Alternate, easy and practical synthesis of allylamines from acetyl derivatives of Baylis-Hillman adducts using methanolic ammonia

Article abstract of DOI:10.1055/s-2006-926337

A methanolic ammonia-mediated alternate, easy and practical stereoselective synthesis of allylamines from the acetyl derivatives of Baylis-Hillman adducts is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926337

PAPER
813
Alternate, Easy and Practical Synthesis of Allylamines from Acetyl Derivatives
of Baylis–Hillman Adducts Using Methanolic Ammonia1
Synthesisof
A
lly
i
lamine
c
s
ha Pathak,a Vijay Singh,a Som N. Nag,a Sanjeev Kanojiya,b Sanjay Batra*a
a
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
Fax +91(522)2623405; fax +91(522)2623938; E-mail: batra_san@yahoo.co.uk
b
SAIF Division, Central Drug Research Institute, Lucknow 226001, India
Received 16 August 2005; revised 16 September 2005
OAc
EWG
N3
EWG
NH2
Abstract: A methanolic ammonia-mediated alternate, easy and
practical stereoselective synthesis of allylamines from the acetyl de-
rivatives of Baylis–Hillman adducts is described.
R
R
EWG
R
EWG = CN Z isomer
EWG = CO2R' E isomer
Key words: Baylis–Hillman, allylamine, methanolic ammonia,
stereoselective
Scheme 1 Synthesis of allylamines from allylazides4
The Baylis–Hillman reaction is now a standard synthetic
method to achieve the synthesis of several synthons, het-
erocycles and natural products.2 In connection with our
project on the synthesis of nitrogen-containing heterocy-
clic systems using Baylis–Hillman chemistry,3 we were
interested in the generation of allylamines from the acetyl
derivatives of the Baylis–Hillman adducts in a syntheti-
cally practical fashion. Indeed we have earlier reported
the stereoselective synthesis of such allylamines by carry-
ing out reduction of the allylazides, obtained from the
acetates of Baylis–Hillman adducts, using the Staudinger
reaction (Scheme 1).4 However, when this reaction is car-
ried out on a large scale large quantities of triphenylphos-
phine oxide were generated. Additionally, the time
consumed for the Staudinger reaction was 16 hours which
made the synthesis lengthy. More recently, Das et al. de-
scribed the ammonium acetate-assisted synthesis of simi-
lar allylamines in stereoselective fashion.5 However, we
have reinvestigated their synthetic protocol and reported
that the products formed during the ammonium acetate-
promoted reactions are not allylamines.6 In view of these
limitations, we probed for alternate options to obtain the
allylamines directly from the acetyl derivative of the Bay-
lis–Hillman products in a more practical fashion. During
the exploratory studies we have discovered that methanol
saturated with ammonia afford the desired allylamines ef-
ficiently from the acetates of Baylis–Hillman adducts in a
short period and the reaction can be successfully carried
out at multi-gram scales without generating any waste re-
agent. The details of our results are presented in this com-
munication.
that was freshly prepared by passing ammonia gas in
methanol. It was gratifying to observe that the reaction
was complete within one hour (Scheme 2). The methanol-
ic ammonia could be easily removed under vacuum on the
rotary evaporator to furnish the crude allylamine 3a,
which was sufficiently pure to be utilized for further reac-
tions. The structure of the amine was established unam-
biguously by comparison with a sample prepared by the
azide route as shown in Scheme 1. In order to assess the
general applicability of this synthetic methodology, acetyl
derivatives of several Baylis–Hillman adducts of acry-
lonitrile 1a–j were evaluated to afford the allylamines 3a–
i in good yields (Table 1). The 1H NMR of the crude prod-
ucts conclusively indicated the reaction was stereoselec-
tive as only the Z isomer was present.2a,8 Mechanistically,
the NH3 present in the methanol being nucleophilic at-
tacks the double bond with subsequent migration of the
double bond and concomitant loss of the acetyl group to
afford the amine. More important, this synthetic method-
ology works efficiently even at multi-gram levels.
methanolic
ammonia
r.t., 1 h
OAc
CN
CN
R
R
NH2
1a–i
3a–i (Z isomers)
Scheme 2 Synthesis of allylamines from Baylis–Hillman adducts
(nitriles)
Once the objective to obtain the desired amine from the
acetyl derivative of Baylis–Hillman product of acryloni-
trile was accomplished we directed our attention towards
the acetyl derivatives of Baylis–Hillman adducts of acry-
lates 2. Similar reaction of methanolic ammonia with
compound 2a was complete within 30 minutes, but the
The starting substrates 1,2 for the study were generated
according to the literature procedure.7 Initially the acetyl
derivative 1a was treated in a closed vessel (screw cap vial
or a flask capped with septum) with methanolic ammonia
product contained
a mixture of two compounds
(Scheme 3, Table 2). Based on the spectroscopic and ana-
lytical evidence, the structure assigned to the less polar
compound on the TLC was that of the secondary amine 5
SYNTHESIS 2006, No. 5, pp 0813–0816
Advanced online publication: 07.02.2006
DOI: 10.1055/s-2006-926337; Art ID: P12505SS
x
x
.
