Synthesis of chiral (indol-2-yl)methanamines and insight into the stereochemistry protecting effects of the 9-phenyl-9-fluorenyl protecting group

Article abstract of DOI:10.1002/ejoc.201500391

Tetrahydro-β-carbolines, a privileged structural feature in natural products and pharmaceutically active compounds, has been the cause for considerable research interest, spanning many decades. Herein is reported the synthesis of the structurally closely related compounds denoted as (indol-2-yl)methanamines, in 99% ee using amino acid starting materials, coupled with a 9-phenyl-9-fluorenyl (Pf) protecting group strategy. Furthermore a conformational study of Pf-protected α-amino carbonyl compounds were undertaken by means of DFT refined molecular mechanics calculation, X-ray crystallography measurements and NMR experiments in order to elucidate the stereochemical protecting properties induced by the Pf group. Herein is presented a highly efficient stereospecific synthesis of (indol-2-yl)methanamines from amino acids together with a mechanistic study on the stereochemistry protecting effects of the 9-phenyl-9-fluorenyl protecting group with the aid of DFT calculations, NMR and X-ray crystallography.

Full text of DOI:10.1002/ejoc.201500391

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DOI: 10.1002/ejoc.201500391
Synthesis of Chiral (Indol-2-yl)methanamines and Insight into the
Stereochemistry Protecting Effects of the 9-Phenyl-9-fluorenyl Protecting
Group
Christopher S. Lood,[a] Aino E. Laine,[a] Antonia Högnäsbacka,[a] Martin Nieger,[b] and
Ari M. P. Koskinen*[a]
Keywords: Asymmetric synthesis / Amino acids / Chiral pool / Protecting groups
Tetrahydro-β-carbolines, a privileged structural feature in
ing group strategy. Furthermore a conformational study of Pf-
natural products and pharmaceutically active compounds, protected α-amino carbonyl compounds were undertaken by
has been the cause for considerable research interest,
spanning many decades. Herein is reported the synthesis of
the structurally closely related compounds denoted as (indol-
2-yl)methanamines, in 99% ee using amino acid starting
materials, coupled with a 9-phenyl-9-fluorenyl (Pf) protect-
means of DFT refined molecular mechanics calculation, X-
ray crystallography measurements and NMR experiments in
order to elucidate the stereochemical protecting properties
induced by the Pf group.
Introduction
Tetrahydro-β-carbolines (THβCs) comprise a large group
of naturally occurring and synthetic indole alkaloids, the
most simple one being tryptoline 1 (Figure 1). The THβCs
represent a privileged structural family containing numer-
ous bioactive substrates. Their pharmacological activity
profile has made them an extensively studied group of com-
pounds as well as attractive targets in organic synthesis dur-
ing several decades and still today nurtures interest within
the scientific community. Notable bioactivities of the
THβCs include the classical antihypertensive effects in-
duced by reserpine (not depicted), as well as antiviral,[1] an-
timalarial,[2] and anticancer[3] activities.[4] Additionally, the
block buster drug Tadalafil® 2, used to treat erectile dys-
function, is a tryptophan derived synthetic THβC.
Figure 1. A selection of THβCs and (indol-2-yl)methanamines.
Herein is presented the synthesis of chiral (indol-2-yl)-
methanamines, structurally closely related to the THβCs,
via a chiral pool approach coupled with a 9-phenyl-9-fluor-
enyl (Pf) protecting group strategy, starting from amino ac-
ids (Figure 2).[5]
Figure 2. this work: synthesis of (indol-2-yl)methanamines from
amino acids; R = amino acid side chain.
To date, only one natural product, vinoxine 4,[6] carrying
the (indol-2-yl)methanamine framework, lacking the tryp-
tamine type ethyl bridge, has been characterized. However
some closely related natural products such as cinchonamine
5[7] and guettardine 6[8] along with the polyamine proto-
aculeine B 8[9] have been isolated. Calindol 7, a synthetic
(indol-2-yl)methanamine, has also gained attention due to
its high affinity towards the calcium sensing receptor (Fig-
ure 3).[10] One characteristic feature joining these seemingly
quite different compounds together is the fact that they are
not accessible by conventional THβC synthetic routes (such
as the Pictet–Spengler or Bischler–Napieralski reaction
approaches).[11,12] Therefore alternative synthetic strategies
are needed.
[a] Department of Chemistry, Aalto University School of Chemical
Technology,
P. O. Box 16100, Kemistintie 1, 00076 Aalto, Finland
E-mail: ari.koskinen@aalto.fi
[b] Department of Chemistry, University of Helsinki,
Helsinki, Finland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500391.
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Due to the propensity for α-amino carbonyl compounds
to racemize/epimerize, the Pf group was introduced as a
more acid stable alternative to the trityl protecting
group.[21,22] The exact mechanism behind this stereochemi-
cal protecting effect has however not yet been elucidated
and no thorough mechanistic investigations have yet to be
undertaken. Therefore, within the framework of this work,
we also aim to offer insight into the stereochemical protect-
ing effects of the Pf-protecting group.
Results and Discussion
In order to exhibit diversity and generality of the syn-
thetic protocol we focused our attention on four structur-
ally different amino acid starting materials. The preparation
of the proline derived ketone 13d has previously been de-
scribed by our group.[23] The synthesis began by preparing
the Pf-protected Weinreb amides of the corresponding
amino acids (Scheme 1).[24] Methyl esters 9a–b were sub-
jected to 9-phenyl-9-fluorenylation, following a known
literature procedure developed for the dimethyl ester of as-
partic acid.[25] Methyl ester 10c was synthesized according
to a known literature procedure,[26,27] The esters 10a–c
where then transformed into the corresponding Weinreb
amides 11a–c, using a Grignard base and the HCl salt of
N,O-dimethylhydroxylamine.
The Weinreb amides 11a–c were then subjected to cou-
pling with a dilithiated Boc-protected o-toluidine 12 species
(Scheme 2).[28] Initial results indicated that an excess of the
Figure 3. Examples of (indol-2-yl)methanamines.
Despite the (indol-2-yl)methanamines’ close connection lithiated substrate was necessary for the reaction to pro-
to the THβC scaffold, only few asymmetric methodologies ceed. When 11a was treated with only a small excess
towards this compound class have been developed. Except (110 mol-%) of 12, a complicated reaction mixture was ob-
for some isolated examples, the more relevant procedures tained. Isolation of the reaction components gave only 5%
include resolution of hydroxyureas,[13] diastereoselective ad- of the desired product 13a together with a large amount of
dition of 2-lithiated indoles to either hydroazones[14] or unreacted starting material. Significant amounts of 14a and
imines[15] carrying a chiral auxiliary directing group, Sono- 15a were also observed. The same decomposition pattern
gashira-type cyclization reaction of chiral propargylamines of Weinreb amides[29] and Weinreb amide like derivatives[30]
and 2-iodo anilines (formally a Larock[16]-type indolization under strongly basic conditions has previously been ob-
approach),[17,18] an enantioselective Friedel–Craft reaction, served by other research groups. When subjecting 11b to
followed by oxidation, of 4,7-dihydroindoles with imines the same reaction conditions, only 3% of product was ob-
catalyzed by chiral phosphoric acids[19] and a three compo- tained and 69% of unreacted starting material could be re-
nent copper catalyzed domino reaction of 2-ethynylanilines, isolated. Interestingly, in this case we were unable to isolate
aldehydes and secondary amines.[20]
the corresponding decomposition products 14b and 15b.
Scheme 1. Preparation of the Pf-protected Weinreb amides 9a–c.
2
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Synthesis of Chiral (Indol-2-yl)methanamines
Scheme 2. Lithiation coupling of toluidine 12 and Weinreb amides 11a–b. Reaction conditions: 12 (110 mol-%) stirred together with sBuLi
(220 mol-%) for 1 h at –30 °C. 11 (100 mol-%) was added and the reaction stirred for 1 h. Isolated yields after silica gel chromatography.
n.d. = not determined.
Increasing the amount of 12 to 250 mol-%, moderate re- Table 1. Temperature dependency in the alkylation of 11.[a]
sults were obtained for the alanine amide 11a and phenyl-
alanine amide 11b substrates, and excellent results were ob-
tained for the serine 11c (Scheme 3).
Entry
11
T
[°C]
t
Yield 13[b]
Yield 11[b]
[min]
[%]
[%]
1
2[d]
3[e]
4
5
6
11a
11a
11a
11b
11b
11b
11b
11b
–30
–41
–78
0
–10
–20
–30
–41
15
60
20
15
15
15
15
60
59
64
0
20
30
38
62
77
n.d.[c]
6
n.d.
n.d.[c]
n.d.[c]
n.d.[c]
n.d.[c]
10
7
8
[a] Reaction conditions: 11 (100 mol-%), 12 (250 mol-%), sBuLi
(500 mol-%). [b] Isolated yield after flash chromatography. [c] Not
determined; based on crude NMR, little or no remaining starting
material. [d] No 14a or 15a could be detected. [e] Crude NMR
indicated mostly starting material and minor presence of 14a and
15a.
Scheme 3. Lithiation coupling between toludine 12 and Weinreb
amides 11a–c. Reaction conditions: 12 (250 mol-%) stirred together
with sBuLi (500 mol-%) for 1 h at –30 °C. 11 (100 mol-%) was
added and the reaction stirred for 15 min after it was quenched.
Isolated yields after purification.
