Et3B-mediated palladium-catalyzed direct allylic substitution reactions of Morita–Baylis–Hillman alcohols with aromatic amines

Article abstract of DOI:10.1080/00397911.2016.1237652

An efficient, direct allylic amination of both cyclic and acyclic Morita–Baylis–Hillman alcohols with aromatic amines, in tetrahydrofuran (THF) at room temperature, catalyzed by Pd(0)/Et₃B, is reported herein. The corresponding amines are obtained with a high α -regioselectivity in 65–87% yields.

Full text of DOI:10.1080/00397911.2016.1237652

Et3B-Mediated Palladium-Catalyzed Direct Allylic Substitution Reactions of
Morita-Baylis-Hillman Alcohols with Aromatic Amines
Ahlem Abidi1, Yosra Oueslati1, Farhat Rezgui1
1Université de Tunis EL Manar, Laboratoire de Chimie Organique Structurale et
Macromoléculaire, Faculté des Sciences Campus Universitaire, Tunis, Tunisia
Correspondence address to Farhat Rezgui. E-mail: rez_far@yahoo.fr
ABSTRACT
An efficient, direct allylic amination of both cyclic and acyclic Morita–Baylis–Hillman
alcohols with aromatic amines, in THF at room temperature, under the catalysis of
Pd(0)/Et3B, is reported herein. The corresponding amines are obtained with a high α-
regioselectivity in 65-87% yields.
GRAPHICAL ABSTRACT
KEYWORDS: Amination; allylic substitution; palladium; catalysis; organic synthesis
1. INTRODUCTION
Palladium-catalyzed C–N bond formation is an established and efficient method for the
synthesis of nitrogen-containing natural compounds of biological interest.[1] Although
1

being the most straightforward and desirable from economical and ecological point of
view, a few reports have dealt with the direct use of allylic alcohols as allylating agents in
Pd-catalyzed amination reaction since the hydroxyl moiety is not a good leaving group.[2]
Some of these methods involve a transition metal catalyzed-Tsuji-Trost type allylation
reaction of amines [3], among them, the catalytic allylic amination of primary and
secondary amines with allylic alcohols reported by Muzart,[4] while other protocols
required the presence of Bronsted[5] or Lewis acid[6] catalysts. In Kimura's study,[7] it was
reported that a catalytic amount of Et3B efficiently promoted Pd-catalyzed direct
allylation of amines with allylic alcohols. The main substrates of these transformations
are restricted to common allylic, benzylic, and propargylic alcohols.[8]
On the other hand, transition metal-catalyzed nucleophilic substitution of allylic Morita–
Baylis–Hillman (MBH) adducts, as multi-functionalized substrates, has not been well
investigated.[9] Over the last decades, the reaction of MBH acetates with various amines,
in the presence of palladium(0) catalyst, has shown interesting reaction profiles under
different conditions.[10] Recently, Wang and co-workers[11] reported a highly α-
regioselective palladium-catalyzed allylic amination of MBH acetates with simple
aromatic amines.
Unfortunately, all these catalytic nucleophilic substitutions are strictly limited to MBH
acetates. We believe that the scope and utility of these types of reactions would be greatly
expanded if an experimental protocol using efficient catalysts could be implemented for
2

