Preparation of tertiary amides via aryl, heteroaryl, and benzyl organozinc reagents; Scope and limitations

Article abstract of DOI:10.1016/j.tetlet.2012.04.114

A facile synthetic protocol for the preparation of tertiary amides has been developed. The title compounds have been successfully obtained by the Pd-catalyzed cross-coupling reactions of readily available aryl and benzyl organozinc reagents with the appropriate carbamoyl chlorides.

Full text of DOI:10.1016/j.tetlet.2012.04.114

Tetrahedron Letters 53 (2012) 3478–3481
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Preparation of tertiary amides via aryl, heteroaryl, and benzyl organozinc
reagents; scope and limitations
Reuben D. Rieke a, Seung-Hoi Kim b,
⇑
a Rieke Metals, Inc., 1001 Kingbird Rd., Lincoln, NE 68521, United States
b Department of Chemistry, Dankook University, 29 Anseo, Cheonan 330-714, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile synthetic protocol for the preparation of tertiary amides has been developed. The title compounds
have been successfully obtained by the Pd-catalyzed cross-coupling reactions of readily available aryl and
benzyl organozinc reagents with the appropriate carbamoyl chlorides.
Received 27 March 2012
Revised 21 April 2012
Accepted 25 April 2012
Available online 1 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Organozinc
Coupling
Tertiary amides
Carbamoyl chlorides
Amides are of special interest in synthetic organic chemistry
because of their wide spectrum in natural compounds. To introduce
this moiety, two general synthetic approaches have been widely
utilized; the addition of an amine to the corresponding carboxylic
acid derivative and the coupling reaction of an organometallic with
a carbamoyl chloride. Among those, the latter has been more
intensively investigated due to the wide variety of organometallic
reagents that are available.
Grignard reagents have been coupled with carbamoyl chlorides
to yield the corresponding amides in the presence of a Ni-catalyst.1
Rouden and co-workers described the preparation of tertiary
amides via the coupling reactions of organocuprates with carbam-
oyl chlorides.2 In this study, organolithium, organomagnesium, and
a limited number of organozinc reagents were used as precursors
for making the organocuprates. The palladium-catalyzed cross-
coupling reactions between organotin and carbamoyl chlorides also
provided the corresponding amides.3 Of the protocols using organo-
metallic reagents, Suzuki-type reactions with a palladium-catalyst
and an appropriate base have been the most widely employed for
the coupling reaction with carbamoyl chlorides.4 Direct use of
benzylic halides with a carbamoylsilane is yet another approach
for the preparation of tertiary amides.5 In addition to these general
synthetic routes, a three-component-coupling reaction, aminocarb-
onylation, for the preparation of a variety of amides was recently
reported. It has been accomplished by employing halides (or
triflates) and a Weinreb amide at atmospheric CO pressure in the
presence of a palladium catalyst along with a ligand such as
Xantphos.6
In spite of the above mentioned methods, a new general
approach generating highly functionalized amides would be highly
desirable. As is well known, organozinc reagents have been widely
utilized in organic synthesis mainly due to their general applicabil-
ity.7 We, herein, report a facile protocol for the preparation of
tertiary amides utilizing a wide range of organozinc halides.
Our initial studies to determine the appropriate reaction
conditions and the best catalyst involved the coupling reaction of
2-ethoxycarbonylphenylzinc bromide (2) with diethylcarbamoyl
chloride (A). The coupling reactions were carried out in THF at
refluxing temperature in the presence of 5 mol % of the following
catalysts; Pd(PPh3)4, Pd(PPh3)2Cl2, Ni(dppe)Cl2, and Ni(PPh3)2Cl2,
respectively. In each case, some of the desired product (1b) was
formed and confirmed by GC–MS analysis of the reaction mixture.
Among these, it was found that the use of Pd(PPh3)2Cl2 gave the
highest conversion to the corresponding coupling product (1b).
Therefore, this catalytic system was employed in this study
yielding the corresponding amides in moderate to good yields.
The results are summarized in Table 1.
A substituted arylzinc reagent, 4-ethylphenylzinc bromide (1)8
was coupled with carbamoyl chloride A in THF at refluxing
temperature in the presence of 5 mol % Pd(PPh3)2Cl2 resulting in
the formation of the corresponding amide (1a) in 50% isolated yield
(Table 1, entry 1). As depicted above, 2-ethoxycarbonylphenylzinc
bromide (2) was also reacted with A under the same conditions
and the title compound (1b) was obtained in 52% isolated yield
(Table 1, entry 2). A higher yield was observed from the coupling
⇑
Corresponding author.
E-mail address: kimsemail@dankook.ac.kr (S.-H. Kim).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.114

