Synthesis of substituted γ-lactam via Pd(0)-catalyzed cyclization of alkene-tethered carbamoyl chloride

Article abstract of DOI:10.1016/j.tetlet.2014.04.019

Pd(0)-catalyzed carboiodonation of but-3-enylcarbamic chloride has been developed with NaI as additive, which provides a ready access to substituted γ-lactam bearing an alkyl iodide group. This reaction features alkyl iodide reductive elimination as a key step in catalytic cycle, indicating the crucial role of additive NaI.

Full text of DOI:10.1016/j.tetlet.2014.04.019

Tetrahedron Letters 55 (2014) 3229–3231
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of substituted c-lactam via Pd(0)-catalyzed cyclization of
alkene-tethered carbamoyl chloride
⇑
Chen Chen, Jian Hu, Jianhua Su, Xiaofeng Tong
Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Pd(0)-catalyzed carboiodonation of but-3-enylcarbamic chloride has been developed with NaI as
Received 6 March 2014
Revised 2 April 2014
Accepted 8 April 2014
Available online 13 April 2014
additive, which provides a ready access to substituted
reaction features alkyl iodide reductive elimination as a key step in catalytic cycle, indicating the crucial
role of additive NaI.
c-lactam bearing an alkyl iodide group. This
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Palladium catalysis
Carboiodonation
Cyclization
c
-Lactam
c
-Lactams are an important substructure widely occurring in
(a) Previous works
numerous biologically active compounds and natural products.1
They have proven to be useful building blocks due to their versatile
reactivity.2 Consequently, various efficient methods have been
R2
10 mol% Pd(OAc)2
30 mol% DPPF
I
R2
R1
I
I
R1
PhMe, reflux, 16 h
X
X
invented for their synthesis. For examples,
c-lactams have been
synthesized via addition of nitrogen radical,3 intramolecular carb-
enoid C–H insertion,4 ring expansion of b-lactam,5 cycloadditions,6
the imino-Mukaiyama-aldol reaction,7 and metal-catalyzed cycli-
zations.8 Among these reported methods, however, there are few
Pd(Q-Phos)2
KI (2 equiv)
Br
PhMe,100 oC, 16 h
O
O
(b) This work
strategies to construct
formation.
c-lactam ring via the C2–C3 bond
I
Recently, we have developed a Pd(0)-catalyzed carboiodonation
of vinyl iodide-tethered alkene, which concurrently forms a new
C–C bond and C–I bond (Scheme 1a).9 In 2011, Lautens and co-
workers reported an elegant example of Pd(0)-catalyzed carboio-
donation of aryl bromide-tethered alkene with the help of KI
(Scheme 1a).10 These two reactions feature the alkyl-Pd(II)-I reduc-
tive elimination as the terminating step in catalytic cycle to deliver
an alkyl iodide product and to regenerate the Pd(0) catalyst. In
sharp contrast to the well-known C–X oxidative addition, the car-
bon halide reductive elimination has been considered to be a ther-
modynamically disfavored process.11 However, some recent
developments have clearly demonstrated that this process can be
a significantly more common reaction than the previous assump-
tion and has exhibited some advantages toward organic halide
synthesis.12 As our continuous efforts on the Pd(0)-catalyzed car-
Pd(0)
Cl
3
O
N
R
2
N
R
1
iodide source
O
2
Scheme 1. Design plan for Pd(0)-catalyzed carboiodonation of 1.
boiodonation,13 we became interested in the extension of the study
to alkene-tethered carbamoyl chloride 1 (Scheme 1b). Herein, we
reported the Pd(0)-catalyzed carboiodonation of 1 with the help
of a iodide source, which constructs both the C2–C3 bond and
the C(alkyl)–I bond to deliver c-lactam 2 (Scheme 1b).
We commenced our study using compound 1a as the model
substrate. When 1a was subjected to our previous reaction condi-
tions9 (10 mol % Pd(OAc)2 and 30 mol % DPPF in refluxing toluene),
product 3a was isolated in 21% yield (Table 1, entry 1). To our
delight, the desired carboiodonation product 2a was obtained in
42% yield with a diastereomeric ratio of 5:1 when 2 equiv of KI
⇑
Corresponding author. Tel./fax: +86 21 64253881.
