Synthesis and conformational properties of N-monoalkyl 1,5-diaza-cis-decalins

Article abstract of DOI:10.1016/S0040-4039(01)01344-2

N-Monoalkyl 1,5-diaza-cis-decalins were synthesized in high yield and purity by derivatization of tetrahydronaphthyridine followed by reduction to the saturated system. The position of the conformational equilibrium between the chair-chair inversion forms of a series of four N-monoalkyl of 1,5-diaza-cis-decalins was measured and was directly related to the size of the N-alkyl group.

Full text of DOI:10.1016/S0040-4039(01)01344-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6451–6454
Synthesis and conformational properties of N-monoalkyl
1,5-diaza-cis-decalins
Xu Xie, Dana A. Freed and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, PA 19104, USA
Received 18 July 2001; accepted 24 July 2001
Abstract—N-Monoalkyl 1,5-diaza-cis-decalins were synthesized in high yield and purity by derivatization of tetra-
hydronaphthyridine followed by reduction to the saturated system. The position of the conformational equilibrium between the
chair–chair inversion forms of a series of four N-monoalkyl of 1,5-diaza-cis-decalins was measured and was directly related to the
size of the N-alkyl group. © 2001 Elsevier Science Ltd. All rights reserved.
Previous efforts in our laboratories have identified the
1,5-diaza-cis-decalins (1) as useful ligands for asymmet-
ric synthesis.1,2 In order to determine the effect of
different N-alkyl groups on the selectivity of these
ligands, monosubstituted derivatives such as 2 were
required (Scheme 1). While many methods have been
devised for the monoalkylation and monoacylation of
diamines,3 none of the reported protocols allowed
efficient monoderivatization of 3. The best of these
methods, simple rapid alkylation under dilute condi-
tions with a substoichiometric amount of MeI produced
a mixture of 3, 4, and 5. The difficulty in monoderiva-
tization of 3 appears to be a consequence of the confor-
mational equilibria of 1,5-diaza-cis-decalins.4 The
parent 3 exists mainly in the 3-in conformation, but the
product of the first alkylation/acylation 2 favors the
2-out conformation. The amine lone pair of 2-out is less
hindered than in the major form of the starting material
3-in. The net result is that alkylation/acylation of the
N-monoalkylated intermediate 2 proceeds more rapidly
than that of the starting diamine 3.
In order to generate the N-monoalkyl 1,5-diaza-cis-
decalins (2), an alternative route has been devised utiliz-
ing
tetrahydronaphthyridine
8
(Scheme
2).
Naphthyridine (7) was previously used to synthesize the
decahydro compound 31 by hydrogenation at 1000 psi
at rt using Rh/Al2O3. By performing the hydrogenation
at atmospheric pressure the partially hydrogenated
intermediate tetrahydronaphthyridine (8) could be
R1
R1
Me
N
Me
N
H
N
N
MeI
MeOH, ∆
N
+
N
N
N
N
N
H
H
H
Me
R2
(+)-3
5
4
1
2
H
R1
N
N
N
N
N
R1
R1
R1X
H
R1X
N
N
R1
H
H
N
N
N
H
H
3-out
3-in
2-in
2-out
6-out
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01344-2

6452
X. Xie et al. / Tetrahedron Letters 42 (2001) 6451–6454
Reduction of these N-acyl derivatives to the N-alkyl
H
N
N
analogs 11b–d was then attempted. Surprisingly, treat-
ment of 9b with LiAlH4 resulted in low yields of
N-alkyl 11b. The intermediate iminium ion formed
during the reduction is likely unstable due to allylic
steric interactions with the peri-hydrogen of the pyri-
dine ring. A more efficient reduction was obtained with
BH3; however, the isolated product was the very stable
pyridinium–borane adduct of 11b. This adduct was
cleaved by heating in 6N HCl to provide 11b in good
overall yield (73%). A similar procedure was applied to
a
N
N
H
3
7
b
N
N
c
N
N
9b
H
8
O
CH3
N
N
Scheme 2. (a) Rh/Al2O3, 1000 psi H2, rt, 90:10 cis:trans
mixture produced, 95%; (b) Rh/Al2O3, H2, rt, 59%; (c) AcCl,
86%.
