Sequential addition reactions of two molecules of Grignard reagents to thioformamides

Article abstract of DOI:10.1021/jo900915n

(Chemical Equation Presented) Sequential addition reactions of two molecules of Grignard reagents to thioformamides were found to yield tertiary amines in an efficient manner. The addition of two different Grignard reagents can be accomplished by using one equivalent of arylmagnesium reagent in the first step. In the second step, a variety of reagents such as alkyl, alkenyl, aryl, and alkynyl reagents were used to afford the corresponding amines in good to high yields.

Full text of DOI:10.1021/jo900915n

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methods employing a combination of aldehydes, secondary
Sequential Addition Reactions of Two Molecules of
Grignard Reagents to Thioformamides
amines, and various organometallic reagents have been ex-
plored. These processes involve addition of a single organo-
metallic reagent to an intermediate iminium ion. In contrast,
we recently described highly efficient addition reactions of
organo-lithium and -magnesium reagents to thioiminium and
selenoiminium salts, and thioformamides that lead to the
formation of tertiary amines.5 In these processes, two different
nucleophiles are sequentially added to the electrophiles in a
single operation. Similar reactions of nitriles with organo-
cerium reagents and of thiolactams with organolithium and
-cerium reagents have also been developed.6 We envisioned
that by using a combination of two different Grignard re-
agents,7 as coupling partners, thioformamides would undergo
transformations as part of a valuable procedure for tertiary
amine synthesis since Grignard reagents are among the most
readily available organometallic reagents and more readily
available than organolithium reagents. However, the use of
two different Grignard reagents in one vessel results in the
formation of several products with no selectivity.
Below, we present the results of an investigation that has
led to the development of a methodology for preparation of
tertiary amines that employs the addition reaction of two of
the same or different Grignard reagents to thioformamides.
In order to explore the possibility that two molecules of a
Grignard reagent could be sequentially added to thioform-
amides, an excess of 4-chlorophenylmagnesium bromide (2a)
was combined with N,N-dimethylthioformamide (1a) at room
temperature (Scheme 1). The double addition of 2a to 1a
proceeds smoothly in Et2O or THF to form tertiary amine 3
in a moderate yield. Importantly, the efficiency of this process is
enhanced by the use of dichloroethane as a solvent.
Toshiaki Murai,* Kazuki Ui, and Narengerile
Department of Chemistry, Faculty of Engineering,
Gifu University, Yanagido, Gifu 501-1193, Japan
mtoshi@gifu-u.ac.jp
Received May 3, 2009
Sequential addition reactions of two molecules of
Grignard reagents to thioformamides were found to yield
tertiary amines in an efficient manner. The addition of
two different Grignard reagents can be accomplished by
using one equivalent of arylmagnesium reagent in the first
step. In the second step, a variety of reagents such as alkyl,
alkenyl, aryl, and alkynyl reagents were used to afford the
corresponding amines in good to high yields.
The development of synthetic methods for the construc-
tion of more than two carbon-carbon bonds in a single
operation, termed multiple-component coupling reactions,1
is of great importance in the field of organic synthesis.
Implementation of these processes leads to a reduction of
the number of steps involved in a preparative route and,
consequently, to minimization of the amounts of solvents
and purification procedures employed. For the synthesis2 of
tertiary arylmethylamines3 and tertiary propargylamines,4
SCHEME 1. Double Addition of Grignard Reagent 2a to Thio-
formamide 1a
ꢀ
(1) Forreviews(a) Multicomponent Reactions; Zhu, J.; Bienayme, H. Eds.;
Wiley-VCH: Weinheim, 2005. (b) Ganem, B. Acc. Chem. Res. 2009, 42, 463.
ꢀ
(2) For a review Kouznetsov, V. V.; Mendez, L. Y. V. Synthesis 2008, 491.
(3) For recent examples (a) Gall, E. L.; Troupel, M.; Nedelec, J.-Y.