The low yield of ketones 13a and 13b and the decomposi-
tion of Weinreb amide 11a, prompted us to investigate the
reaction further. We first performed a simple deuterium reagent almost complete quenching of the nucleophile
quenching experiment, to investigate the degree of benzylic occurs. The quenching of lithiated 12 could most likely be
lithiation under the reaction conditions. Quenching the di- attributed to the free NH proton present on the substrates.
anion of 12 with MeOD and analyzing the crude reaction In contrast, the reaction with Weinreb amide 13c and also
mixture by NMR revealed Ͼ95% deuterium incorporation 13d,[23] lacking free NH protons, occurs more readily (vide
at the benzylic position (Figure S1).
supra). This data suggests that the decomposition of Wein-
The formation of ketone 13a–b was shown to be strongly reb amide 11a into amide 14a and N,O-acetal 15a occurs
dependent on the reaction temperature (Table 1). Higher through an intramolecular process instead of an intermo-
temperature seemed to cause large amounts of decomposi- lecular E2 pathway previously proposed.[29a] It has been
tion (entries 1 and 4–7). At low temperature, –78 °C, the suggested that the formation of amide 14a occurs via depro-
reaction suffered from low conversions. Interestingly, the tonation of the methoxy carbon which then collapses, via
Weinreb amide decomposition seems to take place, albeit at expulsion of formaldehyde, into 14a (Scheme 4). The
a low rate (entry 3). At –41 °C the observed rate of the formation of 14a has also been accompanied by the re-
Weinreb amide decomposition was markedly lower than the addition of formaldehyde, leading to the rearranged prod-
conversion of the Weinreb amides 11a–b to the desired uct 16.[29a,29c] Such a product was however not observed
ketone 13a–b enabling us to obtain 13b in a good 77% yield under these reaction conditions. Instead, the N,O-acetal 15a
(entry 8) as well as a minor yield improvement for 13a was isolated. We suggest, in accordance with previous lit-
(entry 2).
erature,[29d] that the formation of 15a stems from the analo-
The striking difference in the reaction outcomes between gous deprotonation of the N-methyl group, leading to loss
entries 1 and 7 (Table 1) (250 mol-% 13) compared to the of a methoxide and the formation of an N-methylene inter-
outcome discussed in Scheme 2 (110 mol-% 12), indicates mediate. Upon readdition of the methoxide to the N-meth-
that when using near equimolar amounts of the alkylating ylene compound, N,O-acetal 15a is formed.[29d]
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composition under the strongly basic reaction conditions.
The lower reactivity of 17b in respect to 17a could most
likely be accounted for the significantly larger steric bulk of
the phenylalanine side chain.
Scheme 6. Alkylation of morpholine amides 17a and 17b.
With access to ketones 13a–d we turned our attention
to the indolization. Treatment of 13a–d with ethanolic 6 m
H2SO4 in CH2Cl2, facilitated the Boc group removal, with
the subsequent ring closure of the aniline nitrogen provid-
ing indoles 18b and 18d in excellent yield and indole 18a in
a moderate but reasonable yield (Scheme 7). Some decom-
position was observed in the case of 18a, accounting for the
lower yield, most likely due to solvolysis of the Pf group.[32]
Cleavage of the Boc group of 13c was markedly slower
furnishing indole 19 in only 42% yield together with the
Boc-indole 21 in 7% yield and the rearranged indole aminal
20 in 21% yield, due to the inherent instability of oxazolid-
ines under acidic conditions.
Scheme 4. a) Decomposition of Weinreb amide 11a into amide 14a.
b) Decomposition of Weinreb amide 11a into N,O-acetal 15a. c)
Steric repulsion in the cyclic transition states of 11b.
The lack of significant amounts of Weinreb amide de-
composition products 14b and 15b could also be rational-
ized according to an intramolecular decomposition path-
way (Scheme 4 and S1). In an intramolecular pathway, the
amino acid side chain would be brought into close proxim-
ity to one of the reaction centers and perhaps even more
importantly, the cyclic transition states would most cer-
tainly experience extra strain with a bulkier amino acid side
chain, accounting for the increased stability of 11b under
the strongly basic reaction conditions (Scheme 4).
Based on these findings an alternative route to ketones
13a and 13b via the morpholine amides 17 was developed.
The morpholine amides, known to be less expensive substi-
tutes for Weinreb amides, lack the possibility to decompose
in the manner discussed above.[31] Both 17a and 17b where
readily synthesized from the corresponding methyl esters
10a and 10b. (Scheme 5).
Scheme 5. Formation of morpholine amides 17a and 17b.
The less reactive morpholine amides were found to re-
quire higher reaction temperatures to achieve useful conver-
sions. Subjecting morpholine amide 17a to lithiated 7d tolu-
idine 12 at 0 °C satisfyingly furnished the desired ketone
13a in excellent 93% yield. Disappointingly, ketone 13b was
only received in an 18% yield under the same conditions
(Scheme 6). Raising the temperature to room temp. in-
Scheme 7. a) Indolization of ketones 13a–d. b) Biproducts from the
indolization of 13c.
We recognized that when performing the indolization re-
creased the yield of 13b to 29% accompanied by severe de- action on compound 13c in a less acidic reaction medium
4
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Synthesis of Chiral (Indol-2-yl)methanamines
(CH2Cl2/MeOH, 1:1 mixture) the Boc group was left intact, Compounds 22a and 13b where both determined to have
preventing the formation of indole aminal 20. We found it an ee of 99%. The ee of compound 13d, synthesized via the
convenient at this stage also to remove the methylene group, same route, has previosly been assigned to an ee of
which was readily accomplished using the HCl salt of Ͼ99%.[23] A compound derived from 10c has previously
hydroxylamine.[33] Finally, indolyl N-Boc group cleavage been described as enantiopure.[27] Therefore we could safely
could be executed under both basic and acidic condi- assume that the described synthetic routes to the (indol-2-
tions.[34] Refluxing of 26 in MeOH together with NaOH yl)methanamines presented herein yields compounds with
proved superior due to a cleaner reaction profile, giving 18c an ee of at least 99%. As a final conclusion, the successful
in 75% yield over two steps (Scheme 8).
synthesis of enantiopure (indol-2-yl)methanamines using
four structurally very different amino acids shows greater
generality for this substance class than previously published
procedures.[14,15,17,18,19,20]
The complete retention of the stereochemical infor-
mation, from the amino acid starting material to the (indol-
2-yl)methanamines, under the strongly basic reaction condi-
tions showcases yet again the Pf-protecting group’s capa-
bility of shielding the vulnerable α-amino carbonyl
stereocenter from racemization. It has previously been pro-
posed, based on molecular mechanics calculations, that the
Pf group forces the α-amino carbonyl compounds to adopt
a conformation which places the α-hydrogen in the carbonyl
plane, a dihedral angle of 0° or 180°. The conformation
would effectively minimize the overlap between the C-Hα σ
orbital and the C=O π* orbital leading to a lowering of the
α-proton acidity.[37] This stereoelectronic explanation has
indeed found some support in crystallographic data.[38,39]
Another important experimental result showed that treat-
ment of Pf-protected alaninal with triethylamine in re-
fluxing THF destroyed about 50% of the starting material.
Reisolation of the remaining aldehyde however showed no
deterioration of the ee. The other main reaction component
was found to be 9-phenylfluorene, indicating that elimi-
nation of an aromatic 9-phenylfluorenyl anion took place
preferentially over deprotonation/inversion/reprotonation
of the stereogenic center on the aldehyde.[22] The lack of
detailed information regarding the molecular mechanics
calculations,[37] or any publications further addressing the
subject, prompted us to perform the first thorough investi-
gation of the mechanism behind the stereoprotecting effects
of the Pf group, by computational conformational analysis,
supported by X-ray crystal structures and NMR analysis.
As a model for the calculation we chose a simple Pf-
protected amino acid derivative 10a. We first set out to try
to reproduce the previous calculations by performing a con-
formational search using an array of different force fields
Scheme 8. Indolization, aminal cleavage and boc removal of ketone
13c.
The Pf-protecting group was removed via straightfor-
ward hydrogenolysis using 10 wt.-% Pd/C (Scheme 9).[35]
Compound 18a underwent clean cleavage in MeOH, giving
22a in 99% yield after work up. Compound 22c required
more acidic conditions, giving excellent results in AcOH.
Compound 18b suffered from low solubility in MeOH but
underwent smooth Pf cleavage in AcOH. Interestingly, the
hydrogenolysis of 18d under these conditions produced a
mixture of products. However, we recently reported a
hydrogenolysis of the Pf-protecting group on a similar sys-
tem, using ammonium hypophosphite as the hydrogen
source under catalytic transfer hydrogenation (CTH) condi-
tions.[23] The Pf-cleavage under these CTH conditions pro-
vided the desired amine 22d in 86% yield.
Scheme 9. Hydrogenolysis of the Pf protecting group on indoles
18a–d.
(MM2*,[40] MM3*,[41] MMFF[42] and OPLS-2005[43]
(Table S1). The force fields MM2* and MM3* indeed place
)
Finally, the chiral (indol-2-yl)methanamines 22a–d could the α-hydrogen H(4)–C(3) bond (atom numbering accord-
be transformed into a small compound library. Acylation ing to Figure 4) of 10a antiperiplanar (or alternatively syn-
of 18a, 18b and 18d with acetyl chloride and 18c with acetic periplanar) to the C(2)–O(1) double bond. However, when
anhydride gave the corresponding amides in good yields applying the more recently developed force fields, MMFF
(Scheme S2). Reductive amination of 18a–d with formalde- and OPLS-2005, this placement of the α-hydrogen changes
hyde and sodium triacetoxyborohydride gave the corre- noticeably. MMFF gave one dominating conformer (93%
sponding tertiary amines in good yields (Scheme S3).[36]
of the Boltzmann population distribution) with a dihedral
The enantiopurity of compound 22a and 13b were angle of –155°. OPLS-2005 seemed to indicate a more com-
assigned using chiral HPLC. (R)-22a was synthesized from plicated system, giving several conformers with a narrow
d-alanine and (R)-13b was synthesized from d-phenylalan- energy difference (entry 1, Table 2). In fact, for this particu-
ine, by the same routes as the corresponding enantiomers. lar task, OPLS-2005 seemed to be the best parameterized
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force field examined.[44] Further refinement of the OPLS-
2005 conformational search was performed using quantum
mechanical (QM) DFT calculations at the M06-2X/6-
31G**++ level of theory (entry 2, Table 2).[45] Broadly
speaking, the conformers arising from the QM refined con-
formational search could be simplified into two conformers
(entry 2, conformer 1, Table 2 and entry 2, conformer 2,
Table 2), with each of these two conformers having sub-con-
formers (entry 2, conformer 3, Table 2 and entry 2, con-
former 4, Table 2, respectively) where the ester group had
been rotated approximately 180 degrees with respect to the
more energetically favored conformers. The minor con-
former (entry 2, conformer 5, Table 2) is basically identical
to one of these sub-conformers (entry 2, conformer 3,
Table 2), with inversion of the nitrogen (Figure S3 and S4).
The lowest energy conformer (Figure 5) is also largely sup-
ported by the crystal structure of compound 10a (Figure 6).