R. D. Rieke, S.-H. Kim / Tetrahedron Letters 53 (2012) 3478–3481
3479
Table 1
Coupling reaction of arylzinc halides
ZnBr
5 % Pd(PPh3)2Cl2
THF reflux
carbamoyl
chloride
+
Product
X
0.8 eq
1.0 eq
Entry
RZnX
Carbamoyl chloridea
Product
Yieldb (%)
ZnBr
O
N
Y
X
1
X: 4-CH2CH3 (1)
Y: 4-CH2CH3
1a
50
2
3
2-CO2Et (2)
4-CO2Et (3)
2-CO2Et
4-CO2Et
1b
1c
52
70
A
B
C
O
N
Y
O
4
5
X: 4-CO2Et (3)
4-CH3 (4)
Y: 4-CO2Et
4-CH3
1d
1e
68
62
6
7
4-Bromophenylzinciodide (5)
2-CH2CH3 (6)
4-Br
2-CH2CH3
1f
1g
48
52
O
N
Y
8
9
X: 2-OMe (7)
2,6-Me2 (8)
Y: 2-OMe
2,6-Me2
1h
1i
66
42
a
A: Diethylcarbamoyl chloride, B: morpholinecarbonyl chloride; C: piperidinecarbonyl chloride.
Isolated yield (based on carbonyl chloride).
b
reaction of A with an organozinc reagent (3) producing 70% iso-
lated yield (Table 1, entry 3). Interestingly, a similar result was
achieved from the coupling reaction with carbamoyl chloride B.
As shown in entry 4 (Table 1), the coupling reaction of organozinc
3 with morpholinecarbonyl chloride (B) led to the desired product
(1d) in the highest yield. Again, alkyl-substituted organozinc re-
agents (4 and 6) were readily coupled with B affording the amides
(1e and 1g) in 62% and 52% isolated yields (Table 1, entries 5 and
7), respectively. Significantly, a bromine atom remained intact un-
der the conditions used in this study. As described in Table 1, the
coupling reaction of 4-bromophenylzinc iodide (5) with B pro-
ceeded smoothly producing 4-(bromophenylmorpholino)metha-
none (1f) in moderate yield (Table 1, entry 6). Piperidinecarbonyl
chloride (C) can also be used as a coupling partner for the synthesis
of tertiary amides. The cross-coupling reaction of 2-methoxyphe-
nylzinc bromide (7) with C took place under the same conditions
used in previous reactions yielding the amide (1h) in 66% isolated
yield (Table 1, entry 8). Even with a sterically hindered organozinc,
2,6-dimethylphenylzinc bromide (8), the desired coupling product,
2,6-(dimethylphenylpiperidin-1-yl)methanone (1i), was obtained
in moderate yield (Table 1, entry 8).
With these promising results in hand, our studies were ex-
panded to see if this protocol could be used for a much broader
range of amides. Initial studies included several heteroaromatic
organometal reagents, and the results are summarized in Table 2.
The first attempts were conducted with the readily available
organozincs 3-bromo-2-thienylzinc bromide (9) and 3-thienylzinc
iodide (10) under the same reaction conditions used in previous
coupling reactions. The expected coupling products (2a and 2b)
were successfully obtained in 61% and 51% isolated yields (Table
2, entries 1 and 2), respectively. Diethylcarbamoyl chloride (A)
was also effectively coupled with the organozinc 10 to give rise
to the amide 2c in 68% yield (Table 2, entry 3). Unfortunately, other
heteroarylzinc reagents, pyridyl- and coumarinylzinc halides,
failed to yield useful results.9 No reasonable amounts of the de-
sired product were observed by switching the metal catalyst to
Pd(PPh3)4, Ni(dppe)Cl2, and Ni(PPh3)2Cl2. Instead, byproducts from
the ring opening of THF by carbamoyl chloride were the major
components in the reaction mixture (confirmed by GC–MS).10
Cunico and Pandey reported the palladium-catalyzed
preparation of
a-aryl tertiary amides using benzylic halides and
carbamoylsilane5 and, in this report, a disadvantage of using
aminocarbonylation of benzyl halides was also described.11
Accordingly, to expand the scope of our strategy, we next focused
on the use of benzylic organometal reagents to develop a facile
route for the synthesis of
a-aryl tertiary amides. Since the
appropriate benzylzinc halides were easily prepared via the direct
insertion of highly active zinc, they were immediately employed in
the coupling reaction. As depicted below, the coupling reactions
were carried out under the conditions (5 mol % Pd(PPh3)2Cl2/THF/
reflux) used in the previous reactions, and the results are
summarized in Table 3.
As we expected, benzylzinc halides were readily coupled with
carbamoyl chlorides to give rise to the desired amides in moderate
yields. Coupling reactions of 2-chloropyridin-5-yl-methylzinc
chloride (11) with several carbamoyl chlorides (B, C, and D) were
converted to the corresponding amides (3a, 3b, and 3c) in moder-
ate yields (Table 3, entries 1–3). However, the expected product
was not observed from the coupling with diethylcarbamoyl chlo-
ride (A) (Table 3, entry 4). Again, the ring-opening byproduct of
THF was the only product formed in this reaction. It was of interest
that the coupling reaction of A with benzylzinc chloride (12)
proceeded smoothly providing an amide (3d) in 68% isolated yield
(Table 3, entry 5). Coupling reactions of 2-fluorobenzylzinc chlo-
ride (13) and 2-methoxybenzylzinc chloride (14) with B took place
successfully and resulted in the formation of the corresponding
amides (3e and 3f) in moderate yields (50% and 52%, Table 3, en-
tries 6 and 7), respectively. A bulky benzylzinc reagent (15) was

