The amide bond rotation controlled by an unusual C- H···O hydrogen bonding that favors the 1,4-phenyl radical migration

Article abstract of DOI:10.1016/j.tetlet.2011.05.016

Experimental evidence in support of the presence of a weak C-H···O hydrogen bonding that favors 1,4-phenyl radical migration in a chiral amide is provided.

Full text of DOI:10.1016/j.tetlet.2011.05.016

Tetrahedron Letters 52 (2011) 3630–3632
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The amide bond rotation controlled by an unusual C–HꢀꢀꢀO hydrogen
bonding that favors the 1,4-phenyl radical migration
Lilia Fuentes a, Leticia Quintero a, Alejandro Cordero-Vargas b, Cesar Eustaquio a, Joel L. Terán a,
Fernando Sartillo-Piscil a,
⇑
a Centro de Investigación de la Facultad de Ciencias Químicas y Centro de Química del ICUAP, BUAP. 14 Sur Esq. San Claudio, San Manuel., 72570 Puebla, Mexico
b Instituto de Química, UNAM. Circuito Exterior s/n, Ciudad Universitaria., 04510 México, D. F., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Experimental evidence in support of the presence of a weak C–HꢀꢀꢀO hydrogen bonding that favors 1,4-
phenyl radical migration in a chiral amide is provided.
Received 16 February 2011
Revised 29 April 2011
Accepted 5 May 2011
Available online 13 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Among all the carbon-centered free radicals, the
a
-amide radi-
well documented, the presence of the rearranged product 3 instead
of the expected reduced product 4 represents an untypical out-
come. In addition, the increase of stereoselectivity observed in
the cyclization reaction at low temperatures in the presence of
cals represent one of the most useful reactive species that have
found enormous application in synthetic chemistry.1 Besides the
high stability provided by the carbonyl group, another important
feature of these radicals is that the C–N amide bond rotates at a
moderate or slow rate, which is comparable or even slower than
many radical reactions.2 In this sense, researchers have taken
advantages of this controlled dynamic behavior and have reported
unexpected free radical reactions.3 For example, Ishibashi and Ike-
da have made possible what by ionic means appeared impossible
Lewis acid,7 makes the
a-amide radicals (1Z and 1E) an interesting
model of study, especially because in both cases, the existence of a
weak internal hydrogen bonding interaction (e.g., E) was postu-
lated as a favorable interaction that controls the amide bond
rotation and, therefore, favors both reactions (Scheme 1).
In spite of the C–HꢀꢀꢀO hydrogen bond interactions have been
well-established in structural chemistry, it is not fully accepted
that they are involved in chemical transformations, especially
those in solution.8 Questions concerning whether the C–HꢀꢀꢀO
hydrogen bond interactions have biological significance or if these
weak interactions are robust enough for leading chemical
to make: the 5-endo cyclization reaction of an
(A) under either reductive or oxidative conditions to produce
lactam radical (B, eq. 1).4 In a different way, the 5-exo cyclization
of chiral -amide radical (C) under reductive conditions to gener-
ate primary -lactam radical (D, eq. 2), represents a standard free
a-amide radical
c
-
a
c
radical transformation widely employed in organic synthesis, how-
ever, cyclization in stereoselective fashion have been proven to be
uncommon (eq. 2).5
O
O
Ph
Ph
N
Ph
N
Ph
N
R
R
N
N
5-endo
Ph
N
ð1Þ
ð2Þ
O
O
O
H
O
cyclization
1Z
1E
H
O
B
A
4
O
O
Not observed
N
N
N
H
R
R
N
N
5-exo
cyclization
O
O
Ph
2
3
Ph
C
D
Major
Minor
In the latter regard, preparation of 4-alkyl-pyrrolidinone 2 from
Ph
radical rotamer 1E, and the rearranged product 3 from rotamer 1Z,
H
N
LA
N
stereoselective
cyclization
1E
were recently reported.6 Although both radical transformations are
Ph
O
-78 °C
H
H
O
2
major
stereoisomer
E
⇑
Corresponding author. Tel.: +52 222 2295500x7391; fax: +52 222 2295500.
E-mail address: fsarpis@siu.buap.mx (F. Sartillo-Piscil).
Scheme 1. Free radical reactions of chiral a-amide radicals 1Z and 1E.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.016

