Unusual oxidative rearrangement of 1,5-diazadecalin

Article abstract of DOI:10.1016/S0040-4039(02)00559-2

Upon treatment with (PhIO)_n or PhI(OAc)₂, 1,5-diaza-cis-decalin undergoes oxidation at the more hindered position along with fragmentation to yield the ring-expanded bislactam. The cis and trans 1,5-diazadecalins both undergo the sam

Full text of DOI:10.1016/S0040-4039(02)00559-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3747–3750
Unusual oxidative rearrangement of 1,5-diazadecalin
Xiaolin Li, Zhenrong Xu, Erin F. DiMauro and Marisa C. Kozlowski*
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, PA 19104, USA
Received 7 February 2002; revised 8 March 2002; accepted 18 March 2002
Abstract—Upon treatment with (PhIO)n or PhI(OAc)2, 1,5-diaza-cis-decalin undergoes oxidation at the more hindered position
along with fragmentation to yield the ring-expanded bislactam. The cis and trans 1,5-diazadecalins both undergo the same
elimination indicating a potential stereoelectronic preference for oxidation at the more substituted carbon alpha to the nitrogen.
Oxidation at the less hindered positions of 1,5-diaza-cis-decalin was accomplished on the Boc-protected derivative to provide an
intermediate for the synthesis of 2,6-substituted-1,5-diaza-cis-decalins. © 2002 Elsevier Science Ltd. All rights reserved.
Previous efforts in our laboratories have identified the
1,5-diaza-cis-decalins as useful ligands for asymmetric
synthesis.1,2 One drawback to employing these com-
pounds with weakly coordinating species such as alkyl
lithiums, is the presence of an equilibrium between two
conformational forms 1-in and 1-out (Fig. 1). These
conformers readily interconvert by a chair–chair inver-
sion and the position of the equilibrium between 1-in
and 1-out progressively favors the latter upon substitu-
tion with increasingly larger R groups.3 In an effort to
generate compounds disposed toward the conforma-
tional arrangement found in 1-in, we have undertaken
the synthesis of substituted 1,5-diaza-cis-decalins 2.4
The addition of alkyl groups at C2 and C6 with the
illustrated relative stereochemistry should shift the posi-
tion of the equilibrium in these species toward 2-in.
4–7. When the course of this reaction was monitored by
1H NMR spectroscopy, the ratio in Scheme 1 was
achieved after 10 h and did not change substantially
thereafter. In contrast to the work of Rapoport,5 we
subjected the mixture of 4–7 directly to esterification
and cyclization to provide 63% of 7 in three steps from
3a (3.5 g scale).
Since the route from pyrrolidinone did not allow the
facile production of large quantities, a more efficient
entry to bislactam 7 was sought. We had a simple and
rapid method for the preparation of quantities of
resolved 10,1 so the oxidation of 1,5-diazadecalin to the
corresponding lactam was investigated (Scheme 2).
Based upon the precedent for the oxidation of 11 and
13 to the respective lactams 12 and 14 with iodosoben-
zene (Eqs. (1) and (2)),7 it was anticipated that oxida-
Bislactam 7 has been identified as a common intermedi-
ate which would allow the synthesis of derivatives of 2
with various R% groups. First, the reported synthesis of
lactam 7 from pyrrolidinone was reexamined (Scheme
1).5 Photodimerization of pyrrolidinone provided a
ꢀ1:1 ratio of racemic 3a and meso 3b. Yields for this
reaction were low, consistent with prior reports,6 but
large scale reactions with the inexpensive starting mate-
rial easily allowed for the synthesis of 20–50 g quanti-
ties. On the other hand, purification of the racemic 3a
was laborious since recrystallization did not result in
satisfactory enrichment and water needed to be
employed in the silica chromatography of this very
polar compound. With pure 3a in hand, we did find
that formation of 7 could be optimized. Treatment of
3a with 6N HCl provided an equilibrium mixture of
Figure 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00559-2

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X. Li et al. / Tetrahedron Letters 43 (2002) 3747–3750
Scheme 2. (a) m-NO2PhSO3Na, glycerol, H2SO4, 140°C, 64%;
(b) (i) Rh/Al2O3, 1000 psi H2, rt, 90:10 cis:trans mixture
produced, 95%, (ii) recrystallization.
Scheme 1.
tion of 1,5-diaza-cis-decalin (10) would yield bislactam
7.
Scheme 3.
further oxidation of the hydrate of bisimine 17 results
in oxidation at position b to furnish bislactam 15.
(1)
The 1,5-diaza-cis-decalins are conformationally mobile
such that another conformation 16-in may also be
present. This species, with the large iodoso group(s) on
nitrogen, is expected to be less stable than the 16-out
form and also does not provide a stereoelectronically
favorable pathway to oxidation at position a.3 The
1,5-diaza-trans-decalin (18) undergoes a similar frag-
mentation/oxidation reaction although better yields are
obtained when (PhIO)n is generated in situ (Scheme 4).
In this case, conformational exchange is absent and the
two nitrogens are in an anti relationship. In the resul-
tant iodoso intermediate 19, the orbitals of the ring
fusion bond are similarly aligned for a fragmentation to
(2)
When 1,5-diaza-cis-decalin (10) was treated with
(PhIO)n in the presence of water only the ring expanded
macrocyclic bislactam 158 was isolated (Scheme 3).
From this result it appears that oxidation occurs at the
more hindered position b alpha to nitrogen rather than
at the expected less hindered position a. Stereoelec-
tronic control in the elimination of the iodoso species
serves to explain this phenomenon. If an iodosoamine
intermediate 16 is formed with the iodoso group resid-
ing in the less hindered equatorial position, then a clear
pathway for a syn or anti hydrogen elimination is not
available. Rather, the orbitals of the ring fusion bond
are well aligned for elimination in 16-out. In this
unusual Grob-type variant, the leaving group resides on
nitrogen and a second nitrogen functions as an electron
donor causing the formation of a bisimine (17).9 This
reaction may proceed via direct cleavage of the NꢀH
bond or via fragmentation to a nitrogen-stabilized
cation that is subsequently deprotonated. Regardless,
Scheme 4.

