Scalable synthesis of enantiomerically pure cis-1,2-cyclohexanediamine derivatives and conformationally rigid 7-azabicyclo[2.2.1]heptan-2-amines

Article abstract of DOI:10.1002/ejoc.201300253

A scalable approach to the syntheses of enantiomerically pure cis-1,2-cyclohexanediamines as well as exo-and endo-7-azabicyclo[2.2.1]heptan-2- amines is reported that utilizes meso-tert-butyl 2,3-bis(phenylsulfonyl)-7- azabicyclo[2.2.1]hept-2-ene-7-carbox

Full text of DOI:10.1002/ejoc.201300253

FULL PAPER
DOI: 10.1002/ejoc.201300253
Scalable Synthesis of Enantiomerically Pure cis-1,2-Cyclohexanediamine
Derivatives and Conformationally Rigid 7-Azabicyclo[2.2.1]heptan-2-amines
Ganesh Pandey,*[a] Debasis Dey,[a] and Rushil Fernandes[a]
Keywords: Synthetic methods / Amines / Cleavage reactions / Reduction / Diastereoselectivity
A scalable approach to the syntheses of enantiomerically
pure cis-1,2-cyclohexanediamines as well as exo- and endo-
7-azabicyclo[2.2.1]heptan-2-amines is reported that utilizes
meso-tert-butyl 2,3-bis(phenylsulfonyl)-7-azabicyclo[2.2.1]-
hept-2-ene-7-carboxylate as a starting material.
from our ongoing exploitation of 2 in the syntheses of a
variety of natural products/scaffolds[10,11] and the presence
of the phenylsulfonyl moiety at C-3 to act as a handle to
trigger a C-4–N-7 bond cleavage. In this paper, we disclose
our explorations to synthesize 1,2-diaminocyclohexanes
from 2 and our success to realize the synthesis of 6 in up
to a multigram scale without the loss of yield or selectivity.
Introduction
1,2-Diamines are important scaffolds in organic chemis-
try and are routinely used as ligands[1a–1e] in metal-cata-
lyzed asymmetric organic transformations as well as for the
design of thiourea-based organocatalysts.[2a,2b] Such di-
amines are also abundant in a large number of naturally
occurring organic compounds.[3] In particular, cyclohexane-
1,2-diamines constitute a distinct subclass that has diverse
applications in organic chemistry. For example, C2-symmet-
ric trans-1,2-diaminocyclohexane (5) has been used as a li-
gand[1c–1e] in metal-catalyzed asymmetric reactions, and
there are several important organocatalysts[4a–4m] based on
this structural framework. On the other hand, cis-1,2-di-
aminocyclohexanes 6 have shown great promise as thera-
peutic agents in medicinal chemistry.[5a–5l] More recently,
cis-diaminocyclohexane derivatives have emerged as excel-
lent pseudoenantiomeric organocatalysts to produce both
enantiomers of a product.[6a,6b] Although 5 is obtained by
resolution of its racemic mixture by either using chiral rea-
gents or enzymes,[7a,7b] the corresponding compound 6 is
obtained from either trans-2-aminocyclohexanol[5b,5i,5k] or
acrylate cycloaddition with butadiene, using d-pantolact-
one as a chiral auxiliary[8a,8b] and employing a long reaction
sequence. cis-1,2-Diaminocyclohexanes have also been ob-
tained through the desymmetrization of the corresponding
meso-vicinal cyclohexanediamines.[9a,9b]
Scheme 1. Proposed sequence for the synthesis of 1,2-cyclohexane-
diamines (Boc = tert-butoxycarbonyl).
Considering the importance of 1,2-diamines in general
and 1,2-diaminocyclohexanes in particular, we visualized
conformationally rigid 7-azabicyclo[2.2.1]heptane-2-amines
3 and 4 as ideal precursors for the syntheses of 1,2-di-
aminocyclohexanes (see Scheme 1). This idea originated
Results and Discussion
To transform 2 into either 3 or 4, the corresponding
alcohols were selectively obtained by reduction of 2 under
different reaction conditions (see Scheme 2). For example,
7 (exo/endo, 9:1) was preferentially prepared by carrying out
the reduction with LiBH4 in tetrahydrofuran (THF) at am-
bient temperature, whereas 8 (exo/endo, 3:7) was obtained
by performing the reduction at –78 °C. The individual
alcohols were purified by simple column chromatography
[a] Molecular Synthesis Laboratory, CBMR, Sanjay Gandhi
Postgraduate Institute of Medical Sciences Campus,
Raebareli Road, Lucknow 226014, India
Fax: +91-522-2668215
E-mail: gp.pandey@cbmr.res.in
Homepage: http://www.cbmr.res.in/CBMR/Home.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300253.
