Steric Hindrance Underestimated: It is a Long, Long Way to Tri- tert-alkylamines

Article abstract of DOI:10.1021/acs.joc.8b00496

Ten different processes (Methods A-J) were tested to prepare tertiary amines bearing bulky alkyl groups. In particular, S_N1 alkylation of secondary amines with the help of 1-adamantyl triflate (Method D) and reaction of N-chlorodialkylamines with organometallic reagents (Method H), but also attack of the latter reagents at iminium salts, which were generated in situ by N-alkylation of imines (Method J), led to trialkylamines with unprecedented steric congestion. These products showed a restriction of the rotation about the C-N bond. Consequently, equilibration of rotamers was slow on the NMR time scale resulting in distinguishable sets of NMR data at room temperature. Furthermore, tertiary amines with bulky alkyl substituents underwent Hofmann-like elimination when heating in toluene to form an olefin and a secondary amine. Since the tendency to take part in this decay reaction correlated with the degree of steric hindrance around the nitrogen atom, Hofmann elimination at ambient temperature, which made the isolation of the tertiary amine difficult, was observed in special cases.

Full text of DOI:10.1021/acs.joc.8b00496

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Steric Hindrance Underestimated: It´s a
Long, Long Way to Tri-tert-alkylamines
Klaus Banert, Manuel Heck, Andreas Ihle, Julia Kronawitt, Tom Pester, and Tharalla Shoker
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00496 • Publication Date (Web): 09 Apr 2018
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The Journal of Organic Chemistry
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Steric Hindrance Underestimated: It´s a Long, Long Way to Triꢀtertꢀ
alkylamines
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Klaus Banert,* Manuel Heck, Andreas Ihle, Julia Kronawitt, Tom Pester, and Tharallah Shoker
Chemnitz University of Technology, Organic Chemistry, Strasse der Nationen 62, 09111 Chemnitz, Germany
*S Supporting Information
KEYWORDS: amines; Hofmann elimination; molecular dynamics; steric hindrance; synthetic methods
ABSTRACT: Ten different processes (Methods A−J) were tested to prepare tertiary amines bearing bulky alkyl groups.
Especially, SN1 alkylation of secondary amines with the help of 1-adamantyl triflate (Method D) and reaction of N-
chlorodialkylamines with organometallic reagents (Method H), but also attack of the latter reagents at iminium salts,
which were generated in situ by N-alkylation of imines (Method J), led to trialkylamines with unprecedented steric con-
gestion. These products showed a restriction of the rotation about the C−N bond. Consequently, equilibration of rotamers
was slow on NMR time scale resulting in distinguishable sets of NMR data at room temperature. Furthermore, tertiary
amines with bulky alkyl substituents underwent Hofmann-like elimination on heating in toluene to form an olefin and a
secondary amine. Since the tendency to take part in this decay reaction correlated with the degree of steric hindrance
around the nitrogen atom, Hofmann elimination at ambient temperature, which made the isolation of the tertiary amine
difficult, was observed in special cases.
1. INTRODUCTION
Owing to the method of synthesis, several tertiary amines
The amino unit belongs to the most fundamental functional
groups of organic chemistry.1 Consequently, several generaꢀ
tions of chemists have designed a variety of synthetic methods
over the years. The same holds true for sterically hindered
amines,2 for which wide ranges of application were found, for
example, as bases with low nucleophilicity, such as 13 and 2,4
or precursors of persistent nitroxyl radicals, like 3,5 utilized for
spin labeling tools (Figure 1).6 Numerous 2,2,6,6ꢀ
tetramethylpiperidines of type 4 and free radicals derived from
these heterocycles are polymerization inhibitors and thermoꢀ
and photostabilizers, known as hindered amine light stabiꢀ
lizers (HALS).7 Furthermore, sterically hindered amines have
recently come into industrial use in a variety of gasꢀtreating
processes.8 Finally, amines with bulky alkyl groups were
investigated in view of their pharmacological activity.9
with a high degree of steric congestion, such as 5,10a 6,10b and
7,11 include additional functional groups, which strongly influꢀ
ence the molecular structure around the amine nitrogen atom
and the corresponding reactivity (Figure 2). Compound 8 has
been presented as the most highly congested tertiary amine
known to date.12 However, the cyclopropyl group of 8 features
special electronic effects and a bulkiness similar to that of an
ethyl group. Unfortunately, nonꢀfunctionalized amines, such
as 9−15 have not yet been reported, and triisopropylamine (16)
seemed to define the achievable limit for steric distress in a
simple trialkylamine.10b Consequently, studies of the molecuꢀ
lar structure were focussed on 16, which should be very nearly
planar about nitrogen based on the results of electron diffracꢀ
tion studies.13 This outcome was claimed to be confirmed by
NMR investigations,14 whereas lowꢀtemperature singleꢀcrystal
Xꢀray diffraction of 16 led to a height of the NC3 pyramid
(nitrogen at the top) of 0.27−0.29 Å.15 This value is more than
a half of the corresponding height in triethylamine (0.467 Å).15
Thus, the molecule of 16 adopts a somewhat flatter pyramid
instead of a planar structure.
__________________________________________________
In a famous textbook of organic chemistry,16 amine 11 was
compared with the stable tertiary alcohol 17, which is known
since 1945 and easily accessible via different routes.17 It was
stated that 11 should have less steric strain than 17 and it
should be possible to prepare 11 because crowding can be
eased somewhat in the amine, but not in the alcohol, if the
three bulky groups assume a planar instead of the pyramidal
configuration.16 We believe that this argumentation is not
convincing since simple trialkylamines generally avoid planar
Figure 1. Sterically crowded amine derivatives with wide
range of applications.
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structures,15 and steric congestion in 11 is underestimated
Page 2 of 13
1
because different bond lengths were not taken into account.
2
3
4
5
6
7
8
9
by the reaction of iminium salt 23 with MeMgBr is a simple
procedure to generate 9, and Method F is possible with chloꢀ
rine, bromine, or iodine. But in all cases, one equivalent of
hydrogen halide is formed, which blocks half of 16 as an amꢀ
monium salt. Thus, a mixture of 9 and 16 was observed after
addition of MeMgBr, and separation of these amines is inconꢀ
venient. For example, oxidation of 16 with iodine and subseꢀ
quent exposure to MeMgBr/Et2O furnished 9 with 21% yield
after isolation by preparative GC. Transformation of 25, which
was easily available by formylation of 18, into iminium salt 24
and succeeding treatment with MeMgBr produced 9 in 62%
yield (Method G).24 This procedure facilitated purification of 9
by simple distillation on multiꢀgram scale. Activation of 25 by
Oꢀmethylation followed by treatment of the resulting salt 26
with MeMgCl afforded 9 with 23% yield.25
The reaction of Nꢀchlorodialkylamines with alkyl Grignard
reagents has been long known; however, yields of tertiary
amines are very low (4−7%), even without steric hindrance.26
Recently, it was demonstrated that arylation of the same subꢀ
strates with the help of aryl Grignard reagents could be signifꢀ
icantly improved if the reaction was performed in the presence
of a major excess of TMEDA.27 Thus, we treated 2728 with iꢀ
PrMgCl/TMEDA and obtained 9 in an acceptable yield of
46% (Method H). Without TMEDA, 9 was formed with 4%
yield only. Tertiary organometallic reagents are generally less
appropriate as shown by the reaction of 2828 with tꢀ
BuMgCl/TMEDA, which gave 9 in 11% yield. Method H
often led to the dechlorination products in a side reaction;
however, these secondary amines could easily be separated
from the desired tertiary amines. When N,Nꢀdichloroamine
2928 was subjected to iꢀPrMgCl/TMEDA, 9 was generated
besides other products; but the yield of 9 was disappointingly
low (Method I).
10
11
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Figure 2. Molecules with great steric crowding.
__________________________________________________
The C−N bond in 11 should be significantly shorter than the
corresponding C−C bond in 17,18 which will lead to a smaller
distance between the bulky groups in the amine. Moreover,
stability of 11 should be lower than that of 17 since amines
with such steric distress may undergo βꢀelimination to form a
secondary amine and an olefin (Hofmannꢀlike elimination).
The analogous direct βꢀelimination of water is not possible
with 17, and its dehydration is always accompanied by Wagꢀ
ner−Meerwein rearrangement.19
Herein, we describe the syntheses of 9, 10, and 12−14, and
the access to tertiary amines with even more bulky alkyl subꢀ
stituents such as 32−40 and 43. The steric stress in such prodꢀ
ucts is indicated by a surprising tendency to undergo Hofmann
elimination under mild conditions, and by slow rotation about
the C−N bond leading to distinguishable conformers.
