An intramolecular [2 + 2] photocycloaddition approach to conformationally restricted bis-pyrrolidines

Article abstract of DOI:10.1021/jo501302f

With N-Boc-protected 4-(allylaminomethyl)-2(5H)furanones as starting materials, a photochemical approach is presented to give 3,9-diazatricyclo[5.3. 0.0^1,5]decanes as conformationally restricted bis-pyrrolidines. The products are orthogonally protected at the two nitrogen atoms and exhibit, depending on the substitution pattern at positions C5, C6, and C7, latent C ₂ symmetry. When the furanones had a phenyl group at the 3-position (X³), alternative photochemical pathways were observed.

Full text of DOI:10.1021/jo501302f

Article
pubs.acs.org/joc
An Intramolecular [2 + 2] Photocycloaddition Approach to
Conformationally Restricted Bis-Pyrrolidines
Diego A. Fort,†,‡ Thomas J. Woltering,*,‡ Andre M. Alker,§ and Thorsten Bach*,†
́
†Lehrstuhl fur Organische Chemie I, Technische Universitat Munchen, Lichtenbergstrasse 4, 85747 Garching, Germany
̈
̈
̈
§
‡Discovery Chemistry and Biostructure Section, Molecular Design & Chemical Biology, Roche Pharmaceutical Research and Early
Development, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland
S
* Supporting Information
ABSTRACT: With N-Boc-protected 4-(allylaminomethyl)-2-
(5H)furanones as starting materials, a photochemical approach
is presented to give 3,9-diazatricyclo[5.3.0.01,5]decanes as
conformationally restricted bis-pyrrolidines. The products are
orthogonally protected at the two nitrogen atoms and exhibit,
depending on the substitution pattern at positions C5, C6, and
C7, latent C2 symmetry. When the furanones had a phenyl group at the 3-position (X3), alternative photochemical pathways were
observed.
INTRODUCTION
■
Four-membered alicyclics, most notably cyclobutanes1 and
oxetanes,2 combine the rigidity of a small-ring compound
within comparison to three-membered ringsa remarkable
stability toward ring-opening reactions. In searches for
kinetically stable, conformationally restricted analogues of
known scaffolds, the introduction of a four-membered ring is
frequently considered.3 In this context, photochemical [2 + 2]
photocycloaddition reactions play a crucial role in the
construction of conformationally restricted molecules, as they
allow for the formation of cyclobutanes and oxetanes in a single
reaction step. Cyclic α,β-unsaturated carbonyl compounds are
key components in the most important [2 + 2] photo-
cycloaddition approach toward cyclobutane products.4 They
can be readily excited at long wavelength and undergo rapid
intersystem crossing (ISC) to relatively long-lived triplet
states,5 which can be intercepted inter- or intramolecularly by
another olefin to provide the desired cyclobutane products.
When considering potential conformationally restricted var-
iants6 of the pharmacologically relevant7 bis-pyrrolidines 1 and
2, we noted that a cyclobutane backbone connecting the 4,9-
position of the spiro skeleton would result in the 3,9-
diazatricyclo[5.3.0.01,5]decane skeleton A, as depicted in Figure
1, which in turn would position the basic nitrogen atoms in a
defined spatial relationship.8
Figure 1. Structures of the parent 2,7-diazaspiro[4.4]nonane (1), its
protected analogue 2, and related generic pyrrolidine derivatives A and
B.
products A. In this report, we describe the synthesis of both
latently symmetric (X1 = X3) and nonsymmetric (X1 ≠ X3) 3,9-
diazatricyclo[5.3.0.01,5]decanes employing an intramolecular [2
+ 2] photocycloaddition as the key step. We discuss possible
side reactions and show that the chosen protective groups at
the nitrogen atoms allow for orthogonal deprotection in further
synthetic transformations.
RESULTS
■
Parent and Nonsymmetric 3,9-Diazatricyclo-
[5.3.0.01,5]decanes. Before performing an extensive study
on the [2 + 2] photocycloaddition route to compounds of type
B, we screened possible reaction conditions to convert
compounds of type B into the target compounds A. Lactone
ring opening of the previously reported tert-butyloxycarbonyl
(Boc) protected 3-aza-9-oxatricyclo[5.3.0.01,5]decan-8-one
(3)10a was performed with benzylamine. It was found that
the ring opening works best in this case upon heating to reflux
in THF solution, and it delivered γ-hydroxyamide 4 in 87%
yield.13 The cyclization to lactam 5 was preferably performed in
a one-pot procedure by initial mesylation of the free hydroxy
If the substituents X1 and X3 are identical, the molecules will
exhibit latent C2 symmetry, readily manifested by deprotection
of the nitrogen atoms. Although there have been a few scattered
reports on the synthesis of molecules with the 3,9-diazatricyclo-
[5.3.0.01,5]decane skeleton A,9 a general approach has, to the
best of our knowledge, not yet been reported. Since previous
studies have shown10 that lactones of type B can be generated
by intramolecular [2 + 2] photocycloaddition reactions of
appropriately substituted 4-aminomethyl-2(5H)-furanones,11,12
we considered them as potential precursors of the desired
Received: June 11, 2014
Published: July 7, 2014
© 2014 American Chemical Society
7152
dx.doi.org/10.1021/jo501302f | J. Org. Chem. 2014, 79, 7152−7161

The Journal of Organic Chemistry
Article
group with methanesulfonyl chloride (MsCl) and subsequent
treatment with LiOtBu to induce the nucleophilic substitu-
tion.14 Selective lactam reduction with borane−THF complex
delivered after workup the doubly protected 3,9-diazatricyclo-
[5.3.0.01,5]decane as the corresponding ammonium salt, from
which the free base 6 was liberated with triethylamine (Scheme
1).15 It was possible to perform the reduction of amide 4 prior
more convenient to synthesize it from the respective alcohol
(see the Supporting Information) by bromodehydroxylation
with PBr3.10b With bromide 7 as the starting material, the
synthesis of tricyclic lactone was readily accomplished via the
N-Boc-protected 4-(allylaminomethyl)-2(5H)-furanone 8
(Scheme 2). Irradiation of the latter compound at λ 300 nm
Scheme 2. Synthesis of Lactone 9a by Substitution of
Bromide 7 and Subsequent Intramolecular [2 + 2]
Photocycloaddition
Scheme 1. Conversion of Photocycloaddition Product 3 into
the Orthogonally Protected, Conformationally Restricted
Bis-Pyrrolidine 6
furnished the desired product 9a after an extended irradiation
period of 5 days. Attempts to perform the reaction at shorter
wavelength (λ 254 nm) resulted in complete loss of starting
material after 2 h of irradiation time. Despite the fact that the
yield of product 9a was good, a second product was isolated in
minor amounts, which could not be fully characterized but was
assigned a structure on the basis of X-ray crystallographic
evidence (see the Supporting Information for further details).
Other 3-aza-9-oxatricyclo[5.3.0.01,5]decan-8-ones with sub-
stituents at the 7-position (X3 = Ph, Me, F; 9 in Table 1) and at
to the cyclization, but the attempted conversion of the resulting
δ-amino alcohol into product 6 could not be performed in this
case (vide infra).
The synthesis of product 6 was readily performed in the lab
on a multigram scale (up to 27 g of product). Compound 5
could be easily separated into its enantiomers by chiral
preparative chiral HPLC (see the Experimental Section). The
crystal structure of the 1S,5S,7S enantiomer, which is
dextrorotatory, is depicted in Figure 2. It nicely illustrates the
Table 1. Conversion of Lactones 9 and 10 into Orthogonally
Protected, Conformationally Restricted Bis-Pyrrolidines 11
and 12
a
entry
1
X1
X3
substrate
product
yield (%)
H
Ph
Me
F
9a
11a
11b
11c
12a
12b
54
52
52
62
51
b
2
H
9b
b
3
H
9c
4
5
Ph
Me
H
10a
10b
H
a
Total yield over three reaction steps. Specific reaction conditions for
the individual steps: (1) BnNH2 (1.05 equiv) THF, reflux, 14 h; (2)
MsCl (1.4 equiv), NEt3 (1.7 equiv), THF, −78 → 0 °C, 2 h, then −50
°C, LiOtBu (1 M in THF, 2.8 equiv), 25 min; (3) BH3·THF (1 M in
THF, 3.3 equiv), 0 °C → room temperature, 14 h, then NEt3 (5.85
Figure 2. Crystal structure of the enantiomerically pure product (+)-5.
b
equiv), EtOH, H2O, reflux, 90 min. The ring opening with
benzylamine was performed for 72 h at ambient temperature.
rigidity of the molecular skeleton due to the almost planar
cyclobutane ring. Bis-pyrrolidine 6 turned out to be slightly less
basic than the less restricted compound 2, most likely because
the N-benzylpyrrolidine part in 6 adopts an endo conformation
(“boat shaped”) relative to the cyclobutane ring. The pKa of the
corresponding ammonium ion was determined to be 8.2 for 6,
in comparison to 8.4 for 2.
Alkyl bromide 7 was required as a starting material for the
synthesis of 7-phenyl-substituted 3-aza-9-oxatricyclo[5.3.0.01,5]-
decan-8-one (9a). Although the compound has been previously
prepared by 2-fold Wohl−Ziegler bromination of 3-methyl-2-
phenylcrotonic acid and subsequent ring closure by nucleo-
philic displacement of a bromide leaving group,16 we found it
the 5-position (X1 = Ph, Me; 10 in Table 1) have been
previously described.10 In the present study, it was shown that
their conversion to the conformationally restricted bis-
pyrrolidines 11 and 12 could be performed in full analogy to
the previously described conversion 3 → 6. However, the
intermediate products for the reaction sequence were in these
cases not fully characterized but immediately taken into the
next reaction step. The yields provided in Table 1 refer to
overall yields as recorded for the complete sequence, and they
vary between 51% and 62%.
7153
dx.doi.org/10.1021/jo501302f | J. Org. Chem. 2014, 79, 7152−7161

The Journal of Organic Chemistry
Article
In contrast to the conversion 4 → 6, for which a reduction/
cyclization protocol with 1,1′-carbonylimidazole (CDI) as the
reagent had given a product mixture, it was possible for the
ring-opening products of lactones 9a,b to perform the
reduction (BH3·THF, then NEt3) prior to the cyclization
with CDI in CH2Cl2. Apparently, the additional substituent at
the 7-position favors the nucleophilic displacement of the
activated alcohol by the amine and disfavors the formation of
the cyclic carbamate. The two-step procedure proceeded in
nearly quantitative yield and is a viable alternative to the
cyclization/reduction route depicted in Table 1.
prop-2-enylamine10a was facile and delivered after Boc
protection the desired difluorinated substrate 17, the [2 + 2]
photocycloaddition (λ 254 nm) of which generated cleanly the
desired product 18 as a single diastereoisomer.
Similar to the synthesis of the difluorinated product 18, the
diphenylated product 21 (Scheme 4) was synthesized from the
Scheme 4. Formation of the [2 + 2] Photocycloaddition
Product 21 and of the Byproduct 22 upon Irradiation of
Lactone 19 at λ 300 nm
Compounds 11 showed a significantly reduced basicity in
comparison to the parent compound 6. The pKa decrease for
the ammonium salts of 11a (pKa = 6.7) and 11b (pKa = 7.7) is
mainly due to the neopentylic character17 of the amines by
introduction of the angular phenyl (11a) and methyl (11b)
substituents at carbon atom C7. The even further reduced
basicity of the fluoro compound 11c (pKa = 5.7) is testimony to
the strongly inductive electron withdrawing power of the
fluorine substituent. In addition, the fluorine adopts a gauche
position relative to the nitrogen atom N9 in the adjacent boat-
shaped pyrrolidine ring, which is ideal for stabilization of the
corresponding ammonium ion.18
C2-Symmetric 3,9-Diazatricyclo[5.3.0.01,5]decanes. Di-
amines of general structure B (Figure 1) with identical
substituents X1 and X3 exhibit a latent C2 symmetry, which is
only disturbed by the nonsymmetric orthogonal amine
protection at nitrogen atoms N3 and N9. Product 6 represents
the parent member of this compound class, while other
members show substitution at positions C5, C7 (X1 and X3)
and C6 (X2). According to our general strategy for the
synthesis of 3,9-diazatricyclo[5.3.0.01,5]decanes, substituents at
C6 were introduced via the respective allylic amine. With the
known10b bromide 13 as the starting material, nucleophilic
substitution by 3-methylbut-2-enylamine and subsequent Boc
protection delivered the photocycloaddition precursor 14,
which gave upon irradiation (λ 254 nm) in acetonitrile the
desired lactone product 15 (Scheme 3).
respective α-substituted 2(5H)-furanone 7 (Scheme 2).
