Microwave-assisted synthesis of methyl (1S,2R,4S,5S)-7-aza-5- hydroxybicyclo[2.2.1]heptane-2-carboxylate through unexpected stereoselective substitution reaction

Article abstract of DOI:10.1016/j.tetlet.2012.04.098

Methyl (1S,2R,4S,5R)-7-aza-5-bromo-bicyclo[2.2.1]heptane-2-carboxylate was synthesized in high yield in short time from methyl (1R,2S,4R,5R)-2-amino-4,5- dibromocyclohexanecarboxylate through intramolecular cycloamination under microwave-assisted conditio

Full text of DOI:10.1016/j.tetlet.2012.04.098

Tetrahedron Letters 53 (2012) 3710–3712
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Microwave-assisted synthesis of methyl (1S,2R,4S,5S)-7-aza-5-
hydroxybicyclo[2.2.1]heptane-2-carboxylate through unexpected
stereoselective substitution reaction
Satoru Onogi a, Shuhei Higashibayashi a,b, Hidehiro Sakurai a,b,
⇑
a Department of Functional Molecular Science, School of Physical Sciences, The Graduate University for Advanced Studies, Myodaiji, Okazaki 444-8787, Japan
b Research Center for Molecular Scale Nanoscience, Institute for Molecular Science, Myodaiji, Okazaki 444-8787, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Methyl (1S,2R,4S,5R)-7-aza-5-bromo-bicyclo[2.2.1]heptane-2-carboxylate was synthesized in high yield
in short time from methyl (1R,2S,4R,5R)-2-amino-4,5-dibromocyclohexanecarboxylate through intramo-
lecular cycloamination under microwave-assisted conditions. The following substitution reaction by
trifluoro-acetate anion also took place in microwave-assisted conditions to afford methyl (1S,2R,4S,5S)-
7-aza-5-hydroxy-bicyclo[2.2.1]heptane-2-carboxylate. In the acyloxylation reaction, unusual endo-
selectivity was observed owing to 7-azabicyclo[2.2.1]heptane skeleton.
Received 5 March 2012
Revised 17 April 2012
Accepted 20 April 2012
Available online 1 May 2012
Keywords:
Microwave
Ó 2012 Elsevier Ltd. All rights reserved.
Azabicyclo[2.2.1]heptane
Cycloamination
Hydroxylation
Endo-selectivity
7-Azabicyclo[2.2.1]heptane skeleton is a common structure
often found in biologically active compounds and the skeleton has
been synthesized by several methods such as Diels–Alder reac-
tion.1,2 However, there are only a few examples reported for the
asymmetric synthesis of chiral 7-azabicyclo[2.2.1]heptane deriva-
tives, especially with substituent groups on both ethylene carbons.
Among them, Kapferer and Vasella’s synthesis of (1S,2R,4S,5R)-1
from tetrahydrophthalic anhydride (2) seems to be superior
because of the simple synthetic procedure and the potential of 1
as a synthetic chiral precursor (Scheme 1).3 In our view, however,
the synthesis still contains two problems: (1) intramolecular cyclo-
amination to construct 7-azabicyclo[2.2.1]heptane skeleton re-
quires too long reaction time (30 d), (2) conversion of bromo
substituent of 1 to more amenable functional group is not achieved.
In this Letter, we report improved microwave-assisted intramolec-
ular cycloamination as well as unexpected stereo-selective hydrox-
ylation reaction of 7-aza-bicyclo[2.2.1]heptane skeleton to afford
methyl (1S,2R,4S,5S)-7-aza-5-hydroxybicyclo[2.2.1]heptane-2-car-
boxylate derivative (3).
According to Kapferer and Vasella’s report, enantio-enriched
(1R,2S,4R,5R)-4 was prepared from 2 through the intermediates 5
and 6. Boc (t-butoxycarbonyl) group of 4 was deprotected by
CF3CO2H (TFA). After evaporation of CF3CO2H, the resulting trifluo-
roacetate salt 7 was subjected to intramolecular cycloamination in
Scheme 1. Kapferer and Vasella’s synthesis of 1.
the presence of K2CO3 in several kinds of solvents by employing
microwave-assisted heating (Table 1).4 In 1,2-dichloroethane at
150 °C (entry 1), 8 was obtained in 44% yield for 90 min, which is
much shorter time than the reported reaction time (30 d in reflux).