N
N
obtained readily.5 Treatment of 8 with acetyl chloride
produced a single new compound which was pre-
sumably N-acyl 9b.
O
CH3
H3C
O
9b-trans
9b-cis
In the NMR spectra of N-acyl 9b in CDCl3, one proton
signal and three carbon signals were conspicuously
absent. Closer analysis of the H NMR spectrum of 9b
N
N
1
revealed the presence of a very broad (2 ppm) C8
hydrogen signal center at a 7.8 ppm (Fig. 1). In DMSO-
d6 at 60°C all the signals could be observed although
some signals were still broad. The localized broadening
of select signals for compound 9b arises from a slow
equilibration between the cis and trans amide rotamers
(Fig. 2) combined with large chemical shift differences
for the affected signals in the different rotamers.6 The
complete broadening of some signals while other are
unaffected is an unusual extreme.7 Interestingly, the
spectral anomalies found in 9b were not observed in
N-acyltetrahydroisoquinoline 10 (Fig. 2) under identi-
cal conditions, indicating that the pyridyl nitrogen is
responsible for the large chemical shift differences.8
O
CH3
H3C
O
10-trans
10-cis
Figure 2.
.
1) BH3 THF
2) 6N HCl, ∆
N
N
8
O
N
N
11
9
R
Cl
O
R
R
R =
Me CH2OMe tBu
(b)
CF3
(e)
(c)
(d)
8 → 9 86%
9 → 11 73%
73%
62%
88% 75%
60%
With N-acyl 9b in hand, other derivatives including the
methoxyacetyl (9c), pivaloyl (9d), and trifluoroacetyl
(9e) were prepared in a similar manner (Scheme 3).
Scheme 3.
Figure 1. 1H NMR spectra of 9b.

X. Xie et al. / Tetrahedron Letters 42 (2001) 6451–6454
6453
R1
3
9
obtain 11c and 11d, but proved unsuccessful for the
1
N
2
N
N
8
R1
reduction of the trifluoroacyl derivative 9e. The greater
lability of the trifluoroacetyl combined with the steric
strain induced by the peri-hydrogen resulted in rapid
cleavage of the trifluoroacetyl group to generate 8.
4
10
7
H
N
5
2-in
R1
2-out
6
H
To obtain the N-Me analog 11a, Eschweiler–Clarke
methylation of 8 was undertaken (Eq. (1)). Hydrogena-
tion of the pyridine ring of 11a–d with a Rh/Al2O3
catalyst proceeded uneventfully to yield predominantly
the cis ring fused N-monoalkyl compounds 2a–d (Eq.
(2)).
2-in:2-out
a
Me
Et
>90 : 10
75 : 25
75 : 25
<10 : 90
b
c
d
CH2CH2OMe
CH2tBu
CH2O
HCO2H
Figure 3.
N
8
between R1 and C8;4 however, these compounds pos-
sessed a greater tendency to populate the N-in con-
former compared to the N,N%-dialkyl compounds,
indicating their potential utility as stable chelating
diamine ligands.
55%
(1)
N
11a
Me
H
N
H2
Rh/Al2O3
11
1000 psi H2
rt
An efficient synthesis of monoalkyl derivatives of 3 has
been achieved. This method will also allow the synthesis
of unsymmetric N,N%-dialkyl-1,5-diaza-cis-decalins
which may have applications as chiral ligands. A rare
example of chemical exchange causing the absence of
certain signals in otherwise normal NMR spectra is
reported.