Aminodebromination with 2-phenylprop-2-enylamine gave
after Boc protection the desired 2(5H)-furanone 19. As was
already observed with the α-phenyl-substituted substrate 8, the
photophysical and photochemical behavior of these compounds
was different from that of the other N-Boc-4-(allylamino)-
2(5H)-furanones. They exhibit an intense absorption (ε ≅
9500 M−1 cm−1) at ca. 250 nm, which is weak for the other
2(5H)-furanones, and they decomposed upon irradiation in
acetonitrile at this wavelength (λ 254 nm). At longer
wavelength (λ 300 nm) the desired [2 + 2] photocycloaddition
was observed, and it proceeded within 6 h to completion in the
case of substrate 19. Two products could be cleanly isolated
from the product mixture, the major product of which was the
expected lactone 21. On the basis of extensive NMR studies
structure 22 was assigned to an isomeric byproduct, which was
isolated in 22% yield. Mechanistically, the formation of this
byproduct is straightforward, on the basis of the likely
assumption that the photocycloaddition proceeds in the triplet
manifold via 1,4-diradical intermediate 20. Recombination of
the radical centers after ISC leads to cyclobutane ring formation
or alternatively attack at the aromatic ortho position to give a
nonaromatic cyclohexadiene product, which undergoes rapid
tautomerization to 22. Remarkably, irradiation of substrate 19
generated a third product, which was more difficult to isolate
than 21 and 22 and turned out to be unstable (see Supporting
Information).
Scheme 3. Synthesis of Lactones 15 and 18 by
Intramolecular [2 + 2] Photocycloaddition of Substrates 14
and 17
With substrates 15, 18, and 21 in hand, the transformation to
the desired bis-pyrrolidines with latent C2 symmetry was
pursued. In addition, the previously reported10 3-aza-9-
oxatricyclo[5.3.0.01,5]decan-8-one 23 was included in this series
of experiments (Table 2). To our delight, the three-step
sequence of lactone ring opening/lactam formation/reduction
turned out to be general and could be applied nicely to the
synthesis of products 24−27. Yields varied between 43 and
79%. The ammonium salt of product 25 showed an extremely
low pKa value of 4.9, which can be explained by the presence of
two electron-withdrawing fluorine substituents, while the
basicitiy of product 24 (pKa = 8.3) was expectedly found to
For the introduction of substituents at C5, C7 in the final
target, the 2(5H)-furanone component and the tethered olefin
must carry an identical substituent, the 2(5H)-furanone at the
α-position and the olefin at the internal carbon atom. In order
to access the difluorosubstituted product 18, it was therefore
necessary to start the synthesis with the known10b α-fluoro-
2(5H)furanone 16. Nucleophilic displacement with 2-fluoro-
7154
dx.doi.org/10.1021/jo501302f | J. Org. Chem. 2014, 79, 7152−7161

The Journal of Organic Chemistry
Article
An example of an orthogonal disubstitution procedure is
depicted in Scheme 6, which shows how the two amino groups
Table 2. Synthesis of Orthogonally Protected C2-Symmetric
3,9-Diazatricyclo[5.3.0.01,5]decanes 24−27 from [2 + 2]
Photocycloaddition Products
Scheme 6. Decoration of the Nitrogen Atoms in 3,9-
Diazatricyclo[5.3.0.01,5]decane 29 by N-Substitution
Reactions
a
entry
1
X1
X2
substrate
product
yield (%)
H
Me
H
15
18
21
23
24
25
26
27
43
79
56
48
b
2
F
b
3
Ph
Me
H
4
H
a
can be selectively addressed and how the conformationally
restricted bis-pyrrolidine skeleton can be decorated. For the
decoration of the scaffold two pharmacologically relevant
heterocyclic units (pyrimidine, pyrrolidine) were arbitrarily
chosen. Nucleophilic displacement of the 4-chloro group in 2,4-
dichloro-5-fluoropyrimidine was accomplished with mono-
protected diamine 29 to give product 32 in high yields. After
removal of the Boc group, the second amine nitrogen atom was
acylated by a chloroformamide to provide urea 33.
Total yield over three reaction steps. Specific reaction conditions for
the individual steps: (1) BnNH2 (1.05 equiv) THF, reflux, 14 h; (2)
MsCl (1.4 equiv), NEt3 (1.7 equiv), THF, −78 → 0 °C, 2 h, then −50
°C, LiOtBu (1 M in THF, 2.8 equiv), 25 min; (3) BH3·THF (1 M in
THF, 3.3 equiv), 0 °C → room temperature, 14 h, then NEt3 (5.85
equiv), EtOH, H2O, reflux, 90 min. The ring opening with
benzylamine was performed for 72 h at ambient temperature.
b
be almost identical with that of the parent compound 6. A
single-crystal X-ray analysis of compound 25 (see the
Supporting Information) confirmed the notion that the fluorine
atom at the N-benzylpyrrolidine ring is positioned gauche to
the basic nitrogen atom N9 (vide supra).
Further Functionalization of 3,9-Diazatricyclo-
[5.3.0.01,5]decane 6. The known orthogonality of benzyl
and Boc protecting groups allowed us to address the two amine
positions separately. With the parent 3,9-diazatricyclo-
[5.3.0.01,5]decane, i.e. compound 6, as a model substrate, it
was shown that complete reduction of the Boc group with an
excess of lithium aluminum hydride led to the N-methyl
derivative 28 (Scheme 5). With a first pKa value of 9.2 for the
CONCLUSION
■
In summary, 10 members of a new class of rigid scaffolds have
been prepared. They can be best described as conformationally
restricted bis-pyrrolidines but also contain a conformationally
restriced 3,7-diazabicyclo[3.3.1]nonane skeleton. Their cyclo-
butane core is established by an intramolecular 2(5H)-furanone
[2 + 2] photocycloaddition, and the furanone-derived γ-lactone
is transformed into a pyrrolidine by three further reaction steps.
Except for 3-phenyl-2(5H)-furanones, the [2 + 2] photo-
cycloaddition proceeds rapidly (0.5−18 h) and is amenable to
scale-up (>20 g in a single batch). The two nitrogen atoms,
which are orthogonally protected, can be addressed sequen-
tially, and the new scaffolds therefore deliver a great number of
opportunities for further decoration.
Scheme 5. Further Functionalization of Protected 3,9-
Diazatricyclo[5.3.0.01,5]decane 6 Utilizing the Orthogonality
of Its Protecting Groups
EXPERIMENTAL SECTION
■
General Methods. All reactions, sensitive to air or moisture, were
carried out in flame-dried glassware under a positive pressure of argon
using standard techniques. For the photoreactions, the compounds
were dissolved in the corresponding solvent, degassed by purging with
Ar in an ultrasonicator for 15 min, and irradiated in a merry-go-round
reactor, equipped with 16 lamps emitting at λ 254 nm or at λ 300
nm.20 Unless otherwise stated, the reactions were stopped when the
starting material was fully consumed according to thin-layer
chromatography (TLC) and/or LC-MS analysis. The solvent was
then removed, and the residue was purified by column chromatog-
raphy. Unless otherwise noted, only one reaction product could be
isolated. Flash chromatography was performed on silica gel 60 (230−
400 mesh) with the eluent mixtures given for the corresponding
procedures. TLC was performed on silica-coated glass plates (silica gel
60 F254). Compounds were detected by UV (λ 254 nm), CAM
(cerium ammonium molybdate solution), or KMnO4. 1H and 13C
NMR spectra were recorded at 300 K unless otherwise indicated.
Chemical shifts are reported relative to the solvent (CHCl3, δ(1H)
7.26 ppm, δ(13C) 77.0 ppm; DMSO, δ(1H) 2.50 ppm, δ(13C) 39.5
ammonium ion of 28, the basicity of this compound is still
significantly lower than that of N-methylpyrrolidine (pKa =
10.5).19 Selective deprotection of the benzyl group was
achieved by hydrogenolysis of substrate 6 in the presence of
Pearlman’s catalyst to give the mono-Boc-protected diamine
29. The Boc group was conveniently removed by stirring
substrate 6 in a solution of hydrochloric acid in dioxane at
room temperature to produce the monobenzylated diamine 30.
Eventually, the C2-symmetric diamine 31 was available as its
dihydrochloride upon deprotection of compound 29 with HCl
in dioxane.
1
ppm) as reference. Data for H NMR spectra are reported as follows:
chemical shift (ppm), peak shape (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad signal), coupling constant (Hz), and
integration. 13C NMR spectra are proton-decoupled. In some cases,
two rotamers are detectable by NMR spectroscopy. When possible,
7155
dx.doi.org/10.1021/jo501302f | J. Org. Chem. 2014, 79, 7152−7161

The Journal of Organic Chemistry
Article
20
the NMR data of the major rotamer are given. Apparent multiplets
which occur as a result of the accidental equality of coupling constants
with those of magnetically nonequivalent protons are marked as virtual
(virt). The relative configuration of the products and the multiplicity
of the 13C NMR signals were determined by two-dimensional NMR
spectra (COSY, NOESY, HSQC, HMBC). HRMS data were recorded
by electron spray ionization (ESI) on an ion trap mass spectrometer.
The pKa values were all measured by spectrophotometric (UV-metric)
titration methods.21
126−128 °C, 100% ee; [α]D = +111.0° (c = 1.00, CHCl3)) and
(−)-5 is (1R,5R,7R)-9-benzyl-3-tert-butoxycarbonyl-3,9-diazatricyclo-
[5.3.0.01,5]decan-8-one ((−)-5; 3.10 g, 9.05 mmol, 44.5% yield, mp
20
127−129 °C, 98.8% ee, [α]D = −97.7° (c = 1.00, CHCl3)).
9-Benzyl-3-tert-butoxycarbonyl-3,9-diazatricyclo[5.3.0.01,5]-
decane (6). To a suspension of the pyrrolidinone 5 (29.8 g, 87.0
mmol, 1.0 equiv) in THF (50 mL) at 0 °C was added cold borane−
THF complex (1 M in THF) (287 mL, 287 mmol, 3.3 equiv), and the
mixture was stirred at room temperature for 18 h. After the reaction
mixture was concentrated under reduced pressure to give a white solid,
ethanol (430 mL), triethylamine (71.0 mL, 509 mmol, 5.85 equiv),
and water (71 mL) were added at 23 °C (exothermic), and the
mixture was heated to reflux (95 °C) for 1.5 h. After the reaction
mixture was concentrated under reduced pressure, water (500 mL)
and 3 M NaOH (aq) (200 mL) were added, and the mixture was
extracted twice with dichloromethane (2 × ca. 250 mL). The
combined organic layers were dried over Na2SO4 and then filtered.
Removal of the solvent under vacuum left a light yellow oil. The crude
material was purified by column chromatography (heptane/EtOAc 1/
1) to give the pure product 6 (27.0 g, 94%) as a colorless oil which
crystallized later to a white solid. Mp: 73−75 °C. Rf = 0.61 (heptane/
tert-Butyl 7-(Benzylcarbamoyl)-1-(hydroxymethyl)-3-
azabicyclo[3.2.0]heptane-3-carboxylate (4). A mixture of the N-
Boc derivative 3 (5.00 g, 19.7 mmol, 1.0 equiv) and benzylamine (2.24
mL, 20.5 mmol, 1.05 equiv) in dry THF (6.0 mL) was refluxed under
argon for 14 h. Evaporation to dryness and purification of the crude
product by column chromatography (heptane/EtOAc 1/3) afforded
the desired product 4 as a white solid (6.17 g, 87%). Mp: 117−119 °C.