Eur. J. Org. Chem. 2013, 4319–4324
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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G. Pandey, D. Dey, R. Fernandes
FULL PAPER
and were individually and quantitatively converted into the
corresponding mesylates 9 and 10 by treatment with mesyl
chloride (MsCl) in pyridine at room temperature. These mes-
ylates were very stable solids [m.p. 172.4–174.9 °C (for 9),
m.p. 177.3–181.6 °C (for 10)]. Initially, we heated 9 at reflux
with allylamine for 30 min and, surprisingly, isolated 11a in
95% yield. The identical reaction with 10 also gave 11a. To
probe this unexpected result further, a mixture of both 9
and 10 was heated at reflux with allylamine, which also ex-
clusively produced 11a. The reaction with acetamide and
pyrolidine derivatives also yielded the corresponding prod-
ucts 11b and 11c, respectively.
Scheme 3. Support of 12 as an intermediate in amination reaction.
Scheme 4). Removal of the phenylsulfonyl moiety[12] by
heating to reflux in absolute ethanol with Raney-Ni quanti-
tatively gave 14 {[α]2D7 = 5 (c = 1, chloroform)}.
Scheme 4. Synthesis of 1,2-diaminocyclohexane 14.
In addition to transforming 13b into 14, it was also con-
verted into 15 and 16 by performing simple steps as shown
in Scheme 5. Both compounds 15 and 16 provide the re-
quired structural features for further functionalizations. The
reduction of 13b by treatment with Na/Hg and H2, Pd/C
produced 15 {[α]2D4 = –31.1 (c = 0.9, chloroform)} and 16,
respectively, in good yields.
Scheme 5. Exploration of the methodology for other cyclohexane-
diamine analogues.
The presence of the phenylsulfonyl group at C-3 in 16
provides a handle for further transformation of this struc-
tural framework. Conformationally rigid diamines (CRDA)
are important compounds because of their roles in biology,
catalysis, and coordination and supramolecular chemis-
try.[13] Interestingly, exo- and endo-7-azabicyclo[2.2.1]-
heptan-2-amines (18 and 21, respectively) are known sub-
structures of many pharmacologically important com-
pounds. For example, N-6-(endo-7-azabicyclo[2.2.1]hept-2-
yl)adenosines are highly potent A1AR agonists,[14,15]
whereas exo-7-azabicyclo[2.2.1]heptan-2-amine derivatives
act as inhibitors against the plasmepsins of the malarial
parasite Plasmodium falciparum.[16] In spite of the signifi-
cant biological activities associated with these structural
frameworks, their syntheses have mainly relied on the chiral
resolution of racemic amines.[15,17] Although 21 has recently
Scheme 2. Preparation of exo-7-azabicyclo[2.2.1]heptanediamines.
Mechanistically, the possibility of this reaction occurring
through an SN2-type displacement can be ruled out, and an
SN1-type reaction would involve an energetically uphill task
because of the presence of the α-phenylsulfonyl moiety.
Therefore, we hypothesized that this reaction might proceed
through an exo attack of the amine on intermediate 12,
which is produced by elimination of the mesyl group
through an E1cB mechanism (see Scheme 3). To confirm
the involvement of 12 as an intermediate, both 9 and 10
were stirred with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
in dichloromethane (DCM) at room temperature for 1 h,
and the resultant 12 was heated with allylamine to give 11a
exclusively.
By applying an identical procedure, 11b was prepared on been synthesized[18] by an intramolecular cyclization of op-
a multigram (40 g) scale. To effect the C-4–N-7 cleavage, tically active 3,4-diaminocyclohexanol under Mitsunobu
11b was stirred with 4.0 equiv. of MeMgBr (1.4 m solution conditions, the strategy suffers from the need to purify the
in THF) at room temperature for 1 h, and the usual workup diastereomers. Therefore, we visualized the synthesis of 18
was followed by crystallization of the reaction mixture to from 11b by simply removing the phenylsulfonyl moiety. In
give 13b in 80% yield (m.p. Ͼ 240 °C, decomposition; see this context, 11b was heated to reflux in absolute ethanol
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Eur. J. Org. Chem. 2013, 4319–4324

cis-1,2-Cyclohexanediamines and 7-Azabicyclo[2.2.1]heptan-2-amines
used to transfer air- and moisture-sensitive reagents. All melting
points are reported in °C and were recorded with a Büchi melting
point apparatus (B-450). IR spectra were recorded with Perkin–
Elmer infrared spectrometer models 599-B and 1620 FTIR. 1H
NMR spectroscopic data were recorded in deuterated solvents with
Bruker AC-200, AV-400, and DRX-500 instruments. Chemical
shifts are reported in ppm. Proton coupling constants (J) are re-
ported as absolute values in Hz, and the multiplicities are reported
as br. (broad), s (singlet), d (doublet), t (triplet), dd (doublet of
doublet), dt (doublet of triplet), td (triplet of doublet), or m (mul-
tiplet). 13C NMR spectroscopic data were recorded with Bruker
AC-200, AV-400, and DRX-500 instruments that operated at 50,
100, and 125 MHz, respectively. The 13C NMR chemical shifts are
reported in ppm relative to the central line of CDCl3 (δ =
77.0 ppm). High-resolution mass spectrometric data were obtained
with a Thermo Scientific “Q-EXACTIVE” instrument. Optical ro-
tations were measured with a JASCO P-1030 polarimeter.