the corresponding alcohols. Accordingly, Liu and co-workers [12] desribed a highly
regioselective N-nucleophilic substitution of MBH alcohols with aromatic amines
promoted by In(OTf)3.
Based on these results and in continuation of our ongoing interest in the study of the
nucleophilic substitution of cyclic MBH adducts with a large variety of nucleophiles,[13-
17] we hypothesized that the MBH alcohols, bearing both an allyl alcohol and enone
moieties, may also react with amines or other nucleophiles in the presence of suitable
palladium catalysts through a similar pathway. This protocol would be therefore an
efficient synthetic route for a wide range of β’-amino MBH derivatives. [12 and 18] Herein,
we wish to report a highly α-regioselective amination of both cyclic and acyclic MBH
alcohols with aromatic amines, promoted by Et3B and catalyzed by Pd(0), under mild
conditions (THF at room temperature).
2. RESULTS AND DISCUSSION
We have selected the MBH alcohol 1a[16] and simple aniline 2a as typical coupling
partners during the optimization study. The alkylation of aniline (1.2 mmol) 2a with
alcohol 1a (1.0 mmol) in THF was first examined in the presence of Pd(OAc)2 (5 mol%),
PPh3(10 mol%), under nitrogen atmosphere. Under these conditions, no reaction took
place in refluxing THF within 24 h (Table 1, entry 1). Interestingly, the reaction slowly
proceeded when Et3B (1 equiv) was used, as the Lewis acid, providing the allylamine 3a
in 50% isolated yield (Table 1, entry 2). Moreover, the use of an excess of Et3B (2-3
equiv), under the same conditions, gave 3a within a shorter reaction time (2-3h), in a
3

better yield (74-75%) (Table 1, entries 3 and 4) while the use of 2 equiv of Et3B, in THF,
at room temperature, yielded the allylamine 3a in 76% yield, through a cleaner
nucleophilic substitution in 24h (Table 1, entry 5).
Under the previous conditions, when the title reaction was carried out in toluene at reflux,
the allylamine 3a was obtained within 3h in 72% yield (Table 1, entry 6). Therefore,
taking into account all our previous attempts (Table 1, entries 1-6), we decided to carry
out all our further experiments in THF, at room temperature (RT), using Pd(OAc)2 (5
mol%), PPh3(10 mol%) and Et3B (2 equiv) (Table 1, entry 5).
A plausible mechanism for Pd-Et3B catalyzed allylic amination of alcohol 1a, is
presented in Scheme 2.[7] Triethylborane may coordinate to the hydroxyl group of 1a to
help it undergo oxidative addition to Pd(0),[19] generated in situ, affording a π-
allylpalladium intermediate I. Subsequently, this intermediate is attacked directly by
aromatic amine, as a soft nucleophile (pKa up to 25),[20] giving the intermediate II that
undergoes a reductive elimination, releasing the N-allylamine 3a, and closing the
catalytic cycle (Scheme 1).
Next, when various anilines bearing electron-donating or withdrawing groups on the
phenyl group, were allylated with the MBH alcohol 1a in THF, we have also observed an
excellent α-regioselectivity and the corresponding allyl amines 3b-d[12] were prepared in
81-87 % yields (Table 2, entries 2-4).
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Similarly, the reaction worked well with slightly hindered secondary amines 2e-g,
providing tertiary amines 3e-g[12,18] in 66-77 % yields (Table 2, entries 5-7).
Next, we have shown that the amination of alcohol 1b[17] that is slightly hindered at the
β’-position, with primary and secondary amines 2a and 2e, was successful, affording the
desired amines 3h and 3i [12, 18] in 65-66 % yields (Table 2, entries 8 and 9).
We have also investigated the allylation of primary and secondary amines 2a and 2e with
the five-membered alcohol 1c.[17, 21] This study revealed that the protocol still successful
and the corresponding amines 3j and 3k [12, 18] were isolated in 70-74 % yields (Table 2,
entries 10 and 11).
Under the catalysis of a combination of Pd(0) and Et3B, we did not observe any γ-product
along with the α-product 3a-j using primary or secondary alcohols 1a-c. We believe that
this allylic substitution is under thermodynamic control, affording exclusively the α-
product. [10a, 12]
Finally, In order to determine the scope of this direct amination protocol, we have
investigated this time the allylation of aromatic amines with acyclic MBH adducts. The
Literature survey revealed that Pd-mediated allylation of amines with acyclic MBH
acetates, affording a mixture of α- and γ-products resulting from competitive SN2 and
SN2’ reactions (Scheme 2). On the other hand, the common amines reacted, at room
temperature, with acyclic MBH alcohols in methanol, as the solvent, however, in a 1,4-
5