Rf = 0.34 (heptane/EtOAc 1/3). IR (ATR): ν
̃
(cm−1) 3485 (s, C−
OH), 3298 (s, NH), 3024 (m), 1676 (vs, NH−CO), 1645 (w),
1
1414 (m), 1365 (m), 1254 (s), 1174 (s), 732 (s), 697 (s). H NMR
(500 MHz, DMSO-d6): δ (ppm) 8.28 (br. s, 1 H), 7.34−7.28 (m, 2
H), 7.27−7.18 (m, 3 H), 4.64 (t, J = 5.3 Hz, 1 H), 4.28 (dd, J = 15.1
Hz, J = 5.9 Hz, 1 H), 4.22 (dd, J = 15.1 Hz, J = 5.9 Hz, 1 H), 3.58 (br.
s, 1 H), 3.48 (dd, J = 11.0 Hz, J = 4.6 Hz, 1 H), 3.45−3.43 (m, 1 H),
3.41 (dd, J = 11.4 Hz, J = 1.8 Hz, 1 H), 3.25 (br. s, 1 H), 3.16 (br. s, 1
H), 2.90 (t, J = 8.2 Hz, 1 H), 2.53−2.49 (m, 1 H), 2.47−2.42 (m, 1
H), 1.58 (dd, J = 11.3 Hz, J = 2.6 Hz, 1 H), 1.42 (s, 9 H). 13C{1H}
NMR (151 MHz, DMSO-d6): δ (ppm) 171.3, 154.7, 140.1, 128.7,
127.8, 127.2, 78.8, 61.4, 53.3, 52.8, 43.4, 42.7, 40.6, 28.6, 24.3 (one
carbon atom not observed). MS (EI, 70 eV): m/z (%) 361 (11) [(M +
H)+], 306 (100) [(M − C4H8)+]. HRMS (ESI): calculated for
EtOAc 1/1). IR (ATR): ν
̃
(cm−1) 2971 (s, C−H), 2846 (s, C−H),
1676 (vs, CO), 1392 (s), 1394 (m), 1390 (vs), 1117 (m), 770 (w).
1H NMR (600 MHz, CDCl3): δ (ppm) 7.38 (d, J = 7.0 Hz, 2 H), 7.30
(virt t, J ≈ 7.0 Hz, 2 H), 7.25−7.23 (m, 1 H), 3.70 (d, J = 13.4 Hz, 1
H), 3.68−3.65 (m, 1 H), 3.63 (d, J = 13.4 Hz, 1 H), 3.59−3.54 (m, 1
H), 3.28 (br. s, 1 H), 2.98 (d, J = 11.6 Hz, 1 H), 2.86 (d, J = 9.5 Hz, 1
H), 2.82 (d, J = 9.5 Hz, 1 H), 2.57 (dd, J = 12.5 Hz, J = 7.9 Hz, 1 H),
2.40 (br. s, 1 H), 2.21 (dd, J = 9.5 Hz, J = 6.2 Hz, 1 H), 2.03−2.01 (m,
1 H), 1.99 (ddd, J = 12.4 Hz, J = 8.7 Hz, J = 5.0 Hz, 1 H), 1.77 (br. s, 1
H), 1.48 (s, 9 H). 13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 155.2,
136.2, 128.6, 128.2, 126.6, 79.2, 60.3, 60.0, 58.3, 52.2, 50.5, 47.3, 40.1,
39.2, 29.4, 28.6. MS (EI, 70 EV): m/z (%) 329 (100) [(M + H)+], 273
+
C20H29N2O4 [(M + H)]+ 361.2122, found 361.2122.
9-Benzyl-3-tert-butoxycarbonyl-3,9-diazatricyclo[5.3.0.01,5]-
decan-8-one (5). To a solution of alcohol 4 (9.29 g, 25.3 mmol, 1.0
equiv) in dry THF (333 mL) at −78 °C were added methanesulfonyl
chloride (2.76 mL, 35.4 mmol, 1.4 equiv) and then dropwise a solution
of triethylamine (5.98 mL, 42.9 mmol, 1.7 equiv) in dry THF (18.5
mL). The cooling bath was removed, and the mixture was warmed to 0
°C within 30 min. After 2 h at 0 °C the mixture was recooled to −50
°C, lithium tert-butoxide (1 M in THF) (65.0 mL, 65.0 mmol, 2.8
equiv) was added, and the reaction mixture was stirred at 0 °C for 25
min. The reaction mixture was poured into ice−water and brine and
extracted twice with ethyl acetate. The combined organic layers were
dried over Na2SO4 and then filtered. Removal of the solvent under
vacuum left a light yellow oil which was purified by column
chromatography (heptane/EtOAc 1/1) to give the desired product
5 (7.90 g, 92%) as a white solid. Mp: 134−135 °C. Rf = 0.48
+
(53) [(M − C4H7)+]. HRMS (ESI): calculated for C20H28N2O2
[(M)]+ 328.2150, found 328.2157.
tert-Butyl N-Allyl-N-[(2-oxo-3-phenyl-5H-furan-4-yl)methyl]-
carbamate (8). To a solution of 4-(bromomethyl)-3-phenylfuran-
2(5H)-one (7; 320 mg, 1.26 mmol, 1.0 equiv) in THF (7.5 mL) were
added triethylamine (529 μL, 3.79 mmol, 2.0 equiv) and allylamine
(100 μL, 1.33 mmol, 1.1 equiv). The resulting solution was stirred at
room temperature for 12 h. Water was added, the aqueous layer was
extracted with EtOAc, and the extract was dried over Na2SO4, filtered,
and evaporated to dryness. This product was dissolved in dichloro-
methane, and the solution was passed through a short pad of silica gel
(heptane/EtOAc 1/3), concentrated under reduced pressure, and used
in the next step without further purification (250 mg, 87%). To a
solution of this amine (250 mg, 1.09 mmol, 1.0 equiv) in dry THF (3.0
mL) was added Boc2O (238 mg, 1.09 mmol, 1.0 equiv). The resulting
solution was heated to 40 °C for 2 h. After that time, the solvent was
removed under reduced pressure and the residue purified by column
chromatography (heptane/EtOAc 1/1) to afford the Boc-protected
product 8 as a colorless oil (329 mg, 92%). Rf = 0.51 (heptane/EtOAc
(heptane/EtOAc 1/1). IR (ATR): ν
̃
(cm−1) 2973 (s, C−H), 2867 (s,
C−H), 1680 (vs, CO), 1673 (vs), 1400 (s), 1474 (w), 1400 (vs),
1
1145 (m), 1131 (m), 877 (w). H NMR (400 MHz, DMSO-d6): δ
(ppm) 7.39−7.37 (m, 2 H), 7.33−7.26 (m, 3 H), 4.55 (d, J = 14.6 Hz,
1 H), 4.39 (d, J = 14.6 Hz, 1 H), 3.83 (d, J = 11.8 Hz, 1 H), 3.50 (d, J
= 11.8 Hz, 1 H), 3.35 (d, J = 10.3 Hz, 1 H), 3.30 (d, J = 10.2 Hz, 1 H),
3.25 (dd, J = 12.0 Hz, J = 6.6 Hz, 1 H), 3.02 (d, J = 12.0 Hz, 1 H), 2.73
(dd, J = 9.3 Hz, J = 3.7 Hz, 1 H), 2.69−2.67 (m, 1 H), 2.19 (ddd, J =
12.5 Hz, J = 8.5 Hz, J = 3.7 Hz, 1 H), 2.02 (ddd, J = 12.5 Hz, J = 9.3
Hz, J = 6.2 Hz, 1 H), 1.47 (s, 9 H). 13C{1H} NMR (91 MHz, CDCl3):
δ (ppm) 179.1, 154.8, 137.3, 129.2, 128.1, 127.8, 79.2, 53.3, 52.3, 47.3,
46.4, 45.9, 42.8, 41.6, 28.6, 28.4. MS (EI, 70 EV): m/z (%) 343 (100)
[(M + H)+], 287 (13) [(M − C4H7)+]. HRMS (ESI): calculated for
1/1). IR (ATR): ν
̃
(cm−1) 2968 (w, C−H), 1750 (vs, CO), 1697 (s,
1
CO), 1412 (m), 1391 (m), 1365 (m), 1125 (m), 1103 (m). H
NMR (600 MHz, DMSO-d6): δ (ppm) 7.57−7.51 (m, 2 H), 7.50−
7.47 (m, 2 H), 7.45−7.42 (m, 1 H), 5.70 (ddt, J = 16.2 Hz, J = 10.5
Hz, J = 5.7 Hz, 1 H), 5.05 (dd, J = 10.5 Hz, J = 1.1 Hz, 1 H), 4.95−
4.91 (m, 3 H), 4.35 (s, 2 H), 3.90−3.74 (m, 2 H), 1.35 (s, 9 H).
13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 172.9, 161.0, 164.7,
+
C20H26N2O3 [(M)]+ 342.1943, found 342.1952.
133.9, 130.0, 129.3, 129.0, 128.9, 126.2, 118.0, 86.1, 70.9, 50.5, 43.9,
28.4. MS (EI, 70 EV): m/z (%) 328 (90) [(M − H)+], 274 (100) [(M
− C4H7)+]. HRMS (ESI): calculated for C14H16NO2 [(M −
C5H9O2)+] 230.1191, found 230.1182.
The enantiomer separation of 9-benzyl-3-tert-butoxycarbonyl-3,9-
diazatricyclo[5.3.0.01,5]decan-8-one (5; 6.97 g, 20.4 mmol) was
performed on preparative chiral HPLC (Reprosil Chiral-NR;
heptane/EtOH 6/4, flow rate 35 mL/min; (+)-5 tR = 37.00 min;
(−)-5 tR = 45.00 min) in batches of 200 mg each to give (+)-5 (3.18
g) as a light yellow solid and (−)-5 (3.10 g) as a light yellow solid.
Both compounds were crystallized from hot EtOAc/n-heptane and
submitted to single-crystal X-ray analysis, which revealed that (+)-5 is
(1S,5S,7S)-9-benzyl-3-tert-butoxycarbonyl-3,9-diazatricyclo-
[5.3.0.01,5]decan-8-one ((+)-5; 3.18 g, 9.29 mmol, 45.6% yield, mp
N-tert-Butoxycarbonyl-7-phenyl-3-aza-9-oxatricyclo-
[5.3.0.01,5]decan-8-one (9a). The compound was prepared from
photoprecursor 8 (40.0 mg, 0.20 mmol) in 25 mL of acetonitrile by
irradiation for 5 days (5 mM) at λ 300 nm. Purification of the crude
product by column chromatography (heptane/EtOAc 1/1) afforded
the photoproduct 9a as a white solid (28.8 mg, 72%). Mp: 103 °C. Rf
= 0.44 (heptane/EtOAc 1/1). IR (ATR): ν
̃
(cm−1) 2936 (w), 1765 (s,
7156
dx.doi.org/10.1021/jo501302f | J. Org. Chem. 2014, 79, 7152−7161

The Journal of Organic Chemistry
Article
CO), 1687 (vs, CO), 1165 (s), 1013 (s), 876 (w). 1H NMR (400
MHz, DMSO-d6): δ (ppm) 7.42−7.35 (m, 2 H), 7.34−7.27 (m, 1 H),
7.14−7.07 (m, 2 H), 4.51 (d, J = 9.8 Hz, 1 H), 4.34 (d, J = 9.8 Hz, 1
H), 3.54 (d, J = 11.6 Hz, 1 H), 3.46 (d, J = 12.6 Hz, 1 H), 3.24 (dd, J =
11.6 Hz, J = 6.4 Hz 1 H), 2.97 (d, J = 12.6 Hz, 1 H), 2.93−2.91 (m, 1
H), 2.56 (dd, J = 12.5 Hz, J = 8.2 Hz, 1 H), 2.38 (dd, J = 12.5 Hz, J =
6.9 Hz, 1 H), 1.27 (s, 9 H). 13C{1H} NMR (151 MHz, CDCl3): δ
(ppm) 180.4, 154.4, 135.5, 129.1, 127.8, 127.0, 80.0, 71.5, 51.5, 50.9,
49.1, 46.9, 38.1, 31.8, 28.3. MS (EI, 70 EV): m/z (%) 274 (100) [(M
− C4H7)+]. HRMS (ESI): calculated for C14H16NO2 [(M −
C5H9O2)+] 230.1191, found 230.1201.