Figure 5. Lowest energy conformation of 10a (entry 2, conformer
1, Table 2).
Figure 4. Generic Pf-protected α-amino carbonyl compound and
10a. Numbering (does not follow IUPAC guidelines) of relevant
atoms to simplify the conformational (computational and
crystallographic) discussion.
Table 2. Conformational investigation of 10a, using force field
OPLS-2005, showing data for the 5 lowest energy conformations.
Entry
1[c]
Conformer
Dihedral
Population
angle[a] [°]
distribution[b] [%]
1
2
3
4
5
1
2
3
4
5
10
–139
–155
–143
16
–162
–151
19
35.4
29.8
12.4
10.1
2.8
69.6
11.2
10.5
7.4
Figure 6. Crystal structure of 10a (entry 1, Table 3). Displacement
parameters are drawn at 50% probability level. Note that the crys-
tallographic numbering presented in this Figure is not used in the
conformational discussion.
2[d]
35
16
the bulky Pf group in 10a adds a significant amount of
torsional restraints to the system, in comparison to 9a. The
rotation of the C(3)–C(2) bond inadvertently forces the
methyl group of the amino acid side chain closer to the
fluorenyl ring structure of the Pf group, accounting for the
observed energy barrier. After a certain point, the structure
relaxes by rotating the C(3)–N(6) bond (Figure S8), moving
the methyl group away from the fluorenyl rings. The contin-
0.5
[a] Dihedral angle between H(4)–C(3)–C(2)–O(1). [b] Determined
as the Boltzmann distribution at T = 298.15 K. [c] Calculations
performed in gas phase with force field OPLS-2005 using Macro-
Model 10.0 without any constraints; electrostatic treatment was set
to constant dielectric. [d] Calculations performed in gas phase
using Jaguar 8.0; theory: DFT (M06–2X) with the basis set 6-
31G**++.
To investigate the rotational barrier about the C(3)–C(2) ued rotation yet again forces the methyl group into close
bond of the major conformer of 10a we performed a co- proximity to the fluorenyl until the structure is capable of
ordinate scan, by varying the dihedral angle between the once again relaxing by rotation of the C(3)–N(6) bond,
H(4) and O(1). The coordinate scan was performed using completing the coordinate scan cycle. It is noteworthy that
DFT calculations at the B3LYP/6-31G** level of theory.[46] the alignment over the N(6)–C(7) bond is kept all through-
As a comparison, unprotected alanine methyl ester (free out the coordinate scan in a staggered conformation, with
base of 9a) was also subjected to the same calculation the nitrogen lone pair and hydrogen antiperiplanar to the
sequence as 10a (Figure S6) (Figure 7). Not surprisingly, fluorenyl C(9) and C(9Ј) (Figure S9).
6
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Synthesis of Chiral (Indol-2-yl)methanamines
to the minor energy conformation of 10a (entry 2, con-
former 2, Table 2) wherein the α-hydrogen is aligned in the
conformational space between the fluorenyl ring structure
and the phenyl ring of the Pf group (Figure S4). These ob-
servations were further supported by performing a simple
1D-CSSF-NOESY NMR experiment. Selective pulsing of
the α-hydrogen H(4) of 10a gave correlation peaks with
protons on the Pf group, indicating that the Pf group, at
the very least to some extent, is in contact with the α-
hydrogen H(4) in solution. The low chemical shift of the α-
hydrogen H(4) in 10a (δ = 2.78 ppm) could also be ex-
plained by the anisotropic effect, putting the proton in close
proximity to the Pf group, to be compared with the chemi-
cal shift of the corresponding α-hydrogen in N-benzyl-l-
alanine methyl ester (δ = 3.37 ppm) (Figure S2).[47]
Although the Pf group does induce a significant amount
of torsional strain about the C(2)–C(3) bond, compared to
the corresponding unprotected α-amino carbonyl com-
pound, the energy barrier is not high enough to explain the
complete retention of stereochemistry the Pf-protected α-
amino carbonyl compounds experience under strongly basic
conditions through a stereoelectronic effect previously pro-
posed (Figure 7). In order to achieve maximum orbital
overlap between the C(3)–H(4) σ orbital and the C(2)–O(1)
π* orbital only 7 kJ/mol of energy is required (Figure 7).
However, even though the orbital overlap would then be
favorable, the α-hydrogen is still kept in close steric confine-
ment by the Pf group. In order to alleviate the steric shield-
ing, opening up for deprotonation, the C(3)–N(6) bond
would have to be rotated (with or without inversion of the
nitrogen). Such rotation would however put the Pf group in
closer proximity to the amino acid side chain R(5), increas-
ing the energy barrier further. In fact, one such unique
structure was isolated in the conformational search (Figure
S5). The relative energy level of the structure (denoted as
conformer 6) was calculated to be 18 kJ/mol higher than
the global minimum conformation (entry 2, conformer 1,
Table 2), representing a significant energy difference.
Figure 7. Coordinate scan of 9a and 10a, rotation around the C(2)–
C(3) bond in 10° increments. Calculations performed in gas phase
using Jaguar 8.0; theory: DFT(B3LYP) with the basis set 6-31G**.
Energy: relative total electronic energy.
The conformational analysis was extended by X-ray crys-
tallography of eight structures of Pf-protected α-amino acid
derivatives, with the carbonyl at different functionality
states (Figure 8). The crystallographic data further points
to the fact that the H(4)–C(3) bond and the C(2)–O(1)
double bond do not necessarily adopt a periplanar (or anti-
periplanar) conformation as previously suggested (Table 3).
Figure 8. X-ray structures obtained from Pf-protected α-amino
carbonyl compounds.
However, the close proximity of the Pf group to the α-
hydrogen H(4) seems to be evident. In all but one of the
crystal structures (compound 10d is an exception: Table 3,
entry 7) the α-hydrogen H(4) is locked almost dead center
The dihedral angle between H(4) and C(7) (Table 3) (Fig-
over the fluorenyl ring structure, which is also supported by ure S3 and S4) might help to rationalize the loss of 9-phen-
the lowest calculated energy conformation of 10a (Fig- ylfluorene from Pf-protected alaninal, taking place prefer-
ure 5). Compound 10d seems to adopt a conformation, with entially over racemization, under basic conditions.[22] The
respect to the α-hydrogen and the Pf group, closely related orbitals of the H(4)–C(3) bond and of the N(6)–C(7) bond
Table 3. X-ray crystal structure data. Numbering of atoms does not conform to the crystallographic data but instead follows the number-
ing assigned in Figure 4.
Entry
Compound
Dihedral angle [°]
H(4)–C(3)–C(2)–O(1)
Dihedral angle [°]
H(4)–C(3)–N(6)–C(7)
Dihedral angle [°]
C(3)–N(6)–C(7)–C(8)
1
2
3
4
5
6
7
8
10a
11a
23[a]
24
10b
11b[c]
10d
11d
–120
–147
5
23
–175
172
178/178 (179/177)
19/23 (44/45)[b]
–149
–12.5/–24 (19/15)
26
31
29/32
3
177
176
–177/179
61
–153
–153/–150
–149
–161
28
174
[a] Structure data contains four crystallographically independent molecules, two in the NH/COOH state and two in the NH2+/COO–
state (zwitterionic forms shown in brackets). [b] Angle between only one of the carboxylates oxygens presented. [c] Structure data contains
two crystallographically independent molecules.
Eur. J. Org. Chem. 0000, 0–0
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FULL PAPER
[D6]DMSO (13C: δ = 39.5 ppm). Optical rotations were measured
with a Perkin–Elmer 343 Polarimeter equipped with a sodium lamp
and a 10 cm quartz cuvette. HRMS spectra were recorded on a
Waters Micromass LCT Premier (ESI/TOF) mass spectrometer. IR
was recorded on a Bruker ALPHA ECO-ATR FT-IR spectrometer.
Melting points were recorded on a Stuart SMP30.
involved in the observed elimination reaction, being almost
periplanar, are prealigned for a concerted E2 syn-elimi-
nation, making such a process possibly more favorable over
enolization. The same rationale could be applied to the
higher energy conformer, wherein the Pf group has been
rotated away from the α-hydrogen H(4) (Figure S5), with
the only difference that the orbitals now occupy an anti-
periplanar alignment, opening up for a possible concerted
anti-elimination. It is important to note that the discussion
herein does not take into account the possible increased
energy barrier the Pf group might induce in the enolization
transition state, when the sp3 carbon rehybridizes to sp2,
originating from the extra allylic strain the Pf group might
Crystal Structure Determinations: The single-crystal X-ray diffrac-
tion studies were carried out on a Bruker-Nonius Kappa-CCD dif-
fractometer at 123(2) K using Mo-Kα radiation (λ = 0.71073 Å)
(18b, 10a, 11a, 23, 10b, 11b, 10d, 11d), or a Bruker D8 Venture at
123(2) K, using Cu-Kα radiation (λ = 1.54178 Å) (24). Direct Meth-
ods (SHELXS-97[51]) were used for structure solution and refine-
ment was carried out using SHELXL-97 or SHELXL-2013/
SHELXL-2014[51] (full-matrix least-squares on F2). Hydrogen
impose. To further probe such effects more rigorous calcu- atoms were localized by difference electron density determination
and refined using a riding model [H(N), H(O) free].
lations would be necessary.
Semi-absorption corrections were applied for 18b, 23, 10b, 11b, 10d
and 11d, a numerical absorption correction was applied for 24. An
extinction correction was applied for 10a.
Conclusions
The absolute configurations of 18b, 10a, 11a, 23, 10b, 11b, 10d,
11d could not be determined reliably by refinement of Flack’s x-
parameter,[52] Parsons x-parameter[53] nor Hofft’s y-parameter,[54]
using the effects of anomalous scattering. For all structures the
enantiomer (absolute configuration) has been assigned by reference
to an unchanging chiral centre in the synthetic procedure. In 24
the absolute configuration could be determined using the effects
of anomalous scattering and in addition the enantiomer (absolute
configuration) has been assigned by reference to an unchanging
chiral centre in the synthetic procedure.
We have successfully developed a route to chiral (indol-
2-yl)methanamines giving compounds in at least 99% ee.
