The Voight reaction on tertiary α-hydroxy ketones

Article abstract of DOI:10.1016/j.tet.2015.08.069

The Voight reaction is for the transformation of secondary α-hydroxy ketones into corresponding α-amino ketones. Although discovered as early as 1886, it has not enjoyed wide popularity in organic synthesis, as it is applicable to only secondary α-hydroxy

Full text of DOI:10.1016/j.tet.2015.08.069

Accepted Manuscript
The Voight reaction on tertiary α-hydroxy ketones
H.Surya Prakash Rao, Satish Vijjapu
PII:
S0040-4020(15)30023-5
10.1016/j.tet.2015.08.069
TET 27091
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 April 2015
Revised Date: 25 August 2015
Accepted Date: 26 August 2015
Please cite this article as: Prakash Rao HS, Vijjapu S, The Voight reaction on tertiary α-hydroxy ketones,
Tetrahedron (2015), doi: 10.1016/j.tet.2015.08.069.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
The Voight reaction on tertiary α-hydroxy ketones
*
H. Surya Prakash Rao, Satish Vijjapu
Department of Chemistry, Pondicherry University, Pondicherry – 605 014, INDIA
E.mail: hspr.che@pondiuni.edu.in; Telephone: +914132654411; Fax: +914132656230
Graphical Abstract
Abstract
The Voight reaction is for the transformation of secondary α-hydroxy ketones into
corresponding α-amino ketones. Although discovered as early as 1886, it has not enjoyed wide
popularity in organic synthesis, as it is applicable to only secondary α-hydroxy ketones. In terms
of extending the applications of the reaction, we have shown that the reaction takes place on tert-
α-hydroxy ketones also, particularly when present on rigid planar molecular frameworks like
phenanthrene, pyrene and acenaphthylene. The reaction is not a simple substitution of the
hydroxy group with amines, but goes through imine formation followed by 1,2-C migration. The
reaction provides good opportunity for the synthesis of optically active α-amino ketones. We
have achieved facile synthesis of some chromatographically separable and optically active tert-α-
amino ketones by employing S-(-) or R-(+)-α-methylbenzylamines in the Voight amination.
Key words
1

ACCEPTED MANUSCRIPT
Voight reaction, α-Hydroxy ketone, tert-α-Amino ketone.
1
. Introduction
The Voight reaction, first reported in 1886, is an acid mediated condensation of α-hydroxy
1
ketones 1 with primary 2 (or secondary) amines to form α-amino ketones 5 (Scheme 1). Voight
demonstrated phosphorus pentoxide mediated condensation reaction of benzoin and primary
amines to form corresponding α-amino ketones. Apart from phosphorus pentoxide, the reaction
2
also worked well in the presence of strong protic acids like hydrochloric acid or trifluoroacetic
3
acid (Scheme 1). Lutz and co-workers probed the mechanism of the reaction in detail and
showed that the reaction is not a simple substitution of the secondary hydroxyl group in 1, but
4
goes through a rearrangement (Scheme 1). According to the proposed mechanism, initially
generated imines 3 tautomerize to enol 4 and finally to ketone 5. Indeed, the reaction of benzoin
derivative having electron donating OMe groups at C(4) position of the aryl rings was slower
compared to that of simple benzoin owing to lower reactivity of the carbonyl group for the
formation of imine intermediate. Lutz has clearly shown that tertiary α-hydroxy ketones 6 e.g. α-
4
a
methyl and α-phenyl benzoins, do not undergo the Voight reaction (Scheme 2). In such cases,
tautomerization in the intermediate 7 is not possible. In the review article on the Voight reaction
Wang stated "In the absence of such α-proton, the reaction becomes the direct replacement of the
hydroxyl group by the amino group, which proceeds with difficulty, as supported by the failure
1
b
of the reaction between amines and α-methyl and α-phenyl benzoins". Although, α-amino
ketones are important synthetic intermediates, the Voight amination reaction did not enjoy wide
popularity in organic synthesis as it is restricted to secondary α-hydroxy ketones. However, we
2

ACCEPTED MANUSCRIPT
have now discovered that the Voight amination does take place on tertiary α-hydroxy ketones,
when the functional group is present on phenanthrene, pyrene or acenaphthylene motif.
Scheme 1. The Voight reaction on benzoin derivatives 1.
Scheme 2. The Voight reaction on tertiary α-hydroxy ketones 6.
5
While exploring synthesis of polyaryl pyrroles, we attempted to prepare the imine 7a from
1
0-allyl-10-hydroxyphenanthren-9(10H)-one 6a and benzylamine 2a on way to pyrrole
appended phenanthrene 10 (Scheme 3). Surprisingly, however, the reaction conducted under
6
standard conditions for imine generation provided α-amino ketone 8a along with minor amount
of oxazole 9. Vatele and co-workers reported two-step synthesis of tertiary α-amino ketones
7
from aliphatic tertiary α-hydroxy ketones. The tertiary α-hydroxy imines generated in the first-
o
step were heated to 160-170 C to force 1,2-migration of the alkyl group. Observation of Vatele
reinforced earlier findings of Lutz that α-hydroxy ketones are highly reluctant to undergo the
Voight reaction. Our observation that α-amino ketone 8a was formed under relatively mild
conditions is in contrast to earlier observations of Lutz and Vatele. We report herein results from
this study for the preparation of several tertiary α-amino ketones located on phenanthrene,
pyrene and acenaphthylene platform. We demonstrate that the Voight reaction can be used for
3