9-Benzyl-3-tert-butoxycarbonyl-7-phenyl-3,9-diazatricyclo-
[5.3.0.01,5]decane (11a). With the photocycloaddition product 9a
(92.0 mg, 0.27 mmol) as the starting material, conversion to the
pyrrolidine was performed as previously described for 3 → 6. The
intermediate products, however, were not further characterized but
directly taken into the next step. Pure product 11a (61.0 mg, 54%) was
finally obtained as a colorless oil. Rf = 0.51 (heptane/EtOAc 1/1). IR
Rotamers. MS (EI, 70 eV): m/z (%) 347 (100) [(M + H)+]. HRMS
+
(ESI): calculated for C20H27FN2O2 [M]+ 346.2057, found 346.2057.
9-Benzyl-3-tert-butoxycarbonyl-5-phenyl-3,9-diazatricyclo-
[5.3.0.01,5]decane (12a). With the photocycloaddition product
10a10b (352 mg, 1.07 mmol) as the starting material, the conversion
to the pyrrolidine was performed as previously described for 3 → 6.
The intermediate products, however, were not further characterized
but directly taken into the next step. Pure product 12a (268 mg, 62%)
was finally obtained as a colorless oil. Rf = 0.56 (heptane/EtOAc 1/1).
IR (ATR): ν
̃
(cm−1) 2972 (s, C−H), 2931 (s, C−H), 1677 (vs, C
1
O), 1602 (w), 1427 (s), 1104 (s), 876 (m). H NMR (600 MHz,
CDCl3): δ (ppm) 7.35 (d, J = 7.4 Hz, 2 H), 7.27 (t, J = 7.4 Hz, 1 H),
7.18 (d, J = 7.4 Hz, 2 H), 7.11−7.03 (m, 3 H), 6.81−6.74 (m, 2 H),
4.06−3.88 (m, 1 H), 3.85−3.73 (m, 1 H), 3.70 (d, J = 13.9 Hz, 1 H),
3.58−3.44 (m, 1 H), 3.29 (d, J = 10.4 Hz, 1 H), 3.21 (d, J = 13.9 Hz, 1
H), 2.82−2.76 (m, 1 H), 2.75−2.71 (m, 1 H), 2.69 (ddd, J = 12.0 Hz, J
= 5.8 Hz, J = 1.1 Hz, 1 H), 2.59−2.45 (m, 1 H), 2.27 (dd, J = 9.5 Hz, J
= 5.5 Hz, 1 H), 2.24−2.16 (m, 1 H), 1.82−1.69 (m, 1 H), 1.49 (s, 9
H). 13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 154.7, 143.8, 139.5,
128.2, 128.0, 127.5, 127.1, 126.3, 125.9, 79.5, 64.5, 60.1, 59.0, 58.2,
55.3, 52.4, 37.8, 33.0, 30.3, 28.5. MS (EI, 70 EV): m/z (%) 405 (100)
[(M + H)+], 349 (17) [(M − C4H7)+]. HRMS (ESI): calculated for
(ATR): ν
̃
(cm−1) 2972 (w, C−H), 1677 (vs, CO), 1427 (m), 1389
1
(m), 1104 (m), 1085 (m), 1028 (m), 876 (m). H NMR (600 MHz,
CDCl3): δ (ppm) 7.33 (d, J = 7.0 Hz, 2 H), 7.30−7.25 (m, 5 H),
7.14−7.08 (m, 3 H), 3.68 (d, J = 13.2 Hz, 1 H), 3.63 (d, J = 13.2 Hz, 1
H), 3.56 (d, J = 12.2 Hz, 1 H), 3.40−3.25 (m, 1 H), 3.13−3.10 (m, 1
H), 3.07 (d, J = 9.8 Hz, 1 H), 2.92 (d, J = 9.3 Hz, 1 H), 2.76 (d, J =
12.2 Hz, 1 H), 2.66−2.58 (m, 1 H), 2.39−2.37 (m, 2 H), 2.39−2.37
(m, 2 H), 1.07 (s, 9 H). 13C{1H} NMR (151 MHz, CDCl3): δ (ppm)
154.0, 142.8, 139.3, 128.6, 128.2, 128.0, 127.5, 126.9, 125.9, 79.1, 71.2,
61.2, 60.1, 59.8, 51.9, 50.1, 47.8, 37.6, 33.8, 28.1. MS (EI, 70 eV): m/z
(%) 274 (100) [(M − C4H7)+]. HRMS (ESI): calculated for
+
C26H32N2O2 [(M)]+ 404.2464, found 404.2467.
9-Benzyl-3-tert-butoxycarbonyl-5-methyl-3,9-diazatricyclo-
[5.3.0.01,5]decane (12b). With the photocycloaddition product
10b10b (180 mg, 0.68 mmol) as the starting material, the conversion
to the pyrrolidine was performed as previously described for 3 → 6.
The intermediate products, however, were not further characterized
but directly taken into the next step. Pure product 12b (118 mg, 51%)
was finally obtained as a colorless oil. Rf = 0.51 (heptane/EtOAc 1/1).
+
C26H32N2O2 [M]+ 404.2465, found 404.2474.
IR (ATR): ν
̃
(cm−1) 2812 (s, C−H), 2782 (s, C−H), 1683 (vs, C
9-Benzyl-3-tert-butoxycarbonyl-7-methyl-3,9-diazatricyclo-
[5.3.0.01,5]decane (11b). With the photocycloaddition product 9b10b
(318 mg, 1.19 mmol) as the starting material, the conversion to the
pyrrolidine was performed as previously described for 3 → 6. The
intermediate products, however, were not further characterized but
directly taken into the next step. Pure product 11b (212 mg, 52%) was
finally obtained as a colorless oil. Rf = 0.55 (heptane/EtOAc 1/1). IR
1
O), 1390 (s), 1171 (s), 1117 (s), 877 (m). H NMR (600 MHz,
DMSO-d6): δ (ppm) 7.35−7.33 (m, 3 H), 7.26−7.21 (m, 2 H), 3.68
(d, J = 13.9 Hz, 1 H), 3.56 (d, J = 10.0 Hz, 1 H), 3.52 (d, J = 13.9 Hz,
1 H). 3.51−3.47 (m, 1 H), 2.97−2.94 (m, 1 H), 2.89−2.84 (m, 1 H),
2.78 (d, J = 10.0 Hz, 1 H), 2.69 (d, J = 9.3 Hz, 1 H), 2.22 (ddd, J = 9.0
Hz, J = 5.7 Hz, J = 5.7 Hz, 1 H), 2.13 (dd, J = 9.3 Hz, J = 5.7 Hz, 1 H),
1.91 (dd, J = 11.8 Hz, J = 9 Hz, 1 H), 1.87 (d, J = 10.0 Hz, 1 H), 1.55
(dd, J = 11.8 Hz, J = 5.7 Hz, 1 H), 1.40 (s, 9 H), 1.08 (s, 3 H).
13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 155.1, 139.8, 128.4,
(ATR): ν
̃
(cm−1) 2782 (w, C−H), 2782 (s, C−H), 1693 (vs, CO),
1390 (s), 1364 (m), 1235 (w), 1171 (s), 1117 (s), 877 (m). 1H NMR
(600 MHz, CDCl3): δ (ppm) 7.37 (d, J = 7.3 Hz, 2 H), 7.32 (t, J = 7.3
Hz, 1 H), 7.24 (d, J = 7.3 Hz, 2 H), 3.74−3.68 (m, 1 H), 3.65 (d, J =
13.4 Hz, 1 H), 3.60 (d, J = 13.4 Hz, 1 H), 3.46 (d, J = 13.2 Hz, 1 H),
3.26 (d, J = 13.2 Hz, 1 H), 2.87−2.85 (m, 3 H), 2.56−2.49 (m, 1 H),
2.25 (dd, J = 11.9 Hz, J = 9.1 Hz, 1 H), 2.03 (br. s, 1 H), 1.85 (d, J =
8.7 Hz, 1 H), 1.48 (s, 9 H), 1.44−1.37 (m, 1 H), 1.00 (s, 3 H).
13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 154.8, 139.4, 128.6,
128.2, 126.8, 79.2, 67.7, 60.4 and 60.3, 59.8, 55.5 and 54.6, 53.2 and
52.6, 48.0 and 47.7, 41.9, 38.4, 37.5 and 37.4, 28.6, 19.6, and 19.3.
Rotamers. MS (EI, 70 eV): m/z (%) 343 (10) [(M + H)+]. HRMS
128.2, 126.8, 79.2, 61.1, 60.1, 59.6, 55.7, 53.1, 52.6, 38.2, 42.9, 36.9,
28.5, 19.6. MS (EI, 70 EV): m/z (%) 343 (100) [(M + H)+]. HRMS
(ESI): calculated for C21H30N2O2+ [(M)]+ 342.2307, found 342.2313.
tert-Butyl N-(3-Methylbut-2-enyl)-N-[(5-oxo-2H-furan-3-yl)-
methyl]carbamate (14). To a solution of 4-(bromomethyl)furan-
2(5H)-one (13; 1.35 g, 7.63 mmol, 1.0 equiv) in THF (45 mL) were
added triethylamine (3.19 mL, 22.9 mmol, 3.0 equiv) and finally the
3,3-dimethylallylamine (650 mg, 7.63 mmol, 1.0 equiv). The resulting
solution was stirred at room temperature for 12 h. Water was added,
the aqueous layer was extracted with EtOAc, and the extract was dried
over Na2SO4, filtered, and evaporated to dryness. This product was
dissolved in dichloromethane and the solution passed through a short
pad of silica gel (heptane/EtOAc 1/3), concentrated under reduced
pressure, and used in the next step without further purification (445
mg, 35%). To a solution of the crude amine (445 mg, 2.46 mmol, 1.0
equiv) in dry THF (6.2 mL) was added Boc2O (536 mg, 2.46 mmol,
1.0 equiv). The resulting solution was heated to 40 °C for 2 h. After
that time, the solvent was removed under reduced pressure and the
residue purified by column chromatography (heptane/EtOAc 1/1) to
afford the Boc-protected product 14 as a colorless oil (425 mg, 22%
+
(ESI): calculated for C21H30N2O2 [M]+ 342.2307, found 342.2309.
9-Benzyl-3-tert-butoxycarbonyl-7-fluoro-3,9-diazatricyclo-
[5.3.0.01,5]decane (11c). With the photocycloaddition product 9c10b
(408 mg, 1.5 mmol) as the starting material, the conversion to the
pyrrolidine was performed as previously described for 3 → 6. The
intermediate products, however, were not further characterized but
directly taken into the next step. Pure product 11c (271 mg, 52%) was
finally obtained as a colorless oil. Rf = 0.35 (heptane/EtOAc 1/1). IR
(ATR): ν
̃
(cm−1) 2974 (m, C−H), 2794 (m, C−H), 1694 (vs, CO),
1390 (s), 1171 (s), 1108 (m), 876 (m). 1H NMR (600 MHz, CDCl3):
δ (ppm) 7.40−7.37 (m, 3 H), 7.32−7.26 (m, 2 H), 3.94 (d, J = 12.1
Hz, 1 H), 3.72 (d, J = 13.1 Hz, 1 H), 3.60 (d, J = 13.1 Hz, 1 H), 3.46
(d, J = 10.8 Hz, 1 H), 3.23 (dd, J = 11.5 Hz, J = 6.5 Hz, 1 H), 3.18 (dd,
J = 9.5 Hz, JF = 1.0 Hz, 1 H), 3.00−2.90 (m, 1 H), 2.84 (d, J = 9.7 Hz,
1 H), 2.52 (dd, J = 13.2 Hz, JF = 8.9 Hz, 1 H), 2.44 (ddd, JF = 21.6 Hz,
J = 9.5 Hz, J = 1.3 Hz, 1 H), 2.37 (virt quin, J ≈ 7.3 Hz, 1 H), 2.26−
2.24 (m, 1 H), 2.06−2.04 (m, 1 H), 1.48 (s, 9 H). 13C{1H} NMR (151
MHz, CDCl3): δ (ppm) 151.7, 138.4, 128.6, 128.3, 127.2, 95.5 (d, JF =
247.2 Hz), 79.5, 67.7 (d, JF = 27.2 Hz), 59.4, 58.8, 58.2 (d, JF = 17.6
Hz), 57.2, 45.9, 36.5 (d, JF = 24.8 Hz), 34.1 (d, JF = 8.8 Hz), 28.5.
from bromide 13). Rf = 0.57 (heptane/EtOAc 1/1). IR (ATR): ν
̃
(cm−1) 2975 (m, C−H), 1779 (s, CO), 1746 (vs), 1688 (s), 1449
1
(m), 1366 (m), 1159 (s), 1116 (m), 1028 (m). H NMR (600 MHz,
CDCl3): δ (ppm) 4.97−4.87 (m, 1 H), 4.83−4.77 (m, 1 H), 4.68 (s, 2
H), 4.23−4.12 (m, 2 H), 3.84−3.65 (m, 2 H), 1.85 (s, 3 H), 1.69 (s, 3
H), 1.47 (s, 9 H). 13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 178.1,
156.0, 140.7, 124.9, 113.1, 112.9, 80.8, 71.2, 53.2, 41.8, 28.3, 19.7, 8.6.