By using molecular mechanics in combination with DFT
calculations, crystallographic data and NMR experiments
we have also investigated the mechanism of how the 9-
phenyl-fluoren-9-yl protecting group retains the stereo-
chemistry of α-amino carbonyl compounds. The results
indicate that the α-hydrogen is kept in close proximity to
the Pf group and even though an enhanced torsional strain
is introduced in the substrates, stereoelectronic effects alone
could not explain the complete retention of the stereochem-
ical information under strongly basic conditions.
CCDC-1036698 (for 18b), -1036699 (for 10a), -1036700 (for 11a),
-1036701 (for 23), -1036702 (for 24), -1036703 (for 10b), -1036704
(for 11b), -1036705 (for 10d), and -1036706 (for 11d) contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Experimental Section
(S)-Alanine Methyl Ester Hydrochloride (9a): MeOH (240 mL) was
cooled down to 0 °C after which freshly distilled AcCl (47.9 mL,
673 mmol, 200 mol-%) was added drop wise. The reaction mixture
was stirred at 0 °C for 15 min and let warm to room temp. Alanine
(30.0 g, 337 mmol, 100 mol-%) was added and the reaction was
stirred at room temp. for 18 h. Solvents were evaporated to yield a
white solid. The crude product was triturated from MTBE to give
9a: yield 99% (47.0 g); white solid. 1H NMR (400 MHz, CDCl3):
δ = 8.76 (br. s, 3 H), 4.28 (q, J = 7.3 Hz, 1 H), 3.82 (s, 3 H), 1.74
(d, J = 7.3 Hz, 3 H) ppm.
General Information: Compounds 12,[48] 13d,[23] 10c (experimental
details are presented),[26,27] 10d,[23] 23[25] as well as 24[49] were pre-
pared using known literature procedures. All experiment using
moisture sensitive chemicals were performed in flame dried glass
ware under argon atmosphere. Dry solvents (THF, MeCN and
CH2Cl2) were obtained from a solvent drying system (MB SPS-
800, using neutral alumina as desiccant). Other solvents used were
of P.A. quality, with the exception of HPLC grade hexane for the
intended use of HPLC analysis, and used as such straight from the
bottles. TMSCl was distilled from CaH2 prior to use. AcCl was
distilled prior to use. Pb(NO3)2 and K3PO4 were finally powdered
and dried in oven prior to use. sBuLi was titrated from N-benzyl-
benzamide.[50] Reagents were obtained from Sigma Aldrich, TCI
Europe and Johnson Matthey Chemicals Limited. Celite used for
filtration was Celite 535, acquired from Sigma–Aldrich. TLC moni-
toring was performed on Merck silica gel 60 F254 on aluminum
support. Visualization of TLC plates was done using UV light (λ
= 254 nm) and/or staining the plates with ninhydrin solution (1 g
of ninhydrin dissolved in 100 mL of EtOH and 0.2 mLglacial
AcOH) or vanillin solution (2.4 g of vanillin dissolved in 100 mL
of EtOH, 2 mL conc. H2SO4 and 1.2 mLglacial AcOH). NMR
spectra were recorded on a Bruker Avance 400 spectrometer (at
ambient temperature unless otherwise stated) and the peaks were
calibrated to TMS (1H: δ = 0.00 ppm), or residual solvent 1H in
CD3CN (1H: δ = 1.94 ppm) and 13C in CDCl3 (13C: δ = 77.0 ppm),
(S)-Phenylalanine Methyl Ester Hydrochloride (9b): Compound 9b
was prepared using the same procedure as compound 9a. The crude
product was triturated from Et2O: yield 99% (34.1 g); light green
1
solid. H NMR (400 MHz, CD3OD): δ = 7.26–7.39 (m, 5 H), 4.33
(dd, J = 7.2, 6.3 Hz, 1 H), 3.80 (s, 3 H), 3.27 (dd, J = 14.3, 6.2 Hz,
1 H), 3.19 (dd, J = 14.3, 7.1 Hz, 1 H) ppm.
Methyl (S)-2-[(9-Phenyl-9H-fluoren-9-yl)amino]propanoate (10a):
Compound 9a (17.4 g, 125 mmol, 100 mol-%) was dissolved in
MeCN (500 mL) in a Morton flask. K3PO4 (55.5 g, 262 mmol,
210 mol-%), Pb(NO3)2 (35.1 g, 106 mmol, 85 mol-%) and Pf-Br
(50.0 g, 156 mmol, 125 mol-%) were added. The suspension was
stirred vigorously at room temp. for 40 h. MeOH (50 mL) was
added and the reaction mixture was stirred for 30 min. The suspen-
sion was filtered through a pad of celite which was eluted with
CHCl3 (approximately 600 mL) until no UV chromophore (λ =
[D6]acetone (13C: δ = 29.8 ppm), CD3OD (13C: δ = 49.0 ppm) or 254 nm) could be observed. Solvents were evaporated and the resi-
8
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Synthesis of Chiral (Indol-2-yl)methanamines
due was dissolved in Et2O (480 mL). The solution was washed with
H2O (360 mL) and the aqueous phase was extracted with Et2O (2ϫ
210 mL). The combined organic layers were washed with brine,
dried with Na2SO4 and filtered. The solvents were evaporated to
give a light orange cake. Recrystallization from MeOH (120 mL)
gave 10a: yield 82% (34.9 g); Rf 0.45 (Hex/EtOAc, 3:1; visualized
by UV or ninhydrin stain); pale yellow crystals; m.p. 88–90 °C.
(10 mL, 5 wt.-%) and the layers were separated. The aqueous layer
was extracted with Et2O (2ϫ 10 mL). The combined organic layers
were washed with brine, dried with Na2SO4 and filtered. The sol-
vents were evaporated to give a yellow foam. The crude product
was purified by silica gel column chromatography (Hex/EtOAc,
5:1) to give 11b: yield 70% (700 mg); Rf 0.27 (Hex/EtOAc, 5:1;
visualized by UV); white foam. [α]D (S) = –224.4 (c = 1.1 in
[α]D (S) = –226.4 (c = 0.55 in CH2Cl2), (R) +225.4 (c 0.55 in CH2Cl2), (R) +225.0 (c = 1.0 in CH2Cl2). 1H NMR (400 MHz,
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.16–7.70 (m, 13 H),
3.29 (s, 3 H), 2.96 (br. s, 1 H), 2.78 (q, J = 7.0 Hz, 1 H), 1.12 (d, J
= 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 177.1,
149.4, 148.9, 144.5, 140.8, 140.1, 128.2, 127.8, 127.4, 127.1, 126.1,
CDCl3): δ = 7.59 (d, J = 7.3 Hz, 1 H), 7.51 (d, J = 7.5 Hz, 1 H),
7.04–7.34 (m, 14 H), 6.77 (app t, J = 7.4 Hz, 1 H), 6.40 (d, J =
7.3 Hz, 1 H), 3.38 (br. s, 1 H), 3.01 (br. s, 1 H), 2.81 (s, 3 H), 2.85
(s, 3 H), 2.47–2.71 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ
126.0, 125.0, 120.0, 119.8, 73.0, 51.5, 51.4, 21.5 ppm. IR (film): ν = 176.0, 149.2, 148.8, 145.2, 141.3, 139.2, 138.8, 130.1, 128.0, 128.0,
˜
= 3478, 3314, 3061, 2978, 1731, 1447, 1198, 1144, 732, 699 cm–1. 127.9, 127.8, 127.5, 127.1, 126.9, 126.0, 126.0, 125.3, 119.3, 118.9,
HRMS-ESI calculated for C23H21NNaO2 [M + Na] 366.1470, 73.0, 60.2, 54.4, 41.4, 31.8 ppm. IR (film): ν = 3296, 3061, 3027,
˜
found 366.1473.
2936, 1655, 1449, 1178, 732, 698 cm–1. HRMS-ESI calculated for
C30H28N2NaO2 [M + Na] 471.2048, found 471.2048.
Methyl (S)-3-Phenyl-2-[(9-phenyl-9H-fluoren-9-yl)amino]propanoate
(10b): Compound 10b was prepared using the same procedure as
compound 10a. The crude product was recrystallized from EtOH
to give 10b: yield 86% (36.2 g); Rf 0.53 (Hex/EtOAc, 3:1; visualized
by UV or ninhydrin stain); white crystals; m.p. 150–151 °C. [α]D
(S)-Methyl 3-(9-Phenyl-9H-fluoren-9-yl)oxazolidine-4-carboxylate
(10c): Compound 9c (1.55 g, 10 mmol, 100 mol-%) was dissolved
in CH2Cl2 (30 mL) in a Morton flask. TMSCl (3.2 mL, 25 mmol,
250 mol-%) was added and the solution was cooled to 0 °C. Et3N
(4.9 mL, 35 mmol, 350 mol-%) was added dropwise. The reaction
mixture was refluxed for 1 h and cooled to 0 °C. MeOH (0.75 mL,
18.5 mmol, 185 mol-%) in CH2Cl2 (3 mL) was added and the reac-
tion mixture was warmed to room temp. and stirred for 1 h. Et3N
(1.4 mL, 10 mmol, 100 mol-%), Pb(NO3)2 (3.00 g, 9 mmol, 90 mol-
%) and Pf-Br (4.01 g, 12.5 mmol, 125 mol-%) were added. The sus-
pension was stirred vigorously for 72 h. The suspension was filtered
through a pad of celite which was subsequently washed with CHCl3
until no UV chromophore (λ = 254 nm) in the filtrate was detected.