fashion as the hydroxyl moiety is not a good leaving group, providing the corresponding
aminoalcohols (Scheme 2).
In our work, upon treatment of acyclic MBH alcohol 1d [22] with aniline 2a or p-anisidine
2b, under the etablished condtions (Pd(OAc)2 (5 mol%), PPh3(10 mol%) and Et3B (2
equiv)), in THF, at room temperature, the corresponding allylamines 3l and 3m [10a, 11 and
18c] were isolated in 78 and 72 % yields, respectively (Scheme 2, table 2, entries 12 and
13).
Because the allyl substrate 1d is a primary alcohol, the α- and the γ-products, isolated in
every case, are the same. We believe that they were obtained through a reaction
mechanism similar to that of Scheme 2.
All these successful results clearly suggest that, under palladium catalysis, the
straightforward allylation of aromatic amines worked well with both cyclic and acyclic
MBH alcohols.
3. EXPERIMENTAL
3.1. Materials And Methods
General methods 1H and 13C NMR spectra were recorded on a Bruker-AV 300
spectrometer and chemical shifts reported in CDCl3 with tetramethylsilane as an internal
standard. All reactions were carried out in oven dried flasks. Common reagents were
purchased from commercial sources and were used without further purification. The
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Morita–Baylis–Hillman alcohols were prepared according to literature methods.[16, 17, 21
and 22] All the reactions were performed under nitrogen atmosphere.
3.2. Synthesis Of 3a As General Procedure For Allylic Amination Reaction
A solution of 5 mol% Pd(OAc)2 catalyst and 10 mol% of PPh3 in THF (1mL), was stirred
at 25°C for 5 min, then a solution of alcohol 1a (1 mmol), Et3B (2 equiv.) and simple
aniline 2a (1.2 mmol) were added. The reaction mixture was stirred at 25°C and
monitored by TLC until the starting material disappeared. The reaction mixture was
extracted with CH2Cl2. The organic phase was dried over MgSO4, filtered and evaporated
to afford the crude product. Their further purification by flash column chromatography
over silica gel (eluent: Petroleum ether–ether = 90:10) gave the pure allylic amine 3a as
a yellow oil (153 mg, 0.76 mmol, 76%): IR (FT-IR): 3398, 2921, 1661, 1600, 1504,
1
1385, 1247, 1170, 747, 691 cm-1; H NMR (300 MHz, CDCl3): 7.17–7.12 (m, 2H), 6.9
(t, J= 4.5 Hz, 1H), 6.71– 6.66 (m, 1H), 6.57–6.54 (m, 2H), 4.07 (broad s, 1H), 3.93 (d,
J=1.5 Hz, 2H), 2.44 (m, 2H), 2.37–2.32 (m, 2H), 2.02–1.93 (m, 2H); 13C NMR (75
MHz, CDCl3): 199.8, 147.8, 146.5, 136.0, 129.2, 117.5, 113.0, 43.3, 38.4, 25.7, 22.9; MS
(m/z): 77 (63), 106 (53), 124 (40), 201 (C13H15NO, M+, 100); HRMS (ESI+): m/z calcd
for [C13H15NO+H]+: 202.1233; found: 202.1232.
Compounds 3a-m were fully characterized and their spectroscopic data were in
agreement with those of previous work, see Ref. 10a, 11, 12 and 18.
CONCLUSION
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In summary, we have developed a direct amination of cyclic and acyclic MBH alcohols
with aromatic amines, under mild conditions, providing, in good to high yields, the
desired monoallylamines 3. The reaction proceeded in the presence of Et3B as a promoter
and Pd(0), as a catalyst, with exclusive α-regioselectivity. This protocol was found to be
efficient and may open up a new area for various functionalizations of MBH alcohols.
ACKNOWLEDGEMENTS
We thank the Ministry of Higher Education and the Tunisian Government, for financial
support of this work.
SUPPORTING INFORMATION
Full experimental detail, 1H and 13C NMR spectra and Mass spectroscopy of synthesized
materials can be found via the “Supplementary Content’’ section of this article’s
webpage.
REFERENCES
[1]
(a) Johannsen M.; Jørgensen, K. A. Chem. Rev. 1998, 98, 1689 (b); Tsuji, J.
Transition Metal Reagents and Catalysts; Wiley: New York, 2000; (b) Trost, B. M.;
Crawley, M. L. Chem. Rev. 2003, 103, 2921.
[2]
(a) Tao, Y.; Wang, B.; Wang, B.; Qu, L.; Qu, J. Org. Lett. 2010, 12, 2726; (b)
Ghosh, R.; Sarkar, A. J. Org. Chem. 2011, 76, 8508; (b) Sawadjoon, S.; Sjçberg, P. J. R.;
Orthaber, A.; Matsson, O.; Samec, J. S. M. Chem. Eur. J. 2014, 20, 1520; (c) Gumrukcu,
Y.; Bruin, B. d.; Reek, J. N. H. Catalysts 2015, 5, 349;(d) Kayaki, Y.; Koda, T.; Ikariya,
8