ACCEPTED MANUSCRIPT
the synthesis of chiral secondary amino ketones by employing optical active primary amines.
Furthermore, we report on the accrued mechanistic details of this enigmatic reaction.
Scheme 3. Formation of the Voight product 8a and oxazole 9 in the attempted synthesis of
pyrrole appended phenanthrene 10.
2
2
. Results and discussion
.1. The Voight reaction on symmetrical tertiary α-hydroxy ketones
The Barbier reaction of 9,10-phenanthrenequinone with allyl bromide in the presence of
8
indium metal provided 10-allyl-10-hydroxyphenanthren-9(10H)-one 6a. The formic acid
mediated condensation of tert-α-hydroxy ketone 6a with benzylamine 2a in methanol reflux
furnished α-amino ketone 8a in 82% yield along with minor amount of oxazole 9 (Table 1, entry
1
). Formic acid and methanol medium appears to be the best combination for the transformation
since other solvents like dimethylformamide (DMF, entry 2) or toluene (entry 3) lowered the
yield of 8a. Similarly, alternate strong acids like trifluoroacetic acid (entry 4) or p-
toluenesulfonic acid monohydrate (PTSA, entry 5) did not favour the reaction. Benzoic acid in
methanol medium (entry 6) or toluene medium (entry 7) did not improve the yield of α-amino
ketone 8a.
Table 1. Optimization of reaction conditions for conversion of α-hydroxy ketone to α-amino
ketone.
4

ACCEPTED MANUSCRIPT
Entry
Protic acid
Solvent
Yield of α-amino ketone Yield of oxazole
8
a
9
1
2
3
4
5
6
7
HCOOH
HCOOH
HCOOH
MeOH
DMF
82%
29%
18%
21%
10%
26%
10%
2%
5%
10%
25%
45%
-
Toluene
Toluene
Toluene
MeOH
Toluene
CF COOH
3
4-CH C H SO H.H O
3
6
4
3
2
C
C
6
6
H
5
COOH
COOH
H
5
6%
The generality of the transformation of tert-α-hyroxy ketone 6a into tert-α-amino ketone
a by condensation with benzylamine 2a was ascertained by varying the amines 2a-c and the
8
alkyl group on the C(10) carbon bearing hydroxy group of phenanthrene 6b-d. The Voight
amination reactions worked well in each case to provide tert-α-amino ketones 8a-f in 56-88%
yield (Table 2). The reactions with benzylamine 2a (Table 2, entries 1, 4-6) or butylamine 2b
(entry 2) were conducted in methanol and formic acid. However, the reaction with aniline 2c
required organic solvent soluble p-toluenesulfonic acid monohydrate (PTSA) as the acid catalyst
and higher boiling toluene as the solvent (entry 3). The transformation did not work when
5

ACCEPTED MANUSCRIPT
secondary amines like diethylamine, piperidine or pyrrolidine was employed. The tert-α-amino
1
13
ketones 8a-f were characterized by IR, H NMR, C NMR, DEPT-135 NMR and HRMS
spectra. In addition, the structures of 8c and 8f were unambiguously confirmed by X-ray single
crystal structure analysis (Figures 2 and 3).
6

ACCEPTED MANUSCRIPT
Table 2. Transformation of tert-α-hydroxy ketones present on phenanthrene motif 6a-d to
corresponding tert-α-amino ketones 8a-f.
Entry
-Hydroxy ketone
Amine
-Amino ketone
BnHN
O
O
O
O
O
O
OH
OH
OH
OH
OH
OH
O
1.
2.
3.
4.
5.
6.
BnNH2
2a
8a (24 h, 82%)
BuHN
6
6
6
6
a
a
a
b
O
BuNH2
2b
8b (18 h, 86%)
PhHN
O
PhNH2
2c
8c (24 h, 88%)
BnHN
O
BnNH2
2a
8d (36 h, 56%)
BnHN
O
BnNH2
2a
8e (18 h, 75%)
6
c
BnHN
Ph
O
Ph
BnNH2
2a
8f (36 h, 65%)
6d
7

ACCEPTED MANUSCRIPT
Next, we conducted the Voight reaction on tert-α-hydroxy ketones present on pyrene motif
1
1 with three primary amines 2a-c and the results are gathered in Table 3. 5-Allyl-5-
9
hydroxypyren-4(5H)-one 11, generated by the Barbier reaction on pyrene-4,5-dione was
subjected to the Voight reaction with benzylamine 2a (Table 3, entry 1), butylamine 2b (entry 2),
aniline 2c (entry 3) to furnish corresponding tert-α-amino ketones 12a-c in good yield. While the
first two reactions worked in the presence of formic acid in methanol reflux, the last reaction
required PTSA in toluene reflux. Interestingly, in general, the Voight reaction was slower on α-
hydroxy ketone functionality present on pyrene motif compared to α-hydroxy ketone on
phenanthrene motif.
Our final effort on generalization was directed towards the Voight reaction on tert-α-
hydroxy ketone functional group present on acenaphthylene framework 13 (see Table 3). The
Voight reaction of 13 with three primary amines namely benzylamine 2a, butylamine 2b and
aniline 2c worked with facility to provide corresponding tert-α-amino ketones 14a-c in good
yield. Similar to the reactions on phenanthrene and pyrene first two examples (entries 4 and 5,
Table 3) in this series worked in the presence of formic acid in methanol under reflux and last
one worked only when heated in toluene reflux in the presence of PTSA (entry 6). The rate of the
reaction of α-hydroxy ketone on acenaphthylene 13 was perceptibly faster than that of α-hydroxy
ketone on pyrene 11 and comparable to that of α-hydroxy ketone on phenanthrene 6a. We made
several attempts to synthesize 1-hydroxy-1-allyl-2-naphthalenone to evaluate if the Voight
reaction of α-hydroxy ketone on naphthalene skeleton is facile or not. However, even after
repeated attempts, we could not succeed in the preparation of 1-hydroxy-1-allyl-2-
1
0
naphthalenone.
8

ACCEPTED MANUSCRIPT
Table 3. Transformation of tert-α-hydroxy ketones present on pyrene motif 11, acenaphthylene
motif 13 to corresponding tert-α-amino ketones 12a-c and 14a-c.
9