Solvents were evaporated. Citric acid (40 mL, 10 wt.-% in MeOH)
was added and the solution was stirred for 1 h after which the sol-
vents were evaporated. The residue was dissolved in EtOAc
(80 mL). The solution was washed with H2O (40 mL) and the aque-
ous phase was extracted with EtOAc (2ϫ 60 mL). The combined
organic layers were washed with brine, dried with Na2SO4 and fil-
tered. The solvents were evaporated to yield a brown syrup. The
crude could be purified by flash chromatography (Hex/EtOAc, 1:1),
to give the intermediate Pf-protected serine methyl ester, or used in
the next step without further purification: yield 76% (2.71 g); Rf
0.17 (Hex/EtOAc, 3:1; visualized by UV); white solid. [α]D = –321.9
1
(S) = –206.7 (c = 1.2 in CH2Cl2), (R) +208.3 (c 1.1 in CH2Cl2). H
NMR (400 MHz, CDCl3): δ = 7.66 (m, 1 H), 7.61 (m, 1 H), 7.31–
7.36 (m, 3 H), 7.14–7.28 (m, 9 H), 7.02–7.07 (m, 2 H), 6.96 (m, 1
H), 6.63 (m, 1 H), 3.20 (s, 3 H), 2.64–2.92 (m, 4 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 176.2, 148.6, 148.5, 144.6, 141.0, 140.0,
137.6, 129.7, 128.2, 128.2, 128.1, 128.0, 127.8, 127.2, 127.1, 126.4,
126.2, 126.1, 125.0, 119.8, 119.6, 72.9, 57.5, 51.4, 41.4 ppm. IR
(film): ν = 3312, 3061, 3028, 2948, 1733, 1449, 1169, 733, 698 cm–1.
˜
HRMS-ESI calculated for C29H25NNaO2 [M + Na] 442.1783,
found 442.1780.
(S)-N-Methoxy-N-methyl-2-[(9-phenyl-9H-fluoren-9-yl)amino]prop-
anamide (11a): Compound 10a (22.1 g, 64 mmol, 100 mol-%) and
HN(OMe)Me·HCl (7.5 g, 77 mmol, 120 mol-%) were suspended in
THF (80 mL). The suspension was cooled to 0 °C and iPrMgCl
(77 mL, 154 mmol, 2 m in Et2O, 240 mol-%) was added dropwise
via dropping funnel. The reaction was stirred at 0 °C for 3 h before
being quenched with citric acid (200 mL, 5 wt.-%). The layers were
separated and the aqueous layer was extracted with Et2O (3ϫ
150 mL). The combined organic layers were washed with brine,
dried with Na2SO4 and filtered. The solvents were evaporated to
give 11a: yield 99% (23.9 g); Rf 0.18 (Hex/EtOAc, 3:1; visualized
by UV); pale yellow solid; m.p. 125–128 °C. [α]D = –236.0 (c = 1.3
1
(c = 1.0 in CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.66–7.72
(m, 2 H), 7.31–7.42 (m, 5 H), 7.21–7.28 (m, 6 H), 3.44 (m, 1 H),
3.42 (s, 3 H), 3.31 (br. s, 1 H), 3.27 (m, 1 H), 2.77 (dd, J = 5.7,
4.8 Hz, 1 H), 2.67 (br. t, J = 6.3 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 174.2, 148.7, 148.4, 144.0, 141.2, 139.9,
128.7, 128.6, 128.4, 128.3, 127.7, 127.4, 125.9, 125.7, 125.0, 120.2,
1
in CH2Cl2). H NMR (CDCl3): δ = 7.65 (m, 2 H), 7.40–7.46 (m, 3
H), 7.15–7.33 (m, 8 H), 3.56 (br. s, 1 H), 2.86–2.93 (br. m, 7 H),
1.06 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
177.2, 150.3, 149.4, 144.9, 141.2, 139.9, 128.2, 128.2, 128.1, 128.0,
127.5, 127.0, 126.8, 126.1, 125.4, 119.6, 119.5, 73.3, 60.3, 48.2, 31.9,
120.0, 72.6, 63.8, 57.1, 52.1 ppm. IR (film): ν = 3462, 3310, 3060,
˜
2951, 1730, 1600, 1447, 1334, 1175, 1052 cm–1. HRMS-ESI calcu-
lated for C23H21NNaO3 [M + Na] 382.1419, found 382.1414. The
white solid (2.58 g, 7.2 mmol, 100 mol-%) was dissolved in THF
(72 mL). pTsOH·H2O (83 mg, 0.43 mmol, 6 mol-%) and CH2O
21.9 ppm. IR (film): ν = 3298, 3061, 2935, 1650, 1446, 1382, 1178,
˜
991, 727, 698 cm–1. HRMS-ESI calculated for C24H25N2O2 [M +
H] 373.1916, found 373.1907.
(S)-N-Methoxy-N-methyl-3-phenyl-2-[(9-phenyl-9H-fluoren-9-yl)- (8.1 mL, 108 mmol, aq. 37 wt.-%, 1500 mol-%) were added and the
amino]propanamide (11b): Compound 10b (804 mg, 2 mmol, solution was stirred at room temp. for 20 h. The reaction mixture
100 mol-%) and HN(OMe)Me·HCl (234 mg, 2.4 mmol, 120 mol- was washed with satd. aq. NaHCO3 (2ϫ 50 mL) and brine. The
%) were suspended in THF (2.4 mL). The suspension was cooled organic phase was dried with Na2SO4, filtered and the solvents
to 0 °C and iPrMgCl (2.4 mL, 4.8 mmol, 2 m in Et2O, 240 mol-%) were evaporated to give 10c: yield 99 % (2.69 g); Rf 0.54 (Hex/
was added drop wise via a dropping funnel. The reaction was
stirred at 0 °C for 1 h and at room temp. for 3 h. The reaction
EtOAc, 3:1; visualized by UV); white foam. [α]D = +258.0 (c = 1.0
in CHCl3). H NMR (400 MHz, CDCl3): δ = 7.70 (m, 1 H), 7.63
1
mixture was cooled down to 0 °C and HN(OMe)Me·HCl (234 mg, (m, 1 H), 7.55 (m, 1 H), 7.41–7.51 (m, 4 H), 7.16–7.34 (m, 6 H),
2.4 mmol, 120 mol-%) and iPrMgCl (2.4 mL, 4.8 mmol, 2 m in
Et2O, 240 mol-%) were added. The reaction mixture was stirred at
room temp. for 3 h. The reaction was quenched with citric acid
4.93 (d, J = 6.4 Hz, 1 H), 4.74 (d, J = 6.4 Hz, 1 H), 3.62 (d, J =
7.5 Hz, 1 H), 3.62 (d, J = 6.3 Hz, 1 H), 3.56 (s, 3 H), 3.30 (dd, J =
7.5, 6.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.5,
Eur. J. Org. Chem. 0000, 0–0
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A. M. P. Koskinen et al.
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148.7, 146.7, 143.9, 141.5, 139.1, 128.9, 128.5, 128.0, 127.8, 127.5,
127.1, 126.5, 125.8, 119.8, 119.7, 85.0, 77.1, 69.0, 60.8, 51.9 ppm.
(m, 1 H), 7.08–7.39 (m, 14 H), 6.89 (m, 2 H), 3.61 (br. d, J =
9.0 Hz, 1 H), 3.34 (ddd, J = 13.4, 5.4, 3.0 Hz, 1 H), 3.24 (ddd, J =
11.3, 5.5, 3.3 Hz, 1 H), 3.12 (ddd, J = 11.3, 7.7, 3.1 Hz), 2.69–2.93
(m, 5 H), 2.35 (ddd, J = 11.3, 7.5, 3.4 Hz, 1 H), 2.04 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 173.9, 149.5, 149.4, 144.6, 141.0,
139.4, 137.8, 129.6, 128.3, 128.2, 128.2, 128.1, 127.5, 127.1, 126.6,
126.4, 126.0, 125.3, 119.5, 119.5, 73.0, 66.2, 65.3, 53.0, 44.7, 43.1,
IR (film): ν = 3063, 2952, 2870, 1746, 1450, 1173, 723, 646 cm–1.
˜
HRMS-ESI calculated for C24H22NO3 [M + H] 372.1600, found
372.1614.
(S)-N-Methoxy-N-methyl-3-(9-phenyl-9H-fluoren-9-yl)oxazolidine-
4-carboxamide (11c): Compound 10c (2.13 g, 5.7 mmol, 100 mol-
%) and HN(OMe)Me·HCl (670 mg, 6.9 mmol, 120 mol-%) were
suspended in THF (7 mL). The suspension was cooled to 0 °C and
iPrMgCl (6.9 mL, 13.8 mmol, 2 m in Et2O, 240 mol-%) was added
dropwise via a dropping funnel. The solution was stirred at 0 °C
for 1 h. The reaction was quenched with citric acid (20 mL, 5 wt.-
%) and the layers were separated. The aqueous layer was extracted
with Et2O. Combined organic layers were washed with brine, dried
with Na2SO4 and filtered. The solvents were evaporated to give a
pale yellow solid. The crude product was recrystallized from
EtOAc/Hex to give a white powder: yield 59% (1.35 g). The reac-
tion sequence from 9c to 11c could be performed without any inter-
mediate purification. The sequence was scaled up to give 11c after
recrystallization from EtOAc/isooctane: yield 56 % (22.8 g) over
three steps; Rf 0.11 (Hex/EtOAc, 3:1; visualized by UV); white
translucent needles; m.p. 179–182 °C dec. [α]D = +176.0 (c = 1.0 in
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 7.71 (m, 1 H), 7.61 (m,
2 H), 7.49–7.54 (m, 3 H), 7.44 (m, 1 H), 7.34 (m, 1 H), 7.16–7.27
(m, 5 H), 4.98 (d, J = 6.6 Hz, 1 H), 4.82 (d, J = 6.6 Hz, 1 H), 3.63–
3.71 (m, 2 H), 3.40 (m, 1 H), 3.00 (br. s, 3 H), 2.88 (br. s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 173.7, 149.4, 147.3, 144.3,
141.2, 139.1, 128.7, 128.4, 128.2, 128.1, 128.0, 127.3, 127.1, 126.8,
125.8, 119.5, 119.4, 85.8, 77.3, 69.1, 60.2, 58.6, 31.9 ppm. IR (film):
41.6 ppm. IR (film): ν = 3300, 3061, 3024, 2964, 2922, 2858, 1632,
˜
1423, 1113, 697, 646 cm–1. HRMS-ESI calculated for C32H31N2O2
[M + H] 475.2386, found 475.2396.
(S)-tert-Butyl (2-{2-Oxo-3-[(9-phenyl-9H-fluoren-9-yl)amino]-
butyl}phenyl)carbamate (13a): To a solution of 12 (2.59 g,
12.5 mmol, 250 mol-%) in dry THF (25 mL) was added sBuLi
(18.4 mL, 25 mmol, 1.4 m in cyclohexane, 500 mol-%) dropwise at
–30 °C. The solution changed color from colorless to bright yellow
after approximately half the volume of sBuLi had been added. The
yellow solution was left to stir at –30 °C for 1 h. The yellow suspen-
sion was taken to 0 °C. Compound 17a (1.993 g, 5 mmol, 100 mol-
%), dissolved in THF (25 mL) was added to the reaction mixture.
