Microwave-assisted beckmann rearrangement: Convenient synthesis of 1,3-diaza-bicyclo[3.2.2]nonane

Article abstract of DOI:10.1080/00397910500377255

Small heterocyclic amines such as 1,3-diaza-bicyclo[3.2.2]nonane are known to be key components of biologically active molecules. A convenient synthesis of this compound utilizing a key Beckmann rearrangement of (Z)-1-aza-bicyclo[2.2. 2]octan-3-one oxime (6) with conc. H₂SO₄ under microwave irradiation was achieved. The desired compound (1) was obtained in 20% yield overall. Copyright Taylor & Francis LLC.

Full text of DOI:10.1080/00397910500377255

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Microwave‐Assisted Beckmann
Rearrangement: Convenient Synthesis of
1
,3‐Diaza‐bicyclo[3.2.2]nonane
a
a
a
Michael P. Curtis , William H. Bunnelle , Thomas G. Pagano , Murali
a
a
Gopalakrishnan & Ramin Faghih
a
Neuroscience Research, Global Pharmaceutical Research and
Development , Abbott Laboratories , Abbott Park, Illinois, USA
Published online: 19 Aug 2006.
To cite this article: Michael P. Curtis , William H. Bunnelle , Thomas G. Pagano , Murali Gopalakrishnan
&
Ramin Faghih (2006) Microwave‐Assisted Beckmann Rearrangement: Convenient Synthesis of
1,3‐Diaza‐bicyclo[3.2.2]nonane, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 36:3, 321-326, DOI: 10.1080/00397910500377255
To link to this article: http://dx.doi.org/10.1080/00397910500377255
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Synthetic Communications , 36: 321–326, 2006
Copyright # Taylor & Francis LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500377255
Microwave-Assisted Beckmann
Rearrangement: Convenient Synthesis
of 1,3-Diaza-bicyclo[3.2.2]nonane
Michael P. Curtis, William H. Bunnelle, Thomas G. Pagano,
Murali Gopalakrishnan, and Ramin Faghih
Neuroscience Research, Global Pharmaceutical Research
and Development, Abbott Laboratories, Abbott Park, Illinois, USA
Abstract: Small heterocyclic amines such as 1,3-diaza-bicyclo[3.2.2]nonane are
known to be key components of biologically active molecules. A convenient
synthesis of this compound utilizing a key Beckmann rearrangement of (Z)-1-aza-bicy-
2 4
clo[2.2.2]octan-3-one oxime (6) with conc. H SO under microwave irradiation was
achieved. The desired compound (1) was obtained in 20% yield overall.
Keywords: 1-Aza-bicyclo[2.2.2]octan-3-one oxime, Beckmann rearrangement, 1,3-
diaza-bicyclo[3.2.2]nonane, microwave-assisted organic synthesis
INTRODUCTION
Small heterocyclic amines are important components of many biologically
[
1]
active molecules. One of our discovery projects recently had an urgent
need for gram quantities of a particularly interesting small heterocyclic
amine: 1,3-diaza-bicyclo[3.2.2]nonane (1) (Figure 1). This diamine has
purportedly been synthesized from the reduction of 1,4-diaza-bicyclo[3.2.2]-
[
2]
nonan-3-one (2). The amide intermediate (2) was said to be prepared in 94%
yield through a Beckmann rearrangement of 1-aza-bicyclo[2.2.2]octan-3-one
oxime (6) using trifluoroacetic acid (TFA) at room temperature. However, in
Received in the USA July 28, 2005
Address correspondence to Ramin Faghih, Neuroscience Research, Global
Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL
60064-6123, USA. Tel.: (847) 937-2972; Fax: (847) 937-4143; E-mail: ramin.
faghih@abbott.com
3
21