with Raney-Ni for 12 h to produce 17 in 81% yield (see
Scheme 6). The global deprotection of 17 by heating at re-
flux with 6 n HCl quantitatively gave 18 {[α]D27.5= –3 (c =
1.2, methanol)}.
Scheme 6. Synthesis of exo-7-azabicyclo[2.2.1]heptan-2-amine.
As we failed to transform 9 into its corresponding endo
derivative, we decided to proceed with 19, which was ob-
tained easily from 2. Towards this end, 19 was subjected to
reductive amination with benzylamine in the presence of
NaBH(OAc)3 to give 20 in 90% yield (see Scheme 7). Hy-
drogenolysis of 20 in methanolic HCl gave 21 {[α]2D8 = –2.6
(c = 1.5, H2O)} in 95% yield.
(1S,2S,3R,4R)-tert-Butyl
2-[(Methylsulfonyl)oxy]-3-(phenylsulf-
onyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (9): To a solution of
7 (20.0 g, 56.59 mmol) in pyridine (91.3 mL, 1.13 mol) in a round-
bottom flask was added methanesulfonyl chloride (10.95 mL,
141.47 mmol) at 0 °C, and the reaction mixture was stirred at room
temperature for 24 h until TLC revealed no starting material. The
reaction was quenched with water (500.0 mL). The resulting mix-
ture was extracted with EtOAc (3ϫ150.0 mL), and the combined
organic layers were dried with anhydrous sodium sulfate, filtered,
and concentrated by rotary evaporation. The crude material was
dried in vacuo to give 9 (24.4 g, 99.9%) as a white solid; m.p. 172.4–
174.9 °C. [α]2D7.5 = +18.0 (c = 0.525, CHCl ). IR (neat): νmax = 1704,
˜
3
1366, 1177, 1141, 1007, 968, 868 cm–1. 1H NMR (200 MHz,
CDCl3, 25 °C): δ = 8.05–7.94 (m, 2 H), 7.73–7.48 (m, 3 H), 4.92
(d, J = 7.1 Hz, 1 H), 4.67 (d, J = 3.2 Hz, 1 H), 4.40 (br. s, 1 H),
3.56 (d, J = 7.2 Hz, 1 H), 3.18 (s, 3 H), 1.78 (s, 2 H), 1.39 (s, 11 H)
ppm. 13C NMR (100 MHz, [D6]DMSO, 25 °C): δ = 153.7, 139.7,
134.4, 129.5, 129.4, 80.2, 70.3, 61.6, 58, 37.6, 28.3, 28.2, 23.3 ppm.
HRMS (ESI): calcd. for C18H29N2O7S2 [M + NH4]+ 449.1411;
found 449.1411.
Scheme 7. Synthesis of endo-7-azabicyclo[2.2.1]heptan-2-amine.
Conclusions
We have developed a scalable, practical, and relatively
inexpensive strategy towards the syntheses of cis-1,2-di-
aminocyclohexane derivatives and 7-azabicyclo[2.2.1]hept-
2-amines. Explorations using cis-1,2-diaminocyclohexane
derivatives as organocatalysts are currently underway in our
laboratory and shall be disclosed in due course.