__________________________________________________
2. RESULTS AND DISCUSSION
Scheme 1. Unsuccessful attempts to prepare 9
First, we looked for an efficient method to prepare the model
compound 9 by using established methods. Whereas Bruylants
reaction via 2ꢀ(diisopropylamino)propionitrile is wellꢀ
known13,20 to effectively transform 20 into 16, the analogous
attempts with substrate 18 (Method A) were completely unꢀ
successful (Scheme 1). Treatment of 18 with diisopropyl sulꢀ
fate (Method B) also did not lead to 9 although a similar SN2
alkylation of diisopropylamine was reported to produce 16
with 18% yield.20 When we reacted 2 with diisopropyl sulfate,
we did not get the desired product 14 while 2,2,5,5ꢀ
tetramethylpyrrolidine gave 12 in very low yield (2−3%) with
the same reagent. Our experiments to synthesize 9 from 19 via
the corresponding N,Nꢀdiisopropyl(propꢀ2ꢀylidene)ammonium
salt (Method C) were unfruitful.21 The same was true for our
efforts to prepare 9 by SN1 alkylation of 20 (Method D).22
After this frustration, we tested also less established and new
methods. Chlorination of the purchasable sulfur compound 21
and subsequent treatment of the resulting iminium salt 22 with
an excess of MeMgCl led to the wanted product 9 (Scheme 2,
Method E).23 However, the overall yield was low (ca. 5%), and
the separation of 9 was laborious. Halogenation of 16 followed
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Scheme 2. Successful methods to synthesize 9
1
2
3
4
5
6
Method F
Method E
N
X2
HX
7
8
9
S
S
S
Cl2
3 MeMgCl
MeMgBr
N
N
N
S
Cl
Cl
X = Cl, Br, I
N
X
Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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43
44
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N
16
22
23
21
2 i-PrMgCl
TMEDA
ca. 4%
9
Method I
Cl
N
(COCl)2
2 MeMgBr
CHO
N
Cl
Cl
N
Cl
Method H
Method G
24
25
t-BuMgCl
TMEDA
11%
i-PrMgCl
TMEDA
46%
29
CHCl3
NaOH
H2O
OMe
OTf
MeOTf
N
2 MeMgCl
81%
Cl
N
NH
N
26
Cl
28
27
18
_________________________________________________________________________________
Table 1. Synthesis of 12−14 and 32−40a
Next, we transferred the promising methods, which opened
up an access to 9, to the more ambitious synthesis of 10
(Scheme 3). After oxidation of 9 with X2 (X = Cl, Br, or I)
followed by treatment with MeMgBr or MeLi (with or without
TMEDA), however, 10 was not formed (Method F). Unfortuꢀ
nately, exposure of 3028 to (COCl)2 or MeOTf did not lead to a
precipitate of an iminium salt, which could be reacted with
MeMgBr. Consequently, the most likely variations of Method
G could not be realized, and the direct reaction of 30 with
MeMgBr produced 10, after separation by preparative GC,
with 4% yield only. A better yield of 10 (32%) resulted when
3128 was treated with iꢀPrMgCl/TMEDA (Method H). As
might have been expected, the reaction of 27 with tꢀ
BuMgCl/TMEDA did not provide an efficient access to 10.
Further trialkylamines with a high degree of steric congesꢀ
tion, such as 12−14 and 32−40 were prepared with quite
__________________________________________________
Scheme 3. Synthesis of 10
Method F
X2
MeMgBr
or MeLi
N
X = Cl, Br, I
9
aFor the Methods D, F−I, see also Schemes 1−3 and 5. (COCl)2
b
t-BuMgCl
TMEDA
and then MeMgBr were used. cFrom 12 and I2, then MeMgBr was
Cl
MeMgBr
4%
N
N
N
used. dtꢀBuMgCl was used. From 45/AgOTf. 48% yield from
e
f
ca. 1%
CHO
g
h
(Method G)
Method H
44b/Me3SiOTf. 51% yield from 44b/Me3SiOTf. 12% yield from
30
10
27
i
j
k
44b/Me3SiOTf. iꢀPrMgCl was used. EtMgBr was used. From
44a/Me3SiOTf. l1ꢀAdamantylmagnesium bromide was used.
mCyclohexylmagnesium
chloride
Norbornylmagnesium bromide was used.
was
used.
n2ꢀ
i-PrMgCl
Method H
N
TMEDA
32%
Cl
3
31
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Page 4 of 13
1
2
Scheme 4. Hofmann elimination of 38b
3
4
Unwanted Hofmann elimination of trialkylamines led to the
idea to introduce 1ꢀadamantyl groups, which are even more
bulky than tꢀbutyl units, but nearly immune to βꢀelimination.
Furthermore, 1ꢀadamantylꢀsubstituted amines can also be
prepared by using Methods D and J. Thus, 43 was not only
available from 4228 through Method H (Scheme 5). It was
likewise synthesized by SN1 Nꢀalkylation of 18 via 1ꢀ
adamantyl triflate,29 which was generated in situ from acetate
44a,22,28 mesylate 44b,28 or bromide 45 (Method D). The latter
substrate was most convenient and provided the highest yield
(63%), whereas somewhat lower yields of 43 resulted from
44a (46%) and 44b (54%). After exposure of imine 4628 to
45/AgOTf, treatment of the formed iminium salt 47 with MeLi
produced 43 in 42% yield (Method J).
Despite very serious efforts, all our experiments to generate
triꢀtertꢀalkylamines of type 11 or 15 were unsuccessful. For
example, reactions of 31, 42, or 1ꢀchloroꢀ2,2,6,6ꢀ
tetramethylpiperidine28 with tꢀBuMgCl or tꢀBuLi led to prodꢀ
ucts of dechlorination only, and attempts to Nꢀalkylate 2, diꢀ
tertꢀbutylamine,28 1ꢀadamantyl(tertꢀbutyl)amine,28 or diꢀ1ꢀ
adamantylamine28 with the help of 45/AgOTf were also in
vain. Subjection of 4828 to 45/AgOTf followed by treatment
with MeLi gave enamine 49 instead of the desired product
with two tꢀbutyl groups. Such unwanted deprotonation was
similarly observed in the case of other iminium salts with great
steric hindrance. Thus, simple triꢀtertꢀalkylamines include a
very high degree of steric congestion; consequently, they are
sensitive to Hofmann elimination, and cannot be prepared
easily. On the other hand, triꢀtertꢀalkylamines 13 and 32−36,
in which two groups at nitrogen are connected to form a fiveꢀ
membered ring, are available (Table 1). In the cases of 33 and
34, ring opening to synthesize the corresponding openꢀchain
triꢀtertꢀalkylamines is perhaps possible by oxidation or ethenꢀ
olysis (metathesis) at the C=C bond.
5
6
7
8
__________________________________________________
9
different yields by using Methods D and F−I (Table 1). It
turned out that some of these amines underwent Hofmannꢀlike
elimination on heating in toluene. In all cases, a tertiary alkyl
group was split off to generate an olefin and a secondary
amine. For example, 37a gave 18 and tertꢀ
amyl(isopropyl)amine, but no tertꢀamyl(tertꢀbutyl)amine after
heating a toluene solution at 100 °C. The tendency to take part
in Hofmann elimination correlates with the degree of steric
hindrance around the amine nitrogen atom. Whereas 9 and
also alcohol 17 are nearly stable at 100 °C (tolueneꢀd8, 60−140
days), 37a and 38a possess, at the same temperature, a halfꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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43
44
45
46
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life t of ca. 9 days and 1−2 days, respectively. At 40 °C, the
½
decay of 38b to produce 18 and exclusively regioisomer 41 led
to t = 30 h (Scheme 4). The Hofmann elimination of 38a in
½
(tolueneꢀd8, at 100 °C was not enhanced in the presence of
additional bases, such as TMEDA, and even decelerated by
addition of DABCO, but strongly accelerated with one equivaꢀ
lent of trichloroacetic acid or in slightly protic solvents like
toluene, which was previously saturated with water at 20 °C.
Since it was very difficult to isolate unstable 38b, the question
arises whether 11 could be handled at room temperature or
not.
__________________________________________________
Scheme 5. Synthesis of 1ꢀadamantylamines
i-PrMgCl
N
24%
The unprecedented steric congestion of the presented tertiary
amines is demonstrated not only by Hofmann elimination,
occurring under surprisingly mild conditions, but also by
restriction of the rotation about the C−N bond, which is slow
on NMR time scale in several cases. Hence, the tardy rotation
of the secondary alkyl group led to two distinct tꢀbutyl groups
of 10, two distinguishable tꢀamyl groups of 37b, and two
different 1ꢀadamantyl groups of 40 in the NMR spectra at
Cl
5 : 1
42
Method H
N
N
H
H
43
Me3SiOTf
K2CO3
OX
MeLi
AgOTf
K2CO3
44a X = Ac
44b X = Ms
HN
63%
HN
room temperature. A barrier of 79 kJ/mol with Tcoalescence
=
80 °C was estimated for the rotation of the isopropyl group in
10 by utilizing dynamic 1H NMR spectroscopy (Figure 3). For
amines with lower symmetry of substitution, such as 37a, 38b,
18
N
Method D
OTf
18
1
and 43, two complete H and 13C NMR data sets of rotamers
47
Method J
were detected at ambient temperature, and 37a, for example,
showed two 15N NMR signals. Whereas the ratio of the rotaꢀ
mers was nearly 1:1 in the cases of 37a and 38b, a 5:1 mixture
of conformers was observed for 43. Assignment of these conꢀ
N
AgOTf
K2CO3
46
Br
45
1
formers was performed with the aid of H NMR NOE experiꢀ
ments. The conformational dynamics of 10 and similar amines
significantly differ from those of trialkylamines with less
bulky substituents14b,30 but more flexible moieties and that of
AgOTf
K2CO3
MeLi
N
N
49
48
4
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the hydrocarbon 3ꢀisopropylꢀ2,2,4,4ꢀtetramethylpentane,31 i.e.
cover new applications for amines with a high degree of steric
congestion.
1
2
3
4
10 with CH instead of the N atom. Shorter C−N bonds in
comparison with C−C bonds, and underestimated steric conꢀ
gestion of tertiary amines16 may be relevant factors to provide
an explanation.
4. EXPERIMENTAL SECTION
5
6
7
8
General. All the reactions dealing with airꢀ or moistureꢀsensitive
compounds were carried out in a dry reaction vessel under a
positive pressure of nitrogen. Airꢀ and moistureꢀsensitive liquids
and solutions were transferred via a syringe. All reactions were
carried out with freshly distilled, dry solvents. Anhydrous solꢀ
vents were distilled immediately before use. AgOTf was obtained
commercially from abcr (Germany). 1ꢀBromoadamantane (1ꢀAdꢀ
Br), tꢀBuMgCl, MeMgCl, MeMgBr, iꢀPrMgCl, LiCl, NCS,
TMEDA, Me3SiOTf were obtained commercially from Acros
Organics (Belgium). MeLi, iꢀPrMgBr, iꢀPrMgBr·LiCl, CyMgCl,
2ꢀexoꢀbromonorbonane were obtained commercially from Sigmaꢀ
Aldrich (Germany). Diisopropylamine (20) was purchased from
Dr. Grüssing GmbH (Germany). Diisopropylamine hydrobroꢀ
mide (19) was obtained commercially from TCI (Germany).