x
x
.2
0
0
6
© Georg Thieme Verlag Stuttgart · New York

814
R. Pathak et al.
PAPER
Table 1 Compounds 3a–i Prepared
Product
3a
R
Yield (%)
Appearance, mp (°C)
pale yellow solid, 108–110
pale yellow solid, 106–108
pale yellow solid, 102–104
yellow oil
MS (ES+) m/z
159.00
193.30
193.31
176.93
176.93
237.08
173.00
260.20
208.23
264.31
IR (cm–1) n (C≡N), n (NH2)
2211, 3377
Ph
88
84
86
88
82
86
88
81
85
80
3b
3c
2-ClC6H4
4-ClC6H4
2-FC6H4
2211, 3400
2210, 3423
3d
3e
2217, 3400
4-FC6H4
white solid, 88–90
white solid, 106–108
white solid, 78–80
yellow oil
2215, 3406
3f
2-BrC6H4
4-MeC6H4
2-ClC6H4-isoxazol-5-yl
naphth-2-yl
4-OBnC6H4
2244, 3374
3g
2211, 3437
3h
3i
2223, 3397
white solid, 112–114
white solid, 140–142
2212, 3410
3j
2208, 3384
Table 2 Compounds 4-5a,c,f,g Prepared
Product R Yield (%) Appearance, mp (°C)
MS (ES+) m/z
IR (cm–1) n (CO2Me and NH2)
4
5
4
5
4
5
4
5
a
c
f
Ph
44
44
39
38
34
57
35
pale yellow sticky solid yellow oil
192.07 366.13 1709, 3410 1710, 3332
4-ClC6H4
2-BrC6H4
pale yellow oil
yellow oil
pale yellow solid, 100–102 225.93 393.00 1712, 3328 1712, 3403
yellow solid, 80–82
271.87 366.13 1711, 3335 1712, 3430
205.93 436.47 1711, 3412 1708, 3450
g
4-MeC6H4 39
pale yellow sticky solid white solid, 94–96
while the polar compound was the desired amine deriva- spect (spectroscopically and tR on HPLC) to the product
1
tive 4.9 As evident from H NMR data, the reaction was obtained from the reaction between the acetyl derivative
stereoselective for both products 4 and 5 since only E iso- and ammonium acetate for corresponding substitution. Si-
mers were obtained. This observation was in contrast to multaneously, to evaluate a similar possibility in acetyl
reactions of compound 1 where no formation of analogous derivatives of Baylis–Hillman adducts of acrylonitrile, in
secondary amine was observed. The formation of com- a model reaction compound 1c was reacted with the amine
pound 5 was confirmed by carrying out detailed mass 3c. Contrary to the findings with compound 2, this reac-
spectral studies.10 In principle, the product 5 could be gen- tion was complete in two hours and the structure of the
erated by the reaction between the acetate 2 and the amine product was assigned as the secondary amine 7c
4. Further, the product 5 may again act as a nucleophile for (Scheme 5).
the Michael addition on the acetyl derivative to yield the
tertiary amine 6.
R
MeO
MeO
O
OMe
R
methanol
r.t., 6 h
methanolic
ammonia
r.t., 30 min
O
O
O
N
R
MeO
+
OMe
O MeO
H
N
O
R
2g + 4g
OAc O
78%
R
R
OMe
NH2
R
2a,c,g,k
4a,c,g,k
5a,c,g,k
6g
(E isomers)
Scheme 4 Formation of a tertiary amine during the synthesis of
allylamines
Scheme 3 Synthesis of allylamines from Baylis–Hillman adducts
(esters)
methanol
r.t., 2 h
CN
CN
In order to provide the chemical evidence for the forma-
tion of product 4 in a representative reaction the acetyl de-
rivative 2g was subjected to Michael addition with the
amine 4g in methanol. Interestingly, this reaction was
complete in six hours and the product was the tertiary
amine 6g (Scheme 4). This product was similar in all re-
H
N
1c + 3c
83%
R
R
7c
Scheme 5 Model reaction of 1c with 3c affording a secondary
amine
Synthesis 2006, No. 5, 813–816 © Thieme Stuttgart · New York

PAPER
Synthesis of Allylamines
815
Anal. Calcd for C10H9ClN2: C, 62.35; H, 4.71; N, 14.54. Found: C,
62.17; H, 4.55; N, 14.44.
