Synthesis of novel chiral guanidine catalyst and its application in the asymmetric Pictet-Spengler reaction

Article abstract of DOI:10.1016/j.catcom.2016.10.008

A new chiral guanidine catalyst has been synthesized by the reaction of (R)-1-(1-phenylethyl)guanidine and 2,3-diphenylcycloprop-2-enone. The catalyst was evaluated for the Pictet-Spengler reaction in which tetrahydro-β-carbolines were obtained in good yi

Full text of DOI:10.1016/j.catcom.2016.10.008

Synthesis of novel chiral guanidine catalyst and its application in the asym-
metric Pictet-Spengler reaction
Saeed Ahmad, Lakshmi Shukla, Joanna Szawkało, Piotr Roszkowski,
Jan K. Maurin, Zbigniew Czarnocki
PII:
DOI:
Reference:
S1566-7367(16)30373-9
doi:10.1016/j.catcom.2016.10.008
CATCOM 4813
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
30 August 2016
10 October 2016
11 October 2016
Please cite this article as: Saeed Ahmad, Lakshmi Shukla, Joanna Szawkaꢀlo, Piotr
Roszkowski, Jan K. Maurin, Zbigniew Czarnocki, Synthesis of novel chiral guanidine
catalyst and its application in the asymmetric Pictet-Spengler reaction, Catalysis Com-
munications (2016), doi:10.1016/j.catcom.2016.10.008
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ACCEPTED MANUSCRIPT
Synthesis of novel chiral guanidine catalyst and its application in the
asymmetric Pictet-Spengler reaction
Saeed Ahmada, Lakshmi Shuklaa, Joanna Szawkałoa, Piotr Roszkowskia, Jan K.
Maurinb,c, Zbigniew Czarnockia,*
a Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
b National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland
c National Centre for Nuclear Research, Sołtana 7, 05-400 Otwock-Świerk, Poland
ABSTRACT
A new chiral guanidine catalyst has been synthesized by the reaction of (R)-1-(1-
phenylethyl)guanidine and 2,3-diphenylcycloprop-2-enone. The catalyst was
evaluated for the Pictet-Spengler reaction in which tetrahydro-β-carbolines were
obtained in good yields with up to 64% ee.
Keywords: Cyclopropenone, chiral guanidine catalyst, organocatalysis, Pictet-
Spengler reaction, tryptamines.
1

ACCEPTED MANUSCRIPT
1. Introduction
Guanidine containing compounds have been used in various organic reactions as
strong organic bases. Various chiral guanidine derivatives comprising from acyclic
to polycyclic systems have been reported in the literature and have been used in a
variety of asymmetric reactions e.g., Michael, Henry, Mannich, Strecker etc. [1].
They activate the substrates by unique mode of dual hydrogen bonding thus
providing high catalytic as well as high enantioselective activities. Several
effective organocatalysts possessing the guanidinium functional group have been
introduced to organic synthetic methodology. For example, chiral guanidine based
on (R)-(+)-1-phenylethylamine was first developed by Nájera as the catalyst for
asymmetric addition of nitroalkanes to aldehydes [2]. In the following years, many
other scaffolds were introduced as effective and enantioselective chiral guanidine
catalysts. These include Lipton’s dipeptide guanidine [3] and Corey’s bicyclic
guanidine [4], useful for asymmetric Strecker reaction. Selected other chiral
guanidine catalysts like Ishikawa’s bifunctional guanidine [5,6], Terada’s
binaphthyl-based guanidine [7-9], and Tan’s modified Corey-type bicyclic
guanidine [10-15]. Finally, Dixon has developed a class of chiral bifunctional
thiourea imininophosphoranes as effective catalysts for asymmetric nitro-Mannich
reaction [16]. Also recently, Wang introduced a very effective tartarate-derived
guanidine for diastereoselective Michael addition of 3-subtituted oxindoles to
nitroolefins [17]. The introduction of an electron-withdrawing group attached to
the guanidine moiety increases the acidity of the N-H bonds thus allowing the
construction of new effective organocatalysts acting as strong hydrogen bond
donors [18].
Our idea was to develop a new chiral guanidine catalyst with the core skeleton
easily accessible by the reaction of (R)-1-(1-phenylethyl)guanidine and aryl-
substituted cyclopropenone. This type of reaction has already been reported in the
literature [19] but neither its application to catalysis nor its chiral version was
elaborated. We therefore expected that the reaction of (R)-1-(1-
phenylethyl)guanidine with 2,3-diphenylcycloprop-2-enone would afford new
chiral guanidine able to catalyze useful organic transformations. Herein, we report
2