T. J. Org. Chem., 2004, 69, 2595; (e) Bass, J. D.; Solovyov, A.; Pascall, A. J.; Katz, A. J.
Am. Chem. Soc. 2006, 128, 14306; (f) Kinoshita, H.; Shinokubo, H.; Oshima, K. Org.
Lett., 2004, 6, 4085; (g) Utsunomiya, M.; Miyamoto, Y. ; Ipposhi, J.; Ohshima, T. ;
Mashima, K. Org. Lett., 2007, 9, 3371; (h) Butt, N. A.; Zhang, W. Chem. Soc. Rev. 2015,
44, 7929.
[3]
M. J. Am. Chem. Soc. 2002, 124, 10968.
[4] Muzart, J. Eur. J. Org. Chem. 2007, 3077.
Ozawa, F.; Okamoto, H.; Kawagishi, S.; Yamamoto, S.; Minami, T.; Yoshifuji,
[5] (a) Zhuang, M.; Du, H.; Org. Biomol. Chem. 2014, 12, 4590. (b) Kang, K.; Kim,
J.; Lee, A.; Kim, W. Y.; Kim, H. Org. Lett. 2016, 18, 616.
[6] (a) Hsu, Y.-C.; Gan, K.-H.; Yang, S.-C. Chem. Pharm. Bull. 2005, 53, 1266; (b)
Tamaru, Y. Eur. J. Org. Chem. 2005, 2647.
[7]
Kimura, M.; Futamata, M.; Shibata, K.; Tamaru, Y. J. Chem. Soc., Chem.
Commun. 2003, 234.
[8] Muzart, J. Tetrahedron 2005, 61, 4179.
[9] For Recent Advances in the Baylis-Hillman Reaction see: (a) Kim, J. N.; Lee, K.
Y. Curr. Org. Chem. 2002, 6, 627; (b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T.
Chem. Rev. 2003, 103, 811; (c) Gowrisankar, S.; Lee, H. S.; Kim, S.H.; Lee, K. Y.; Kim,
J. N. Tetrahedron 2009, 65, 8769; (d) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem.
Rev. 2010, 110, 5447.
[10] (a) Rajesh, S.; Banerji, B.; Iqbal, J. J. Org. Chem. 2002, 67, 7852; (b) Fukuyama,
T.; Yamamoto, E.; Tamura, S.; Fukuda, T.; Matsumoto, T.; Akimoto, Y.; Hamada, Y.
Org. Lett. 2007, 9, 927; (c) Cao, H.; Vieira, T. O.; Alper, H. Org. Lett. 2011, 13, 11.
9