ꢀ ꢀ
The broad scope of this methodology was demonstrated by
using a range of thioformamides 1 and Grignard reagents 2
(Table 1). In these processes, N-thioformylmorpholine (1b),
N-arylmethyl and N-Boc N-formylpiperazines 1c-1f,8 and
optically active N-allyl-N-1-phenethyl thioformamide (1 g)8
Tetrahedron 2006, 62, 9953. (b) Yadav, J. S.; Subba Reddy, B. V.; Lakshmi,
P. N. J. Mol. Cat. A 2007, 274, 101. (c) Sengmany, S.; Gall, E. L.; Troupel, M.
Synlett 2008, 1031. (d) Tanaka, Y.; Hasui, T.; Suginome, M. Synlett 2008,
1239. (e) Font, D.; Heras, M.; Villalgordo, J. M. Tetrahedron 2008, 64, 5226.
(4) For recent examples (a) Lo, V. K.-Y.; Liu, Y.; Wong, M.-K.; Che,
C.-M. Org. Lett. 2006, 8, 1529. (b) Gommermann, N.; Knochel, P. Chem.;
Eur. J. 2006, 12, 4380. (c) Reddy, K. M.; Babu, N. S.; Suryanarayana, I.;
Prasad, P. S. S.; Lingaiah, N. Tetrahedron Lett. 2006, 47, 7563. (d) Sharifi, A.;
Mirzaei, M.; Naimi-Jamal, M. R. J. Chem. Res. 2007, 129. (e) Ramu, E.;
Varala, R.; Sreelatha, N.; Adapa, S. R. Tetrahedron Lett. 2007, 48, 7184.
(f) Kantam, M. L.; Balasubrahmanyam, V.; Kumar, K. B. S.; Venkanna,
G. T. Tetrahedron Lett. 2007, 48, 7332. (g) Likhar, P. R.; Roy, S.; Roy, M.;
Subhas, M. S.; Kantam, M. L.; De, R. L. Synlett 2007, 2301. (h) Sreedhar, B.;
Reddy, P. S.; Krishna, C. S. V.; Babu, P. V. Tetrahedron Lett. 2007, 48, 7882.
(i) Gommermann, N.; Knochel, P. Org. Synth. 2007, 84, 1. (j) Maggi, R.;
Bello, A.; Oro, C.; Sartori, G.; Soldi, L. Tetrahedron 2008, 64, 1435.
(k) Kantam, M. L.; Laha, S.; Yadav, J.; Bhargava, S. Tetrahedron Lett.
2008, 49, 3083. (l) Zhang, X.; Corma, A. Angew. Chem., Int. Ed. 2008, 47,
4358. (m) Madhav, J. V.; Kuarm, B. S.; Someshwar, P.; Rajitha, B.; Reddy,
Y. T.; Crooks, P. A. Synth. Comun. 2008, 38, 3215. (n) Omote, M.; Eto, Y.;
Tarui, A.; Sato, K.; Ando, A. Tetrahedron: Asymmetry 2009, 20, 602.
(o) Chen, W.-W.; Nguyen, R. V.; Li, C.-J. Tetrahedron Lett. 2009, 50, 2895.
(5) (a) Murai, T.; Mutoh, Y.; Ohta, Y.; Murakami, M. J. Am. Chem. Soc.
2004, 126, 5968. (b) Murai, T.; Toshio, R.; Mutoh, Y. Tetrahedron 2006, 62,
6312. (c) Murai, T.; Asai, F. J. Am. Chem. Soc. 2007, 129, 780. (d) Murai, T.;
Nogawa, S.; Mutoh, Y. Bull. Soc. Chem. Jpn. 2007, 80, 2220. (e) Murai, T.;
Asai, F. J. Org. Chem. 2008, 73, 9518.
(6) (a) Ciganek, E. J. Org. Chem. 1992, 57, 4521. (b) Agosti, A.; Britto, S.;
Renaud, P. Org. Lett. 2008, 10, 1417.
(7) For reviews, see (a) Main Group Metals in Organic Synthesis;
Yamamoto, H.; Oshima, K. Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1.
(b) Handbook of Functionalized Organometallics; Knochel, P. Ed.; Wiley-VCH:
Weinheim, 2005; Vol. 1.
(8) New thioformamides 1d, 1e and 1g were prepared by thionation of the
corresponding formamides with Lawesson’s reagents, see Jesberger, M.;
Davis, T. P.; Barner, L. Synthesis 2003, 1929.
DOI: 10.1021/jo900915n
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Published on Web 06/18/2009
J. Org. Chem. 2009, 74, 5703–5706 5703
2009 American Chemical Society

Murai et al.