ACCEPTED MANUSCRIPT
on the synthesis of such organocatalyst and its application in the asymmetric
Pictet-Spengler reaction.
2. Experimental:
2.1. Synthesis of guanidine 3. To a cooled 15-20 °C solution of (R)-(+)-1-
phenylethylamine 1 (2.4 g, 19.8 mmol) in dioxane (3 mL) conc. HCl (2.1 mL) was
added dropwise over a period of 10 min and then the solution was stirred for 15
min at the same temperature. Then, all volatiles were removed under reduced
pressure till dryness. The white crystalline solid was washed with Et2O (3 x 10
mL) to get compound 2 (3.1 g, 99%) as white crystals. Compound 2 (3.1 g, 19.8
mmol) was dissolved in water (12 mL) and then cyanamide (NH2CN, 0.82 g, 19.5
mmol) was added, and the solution was adjusted to pH 8-9 by the addition of (R)-
(+)-1-phenylethylamine (few drops). After 5h of reflux, the reaction mixture was
allowed to cool and then all volatiles were removed under reduced pressure. The
resulted sticky mass was triturated with Et2O to get white solid which was
dissolved in a minimum volume of water and was passed through Amberlite IRA-
401 column (hydroxide ion, eluted with water) to get guanidine 3 as a colourless
oil (2.31 g, 72%). [α]22D +28.9 (c 1.0, EtOH); {For enantiomer lit. [20] [α]22D -29.3
1
(c 3.52, EtOH), 99% ee}; H NMR (300 MHz, DMSO-d6) δ 7.33-7.25 (m, 4H),
7.21-7.16 (m, 1H), 5.09 (br s, 4H), 4.58 (q, J = 6.8 Hz, 1H), 1.28 (d, J = 6.8 Hz,
13
3H); C NMR (75 MHz, DMSO-d6) δ 160.5, 156.9, 143.8, 128.9, 127.7, 126.2,
50.5, 23.5; LRMS (ESI): [M + H]+ (100%) 164.2. HRMS (ESI+): m/z calcd for
C9H14N3 [M+H]+ 164.1188; found 164.1197.
2.2. Synthesis of catalyst 5 ((5S,6R)-5,6-diphenyl-2-((R)-1-phenylethylamino)-
5,6-dihydropyrimidin-4(1H)-one).
To
a
solution
of
(R)-1-(1-
phenylethyl)guanidine 3 (1.15 g, 7.0 mmol) in EtOH:benzene (1:1) (70 mL) 2,3-
diphenylcycloprop-2-enone 4 (1.44 g, 7.0 mmol) was added at room temperature
and the mixture was stirred for 18 h. All volatiles were then removed under
reduced pressure and the residue was purified by silica gel column chromatography
(10-80% EtOAc/hexane) to get oily product, which was recrystallized from EtOH
to get compound 5 (1.40 g, 55%) as a white solid. Mp 230-233°C; [α]25D +25.8 (c
1
1.0, MeOH); H NMR (300 MHz, CDCl3:DMSO-d6 (10:1)) δ 7.42-7.30 (m, 5H),
3