2,2,6,6ꢀTetramethylpiperidine was obtained commercially from
Merck KGaA (Germany).The Grignardꢀreagents 2ꢀexoꢀ
norbornylMgBr, 1ꢀAdMgBr, EtMgBr, and tꢀBuMgBr were preꢀ
pared from the corresponding alkyl bromide and magnesium
turnings following a general literature procedure and used immeꢀ
diately after preparation.33,34 Compounds 16,20 18,35 21,36 44a,37
44b,38 46,39 48,40 diꢀtertꢀbutylamine,42 2,2,5,5ꢀtetramethylꢀ
pyrrolidine,43 1,1,3,3ꢀtetramethylisoindoline,45 1,1,3,3ꢀtetraethylꢀ
isoindoline,45 tertꢀamylꢀtertꢀbutylamine,46 diꢀtertꢀamylꢀamine,47
tertꢀbutylꢀtertꢀoctylamine,48 diꢀ1ꢀadamantylamine,49 1ꢀadamantylꢀ
tertꢀbutylamine,50 30,51 and 1ꢀformylꢀ2,2,6,6ꢀtetramethylꢀ
piperidine,52 were analogously prepared according to reported
literature.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. 1H NMR spectra of 10 in tolueneꢀd8 at different
temperatures (400 MHz, upfield region).
_____________________________________________
3. CONCLUSIONS
In summary, we have shown that model compound 9 can be
prepared by using different methods; but several procedures,
which provided an access to triisopropylamine (16), failed in
the case of 9. Diꢀtertꢀbutyl(isopropyl)amine (10) and tertiary
amines with an even higher degree of steric congestion were
effectively available by three processes (methods D, H, J)
only, and these methods were never previously utilized to
prepare sterically hindered amines. The presented trialkylaꢀ
mines establish new records of steric distress and show surꢀ
prising spectroscopic and chemical properties. However, the
negative results in our attempts to prepare simple triꢀtertꢀ
alkylamines may indicate a limit of steric congestion. This
impression is intensified by the dramatic drop of the yield
when the synthesis of 43 (63%, Method D) is compared with
the completely unsuccessful efforts to prepare 1ꢀadamantylꢀdiꢀ
tertꢀbutylamine by the same method. Moreover, it is doubtful
whether triꢀtertꢀbutylamine (11) can be isolated at room temꢀ
perature, because even the less sterically hindered amine 38b
undergoes a rapid Hofmann elimination under such conditions.
Nevertheless, the potential existence and properties of 11 as
well as the calculated structure and the stability of the correꢀ
sponding Lewis pairs were discussed intensively.32
NMR spectra were recorded with a UNITY INOVA 400 FT specꢀ
trometer (Varian Inc., Palo Alto, CA, USA) operating at 400 MHz
1
for H NMR, 100.6 MHz for 13C NMR, and 40.5 MHz for 15N
NMR; ULTRASHIELD 500 FT spectrometer (Bruker Corp.,
1
Billerica, MA, USA) operating at 500 MHz for H NMR, 125.8
MHz for 13C NMR, and 50.6 MHz for 15N NMR; ASCEND 600
FT spectrometer (Bruker Corp., Billerica, MA, USA) operating at
1
600 MHz for H NMR, 150.9 MHz for 13C NMR, and 60.8 MHz
1
for 15N NMR. H NMR and 13C NMR signals were referenced
with the help of the solvent signals and recalculated relative to
TMS. 15N NMR was referenced indirectly to external MeNO2 (δ =
0). Data are presented as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext =
sextet, sept = septet, m = multiplet, br = broad), coupling constant
in Hertz (Hz) followed by the number of hydrogen atoms. In all
cases of 13C NMR spectra, DEPT135 experiments were also
performed. Assignments of NMR signals were further supported
by COSY, HSQC, HMBC 2DꢀNMR methods and also by comparꢀ
ison of the data of homologous compounds in several cases. Sigꢀ
nal assignment was omitted if it was unclear. IRꢀspectra were
messured on a NicoletTM iSTM 5 spectrometer (Thermo Fisher
Scientific Inc., Waltham, MA, USA) in KBrꢀmatrix for solids or
in KBrꢀcuvette for liquids. Mass spectra were obtained from
micrOTOF QII spectrometer (Bruker Corp., Billerica, MA, USA)
utilizing electrosprayꢀionization technique (source: Apollo II ESI).
Quantitative elementary analyses were performed on a vario
Micro cube (Elementar Analyensysteme GmbH, Langenselbold,
HE, Germany). Melting points (m.p.) were measured by
BOETIUSꢀmethod on a heating apparatus from VEB Analytik
Dresden PHMK 74/0032. Reaction tracking was realized via
analytical gas chromatography using a gas chromatograph 5890
Currently, we are investigating conformational dynamics of
trialkylamines with bulky substituents by using NMR methꢀ
ods, and we try to find correlations between 15N NMR chemiꢀ
cal shifts and increasing steric hindrance around the N atom.
Work on single crystals to perform analysis of the molecular
structures by Xꢀray diffraction is also in progress. Finally, we
would like to support all colleagues who will attempt to disꢀ
5
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Page 6 of 13
Series II (Hewlett Packard Inc., Palo Alto, CA, USA; column:
adamantyl)amine49 as a pure white solid (84% yield). m.p. = 172–
HPꢀ5 M.S. (crosslinked 5% Ph Me Silicone) 30 m x 0.25 mm x
0.25 µm). For the separation of complex mixtures, a preparative
gas chromatograph GCꢀ8A (Shimadzu Corp., Kyoto, Japan) was
used with a Carbowaxꢀcolumn (KOH, 1 m or 3 m, Inj.ꢀTemp.:
70 °C, Col.ꢀTemp.: 60°C, Carrier Gas: Helium 5.0, 30 mL/min).
NꢀtertꢀButylꢀNꢀisopropylformamide (25). The product was
analogously synthesized according to a reported procedure51 for
compound 30 and was obtained as a white crystalline solid in 81%
173 °C. 1H NMR (400 MHz, C6D6): δ = 1.47–1.55 (m, 12H), 1.96
(bs, 6H), 2.21 (bs, 12H). 13C NMR (100.6 MHz, C6D6): δ = 30.7
(d, CH), 36.4 (t, CH2), 43.3 (t, CH2), 66.6 (s, C). Anal. Calcd. for
C20H30ClN (319.21): C, 75.09; H, 9.45; N, 4.38; found: C, 75.20;
H, 9.48; N, 4.34.
1
2
3
4
5
6
7
8
Preparation of Tertiary Amines.
Method Dꢀ1 (General SN1 protocol between secondary amines
and 45): A twoꢀneckꢀround bottom flask (50 mL) was equipped
with a magnetic stirring bar and gas inlet valve. The whole system
was flameꢀdried under vacuum followed by purging with nitroꢀ
gen. Under nitrogen and dark, 1ꢀbromoadamantane (45, 0.25 g,
1.16 mmol) and silver trifluoromethanesulfonate (0.30 g, 1.16
mmol) were dissolved in 20 mL dry methylene chloride at 0 °C.
The reaction mixture was stirred at 0 °C for at least 4 h. Anhyꢀ
drous potassium carbonate (0.60 g, 5.79 mmol) was added folꢀ
lowed by the addition of amine (1.74 mmol). The mixture was
stirred at 0 °C for 4 h under dark. After cooling to –10 °C, the
reaction mixture was quenched with saturated solution of sodium
bicarbonate (20 mL). The neutralized reaction mixture was exꢀ
tracted with more DCM (2 x 25 mL). The organic layers were
collected, dried over potassium carbonate, and the solvent was
removed under vacuum.
Method Dꢀ2 (General SN1 protocol between secondary amines
and 44b): A twoꢀneckꢀround bottom flask (50 mL) was equipped
with a magnetic stirring bar and gas inlet valve. The whole system
was flameꢀdried under vacuum followed by purging with nitroꢀ
gen. Under nitrogen, trimethylsilyl trifluoromethanesulfonate
(TMSOTf, 0.26 g, 1.17 mmol) and anhydrous potassium carꢀ
bonate (0.60 g, 5.79 mmol) were added to a solution of 1ꢀ
adamantyl mesylate38 (44b, 0.27 g, 1.16 mmol) in 20 mL dry
methylene chloride. The reaction mixture was stirred at 0 °C for
30 minutes followed by the addition of amine (1.74 mmol). The
reaction mixture was stirred at r.t. for 3 h. The neutralized reacꢀ
tion mixture was extracted, worked up, and purified as mentioned
in Method Dꢀ1.