3
22
M. P. Curtis et al.
Figure 1. Attempts to reproduce published data.
our hands, this methodology afforded only starting material after several
attempts. Compound 2 has also appeared in the literature as the product of a
Schmidt reaction from 3-quinuclidone using sodium azide and conc. H SO
2
4
[
3]
in chloroform.
However, our attempts at utilizing these conditions
resulted only in the formation of 1,3-diaza-bicyclo[3.2.2]nonan-4-one (3)
and piperidin-1-yl-acetonitrile (4).
The Beckmann rearrangement of oximes to amides is well known and
[4]
appears frequently in the literature employing a variety of reagents such
as conc. H SO , PCl , 2,4,6-trichloro[1,3,5]triazine (TCT), TFA, methanesul-
2
4
5
.
fonyl chloride, formic acid, AlCl , BF OEt , PPh /CCl , and silica gel.
3
3
2
3
4
Therefore, we decided to approach this synthetic challenge by quickly imple-
menting some of these conditions. We herein report a convenient synthesis of
1,3-diaza-bicyclo[3.2.2]nonane (1) made possible through a Beckmann
rearrangement of (Z)-1-aza-bicyclo[2.2.2]octan-3-one oxime (6) in conc.
H SO under microwave irradiation.
2
4
RESULTS AND DISCUSSION
Beginning with commercially available 3-quinuclidone (5), (Z)-1-aza-bicy-
clo[2.2.2]octan-3-one oxime (6) was obtained in excellent yields using
.
NH OH HCl and sodium acetate or pyridine in ethanol (Scheme 1). The
2
(Z) isomer of the oxime is necessary to afford the correct amide (2) because
of the stereospecific nature of the Beckmann rearrangement. Therefore,
NMR studies were performed on the oxime (6) to confirm the correct configur-
ation. (Based on the NOE difference spectrum for 6 (DMSO-d ), irradiation
6
of the OH at 10.17 ppm shows an NOE to the singlet at 3.41 ppm assigned
to the methylene group between the oxime and the nitrogen atom. This
indicates that the oxime is pointing toward the methylene group and only
the (Z) stereoisomer is present.) Intermediate 6 was next treated with
[2]
TFA according to De Costa et al.; however, no reaction progress was
apparent from TLC analysis after 2 h as reported or after prolonged (18 h)
reaction time with or without heat (Table 1). Consequently a convenient
[
5]
literature method reporting the conversion of a variety of oximes to
amides through the use of 2,4,6-trichloro[1,3,5]triazine (TCT) in DMF at

Synthesis of 1,3-Diaza-bicyclo[3.2.2]nonane
323
Scheme 1.
room temperature was tried. Unfortunately, this methodology also afforded
only starting material.
Recent success of application of microwave-assisted organic synthesis
[
6]
(MAOS) to solve challenging synthetic situations prompted us to try the
conditions reported by De Costa et al. under microwave irradiation.
Treatment of compound (6) with TFA under microwave irradiation (300 W)
[2]
Table 1. Beckmann and Schmidt reaction conditions
Product
isolated
Yield
(%)
Entry
A
Substrate
Conditions
NaN , H SO
2
3
4
3, 4
15, 40
CHCl , 808, 2 h
3
TFA, rt or heat,
8 h
B
C
No reaction
No reaction
0
0
1
TCT, DMF, rt
TFA, 708, mW,
D
E
No reaction
0
1
5 min
H SO , 1808,
2
4
2
24
mW, 15 min

3
24
M. P. Curtis et al.
resulted in no product formation (Table 1). Next, we chose concentrated
H SO and heated the oxime (6) under microwave irradiation (150 W) at
2
4
1808C for 15 min. To our delight the TLC analysis showed a new, less
polar major product and no detectable starting material along with a trace
1
of a minor product. The H NMR spectrum of the major product clearly
revealed a downfield shift in the methine proton of the migrating carbon
due to the deshielding effects of nitrogen (3.44 ppm vs. 2.59 ppm for 6).
Accordingly, the singlet assigned to the methylene protons of the carbon
between the oxime and nitrogen atom of 6 shifts very little in the product
lactam (2): 3.67 ppm vs. 3.71 ppm, respectively. The reaction was next
carefully repeated on a 2-g scale to afford 24% of 1,4-diaza-bicyclo[3.2.2]no-
nan-3-one (2) and ꢀ3% of piperidin-1-yl-acetonitrile (4) after chromato-
graphy. Although not necessary for our needs, it is likely that because no
starting material and only compounds 2 (major) and 4 (trace) were
recovered from this Beckmann rearrangement, techniques such as continuous
[
7]
liquid–liquid extraction could increase the yield. Compound 2 was next
quantitatively reduced to 1,3-diaza-bicyclo[3.2.2]nonane (1) with LAH in
THF (Scheme 1).
In conclusion, we have reported a convenient synthesis of 1,3-diaza-bicy-
clo[3.2.2]nonane (1) utilizing a key Beckmann rearrangement of the (Z)-oxime
(6) in conc. H SO under microwave irradiation. This methodology is rapid and
scalable, allowing for the quick preparation of more than 5 g of final material.
2 4
EXPERIMENTAL
1
H NMR spectra were recorded on a Varian Unity 300- and 500-MHz spec-
trometers with chemical shifts in ppm downfield from an internal TMS
standard. Desorption chemical ionization (DCI/NH ) were recorded on a
3
Finnigan SSQ 7000. Microwave reactions were performed using an Emrys
Creator (300 W) from Biotage either in 5- or 20-ml vessels. Elemental
analyses were performed by Quantitative Technologies. Starting material
and reagents were obtained from Aldrich. Solvents were of analytical
reagent quality. Some reactions were carried out under an inert atmosphere
of dry nitrogen using oven- or flame-dried glassware. Progress of all
reactions was monitored by TLC on E. Merck precoated silica-gel plates
(
0.2-mm layer) using a CH Cl /MeOH (9 : 1) system. Detection was with
2 2
iodine. Flash chromatography was performed with Redi-Sep silica-gel
cartridges using an Isco Sg100c purification system.
(Z)-1-Aza-bicyclo[2.2.2]octan-3-one Oxime (6)
.
NaOAc 3H O (100.8g, 740.6 mmol) was added to a stirred solution of 3-quinu-
2
.
clidone HCl (5) (40.0 g, 247 mmol) and NH OH HCl (20.64 g, 297.0 mmol) in
.
2