L. Fuentes et al. / Tetrahedron Letters 52 (2011) 3630–3632
3631
synthesis, are very difficult to be answered. One of the main prob-
lems here is to accept that the delocalization of an oxygen lone pair
(n) into the C–H antibonding orbital (r⁄) can overcome Pauli repul-
Thus, chiral amides 6–9 were prepared according to Scheme 2. It is
important to mention that, to suppress the highly favorable 5-exo
cyclization, the N-allyl substituent in 5 was switched (in all cases,
6–9) to a substituent that is not a free radical acceptor.
sion between n orbital and the C–H
r
bonding orbital (1,3-allylic
strain, eq. 3).9
Ph
Ph
R
N
R
H
N
N
H
N
ð5Þ
ð6Þ
ð7Þ
Br
versus
δ: 5.91 ppm
δ: 5.19 ppm
O
H
O
ð3Þ
H
O
O
Br
6E
6Z
Z/E=60:40
Pauli repulsion
(1,3-allylic strain)
hydrogen bonding
interaction
O
Ph
Ph
O
O
H
N
In this sense, this Letter attempts to provide further experimen-
tal evidences for the existence of unusual C–HꢀꢀꢀO hydrogen bond-
ing, and determine whether this weak intramolecular interaction
influences on the amide bond rotation and, therefore, interferes
N
H
O
δ: 5.96 ppm
Br
Br
δ: 5.12 ppm
O
7E
O
Br
Z/E=63:37
7Z
O
Ph
Ph
O
in the 1,4-phenyl radical migration of the chiral
a-amide radical
H
N
N
H
1Z (see Scheme 1).
H
In previous work,6 the chiral
a
-bromoamide 5 (precursor of the
δ: 5.18 ppm
Z/E=23:77
δ: 5.95 ppm
O
O
amide radicals 1E and 1Z) was shown to exist as a mixture of rota-
mers Z/E (3:1) at room temperature, and after treatment with
Bu3SnH/AIBN afforded cyclization product 2 and rearranged prod-
uct 3 in similar product distribution as that of the rotamer ratio.
This observation led us to conclude that the presence of the E-rot-
amer is responsible for the rearranged product 3.
Br
8E
8Z
EtO
Ph
EtO
Ph
O
H
O
H
N
N
H
ð8Þ
δ: 6.03 ppm
Br
δ: 5.27 ppm
O
O
Br
Z/E=46:54
It is important to note that, the structural assignment and ratio
9E
9Z
of Z/E rotamers for 5 were determined by 1H NMR and computa-
Chiral amides 6 and 7 were designed with the expectation to
observe similar rotational behavior to that of amide 5. On the other
hand, due to the presence of an electron-withdrawing group
(EWG) in amides 8 and 9; we expected to invert the Z/E equilib-
rium by means of a stronger C–HꢀꢀꢀO hydrogen bond interaction.
This was an attempt to show the presence of the unusual C–HꢀꢀꢀO
hydrogen bond by attenuating this weak interaction with a stron-
ger one, by forming a five-membered ring structure (9Z, eq. 8), and
a six-membered ring structure for amide 9 (8Z, eq. 7).
tional calculations. The benzylic hydrogen atom (Ha) in 5 was used
as a stereochemical marker that permitted to establish the orienta-
tion of the carbonyl group and, therefore, to establish the geometry
of the Z/E-rotamers. In this sense, a quartet signal at 6.0 ppm was
assigned to Ha for the Z-rotamer (due to its close proximity toward
the oxygen atom of the carbonyl group), meanwhile a quartet sig-
nal at 5.17 ppm for E-rotamer (eq. 3).
Ph
Ph
The 1H NMR spectra of amides 6 and 7 were very similar to
amide 5, exhibiting a pair of sharp well-resolved signals, wherein
Hα
N
N
Hα
δ, 6.0 ppm
ð4Þ
δ, 5.17 ppm
Br
O
O
the Ha atoms in each rotamer resonances at the same frequencies
Br
to that in amide 5, favoring in both cases the Z-rotamers (Eqs. 5 and
6). As anticipated, due to the electronic nature of the EWG, the rot-
amer ratios for the amides 8 and 9 were shifted toward the E-rot-
amer, showing now that the stronger hydrogen bonding is
responsible for the major rotamer population (Eqs 7 and 8). Thus,
these conformational behaviors provide significant evidence to
the existence of the unusual C–HꢀꢀꢀO hydrogen bond interaction.
This also suggests that it plays a key role in the rotational barrier
5Z
5E
Z/E=70/30
In order to demonstrate that the benzylic hydrogen atom (Ha)
was the responsible for the higher Z-rotamer population, it was
necessary to prepare other chiral amides (6–9) that would allow
observation of the Z/E rotamer ratios under the same NMR criteria.
EtO
N
O
of chiral amides bearing the chiral
a-methylbenzylamine group,
which it is a very important chiral auxiliary widely used in asym-
Ph
metric synthesis.10
Br
O
9
Having demonstrated the significant influence of the unusual
C–HꢀꢀꢀO hydrogen bond interaction in the Z/E-rotamer ratios, we
moved out to corroborate the initial hypothesis, which postulated
that the weak interaction favors the formation of the rearranged
product 3 (Scheme 1). Slow addition of Bu3SnH and catalytic
amounts of AIBN to amides 6–9 in toluene at 80 °C provided a mix-
ture of expected rearranged/reduced products. As predicted, the
product distribution varied as a function of the rotamer ratios.
Higher amounts of reduced products were observed for amides 6
and 7 (Z-rotamer predominantly); while the rearranged product
was predominant for amide 8 (where E-rotamer is favored). Unfor-
tunately, amide 9 was not a suitable substrate, giving a complex
mixture of side products (Scheme 3).
d
Ph
Ph
N
N
a
Ph
NH2
Br
O
O
O
b
6
8
O
O
c
Ph
N
Br
O
Br
7
Scheme 2. Preparation of amides 6–9. Reagents and conditions: (a) (i) PrI
(1.2 equiv), NEt3 (1.2 equiv), rt 3 h, 86%, (ii) bromoacethyl bromide (1.2 equiv),
DMAP (1.2 equiv), 0 °C, 1 h, 60%; (b) (i) 2-(2-Bromoethyl)-[1.3]-dioxolane
(1.0 equiv), K2CO3 (1.1 equiv), reflux 5 h, 84%, (ii) bromoacethyl bromide
(2.7 equiv), K2CO3 (1.4 equiv), rt, 2 h, quantitative; (c) HCl 4.5 N, rt, 8 h, 97%; (d)
(i) ethyl bromoacetate (1.2 equiv), NEt3 (1.2 equiv), rt (ii) bromoacethyl bromide
(1.2 equiv), NEt3 (1.2 equiv), 0 °C, 2 h, 60%.
Because the free radical reactions are run at 80 °C, it was neces-
sary to investigate whether the rotamer ratio changes at elevated
temperature or keeps the same ratio. The amides 5 and 8 were se-
lected for VTNMR studies in toluene-d8 and demonstrated that the