The reaction was quenched after 10 min with satd. NH4Cl (25 mL)
and H2O (5 mL) and taken to room temp. The reaction mixture
was extracted with Et2O (3 ϫ 30 mL). The combined organic
phases were washed with brine (50 mL) dried with Na2SO4, filtered
and the solvents were evaporated affording a pale yellow syrup.
Silica gel chromatography (Hex/EtOAc, 95:5 followed by Hex/
EtOAc, 90:10) gave 13a: yield 93% (2.421 g); Rf 0.65 (Hex/EtOAc,
3:1; visualized by UV or vanillin stain); white foam. [α]D (S) =
–148.0 (c = 1.2 in CH2Cl2), (R) +143.6 (c 0.57 in CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 7.70 (m, 3 H), 7.34–7.42 (m, 4 H),
7.06–7.30 (m, 9 H), 6.90 (m, 1 H), 6.67 (m, 1 H), 3.29 (d, J =
15.6 Hz, 1 H), 3.27 (br. s, 1 H), 2.96 (d, J = 15.4 Hz, 1 H), 2.86 (q,
J = 7.1 Hz, 1 H), 1.53 (s, 9 H), 1.02 (d, J = 7.1 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 213.6, 153.5, 149.6, 149.1, 144.2,
140.9, 140.0, 137.1, 130.3, 128.5, 128.4, 128.3, 128.1, 127.9, 127.7,
127.2, 126.2, 126.1, 125.1, 124.1, 123.6, 119.9, 119.8, 80.1, 73.1,
ν = 3057, 2966, 2938, 2972, 1660, 1449, 1176, 1021, 889, 735,
˜
701 cm–1. HRMS-ESI calculated for C25H25N2O3 [M + H]
401.1865, found 401.1869.
(S)-1-Morpholino-2-[(9-phenyl-9H-fluoren-9-yl)amino]propan-1-one
(17a): A round bottomed flask was charged with dry THF (20 mL),
10a (1.374 g, 4 mmol, 100 mol-%) and morpholine (0.52 mL,
6 mmol, 150 mol-%) and the resulting solution was cooled to 0 °C.
To the reaction mixture was added iPrMgCl (3 mL, 6 mmol, 2 m in
Et2O, 150 mol-%) dropwise. The solution was stirred for 2 h. Citric
acid (20 mL, 5 wt.-%) was added and the resulting suspension was
warmed to room temp. H2O (5 mL) and CH2Cl2 (60 mL) was
added and the phases separated. The aqueous phase was extracted
with CH2Cl2 (2ϫ 100 mL) and the combined organic phases were
dried with Na2SO4, filtered and the solvents were evaporated. The
pale yellow solid was subjected to silica gel chromatography (Hex/
EtOAc, 1:1) to give 17a: yield 93% (1.488 g); Rf 0.15 (Hex/EtOAc,
3:1; visualized by UV); white solid; m.p. 189–195 °C dec. [α]D (S)
57.2, 43.7, 28.4, 20.4 ppm. IR (film): ν = 3326, 3062, 2977, 2930,
˜
1710, 1589, 1515, 1449, 1234, 1153, 1047, 1025, 731, 699 cm–1
.
HRMS-ESI calculated for C34H35N2O3 [M + H] 519.2648, found
519.2642.
(S)-tert-Butyl (2-{2-Oxo-4-phenyl-3-[(9-phenyl-9H-fluoren-9-yl)-
amino]butyl}phenyl)carbamate (13b): To a solution of 12 (1.55 g,
7.5 mmol, 250 mol-%) in dry THF (22.5 mL) was added sBuLi
(11.5 mL, 15 mmol, 1.3 m in cyclohexane, 500 mol-%) dropwise at
–30 °C. The solution changed color from colorless to bright yellow
after approximately half the volume of sBuLi had been added. The
yellow solution was left to stir at –30 °C for 1 h. The yellow suspen-
sion was cooled to –41 °C. 11b (1.35 g, 3 mmol, 100 mol-%) dis-
solved in THF (7.5 mL) was added to the reaction mixture. After
1 h the reaction was quenched with satd. NH4Cl (30 mL) and H2O
(5 mL) and taken to room temp. The reaction mixture was ex-
tracted with Et2O (3ϫ 30 mL). The combined organic phases were
washed with brine (60 mL) dried with Na2SO4, filtered and the
solvents were evaporated affording a pale yellow syrup. Silica gel
chromatography (Hex/EtOAc, 9:1) gave 13b: yield 77% (1.38 g); Rf
0.62 (Hex/EtOAc, 3:1; visualized by UV or by vanillin stain); white
foam; Chiral HPLC analysis [Chiralpak IB, 99:1 Hexane/EtOH,
1 mL/min, retention times: (R)-enantiomer = 8.0 min, (S)-enantio-
1
= –256.2 (c = 0.86 in CH2Cl2), (R) +252.9 (c 0.58 in CH2Cl2). H
NMR (400 MHz, CDCl3): δ = 7.68 (m, 2 H), 7.16–7.44 (m, 11 H),
3.74 (br. s, 1 H), 3.44 (m, 1 H), 3.22–3.32 (m, 4 H), 2.98 (m, 1 H),
2.80 (m, 2 H), 2.49 (ddd, J = 13.3, 6.26, 2.96 Hz, 1 H), 1.02 (d, J
= 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 175.2,
150.1, 149.3, 144.5, 141.0, 139.7, 128.2, 128.2, 128.1, 127.5, 127.0,
126.8, 126.0, 125.3, 119.6, 119.5, 73.2, 66.5, 65.9, 47.0, 44.9, 41.9,
21.8 ppm. IR (film): ν = 3286, 2964, 2921, 2859, 1631, 1427, 1114,
˜
1028, 733, 702 cm–1. HRMS-ESI calculated for C26H27N2O2 [M +
H] 399.2073, found 399.2072.
(S)-1-Morpholino-3-phenyl-2-[(9-phenyl-9H-fluoren-9-yl)amino]- mer = 8.9 min], (S) Ͼ99% ee, (R) = 99% ee. [α]D (S) = –146.7 (c =
propan-1-one (17b): Prepared in the same manner as 17a. Reaction
time: 20 h. Product purified by silica gel chromatography (Hex/
EtOAc, 7:3): yield 80% (382 mg); Rf 0.23 (Hex/EtOAc, 3:1, visual-
1.2 in CH2Cl2), (R) +148.9 (c 1.0 in CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 7.65 (m, 3 H), 6.85–7.38 (m, 18 H), 6.64 (m, 1 H),
6.48 (m, 1 H), 3.20 (br. s, 1 H), 2.99 (d, J = 15.9 Hz, 1 H), 2.93
(br. m, 1 H), 2.73 (d, J = 15.9 Hz, 1 H), 2.57 (dd, J = 13.8, 5.9 Hz,
ized by UV); white solid; m.p. 150–152 °C. [α]D = –220.8 (c = 0.86
1
in CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.66 (m, 1 H), 7.62 1 H), 2.51 (dd, J = 13.6, 8.3 Hz, 1 H), 1.53 (s, 9 H) ppm. 13C NMR
10
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50391
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Date: 30-04-15 16:19:01
Pages: 14
Synthesis of Chiral (Indol-2-yl)methanamines
(100 MHz, CDCl3): δ = 213.2, 153.4, 149.0, 148.8, 144.2, 141.0, structure was obtained of 18b. Crystals obtained by recrystalli-
139.6, 137.2, 137.1, 130.5, 129.6, 128.6, 128.3, 128.2, 128.1, 128.0,
127.9, 127.7, 127.2, 126.6, 126.5, 126.0, 125.1, 125.0, 123.9, 123.3,
zation from EtOAc/Hex: white translucent crystals; m.p. 172–
174 °C. [α]D = –127.9 (c = 1.1 in CH2Cl2). 1H NMR (400 MHz,
CDCl3): δ = 7.86 (br. s, 1 H), 7.70 (d, J = 7.5 Hz, 1 H), 7.55 (d, J
= 7.7 Hz, 1 H), 7.31–7.38 (m, 4 H), 7.15–7.21 (m, 7 H), 6.09–7.09
119.7, 119.5, 80.1, 72.9, 63.0, 45.2, 40.5, 28.4 ppm. IR (film): ν =
˜
3311, 3062, 3027, 2978, 2930, 1716, 1450, 1155, 732, 699 cm–1
.
HRMS-ESI calculated for C40H39N2O3 [M + H] 595.2961, found (m, 4 H), 6.89 (m, 2 H), 6.74 (d, J = 7.7 Hz, 1 H), 6.57 (d, J =
595.2967.
7.6 Hz, 1 H), 6.50 (m, 1 H), 5.73 (m, 1 H), 3.40 (dd, J = 8.0, 6.1 Hz,
1 H), 2.88 (dd, J = 13.5, 6.1 Hz, 1 H), 2.84 (dd, J = 13.5, 8.0 Hz,
1 H), 2.62 (br. s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
148.9, 148.4, 144.8, 142.6, 141.1, 139.5, 138.1, 135.0, 129.4, 128.7,
128.5, 128.3, 128.1, 127.8, 127.7, 127.1, 127.0, 126.5, 126.0, 125.3,
124.7, 120.8, 119.9, 119.4, 119.4, 119.1, 110.5, 98.6, 73.0, 53.1, 44.8
(S)-tert-Butyl(2-{2-oxo-2-[3-(9-phenyl-9H-fluoren-9-yl)oxazolidin-4-
yl]ethyl}phenyl)carbamates (13c): Compound 12 (15.54 g,
67.5 mmol, 250 mol-%) was dissolved in THF (140 mL) and cooled
down to –30 °C. sBuLi (102 mL, 125 mmol, 1.2 m in cyclohexane,
500 mol-%) was added dropwise. The solution changed color from
colorless to bright yellow after approximately half the volume of
sBuLi had been added. The reaction was stirred at –30 °C for 1 h.