MS (EI, 70 EV): m/z (%) 226 (100) [(M − C4H8)+]. HRMS (ESI):
calculated for C10H15NO2 [(M − C5H8O2)+] 181.1182, found
181.1177.
7157
dx.doi.org/10.1021/jo501302f | J. Org. Chem. 2014, 79, 7152−7161

The Journal of Organic Chemistry
Article
N-tert-Butoxycarbonyl-6,6-dimethyl-3-aza-9-oxatricyclo-
[5.3.0.01,5]decan-8-one (15). The compound was prepared from
photoprecursor 14 (400 mg, 1.42 mmol) in 284 mL of acetonitrile by
irradiation for 12 h (5 mM) at λ 254 nm. Purification of the crude
product by column chromatography (heptane/EtOAc 1/1) afforded
the photoproduct 15 as a white solid (173 mg, 44%). Mp: 151 °C. Rf =
the aqueous layer was extracted with EtOAc, and the extract was dried
over Na2SO4, filtered, and evaporated to dryness. This product was
dissolved in dichloromethane and the solution passed through a short
pad of silica gel (heptane/EtOAc 1/3), concentrated under reduced
pressure, and used in the next step without further purification (501
mg, 82%). To a solution of the crude amine (364 mg, 1.19 mmol, 1.0
equiv) in dry THF (3.0 mL) was added Boc2O (260 mg, 1.19 mmol,
1.0 equiv). The resulting solution was heated to 40 °C for 2 h. After
that time, the solvent was removed under reduced pressure and the
residue purified by column chromatography (heptane/EtOAc 1/1) to
afford the Boc-protected product 19 as a colorless oil (426 mg, 88%).
0.51 (heptane/EtOAc 1/1). IR (ATR): ν
̃
(cm−1) 2965 (m), 2869 (w),
1753 (m, CO), 1696 (s, CO), 1476 (w), 1417 (s), 1365 (s), 1170
1
(s), 1134 (s), 1013 (w). H NMR (600 MHz, CDCl3): δ (ppm) 4.44
(d, J = 9.8 Hz, 1 H), 4.19 (d, J = 9.8 Hz, 1 H), 3.94−3.84 (m, 1 H),
3.83−3.74 (m, 1 H), 3.23 (dd, J = 12.6 Hz, J = 7.5 Hz, 1 H), 3.03 (d, J
= 12.1 Hz, 1 H), 2.60 (s, 1 H), 2.44 (d, J = 7.5 Hz, 1 H), 1.48 (s, 9 H),
1.18 (s, 3 H), 1.17 (s, 3 H). 13C{1H} NMR (91 MHz, CDCl3): δ
(ppm) 176.6, 154.3, 80.1, 73.6, 52.7, 51.6, 51.4, 47.4, 35.7, 28.5, 26.4,
23.5. (one carbon atom not observed). MS (EI, 70 EV): m/z (%) 226
(100) [(M − C4H8)+]. HRMS (ESI): calculated for C10H15NO2 [(M
− C5H8O2)+] 181.1182, found 181.1187.
Rf = 0.62 (heptane/EtOAc 1/1). IR (ATR): ν
̃
(cm−1) 2971 (m, C−
H), 1764 (vs, CO), 1679 (s), 1496 (w), 1396 (m), 1367 (m), 1214
(m), 1154 (s), 1116 (vs), 1043 (s), 957 (m), 786 (m). 1H NMR (400
MHz, DMSO-d6): δ (ppm) 7.46−7.36 (m, 5 H), 7.31−7.26 (m, 5 H),
5.25 (virt q, J ≈ 1.1 Hz, 1 H), 4.93 (virt q, J ≈ 1.1 Hz, 1 H), 4.67 (s, 2
H), 4.29 (s, 2 H), 4.17 (virt t, J ≈ 1.1 Hz, 2 H), 1.37 (s, 9 H). 13C{1H}
NMR (151 MHz, CDCl3): δ (ppm) 172.3, 160.1, 164.2, 130.0, 129.4,
128.9, 128.8, 128.5, 127.6, 126.9, 126.7, 125.9, 125.8, 114.8, 85.6, 70.2,
50.9, 42.8, 27.8. MS (EI, 70 EV): m/z (%) 404 (90) [(M − H)+], 350
(100) [(M − C4H7)+]. HRMS (ESI): calculated for C21H19NO4 [(M
− C4H8)+] 349.1314, found 349.1309.
tert-Butyl 2-Fluoroallyl[(3-fluoro-2-oxo-5H-furan-4-yl)-
methyl]carbamate (17). To a solution of 4-(bromomethyl)-3-
fluorofuran-2(5H)-one (16; 1.5 g, 7.69 mmol, 1.0 equiv) in THF (45
mL) were added triethylamine (3.22 mL, 23.1 mmol, 3.0 equiv) and
then 2-fluoroallylamine (866 mg, 11.5 mmol, 1.5 equiv). The resulting
solution was stirred at room temperature for 14 h. Water was added,
the aqueous layer was extracted with EtOAc, and the extract was dried
over Na2SO4, filtered, and evaporated to dryness. This product was
dissolved in dichloromethane and the solution passed through a short
pad of silica gel (heptane/EtOAc 1/3), concentrated under reduced
pressure, and used in the next step without further purification (1.30 g,
89%). To a solution of the crude amine (1.11 g, 5.87 μmol, 1.0 equiv)
in dry THF (14.7 mL) was added Boc2O (1.34 g, 6.16 mmol, 1.1
equiv). The resulting solution was heated to 40 °C for 2 h. After that
time, the solvent was removed under reduced pressure and the residue
purified by column chromatography (heptane/EtOAc 1/1) to afford
the Boc-protected product 17 as a colorless oil (1.68 g, 88% from
N-tert-Butoxycarbonyl-5,7-diphenyl-3-aza-9-oxatricyclo-
[5.3.0.01,5]decan-8-one (21). The compound was prepared from
photoprecursor 19 (281 mg, 0.70 mmol) in 140 mL of acetonitrile by
irradiation for 6 h at λ 300 nm (5 mM). Purification of the crude by
column chromatography (heptane/EtOAc 1/1) afforded the photo-
product 21 as a white solid (169 mg, 60%). Mp: (107−108) °C. Rf =
0.53 (heptane/EtOAc 1/1). IR (ATR): ν
̃
(cm−1) 2868 (w), 1773 (s,
CO), 1690 (vs, CO), 1458 (m), 1250 (m), 1233 (w), 1065 (s),
1
940 (w), 749 (m). H NMR (400 MHz, DMSO-d6): δ (ppm) 7.47−
7.45 (m, 3H), 7.43−7.41 (m, 2 H), 7.35−7.32 (m, 3 H), 7.20−7.18
(m, 2 H), 4.21 (d, J = 9.3 Hz, 1 H), 4.13−4.08 (m, 2 H), 3.76 (d, J =
12.6 Hz, 1 H), 3.45 (d, J = 12.1 Hz, 1 H), 3.41 (d, J = 13.5 Hz, 1 H),
3.11 (d, J = 12.6 Hz, 1 H), 2.95 (d, J = 13.5 Hz, 1 H), 1.35 (s, 9 H).
13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 180.1, 153.8, 137.0,
bromide 16). Rf = 0.41 (heptane/EtOAc 1/1). IR (ATR): ν
̃
(cm−1)
2979 (m, C−H), 1778 (s, CO), 1693 (s, CO), 1454 (m), 1408
1
(m), 1368 (m), 1155 (vs), 1104 (s), 874 (m). H NMR (600 MHz,
135.2, 129.2, 129.1, 128.0, 127.6, 127.3, 127.2, 80.0, 67.9, 61.5, 60.5,
50.3, 49.0, 48.2, 34.2, 28.2. MS (EI, 70 EV): m/z (%) 350 (100) [(M
− C4H7)+]. HRMS (ESI): calculated for C20H19NO2 [(M −
C5H8O2)+] 305.1416, found 305.1419.
CDCl3): δ (ppm) 4.82−4.70 (m, 3 H), 4.55−4.39 (m, 1 H), 4.26 (s, 2
H), 4.07−3.88 (m, 2 H), 1.48 (s, 9 H). 19F NMR (235 MHz, DMSO-
d6): δ (ppm) −103.7 (m), −148.4 (m). 13C{1H} NMR (151 MHz,
1
CDCl3): δ (ppm) 164.7 (d, JF = 31.1 Hz), 160.7 (d, JF = 260.2 Hz),
tert-Butyl 1-Oxo-6a-phenyl-1,4,6,6a,7,11b-hexahydrobenzo-
furo[3,4]isoindole-5(3H)-carboxylate (22). The compound was
obtained as a byproduct (white solid; 56.0 mg, 20%) upon irradiation
of photoprecursor 19 (281 mg, 0.70 mmol) (see previous procedure).
155.2, 144.3 (d, 1JF = 273.4 Hz), 134.8 (d, 2JF = 31.1 Hz), 93.3 (d, JF =
5.0 Hz), 81.8, 67.5, 48.5 (d, JF = 31.4 Hz), 40.8, 28.2. MS (EI, 70 eV):
m/z (%) 234 (100) [(M − C4H7)+]. HRMS (ESI, 70 eV): calculated
for C13H17F2NO4 [M+] 289.1125, found 289.1119.
Mp: 104 °C. Rf = 0.49 (heptane/EtOAc 1/1). IR (ATR): ν
̃
(cm−1)
2875 (w), 1768 (s, CO), 1650 (vs, CO), 1400 (m), 1215 (m),
N-tert-Butoxycarbonyl-5,7-difluoro-3-aza-9-oxatricyclo-
[5.3.0.01,5]decan-8-one (18). The compound was prepared from
photoprecursor 17 (1.50 g, 5.19 mmol) in 1.04 L of acetonitrile by
irradiation for 1 h (5 mM) at λ 254 nm. Purification of the crude by
column chromatography (heptane/EtOAc 1/1) afforded the photo-
product 18 as a white solid (1.08 g, 72%). Mp: 110−112 °C. Rf = 0.37
1
1200 (w), 1000 (s), 938 (w). H NMR (400 MHz, DMSO-d6): δ
(ppm) 7.52−7.51 (m, 1 H), 7.34−7.30 (m, 7 H), 7.27−7.25 (m, 1 H),
4.15 (d, J = 9.8 Hz, 1 H), 4.11 (s, 1 H), 4.03 (d, J = 9.8 Hz, 1 H), 3.90
(d, J = 11.6 Hz, 1 H), 3.72 (d, J = 11.8 Hz, 1 H), 3.57 (d, J = 11.8 Hz,
1 H), 3.35 (d, J = 11.6 Hz, 1 H), 3.31 (d, J = 16.4 Hz, 1 H), 3.04 (d, J
= 16.4 Hz, 1 H), 1.44 (s, 9 H). 13C{1H} NMR (151 MHz, CDCl3): δ
(ppm) 175.2, 154.8, 141.2 and 140.7, 134.3 and 134.2, 129.7 and
129.6, 129.0 and 128.9, 128.8, 128.3 and 128.2, 127.8, 127.7, 127.4 and
127.3, 126.3 and 126.2, 80.4 and 80.3, 71.8 and 71.4, 55.6 and 55.4,
55.1 and 54.7, 51.14 and 51.11, 48.6 and 48.2, 47.8 and 46.9, 36.1 and
36.0, 28.4. Rotamers. MS (EI, 70 EV): m/z (%) 350 (100) [(M −
C4H7)+]. HRMS (ESI): calculated for C20H19NO2 [(M − C5H8O2)+]
305.1416, found 305.1416.
