′′ = Et,
1-Pr, 1-Bu, Ph, 2,6-Me2Ph) and 0.5 mL of C6D6 or CDCl3 and sealed under vacuum or under inert
atmosphere. The reactions were performed at room temperature and progress was monitored by
13C, 29Si NMR spectroscopy; however, the formation of the products was essentially instantaneous.
The products were purified by distillation or in the case of 4c and 2d, simply washed with cold
hexanes and recrystallized.
MeO-CH2NMe2, 2a.21 Yield 53%, b.p. 25 °C/30 mm Hg. 1H NMR (C6D6, 300 MHz): 2.31 (s, 6
H, (Me2N), 3.15 (s, 3 H, Me), 3.85 (CH2). 13C NMR (C6D6, 300 MHz): 41.50 (Me2N), 55.57 (Me),
90.82 (CH2).
EtO-CH2NMe2, 2b.22 Yield: 62%, b.p. 30 °C/25 mm Hg. 1H NMR (C6D6, 300 MHz): 1.52 (t, 3
H, -CH2Me), 2.68 (s, 6 H, Me2N), 3.82 (q, 2 H, -CH2Me), 4.31 (CH2). 13C NMR (C6D6, 300 MHz):
15.1, 63.4 (Et), 41.2 (Me2N), 89.1 (CH2).
iPrO-CH2NMe2, 2c.22 Yield 67%, b.p. 24 °C/30 mm Hg. 1H NMR (C6D6, 300 MHz): 1.04 (d, 6
H, CH(Me)2), 2.23 (s, 6 H, Me2N), 3.52 (sept, 1 H, CHMe2), 3.89 (s, 2 H, CH2) ppm. 13C NMR
(C6D6, 300 MHz): 22.5 (CH(Me)2), 41.5 (Me2N), 69.2 (CHMe2), 87.3 (CH2).
Reaction of Et3SiOCH2NMe2 with cholesterol to form 2d.
In a typical experiment, a 15-mL round-bottom flask was charged with cholesterol (1.78 g
(4.60 mmol) dissolved in 2 mL of benzene, and 1a (1.0 g (5.28 mmol) under an inert atmosphere
at room temperature. The reaction was monitoring by NMR spectroscopy using C6D6 or CDCl3 as
11
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
solvent and once the reaction finished, the benzene was evaporated, the solid was washed with
cold hexanes and recrystallized to yield the product.
13
Cholesteromethyl(N,N-dimethyl)amine, 2d: yield: 73%, m.p. 103-105 °C, white crystals. C
NMR (CDCl3, 300 MHz): 12.07, 19.03, 13.54, 21.44, 22.76, 23.00, 24.34, 24.60, 28.39, 28.62,
29.33, 32.23, 32.38, 36.20, 36.67, 37.13, 37.72, 39.92, 40.16, 40.20, 41.68, 42.60, 50.67, 56.56,
57.03, 77.12, 87.46, 121.55, 141.39 ppm; Calcd. for C30H53ON: C, 81.19; H, 12.05; Found: C,
81.72; H, 12.67
EtSCH2NMe2, 3a.23 Yield: 67%, b.p. 44-45 °C/25 mm Hg. 1H NMR (C6D6, 300 MHz): 1.66 (t, 3
H, -CH2Me), 2.68 (s, 6 H, Me2N), 3.03 (q, 2 H, -CH2Me), 4.27 (CH2). 13C NMR (C6D6, 300 MHz):
16.1, 27.6 (Et), 43.2 (Me2N), 64.5 (CH2).
PrSCH2NMe2, 3b. Yield: 75%, b.p. 48-50 °C/20 mm Hg. 1H NMR (C6D6, 300 MHz): 1.37 (t, 3
H, -CH2CH2Me, 2.00 (sext, 2 H, -CH2CH2Me), 2.64 (s, 6 H, Me2N), 2.93 (t, 2 H, -CH2CH2Me),
4.24 (s, 2 H, CH2). 13C NMR (C6D6, 300 MHz): 13.9, 24.4, 35.9 (Pr), 43.1 (Me2N), 65.0 (CH2).