11c (10.03 g, 25 mmol, 100 mol-%) in THF (65 mL) was added and
the reaction was stirred for an additional 15 min. The reaction was
ppm. IR (film): ν = 3433, 3312, 3058, 3026, 2922, 2857, 1454, 1287,
˜
729, 698 cm–1. HRMS-ESI calculated for C35H29N2 [M + H]
477.2331, found 477.2325.
(R)-2-(1H-Indol-2-yl)-2-[(9-phenyl-9H-fluoren-9-yl)amino]ethanol
quenched with satd. NH4Cl (60 mL), taken to room temp. and H2O (18c): Compound 13c (1.09 g, 2 mmol, 100 mol-%) was dissolved
(50 mL) was added to dissolve the white precipitate. The aqueous
layer was extracted with EtOAc (2ϫ 150 mL) and the combined
organic layers were washed with brine, dried with Na2SO4 and fil-
tered. The solvents were evaporated to give a white solid. The crude
product was triturated with Et2O to give 13c: yield 90% (12.3 g);
Rf 0.43 (Hex/EtOAc, 3:1; visualized by UV or by vanillin stain);
white powder; m.p. 175–177 °C. [α]D = +139.6 (c = 1.0 in CH2Cl2).
in MeOH/CH2Cl2 (1:1, 20 mL) and the resulting solution was
cooled to 0 °C. H2SO4 (3.4 mL, 20 mmol, 6 m in EtOH, 1000 mol-
%) was added and the reaction mixture was stirred at 0 °C for 1 h
and at room temp. for 1 h. NH2OH·HCl (1.40 g, 20 mmol,
1000 mol-%) was added and the reaction was stirred at room temp.
for 1.5 h. The reaction mixture was poured very carefully to satd.
NaHCO3 (60 mL), CAUTION! vigorous gas evolution, and the
1H NMR (400 MHz, CDCl3): δ = 7.66–7.74 (m, 3 H), 7.56 (d, J = aqueous layer was extracted with CH2Cl2 (2ϫ 50 mL). Combined
7.5 Hz, 1 H), 7.45–7.51 (m, 4 H), 7.18–7.36 (m, 7 H), 7.12 (br. s, 1
H), 6.99 (m, 1 H), 6.83 (m, 1 H), 5.06 (d, J = 6.4 Hz, 1 H), 4.73
(d, J = 6.6 Hz, 1 H), 3.83 (d, J = 15.6 Hz, 1 H), 3.65 (d, J =
organic layers were dried with Na2SO4, filtered and the solvent
were evaporated. The residual was dissolved in MeOH (20 mL) and
NaOH (5.0 mL, 10 mmol, aq. 5 m, 500 mol-%) was added. The
15.6 Hz, 1 H), 3.62 (m, 1 H), 3.30 (m, 2 H), 1.52 (s, 9 H) ppm. 13C reaction mixture was refluxed for 0.5 h after which H2O (20 mL)
NMR (100 MHz, CDCl3): δ = 209.3, 153.6, 148.7, 146.0, 143.1,
141.5, 139.4, 137.3, 130.5, 129.2, 128.9, 128.7, 128.2, 128.1, 128.0,
127.7, 127.0, 126.9, 125.8, 125.7, 124.3, 123.9, 120.1, 119.8, 85.0,
and CH2Cl2 (40 mL) were added. The layers were separated and
the aqueous layer was extracted with CH2Cl2 (2ϫ 40 mL). The
combined organic layers were dried with Na2SO4, filtered and the
80.3, 77.2, 67.5, 66.2, 43.3, 28.4 ppm. IR (film): ν = 3341, 3062, solvents were evaporated. The crude product was purified by tritu-
˜
2978, 2870, 1718, 1515, 1450, 1236, 1156, 734 cm–1. HRMS-ESI ration from MeOH to give 18c: yield 75% (630 mg) over two steps;
calculated for C35H35N2O4 [M + H] 547.2597, found 547.2597.
Rf 0.22 (Hex/EtOAc, 3:1; visualized by UV or by ninhydrin stain-
ing); white powder; m.p. 183–186 °C dec. [α]D = –229.6 (c = 1.0 in
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.25 (br. s, 1 H), 7.73
(m, 2 H), 7.38–7.44 (m, 5 H), 7.19–7.34 (m, 6 H), 7.11 (m, 1 H),
6.99–7.04 (m, 3 H), 5.93 (m, 1 H), 3.50 (br. m, 1 H), 3.37 (app t, J
= 4.5 Hz, 1 H), 3.24 (dd, J = 11.0, 4.6 Hz, 1 H), 2.69 (br. m, 1 H),
2.55 (br. m, 1 H) ppm. 13C NMR (100 MHz, [D6]acetone): δ =
150.9, 150.1, 146.8, 142.2, 142.1, 140.5, 136.9, 129.6, 129.2, 128.9,
128.6, 128.4, 127.8, 127.6, 127.1, 126.3, 126.0, 121.0, 120.6, 120.3,
(S)-N-[1-(1H-Indol-2-yl)ethyl]-9-phenyl-9H-fluoren-9-amine (18a):
Compound 13a (3.27 g, 6.3 mmol, 100 mol-%) was dissolved in
CH2Cl2 (70 mL) and cooled to 0 °C. H2SO4 (10.5 mL, 63 mmol,
6 m in EtOH, 1000 mol-%) was added and the reaction mixture
was stirred at 0 °C for 1.5 h. The reaction was quenched with satd.
NaHCO3 (300 mL), CAUTION! vigorous gas evolution, and the
aqueous layer was extracted with CH2Cl2 (2ϫ 150 mL). Combined
organic layers were dried with Na2SO4 and filtered. The solvents
were evaporated to give a reddish foam. The crude product was
purified by silica gel chromatography (Hex/EtOAc, 9:1) to give 18a:
yield 65% (1.65 g); Rf 0.47 (Hex/EtOAc, 5:1; visualized by UV or
1
120.2, 119.3, 111.7, 99.6, 74.1, 66.7, 54.7 ppm. IR (film): ν = 3548,
˜
3425, 3330, 3057, 2948, 2875, 1449, 733, 699 cm–1. HRMS-ESI cal-
culated for C29H24N2NaO [M + Na] 439.1786, found 439.1788.
by ninhydrin staining); white foam. [α]D (S) = –147.2 (c = 1.0 in (S)-2-[1-(9-Phenyl-9H-fluoren-9-yl)pyrrolidin-2-yl]-1H-indole (18d):
CH2Cl2), (R) +145.7 (c 0.67 in CH2Cl2). 1H NMR (400 MHz, Compound 18d was prepared using the same procedure as com-
CDCl3): δ = 8.05 (br. s, 1 H), 7.74 (m, 1 H), 7.64 (m, 1 H), 7.16– pound 18a, giving after work up 18d: yield 99% (462 mg); Rf 0.83
7.46 (m, 11 H), 7.04–7.10 (m, 2 H), 6.99 (m, 1 H), 6.88 (m, 1 H), (Hex/EtOAc, 5:1, visualized by UV or by ninhydrin staining); yel-
1
5.88 (m, 1 H), 3.47 (q, J = 6.8 Hz, 1 H), 2.32 (br. s, 1 H) 1.17 (d,
J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 150.2,
149.0, 144.9, 144.1, 141.0, 139.9, 135.1, 128.7, 128.4, 128.3, 128.1,
127.9, 127.5, 127.2, 126.0, 125.1, 124.8, 120.9, 120.0, 119.9, 119.9,
low solid; m.p. 156–160 °C. [α]D = –49.4 (c = 1.2 in CH2Cl2). H
NMR (400 MHz, CDCl3): δ = 8.12 (br. s, 1 H), 7.75 (m, 1 H), 7.58
(m, 1 H), 6.96–7.54 (m, 14 H), 6.53 (m, 1 H), 5.70 (m, 1 H), 3.73
(m, 1 H), 3.41 (m, 1 H), 3.15 (m, 1 H), 1.69–1.90 (m, 4 H) ppm.
119.3, 110.5, 97.7, 73.1, 46.8, 24.0 ppm. IR (film): ν = 3429, 3057, 13C NMR (100 MHz, CDCl3): δ = 149.0, 147.0, 144.8, 143.7, 142.2,
˜
2966, 2867, 1616, 1599, 1449, 1295, 1156, 732, 699 cm–1. HRMS-
ESI calculated for C29H25N2 [M + H] 401.2018, found 401.2014.
138.6, 135.0, 129.2, 128.5, 128.2, 127.7, 127.4, 127.2, 127.1, 127.0,
126.5, 125.8, 120.5, 119.8, 119.8, 119.2, 119.1, 110.4, 97.6, 77.2,
56.7, 50.8, 35.2, 25.2 ppm. IR (film): ν = 3448, 3056, 2965, 2868,
˜
(S)-N-[1-(1H-Indol-2-yl)-2-phenylethyl]-9-phenyl-9H-fluoren-9-
amine (18b): Compound 18b was prepared using the same pro-
cedure as compound 18a, giving, after work up 18b as a yellow
solid with acceptable purity: yield 99% (710 mg); Rf 0.38 (Hex/
1449, 1285, 736, 702 cm–1. HRMS-ESI calculated for C31H27N2 [M
+ H] 427.2174, found 427.2174.
(S)-1-(1H-Indol-2-yl)ethanamine (22a): Compound 18a (400 mg,
EtOAc, 9:1; visualized by UV or by ninhydrin staining); An X-ray 1 mmol, 100 mol-%) was dissolved in MeOH (8 mL) and the re-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11

Job/Unit: O50391
/KAP1
Date: 30-04-15 16:19:01
Pages: 14
A. M. P. Koskinen et al.
FULL PAPER
sulting solution was degassed with argon. Pd/C (45 mg, 0.05 mmol,
10 wt.-%, 5 mol-%) was added and hydrogen (1 atm, balloon) was
introduced and the reaction was stirred for 18 h at room temp. The
reaction mixture was filtered through a pad of celite and the sol-
vents were evaporated. The residue was partitioned between HCl
(50 mL, aq. 1 m) and Et2O (100 mL) and the phases were separated.
The organic phase was extracted with HCl (50 mL, aq. 1 m). The
combined aqueous phases were basified with NaOH (aq. 1 m) until
pH Ͼ8. The aqueous phase was extracted with Et2O (3ϫ 100 mL).