ACCEPTED MANUSCRIPT
2
.2. Mechanism of the Voight reaction
Generation of tert-α-amino ketones 8, 12 or 14 from condensation of corresponding tert-α-
hydroxy ketones 6, 11 or 13 and primary amines 2 could be through the Voight pathway, that is,
through initial formation of the imine followed by 1,2-migration of the allyl group. Alternatively,
since the protonated hydroxy group is tertiary, benzylic and a good leaving group, substitution
through S 1 pathway is a clear possibility. To probe the mechanism, we synthesized tert-α-
N
1
1
hydroxy ketones 15 and 16 (Figure 1) from corresponding acenaphthylene-1,2-diones and allyl
bromide via indium mediated Barbier reaction. The regiochemistry of allylation at C(2) was,
according to anticipated electronic characteristics of the carbonyl group influenced by para-
positioned substituents namely OMe in 15 and NO in 16. The regiochemistry of allylated
2
1
13
products 15 and 16 were confirmed by analysis of H, C NMR, DEPT-135 and 2-D NMR
(
HSQC, HMBC and COSY) spectral data and finally by single crystal X- ray structure analysis
Figures 4 and 5).
(
Figure 1. Structure of tert-α-hydroxy ketones 15 and 16.
The Voight reaction of tert-α-hydroxy ketone 15 with benzylamine 2a conducted in
methanol reflux in the presence of formic acid furnished tert-α-amino ketone 17a exclusively
(Table 4, entry 1). Structure of 17a and location of the tert-amino and the allyl groups was
1
13
confirmed by H, C NMR, DEPT-135 and 2-D NMR (HSQC, HMBC and COSY) spectral
1
0

ACCEPTED MANUSCRIPT
1
analysis. As anticipated the H NMR spectrum of 17a displayed downfield shifted doublet, now
located at δ 8.36 ppm, for C(6)H compared to its parent 15 where it was located at δ 8.06 ppm.
From the isolation of 17a we deduced that the transformation of 15 to 17a had indeed gone
through the Voight pathway, that is initial formation of the imine followed by 1,2-carbon
migration. To confirm the Voight pathway, we subjected tert-α-hydroxy ketone 16 to reaction
with benzylamine in methanol reflux in the presence of formic acid to realize 18 as the exclusive
1
product (entry 4). As anticipated the H NMR spectrum of 18 displayed upfield shifted doublet,
now located at δ 8.63 ppm, for C(5)H compared to its parent 16 where it was located at δ 9.10
ppm. Since the carbonyl group in 15 is in the para position to that of electron-donating methoxy
group, reactivity of 15 was lower compared to that of 16. To evaluate the electronic effect on the
benzylamine towards the outcome of the Voight reaction, we conducted two reactions on the
tert-α-hydroxy ketone 15 with 4-chlorobenzylamine 2d and 4-methoxybenzylamine 2e (entries 2
and 3). Although reaction with 2e was slower, both the reactions respectively provided the
Voight products 17b-c exclusively.
1
1

ACCEPTED MANUSCRIPT
Table 4. Results from the mechanistic probing of the Voight reaction on tert-α-hydroxy ketones
1
5 and 16 with benzylamines.
Based on the results accumulated, we propose a mechanism as given in Scheme 4. In the
first step, assisted by protic acid, the primary amine 2 reacts with the keto group in tert-α-
hydroxy ketone to form the iminium ion 21, which then undergoes 1,2-carbon migration
(rearrangement) to form 17a. It is interesting to note that 1,2-allyl or propargyl migration appear
1
2

ACCEPTED MANUSCRIPT
to be more facile compared to propyl migration (see entries 1,4 and 5, Table 2) which could
reflect their migratory aptitude. Finally, it is pertinent to note that the Voight reaction did not
1
take place when it was conducted on 2-hydroxy-1,2-diphenylpent-4-en-1-one (Ar = Ph, R =
allyl, Scheme 2) with benzylamine 2a, n-butyl amine 2b or aniline 2c in the presence of formic
acid in methanol reflux or PTSA in toluene reflux. This result indicates that the imine and both
the aromatic rings should be planar like in 21 for the Voight reaction to take place.
Scheme 4. Mechanism for the formation of 2-allyl-2-(benzylamino)-6-methoxyacenaphthylen-
1
(2H)-one 17a from 2-allyl-2-hydroxy-6-methoxyacenaphthylen-1(2H)-one 15.
The plausible mechanism for the formation of oxazole 9 from tert-α-hydroxy ketone 6a is
given in Scheme 5. Similar to an earlier case, the first step is the formation of the iminium ion
2. Subsequent loss of propene via [3,3]-sigmatropic shift leads to the intermediate 23. An
electrocyclic rearrangement initiated by the abstraction of the benzylic hydrogen by the carbonyl
2
1
3

ACCEPTED MANUSCRIPT
and concomitant restoration of aromatic character of the phenanthrene ring leads to 24.
Formation of dihydrooxazole ring through intra-molecular nucleophilic atatck of the oxygen on
the electrophilic carbon of the iminium ion in 24 leads to 25. Finally, dehydrogenation by aerial
oxidation furnishes oxazole 9.
Scheme 5. Mechanism for the formation of oxazole 9 from tert-α-hydroxy ketone 6a.
2
.3. The Voight reaction of tert-α-hydroxy ketones with chiral amines
The Voight reaction provides unique opportunity for the synthesis of chiral secondary
amino ketones by employing commercially available optically active primary amines like S-(-)-
α-methylbenzylamine 2f and R-(+)-α-methylbenzylamine 2g. Chiral α-amino ketones are sought-
1
2
after molecule for their use in stereo selective drug synthesis. The reaction of 13 with S-(-)-α-
methylbenzylamine 2f in methanol reflux in the presence of formic acid provided two
diastereomers 26a and 26b in 1:1 ratio (Scheme 6) which were easily separated by column
chromatography and the isomers were characterized independently. The structure of the S,S-
1
4

ACCEPTED MANUSCRIPT
isomer 26b was unambiguously assigned on the basis of single crystal X-ray structure analysis
(
Figure 6). We attempted selective reductive removal of the ethylbenzene moiety in 26b by
hydrogenolysis using Pd/C (10%) or Pd(OH) /C (20%) to check proof-of-the-principle of
2
synthesis of α-amino ketones. Unfortunately, in both the instances, we isolated only the double
1
3
bond reduced product. Next, we carried out the Voight reaction of 13 with R-(+)-α-
methylbenzylamine 2f and the reaction provided the two optically active antipodes 26c (R,S) and
2
6d (R,R) in 1:1 ratio (Scheme 6). As to be anticipated for the enantiomeric pairs, the NMR
spectra of 26a and 26c matched perfectly. Similarly, the NMR spectra of 26b matched with 26d.
1
We note that in the H NMR spectra, the chemical shift of methine proton of 26b and 26d
appeared at δ 3.61 ppm, which is in deshielded zone compared to the chemical shift value of δ
3
.37 ppm for this proton in 26a and 26c.
Scheme 6. The Voight reaction of tert-α-hydroxy ketone present on acenaphthylene motif 13
with chiral amines 2f-g to corresponding tert-α-amino ketones 26a-d.
1
5