In conclusion, we have described an easy, efficient, envi-
ronmentally friendly, multi-gram, stereoselective proce-
dure for the synthesis of allylamines from the acetyl
derivatives of the Baylis–Hillman adducts. The inexpen-
sive reagent and simple reaction conditions makes this
method an attractive option for generation of allylamines.
The synthetic utility of these allylamines will be a subject
of our future communications.
2-Aminomethyl-3-(2-fluorophenyl)acrylonitrile (3d)
1H NMR (200 MHz, CDCl3): d = 3.67 (s, 2 H, CH2NH2), 7.06–7.18
(m, 3 H, 1 H, =CH, 2 H, ArH), 7.37–7.46 (m, 2 H, ArH).
2-Aminomethyl-3-(4-fluorophenyl)acrylonitrile (3e)
1H NMR (200 MHz, CDCl3): d = 3.68 (s, 2 H, CH2NH2), 7.07 (s, 1
H, =CH), 7.17–7.26 (m, 2 H, ArH), 7.37–7.43 (m, 2 H, ArH).
Melting points were determined in capillary tubes on a hot-stage ap-
paratus containing silicon oil and are uncorrected. IR spectra were
recorded using a Perkin-Elmer RX I FTIR spectrophotometer. H
2-Aminomethyl-3-(2-bromophenyl)acrylonitrile (3f)
1H NMR (200 MHz, CDCl3): d = 3.52 (s, 2 H, CH2NH2), 7.25 (s, 1
H, =CH), 7.30–7.42 (m, 2 H, ArH), 7.84 (d, 2 H, J = 8.4 Hz, ArH).
1
NMR and 13C NMR spectra were recorded on a 200 MHz FT spec-
trometer, using TMS as an internal standard (chemical shifts in d
values, J in Hz). The FABMS were recorded on JEOL SX-102 spec-
trometers and ESMS were recorded through direct flow injections
in Merck M-8000 LCMS system. The electrospray mass spectral
studies were performed on a MICROMASS QUATTRO II triple
quadrupole mass spectrometer. The samples (dissolved in MeOH)
were introduced into the ESI source through a syringe pump at the
rate of 5 mL/min. The ESI capillary was set at 3.5 kV and the cone
voltage was variable (10 V, 25 V, 40 V, 90 V). The spectra were col-
lected in 6 average scans. These allylamines were found to have a
very short shelf life and start disintegrating within 24–48 h. There-
fore, only representative amines were subjected to microanalysis on
an Elementar’s Vario EL III microanalyzer. The amine 3h was im-
mediately utilized for further reactions, hence no NMR data are giv-
en.
2-Aminomethyl-3-(4-methylphenyl)acrylonitrile (3g)
1H NMR (200 MHz, CDCl3): d = 2.38 (s, 3 H, ArCH3), 3.62 (s, 2 H,
CH2NH2), 7.05 (s, 1 H, =CH), 7.25 (d, 2 H, J = 8.2 Hz, ArH), 7.65
(d, 2 H, J = 8.2 Hz, ArH).
Anal. Calcd for C11H12N2: C, 76.71; H, 7.02; N, 16.27. Found: C,
76.49; H, 6.90; N, 16.00.
2-Aminomethyl-3-(naphth-2-yl)acrylonitrile (3i)
1H NMR (200 MHz, CDCl3): d = 3.69 (s, 2 H, CH2NH2), 7.02 (s, 1
H, =CH), 7.26 (s, 2 H, ArH), 7.51–7.55 (m, 2 H, ArH), 7.82–7.98
(m, 3 H, ArH).
2-Aminomethyl-3-(4-phenoxymethylphenyl)acrylonitrile (3j)
1H NMR (200 MHz, CDCl3): d = 3.55 (s, 2 H, CH2NH2), 5.10 (s, 2
H, OCH2), 6.98–7.02 (m, 3 H, 1 H, =CH, 2 H, ArH), 7.39–7.42 (m,
5 H, ArH), 7.72 (d, 2 H, J = 8.0 Hz, ArH).
Reaction of Methanolic Ammonia with Baylis–Hillman
Adducts 1 and 2; General Procedure
2-Aminomethyl-3-phenylacrylic Acid Methyl Ester (4a)
1H NMR (200 MHz, CDCl3): d = 3.64 (s, 2 H, CH2NH2), 3.89 (s, 3
H, CO2CH3), 4.19 (s, 2 H, CH2NH2), 7.36–7.42 (m, 5 H, ArH), 7.97
(s, 1 H, =CH).