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7.25-7.04 (m, 11H), 6.78 (br s, 1H), 5.31 (br s, 1H), 4.62 (d, J = 9.0 Hz, 1H), 3.60
(d, J = 9.0 Hz, 1H), 3.13 (br s, 1H), 1.44 (d, J = 6.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3:DMSO-d6 (10:1)) δ 143.2, 140.1, 137.7, 133.6, 128.8, 128.0, 127.90,
127.87, 127.7, 127.4, 127.3, 127.0, 126.5, 126.3, 126.0, 125.5, 59.1, 53.9, 48.9,
22.5; IR (KBr) 3249, 3060, 2939, 2775, 1640, 1358, 1065, 860, 681 cm−1; HRMS
(ESI+): m/z calcd for C24H24N3O [M+H]+ 370.1919; found 370.1927. The deposit
number CCDC 1498781 [21].
2.3. Representative procedure for the Pictet-Spengler reaction (compound 8e,
Table 2, Entry 4):
To a suspension of catalyst 5 (3.7 mg, 0.01 mmol, 10 mol%), in THF (1.5 mL) N-
(4-nitrobenzyl) tryptamine 6b (29.5 mg, 0.1 mmol), malonic acid (1.0 mg, 0.01
.
mmol, 10 mol%), BF3 Et2O (1.4 mg, 1.2 µl, 0.01 mmol, 10 mol%), and 3 Å
molecular sieves (200 mg, powdered) were added at room temperature and stirred
for 5 min. Then p-nitrobenzaldehyde 7c (45.3 mg, 0.3 mmol) was added and stirred
at room temperature for 120 h. Then the reaction was quenched by the addition of
saturated aqueous Na2CO3 (3 mL) and extracted with EtOAc (3 × 6 mL). Organic
layers were washed with brine, dried over anhydrous Na2SO4 and concentrated.
Compound 8e was purified by silica gel column chromatography (1-20%
EtOAc/hexane).
2-(4-nitrobenzyl)-1-(4-nitrophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
(8e).
1
White solid (42.1 mg, 98%). [α]28 15.9 (c 1.0, DMSO); H NMR (300 MHz,
D
DMSO-d6) δ 8.34-8.11 (m, 4H), 7.79-7.55 (m, 4H), 7.45 (d, J = 7.52 Hz, 1H), 7.23
(d, J = 7.70 Hz, 1H), 7.12-6.90 (m, 2H), 4.98 (s, 1H), 3.90-3.67 (m, 2H), 3.05-2.88
(m, 1H), 2.86-2.61 (m, 3H); HPLC (Chiracel OD-H, hexane/i-PrOH = 90:10, 1.0
mL/min); tR (minor) = 24.6 min and tR (major) = 28.0 min, 64% ee.
4

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3. Results and Discussion
The construction of chiral guanidine catalyst 5 is depicted in Scheme 1. The
synthesis started with the transformation of (R)-(+)-1-phenylethylamine 1 into its
hydrochloride salt 2 which was then treated with cyanamide (NH2CN) at pH 8-9 in
water under reflux to afford guanidine hydrochloride [19] which was subsequently
converted into the free guanidine 3 by passing through Amberlite IRA-401 column
(hydroxide form). Guanidine 3 was then reacted with 2,3-diphenylcycloprop-2-
enone 4 in benzene:EtOH (1:1) at room temperature affording compound 5 in 55%
yield as a single diastereomer in the form of crystalline solid. Other stereoisomer
1
was not detected. As indicated in the H NMR spectrum, phenyl substituents at
dihydropyrimidinone ring were in trans disposition to each other having the value
of the coupling constant of the adjacent methine protons of 9.0 Hz. The structure
and stereochemistry of compound 5 was unambiguously established by X-ray
analysis (Figure 1).
a
b,c
NH2
NH3Cl
1
2
O
O
NH
NH2
d
N
N
H
N
H
N
H
5
3
4
a) Conc. HCl, 1,4-dioxane, 15-20 oC, 15 min, 99%;
b) NH2CN, pH 8-9, water, reflux, 5 h; c) passed through Amberlite IRA-401 (hydroxide form);
d) Benzene:EtOH (1:1), rt, 18 h, 5 55%;
Scheme 1. Synthesis of chiral guanidine catalyst 5.
5

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Figure 1. ORTEP diagram of 5. The non H-atoms are shown as 30% probability
ellipsoids.
To verify the effectiveness of the newly synthesized guanidine catalysts 5, we first
employed it in the Pictet-Spengler reaction [22] of protected tryptamine 6a and p-
bromobenzaldehyde 7a in dichloromethane (Table 1). The cyclized product 8a was
formed in 28% yield and with 13% ee (Entry 1). Further, we checked the catalytic
activity of 5 in different solvents. In less polar solvents (e.g. benzene, toluene and
xylene) (Entry 2-4) it gave the product in 8-15% yield and 2-8% ee, while the
reaction in CHCl3 (Entry 5) gave 15% yield and 9% ee. In polar solvents, like THF
(Entry 6), it gave similar chemical yield (17%) of the product with 17% ee. When
the reaction was carried out in protic solvents (like MeOH, i-PrOH) (Entry 7, 8),
the product was not detected. We then assumed THF as the best solvent for further
optimization. Longer reaction time (Entry 9, 10) allowed for better chemical yield
(up to 65%), but very low ee. The change of the type of molecular sieves from 4Å
to 3Å (Entry 11) gave better yield (69%) and improved ee (36% ee). The use of
MgSO4 (Entry 12) or Na2SO4 (Entry 13) as dehydrating agents instead of
molecular sieves caused a substantial decrease of the yield (5% and 2%,
respectively).
6