ACCEPTED MANUSCRIPT
In continuation, we conducted the reaction of tert-α-hydroxy ketone present on
phenanthrene motif 6a with S-(-)-α-methylbenzylamine 2f and the reaction provided two
chromatographically separable diastereomers 27a and 27b in 32:68 ratio (entry 1, Table 5). The
isomers were separated and characterized independently. The ratio of the isomers was calculated
1
on the basis of integration of relevant signals in H NMR spectra of the reaction mixture. The
1
13
structure of the isomers was assigned on comparison of H and C chemical shifts of relevant
hydrogen and carbon atoms with those of 26a and 26b. Similarly, the reaction of 6a with R-(+)-
α-methylbenzylamine 2g provided optical antipodes 27c and 27d in 32:68 ratio (entry 2). Since
the final 1,2-C migration step is kinetically controlled, we believe that stereochemistry of the
imine intermediate dictates final stereochemical outcome favouring one of the two diasteromers.
Finally, we conducted the Voight reaction with S-(-)-α-methylbenzylamine 2f on tert-α-
hydroxy ketone 11 present on pyrene motif and the reaction provided chromatographically
separable diastereomers 28a and 28b in 42:58 ratio (entry 3, Table 5). The reaction of 11 with R-
(+)-α-methylbenzylamine 2g under the similar reaction conditions provided the optical antipodes
2
8c and 28d in 42:58 ratio (entry 4). Each isomer was separated and characterized
independently. Structures of the isomers were assigned on comparison of the spectra with those
derived from acenaphthylene or phenanthrene.
1
6

ACCEPTED MANUSCRIPT
Table 5. Transformation of tert-α-hydroxy ketones present on phenanthrene motif 6a, pyrene
motif 11 to corresponding tert-α-amino ketones 27a-d and 28a-d.
3
. Conclusion
1
7

ACCEPTED MANUSCRIPT
We have extended scope of the Voight amination for the synthesis of several tert-α-
amino ketones present on phenanthrene, pyrene and acenaphthylene motif. We have shown that
the acid mediated condensation of primary amines and tert-α-hydroxy ketones present on rigid
planar molecular frameworks takes place readily to provide corresponding tert-α-amino ketones.
The reaction goes through imine formation followed by 1,2-C migration. It works best with
HCOOH in methanol reflux or PTSA in toluene reflux. The reaction has been applied for
synthesis of optically active tert-α-amino ketones by employing S-(-) or R-(+)-α-
methylbenzylamines.
4
4
. Experimental section
.1. General
All reactions and chromatographic separations were monitored by thin layer chromatography
TLC). Glass plates coated with silica gel GF-254 was used for TLC. Column chromatography
(
was carried on neutral alumina (60-120 mesh, SRL chemicals) or silica gel (100-200 mesh,
AVRA synthesis private limited) using increasing percentage of ethyl acetate in hexanes.
Melting points were uncorrected and were determined using open-ended capillary tubes on
VEEGO VMP-DS instrument. IR spectra were recorded as KBr pellets on a Nicolet-6700
1
13
spectrometer. H NMR spectra (400 MHz), C NMR (100MHz) and DEPT-135 spectra were
recorded for (CDCl or CDCl + CCl , 1:1) solutions on Bruker-Avance 400 MHz spectrometer
3
3
4
1
with TMS as internal standard. H-NMR data are reported as follows: chemical shift (multiplicity
s = singlet, d = doublet, t = triplet, m = multiplet, dd = doublet of the doublet, dt = doublet of the
triplet, td = triplet of the doublet and br s = broad singlet), coupling constant (J) and
(
1
3
integrations). Coupling constant J values are given in Hz. The C NMR spectra were recorded
1
with broadband H decoupling. The DEPT-135 NMR spectra were recorded for each sample to
1
8

ACCEPTED MANUSCRIPT
support assigned structure. High resolution mass spectra were recorded on a Water Q-TOF micro
mass spectrometer using electron spray ionization mode. The X- ray diffraction measurements
were carried out at 298 K on Oxford CrysAlis CCD area detector system equipped with a
graphite monochromator and a Mo-Kα fine-focus sealed tube (λ = 0.71073 Å). Phenanthrene-
9
,10-dione, pyrene, acenaphthylene-1,2-dione, formic acid (98-100%), PTSA and benzylamines
1
4
were procured from commercial sources and used as received. Pyrene-4,5-dione and tertiary α-
hydroxy ketones 6a, 6c, 6d, 5, 7 and 2-hydroxy-1,2-diphenylpent-4-en-1-one were prepared
8
according to literature procedure.
4
.2. General procedure for synthesis of α-amino ketones: α-Hydroxy ketone (1 equiv) was
taken in a 25 mL two neck round bottom flask and dissolved in dry methanol or dry toluene. To
the resulting solution amine (4 equiv) and formic acid or p-toluenesulfonic acid monohydrate (1
equiv) was added under a nitrogen atmosphere and stir at room temperature for 10 min. Then, the
reaction mixture was refluxed under vigorous stirring. After completion of the reaction (absence
of α-hydroxy ketone by TLC) reaction mixture was cooled to room temperature. Methanol or
toluene was evaporated under reduced pressure and the crude product was extracted using
dichloromethane (30 mL). The organic layer was washed with 0.1 N NaOH (2 × 20 mL), 0.01 N
HCl (2 × 20 mL), brine solution (2 × 20 mL) and then dried over anhydrous sodium sulfate.
Then the concentrated crude product was purified by column chromatography using neutral
alumina (60-120 mesh SRL chemicals) and increasing amount of ethyl acetate in hexanes (100%
hexane to 98% hexane) as eluent.
1
9