E-mail address: tongxf@ecust.edu.cn (X. Tong).
http://dx.doi.org/10.1016/j.tetlet.2014.04.019
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

3230
C. Chen et al. / Tetrahedron Letters 55 (2014) 3229–3231
Table 1
10 mol% Pd(OAc)2
30 mol% DPPF
Reaction condition’s optimizationa
I
Cl
R2
O
N
4 equiv NaI
I
R2
O
10 mol% Pd(OAc)2
x mol% ligand
y equiv additive
toluene, reflux, 24h
N
R1
toluene, reflux, 24h
R1
Cl
+
Ph
O
Ph
O
2
1
N
PMP
N
PMP
N
PMP
Ph
O
I
1a
2a
3a
anti-2a
: 56% yield,
syn-2a
: 11% yield
R = OMe,
Ph
O
N
anti-2b
syn-2b
: 10% yield
R = H,
R = Cl,
: 52% yield,
: 53% yield,
Entry
Ligand
(x)
Additive
(y)
2a
3a
Yieldb (%)
drc
Yieldb (%)
anti-2c
syn-2c
: 14% yield
1
2
3
4
5
6
7
8
DPPF (30)
DPPF (30)
DPPF (30)
DPPF (30)
DPPF (30)
DPPF (30)
—
ND
42
ND
48
67
51
44
25
ND
5:1
ND
5:1
21
6
ND
4
12
14
6
R
KI (2.0)
LiI (2.0)
NaI (2.0)
NaI (4.0)
NaI (6.0)
I
I
I
MeO
MeO
O
O
O
O
N
PMP
N
PMP
N
PMP
5:1
Cl
5.4:1
5.3:1
2.6:1
(Ad)2P(Bu)d
(tBu)3Pd
NaI (4.0)
NaI (4.0)
anti-2d
anti-2e
anti-2f
: 32% yield
syn-2f: trace
: 53% yield
syn-2d: trace
: 42% yield
syn-2e: trace
5
The bold format means the optimized conditions.
I
I
I
a
Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (0.02 mmol), ligand (0.06 mmol),
O
Bu
N
O
O
N
Ph
N
PMP
3 mL toluene.
b
c
PMP
Isolated yield.
Determined by 1H NMR analysis of the crude reaction mixture.
60 mol % ligand was used.
: 50% yield
syn-2g: 6% yield
: 53% yield
syn-2h: 9% yield
anti-2g
anti-2h
2i
: 23% yield
d
Scheme 2. The reaction scope. Reaction conditions:
1 (0.2 mmol), Pd(OAc)2
(0.02 mmol), DPPF (0.06 mmol), 3 mL toluene.
was added (Table 1, entry 2). The anti-isomer was unambiguously
identified as the major product on the basis of NOE NMR experi-
ments (see Supporting information). These results clearly demon-
strated the importance of external iodide source. Thus, different
iodide sources were further tested. LiI (2 equiv) was found to inhi-
bit the reaction and 88% of substrate 1a was recovered (Table 1,
entry 3). NaI (2 equiv) gave a somewhat better result, increasing
the yield of 2a to 48% (Table 1, entry 4). The isolated yield of 2a
could be further improved to 67% when the NaI loading was
increased to 4 equiv (Table 1, entry 5). However, increasing the
loading of NaI to 6 equiv caused a decrease in yield (51%) while
the diastereoselectivity was improved to 5.4:1 (Table 1, entry 6).
Ligand screening disclosed that sterically hindered monodentate-
phosphines (Ad)2P(Bu) and (tBu)3P were also able to realize this
transformation although the corresponding yields were 44% and
25%, respectively (Table 1, entries 7 and 8). At this stage, we could
not improve the reaction performance, with respective to yield and
diastereoselectivity, although other reaction parameters, such as
ligand, catalyst precursor, as well as solvent, were thoroughly
investigated (see Supporting information).
stereoselectivity of 8:1 (Scheme 2). Likely due to the lack of the
Thorpe–Ingold effect, the cyclization of the substrate with R2 = H
afforded product 2i only in the yield of 23%. It should be noted that
ca. 10% yield of the corresponding hydrolysis product was concur-
rently isolated for every case.