3480
R. D. Rieke, S.-H. Kim / Tetrahedron Letters 53 (2012) 3478–3481
Table 2
Coupling reaction of heteroarylzinc halides
5 % Pd(PPh3)2Cl2
amides
HetAr-ZnX
1.0 eq
+
Carbamoyl chloride
0.8 eq
THF
reflux
2a - 2c
Entry
1
RZnX
Carbamoyl chloridea
Product
Br
Yieldb (%)
61
Br
B
O
2a
2b
N
ZnBr
S
S
9
( )
ZnI
O
O
O
B
A
N
2
3
51
68
S
(
O
S
S
10
)
ZnI
2c
N
S
(
10
)
B
B
4
5
NRc
NRc
N
Br
ZnBr
N
ZnI
ZnBr
B
B
6
7
NRc
NRc
N
ZnBr
O
O
a
b
c
A: Diethylcarbamoyl chloride, B: morpholinecarbonyl chloride.
Isolated yield (based on carbonyl chloride), otherwise mentioned.
No desired product, instead, byproducts only (confirmed by GC–MS).
Table 3
Coupling reaction of benzylzinc halides
5 % Pd(PPh3)2Cl2
THF reflux
+
Benzylzinc
1.0 eq
Carbamoyl chloride
0.8 eq
Product
3a 3g
-
Entry
1
RZnX
Carbamoyl chloride
Product
Yielda (%)
54
O
O
ZnCl
N
N
Cl
)
Cl
N
O
3a
3b
11
O
(
)
B
(
Cl
N
O
N
N
N
Cl
2
3
4
(11)
(11)
(11)
46
O
O
C
)
(
Cl
Cl
N
O
N
Cl
51
3c
D
(
)
N
N
O
N
NRb
N
Cl
)
A
(
O
Cl