1
yield. m.p. = 38–40 °C. H NMR (400 MHz, CDCl3): δ =1.34 (s,
3
9H, ꢀC(CH3)3), 1.43 (d, JH,H = 6.8 Hz, 6H, ꢀCH(CH3)2), 3.52
9
(sept,3JH,H = 6.8 Hz, 1H, ꢀCH(CH3)2), 8.35 (s, 1H, ꢀCHO). 13C
NMR (100.6 MHz, CDCl3): δ = 20.0 (q, ꢀCH(CH3)2), 29.1 (q,ꢀ
C(CH3)3), 47.1 (d, ꢀCH(CH3)2), 56.3 (s, ꢀC(CH3)3), 161.0 (d, ꢀ
CHO). IR [cm–1]: ῦ = 1659. HRMS: m/z calcd for C8H18NO (M +
H+) 144.1383; found 144.1394.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compounds 27,54 28,55,56 29,57 31,55 42, N,Nꢀ
dichloroadamantaneꢀ1ꢀamine,58
1ꢀchloroꢀ2,2,5,5ꢀtetramethylꢀ
pyrrolidine, 1ꢀchloroꢀ2,2,5,5ꢀtetramethylpyrroline, NꢀtertꢀbutylꢀNꢀ
chloroꢀtertꢀamylamine,55 Nꢀchloroꢀdiꢀtertꢀamylamine, and Nꢀtertꢀ
butylꢀNꢀchloroꢀtertꢀoctylamine were analogously prepared acꢀ
cording to reported literature.59
Nꢀ(tertꢀButyl)ꢀNꢀchloroꢀadamantanꢀ1ꢀamine (42). The prodꢀ
uct was prepared analogously to the general procedure59 from Nꢀ
(tertꢀbutyl)adamantanꢀ1ꢀamine50 as a pure white solid (0.93 g,
1
80% yield); m.p. = 140–142 °C. H NMR (400 MHz, C6D6): δ =
1.35 (s, 9H, C(CH3)3), 1.47 (bs, 6H), 1.93 (bs, 3H), 2.08 (bs, 6H).
13C NMR (100.6 MHz, C6D6): δ = 30.4 (d, CH), 31.5 (q, CH3),
36.3 (t, CH2), 42.4 (t, CH2), 64.7 (s, C), 66.1 (s, C). HRMS m/z
calcd for C14H25ClN (M+H+) 242.1670; found 242.1660.
NꢀChloroꢀ2,2,5,5ꢀtetramethylpyrrolidine. The product (2.3 g)
was isolated by removing solvents in vacuum and recondensed as
1
yellowish liquid in 90% yield. H NMR (400 MHz, CDCl3): δ =
1.20 (s, 12H, CH3), 1.75 (s, 4H, CH2). 13C NMR (100.6 MHz,
CDCl3): δ = 27.0 (q, CH3), 35.6 (t, CH2), 65.6 (s, C(CH3)2).
HRMS m/z calcd for C8H18N (M–Cl+2H)+ 128.1434; found
128.1474.
NꢀChloroꢀ2,2,5,5ꢀtetramethylpyrroline. The product (1.01 g)
was isolated by removing solvents with a 25 cm Vigreux column
at 50 °C and recondensed in vacuum as yellowish liquid in 53%
Method Dꢀ3 (General SN1 protocol between secondary amines
and 44a): A twoꢀneckꢀround bottom flask (50 mL) was equipped
with a magnetic stirring bar and gas inlet valve. The whole system
was flameꢀdried under vacuum followed by purging with nitroꢀ
gen. Under nitrogen, trimethylsilyl trifluoromethanesulfonate
(TMSOTf, 0.26 g, 1.17 mmol) and anhydrous potassium carꢀ
bonate (0.60 g, 5.79 mmol) were added to a solution of 1ꢀ
adamantyl acetate37 (44a, 0.23 g, 1.16 mmol) in 20 mL dry methꢀ
ylene chloride. The reaction mixture was stirred at 0 °C for 30
minutes followed by the addition of amine (1.74 mmol). The
mixture was stirred at r.t. for 12 h. The neutralized reaction mixꢀ
ture was extracted, worked up, and purified as mentioned in
Method Dꢀ1.
Method E: Into a solution of 21 (3.0 g, 8.5 mmol) in anhydrous
chloroform was bubbled Cl2 at –10 °C for 30 min. After the temꢀ
perature was not rising, Cl2 was bubbled into the solution for
another 10 min followed by purging with nitrogen gas. After
removing the solvent, the white residue was filtered and washed
well with dry hexane and suspended in 20 ml dry THF. To the
mixture was added a solution of methylmagnesium chloride (11.5
mL, 3 M in THF, 34.5 mmol) at –10 °C. The reaction mixture was
stirred for another 10 min and then quenched with iceꢀwater folꢀ
lowed by addition of conc. HCl to adjust pH 1. The acidic mixture
was washed three times with diethyl ether, basified with NaOH to
pH 14, and extracted four times with diethyl ether. The organic
phases of the alkaline extraction were collected, dried over
MgSO4, and the solvent was removed by distillation with a 25 cm
1
yield. H NMR (400 MHz, CDCl3): δ = 1.25 (s, 12H, ꢀC(CH3)2),
5.68 (s, 2H, ꢀCH). 13C NMR (100.6 MHz, CDCl3): δ = 26.2 (q, ꢀ
C(CH3)2), 71.4 (s, ꢀC(CH3)2), 134.6 (d, =CHꢀ). HRMS m/z calcd
for C8H16N (M–Cl+2H)+ 126.1277; found 126.1289.
NꢀChloroꢀdiꢀtertꢀamylamine. The product (5.3 g) was syntheꢀ
sized by general procedure59 by using di(tertꢀamyl)amine47 and
1
was obtained as a colorless oil (83% yield). H NMR (400 MHz,
tolueneꢀd8): δ = 0.96 (t, 3JHH = 8 Hz, 6H, ꢀCH2CH3), 1.15 (s, 12H,
3
ꢀC(CH3)2), 1.56 (q, JHH = 8 Hz, 4H, ꢀCH2CH3). 13C NMR (100.6
MHz, C6D6): δ = 8.4 (q, ꢀCH2CH3), 27.4 (q, ꢀC(CH3)2), 38.4 (t,
CH2CH3), 66.2 (s, CN). HRMS m/z calcd for C10H24N (M–
Cl+2H)+ 158.1903; found 158.1887.
NꢀtertꢀButylꢀNꢀchloroꢀtertꢀoctylamine. The product was preꢀ
pared analogously to the general procedure59 from Nꢀtertꢀbutylꢀ
tertꢀoctylamine48 as a yellow oil (1.88 g, 8.6 mmol, 70% yield).
1H NMR (400 MHz, CDCl3): δ (ppm) = 1.03 (s, 9H, (CH3)3ꢀCꢀ
CH2), 1.37 (s, 9H, (CH3)3ꢀCꢀN), 1.41 (s, 6H, (CH3)2ꢀCꢀN), 1.66 (s,
2H, (CH2)ꢀCꢀN). 13C NMR (100.6 MHz, CDCl3): δ (ppm) = 30.6
(q, (CH3)2ꢀCꢀN), 31.4 (q, (CH3)3ꢀCꢀN), 31.7 (q, (CH3)3ꢀCꢀCH2),
31.8 (s, (CH3)3ꢀCꢀCH2), 53.9 (t,ꢀCH2ꢀ), 65.1 (s, (CH3)3ꢀCꢀN), 69.3
(s, CH2ꢀCꢀN). HRMS m/z calcd for C12H28N (M–Cl+2H)+
186.2216; found 186.2212.
N,NꢀDi(1ꢀadamantyl)ꢀNꢀchloroꢀamine. The product was
prepared analogously to the general procedure59 from di(1ꢀ
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The Journal of Organic Chemistry
Vigreux column. The residue was then recondensed at room
The reaction mixture was stirred at –78 °C for 2 h. The reaction
was quenched with saturated solution of ammonium chloride (20
mL).
temperature into a liquid nitrogen trap to afford the crude product.
Method F: To a solution of a tertiary amine (2.48 mmol) in 2 mL
Et2O was added Br2/Cl2/I2 (9.8 mmol) in 15 mL Et2O at 0 °C.
After stirring for 1 h at 25 °C, the mixture was decanted and the
black precipitate was washed ten times with Et2O. The black
residue was suspended in dry THF (10 mL). To the mixture was
added a solution of methylmagnesium bromide (10 mL, 3 M in
Et2O, 30 mmol) at – 5 °C. The reaction mixture was stirred at
room temperature for 30 min, and then quenched with iceꢀwater
followed by addition of conc. HCl to adjust pH 1. The acidic
mixture was washed three times with diethyl ether, then conc.
NaOH was added to get pH 14. The alkaline solution was extractꢀ
ed four times with diethyl ether. The organic phases were collectꢀ
ed, dried over MgSO4, and the solvent was removed by distillaꢀ
tion with a 25 cm column. The remaining part of solvent was
removed under vacuum (250 mbar). The residue was recondensed
at 0.05 mbar and then further purificated by preparative gas chroꢀ
matography to afford the desired product.
Method G: The formamide (6.9 mmol) was dissolved in toluene
(20 mL) under nitrogen atmosphere. At −78 °C oxalyl chloride
(10.5 mmol) or MeOTf (7 mmol) was added and the mixture was
warmed to room temperature and stirred for two hours. All volaꢀ
tiles were removed in vacuo and the residue was washed with dry
Et2O. THF or Et2O was added again, the suspension was cooled to
−78 °C and MeMgBr (35 mmol, 11.6 mL, 3 M in Et2O) or
MeMgCl (35 mmol, 11.6 mL, 3 M in Et2O) was added. The reacꢀ
tion mixture was stirred overnight at r.t. and quenched with iceꢀ
cold water, extracted with Et2O and dried over K2CO3. The solꢀ
vent was distilled off and the product was purified by condensaꢀ
tion at 4 mbar to gain the desired compound.
Method H (electrophilic amination): A twoꢀneckꢀround bottom
flask (50 mL) was equipped with a magnetic stirring bar and gas
inlet valve. The whole system was flameꢀdried under vacuum
followed by purging with nitrogen. Under nitrogen, Nꢀchloroꢀ
amine (1.00 mmol) was added to a solution of isopropylmagnesiꢀ
um chloride (0.75 mL, 2 M in THF, 1.5 mmol) and TMEDA (3.00
g, 26.0 mmol) in diethyl ether (10 mL) at 0 °C. The reaction
mixture was stirred at room temperature for 3 h. The reaction was
quenched with water (10 mL) and extracted with nꢀpentane (3 x
25 mL). The organic layer was washed with water (2 x 20 mL),
dried over potassium carbonate, and the solvent was evaporated.