(heptane/EtOAc 1/1). IR (ATR): ν
̃
(cm−1) 2978 (w, C−H), 1768
(vs, CO), 1683 (s, CO), 1403 (s), 1171 (s), 1098 (s, C−F), 868
(w). 1H NMR (500 MHz, CDCl3): δ (ppm) 4.67 (dd, J = 10.4 Hz, JF
= 3.2 Hz, 1 H), 4.26−4.05 (m, 3 H), 3.50−3.46 (m, 1 H), 3.26 (dd, J =
12.6 Hz, JF = 1.0 Hz, 1 H), 3.02 (dddd, JF = 15.2 Hz, JF = 15.1 Hz, J =
8.4 Hz, J = 1.3 Hz, 1 H), 2.86 (ddd, JF = 15.2 Hz, JF = 15.1 Hz, J = 8.4
Hz, 1 H), 1.49 (s, 9 H). 19F NMR (235 MHz, DMSO-d6): δ (ppm)
−170.8 (m), −177.5 (m). 13C{1H} NMR (91 MHz, CDCl3): δ (ppm)
171.5 (d, JF = 25.6 Hz), 154.9, 89.5, 83.9 (d, JF = 240.7 Hz), 81.2, 65.7,
58.0 (d, JF = 4.4 Hz), 57.7 (d, JF = 25.6 Hz), 46.1, 41.1 (t, JF = 27.0
Hz), 28.3. MS (EI, 70 eV): m/z (%) 234 (100) [(M − C4H7)+].
HRMS (ESI, 70 eV): calculated for C13H17F2NO4 [(M)+] 289.1125,
found 289.1123.
9-Benzyl-3-tert-butoxycarbonyl-6,6-dimethyl-3,9-diazatri-
cyclo[5.3.0.01,5]decane (24). With the photocycloaddition product
15 (103 mg, 0.37 mmol) as the starting material, the conversion to the
pyrrolidine was performed as previously described for 3 → 6. The
intermediate products, however, were not further characterized but
directly taken into the next step. Pure product 24 (56.2 mg, 43%) was
finally obtained as a colorless oil. Rf = 0.68 (heptane/EtOAc 1/1). IR
̃
tert-Butyl 2-Phenylallyl[(3-phenyl-2-oxo-5H-furan-4-yl)-
methyl]carbamate (19). To a solution of 4-(bromomethyl)-3-
phenylfuran-2(5H)-one (7; 507 mg, 2.0 mmol, 1.0 equiv) in THF (12
mL) were added triethylamine (838 μL, 6.0 mmol, 3.0 equiv) and the
2-phenylallylamine (680 mg, 4.01 mmol, 1.0 equiv). The resulting
solution was stirred at room temperature for 14 h. Water was added,
(ATR): ν (cm−1) 2799 (s, C−H), 2780 (s, C−H), 1663 (vs, CO),
1299 (m), 1154 (s), 1110 (m), 811 (m). 1H NMR (600 MHz,
CDCl3): δ (ppm) 7.39−7.36 (m, 2 H), 7.34−7.30 (m, 2 H), 7.26−
7.23 (m, 1 H), 3.74−3.71 (m, 1 H), 3.67−3.63 (m, 2 H), 3.62−3.55
7158
dx.doi.org/10.1021/jo501302f | J. Org. Chem. 2014, 79, 7152−7161

The Journal of Organic Chemistry
Article
(m, 1 H), 3.05 (d, J = 12.3 Hz, 1 H), 2.99 (d, J = 13.1 Hz, 1 H), 2.97
(d, J = 10.6 Hz, 1 H), 2.88 (d, J = 9.5 Hz, 1 H), 2.19 (d, J = 7.6 Hz, 1
H), 2.14 (dd, J = 10.6 Hz, J = 7.6 Hz, 1 H), 2.00−1.95 (m, 1 H), 1.94−
1.90 (m, 1 H), 1.47 (s, 9 H), 1.10 (s, 3 H), 0.96 (s, 3 H). 13C{1H}
NMR (151 MHz, CDCl3): δ (ppm) 154.7, 139.5, 128.6, 128.2, 126.9,
79.2, 60.1, 60.0, 55.6, 51.2, 50.4, 49.5, 46.9, 32.1, 28.6, 23.9, 23.8 (one
carbon atom not observed). MS (EI, 70 EV): m/z (%) 357 (100) [(M +
9-Benzyl-3-methyl-3,9-diazatricyclo[5.3.0.01,5]decane (28).
Substrate 6 (250 mg, 761 μmol, 1.0 equiv) was dissolved in THF
(5.00 mL), and the solution was cooled to 0 °C. LiAlH4 (31.8 mg, 837
μmol, 1.1 equiv) was added carefully, and the reaction mixture stirred
at room temperature for 12 h. After that time, wet Na2SO4 was added
and the solution was filtered. Evaporation of the solvent and
purification of the crude by column chromatography (heptane/
EtOAc 1/1) afforded product 28 (172 mg, 93%) as a colorless oil. Rf =
+
H)+]. HRMS (ESI): calculated for C22H32N2O2 [(M)]+ 356.2464,
0.13 (heptane/EtOAc 1/1). IR (ATR): ν
̃
(cm−1) 2936 (w), 1453 (w),
found 356.2465.
1240 (w), 1138 (w), 738 (m). 1H NMR (600 MHz, CDCl3): δ (ppm)
7.39 (d, J = 7.4 Hz, 2 H), 7.32 (t, J = 7.4 Hz, 2 H), 7.24 (d, J = 7.4 Hz,
1 H), 3.72 (d, J = 13.4 Hz, 1 H), 3.60 (d, J = 13.4 Hz, 1 H), 2.85−2.80
(m, 3 H), 2.78 (d, J = 9.5 Hz, 1 H), 2.45 (virt dt, J = 8.6 Hz, J ≈ 6.0
Hz, 1 H), 2.41 (virt dt, J = 8.6 Hz, J ≈ 5.7 Hz, 1 H), 2.38 (s, 3 H), 2.20
(dd, J = 9.3 Hz, J = 6.0 Hz, 1 H), 2.09 (dd, J = 9.5 Hz, J = 6.0 Hz, 1
H), 1.99 (d, J = 9.4 Hz, 1 H), 1.93 (d, J = 9.5 Hz, 1 H), 1.90−1.81 (m,
2 H). 13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 139.7, 128.6,
128.1, 126.7, 63.1, 62.8, 60.7, 60.0, 59.9, 55.3, 42.7, 40.8, 39.9, 29.2.
MS (EI, 70 EV): m/z (%) 243 (100) [(M + H)+]. HRMS (ESI):
9-Benzyl-3-tert-butoxycarbonyl-5,7-difluoro-3,9-diazatri-
cyclo[5.3.0.01,5]decane (25). With the photocycloaddition product
18 (841 mg, 2.91 mmol) as the starting material, the conversion to the
pyrrolidine was performed as previously described for 3 → 6. The
intermediate products, however, were not further characterized but
directly taken into the next step. Pure product 25 (837 mg, 79%) was
finally obtained as a colorless oil, which crystallized upon standing.
Mp: 98 °C. Rf = 0.39 (heptane/EtOAc 1/1). IR (ATR): ν
̃
(cm−1)
2941 (w, C−H), 1678 (s, CO), 1400 (s), 1199 (s), 1089 (s, C−F),
870 (w). 1H NMR (600 MHz, CDCl3): δ (ppm) 7.37−7.30 (m, 3 H),
7.26−7.24 (m, 2 H), 4.12−4.05 (m, 1 H), 3.95−3.85 (m, 1 H), 3.73
(d, J = 13.3 Hz, 1 H), 3.60 (d, J = 13.3 Hz, 1 H), 3.55−3.40 (m, 1 H),
3.25−3.20 (m, 1 H), 3.14 (d, J = 9.0 Hz, 1 H), 3.15−3.08 (m, 1 H),
2.87 (dd, JF = 29.0 Hz, J = 12.2 Hz, 1 H), 2.70−2.60 (m, 1 H), 2.47
(dd, JF = 16.4 Hz, J = 9.0 Hz, 1 H), 2.30−2.20 (m, 1 H), 1.46 (s, 9 H).
13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 154.1, 137.9, 128.5,
+
calculated for C16H22N2 [(M)]+ 242.1783, found 242.1787.
N-tert-Butoxycarbonyl-3,9-diazatricyclo[5.3.0.01,5]decane
(29). A solution of substrate 6 (500 mg, 1.52 mmol, 1.0 equiv) in
methanol (11.4 mL) was hydrogenated (hydrogen balloon) at 23 °C
for 16 h in the presence of palladium hydroxide on carbon (20% Pd;
moisture ca. 60%; Pearlman’s catalyst; 114 mg, 162 μmol, 0.11 equiv).
The catalyst was filtered off, and washed with methanol, and all
volatiles were removed under vacuum to give N-tert-butoxycarbonyl-
3,9-diazatricyclo[5.3.0.01,5]decane (29; 362 mg, 99%) as a colorless oil.
1
128.4, 127.2, 95.5 (d, JF = 226.4 Hz), 94.8 (d, JF = 228.1 Hz), 80.1,
61.6 (d, JF = 26.2 Hz), 59.1, 58.2 (d, JF = 17.6 Hz), 57.6, 57.2, 52.4,
47.1, 43.3 (dd, JF = 27.8 Hz, JF = 23.7 Hz), 28.5. Rotamers. MS (EI, 70
EV): m/z (%) 365 (100) [(M + H)+]. HRMS (ESI): calculated for
IR (ATR): ν
̃
(cm−1) 2929 (w, C−H), 2850 (w, C−H), 1688 (vs, C
1
+
C20H26F2N2O2 [(M)]+ 364.1962, found 364.1968.
O), 1389 (vs), 1364 (s), 1242 (m), 1164 (s), 1125 (s), 877 (m). H
NMR (600 MHz, CDCl3): δ (ppm) 3.75−3.63 (m, 1 H), 3.62−3.47
(m, 1 H), 3.36−3.33 (m, 1 H), 3.07 (d, J = 11.6 Hz, 1 H), 2.98 (d, J =
11.2 Hz, 1 H), 2.89−2.85 (m, 2 H), 2.64 (d, J = 9.1 Hz, 1 H), 2.47
(dd, J = 13.1 Hz, J = 5.9 Hz, 1 H), 2.21 (dd, J = 12.7 Hz, J = 7.3 Hz, 1
H), 1.82 (br. s, 1 H), 1.79−1.75 (m, 1 H), 1.48 (s, 9 H). Rotamers.
13C{1H} NMR (151 MHz, CDCl3): δ (ppm) 155.2, 79.3, 56.2 and
55.3, 53.8, 53.7, 53.4, 52.4, 41.0 and 40.9, 39.6 and 38.7, 28.8, 28.6.
Rotamers. MS (EI, 70 EV): m/z (%) 239 (100) [(M + H)+]. HRMS
(ESI): calculated for C13H22N2O2+ [(M)]+ 238.1680, found 238.1680.