N
2
(2)
R
R
yield cis:trans
a H
b Me
62% 72:18
84% 74:16
c CH2OMe 62% 73:17
d tBu
54% 73:17
Acknowledgements
The NMR spectra of 2a–d were complex, presumably
due to chair–chair inversion occurring on the NMR
time scale, and did not permit an unambiguous assign-
ment of these compounds. As such, compound 2b was
converted to the known N,N%-diethyl-1,5-diaza-cis-
decalin 12 with EtI (Eq. (3)). The N,N%-dialkyl 12 was
identical in all respects to the material generated
directly from 3.
Financial support was provided by the National Insti-
tutes of Health (GM-59945), Merck Research Labora-
tories, and DuPont. Acknowledgement is made to the
donors of the Petroleum Research Fund, administered
by the ACS, for partial support of this research. The
invaluable assistance of Dr. George Furst and Puay-
Wah Phuan in obtaining the spectral data is gratefully
acknowledged. We thank Dr. Ed Thornton for helpful
discussions.
Et
EtI, THF
N
NaOH
(3)
2b
92%
N
References
12
Et
1. Li, X.; Schenkel, L. B.; Kozlowski, M. C. Org. Lett.
2000, 2, 875–878.
2. Li, X.; Yang, J.; Kozlowski, M. C. Org. Lett. 2001, 3,
1641–1644.
With the monoalkyl derivatives 2a–d in hand, the con-
formational equilibria of these compounds were investi-
gated by means of NMR spectroscopy. At room
temperature, the spectra were broadened indicating
rapid interchange between the N-in and N-out forms
3. (a) Wang, T.; Zhang, Z.; Meanwell, N. A. J. Org. Chem.
1999, 64, 7661–7662 and references cited therein; (b) Xu,
D.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron
Lett. 1995, 36, 7357–7360; (c) Jabobson, A. R.; Makris,
A. N.; Sayre, L. M. J. Org. Chem. 1987, 52, 2592–2594.
4. Ganguly, B.; Freed, D. A.; Kozlowski, M. C. J. Org.
Chem. 2001, 66, 1103–1108.
5. Satisfactory characterization was obtained for all new
compounds. 8: mp 107–109°C; 1H NMR (200 MHz,
CDCl3) l 1.96–2.08 (m, 2H), 2.92 (t, 6.5 Hz, 2H), 3.30 (t,
4.8 Hz, 2H), 3.81 (brs, 1H), 6.72 (dd, 8.0 Hz, 1.4 Hz, 1H),
6.88 (dd, 7.9 Hz, 4.5 Hz, 1H), 7.85 (dd, 4.6 Hz, 1.4 Hz,
1H); 13C NMR (125 MHz, CDCl3) l 21.6, 30.2, 41.4,
120.0, 121.7, 137.7, 140.9, 142.6; IR (film) 3229, 2949,
1
(Fig. 3). At lower temperatures (250 K), the H NMR
spectra were still very complex, but two distinct sets of
peaks were observed in the 13C NMR spectra of 2a–d.