To improve the yield, the solvent and the temperature were
⇑
Corresponding author.
E-mail address: hsakurai@ims.ac.jp (H. Sakurai).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.098

S. Onogi et al. / Tetrahedron Letters 53 (2012) 3710–3712
3711
Table 1
Table 3
Cycloamination under microwave-assisted conditions
Hydroxylation of 8 under microwave-assisted conditions
Entry
Base (mol %)
Additive (mol %)
Yielda (%)
Entry
Solvent
Temp. (°C)
Time (min)
Yield of 1 (%)
1
2
3
4
K2CO3 150
—
K2CO3 440
—
—
Complex mixture
15
30
CF3CO2K 440
CF3CO2H 200
CF3CO2H 1000
1
2
3
4
(CH2Cl)2
THF
CH3CN
DMA
150
60
60
90
30
30
30
44a
42
67
81
Complex mixture
a
60
Yield of endo-3.
a
Yield of 8.
screened. The reactions in THF (entry 2) and CH3CN (entry 3) affor-
ded the desired product 1 in 42% and 67% yields, respectively, even
at 60 °C after treatment of 8 with Boc2O and NEt3. Finally, 1 was
obtained in 81% yield from the reaction in DMA (Me2NAc) at
60 °C for 30 min (entry 4). In order to check the effect of micro-
wave a controlled experiment of entry 4 was carried out using
oil bath heating with a sealed tube in place of microwave irradia-
tion, and it gave only 42% of 1 with 41% recovery of 4. The micro-
wave-assisted heating shortened the time to complete the
reaction.
During the optimization of cycloamination reaction, alcohol
endo-35 was unexpectedly obtained in 18% yield through steps of
Boc deprotection, reaction in DMA at 150 °C for 60 min, and pro-
tection of amine by Boc group again (Table 2, entry1). By optimiza-
tion of the temperature, the reaction at 140 °C afforded a slightly
better yield (entry 1–4) than those at 150 or 180 °C. The hydroxyl-
ation did not take place at 120 °C. Based on the assumption that
the trace of water in DMA is the source of the hydroxy group of
endo-3, DMF/water (7:1) was used for the reaction (entry 5). How-
ever, the yield was even decreased to 7%, which is an incompatible
result with our expectation.
Scheme 2. Acetoxylation of 8 under microwave-assisted conditions.
investigated (Table 3). The reaction of 8 with K2CO3 in DMA at
140 °C for 90 min (Table 3, entry1) was supposed to be under sim-
ilar reaction conditions to entry 3 in Table 2. However, the desired
endo-3 was not obtained at all, resulting in a complex mixture.
Since trifluoroacetate salt 7 was used for the reaction in Table 2,
CF3CO2H or the salt could affect the hydroxylation reaction. Indeed,
the hydroxylation took place to afford endo-3 by using CF3CO2K
(entry 2) or a combination of K2CO3 and CF3CO2H (entry 3). In
contrast, using only CF3CO2H did not afford endo-3 (entry 4). These
results suggest that the trifluoroacetate anion could act as a nucle-
ophile for 8 to produce trifluoroacetate ester of 9, which undergoes
hydrolysis in situ to afford alcohol 9. To confirm the reaction path-
way, CH3CO2H instead of CF3CO2H was used for the reaction, giving
the expected acetate ester endo-10. After treatment of endo-10
with Boc2O and NEt3 endo-11 was obtained without hydrolysis
(Scheme 2). This result supports that a carboxylate anion is the
nucleophile in the hydroxylation reaction.