N-Benzyl-3,9-diazatricyclo[5.3.0.01,5]decane (30). Substrate 6
(300 mg, 913 μmol, 1.0 equiv) was dissolved in HCl (4 M in dioxane)
(2.28 mL, 9.13 mmol, 10 equiv), and the reaction mixture was stirred
at room temperature for 3 h. After that time, the solvent was removed
and saturated aqueous NaHCO3 was added. The aqueous solution was
extracted twice with dichloromethane. The organic phase was dried
over Na2SO4, filtered, and evaporated to dryness to give N-benzyl-3,9-
diazatricyclo[5.3.0.01,5]decane (30; 209 mg, quantitative) as a colorless
9-Benzyl-3-tert-butoxycarbonyl-5,7-diphenyl-3,9-diazatri-
cyclo[5.3.0.01,5]decane (26). With the photocycloaddition product
21 (166 mg, 0.41 mmol) as the starting material, the conversion to the
pyrrolidine was performed as previously described for 3 → 6. The
intermediate products, however, were not further characterized but
directly taken into the next step. Pure product 26 (110 mg, 56%) was
finally obtained as a colorless oil. Rf = 0.57 (heptane/EtOAc 1/1). IR
(ATR): ν
̃
(cm−1) 2931 (w, C−H), 1690 (vs, CO), 1490 (w), 1419
1
(m), 1099 (m), 1085 (m), 1028 (m), 870 (m). H NMR (300 MHz,
CDCl3): δ (ppm) 7.41−7.39 (m, 5 H), 7.36−7.34 (m, 5 H), 7.30−
7.28 (m, 3 H), 7.25−7.24 (m, 2 H), 4.32 (d, J = 11.9 Hz, 1 H), 4.0 (d,
J = 13.1 Hz, 1 H), 3.86 (d, J = 11.1 Hz, 1 H), 3.61 (d, J = 13.1 Hz, 1
H), 3.53 (d, J = 11.1 Hz, 1 H), 3.42 (d, J = 10.9 Hz, 1 H), 3.29 (d, J =
11.9 Hz, 1 H), 3.26 (d, J = 12.6 Hz, 1 H), 3.14 (br. s, 1 H), 2.99 (br. s,
1 H), 2.91 (d, J = 13.1 Hz, 1 H), 2.40 (d, J = 13.1 Hz, 1 H), 1.48 (s, 9
H). 13C{1H} NMR (91 MHz, CDCl3): δ (ppm) 153.9, 142.1, 139.3,
128.8, 128.5, 128.3, 127.5, 127.0, 126.5, 79.2, 69.9, 66.3, 60.7, 59.0,
55.1, 49.8, 48.3, 34.0, 28.4, 28.1. MS (EI, 70 eV): m/z (%) 481 (10)
oil. IR (ATR): ν
̃
(cm−1) 3025 (w), 2936 (w, C−H), 2778 (w, C−H),
+
[(M + H)+]. HRMS (ESI): calculated for C32H36N2O2 [M]+
1466 (w), 1453 (w), 1240 (w), 1138 (w), 1115 (w), 879 (m), 738
(m). 1H NMR (600 MHz, CDCl3): δ (ppm) 7.38 (d, J = 7.6 Hz, 2 H),
7.30 (t, J = 7.6 Hz, 2 H), 7.24 (t, J = 7.6 Hz, 1 H), 3.72 (d, J = 13.3 Hz,
1 H), 3.62 (d, J = 13.3 Hz, 1 H), 2.89−2.86 (m, 3 H), 2.86−2.82 (m, 3
H), 2.48 (dd, J = 8.9 Hz, J = 4.5 Hz, 1 H), 2.27−2.23 (m, 1 H), 2.22
(dd, J = 9.4 Hz, J = 6.5 Hz, 1 H), 2.03 (d, J = 9.4 Hz, 1 H), 1.92 (ddd, J
= 12.5 Hz, J = 8.5 Hz, J = 4.5 Hz, 1 H), 1.65 (ddd, J = 12.5 Hz, J = 8.4
Hz, J = 4.5 Hz, 1 H). 13C{1H} NMR (151 MHz, CDCl3): δ (ppm)
139.5, 128.6, 128.1, 126.7, 60.6, 60.0, 59.5, 56.1, 53.8, 53.4, 40.8, 39.4,
28.6. MS (EI, 70 EV): m/z (%) 229 (100) [(M + H)+]. HRMS (ESI):
480.2776, found 480.2770.
9-Benzyl-3-tert-butoxycarbonyl-5,7-dimethyl-3,9-diazatri-
cyclo[5.3.0.01,5]decane (27). With the previously reported10 photo-
cycloaddition product 23 (419 mg, 1.49 mmol) as the starting
material, the conversion to the pyrrolidine was performed as
previously described for 3 → 6. The intermediate products, however,
were not further characterized but directly taken into the next step.
Pure product 27 (255 mg, 48%) was finally obtained as a colorless oil.
Rf = 0.64 (heptane/EtOAc 1/1). IR (ATR): ν
̃
(cm−1) 2858 (m, C−
+
calculated for C15H20N2 [(M)]+ 228.1620, found 228.1620.
H), 1690 (vs, CO), 1310 (s), 1290 (m), 1115 (m), 1082 (s), 810
1
3,9-Diazatricyclo[5.3.0.01,5]decane (31) Dihydrochloride. N-
Boc-protected amine 29 (300 mg, 913 μmol, 1.0 equiv) was dissolved
in HCl (4 M in dioxane) (2.28 mL, 9.13 mmol, 10 equiv), and the
reaction mixture was stirred at room temperature for 3 h. After that
time, the solvent was removed and the residue was dried to give 3,9-
diazatricyclo[5.3.0.01,5]decane (31) dihydrochloride as a white solid
̃
(m). H NMR (600 MHz, CDCl3): δ (ppm) 7.38−7.35 (m, 2 H),
7.33−7.29 (m, 2 H), 7.26−7.22 (m, 1 H), 3.70−3.64 (m, 1 H), 3.60
(d, J = 13.1 Hz, 1 H), 3.59−3.57 (m, 1 H), 3.56 (d, J = 13.1 Hz, 1 H),
2.97 (d, J = 11.5 Hz, 1 H), 2.87 (d, J = 10.0 Hz, 1 H), 2.85 (d, J = 11.4
Hz, 1 H), 2.79 (d, J = 9.2 Hz, 1 H), 1.97 (d, J = 10.0 Hz, 1 H), 1.93−
1.91 (m, 1 H), 1.78 (d, J = 9.2 Hz, 1 H), 1.67 (d, J = 11.7 Hz, 1 H),
1.46 (s, 9 H), 1.19 (s, 3 H), 1.02 (s, 3 H). 13C{1H} NMR (151 MHz,
CDCl3): δ (ppm) 154.3, 139.8, 128.5, 128.2, 126.8, 79.2, 67.5, 61.3,
60.2, 56.6, 48.9, 45.2, 42.7, 40.4, 30.4, 28.6, 19.9, 18.9. MS (EI, 70 EV):
m/z (%) 357 (100) [(M + H)+]. HRMS (ESI): calculated for
(255 mg, 96%). IR (ATR): ν (cm−1) 2900 (s), 2861 (s), 2745 (vs),
2651 (s), 2522 (m), 2436 (w), 2255 (w), 1594 (s), 1426 (m), 1399
1
(m), 1377 (m), 993 (m). H NMR (300 MHz, DMSO-d6): δ (ppm)
10.11 (br. s, 2 NH), 9.86 (br. s, 2 NH), 3.45 (dd, J = 11.9 Hz, J = 4.6
Hz, 2 H), 3.26 (dd, J = 11.7 Hz, J = 4.4 Hz, 2 H), 3.20−3.11 (m, 2 H),
+
C22H32N2O2 [(M)]+ 356.2464, found 356.2461.
7159
dx.doi.org/10.1021/jo501302f | J. Org. Chem. 2014, 79, 7152−7161

The Journal of Organic Chemistry
Article
3.09−3.02 (m, 2 H), 2.91 (virt q, J ≈ 7.3 Hz, 2 H), 1.99 (t, J = 7.3 Hz,
2 H). 13C NMR (151 MHz, DMSO-d6): δ (ppm) 54.2, 51.5, 49.6,
37.8, 26.0. MS (EI, 70 EV): m/z (%) 139 (100) [(M + H)+]. HRMS
spectra of all compounds reported in the Experimental Section,
and X-ray data for the crystal structures of 5a, 25, and 37a
(tosyl derivative). This material is available free of charge via
the Internet at http://pubs.acs.org.
+
(ESI): calculated for C8H14N2 [(M)]+ 138.1160, found 138.1154.
N-tert-Butoxycarbonyl-9-(2-chloro-5-fluoropyrimidin-4-yl)-
3,9-diazatricyclo[5.3.0.01,5]decane (32). N-tert-Butoxycarbonyl-
3,9-diazatricyclo[5.3.0.01,5]decane (29; 363 mg, 1.52 mmol, 1.0
equiv) was dissolved in MeCN (5.00 mL). 2,4-Dichloro-5-fluoropyr-
imidine (254 mg, 1.52 mmol, 1.0 equiv) and triethlyamine (276 μL,
1.98 mmol, 1.3 equiv) were added, and the mixture was stirred at room
temperature for 12 h. The solvent was removed and the residue
purified by column chromatography (heptane/EtOAc 1/1) to give the
desired product as a white solid (32; 494 mg, 88%). Mp: 138−139 °C.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail for T.J.W.: thomas.woltering@roche.com.
*E-mail for T.B.: thorsten.bach@ch.tum.de.
Notes
The authors declare no competing financial interest.
Rf = 0.39 (heptane/EtOAc 1/1). IR (ATR): ν
̃
(cm−1) 2975 (w, C−H),
2941 (w), 2857 (w, C−H), 1687(vs, CO), 1596 (vs), 1556 (m),
ACKNOWLEDGMENTS
1
■
1376 (s), 1363 (s), 1242 (s), 1119 (s), 1021 (m), 880 (m). H NMR
(600 MHz, CDCl3): δ (ppm) 7.93 (d, 3JF = 5.1 Hz, 1 H), 4.25 (dd, J =
12.3 Hz, 5JF = 1.9 Hz, 1 H), 4.04 (d, J = 12.3 Hz, 1 H), 3.94−3.73 (m,
1 H), 3.66 (dd, J = 11.9 Hz, J = 7.7 Hz, 1 H), 3.54−3.41 (m, 1 H),
3.36 (dd, J = 11.9 Hz, J = 6.5 Hz, 1 H), 3.35−3.34 (m, 1 H), 3.16 (d, J
= 11.0 Hz, 1 H), 2.75 (dd, J = 11.4 Hz, J = 6.5 Hz, 1 H), 2.62 (ddd, J =
13.6 Hz, J = 7.2 Hz, J = 6.3 Hz, 1 H), 2.03−1.98 (m, 1 H), 1.94 (ddd, J
= 13.6 Hz, J = 8.6 Hz, J = 4.9 Hz, 1 H), 1.50 (s, 9 H). 13C{1H} NMR
(151 MHz, CDCl3): δ (ppm) 155.2, 154.3 (d, 4JF = 2.2 Hz), 152.4 (d,
2JF = 8.8 Hz), 145.6 (d, 1JF = 256.7 Hz), 142.7 (d, 3JF = 25.1 Hz), 79.8,
D.A.F. wishes to acknowledge funding by the Roche Postdoc
Fellowship (RPF) Program. We thank Professor Klaus Muller
for helpful discussions.
̈
REFERENCES
■
(1) General reviews on cyclobutanes: (a) The Chemistry of
Cyclobutanes; Rappoport, Z., Liebman, J. F., Eds.; Wiley: Chichester,
U.K., 2005. (b) Lee-Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103,
1449−1484. (c) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003,
103, 1485−1538.
4
4
55.5 (d, JF = 6.1 Hz), 54.6 (d, JF = 5.0 Hz), 53.1, 51.7, 40.6, 39.3,
29.4, 28.5. MS (EI, 70 EV): m/z (%) 369 (100) [(M + H)+]. HRMS
+
(ESI): calculated for C17H22ClFN4O2 [(M)]+ 368.1415, found
(2) General reviews on oxetanes: (a) Burkhard, J. A.; Wuitschik, G.;
Rogers-Evans, M.; Muller, K.; Carreira, E. M. Angew. Chem., Int. Ed.
̈
368.1416.
2010, 49, 9052−9067. (b) Griesbeck, A. G.; Sokolova, T. Sci. Synth.
