Novel tricyclic diamines 3. Synthesis of 1,4-diazaadamantane

Article abstract of DOI:10.1016/j.tetlet.2018.01.031

Synthesis of the previously unreported 1,4-diazaadamantane is described. The overall strategy involves complete saturation of a flat, aromatic heterocycle, appropriate functionalization and intramolecular double alkylation. The alkylation takes place via an iminophosphorane under anhydrous conditions, which produced superior results vs. alkylation of the corresponding primary amine.

Full text of DOI:10.1016/j.tetlet.2018.01.031

Accepted Manuscript
Novel tricyclic diamines 3. Synthesis of 1,4-diazaadamantane
Ivar M. McDonald, Alicia Ng
PII:
S0040-4039(18)30055-8
https://doi.org/10.1016/j.tetlet.2018.01.031
TETL 49618
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 September 2017
5 January 2018
10 January 2018
Please cite this article as: McDonald, I.M., Ng, A., Novel tricyclic diamines 3. Synthesis of 1,4-diazaadamantane,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.01.031
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Ivar M. McDonald, Alicia Ng

1
Tetrahedron Letters
Novel tricyclic diamines 3. Synthesis of 1,4-diazaadamantane
a,
b
Ivar M. McDonald  Alicia Ng
a
Bristol-Myers Squibb Drug Discovery, Wallingford, CT 06492, USA
Bristol-Myers Squibb, Drug Product Science & Technology, Princeton, NJ 08543, USA
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Synthesis of the previously unreported 1,4-diazaadamantane is described. The overall strategy
involves complete saturation of a flat, aromatic heterocycle, appropriate functionalization and
intramolecular double alkylation. The alkylation takes place via an iminophosphorane under
anhydrous conditions, which produced superior results vs. alkylation of the corresponding
primary amine.
Available online
2
017 Elsevier Ltd. All rights reserved.
Keywords:
Diazaadamantane
Tricyclic diamine
Intramolecular alkylation
iminophosphorane
—
——

Corresponding author. Tel.: +1-203-677-5658; e-mail: ivar.mcdonald@bms.com

2
Tetrahedron
We have recently described the synthesis of a series of novel
Figure 2. Isomers of diazaadamantane
1,2,3
tricyclic diamines,
each of which contained one tertiary
Unlike the examples from the previous communications (3-7,
Figure 1), 1,4-diazaadmantane 10, when viewed
amine and one secondary amine. In each, an appropriately
substituted azaindole (exemplified by 1) was first converted to
the corresponding saturated bicycle by ring hydrogenation.
Appropriate functionalization (as in 2) and intramolecular
cyclization afforded the desired tricyclic diamine (exemplified by
retrosynthetically, doesn’t contain any disconnections that lead to
a ring fused bicycle. In every case, any single retrosynthetic
disconnection leads to a bridged ring system (14-16). Figure 3
shows the three possible disconnections, labeled a, b and c. Due
to symmetry, disconnections a and b are equivalent (14 & 15).
While all three of these disconnections individually lead to
bridged systems, if disconnections a and b are combined, this
would lead retrosynthetically to symmetrical monocyclic
piperidine 17. This could in turn arise from ring saturation of the
corresponding pyridine 19 (via 18). This strategy would
therefore continue the theme of using flat aromatic heterocycles
as the initial sources for saturated tricyclic systems.
3
, Figure 1).
Figure 1. General approach to tricyclic diamines, represented by the synthesis
of 1,4-diazaisotwistane. This figure shows the five novel tricyclic diamines
prepared by this approach.
In each case, the tertiary amine was formed last from an
intermediate ring-fused cyclic secondary amine. This strategy
allowed for the successful creation of a several novel isomeric
tricyclic diamines (3-7, Figure 1) in racemic form. We
demonstrated that access to the homochiral amines could be
achieved via chiral separation (super critical fluid
chromatography, SFC) at an intermediate stage. While this was
effective for our needs, it was somewhat inefficent. We were
intrigued if this strategy could be extended to prepare the
isomeric achiral 1,4-diazaadamantane (10, Figure 2).
The synthesis of the isomeric 1,3-diazaadamantane 8 (in
which both amines are tertiary) was first reported more than sixty
Figure 3. 1,4-diazaadamantane retrosyntheses
4
years ago and the synthesis of 2,6-diazaadamantane 9 (in which
Synthesis began with the relatively inexpensive (~$3/gram)
both amines are secondary) was first reported more than forty
dimethyl 2,6-pyridinedicarboxylate 20, which was subjected to
5
6
years ago. We are unaware of any literature examples of the
Minisci conditions according to a literature protocol to append
1,4-diazaadamantane core. There are no syntheses reported for
the requisite hydroxymethyl group in hydroxymethylpyridine 19.
The yield in this transformation was only moderate, as pushing
this transformation to higher conversion led to significantly
decreased yields, but given the availabilty of the starting material,
this was deemed acceptable. Hydrogenation proceeded in
the remaining two isomers of diazaadamantane, 1,2-
diazaadamantane 11 and 2,4-diazaadamantane 12 (all other
structures are degenerate with one of these five).
considerably higher yield than had previously been reported
7
(
76% vs 34%) upon hydrogenation over palladium on carbon to
afford the saturated all-cis piperidine 21. Treatment with TsCl
provided for both the protection of the piperidine nitrogen and
activation of the primary alcohol in tosylate 22. In our earlier
work, final ring cyclization occurred by intramolecular alkylation
of a secondary amine. In this case, a protected primary amine was
required. Installation of the amine synthon was accomplished in
nearly quantitative yield by treatment with sodium azide to afford
azido-diester 23. The diesters were next selectively reduced by