To an appropriate acetyl derivative 1 (1.0 g), was added freshly pre-
pared methanolic ammonia solution (ca. 20 mL, the solution can be
stored in the fridge and works well for more than a month) in a flask
that was later capped with septum (or screw cap vial) so as to pre-
vent the loss of ammonia. The flask was left at r.t. (no mixing or stir-
ring was required). After the completion of reaction, the excess
solvent was evaporated and the crude product was purified by col-
umn chromatography over silica gel. A mixture of CHCl3–MeOH
(99:1) was used as eluent to obtain amines 3a–j, while a mixture of
hexane–EtOAc was used to obtain products 5a,c,f, g (15% EtOAc)
and 4a,c,f,g (neat EtOAc).
2-Aminomethyl-3-(4-chlorophenyl)acrylic Acid Methyl Ester
(4c)
1H NMR (200 MHz, CDCl3): d = 3.51 (s, 2 H, CH2NH2), 3.71 (s, 3
H, CO2CH3), 7.12 (d, 2 H, J = 8.1 Hz, ArH), 7.54 (d, 2 H, J = 8.1
Hz, ArH), 7.85 (s, 1 H, =CH).
2-Aminomethyl-3-(2-bromophenyl)acrylic Acid Methyl Ester
(4f)
2-Aminomethyl-3-phenylacrylonitrile (3a)
1H NMR (200 MHz, CDCl3): d = 3.08 (s, 2 H, CH2NH2), 3.76 (s, 3
H, CO2CH3), 7.15–7.23 (m, 2 H, ArH), 7.39–7.44 (m, 1 H, ArH),
7.52–7.57 (m, 1 H, ArH), 7.85 (s, 1 H, =CH).
1H NMR (200 MHz, CDCl3): d = 3.64 (s, 2 H, CH2NH2), 3.77 (s, 2
H, CH2NH2), 7.10 (s, 1 H, =CH), 7.38–7.44 (m, 3 H, ArH), 7.72–
7.77 (m, 2 H, ArH).
Anal. Calcd for C11H12BrNO2: C, 48.91; H, 4.48; N, 5.19. Found: C,
48.86; H, 4.50; N, 5.15.
13C NMR (50 MHz, CDCl3): d = 21.8, 46.0, 129.3, 130.0, 13.7,
141.6, 145.1.
2-Aminomethyl-3-(4-methylphenyl)acrylic Acid Methyl Ester
(4g)
2-Aminomethyl-3-(2-chlorophenyl)acrylonitrile (3b)
1H NMR (200 MHz, CDCl3): d = 3.62 (s, 2 H, CH2NH2), 7.04 (s, 1
H, =CH), 7.52–7.64 (m, 4 H, ArH).
1H NMR (200 MHz, CDCl3): d = 2.38 (s, 3 H, ArCH3), 3.72 (s, 2 H,
CH2NH2), 3.85 (s, 3 H, CO2CH3), 4.40 (s, 2 H, CH2NH2), 7.22 (d, 2
H, J = 8.3 Hz, ArH), 7.38 (d, 2 H, J = 8.3 Hz, ArH), 7.80 (s, 1
H, =CH).
Aminomethyl-3-(4-chlorophenyl)acrylonitrile (3c)
1H NMR (200 MHz, CDCl3): d = 3.64 (s, 2 H, CH2NH2), 3.71 (s, 2
H, CH2NH2), 7.06 (s, 1 H, =CH), 7.35 (d, 2 H, J = 8.2 Hz, ArH),
7.69 (d, 2 H, J = 8.2 Hz, ArH).
13C NMR (50 MHz, CDCl3): d = 21.7, 37.6, 52.7, 129.8, 129.9,
132.5, 140.1, 143.9, 168.2, 177.4.
13C NMR (50 MHz, CDCl3): d = 46.6, 129.6, 130.4, 132.0, 136.8,
142.3.
Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C,
69.95; H, 7.07; N, 6.83.
Synthesis 2006, No. 5, 813–816 © Thieme Stuttgart · New York

816
R. Pathak et al.
PAPER
Note added in proof
The Baylis–Hillman adducts obtained by reaction between alde-
hydes and acrylonitrile react with ammonia to afford the 1,3-ami-
noalcohol (A) in good yields (Scheme 6).
Rajasingh, P. Tetrahedron Lett. 2005, 46, 3369.
(g) Shanmugam, P.; Rajasingh, P. Synlett 2005, 939.