Method I: The reaction was carried out for the preparation of
tertiary amines by using N,Nꢀdichloroꢀamine (2.28 mmol),
TMEDA (3.00 g, 26.20 mmol), and isopropylmagnesium chloride
(2.85 mL, 2 M in THF, 5.70 mmol) in diethyl ether (10 mL) at 0
°C. The reaction mixture was stirred at room temperature for 3 h.
The reaction was quenched with water (10 mL) and extracted with
nꢀpentane (3 x 25 mL). The organic layer was washed with water
(2 x 20 mL), dried over potassium carbonate, and the solvent was
evaporated.
Method J (General SN1 protocol between imines and 1ꢀAdOTf): A
twoꢀneckꢀround bottom flask (50 mL) was equipped with a magꢀ
netic stirring bar and gas inlet valve. The whole system was
flameꢀdried under vacuum followed by purging with nitrogen.
Under nitrogen and dark, silver trifluoromethanesulfonate
(AgOTf, 0.30 g, 1.16 mmol) and 1ꢀbromoadamantane (45, 0.25 g,
1.16 mmol) were dissolved in dry methylene chloride (20 mL) at
0 °C. The reaction mixture was stirred at 0 °C for at least 4 h.
Anhydrous potassium carbonate (0.60 g, 5.79 mmol) was added
followed by the addition of imine (1.16 mmol), and the reaction
mixture was stirred at 0 °C for 4 h under dark. The reaction mixꢀ
ture was cooled to –78 °C followed by the dropwise addition of
methyllithium (0.75 mL, 3.10 M in diethoxymethane, 2.32 mmol).
1
2
3
4
5
6
7
8
N,NꢀDiisopropylꢀtertꢀbutylamine (9).
Method H: Using NꢀchloroꢀNꢀisopropylꢀtertꢀbutylamine54 (27,
0.50 g, 3.34 mmol) and isopropylmagnesium chloride (3.3 mL,
2.0 M in THF, 6.8 mmol). The crude product was recondensed at
25 °C and 0.05 mbar to yield a mixture of compound 9 (0.25 g,
46% yield) and the side product 18 (0.05 g, 14% yield) as colorꢀ
less liquid.
Method H: Using NꢀchloroꢀN,Nꢀdiisopropylamine55,56 (28, 0.5 g,
3.7 mmol), TMEDA (5.0 g, 43.1 mmol), and tertꢀbutylmagnesium
chloride (4.3 mL, 1.7 M in diethyl ether, 7.4 mmol). The crude
product was recondensed at 25 °C and 0.05 mbar to yield a mixꢀ
ture of compound 9 (70.0 mg, 11% yield) and the side product 20
(30.0 mg, 9% yield) as a colorless liquid.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Method E: The crude product contains a proportion of 9 (0.126 g,
4.7%, calculated by 1H NMR).
Method F: Using iodine and then MeMgBr (3 M in Et2O), the
product (978 mg) was isolated by preparative GC in 21% yield.
Method G: From 25 using oxalyl chloride and MeMgBr (3 M in
Et2O) and isolation of 9 (3.51 g) by distillation in 62% yield or
with MeOTf and MeMgCl (3M in Et2O) in 23% yield (250 mg).
Method I: From 29 using iPrMgCl (2 M in THF), the product 9
(250 mg) was isolated in 4% yield.
3
1H NMR (400 MHz, tolueneꢀd8): δ = 1.08 (d, J = 6 Hz, 12H,
CH(CH3)2), 1.12 (s, 9H, C(CH3)3), 3.15 (sept, 3J = 6 Hz, 2H,
CH(CH3)2). 1H NMR (400 MHz, CDCl3): δ = 1.11 (d, 3J =6.9 Hz,
3
12H, CH(CH3)2), 1.16 (s, 9H, C(CH3)3), 3.26 (sept, J = 6.9 Hz,
2H, CH(CH3)2). 13C NMR (100.6 MHz, CDCl3): δ = 24.6 (q,
CH(CH3)2), 31.00 (q, C(CH3)3), 46.3 (d, CH(CH3)2), 55.9 (s,
C(CH3)3). 13C NMR (100.6 MHz, C6D6): δ = 24.4 (q, CH(CH3)2),
30.8 (q, C(CH3)3), 46.2 (d, CH(CH3)2), 58.0 (s, C(CH3)3). HRMS:
m/z calcd for C10H23N (M+H+) 158.1903; found 158.1894.
N,NꢀDi(tertꢀbutyl)isopropylamine (10). Method H: The prodꢀ
uct was prepared by using Nꢀchloroꢀdi(tertꢀbutyl)amine55,59 (31,
0.50 g, 3.07 mmol), TMEDA (5.0 g, 43.11 mmol), and isoꢀ
propylmagnesium chloride (3.1 mL, 2.0 M in THF, 6.1 mmol).
The crude product was recondensed at 25 °C and 0.05 mbar to
yield a mixture of 10 (0.17 g, 32% yield) and diꢀtertꢀbutylamine
as side product (0.06 g, 16% yield) as colorless liquid.
Product 10 was also synthesized via Method H using NꢀchloroꢀNꢀ
isopropylꢀtertꢀbutylamine (27) and tꢀBuMgCl with 1% yield and
from 30 and MeMgBr through Method G (without forming an
iminium salt) with 4% yield.
1H NMR (400 MHz, tolueneꢀd8): δ = 1.20 (s, 9H, ꢀC(CH3)3), 1.24
3
(d, JH,H = 7.0 Hz, 6H, ꢀCH(CH3)2), 1.31 (s, 9H, ꢀC(CH3)3), 3.37
(sept, 3JH,H = 7.0 Hz, ꢀCH(CH3)2. 13C NMR (100.6 MHz, tolueneꢀ
d8): δ = 26.2 (q, ꢀCH(CH3)2), 32.6 (q, ꢀC(CH3)3), 34.6 (q, ꢀ
C(CH3)3), 48.7 (d, ꢀCH(CH3)2), 57.2 (s, ꢀC(CH3)3), 58.8 (s, ꢀ
C(CH3)3). HRMS: m/z calcd for C11H26N (M + H+) 172.2060;
found 172.2068.
NꢀIsopropylꢀ2,2,5,5ꢀtetramethylpyrrolidine (12). Method G:
The product was synthesised using 1ꢀformylꢀ2,2,5,5ꢀ
tetramethylpyrrolidine53, (COCl)2, and then MeMgBr (3 M in
Et2O), and isolated by removing of solvents as yellowish oil in
38% yield.
1H NMR (400 MHz, CDCl3): δ = 1.12 (s, 12H, CꢀCH3), 1.15 (d,
3
3J = 7.0 Hz, 6H, CHꢀCH3), 1.58 (s, 4H, CH2), 3.20 (sept, J = 7.0
Hz, CHꢀCH3). 13C NMR (100.6 MHz, CDCl3): δ = 26.0 (q, CHꢀ
CH3), 30.2 (q, CꢀCH3), 40.1 (t, CH2), 44.7 (d, CH), 61.6 (s,
CꢀCH3). HRMS: m/z calcd for C11H24N 170.1903; found
170.1903.
NꢀtertꢀButylꢀ2,2,5,5ꢀtetramethylpyrrolidine (13).
7
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Method F: From 12 and I2, then MeMgBr, preparative gas chroꢀ
0.65 mmol), and 1ꢀbromoadamantane (0.14 g, 0.65 mmol). After
matography afforded 13 (31 mg, 0.17 mmol, 6.9 %) as a white
solid; m.p. = 86 °C.
acid/base extraction, the crude product was subjected to column
chromatography (or thick layer chromatography) by using basic
aluminum oxide and nꢀhexane as solvent. The least polar fraction
was collected, and the solvent was removed under vacuum to
yield the desired product 35 as white solid (0.14 g, 68% yield);
m.p. = 117–118 °C (soften at 110°C).
1
2
3
4
5
6
7
8
Method
H:
Synthesized
from
1ꢀchloroꢀ2,2,5,5ꢀ
tetramethylpyrrolidine using tꢀBuMgBr (3 M in Et2O) and isolatꢀ
ed as white solid in 4% yield.
1H NMR (400 MHz, tolueneꢀd8): δ = 1.26 (s, 12H, CH3), 1.28 (s,
9H, CH3), 1.54 (s, 4H, CH2). 13C NMR (100.6 MHz, tolueneꢀd8):
δ = 32.6 (q, CH3), 34.0 (q, CH3), 42.7 (t, CH2), 54.7 (s), 63.7 (s).
HRMS m/z calcd for C12H26N (M+H+) 184.2060; found 184.2058.
NꢀIsopropylꢀ2,2,6,6ꢀtetramethylpiperidine (14). Method G:
The product (3.66 g) was synthesized using 1ꢀformylꢀ2,2,6,6ꢀ
tetramethylpiperidine,52 (COCl)2, and then MeMgBr (3 M in
Et2O), and isolated by recondensation as colorless oil in 36%
yield.