3
treatment with lithium borohydride and the resultant diol was
During the course of these experiments however, we attempted
doubly activated as the bis-tosylate 24.
alternative conditions for the reduction of the azide functionality,
specifically by Staudinger reduction of azide 24 as an alternative
to hydrogenation. Initial efforts (Ph P or Me P in wet THF) led to
3 3
poor results, but to our surprise, when trimethylphosphine was
used in anhydrous THF, complete consumption of the starting
material was observed within a few hours, and when the reaction
mixture was subsequently treated with aqueous sodium
bicarbonate, with the intention of freeing the primary amine, the
tosyl-protected 1,4-diazaadamantane 26 was instead obtained in
significantly improved yield. Surprisingly, this occurred without
the need to warm the reaction mixture. This unexpected result
warranted further mechanistic investigation. Attempts to follow
1
31
this transformation by HNMR or PNMR were unsuccessful, as
there were a number of components present which were difficult
to identify.
Scheme 1. First approaches to 2-hydroxymethyl azaindole core
With bis-tosylate 24 in hand, we were prepared to attempt the
key intramolecular bis-cyclization. In the event, hydrogenation of
azide 24 over palladium on carbon appeared to efficiently reduce
the azide to the corresponding amine. Upon heating 25 in the
presence of base, the amine was successfully cyclized to afford
the desired tosyl-protected 1,4-diazaadamantane 26. This
cyclization was considerably less efficient than we had observed
in our earlier tricyclic diamine syntheses as it required more
forcing conditions and afforded significantly lower yields.
Scheme 4. Possible mechanism for 1,4-diazaadamante synthesis via
iminophosphorane
product
M+H
293
r.t.
t=5min
t=70min t=4h
t=21h
0.31
0.22
0.10
0.33
0.05
2
2
2
2
2
6
8
5
7
4
1.56min 0.03
0.06
0.48
0.13
0.28
0.05
0.09
0.46
0.12
0.28
0.05
539,M+ 2.37min 0.30
637
711
663
2.65min 0.26
2.79min 0.17
3.76min 0.25
Table 1. LC/MS data from reaction monitoring of iminophosphorane
cyclization. All data is normalized to the sum of the five components shown
here, and reported as detected by UV at 220nm.
Scheme 2. Cyclization to form 1,4-diazaadamantane core
While we were pleased that we had succeeded in our attempts to
prepare this novel tricyclic system, we were disappointed in the
poor efficiency in the key step and set out to optimize this
transformation. Unfortutately, we were unable to improve upon
the yield of this compound via the cyclization of 25.
In a follow-up experiment, the reaction was repeated under the
same conditions, but with regular LC/MS monitoring, which
provided insight into the experiment.
Table 1 summarizes the LC/MS data obtained in this
experiment, and Figure 4 shows overlaid LC/MS traces at the 5
minute (black) and 21 hour (red) timepoints. As a caveat, the data
is represented as the area percentage observed by UV detection at
220nm; the results do not take into account differences in the
extinction coeffiecients in the various components. Additionally,
the results are normalized to the sum of these five components,
thus removing other minor unassigned peaks as well as a major
Scheme 3. Improved synthesis of 1,4-diazaadamantane core