9-(2-Chloro-5-fluoropyrimidin-4-yl)-3-pyrrolidin-1-ylmetha-
none-3,9-diazatricyclo[5.3.0.01,5]decane (33). Substrate 32 (26.3
mg, 71.3 μmol, 1.0 equiv) was dissolved in HCl (4 M in dioxane) (178
μL, 713 μmol, 10 equiv), and the reaction mixture was stirred at room
temperature for 12 h. Subsequently, the solvent was removed,
saturated aqueous NaHCO3 was added, and the product was extracted
with dichloromethane. The organic phase was dried over Na2SO4 and
filtered and the solvent removed to give 3,9-diazatricyclo[5.3.0.01,5]-
decane as a colorless oil that was used without further purification in
the next step (25.8 mg, 99.3%). The crude amine (21.8 mg, 71.4 μmol,
1.0 equiv) was dissolved in dichloromethane (2 mL). Triethylamine
(29.9 μL, 214 μmol, 3.0 equiv) and pyrrolidine-1-carbonyl chloride
(9.54 mg, 71.4 μmol, 1.0 equiv) were added, and the reaction mixture
was stirred at room temperature for 2 h. The solvent was then
removed and the crude product purified by column chromatography
(heptane/EtOAc 1/1) to give the desired product 33 as a white solid
(23.0 mg, 88%). Mp: 100−101 °C. Rf = 0.21 (heptane/EtOAc 1/1).
2008, 37, 433−471.
(3) (a) Vasiuta, R. I.; Gorichko, M. V. Tetrahedron Lett. 2014, 55,
466−468. (b) Dardcheno, D. S.; Michurin, O. M.; Grygorenko, O. O.;
Scheinpflug, K.; Dathe, M.; Komarov, I. V. Tetrahedron 2013, 69,
505−511. (c) Marson, C. M. Chem. Soc. Rev. 2011, 40, 5514−5533
and references cited therein.
(4) Reviews: (a) Hehn, J. P.; Muller, C.; Bach, T. In Handbook of
̈
Synthetic Photochemistry; Albini, A., Fagnoni, M., Eds.; Wiley-VCH:
Weinheim, Germany, 2010; pp 171−215. (b) Iriondo-Alberdi, J.;
Greaney, M. F. Eur. J. Org. Chem. 2007, 4801−4815. (c) Fleming, S. A.
In Molecular and Supramolecular Photochemistry; Griesbeck, A. G.,
Mattay, J., Eds.; Marcel Dekker: New York, 2005; Vol. 12, pp 141−
160. (d) Margaretha, P. In Molecular and Supramolecular Photo-
chemistry; Griesbeck, A. G., Mattay, J., Eds.; Marcel Dekker: New York,
2005; Vol. 12, pp 211−237. (e) Bach, T. Synthesis 1998, 683−703.
(g) Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297−588.
(h) Becker, D.; Haddad, N. Org. Photochem. 1989, 10, 1−162.
(i) Crimmins, M. T. Chem. Rev. 1988, 88, 1453−1473. (j) Baldwin, S.
V. Org. Photochem. 1981, 5, 123−225. (k) Bauslaugh, P. G. Synthesis
1970, 287−300. (f) Mattay, J.; Conrads, R.; Hoffmann, R. Methoden
Org. Chem. (Houben-Weyl), 4th Ed. 1995, E21c, 3085−3132.
(5) Schuster, D. I.; Lem, G.; Kaprinidis, N. A. Chem. Rev. 1993, 93,
3−22.
IR (ATR): ν
̃
(cm−1) 2930 (w, C−H), 1865 (w, C−H), 1744 (w),
1692 (s, CO), 1591 (vs), 1559 (m), 1465 (m), 1364 (s), 1323 (m),
1239 (m), 1118 (m), 1010 (m), 752 (m). 1H NMR (600 MHz,
CDCl3): δ (ppm) 7.93 (d, 3JF = 5.1 Hz, 1 H), 4.23 (dd, J = 12.3 Hz, J
= 2.0 Hz, 1 H), 4.04 (d, J = 12.0 Hz, 1 H), 3.85 (d, J = 11.5 Hz, 1 H),
3.67 (dd, J = 12.0 Hz, J = 7.9 Hz, 1 H), 3.63 (d, J = 11.1 Hz, 1 H),
3.46−3.42 (m, 4 H), 3.37 (d, J = 12.3 Hz, 1 H), 3.28 (dd, J = 11.1 Hz,
J = 2.0 Hz, 1 H), 3.13 (d, J = 11.5 Hz, 1 H), 2.74 (dd, J = 12.7 Hz, J =
7.9 Hz, 1 H), 2.63−2.53 (m, 1 H), 2.00 (ddd, J = 13.5 Hz, J = 8.8 Hz, J
= 5.1 Hz, 1 H), 1.91 (ddd, J = 13.5 Hz, J = 7.9 Hz, J = 4.9 Hz, 1 H),
1.87 (dt, J = 6.6 Hz, J = 3.3 Hz, 4 H). 13C{1H} NMR (151 MHz,
CDCl3): δ (ppm) 161.8, 154.3 (d, JF = 2.2 Hz), 152.4 (d, JF = 8.8 Hz),
145.6 (d, JF = 259.7 Hz), 142.6 (d, JF = 25.1 Hz), 55.6 (d, JF = 6.1 Hz),
54.4 (d, 4JF = 5.2 Hz), 54.3, 53.6, 53.2, 48.3, 40.2, 38.9, 29.2, 26.0. MS
(EI, 70 EV): m/z (%) 357 (100) [(M + H)+]. HRMS (ESI):
calculated for C17H21ClFN5O+ [(M)]+ 365.1419, found 365.1426.
(6) Review on bicyclic conformationally restricted diamines:
Grygorenko, O. O.; Radchenko, D. S.; Volchnyuk, D. M.;
Tolmachev, A. A.; Komarov, I. V. Chem. Rev. 2011, 111, 5506−5568.
(7) Examples: (a) Breitenbucher, J. G.; Brown, S. M.; Chang, L.;
Chaplan, S. R.; Jones, W. M.; Karbarz, M. J.; Keith, J. M.; Luo, L.;
Palmer, J. A.; Pierce, J. M.; Rizzolio, M.; Rynberg, R.; Scott, B. P.;
Seierstad, M.; Webb, M.; Wennerholm, M. L.; Wilson, S. J. Bioorg.
Med. Chem. Lett. 2014, 24, 737−741. (b) Gallagher, T.; Haddow, M.
F.; Weinberg, K.; Kruse, C. G.; Stoit, A. Tetrahedron 2013, 69, 4694−
4707. (c) Chen, X.-F.; Du, Y.; Hong, B.; Jia, X.-J.; Jiang, W.; Si, S.-Y.;
Wang, L.; Yang, Y. Molecules 2012, 17, 7379−7386.
(8) Structure A also represents a conformationally restricted 3,7-
diazabicyclo[3.3.1]nonane, the core structure of a class of antiar-
rhythmic agents and β2-adrenergic receptor agonists: (a) Schoen, U.;
Messinger, J.; Brueckner, R.; Ziegler, D. US Patent US2003/109541
A1, 2003. (b) Moran, E. J.; Griffin, J. H.; Choi, S.-K. US Patent
US2002/6362371 B1, 2002.
ASSOCIATED CONTENT
■
S
* Supporting Information
Text, figures, tables, and CIF files giving schemes and
explanations for the synthesis of the alcohol precursor to
compound 7 and for the formation of side products upon [2 +
2] photocycloaddition of substrates 8 and 19, 1H and 13C NMR
7160
dx.doi.org/10.1021/jo501302f | J. Org. Chem. 2014, 79, 7152−7161

The Journal of Organic Chemistry
Article
(9) (a) Zefirov, N. S.; Zyk, N. V.; Vatsadze, S. Z.; Tyurin, V. S. Bull.
Russ. Acad. Sci. Div. Chem. Sci. 1992, 41, 2687−2688. (b) Dotsenko, F.;
Krivokolysko, L. Chem. Heterocycl. Compd. 2010, 46, 1142−1143.
(10) (a) Fort, D. A.; Woltering, T. J.; Nettekoven, M.; Knust, H.;
Bach, T. Chem. Commun. 2013, 49, 2989−2931. (b) Fort, D. A.;
Woltering, T. J.; Alker, A. M.; Bach, T. Heterocycles 2014, 88, 1079−
1100.
(11) For intramolecular [2 + 2] photocycloaddition reactions of
2(5H)-furanones, see: (a) Coates, R. M.; Muskopf, J. W.; Senter, P. A.
́
J. Org. Chem. 1985, 50, 3541−3557. (b) Alibes, R.; Bourdelande, J. L.;
Font, J.; Gregori, A.; Parella, T. Tetrahedron 1996, 52, 1267−1278.
(c) Hue, B. T. B.; Dijkink, J.; Kuiper, S.; van Schaik, S.; van
Maarseveen, J. H.; Hiemstra, H. Eur. J. Org. Chem. 2006, 127−137.
(d) Miao, R.; Gramani, S. G.; Lear, M. J. Tetrahedron Lett. 2009, 50,
1731−1733. (e) Lutteke, G.; Kleinnijenhuis, R. A.; Jacobs, I.;
Wrigstedt, P. J.; Correia, A. C. A.; Nieuwenhuizen, R.; Hue, B. T.
B.; Goubitz, K.; Peschar, R.; van Maarseveen, J. H.; Hiemstra, H. Eur. J.
Org. Chem. 2011, 3146−3155. (f) Lu, P.; Bach, T. Angew. Chem., Int.
́ ́
Ed. 2012, 51, 1261−1264. (g) Pares, S.; Alibes, R.; Figueredo, M.;
Font, J.; Parella, T. Eur. J. Org. Chem. 2012, 1404−1417. (h) Lu, P.;
Bach, T. Chem. Asian J. 2012, 7, 1947−1958.
(12) For a review on photochemical reactions of 2(5H)-furanones,
see: Hashem, A. I.; Senning, A.; Hamad, A.-S. S. Org. Prep. Proced. Int.
1998, 30, 401−425.
(13) Unless mentioned otherwise, all chiral compounds in this paper
were used or obtained as racemic mixtures. The relative configurations
of racemates are displayed by straight bonds (bold or hashed), while
the absolute and relative configurations of enantiopure compounds are
drawn as wedged bonds (bold or hashed) following a convention
suggested previously: Maehr, H. J. Chem. Educ. 1985, 62, 114−120.
(14) Abrecht, S.; Adam, J.-M.; Bromberger, U.; Diodone, R.; Fettes,
A.; Fischer, R.; Goeckel, V.; Hildbrand, S.; Moine, G.; Weber, M. Org.
Process Res. Dev. 2011, 15, 503−514.
(15) Kawakami, K.; Takahashi, H.; Ohki, H.; Kimura, K.; Miyauchi,
S.; Miyauchi, R.; Takemura, M. Chem. Pharm. Bull. 2000, 48, 1667−
1672.
(16) Raap, R.; Chin, C. G.; Micetich, R. G. Can. J. Chem. 1971, 49,
2143−2151.
(17) Milletti, F.; Storchi, L.; Sforna, G.; Cruciani, G. J. Chem. Inf.
Model. 2007, 47, 2172−2181.
(18) Gooseman, N. E. J.; O’Hagan, D.; Peach, M. J. G.; Slawin, A. M.
Z.; Tozer, D. J.; Young, R. J. Angew. Chem., Int. Ed. 2007, 46, 5904−
5908.
(19) Hall, H. K., Jr. J. Am. Chem. Soc. 1957, 79, 5441−5444.
(20) For emission spectra, see the following. λ 300 nm: (a) Maturi,
M. M.; Wenninger, M.; Alonso, R.; Bauer, A.; Pothig, A.; Riedle, E.;
̈
Bach, T. Chem. Eur. J. 2013, 19, 7461−7472. λ 254 nm:
(b) Schnapperelle, I.; Bach, T. Chem. Eur. J. 2014, DOI: 10.1002/
chem.201402765.
(21) Tam, K. Y.; Takac
167.
́ ́
s-Novak, K. Anal. Chim. Acta 2001, 434, 157−
7161
dx.doi.org/10.1021/jo501302f | J. Org. Chem. 2014, 79, 7152−7161