BuSCH2NMe2, 3c.24 Yield: 80%, b.p. 34-35 °C/3 mm Hg. 1H NMR (C6D6, 300 MHz): 1.29 (t, 3
H, -CH2CH2CH2Me), 1.79 (sext, 2 H, -CH2CH2CH2Me), 1.93 (quint, 2 H, -CH2CH2CH2Me), 2.63
(s, 6 H, Me2N), 2.93 (t, 2 H, -CH2CH2CH2Me), 4.22 (s, 2 H, CH2). 13C NMR (C6D6, 300 MHz):
14.2, 22.60, 33.3, 33.5 (Bu), 43.1 (Me2N), 64.9 (CH2). HRMS (DART), Calcd. for C7H18NS, M+1,
148.11599, Found 148.1143.
1
[(N,N-dimethylamino)methyl]thio-benzene, 4a.24 Yield: 79%, b.p. 97 °C/3 mm Hg. H NMR
(CDCl3, 300 MHz): 2.32 (s, 6 H, Me2N), 4.52 (s, 2 H, CH2), 7.17 (t, 1 H, CH), 7.26 (t, 2 H, CH),
13
7.55 (d, 2 H, CH). C NMR (CDCl3, 300 MHz): 40.0 (Me2N), 68.2 (CH2), 125.7, 128.4, 131.1,
137.9 (Ph).
12
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Synthesis of 2-[(N,N-dimethylamino)methyl]thio-napthalene, 4b.27 2-Naphthalene thiol, 0.2 g
(1.25 mmol) was dissolved in 1 ml of benzene and 0.24 g of 1a (1.26 mmol) was added to the
solution. After evaporation of solvent the crude mixture was left under vacuum at 60 ºC for 2 h to
remove Et3SiOH and the oily product was isolated in 61 % yield.
1H (300 MHz, CDCl3) 2.4 (s, 6H), 4.6 (s, 2H), 7.4-8.1 (Ar-H, complex, 7H) 13C (75, CDCl3) 42.8,
69.0, 125.8, 126.5, 127.2, 127.7, 128. 5, 129.5, 130.0, 132.0, 134.0, 135.7; Anal. Calcd. for
C13H15NS: C, 71.84; H, 6.96; Found: C, 71.71; H, 7.25.
1- [(N,N-dimethylamino)methyl]thio-2,6-dimethylbenzene, 4c. Yield: 74%, b.p. 105-108 °C/3
mm Hg. 1H NMR (CDCl3, 600 MHz): 2.39 (s, 6 H, Me2N), 2.65 (s, 6 H, Me2), 4.30 (s, 2 H, CH2),
7.11 (s, 3 H, Ph). 13C NMR (CDCl3, 600 MHz): 22.4 (Me), 42.6 (Me2N), 69.3 (CH2), 127.6, 128.3,
135.9, 142.2 (Ph). HRMS (DART), Calcd. for C11H18NS, M+1, 196.11599, Found 196.1193.
1
2-[(N,N-dimethylamino)methyl]-phenol, 5.25 Yield: 51%, b.p. 75 °C/3 mm Hg. H NMR
(CDCl3, 300 MHz): 2.26 (s, 6 H, Me2N), 3.58 (s, 2 H, CH2), 6.75 (t, 1 H, C-4), 6.83 (d, 1 H, C-6),
13
6.93 (d, 1 H, C-3), 7.15 (t, 1 H, C-5), 11.00 (s, 1 H, OH). C NMR (CDCl3, 300 MHz): 44.13
(Me2N), 62.6 (CH2), 115.8, 118.7, 121.8, 128.1, 128.5, 158.06 (Ph).