3632
L. Fuentes et al. / Tetrahedron Letters 52 (2011) 3630–3632
Supplementary data
Bu3SnH
AIBN
Toluene
80 °C
N
R
Ph
N
R
Ph
N
R
Br
+
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.016.
O
O
O
Ph
Chiral amide
Reduced
product
Rearranged
product
References and notes
Precursor
6, R = CH2CH3
Rearrenged (%)a
11 (25)
Reduced (%)a
12 (52)
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7, R = CH2-1,3-dioxolane
8, R = CO2Et
13 (22)
14 (55)
15 (48)
16 (31)
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a) Yields after purification
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Scheme 3. Rearranged products versus reduction products of chiral amides 6–9.
ratio of rotamers remains consistent at the reaction temperature
(80 °C). Therefore, the proposal regarding the relationship between
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tion barriers for 5 and 8, wherein 15.8 kcal/mol was determined
for 5 and 17.1 kcal/mol for 8.11 Although these numbers fall in
the range for typical tertiary amides,12 the energy difference of
1.3 kcal/mol between 5 and 8 might reflect the contribution of an
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this interaction is strong enough to overcome the Pauli repulsion
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between n orbital and the C–H
r bonding orbital (1,3-allylic strain)
and therefore, favors the 1,4-phenyl radical migration. It is impor-
tant to mention that, although there are various reports describing
1,4-aryl migration reactions in better yields,13 this report repre-
sents the first example where phenyl-migration product is favored
by a weak and unusual hydrogen bonding interaction. Further
experimental and theoretical studies are currently underway.
10. Juaristi, E.; León-Romo, J. L.; Reyes, A.; Escalante, J. Tetrahedron: Asymmetry
1999, 10, 2441–2495.
11. The rate constants k for the present dynamic process were calculated at the
coalescence temperature (Tc) employing the Gutowsky-Holm equation
(kc = pDt
/2ꢁ1/2). Assuming the transmission coefficient to be unity, the free
energies of activation (D
G–) were calculated according to the Eyring equation
G– = RTc[ln Tcꢁln kc + 23.76]); See reference: Modarresi-Alam, A. R.; Najafi,
Acknowledgments
(
D
P.; Rostamizadeh, M.; Keykha, H.; Bijanzadeh, H.-R.; Kleinpeter, E. J. Org. Chem.
2007, 72, 2208–2211.
We thank VIEP-BUAP for financial support. L.F. Thanks CONA-
CyT (grant: 294700513) for graduate scholarship. We also thank
Dr. Isabel Chávez Uribe (I.Q. UNAM) for VTNMR studies and Dr. Luis
Hernández-Garcia (University of Iowa) for helpful discussions.
12. Wunderlich, M. D.; Leung, L. K.; Sandberg, J. A.; Meyer, K. D.; Yoder, C. H. J. Am.
Chem. Soc. 1978, 100, 1500–1503.
13. Studer, A.; Bossart, M. Tetrahedron 2001, 57, 9649–9667. And references cited
herein.