(1S,2R,3S,4R)-tert-Butyl
2-[(Methylsulfonyl)oxy]-3-(phenylsulf-
onyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (10): By applying the
above-mentioned procedure, the corresponding mesylate 10 (99.5%
yield) was obtained as a white solid; m.p. 177.3–181.6 °C. [α]2D7.6
=
13.0 (c = 0.475, CHCl ). IR (neat): ν
= 1706, 1638, 1364, 1152,
˜
3
max
1029, 863 cm–1. H NMR (500 MHz, CDCl3, 25 °C): δ = 7.89 (d,
J = 7.6 Hz, 2 H), 7.74–7.67 (m, 1 H), 7.65–7.56 (m, 2 H), 5.22 (dd,
J = 4.4, 9.3 Hz, 1 H), 4.56–4.47 (m, 1 H), 4.05 (t, J = 4.4 Hz, 1 H),
3.72 (ddd, J = 1.5, 4.3, 9.8 Hz, 1 H), 3.20 (s, 3 H), 2.80–2.71 (m, 1
H), 2.40–2.30 (m, 1 H), 1.85–1.71 (m, 2 H), 1.39 (s, 9 H) ppm. 13C
NMR (125 MHz, CDCl3, 25 °C): δ = 154.0, 139.8, 134.3, 129.6,
128.0, 81.5, 73.9, 64.0, 60.9, 58.5, 38.7, 28.1, 23.0, 21.9 ppm.
HRMS (ESI): calcd. for C18H29N2O7S2 [M + NH4]+ 449.1411;
found 449.1409.
1
Experimental Section
General Methods: All reactions were performed under argon unless
otherwise mentioned. All glassware was dried prior to use in an
oven at 125 °C. Dry tetrahydrofuran was obtained by passing com-
mercially available predried oxygen-free formulations through acti-
vated alumina columns and distilling from sodium benzophenone
ketyl. DCM was distilled from calcium hydride and stored over
molecular sieves (MS, 4 Å). Pyridine was distilled from KOH. The
solvents for chromatography were distilled at their respective boil-
ing points. All commercial reagents were obtained from Sigma–
Aldrich Chemical Co. and S. D. Fine Chemical Co. (India). The
reactions were monitored by thin layer chromatography (0.25 mm
E. Merck silica gel plates, 60F254) and visualized by using UV light,
an ethanolic solution of phosphomolybdic acid, and iodine. Col-
umn chromatography was performed on silica gel (60–120/100–200/
(1S,2S,3R,4R)-tert-Butyl 2-(Allylamino)-3-(phenylsulfonyl)-7-aza-
bicyclo[2.2.1]heptane-7-carboxylate (11a): A solution of 9 (10.0 g,
23.2 mmol) in allylamine (34.7 mL, 463.5 mmol) was heated to
55 °C for 1 h. When TLC revealed that there was no starting mate-
rial, the allylamine was evaporated under reduced pressure to ob-
tain 11a (8.75 g, 96%) as a colorless liquid. [α]2D5 = +29.3 (c = 1.1,
1
CHCl ). IR (neat): ν
= 1699, 1639, 1368, 1149 cm–1. H NMR
˜
3
max
(500 MHz, CDCl3, 25 °C): δ = 7.87 (d, J = 7.3 Hz, 2 H), 7.67–7.59
(m, 1 H), 7.59–7.51 (m, 2 H), 5.65 (br. s, 1 H), 5.11–4.96 (m, 2 H),
230–400 mesh) that was obtained from S. D. Fine Chemical Co. 4.29 (br. s, 1 H), 4.17 (br. s, 1 H), 3.41–2.91 (m, 4 H), 2.39 (t, J =
India or SRL India. Typical syringe and cannula techniques were 9.2 Hz, 1 H), 1.90–1.78 (m, 1 H), 1.66–1.49 (m, 2 H), 1.38 (s, 9 H)
Eur. J. Org. Chem. 2013, 4319–4324
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G. Pandey, D. Dey, R. Fernandes
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ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 155.3, 139.7, 135.9,
133.8, 129.3, 127.9, 116.3, 80.4, 72.9, 63.7, 61.3, 57.3, 50.0, 28.1,
28.0, 26.0, 23.9 ppm. HRMS (ESI): calcd. for C20H29N2O4S [M +
H]+ 393.1843; found 393.1847.
low. The reaction was quenched with a saturated solution of am-
monium chloride (20 mL) after 4 h. The resulting mixture was ex-
tracted with EtOAc (3ϫ25.0 mL), and the combined organic layers
were dried with anhydrous sodium sulfate, filtered, and concen-
trated by rotary evaporation. The crude material was purified by
column chromatography (petroleum ether/ethyl acetate, 70:30) to
give 13a (1.72 g, 86%) as a white crystalline solid; m.p. 137–138 °C.