SCHEME 2. Reaction of 1b (1 equiv) with 2a (1 equiv)
JOCNote
TABLE 1. Double Addition of Grignard Reagents2 to Thioformamides 1a
diastereomeric mixture (entry 3). In addition, the 3-amino-1,4-
diyne 79 is quantitatively formed (entry 4) by using this
method. No significant decrease in the efficiency of this process
is observed when arylmangesium bromides 2a, 2g, and 2h,
containing both electron-donating and -withdrawing substit-
uents on the aromatic rings (entries 1, 7-10) are employed. A
combination of 4-FC6H4MgBr (2h) and N-2,3,4-trimethoxy-
phenylmethyl-N’- thioformylpiperazine (1e) leads to the pro-
duction of lomerizine (12),10 a substance known to have
calcium antagonist and antimigraine properties (entry 9).12
Our attention next turned to addition reactions in which
two different Grignard reagents are added to thioforma-
mides. As an initial test of this process, reaction of 1
equivalent of 2a with 1b was carried out using ClCH2CH2Cl
as solvent (Scheme 2).
Analysis of the product mixture showed that it contained
near equal amounts of tertiary amine 4 and starting thiofor-
mamide 1b. This observation indicates that, in the initial stage
of this process, reaction of the intermediate 15 with 2a is faster
than that with 1b. Various solvents were explored in order to
determine if the rate of addition of 2a to 1b rather than 15
could be enhanced. Importantly, reaction in THF followed by
aqueous workup leads to production of a complex product
mixture that does not contain tertiary amine 4.
This result suggests that addition of 2a to 1b is faster than
that to 15 in THF and that 15 undergoes a complex array of
reactions under the aqueous workup conditions.
A variety of combinations of two different Grignard reagents
were employed in reactions with thioformamide 1b in THF
(Table 2).11 The process involving initial addition of 2a fol-
lowed by addition of allylmagnesium bromide (2b) leads to
efficient production of the amine 16 (entry 1). Significantly,
products arising by addition of two molecules of 2a or 2b are
not formed in detectable amounts in this reaction. In contrast,
addition of these Grignard reagents to 1b in a reverse sequence
(i.e., 2b first and then 2a) leads to generation of 16 in 11% yield
along with 5 (45%) and 4 (20%) derived from addition of two
molecules of 2b and 2a, respectively (entry 2). This finding
suggests that the less reactive Grignard reagent should be added
in the first step in sequential addition reactions at this stage. The
generality of this process, was probed by adding a variety of
a A THF solution of thioformamides 1 (1 mmol) was treated with
Grignard reagents 2 (2.0-3.0 equiv) at rt in ClCH2CH2Cl.
are used along with alkyl- (2e), allyl- (2b and 2c), alkynyl- (2d)
and aryl- (2a, 2g and 2h) Grignard reagents. Solutions of the
Grignard reagents in either Et2O or THF are added to room
temperature dichloroethane solutions of the thioformamides.
The resulting mixtures are stirred at room temperature until
TLC analysis shows that the reactions are complete. Sequential
additions of 1-methyl-2-propenylmagnesium bromide (2c) to
the thioformamide 1b take place selectively at the methyl-
substituted allylic carbon of 2c to produce amine 6 as a
(10) Hara, H.; Toriu, N.; Shimazawa, M. Cardiovascular Drug Rev. 2004,
22, 199.
(11) Very recently, Me3SiCl-mediated double addition of Grignard
reagents to formamides in the presence of a catalytic amount of Ti(OPr-i)4
has been reported. For the use of two different Grignard reagents, the
corresponding amines were formed in at most 60% yield Tomashenko, O.;
Sokolov, V.; Tomashevskiy, A.; Buchholz, H. A.; Welz-Biermann, U.;
Chaplinski, V.; de Meijere, A. Eur. J. Org. Chem. 2008, 5107.
(12) Handbook of Grignard Reagents; Silverman, G. S.; Rakita, P. Eds.;
Dekker: New York, 1996; p. 645.
(9) Amine 7 was previously obtained in moderate yield by reacting the
thioiminium salt derived from 1b and zinc acetylide Murai, T.; Mutoh, Y.;
Ohta, Y. Tetrahedron. Lett. 2005, 46, 3637.
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Murai et al.