Synthesis of 1,3-Diaza-bicyclo[3.2.2]nonane
325
5
00 ml of EtOH. The resulting mixture was stirred at room temperature for 18h.
Contents were concentrated under vacuum and dissolved in 400 ml of
water. The solution was made alkaline with K CO , forming a precipitous
2
3
mixture. The mixture was filtered, washed with ice water (3ꢀ, 200 ml), and
dried for 24h under vacuum to afford 28.4g (83%) of 6 as a white solid.
1
H NMR (CDCl , 300 MHz), d 1.81 (m, 4H), 2.59 (m, 1H), 2.91 (m, 4H), 3.67
3
1
s, 2H), 7.87 (bs, 1H); H NMR (DMSO-d , 500 MHz), d 1.64 (m, 2H), 1.73
(
6
(
m, 2H), 2.42 (m, 1H), 2.71 (m, 2H), 2.79 (m, 2H), 3.41 (s, 2H), 10.17 (s, 1H);
þ
MS (DCI/NH ) m/z 141 (M þ H) ; anal. (C H N O) calculated: C, 59.98;
3
7 12 2
H, 8.63; N, 19.98. Found: C, 59.79; H, 8.52; N, 19.82.
1
,4-Diaza-bicyclo[3.2.2]nonan-3-one (2)
(Z)-1-Aza-bicyclo[2.2.2]octan-3-one oxime (6) (2.00 g, 14.27 mmol) was
slowly added to a stirred solution (12.5 ml) of conc. H SO at 08C. The
2
4
reaction mixture was allowed to warm to room temperature for 10–
5 min while stirring and then heated at 1808C for 15 min under
microwave irradiation (150 W). After cooling, the dark brown solution
1
was poured onto 100 g of ice, and carefully brought to pH ꢀ14 with 50%
NaOH solution. The crude product was extracted with CHCl (3ꢀ,
3
1
with flash chromatography (100% CH Cl to 90 : 10 : 0.5 CH Cl –MeOH–
50 ml), dried with Na SO , and concentrated under vacuum. Purification
2 4
2
2
2
2
1
NH OH) afforded 0.480 g (24%) of 2 as a white solid. H NMR (CDCl ,
4
3
3
3
00 MHz), d 1.90 (m, 2H), 2.13 (m, 2H), 3.11 (m, 4H), 3.44 (m, 1H),
þ
.71 (s, 2H), 6.72 (bs, 1H); MS (DCI/NH ) m/z 141 (M þ H) ; Anal.
3
(C H N O) calculated: C, 59.98; H, 8.63; N, 19.98. Found: C, 59.75; H,
7 12 2
8
.69; N, 19.80.
1
,4-Diaza-bicyclo[3.2.2]nonane (1)
A solution of LAH (22.0 ml, 1M in THF) was added dropwise to a stirred
solution of 1,4-diaza-bicyclo[3.2.2]nonan-3-one (2) (6.085 g, 43.4 mmol) in
anhydrous THF (50 ml). A large gas evolution was noticed upon addition,
and the reaction mixture became a cloudy gray solution. The resulting
solution was heated to reflux for 2 h and cooled to room temperature.
Water (3 ml) was slowly added while stirring, followed by 3 ml of 15%
NaOH and an additional 3 ml of water. Contents were stirred for 20 min,
filtered, and washed with THF (2ꢀ, 25 ml). The filtrate was dried
(
Na SO ) and concentrated under vacuum to afford 5.41 g (98%) of (1)
2 4
1
as an oil. H NMR (CDCl , 300 MHz), d 1.73 (m, 2H), 1.90 (m, 2H),
3
1
.96 (bs, 1H), 3.01 (t, J ¼ 7.5 Hz, 8H), 3.33 (m, 1H); MS (DCI/NH )
3
þ
m/z 127 (M þ H) .