(1S,2S,3R,4R)-tert-Butyl 2-Acetamido-3-(phenylsulfonyl)-7-azabi-
cyclo[2.2.1]heptane-7-carboxylate (11b): Acetamide (13.7 g,
231.7 mmol) was added to 9 (5.0 g, 11.6 mmol) in a round-bot-
tomed flask, and the mixture was heated until the acetamide melted
(approximately 90 °C). Potassium carbonate (0.320 g, 2.3 mmol)
was then added, and the reaction mixture was stirred at that tem-
perature for 2 h. The reaction was quenched by the addition of
water (200.0 mL), and the resulting solution was extracted with
EtOAc (3ϫ100.0 mL). The combined organic layers were dried
with sodium sulfate and concentrated to give 11b (4.0 g, 87%) as a
white solid. The reaction with a mixture of 9 and 10 (50.0 g,
[α]2D7 = –52.4 (c = 0.35, MeOH). IR (neat): ν
= 2927, 1637,
˜
max
1149 cm–1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.86 (d, J =
7.6 Hz, 2 H), 7.66–7.59 (m, 1 H), 7.58–7.50 (m, 2 H), 7.14 (dd, J
= 2.7, 4.6 Hz, 1 H), 5.88–5.73 (m, 1 H), 5.22–5.10 (m, 2 H), 5.05
(d, J = 10.1 Hz, 1 H), 3.51 (dd, J = 6.0, 13.6 Hz, 1 H), 3.45–3.37
(m, 1 H), 3.32 (br. s, 1 H), 3.22 (dd, J = 6.0, 13.6 Hz, 1 H), 2.48–
2.26 (m, 2 H), 1.76–1.60 (m, 2 H), 1.41 (s, 9 H) ppm. 13C NMR
(125 MHz, CDCl3, 25 °C): δ = 155.1, 142.0, 141.0, 139.6, 136.5,
133.4, 129.3, 127.8, 116.1, 79.3, 52.9, 52.4, 49.7, 28.3, 25.3,
23.0 ppm. HRMS (ESI): calcd. for C20H29N2O4S [M + H]+
393.1843; found 393.1847.
115.9 mmol) gave 11b (40 g, 87%); m.p. 138.5–140 °C. [α]2D7.2
+24.7 (c = 2.1, CHCl ). IR (neat): ν = 1651, 1371, 1308,
=
˜
3
max
1151 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.92 (d, J =
7.5 Hz, 2 H), 7.68–7.61 (m, 1 H), 7.59–7.52 (m, 2 H), 5.57 (d, J =
9.0 Hz, 1 H), 4.63–4.52 (m, 2 H), 4.09 (d, J = 5.3 Hz, 1 H), 3.25
(t, J = 3.8 Hz, 1 H), 2.46 (ddd, J = 3.1, 8.5, 12.2 Hz, 1 H), 1.94–
1.83 (m, 1 H), 1.76 (t, J = 5.5 Hz, 2 H), 1.70 (s, 3 H), 1.43 (s, 9 H)
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 168.6, 155.2, 139.5,
134.0, 129.3, 128.2, 81.1, 73.5, 64.2, 58.1, 54.8, 28.1, 26.0, 24.1,
22.9 ppm. HRMS (ESI): calcd. for C19H27N2O5S [M + H]+
395.1635; found 395.1632.
tert-Butyl [(1S,2S)-2-Acetamido-3-(phenylsulfonyl)cyclohex-3-en-1-
yl]carbamate (13b): To a solution of 11b (0.5 g, 1.27 mmol) in THF
(5 mL) in a round-bottomed flask equipped with a magnetic stir
bar was added dropwise methylmagnesium bromide solution (1.4 m
solution in THF, 3.6 mL, 5.07 mmol) at room temperature. After a
period of time, the solution changed from colorless to yellow. The
reaction was quenched with a saturated solution of ammonium
chloride (10.0 mL) after 1 h. The reaction mixture was extracted
with EtOAc (3ϫ15.0 mL), and the combined organic layers were
dried with anhydrous sodium sulfate, filtered, and concentrated by
rotary evaporation. The crude material was recrystallized (EtOAc/
petroleum ether, 90:10) to give 13b (0.4 g, 80%) as a white solid;
m.p. 243–245 °C (decomposition). [α]2D7.5 = 154 (c = 0.8, MeOH).
(1R,2S,3S,4S)-tert-Butyl
azabicyclo[2.2.1]heptane-7-carboxylate (11c): To a stirring solution
of pyrrolidine (11.40 mL, 139.0 mmol) was added (6.0 g,
2-(Phenylsulfonyl)-3-(pyrrolidin-1-yl)-7-
9
13.90 mmol), and the reaction mixture was heated to 90 °C for 1 h.
The reaction mixture was concentrated under reduced pressure to
give 11c (5.5 g, 97%) as a pale yellow solid; m.p. 123–124 °C.