There are two questions in the cycloamination/hydroxylation:
(1) the source of hydroxy group, (2) the unusual endo-stereoselec-
tivity for the hydroxylation in spite of the general exo-stereoselec-
tivity of substitution or addition reactions on bicyclo[2.2.1]heptane
skeleton.6
Hydroxylation is believed to take place after cycloamination
from 7 to 8. To simplify the possible factors and look into the
reaction mechanism, the hydroxylation of isolated amine 8 was
Concerning the second question, the importance of unprotected
amino group of 8 for the substitution reaction was confirmed by
the fact that the reaction of 1 with Boc-protected amino group
did not take place to produce endo-3 under the reaction conditions
(Scheme 3).7
In order to check the effect of unprotected amino group on the
endo/exo-stereoselectivity of the substitution reaction, the stere-
oselectivity of simple exo-2-bromobicyclo[2.2.1]heptane (12) and
exo-7-aza-2-bromobicyclo[2.2.1]heptane (14) for the hydroxyl-
ation was compared (Scheme 4). It was reported that a substitution
reaction of 12 using AgBF4 in DMF/MeNO2 at 0 °C took place to af-
ford exo-2-bicyclo[2.2.1]heptanol (13) exclusively (Scheme 4-(1)).6
Although the hydroxylation of 12 with CF3CO2H and K2CO3 in DMA
Table 2
Cycloamination/hydroxylation under microwave-assisted conditions
Entry
Solvent
Temp. (°C)
Time (min)
Yielda (%)
1
2
3
4
5
DMA
DMA
DMA
DMA
150
180
140
120
150
60
90
90
60
60
18
21
24
0
DMA/H2O (7:1)
7
a
Yield of endo-3.
Scheme 3. Hydroxylation of Boc-protected 1 under microwave-assisted conditions.

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S. Onogi et al. / Tetrahedron Letters 53 (2012) 3710–3712
Boc group of 4 by CF3CO2H and evaporation of CF3CO2H, the result-
ing trifluorocarboxylate salt 7 was subjected to microwave-as-
sisted cycloamination reaction at 60 °C for 30 min, followed by
hydroxylation at 140 °C for 90 min. After treatment with Boc2O,
endo-3 was obtained in 30% yield from 4. It should be noted
endo-3 was not obtained when the microwave irradiation was re-
placed by oil bath heating. The observation strongly suggests that
microwave irradiation is crucial to the hydroxylation reaction.
Endo-3 was oxidized by 1-Me-AZADO catalyzed reaction to give
ketone 16.10
In summary, the intramolecular cycloamination of methyl
(1R,2S,4R,5R)-2-amino-4,5-dibromocyclohexanetrifluorocarboxy-
late (7) was improved to give methyl (1S,2R,4S,5R)-7-aza-5-bromo-
bicyclo[2.2.1]heptan-2-carboxylate (8) in high yield in short time
by employing microwave-assisted conditions. Substitution reac-
tion of 8 by carboxylate anion was also achieved to afford alcohol
endo-3. In the substitution reaction, unusual endo-stereoselectivity
was observed owing to the participation of the nitrogen atom of 7-
azabicyclo[2.2.1]heptane skeleton. The prepared endo-3 and 16
could be amenable synthetic intermediates for chiral 7-aza-
bicyco[2.2.1]heptane derivatives with multi-functional groups.
0
Scheme 4. Hydroxylation of 12 and 14.
References and notes
1. Carroll, F. I. Bioorg. Med. Chem. Lett. 1889, 2004, 14.
2. (a) Chen, Z. M.; Trudell, M. L. Chem. Rev. 1996, 96, 1179; (b) Olivo, H. F.;
Hemenway, M. S. Org. Prep. Proc. Int. 2002, 34, 1.
3. Kapferer, P.; Vasella, A. Helv. Chim. Acta 2004, 87, 2764.
4. Other cycloamination condition of 3,4-dibromocyclohexanamine derivatives
with NaH was reported in the following literature, and we applied the
condition to cycloamination of 4. But desired product 8 was not formed. See the
following reference; Gomez-Sanchez, E.; Soriano, E.; Marco-Contelles, J. J. Org.
Chem. 2007, 72, 8656.