ACCEPTED MANUSCRIPT
4
.2.1. 10-Hydroxy-10-propylphenanthren-9(10H)-one (6b): 10-Allyl-10-hydroxyphenanthren-
(10H)-one (200.1 mg, 0.80 mmol) was taken in a hydrogenator, dissolved in methanol (5 mL)
9
and then 10% Pd/C (8.6 mg, 0.08 mmol) was added. The reaction was done at 70 psi for 24 h.
After completion of starting material in the reaction mixture, filter the Pd/C through celite and
concentrated the mother liquor to afford 10-hydroxy-10-propylphenanthren-9(10H)-one 6b
-1
(
191.6 mg) as a semi solid in 95% yield, R (98% Hexane/EtOAc) 0.6; IR (KBr, cm ) 3489,
f
3
1
2
4
067, 2960, 2934, 2872, 1691, 1600, 1479, 1450, 1385, 1284, 1246, 1199, 1162, 1108, 1072,
1
012, 962, 916, 758, 734, 620; H NMR (400 MHz, CDCl + CCl ; 1:1) δ 7.90 (t, J = 8.0 Hz,
3
4
H), 7.79-7.75 (m, 1H), 7.73-7.70 (m, 1H), 7.63 (td, J = 7.2, 1.6 Hz, 1H), 7.40-7.31 (m, 3H),
1
3
.07 (s, 1H), 1.78-1.60 (m, 2H), 1.34-1.14 (m, 2H), 0.73 (t, J = 7.4 Hz, 3H); C NMR (100
+ CCl ; 1:1) δ 204.0 (C=O), 141.2 (C), 137.7 (C), 135.0 (CH), 129.09 (CH), 129.05
C), 128.7 (C), 128.4 (CH), 128.0 (CH), 127.3 (CH), 126.3 (CH), 124.1 (CH), 123.2 (CH), 79.9
C), 46.9 (CH ), 17.3 (CH ), 14.0 (CH ) ppm; HRMS (ESI) calcd for C H O Na (M + Na)
MHz, CDCl
3
4
(
(
2
2
3
17 16
2
2
75.1048, found 275.1053.
4
.2.2. 10-Allyl-10-(benzylamino)phenanthren-9(10H)-one (8a): Following the general
procedure, the reaction of 10-allyl-10-hydroxyphenanthren-9(10H)-one (200.2 mg, 0.80 mmol),
2
0

ACCEPTED MANUSCRIPT
benzylamine (172.3 mg, 3.2 mmol), formic acid (36.8 mg, 0.80 mmol) and methanol (5 mL)
afforded 10-allyl-10-(benzylamino)phenanthren-9(10H)-one 8a (222.5 mg) as a light yellow
-1
semi solid in 82% yield, R (98% Hexane/EtOAc) 0.7; IR (KBr, cm ) 3351, 3066, 3028, 2924,
f
1
2
854, 1680, 1600, 1452, 1278, 1219, 1158, 1110, 993, 966, 921, 758, 732, 699, 648; H NMR
(
400 MHz, CDCl + CCl ; 1:1) δ 8.10 (dd, J = 7.8, 1.3 Hz, 1H), 8.06-7.98 (m, 3H), 7.71-7.64 (m,
3 4
1
4
H), 7.48-7.34 (m, 5H), 7.29 (t, J = 7.4 Hz, 2H), 7.22 (d, J = 7.2 Hz, 1H), 5.47-5.36 (m, 1H),
.89-4.83 (m, 2H), 3.44 (d, J = 12.2 Hz, 1H), 3.29 (d, J = 12.2 Hz, 1H), 2.53-2.44 (m, 2H), 2.10
1
3
(
br s, 1H) ppm; C NMR (100 MHz, CDCl
3
+ CCl
37.5 (C), 134.8 (CH), 131.3 (CH), 131.2 (C), 130.1 (C), 129.6 (CH), 128.5 (CH), 128.43 (CH),
28.41 (CH), 128.0 (CH), 127.6 (CH), 127.1 (CH), 123.8 (CH), 123.2 (CH) , 119.8 (CH ), 69.3
4
; 1:1) δ 202.4 (C=O), 140.9 (C), 139.9 (C),
1
1
2
(
C), 49.6 (CH ), 48.8 (CH ) ppm; HRMS (ESI) calcd for C H NO (M + H) 340.1701, found
2 2 24 22
3
40.1700.
4
.2.3. 10-Allyl-10-(butylamino)phenanthren-9(10H)-one (8b): Following the general
procedure, the reaction of 10-allyl-10-hydroxyphenanthren-9(10H)-one (200.1 mg, 0.80 mmol),
butylamine (234.1 mg, 3.2 mmol), formic acid (36.9 mg, 0.80 mmol) and methanol (5 mL)
afforded 10-allyl-10-(butylamino)phenanthren-9(10H)-one 8b (209.9 mg) as a light yellow semi
-1
solid in 86% yield, R
f
(98% Hexane/EtOAc) 0.7; IR (KBr, cm ) 3476, 3071, 2957, 2926, 2859,
1
1
678, 1642, 1601, 1475, 1451, 1279, 1223, 1143, 1107, 994, 920, 760, 733, 635; H NMR (400
3 4
MHz, CDCl + CCl ; 1:1) δ 8.06 (dd, J = 7.8, 1.2 Hz, 1H), 8.01-7.93 (m, 2H), 7.89 (dd, J = 7.6,
1
.4 Hz, 1H), 7.64 (td, J = 8.1, 1.5 Hz, 1H), 7.43-7.33 (m, 3H), 5.44-5.32 (m, 1H), 4.90-4.81 (m,
2
1