IR (neat): νmax = 1645, 1306, 1146, 1025 cm–1. 1H NMR (200 MHz,
˜
CDCl3, 25 °C): δ = 7.92–7.79 (m, 2 H), 7.70–7.50 (m, 3 H), 7.32 (t,
J = 3.6 Hz, 1 H), 5.81–5.60 (m, 1 H), 5.32–5.08 (m, 1 H), 4.87–
4.70 (m, 1 H), 3.60–3.40 (m, 1 H), 2.56–2.39 (m, 2 H), 2.11–1.89
(m, 5 H), 1.39 (s, 9 H) ppm. 13C NMR (125 MHz, [D6]DMSO,
25 °C): δ = 168.7, 154.7, 142.6, 140.1, 137.9, 133.3, 129.0, 127.6,
77.6, 49.6, 42.5, 28.3, 25.3, 22.4, 21.1 ppm. HRMS (ESI): calcd. for
C19H27N2O5S [M + H]+ 395.1635; found 395.1632.
[α]2D5 = +15.2 (c = 2.3, CHCl ). IR (CHCl ): ν
= 2972, 2067,
˜
max
3
3
1637, 1447, 1367 cm–1. 1H NMR (500 MHz, CDCl3, 25 °C): δ =
7.90 (dd, J = 1.1, 8.4 Hz, 2 H), 7.66–7.60 (m, 1 H), 7.58–7.51 (m,
2 H), 4.31 (br. s, 1 H), 4.18 (br. s, 1 H), 3.59 (br. s, 1 H), 3.06 (br.
s, 1 H), 2.50–2.27 (m, 5 H), 1.91–1.82 (m, 1 H), 1.68–1.52 (m, 6
H), 1.39 (s, 9 H) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ =
155.3, 139.9, 133.7, 129.2, 128.1, 80.0, 70.3, 69.3, 61.5, 57.5, 51.4,
28.1, 26.2, 24.4, 23.2 ppm. HRMS (ESI): calcd. for C21H31N2O4S
[M + H]+ 407.1999; found 407.2002.
tert-Butyl [(1S,2R)-2-Acetamidocyclohexyl]carbamate (14): To a
stirred solution of 13b (100 mg, 0.254 mmol) in absolute ethanol
(5 mL) was added Raney-Ni (38 mg, 0.632 mmol) in one portion,
and the reaction mixture was heated at reflux for 12 h. The reaction
mixture was cooled and then passed through a pad of Celite. The
filtrate was concentrated by rotary evaporation to give 14 (65 mg,
100%) as a colorless liquid. [α]2D7 = +5 (c = 1, CHCl3). IR (CHCl3):
(1R,4S)-tert-Butyl 2-(Phenylsulfonyl)-7-azabicyclo[2.2.1]hept-2-ene-
7-carboxylate (12): To a solution of 9 and 10 (1.0 g, 2.32 mmol)
in dichloromethane was added DBU (0.7 mL, 4.64 mmol) at room
temperature, and the reaction mixture was stirred for 1 h, in which
time TLC revealed no starting material. The reaction was quenched
with water (10.0 mL), and the resulting solution was extracted with
of EtOAc (3ϫ10.0 mL). The combined organic layers were concen-
trated, and the crude material was dried in vacuo to give 12 (0.77 g,
99%) as a white solid. [α]2D5.4 = +6 (c = 2.5, CHCl3) To this was
added allylamine (1.72 mL, 23.0 mmol), and the reaction mixture
was heated at 55 °C for 1 h. When TLC revealed no starting mate-
rial, the reaction mixture was concentrated under reduced pressure.
The crude material was dried in vacuo to give 11a (0.860 g, 95%)
as a colorless liquid. The analytical data matched that of previously
synthesized 11a.
ν
max = 3333, 2933, 2859, 1694, 1645, 1532, 1455, 1367, 1335, 1312,
˜
1249, 1172, 1050, 979, 755 cm–1. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 6.42 (br. s, 1 H), 5.01 (br. s, 1 H), 3.94 (br. s, 1 H), 3.81
(br. s, 1 H), 1.95 (s, 3 H), 1.84–1.53 (m, 4 H), 1.43 (s, 13 H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 170.1, 156.3, 79.7, 50.6,
50.1, 29.4, 28.3, 27.8, 23.4, 22.8, 21.2 ppm. HRMS (ESI): calcd. for
C13H25N2O3 [M + H]+ 257.1860; found 257.1853.
tert-Butyl [(1S,2R)-2-Acetamidocyclohex-3-en-1-yl]carbamate (15):
To a stirred solution of 13b (0.2 g, 0.51 mmol) in methanol (10 mL)
at –20 °C was added in one portion 6% sodium amalgam (0.58 g,
tert-Butyl [(1S,2S)-2-(Allylamino)-3-(phenylsulfonyl)cyclohex-3-en- 1.52 mmol), and the resultant reaction mixture was stirred at that
1-yl]carbamate (13a): To a solution of 11a (2.0 g, 5.10 mmol) in
THF (20 mL) in a round-bottom flask equipped with a magnetic
stir bar was added dropwise methylmagnesium bromide solution
(1.4 m solution in THF, 14.6 mL, 20.4 mmol) at room temperature.