[11] Wang, Y.; Liu, L.; Wang, D.; Chen, Y.-J. Org. Biomol. Chem. 2012, 10, 6908.
[12] Liu, Y.-L.; Liu, L.; Wang, D.; Chen, Y.-J. Tetrahedron 2009, 65, 3473.
[13] Mhasni, O.; Rezgui, F.; Tetrahedron Lett. 2010, 51, 586.
[14] Erray, I.; Oble, J.; Poli, G.; Rezgui, F. J. Sulfur. Chem 2014, 35, 128.
[15] Elleuch, H.; Ayadi, M.; Bouajila, J.; Rezgui, F. J. Org. Chem. 2016, 81, 1757.
[16] Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39, 5965.
[17] Gatri, R.; El Gaied, M. M. Tetrahedron Lett. 2002, 43, 7835.
[18] (a)Tamura, R.; Katayamaa, H.; Watabea, K.; Suzuki, H. Tetrahedron 1990, 46,
7557; (b) Okamoto, S.; Kobayashi, Y.; Kato, H.; Takashi, H. ; Jiro Tsuji, T.; Sato, F. J.
Org. Chem. 1988, 53, 5590; (c) K. Y. Lee, H. S. Lee, J. N. Kim, Bull. Korean Chem.
Soc., 2008, 29, 1099.
[19] For evidence of the formation of Pd(0) species from Pd(OAc)2 and PPh3, see: (a)
Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics 1992, 11, 3009; (b) Fors, B.
P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett., 2008, 10, 3505.
[20] Poli, G.; Prestat, G. ; Liron, F.; C. Kammerer-Pentier, C. Top. Organomet. Chem.
2012, 38, 1-64. Selectivity in Palladium-Catalyzed Allylic Substitution. Springer-Verlag
Berlin Heidelberg 2011.
[21] Luo, S.; Wang, P. G.; Cheng, J.-P. J. Org. Chem., 2004, 69, 555.
[22] Villiéras, J.; Rambaud, M. Org. Synth. 1993, 8, 265.
[23] Amri, H.; El Gaied, M. M.; Ben Ayed, T.; Villiéras, J. Tetrahedron Lett. 1992, 33,
6159.
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Table 1. Optimization of the reaction conditions for the amination of MBH alcohol 1a
with aniline 2aa
Entry Et3B (equiv) Solvent
T (°C), time (h) Yield 3 (%)a,b
1
2
3
4
5
6
None
THF
THF
Reflux/24
Reflux/24
Reflux/3
Reflux/2
R.T/24
N.R
50
1
2
3
2
2
THF
75
THF
74
THF
Toluene
76
Reflux/3
72
aReaction conditions: MBH alcohol (1.0 mmol), aniline (1.2 mmol),
solvent (1mL) under nitrogen atmosphere. b Yields of isolated products.
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Table 2. Pd.Et3B-catalyzed amination of MBH alcohols 1a-d with aromatic amines 2a-
ga
Entry Alcohol 1
Amine 2
Time (h)
Compound 3
Yield 3 (%)a
1
24
76c
2a
1a
3a
2
3
4
5
6
1a
1a
1a
1a
1a
20
20
24
12
24
84c
87c
2b
3b
2c
3c
81b,c
2d
3d
77c
2e
3e
3f
72c
2f
12

7
8
1a
1b
22
24
66c
65c
2g
2a
3g
1b
3h
9
20
24
66c
70c
2e
2a
3i
3j
10
1c
11
12
1c
24
2
74c
78d
2e
2a
3k
1d
3l
13
1d
24
72d
2b
3m
aReaction conditions: Pd(OAc)2 (5 mol%), PPh3 (10 mol %), Et3B(2 equiv), MBH alcohol
b
(1.0 mmol), aniline (1.2 equiv), THF (1mL), under nitrogen atmosphere at r.t using 1
equiv of aniline.
c Analogous as described in [12,18].
d Analogous as described in [10a,11]
13

Scheme 1. Plausible reaction mechanism for Pd·Et3B catalyzed allylic alkylation of
aniline 2a with MBH alcohol 1a
14

Scheme 2. Reactions of acyclic MBH adducts with amines under different conditions
15