Furthermore, the N-in and N-out conformations could
be assigned on the basis of the 13C NMR chemical
shifts9 and the relative populations of the conforma-
tional isomers could be measured (Fig. 3).10 Similar
trends were observed for these derivatives as had been
observed for the N,N%-dialkyl compounds.4,11 Increas-
ing the steric bulk of the N-alkyl group caused a shift
toward the N-out form due to torsional interactions

6454
X. Xie et al. / Tetrahedron Letters 42 (2001) 6451–6454
13C NMR (125 MHz, CDCl3, rt) l 9.0, 22.1, 29.7, 46.4,
1456 cm−1; HRMS (ES) calcd for C8H11N2 (MH+)
135.0922, found 135.0927. 9b: oil; 1H NMR (500 MHz,
CDCl3) l 2.08 (m, 2H), 2.27 (s, 3H), 2.99 (t, 6.8 Hz, 2H),
3.79 (t, 5.9 Hz, 2H), 7.13 (dd, 8.2 Hz, 4.7 Hz, 1H), 8.3 (d,
4.1 Hz, 1H); 1H NMR (360 MHz, DMSO-d6, rt) l
1.92–1.99 (m, 2H), 2.20 (s, 3H), 2.86 (t, 6.7 Hz, 2H), 3.71
(t, 6.1 Hz, 2H), 7.17 (dd, 8.2 Hz, 4.7 Hz, 1H), 8.00 (brs,
54.7, 57.3; 13C NMR (125 MHz, CDCl3, 250 K) N-in:
7.0, 20.5, 21.1, 27.2, 30.6, 45.8, 46.8, 51.8, 54.3, 55.7;
N-out: 12.6, 14.6, 23.2, 25.8, 29.7, 39.7, 45.5, 47.2, 53.0,
56.7; IR (film) 3281, 2931 cm−1; HRMS (ES) calcd for
C10H21N2 (MH+) 169.1705, found 169.1706. 2c: oil, 1H
NMR (500 MHz, CDCl3) l 1.22–1.25 (m, 1H), 1.41–1.46
(m, 3H), 1.58–1.73 (m, 3H), 2.03 (br., 1H), 2.23–2.34 (m,
3H), 2.50–2.55 (m, 1H), 2.61–2.66 (m, 1H), 2.77–2.84 (m,
3H), 2.99–3.01 (m, 1H), 3.31 (s, 3H), 3.41–3.50 (m, 2H);
13C NMR (125 MHz, CDCl3, rt) l 22.2, 26.5, 29.1, 29.6,
46.4, 52.2, 54.6, 58.8, 70.1; 13C NMR (125 MHz, CDCl3,
250 K) N-in: 20.2, 21.0, 27.7, 30.6, 46.7, 51.3, 53.4, 54.5,
57.8, 58.9, 68.7; N-out: 15.4, 23.0, 24.2, 26.1, 29.6, 39.6,
1
1H), 8.21 (dd, 4.3 Hz, 1.1 Hz, 1H); H NMR (360 MHz,
DMSO-d6, 60°C) l 1.93–2.02 (m, 2H), 2.20 (s, 3H), 2.87
(t, 6.7 Hz, 2H), 3.72 (t, 6.1 Hz, 2H), 7.17 (dd, 8.2 Hz, 4.7
Hz, 1H), 8.00 (d, 8.2 Hz, 1H), 8.21 (dd, 4.3 Hz, 1.1 Hz,
1H); 13C NMR (125 MHz, CDCl3) l 23.2, 30.3, 121.0,
131.6, 145.2, 169.9; 13C NMR (125 MHz, DMSO-d6) l
23.5, 23.6, 30.7, 45.1, 121.8, 132.2, 135.6, 145.3, 151.3,
170.6; IR (film) 2931, 1661 cm−1; HRMS (ES) calcd for
C10H13N2O (MH+) 177.1028, found 177.1030. 11b·BH3:
mp 102–104°C; 1H NMR (200 MHz, CDCl3) l 1.10 (t,
7.1 Hz, 3H), 1.98 (tt, 6.6 Hz, 6.6 Hz, 2H), 3.17–3.38 (m,
6H), 6.93–7.04 (m, 2H), 7.93–7.96 (m, 1H); 13C NMR (90
MHz, CDCl3) l 10.2, 20.4, 27.4, 45.4, 47.2, 118.4, 122.3,
135.2; IR (film) 2959, 2324, 1185 cm−1; anal. calcd for