5. Identical data of methyl (1S,2R,4S,5S)-7-aza-5-hydroxybicyclo[2.2.1]heptane-
2-carboxylate (endo-3): ½a D26
ꢀ
: 22.9 (c = 1.0, CHCl3). IR (neat) m 3439, 2977, 1739,
1703, 1681 cmꢁ1. HRMS (EI): m/z Calcd for C13H21N1O5 [M+]: 271.1420. Found:
271.1412. 1H NMR (CDCl3): d 4.40 (1H, brs), 4.30 (1H, ddd, J = 3.2, 4.0, 10.0 Hz),
4.20 (1H, brs), 3.68 (3H, s), 2.65 (1H, dd, J = 5.2, 9.2 Hz), 2.62 (1H, brs), 2.35 (1H,
dd, J = 9.2, 12.8 Hz), 2.24 (1H, ddd, J = 5.2, 10.0, 12.8 Hz), 2.14 (1H, ddd, J = 4.0,
5.2, 12.8 Hz), 1.39 (9H, s), 1.12 (1H, dd, J = 3.2, 10.0 Hz) ppm. 13C NMR (CDCl3):
d 173.7, 154.6, 80.1, 69.7, 60.2, 59.6, 52.1, 47.4, 39.3, 28.1, 24.4 ppm. The
relative configuration of hydroxyl group was determined by NOESY spectrum.
6. Abad, A.; Agulló, C.; Cuñat, A. C.; Navarro, I. Synthesis 2005, 19, 3355.
7. endo-Selective substitution reaction of Boc-protected 7-aza-2-bromo-
bicyclo[2.2.1]heptane by azido anion was reported; Gomez-Sanchez, E.;
Marco-Contelles, J. Lett. Org. Chem. 2006, 3, 827.
Scheme 5. One-pot synthesis of endo-3 under microwave-assisted conditions.
under microwave-assisted heating proceeded very slowly to give a
mixture of exo-13 (12%) and endo-13 (7%) in low yield, exo-13 was
still observed as a major isomer (Scheme 4-(2)). In contrast, only
endo-15 was obtained in the hydroxylation of 14 under similar
conditions (Scheme 4-(3)), which proves that the endo-stereoselec-
tivity derives from the existence of unprotected amino group at 7-
position of bicyclo[2.2.1]heptane skeleton. In the case of 12, the
carbocation, generated by elimination of bromide, can be stabilized
by a non-classical carbocation mechanism, which causes a struc-
tural change to open the exo-face of cationic center.8 In contrast,
the generated carbocation of 14 could be stabilized by an interac-
tion with the lone pair of non-bonding electrons of nitrogen. The
endo-face of the cationic center can be opened to facilitate the
endo-substitution.
8. (a) Olah, G. A.; Prakash, G. K. S.; Saunders, M. Acc. Chem. Res. 1983, 16, 440; (b)
Olah, G. A. Angew. Chem. Int. Ed. Engl. 1995, 34, 1393.
9. Experimental procedure of one-pot synthesis of endo-3 from 4: 4 (83.0 mg,
0.2 mmol) was placed and dissolved in CH2Cl2 (0.8 mL) in a microwave reactor
vessel under Ar atmosphere. Trifluoroacetic acid (0.2 mL) was added and
stirred for 30 min. The reaction solvent and excess amount of reagent were
removed under reduced pressure. The trifluoroacetate salt 7 was mixed with
Me2NAc (1.4 mL) and K2CO3 (99.5 mg, 0.72 mmol), and then sealed after
purging with Ar. Initially the cycloamination reaction was carried out for
30 min at 60 °C, and then the hydroxylation reaction was carried out for 90 min
at 140 °C. After the reaction mixture cooled down to room temperature, Boc2O
(44 lL, 0.24 mmol) and NEt3 (83 lL, 0.6 mmol) were added and the reaction
mixture was stirred overnight. The reaction mixture was quenched by 1 M HCl,
extracted by tert-butylmethylether (5 mL ꢂ 3), and washed by water and brine.
The combined organic layer was dried over Na2SO4, filtered and concentrated.
Purification by using PTLC (hexane:AcOEt = 1:1) gave endo-3 (16.5 mg, 30%) as
pale yellow oil.
By applying the optimized reaction conditions for the cycloam-
ination and hydroxylation under microwave-assisted conditions,
endo-3 was prepared in one-pot from 4 in slightly better yield than
that of the stepwise procedure (Scheme 5).9 After deprotection of
10. Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am. Chem. Soc. 2006, 128,
84.