To our delight, five-membered benzo-fused lactam 4 was also
readily isolated in the yield of 42% when compound 3 was
employed as a substrate under these reaction conditions (Eq. 1).
Along with the carboiodonation product 4, Heck-reaction product
514 was obtained in 32% yield likely via the fashion of 6-endo
cyclization.
10 mol% Pd(OAc)2
I
30 mol% DPPF
Cl
O
O +
ð1Þ
NaI (4 equiv)
toluene, reflux, 24h
N
N
O
N
Bn
Bn
Bn
3
4:
5
42% yield
: 32% yield
This methodology was further applied to the synthesis of bicy-
clic lactams 7 (Scheme 3). The starting materials 6a–6c were readily
synthesized in three steps (See Supporting information). Cyclopen-
tane-fused lactam 7a was obtained in 47% yield (Scheme 3, entry 1)
while cyclohexane-fused analogue 7b was isolated as a single
diastereomer in somewhat better yield (Scheme 3, entry 2).
Remarkably, this reaction is tolerant toward N-atom. Indeed,
piperidine-fused lactam 7c was also formed as a single diastereo-
mer in 55% yield (Scheme 3, entry 2).
With the optimized catalytic conditions in hand, we then
explored the effect of N-substituent at the carbamoyl chloride moi-
ety. We were pleased to find that a variety of N-aryl carbamoyl
chlorides 1a–1c proved to be suitable substrates with optimal
results being accomplished with N-PMP substituted substrate 1a
(Scheme 2).
Subsequently, we tested the scope of the Pd(0)-catalyzed car-
boiodonation with respect to N-PMP substituted carbamoyl chlo-
rides
1 and the results are summarized in Scheme 2. The
transformation proceeded smoothly to afford the desired products
in moderate yields as well as moderate to high level of diastereose-
lectivity. More importantly, from the synthetic point of view, the
resultant two isomers could be easily separated by silica gel col-
umn chromatography. For the substituent R2, reactions tolerated
the installations of not only electron-deficient and electron-rich
benzene rings (Scheme 2, 2d and 2e) but also a furyl moiety
(Scheme 2, 2f). Albeit in moderate yields, these three cases only
produced anti products, showing high diastereoselectivity. Alkyl
groups could also be installed at the R2 position. Butyl-substituted
2h was isolated in 62% yield and with 6:1 diastereoselectivity and
i-propyl containing 2g was obtained with the yield of 56% and dia-
X
N
( )n
X
10 mol% Pd(OAc)2
30 mol% DPPF
( )n
I
Cl
NaI (4 equiv)
toluene, reflux, 24h
O
N
O
Ph
Ph
6
7
entry
7
6 (X, n)
(yield)
6a (X = CH2, n = 1)
6b (X = CH2, n = 2)
6c (X = NBoc, n = 2)
7a
7b
1
2
3
(47%)
(63%)
7c (55%)
Scheme 3. The synthesis of bicyclic lactams.

C. Chen et al. / Tetrahedron Letters 55 (2014) 3229–3231
3231
Acknowledgments
PdCl
Cl
PdCl
O
without NaI
R2
O
R2
O
N
N
We thank NSFC (Nos. 21002025 and 21272066), the Fundamen-
tal Research Funds for the Central Universities, Fok Ying-Tong Edu-
cation Foundation for Young Teachers in the Higher Education
Institutions of China (131011), and NCET (No. 12-0851) for funding
this research.
R2
N
R1
B
R1
R1
A
not observed
with NaI
1
Pd(0)
PdI
O
2
Supplementary data
R2
N
R1
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
04.019.
C
Scheme 4. The proposed mechanism.
References and notes
Me
1. For reviews, see: (a) Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245;
(b) Smith, M. B. Sci. Synth. 2005, 21, 647; (c) Katritzky, A. R. Chem. Rev. 2004,
104, 2125.