Method Dꢀ2: The reaction was carried out using 1,1,3,3ꢀ
tetramethylisoindoline (0.20 g, 1.14 mmol), TMSOTf (0.17 g,
0.76 mmol), and 1ꢀadamantyl mesylate38 (44b, 0.18 g, 0.76
mmol). After acid/base extraction, the crude product was subjectꢀ
ed to column chromatography (or thick layer chromatography) by
using basic aluminum oxide as the stationary phase and nꢀhexane
as the mobile phase. The least polar fraction was collected, and
the solvent was removed under vacuum to yield the desired prodꢀ
uct 35 as white solid (0.12 g, 51% yield).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (400 MHz, CDCl3): δ = 1.17 (s, 12H, C–CH3), 1.21 (d,
3J = 7.2 Hz, 6H, CH–CH3), 1.37 (m, 4H, 3–H and 5–H), 1.5 (m,
1H NMR (400 MHz, C6D6): δ = 1.58–1.68 (m, 18H), 1.98–2.05
(m, 3H), 2.15–2.21 (m, 6H), 6.92–6.97 (m, 2H), 7.11–7.15 (m,
2H). 13C NMR (100 MHz, C6D6): δ = 30.6 (d, CH), 34.8 (q, CH3),
36.7 (t, CH2), 44.8 (t, CH2), 57.3 (s, C), 67.0 (s, C), 120.9 (d, CH),
126.5 (d, CH), 148.7 (s, C). HRMS m/z calcd for C22H32N
(M+H+) 310.2529; found 310.2529.
3
2H, 4–H), 3.46 (sept, J = 7.2 Hz, 1H, N–CH). 13C NMR (100.6
MHz, CDCl3): δ = 18.0 (t, C–4), 26.5 (q, CH–CH3), 30.0 (q, C–
CH3), 44.4 (br. d, N–CH), 47.1 (t, C–3 and C–5), 55.1 (s, C–2 and
C–6). HRMS: m/z calcd for C12H25N (M+H+) 184.2060; found
184.2074.
1ꢀ(1ꢀAdamantyl)ꢀ2,2,5,5ꢀtetramethylpyrrolidine (32).
2ꢀ(1ꢀAdamantyl)ꢀ1,1,3,3ꢀtetraethylisoindoline (36).
Method Dꢀ1: The reaction was carried out using 2,2,5,5ꢀ
tetramethylpyrrolidine43 (0.08 g, 0.65 mmol), AgOTf (0.17 g,
0.65 mmol), and 1ꢀbromoadamantane (0.14 g, 0.65 mmol). Furꢀ
ther purification was achieved by washing with MeOH. The deꢀ
sired product (32) was collected as white solid (0.11 g, 65%
yield); m.p. = 92–93 °C.
Method Dꢀ2: The reaction was carried out using 2,2,5,5ꢀ
tetramethylpyrrolidine (0.20 g, 1.57 mmol), TMSOTf (0.23 g,
1.05 mmol), and 1ꢀadamantyl mesylate38 (44b, 0.24 g, 1.05
mmol). After acid base/extraction, further purification was done
by washing with MeOH. The desired product (32) was collected
as white solid (0.13 g, 48% yield).
Method Dꢀ1: The reaction was carried using 1,1,3,3ꢀ
tetraethylisoindoline45 (0.15 g, 0.65 mmol), AgOTf (0.17 g, 0.65
mmol), and 1ꢀbromoadamantane (0.14 g, 0.65 mmol). After acꢀ
id/base extraction, the crude product was subjected to column
chromatography (or thick layer chromatography) by using basic
aluminum oxide as the stationary phase and nꢀhexane as the moꢀ
bile phase. The least polar fraction was collected, and the solvent
was removed under vacuum to yield the desired product 36 as
white solid (42.7 mg, 18% yield); m.p. = 126–128 °C.
Method Dꢀ2: The reaction was carried out using 1,1,3,3ꢀ
tetraethylisoindoline (0.20 g, 0.86 mmol), TMSOTf (0.13 g,
0.57 mmol), and 1ꢀadamantyl mesylate38 (44b, 0.13 g, 0.57
mmol). After acid/base extraction, the crude product was subjectꢀ
ed to column chromatography (or thick layer chromatography) by
using basic aluminum oxide as the stationary phase and nꢀhexane
as the mobile phase. The least polar fraction was collected, and
the solvent was removed under vacuum to yield the desired prodꢀ
uct 36 as white solid (25.3 mg, 12% yield).
1H NMR (400 MHz, C6D6): δ = 1.29 (s, 12H, CH3), 1.51 (s, 4H,
CH2CH2), 1.52–1.58 (m, 6H), 1.93–2.01 (m, 9H). 13C NMR
(100.6 MHz, C6D6): δ = 30.5 (q, CH3), 33.2 (d, CH), 36.8 (t,
CH2), 42.7 (t, CH2), 44.9 (t, CH2), 56.6 (s, C), 63.3 (s, C). HRMS
m/z calcd for C18H32N (M+H+) 262.2529; found 262.2531.
Nꢀ(tertꢀButyl)ꢀ2,2,5,5ꢀtetramethylpyrroline (33). Method H:
The product was synthesised using tꢀBuMgCl (3 M in Et2O) and
1ꢀchloroꢀ2,2,5,5ꢀtetramethylpyrroline, and isolated by removing
the solvents in vacuum followed by purification by preparative
gas chromatography to get a colorless oil in 8% yield.
1H NMR (400 MHz, C6D6): δ = 0.89 (t, 3J = 7.6 Hz, 12H,
CH2CH3), 1.56–1.69 (m, 6H), 1.99–2.16 (m, 11H), 2.25–2.30 (m,
6H), 6.86–6.91 (m, 2H), 7.09–7.13 (m, 2H). 13C NMR (100.6
MHz, C6D6): δ = 10.9 (q, CH2CH3), 30.6 (d, CH), 36.2 (t, CH2),
36.7 (t, CH2), 43.8 (t, CH2), 58.6 (s, C), 74.6 (s, C), 121.9 (d, CH),
125.7 (d, CH), 145.1 (s, C). Anal. Calcd for C26H39N (365.30): C,
85.42; H, 10.75; N, 3.83; found: C, 85.02; H, 10.66; N, 3.80.
Nꢀ(tertꢀButyl)ꢀNꢀisopropylꢀtertꢀamylamine (37a).
1H NMR (400 MHz, tolueneꢀd8): δ = 1.31 (s, 9H, CH3), 1.34 (s,
12H, CH3), 5.11 (s, 2H, CH). 13C NMR (100.6 MHz, tolueneꢀd8):
δ = 32.1 (q, CH3), 33.7 (q, CH3), 54.7 (s), 69.5 (s), 135.9 (d, CH).
HRMS m/z calcd. for C12H24N (M+H+) m/z 182.1903; found
182.1903.
Method H: The product was prepared using Nꢀ(tertꢀbutyl)ꢀNꢀ
chloroꢀtertꢀamylamine55 (0.50 g, 2.82 mmol), TMEDA (5.0 g,
43.11 mmol), and isopropylmagnesium chloride (2.82 mL, 2.0 M
in THF, 5.6 mmol). The crude product was recondensed at 25 °C
and 0.05 mbar to yield a mixture of 37a (0.14 g, 26% yield) and
Nꢀ(tertꢀbutyl)ꢀtertꢀamylamine as side product (0.16 g, 41% yield)
as colorless liquid.
1ꢀ(1ꢀAdamantyl)ꢀ2,2,5,5ꢀtetramethylꢀ2,5ꢀdihydroꢀ1Hꢀpyrrole
(34). Method Dꢀ1: The reaction was carried out using 2,2,5,5ꢀ
tetramethylꢀ2,5ꢀdihydroꢀ1Hꢀpyrrole44 (0.08 g, 0.65 mmol),
AgOTf (0.17 g, 0.65 mmol), and 1ꢀbromoadamantane (0.14 g,
0.65 mmol). After acid/base extraction, the desired product 34
was obtained as thick oil (25.3 mg, 15% yield).
1H NMR (400 MHz, C6D6): δ = 1.42 (s, 12H, CH3), 1.60–1.63 (m,
6H), 1.99–2.03 (m, 3H), 2.07–2.10 (m, 6H), 5.14 (s, 2H). 13C
NMR (100.6 MHz, C6D6): δ = 30.2 (q, CH3), 32.5 (d, CH), 36.9
(t, CH2), 44.8 (t, CH2), 57.0 (s, C), 69.0 (s, C), 135.7 (d, CH).
HRMS m/z calcd for C18H30N (M+H+) 260.2373; found 260.2373.
2ꢀ(1ꢀAdamantyl)ꢀ1,1,3,3ꢀtetramethylisoindoline (35).
1H NMR (400 MHz, tolueneꢀd8): δ = 0.94 (t, J = 7.3 Hz, 3H,
3
CH3ꢀCH2 ), 1.15 (s (3H, C(CH3)2), 1.18 (s, 4.5H, C(CH3)3,), 1.23
(d, 3J = 7.1 Hz, 3H, CH3ꢀCH), 1.24 (d (overlapped, 3H, CH3ꢀCH),
1.24 (s, C(CH3)2, overlapped), 1.30 (s,
, 4.5H, C(CH3)3,
overlapped), 1.32 (q, 3J = 7.3 Hz, 1H, CH2, overlapped), 1.50 (q ,
3
3J = 7.3 Hz, 1H, CH2), 3.27 (sept, J = 7.1 Hz, CH3ꢀCH, 0.5H),
3
Method Dꢀ1: The reaction was carried out using 1,1,3,3ꢀ
3.37 (sept, J = 7.1 Hz, CH3ꢀCH, 0.5H). 13CꢀNMR (100.6 MHz,
tetramethylisoindoline45 (0.11 g, 0.65 mmol), AgOTf (0.17 g,
tolueneꢀd8): δ = 9.5 (q, CH2CH3), 9.6 (q, CH2CH3), 26.2 (q), 26.3
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The Journal of Organic Chemistry
(q), 29.6 (q), 30.9 (q), 32.1 (q), 34.7 (q), 36.9 (t), 38.4 (t), 47.9 (d),
ed, and the solvent was removed under vacuum to yield the deꢀ
sired product 39 as yellowish oil (64 mg, 12% yield).