4
Tetrahedron
non-ionizing , UV-active peak (at rt=0.46 min) which was
the aqueous workup was omitted, the yield was decreased from
consistent with the tosylate counterion.
the previous example (42% vs. 61% yield).
Within 5 minutes, three quarters of the starting material was
consumed with four new components present. The expected
primary amine 25 was present (m/z= 637.3 for M+H). A second
major component was consistent with the intermediate
iminophosphorane 27 (m/z= 711.3 for M+H). We were surprised
that iminophosphorane 27 appeared to survive chromatography
in the presence of water/methanol +0.01% TFA, although it may
be the case that the primary amine (25) which is observed was an
artifact due to decomposition of the iminophosphorane during the
quenching & LC/MS analysis conditions. More surprising was
the observation that the main component was consistent with
bridged bicycle 28, in which the iminophosphorane partially
cyclized to form a bridged bicyclic piperidinyl phosphonium ion
Taken together, these results suggest the reaction proceeds by
intial iminophosphorane formation (27), followed by
intramolecular alkylation of the iminophosphorane nitrogen.
Iminophosphoranes have been shown to be strongly nuclephilic
8
9
at nitrogen, participating in both intra- and intermolecular
alkylations. The resultant monocycle 28 can slowly cyclize to the
tricyclic 26, either in the presence or absence of water, although
it appears in the aqueous conditions the yield is significantly
improved. In this mechanism, the amine 25 could be rationalized
as occuring through iminophosphorane decomposition either
through adventitious water or as an artifact of the LC/MS
analysis. Unanswered in this proposal however is the question of
why significant amounts of iminophosphorane 27 remained after
21 hours when the initial cyclization of iminophosphorane 27 to
bicycle 28 had occurred very rapidly within the first 5 minutes.
As our mechanistic insights are essentially based solely on
LC/MS analysis, we cannot at this time rule out other
(observed m/z= 539.3, consistent with M+ for 28). While we did
not find precedent for this type of transformation, this structure
was generally consistent with the observed reactivity. At the 5
minute time-point, small amounts of tricyclic product 26 were
already observed.
possibilities as to the course of this reaction.
At approximately one hour, almost all of the starting material
was consumed and nearly half of the total was monocyclized 28.
At this time, the amount of amine 25 observed was significantly
decreased compared to the 5 minute time point, and the fully
cyclized tricycle 26 was increased.
The structure of tricycle 26 was confirmed by single-crystal X-
ray analysis of the compound as its p-TsOH salt (Figure 5).
With tricycle 26 in hand, protected as the tosamide, the final step
was to deprotect the sulfonamide. In the event, reaction of
sulfonamide 26 with lithium naphthalenide accomplished
deprotection of this group. Isolation of the free 1,4-
Whereas in the earlier reaction, the mixture was quenched after
3
h, when complete consumption of the starting material was
diazaadamantane 10 from the reaction mixture was challenging,
so instead the resultant free amine was trapped with di-tert-
butyldicarbonate to provide the Boc-protected 1,4-
observed, this time the reaction was allowed to age overnight, as
it appeared that there was a significant amount of
iminophosphorane 27 remaining. Surprisingly, a significant
amount of solid material had crystallized from the reaction
mixture after aging overnight. These were collected and
identified as the p-TsOH salt of tricycle 26. In this case, where
diazaisoadamantane 29. This material was isolated in a
straightforward manner, and could be deprotected to afford the
free 1,4-diazaadamantane 10 as a TFA salt without purification.
Figure 4. LC/MS traces for aliquots removed from the reaction at 5 minutes (black trace) and 21 hours (red trace). Detection by UV monitoring at 220nm.

5
Figure 5. ORTEP of X-ray crystal structure of 1,4-diazaadamantane 26.
.
3
.
The work described in this manuscript is described in the
following patent application: McDonald, I.M., Zusi, F.C., Olson,
R.E., WO 2015/191403.
4
5
.
.
a) Stetter, H.; Horst, H. Chem. Ber. 1955, 88, 789-795. b)
Galinovsky, F.; Langer, H. Monat. Chem. 1955, 88, 449-453.
a) Stetter, H.; Heckel, C. Tetrahedron Lett. 1972, 13, 1907-1908.
b) Dupeyre, R.M.; Rassat, A. Tetrahedron Lett. 1973, 14, 2699-
2
701.
Tang, R-R.; Zhao, Q.; Yan, Z.-E.; Luo, Y.-M. Synth. Comm. 2004,
6, 2027-2034.
Hartung, J.; Stapf, G.; Bergstraesser, U. Acta Crystallogr. Sect. E.
010, o1013.
Mulzer, J.; Becker, R.; Brunner, E. J. Am.Chem. Soc. 1989, 111,
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Katritzky, A.R.; Jiang, J.; Urogdi, L. Synthesis, 1990, 565-567.
6
7
8
9
.
.
.
.
3
2
7
Scheme 5. Deprotection of sulfonamide 26.
Supplementary Material
In summary, we prepared a new diazaadamantane isomer, 1,4-
diazaadamantane (10), which contains one secondary amine and
one tertiary amine. This complements the five new tricyclic
diamines (3-7) described in the previous two communications in
this series. Notably, this has the advantage of being achiral. The
synthesis was accomplished by a route which drew inspiration
from the synthesis of these other tricycles, that is the synthesis
began by derivitization and saturation of a flat, aromatic
heterocycle, followed by intramolecular cyclization. In this case,
this double cyclization took advantage of an unexpected
iminophosphorane-driven intramolecular bis-alkylation to form
the novel 1,4-diazaadamantane. The use of this amine, in addition
to the other tricyclic diamine cores from the previous two
communications in this series in the course of a medicinal
chemistry project will be reported in a forthcoming publication.
Supplementary data associated with this article can be found,
in the online version, at
Highlights


Novel 1,4-diazaadamantane was prepared.
Synthesis relies on saturation of trisubstituted
pyridine followed by intramolecular cyclization.
Final ring closure appears to proceed via

iminophosphorane displacement of a tosylate.
Acknowledgments
Jim Cook is gratefully acknowledged for his helpful
proofreading and comments during preparation of this
manuscript.
References and notes
1
2
.
.
McDonald, I.M.; Ng, A.; Olson, R.E. Tetrahedron Lett. 2016 (first
paper in this series)
McDonald, I.M.; Sun, J.-H.; Ng, A.; Olson, R.E. Tetrahedron Lett.
2
016 (previous paper in this series)