(h) Hong, W. P.; Lee, K.-J. Synthesis 2005, 33. (i) Li, J.;
Wang, X.; Zhang, Y. Synlett 2005, 1039. (j) Heim, R.;
Wiedemann, S.; Williams, C. M.; Bernhardt, P. V. Org. Lett.
2005, 7, 1327. (k) Ramachandran, P. V.; Burghardt, T. E.;
Reddy, M. V. R. Tetrahedron Lett. 2005, 46, 2121. (l) Lee,
C. G.; Lee, K. Y.; Lee, S.; Kim, J. N. Tetrahedron 2005, 61,
1493.
OH
methanolic
ammonia
OH
R
N
R
N
r.t., 6–8 h
60–75%
NH2
(3) (a) Singh, V.; Saxena, R.; Batra, S. J. Org. Chem. 2005, 70,
353. (b) Pathak, R.; Roy, A. K.; Batra, S. Synlett 2005, 848.
(c) Pathak, R.; Roy, A. K.; Kanojiya, S.; Batra, S.
Tetrahedron Lett. 2005, 46, 5289.
A
Scheme 6
(4) Patra, A.; Roy, A. K.; Batra, S.; Bhaduri, A. P. Synlett 2002,
1819.
(5) Das, B.; Mahender, G.; Chowdhury, N.; Banerjee, J. Synlett
2005, 1000.
On the other hand, the allyl derivatives obtained from the reaction
between the acetates of Baylis–Hillman adducts and sodium boro-
hydride in the presence of DABCO in aqueous medium also react
with ammonia to yield the corresponding amines (B) in excellent
yields (Scheme 7).
(6) Singh V., Pathak R., Kanojiya S., Batra S.; Synlett; 2005,
2465.
(7) (a) Patra, A.; Batra, S.; Kundu, B.; Joshi, B. S.; Roy, R.;
Bhaduri, A. P. Synthesis 2001, 276. (b) Cai, J.; Zhou, Z.;
Zhao, G.; Tang, C. Org. Lett. 2002, 4, 4723.
(8) (a) Foucaud, A.; El Guemmout, F. Bull. Soc. Chim. Fr. 1989,
403. (b) Lee, J. L.; Chung, Y. M.; Lee, K. Y.; Kim, J. N. Bull.
Korean Chem. Soc. 2000, 21, 843. (c) Batra, S.; Roy, A. K.;
Patra, A.; Bhaduri, A. P.; Surin, W. S.; Raghavan, S. A. V.;
Sharma, P.; Kapoor, K.; Dikshit, M. Bioorg. Med. Chem.
2004, 12, 2059.
(9) During extensive exploratory studies on the Baylis–Hillman
derivatives we have observed that reaction between acetyl
derivatives of Baylis–Hillman adducts and primary amines
(ca 1–1.5-fold) always lead to tertiary amines (Figure 1) as
the major product. However, the formation of such an amine
can be reduced by using excess amine (ca. 4-fold) and
adding acetyl derivative slowly under cold conditions.
DABCO,
NaBH4
F
OAc
N
N
THF–H2O
r.t., 15 min
F
methanolic
ammonia
N
r.t., 24 h
88%
NH2
B
Scheme 7
Acknowledgment
Three of the authors (R.P., V.S., S.N.N.) gratefully acknowledge
the financial support from CSIR, DST and UGC, New Delhi, re-
spectively, in the form of fellowships. The work was supported by
the financial grant under DST Project no. SR/SI/OC-04/2003.
R' R
N
EWG
R
EWG
References
Figure 1 Structure of tertiary amines formed in the reaction of pri-
mary amines with Baylis–Hillman adducts.
(1) CDRI Communication No. 6786.
(2) (a) Basavaiah, D.; Jaganmohan Rao, A.; Satyanarayana, T.
Chem. Rev. 2003, 103, 811. (b) Kim, J. N.; Lee, K. Y. Curr.
Org. Chem. 2002, 6, 627. (c) Cho, H. I.; Lee, S. W.; Lee, K.-
J. J. Heterocycl. Chem. 2004, 41, 799. (d) Basavaiah, D.;
Rao, J. S.; Reddy, R. J. J. Org Chem. 2004, 69, 7379.
(e) Lee, C. G.; Lee, K. Y.; GowriSankar, S.; Kim, J. N.
Tetrahedron Lett. 2004, 45, 7409. (f) Shanmugam, P.;
(10) Several experiments using ESI mass spectrometry technique
in the presence of NH4OH and/or NH4OAc (5–6 mM) were
carried out to establish the exact molecular weight of
products.
Synthesis 2006, No. 5, 813–816 © Thieme Stuttgart · New York