2. For a selected review, see: (a) Ordonez, M.; Cativiela, C. Tetrahedron: Asymmetry
2007, 18, 3; For selected examples, see: (b) Xiao, K.-J.; Wang, A.-E.; Huang, P.-Q.
Angew. Chem., Int. Ed. 2012, 51, 8314; (c) Lin, G.-J.; Zheng, X.; Huang, P.-Q. Chem.
Commun. 2011, 1545; (d) Agosti, A.; Britto, S.; Renaud, P. Org. Lett. 2008, 10,
1417; (e) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem.
Soc. 2005, 127, 119.
3. For a review, see: Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543.
4. (a) Zhang, B.; Wee, A. G. H. Org. Lett. 2010, 12, 5386; (b) Grohmann, M.; Buck, S.;
Schaffler, L.; Maas, G. Adv. Synth. Catal. 2006, 348, 2203; (c) Candeias, N. R.;
Gois, P. M. P.; Afonso, C. A. M. J. Org. Chem. 2006, 71, 5489; (d) Wee, A. G. H.;
Duncan, S. C.; Fan, G. J. Tetrahedron: Asymmetry 2006, 17, 297; (e) Choi, M. K.-
W.; Yu, W.-Y.; Che, C.-M. Org. Lett. 2005, 7, 1081; (f) Yoon, C. H.; Nagle, A.; Chen,
C.; Gandhi, D.; Jung, K. W. Org. Lett. 2003, 5, 2259.
PdCl
O
R2
N
anti-2
major
R2
O
R1
N
Pd
H
Cl
R1
TS1: favourable
anti-B
A
PdCl
R2
N
R2
O
Pd
Cl
syn-2
R1
N
O
Me
minor
R1
H
syn-B
TS2: disfavoured
Scheme 5. Rational for the observed stereoselectivity.
5. (a) Alcaide, B.; Martin-Cantalejo, Y.; Perez-Castells, J.; Sierra, M. A.; Monge, A. J.
Org. Chem. 1996, 61, 9156; (b) Brabandt, W. V.; Kimpe, N. D. J. Org. Chem. 2005,
70, 3369; (c) Almendros, P. A.; Cabrero, G.; Ruiz, M. P. Org. Lett. 2005, 7, 3981;
(d) Park, J. H.; Ha, J. R.; Oh, S. J.; Kim, J. A.; Shin, D. S.; Won, T. J.; Lam, Y. F.; Ahn,
C. Tetrahedron Lett. 2005, 46, 1755; (e) Li, G. Q.; Li, Y.; Dai, L. X.; You, S. L. Org.
Lett. 2007, 9, 3519.
6. (a) Lettan, R. B.; Galliford, C. V.; Woodward, C. C.; Scheidt, K. A. J. Am. Chem. Soc.
2009, 131, 8805; (b) Comesse, S.; Sanselme, M.; Daich, A. J. Org. Chem. 2008, 73,
5566; (c) Sun, P.-P.; Chang, M.-Y.; Chiang, M. Y.; Chang, N.-C. Org. Lett. 2003, 5,
1761; (d) Roberson, C. W.; Woerpel, K. A. J. Org. Chem. 1999, 64, 1434; (e) Ng, P.
Y.; Masse, C. E.; Shaw, J. T. Org. Lett. 2006, 8, 3999; (f) Wei, J.; Shaw, J. T. Org.
Lett. 2007, 9, 4077.
Although we could not provide further details to elucidate the
precise reaction mechanism, a proposal is present in Scheme 4.