48.3 (d), 56.9 (s), 58.5 (s), 60.1 (s), 61.2 (s). HRMS m/z calcd for
1
2
3
4
5
6
7
8
C12H28N (M+H+) 186.2216; found 186.2217.
Method H: Nꢀchloroꢀdiisopropylamine55,56 (28, 0.50 g, 3.70
mmol), TMEDA (3.00 g, 26.20 mmol), and 1ꢀ
adamantylmagnesium bromide (11.11 mL, 0.5 M in diethyl ether,
5.55 mmol) were used for the preparation. The crude product was
dissolved in ether, and HCl(g) was bubbled inside the solution for
20 seconds. The formed amine hydrochloride salts were filtered
and washed well with ether. The salt was dissolved in dichloroꢀ
methane, and a cold saturated solution of sodium bicarbonate, or
NaOH (5%), was added slowly. The neutralized mixture was
transferred to a separatory funnel and extracted using dichloroꢀ
methane and water. The organic phase was collected, dried over
K2CO3, and the solvent was removed under vacuum to yield the
desired product 39 as yellowish oil (60.9 mg, 7% yield).
NꢀIsopropylꢀdi(tertꢀamyl)amine (37b). Method H: The reacꢀ
tion was carried out using Nꢀchloroꢀdi(tertꢀamyl)amine (0.5 g, 2.6
mmol), TMEDA (5.0 g, 43.1 mmol), and isopropylmagnesium
chloride (2.5 mL, 2.0 M in THF, 5.0 mmol). The crude product
was subjected to recondensation method via liquid nitrogen trap.
The side product diꢀtertꢀpentylamine was collected first at 60 °C
and 10 mbar for a period of 4 h, and the desired product 37b was
collected at 60 °C and 1 mbar as pure colorless oil (0.1 g, 19%
yield); m.p. = 6–7 °C.
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10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1H NMR (400 MHz, tolueneꢀd8): δ = 0.90 (t, 3J = 8 Hz, 3H,
CH2CH3), 0.92 (t, 3J = 8 Hz, 3H, CH2CH3), 1.13 (s, 6H, C(CH3)2),
1.22 (d, 3J = 8 Hz, 6H, CH(CH3)2), 1.24 (s, 6H, C(CH3)2), 1.40 (q,
3
3J = 8 Hz, 2H, CH2CH3), 1.57 (q, J = 8 Hz, 2H, CH2CH3), 3.29
Method Dꢀ3: Using diisopropylamine (20, 0.20 g, 1.98 mmol),
TMSOTf (0.29 g, 1.32 mmol), and 1ꢀadamantyl acetate37 (44a)
(0.26 g, 1.32 mmol). After the acid/base extraction, the desired
product 39 was collected as yellowish oil (0.20 g, 66% yield).
1H NMR (400 MHz, C6D6): δ = 1.17 (d, 3J = 8 Hz, 12H,
CH(CH3)2), 1.59 (bs, 6H, CH2), 1.82 (bs, 6H, CH2), 1.99 (bs, 3H,
CH), 3.27 (sept, 3J = 8 Hz, 2H, CH(CH3)2). 13C NMR (100.6
MHz, C6D6): δ = 25.5 (q, CH(CH3)2), 30.5 (d, CH), 37.2 (t, CH2),
43.4 (t, CH2), 45.4 (d, CH(CH3)2), 56.9 (s, C). HRMS m/z calcd
for C16H30N (M+H+) 236.2373; found 236.2378.
(sept, 3J = 8 Hz, 1H, CH(CH3)2). 13C NMR (100.6 MHz, CDCl3):
δ = 9.6 (q, CH2CH3), 10.0 (q, CH2CH3), 26.6 (q, CH(CH3)2), 29.0
(q, C(CH3)2), 31.6 (q, C(CH3)2), 37.2 (t, CH2), 37.7 (t, CH2), 47.6
(d, CH(CH3)2), 60.2 (s, C(CH3)2), 61.4 (s, C(CH3)2). HRMS: m/z
calcd for C13H30N (M+H+) 200.2373; found 200.2385.
NꢀtertꢀButylꢀNꢀethylꢀtertꢀoctylamine (38a). Method H: The
product was synthesised using NꢀtertꢀbutylꢀNꢀchloroꢀtertꢀ
octylamine and EtMgBr (3 M in Et2O), and isolated by column
chromatography (basic Al2O3, hexane:Et2O = 1:1) as a colorless
liquid (43% yield).
N,NꢀDi(1ꢀadamantyl)isopropylamine (40a). Method H: The
reaction was carried using Nꢀchloroꢀdi(1ꢀadamantyl)amine (0.3 g,
1.0 mmol), TMEDA (3.0 g, 26.2 mmol), and isopropylmagnesium
chloride (1 mL, 2 M in THF, 2.0 mmol). The crude product was
dissolved in MeOH (20 mL), heated at 50 °C, and the product
filtered off while hot. The desired product 40a was collected as
pure white solid (92.0 mg, 30% yield). m.p. = 160–162 °C.
1H NMR (400 MHz, C6D6): δ = 1.42 (d, 3J = 6 Hz, 6H,
CH(CH3)2), 1.56–1.69 (m, 12H), 2.02 (bs, 6H), 2.07 (bs, 6H),
1HꢀNMR (400 MHz, CDCl3): δ = 0.99 (s, 9H, (CH3)3ꢀCꢀCH2),
1.04 (t, 3J = 7.0 Hz, 3H, CH3ꢀCH2ꢀN) , 1.20 (s, 9H, (CH3)3ꢀCꢀN),
3
1.29 (s, 6H, (CH3)2ꢀ CꢀN), 1.55 (s, 2H, CH2ꢀCꢀN), 2.60 (q, J =
7.0 Hz, 2H, CH3ꢀCH2ꢀN). 13CꢀNMR (100.6 MHz, CDCl3): δ =
21.6 (q, NꢀCH2ꢀCH3), 31.6 (s, (CH3)3ꢀCꢀCH2), 32.1 (q, tBu), 32.2
(q, tBu), 32.6 (q, (CH3)2ꢀCꢀN), 40.9 (t, NꢀCH2ꢀCH3), 52.8 (t, CH2ꢀ
CꢀN), 57.8 (s, (CH3)3ꢀCꢀN), 62.5 (s, (CH3)2ꢀCꢀN). HRMS: m/z
calcd for C14H32N (M+H+) 214.2529; found: 214.2513.
3
NꢀtertꢀButylꢀNꢀisopropylꢀtertꢀoctylamine (38b). Method H:
The product was prepared using iꢀPrMgCl (2 M in THF) and Nꢀ
tertꢀbutylꢀNꢀchloroꢀtertꢀoctylamine, and then removing all volaꢀ
tiles at 0 °C and 10−2 mbar to get a colorless liquid (15% NMRꢀ
yield). The product is highly unstable and cannot be isolated.
1HꢀNMR (400 MHz, tolueneꢀd8, synꢀrotamer): δ = 1.00 (s, 9H, Cꢀ
tꢀBu), 1.24 (s, 9H, NꢀtꢀBu), 1.28 (d, 3J = 7.1 Hz, 6H, iPr), 1.40 (s,
6H, CH2CMe2), 1.83 (s, 2H, CH2), 3.39 (sept, 1H, 3J = 7.1 Hz, Nꢀ
2.22 (bs, 6H), 3.61 (sept, J = 6 Hz, 1H, CH(CH3)2). 13C NMR
(100.6 MHz, C6D6): δ = 28.2 (q, CH(CH3)2), 31.2 (d, CH), 31.3
(d, CH), 37.2 (t, CH2), 37.3 (t, CH2), 45.3 (t, CH2), 45.4 (t, CH2),
46.4 (d, CH(CH3)2), 60.3 (s, C), 62.0 (s, C). Anal. Calcd. for
C23H37N (327.29): C, 84.34; H, 11.39; N, 4.28; found: C, 84.02;
H, 11.31; N, 4.30.
N,NꢀDi(1ꢀadamantyl)cyclohexanamine (40b). Method H: The
reaction was carried out using Nꢀchloroꢀdi(1ꢀadamantyl)amine
(0.32 g, 1.00 mmol), TMEDA (3.00 g, 26.20 mmol), and cycloꢀ
hexylmagnesium chloride (0.75 mL, 2 M in diethyl ether, 1.50
mmol). The crude product was added to MeOH (30 mL), heated at
50 °C, and the product filtered off while hot. The desired product
40b was collected as pure white solid (0.09 g, 25% yield); m.p. =
201–202 °C.
1
CH). HꢀNMR (400 MHz, tolueneꢀd8, anti rotamer): δ = 1.01 (s,
9H, CꢀtꢀBu), 1.27 (d, 3J = 7.1 Hz, 6H, iPr), 1.31 (s, 6H,
CH2CMe2), 1.32 (s, 9H, NꢀtꢀBu), 1.59 (s, 2H, CH2), 3.42 (sept,
1H, 3J = 7.1 Hz, NꢀCH). 13CꢀNMR (100.6 MHz, tolueneꢀd8,
syn/antiꢀrotamer): δ = 26.6 (q, iPr), 26.7 (q, iPr), 31.8 (s,
CH2CMe2), 31.9 (q, CH2CMe2), 32.1 (s, CꢀtꢀBu), 32.4 (q, CꢀtꢀBu),
32.5 (q, CꢀtꢀBu), 32.9 (q, NꢀtꢀBu), 34.9 (q, NꢀtꢀBu), 35.0 (q,
CH2CMe2), 48.6 (d, NꢀCH), 48.9 (d, NꢀCH), 54.5 (t, CH2), 55.9 (t,
CH2), 57.6 (s, NꢀtꢀBu), 59.0 (s, NꢀtꢀBu), 62.4 (s, CH2CMe2), 63.7
(s, CH2CMe2). 15NꢀNMR (40.6MHz, tolueneꢀd8, syn rotamer): δ =
_299.1. 15NꢀNMR (40.6MHz, tolueneꢀd8, anti rotamer): δ =
_302.4.