R. D. Rieke, S.-H. Kim / Tetrahedron Letters 53 (2012) 3478–3481
3481
Table 3 (continued)
Entry
RZnX
Carbamoyl chloride
Product
Yielda (%)
ZnCl
)
N
N
5
6
(A)
68
50
12
(
O
O
3d
3e
ZnCl
F
O
O
(B)
(B)
F
13
(
)
ZnCl
OCH3
14
OCH3
N
N
7
52
55
O
O
(
)
3f
ZnBr
8
(B)
O
3g
15
(
)
a
Isolated yield (based on carbonyl chloride).
No desired product, instead, byproducts only (confirmed by GC–MS).
b
4. (a) Lysén, M.; Kelleher, S.; Begtrup, M.; Kristensen, J. L. J. Org. Chem. 2005, 70,
5342; (b) Duan, Y.-Z.; Deng, M.-Z. Synlett 2005, 355; (c) Yasui, Y.; Tsuchida, S.;
Miyabe, H.; Takemoto, Y. J. Org. Chem. 2007, 72, 5898; (d) Krishnamoorthy, R.;
Lam, S. Q.; Manley, C. M.; Herr, R. J. J. Org. Chem. 2010, 75, 1251.
also efficiently coupled with B leading to the amide 3g in 55% yield
(Table 3, entry 8).
In summary, we have described the development of a facile and
general protocol for the synthesis of tertiary amides. It has been
accomplished by a transition metal-catalyzed cross-coupling reac-
tion of organozinc reagents with several carbamoyl chlorides under
mild conditions.11 The use of Pd(PPh3)2Cl2 as a catalyst was impor-
tant for the success. Both functionalized and non-functionalized
aryl and benzyl organozinc reagents have shown a good reactivity
providing the corresponding amides in good to moderate yields.
The method has been extended to utilize heteroaromatic zinc ha-
lides. However, some limitations have also been found in this study.
Nevertheless, this method provides an alternative protocol and
reaction conditions that avoid the use of carbon monoxide as a car-
bonylating reagent for the preparation of tertiary amides. Addi-
tional studies are currently in progress to optimize reaction
conditions and expand the scope to a variety of organozincs.
5. Cunico, R. F.; Pandey, R. K. J. Org. Chem. 2005, 70, 9048.
6. (a) Martinelli, J. R.; Watson, D. A.; Freckmann, D. M. M.; Barder, T. E.; Buchwald,
S. L. J. Org. Chem. 2008, 73, 7102; (b) Martinelli, J. R.; Freckmann, D. M. M.;
Buchwald, S. L. Org. Lett. 2006, 8, 4843; (c) Zhuang, L.; Wai, J. S.; Embrey, M. W.;
Fisher, T. E.; Egbertson, M. S.; Payne, L. S.; Guare, J. P., Jr.; Vacca, J. P.; Hazuda, D.
J.; Felock, P. J.; Wolfe, A. L.; Stillmock, K. A.; Witmer, M. V.; Moyer, G.; Schleif,
W. A.; Gabryelski, L. J.; Leonard, Y. M.; Lynch, J. J., Jr.; Michelson, S. R.; Young, S.
D. J. Med. Chem. 2003, 46, 453; (d) Deagostino, A.; Larini, P.; Occhiato, E. G.;
Pizzuto, L.; Prandi, C.; Venturello, P. J. Org. Chem. 2008, 1941, 73.
7. Meijere, A.; Diederich, F., 2nd ed. In Metal-Catalyzed Cross-Coupling Reactions;
Wiley-VCH Verlag Gmbh & Co., 2004; Vol. 2,.
8. Organozinc reagents used in this study were prepared by the direct insertion of
highly active zinc to the corresponding aryl halide. For details, see: Rieke, R. D.;
Hanson, M. V. Tetrahedron 1997, 1925, 53.
9. (a) A limited number of examples of pyridinyl amide via aminocarbonylation
appeared in Buchwald’s report, see: Ref. 6a.; (b) For the low reactivity of 3-
pyridylboronic acid in the coupling reaction with carbamoyl chloride, see: Ref.
4d.
10. A transition metal-catalyzed ring opening of THF, see: Friour, G.; Alexakis, A.;
Cahiez, G.; Normant, J. Tetrahedron 1984, 40, 683.
Supplementary data
11. A representative procedure: Into a 25 mL round-bottomed flask were added
Pd(PPh3)2Cl2 (0.18 g, 5 mol %) and 10 mL of 4-ethoxycarbonylphenylzinc
bromide chloride (0.5 M in THF, 5.0 mmol). Next, diethylcarbamoyl chloride
(0.54 g, 4.0 mmol) was added via a syringe. The resulting mixture was stirred
at refluxing temperature for 24 h. Cooled down to room temperature and
quenched with saturated NH4Cl solution, then extracted with ethyl acetate
(10 mL Â 3). Washed with saturated Na2S2O3 solution and brine, then dried
over anhydrous MgSO4. Purification by column chromatography on silica gel
(20% ethyl acetate/80% heptane) afforded ethyl 4-(diethylcarbamoyl)benzoate
(1c, 0.70 g) as a yellow oil in 70% isolated yield. 1H NMR (CDCl3, 500 MHz)
d = 8.08 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 4.40 (q, J = 6.5 Hz, 2H), 3.55
(br s, 2H), 3.21 (br s, 2H), 1.41 (t, J = 6.5 Hz, 3H), 1.26 (br s, 3H), 1.10 (br s, 3H);
13C NMR (CDCl3, 125 MHz) d = 170.3, 166.0, 141.5, 131.0, 129.8, 126.3, 61.2,
43.2, 39.3, 14.3, 14.2, 12; GC–MS (EI, 70 eV): m/z (%) = 248 (MÀH, 70), 220 (20),
177 (100), 149 (33).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
114.
References and notes
1. Lemoucheux, L.; Rouden, J.; Lasne, M.-C. Tetrahedron Lett. 2000, 41, 9997.
2. Lemoucheux, L.; Seitz, T.; Rouden, J.; Lasne, M.-C. Org. Lett. 2004, 6, 3703.
3. (a) Balas, L.; Jousseaume, B.; Shin, H.; Verlhac, J.-B.; Wallian, F. Organometallics
1991, 10, 366; (b) Jousseaume, B.; Kwon, H.; Verlhac, J.-B.; Denat, F.; Dubac, J.
Synlett 1993, 117; (c) Murakami, M.; Hoshino, Y.; Ito, H.; Ito, Y. Chem. Lett. 1998,
163.