On the basis of the well-known metal-catalyzed transformations
of carbamoyl chloride,15 we believed that the reaction would be
initiated by oxidative addition of carbamoyl chloride 1 to Pd(0)
center, resulting in the formation of intermediate A. Then, alkyl-
Pd(II)-Cl intermediate B is formed via intramolecular insertion of
alkene into the carbonyl-Pd(II) bond of intermediate A. After ligand
exchange between chloride and iodide, intermediate B is converted
to alkyl-Pd(II)-I intermediate C, which is followed by reductive
elimination of alkyl-Pd(II)-I to yield alkyl iodide product 2 and
regenerate the Pd(0) catalyst. The fact that the corresponding alkyl
chloride product could not be detected without external iodide
source strongly demonstrated that alkyl chloride reductive elimi-
nation should be much less efficient than the iodide case. This
observation is consistent with Houk’s computational study on
the alkyl halide reductive elimination.16
The observed stereoselectivity is believed to be determined by
the process of alkene insertion, in which the transition state TS1
might be more favorable than TS2 in order to the minimize the
axial–axial interaction between Me and H groups (Scheme 5). Thus,
the former would lead to anti-2 as the major product.
In summary, we have developed the Pd(0)-catalyzed carboiodo-
nation of alkene-tethered carbamoyl chloride with the help of NaI,
which provides a facile method for the synthesis of substituted c-
7. Pohmakotr, M.; Yotapan, N.; Tuchinda, P.; Kuhakarn, C.; Reutrakul, V. J. Org.
Chem. 2007, 72, 5016.
8. (a) Masse, C. E.; Panek, J. S. Chem. Rev. 1995, 95, 1293; (b) Lee, S.; Hartwig, J. F. J.
Org. Chem. 2001, 66, 3402; (c) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2003, 42, 2892; (d) Madec, D.; Prestat, G.;
Martini, E.; Fristrup, P.; Poli, G.; Norrby, P. O. Org. Lett. 2005, 7, 995; (e) Craig,
D.; Hyland, C. J. T.; Ward, S. E. Chem. Commun. 2005, 3439; (f) Umemura, S.;
McLaughlin, M.; Micalizio, G. C. Org. Lett. 2009, 11, 5402.
9. Liu, H.; Li, C.; Qiu, D.; Tong, X. J. Am. Chem. Soc. 2011, 133, 6187.
10. Newman, S. G.; Howell, J. K.; Nicolaus, N.; Lautens, M. J. Am. Chem. Soc. 2011,
133, 14916.
11. (a) Vigalok, A. Chem. Eur. J. 2008, 14, 5102; (b) Grushin, V. V. Chem. Eur. J. 2002,
8, 1007; (c) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160.
12. (a) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 1232; (b) Watson, D. A.;
Su, M.; Teverovskiy, G.; Zhang, Y.; García-Fortanet, J.; Kinzel, T.; Buchwald, S. L.
Science 2009, 325, 1661; (c) Quesnel, J. S.; Arndtsen, B. A. J. Am. Chem. Soc. 2013,
135, 16841; (d) Shen, X.; Hyde, A. M.; Buchwald, S. L. J. Am. Chem. Soc. 2010,
132, 14076; (e) Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 1778; (f)
Jia, X.; Petrone, D. A.; Lautens, M. Angew. Chem., Int. Ed. 2012, 51, 9870; (g)
Petrone, D. A.; Lischka, M.; Lautens, M. Angew. Chem., Int. Ed. 2013, 52, 10635.
13. Liu, H.; Chen, C.; Wang, L.; Tong, X. Org. Lett. 2011, 13, 5072.
14. (a) Cropper, E. L.; White, A. J. P.; Ford, A.; Hii, K. K. J. Org. Chem. 2006, 71, 1732;
(b) Ferguson, J.; Zeng, F.; Alwis, N.; Alper, H. Org. Lett. 2013, 15, 1998.
15. (a) Tsukano, C.; Okuno, M.; Takemoto, Y. Angew. Chem., Int. Ed. 2012, 51, 2763;
(b) Iwai, T.; Fujihara, T.; Terao, J.; Tsuji, Y. J. Am. Chem. Soc. 2010, 132, 9602.
16. Lan, Y.; Liu, P.; Newman, S. G.; Lautens, M.; Houk, K. N. Chem. Sci. 2012, 3, 1987.
lactams. The fact that no reaction occurred without additive NaI
clearly indicated that it plays a crucial role in this transformation.
The further application of this finding to develop asymmetric syn-
thesis of substituted c-lactam is currently under investigation.