ACCEPTED MANUSCRIPT
2
1
H), 2.43 (dd, J = 7.4, 3.6 Hz, 2H), 2.35 (br s, 1H), 2.29-2.22 (m, 1H), 2.13-2.06 (m, 1H), 1.49-
1
3
.40 (m, 2H), 1.35-1.26 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H) ppm; C NMR (100 MHz, CDCl +
3
CCl ; 1:1) δ 202.7 (C=O), 140.2 (C), 137.4 (C), 134.7 (CH), 131.4 (CH), 130.9 (C), 130.0 (C),
4
1
29.4 (CH), 128.5 (CH), 128.3 (CH), 127.8 (CH), 127.5 (CH), 123.6 (CH), 123.1 (CH), 119.6
(
CH ), 69.1 (C), 49.6 (CH ), 44.3 (CH ), 33.1 (CH ), 20.6 (CH ), 14.3 (CH ) ppm; HRMS (ESI)
2
2
2
2
2
3
calcd for C H NO (M + H) 306.1858, found 306.1858.
2
1
24
4
.2.4. 10-Allyl-10-(phenylamino)phenanthren-9(10H)-one (8c): Following the general
procedure, the reaction of 10-allyl-10-hydroxyphenanthren-9(10H)-one (199.9 mg, 0.80 mmol),
aniline (296.1 mg, 3.2 mmol), p-toluenesulfonic acid monohydrate (152.0 mg, 0.80 mmol), 4 Å
molecular sieves and toluene (5 mL) afforded 10-allyl-10-(phenylamino)phenanthren-9(10H)-
one 3c (228.6 mg) as a light yellow color solid in 88% yield, R (98% Hexane/EtOAc) 0.6; mp
f
°
-1
1
1
21-122 C; IR (KBr, cm ) 3389, 3064, 3022, 2926, 2855, 1690, 1602, 1502, 1478, 1450, 1432,
1
313, 1289, 1256, 1222, 1159, 1024, 993, 923, 754, 734, 691; H NMR (400 MHz, CDCl
3
+
CCl
4
; 1:1) δ 8.13-8.03 (m, 3H), 7.75-7.70 (m, 2H), 7.48-7.36 (m, 2H), 7.33 (td, J = 7.7, 1.0 Hz,
1
1
H), 6.93 (t, J = 8.1 Hz, 2H), 6.58 (t, J = 7.3 Hz, 1H), 6.18 (d, J = 7.8 Hz, 2H), 5.63-5.50 (m,
1
3
H), 5.21-5.10 (m, 2H), 4.68 (s, 1H), 2.65-2.52 (m, 2H) ppm; C NMR (100 MHz, CDCl +
3
CCl ; 1:1) δ 199.6 (C=O), 145.3 (C), 140.6 (C), 137.1 (C), 134.9 (CH), 131.1 (CH), 130.0 (C),
4
1
29.82 (C), 129.75 (CH), 128.9 (CH), 128.5 (CH), 128.3 (CH), 128.1 (CH), 127.6 (CH), 124.4
2
2

ACCEPTED MANUSCRIPT
(
CH), 123.3 (CH), 121.2 (CH), 118.3 (CH), 115.8 (CH), 66.7 (C), 48.5 (CH ) ppm; HRMS (ESI)
2
calcd for C H NONa (M + Na) 348.1364, found 348.1365.
2
3
19
Figure 2. ORTEP diagram of 10-allyl-10-(phenylamino)phenanthren-9(10H)-one 8c (CCDC
025149) with crystallographic numbering.
Crystal data for 8c: Empirical formula, C23
1
H19NO; Formula weight, 325.39; Crystal color,
habit: light yellow color, rectangular block; Crystal system, orthorhombic; Crystal dimensions,
3
0
.4 x 0.2 x 0.05 mm ; Lattice parameters, a = 15.2385(6) Å, b = 23.0797(11) Å, c = 9.9974(6) Å;
3
α = 90.00, β = 90.00, γ = 90.00; V = 3516.1(3) A ; Space group P2-1; Z = 8; D
= 1.229
calcd
3
2
g/cm ; F = 1376; λ(Mo Kα) = 0.7107 Å; R (I≥2σ ) = 0.0674, wR = 0.1738. Detailed X-ray
0
00
1
crystallographic data is available from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK (for compound 8c CCDC # 1025149).
2
3

ACCEPTED MANUSCRIPT
4
.2.5. 10-(Benzylamino)-10-propylphenanthren-9(10H)-one (8d): Following the general
procedure, the reaction of 10-hydroxy-10-propylphenanthren-9(10H)-one (199.8 mg, 0.80
mmol), benzylamine (340.8 mg, 3.2 mmol), formic acid (36.6 mg, 0.80 mmol) and methanol (5
mL) afforded 10-(benzylamino)-10-propylphenanthren-9(10H)-one 8d (151.4 mg) as a light
-1
yellow semi solid in 56% yield, R (98% Hexane/EtOAc) 0.7; IR (KBr, cm ) 3385, 3063, 3030,
f
2
959, 2930, 2811, 2734, 1702, 1600, 1491, 1453, 1307, 1203, 1166, 1026, 916, 828, 742, 695;
1
H NMR (400 MHz, CDCl
3
+ CCl
.71 (td, J = 8.1, 1.5 Hz, 1H), 7.47-7.35 (m, 5H), 7.33-7.28 (m, 2H), 7.24 (d, J = 7.2 Hz, 1H),
.41 (d, J = 12.1 Hz, 1H), 3.26 (d, J = 12.1 Hz, 1H), 1.83 (br s, 1H), 1.77-1.69 (m, 2H), 1.10-
4
; 1:1) δ 8.14 (dd, J = 7.8, 1.2 Hz, 1H), 8.09-8.01 (m, 3H),
7
3
0
1
3
.97 (m, 2H), 0.66 (t, J = 7.3 Hz, 3H) ppm; C NMR (100 MHz, CDCl + CCl ; 1:1) δ 204.0
3
4
(
C=O), 141.0 (C), 140.1 (C), 137.5 (C), 135.0 (CH), 131.1 (C), 130.0 (C), 129.5 (CH), 128.5
CH), 128.40 (CH), 128.37 (CH), 127.8 (CH), 127.4 (CH), 127.0 (CH), 123.7 (CH), 123.3 (CH),
(
6
9.3 (C), 48.9 (CH
2 2 2 3
), 48.1 (CH ), 16.9 (CH ), 14.2 (CH ) ppm; HRMS (ESI) calcd for C24H24NO
(M + H) 342.1858, found 342.1858.
2
4