1H NMR (400 MHz, C6D6): δ = 1.00–1.13 (m, 1H), 1.25–1.38 (m,
2H), 1.55–1.81 (m, 15H), 1.85–2.08 (m, 10H), 2.10 (bs, 6H), 2.21
(bs, 6H), 3.02 (tt, 3J1 = 11.6 Hz, 3J2 = 2.8 Hz, 1H, CH). 13C NMR
(100.6 MHz, C6D6): δ = 26.6 (t, CH2), 28.6 (t, CH2), 30.7 (d, CH),
30.9 (d, CH), 36.8 (t, CH2), 36.9 (t, CH2), 38.8 (t, CH2), 45.1 (t,
CH2), 45.6 (t, CH2), 58.0 (d, CH), 59.5 (s, C), 61.7 (s, C). HRMS:
m/z calcd for C26H42N (M+H+) 368.3312; found 368.3306.
N,NꢀDi(1ꢀadamantyl)ꢀexoꢀ2ꢀnorbornylamine (40c). Method
H: The reaction was carried out using Nꢀchloroꢀdi(1ꢀ
adamantyl)amine (0.32 g, 1.00 mmol), TMEDA (3.00 g,
26.20 mmol), and 2ꢀnorbornylmagnesium bromide33 (1.50 mL, 1
M in diethyl ether, 1.50 mmol). The crude product was added to
MeOH (30 mL), heated at 50 °C, and the product filtered off
while hot. The desired product 40c was collected as pure white
solid (60.8 mg, 16% yield); m.p. = 225–226 °C.
N,NꢀDiisopropyladamantanꢀ1ꢀamine (39).
Method I: Using N,Nꢀdichloroꢀadamantanꢀ1ꢀamine58 (0.50 g, 2.28
mmol), TMEDA (3.00 g, 26.20 mmol), and isopropylmagnesium
chloride (2.85 mL, 2 M in THF, 5.70 mmol), the crude product
was added to MeOH (15 mL) and stirred for 5 min at 40 °C. The
side product 1,2ꢀdi(adamantanꢀ1ꢀyl)diazene was removed as white
solid by filtration (35% yield). The mother liquor was collected,
concentrated under vacuum, and purified over column chromatogꢀ
raphy using basic aluminum oxide as the stationary phase and nꢀ
hexane as the mobile phase. The least polar fraction was collectꢀ
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1H NMR (400 MHz, C6D6): δ = 1.12 (d, 3J = 9.5 Hz, 1H), 1.17–
(s, C). HRMS m/z calcd for C17H32N (M+H+) 250.2529; found
250.2506.
Nꢀ(tertꢀButyl)ꢀNꢀ(propꢀ1ꢀenꢀ2ꢀyl)adamantanꢀ1ꢀamine
1.24 (m, 1H), 1.40–1.48 (m, 1H), 1.53–1.68 (m, 15H), 1.97–2.27
(m, 22H), 3.26 (t, 3J = 9.5 Hz, 1H, CHN). 13C NMR (100.6 MHz,
C6D6): δ = 27.5, 30.1, 30.8, 33.5, 36.7, 36.8, 38.3, 44.9, 45.4,
45.6, 45.7, 46.7, 58.7 (s, C), 59.7 (d, CH), 61.2 (s, C). Anal.
Calcd. for C27H41N (379.32): C, 85.42; H, 10.89; N, 3.69; found:
C, 85.35; H, 10.81; N, 3.62.
1
2
3
4
5
6
7
8
(49).
Method J: The reaction was carried out using Nꢀ(tertꢀ
butyl)propanꢀ2ꢀimine40 (48, 0.74 g, 6.53 mmol), 1ꢀ
bromoadamantane (45, 1.41 g, 6.53 mmol), AgOTf (1.67 g, 6.53
mmol), and methyllithium (4.21 mL, 3.10 M in diethoxymethane,
13.06 mmol). Further purification was achieved via thick layer
chromatography by using basic aluminum oxide as the stationary
phase and nꢀhexane as the mobile phase. The compound 49 was
collected as thick oil (0.37 g, 23% yield).
Nꢀ(tertꢀButyl)ꢀNꢀisopropyladamantanꢀ1ꢀamine (43).
Method H: Using Nꢀ(tertꢀbutyl)ꢀNꢀchloroadamantanꢀ1ꢀamine (42,
0.24 g, 1.00 mmol), isopropylmagnesium chloride (0.75 mL, 2 M
in THF, 1.5 mmol) and TMEDA (3.00 g, 26.0 mmol) in diethyl
ether (10 mL, the crude product, which contains the secondary
amine Nꢀtertꢀbutyladamantanꢀ1ꢀamine (37% yield), was added to
cold MeOH (5 mL) and stirred for 5 min. The desired product 43
was collected by filtration as pure white solid (59.5 mg, 24%
yield). Further purification can be achieved by dissolving in minꢀ
imum quantity of methanol at 50 °C, and left to crystalize at –20
°C; m.p. = 55–56 °C.
9
1H NMR (400 MHz, C6D6): δ = 1.36 (s, 9H, CH3), 1.55–1.58 (m,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
6H), 1.82 (s, 3H, CH3), 1.99–2.02 (m, 9H), 4.71 (d, J = 2 Hz,
1H), 5.07 (m, 1H). 13C NMR (100.6 MHz, C6D6): δ = 29.9 (q,
CH3), 30.6 (d, CH), 33.5 (q, CH3), 36.6 (t, CH2), 44.4 (t, CH2),
55.3 (s, C), 56.6 (s, C), 115.6 (d, CH2), 150.2 (s, C). HRMS m/z
calcd for C17H30N (M+H+) 248.2373; found 248.2373.
Method Dꢀ1: 1ꢀBromoadamantane (0.25 g, 1.16 mmol), silver
trifluoromethanesulfonate (AgOTf, 0.30 g, 1.16 mmol) and Nꢀ
tertꢀbutylꢀNꢀisopropylamine (18, 0.20 g, 1.74 mmol) were used.
After the reaction, the residue was dissolved in ether, and the
formed solid, if any, was filtered off. The clear ether solution was
cooled down to –10 °C, and HCl(g) was bubbled inside the soluꢀ
tion for 20 seconds. The formed amine hydrochloride salt was
filtered and washed well with diethyl ether. The salt was dissolved
in dichloromethane, cooled to –10 °C, and a cold saturated soluꢀ
tion of sodium bicarbonate, or NaOH (5%), was added slowly.
The neutralized mixture was transferred to a separatory funnel and
extracted using dichloromethane and water. The organic phase
was collected, dried over K2CO3, and the solvent was removed
under vacuum. Further purification was achieved by washing with
methanol to yield compound 43 as pure white solid (0.18 g, 63%
yield).
Method Dꢀ2: Trimethylsilyl trifluoromethanesulfonate (TMSOTf,
0.26 g, 1.17 mmol), 1ꢀadamantyl mesylate (44b, 0.27 g, 1.16
mmol), NꢀtertꢀbutylꢀNꢀisopropylamine (18, 0.20 g, 1.74 mmol)
were used in the reaction. The neutralized reaction mixture was
extracted, worked up, and purified as mentioned in method Dꢀ1 to
yield compound 43 as pure white solid (0.16 g, 54% yield).
Method Dꢀ3: Trimethylsilyl trifluoromethanesulfonate (TMSOTf,
0.26 g, 1.17 mmol), 1ꢀadamantyl acetate (44a, 0.23 g, 1.16 mmol)
and NꢀtertꢀbutylꢀNꢀisopropylamine (18, 0.20 g, 1.74 mmol) were
used in the preperation. The neutralized reaction mixture was
extracted, worked up, and purified as mentioned in method Dꢀ1 to
yield compound 43 as pure white solid (0.13 g, 46% yield).
Method J: Silver trifluoromethanesulfonate (AgOTf, 0.30 g, 1.16
mmol), 1ꢀbromoadamantane (45, 0.25 g, 1.16 mmol), Nꢀ
ethylideneꢀtertꢀbutylamine39 (46, 0.11 g, 1.16 mmol), and methylꢀ
lithium (0.75 mL, 3.10 M in diethoxymethane, 2.32 mmol) were
used to prepare the title compound. The reaction mixture was
extracted, worked up, and purified as mentioned in method Dꢀ1 to
yield compound 43 as pure white solid (0.12 g, 42% yield).
1H NMR (400 MHz, C6D6): (signals for the major rotamer where
distinguishable are marked as “*”; signals for the minor rotamer
where distinguishable are marked as “**”) δ = 1.24** (s, 1.8H,
5. ASSOCIATED CONTENT
*S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Spectroscopic data of known compounds, course of
the reaction of 38a to form 41, and IR and NMR spectra
(PDF)
6. AUTHOR INFORMATION
Corresponding Author
*klaus.banert@chemie.tu-chemnitz.de
ORCID
Klaus Banert: 0000-0003-2335-7523
Notes
The authors declare no competing financial interest.
7. ACKNOWLEDGMENTS
Generous support by the Deutsche Forschungsgemeinschaft
(BA903/17-1) is gratefully acknowledged. We thank Julia
Hänchen, Niels Klein, Pankaj Lathiya, Ioana Müller, Daniel
Schmidtke, and Alexander Voigt for performing some of the
syntheses, and Dr. Manfred Hagedorn for his assistance with
NMR measurements.
8. DEDICATION
This work is dedicated to Prof. Ernst-Ulrich Würthwein on
the occasion of his 70th birthday.
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