After a period of time, the solution changed from colorless to yel-
temperature for 24 h. The reaction was quenched with a saturated
aqueous solution of ammonium chloride (10.0 mL), and the result-
ant solution was extracted with EtOAc (3ϫ15.0 mL). The com-
bined organic layers were dried with anhydrous sodium sulfate, fil-
tered, and concentrated by rotary evaporation. The crude material
4322
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cis-1,2-Cyclohexanediamines and 7-Azabicyclo[2.2.1]heptan-2-amines
was purified by column chromatography (EtOAc/petroleum ether,
temperature for 24 h until TLC showed complete conversion of the
starting material and then was quenched with NaOH (2 n solution,
5.00 mL). The layers were separated, and the aqueous layer was
70:30) to give 15 (0.11 g, 85%) as a colorless liquid. [α]2D4 = –31.1
(c = 0.9, CHCl ). IR (CHCl ): νmax = 3435, 2094, 1642, 1369, 1169,
˜
3
3
1048 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 5.88–5.80 (m, extracted with DCM (3ϫ10.0 mL). The combined organic layers
1
1 H), 5.68 (br. s, 1 H), 5.62–5.50 (m, 1 H), 5.03 (br. s, 1 H), 4.62
(br. s, 1 H), 3.90 (tt, J = 4.0, 7.8 Hz, 1 H), 2.13 (br. s, 2 H), 2.02
(s, 3 H), 1.78 (br. s, 1 H), 1.68–1.61 (m, 1 H), 1.45 (s, 9 H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 170.4, 155.9, 130.4, 126.2,
79.5, 48.8, 47.2, 28.3, 24.7, 23.5, 22.8 ppm. HRMS (ESI): calcd. for
C13H22N2O3Na [M + Na]+ 277.1523; found 277.1517.
were dried with sodium sulfate, filtered, and concentrated by rotary
evaporation. The crude material was purified by column
chromatography (EtOAc/petroleum ether, 60:40) to give 20 (0.27 g,
94%) as a colorless liquid. [α]2D8.9 = +12.2 (c = 0.5, CHCl3). IR
(neat): νmax = 3087, 3063, 3006, 2975, 2871, 2090, 1698, 1641, 1496,
˜
1456, 1366, 1165 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
7.24–7.18 (m, 4 H), 7.18–7.12 (m, 1 H), 4.19–3.93 (m, 2 H), 3.59
(s, 2 H), 3.23–3.10 (m, 1 H), 2.13–2.01 (m, 1 H), 1.96 (ddd, J =
4.5, 9.2, 12.2 Hz, 1 H), 1.34 (s, 9 H), 0.78 (dd, J = 4.6, 12.1 Hz, 1
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 155.7, 140.0,
128.4, 128.2, 127.1, 79.5, 58.8, 58.5, 56.8, 52.9, 37.9, 30.1, 28.3,
tert-Butyl [(1S,2S)-2-Acetamido-3-(phenylsulfonyl)cyclohexyl]carb-
amate (16): To a solution of 13b (200 mg, 0.507 mmol) in methanol
(20 mL) in a round-bottomed flask equipped with a magnetic stir
bar was added 10% Pd/C (54 mg, 0.05 mmol) at room temperature.
A hydrogen balloon was then attached, and the reaction mixture
was stirred vigorously for 24 h until TLC revealed no starting mate-
rial. The reaction mixture was passed through a pad of Celite, and
the filtrate was concentrated in vacuo to give 16 (0.2 g, 99%) as a
colorless liquid. [α]2D6 = +24.8 (c = 1.3, CHCl3). 1H NMR
(200 MHz, CDCl3, 25 °C): δ = 7.89–7.79 (m, 2 H), 7.75–7.51 (m, 3
H), 6.38 (d, J = 7.3 Hz, 1 H), 4.33–4.19 (m, 1 H), 3.91 (t, J =
10.4 Hz, 1 H), 3.27 (dt, J = 3.9, 10.5 Hz, 1 H), 2.28–2.14 (m, 1 H),
1.98 (s, 3 H), 1.89–1.70 (m, 2 H), 1.61–1.49 (m, 1 H), 1.43 (s, 9 H)
ppm. HRMS (ESI): calcd. for C19H29N2O5S [M + H]+ 397.1792;
found 397.1799.