JOCNote
TABLE 2. Addition Reaction of Two Different Grignard Reagents 2 to
Thioformamide 1ba
SCHEME 3. Addition Reaction of Grignard Reagents 2a and 2b
to Thioformamides 1a and 1c
SCHEME 4. Reaction of 26 with 27
and 2 L with allyl- (2b), 2-methyl-1-propenyl- (2f), and methyl-
(2m) magnesium bromides are employed, lead to highly efficient
formation of the corresponding amines 21-23 (entries 8-10).
The process, initiated by addition of 2a to 1c at room
temperature followed by addition of 2b, forms the correspond-
ing amine 24 in only a 49% yield (Scheme 3). Also, sequential
reaction of 1a at room temperature with Grignard reagents 2a
and then 2b gives the amine 3 derived only from 2a as the sole
product. However, amines 24 and 25 can be efficiently pro-
duced in these cases by carrying out the initial Grignard
additions at lower temperatures. In the process described
above, dimagnesium sulfides that can be formulated as
[XMgSMgX, X = Cl, Br] are formed as byproducts via the
elimination of an SMgX group.13 Based on the previously
described reaction of [BrMgSMgBr] (26),14 generated from
EtMgBr and H2S, with alkyl halides, these sulfides should
be good thiolating and thionating agents. As a matter of
fact, byproduct 26, derived from reaction of 1a with excess
2m, reacts with benzoyl chloride (27) followed by aqueous
workup to give thiobenzoic acid (28) in good yield (Scheme 4).
In summary, sequential addition reactions of two mole-
cules of Grignard reagents with thioformamides have been
investigated. The observations made in this effort show that
the use of aromatic reagents in the first step15 enables
a A THF solution of thioformamides 1 (1 mmol) was treated with
Grignard reagents 2 (1 equiv) and 2’ (2.0-3.0 equiv) at rt in THF.
Grignard reagents to mixtures generated by the reaction of
equimolar amounts of 1b and 2a at room temperature. Reac-
tions, in which phenyl- (2i), 4-dimethylaminophenyl- (2g),
vinyl- (2j), and phenylethynyl-magnesium (2d) were used as
the second reagent, produce the corresponding amines 17-20
(entries 3-6). Reaction of 1b with a combination of 2a and 2d,
in which 2d is added first, forms amine 20 in only a moderate
yield (entry 7). The reactivity of these two reagents 2a and 2d
toward electrophiles is not simply compared since 2d may be less
reactive than 2a on the basis of the acidity of pKa of the parent
hydrocarbons.12 Nevertheless, these results have suggested that
the use of aromatic Grignard reagents in the first step leads to
the desired products with high efficiency.
(13) The reactions where OMgX and OLi groups formally work as a
leaving group have been reported. For examples, see (a) Kabalka, G. W.;
Wu, Z.; Ju, Y. Org. Lett. 2004, 6, 3929. (b) Kabalka, G. W.; Yao, M.-L.;
Borella, S.; Wu, Z.-Z. Org. Lett. 2005, 7, 2865. (c) Kabalka, G. W.; Yao,
M.-L.; Borella, S. Org. Lett. 2006, 8, 879. (d) Kabalka, G. W.; Yao, M.-L.;
Borella, S. J. Am. Chem. Soc. 2006, 128, 11320. (e) Kabalka, G. W.; Yao,
M.-L.; Borella, S.; Goins, L. K. Organometallics 2007, 26, 4112. (f) Fuchter,
M. J.; Levy, J.-N. Org. Lett. 2008, 10, 4919.
(14) Nedugov, A. N.; Pavlova, N. N. Z. Org. Khim. 1991, 28, 1401.
(15) The use of alkyl and vinylic Grignard reagents as the first reagents
resulted in the formation of the mixture of the desired products derived from
the addition of two different Grignard reagents and the products derived
from the double addition of identical Grignard reagents. The reaction at
lower temperatures slightly improved the selectivity, but further optimiza-
tion of the reaction is still necessary.
Reactions of thioamide 1b, in which combinations of
4-methoxy- and 2-methoxy-phenylmagnesium reagents 2k
J. Org. Chem. Vol. 74, No. 15, 2009 5705

Murai et al.
JOCNote
efficient addition of two different Grignard reagents as part
of processes that produce tertiary amines bearing chiral
secondary alkyl groups. The efficiencies of sequential reac-
tions of thioformamides, in which the first Grignard reagent
used displays high reactivity, can be controlled by using low
reaction temperatures. Further development of this multi-
component coupling methodology, using thiocarbonyl com-
pounds as key substrates, is underway.