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Table 1. Optimization of the Pictet-Spengler Reactiona
CHO
N
N
H
*
catalyst 5 (10 mol%)
N
H
additive, 4 Å M.S.
solvent, rt, time
N
H
Br
Br
6a
7a
8a
ee (%)c
Entry Solvent
Additive (mol%)
Time
(h)
48
48
48
48
48
48
48
48
72
120
48
48
48
48
Yield
(%)b
28
8
15
10
15
17
nd
1
2
3
4
5
CH2Cl2
Benzene
Toluene
Xylene
CHCl3
THF
-
-
-
-
-
-
-
-
-
-
13 (R)
2 (R)
8 (R)
5 (R)
9 (R)
17 (R)
-
6
7
8
9
MeOH
i-PrOH
THF
nd
65
-
(S)
(S)
36 (S)
<1
<1
(S)
10
THF
72
11
12
13
14
THF
THF
THF
THF
-
-
-
69d
5e
2f
trifluoroacetic acid
(100)
65
15
16
17
18
19
20
21
22
23
24
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
benzoic acid (100)
acetic acid (100)
TsOH (100)
isophthalic acid (100)
malonic acid (100)
malonic acid (10)
malonic acid (10)
citric acid (100)
BF3∙Et2O (10)
48
48
48
48
48
72g
72h
48
48
48
84
91
33
82
99
36
22
78
99
99
<1
(S)
<1

(S)
8
14
(S)
31
58
malonic acid (10),
BF3∙Et2O (10)
7

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25
26
27
THF
THF
THF
Et3N (100)
i-Pr2NEt (100)
Pyridine (100)
48
48
48
traces
traces
22
-
-
(S)
a
Reaction conditions: 6a (0.1 mmol), 7a (0.3 mmol), catalyst 5 (0.01 mmol, 10
mol%), solvent (1.5 mL), molecular sieves (200 mg) and additive (as given) at the
b
mentioned temperature and time. Isolated yields of products. nd: product not
c
detected. Enantiomeric excess was determined by chiral HPLC analysis. The
absolute configuration was established on the basis of literature values of the sign
d
e
f
of optical rotation. Freshly activated 3 Å M.S. were used. MgSO4 was used.
Na2SO4 was used. g Reaction was carried out at 0 °C. h Reaction was carried out at
30 °C.
In further investigation of the Pictet-Spengler reaction, we applied certain additives
(acidic or basic; Table 1). First, we screened organic acids like trifluoroacetic acid,
benzoic acid, acetic acid, p-toluenesulfonic acid and isophthalic acid (Entry 14-18)
in equimolar ratio, and these all gave the product in yields up to 99%, but
unfortunately no acceptable enantioenrichment was observed. Lowering the
temperature to 0°C (Entry 20) and 30°C (Entry 21) considerably slowed down the
reaction but employing an equimolar amount of malonic acid at room temperature
(Entry 19) we obtained the product in almost quantitative yield and in 18% ee.
When simple Lewis acid (BF3∙Et2O, 10 mol%) (Entry 23) was employed as an
additive, more encouraging results were obtained. The chemical yield was almost
quantitative with 31% ee of enantiomeric enrichment. Surprisingly, we found that
the combination of malonic acid with BF3∙Et2O (both 10 %mol) (Entry 24) resulted
in a non-linear cooperative effect. With the same excellent chemical yield, we were
able to obtain the desired product with 58% ee. The mechanism of the above
cooperative effect is unclear to us at the moment and obviously requires further
investigation. It might be speculated, however, that the Brønsted acid facilitates the
Pictet-Spengler reaction by protonation of the imine intermediate, whereas the
Lewis acid, by coordination to the carbonyl group of compound 5, makes N-H
bonds in the catalyst even more acidic.
8