1
2,6-bis-[(N,N-dimethylamino)methyl]-phenol, 5a.13d Yield: 75%, H NMR: 1.97 (s, 12 H,
((CH3)2N), 3.38 (s, 4 H, CH2), 6.69 (t, 1H), 6.98 (d, 2H), Ph. 13C NMR: 44.5 ((CH3)2N), 59.9
(CH2), 118.7, 123.4, 129.1, 157.1 (Ph).
2,4,6-tris-[(N,N-dimethylamino)methyl]-phenol, 5b.13d Yield: 90%, 1H NMR (C6D6, 300 MHz):
2.00 (s, 12 H, p-Me2N), 2.13 (s, 6 H, o-Me2N), 3.30 (s, 2 H, CH2), 3.47 (s, 4 H, CH2), 7.23 (s, 2H
(Ph). 13C NMR (C6D6, 300 MHz): 44.8 (o-(CH3)2N), 45.4 (p-Me2N), 60.2 (o-CH2), 64.4 (p-CH2),
123.7, 129.3, 129.6, 156.0 (Ph).
13
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
4-[(N,N-dimethylamino)methyl]-2,6-dimethylphenol, 6.25c, 9d Yield 78%, m.p. 116-117 °C,
colorless crystals. 1H NMR (CDCl3, 600 MHz): 2.17 (s, 6 H, Me2), 2.21 (s, 6 H, Me2N), 3.29 (s, 2
H, CH2), 6.87 (s, 2 H, Ph). 13C NMR (CDCl3, 600 MHz): 16.13 (Me2), 45.3 (Me2N), 63.9 (CH2),
123.7, 129.6, 129.9, 151.7 (Ph).
Reactions of Et3SiOCH2NMe2 with 1- and 2-Naphthol
1-[(N,N-dimethylamino)methyl]-2-naphthalenol, 7,25 2-Naphthol (0.3 g, 2.08 mmol) and 1a
(0.4 g, 2.1 mmol) were dissolved in 2 mL of benzene. After 10 minutes the solvent was removed
under vacuum and the residual oil was dissolved in small amount of hexane and left at 5 ºC
overnight. The yellow-brown crystals formed were washed with cold hexane to remove any
residual silanol. The final yield of the product was 63%, m.p. 71-72 ºC; NMR, 1H (C6D6): 1.9 (s,
6H), 3.7 (s, 2H), 7.3-7.9 (Ar-H, complex, 6H), 12.1 (s, 1H).13C (C6D6): 44.0 (Me2N), 57.8 (CH2-
N), 111.7, 119.8, 121.2, 122.4, 126.4, 129.0, 129.3, 129.6, 133.3, 157.7.
2-[(N,N-dimethylamino)methyl]-1-naphthalenol, 8.26 1-Naphthol (0.3 g, 2.08 mmol) and 1a
(0.4 g, 2.1 mmol) were dissolved in 2 mL of benzene. After 10 minutes the solvent was removed
under vacuum, and the residue was passed through a small silica gel column. The column was
eluded with hexane followed by (1:2) hexane-THF mixture. The final yield of the product was
1
57%. NMR, H (C6D6): 1.8 (s, 6H), 3.3 (s, 2H), 6.9-7.9 (Ar-H, complex, 6H), 8.9 (1H).13C
(CDCl3): 44.6 (Me2N), 63.2 (CH2-N), 114.4, 118.2, 122.2, 124.9, 125.1, 126.1, 126.5, 127.4,
134.1, 153.9.
2,4-bis[(N,N-dimethylamino)methyl]-1-naphthalenol, 9.26 In a typical experiment, a 15-mL
round-bottom flask was charged with 1-naphthol (0.5g, 0.35 mmol) and 1a (1.31g, 0.73 mmol)
dissolved in 4 mL of benzene, under an inert atmosphere at room temperature. The reaction was
agitated and monitored by NMR spectroscopy and when the reaction was finished, the solvent was
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
evaporated and the residual solid washed with cold hexanes, and recrystallized to yield the product.