N-[1-(4-Methoxyphenyl)-3-butenyl]morpholine (21). To a sol-
ution of thioformylmorpholine (1b) (0.262 g, 2.0 mmol) in THF
(3.0 mL) was added slowly 0.89 M solution of 4-methoxyphe-
nylmagnesium bromide (2k) in THF (4.0 mL, 2.0 mmol) at room
temperature, and the mixture was stirred at this temperature for
3 h. To this was added 0.56 M solution of allylmagnesium
bromide (2b) in Et2O (5.4 mL, 4.0 mmol) at room temperature,
and the mixture was stirred at this temperature for 1 h.
The resulting mixture was poured into a saturated aque-
ous solution of NH4Cl, and extracted with Et2O. The organic
layer was dried over MgSO4 and concentrated in vacuo.
The residue was purified by column chromatography (SiO2,
hexane/EtOAc/Et3N=1: 1: 0.01) to afford the amine 21 (0.364 g,
74%) as a yellow oil; IR (neat) 2908, 1607, 1512, 1347, 1030,
986, 920, 827, 641, 576 cm-1; 1H NMR (CDCl3) δ 2.35-2.45 (m,
4H), 2.49-2.62 (m, 2H), 3.24 (t, J=4.9 Hz, 1H), 3.65 (t, J=
4.6 Hz, 4H), 3.78 (s, 3H), 4.88-4.95 (m, 2H), 5.58 (ddt, J=15.1,
10.2, 6.8 Hz, 1H), 6.83 (d, J=8.6 Hz, 2H), 7.13 (d, J=8.2 Hz,
2H); 13C NMR (CDCl3) δ 37.2, 51.0, 55.2, 67.2, 69.6,
113.5, 116.5, 129.7, 132.1, 135.7, 158.7; MS (EI) m/z 247 (Mþ);
HRMS (EI) Calcd for C15H21NO2 (Mþ) 247.1567. Found:
247.1580.
Experimental Section
N-[1-(4-Dichlorophenyl)-2-propenyl]morpholine (16). To a sol-
ution of thioformylmorpholine (1b) (0.262 g, 2.0 mmol) in THF
(3.0 mL) was added slowly 0.89 M solution of 4-chlorophenyl-
magnesium bromide (2a) in Et2O (2.25 mL, 2.0 mmol) at room
temperature, and the mixture was stirred at this temperature for
1 h. To this was added 1.0 M solution of allylmagnesium
bromide (2b) in Et2O (4.0 mL, 4.0 mmol) at room temperature,
and the mixture was stirred at this temperature for 1 h. The
resulting mixture was poured into a saturated aqueous solution
of NH4Cl, and extracted with Et2O. The organic layer was dried
over MgSO4 and concentrated in vacuo. The residue was
purified by column chromatography (SiO2, hexane/EtOAc/
Et3N = 5: 1: 0.01) to afford the amine 16 (0.420 g, 83%) as
a yellow oil; IR (neat) 2852, 1640, 1490, 1410, 1119, 1014,
Acknowledgment. This work was supported by a Grant-in-
Aid for Scientific Research on Priority Area (No. 19020020,
‘‘Advanced Molecular Transformations of Carbon Re-
sources’’) from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
1
841, 541, 411 cm-1; H NMR (CDCl3) δ 2.34-2.39 (m, 4H),
2.44-2.66 (m, 2H), 3.47 (ddt, J=17.1, 7.1, 4.9 Hz, 1H), 3.67 (t,
J=4.6 Hz, 4H), 4.91-4.95 (m, 2H), 5.50-5.60 (m, 1H), 7.18 (d,
J=8.3 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H); 13C NMR (CDCl3)
δ 37.1, 51.0, 67.2, 69.6, 117.1, 117.5, 128.4, 130.0, 135.0, 139.0;
MS (EI) m/z 251 (Mþ); HRMS (EI) Calcd for C11H13ClNO
(Mþ- C3H5) 210.0680. Found: 210.0660.
Supporting Information Available: Experimental details and
spectroscopic data. This material is available free of charge via
the Internet at http://pubs.acs.org.
5706 J. Org. Chem. Vol. 74, No. 15, 2009