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Organic bases like Et3N (Entry 25) or i-Pr2NEt (Entry 26) gave trace amount of
product 8a, while pyridine (Entry 27) gave rather poor yield of the product with
only 9% ee.
Further, we screened the effect of shielding groups on tryptamine molecule as well
as the role of the substituent at benzaldehydes (Table 2). When p-
methoxybenzaldehyde 7b reacted with tryptamine 6b (Entry 1), it gave the
cyclized product 8b in excellent yield, but with moderate ee, while tryptamine 6c
(Entry 2), containing electron donating group, gave poor yield of the product and
comparable ee. Tryptamine 6d (Entry 3), possessing more sterically demanding 9-
anthracenyl substituent, gave low yield of product. p-Nitrobenzaldehyde 7c on
reaction with tryptamine 6b (Entry 4) and 6c (Entry 5) gave the products in
excellent yields and with acceptable level of enantioenrichment (up to 64% ee). p-
Bromobenzaldehyde 7a on reaction with tryptamine 6d (Entry 6) gave a good yield
of the product and with only 23% ee, when the reaction was carried out in CH2Cl2
(Entry 7) it gave the same yield, but with improved ee (55% ee).
Table 2. Screening of guanidine catalyst 5 in the reaction of protected tryptamines
6b-d and adehydes 7a-c
CHO
Ar
N
N
*
H
Ar
catalyst 5 (10 mol %)
N
H
N
H
3 Å M.S., THF or CH2Cl2
rt, time
R
6b-d
7a R = Br
7b R = OMe
8b-g
R
7c R = NO2
En Subst
try rate
Ar
Aldeh Pro Solven Additive Tim Yiel
ee
(%)c
yde
-
duc
t
t
s
e
d
(%)b
(10
(h)
mol%
each)
1
2
p- NO2C6H4
p-MeOC6H4
THF
THF
Malonic
acid,
BF3∙Et2O
Malonic
72
72
81
33
58
6b
6c
7b
7b
8b
8c
46
9

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acid,
BF3∙Et2O
3
4
5
6
7
9-anthracenyl
p- NO2C6H4
p-MeOC6H4
9-anthracenyl
9-anthracenyl
THF
THF
THF
THF
Malonic
acid,
BF3∙Et2O
Malonic 120
acid
BF3∙Et2O
Malonic 120
acid,
72
18
98
96
84
33
64
63
23
6d
6b
6c
6d
6d
7b
7c
7c
7a
7a
8d
8e
8f
BF3∙Et2O
Malonic
acid,
72
72
8g
8g
BF3∙Et2O
CH2Cl2 Malonic
acid,
84 55 (S)
BF3∙Et2O
a
Reaction condition: 6 (0.1 mmol), 7 (0.3 mmol), catalyst 5 (0.01 mmol, 10
mol%), THF or CH2Cl2 (1.5 mL), additive or no additive, molecular sieves (200
mg) at room temperature and the time as mentioned. b Isolated yields of products. c
Enantiomeric excess was determined by chiral HPLC analysis. The absolute
configuration was established on the basis of literature values of the sign of optical
rotation.
4. Conclusion
In summary, we have synthesized a novel chiral guanidine catalyst and we used it
in the Pictet-Spengler reaction between protected tryptamine derivatives and
aromatic aldehydes. After careful optimization, we selected conditions allowing for
good chemical yield and chirality transfer (up to 64% ee). Further study on the
described organocatalyst in the asymmetric synthesis is in progress and will be
published in due course.
10

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Acknowledgement
SA thanks, NAMASTE consortium (Erasmus Mundus Action 2) for the
fellowship. The study was partly supported by the Foundation for Development
Diagnostics and Therapy, Warsaw, Poland (J.K.M.).
Supplementary Data
Supplementary data associated with this article can be found in the online version.
11

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21. CCDC 1498781 contains the supplementary crystallographic data for this
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Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request.cif
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Synthesis of novel chiral guanidine catalyst and its application in the Pictet-
Spengler reaction
Saeed Ahmada, Lakshmi Shuklaa, Joanna Szawkałoa, Piotr Roszkowskia, Jan K.
Maurinb,c, Zbigniew Czarnockia,*
Graphical Abstract
CHO
R
O
Ar
N
N
H
Ar

catalyst (10 mol%)
3 Å M.S., THF, rt
N
Me
N
N
H
H
N
H
N
H
up to 64% ee
R
14

ACCEPTED MANUSCRIPT
Highlights
 A new chiral guanidine catalyst has been synthesized
 The structure and stereochemistry of the catalyst was established by X-ray
method
 The catalyst proved to be effective in the asymmetric Pictet-Spengler
reaction
15