ACCEPTED MANUSCRIPT
4
.2.6. 10-(Benzylamino)-10-(prop-2-yn-1-yl)phenanthren-9(10
general procedure, the reaction of 10-hydroxy-10-(prop-2-yn-1-yl)phenanthren-9(10H)-one
200.1 mg, 0.80 mmol), benzylamine (345.0 mg, 3.2 mmol), formic acid (37.0 mg, 0.80 mmol)
H)-one (8e): Following the
(
and methanol (5 mL) afforded 10-(benzylamino)-10-(prop-2-yn-1-yl)phenanthren-9(10H)-one 8e
-
(
212.0 mg) as a light yellow semi solid in 75% yield, R (98% Hexane/EtOAc) 0.7; IR (KBr, cm
f
1
)
3292, 3065, 2911, 2855, 3028, 1684, 1601, 1468, 1451, 1275, 1217, 1109, 939, 795, 758, 731,
1
7
02; H NMR (400 MHz, CDCl
3
+ CCl
4
; 1:1) δ 8.14 (d, J = 7.2 Hz, 1H), 8.08-8.00 (m, 3H), 7.69
(t, J = 7.6 Hz, 1H), 7.49-7.40 (m, 3H), 7.38 (d, J = 7.3 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 7.23 (d,
J = 9.6 Hz, 1H), 3.46 (d, J = 12.2 Hz, 1H), 3.31 (d, J = 12.2 Hz, 1H), 2.84 (br s, 1H), 2.65 (qd, J
1
3
=
16.5, 2.6 Hz, 2H), 1.88 (t, J = 2.5 Hz, 1H) ppm; C NMR (100 MHz, CDCl + CCl ; 1:1) δ
3 4
2
1
00.7 (C=O), 140.6 (C), 138.6 (C), 137.4 (C), 135.0 (CH), 131.4 (C), 129.8 (C), 129.7 (CH),
28.5 (CH), 128.4 (CH), 128.2 (CH), 127.8 (CH), 127.1 (CH), 124.0 (CH), 123.2 (CH), 77.9
(
CH), 73.0 (C), 67.7 (C), 48.8 (CH ), 34.9 (CH ) ppm; HRMS (ESI) calcd for C H NO (M +
2 2 24 20
H) 338.1545, found 338.1545.
4
.2.7. 10-Benzyl-10-(benzylamino)phenanthren-9(10
H)-one (8f): Following the general
procedure, the reaction of 10-benzyl-10-hydroxyphenanthren-9(10H)-one (200.2 mg, 0.66
mmol), benzylamine (285.6 mg, 2.6 mmol), formic acid (31.4 mg, 0.66 mmol) and methanol (5
mL) afforded 10-benzyl-10-(benzylamino)phenanthren-9(10H)-one 8f (168.6 mg) as a solid in
°
-1
6
5% yield, R (98% Hexane/EtOAc) 0.7; mp 48-49 C; IR (KBr, cm ) 3320, 3061, 3028, 1670,
f
2
5

ACCEPTED MANUSCRIPT
1
1
1
601, 1495, 1451, 1277, 1123, 1028, 941, 764, 729, 700; H NMR (400 MHz, CDCl
3
+ CCl
4
;
:1) δ 8.02 (t, J = 7.7 Hz, 2H), 7.88 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.6
Hz, 1H), 7.45-7.33 (m, 5H), 7.28 (t, J = 7.4 Hz, 2H), 7.23-7.17 (m, 1H), 7.00-6.88 (m, 3H), 6.58
(d, J = 7.6 Hz, 2H), 3.39 (d, J = 12.3 Hz, 1H), 3.30 (d, J = 12.3 Hz, 1H), 3.01 (s, 2H), 2.63 (br s,
1
3
1
H) ppm; C NMR (100 MHz, CDCl + CCl ; 1:1) δ 202.3(C=O), 141.0 (C), 139.3 (C), 137.3
3 4
(
C), 134.6 (CH), 134.4 (C), 131.7 (C), 130.4 (CH), 129.4 (CH), 128.6 (CH), 128.5 (CH), 128.4
CH), 128.2 (CH), 128.0 (CH), 127.6 (CH), 127.4 (CH), 127.0 (CH), 126.9 (CH), 123.6 (CH),
(
1
3
23.0 (CH), 70.5 (C), 52.3 (CH
90.1858, found 390.1858.
2 2
), 48.8 (CH ) ppm; HRMS (ESI) calcd for C28H24NO (M + H)
Figure 3. ORTEP diagram of 10-benzyl-10-(benzylamino)phenanthren-9(10H)-one 8f (CCDC
025150) with crystallographic numbering.
1
2
6

ACCEPTED MANUSCRIPT
Crystal data for 8f: Empirical formula, C28H23NO; Formula weight, 389.47; Crystal color,
3
habit: colorless, plate; Crystal system, triclinic; Crystal dimensions, 0.45 x 025 x 0.20 mm ;
Lattice parameters, a = 8.4602(8) Å, b = 10.6685(10) Å, c = 12.1284(12)Å; α = 80.86(8), β =
3
3
7
4
6.81(9), γ = 88.58(8); V = 1052.22(18)A ; Space group P-1; Z = 2; D
= 1.229 g/cm ; F
=
calcd
000
2
12; λ(Mo Kα) = 0.7107 Å; R (I≥2σ ) = 0.0619, wR = 0.1478. Detailed X-ray crystallographic
1
data is available from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK (for compound 8f CCDC # 1025150).
4
.2.8. 5-Allyl-5-(benzylamino)pyren-4(5
reaction of 5-allyl-5-hydroxypyren-4(5H)-one (100.3 mg, 0.37 mmol), benzylamine (157.8 mg,
.47 mmol), formic acid (17.2 mg, 0.37 mmol) and methanol (3 mL) afforded 5-allyl-5-
benzylamino)pyren-4(5H)-one 12a (96.4 mg) as a yellow color semi solid in 72% yield, Rf
H)-one (12a): Following the general procedure, the
1
(
(
-1
98% Hexane/EtOAc) 0.7; IR (KBr, cm ) 3328, 3056, 2958, 2924, 2853, 1677, 1618, 1583,
1
1
494, 1454, 1431, 1341, 1261, 1174, 1117, 1032, 992, 920, 837, 724, 700; H NMR (400 MHz,
CDCl + CCl ; 1:1) δ 8.40 (d, J = 7.4 Hz, 1H), 8.26 (d, J = 7.4 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H),
3
4
7
7
.89-7.79 (m, 2H), 7.78-7.69 (m, 3H), 7.37 (d, J = 7.4 Hz, 2H), 7.28 (t, J = 7.5 Hz, 2H), 7.23-
.17 (m, 1H), 5.45-5.32 (m, 1H), 4.84-4.78 (m, 2H), 3.49 (d, J = 12.3 Hz, 1H), 3.40 (d, J = 12.2
1
3
Hz, 1H), 2.64-2.54 (m, 2H) ppm; C NMR (100 MHz, CDCl + CCl ; 1:1) δ 202.9 (C=O), 140.8
3
4
(C), 139.7 (C), 134.1 (CH), 132.1 (C), 131.4 (C), 131.2 (CH), 130.0 (C), 129.0 (C), 128.5 (CH),
2
7