C10H17BN2: C, 68.22; H, 9.73; N, 15.91; found C, 68.17;
45.6, 52.5, 53.2, 58.5, 70.2; IR (film) 2946, 1357 cm−1
;
HRMS (ES) calcd for C11H23N2O (MH+) 199.1810,
1
found 199.1809. 2d: oil, H NMR (500 MHz, CDCl3) l
0.81 (s, 9H), 1.19–1.40 (m, 2H), 1.49–1.56 (m, 3H),
1.70–1.87 (m, 3H), 2.08–2.15 (m, 2H), 2.28–2.31 (m, 1H),
2.39 (br., 1H), 2.57–2.66 (m, 3H), 2.77 (m, 1H), 3.01 (m,
1H); 13C NMR (125 MHz, CDCl3, rt) l 19.3, 23.1, 24.9,
27.7, 33.5, 41.2, 49.0, 53.4, 61.3, 65.9; 13C NMR (125
MHz, CDCl3, 250 K) 17.1, 22.6, 24.7, 26.1, 27.2, 33.6,
1
H, 10.24; N, 15.98. 11b: oil; H NMR (200 MHz, CDCl3)
39.5, 47.1, 52.6, 60.7, 65.4; IR (film) 2931, 1118 cm−1
;
l 1.06 (t, 7.1 Hz, 3H), 1.92–2.04 (m, 2H), 2.86 (t, 6.6 Hz,
2H), 3.08–3.31 (m, 4H), 6.75 (d, 8.3 Hz, 1H), 6.89 (dd,
8.3 Hz, 4.6 Hz, 1H), 7.72 (d, 4.6 Hz, 1H); 13C NMR (90
MHz, CDCl3) l 10.4, 18.4, 31.1, 44.6, 47.8, 116.1, 121.9,
HRMS (ES) calcd for C13H27N2 (MH+) 211.2174, found
211.2179.
6. Sanders, J. K.; Hunter, B. K. Modern NMR Spec-
troscopy, 2nd ed.; New York: Oxford, 1993; pp. 216–220.
7. For examples of this phenomenon, see: Reference 6, p.
219 and: (a) Binsch, G.; Kessler, H. Angew. Chem., Int.
Ed. Engl. 1980, 19, 4511–428; (b) Drankenberg, T.;
Forsen, S. J. Phys. Chem. 1970, 74, 1–7.
135.7, 140.9, 141.3; IR (film) 2967, 1577, 1456 cm−1
;
HRMS (ES) calcd for C10H15N2 (MH+) 163.1235, found
163.1232. 2a: oil, 1H NMR (500 MHz, CDCl3) l 1.19–
1.23 (m, 1H), 1.37–1.49 (m, 3H), 1.56–1.63 (m, 1H),
1.67–1.76 (m, 2H), 1.89 (br., 1H), 1.98–2.11 (m, 2H), 2.17
(m, 4H), 2.61–2.69 (m, 2H), 2.74–2.76 (m, 1H), 3.05–3.07
(m, 1H); 13C NMR (125 MHz, CDCl3, rt) l 21.2, 21.6,
24.4, 29.1, 42.5, 46.9, 54.7, 56.8, 59.8, 61.7; 13C NMR
(125 MHz, CDCl3, 250 K) 20.3, 21.0, 27.7, 30.5, 42.5,
46.7, 54.0, 57.2, 61.3; IR (film) 2933 cm−1; HRMS (ES)
calcd for C9H19N2 (MH+) 155.1548, found 155.1547. 2b:
oil, 1H NMR (500 MHz, CDCl3) l 0.96 (t, J=7.1 Hz,
3H), 1.05–1.29 (m, 3H), 1.42–1.50 (m, 3H), 1.62–1.78 (m,
3H), 2.06 (br., 1H), 2.20–2.78 (m, 6H), 3.03–3.06 (m, 1H);
8. With the exception of slight broadening of the C2 signal
of 10 in the 13C NMR spectrum.
9. The 13C NMR shift of C8 was particularly diagnostic,
occurring at ꢀ21 ppm for the N-in form and at ꢀ16
ppm for the N-out form.
10. For 2a and 2d, peaks for the minor isomer were observed
but with low intensity corresponding to <10%.
11. Santos, A. G.; Klute, W.; Torode, J.; Bo¨hm, V. P. W.;
Cabrita, E.; Runsink, J.; Hoffmann, R. W. New J. Chem.
1998, 993–997.