X. Li et al. / Tetrahedron Letters 43 (2002) 3747–3750
3749
yield bisimine 17 whereas none of the alpha hydrogens
are oriented periplanar to the NꢀI bond.
Other oxidants were examined to see if the regiochemi-
10
cal results might be reversed. The use of RuO2/NaIO4
or CrO3·pyridine11 led only to decomposition. As such,
an approach towards 7 was undertaken in which free
diamine 10 was protected in the form of bis-Boc carba-
mate 20 (Scheme 5). Protection of the amines as carba-
mates was anticipated to lessen the electron rich
character of the nitrogen making it a poorer initiator
for the fragmentation. Subsequent oxidation with
RuO2/NaIO4 generated bislactam 21 cleanly in 84%
yield with oxidation taking place at the less hindered
centers. Deprotection of 21 afforded 7 in quantitative
yield. The regiochemistry of the oxidation and the
stereochemistry of the ring fusion in 7 was secured from
the X-ray crystal structure (Fig. 2).12
The X-ray structure also reveals several unusual fea-
tures for 7. The conformation of 7 is assigned as 7-in
since the two nitrogens are in a gauche arrangement
(Fig. 2). Each lactam ring of this strained bicyclic
compound adopts a half-chair conformation. This
structure is surprisingly bent with a ꢀ75° angle
between the two carbonyl groups. Apparently, the 1,4-
interactions of 7-out are more severe than the A1,3-inter-
actions arising from the endocyclic amides of 7-in. This
stands in contrast to 20 which contains exocyclic amide
bonds and adopts the ‘out’ conformation in
solution3a,13 and in the X-ray structure (Fig. 2).12 In this
case, the A1,3-interactions of 20-in are more severe than
the 1,4-interactions of 20-out.
Figure 2.
With the required intermediate 21 in hand, compounds
such as 2 could be prepared (Scheme 6). For example,
enolization of 21 and trapping with N-(5-chloro-2-
pyridyl)triflimide was readily performed to yield bistrifl-
ate 22 in 93% yield.14 Suzuki coupling then provided
bisenamide 23 in 97% yield. Removal of the Boc pro-
tecting groups was accompanied by isomerization of
the double bond into the internal position to afford
bisimine 24. Stereoselective reduction of this bisimine
from the exo face of the fused bicyclic ring system
provided the 2,6-diphenyl derivative 2a. The stereo-
chemistry of the reduction was very sensitive to the
reducing agent with a rhodium-catalyzed hydrogena-
tion proving the most effective in providing the indi-
cated diastereomer.
Scheme 6. (a) (i) LiHMDS, −78°C, (ii) ArNTf2, 93%; (b)
(Ph3P)2PdCl2, PhB(OH)2, Na2CO3, 50°C, 97%; (c) TFA; (d)
H2, Rh/Al2O3, HOAc, 43% from 23.
Acknowledgements
Financial support was provided by the National Sci-
ence Foundation (CHE-0094187). Acknowledgment 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. Patrick Car-
roll in obtaining and analyzing the X-ray structures is
gratefully acknowledged.
References
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X. Li et al. / Tetrahedron Letters 43 (2002) 3747–3750
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8. 1,5-Diaza-cis-decalin (10, 35 mg, 0.25 mmol) was added
to a stirred suspension of (PhIO)n (230 mg, 1.04 mmol) in
distilled water (5 mL) in an ice-water bath. After stirring
for 1 h at 9°C and 24 h at rt, the slurry was filtered. The
filtrate was extracted with CH2Cl2 and the combined
extracts were dried over MgSO4. After filtration and
concentration, the crude product was purified by chro-
matography (SiO2, 10% MeOH/CH2Cl2) to yield 15 in
50% yield (21 mg, 0.12 mmol) as an oil. 1,5-Diaza-trans-
decalin (18, 138 mg, 0.98 mmol) was oxidized in a similar
manner to provide 15 in 31% yield (52.7 mg, 0.31 mmol)
as an oil. 1H NMR (500 MHz, CDCl3) l 6.85 (br, 2H,
2NH), 3.36 (t, J=7.1 Hz, 4H, 2COCH2CH2), 2.25 (t,