ACCEPTED MANUSCRIPT
1
28.4 (CH), 128.2 (CH), 128.0 (CH), 127.2 (CH), 127.0 (CH), 127.0 (CH), 126.2 (CH), 126.0
(
CH), 119.8 (CH ), 70.1 (C), 50.2 (CH ), 48.9 (CH ) ppm; HRMS (ESI) calcd for C H NO (M
2
2
2
26 22
+
H) 364.1701, found 364.1701.
4
.2.9. 5-Allyl-5-(butylamino)pyren-4(5
reaction of 5-allyl-5-hydroxypyren-4(5H)-one (100.3 mg, 0.37 mmol), n-butyl amine (107.3 mg,
.47 mmol), formic acid (17.4 mg, 0.37 mmol) and methanol (3 mL) afforded 5-allyl-5-
benzylamino)pyren-4(5H)-one 12b (92.2 mg) as a yellow color semi solid in 76% yield, Rf
H)-one (12b): Following the general procedure, the
1
(
(
-1
98% Hexane/EtOAc) 0.7; IR (KBr, cm ) 3428, 3062, 2958, 2927, 2858, 1675, 1620, 1342,
1
1
1
4
1
260, 1173, 1118, 992, 924, 838, 723; H NMR (400 MHz, CDCl
3
) δ 8.37 (dd, J = 7.4, 1.0 Hz,
H), 8.14 (d, J = 7.9 Hz, 2H), 7.87-7.81 (m, 2H), 7.80-7.70 (m, 3H), 5.39-5.28 (m, 1H), 4.88-
.76 (m, 2H), 2.61-2.51 (m, 2H), 2.36-2.20 (m, 2H), 1.86 (br s, 1H), 1.53-1.43 (m, 2H), 1.35-
1
3
.24 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H) ppm; C NMR (100 MHz, CDCl ) δ 203.5 (C=O), 134.2
3
(
(
(
(
CH), 132.0 (C), 131.4 (C), 131.2 (CH), 129.9 (C), 128.9 (C), 128.1 (CH), 128.0 (CH), 127.1
CH), 127.0 (CH), 126.3 (CH), 126.2 (CH), 125.9 (CH), 125.8 (C), 119.6 (CH), 70.0 (C), 50.2
CH ), 44.6 (CH ), 33.0 (CH ), 20.5 (CH ), 14.1 (CH ) ppm; HRMS (ESI) calcd for C H NO
2
2
2
2
3
23 24
M + H) 330.1858, found 330.1858.
2
8

ACCEPTED MANUSCRIPT
4
.2.10. 5-Allyl-5-(phenylamino)pyren-4(5H)-one (12c): Following the general procedure, the
reaction of 5-allyl-5-hydroxypyren-4(5H)-one (100.1 mg, 0.37 mmol), aniline (136.7 mg, 1.47
mmol), p-toluenesulfonic acid monohydrate (69.8 mg, 0.37 mmol), 4 Å molecular sieves and
toluene (3 mL) afforded 5-allyl-5-(phenylamino)pyren-4(5H)-one 12c (109.3 mg) as a semi solid
-1
in 80% yield, R (98% Hexane/EtOAc) 0.6; IR (KBr, cm ) 3398, 3052, 2957, 2927, 2855, 1686,
f
1
1
603, 1499, 1341, 1314, 1292, 1260, 1120, 1073, 1040, 993, 923, 839, 728, 692; H NMR (400
MHz, CDCl
.5 Hz, 1H), 7.91-7.85 (m, 3H), 7.75 (t, J = 7.7 Hz, 1H), 7.63 (t, J = 7.7 Hz, 1H), 6.87 (t, J = 7.9
Hz, 2H), 6.55 (t, J = 7.3 Hz, 1H), 6.26-6.19 (m, 2H), 5.59-5.46 (m, 1H), 5.14-5.06 (m, 2H), 4.89
3 4
+ CCl ; 1:1) δ 8.39 (dd, J = 7.4, 1.1 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.96 (d, J =
7
1
3
(
s, 1H), 2.71-2.57 (m, 2H) ppm; C NMR (100 MHz, CDCl + CCl ; 1:1) δ 200.2 (C=O), 145.3
3 4
(
C), 140.4 (C), 134.2 (CH), 132.6 (C), 131.6 (C), 130.9 (CH), 129.6 (C), 129.0 (CH), 128.8 (C),
28.3 (CH), 128.1 (CH), 127.3 (CH), 127.1 (CH), 126.8 (CH), 126.5 (CH), 125.3 (CH), 124.8
C), 121.2 (CH ), 118.3 (CH), 115.7 (CH), 67.4 (C), 48.9 (CH ) ppm; HRMS (ESI) calcd for
19NONa (M + Na) 372.1364, found 372.1369.
1
(
2
2
C
25
H
2
9