Yield: 73%, m.p. 75-77 °C. 1H NMR (CDCl3, 600 MHz): 2.28 (s, 6 H, Me2N), 2.37 (s, 6 H, Me2N),
3.71 (s, 2 H, CH2), 3.77 (s, 2 H, CH2), 6.99 (s, 1 H, aromat. H), 7.43-7.46 (t, 1 H, aromat. H), 7.48-
13
7.50 (t, 1 H, aromat. H), 8.11-8.12 (d, 1 H, aromat. H), 8.26-8.27 (d, 1 H, aromat. H) ppm. C
NMR (CDCl3, 600 MHz): 44.7 (Me2N), 45.6 (Me2N), 62.0 (CH2), 63.0 (CH2), 113.3, 122.4, 124.1,
124.6, 125.4, 126.2, 128.2, 132.8, 153.6 (aromat.).
Synthesis of [(N,N-dimethylamino)methyl)]-diphenylphosphine, 10. A 5 mm Pyrex NMR tube
was charged with 0.1 g (0.53 mmol) of Et3SiOCH2NMe2, 0.1 g (0.53 mmol) of Ph2PH, and 0.5
mL of C6D6 and 5 mole% of (ƞ5-C5H5)Mo(CO)3-Me as a catalyst. The tube was sealed under
vacuum and the NMR monitoring after 15 h of the reaction by 1H, 29Si and 13C NMR spectroscopy
showed the formation of Ph2PCH2NMe2 and Et3SiOH. Et3SiOH was removed leaving the reaction
mixture under vacuum at 70 oC for 2 hrs. An oil of pure Ph2CH2NMe2, 12, was obtained in 85%
yield. 1H NMR: 2.23 (s, 6 H, Me2N), 2.97, (d, 2 H, (2JP-H =4 Hz, CH2), 7.04, 7.42-7.47 (m, 10 H,
Ph). 13C NMR: 46.8 (d, 3JP-C =9 Hz, Me2N), 63.4 (d, 1JP-C =2.3 Hz, CH2) 128.6 (d) 128.6, (s), 133.3
(d), 139.4 (d); 31P NMR: -26.6.
Synthesis of [(N,N-dimethylamino)methyl]-diphenylphosphine oxide, 11. A sample of pure
Ph2PCH2NMe2 exposed to air for 2 minutes immediately forms a white solid Ph2P(O)CH2NMe2,
which was recrystallized from CH2Cl2/hexane mixture. 1H NMR (CDCl3): 2.38 (s, 6 H, Me2N),
3.12, (d, 2 H, (2JP-H = 6 Hz, CH2), 7.44-7.48,7.74-7.78 (m, 10 H, Ph). 13C NMR:  ppm, 48.1 (d,
3JP-C = 9 Hz, NMe), 59.5 (d, 1JP-C = 88 Hz, CH2) 128.5 (d) 131.1 (d),131.8 (s), 133.1 (d); 31P NMR:
26.9.
Acknowledgements
Support of this research by the Welch Foundation (Grant # AH-0546) is gratefully acknowledged.
15
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10.1002/ejoc.201700902
European Journal of Organic Chemistry
Support for the upkeep of the NMR instrumentation by an endowment from the Kresge Foundation
is gratefully acknowledged.
Supplementary Material
1H and 13C NMR data for materials; cif data for CCDC-1428932 for 2d, 1428937 for 6, 1428933
for 7, 1535575 for 9 and 1535574 for 11 which can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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European Journal of Organic Chemistry
Graphical Abstract
C8H
17
Me
Me
CH2
Me2N
O
OH
Ph2PCH2NMe2
Cholesterol
Me
CH2
NMe2
2-NpOH
Ph2PH
NMe2
CH2
OH
N
OSiEt3
C10H7-2-SH
C
Me
H
H
1-NpOH
CH2
S
Me2N
CH2
R= aliphatic
ROH
Me2N
ROCH2NMe2
18
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