Combined organic layers were dried with Na2SO4 and filtered. The
solvents were evaporated to give 22a: yield 99% (160 mg); Rf 0.19
(CH2Cl2/MeOH, 9:1; visualized by UV or by ninhydrin staining);
pale yellow solid; m.p. 64–67 °C. [α]D (S) = +4.3 (c = 1.3 in
CH2Cl2), (R) –3.9 (c 1.1 in CH2Cl2). 1H NMR (400 MHz, CDCl3):
δ = 8.52 (br. s, 1 H), 7.55 (m, 1 H), 7.34 (m, 1 H), 7.14 (ddd, J =
8.1, 7.1, 1.1 Hz, 1 H), 7.07 (ddd, J = 8.0, 7.1, 1.1 Hz, 1 H), 6.30
(m, 1 H), 4.33 (br. q, J = 6.6 Hz, 1 H), 1.52 (d, J = 6.6 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 144.1, 135.6, 128.5, 121.4,
1 H), 3.85 (dd, J = 10.8, 4.8 Hz, 1 H), 3.70 (dd, J = 10.8, 7.3 Hz,
1 H) ppm. 13C NMR (100 MHz, CD3OD): δ = 141.2, 137.8, 129.7,
122.0, 120.9, 120.1, 111.8, 99.5, 67.7, 53.0 ppm. IR (film): ν = 3392,
˜
3347, 3284, 3082, 3055, 2918, 2869, 1587, 1456, 1342, 1289, 1035,
792, 743 cm–1. HRMS-ESI calculated for C10H13N2O [M + H]
177.1028, found 177.1027.
(S)-2-(Pyrrolidin-2-yl)-1H-indole (22d): Compound 18d (427 mg,
1 mmol, 100 mol-%) was suspended together with NH4H2PO2
(498 mg, 6 mmol, 600 mol-%) in EtOH (10 mL). Pd/C (53 mg,
0.05 mmol, 10 wt.-%, 5 mol-%) was added. The reaction mixture
was refluxed for 1.5 h after which it was cooled to room temp. The
suspension was filtered through a pad of celite and eluted with
CH2Cl2 (20 mL) and MeOH (30 mL). The solvents were evapo-
rated and the crude mixture portioned between Et2O (50 mL) and
HCl (30 mL, aq., 1 m). The aqueous phase was washed once with
Et2O (10 mL). The aqueous phase was basified with NaOH (aq., 1
m), until pH = 12, and extracted with CH2Cl2 (3ϫ 20 mL). The
combined organic phases were dried with Na2SO4, filtered and the
solvents were evaporated. One portion of hexane (10 mL) was
added and the solvent was evaporated to give 22d: yield 86%
(160 mg); Rf 0.19 [CH2Cl2/MeOH/NH3 (aq., 25 wt.-%), 90:10:1;
visualized by UV or by ninhydrin staining]; beige solid; m.p. 105–
120.1, 119.6, 110.7, 97.7, 45.3, 24.9 ppm. IR (film): ν = 3600, 3398,
˜
3150–3350, 3050, 2969, 2869, 1587, 1457, 1341, 1302, 943, 789,
751 cm–1. HRMS-ESI calculated for C10H13N2 [M + H] 161.1079,
found 161.1078.
(S)-1-(1H-Indol-2-yl)-2-phenylethanamine (22b): Compound 18b 107 °C. [α]D = –26.6 (c = 1.6 in CH2Cl2). 1H NMR (400 MHz,
(420 mg, 0.9 mmol, 100 mol-%) was dissolved in AcOH (16 mL) CDCl3): δ = 9.35 (br. s, 1 H), 7.53 (m, 1 H), 7.28 (m, 1 H), 7.11
and degassed with argon. Pd/C (46 mg, 0.05 mmol, 10 wt.-%,
5 mol-%) was added and hydrogen (1 atm, balloon) was introduced.
The reaction mixture was stirred at room temp. for 18 h. The reac-
tion mixture was filtered through a pad of celite and solvents were
evaporated. The residue was partitioned between HCl (50 mL, aq.
1 m) and Et2O (100 mL). The phases were separated and the or-
ganic phase was extracted with HCl (50 mL, aq. 1 m). The com-
bined aqueous phases were basified with NaOH (aq. 1 m) until pH
Ͼ8. The aqueous phase was extracted with CH2Cl2 (3ϫ 100 mL).
Combined organic phases were dried with Na2SO4 and filtered.
The solvents were evaporated to give 22b: yield 87% (180 mg); Rf
0.43 (CH2Cl2/MeOH, 9:1; visualized by UV or by ninhydrin stain-
ing); orange solid; m.p. 66–71 °C. [α]D = +20.1 (c = 0.9 in CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 8.91 (br. s, 1 H), 7.55 (m, 1 H),
7.05–7.33 (m, 8 H), 6.34 (m, 1 H), 4.35 (dd, J = 9.1, 4.6 Hz, 1 H),
3.23 (dd, J = 13.4, 4.6 Hz, 1 H), 2.85 (dd, J = 13.4, 9.2 Hz, 1 H),
1.96 (br. m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 142.1,
138.2, 135.6, 129.3, 128.6, 128.4, 126.7, 121.4, 120.2, 119.6, 110.8,
(m, 1 H), 7.05 (m, 1 H), 6.30 (s, 1 H), 4.34 (m, 1 H), 2.96–3.11
(m, 2 H), 2.08–2.22 (m, 2 H), 1.77–1.97 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 141.9, 135.7, 128.7, 121.1, 120.0, 119.4,
110.7, 98.0, 56.2, 46.7, 32.6, 25.6 ppm. IR (film): ν˜ = 3398, 2966,
2873, 1455, 1417, 1303, 1059, 784, 728, 646 cm–1. HRMS-ESI cal-
culated for C12H15N2 [M + H] 187.1235, found 187.1243.
Computational Information: The molecular modeling was per-
formed using MacroModel (V. 10.0). Conformational searches were
performed using force fields MM2*, MM3*, MMFF, MMFFs and
OPLS-2005 using a mixed torsional/low-mode sampling method.
The amount of minimization iterations was set high enough (typi-
cally 3000 iterations) so that no unconverged structures were ob-
tained. DFT calculations were performed in Jaguar (v. 8.0). The
refinement of the OPLS-2005 conformational search was per-
formed at the M06-2X/6-31G**++ level of theory. Structures with
high similarity to one another were judged not to be unique energy
minima and therefore removed. The coordinate scan of the lowest
energy conformation was performed at the B3LYP/6-31G** level
of theory. All calculations were performed in the gas phase.
98.5, 51.3, 44.9 ppm. IR (film): ν = 3403, 3345, 3281, 3186, 3058,
˜
2919, 2854, 1584, 1455, 1289, 750, 699 cm–1. HRMS-ESI calculated
for C16H17N2 [M + H] 237.1392, found 237.1391.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra of all products; chiral
HPLC spectra of compounds 25a and 13b; analytical data of com-
pounds 14a, 15a, 19, 20 and 12-d2; experimental and analytical data
of a stepwise approach to 18c; experimental and analytical data of
the acylation and methylation of compounds 22a–d; computational
data of 9a and 10a as well as crystallographic data.
(R)-2-Amino-2-(1H-indol-2-yl)ethanol (22c): Compound 18c
(1.67 g, 4 mmol, 100 mol-%) was dissolved in AcOH (32 mL) and
degassed with argon. Pd/C (180 mg, 0.2 mmol, 10 wt.-%, 5 mol-
%) was added and hydrogen (1 atm, balloon) was introduced. The
reaction mixture was stirred at room temp. for 18 h. The reaction
mixture was filtered through a pad of celite and solvents were evap-
orated. The residue was partitioned between HCl (50 mL, aq. 1 m)
and Et2O (100 mL). The phases were separated and the organic
phase was extracted with HCl (25 mL, aq. 1 m). The combined
aqueous phases were basified with NaOH (aq. 1 m) until pH Ͼ 8.
The aqueous phase was extracted with CHCl3/2-propanol (4:1, 5ϫ
200 mL). Combined organic layers were dried with Na2SO4 and
filtered. The solvents were evaporated to give 22c: yield 95%
(670 mg); Rf 0.05 (CH2Cl2/MeOH, 9:1; visualized by UV or by
ninhydrin staining); light grey solid; m.p. 96–98 °C. [α]D = –21.7 (c
Acknowledgments
The authors are grateful for the financial support provided by the
National Graduate School of Organic Chemistry and Chemical
Biology, Finland and Aalto University. M. Sc. Essi Karppanen
(Aalto University School of Chemical Technology) is kindly ac-
knowledged for providing crystals of compound 24. The authors
thank Bruker-AXS, Karlsruhe, Germany, for collecting the data of
= 1.1 in MeOH). 1H NMR (400 MHz, CD3OD): δ = 7.45 (m, 1 compound 24. Professor Antti Poso (University of Eastern Fin-
H), 7.30 (m, 1 H), 7.04 (ddd, J = 8.1, 7.0, 1.3 Hz, 1 H), 6.95 (ddd,
J = 8.2, 7.0, 0.9 Hz, 1 H), 6.35 (m, 1 H), 4.13 (dd, J = 7.2, 4.7 Hz,
land) and M. Sc. Marko Melander (Aalto University School of
Chemical Technology) are acknowledged for valuable advice re-
12
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Synthesis of Chiral (Indol-2-yl)methanamines
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Received: March 24, 2015
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Published Online: ᭿
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13

Job/Unit: O50391
/KAP1
Date: 30-04-15 16:19:01
Pages: 14
A. M. P. Koskinen et al.
FULL PAPER
Indole Synthesis
Herein is presented
a
highly efficient
C. S. Lood, A. E. Laine, A. Högnäsbacka,
M. Nieger, A. M. P. Koskinen* ....... 1–15
stereospecific synthesis of (indol-2-yl)meth-
anamines from amino acids together with
a mechanistic study on the stereochemistry
protecting effects of the 9-phenyl-9-fluor-
enyl protecting group with the aid of DFT
calculations, NMR and X-ray crystallogra-
phy.
Synthesis of Chiral (Indol-2-yl)methan-
amines and Insight into the Stereochemis-
try Protecting Effects of the 9-Phenyl-9-
fluorenyl Protecting Group
Keywords: Asymmetric synthesis / Amino
acids / Chiral pool / Protecting groups
14
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Eur. J. Org. Chem. 0000, 0–0