21.4 ppm. HRMS (ESI): calcd. for C18H27N2O2 [M
303.2067; found 303.2079.
+
H]+
(1S,2S,4R)-7-Azabicyclo[2.2.1]heptan-2-amine Hydrochloride (21):
To a solution of 20 (100 mg, 0.33 mmol) in distilled methanol
(5 mL) were added HCl (6 n solution, 5 mL) and Pd(OH)2/C
(46 mg, 0.66 mmol), and the reaction mixture was put into a Parr
shaker and shaken under hydrogen pressure (60 psi) at room tem-
perature for 4 h. The solution was filtered, and the filtrate was con-
centrated under reduced pressure to give 21 (59 mg, 97%) as a col-
orless solid. [α]2D8 = +2.2 (c = 2, H O). IR (neat): νmax = 2068, 1637,
˜
2
1422, 1022 cm–1. 1H NMR (400 MHz, D2O, 25 °C): δ = 4.43 (br.
s, 1 H), 4.28 (t, J = 4.5 Hz, 1 H), 3.97–3.89 (m, 1 H), 2.50–2.39 (m,
1 H), 2.08–1.96 (m, 3 H), 1.87–1.77 (m, 1 H), 1.64 (dd, J = 4.4,
14.4 Hz, 1 H) ppm. 13C NMR (100 MHz, D2O, 25 °C): δ = 59.4,
59.2, 48.2, 31.3, 26.3, 19.7 ppm. HRMS (ESI): calcd. for C6H13N2
[M + H]+ 113.1073; found 113.1044.
(1S,2R,4R)-tert-Butyl
2-Acetamido-7-azabicyclo[2.2.1]heptane-7-
carboxylate (17): To a solution of 11b (200 mg, 0.507 mmol) in ab-
solute ethanol (10 mL) was added freshly prepared Raney-Ni
(90 mg, 1.5 mmol). The reaction mixture was heated at reflux for
12 h until TLC revealed no starting material. The mixture was co-
oled and then passed through a pad of Celite. The filtrate was con-
centrated in vacuo to give 17 (105 mg, 81%) as a colorless liquid.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra for the compounds synthesized.
[α]2D9.2 = +71.6 (c = 2, CH OH). IR (neat): νmax = 2978, 1648, 1638,
˜
3
1368, 1168, 1138, 1020 cm–1. H NMR (400 MHz, CDCl3, 25 °C):
1
δ = 5.93 (br. s, 1 H), 4.22 (t, J = 4.9 Hz, 1 H), 4.07 (d, J = 5.0 Hz,
1 H), 3.97 (dt, J = 3.3, 7.9 Hz, 1 H), 1.94 (s, 3 H), 1.81–1.61 (m, 2
H), 1.53–1.46 (m, 2 H), 1.44 (s, 9 H), 1.40 (dd, J = 2.9, 17.2 Hz, 2
H) ppm. 13C NMR (100 MHz, [D6]DMSO, 25 °C): δ = 169.4,
156.4, 80.1, 61.3, 55.9, 53.0, 40.4, 28.3, 28.2, 25.9, 23.2 ppm.
HRMS (ESI): calcd. for C13H23N2O3 [M + H]+ 255.1703; found
255.1700.
Acknowledgments
We thank the Department of Science & Technology (DST), New
Delhi for its generous financial support. D. D. and R. F. thank the
Council of Scientific and Industrial Research (CSIR) and the Uni-
versity Grants Commission (UGC), respectively, for their fellow-
ships. We are grateful to Dr. Kunte and Mr. Shrikant for helping
(1S,2R,4R)-7-Azabicyclo[2.2.1]heptan-2-amine Hydrochloride (18): with the HPLC analyses and for recording the NMR spectra,
A solution of 17 (100 mg, 0.393 mmol) in HCl (6 n solution, 5 mL)
in a round-bottom flask equipped with a magnetic stir bar and a
reflux condenser was heated to reflux for 12 h until TLC reveal no
starting material. The reaction mixture was concentrated by rotary
evaporation, and the crude material was dried in vacuo to give 18
(71 mg, 98%) as a brown solid. [α]2D7.5 = 3 (c = 1.2, CH3OH). IR
respectively.
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Received: February 18, 2013
Published Online: May 16, 2013
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Eur. J. Org. Chem. 2013, 4319–4324