3
26
M. P. Curtis et al.
REFERENCES
1
. (a) Faghih, R.; Dwight, W.; Vasudevan, A.; Dinges, J.; Conner, S. E.;
Esbenshade, T. A.; Bennani, Y. L.; Hancock, A. A. Bioorg. Med. Chem. Lett.
2
002, 12, 3077; (b) Faghih, R.; Dwight, W.; Pan, J. B.; Fox, G. B.;
Krueger, K. M.; Esbenshade, T. A.; McVey, J. M.; Marsh, K.; Bennani, Y. L.;
Hancock, A. A. Bioorg. Med. Chem. Lett. 2003, 13, 1325; (c) Apodaca, A.;
Dvorak, C. A.; Xiao, W.; Barbier, A. J.; Boggs, J. D.; Wilson, S. J.;
Lovenberg, T. W.; Carruthers, N. I. J. Med. Chem. 2003, 46, 3938;
(
4
d) Bunnelle, W. H.; Dart, M. J.; Schrimpf, M. R. Curr. Top. Med. Chem. 2004,
, 229; (e) Lin, N. H.; Dong, L.; Bunnelle, W. H.; Anderson, D. J.; Meyer, M. D.
Bioorg. Med. Chem. Lett. 2002, 12, 3321; (f) Kim, M. G.; Bodor, E. T.;
Harden, T. K.; Kohn, H. Bioorg. Med. Chem. 2004, 12, 2357; (g) Grellepois, F.;
Chorki, F.; Ourevitch, M.; Charneau, S.; Grellier, P.; McIntosh, K. A.;
Charman, W. N.; Pradines, B.; Crousse, B.; Bonnet-Delpon, D.; Begue, J. P.
J. Med. Chem. 2004, 47, 1423; (h) Moreno-Vargas, A. J.; Schutz, C.;
Scopelliti, R.; Vogel, P. J. Org. Chem. 2003, 68, 5632.
2
. De Costa, B. R.; He, X. S.; Linders, J. T.; Dominguez, C.; Gu, Z. Q.; Williams, W.;
Bowen, W. D. J. Med. Chem. 1993, 36, 2311.
3
4
. Mikhlina, E. E.; Rubtsov, M. V. Zh. Obshchei Khimii 1963, 33, 2167.
. (a) March, J. Advanced Organic Chemistry, 3rd ed.; Wiley-Interscience: New York,
1
985; p. 987; (b) His, S.; Meyer, C.; Cossy, J.; Emeric, G.; Greiner, A. Tetrahedron.
Lett. 2003, 44, 8581; (c) Hunt, P. A.; Moody, C. J.; Slawin, A. M.; Williams, D. J.;
Myers, P. L.; Smith, C. J. Chem. Soc. 1992, 831; (d) Tivan, E. S. J. Chem. Soc. 1965,
3
881; (e) Ghiaci, M.; Imanzadeh, G. H. Synth. Comm. 1998, 28, 2275;
(
(
f) Anilkumar, R.; Chandrasekhar, S. Tetrahedron Lett. 2000, 41, 5427;
g) Waters, R. M.; Wakabayashi, N.; Fields, E. S. Org. Prep. Pro. Int. 1974, 6,
53; (h) Gupton, J. T.; Idoux, J. P.; Leonard, R.; Decrescenzo, G. Synth. Comm.
1983, 13, 1083; (i) Costa, A.; Mestres, R.; Riego, J. M. Synth. Comm. 1982, 12,
1003; (j) Eshghi, H.; Gordi, Z. Synth. Comm. 2003, 33, 2971.
5
6
7
. De Luca, L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2002, 67, 6272.
. http:// www.maos.net/
. Vogel, A. I. Textbook of Practical Organic Chemistry, 5th ed.; Longman:
Edinburgh Gate, 1996; p. 160.